New perspectives on saw palmetto - UCL Discovery

New perspectives on saw palmetto

{Serenoo repens):

a medico historical/ analytical comparison

of preparations derived from it and a clinical

pilot trial in patients with benign prostatic

hyperplasia and sexual dysfunctions

Andy Suter

Submitted for degree of Doctor of Philosophy

Centre for Pharmacognosy and Phytotherapy

The School of Pharmacy

University of London

ProQuest Number: 10104226

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For my parents

and

Maja and Matthias

Andy Suter

This thesis describes research conducted in the School of Pharmacy, University of

London/University College of London between May 2008 and April 2012 under the

supervision of Professor Michael Heinrich.

I certify that the research described is original and that any parts of the work that have

been conducted by collaboration are clearly indicated. I also certify that I have written

all the text herein and have clearly indicated by suitable citation any part of this

dissertation that has already appeared in publication.

O c h é ^ '2 ^ ( 7 -

Signature Date

Anc/y Suter

Acknowledgements

Acknowledgements

I would like to express my gratitude to :

My supervisor Prof. Michael Heinrich for giving me the opportunity to carry out this

thesis, the interesting talks we had, his critical advice, and the entertaining group

meetings. I really enjoyed carrying out this phD in the good atmosphere of his research

group, it felt good being a student again!

A.Vogel Bioforce AG in RoggwiI, Switzerland and in particular Martin Tobler, Head of

Research and Quality, for enabling me to do this thesis and the financial funding.

Prof. Reinhard Sailer from the Department of Internal Medicine, Institute of Natural

Medicine, University Hospital of Zurich, for his advice on the study design and the

critical interpretation of the study results.

Roy Upton from the American Botanical Council and David Winston, head of the David

Winston's Center for Herbal Studies in New Jersey, U.S.A. for providing me documents

and sources on the first uses of saw palmetto by U.S. American physicians.

Monika Huber from the library of the Medical Historic Institute of the University of

Zurich for her help and support in finding historical medical literature.

Brigitte Strassel and Ana Krnjic from the Analytical département of A.Vogel Bioforce AG

for their great help with the analytical work of the saw palmetto preparations.

All the physicians and patients who attended in the clinical trial and invested a lot of

their time and efforts to make this a successful study.

Peter Klein, from d.s.h. statistical services GmbH, Rohrbach, Germany for helping in

solving statistical problems and his ideas for a proper analysis of the clinical trial.

All the people from the research group from Michael Heinrich for the inspiring and

enjoyable discussions at the group meetings.

And last but not least to Maja for her support, patience, and her great help to make this

thesis happen.

Andy Suter 4

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Table of contents

Abstract................................................................................................................................ 14

Aims..............................................................................................................................15

Thesis Layout...............................................................................................................16

1 Chapter 1; General Introduction..................................................................................... 18

1.1 Saw palmetto - the plant (Sabal serrulata, Serenoa repens)............................. 18

1.1.1 Discovery and taxonomic description............................................................. 18

1.1.2 Botanical Description..........................................................................................19

1.1.3 Distribution and Ecology.................................................................................... 20

1.1.4 Wildlife Use.......................................................................................................... 22

1.2 Pharmacological data of saw palmetto................................................................... 23

1.2.1 Constituents......................................................................................................... 23

1.2.2 Antiandrogenic properties.................................................................................25

1.2.3 Anti-inflammatory activity.................................................................................28

1.2.4 Muscle relaxation and vasodilatative effects................................................. 29

1.2.5 Interactions with P450 enzymes....................................................................... 30

1.3 lexicological assessment of saw palmetto............................................................ 31

1.3.1 Acute Toxicity..................................................................................................... 31

1.3.2 Repeat Dose Toxicity..........................................................................................31

1.3.3 Reproductive and developmental toxicity..................................................... 32

1.4 Clinical efficacy and safety of saw palmetto.......................................................... 33

1.4.1 Benign Prostatic Hyperplasia - the disease.................................................... 33

1.5 Clinical data from saw palmetto preparations.......................................................47

1.5.1 Monographs on saw palmetto, recommendedpreparations and daily dosages......................................................................47

1.5.2 Clinical studies with saw palmetto preparations.......................................... 48

1.6 Final remarks............................................................................................................... 49

Table o f conten i i

2 Chapter 2: Historical part.................................................................................................. 51

2.1 Introduction.................................................................................................................. 51

2.2 Research Strategy and Methods............................................................................... 52

2.2.1 Research strategy............................................................................................... 52

2.3 Results........................................................................................................................... 56

2.3.1 The history of benign prostatic hyperplasia and its treatment...................56

2.3.2 History of human use of saw palm etto...........................................................62

2.4 Discussion..................................................................................................................... 80

3 Chapter 3: Phytochemical analysis..................................................................................88

3.1 Introduction.................................................................................................................. 88

3.2 Material and Methods............................................................................................... 92

3.2.1 Reference samples..............................................................................................92

3.2.2 Thin layer chromatography (TLC) for identification..................................... 95

3.2.3 Gas chromatography for analysis of fatty acids............................................ 97

3.3 Results.........................................................................................................................103

3.3.1 Identification of the test samples with TLC..................................................103

3.3.2 Analysis of fatty acids...................................................................................... 110

3.4 Discussion................................................................................................................... 122

4 Chapter 4: Clinical pilot study........................................................................................ 135

4.1 Introduction................................................................................................................135

4.1.1 Epidemiological data of SDys in the elderly male population................... 136

4.1.2 Pathophysiology of sexual dysfunctions and BPH.......................................138

4.1.3 Sexual adverse events of BPH standard medication.................................. 139

4.1.4 Data from clinical studies on saw palmetto in SDys....................................140

4.1.5 Summary and Study Rationale.......................................................................141

4.2 Material and Methods............................................................................................. 142

4.2.1 Study design.......................................................................................................142

4.2.2 Investigators......................................................................................................144

4.2.3 Patients.............................................................................................................. 144

4.2.4 Study medication..............................................................................................145

/cù/c of con I erf:

4.2.5 Questionnaires.................................................................................................. 145

4.2.6 Assessment of adverse and serious adverse events.................................. 151

4.2.7 Assessed parameters....................................................................................... 152

4.2.8 Quality Standards and patient's safety......................................................... 152

4.2.9 Statistical analysis.............................................................................................153

4.3 Results.........................................................................................................................155

4.3.1 Patients and centres........................................................................................ 155

4.3.2 Efficacy............................................................................................................... 158

4.3.3 Acceptance and practice and policy questions...........................................164

4.3.4 Safety................................................................................................................. 165

4.3.5 Subgroup analyses........................................................................................... 166

4.3.6 Correlation analysis of changes and relationshipbetween bSFI and Urolife QoL-9 sex score.................................................. 167

4.4 Discussion...................................................................................................................170

5 Chapter 5: General discussion and conclusion...........................................................178

5.1 General discussion.....................................................................................................178

5.2 Final conclusion........................................................................................................183

6 Literature...........................................................................................................................184

7 Appendix........................................................................................................................... 215

7.1 Appendix 1................................................................................................................. 215

7.2 Appendix 2................................................................................................................. 221

7.3 Appendix 3................................................................................................................. 226

7.4 Publications................................................................................................................240

A no'/ Sivfcr

Figures

Figure 1: Saw palmetto plant with ripe berries (Source; A.Vogel Bioforce AG)..............20

Figure 2: The local distribution of Serenoa repens indicated with green colour,after United States Geological Survey USGS, 2006 (2)...................................... 21

Figure 3: Structure of the phytosterols a) p -sitosterol, b) cam peste ro I, c) stigmasterol, d) mannitol, e) ferulic acid, f) vanillic acid, g) y-tocopherol, and h) tyramine.......................................................................... 25

Figure 4: Schematic drawing of prostate gland (1 )............................................................. 34

Figure 5: Presence of histologic BPH at autopsy by age group (3)....................................38

Figure 6: Chromatogram of a saw palmetto preparation with the identified peaks.. 102

Figure 7: TLC finger print profile of six different tablets.................................................. 103

Figure 8: TLC finger print profile of the tablet preparation SPSS...................................104

Figure 9: TLC fingerprints of nine products in hard gel capsules....................................105

Figure 10: TLC fingerprints of three hard gel capsules.......................................................105

Figure 11: TLC fingerprint of the six Swiss saw palmetto preparations........................... 106

Figure 12: TLC fingerprints of 14 different saw palmetto preparationswith soft gel capsules........................................................................................... 107

Figure 13: TLC fingerprints of two preparations made with soft gel capsules 108

Figure 14: TLC fingerprint of five saw palmetto preparations with soft gel capsules.. 108

Figure 15: Amount fatty acids per day of the lowest daily dosage givenon the package for each analysed product [mg/d] of all 46 investigated

commercial preparations...................................................................................... 112

Figure 16: Total amount of fatty acids per minimal daily dosage [mg/d]for mono products sorted by their country of origin.....................................113

Figure 17: Daily amount of total fatty acids for combination products accordingto the minimal dose of every preparation [mg/d], divided by country of origin........................................................................................................................ 114

Figure 18: Relative amount of the analysed single fatty acids compared to the total fatty acid content for each investigated combination product. (n=27).......................................................................................................117

Figure 19: Relative amount of the analysed single fatty acids compared to thetotal fatty acid content for each investigated mono product. (n=19).......... 119

Figure 20: Ellipse scores of saw palmetto soft extracts (SP25-37) versuscombination products (SP16-SP21) in chloroform...........................................121

Andv Suter 8

Figure 21: Urolife BPH QoL9-subscale 'patient's perceived sexual life' (from (446))... 149

Figure 22: The brief Sexual Function Inventory bSFI questionnaire (4 )........................... 150

Figure 23: Number of patients per study centre, the blue bars comprise theintention to treat- (n=84), the red bars the per protocol population which was used for the efficacy anaylsis (n=69)...............................................155

Figure 24: Change of International Prostate Symptom Score IPSS betweenthe start and end of treatment (Per Protocol population, n = 69)................ 158

Figure 25: Relative changes of the single IPSS items and the subscores fromvisit 2 to visit 3 (Per Protocol population, n=69).............................................. 159

Figure 26: Improvement of brief Sexual Function Inventory bSFI at start andend of therapy (Per Protocol population, n = 6 9 ).............................................160

Figure 27: Single item scores of the bSFI at the start and end of treatment, normalised to a scale of 0-10 (0 = worst state, 10 = best)(PP population, n = 69)..........................................................................................161

Figure 28: Relative improvements of the bSFI and Urolife QoL-9 total scores and single items between begin and end of treatment (PP-population, n=69)...........................................................................................163

Figure 29: Assessment of efficacy at end of treatment by patient andinvestigator for the PP-population (n=69).........................................................164

Figure 30: Assessment of tolerability at end of treatment by patient andinvestigator for the safety population (n=82)................................................... 165

Figure 31: Correlation between change in IPSS and changes in bSFI,compared between all visits. PP-population (n=69)........................................ 167

Figure 32: Correlation between change in IPSS and changes inUrolife QoL-9 for all visits, PP-population (n=69).............................................167

Figure 33: Correlation between IPSS and total Urolife QoL-9 for all visits,PP population (n=69)............................................................................................. 168

Figure 34: Correlation between total bSFI and total Urolife QoL-9 sex for all visits,PP population (n=69)............................................................................................. 168

:L:ier

Table:

Tables

Table 1: Treatment scheme for BPH patients with regard to their LUTS, prostate size, severity of symptoms, and complications after Issa, 2007 (100) with modifications regarding the use of saw palmetto after Geavlete (144) and Gregorin (145 )............................................................. 46

Table 2: Requirements on daily dosages and extractants from themonographs on saw palmetto...............................................................................48

Table 3: Libraries and online resources for the literature search..................................55

Table 4: Documented use of the whole plant of saw palmetto in historyin the United States and first mentioning in monographs and pharmacopoeia.........................................................................................................71

Table 5: Documented historical use of saw palmetto in Germanscientific literature.................................................................................................. 79

Table 6: Details of the 46 preparations containing saw palmetto whichwere included in the analytic comparison..........................................................94

Table 7: The elemental formula, lipid number, structure, and pharmacologicalactivities of the gaschromatographically analysed fatty acids...................... 110

Table 8: Differences between the amount of saw palmetto extract as statedon the package and the measured concentration of total fatty acids per tablet or capsule.....................................................................................................116

Table 9: The frequency of nine fatty acids in different saw palmettopreparations, the whole fruit, and extracts from Pygeum africanum, pumpkin seeds, olive, and coconut oil as comparison..................................... 125

Table 10: Mean content of the phytosterols campesterol, stigmasteroland ^-sitosterol in different preparations containing saw palmetto according to (340).................................................................................................. 130

Table 11: Study design of the pilot study with saw palmetto on SDysin BPH patients (Prostasan® Libido trial)............................................................143

Table 12: The International Prostate Symptom Score IPSS (99).....................................146

Table 13: Study procedure for a patient............................................................................ 154

Table 14: Demographic characteristics of the Intention to Treat andthe Per Protocol population.................................................................................157

Table 15: Single item scores of the bSFI and Urolife BPH QoL-9 at the startand end of treatment (n = 69)............................................................................. 160

A/io'y 10

Abbreviations

List of Abbreviations

AOAC

AP

ASEX

AST

AUASI

AUR

B.C.

BfArM

BPH

bSFI

bw

COX

CRF

CYP

DAN-PSSsex

DER

DMT

DISF/DISF-SR

ECso

ED

ESCOP

FAME

FDA

FID

GC

GCP

HPTLC

Association of Official Analytical Chemists

Sum of area of fatty acids in a sample

Arizona Sexual Experience Scale

Area of internal standard

American Urological Association Symptom Index

Acute urinary retention

Before Christ

Bundesinstitut für Arzneimittel und Medizinprodukte

Benign Prostatic Hyperplasia

Brief Sexual Function Inventory

Body weight

Cyclooxygenase

Case record form

Cytochrome

Danish Prostatic Symptom Score questionnaire for sexual dysfunction

Drug extractant ratio

Dihydrotestosterone

Derogatis Interview for Sexual Functioning

Half maximal effective concentration

Erectile dysfunctions

European Scientific Cooperative on Phytotherapy

Fatty acid methyl esters

Food and Drug Administration

Flame ionization detector

Gas chromatography

Good Clinical Practice

High performance thin layer chromatography

Andy Suter 11

Abbreviations

IC50

iD

IIEF

IIEF-5

IIEF-ED

IL

INF

IPSS

ITT

ITT

LNCaP

LOX

LUTS

kPa

MSHQ-EjD

MTOPS

NMR

NO

NSAID

PCA

PDE

PP

PRV

PSA

Q .m ax

QoL

RCT

Rf

Half maximal inhibitory concentration

Internal diameter

International Index of Erectile Function Questionnaire

Short version of the International Index of Erectile Function Questionnaire with only 5 questions

International Index of Erectile Function Questionnaire- erectile dysfunction subscale

Interleukine

Interferone

International Prostate Symptom Score

Intention to treat population

Intention to treat population

Human prostate adenocarcinoma cell line

Lipoxygenase

Lower urinary tract symptoms

kiloPascal

Male Sexual Health Questionnaire to assess ejaculatory dysfunction

Medical Therapy of Prostatic Symptoms study

Nuclear magnetic resonance

Nitric oxide

Non steroidal antiinflammatory drug

Principal component analysis

Phosphodiesterase

Per protocol population

Post-void residual urine

Prostatic specific antigen

Maximum Urinary Flow Rate

Quality of Life

Randomised clinical trial

Retardation factor

Andy Suter 12

Abbreviations

SDys

SHGB

SP

TID

TLC

Urolife QoL-9

Urolife QoL-9 sex

UV

Vklin

WHO

WIT

WS

Sexual dysfunctions

Sex hormone binding globulin

Sample (for the phytochemical analysis)

Three times daily

Thin layer chromatography

Urolife BPH Quality of Life 9-questionnaire

Urolife BPH Quality of Life 9-questionnaire subscale for 'patient's perceived sexual life'

Ultraviolet

Verordnung für klinische Studien

World Health Organisation

Weight of internal standard

Weight of sample

Andy Suter 13

Abstract

Saw palmetto berries {Serenoa repens) are used today for treatment of symptoms of

benign prostatic hyperplasia (BPH) which is an age dependent disease leading to lower

urinary tract symptoms (LUTS) and impacts negatively sexual functions.

I carried out the first clinical pilot trial to assess if a saw palmetto treatment in patients

with BPH and concomitant sexual dysfunctions (SDys) is effective and safe in both

groups of symptoms. After 8 weeks of treatment with 320mg saw palmetto extract

daily, BPH symptoms measured with the International Prostate Symptom Score IPSS

were reduced from 14.4 ± 4.7 to 6.9 ± 5.2 (p<0.0001). At the same time SDys measured

with the brief Sexual Function Inventory bSFI improved from 22.4 ± 7.2 to 31.4 ± 9.2

(p<0.0001), and with the Urolife BPH QoL-9 sex questionnaire from 137.3 ± 47.9 to

195.0 ± 56.3 (p<0.0001). The treatment was very well tolerated and accepted by the

patients.

Another subject of this thesis was to examine the quality of commercial preparations

from eight countries which contained saw palmetto and are sold as treatments for BPH

symptoms. For each of the 46 analysed products the amount of the main active

constituents, the fatty acids was determined using gas chromatography. The quantity of

fatty acids per daily dosage varied widely between the products and also the

composition of the samples was very heterogeneous.

A medico-historical investigation how saw palmetto was introduced firstly into U.S.

American medicine and how the plant became popular as a treatment in Germany was

the last aspect of the thesis. The eclectic physicians pioneered in using this plant in the

United States supported by homeopathic doctors and pharmacists. In Germany, mainly

the homeopaths favoured the use of saw palmetto and were the trailblazers making it a

popular treatment for BPH symptoms.

In conclusion, this thesis shows comprehensively how saw palmetto made its way into

medical practice in the United States and Germany, that preparations on the markets

containing saw palmetto differ widely in their content of the main active constituents,

the fatty acids, and thus higher quality demands from regulatory authorities are

warranted, and in a pilot trial it could be shown that saw palmetto is not only an

effective and safe treatment for BPH symptoms but also for concomitant SDys.

Andy Suter 14

Aims

Aims

In this thesis new data on historical, phytochemical, and clinical aspects of saw

palmetto as a medical treatment should be presented . This includes in more detail

• A historical review how saw palmetto became a popular treatment in the United

States and how the plant made it into the medical practice in Germany, this all

embedded in the historical context of treatment of benign prostatic hyperplasia

(BPH)

• A phytochemical analysis of 46 commercial preparations containing saw palmetto

on their amount of the main active constituents, the fatty acids

• A clinical pilot trial with a standardised saw palmetto product in patients with BPH

and sexual dysfunctions to assess if this treatment may improve not only urinary

symptoms but also concomitant sexual disorders

Andy Suter 15

Thesis Layout

Thesis Layout

The Chapter 1 presents a general introduction into botanical, pharmacological,

toxicological, and clinical particulars of saw palmetto and provides also an introduction

into the disease benign prostatic hyperplasia (BPH).

In Chapter 2 the history of treatments for BPH are laid out, followed by a

comprehensive review on the history of the use of saw palmetto. This includes the

traditional use by the indigenous population of the Florida region, the first mentioning

of the plant in Western literature and how the plant became a popular treatment in the

United States. The last part of this chapter depicts how saw palmetto was introduced

into the German scientific community and when the plant was acknowledged as a

medical treatment for BPH.

The Chapter 3 provides a phytochemical analysis of 46 commercial preparations which

contain saw palmetto and are sold as treatments for BPH.

Chapter 4 shows results from a clinical pilot trial in patients with BPH and concomitant

sexual dysfunctions.

Finally, Chapter 5 includes the final discussion and conclusions of all results gathered in

this phD thesis.

Andy Suter 16

Chapter 1

An introduction to saw paimetto, the plant, its pharmacology and efficacy

and

to benign prostatic hyperplasia BPH, the disease, its diagnosis, and treatments

Andy Suter 17

Chapter 1: General Introduction

1.1 Saw palmetto - the plant (Sabal serrulata, Serenoa

repens)

1.1.1 Discovery and taxonomie description

The first European mentioning of a tree which could have been saw palmetto was in

1575 by Hernando Descalante Fontaneda, a Spanish shipwreck survivor who lived with

the Indians of Florida for 17 years (5). In his memoirs he called the shrubs 'palma' and

'palmito' and how important they were to the indigenous people of Florida (6). Later

then, the quaker merchant Jonathan Dickinson, another shipwreck survivor, named a

tree around 1690 a 'shrubby palmetto'. This could have been with a high certainty also

saw palmetto as he fed from the berries to avoid starvation (7, 8).

It was the botanist William Bartram in 1792 who was the first to give an accurate

description of saw palmetto. In his botanical book 'Travels', which is a comprehensive

report of the flora of North and South Carolina, Georgia, and Florida, he wrote about a

'dwarf saw palmetto' and Coryphha repens. This is considered today as the first

description in literature which can be attributed with great certainty to Serenoa repens

(9).

Today the two most commonly used botanical names are Sabal serrulata, referring to

the fan-shaped serrated leaves and Serenoa repens which goes back to the botanist

J.D. Hooker. The genus is named in honour to Sereno Watson (1826-1892) an assistant

of Asa Gray, a well known botanist who in the 19 century described the flora of the

south-eastern coastal areas of the United States (10).

The accepted taxonomical name is now Serenoa repens (W. Bartram) Small (11). It

belongs to the genus Serenoa, family Arecaceae (palm trees), the subfamily

Coryphoideae, tribe Coryphea, and subtribe Lvistoninae (12). Serenoa repens is the only

representative of the genus Serenoa (13).

Nevertheless, the first official botanical name was Chaemerops serrulata (Michx.) which

was issued in 1803 (14) but this name was sometimes also mistakenly taken for the

Andy Suter 18

cabbage palm, a tree often to find in the same regions where saw palmetto grows (15).

Other common names for the plant are saw palmetto, in older literature the plant was

also often cited as dwarf palm (16) or Brahea serrulata (Michx.) or Digiossophyiium

serrulatum (Michx.) (14).

In the following only the term Serenoa repens will be used as it is the accepted name in

the botanical literature (17).

1.1.2 Botanical Description

The name of the saw palmetto is due to the saw-like leafs. These characteristic fan

shaped leaves are bright green and are up to one meter wide. Approximately three to

seven leaves are produced each year and remain alive on the plant for about two years.

The plant bears a densely cluster of white flowers, the so called spadix, which is shorter

than the leaves (18). The palm has a creeping and branching prostrate stem, which can

occasionally reach the height of two meters (Figure 1) (19, 20).

Saw-palmetto produces one to three prominent spadices during spring, and fruits

mature during summer. However, individual plants may flower throughout the year,

but fruit seldom matures outside the summer period.

The drupes are about the size of an olive, in its mature stages of green to orange colour

and harbour the pharmacologically active constituents. During ripening, the fruits turn

in colour from green (May-June) to yellow (mid-August), to orange (September), and to

bluish-black (September-October). Fruit production can be variable among years.

Annual average number of seeds per plant has been measured to vary between 100

and 500 in mid to late June, but decrease rapidly until mid-October when no fruits

remain on the plants (21).

Saw palmetto flowers are in densely-branched, interfoliar inflorescences, which are

about half a meter in size. The trees commonly produce one to three, at maximum five

inflorescences at the time whereas one contains several thousand individual flowers

(22).

Andv Suter 19


By judging from their leaf scars and the length of their growing stems, it has been

estimated that the oldest saw palmetto plants in Southern Florida have an age of about

500 to 700 years (23).

Figure 1: Saw palm etto plant w ith ripe berries (Source: A.Vogel Bioforce AG)

1.1.3 Distribution and Ecology

Serenoa repens is one of the most abundant plants in the Southeastern United States. It

can be found in pine flatwoods, which are special soils formed from marine sediments,

prairies, and scrubs as well as in dunes and maritime forests but seems to be sensitive

to salt spray. Interestingly, saw palmetto is well adapted to fire and is one of the most

fire-tolerant among the pyric species (19).

Andy Suter 20


The plant is endemic in Florida and according to the plant database of the United States

Department of Agriculture can be found also in the states of Texas, Louisiana,

Mississippi, Alabama, Indiana, Georgia, and South Carolina (24). In a similar database of

the United States Geological Survey, the same states as above are mentioned except

Texas. The map of the distribution shows that Serenoo repens occurs mainly in Florida

and in the other mentioned states mainly in the Southern coastal areas (2) (Figure 2).

Figure 2: The local distribution of Serenoa repens indicated w ith green colour, a fter United States Geological Survey USGS, 2006 (2).

A

«

— A-500 0 500 1000 1500 Kilometers ‘ X. A

EUSGS••V*

The Catalogo de las Plantas Vasculares de Panama describes the occurrence of Serenoo

repens also in Panama, which would be contradictory to the data above (25).

Generally, the plant grows best in regions with an average annual rainfall of 100-163 cm

and a minimum to maximum temperature range of -4° to 36°C. It seems to be

cultivated only in Northern America (13).

Andy Suter 21

j ; Gcncrc/

1.1.4 Wildlife Use

A wide variety of species use saw palmetto either as a source for food or for nesting or

protective cover.

Animals known to use it for nesting cover are the endangered Florida grasshopper

sparrow (Ammodramus savannarum), the Florida wood rat {Neotoma floridana), the

wild turkey {Meleagris gallopavo), the Florida panther {Felis concolor) (26), and the

Florida black bear {Ursus americanus ssp. floridanus) (19). As escape cover or bedding

cover during windy, cold days it is used by the white-tailed deer {Odocoileus

virginaniana) (27).

Not only the berries but also the apical meristem, the so-called heart of the plant are

eaten. It is physically extracted and eaten by black bears and feral pigs (Sus scrofa).

They usually eat on the freshly regrown plants after a fire (26). Cattle are known to

consume the leaves only if there is no better forage (28) or they consume the fronds

during winter (26).

However, generally, the herbal parts or the stem of the plant has little value as livestock

forage (29), in particular since the frond is less than 30% digestible even though its

phosphorous content is relatively high (26).

Over 300 species of insects have been observed visiting saw palmetto flowers. Some of

these flower visitors collect nectar and/or pollen, while others find mates or prey near

or on the flowers. The main visitors of the flowers and thus the primary pollinators

appear to be bees; the other most frequently observed insects were mostly dipterans

or hymenopterans (30).

The berries are the main source of food from saw palmetto for animals. A large variety

of animals have been observed consuming them, such as raccoons, foxes, rats, gopher

tortoises, white tail deer, black bears, feral hogs, and even fish and waterfowl (19). The

fruit or more precisely the drupe is an excellent source for carbohydrates and oils. In

late summer when the fruits are ripe, they are eaten extensively by black bears. A road

killed adult female bear was found to have more than 13,5 kg of saw palmetto fruit in

its stomach (26). White tailed deer favour the berries as an important late autumn and

Andy Suter 22

early-winter food, whilst given to cows it has been observed that they produce more

and better milk (19).

Generally, the animals eating the drupes serve as dispersal agents as the seeds are

distributed throughout the landscape in faeces (26). The fruit's endocarp and seed coat

are impermeable to oxygen and it takes four to six months for these tissues to

deteriorate (24).

In total, the plant itself provides food or cover for more than 100 bird, 27 mammal, 25

amphibian, and 61 reptile species (31).

1.2 Pharmacological data of saw palmetto

1.2.1 Constituents

The dried saw palmetto berries consist to about 36% of pericarp, 16% pulp, 10% testa

of the seed, and 38% of the seed. The pulp contains a highly active lipase which

dissociates triglycerides during ripening and drying to single fatty acids (32). The fruits

primarily contain free fatty acids such as capric, caproic, caprylic, lauric, myristic, oleic,

linoleic, linolenic, stearic, and palmitic acids (17) and their ethyl esters and glycerides

(33) which occur most likely during the extraction process (17). This process is catalysed

by an esterase which is to be found in the pulp (32). An analysis of 14 saw palmetto

berry extracts showed that up to 52.15 % of the total extract were methyl- or ethyl

esters and glycerides (34), while an investigation of the pressed juice of the berries

estimated that about one third of the oil were ethyl esters (32). Schantz et al. found in

an analysis of the saw palmetto fruit and a hexane/acetone (4:1 v/v) extract that the

ratio of triglycerides to free fatty acids in the fruit and the extract was about 2:1 (35). A

more extensive description of the fatty acids with the structure formulae is given in

chapter 3.3.2.

Further sterols (17) and specially the phytosterols such as ^-sitosterol and p-sitosterol

3-0-D-glucoside, (33) campesterol and stigmasterole can be found (Figure 3) (36). The

amount of phytosterols is rather low compared to the whole extract, the analyzed

amounts are in the range from 0.45 (35) to 0.1% of total mass in ripe fruits (37) to 1.9-

55.4mg campesterol, 4 -28 .6mg stigmasterol, and 6.9-174mg ^-sitosterol per lOOg in

Ar:dySi‘tcr 23

several investigated saw palmetto preparations like powdered berries, aquaeous,

ethanolic, and CO2 extracts (36).

An investigation on the substances of the hydrodistillate of saw palmetto berries

identified 144 compounds whereas lauric acid was with an amount of 40.4% the main

detected component (38).

Other constituents are carbohydrates such as mannitol and polysaccharides with

galactose and arabinose (33), triterpenes (17), aromatic acids like ferulic and vanillic

acid (33), |3-carotens, the vitamine E dérivâtes y-tocopherol and 6-tocopherols (35), and

the monoamine tyramine which was reported to be 0.72% of the total mass of an

ethanolic saw palmetto extract (Figure 3) (39).

In total, in lipophilic saw palmetto berry extracts, the fatty acids and its esters are

predomintant and comprise to about 75-95% of the total extract (40).

It is assumed that the fatty acids together with the phytosterols are the main active

principles of saw palmetto, particularly in treatment of prostate problems (41).

Since the main use of saw palmetto preparations is in benign prostatic hyperplasia

(BPH), the majority of the pharmacological experiments have been carried out targeting

this disease. These are primarily investigations on anti-androgenic, anti-inflammatory

and on muscle relaxation or vasodilatative effects where always lipophilic saw palmetto

berries extracts were used. They are abbreviated in the following as saw palmetto

extracts.

An civ Suter 24


Figure 3: S tructure o f the phytosterols a) P -sitosterol, b) campesterol, c) stigm asterol, d) m annlto l, e) fe ru llc acid, f) vanillic acid, g) y-tocopherol, and h) tyram ine

HO'HO'

HO'

OH OH

OH OH

H3CO

OH

OH

1.2.2 Antiandrogenic properties

In human foreskin fibroblasts, a saw palmetto extract inhibited the binding of [^H]-DHT

to both cytosolic and nuclear androgen receptors by 90% and 70%, respectively (IC50 7.1

units/mL). lOOmg/mL of the total extract inhibited the 5-alpha-reductase activity in the

rat ventral prostate by 50%, and reduced conversion of testosterone into

dihydrotestosterone (DHT) in human foreskin fibroblasts by 90% (42).

Another study showed only marginal effects of several saw palmetto extracts on the

activity of 5-alpha-reductase from human prostate or on DHT binding to the rat

prostatic androgen receptor. In concentrations up to 100mg/mL, various saw palmetto

preparations (Permixon, drug extractant ratio (PER) 6-12:1, extractant hexane; Talso,

PER 10:1, lipophilic extract; Strogen Forte, PER 10:1, lipophilic extract, and Prostagutt,

PER 11.8:1, lipophilic extract) showed in vitro weak 5-alpha-reductase compared to

finasteride (43).

Andy Suter 25

i; Gr/ierc./ /r'r''cc/üTf'b.'i

The mode of action of saw palmetto and finasteride appears to be different. While the

addition of saw palmetto extract inhibited metabolism of [^H]-testosterone (0.1 pM) in

human prostate epithelial cells and fibroblasts to all metabolites (DHT, androst-4-ene-

3.17-dione, 5a-androstane-3,17-dione), finasteride blocked conversion of [^H]-

testosterone (0.1 pM) to DHT and 5a-androstane-3,17-dione, but not androst-4-ene-

3.17-dione. If this difference is relevant in the in vivo situation is questionable (44). The

inhibition of the two isoforms of 5-alpha-reductase by saw palmetto extract seems to

be non-competitive and less potent with a Ki level about ten times higher than

finasteride, which was a competitive inhibitor (45).

Of a fractioned saw palmetto extract - i) saponifiable, ii) non-saponifiable, and iii)

hydrophilic sub fractions - only the saponifiable sub-fraction (consisting mainly of lauric,

oleic, myristic and palmitic acids) was active in inhibiting 5-alpha-reductase.

Of the fatty acids investigated, lauric acid was the most active: It inhibited epithelial

and stromal 5-alpha-reductase activity by 51% and 42%, respectively, non-

competitively and dose dependently up to a concentration of O.2mmol/L. The non-

saponifiable fraction, consisting mainly of phytosterols, was weakly active, while the

hydrophilic sub fractions, containing carbohydrates, amino acids and polysaccharides,

were inactive (46). Raynaud, 2002 confirmed these findings, he showed that the dual

inhibitory activity of saw palmetto extract on 5-alpha-reductase type 1 and type 2 can

be attributed to its high content in free fatty acids (47). Also, lipophilic saw palmetto

extract effectively inhibited in LNCaP prostate cancer cell lines 5-alpha-reductase

activity (48).

A further confirmation of the in vitro results was seen in a rat model of prostate

hyperplasia induced by androgen stimulation. After oral administration of saw palmetto

extract, 200mg/d for six days, the hormone-induced increase in prostate weight was

stopped (49). Another trial showed similar findings : 50mg/kg bw/d saw palmetto

extract inhibited hormone-induced prostate weight as well. The maximum effect was

reached after 60 and 90 days for the dorsal and lateral regions of the rat prostate, and

for ventral region after 30 days and 60 days, respectively (50). Furthermore, in rats a

saw palmetto extract decreased testosterone-induced prostate weight by 38% (150mg

extract/d) or 76% (300mg extract/d) (51). Similar effects were reported by de Lourdes,

An dy Suter 26

2007 for 400mg/kg/d for 14 days, also in a rat model (52). The reduction of prostate

weight was 44%, while Jaipur, 2003 reported a reduction to the size of the control

group (53).

In dogs with asymptomatic mild to moderate prostate enlargement, a dose of 1,500

mg/d TID saw palmetto extract which is about five times of the human dose of 320mg

or 300mg/d TID for 90 days did not affect prostatic weight, volume or histology. In a

similar trial set up saw palmetto extract did not affect the prostate in the same way as

finasteride (54).

The in vitro results suggest that saw palmetto inhibits the 5-alpha-reductase due to its

content of fatty acids. But the interaction with the enzymes seems to be different from

that of finasteride. To which extent the inhibition is clinically relevant is still part of

discussion and needs further investigation but animal testing showed that this mode of

action could be of relevance for saw palmetto. In trials with biopsies of BPH patients no

clear confirmation of these findings could be observed. Di Silverio, 1992, saw small

antiandrogenic and antiestrogenic effects (55) and in removed prostate tissue after saw

palmetto berries treatment, effects on oestrogen, progesterone and androgen

receptors were seen in the nuclear, but not in the cytosolic fraction. In a subsequent

trial the decrease of DHT - as marker of 5-alpha-reductase activity in vivo - in that

region correlated with clinical improvements (56).

Andv Suter 27

C/73'/:f'cr ] Gc.ncrc,'

1.2.3 Anti-inflammatory activity

As will be shown below (Chapter 2), saw palmetto preparations were used traditionally

for diseases with a certain inflammatory component like cough or epididymitis. Even

though an anti-inflammatory activity could be of therapeutical relevance, only few

experimental data on this subject is available.

An older experiment showed moderate antiinflammatory activity. In a guinea pig model

lipophilic 1-5ml/kg bw saw palmetto extract one hour before exposure to UV light

inhibited erythema. But carrageenan induced rat paw oedema was not reduced, in line

with this that saw palmetto extract did not inhibit platelet cyclooxygenase (57).

Adult male Wistar rats, receiving 50 or 100mg/kg bw saw palmetto extract for 90 days

displayed a reduced accumulation of mast cells in proximal stroma in a dose dependent

manner (58) and Sabal extract prepared with supercritical carbon dioxide inhibited

cyclooxygenase and 5-lipoxygenase in vitro ( I C 5 0 28.1 and 18.0pg/mL, respectively) (59).

Further evidence of the antiinflammatory activity could be shown in vitro using LPS-

induced IL-12 formation with androgen-independent human prostate cancer PC-3 cells.

Saw palmetto extract 50pg/mL reduced this LPS-induced IL-12 formation by 40% (60).

Anti-inflammatory activity in vivo was investigated by Vela-Navarrete, 2005. The pilot

study showed a significant reduction of inflammatory parameters in prostatic tissues of

patients treated with saw palmetto extract. Interestingly, a correlation with clinical

improvement was observed (61).

AndvSulcr 28

1.2.4 Muscle relaxation and vasodilatative effects

The traditional use of saw palmetto particularly in bladder problems in women as will

be described in chapter 2, points to the possibility that extracts of the plant could also

interaction with specific receptors in the bladder. To some extent, positive results have

been seen but there is clear evidence yet lacking.

A saw palmetto extract inhibited specific binding of [H]-[N-methyl-H] scopolamine

methyl chloride (bladder) and [H]-prazosin (prostate) with IC50 values of 46.1 and 183

pg/ml, respectively (62). Another study showed that various saw palmetto extracts

inhibited radioligand binding to human prostatic alphal-adrenoceptors and agonist-

induced [^H]inositol phosphate formation in vitro noncompetitively (63). But the results

could not be confirmed in a subsequent clinical trial in 12 healthy volunteers (64).

In a series of in vitro experiments, saw palmetto extract inhibited the muscarinic M3

receptor with an I C 5 0 of 3-30pg/ml but not on the M l and M2 receptor. The M3

receptor is seen as the relevant receptor which needs to be inhibited to influence

overactive bladder syndrome (65).

Saw palmetto extract exerted significant binding activity on autonomic receptors in the

lower urinary tract under in vitro and in vivo conditions. Oral administration of saw

palmetto extract to rats significantly changed the maximal number of binding sites for

prostatic [^H]-prazosin binding and for bladder [^H]NMS binding. This alteration by saw

palmetto extract was selective to the receptors in the lower urinary tract (6 6 ).

A single dose of 60mg/kg saw palmetto extract caused in a hyperactive rat bladder

model a significant improvement of the micturition interval, micturition volume and

bladder capacity during intravesical saline infusion. Also, doses of 12 and 20mg/kg

significantly reversed the reduced micturition interval as well as the decreased

micturition volume and bladder capacity due to 0 .1 % acetic acid infusion dose

dependently. Repeated administration to conscious, freely moving rats of 6 mg/kg saw

palmetto extract daily constantly increased the micturition interval and concomitantly

decreased voiding frequency. These experiments showed that saw palmetto worked, at

least in the animal model, also in overactive bladder (62).

Andy Suter 29

1.2.5 Interactions with P450 enzymes

Based on in vitro and in vivo trials there are almost no signais for a relevant interaction

potential for saw palmetto. These findings correspond well with the clinical situation as

in patients so far no cases have been reported (17). The majority of BPH patients are

older than 60 years of age (67) and usually use more than only one medication (6 8 ).

The findings from the P450 studies imply that patients with concomitant medication

which is metabolised by P450 enzymes are not at risk of any interactions by taking

alongside a saw palmetto preparation.

Yale, 2005 reported a slight inhibition in vitro of CYP3A4, CYP2D6, and CYP2C9 with a

lipophilic saw palmetto extract which contained 85-95% fatty acids and sterols and 0.1-

0.3% d-sitosterol (producer PhytoPharmacia, Green Bay, U.S.A.). For the experiments

the extract was drained and diluted 1:10 in 2% methanol. The IC50 for the test items

were 0.8% of the enzyme activity for CYP2D6,0.14% or 0.24% for CYP3A4 depending on

substrate, and 0.43% for CYP2C9 calculated from the inhibitory concentrations of the

undiluted primary test samples (69). Budzinski, 2000 found only moderate inhibitory

potential on CYP3A4 when compared to the test substance 7-benzyloxyresorufin.

Among 21 investigated herbal products, the assessed saw palmetto preparation was

ranked 13 regarding its interaction potential, Hydrastis canadensis and Hypericum

perforatum had the lowest inhibitory concentrations. The tested saw palmetto product

was only described as a commercial product available in Canada. Echinacea purpurea

herb and ginkgo biloba, which were tested by both groups, had comparable results like

saw palmetto in both trials (69, 70).

An investigation on the ability of different herbal preparations to inhibit UDP-

glucuronosyltransferase showed a moderate inhibitory potential of 55.2 ± 9.2pg/ml for

a 96% ethanolic saw palmetto extract with more than 85% fatty acids and more than

0.1% sterols (Finzelberg and Co. KG, Andernach, Germany), but the clinical relevance of

this finding is unclear (71).

An dy Suter 30

C/ijprcr J. Gcnr.";?!/.'-!"'

In two clinical trials this topic was addressed in twelve healthy subjects of both sexes in

each trial. Markowitz, 2003 showed that 320mg saw palmetto extract four times daily

for 14 days did not change the enzyme activities of CYP2D6 and CYP3A4. There were no

significant differences between the mean ratios at baseline and after saw palmetto

exposure for dextrometorphane (CYP2D6 activity) and alprazolam (CYP3A4 activity).

The authors conclude that when taken at the recommended doses, saw palmetto

extracts are unlikely to lead to interaction with other medication which use the same

cytochromes for clearance (72).

Gurley, 2004 administered 320mg saw palmetto extract twice daily, containing

85 - 95 % of fatty acids, for 28 days. The extract had no influence on the activity of

CYP1A2, CYP2E1, CYP2D6 and CYP3A4. The authors stated as well that prolonged use of

saw palmetto poses a minimal risk of drug interactions related to interference with

these CYP enzymes (73).

1.3 Toxîcological assessment of saw palmetto

1.3.1 Acute Toxicity

In experiments to determine the anti-oedematous effect of a hexane extract of saw

palmetto maximum an oral dose of 10mI/kg exerted no 'toxic effects'. The calculated

LDso added up to 54mL/kg in male rats. However, no details were provided in support

of this statement. A dosage of 50mL/kg lead mice to no deaths after oral administration

of a saw palmetto extract (57).

1.3.2 Repeat Dose Toxicity

Following a report that a product containing a saw palmetto preparation caused

cholestatic hepatitis, the effect of saw palmetto on rat liver function was assessed.

Investigated were the effects of a saw palmetto extract on several enzymes and

formation of malondialdehyde (MDA), a by-product of lipid peroxidation. A significant

increase in these parameters is considered to be an indicator of liver toxicity. Thirty-six

rats were treated for two or four weeks with a placebo or saw palmetto at doses of

Andv Suter 31

9.14 or 22.86mg/kg/bw/day; that is, 2 x and 5 x the maximum recommended daily

human dosages. After two or four weeks, the results showed no significant difference in

animal body weight, enzyme activity, or MDA formation at either time or dosage level,

as compared to controls. The data indicate that saw palmetto is not involved in a

mechanism causing liver toxicity (74).

These results are in line with reports on animal toxicity. In male Wistar rats 50 and 100

mg/kg bw saw palmetto extract given by oral gavage, showed no toxicity. Also, no

changes in body and prostate weight at necropsy, and macroscopic examination of

prostate were noted (58).

No adverse effects were observed at higher levels for a shorter period of time. Rats

tolerated 100, 320 and 640mg/kg/d saw palmetto extract in 2.5% ethanol well for 30

days (75).

1.3.3 Reproductive and developmental toxicity

There is only limited data available on reproductive toxicity. In an in vitro study with

hamster oocytes and sperm, a lipophilic saw palmetto extract produced no significant

effect on sperm motility at doses of 0.9mg/mL. The extract had no inhibitory effect on

the penetration of oocytes by sperm nor were dénaturations or mutations of DNA

detected after prolonged exposure to this herb (76). Also, a newer study showed no

influence of saw palmetto in a mice model to induce DNA damage (77) nor did they

observe any mutagenic signals in Ames tests (78, 79).

Overall, saw palmetto extract appears to be safe for use in men with BPH in particular

in the recommended daily dosage of 320mg. In the period of January 2003 to

December 2007, 61.4 million daily dosages of Prostasan®, the preparation used in the

trial in this thesis, have been sold worldwide. During this time, only one minor case was

reported to the Pharmacovigilance Department of A.Vogel Bioforce AG (80).

A n d y Suter 32

i; Gcicrc.'

1.4 Clinical efficacy and safety of saw palmetto

More than 90 publications on clinical trials with saw palmetto extracts are available; all

were carried out in benign prostatic hyperplasia (BPH).

Thus, in the following the disease BPH will be explained before discussing the results of

the studies with saw palmetto. The next chapters will give information on the aetiology

and course of the disease, its diagnosis and the therapy options. A more detailed

description of the history of BPH and its treatments are given in chapter 2.

1.4.1 Benign Prostatic Hyperplasia - the disease

1.4.1.1 Aetiology of the disease

Generally, benign prostate hyperplasia (BPH) is defined by a non-malignant overgrowth

of the prostatic tissue surrounding the urethra. This finally leads to a constriction of the

urethra and then to lower urinary tract symptoms (LUTS) such as urgency, frequency,

nocturia (synonym: nycturia), incomplete bladder emptying, and weak urine stream (3).

It is the most commonly occurring neoplastic disease in men (67).

The exact aetiology of BPH is not yet understood. The main theories are that the

disease is a result from reactivation of embryonic induction processes in the prostatic

tissue which originates in the innermost aspect of the prostate gland - the so called

transition zone which is located along the axis of the urethra (81). The prostate itself is

a male fibromuscular sex gland about the size of a chestnut with exocrine but no

established endocrine secretory function. It produces a volume expanding vehicle for

sperm, which seems to be the only function of this gland and the secretions provide

fluid that constitutes less than 20% of the ejaculate (82). The seminal fluid is excreted

by ejaculatory ducts, which pierce the posterior surface of the urethra (83) (Figure 4).

Andy Suter 33


Figure 4: Schematic drawing o f prostate gland (1)

Ureter opening

Bladder

Prostate

Opening of: Prostatic duct Ejaculatory

Sphincter

Verumontanum

Urethra

As mentioned the reason for the prostatic growth is not yet clearly understood. The

central factor is certainly age as it affects men above the age of 40 (67). There are some

theories for the reasons of the prostate growth postulated so far:

One is the hyperactivity of the membrane-bound 5-alpha-reductase, the enzyme that

converts testosterone to DHT, which in the end then leads to an increased cell

proliferation. Patients suffering from a 5-alpha-reductase deficiency show prostatic

volumes, which are approximately 1/10^ of age-matched normal controls highlighting

the importance of DHT for the normal formation of the prostate (84). On the other

hand, there is certainty that the development of BPH is exclusively dependent on

androgens since BPH does not occur in men castrated prior to puberty (85). The

reasons why the two isoforms of the 5-alpha-reductase should be overexpressed can

not be explained yet (86).

Andy Suter 34

Another influence on the prostate growth may be the shift in the balance of

testosterone to oestrogen, which tends towards oestrogen in the aging men. The

reason for this is that more testosterone is converted to DHT and bioavailable

testosterone levels decline due to decreased production by the testis and increased sex

hormone binding globulin (SHGB) levels which combine to lower free circulating

testosterone (87). However, circulating levels of free estradiol which is secreted mainly

by the adrenal gland remain constant in the aging male due to an age-related increase

in body weight and adipose cells which express high levels of aromatase and convert

androgens to oestrogens. The outcome is a significant increase in the

oestrogen/testosterone ratio allowing the balance of prostate growth to shift towards

oestrogen dominance. It has been proposed that increased estrogenic stimulation of

the prostate in the aging male may lead to reactivation of growth and subsequent

neoplastic transformation (88) mainly by activation of estrogenic receptors in the

prostatic tissue (89).

Another theory, which has received increasing attention postulates that BPH may be

triggered or at least catalysed by inflammatory conditions (90).

Histologically, the association of BPH and inflammation is well recognised. Already in

1979, it was noted that 98% in a series of 162 resected prostates had inflammatory

lesions (91). There is also clinical evidence for this hypothesis, two studies found a clear

correlation between inflammatory stages such as prostatitis and either the prostate

size (92) or symptom progression and prostate resection (93). A long term study carried

out between 1988 and 1994 in 2337 men in the United States revealed that those

having an increased C-reactive protein level of 3mg/l which acts as a marker of acute

inflammations were 1.47 times more likely to have more BPH symptoms than those

with lower values (94).

There are a lot of cytokines such as IL-2, IL-4, IL-6, IL-8, IL-15, IL-17 and INF-y involved in

inflammatory processes in BPH and have been found with rates of increased expression

and higher amounts at all in enlarged prostates. This lead to the hypothesis that BPH is

not only an inflammatory but as well an immuno-inflammatory disease since some of

the cytokines are not inflammatory at all but rather immune modulatory like IL-4 or

INF-y (95).

A ndy Suter 35

C/iGcrc," G cnerov

So far there is one clinical trial available which has investigated the influence of an anti

inflammatory drug on BPH symptoms. Patients suffering from BPH taking the COX-2

inhibitor celecoxib had, after only one month of treatment, significantly less nocturia

and a significantly lower score in the International Prostate Symptom Score IPSS than

those taking placebo (96). This trial indicated that the inhibition of the inflammatory

component of the BPH may lead to fast symptom relief for the patients.

The latest theory postulates that the prostate growth is a secondary condition caused

by insufficient veins in the testicles. Because of the inadequate transport of blood from

the testicular veins to the upper body, the prostate which is penetrated by this vein, is

exposed to blood which contains up to 130-fold the serum level of testosterone. This

testosterone is then converted to DHT and leads subsequently to prostatic cell

proliferation (97). This theory is plausible as it is the only one explaining why and how

an increased amount testosterone is available in the prostate as in elderly men the

serum levels of this hormone are decreasing (98). First results from 28 patients where

the insufficient veins were obliterated showed good treatment results in reducing their

BPH symptoms (97).

1.4.1.2 Course of the disease and diagnosis

BPH symptoms occur in men over the age of 40 who have testosterone-producing

testes, whereas morphologically it can already be detected in men over 30 years of age

(99). The main symptoms which have static and dynamic components (100) are

increased frequency of urination with nocturia, difficulty starting and stopping

urination, weak urine stream, feeling that the bladder has not emptied completely with

residual urine and in later stages urinary retention and painful urination (101).

The symptoms may not progress over time. Studies have shown that in populations

over a period of three years about 25% of all patients who had primary symptoms of

BPH respectively lower urinary tract symptoms (LUTS) had an improvement in their

symptoms without treatment (99).

Andy Suter 36

i; Ge/iem/ /nfroc-'ucf;,:

BPH is not a life threatening disease except when urinary retention is not treated since

this could lead to renal failure (102). Nevertheless, it may affect the quality of life of

patients in many ways be it by causing lack of sleep by nocturia, pressure to visit the

toilet very frequently or fear of urine smell due to terminal dribbling.

The disease is mainly diagnosed by assessment of the symptoms. The standard

instrument is a validated questionnaire, the International Prostate Symptom Score IPSS

(99) or the American Urological Association (AUA) symptom score (103). The difference

to the IPSS is that there is an additional quality of life question amended (99).

The severity of the disease is furthermore defined in two classifications, one from

Aiken, 1955 (104) and the other from Vahlensieck, 1985 (105), which are mostly used in

Germany. Whereas Aiken defines the three stages mild, moderate and severe as the

irritative, the residual urine and the decompensation-stages, in the definition of

Vahlensieck there are four stages with the first three being similar to the Aiken

definition, but he adds an initial stage where no symptoms occur at all.

A common diagnosis of BPH is via rectal examination, but it is important to note that

enlargement does not correlate with the severity of symptoms (106). With the physical

exam prostatic cancer can be excluded since cancerous tissue is different at palpation

than smooth BPH-tissue. A marker for prostatic cancer is additionally the measurement

of the prostate-specific antigen PSA, even though its values may be influenced by other

conditions like for example inflammations (107).

Optional tests for the evaluation of the BPH or LUTS include urinary flow rate

measurements, post void residual urine measurements, pressure flow studies and

ultrasonography to determine the size of the prostate (106).

Andy Suter 37


1.4.1.3 Epidemiology

Histologically BPH is shown in 8% of men aged 31 to 40 years. This number rises

progressively with age and can be distinguished in the 9 decade in about 90% of all

men. Figure 5 shows the frequency of histologic BPH in different age groups (3).

Figure 5: Presence of histologic BPH at autopsy by age group (3)

100 ^90

60 - *

0

31-40 51-60 61-70 81-90

Age Group (y)

Prostatic enlargement is a necessary but not sufficient condition for the development

of LUTS. This means that not all men having an enlarged prostate finally also suffer

from the symptoms of a BPH as mentioned previously (67).

Epidemiological studies have shown that nearly 50% of all men of age 80-90 suffer from

symptoms (108). The prostate size nevertheless seems to be the main factor for

inducing the symptoms; The odds to develop moderate to severe symptoms after the

age of 50 were 3.5 higher in men with a prostate volume >50mL than those with

smaller prostate volume (109).

Andy Suter 38

Comparison of data for development of microscopic BPH from the USA, England,

Denmark, Austria, India, and Japan showed that there is almost no difference in

frequency related to age group (67). Another large epidemiological study indicated that

black and Hispanic men were at higher risk of having BPH symptoms (110) whereas in a

large survey in the United States no difference in frequencies for BPH surgery between

Black, Asian and White males could be found (111).

In the study of Kristal with 5667 BPH patients obesity, particularly abdominal obesity,

was one of the main risk factors leading to BPH symptoms (110). Another survey

detailed that in addition intake of alcohol, lack of physical activity, and diabetes were

risk factors, it could not be established if smoking, diet, hypertension, and

environmental factors were connected to increased BPH symptoms (112). Genetic

factors and diet may nevertheless have an important influence on the progression of

BPH. The occurrence of BPH is less frequent in Asian countries as compared to the

United States. However, on entering the USA, Asians immigrants develop BPH mirroring

the rates of US American men (101).

Because of its high prevalence in the older male population, BPH is an increasing

burden for the health systems.

It is the fourth most diagnosed disease in men older than 50 years with a prevalence

rate of 13.5%, which is in the same range as osteoarthritis (113). For the U.S.A., the

direct costs of medical services for treatment of BPH are estimated to about

1.1 billion $ per year (114) whereas a Spanish study assessed the costs for only

medicine for one BPH patient per year to about 300 Euro (115).

Ai i c ' yS.uter 39

CAcp i?.'' j. Ge/icrc' A'lr.' ooyc Vc.".

1.4.1.4 Treatment of BPH

1.4.1.4.1 Watchful waiting

The first treatment option for patients with an IPSS up the total score of seven points is

watchful waiting (106). Studies have shown that for these patients medical treatments

are not better than placebo. The patient needs to be monitored during this phase as

well as spontaneous exacerbations and remissions of BPH may occur (116).

1.4.1.4.2 Medical treatments

1.4.1.4.2.1 Herbal preparations

Even though not stated in any of the actual treatment guidelines on BPH such as the

U.S. American, British, Australian, European, and Canadian guidelines (117)

phytomedicinal products are often applied as first line treatments to reduce BPH

symptoms.

The main used herbal products are saw palmetto preparations or combinations of saw

palmetto with stinging nettle which provide good treatment results in patients with

mild to moderate symptoms of BPH also showing good tolerability (118). Since there is

a strong patient demand for saw palmetto it is stated in one treatment guideline that

doctors nevertheless should become familiar with this treatment (106).

There are further herbal treatments available for the treatment of BPH.

Preparations made from African plum (Pygeum africanum) showed positive effects on

the symptoms of BPH. The authors of a Cochrane analysis including 18 controlled

clinical trials concluded that despite of weak methodologies, small number of patients

in the trials, and the short study durations a small but significant improvement

compared to placebo could be observed. In these studies lipophilic extracts containing

mainly fatty acids with a daily amount of lOOmg were applied (119,120).

Andy Suter 40

Since men in Asia suffer less from BPH it is assumed that probably a soy-rich diet may

be a treatment option for BPH or its prevention. A short term clinical trial (one month)

with an isoflavone product derived from red clover ('Trinovin') showed in dosages of 40

mg and 80mg per day a rapid relief of BPH symptoms with a very good safety profile

(121).

In several placebo controlled studies ^-sitosterol exerted promising effects in patients

with BPH (122-126). A shortcoming of these trials is their big heterogeneity regarding

the investigated products and the number of participants which ranged from 62 (122)

to 200 (124). The used preparations contained pure ^-sitosterol or ^-sitosterol-

glucoside of diverse origin, with different daily dosages. In the trial of Berges 60mg p-

s/tostero/from Cucurbita pepo were applied daily which were described as 'containing a

variety of phytosterols' (124), Kadow used 0.3mg of a ^-sitosterol glucoside (122) and

Fischer 195mg ^-sitosterol (126) per day, and Klippel 130mg free ^-sitosterol from

Hypoxis rooperi, Pinus pinaster, and Picea abies (125). Except for the lowest dose of

0.3mg ^-sitosterol glucoside, the trials showed good efficacy and safety. A Cochrane

analysis (2000) carried out on the use of ^-sitosterol in the treatment of BPH symptoms

based on these few trials suggested that the use of non-glucosidic ^-sitosterol could

improve urinary symptoms and flow measurements but gave no recommendation on

the daily dosage (127).

Three placebo controlled clinical trials have been carried out with a rye grass pollen

extract. The available evidence suggests that rye pollen extract was well tolerated and

modestly improved overall urological symptoms, including nocturia. In one trial rye

grass pollen was superior in its efficacy to a Pygeum africanum preparation. Since the

trials were mostly not carried out with state of the art parameters and were of short

treatment duration, currently a conclusive statement if rye-grass pollen extract is a

reasonable treatment option cannot be made (128).

\nc'y Suter 41

j . Ccnerj,'

1.4.1.4.2.2 Alpha blockers

For patients with an IPSS > 7 or bothersome symptoms, the main treatment prescribed

are a-blockers. This therapy is based on the concept that LUTS are partly caused by

al-adrenergic-mediated contraction of prostatic smooth muscle and bladder neck

(129). The main substances used are doxazosin, tamsulosin, alfuzosin, and terazosin.

They all have been widely studied in the treatment of BPH and LUTS (117).

The most selective of these four substances is tamsulosin since it targets the

a -lA adrenoreceptor subtype which accounts for 70% of all adrenoreceptors in the

prostate and is 13 times more specific in targeting these prostatic receptors than those

in the urethra (130).

Meta-analytical data on alpha-blockers derived from the AUA guideline showed that all

four substances have about the same efficacy whereas tamsulosin was slightly better

leading to an improvement of 4 to 6 points on the IPSS. The main advantage of a-

blockers is the fast onset of activity (131).

Side effects of these medications may differ; orthostatic hypotension, dizziness,

weakness, nasal congestion and abnormal or retrograde ejaculation were reported

most frequently (132).

1.4.1.4.2.3 5-alpha-reductase inhibitors

Currently, there are two 5-alpha-reductase inhibitors available, finasteride and

dutasteride. Dutasteride is selective for both isoforms of the 5-alpha-reductase

whereas finasteride more selectively blocks the isoform type 2 (133). Both treatments

lead to a symptom relief after 6-9 months of therapy and to a shrinking of the prostate

size by about 20% (106). The advantage of these therapies is that they significantly

prevent the incidence for surgery and urinary retention whereas alpha-blockers can

only lead to a delay of 2-2.5 years of these two items (134). The disadvantages are the

long onset of action, the efficacy seen on BPH symptoms are lower than with a-blockers

or surgery (116), and that PSA values are decreased by about 50% (135).

A:idy Suter 42

j ; Gc;:e,''c/ /ruTOo'c/cf/o.":

If long term use of 5-alpha-reductase inhibitors is favourable for chemoprevention

(prevention of prostatic cancer in particular) is still a topic for discussion. The Prostate

Cancer prevention trial with 19'000 men receiving either placebo or finasteride

revealed a significantly lower frequency of cancers in the finasteride groups but the

tumours were more aggressive than those found in the placebo group (136).

Which of the two Sa-reductase inhibitors is more efficacious is still a matter of

discussion. A large study with 5090 patients found a significant difference regarding

acute urinary retention (AUR) and prostate-related surgeries in favour of dutasteride.

Even though the differences were statistically significant they may not have been

clinically relevant as they were quite low (12% for dutasteride vs. 14.7% for finasteride)

(137).

Most often cited side effects were ejaculatory dysfunction, erectile dysfunction, and

decreased libido (138).

Regarding the choice for the right medication to treat BPH it seems that finasteride and

dutasteride are most favourable for patients with a large prostate (>50mL) whereas

a-blockers can be used in patients with all kind of prostate sizes (106).

1.4.1.4.2.4 Combination therapy

The largest trial, evaluating if a combination of an alpha blocker with a 5-alpha-

reductase inhibitor is useful in the treatment of BPH was the Medical Therapy of

Prostatic Symptoms (MTOPS) study. More than 3000 men received either placebo,

doxazosin, finasteride, and a combination of doxazosin and finasteride. After 4.5 years,

in the placebo group the AUA score had declined to a median value of 4, with doxazosin

to six points, with finasteride five points and with the combination seven points were

reached (p<0.05). With the combination the risk of progression was reduced by 66%

compared to a 39% reduction with doxazosin and 34% with finasteride (134).

An dy Suter 43

The overall outcome from this study was that the combination was more effective not

only in treatment but also in terms of a favourable progression of the BPH. The

combined use of 5-alpha-reductase inhibitors and a-blockers is generally used in every

day practice (106).

1.4.1.4.3 Surgical treatments

1.4.1.43.1 Open prostatectomy

This is the oldest and most effective treatment for relieving BPH symptoms (106). It is

still performed and recommended for large prostates (138) and the symptomatic

improvement occurs in 98% of all patients (106).

1.4.1.4.3.2 Transurethral resection of the prostate (TURP)

The method was developed in the 1920's (106) and is still the gold standard for surgical

treatment of BPH. It is a surgical procedure in which portions of the prostate gland are

removed through the urethra with a unipolar wire loop-electrocautery device. Sterile

glycine irrigation fluid is used to distend the bladder and urethra during the procedure.

After the surgery, which lasts about one hour, a catheter is placed for about one day

(138).

TURP reduces symptoms of BPH by 88% (116) and is the most effective treatment for

BPH with respect to the improvement of symptoms and flow rates (138) but morbidity

associated with the procedure is still an important issue (139). Immediate post

operative side effects include bleeding, and urinary tract infections (139), whereas long

term complications comprise retrograde ejaculation (70% of the treated patients),

impotence (14%; range 3-32%), partial incontinence (6%) and total incontinence (1%)

(140). About one in ten patients needs retreatment within five years after surgery

(116).

Andy Suter 44

C/Tcpf-E/' ' Genera/ //i/roa'ac/Vcr.

1.4.1.4.4 Other surgical treatment options

Since many elderly patients are poor surgical candidates and younger patients find the

risk of sexual dysfunction unacceptable, 'minimally invasive' surgical techniques have

been developed (106).

The transurethral microwave thermotherapy is a method where by insertion of a device

the temperature within the prostate (via the urethra) is increased to above 45“C, which

leads to necrosis of the prostatic tissue (139). The advantage of this method is that long

term complications such as impotence and retrograde ejaculation occur much less

frequently than with TURP (141) and the surgery can be performed in an ambulatory

setting (138). However, only a small patient population is eligible for this treatment

(139).

Transurethral needle ablation is a further non-invasive method where low-level

radiofrequency is delivered via a needle into the prostatic tissue. The results of this

treatment may be limited since the bladder neck and the median prostate lobe cannot

be treated but it is safe and generally well tolerated without further long term side

effects (106).

Instead of using a electrocautery device to resect the prostate tissue, laser is also

applied (laser prostatectomy). This method seems to be as effective as TURP (142) by

leading to less long term side effects but the method is not easy to apply and needs

'significant endoscopic skills' (139).

The latest minimally surgical intervention is the above mentioned so called Gat-Goren

method which aims at sclerosing insufficient testicular veins and reduces thus the

venular hypertension in the prostatic tissue and subsequently the extensive

testosterone concentration. This method is still in a pilot phase and should be

established with larger clinical trials (97).

In summary, the medical treatments fall short of achieving a patient perception of more

than fair to good improvement in most cases. The awareness of very good to excellent

improvement is reserved for surgical interventions. Patients, who are dissatisfied with

An dy Suter 45

the efficacy or safety of their medical treatment, are initially advised to seek minimal

invasive surgical treatment and then TURP (143).

A treatment layout for BPH patients which summarises the knowledge of the actual

urological guidelines is given in Table 1 (100) with modifications after Geavlete (144)

and Gregorin (145).

Table 1: Treatm ent scheme fo r BPH patients w ith regard to the ir LUTS, prostate size, severity ofsymptoms, and complications after Issa, 2007 (100) w ith m odifications regarding the use o f saw palm etto a fter Geavlete (144) and Gregorin (145).

BothersomeLUTS severity Prostate size Complications Treatment options

symptoms

AUASI<7W atchful waiting

Saw palm etto

AUASI>8 <30 cc(m l) No W atchful waiting

Saw palm etto

YesW atchful waiting

Alpha blocker

Saw palm etto

>30 cc (ml) NoW atchful waiting

5-a-reductase inh ib ito r (SARI)

Yes |yjQ W atchful waiting

Alpha blocker (monotherapy)

SARI

Alpha blocker + SARI

M inim ally invasive therapy

Surgical therapy

Yes Surgical therapy

A c'v 46

C/'iuCf-c/' J, Gc/icm.''

1.5 Clinical data from saw palmetto preparations

Monographs and meta analyses are the two major sources which give an assessment

on the clinical efficacy and safety of a treatment. The main difference between these

two documents is that monographs for herbal medicines consider also the traditional

use of a plant, whereas meta analyses rely only on published clinical data.

In the following, a short summary on the present monographs on saw palmetto and the

most recent important reviews is given.

1.5.1 Monographs on saw palmetto, recommended preparations and daily

dosages

Currently, there are four monographs available on saw palmetto, an older German

Commission E monograph (146), a WHO (147) and an ESCOP monograph (17) and one

from the Canadian health authority (40). They all recommend the use of saw palmetto

in mild to moderate forms of BPH. As side effects stomach problems, nausea, diarrhoea

or other minor gastrointestinal complaints are cited. No interaction with other

medications are quoted nor any restrictions of use or contraindications.

As daily dosage 320mg of a lipophilic saw palmetto berry extract are recommended in

all monographs, the WHO monograph advices to apply this dosage as a single dose or

twice daily at ISOmg (147). The monographs advise to use extractants such as hexane

(40, 146, 147), ethanol 90% (40, 146, 147), supercritical CO2 (147) or equivalent agents

(17, 40, 146, 147). Only the Canadian monograph addresses further requirements on

the extract quality i.e. it should contain between 70-95% free fatty acids and

corresponding ethyl esters (40). Table 2 summarises the data from the monographs on

the different extractants and recommended daily dosages.

Andv Suter 47

Chapter 1 General Introduction

Table 2: Requirements on daily dosages and extractants from the monographs on saw palm etto

Reference Daily dose Preparations

Health Canada (40)

ESCOP (17)

320mg lipidosterolic extract w ith 320mg lipophilic ingredients

320mg lipophilic extract

Extracted w ith lipophilic solvents such as hexane or ethanol 90 % v/v

No details on solvents provided; equivalent preparations acceptable

WHO (147) 320mg (as a single dose or160mg tw ice daily) of a lipidosterolic extract

Extracted w ith n-hexane, ethanol 90 %, or supercritical fluid carbon dioxide to contain between 70 and 95% free fa tty acids and corresponding ethyl esters or equivalent preparations

German Commission E Monograph (146)

320mg lipophilic extract Extracted w ith solvents such as hexane or ethanol 90 % v/v; equivalent preparations

1.5.2 Clinical studies w ith saw palm etto preparations

Based on Medline, EMBASE and the Cochrane more than 90 clinical trials available on

saw palmetto and BPH have so far been published. In a meta analyses on saw palmetto

only randomised controlled clinical trials which fulfil a defined quality level, measured

either with the Jadad score (148) or the criteria from Schulz (149), are usually included.

For example, the latest reviews on saw palmetto by the Cochrane Collaboration

included only 21 studies in 2002 (118) and 30 trials in 2009 (150). These Cochrane

reviews are regarded as the gold standard among meta-analyses and are the basis to

assess if a treatment can be called evidence-based.

In all trials lipophilic saw palmetto extracts with a daily dosage of 320mg were applied

with treatment durations from 4 to 60 weeks. The studies were placebo-or reference-

controlled; reference compounds were alpha blocking agents like tamsulosin or

5-alpha-reductase inhibitors like finasteride. As endpoints either BPH symptoms,

measured with the IPSS or the AUA score or urinary flow parameters were chosen

(150).

Andy Suter 48

In 2000 and 2002 the reviews from the Cochrane Collaboration gave a positive

statement on the efficacy and safety of saw palmetto in treatment of BPH symptoms.

LUTS and flow parameters were assessed as having improved significantly compared to

placebo and were as good as under finasteride treatment (118,151).

After a large placebo controlled clinical trial, carried out in the United States, with

negative outcome was published (152), the next Cochrane review in 2009 regarded the

efficacy of saw palmetto as doubtful but paradoxically still as good as finasteride or an

alpha blocking agent in longer term treatment of more than 16 weeks (150).

The findings from this review are thus often cited to question the efficacy of saw

palmetto like in the latest BPH treatment guideline from the American Urological

Association (153). In all trials, the safety of the saw palmetto preparations was

excellent, the treatments were very well tolerated and no severe side effect occurred

(154).

The conclusions from the Cochrane analyses are debatable since these reviews had a

restricted view on a treatment. They neglected not only the traditional use of the plant

but also personal experiences from urologists which regard saw palmetto as a good

symptomatic first line treatment for BPH patients (144,145). Also the trials which were

chosen in the analyses may have shortcomings as well. It is for instance not explainable

why trials from France (155-157), Italy (158, 159) or Germany (160, 161) yielded

positive results but why the latest U.S. American studies on saw palmetto in BPH

produced only negative outcomes (152,162).

1.6 Final remarks

In conclusion, there is sufficient scientific evidence from in vitro testings and animal

experiments to explain the mode of action of saw palmetto in patients with BPH.

Furthermore, there are plenty of clinical trials and personal experiences showing that

saw palmetto acts as a very well tolerated and efficacious treatment in patients with

mild to moderate BPH symptoms; this is also widely accepted and used in the

recommendations by four respected monographs.

A ndy Suter 49

Chapter 2

A short history o f the treatments fo r BPH, the use o f saw palmetto in the United

States until the 1930's and the introduction o f saw palmetto into Germany

Andy Suter 50

Chapter 2: Historical part

A short history of the treatments for BPH, the use of saw

palmetto in the United States until the 1930's and the

introduction of saw palmetto to Germany

2.1 Introduction

Today saw palmetto is a well known treatment option for mild to moderate symptoms

of BPH. In the United States, Saba I ranks third among the food supplements with an

annual sales volume of 200 million dollars (163) and an estimated number of 2.5 million

users (164). The worldwide turnover is likely to be 700 million dollars per annum (163)

reaching almost blockbuster status in pharmaceutical terms and in Germany half of the

urologists prescribe herbal treatments for BPH symptoms with saw palmetto being the

favourite one (164). The same situation is reported for France (165) and Italy where five

times more saw palmetto products are prescribed than alpha antagonists for treatment

of BPH symptoms (166).

Surprisingly, despite of the status as being one of the most popular phytomedicines

little is known about the origins of saw palmetto as a treatment for BPH. Only two

publications dealt so far to some extent with the history of the use of saw palmetto.

The book by David Winston (167) and the review by Bennett (19) give some details on

how the plant was applied by the indigenous population of the Florida region as well as

the first medical uses of saw palmetto among white settlers in the United States.

Bennett gives a good and comprehensive description of the indications where saw

palmetto was used traditionally but lacked historical data on when, how and by whom

the species was used nor did it assess the timeline of its introduction into medical

practice. Winston quotes interesting sources documenting the first use of saw palmetto

among white settlers but the historical part in his book is rather short and is not the

main scope of the book which lies in the medical use of the plant.

Andy Suter 51

C/iOjCfer 2; H / s po/i'

A coherent review on how saw palmetto made its way to become an acknowledged

treatment in the United States is lacking. The same applies also for Germany where the

plant has a special status as it is not a traditional European medicinal plant but was

introduced from the United States. There are no data who introduced saw palmetto

into Germany, how it became known and who used it first as a medical treatment or as

a food. Additionally there is no literature available which puts saw palmetto as a

treatment for BPH into the context to available and generally applied cures for this

disease until 1930.

With the medical historic part of my thesis I aimed to provide new insights about these

topics. The goal was to find out how saw palmetto was used among the Indians of the

Florida region, then how the white settlers gained knowledge about the plant, for

which indications they used it and how it was described in literature. One main interest

was further to assess if a group of practitioners favoured the use of saw palmetto and

then how this treatment became popular and made its way into the official U.S.

American compendiums.

In a last step I wanted then to find out how saw palmetto made its way over the

Atlantic and became known in Germany. The goal was to show how the knowledge

grew about saw palmetto in Germany over time, how was the plant used and who were

the first practitioners to use it as a remedy.

2.2 Research Strategy and Methods

2.2.1 Research strategy

In order to understand how the disease BPH evolved in medical literature first I

searched for publications on the history of BPH and checked all available medical

standard textbooks from 1870 to 1930 on the treatment of the prostate disorders in

the Wellcome Library in London as well as in the library of the Medical Historic Institute

of the University of Zurich.

Andv Suter 52

2; h'lStcr/cc;

Secondly, literature searches on when saw palmetto was first mentioned in the

medicinal literature of English language allowed an understanding of how it was

introduced into medical or alternative practice. The timeframe 1870 to 1930 was

chosen as saw palmetto was apparently first mentioned in American medical literature

in the period after the American civil war, i.e. post 1870 (167) and in 1926 it was

included in the official U.S. formulary, showing that the plant had an official status as

medical agent (19).

In a third step, the relevant literature was assessed to determine how and when saw

palmetto appeared for the first time in popular, medicinal or scientific German

literature. This country was chosen as subject of research as I am of German mother

tongue and since saw palmetto is today an important herbal remedy in this country.

I also preferred Germany to the other German speaking countries Austria or

Switzerland as it is the biggest country and the majority of literature was assumingly

published there.

As a framework how to find historical sources I used the methodology and

considerations given by Brundage in his book 'Going to the Sources' (168).

He divides the most important research material, the primary sources in two classes.

The first are manuscript sources like handwritten records which were not intended for

publication, the others published sources. These encompass two categories, manuscript

materials such as letters, diaries which were later published and materials that were

intended to be made public like newspaper articles, annual reports, books or the like

(168).

For this research I used almost only published sources like journal articles and books

but no manuscript sources or archive material. Like this, my work is a comprehensive

medico-historical collection of published material on saw palmetto covering how the

plant was used first in the United States by indigenous people and physicians and its

introduction into German medical society.

A nd y Suter 53

To assess the quality of a source I used the guidance given for source criticism in the

book of Howell and Prevenier, 'From reliable sources - an introduction to historical

methods' (169). This involves the evaluation of the genealogy, genesis, originality, and

interpretation of a document as well as the authority of its author and his or her

competence and trustworthiness. Regarding the genealogy, genesis, and originality I

tried to find out if the document was an original or copy and where, by whom and

when the source was produced. In a second step I interpreted the document by

understanding its intended meaning, for example was it a research article to inform the

scientific community or rather intended to promote a commercial product.

At last I assessed the authorial authority of a document by finding out who was its

writer and what was the competence and trustworthiness of the author regarding the

content of the article or document. For these evaluations I carried out in the majority

internet searches by using the name or institution of the author as search term, which

often provided good background information.

All literature searches were carried out either online or in the named libraries from

January 2010 until January 2012. A literature was marked as a hit when it provided

sufficient evidence for the use of saw palmetto as a medicinal treatment or as a hint

that the saw palmetto was known but not used as a medicinal treatment (but for

example as a garden plant).

Table 3 lists the libraries or resources I used for my searches with the search terms,

limitations in year of publication and the hits. When a hit was of special interest or

needed further clarification, then the biggest historical U.S. online library, Hathi Trust

(170) or in case of a German reference, the 'Karlsruhe virtual catalog' (171), the biggest

German library resource were searched or individual libraries where a certain reference

was kept in original.

In the end I had assessed more than 1700 documents for use in this medico-historical

overview.

Andy Suter 54

> hnr :P:

Table 3: Libraries and online resources fo r the literature search from January 2010 until January 2012 w ith search terms, lim its on publication dates, num ber o f hits, and the hits which could be used fo r the analysis.

Library/Resource

ZVAB (Zentrales Verzeichnis Antiquarischer Bûcher [central register of antiquarian books]) zvab.com

Google books (books.google.com)



Medical historic library university of Zurich

The Wellcome library, London

Swissbib.ch (all Swiss libraries)

Zentralbibliothek Zürich (central library Zurich, it combines the libraries of the ETH Zurich, University of Zurich and the Canton of Zurich

PubMed Medline(h t tp : / /w w w .n c b i .n lm .n ih .g O v /p

ubmed/)

American Botanical Council ABC


Search terms1

Period Number of j hits

Usable hits

Serenoa ; Sabal ; Sagepalme 1870-1920 None None

Sagepalme 1870-1930 53 15

Serenoa 1870-1930342 german hits

13

Sabal 1870-19306750 german hits, viewed around 1000

14

Serenoa, Sabal, Sagepalme 1870-1930 50 50

Prostate, prostatic hyperplasia ; saw palmetto

1870-1930 200 15

Sabal, Sagepalme, Serenoa, Hagers Handbuch, Homoopathisches Arzneibuch, Homoopathische Arzneibücher

1870-1930 80 ca. 20

Hagers Handbuch, Homoopathisches Arzneibuch, Sagepalme, Prostata

1870-1930 50 15

Saw palmetto AND historic; prostate AND history; benign prostatic hyperplasia AND historic; historical AND prostate

No limits 517 10

Literature on traditional use of saw palmetto, sent on request by Roy Upton, president of the American Herbal Pharma - copoeia and David Winston, American Botanical Council

10

Chaemerops serrulata, Brahea serrulata, Diglossophyllum 1800-1930 200 10serrulatum

55

http://www.ncbi.nlm.nih.gOv/p

Cnc/;Z'e,''2 ' H/s ter,'ce; pa,';

2.3 Results

2.3.1 The history of benign prostatic hyperplasia and its treatment

2.3.1.1 The discovery of the prostate and benign prostatic hyperplasia

The first mentioning of the prostate in medicinal literature is credited to Herophilus of

Alexandria (ca. 300 B.C.) but it is questionable if the organ he described as 'parastates'

(172) or as 'prostatae glandulosae' and 'prostatae cirsoides' was really the prostate and

were not the seminal vesicles and the ampulae of the ductus deferens (173).

Erasistratos, a Greek anatomist living from 320-250 B.C., wrote about the prostate in

the same manner several years later as Herophilus. It was then Rufus of Ephesos, a

physician who lived between the 2" and the 1* century B.C. who was apparently the

first author to give a good description of the glandular nature of the prostate. He was

followed by the dominant medical doctor of this era, Galen (131-201 B.C.) who gave in

his explanations of anatomical procedures an account of the prostate as ,spongy flesh

at the side of the neck of the urinary bladder' (174). Interestingly, benign prostatic

hyperplasia as a disease was not mentioned by earlier ancient authors, be it by

Hippocrates (ca. 406-377 B.C.) who was considered to be first urologist nor by ancient

Egypt authors (172).

Surprisingly from the Hippocratic period to the 16 century, the prostate or prostatic

hyperplasia were only vaguely portrayed in medical literature (175). The famous

anatomist Vesalius (1514-1564) reported the existence of the prostate only in very

general terms and Leonardo da Vinci (1452-1519) ignored the prostate in his drawings

of the male urogenital tract completely (173).

Nicolo Massa of Padua is believed to be the author who around 1550 'rediscovered' the

prostate as an organ (175) and in 1648 Jean Riolan, the younger (1577-1657), was the

first person to find the relationship between an enlarged prostate and urinary problems

(176). Previously the French surgeon Ambroise Paré (1510-1590) had observed that

male urinary problems occurred more frequently in the elderly and that these LUTS

arose age-dependently (172).

A'rc'y Sutci ' 56

2; H.'sfc/vcû/' /:jr:

That the prostate or BPH symptoms were not more frequently a topic in medical books

during the 16 * to the 17 century may be attributed to only few men reaching the

'prostate-age of sixty years' as the historian Shelley names it and the average life-span

of forty years at that time (173). But there is evidence that BPH was apparent in

medieval times as could be shown with the autopsy of the mummy from one of the

leading figures of the Italian Renaissance, Pandolfo III Malatesta (1370-1427).

Macroscopic and histological findings showed that he suffered from an enlarged

prostate which is the first paleopathological record (177).

Even though several physicians and anatomists like Thomas Bartholin (1616-1680),

Pierre Dionis (1650-1718) or Giovanni Domenico Santorini (1681-1737) tried to dissolve

the mechanism behind BPH it was until 1761 that the Italian anatomist Giovanni

Battista Morgagni gave in his comprehensive work 'De sedibus et causis morborum per

anatomen indagatis' a proper account of prostatic hypertrophy and he realised the

relationship between retention symptoms and pathological findings.

His mechanical view on the disease that an enlarged prostate leads to urinary problems

was a breakthrough since until then it was believed that urinary symptoms in elderly

men were caused by a paralysis of the bladder or leniency of the urinary tract (176).

Although several anatomists tried thereafter to explain the real nature of prostatic

growth, it was in 1862 Rudolf Virchow who established that prostatic hypertrophy was

a hyperplastic disease (178). In 1911 Lendorf set a milestone in BPH research

confirming the concept that the hyperplastic growth was in fact a growth in the

periurethral glands (176) which is the actual understanding of the disease (3).

Andy Suter 57

2.3.1.2 The history of BPH treatments

2.3.1.2.1 Catheterisations and surgical interventions in BPH in history until 1930

Not many treatments for patients suffering from BPH symptoms have been reported

until the beginning of the 20 century. Mainly catheterisations or needle punctuations

of the distended bladder were recommended indicating that only patients with

moderate to severe obstructive symptoms were treated (173).

Already in ancient Greek catheterisations were carried out, Erasistratos was the first to

describe one with an S-shaped catheter. In the 16 to the 19 century catheterisations

became popular again and different catheters and methods were developed and tried

out (175). Major milestones were then the invention of the gum-elastic catheter in

1777 by Theden (179), around 1840 the bladder catheter of Mercier called the ,cathéter

condé' and in 1853 the balloon catheters by Reybard (176). At the end of the 18 and

until the begin of the 20 century catheterisation was the general accepted treatment

for prostatic problems; for one patient in the early nineteenth century even the

number of 6892 catheterisations is documented (173).

The first operative procedure on the prostate was performed by the French surgeon

Ambrose Paré in 1575 using a genius punch-type instrument to cut out tissue. His

method of inserting a hollow tube with a cutting or crushing implement into the

urethra to remove prostate tissue was the same construction as is used today in

endoscopes for prostatic surgery (175). On the principle of the Pa re's method different

approaches with dilating, compressing or cutting the prostate were exercised until the

end of the 19 * century (176).

In the last quarter of the 19 century bladder puncture was carried out often where a

coarse needle was inserted via the transrectal, perineal, or suprapubic route and the

bladder was then emptied through the punctuation (173). A further development was

open adectomy which was performed from the end of the 19 century when

anaesthetics and antiseptic surgery were established. The transurethral procedures

were further developed, leading to the method of transurethral resection of the

A ndy Su 1er 58

C/7cp"c/- 2; Hfsfcntcz;'

prostate (TURP) with an electrocautery device. This surgery first was tried out in 1926

and is the gold standard for prostatic surgery today (175).

In the late 19* century castration was also advocated as a treatment because of

observations made with animals and the apparent similarity of prostatic adenoma and

uterine myoma which decreased in volume after oophorectomy (175). This treatment

attained a ,short and hectic period of glory' (176) but soon disappeared as method of

choice because of the lack of efficacy and the obvious mental and aesthetic burden for

the patients (175).

2.3.1.2.2 Medication used for BPH from 1820 until 1930

Non-surgical therapies for BPH were rarely ever mentioned in medicinal literature. The

leading opinion at the end of the 19 century was that BPH was an ,incurable disease'

(180) and earlier, in 1874 it was stated by the doctors van Buren and Keys that ,ln the

present state of our knowledge, hypertrophy of the prostate is not curable by any

means that have yet been used' (181).

The main medical books on genitourinary diseases in the period of 1870 to 1930

recommended in the majority catheterisations or surgical interventions as efficacious

treatments particularly for moderate to severe BPH symptoms (181-190).

In 1810 Hunter advocated sea bath cures, blistering to the perineum, opiate blisters

against pain, and drugs such as hemlock (most probably Conium maculatum) or

mezereon (Daphne mezerum) which was often used as powder or decoction to treat

syphillis (191). The British surgeon Henry Thompson described in his book 'The enlarged

prostate' a holistic treatment regimen for the patients affected by BPH which included

moderate and well digestible food and beverages, sufficient physical activity, modest

sexual behaviour, and a positive mind-set. He also discussed the use of hemlock as

proposed by Hunter but was more sceptical about the efficacy of the plant in BPH as it

was then used successfully 'in enlargements of the lymphatic and mammary glands'.

Furthermore, he opposed the use of mercury in BPH patients, a treatment which was

obviously administered quite often these days. He also promoted the use of ,the

An d y Suter 59

r/7cpücr 2; H.'rro.'Vcn,'

hydrochlorate of ammonia' which was a treatment administered in Germany and

France where 4-12 grams had to be taken for a duration of 4-8 weeks (192).

A further treatment was the application of iodine either as suppository, orally or as

topical treatment on th e ,urethral surface of the prostate'. Thompson cited the findings

of Stafford, who reported good efficacy in treatment of enlarged prostates (193) but

also advocated the use of bromine but both, iodine and bromine should only be

administered cautiously (192). He was impressed by the waters of the springs of

Kreuznach in Germany which were rich in iodine and bromine. He had visited the baths

and subsequently, recommended hip baths to British patients suffering from BPH using

the Kreuznach waters from the Elizabeth-Quelle which could be bought then in the

United Kingdom. The spring water contained also other minerals such as sodium,

calcium and carbonic acid gas (192).

The treatment with iodine and bromide was also described later by the physician

William T. Belfield and he proposed further an injection to the bladder containing a

solution of tannin in glycerine and water with 0.5-1% zinc citrate as treatment of BPH

(185). Van Buren and Keys regarded the treatment with iodine and bromide as not

efficacious and wrote that ,the advocates of these and other methods have failed to

establish their claims' (181).

The U.S. American urologist Eugene Fuller recommended for BPH patients as

medicamentous treatments mild diuretics such as ,sweet spirits of nitro, terpentine,

and juniper' where citrate of potash, buchu (Barosma betulina) and a fluid extract of

corn silk (Stigmatis maidis) should be added for best efficacy (187).

Another American urologist, Robert W. Taylor endorsed only few non-surgical

treatments, aside from hot bathes and lifestyle changes like a balanced diet or enough

physical activity. He suggested 'strychnine, quinine, and tonics ... in run down and

debilitated subjects' (188). The American urologist Hugh Cabot advised not to use

'palliative measures' but promoted catheterisation or operations (189). Abrahams and

Morson, two American urologists, were even stricter by declaring that 'the correct

treatment for this disease is removal of the whole gland by operation' (194).

Andy Su ter 60

C/: o;: tc /' / . /-f.': Cc; ,Tc / c/'^

Among German urologists medications or palliative treatment, as it was called, was not

highly regarded as method of choice. This is also shown in the standard work of

Schlagintweit, 1921 who recommended catheterisation and then surgery but no

medicamentous or other treatments (190).

In summary, until 1930 no standard medications for BPH patients were available and

saw palmetto was never mentioned in the standard books on urology.

Catheterisation and surgery were the methods of choice and the medicamentous

breakthrough was achieved in the late 1970's after the discovery that alpha blocking

agents like phenoxybenzamine, a nonselective a-adrenoreceptor antagonist, were

effective in treating BPH symptoms (195). In 1992, then the first 5-alpha-reductase

inhibitor, finasteride, was granted marketing authorisation by the U.S. Food and Drug

Administration for treatment of BPH symptoms (196).

These two classes of drugs are at the time the main synthetical drugs for BPH

symptoms (197). Further details of current treatments of BPH were already given in

chapter I.4 .I.4 .

A n d y Suter 51

C/fOptc/ 2. H.'r -c.n'co.'pc.''-

2.3.2 History of human use of saw palmetto

2.3.2.1 Use as material and wax

The fibres were important to Florida's indigenous people, the Seminole. Since saw

palmetto leaves and stems are rich in fibres, they were used to fabricate brushes (19),

served as basic material for the production of paper (7), and in some specialised cases

during World War II even for cartridge plugs and wallboards (198). The Seminole made

thatches for their houses and constructed huts and used the fibre to braid fruit

collecting, corn sifting and ritual baskets (7) either for their own use or these days

mainly as souvenirs for tourists (199). Further use of the fibres of saw palmetto was

made for production of fire fans and ceremonial dance fans. Even baby rattles were

produced from the leaves by producing a little closed basket, which held pieces of

charcoal (19) and with the fibres also mattresses and straw hats were manufactured

(20).

Palmetto leaves may also be a source of wax. Wilder and Kitzke described a yield of 1.4

to 2.7g of the free flaking wax per lOOg of leafs. But as most of the palm wax of other

species is also free flaking and easy to collect, the costs for collecting and processing

saw palmetto wax is economically questionable (28).

2.3.2 2 Use as food

Since saw palmetto berries are rich in oils, they formed an important part of the diet of

Florida's indigenous people and the berries are ubiquitous in archaeological sites in

Florida. In the 1990's older Seminole Indians still ate the fruit raw but they advised not

to eat more than five fruits per day since they are bitter and moreover it is

recommended not to eat them with hot liquids as this may burn the mouth (19). The

Indians also prepare a sweetened traditional drink with the berries, which is called

'shiopee sofkee' (33).

An dy Suter 62

C/'jprcr 2/ jCC.'T

The use among non-indigenous residents was detected in settlements from the

16 * century from Spanish Florida (200) and there in particular at Lake Okeechobee (8 ).

Generally, records of the plant have been found among the indigenous groups of the

Timucua and Apalachee, the Cochtaw living near the Mississippi river who used the

dried berries for winter use, and also among the Sioux Indians (8 ).

The known first record of non-indigenous habitants of America eating saw palmetto

fruit was by a young Quaker merchant, Jonathan Dickinson, who wrote in a book 1796

about the misadventures of a boat full of Quakers shipwrecked on August 23, 1696 on

Florida's east coast. They were captured by indigenous people and kept as prisoners for

several weeks. They almost starved and all they could eat were fish and saw palmetto

berries. He describes this often cited experience of eating saw palmetto fruits: 'We

tasted them, but not one among us could suffer them to stay in our mouths, for we

could compare the taste of them to nothing else but rotten cheese steeped in tobacco

juice.'(7).

The botanist Bartram to the other hand, wrote in 1792 that the berries were 'delicious

and nourishing food' but as he interviewed later the Creek Indians about the berries

they defined them as 'bitterish and stinging on the palate, at first using it, but soon

become familiar and desirable' (8 , 9).

The mentioning of the species' use as a beverage by white settlers or in later centuries

by the inhabitants of Florida is firstly as a soft drink, which in the early 1900's was sold

by Miami pioneers. This drink was called 'metto' and was a mixture of saw palmetto

berries with carbonated water (201). Secondly, it was tried as an aromatic in cognac

(202).

In 1866, a German book already mentioned that the saw palmetto tree was used to get

a starch flour (203). In 1888, the same was described in detail in an article where the

production of a flour used by the Seminole Indians made from the root of saw palmetto

was detailed (204). A newer source, the book 'Field Guide to Edible Wild Plants'

explained further that the palm heart is 'tender and makes an excellent salad or cooked

vegetable' (205).

A nd y Suter 63

C/7Cprc." 2; H/sic/Vcr;,'' pcr/T

23.2.3 Use as a medicine

2.3.2.3.1 Medical uses by indigenous people

The indigenous people of Florida knew saw palmetto as a medication with diuretic,

sedative and aphrodisiac properties. The steam from cooking fruits was inhaled as a

treatment for bronchitis, as expectorant and to soothe irritated mucous membranes

(206). Infusions of the leaves and roots were taken to treat dysentery and stomach

pains by 'Gulf Coast Indians' (most probably referring to the Seminole Indians) and they

applied the inner trunk bark as a dressing or poultice for insect and snakebites and skin

ulcers. The indigenous group of the Houma (Louisiana) administered a decoction of the

root for sore eyes, high blood pressure, and kidney problems (207).

2.3.2.3 2 Use in U.S. American, Non-indigenous medicine

The first mentioning of the use of saw palmetto in Western medicine appeared in an

article published in the journal 'The Medical Brief from St. Louis by Dr. J. B. (James

Bond) Reed of Savannah, Georgia in 1877 (208). Despite of an extensive search, I could

not find the original literature as the first issues available in the largest American library

catalogue, Hathi Trust from this journal are from 1882 on onwards (209) and libraries in

St. Louis hold no old issues of this journal either. His real name was actually James B.

Read and he was from 1878 to 1879 president of the Georgia Medical Society (210), in

the following he will be named as 'Read' and not Reed.

The article from Read was cited in the journal 'New Preparations' under the title 'a new

remedy-Sobo/ serrulata-Savj palmetto' in 1879. He wrote that 'settlers of the South'

observed that animals feeding from the berries 'grew sleek and fat' and noticed that

the animals were in a 'marked health'. The settlers seemingly prepared a decoction of

the fruits for medical purposes. In his neighbourhood several people tried preparations

of the berry and obviously Read tried them also in humans and reported that the

berries improved digestion, increased 'flesh, strength and weight' and relieved

irritations of the mucous tissues, in particular of the airways and were a good remedy

for bronchial coughs and common colds (211). In 1911, the same article was also cited

AndyS i : t e r 64

C/?i7pLp/' 2." /JOff

in a publication called 'History of the vegetable drugs of the pharmacopeia of the

United States' by John Uri Lloyd. He was an influential pharmacist and follower of the

eclectic philosophy of that time and owned together with his brothers one of the

biggest factories for production of herbal medicines, the Lloyd Brothers, Pharmacists,

Inc. in Cincinatti, Ohio (212). He confirmed the cited data from 'Reed' in his article and

also mentioned that saw palmetto was before 1879 practically unknown in medicine

(213).

'Reed' was later often cited correctly as J.B. Read and appears like this in the Archiv der

Pharmazie, 1879 (214), in the Materia Medica, 1900 (215) and the books of Madaus,

1938 (216); Read is regarded as the first person bringing saw palmetto into the U.S.

medical society of these days.

In the same year, 1879, a description of saw palmetto berries of J.B. Read was given in

the American Journal of Pharmacy (217) and in 'The Planter's Gazette' (218) with a

broad description of the plant, its appearance, where it grows. He reported that he

observed three imiscible phases as the expressed liquid from the fresh fruits settled: A

volatile yello essential oil, a brown lipidic oily phase, and an aqueous yellowish phase

with sugary taste. The articles cite the medical use, adding that indigenous people like

the berries as food and that even fish ate the berries greedily once the fell into the

water. The article cited here is not the original article but a German translation which

was published the same year in a German journal (219).

Further reports of medicinal uses of saw palmetto were mainly from eclectic doctors.

Eclectic medicine combined herbal medicine with physical therapy practices and was a

direct reaction to the academic medicine of that time which, as described above,

involved a lot of harmful therapies like the application of mercury-based remedies or

excessive bloodletting (220). The term eclectic was first used by Constantine Samuel

Rafinesque (1783-1840), a French polymath who lived among native Northern

American Indians and observed their use of medicinal herbs (221). The word 'eclectic'

was derived from the Greek word 'ekiego' meaning 'to choose from' and should refer

to physicians who chose anything beneficial to help their patients (2 2 0 ).

An d y Suter 65

In 1829, a medical doctor called Wooster Beach founded in New York the 'Reformed

Medical College' to teach eclectic medicine. This school was soon followed by about a

dozen other privately funded eclectic medical schools, generally located in the

Midwestern United States. The best known college was the 'Eclectic Medical Institute'

in Worthington, Ohio, which later moved to Cincinnati; this was also the last eclectic

institution to teach students and closed in 1939.

Eclectic medicine expanded during the 1840's and peaked in the 1880's and 1890's and

was described as a 'large populistic, anti-regular medical movement in North America'

(222 ).

The eclectic schools failed to gain approvement by the 'Flexner Report' in 1910, which

was used to decide on accreditation of medical schools in the United States (223). This

forced the eclectic colleges either to change their curriculum and to become 'normal'

medical schools or they had sooner or later to close down (2 2 0 ).

In 1879, saw palmetto was introduced to the eclectic community by a doctor called

I.J.M. Goss of Marietta, Georgia (220, 224). He recommended the use of the plant for

the same indications previously mentioned by Read.

In the Kings dispensatory, the main book of the eclectic doctors the plant was already

mentioned in 1894 demonstrating its wide spread recognition and semi-official use

(225). Saw palmetto was indicated for irritated mucous membranes, such as caused by

coughs, pertussis, sore throats, acute catarrh, and asthma. For genitourinary

conditions, it was found to be effective for irritations associated with gonorrhoea,

epididimytis, and ovarian pain. It was also recommended for the treatment of enlarged

prostates as well as for atrophied breasts, testes, and ovaries (225, 226).

Other eclectic physicians such as Herbert T. Webster from California gave details about

the use of saw palmetto berries for an indication called 'the relaxation of the urinary

organs of the nervous system' which included frequent urination and vesical irritation

with BPH. He also mentioned administration of Sabal for female reproductive problems

such as 'dragging sensation in the pelvis and abdominal tenderness' (227). A further

eclectic physician, Eli G. Jones, later well known for his books on herbal medicines and

Andv Su te r 66

Chapter 2. Histcr'ca! p

cancer (228) wrote that he considered palmetto useful for 'deficient sexual

performance/drive, loss of libido, infertility due to overwork, exhaustion and excessive

childbearing' (229).

Around 1895 Dr. A. L. Davidson from Mount Pleasant, Utah, also an eclectic physician

wrote an article describing a single case of a man of 51 years who had lost his sexual

potency (given the description of the symptoms most probably due to BPH) and that he

could not satisfy his 'wife, a buxom blonde, several years his junior' any longer. Having

prescribed him 15 drops of a saw palmetto tincture four times daily, the patient noticed

within two weeks an improvement of his urine flow, an increase of his testicle size and

his 'vigor of life' had returned (230). In 1896, Dr. William. E. Bloyer, a professor at the

Eclectic Medical Institute in Cincinnati wrote in the Eclectic Medical Journal an article

on saw palmetto describing its medical uses ranging from bronchitis to treatment of

BPH (231).

An interesting view on the use of saw palmetto can also be found in the Journal of the

North American Eclectic Materia Medica Association (around 1895 to 1900, edition

unknown). Here the tonsils and the prostate were described as being similar in tissues

and therefore, saw palmetto was recommended not only for genitourinary ailments but

also for the treatment of tonsillitis, croup, for snoring, and chronic sore throat (167). In

the book of Winston, a J.W. Fyfe is cited who advocated the use of saw palmetto also

for respiratory tract symptoms and a J.D. Hatton published in 1897 in the 'Medical

Gleaner', an eclectic medical journal, on saw palmetto recommending it for 'prostatic

troubles of old men' and for symptoms of chronic gonorrhoea (232).

But it was not only among the eclectic community that saw palmetto gained already

soon after the publication of Read attention. A pharmacist, J.M. Dixon made around

1880 the first mention of saw palmetto as a treatment for disorders of the genito

urinary tract. He described a special effect of the fluid extract on the reproductive

glands, the ovaries, prostate, and testes, for 'sexual debility' but said that 'the remedy

seems to have a special affinity to the prostate, and a specific effect upon it' (167, 233).

Andy Suter 67

Also in 1880 a physician, Stephen F.Dupore of Savannah, Georgia wrote that saw

palmetto worked well in affections of the throat, bronchial tubes, lungs, and even in

haemorrhage of the lungs (234).

Around 1885 a doctor F.A. Evans wrote in the journal The Medical Brief that he found

approximately 15 drops of the fluid extract to be effective against paroxysms of

migraine. In addition to the already mentioned effects on the genitourinary system, he

also promoted saw palmetto for 'all cases of wasting of the testes' which in his view

was often a cause for impotence. Even though he favoured also the use in

gynaecological practice to promote the ,use of the mammae', he believed that the best

effects were generally seen on enlarged prostates (167). The same indications were

also reported in an article in the Western Druggist by Dr. H. Knapp who thought it had

the action of a 'great vitalized (235).

In the same year, 1895, in the 'Proceedings of the American Pharmaceutical

Association' a pharmaceutical chemist gave a comprehensive description of saw

palmetto, the plant, the chemistry of different extracts of the drug as well as different

accounts of medical use citing Read, Dixon, the below mentioned Evans and a Dr.

Kinnicut who had published in 1892 in the New York Medical Journal that saw palmetto

was in his view a good remedy for patients suffering from tuberculosis and in laryngitis

(236). Two years later in the same journal, saw palmetto berries were discussed with an

extensive description of the appearance of the fruit and some data on its chemistry

(237).

Interestingly, some of the medicinal standard text books of the United States of that

time such as Drugs And Medicines of North America by Lloyd, 1884 (238) and the

Specific Medication and Specific Medicines, 1870 (239) made no notice yet of saw

palmetto nor did the earlier works from Jonathan Pereira in 1842 and 1852 about the

'Elements of the Materia medica and Therapeutics' (240, 241) which described the

plants in use in the United States.

An dy Suter 68

By the late 1890's, the use of saw palmetto in eclectic, homeopathic, and allopathic

medicine in the United States became widespread. Pharmaceutical companies like

Wyeth Laboratories, Lilly, Squibb, and Merck all produced saw palmetto preparations

(242).

In 1898, the homeopathic physician Edwin Moses Hale from Chicago published his

standard book on saw palmetto which was a milestone as this was a comprehensive

compendium on the history, the use and the preparations of saw palmetto which were

available in the United States. They included the whole range of watery to oily

preparations of the berries such as tinctures, fluid extracts, pure oil, saccharated oil,

malto-sabal (saw palmetto oil mixed with maltose), aqua oleum sabal, and

suppositories (7).

The most detailed portrayal those days on the use of Sabal serrulata in a standard book

was given soon after the book of Hale, in 1900, in the 'Dictionary of Materia Medica' by

J.H. Clarke. He referred mainly to the book of Hale, but also discussed several cases in

women where overactive bladder, kidney problems, irregular menses and breast

atrophies and peritonitis were treated successfully with saw palmetto. He described a

wide variety of indications for saw palmetto with main emphasis on urinary problems

but recommended it also as a remedy to improve sexual dysfunctions, such as erectile

dysfunction and lack of drive in men, as well as to increase libido in women and as a

treatment for ovarian pain (215).

The homeopath William Boericke issued in 1901 his own 'Boericke's Materia Medica

(Materia medica: the Tinctures)' where he described the use of saw palmetto mainly for

'irritability of the genito-urinary organs' and in particular for 'prostatic troubles' but

indicated the plant also for various disorders like a 'confused, full head; makes her

angry' (243).

In 1903 John William Fyfe gave in an eclectic manual of a modern materia medica for

saw palmetto the dosage recommendation of 10-30 drops thrice daily in water, mainly

for treatment of BPH and 'functional inactivity of the reproductive system' (244).

Ai : c ' y Suter 69

The journal 'Kew Bulletin' reported 1899 that in this year 250 tons of liquid extracts of

saw palmetto berries were consumed in the United States as a remedy (245).

The widespread use of saw palmetto found at the begin of the 20 century recognition

by the U.S. American health authorities and the plant gained an official status as a

remedy: From 1906 onwards it was listed and then mentioned in the United States

Pharmacopeia (1916) and then in the National Formulary from 1926 until 1950 (19).

These official records were a milestone for saw palmetto as a treatment in the United

States. The plant was not any further a treatment solely favoured by a special and

marginal group of physicians like the eclectics but were an officially accepted

medication of that time.

A n d v Suter 70

An overview on the use of saw palmetto in the United States and the first mentioning in

monographs and pharmacopeia in chronological order is given in Table 4.

Table 4: Documented use o f the whole plant of saw palm etto in history in the United States and first m entioning in monographs and pharmacopoeia.

Date Use o f saw palm etto and m entioning in scientific lite rature

15'^ (or earlier) to

16^ century

Use as food among Native Indians of Florida region. Probably also use as material fo r construction o f huts, basket, fans, etc.

Traditional use by Indians

Medicinal use by Native Indians of Florida region: steam from cooking fruits, inhalations fo r trea tm ent o f bronchitis, expectorant, irrita ted mucous membranes.

Infusions fo r trea tm ent of dysentery, stomach pains; dressing and poultice fo r insect and snakebites, skin ulcers; use fo r sore eyes, high blood pressure, kidney

problems.

1877Dr. Read, Savannah, Georgia: Use in respiratory tract infections like common colds

or bronchitis

1879Two fu rthe r articles from Read, description o f the plant and o f its chemistry, use in

respiratory tract infections like common colds or bronchitis described

Around 1880J.M. Dixon: use o f saw palm etto in genito-urinary disorders and as a sexual

stim ulant

1880 Treatm ent o f bronchitis and upper respiratory tract infections

1885? Use in BPH

1892 Dr. Kinnicut : Treatm ent o f tuberculosis and laryngitis

1892 Saw palm etto described as a 'great vitalizer' (Knapp)

1894 Saw palm etto cited in the King's dispensatory

1894Description o f the plant in the Proceedings of the American Pharmaceutical

Association

1896 Description o f the appearance o f the berries and the ir chemistry

1896 Portrayal of saw palm etto in the Eclectic Medical Journal (Bloyer)

1898 Standard book of Hale on saw palm etto

1900 Chapter in the Dictionary o f the Materia Medica by Clarke

Early 1900 Soft drink of Miami pioneers, called 'm etto '

1906 First mentioned in the United States pharmacopeia

1926 First mentioned in the U.S. National Formulary

71

2.3.2.33 The appearance of saw palmetto in German scientific literature

In 1835, a plant was described in a German book on general botany under the name

'Chaemerops palmetto' as an example for a palm tree without thorns but it is not clear

if really saw palmetto was meant (246). In the 'Nomenclator botanicus hortensis', an

enumeration of 'European cultivated plants' from 1840, Chaemerops was named

'Zwergpalme' [dwarf palm] and 'Chaemerops serrulate' as the finely serrulated

[feingesagt] dwarf palm tree, growing in Georgia, USA (247). In a story about the

garden show 1850 in Gent, Belgium, the same palm tree, 'Chaemerops serrulata' was

mentioned as being one of the objects in a special exhibition on palm trees (248).

The first mentioning of saw palmetto in German literature as 'Sagepalme' is from a

description of a Journey to Effingham County in Georgia, U.S.A, in 1862 (249). The

author mentioned that 'the ground is covered for hours with saw palmetto

(Chaemerops serrulata)' ['..der Boden stundenweit mit Sage-Palme, Chaemerops

serrulata, als Unterholz bedeckt']. And in a book on Northern-American agriculture,

'Sagepalme Chaemerops serrulata' was cited as a tree used from Indians to gain a

starch flour from it (203).

'Sabal serrulata' appeared around the same time also in a book on palm trees, the

origins of the plant were stated as Georgia and Florida (250). Later, the plant was

described in an account of the flora of Northern America as 'Sabal palmetto, serrulata'

(251).

In 1879 the first citation of saw palmetto in non botanical but medicinal German

literature appeared. In the journal 'Archiv der Pharmazie', a journal for German

pharmacists, the article from the above mentioned American Journal of Pharmacy on

saw palmetto was published as a German translation (219).

In 1890, the plant 'Sabal serrulata' was quoted in the 'Real-encyclopadie der

gesammten pharmacie', a dictionary for pharmacists and physicians (252).

'^,ndy Suter 72

2; H/sfcnra/ /rcr/

A year later, in 1891, the medical use of saw palmetto was described for the first time:

Brestowski cited in his book 'Die neueren und neusten Arzneimittel' a plant he called

'Sabiana serrulata'. He referred in the description of the drug to Dixon, meaning by this

maybe not only the pharmacist named from the article of Davis, 1892 (233), but

probably 'Dixon's saw palmetto', a saw palmetto preparation sold those days by the

Dixon saw palmetto medicine company from Jacksonville, Florida (253). Brestowski

wrote that the berries were 'calming, sleep-inducing and at the same time diuretic' and

that they had a positive effect on the digestion and a 'specific action' on the glands of

the sexual organs. The fluid should be used in weakness of the sexual organs, muscle

atony, nervous disorders which leads to digestive complaints, male impotence and

vaginal balls made with cocoa butter and saw palmetto fluid should be applied in

proplapsus uteri, leucorrheoa, exhaustion caused by frequent parturation or sexual

excesses (254).

In 1897, the well known German chemist and pharmacognost Carl Hartwich gave

details on 'Sabal serrulata'. He described the appearance of the fruits and that they

could be used for phthisis and diseases of the lung and that they may have a diuretic

effect (255).

In his posthumously published standard work on healing plants Dragendorff mentioned

1898 also 'Sabal serrulatum' shortly and wrote about the medical use of the 'fruit

nutrititvum [Frucht nutritivum] by phthisis, bronchitis, etc.' and to use a as a 'diurectic,

sedativum and stimulant remedy for the glands of the genitals' (256).

Aside from the three cited sources cited, until 1900 no other German pharmaceutical

standard book mentioned saw palmetto nor gave an account on its medical use.

'Hagers Handbuch', 1878, 1883 (257, 258), 'Die neueren Arzneimittel für Apotheker,

Aerzte und Drogisten ', 1888 (259), the 'Handbuch der allgemeinen und speciellen

Arzneiverordnungs-Lehre', 1873 (260), 'die wichtigsten Arzneimittel', 1886 (261),

'Compendium der Arzneimittelverdordnung', 1891 (262), the ,Pharmacopoea

Helvetica', 1891 (263) or the 'Vergleichende Arzneimittellehre', 1892 (264) made no

citation of the plant.

A n d y Suter 73

C/icprer 2; H/stor/cc?,'

Also homeopathic standard books of that time from two of the German opinion leaders

in homeopathy, Carl Heinigke and Arthur Lutze (265) the 'Handbuch der

homoopathischen Arzneiwirkungslehre', 1880 by Heinigke (266) or ,Dr. Lutze's

Lehrbuch der Homoopathie', 1860,1878,1887 (267-269) did not quote Sabal nor was it

included in the 'Arzneibuch für das deutsche Reich', the German pharmacopoeia, of the

years 1891 and 1900 (270, 271) or on a pharmacognostic map of the world of 1899

(272).

For a short period of time, the stem of saw palmetto gained some interest as a tanning

agent in German literature. In 1896, 'palmetto extract from Serenoa serrulata' was

described as a new tanning agent in a German chemical technical repertory with

reference to an U.S. American publication (273), in 1898 the content of tannins of

'Serenoa serrulata' was discussed in another scientific publication (274), and in 1899 a

botanical annual report detailed the tannin content of the stem and roots of 'Serenoa

serrulata' (275). Later, the use of saw palmetto for tanning appeared no longer in

literature.

In 1900, in the ,Zeitschrift des Berliner Vereines Homoopathischer Aerzte' the journal of

the homeopathic doctors of Berlin cited under the chapter ,Lesefrüchte aus

homoopathischen Zeitungen' [News from (literally 'reading fruits') homeopathic

Journals] a lecture given on the 7 of December 1899 by a Dr. E. M. Madden at the

British Homeopathic Society on saw palmetto (the article was entitled as 'Sabal

serrulata oder Saw palmetto'). He gave a description of the fruits and recommended

the use for enlargement of the prostate, explained one case of successful treatment of

enuresis in a boy and cited then some cases from the book of Hale (276). In the

meantime, the book from Hale had seemingly been translated to German by F.G.

Oehnme, then a well known homepathic scientist. I could not find the book itself but

only a citation that he had translated the book and used himself saw palmetto with

success (277).

Andy Su te r 74

C/icTCler 2; H/;

A year later, in 1901, saw palmetto was to be found in the German homeopathic

dispensatory (Homoopathisches Arzneibuch) issued by the Association of German

Pharmacists. Under 'Sabal serrulata' a description of the fruits was given and the

receipt for the preparation of a mother tincture : one part of the fruit and two parts

'spirit of wine' [Weingeist] (278). In the 'Pharmacopoea homoeopathica polyglotta' by

Willmar Schwa be which came out in the same year, saw palmetto was interestingly not

mentioned (279).

At the same time, in a book on homeopathic remedies, ‘Sabal serrulata' was discussed

using mainly Hale, 1898 as source, for urinary problems as well as a therapy causing

'a curious juvenilisation with return of the potency and increase of the vitality'. The

author recommended silicea as an antidote in 'excited states' under saw palmetto

(280).

In 1903 the book 'Deutsche homoopathische Arzneimittellehre' stated that a catheter

may not be used any longer after having taken a saw palmetto remedy (281).

Later on in the book 'Handbuch der homoopathischen Arzneiwirkungslehre' of 1905 by

the homeopath Karl Heinigke the medical use of 'Sabal serrulata' was explained in

detail with reference to the existing Northern American knowledge of Hale. Heinigke

recommended five drops of a mother tincture in water taken several times daily for

treatment of prostate disorders, lack of drive, testicular inflammations in men and in

women for ovarian inflammations, urethritis, mastitis, and dysmenorrhea; furthermore

for venereal diseases, enuresis, and inflammations of the bladder in men and women

(282).

The journal of the customs of the Germany ('Reichszollblatt') demanded 1906 for

1 deciliter of 'saw palmetto fruits drenched in wine spirit ' [mit Weingeist getrankte

Früchte der Sagepalme] a duty rate of 80 German mark indicating that saw palmetto

fruits had been imported on a regular basis (283).

Anc'yS'Jtcr 75

2; pa;

In 1908, saw palmetto was described as a remedy for nycturia in a homeopathic book

which was published by the homeopathic doctors of Berlin (284) and in 1909 the plant

was cited as an aphrodisiac in a journal of German pharmacists (285). Sabal was also

briefly quoted that it appeared in Northern America in a book on pharmacognosy by

Tschirch but no further information on the plant or its use was given (286).

In 1914 saw palmetto was mentioned in an article about an exam in a university or

school [Lehranstalt] in Hamburg where fruit kernels had to be determined and saw

palmetto was among one of those (287).

During World War I, saw palmetto was several times a topic in German scientific

literature; at a time when no saw palmetto could be delivered from the United States

because of the British naval blockade (288). In 1916 the 'Chemisches Zentralblatt'

described the fluid extract of saw palmetto, its appearance and main constituents

(289), and in 1917 the berries and the plant were characterised in the ,Zeitschrift für

angewandte Chemie' (290), in the ,Therapeutische Monatshefte' a short description of

Sabal was alluded (291), the ,Zeitschrift für Untersuchung der Nahrungs- und

Genussmittel' gave a morphological description of the berries (292), and ,the

Hygienische Rundschau' gave details on the plant (293). In 1918 saw palmetto was

depicted in the 'Jahresbericht der Pharmazie' as a , little known preparation which was

mentioned in literature as an aphrodisiac' (294).

In 1922, Rosenberg cited saw palmetto in a guide to the different official compendiums

(295) and in 1924 Sabal serrulatum was quoted in Dr. Wilmar Schwabe's homeopathic

compendium for the first time but only in the appendix under 'seldomly used

homeopathic remedies' very shortly with name and that with ripe fresh berries an

essence with 90% ethanol should be prepared (296).

In 1928, the use of saw palmetto berries to aromatise cognac could be found in a book

on etheric oils (297).

A n d y S u t e r 76

These citations show that saw palmetto between 1901 to 1930 was known among

homeopathic doctors, pharmacists, chemists, and nutrition scientists in Germany.

However, the use may not been that wide spread as several homeopathic standard

books of that time make no reference to saw palmetto, like the 'Arzneiwirkungslehre

neuerer homoopathischer Heilmittel by Voorhoeve', 1910 (298), the , Kurze Anieitung

zum richtigen Gebrauch der wichtigsten homoopathischen Arzneimittel' in 1913 (299),

the 'Lehrbuch der homoopathischen Therapie' in 1914 (300), 'Ottinger's Homoopathie'

in 1921 (301) or the ,Handbuch der homoopathischen Arzneiwirkungslehre' from 1922

(302), and 1927 the 'Lehrbuch der Homoopathie' (303).

The plant was also not too well known among herbalists and in the pharmacognostic

society since most pharmacognostic or herbal books of that time make no quote of saw

palmetto such as 1909 the 'Vergleichende Volksmedizin' (304), 1911 'Schroters

Schatzkastlein der Pfianzenheilkunde' (305), 1914 the book 'Volkstümliche Namen der

Arzneimittel, Drogen und Chemikalien' (300), 1920 ,Schreibers kleiner Atlas der

wichtigeren Heilpflanzen' (306) and 1924 ,Pharmakognosie als Vademecum für Aerzte'

(307).

Also until 1930 in academic medicine, among general practitioners or medicinal

authorities saw palmetto was not well known and accepted generally as a treatment.

Books on new pharmaceutical drugs like 'Die neueren Arzneimittel in der arztlichen

Praxis', 1908 (308), the 'Arzneimittel der heutigen Medizin', 1919 (309), and 'Neue

Arzneimittel und pharmazeutische Spezialitaten', 1926 (310) make no mentioning of

the plant nor does the official German Pharmacopeia, the 'Arzneibuch für das deutsche

Reich', 1910 (311), its supplement 1916 (312) and the issue of the Arzneibuch of 1926

(313).


In 1938, Madaus described saw palmetto in his work on 'biological remedies' as a good

treatment for BPH and that homeopaths used the plant mainly for this indication. He

showed the results of a survey he had carried out among 'outstanding adepts of

medicinal plants' [hervorragende Heilpflanzenkenner] which included not more than

hundred persons but also 'heads of clinics and sanatoria'. Of them, 41.2% stated that

they used saw palmetto for the treatment of BPH as the primary treatment, followed

by Populus tremulus with 12.4% and Pareira brava with 9.4%. This survey showed that

among at least a certain group of German doctors saw palmetto was broadly applied in

patients with BPH (216).

The most comprehensive German book on herbal drugs and medications, 'Hagers

Handbuch' also reflected the status of saw palmetto as a well known treatment as the

plant was first mentioned in the issue of 1944 (314) whereas it was not cited in any

previous editions of the book in 1903 (315), 1913 (316), 1925 (317), 1927 (318), and

1930 (319).

The chapter on saw palmetto gives a description of the partially dried, ripe berries and

their use as a 'diureticum, sedativum, stimulant; and a fluid extract for lung disorders'

with reference to the National Formulary, sixth edition, 1938 of the United States. The

chapter cites the production of an essence according to the homeopathic dispensatory

('Homoopathisches Arzneibuch'), the production of an elixir with sandalwood and of a

fluid extract of saw palmetto also according to the National Formulary (314).

I regard this first mentioning of saw palmetto in Hagers Handbuch as the breakthrough

of the plant as a remedy in Germany. A quotation in this standard book reflects that

saw palmetto was used as a treatment in Germany and an acceptance as an important

medication. This might have also been the trailblazer for its general introduction and

recognition to the pharmaceutical and medical community in Germany after World

War II until today.

A chronological description of the citations of saw palmetto in German literature is

given in Table 5.

A n d v S u t e r 78

Table 5: Documented historical use of saw palmetto in German scientific literature

Time Reference of saw palmetto in German literature

1835 First m entioning of'Chaem erops pa lm etto ' in a book on general botany

1840, 1850,1862, 1866, 1863, 1878

Botanical description o f saw palm etto and its habita t as 'Chaemerops serrulata' or 'Sagepalme'

1879First citation o f saw palm etto in a pharmaceutical journal, translation o f an U.S. American article

1890 'Sabal serru lata ' cited in a dictionary fo r pharmacists and physicians

1891First description o f medical use of saw palm etto ('Sabiana serrulata') as a calming, sleep inducing, d iuretic trea tm ent w ith effects on the sexual organs in men and women, and as therapy fo r prolapsus uteri and others in women

1897M entioning by a pharmacognost, Carl Hartwich fo r phthisis and diseases o f the lung, w ith d iuretic properties

1898Quotation by Dragendorff, same indications as Hartwich and as a' stim ulatory remedy' fo r the genitals

1896, 1898, 1899 Discussion in literature of saw palm etto as a tanning agent

1900Article on the use of saw palm etto in a homeopathic journal of homeopaths from Berlin

1900 German translation o f the book of Hale

1901'Sabalserru la ta ' in the German homeopathic dispensatory, issued by pharmacists

1901Description of 'Sabalserrulata ' in a book on homeopathic remedies. Silicea recommended as antidote in excited states from saw palm etto

1903 Saw palm etto cited in a book on homeopathic drugs, w ith use in BPH

1905Detailed in form ation on saw palmetto, use as mentioned in Hale but also fo r enuresis, venereal diseases and bladder inflammations

1906 M entioning o f saw palm etto in the journal o f the customs o f Germany

1908Saw palm etto fo r nycturia described in a homeopathic book from homeopaths from Berlin

1909Quoting of saw palm etto as an aphrodisiac drug in a journal o f German pharmacists

1914 Article on the an exam in Hamburg where saw palm etto had to be determ ined

1916 Inform ation in a chemistry journal on saw palm etto and the flu id extract

1917, 1918Details about saw palm etto in medical, food, and pharmaceutical scientific journals

1924 Saw palm etto in W illm ar Schwabe's homeopathic compendium

1938 Chapter on saw palm etto in Madaus' book on biological remedies

1944 Hagers Handbuch cites saw palm etto fo r the firs t tim e

79

CAr p : HA t c . 'Vc r . ' pc/'

2.4 Discussion

Being a patient suffering from BPH at the end of the 19 century in the Western world

was a miserable thing. The disease itself was quite new, it was not well understood nor

was properly known how it developed. As medicamentous treatments baths, some

herbal medicines or iodine, bromide or even mercury were applied which in the end

might have done more harm than being any good at all. The standard treatment were

catheterisations, an often painful procedure and if it was not carried out under sterile

conditions secondary infections of the bladder or prostate regularly occurred (320). This

again impaired the quality of life of a patient, not to talk about the mental burden of

this intervention.

As a final procedure surgeries were carried out but the operation techniques were not

very advanced and involved castration or the total resection of the prostate. Severe

side effects must have occurred frequently regarding the still high rate of side effects in

TURP these days (81).

Regarding the circumstances a BPH patient was in around 1870, it was no surprise that

saw palmetto soon was tested in this patient group. Interestingly, it was not the

traditional knowledge of the Indians on saw palmetto that was copied by practitioners

but the observation of settlers that the berries had a positive effect on animals feeding

them. Thanks to the settlers and Dr. Reads curiosity, openness and attention, saw

palmetto was tried out as a new remedy which soon spread among the eclectic medical

community.

And it is no wonder that the eclectic doctors were the ones trying out saw palmetto and

evaluating whether it worked best in common colds, bronchitis, in BPH, in urogenital

inflammations and disorders for men and women, and that the plant had vitalizing and

aphrodisiac properties. The eclectic philosophy based on the use of herbal medicine

and physical therapy with the goal to find new treatments in alignment with nature

which were well tolerated and in a way 'softer' than the existing often harming

medication and surgical treatments (220). Therefore the eclectic doctors were open to

try out new herbal treatments and since they were well connected, had their own

journals and even medical schools, they could teach and spread their knowledge widely


and rapidly (222). It is thanks to them and also the coincidence that the eclectics were

most popular in the time saw palmetto was rediscovered that within 2 0 years saw

palmetto became a broadly used treatment in the United States. The number of 250

tons of saw palmetto tincture produced in the U.S.A. in 1900, which equals to 50 million

daily dosages of 5ml and this in a population of then of 76 million people shows this

clearly.

The second group of practitioners which helped saw palmetto to become a well known

treatment in the United States were the homeopaths. Their medication consisted

mainly of herbal medicines and as they were not part of academic medicine they were

by their nature more open to new therapies. By having their own journals and medical

schools, the homeopaths, too, could spread the knowledge on saw palmetto effectively

like the eclectics. Hale for example, who wrote the standard book on saw palmetto was

a homeopath himself, teaching at the Hahnemann Medical College of Chicago (321).

And the third group of groundbreakers for saw palmetto in the United States were the

pharmacists as they occupied themselves as early as 1879 with saw palmetto. They

were experts on the production and quality of saw palmetto preparations and played

thus an important role that the plant was soon mentioned in the official U.S.

pharmacopeia and then in the National Formulary.

So, in short, the combination of the eclectics as the discoverers and pioneers on saw

palmetto, the homeopaths as the catalysts, and the pharmacists as the ones who had

the pharmaceutical quality and production of the tincture in their scope made saw

palmetto an officially acknowledged treatment.

In Germany in the meantime, it took some years longer until saw palmetto became a

well known remedy. The plant was known in German literature in botanical terms and

some scientific knowledge was summarised soon after its publication in the United

States. However, it was not until the turn of the century that the scientific community

showed a wider interest in the plant. Until 1900 the use of saw palmetto was not

widespread and the knowledge about the plant confined to some experts as shown by

the fact that it was only rarely mentioned in scientific books and articles.

81

( 2 ' H /f for.'To/ pn / "

In the time from 1900 to 1910 saw palmetto was mainly included in homeopathic

books. It looks thus as if the homeopaths were the ones giving saw palmetto a special

attention as a remedy but that the pharmacists knew already earlier about the plant.

Both together then were the ones making saw palmetto known and popular as a

treatment. This is corroborated by the fact that in 1901 the German Homeopathic

Dispensatory issued by the Association of German Pharmacists mentioned saw

palmetto but that the Homeopathic Pharmacopoeia (also 1901) by Schwabe, an

enthusiastic homeopath himself, did not mention saw palmetto.

However, by the end of World War I the plant was known and investigated in Germany

also by chemists and nutritional scientists. It looks that they became interested in saw

palmetto as German practitioners used it more frequently and it was more often a topic

in U.S. scientific journals. Taken as a whole, by the 1920's there were plenty of people

in the scientific community who had worked on saw palmetto and there was sufficient

knowledge on the plant available in Germany. I suppose this assisted saw palmetto

further to become an acknowledged treatment.

To which extent saw palmetto was used in medical practice as a remedy between 1920

and the 1930's is difficult to assess with the public sources available. In 1924 Schwabe

cited saw palmetto in the chapter of 'seldomly used remedies' (296), but Madaus

showed in his survey in 1938 that saw palmetto was the favourite herbal treatment for

BPH at least among practitioners he had asked (216). It seems that between 1920 and

1930 saw palmetto became popular resulting in the mid 1940's in the standard book on

German drugs and pharmaceutical preparations, the Hagers Handbuch (314).

Nevertheless, I could not identify a single brand, company or a practitioner which was

the main promoter of saw palmetto in Germany. I had asked several German

phytomedical companies like Schwabe for data on their product portfolio between

1900 to the 1930's but none had any archive material available (322). The only saw

palmetto preparation I found was a fresh plant trituration of saw palmetto berries from

Madaus in 1938, one of his so called 'Teep' products which were a mixture between a

homeopathic and a herbal remedy containing 0.025 g Sabal fruits per tablet.


The reason why not more saw palmetto brands were identified could be because the

available public sources were limited in its number and content or that due to the

volatile economic situation in Germany after World War I with several phases of

hyperinflation (323) it was difficult to market sustainably a saw palmetto product and

create a strong Sabal brand. To verify these hypotheses searches in archives are

mandatory.

What made saw palmetto as a treatment popular in the end is difficult to say but it

must have been primarily the same reasons as in the United States : There was no

medication for BPH, by the standards of the period saw palmetto was obviously

efficacious and safe - and probably also that it was a remedy from another continent

piquing people's curiosity might have helped as well. The strong interest in Germany

that time for foreign plants is reflected by the fact that in 1933 for more than 20 million

Reichsmark different herbal drugs were imported (324).

Further, German homeopathy was significantly influenced at least until 1900 by the

American homeopaths and their publications. Like this, knowledge about treatments

was extensively exchanged between the two homeopathic communities and it is highly

likely that a new therapy like the use of saw palmetto was promoted by this channel

(265).

The success of saw palmetto in treating BPH could not have been foreseen. The Indians

used inhalations from the berries for infections of the respiratory tract such as

bronchitis and for treatment of irritated mucous membranes (206). Further, external

treatments made from the inner trunk bark against insect or snake bites or skin ulcers

were applied or teas from the leaves and roots for treatment of gastrointestinal

disorders. From one Indian tribe even the treatment of sore eyes or kidney problems

were reported (207). The settlers trying out saw palmetto concentrated themselves

only on the use of the berries. There were no records that parts of the stem or the

leaves were applied by the settlers, thus confirming the story of Read.

Andy Sutei 83

2; H/sfoncny pg/i'

One major difference between the preparations used by the Indians and those by the

settlers were that the latter used alcohol as an extractant. Therefore the tinctures were

rich In lipophilic substances which are today considered as the main active constituents

(41). These tinctures were certainly more potent than watery preparations as they

contain substances with good antl-lnflammatory (59), antl-gonadotropic (48), muscle

relaxating (62) and vasodilating effects (6 6 ).

Interestingly, the settlers used preparations from the berries like the Indians firstly for

treatment of Infections of the respiratory tract, even though some positive effects on

digestive function were observed as well (208). It was already three years later, 1880,

that the first mention of saw palmetto as a therapy of genitourinary ailments appeared:

Its effects on ovaries, the prostate and testes were described and the aphrodisiac

properties of the plant. Remarkably, already In this publication It was noted that the

best effect was seen In BPH (167, 233). But from then on until the 1920's, saw palmetto

was seen as a remedy for three main Indications: Severe Infections of the respiratory

tract like bronchitis, genitourinary diseases In women and men like prostate problems

or Inflammations of the ovaries, and, finally, sexual dysfunctions like erectile

dysfunctions or testicular atrophy In men. Infertility and breast atrophy In women and

as a sexual stimulant for both, men and women (7 ,19,167, 215, 226).

Why saw palmetto In the end became a treatment Indicated today only for mild to

moderate stages of BPH (17) Is obvious. The plant showed In this Indication a very good

efficacy and at the same time almost no other medicamentous treatments were

available. Moreover, BPH Is a disease where Improvements can be observed well and

fast (99), contrarlly to other Indications where the plants was used for example like

Inflammations of the genitourinary tract (325).

But nevertheless, looking at the successful use of saw palmetto In other Indications

than BPH, further or new research Is warranted to confirm the reported findings.

Therefore, I carried out a clinical pilot trial In BPH patients with sexual dysfunctions to

assess If saw palmetto Is efficacious In this Indication and to see If old knowledge could

thus be confirmed.


C/ÿGpCc/' 2;

Even though I presented in this chapter a wealth of data, this historical part has several

shortcomings.

First of all, I have no training in historical research nor any education in historical

sciences. My searches were carried out and assessed according to my best knowledge,

helped by two standard books (168, 169) and sometimes with tips from the people

from the medical historic library in Zurich.

Secondly, I carried out the majority of the searches and views of the literature via the

internet using public online resources. Even though historians recommend the use of

internet searches as they are faster, more comprehensive and lead in the end to same

results as visiting libraries and looking at original literature (326, 327), it still not seen as

state of the art in historical research (168). Furthermore, the view of original literature

is due to copyright problems and fraudulent behaviour of users issuing reprints form

online books more and more limited to so called snippet views where only parts of the

literature can be viewed (328).

Thirdly, this use of only public material is a further important limitation of the whole

medico-historical part. For almost any aspect of this investigation, like which were in

the U.S.A. or in Germany the most important saw palmetto products, who were the key

promoters of Sabal or where and how many preparations of the plant were sold in both

countries until 1930, deeper research using archive material is warranted. Since this

historical investigation forms only a third of this thesis and time was limited, I could not

address all these additional questions.

Fourthly, it was difficult for me sometimes to assess the importance of a single

reference and to carry out a proper source criticism. How far spread was a journal for

example, who read it and how did it influence practicioners or how important was the

opinion of a certain author is difficult to judge and would need also further and deeper

research, mainly in archives.


C/:rrptc,'

Yet, with this research I could show for the first time, embedded in the treatment

context for BPH until the beginning of the 20 * century, at least trends which groups of

practitioners pioneered in using saw palmetto in the United States and in Germany and

how it became a popular treatment.

And, finally, that saw palmetto was quoted for the first time in Hagers Handbuch in

1944, at a time when Germany was at war with the United States, gives this research

chapter an almost political or maybe at least a philosophical final twist. The boldness of

the authors to include saw palmetto with reference to the U.S. National Formulary

shows that on one hand the plant must have been a really good remedy but to the

other hand that scientific evidence is in the end stronger than political ideology.


Chapter 3The phytochemical analysis of 46 commercial preparations containing saw palmetto by

using thin iayer and gas chromatography

AndySuter 87

Chapter 3: Phytochemical analysis

The phytochemical analysis of 46 commercial preparations

containing saw palmetto by using thin layer and gas

chromatography

3.1 Introduction

As described in the previous chapters, saw palmetto preparations are the most popular

herbal therapies for treatment of BPH. In general, they are produced by using a

lipophilic extractant like N-hexane, 90-96% V/V ethanol or supercritical carbon dioxide

(17, 40). For example, a common extraction procedure using ethanol is to crush the

fruits in a mill, then macerate them for 1-2 days in the extractant. After this an

exhaustive extraction for 4-5 hours is performed using percolation and hot ethanol at a

temperature of about 55“C. In the end, the percolate is concentrated to an ethanolic

spissum extract which will be encapsulated (329).

For supercritical fluid with carbon dioxide conditions which equal or exceed its critical

temperature of 31.1° C and its critical pressure of 73.8 bar (330) are used. Therefore,

extraction conditions like, for example, of at least about SOObar and a temperature of

less than 80° C are used (331).

The majority of these products are at the time sold worldwide as food supplements

(332, 333) and only in a few countries like Germany or Switzerland they are registered

and have to fulfil high quality requirements regarding the amount of active constituents

and their stability (334). Therefore, I intended to assess the composition and quality of

different preparations containing saw palmetto which are marketed for treatment of

BPH symptoms.

Currently, there are only a few publications available which address the quality of

different saw palmetto products even though in 2 0 0 0 a consultation paper on

treatments for BPH demanded further research on this topic (335).

A; ic'y SLiter 88

C/7(7p 'e.'' S; Pr'/rcc/'c.'ii'cr''' r r

The four monographs on saw palmetto all demand a daily amount of 320mg lipophilic

saw palmetto extract (17, 40, 146, 147). As the main active constituents of these

extracts free fatty acids and their ethyl esters are seen as well as phytosterols (17, 40,

62,146,147, 336). The only official quality marker so far for saw palmetto preparations

is to be found in the European Pharmacopeia which requires lauric acid to be at least

20% of the total fatty acid (336). Thus, the quantity of fatty acids in saw palmetto

preparations may serve as an important good quality marker. A more detailed

description of the fatty acids in saw palmetto are given in chapter 3.3.2.

Feifer et al. examined six commercial preparations analytically and compared the

amount of total fatty acids per unit with the information given on the package. They

could show that there were large differences for three of the products between the

stated information and the quantity of fatty acids determined in this analysis (337).In

another publication, fourteen Sabal products were compared regarding their content of

free fatty acids, methyl, ethyl, and long chain esters, triglycerides, and unsaponified

matter. The results indicated large differences in the proportion of free fatty acids and

their esters and the authors concluded that only those products with sound clinical data

can be seen as effective (34).

In two further series of experiments the difference on bioactivity of different saw

palmetto preparations was investigated. Scaglione et al. tested eight commercially

available saw palmetto products on their ability to inhibit the two isoforms of the

5-alpha-reductase in vitro. The EC50 for both isoforms differed widely for the products

and in the majority also between different batches of a product. Nevertheless, the

authors were cautious to relate these data to clinical efficacy (338).

In 2004 the German authority BfArM initiated a comparison of the bioactivity of three

different saw palmetto extracts produced with ethanol 90%, ethanol 96% and hexane.

The three preparations were similar in this in vitro setting in their activity to inhibit the

5-alpha-reductase (339).

The cited investigations focussed always on products from one country and the sample

number was at all times small. Therefore, I wanted to carry out a broader investigation

which included many test products from different countries to assess the daily amount

of fatty acids and the composition of fatty acids in each product.


I collected 46 preparations containing saw palmetto from eight countries worldwide,

with 19 of these products containing saw palmetto only as active constituent (mono

preparations) and the other 27 where combined with other components such as

vitamins, herbal extracts or minerals (combi preparations).

As quality reference, in each preparation the amount of the fatty acids lauric acid,

capric acid, caprylic acid, myristic acid, palmitic acid, linolenic acid, oleic/linoleic acid,

and stearic acid was determined using gas chromatography.

With this investigation I wanted to evaluate if the analysed products varied in their

daily amount of total fatty acids and if these differences were country-specific or

related to the regulatory status of a product.

Of further interest was, if the preparations differed in their proportion of fatty acids

and if there were general differences between mono and combination products

regarding their composition of fatty acids.

An additional goal was to assess how conform the measured fatty acid values were with

the requirement of the monographs, the European Pharmacopeia, and the information

given on the package.

In total, an overview on the quality of commercial preparations containing saw

palmetto from different countries should be presented in the end.

The method of choice for this assessment was gas chromatography. This is a robust and

uncomplicated method but the outcome is limited to the determination of nine fatty

acids.


C/Y:7,c:L' 5 F /:;T c r/7 c r7 ,'c c /(/n j'} '5 .'':

Even though the fatty acids are the group of the active constituents to be found in the

highest amount in saw palmetto extracts (40) there are also other active constituents in

the extract like the phytosterols ^-sitosterol, campesterol or stigmasterol, (340)

polysaccharides (17) (3-carotens, tocopherols (35) or the monoamine tyramine (39).

As it was not possible, due to lack of time and too few available test samples to carry

out further analysis to quantify other active constituents, a further analytical

investigation was carried out on the same samples using proton-NMR-spectroscopy in a

Master thesis with a metabolomic approach using Principal Component Analysis (PGA)

as statistical method (341). The goal of this thesis was to establish a fast and

reproducible method to analyse saw palmetto products which should give a

comprehensive answer on the characteristics of the products by using PGA (342).

The results from the NMR-analysis are compared in the end with the gas-

chromatographic analysis.

Anc'y ^U ic r 91

C/iuOfcr j; F/ntcc/'cnT.'Cc/ r.'TC.'iT.:

3.2 Material and Methods

3.2.1 Reference samples

Forty-six commercial products containing saw palmetto, indicated for treatment of BPH

and which were known to sell well in their country were obtained from retail outlets or

pharmacies. The preparations came from eight different countries, namely Canada,

Finland, Germany, the Netherlands, the United Kingdom, South Korea, Spain,

Switzerland, and the United States. Only the products from Switzerland were registered

herbal products which needed to fulfil quality standards as demanded in the ESCOP

monograph (17) and the European Pharmacopeia (336). The samples from Finland and

Canada were also registered but no strict quality requirements have to be fulfilled, the

registration acts rather as an official sales license.

The 46 products were tablets, soft gel or hard gel capsules, and the combination

partners in combi products were mostly pumpkin seed oil [Cucurbita pepo),

preparations from Pygeum africanum or stinging nettle {Urtica dioica) or single plant-

derived substances like \i-sitosterol or lycopene. Further from vitamins in the majority

vitamins D and E and as minerals selenium or zinc were supplemented.

The daily dosages of all preparations were heterogeneous. Regarding the minimal daily

dosage this was one unit per day for 2 0 products, for 2 1 products twice and for one

preparation thrice daily, for three products there was a 4 x daily and for one product

even a six times daily consumption. From the products containing only saw palmetto as

active constituent only eight products were dosed once daily and six brands twice daily.

Also the amount of saw palmetto extract declared for one tablet or capsule varied

widely reaching from 2.5mg to SOOmg per unit.

The extracts were in the majority not well declared on the packages or package leaflets,

so only for a few products proper drug extractant ratios (DER) and the extractant were

available. The given declarations showed that the greater number of the saw palmetto

extracts were highly lipophilic, at least one (SP 14) contained also crude saw palmetto

berry powder. None of the investigated products had reached expiry date.

A n d y i L ' t c r 92

C/icpfcr 3; P/:yfoc,^er:.'cc.' r.io /y j/i

Table 6 gives details on the test products, a more comprehensive description of each

item including additionally the brand name, manufacturer, drug-extractant ratio, other

active substances, and batch number is given in Appendix 1.

In the following the test samples can be identified with their reference number given in

Table 6 , abbreviated as SP and the number whereas SP stands for specimen.


Table 6: Details o f the 46 preparations containing saw palm etto which were included in theanalytic comparison

Samp le nr. (SP)

Country

Regulatorystatus

Registered (R ) Food supplement

(PS)

monoor

combination

Tablet(T).

capsule(C)

Tabletor

capsuleweight

[mg]

Amount of saw palmetto per unit

[mg]as given on package

Daily dosage (units/d)

1 CAN R combi C 1800 160 2x1

7 UK FS combi C 450150mg SP extract,

132mg SP berry 1x1

8 ESP FS mono I 450 80 4x1

11 UK FS mono c 450 450 2x2

12 ESP FS mono c 410 160 2x1

13 CAN R mono c 500 500 3x114 UK FS mono c 520 300 1-3x1

15 UK FS combi c 400 120 1-3x1

16 Korea FS combi c 750 500 1x117 USA FS combi c 550 333.5 2x1

18 Korea FS combi c 800 500 1x1

19 CAN R combi c 1362 80 1-2x220 USA FS combi c 1800 160 2x121 NL FS combi c 1400 160 1x1

22 ESP FS combi c 365 365 2x123 UK FS combi T 1200 160 1-2x124 NL FS combi c 500 40 2-3x127 SWI R mono c 500 320 1x1

29 Korea FS mono c 500 320 1x1

30 SWI R mono c 480 320 1x1

31 SWI R mono c 480 320 1x132 Korea FS mono c 500 320 1x1

33 FIN R mono c 480 320 1x1

34 USA FS mono c 600 160 1x2

35 SWI R mono c 485 320 1x1

36 SWI R mono c 260 160 2x1

37 CAN R mono c 400 80 2x1

38 NL FS combi T 1450 100 2x1

40 SWI R combi c 675 160 2x1

41 NL FS combi c 550 320 2-3x1

42 NL FS combi I 1450 100 1-2x1

43 NL FS combi c 666 160 2x1

44 NL FS combi c 1400 2.5 1-3x1

45 CAN R mono c 350 350 4-6

46 UK FS combi c 2000 30 1x147 USA FS combi c 600 160 2x1

48 CAN R combi c 1800 80 2-4x1

49 USA FS mono c 480 320 1x1

50 USA FS combi c 750 160 2x1



53 USA FS mono c 570 160 1x1-254 USA FS mono c 700 320 1x2

55 ESP FS combi I 600 160 2x1

56 USA FS combi I 1600 50 2x1

57 ESP FS combi T 450 25 2x3

94

3.2.2 Thin layer chromatography (TLC) for identification

3.2.2.1 Main principle

TLC is a simple and well known chromatographic technique to analyse drugs quickly and

with great certainty (343) and is known to be 'the workhorse' for screening tests in

laboratories (344). The method was first established by Izmailov and Sraiber in 1938

who separated galenic formulations using loose layers of aluminium oxide on glass

plates by continuously dropping a solvent on the point of application. The breakthrough

for TLC was achieved when Stahl in 1958 developed high quality equipment for

preparation and separation together with a standardised fine-grained silica gel. He was

also the first person to propose the name TLC for this analytic method (345).

The method is based on the principle that the flat layer of the material serves as a

stationary phase and that the mobile liquid phase is moved by capillary forces across

this layer. Like this, compounds in mixtures are separated by their migration speed on

the plate. The distance they migrate per time depends on the adsorption of the specific

molecule to the stationary phase and, therefore, depends on its distribution between

the two phases. The more a substance is adsorbed, the slower it moves (343,344).

The detection is carried out by locating the spots on the plate and identifying the

substances (344). Several methods are available to locate the spots on the plate. This

can be by exploiting the luminescence characteristics of the analyte either by a

fluorescence or phosphorescence or by impregnating the layer bed with a fluorescent

indicator substance and afterwards inspection under UV light. Furthermore the layer

can be sprayed with a nonspecific strong oxidant or with a group - or substance specific

reagent solution (344, 346). A substance is much easier to identify when an authentic

reference substance is applied as well and the separated spots can be compared to it

(344).

Like this, TLC is the standard method for identification of herbal drugs which can also

give answers on the quality and even on the quantity of certain compounds (343).

Furthermore, the procedures and results are documented in pharmacopoeias (336,

343) and are easy to reproduce.


3.2 2.2 Protocol for analytical TLC

The method applied was in accordance with the requirements of the European

Pharmacopoeia on thin layer chromatography, chapter 2.2.27 and the monograph on

saw palmetto fruit (336). The principle of this TLC method was that with an a polar,

acidic mobile phase the lipophilic substances of the saw palmetto preparation were

separated on a silica gel layer. After spraying with anisaldehyde reagent and heated to

llO 'C , the zones were analysed at daylight.

This TLC method was already used routinely at A.Vogel Bioforce AG quality assurance

for identification of the saw palmetto preparation Prostasan®. This is a registered

product containing 320mg saw palmetto extract per capsule extracted with ethanol

96% V/V and fulfils the requirements of the European pharmacopoeia and the

monographs (17, 40,146 ,147, 336). The amount of each test preparations for TLC was

calculated using a modified formula after having carried out previous experiments.

The formula for Prostasan® is as follows :

0.25x320 ^ = 0.16

485 =[g]

0.25 = [g] necessary Prostasan® content

320 = [mg] Saw Palmetto extract per Prostasan® capsule

485 = [mg] Prostasan® capsule weight

The adjusted formula for soft gel capsules and tablets was :

0.16x bCalculation formula: x =

a

X = [g] necessary capsules (tablets) content

a = [mg] Saw Palmetto per capsule (tablet) as given on the package

b = [mg] capsule (tablet) weight

for hard eel capsules the formula was adjusted to

0.4x bX —

a


C/7(7jTLC.' z'

The amount of a capsule content or tablet was dissolved in 4ml toluol. As reference

substances lOmg ^-sitosterol and 4mg p-amyrin were separately dissolved in 10ml

ethanol (96%). 4pl of the saw palmetto preparation, which was a clear yellow solution

as well as 2pl each of the reference solutions and additionally also Prostasan® as a

reference saw palmetto product were applied to a silica gel F254 HPTLC plate with SOnm

pore size from Merck.

As mobile phase acted a mixture of toluene, ethlyacetate and acetic acid mixed in the

ratio of 70:30:1 V/V. The runtime was about 20 minutes and the dried plate was

thereafter sprayed with anisaldehyde reagent. After heating the plate up for 5-10

minutes to 1 1 0 ”, the zones were visible and the plate could be analysed.

The method applied here serves only for the identification and not for quantification of

substances.

3.2.3 Gas chromatography for analysis of fatty acids

3.2.3.1 Main principle

In gas chromatography (GC), the mobile phase is an inert carrier gas which is generally

helium, argon, or nitrogen which has no significant interactions with the analyte. The

main function of the carrier gas is to transport the compounds to be analysed from the

injector to the detector. The stationary phase is either solid or liquid where the

constituents to be separated can be adsorbed (344).

GC is applicable to substances or their derivatives which can be volatilised under the

temperatures which are applied (336), mainly organic and anorganic materials with

molecular weight ranging from 2 to 1000 Daltons and is the premier technique to

separate and analyse volatile compounds (347). The method is based on the works of

Prior and Cremer who were the first to develop a solid gas chromatography method in

1947 which was published officially in 1951 (348).


Chapter 3: Fhy iochcnCcal anolys i r

The basic principle of a gas chromatograph is quite simple and the differences in gas

chromatographic systems lay generally in the use of the carrier gases. The system is

that gas is directed through the injector to the column and the sample is injected either

into a special injector or to the column itself. The analytes are then separated in the

column which is heated by an oven and usually temperature gradients are used to

improve the separation. The separated compounds are then recognised in the detector

(344, 349).

The choice of the gas is often important, even though it is inert, as it determines by its

molar mass, density, and viscosity how long the analytes stay in the column. A longer

diffusion time leads in the end to a better peak broadening and a better resolution

(344).

Also, there are several injection systems used but the oldest and most popular is split

injection. Here, a small proportion of the sample is transferred to the column with a

standard syringe on the heated injection port which contains a deactivated glass liner.

The sample is rapidly evaporised and the major part is discharged as waste through the

split which is an opening right at the top of the column (347).

There are a wide variety of columns in use for GC like packed columns where the

stationary phase is coated on a granular support material or capillary columns with a

liquid stationary phase deposed on the column wall. Depending on the type of column

they differentiate in their diameter and length, whereas capillary columns are generally

narrower and much longer, up to 100 m, than the packed ones (344).

More than 60 detectors have been tried out in GC (347) but most often flame ionization

detectors (FID) are used. The principle of this detection system is the measurement of

the electric conductivity of a hydrogen flame between two electrodes. When an organic

compound enters the flame the substance is ionised causing an electric current and this

allows to detect this compound (344, 350).

The advantages of GC is that it is a fast, efficient, and sensitive analysis providing a high

resolution. Further the method is non destructive making it possible for online-coupling

for example to a mass spectrometer and is easy to apply, reliable and inexpensive

(347).


3 2.3.2 Protocol for fatty acids analysis with GC

The method used was based on the principle that the lipophilic constituents of the saw

palmetto preparations were extracted with hexane, then saponified with sodium-

hydroxide and finally esterified to fatty acid methyl esters (FAME) with boron

trifluoride-methanol complex. The FAME were then separated with GC and analysed

using heptadecanoic acid as internal standard. Like this the esters and free fatty acids

are determined together, counted as free fatty acids.

This was a modified standard method of the German Society for Fat Science for fatty

acid methyl esters (351) which is in alignment with the recommendations of the

European Pharmacopoeia for gas chromatography and for determination of fatty acids

in saw palmetto products (336). Tablets, soft and hard gel capsules had each to be

prepared with different protocol for GC as will be shown in the following.

a) Preparation of tablets

For tablets this formula was applied to determine the amount needed for analysis:

1000x0.16x6x = -----------------

a

X = [mg] necessary tablet content

a = [mg] Saw Palmetto extract per tablet as given on the package

b = [mg] tablet weight as given on the package

1 0 0 0 = coefficient on mg

0.16 = calculations coefficient based on preliminary experiments

The corresponding amount of tablets were pulverised and combined with 4ml ethanol

40%, 8 ml water and 5ml internal standard solution in a 40ml centrifuge tube.

Afterwards the mixture was extracted with 3 times with 15ml hexane. The hexane

phases were then combined and dried with sodium sulphate and then concentrated in

a rotary evaporator.


b) Preparation of soft gel capsules

The amount of the content of soft gel capsules needed for the analysis was calculated

as follows:

1000x0.13xZ?x = ------------------

a

X = [mg] necessary capsule content

a = [mg] Saw Palmetto per capsule as given on the package

b = [mg] capsule weight as given on the package

1 0 0 0 = coefficient in mg

0.13 = calculations coefficient based on preliminary experiments

From each soft gel capsule the calculated capsule content was added to a 50ml

centrifuge tube and mixed with 5ml of the internal standard solution (BOOmg

heptadecanoic acid dissolved in 50ml petroleum ether) and then dissolved in 10ml

petroleum ether. After addition of Ig water-free sodium sulphate the tube was

centrifuged for 5 minutes at 3000U/min. Of the supernatant, 10ml were then

concentrated to dryness in a rotary evaporator.

c) Hard gel capsules

The quantity from the content of hard gel capsules mandatory for the GC analysis was

calculated using the following formula :

1000x6x = ----------

a

X = [mg] necessary capsule content

a = [mg] Saw Palmetto extract per capsule as given on the package

b = [mg] capsule weight as given on the package

1 0 0 0 = [g] amount of herb for the analysis

An dy SLiter 100

5; P/7'/foc/7cni,'cc/ nnoâ/f/:

The calculated amount of the capsule content was transferred to a Soxhlet extraction

thimble, covered with wool and extracted for 45 minutes with 70ml hexane and 5ml

internal standard solution. The extraction solution was thereafter concentrated on the

rotary evaporator to ca. 2ml and then dried with water-free sodium sulphate. The clear

solution was then evaporated until dry on the rotary evaporator.

The next preparatory steps were the same for all investigated galenic forms.

Six ml of 2% methanolic sodium hydroxide-solution were added to the residue and

heated up to the boiling point for 10 minutes, then 5ml boron trifluoride-methanol

complex were added and the whole mixture was boiled for another 2 minutes. Finally,

2 0 ml heptane were added, stirred and cooled down.

Afterwards saturated sodium chloride solution was added until the heptane phase

ascended into the flask neck. About 1ml of the resulting heptane phase was dried in a

centrifuge tube with water-free sodium sulphate; the clear yellowish green solution

was used for the chemical analysis.

The analysis was performed twice for each test preparation with a gas chromatograph

(Trace GC ultra. Thermo electro-cooperation) using an Optima 5 capillary column, 25m

X 0.32mm ID with 0.25pm layer thickness.

The column was held isothermally at 100°C, then the temperature was programmed to

increase at a rate of 5°C /min to 190“C where it was kept for 5 minutes. The injector

was set to 250°C and an amount of Ip l solution was injected using the split mode with

hydrogen as carrier gas at a constant pressure of 40 kPa.

The system suitability was given when in the chromatogram the resolution between the

main peak lauric acid and myristic acid amounted to at last ten. The single fatty acids

which were assigned according to the retention time of the peaks and were calculated

in reference to the area of heptadecanoic acid. The areas were integrated by using

Chromcard software. The methods precision is 0.9% and the correlation in linearity

0.998.

Fig. 6 shows a typical chromatogram of an analysis with the identification of the peaks.

Andy Safer 101

Chapter 3; Phytochemical analysis

Figure 6: Chromatogram of a saw palm etto preparation w ith the identified peaks

900-

800-

700-

500-mV

400-

min

For capric acid, caprylic acid, lauric acid, myristic acid, palmitic acid, linolenic acid,

oleic/linoleic acid, and stearic acid the amount was calculated in reference to

heptadecanoid acid as follows:

Fatty acid [mg/unit] =AP WIT 320

AST 10 WS

AP = sum of area of fatty acids in a sample

AST = area of internal standard

WIT = weight of internal standard [mg]

1 0 = dilution of internal standard

WS = weight of sample [mg]

320 = standard weight of capsule content

Each test preparations was analysed twice. The corresponding mean value of every

product was used for the analysis. All analyses were carried in the analytical

laboratories of A.Vogel Bioforce AG, RoggwiI, Switzerland with the assistance of

laboratory technicians.

Andy Suter 102


3.3 Results

3.3.1 Identification of the test samples with TLC

The products were applied grouped together according to their galenic form, means

tablets, soft and hard gel capsules on separate silica gel plates.

On Figure 7 and 8 are the TLC fingerprints of the tablet samples. Except for the

preparation on position 2 in Figure 7 and the reference substance Prostasan® on

position 7, these were all combination products. The two products on lane 5 and 6 were

sold by different manufacturers but had the same composition given on the package

containing a large variety of herbal substances, vitamins and minerals. The fingerprint

identifies them as similar products.

Figure 7: TLC finger print profile o f six d iffe rent tablets on band 1-6, band 7 is the reference product Prostasan capsules, band 8 are the reference substances P-sitosterol (upper band) and p-amvrin (lower band)

f f

#; - e # #

1= SP 57, Spasmo-Urgenin, Madaus, Spain 5 = SP 38, Prostaat, Phital, Netherland2 = SP 8, Sereprostat, Robapharm Espaha S.A., Spain 6 = SP 42, Prosta Totaal, Distributie care bv, NL3 = SP 55, Prosta-Fort, GSN, Spain 7 = SP 10, Prostasan, Bioforce AG, Switzerland4 = SP 23, Saw Palmetto Complex, Natures Aid Ltd., UK 8 = Reference solution: p-Sitosterol; P-Amyrin

Andy Suter 103


Figure 8: TLC finger prin t profile of the tab le t preparation SP56 on band 1, band 2 is the reference product Prostasan capsules, band 3 are the reference substances (3-sitosterol (upper band) and p-am yrin (lower band, barly visible)

9 ##

Among the hard gel capsule products, Figure 9 shows that all the mono preparations

presented almost the same TLC fingerprint (lane 1, 3, 4, 5, 7). The fingerprints of the

two Dutch products in Figure 9 on lane 8 and 9 indicated that they were combination

products. The products in lane 2 and 6 were also combinations but they were for this

assay maybe not sufficiently concentrated. The three further hard capsule preparations

in Figure 10 were all combination products whereas the product on lane 2, a

combination product with vitamin D and minerals showed almost the same pattern like

the reference product Prostasan.

Andy Suter 104


Figure 9: TLC fingerprints o f nine products in hard gel capsules, on position 10 is the reference product Prostasan capsules, on position 11 are the reference substances p-sitosterol (upper band) and p-amyrin (lower band)

1 = SP 12 Permlxon, Pierre Fabre Iberica S.A., Spain 7 =2 = SP 22 Biprostat, Dietéticos Intersa S.A., Spain 8 =3 = SP 13 Saw Palmetto Berries, , Natural Factors, 9 =

Canada 10 =4 = SP 45 Saw Palmetto, Homeocan, Canada 11 =5 = SP 14 Saw Palmetto Berries, Solgar Vitamin and

Herb, UK

SP 11 Saw Palmetto, Holland and Barret, UK SP 24, ProstaFleur Extra Forte, Bloem Natupr. NL SP 41, Prostalife, Bloem Natuurprodukten NL SP 35, Prostasan, Bioforce AG, Switzerland Reference solution: p-Sitosterol; p-Amyrin

Figure 10: TLC fingerprints o f three hard gel capsules on lane 1-3 , the reference substance Prostasan on lane 4 and on lane 5 ^-sitostero l (upper band) sand p-am yrin (lower band)

1 = SP 15, Saw Palmetto & Pygeum Bark, Higher Nature, UK 2= SP 17, Prostate Health, Schiff Nutrition Group Inc, USA3 = SP 47, Saw Palmetto & Pygeum Extract, Country Life,

USA4 = SP 10, Prostasan, Bioforce AG, Switzerland5 = Reference solution: P-Sitosterol; p-Amyrin

Andy Suter 105


The majority (n=29) of the commercial preparations were made with soft gel capsules.

Figure 11 shows the fingerprints of the six saw palmetto brands from Switzerland.

All except the sample on position 4 which contained also an Urtica dioica extract were

mono preparations. They displayed an almost uniform TLC fingerprint and could

evidently be identified as a lipophilic saw palmetto preparation when compared to the

reference product Prostasan® (Figure 11).

Figure 11: TLC fingerprin t o f the six Swiss saw palm etto preparations which were all made w ith soft gel capsules. On lane 7 are the reference substances ^-sitoste ro l (upper band) and P- amyrin (lower band)

14^

s g g

5 6

1 = SP 30, Prosta Urgenin, Max Zeller Sdhne AG, CH2 = SP 31, SabCaps, Vifor SA, CH3 = SP 27, Prostagutt Uno, Schwabe Pharma AG, CH

4 = SP 40, Prostagutt F, Schwabe Pharma AG, CH5 = SP 36, Prostadyn, Dr. Dünner AG, CH6 = SP 10, Prostasan, Bioforce AG, CH7 = Reference solution: ^-Sitosterol; p-Amyrin

Andy Suter 106


In Figure 12, 13, and 14 the mono preparations always showed similar signals as

compared to the reference product Prostasan®. Combination samples produced in four

cases no clear bands but rather big black spots (Fig.l2, SP46; Fig. 13, SP51; Fig 14, SP

44, SP 21). These could be due to either to the concentration being too high but also to

pumpkin seed oil extracts in SP 44, 46, and 51 which usually in TLCs evokes signals

similar to the ones seen here (343).

Two combination products in Figure 12 on position 12 and 13 showed displayed almost

the same pattern like the reference product Prostasan® even though they contained

additionally pumpkin seed or soy oil.

Figure 12: TLC fingerprints o f 14 d iffe rent saw palm etto preparations w ith soft gel capsules. On lane 15 is the reference product Prostasan, on lane 16 are the reference substances ^-s itoste ro l (upper band) and P-amyrin (lower band)

1 = SP 3 7 , S aw P a lm e tto , Swiss H e rb a l R em ed ies Ltd., CAN

2 = SP 3 4 , S aw P a lm e tto E xtrac t, N o w Foods, USA

3 = SP 1 9 , P rost-Force , P ra irie N a tu ra ls , Canada

4 = SP 1, P ro s ta te P e rfo rm , N e w Roots H e rb a l, C anada

5 = SP 4 8 , S aw P a lm e tto & P ygeum , P re fe rre dN u tr it io n , CAN

6 = SP 2 0 , Life E xtens ion , Q u a lity S u p p lem e n ts and

V ita m in s Inc., USA

7 = SP 3 3 , C urb isal, P harb io , Fin land

8 = SP 4 3 , P rostalan F o rte , V S M , N e th e rla n d

9 = SP 5 3 , S aw P a lm e tto B arry E xtract, S o laray, USA

10 = SP 4 6 , P ro stav ita l, H e a lth A id , UK

11 = SP 2 9 , Saw P a lm e tto M o n o P ro d u ct 1

(HFS),CJ N u tra , Korea

12 = SP 16, S aw P a lm e tto C o m b in a tio n P roduct 1 (HFS),

CJ N u tra , Korea

13 = SP 18, S aw P a lm e tto C o m b in a tio n P roduct 2

(HFS), C hung W a e P h arm a C o rp o ra tio n ,

Korea

1 4 = SP 3 2 , S aw P a lm e tto M o n o P ro d u ct 2 (HFS),

C hong Kun D ang H e a lth , Korea

15 = SP 1 0 , P rostasan , B io force AG , S w itze rlan d

1 6 = R e fe ren c e s o lu tion : p -S ;tosfero /; P -A m y rin

Andy Suter 107


Figure 13: TLC fingerprin ts o f tw o preparations made w ith soft gel capsules. On lane 3 is the reference product Prostasan, on lane 4 are the reference substances ^-sitosterol (upper band) and g-am yrin (lower band)

1 = SP 44, Prostavit, Bional, Netherland2 = SP 21, Prostavit Forte, Bional, Netherlands3 = SP 10, Prostasan, Bioforce AG, Switzerland4 = Reference solution: [i-Sitosterol-, p-Amyrin

1 2 3 4

Figure 14: TLC fingerp rin t of fiye saw palm etto preparations w ith soft gel capsules. On lane 6 is the reference product Prostasan, on lane 7 are the reference substances ^-sitoste ro l (upper band) and p-am yrin (lower band)

: r n m # •

1 = SP 4 9 , P rostA ctive , N a tu re 's W a y , USA

2 = SP 5 0 , P ro s ta te 5LX, N e w C h a p te r Inc., USA

3 = SP 5 1 , P ro state A d v a n ta g e , E nzym atic T h e r., USA

4 = SP 5 2 , Saw P a lm e tto & P ygeum , N a tu re 's W a y , USA

5 = SP 5 4 , S aw P a lm e tto E xtrac t, Source N a t., USA

6 = SP 1 0 , P rostasan , B io force AG, S w itze rlan d

7 = R e fe ren c e so lu tion : P -S /tosfero /; P -A m y rin

Andy Suter 108

5" r,'10 ,

In conclusion, the results show that the applied concentrations were sufficient to cause

a good signal strength. The TLC fingerprints displayed that the saw palmetto mono

preparations could well be identified when compared to the reference product

Prostasan® no matter the galenic form of a product. Also, in general the mono

preparations could be differed from the combination products. Answers on quantity of

the saw palmetto extracts or which were the components in a combination product

could not be given with this TLC methodology.

Methodological aspects, how ^-sitosterol could be determined qualitatively and

quantitatively by also using TLC are presented in the discussion section.

Andy Suter 109


3.3.2 Analysis of fatty acids

For each of the tested products the amount of the fatty acids lauric acid, capric acid,

caprylic acid, myristic acid, palmitic acid, linolenic acid, oleic acid, linoleic acid, and

stearic acid were determined whereas for oleic and linoleic acid the sum for both were

assessed since the resolution of the peak was not satisfactory. The chosen fatty acids

are known to form the majority of lipophilic constituents of saw palmetto fruits and are

thus a good marker for the botanical drug's active constituents (352). A detailed

description of the fatty acids analysed is given in Table 7.

Table 7: The elemental form ula, lipid number, structure, and pharmacological activities o f thegaschromatographically analysed fa tty acids

Fatty acid (lUPAC name)

Elemental formula/

lipid numberStructure Pharmacologically known activities

C aprylic acid

(o c ta n o ic ac id )CsHieOî

C 8:0

0

HQ

A n tib a c te r ia l (3 5 3 -3 5 7 )

C apric acid

(d ecan o ic a c id )

C10H 20O 2

C 10:0

0A n tiv ira l (3 5 8 )

Lauric acid

(d o d ec an o ic acid )C12H 24O 2

C 12:0

0A n tib a c te r ia l (3 5 9 ), in su lin o tro p ic (3 6 0 ),

increasing high d en sity lip o p ro te in

(H DL) (3 6 1 ), an tim u sc a rin ic ,

a n tia n d ro g e n ic (4 1 , 4 6 , 4 7 )

M y ris tic acid

(te tra d e c a n o ic acid )

C14H 28O 2

C 1 4:0

0 A n tib a c te r ia l (3 6 2 ), a n tip a ra s itic (3 6 3 ),

H y p e rc h o le s te ro la e m ic (3 6 4 )

P a lm itic acid

(h e x ad e c an o ic acid )C16H 32O 2

C 1 6:0

0H y p e rc h o le s te ro la e m ic (3 6 4 , 3 6 5 )

S te aric acid

(o c ta d e c a n o ic acid)

C18H 36O 2

1 8 :0

0

a n ti-a d ip o g e n ic (3 6 6 -3 6 8 )

O le ic acid

((9Z ) o c ta d e c -9 -e n o ic

a c id )

Cj8H3402

18:1

0 A ntic a rc in o g e n ic (3 6 9 ), hy p o te n siv e

(3 7 0 ) an tim u sc a rin ic , a n tia n d ro g e n ic

(4 1 )

L inoleic acid

(cis, c is -9 ,1 2 -

o c ta d e c a d ie n o ic acid )

C18H 32O 2

1 8 :2 HO

a n ti-a d ip o g e n ic (3 7 1 ), in fla m m a to ry (?)

( 3 7 2 ,3 7 3 )

c t-lino len ic acid

((9 Z ,1 2 Z ,1 5 Z )-

o c ta d e c a -9 ,1 2 ,1 5 -

tr ie n o ic a c id )

C18H 30O 2

1 8 :3' ---------------------------------—

A n tiin f la m m a to ry , im m u n e m o d u la to ry ,

a n ti-a d ip o g e n ic , radical scavenger,

increasing lip o p ro te in p e ro x id a tio n ,

an tica rc in o g en ic (3 7 4 )

Andy Suter 110

3.3.2.1 Total daily amount of fatty acids per preparation

The test samples varied widely in their amount of saw palmetto extract as declared by

the producer, the capsule or tablet weight, and the daily dosages (Table 6). Thus in the

following the results of the fatty acid analysis will be shown for the lowest daily dosage

as given on the package as this is the amount of tablets or capsules which the

manufacturer of the product still considers to be efficacious.

The results showed there great heterogeneity between the products in the amount of

fatty acids per day as can be seen in Figure 15 for the lowest daily dosage per

preparation. The concentrations were in the range between 8.43mg for the product

with the lowest daily amount of fatty acids to 1473mg for the item with the highest

value. The mean reached 372.4 ± 333.7mg fatty acids per day and the median value

was 283.5mg/d.

Mono and combination products differed slightly in the average when looking at all test

items regarding the content of fatty acids but the combinations displayed a larger

variability. Products containing only saw palmetto result in 230.5 ± 127.2mg fatty acids

per day with values ranging from 30.89 to 1473.2mg, combination products in 261.0 ±

247.5mg with a range from 8.34 to 1173.02mg daily; the corresponding median values

were 271.9mg for mono preparations, respectively 239.3mg per day for combinations

(Figure 15).

Andv Suter 111


Figure 15 : Am ount fa tty acids per day o f the lowest daily dosage given on the package fo r each analysed product [m g/d] of all 46 investigated commercial preparations. W hite bars indicate mono preparations containing only saw palm etto as active constituent, red bars combination oroducts.

w. ^ i > =0f BJWf,

200 400 600 800 1000 1200

mg fatty acids/day

1400 1600

Andy Suter 112


The differences in the daily amount of fatty acids per product were more pronounced

when looking at the country of origin. The mono preparations from Switzerland and

South Korea showed all similar concentrations while the highest dosed U.S. American

product contained 2.7 times the amount of the preparation with lowest dose, for

Canada this ratio was 3.0, and for Spain even 13.3 (Figure 16).

Figure 16: Total am ount o f fa tty acids per minimal daily dosage [m g/d] fo r mono products sorted by the ir country o f origin

>- 800

600

SP SP SP SP32 29 8 12

SP SP SP SP37 45 13 33

Canada Finland Korea Spain

SP SP SP SP SP 36 35 27 31 30

Switzerland

SP SP 11 14

UK

SP SP SP SP 34 54 53 49

U.S.A

Combination products when analysed by their country of origin showed an even more

ambiguous picture regarding the amount of total fatty acids. The mean values were

highest for the Canadian products (n=3) with 1008.5 ± 219.6mg/d, followed

preparations from the U.S.A (n=7) with 378.3 ± 288.6mg/d, and South Korea (n=2) with

358.7 ± 61.1mg/d. The lowest average value for the total fatty acid content displayed

the Spanish products (n=3) with 129.2 ± 193.7mg/d.

The enormous standard deviations highlight that there was a large variability between

the daily amount of fatty acids between the preparations within one country. The

highest dosed brand in Spain contained 42.3 times more fatty acids than the lowest

dosed, for the products from the United Kingdom this factor was 27.9, for those from

the Netherlands 14.4, from the U.S.A. 9.0, from Canada 1.6, and from South Korea 1.3.

Andy Suter 113


The total amount of fatty acids in combination products cannot be explained by other

botanical drugs included in a preparation. Samples containing one or both of these

extracts could contain high amounts of fatty acids like for example for the Canadian

SP19 with 1173.02mg/d but also very low daily concentrations like 26.64mg of the

Spanish sample SP 15 (Figure 17).

Figure 17: Daily am ount o f to ta l fa tty acids fo r combination products according to the minimal dose of every preparation [m g/d], divided by country o f origin. The darker bar indicates fo r each country the mean value w ith standard deviation.

1400

r . 600

(T3 CM LT) LD

l/> LO I /) CO t/> LO UO

Canada Korea Netherlands Spain Switz. United Kingdom U.S.A

Andy Suter 114

Chapter 3: Fhytocheni ical cnciys:

3.3.2 2 Comparison of measured fatty acid quantities to the amounts given on

the packages of mono preparations

The differences in the total amount of fatty acids between the products might not be

that relevant for a customer when the quantities of extract are declared correctly. Thus

for the mono preparations I compared the measured quantities of fatty acids to the

amounts given on the packages or the package leaflet. For the calculation of the

difference between the stated and measured amount I assumed that an extract would

consist of 100% fatty acids.

There were large dissimilarities between the measured values and the package

information ranging from about 10 times less fatty acids up to 4.6 more fatty acids than

what was stated by the manufacturer.

Usually lipophilic saw palmetto extracts contain 70-95% fatty acids (147, 352). Only for

eight of the analysed 19 preparations a percentage of fatty acids per capsule or tablet

in this range could be calculated by comparing the measured amount of fatty acids to

the written quantity of extract by the manufacturer. Interestingly, all registered Swiss

products were among these eight products as well as the also registered Finnish

product and one Korean product. The only U.S. American preparation (SP49) which was

in the calculated range is actually a German preparation similar to SP 27 as both are

produced by the same manufacturer, Schwabe Pharma in Germany (375).

Surprisingly, for SP12, Permixon®, a saw palmetto product with a good preclinical and

clinical background and known to be a reputed product (34, 338) only a value of 34.8%

fatty acids of the extract could be determined (Table 8).

A ndy Suter 115

Table 8: Differences between the am ount of saw palm etto extract as stated on the package and the measured concentration o f to ta l fa tty acids per tab le t or capsule assuming the extract consists o f 100% o f fa tty acids.

Samplenr. Country

Unit: Tablet (t)

orcapsule (c)

Amount of saw palmetto

extract per unit [mg]

asdeclared on

package

Total fatty acids [mg] per unit

measured

Difference in % of information on package vs. measurement

SP8 ESP t 80 368.3 460.4%

SP 37 CAN c 80 253.06 316.3%

SP 34 USA c 160 378.2 236.4%

SP 53 USA c 160 354.61 221.6%

SP 54 USA c 320 444.31 138.8%

SP 36 SWI c 160 151.56 94.7%

SP 33 FIN c 320 290.24 90.7%

SP 49 USA c 320 285.68 89.3%

SP 35 SWI c 320 281.34 87.9%

SP 27 SWI c 320 274.53 85.8%

SP31 SWI c 320 274.45 85.8%

SP 32 Korea c 320 271.9 85.0%

SP 30 SWI c 320 271.82 84.9%

SP 29 Korea c 320 237.74 74.3%

SP 12 ESP c 160 55.68 34.8%

SP 45 CAN c 350 51.01 14.6%

SP 14 UK c 300 34.5 11.5%

SP 13 CAN c 500 56.8 11.4%

SP 11 UK c 450* 44.57 9.9%

♦Contains also saw palmetto powder

116


3.3.2.3 The relative amount of the single fatty acids per preparations giving and

indicator for their inner composition

a) Combination products

For each of the analysed products the relative amount of every single fatty acid was

assessed compared to the total amount of fatty acids. Like this, a fingerprint on the

composition for each product can be produced.

For the combination preparations, the relative amount of fatty acids and the resulting

pattern varied widely. For example, only eleven products had a lauric acid content of

more than 20% of the total fatty acids, three test items, SP44, SP46, and SP56

contained almost none at all. To link the amount of certain fatty acids to extracts like

Pygeum africanum, soy, or pumpkin seeds which were part of the combinations was

not possible (Figure 18).

Figure 18: Relative amount o f the analysed single fa tty acids compared to the tota l fa tty acidcontent fo r each investigated com bination product. The bar at the very right shows the average value of all investigated combi products (n=27).

100%

90%

80%

70%

M 60%

50%

° 40%

è 30%

20%

10%

f N p v r H r ^ f N L n ^ L n k D r ^ r ^ n n o o o r o o r ^ r M t H ^ - i r s o o o ^ o o t D ^ û ^ o;

Û - t / ) Û . Û . Q . Û . Û . Q . C L C L Q . Q . a . a . Û . Q . Q . C L t / ) Q . Û . Q . Q . Q . Q . O . Û . 2 00 L O L O L O L O L O L O L O t / ) ( / ) l / l L O ( / l L O L O O O U O L O L O L / I L O L O L O O O O O Qj

■ Lauric acid■ Myristic acid■ Oleic+/Linoleic acid

I Caprylic acid I Palmitic acid I Stearic acid

I Capric acid I Linolenic acid

Andy Suter 117

r S . - Fny(or/i(?nj'rr/ o.no,'ys.''r

b) Mono products

The composition of the saw palmetto mono extracts was in the majority comparable as

can be seen in Figure 19. The percentage of the eight different single fatty acids was

more or less comparable in about 14 of the mono preparations, the samples SP54, 34,

53, 8, and 37 differed the most from the average values.

Saw palmetto fruits contain high amounts of oleic and lauric acid, each is present with

around 30-40% of the total fatty acids (352), the above mentioned 14 preparations

showed high concentrations of lauric and oleic/linoleic acid as well. The amount of 20%

lauric acid per saw palmetto extract as demanded in the European Pharmacopeia (336)

was reached by all but four mono preparations. Three of these four products, SP34,

SP54, and SP8 had larger amounts of oleic and linoleic acid and one item, SP37,

contained a very high concentration of linolenic acid which is unusual for saw palmetto

berries and gave raise to a suspected adulteration with another plant oil.

In general the pulp of the saw palmetto fruit contains more myristic acid compared to

the whole drupe (352). None of the test items had increased values of this fatty acid

which indicates that in all cases the whole fruits were extracted.

The extractant was available from the package or patient information leaflet for SP27,

30, 31, 33, 35, and 36; either 90% or 96% ethanol was used and all these products had

comparable drug extractant ratios. These ethanolic preparations showed the same

relative amount of the fatty acids compared to the only product extracted with hexane,

SP12 (Figure 19).

Andy Suter 118


Figure 19: Relative am ount o f the analysed single fa tty acids compared to the to ta l fa tty acid content fo r each investigated mono product. The bar at the very right shows the average value o f all investigated mono products (n=19)

100%

90%

T3Uns>-

80%

70%

djM 60%

50%

40%

> 30%mO)oc 20%

10% -

0%

Q - Û - Q u a - Q - Q - Q - Q - (✓) 1/1 I/) I/)

Lauric acid ■ Caprylic acid ■ Capric acid ■ M yristic acid

Palmitic acid ■ Linolenic acid mOleic+/Linoleic acid ■ Stearic acid

In summary, on average the combination products showed a different pattern

compared to saw palmetto preparation. They contained less lauric, oleic/linoleic, and

myristic acid but higher concentrations of palmitic, linolenic and stearic acid. Among

the mono items, four products displayed different patterns compared to the other

extracts whereas one contained a high amount of linolenic acid which is not a main

constituent of saw palmetto berries.

The chromatograms of the investigated samples are displayed in the appendix.

Andy Suter 119

C/iopfer 3; Pnytcc/iFni.co,' o/io-ys;

3.3.2 4 Main results from proton-NMR-analysis from the master thesis of Tony

Booker(2010)

In the NMR analysis the test items SPl to SP37, except SP8 were analysed and

additionally four saw palmetto mono tinctures and one German lipophilic mono extract

(Prostess uno, TAD Pharma) and a British product from Chapmans which contained saw

palmetto powder extract.

For better comparison of the two analytical methods, GC and NMR-spectroscopy,

I focus in the following only on products which were analysed using both techniques.

For sample preparation, the test items were first extracted with methanol and then

analysed, but as with this extraction method the soft extracts dissolved insufficiently,

deuterated chloroform was used thereafter as extractant.

With the NMR analysis the compounds gallic acid, absorbic acid, galactose, sitosterol,

stigmasterol, caproic acid ethyl ester, and oleic acid could be analysed. The latter two

substances could be positively identified from the spectra of the methanolic sub

extracts from the saw palmetto products and could be used for quantitative work.

In general, the analysis showed that tinctures and preparations containing dried saw

palmetto powder could be differentiated with the principal component analysis (PCA)

from powder extracts.

Among the soft gel extracts, the hexane extract Permixon (SP12) presented a different

metabolomic fingerprint than the others which partly might be due to the excipient

polyoxethylene glycol but it contained also more methyl and ethyl esters.

Three other preparations, SP26, SP34, and SP37 were different from the main group of

soft gel extracts.

Andy Satcr 120

Further small differences between the test items, also between combination and mono

products could not be detected with NMR nor were at this stage any quantifications of

constituents in the extracts possible. But the NMR-method, here used for the first time

for a metabolomic approach for different saw palmetto preparations proved to be

robust and reproducible and the clustering allowed well to identify outliers.

A good example for a PCA is shown in Figure 20 for soft extracts in chloroform. The saw

palmetto mono extracts build in the majority one cluster whereas combi preparations

deviated from it (Figure 20).

Figure 20: Ellipse scores of saw palm etto soft extracts (SP25-37) versus com bination products (SP16-SP21) in chloroform .

Scores0.3

0,2

0.1

-0 1

-0.2

SP20

1 SF 18 IY mê6 ' J

SP19 /

SP37

-0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6PC-1 (82%)

121

5 ' r . r c f / f

3.4 Discussion

This phytochemical analysis of 46 commercial preparations from eight different

countries which contain saw palmetto is at the time the most comprehensive

investigation of saw palmetto products carried out so far.

The study showed that with the TLC methodology lipophilic saw palmetto mono

extracts could be identified well and that the total amounts of fatty acids measured

with GC were very heterogeneous between all analysed products. The relative amounts

of the nine investigated fatty acids were similar in ethanolic mono preparations but

rather different in combinations. Furthermore, this investigation provided evidence

that the mono preparations sold as food supplements displayed large differences

between the declared and the measured amount of fatty acids.

The analysis confirmed that the TLC method of the European Pharmacopoeia (336)

showed good results in identifying saw palmetto mono products.

With this TLC method saw palmetto preparations with different extractants could be

distinguished since SP12, the only investigated hexane-based extract, showed a

different TLC fingerprint than the ethanolic mono extracts. More test samples with

hexane as extractant for comparison would be needed to confirm this finding.

Otherwise, the TLC fingerprints were very heterogeneous and only in some cases the

saw palmetto component was to some extent identifiable. Also for preparations

containing same combination partners like Pygeum africanum- or pumpkin seed

extracts no uniform fingerprints which could be related to one of the components could

be observed. Thus, this TLC method is best applied in saw palmetto mono preparations

and solely for identification and not for quantification or qualitative determination of

substances like ^-sitosterol.

A better method to evaluate the quality of a product with Saba I is the analysis of its

amount of fatty acids which are seen as the main active constituents in saw palmetto

preparations (17, 40) and are known to influence positively pathological mechanisms of

BPH (41, 48, 52, 376).

With the applied GC standard method nine fatty acids were analysed which comprise

more than 95% of the fatty acids of saw palmetto berries. Other fatty acids not

Andy Suter 122

Cncptcr 3; P/iyfoc/iEni/cc/ rnaf/i.':

determined in this analysis like tridecanoic acid, pentadecanoic acid, arachic acid,

behenic acid, and lignoric acid are only to be found in very low quantities in saw

palmetto extracts of less than 0.2% each (35). Caproic acid which also could not be

analysed with the applied GC methodology, accounts for about 3% of all fatty acids in

saw palmetto (352, 377).

The analysis demonstrated that the total amount of these nine fatty acids per lowest

daily dosage were very heterogeneous between the test samples and that they varied

widely with a factor of about 177 between the minimum and maximum concentration

in mono products, respectively with a factor of 38 for combinations.

In general saw palmetto monographs recommend a daily dosage of 320mg lipophilic

berry extract with 70-95% fatty acids (17, 40,146, 147). When this daily dosage of 224-

304 mg fatty acids is taken as an acceptable quality standard, then only nine mono

preparations were in this range. Sixteen combinations and five saw palmetto only

brands displayed higher daily fatty acid values, five mono and eleven combination items

lower quantities.

A too low daily amount of fatty acids may lead to a lack of efficacy, too high

concentrations may not results in immediate health hazards as these fatty acids have a

very low toxicity (378) and higher dosages of saw palmetto extract for example were

still very well tolerated (162) but it makes it impossible to compare these products in

terms of their efficacy. If a higher daily dosage of these fatty acids would result in

improved efficacy in BPH patients is unclear as clinical data is lacking.

In general there is no need to exceed the recommended dosages for these fatty acids as

with 320mg lipophilic saw palmetto extract and with lOOmg lipophilic Pygeum

africanum extract satisfying results in BPH patients were achieved (17, 40, 119, 146,

147).

A higher dosed long term supplementation with some fatty acids may have negative

health effects. Palmitic acid and myristic acid are suspected to be a risk factor for

cardiovascular disease (364) and linoleic acid as it is a precursor of arachidonic acid

which is converted to prostaglandins can also be pro-inflammatory (372, 373).

A n d y Suter 123

Cnrpte/ 3; Fn)for/ip,'?' TC,'G.'?G.Y5.:

Whether increasing the amount of fatty acids by combining saw palmetto with another

herbal extract like Pygeum africanum or Urtica dioica or by fortifying it with vitamins

and mineral leads to a better efficacy in treatment of BPH symptoms is doubtful.

Studies of products containing saw palmetto and urtica, saw palmetto and Pygeum

africanum or even a combination of saw palmetto with cernitin, 3 -sitosterol, and

vitamin E showed no better efficacy in reducing BPH symptoms than what is known

from saw palmetto mono-preparations (379-381).

The total daily amount of fatty acids is one important quality marker to assess the

investigated products. Another one is the relative concentration of each investigated

fatty acid to know about the composition of the total fatty acids.

The only quality requirement for the composition of saw palmetto extracts is the

demand of the European Pharmacopoeia that saw palmetto extracts must contain at

least 20% lauric acid (336). The majority of the evaluated mono preparations fulfilled

this criterion, from the combination products only twelve did. There was no clear

differentiation between registered and unregistered brands concerning the amount of

lauric acid; two food supplements from the UK, SP14 and S P ll, presented the highest

relative concentrations of lauric acid, one licensed product from Canada, SP37, the

lowest ones.

The composition of fatty acids acts like a fingerprint for a preparation and can thus be

compared to other products. In Table 9 the mean frequency of the single fatty acids are

given for seven ethanolic saw palmetto mono products who fulfilled the criteria of the

monographs (SP27, SP30, SP31, SP33, SP35, SP36, SP49; Table 9)(17, 40, 146, 147). For

comparison further fatty acid compositions for saw palmetto fruits, other saw palmetto

extracts, the average values of all combination products, and other herbal extracts are

listed as well.

124


Table 9: The frequency o f nine fa tty acids in d iffe rent saw palm etto preparations, the whole fru it, and extracts from Pygeum africanum, pumpkin seeds, olive, and coconut oil as comparison.

%Capric

acidCapryMc

acidLaurieacid

Myristicacid

Palmiticacid

Linolenicacid

O le ic+ /Unoleic

acid

Stearicacid

Average monographed saw palm etto mono products (n=7)

2.4 1.93 30.41 12.37 9.76 6.28 35.16 1.69

Average all saw palm etto m ono products (n=19) 2.28 1.69 27.2 10.52 9.92 7.64 37.83 2.91

Saw pa lm etto whole fru it (352) (n=143 sites) 2.7 2.7 31.7 12.86 9.79 3.92 34.41 1.83

Saw pa lm etto ethanolic extract (382)( Indena)

1.82 2.11 30.86 13.68 10.06 0.92 39.04 1.51

Saw pa lm etto CO2 extract (382)(lndena) 2.78 2.36 33.3 12.51 9.26 0.99 36.89 1.9

Permixon SP12 2.59 1.99 32.04 12.97 9.64 4.2 34.99 1.69

Permixon (hexane) (47) ? ? 30 11 ? ? 40 ?

Hexane/acetone saw pa lm etto extract 4:1 (v/v) (35)

- 1.2 11.9 10.6 13.5 1.5 59.4 1.9

Average all combination products (n=27) 2.34 2.55 16.61 6.32 16.05 13.93 31.35 10.85

Pygeum africanum(382) - - 0.38 0.94 28.3 4.3 55.5 10.58

Cucurbita(382) - - - - 20.24 - 79.76 -

Cucurbita (383) - - - - 4 14 -0:21-47

1:35-595-6

Coconut oil (383) 6.4 8.0 48.5 17.5 8.4 1.5 6.5 2.5

Olive oil (383) - - - - 12.2 0.9 84.5 2.2

Andy Suter 125

C/lopf-e/' S; P/iyfoc/iP/iT/'cc/ ano/ys'f

Interestingly, the average fatty acid frequencies of the seven mono products comply

almost exactly with the values given for the whole fruit by Bubrick et al. (352) who

investigated saw palmetto berries collected from 143 sites in Florida. An ethanolic and

a CO2 saw palmetto extract analysed by Ganzera et al. also showed similar results like

the average frequencies of the seven mono preparations only with a smaller linolenic

acid content (382).

The hexane extract Permixon® displayed in our analysis an almost congruent fatty acid

pattern compared to the seven ethanolic extracts and similar values for lauric, myristic,

oleic, and linoleic acid as reported in literature (47).

Only a hexane/acetone standard extract which was developed by the U.S. American

National Institute of Standards and Technology in cooperation with the Food and Drug

Administration FDA presented a different fingerprint than the mentioned extracts. It

had almost threefold less lauric acid than the ethanolic extracts but almost twice as

much oleic and linoleic acids and more palmitic acid (35).

Mature saw palmetto fruits yield twice as much lauric acid than immature fruits, very

mature fruits contain more oleic acid than lauric acid (377). The pattern from the eight

ethanolic preparations showed that the majority of the manufacturers of the extracts

obviously used the same mixture of immature and mature fruits and that they were a

mixture from all regions of Florida as the fatty acid pattern varies significantly between

the different regions in Florida (352). The only samples that differed from the average

fatty acid content were SP34, SP54, and SP8 which contained more oleic/linoleic acid

than the other test items. This could be due to using more very mature fruits and/or

that they were from one cultivation where the berries contain more oleic acid. In an

unpublished report Berries from central Florida displayed a twice as high laureate to

oleate ratio compared to samples from northern Florida (377). Bubrick et al. found also

geographic variation in the content of oleic to lauric acid throughout Florida, they

observed the highest ratio in a cultivations towards central Florida but the lowest ratio

in a plantation on the East coast of Florida. Interestingly, the amount of ^-sitosterol,

cam peste ro I, and stigmasterol remained throughout the saw palmetto berries samples

of 143 investigated sites in Florida almost the same (352).

Andy Suter 126

C/fCpZer r - F / . o / i n . ' y s . ' r

One test item, SP37, showed a very high concentration of linolenic acid which is

unusual for saw palmetto berries, this product was suspected to be adultered with

another plant oil (383). A later inspection of the package showed that it contained soy

bean oil which was mentioned as an excipient but not as an active, this oil is rich

linolenic acid (384).

With this fingerprint, the mono preparations could well be distinguished from

combination products as they offered in the average a different fatty acid pattern. In

general combination products had lower amounts of lauric and myristic acid but higher

amounts of palmitic, linolenic, and stearic acid. These differences could be mainly

contributed to fatty oils from Pygeum africanum and Cucurbita pepo extracts which are

known to contain more linolenic and stearic acid than saw palmetto extracts.

Saw palmetto is unique in its composition of fatty acids if one compares it for example

with the amount of fatty acids of coconut and olive oils (Table 9).

In summary, an extract can well be characterised by its composition of fatty acids which

acts like a fingerprint for a product.

Thus, to guarantee a good extract quality I would propose that not only the minimum

percentage of lauric acid should be recommended by the pharmacopoeia but also

minimum relative amounts from other important fatty acids like oleic and myristic acid.

A broader analysis of saw palmetto mono preparations with known extraction

conditions could define where the margin would lie. This analysis and data from

literature in Table 9 show that for ethanolic extracts an amount of at last 30% oleic and

1 0 % myristic acid could be suitable.

Nevertheless, the GC method applied is limited as only fatty acids could be analysed.

Other substances like ii-sitosteroi (127, 385) or 8 -carotene (386) which influence

symptoms associated with BPH positively should also be determined in these extracts

and a certain amount could be required as quality marker as well. In particular

\i-sitosterol which exerted in vitro a positive influence on several mechanism associated

with BPH as showing antiandrogenic (385), apoptotic (387), and antiinflammatory (388)

A n d y Suter 127

activity and for which at least in higher dosages also clinically significant improvements

of BPH symptoms could be shown (127) is a good further quality marker besides the

fatty acids. As a clinical trial with 0.3mg H-sitosterol per day showed no clinical efficacy

in BPH patients (122) the amount of about Im g \i-sitosterol/g which can be found in

saw palmetto extracts (340) is obviously not the main active principle of a berry extract

but may have an positive supportive role in improving LUTS.

Whether ^-sitosterol was present in the test items could not have been detected using

our TLC-system, the method used in this thesis was solely for the identification of saw

palmetto preparations. The majority of the preparations showed a signal with similar Rf

of the ^-sitosterol reference but they were often rather large dark spots in contrast to

the the violet-pink zone which is characteristic for H-sitosterol (336), they contained

most probably fatty acids and their esters.

A more precise way by using TLC to determine the presence of H-sitosterol would be to

quantify its amount densitrometrically. Numerous validated TLC methods are described

in literature but mainly for plants containing only a small amount of fatty acids or

triglycerides. To use one of these methods, our test items must have been prepared

previously to omit the fatty acids and its esters for example by extraction with hexane.

These prepared test items could be applied on silica gel plates (F254 HPTLC plate with

60Â pore size) using toluene:chloroform:methanol (4:4:1 [v/v/v]) as mobile phase with

ii-sitosterol as control. After derivatisation with anisaldehyde-sulphuric acid reagent

Murthy et al. could quantify the amount of H-sitosterol from the Indian medical plant

Mucuna pruriens densitographically at 527nm by comparing it to a calibration curve

with i^-sitosterol (389). A similar technique was described by Sparzak et al. who showed

a robust and validated method for identification and quantification of {i-sitosterol in

Phyllanthus species by using the same plates as mentioned above with a mobile phase

consisting of chloroform:hexane:methanol (65:30:5 [v/v/v]) and subsequent deri -

vatisation with vanillin reagent. Compared to a calibration curve with different

\i-sitosterol concentrations densitrometrically at 525nm wavelength they determined

the amount of ii-sitosterol in each test item (390).

Andy Suter 128

S' P/iyfoc/icm/co/ ano/yffs

Also, various HPLC (391, 392) and gas chromatographic methods are available for the

separation, identification, and quantification of phytosterols whereas GC, often

combined with mass spectrometry is the method of choice these days to determine

phytosterols. There are several standardized GC methods for phytosterol analysis

available which are approved by for example the German government (393), the

Association of Official Analytical Chemists (AOAC)(394) or the International

Organisation for Standardisation (ISO)(395). A common principle for the analysis of

phytosterols is that the test samples are saponified at high temperature with ethanolic

KOH solution to obtain the free sterols. The unsaponifiable fraction containing

phytosterols is then extracted with toluene, reduced and the phytosterols are

derivatized to trimethylsilyl (TMS) ethers so they become volatile. They are then

quantified by gas chromatography (GC) with hydrogen flame ionization detection (FID)

(36). Samples that contain 50-150pg of a mixture of phytosterols can well be analysed

(396).

A survey on the concentration of the phytosterols campesterol, stigmasterol, and

^-sitosterol in different preparations containing saw palmetto has already been carried

out by Sorenson et al. in 2006 (340). Since the amount of these three phytosterols is

similar in saw palmetto berries from all over Florida (352) the major influencing factor

in saw palmetto mono-preparations is the extraction method used (Table 10). An

alcohol-free extract and a liquid extract had the lowest phytosterol quantities, a CO2

extract the highest amounts. Two ethanolic extracts, Prostasan and ProstActive

capsules, also investigated in our survey, exerted similar phytosterol values. The

combination with pygeum increases the amount of \i-sitosterol but seemingly not of

campesterol and stigmasterol (340).

Andy Suter 129

Table 10: Mean content of the phytosterols campesterol, stigmasterol and \i-sitosterol In d iffe rent preparations containing saw palm etto according to (340).

Mean phytosterol content, mg/g

Campesterol Stigmasterol H-sitosterol

Saw palmetto 45% powdered extract 0.35 0.17 1.09

Alcohol-free saw palmetto 0.025 0.013 0.069

Liquid herbal extract: saw palmetto 0.019 0.014 0.076

ProstActive once daily ( A SP49) 0.363 0.193 1.07

ProstActive Plus saw palmetto with stinging nettle 0.334 0.099 1.22

Prostasan capsules ( A SPIO) 0.395 0.201 1.12

Pygeum and saw palmetto 0.223 0.087 2.73

Saw palmetto pygeum lycopene complex tablets 1.17 1.04 2.76

Saw palmetto CO2 extract 0.554 0.286 1.74

Saw palmetto berry 0.054 0.040 0.322

Even though the quantification of another active substance like H-sitosterol in the test

samples would have given additional information, we decided to use a different

approach for further assessment of the preparations.

Our method of choice was proton-NMR-spectroscopy and PCA for statistical evaluation.

This allows not only to focus on one or two substance groups like fatty acids or

phytosterols but on all with NMR detectable constituents. By using the statistical

procedure of PCA, preparations with similar characteristics can be grouped in clusters.

In the Master thesis of Tony Booker which was the first to use this methodology to

evaluate different products containing saw palmetto, he could arrange preparations

with similar compositions and could identify outliers. He showed that SP12, SP26, SP34,

and SP37 did not belong to a cluster. The difference to other extracts was most

probably explicable as SP12 contained polyoxethylene glycol as excipient, SP26 used

super critical fluid extraction, SP34 had added extra, glycerine, carob, and zinc oxide.

130

3; P/?yror/7(:.m;'crT' o/ia.Y:':

and SP37 additionally to the saw palmetto extract soy bean oil and glycerine as was

already discussed in the fatty acid analysis.

For a broad analysis of saw palmetto products the method is superior to GC-analysis as

it is not only robust, easy to apply but has the asset that with PCA a statistical method is

applicable with which in short time relationships between different preparations can be

assessed.

To compare the results from the NMR-analysis from single substances with the ones

from the GC analysis is difficult as one identified substance, caproic acid ethyl ester was

not determined with GC. However, in general, the ethanolic mono-preparations which

were similar in the GC analysis were also related in the PCA of the proton-NMR-

analysis.

Further work on the NMR-methodology is thus recommended with more products to

have more data to form more and clearer clusters to differentiate the various products

on the markets as well as outliers.

However, whether an extract with a certain composition is efficacious can in the end

only be shown in a clinical trial. In vitro testing of preparations, focussing mostly on one

assay only like inhibition of the 5-alpha-reductase may give an idea about the clinical

efficacy but can not exclude nor predict a clinical outcome (34, 338).

Looking at it from a patient's perspective, the results of this phytochemical study are

even of greater importance. A BPH patient buying an unregistered food supplement

containing saw palmetto which is marketed for treatment of prostate problems has no

certainty what kind of quality or quantity of active constituents he receives as they are

mostly not declared on the package. And when they are stated, then in case of the saw

palmetto mono preparations sold as food supplements they were in the majority faulty.

This finding is in accordance with the analysis of Feifer et al. (337) who showed that

only three of six investigated saw palmetto preparations from the U.S.A. presented the

amount of fatty acids correctly. Another survey published in the American journal

'Consumer Reports' reported that of 13 assessed brands containing saw palmetto only

eight complied with the declared amount (397).

Andy Suter 131

C/;C7/:re.'' S. n.'io.'y-

Saw palmetto serves consequently as a good example for discussion if herbal

preparations should be on the market as unregulated food supplements or as

registered medicinal products.

From a legal perspective, in Europe food supplements are defined as 'concentrated

sources of nutrients or other substances with a nutritional or physiological effect,

whose purpose is to supplement the normal diet' (398), they are not intended for

treatment of diseases but to maintain 'functions of the organism or to support health'

(399). Medicinal products are by definition of the European Union 'substances or

combination of substances for treating or preventing disease in human beings or which

may be used in or administered to human beings either with a view to restoring,

correcting or modifying physiological functions'(400).

Saw palmetto preparations are used to treat symptoms of BPH which is a disease (401)

and therefore should be regarded at least from a legislative point of view as medicinal

products and be registered. This regulatory framework applies not only for prescription

but also for non-prescription medication, the over-the-counter (OTC) products to which

herbal medicines belong (402).

Nevertheless, one could still argue that food supplements and herbal products are both

moderately efficacious and well tolerated and for that reason phytomedical

preparations should be available as food supplements. This would reflect for example

the U.S. American or Dutch situation for herbal medicinal products.

Regarding the heterogeneous results from this phytochemical analysis of saw palmetto

products I favour the approach to register these preparations also based on the

following considerations.

A registration allows not only to use an herbal product in a certain indication but

demands from the manufacturers to adhere to high quality requirements. The quality

part of a registration dossier for a traditional herbal medicinal product demands the

same data on quality as for any synthetical medication. This includes not only validated

production processes but also that a manufacturer has to provide stable products with

same uniformity of dose (402).

Andy Suter 132

Like this, the customer is protected from incorrect declarations on the packages and is

assured to obtain a good quality product for his or her disease. With the situation

present in many countries where herbal products are unregulated, patients are often

mislead regarding the amount of active constituents and declarations as could be

shown in this phytochemical analysis.

An often heard argument from opponents of a regulation for herbal medicinal products

is that this would confine the patient's freedom of choice for natural medicines and

that rather the public needs to be educated to differentiate between good and low

quality products instead of registrating them (403). These arguments are in reality

nothing more than excuses from companies which cannot provide good quality nor

clinical data for their preparations. A registration would answer the question about the

quality of a product and is much easier to carry out than a public education of

consumers.

Another reason why I advocate the registration of Sabal preparations and herbal

medicinal products is that they show generally moderate efficacy with a very good

safety profile. To guarantee this at least mite efficacy a good product quality is

mandatory, this can be reached best by registrations.

With this good benefit/risk ratio, herbal medicinal products could become at least in

Europe an interesting treatment alternative to synthetical drugs for several mild to

moderate disorders. It would be a pity if patients could not profit from this therapy

option - due to lack of quality.

Ar,dv 133

Chapter 4A clinical pilot study with saw palmetto in patients with BPH and concomitant sexual dysfunctions

Andy Suter 134

Chapter 4: Clinical pilot study

A clinical pilot study with saw palmetto in patients with BPH

and concomitant sexual dysfunctions

4.1 Introduction

The first U.S. American physicians using saw palmetto discovered that the plant was not

only efficacious in respiratory tract infections and genitourinary disorders but also as

treatment for sexual dysfunctions (SDys).

As outlined in chapter 2.3.2.3.2, already in 1880 the pharmacist Dixon indicated the use

of Sabal for 'sexual debility' (233), in 1885 a doctor Evans wrote that the plant had a

good effect on 'wasting of the testes', in his view the reason for impotence (167), and

Knapp in 1892 (235) and Davidson in 1895 (230) substantiated Sabal as treatment of

male SDys such as impotence or lack of drive. Also in current literature saw palmetto is

often cited as a herbal treatment for testicular atrophy (404, 405) and for erectile

dysfunctions (406) or as an aphrodisiac (407).

Nevertheless, even though the properties of saw palmetto on SDys are known only a

few clinical studies assessed this topic. Therefore I carried out a clinical pilot trial in BPH

patients with concomitant SDys to evaluate if a saw palmetto treatment could improve

BPH and SDys symptoms as well.

In the following, an overview is given about the epidemiology of male SDys, their

relation to BPH, the possible underlying pathophysiology, the detrimental effect of BPH

standard medication on SDys, and clinical data of saw palmetto in SDys.

A ndv Suter 135

C/.n.rCf'

4.1.1 Epidemiological data of SDys in the elderly male population

Generally, sexual functions are divided into the four domains desire (libido), erection

(arousal), ejaculation (force, volume) and orgasm/satisfaction (408). Until the begin of

the new millennium, it was assumed that SDys, meaning dysfunctions of one of the

above mentioned four domains in men are a natural consequence of the ageing

process. Recent studies showed that a decrease in sexual functions is not inevitably a

consequence of ageing (409). A variety of large-scale epidemiological studies showed

that BPH in particular is an important factor for SDys.

In a large epidemiological survey with 15'496 men aged between 40-69 years a clear

correlation between age and erectile dysfunctions and lack of libido was shown.

Whereas more than 60% of men aged 40 stated no erectile problems, only about 10%

of all men in the age group of 65-69 years were in the identical situation. The same

went for libido where 60% of all around 40 year old faced no problems but only around

18% of all men aged 65-69 years had still a good libido. The study did not investigate

the prevalence of LUTS as well but acts as a good marker for the general prevalence of

SDys. Interestingly, men with moderate to severe sexual problems were up to three

times more frequently seeing a doctor than those with none or light symptoms (410).

The most comprehensive trial to date which investigated LUTS and SDys was the

Multinational Survey of the Ageing Male (MSAM-7) study in 2003 with 12'815 men

aged between 50 and 80 years from the USA and six European countries. About 49% of

all men experienced erectile dysfunctions with a higher proportion in the USA (55%)

compared to Europe (45%) and around 45% of all patients suffered from ejaculatory

dysfunctions. LUTS were prevalent in around 90% of all patients. The more severe the

symptoms of LUTS, the more frequent and more severe the mentioned SDys occurred.

Age and LUTS were stronger risk factors for erectile dysfunction and ejaculatory

disorders than diabetes, hypertension, heart disease, or hyperlipidaemia (411).

A n d y S i ' t e r 136

In a large study carried out in Germany, the Cologne Male Survey, which examined

4489 men between 30 to 80 years, the overall prevalence of erectile dysfunctions was

19%. Interestingly, the incidence of LUTS was 72% in patients with erectile dysfunctions

versus 38% in those without erectile dysfunctions. In addition to age, diabetes,

hypertension, and pelvic surgery, LUTS was seen as an independent risk factor for

erectile dysfunction (412).

The same findings were observed in the UrEpik study which assessed the relationship

between erectile dysfunction and LUTS in 4800 men from the United Kingdom, the

Netherlands, France, and Korea. Erectile disorders were present in 21% of all men

which was significantly associated with age (p>0.001) and LUTS was seen as an

important co-factor for erectile dysfunctions and lack of libido (413).

LUTS as an important and independent comorbidity for erectile dysfunction was also

shown in a survey investigating 2476 men between 25-70 years in Spain (414) and a

study with 2412 men from Brazil, Italy, Japan and Malaysia aged 50 to 78 years also

reported that LUTS were the most significant predictor of moderate to severe erectile

dysfunctions (415).

Overall, the epidemiological studies presented a clinically significant association

between LUTS and various types of SDys in ageing men worldwide.

Rosen assumed from the epidemiological data that the relative risk of developing

erectile dysfunction is 3.7 higher in patients with BPH-symptoms than those without

symptoms in a time period of two years after first reporting them (409).

Andy Suter 137

4.1.2 Pathophysiology of sexual dysfunctions and BPH

The pathophysiologic mechanisms which lead to erectile dysfunction, ejaculatory

disorders, and lack of libido after enlargement of the prostate are still not clear and yet

not very well investigated.

There are several hypotheses on possible mechanisms of action for SDys caused by

BPH. One theory assumes that an imbalance in the autonomic control of smooth

muscle contraction may lead to SDys. The main reason for this might be an over

presence of al-adrenergic receptors in patients with LUTS in the prostatic capsule and

the bladder neck which results in an increased smooth muscle tone (416).

Noradrenaline is involved in the contraction of the penile tissues, in particular the

corpus cavernosum smooth muscle, via activation of al-adrenergic receptors which are

most probably regulated by androgens (417). Any impairment of these receptors may

therefore lead to erectile dysfunctions and ejaculatory disorders (409), also since

contraction and growth of vascular smooth muscle cells are mediated by al-adrenergic

receptors (418).

Another hypothesis states that endothelial dysfunction is a possible mechanism which

refers to impaired endothelium dependent relaxation (i.e. vasodilatation) due to

decreased activity of nitric oxide (NO) (419). Noardrenaline acts as the major

sympathetic neurotransmitter, whereas NO is the major parasympathetic

neurotransmitter. To produce an erection, the balance has to change: The

noradrenaline effect must be minimised and the NO effect increased (420).

In prostatic tissue from men with BPH, the innervation which leads to NO secretion

(nitrergic innervation) is decreased compared to normal prostatic tissue assuming that

this change in the endothelium leads to erectile dysfunctions (421).

A further risk factor to decrease endothelial function is chronic inflammations (422).

Since low grade systematic inflammations seem to be the connection between

metabolic syndrome, coronary artery diseases and erectile dysfunctions, anti

inflammatory therapy might be an additional treatment option for erectile problems

(423).

A n d / S u t e r 138

CA'n/rc/

Another theory assumes that a change in sex hormones impacts sexual functions. Data

from a longitudinal study, the Massachusetts Male Aging Study, with 1290 men

aged 40 to 70 years, showed that the serum levels of total testosterone,

dehydroepiandrosteron, cortisol, and oestrone decreased, whilst the levels of DHT, sex

hormone binding globuline, luteinizing hormone and prolactin increased during an

observation period of seven to ten years (424). Since hormones itself are produced and

secreted in one tissue but have the ability to regulate or induce signal cascades in their

target tissues either by enzyme activities or by the receptors (425) it is assumed that a

change in the concentration of these hormones may have an influence in the

pathophysiology of BPH and sexual dysfunctions (409).

If it is correct, that LUTS/BPH and SDys share a common mechanism, the optimal

treatment strategy would be a single agent which improves both conditions (411). Our

pilot study with saw palmetto tried to assess if saw palmetto could be one of these

desired therapies.

4.1.3 Sexual adverse events of BPH standard medication

As outlined in chapter 1.4.1.4, the main medical treatments for BPH symptoms include

alpha blockers such as tamsulosin, doxazosin, and alfuzosin (117) which provide fast

relief of LUTS symptoms (131) or the 5-alpha-reductase-inhibitors finasteride and

dutasteride, which lead to symptom relief after 6-9 months and are most favourable in

patients with large prostates (106). Both treatment options show beneficial effects on

BPH symptoms; however, they also each have a significant negative impact on sexual

functions.

The main SDys reported under alpha blocker therapy were retrograde or abnormal

ejaculation, which occurred in 4-18% of patients taking tamsulosin, with rise to 30%

during long term use (426), under silodosin treatment a rate of ejaculatory disorders of

28% ensued (427). Studies on 5-alpha-reductase inhibitors stated SDys with a frequency

of 2.1% to 38%, with erectile dysfunctions being most prominent, followed by

decreased libido and ejaculatory disorders (428). SDys were the most often observed

Andy Suter 139

adverse events under 5-alpha-reductase-inhibition, with similar frequencies reported

for finasteride and dutasteride (429).

The latest American Urological Association guideline on treatment of BPH

recommended the combination of an alpha blocking agent with a 5-alpha-reductase-

inhibitor for better efficacy but neglecting safety (197). Two trials assessing

combination treatments, one with dutasteride and tamsulosin (430), the other with

finasteride and doxazosin (134) showed that the incidence of sexual adverse events was

higher in the combinations than with monotherapy alone.

Summarised, a BPH patient is at a significant risk to cause or deteriorate existing SDys

by taking one or a combination of these standard therapies for prostate problems.

4.1.4 Data from clinical studies on saw palmetto in SDys

Five previous clinical trials of saw palmetto treatment for BPH also evaluated changes in

SDys as a secondary parameter, with mixed results. However, patients in these trials

had mainly BPH symptoms, not necessarily SDys as well. Using the International Index

of Erectile Function (IIEF), Willetts, 2003 observed a trend of improvement, with an

increase from 51.5 to 55.1 after 12 weeks of saw palmetto treatment compared to a

small decrease from 49.4 to 48.7 with placebo (431), and Sinescu et al. reported under

saw palmetto a significant improvement of the IIEF from 44.4 to 50.8 after 24 months

of treatment (432). In the trial conducted by Gerber (2001) patients had to fill out a

non-specified "sexual function questionnaire" which did not change either with placebo

or saw palmetto (433). In an open study, Bauer (1999) asked if the treatment had an

influence on patient's "sexual activity"; responses indicated that it mostly remained

unchanged with two patients reporting an increase (160). The placebo controlled Sabal

study from Barry et al. observed after 72 weeks of treatment no change in IPSS and

urinary flow rates and also not in the IIEF erectile function subscale (p=0.29) and in the

Male Sexual Health Questionnaire to assess ejaculatory dysfunction MSHQ-EJD (p=0.16)

(162).

Taken together, data from these trials is insufficient to show convincingly that saw

palmetto had a positive influence on BPH-related SDys.

Andy Suter 140

C/iGC'TEr CA'.'i.c o.' j ' u C i

4.1.5 Summary and Study Rationale

Epidemiological studies gave evidence that BPH is one of the strongest co-factors to

cause SDys in the ageing male population. Standard therapies for BPH symptoms like

alpha-blockers or 5-alpha-reductase inhibitors cause frequently sexual adverse events

and may so deteriorate existing SDys. Thus, therapies are sought which are efficacious

and safe in the treatment of BPH symptoms and SDys as well.

Historically saw palmetto was also used as treatment of male SDys but clinical trials

could not confirm efficacy in this indication so far for Sabal. In all the above discussed

saw palmetto studies, BPH symptoms were always the primary parameter which means

the patients could have suffered from SDys but they were never mandatory an

inclusion criterion.

Thus, the pilot trial presented here is the first study ever to investigate if saw palmetto

is efficacious and safe as treatment of SDys in BPH patients.

Andy Suter 141

C/?opfe/' 4; C//Vi/cn,' pA'ot

4.2 Material and Methods

4.2.1 Study design

The trial was initiated by the urologist Dr. Eugen Riedi, then head of the urology

department at the Kantonsspital Chur, Switzerland. He observed that BPH patients he

had prescribed a saw palmetto treatment often reported an improvement in their

concomitant SDys. Together with him and Prof. Reinhard Sailer, head of the Institute of

Complementary Medicine of the University hospital of Zurich, the study design was set

up (Table 11).

As this was a pilot trial to gain data for generation of hypotheses for a larger study an

uncontrolled study design was chosen. This open design was in accordance with other

pilot studies on SDys in BPH patients, for example from alpha blocking agents (434,

435).

The study period for our trial consisted of a one-week untreated run-in phase and a

subsequent treatment period of eight weeks. At each visit, efficacy parameters were

recorded as detailed below. The run-in phase was carried out to observe if BPH

symptoms and SDys remained stable. The treatment duration of eight week was chosen

since in other saw palmetto trials after this period already good results were observed

(118,436).

Andy Suter 142

Table 11: Study design of the p ilo t study w ith saw palm etto on SDys in BPH patients (Prostasan" Libido tria l)

Title Clinical p ilo t tria l to investigate the influence o f a saw palm etto berry preparation (Prostasan®) on sexual functions in patients w ith benign prostatic hyperplasia (Prostasan® Libido trial)

Phase IV (lllb )

Study number 920'136

Principal investigator Dr.med. Eugen Riedi, urologist, Chur, Switzerland

Other study centres About ten GPs or urologists in the cantons of Zurich, Berne, Grisons, St. Gallen and Zug in Switzerland

Reimbursement For each investigator: 500 Swiss franks/patient; fo r each patient: 100 Swiss franks/patient

Study duration per patient 1 week untreated, run-in phase; 8 weeks w ith trea tm ent (56 ± 5 days), to ta l 9 weeks

Number of patients At least 40 patients

Medication, dosage 1x1 capsule Prostasan® daily (320mg extract per capsule, 96%V/V ethanolic Serenoo repens berries extract)

Study design Open m ulticentric clinical tria l(planned to generate hypothesis fo r a larger tria l, thus a p ilo t tria l)

Inclusion criteria Patients w ith BPH and sexual dysfunctions (erectile dysfunction and/or decrease of libido) which existed fo r at least tw o months and are defined by:

• Age 18-80 years old• International Prostate Symptom Score IPSS Score >7• Sexual drive from bSFI (brie f Sexual Function Inventory) <5• Patient is not satisfied w ith his sexual performance• Notion and possibility to practise his sexuality (masturbation,

intercourse)• No organ-dependent damages which rule out the performance

of sexual activities.• Willingness to answer honestly to questions on sexuality• W ritten informed consent

Exclusion criteria Lack of libido which is due to a psychiatric disease or a depressive moodLack of libido in the judgm ent o f the investigator w ith in the last tw o monthsPatients w ith severe vascular disorders (microangiopathies)Severe diabetes mellitusPatients w ith hypertension who are on a stableantihypertensive medication fo r less than tw o monthsKnown neuropathiesKnown bad compliance o f the patientParticipation in a clinical tria l w ith in the last 2 month beforestudy startAlcohol-, drugs-abusePlanned surgeries w ith in the observation tim e

A S X 143

Not allowed concom itant medication:with the exception of stable application since at least 3 months:Application of 5-alpha-reductase inhib itorsApplication of alpha-antagonistsLong-term application of NSAIDs (synthetics andphytochemicals) and paracetamolApplication of synthetic antidepressive agentsRegularly application (>1 un it/2 weeks) o f phosphodiesteraseinhibitorsApplication of phosphodiesterase inhib itors less than 4 days prior to the study visit_____________________________________

Illicit concomitant medication

All of the following medication is not permitted if it has not been taken stable for at least during three months:5-alpha-reductase-inhibitorsalpha-blockerslong term intake of synthetical and herbal NSAID and paracetamol as well as synthetical antidepressants

Continuous intake o f phosphodiesterase-inhibitors, defined as more than one u n it/ tw o weeks, and intake of a phosphodiesterase-inhibitor less than four days prior to the first study visit

4.2.2 Investigators

More than 50 physicians in Switzerland were asked with a letter to participate in the

trial and followed up with a personal contact, in the end nine doctors agreed to take

part. Together with the main investigator, the urologist Dr. Eugen Riedi, a total of three

urologists and seven general practitioners were the study centres.

4.2.3 Patients

Eligible were ambulatory patients with a confirmed BPH diagnosis with at least

moderate symptoms measured with an IPSS>7 and not older than 80 years. They had to

fulfil the inclusion and the exclusion criteria as given in Table 11 and sign the informed

consent form after having read the detailed patient information on the study. The

participants were recruited by their physician, in each practice leaflets and a poster

about the trial were displayed to attract study participants.

144

C/iopfer 4; C/zVnro/ cfù'c')

4.2.4 Study medication

The patients received at the second visit a brown glass with 90 capsules of Prostasan®.

One capsule contained 320mg saw palmetto berry extract (batch: 025070) which was

extracted with 96% ethanol (V/V) and had a DER of 9.0-12.0 : 1. The berries were from

A.Vogel Bioforce's own organic certified cultivation in Florida, USA.

Patients had to take one capsule daily after eating, the time point for intake was not

defined. The compliance was checked by counting the remaining tablets at the final

study visit.

4.2.5 Questionnaires

4.2.5.1 Questionnaire for BPH symptoms

The main symptoms of BPH, which include static and dynamic components (100), are

increased frequency of urination with nocturia, difficulty starting and stopping

urination, weak urine stream, feeling that the bladder has not emptied completely with

residual urine, and in later stages urinary retention and painful urination (101). The

International Prostate Symptom Score IPSS is the validated standard instrument to

measure the severity of these symptoms (99) (Table 12). The investigator needed to fill

it out with the patient which takes about 10-15 minutes time. A validated German

version was available and used in this trial (437).

Andy Suter 145

Table 12: The International Prostate Symptom Score IPSS (99)

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1. Incomplete emptyingOver the past month, how often have you had a sensation of not 0 1 2 3 4 5emptying your bladder completely after you finish urinating?

2. FrequencyOver the past month, how often have you had to urinate again 0 1 2 3 4 5less than two hours after you finished urinating?

3. IntermittencyOver the past month, how often have you found you stopped and 0 1 2 3 4 5started again several times when you urinated?

4. UrgencyOver the last month, how difficult have you found it to postpone 0 1 2 3 4 5urination?

5. Weak streamOver the past month, how often have you had a weak urinary 0 1 2 3 4 5stream?

6. StrainingOver the past month, how often have you had to push or strain to 0 1 2 3 4 5begin urination?

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7. NycturiaOver the past month, many times did you most typically get up to 0 1 2 3 4 5urinate from the time you went to bed until the time you got up inthe morning?

Total Score

A total score of 0-7 indicates mild, 8-18 moderate, and above 18 points severe BPH

symptoms. To assess irritative symptoms the points of questions 2, 4, and 7 are

summarised and for the obstructive symptoms the scores are added of the questions 1,

3, 5, and 6. Nocturia is evaluated only with the single score of question 7.

146

Cnnpfer ' C/ n/i 0/ r.'.'or ; ;

4 2.5.2 Questionnaires for sexual dysfunctions

Attempts to measure human sexual functions appeared first in literature in the early

1960's (438). The central problem lied first in the definition of a SDys since sexual

functioning, hypoactive sexual desire disorder, and sexual satisfaction are merely

hypothetical constructs. Therefore the measurement of these parameters and the

instruments used are generally not as powerful as those used in physical sciences (439).

The current instruments, namely questionnaires, are mostly a product of the thinking of

Masters and Johnson (440, 441), a team which pioneered in the research of diagnosis

and treatment of SDys, and Helen Kaplan who examined hypoactive sexual desire and

so called 'inhibited sexual desire' (442). With their knowledge the sexual response cycle

was defined which strongly emphasized on the above mentioned phases of desire,

arousal, orgasm, and resolution (408). In this model a dysfunction or disturbance may

occur in any or multiple phases of the cycle and the diagnosis is usually made without

statement of the aetiology (439).

For setting up the design of this clinical trial, I investigated and compared available

validated questionnaires for male SDys which are discussed in the following.

4.2.5.2.1 The Derogatis Interview for Sexual Functioning (DISF/DISF-SR)

The Derogatis Interview for Sexual Functioning (DISF/DISF-SR) is an instrument

designed to assess an individual current sexual functioning. It consists of 25 questions

and is available for men and women as separate issues and covers five separate

domains which are sexual cognition/fantasy, sexual arousal, sexual

behaviour/experience, orgasm and sexual drive (443). As this score is also dedicated to

areas such as relationship and behaviour but not mainly on male SDys and is with 25

questions too long to apply, it was not selected for the planned clinical trial.

Andv Suter 147

Chapter 4: Chnical pi lot study

4.2.5.2 2 The Arizona Sexual Experience Scale (ASEX)

The Arizona Sexual Experience Scale (ASEX) is a self reporting inventory to evaluate

SDys in men and women covering the items drive, arousal, penile erection/vaginal

lubrication, ability to reach orgasm, and satisfaction with orgasm (444). The limitations

of this instrument are that it was developed for patients taking psychotropic drugs and

not many epidemiological data is available.

4.2.5 2.3 The International Index of Erectile Function (IIEF)

The International Index of Erectile Function (IIEF) has become the standard

questionnaire in assessing erectile dysfunctions and was used so far in more than 50

clinical trials (439). Patients have to fill out 15 questions covering erectile function,

orgasmic function, sexual desire and satisfaction, and overall satisfaction (445). Even

though this instrument is sensitive, highly reliable and also very well available, it was

not selected for this trial as it only focuses on erectile functions.

4.2.5.2.4 Urolife BPH QoL9-questionnaire

A simple, reliable instrument for the measurement of SDys related to BPH is the

subscale for 'patient's perceived sexual life' of the Urolife BPH Quality of Life 9-

questionnaire (Figure 21). The total score consists of nine questions covering quality of

life items, the subscore on SDys consists of three questions covering sexual desire,

satisfaction with erections, and satisfaction with sex life which have to be answered on

a 10 cm visual analogue scale (446). The score ranges from 0 to 300 or from 0 to 30.

The Urolife BPH QoL-9 'patient's perceived sexual life' subscale is recommended for the

evaluation of SDys in BPH (447), easy to apply, and validated patient data from a large

trial with 2289 men with BPH are available (448).

Due to its validity and easy application, I decided to use this instrument in this pilot trial

with saw palmetto. In the following, this 'patient's perceived sexual life' subscale will be

abbreviated as 'Urolife BPH QoL-9 sex'.

Andy Suter 148


Figure 21: Urolife BPH QoL9-subscale 'patient's perceived sexual life ' (from (446)). Patients have to mark the intensity of the corresponding item.

You are satisfied with yourCurrently your sexual desire is

erectionsYou are satisfied with your sex life

STRONG

WEAK

VERY SATISFIED

NOT SATISFIED AT ALL

FREQUENTLY

RARELY

4.2.5.2 5 brief Male Sexual Function Inventory (bSFI)

The other questionnaire chosen for this study to assess efficacy was the brief Male

Sexual Function Inventory (bSFI). It consists of two questions on sexual drive, three on

erections, two on ejaculations, three on problems in each area, and one on overall

satisfaction (Figure 22). The instrument is easy to apply, well understandable and takes

about 10-15 minutes per patient to fill out alone.

Andy Suter 149

Chapter 4: Clinical p ilo t study

Figure 22: The brief Sexual Function Inventory bSFI questionnaire (4)

Sexual Drive

Let’s define sexual drive as a feeling that may include wanting to have a sexual experience (masturbation or intercourse), thinking about having sex, or feeling frustrated because of lack of sex.

No days Only a few days

Some days Most days Almost every day

1. During the past 30 days, on how many days have you felt sexual drive? B 0 1 1 B

None at all Low Medium Medium high High

2. During the past 30 days, how would you rate your level of sexual drive? B 0 1 1 BErections Not at all A few times Fairly often usually always

3. Over the past 30 days, how often have you had partial or full sexual erections when you were sexually stimulated in any way?

B 0 1 1 B

4. Over the past 30 days, when you had erections, how often were they firm enough to have sexual intercourse?

B 0 1 B BDid not get erections at

all

A lot of difficulty

Somedifficulty Little difficulty No difficulty

5. How much difficulty did you have getting an erection during the past 30 days?

B 0 1 1 B

EjaculationHave had no

sexual stimulation in past month

A lot of difficulty

Somedifficulty Little difficulty No difficulty

6. In the past 30 days, how much difficulty have you had ejaculating when you have been sexually stimulated?

B 0 1 B BDid not climax

Big problem Mediumproblem

Smallproblem

No problem

7. In the past 30 days, how much did you consider the amount of semen you ejaculate to be a problem?

B 0 B B

Problem Assessment Big problem Mediumproblem

Smallproblem

Very small problem No problem

8. In the past 30 days, to what extent have you considered a lack of sex drive to be a problem?

B 0 I B B9. In the past 30 days, to what extent have you considered your ability to get and keep erections to be a problem?

B 0 I B B10. In the past 30 days, to what extent have you considered your ejaculation to be a problem?

B 0 § B BOverall satisfaction Very

dissatisfiedMostly

dissatisfiedNeutral or

mixedMostly

satisfiedVery satisfied

11. Overall, during the past 30 days, how satisfied have you been with your sex life?

a 1 a

Andy Suter 150

Chapter 4: Ci inicai p i i c t s tudy

It is a thoroughly validated instrument which evolved in the validation process from a

41-item questionnaire to a score with 11 questions (4).

An advantage of using the bSFI in this pilot trial is that it was already used in two large

epidemiological studies. O'Leary and his colleagues tested 2'115 men aged 40 to 79

years (449) and a survey investigated in Norway 1185 men between 20 to 79 years

(450) both with the bSFI and thus good epidemiological data for comparison is

available.

Two questionnaires, the bSFI and the Urolife BPH QoL-9 sex were used instead of only

one to achieve a better soundness of changes in SDys. No validated German version

was available for the Urolife BPH QoL-9 sex - and the bSFI questionnaire, and thus they

were first translated to German by two independent translators. From these two

translated versions, one German version was compiled, which was then re-translated to

English by two other translators, to be compared to the original version. The German

version was then corrected and used by a German speaking doctor in his daily practice.

Based on his experiences, further corrections were made and final versions of the

German scores completed.

4.2.6 Assessment of adverse and serious adverse events

An adverse event is defined as any untoward medical occurrence in a patient and does

not need to have a causal relationship to the treatment (451). Any occurring adverse

event needed to be documented on a special form in the case record form where the

following items were noted: Nature of the adverse event, seriousness, date of onset,

severity (light, medium, severe), relationship to treatment, measures taken, outcome,

end of the adverse event, and if a concomitant medication had been given for

treatment of the adverse event.

A serious adverse event is any adverse event which is lethal, life threatening, leads to

hospitalisation or prolongs a hospitalisation, causes continuous damages, as well as any

malignant deformation or congenital anomaly (451).

Serious adverse events had to be reported within one workday on a special form by fax

to A.Vogel Bioforce AG and the responsible ethical committee.

Andy Suter 151

4.2.7 Assessed parameters

Changes in BPH symptoms were evaluated using the IPSS, SDys with the bSFI and the

Urolife BPH QoL-9 sex questionnaire. At end of the treatment, global assessment of

efficacy by patient and investigator was given on a four point scale (very good, good,

moderate, or unchanged). Additionally, it was examined if the patient observed the

best effect of the treatment on libido, erections or both and about the patients' daily

routines. Patients were asked the practice and policy questions if they would take the

medication again, how important it was for them to use a herbal treatment, and

whether they would prefer a herbal remedy over a synthetic compound. Investigators

were addressed if they would use the test medication again and were asked to provide

reasons if they answered affirmatively.

Safety parameters included the occurrence of adverse events and the global

assessment of safety by patient and investigator at the end of the treatment as very

good, good, moderate, or poor.

4.2.8 Quality Standards and patient's safety

The study was carried out according to the provisions of Good Clinical Practice GCP

(452) which is a legally binding law for Switzerland written down in the regulations for

clinical trials, the 'Verordnung für klinische Studien, VKlin' (453) and the ethical

obligations of the Declaration of Helsinki were also respected (454).

The trial was approved by the cantonal ethical committees of the cantons St. Gallen on

the 13 of May 2009, from Zurich and Grisons on the 30 * of June 2009, from Zug on

the of August 2009, and from Berne on the 27 of August. The Swiss regulatory

authority Swissmedic notified the study on the 6 of August 2009, the trial is registered

in the international clinical trial registry ClinicalTrials.gov, identifier number

NCT01021267. The School of Pharmacy Research Ethics Working Group was informed

about the trial on the 16 of July 2009, they confirmed the acceptance of the

information on the 5 of August 2009.

Andy Suter 152

C/iopfe/- 4; CAn/co/ p.Vcf' j Tuc')

Each study participant was covered by an insurance (Gerling, Policy Nr. 01050561-

14042) against any potential harmful event, which could have taken place throughout

the whole study. The whole trial was insured for the sum of 10 million Swiss franks and

one single patient for personal harm up to 1 million Swiss franks.

Furthermore, A.Vogel Bioforce guaranteed that damages which would exceed the sum

of 1 million per patient would be covered by the company itself and its liability

insurance.

The study could be terminated at any time by a single patient without giving details or

reasons why.

During the trial I visited each physician thrice for monitoring of the data quality and to

assure the study procedure was carried out as outlined in the study protocol.

4.2.9 Statistical anaiysis

All variables measured in the study, were described descriptively using Excel and SAS

Version 9.2. For continuous variables, the following descriptive statistics were

calculated: mean, standard deviation, number non-missing, median, 25 percentile,

75 percentile, minimum, and maximum. For categorical or binary variables, absolute

and relative frequencies were displayed.

For the outcome measures IPSS, bSFI and Urolife BPH QoL-9 sex within group

comparisons of changes from visit 1 to visit 2, from visit 1 to visit 3 and from visit 2 to

visit 3 were performed using the Wilcoxon test for paired differences. Correlation of

changes between IPSS and bSFI, between IPSS and Urolife BPH QoL-9 sex and between

bSFI and Urolife BPH QoL-9 sex were analysed calculating Pearson's coefficient of

correlation.

All statistical analyses were checked for correctness by Peter Klein from the d.s.h.

statistical services GmbH, Rohrbach, Germany.

An outline on the study procedure for every patient is given in Table 13.

Andy Suter 153

Table 13: Study procedure for a patient

Patient in form ation and informed consent

Check o f inclusion and exclusion criteria

Documentation o f diagnostic criteria

Documentation o f concom itant therapies

Documentation o f concom itant medication

Filling out o f IPSS

Filling out o f bSFI

Filling out o f Urolife BPH QoL-9 sex

Handing out of study medication

Assessment of efficacy by investigator and patient

Assessment o f to le rab ility by investigator and patient

Documentation o f adverse events

Questions fo r practice

Return of test medication

Reimbursement fo r travel costs and study participation

Run in phase

Treatment phase

Visit 1

(d a y -7 )

X

X

X

X

X

X

X

X

Visit 2 Visit 3

(dayO) (day 56±5)

A nd y Suter 154


4.3 Results

4.3.1 Patients and centres

Eighty two patients were included in the trial between June 24 2009 and October 29 '

2010. This was the period from inclusion of the first patient until final visit of the last

study participant. Only six of the ten study centres recruited participants, whereas

centre 7, a practice specialised in complementary medicine in the centre of Zurich

recruited the majority of the patients (Figure 23). The baseline characteristics of the

patients from this one centre did not differ significantly from those form the other

centres.

Figure 23: Number o f patients per study centre, the blue bars comprise the in tention to trea t- (n=84), the red bars the per protocol population which was used fo r the efficacy anaylsis (n=69)

7 0 1

ro 4 0

^ 30

C e n tre 1, u ro log ist C e n tre 3, GP C e n tre 5, u ro log ist C e n tre 7, GP C e n tre 8, GP C e n tre 9 , GP

The patient population was separated for the analysis in three sub-populations. The

safety population which was used for safety analysis comprised all patients who were

included and treated once, the intention to treat (ITT) - population those patients who

had additionally at least one efficacy assessment, and in the Per Protocol (PP)-

population were all patients which completed the study without one major protocol

violation which was defined as use of less than 80% or more than 120% of the study

Andy Suter 155

CAn/'co/

medication, treatment duration less than 51 days or longer than 63 days, and violation

of an exclusion or inclusion criterion. The safety and the ITT population were identical

with the totally recruited 84 patients.

Thirteen patients had at least one major protocol deviation and were excluded from

the PP population which was used for final analysis with 69 patients. Deviations

included one patient with IPSS <7 at inclusion, one with sexual drive component of bSFI

>5 at inclusion, four patients with disallowed concomitant medication, and seven

patients who did not return to the participating practice after the first visit. Reasons for

discontinuation of treatment included one instance of the death of a patients wife, two

adverse events (nausea that was seen as related to the study medication and an

unrelated transient ischemic attack), and in four cases patients did not show up at all to

the follow-up visits.

The demographic parameters of the ITT- and the PP-population were comparable thus

to take the PP as the population for efficacy analysis was justified (Table 14).

Andy Suter 156


Table 14: Demographic characteristics of the Intention to Treat and the Per Protocol population

Number of patients 82 69

Age (mean ± SD) 56.6 ± 11.4 years 5 7 .3 1 1 1 .1 years

Age (median) 60.0 years 60.0 years

Body weight (mean ± SD) 79.5 ± 1 2 .5 kg 8 0 .3 1 1 3 .0 kg

Systolic blood pressure (mean ± SD) 132.5 ± 14.1 mmHg 132.5 1 1 4 .8 mmHg

Diastolic blood pressure (mean ± SD) 84.9 ± 8.4 mmHg 84.3 1 8 .3 mmHg

Heart rate (mean ± SD) 7 1 .8 1 1 1 .5 bpm 71.4 11 1 .2 bpm

IPSS at inclusion 1 4 .4 1 4 .9 1 4 .6 1 4 .9

Total bSFI at inclusion 2 2 .2 1 7 .3 2 2 .0 1 7 .7

Total Urolife BPH QoL-9 sex at inclusion 139.7 1 50.6 1 3 8 .1 1 4 7 .9

Age distribution (N)

Age 21-30 years 1 ( 1.2%) -

Age 31-40 years 6 ( 7.3%) 5 (7.2%)

Age 41-50 years 19 ( 23.2%) 16 (23.2%)

Age 51-60 years 21 ( 25.6%) 19 (27.5%)

Age 61-70 years 28 ( 34.1%) 22 (31.9%)

Age 71-80 years 7 ( 8.5%) 7 (10.1%)

Twenty seven of all patients were treated with a concomitant medication at baseline

visit, none took a PDE-5-inhibitor. Only six participants changed the medication during

the treatment period, in all other patients the concomitant treatment remained stable.

Compliance during the treatment period was assessed as good when 80-120% of the

test medication was taken; 78.6% of the patients fulfilled this criterion, only 7.1% of the

participants took less than 80% of the medication.

Andy Suter 157


4.3 .2 Efficacy

For all efficacy parameters there was no statistically significant difference between the

first and the second visit showing that the symptoms were stable in the treatment free

run-in week. In the following only efficacy data from the treatment phase, means from

visit 2 to visit 3 will be shown.

4.3.2.1 International Prostate Symptom Score IPSS

The IPSS was reduced by 51%, from 14.4 ± 4.7 to 6.9 ± 5.2, after 8 weeks of treatment

(P< 0.0001) (Figure 24).

Figure 24: Change o f International Prostate Symptom Score IPSS between the start and end o f treatm ent (Per Protocol population, n = 69; P < 0.0001)

COCOo_

20 1

16 -

12 -

8 -

4 -

day 0

day 56

0

A score between 0-7 is defined as mild, 8-19 as moderate, and 20-35 as severe BPH

symptoms. At the beginning of the treatment, 18.8% of all patients had severe and

78.3% had moderate symptoms; by the final visit, this shifted to 63.8% patients with

mild, 31.9% with moderate, and only 4.3% with severe symptoms.

Looking at the single items contributing to the score, they were all significantly

improved to the same extent except for nycturia which had the lowest relative change.

Andy Suter 158


The average nycturia score changed from 1.7 ± 1.1 to 1.0 ± 0.8, the obstructive sub

score from 8.1 ± to 3.9 to 3.7 ± 3.7, and the irritative sub score from 6.3 ± 2.6 to 3.2 ±

2.3. Figure 25 shows the relative change of all single IPSS items and the sub scores

(Figure 25).

Figure 25: Relative changes o f the single IPSS items and the subscores from visit 2 to visit 3 (Per Protocol population, n=69). All changes were statistically significant (p<0.05)

I

Incomplete emptying

Urgency

Nycturia

Frequency

Weak stream

Obstructive subscore

■ Interm ittency

Straining

ir Irrita tive subscore

Andy Suter 159

Chapter 4: Clinical pilo t study

4.3.2.2 Brief Sexual Function Inventory (bSFI)

The total bSFI score improved from 22.4 ± 7.2 to 31.4 ± 9.2 (P < 0.0001) (Figure 26).

Figure 26: Improvem ent o f brief Sexual Function Inventory bSFI at start and end of therapy (Per Protocol population, n = 69; P < 0.0001)

40 -

30 -

.o 20 -

10 -

0

day 0 day 56

The single item scores for sexual drive, erectile function, ejaculatory function, problem

assessment, and sexual satisfaction were each also significantly improved (P < 0.0001)

(Table 15).

Table 15: Single item scores of the bSFI and Urolife BPH QoL-9 sex at the start and end o f trea tm ent (n = 69)

Score item w ith range (min-max)Start o f treatm ent

day 0End o f trea tm ent

day 56P-value

bSFI

Sexual drive (0-8) 2.0 ±0 .8 2.9 ±0 .9 <0.0001

Erectile function (0-12) 6.2 ±3 .0 8.5 ±3 .5 <0.0001

Ejaculatory function (0-8) 5.0 ±2 .0 6.3 ±2 .4 <0.0001

Sexual problem assessment (0-12) 5.8 ±2 .4 9.2 ±3 .0 <0.0001

Sexual satisfaction (0-4) 2.0 ±0 .8 2.9 ±0 .9 <0.0001

Urolife BPH QoL-9 sex

Sexual drive (0-100) 48.7 ±20.6 66.1 ±20.0 <0.0001

Erections (0-100) 45.0 ±21.0 65.2 ±24.2 <0.0001

Sexual satisfaction (0-100) 43.6 ± 19.7 63.7 ±22.4 <0.0001

* Wilcoxon signed rank test

Andy Suter 160


The biggest relative improvements in single questions were seen in the problem

assessment domain, where "getting and keeping an erection" improved by 64%, and

"having problems with lack of drive" and "ejaculation" each increased by 54%. "Feeling

sexual drive within the last 30 days" progressed by 47% and "having an erection firm

enough to have sexual intercourse" was scored as 42% better, which, in absolute

values, is a change from below "fairly often" to "usually"(Figure 27).

Figure 27: Single item scores o f the bSFI at the start and end o f treatm ent, normalised to a scale o f 0-10 (0 = worst state, 10 = best) (PP population, n = 69)

Sexual drive •start of treatm ent

end of treatm ent

Sexualsatisfaction

V Erectile / function

Sexualproblem

Ejaculatoryfunction

assessment

There was a centre effect, as mean values of the centre with the most patients

exhibited a significant improvement, whereas the other 15 patients pooled together

from the other centres only exhibited a trend (P = 0.12). Of these 15 patients, eight saw

an improvement, four no change, and three a worsening of their state, whereas the

vast majority of the patients from the single centre experienced at least some

improvement of their SDys.

Andy Suter 161


4.3.2.3 Urolife BPH QoL-9 sex

The results were first published incorrectly in the Phytotherapy Research as the value of

0 was rated as the most severe symptom and 100 as being symptom free (455) but

were corrected with an erratum.

The Urolife BPH QoL-9 sex total score saw an improvement from 137.3 ± 47.9 to 195.0 ±

56.3 (P< 0.0001) (Figure 28).

Figure 28: Improvement o f The Urolife BPH QoL-9 sex to ta l score between the start and end of therapy (Per Protocol population, n = 69; P < 0.0001)

day 56

O' 150

= 100

Contrarily to the bSFI, the improvements in Urolife BPH QoL-9 sex were significant at all

centres. All three single questions were also statistically significantly improved, as

detailed in Table 14.

Figure 29 shows the relative changes from begin to end of treatment in both scores for

SDys with the single sub scores (Figure 29).

Andy Suter 162


Figure 29: Relative im provem ents of the bSFI and Urolife QoL-9 sex to ta l scores and single items between begin and end of trea tm ent (PP-population, n=69)

70

60

50

40

30

20

10

Urolife QoL-9 sex

Andy Suter 163


4.3.2.4 Global assessment of efficacy

The majority of the patients rated the efficacy as very good (22%) or good (54%) and

only 15% saw a small effect. The investigators assessed efficacy more favourably,

reporting 38% of the cases as being very good, 44% good, and only 7% patients with

unchanged condition (Figure 30).

Figure 30: Assessment of efficacy at end of trea tm ent by patient and investigator fo r the PP- population (n=69)

unchanged

■ moderate■ good■ very good

60 n

50 -

40 -

^ 30 -

20 -

10 - - '.,1" ': i..

0 - * 1Patient Investigator

When asked on what parameters the study medication had the best effect, 8% of the

patients indicated erectile function, 26% libido, and 66% erectile function and libido

together.

4.3.3 Acceptance and practice and policy questions

Of the total 82 patients, 62 patients would take the capsules again (data are missing

from six patients) and in 91% of all cases the investigators would use the medication

again.

For 61% of the patients, it was very important that the medication was of herbal origin

and 97% of them would, given the same efficacy and safety, prefer a herbal to a

synthetic drug. Investigators stated that the most important reason to apply this saw

Andy Suter 164


palmetto preparation was the good safety assessed in 95% of all cases, followed by the

efficacy observed in 93% of patients.

4 .3 .4 Safety

Five patients reported six adverse events, including nausea, eructation, and acid

regurgitation, all of which were mild in nature and seen as related to the study

medication, and two incidents of a transient ischemic attack in the same patient and a

mild pruritus, which were not related to the study medication. From the total 82

patients, data from six patients were missing on the safety assessment; from the

remaining patients, 89.5% rated tolerability as very good and 6.6% as good. Similarly,

investigators regarded tolerability in 90.8% of the cases as very good and 5.3% as good

(Figure 31).

Figure 31: Assessment o f to le rab ility at end o f trea tm ent by patient and investigator fo r the safety population (n=82), values from six patients are missing

80

70 -

60 -

40

E 30 -

20 -

10

bad moderate

good ■ very good

Patient Investigator

Andy Suter 165

4 .3 .5 Subgroup analyses

The mean total bSFI improved significantly in centre 7, the general practice recruiting

the majority of study participants, but not in the average in all the other study centres.

Therefore, sub analyses were carried out to assess if the patient population of centre 7

was different than that of all the other centres.

Baseline characteristics for age, body weight, blood pressure, heart rate, as well as for

initial IPSS, total bSFI, and total Urolife QoL-9 sex score were not significantly different

between the 54 patients from centre 7 compared to the other 15 patients. The IPSS

decreased in participants from centre 7 in the average by 8.43 points, in all the other

centres by 4.33 points. The total bSFI improved in almost all patients in centre 7 (98.1%)

and in 53.3% of all other study participants, but a big part of these patients (40%)

experienced already an improvement in the treatment free run in-phase. Thus when

compared the total bSFI between visit 1 and visit 3, for 73.3% of these patients an

improvement was observed. Also the administration of co-medication was not different

between the study participants from centre 7 compared to all the other patients.

The main difference was that centre 7 was a well known practice in Zurich specialised

on complementary medicine and it was easy for the physician to recruit patients. The

other investigators reported that they barely found patients who were eager to

participate in the trial.

Because of the small patient numbers per centre, no distinct pattern or parameters

could be elucidated why some of them showed not the same improvement in the bSFI

than those from centre 7.

Additional subgroup analyses were performed for all patients by using age, symptom

severity, and concomitant medication as co-factors for efficacy.

They showed that patients with a higher IPSS at inclusion (IPSS 20-35) exhibited better

improvements in their bSFI (P = 0.029) and in their Urolife QoL-9 sex (P = 0.031) values

than did patients with lower IPSS (8-19). Comparing younger patients (21-50 years) to

older patients (51-80 years) did not reveal a significant difference regarding changes of

IPSS, bSFI, and Urolife QoL-9 sex, nor did concomitant medication have an influence on

these parameters.

Anc'v Suter 166


4.3 .6 Correlation analysis o f changes and relationship betw een bSFI and

Urolife QoL-9 sex score

In cooperation with the statistician Peter Klein, I carried out correlation analyses to

assess if changes in IPSS, bSFI, and Urolife Q.oL-9 sex were associated. Reason was to

see firstly, if the known influence of BPH symptoms on SDys was linearly related and

secondly, if for an assessment of total SDys symptoms rather the easier to fill out

Urolife QoL-9 sex score than the bSFI could be used.

There was a negative correlation between changes from visit 2 to visit 3 in the IPSS

score and the bSFI (Pearson's rho = -0.366; P = 0.002) (Figure 32) and between changes

in the IPSS and the Urolife QoL-9 sex (Pearson's rho = -0.365; P = 0.002) (Figure 33),

indicating that less urinary problems were associated with better assessment of sexual

function. Both correlations were statistically significant but of rather moderate extent.

Correlation between change in IPSS and changes in bSFI - Per-Protocol population

30A Change V1 vs. V2 (N = 69)• Change V1 vs. V3 (N = 69)■ Change V2 vs. V3 (N = 69)

20

Li_CO-Q0)O)c05x:O

-10-20 -15 -10 5 0 5

Change IPSS

Andy Suter 167

Chapter 4: Clinical p ilot study

Figure 33: Correlation between change in IPSS and changes in Urolife QoL-9 fo r all visits. PP-population (n=69)

OO

&TOÜ

200

150

100

50

0

-50 Change V I vs. V2 (N = 69) Change V I vs. V3 (N = 69) Change V2 vs. V3 (N = 69)

-100-20 15 -10 5 0 5

Change IPSS

Furthermore, there was a more pronounced positive correlation between the bSFI and

Urolife QoL-9 sex, showing that both questionnaires were valid for evaluating SDys and

consequently assessed changes to the same degree (Pearson's rho = 0.607; P < 0.0001)

(Figure 34)

F Correlation between change in bSFI and changes in UQol - Per-Protocol population

200

150

100—I

83500)D)cTO

s zÜ

-50 Change V I vs. V2 (N = 69) Change V I vs. V3 (N = 69) Change V2 vs. V3 (N = 69)

-1005 0 5 15 20 2510

Change bSFI

Andy Suter 168

C.'.'i.'rrN?

A further regression analyses of the subdomains of the bSFI and Urolife QoL-9 sex

based of actual scores showed that the erection sub scores of both questionnaires were

correlated best at visit 3 (Pearson's rho = 0.806; P < 0.0001). A good correlation is given

with a Pearson's rho of > 10.7 [ (456).

The sexual drive subscale of the bSFI and Urolife QoL-9 sex score (Pearson's rho =

0.645; P<0.0001) and the Urolife satisfaction and the bSFI satisfaction subscale

(Pearson's rho = 0.657; P<0.0001) were thus comparatively weaker correlated

compared to the total score and the erection sub scores, showing a rather moderate

but still significant correlation.

The Urolife QoL-9 sex satisfaction question was less prominently correlated to the bSFI

problem assessment sub score (Pearson's rho = 0.559; P<0.0001).

An analysis using the Spearman coefficient which is used in non-normally distributed

data yielded about the same results as with the Pearson's coefficient.

Summarised, the analysis showed a good correlation of BPH symptoms and SDys

measured either with the bSFI or the Urolife QoL-9 sex score. The two total scores for

SDys correlated well and also the sub scores for erection, sexual drive, and satisfaction.

5:;r 169

Chapter 4: Ctinical p i l o t r t u c y

4.4 Discussion

In this pilot trial we wanted to assess if a saw palmetto berry preparation had an

influence on both, prostate symptoms and SDys. We first examined the improvement in

BPH symptoms as measured with the IPSS, which is the standard instrument to quantify

severity of BPH symptoms (99). We saw a greater than 50% reduction, indicating a good

treatment response that was in the range observed for saw palmetto treatments in

other trials on BPH and larger than the effect of placebo. A survey of seven clinical trials

for a lipophilic saw palmetto preparation with a total of 2555 patients described an

average treatment duration of 300 days and a mean initial IPSS value of 14.72. At the

end of the treatment, IPSS was reduced on average by 31.2% (457). In two other clinical

trials, 320mg lipophilic saw palmetto berry extract was used daily and, after 6 months,

the IPSS was reduced by 26.3% (433) and 37% (160) with respective reductions under

placebo of 13.9% and 13.6%.

Secondly and more importantly, we assessed whether the treatment had a positive

influence on concomitant SDys.

To determine this, it was important to confirm at inclusion that the patients in our trial

definitely suffered from SDys; all patients here had obvious SDys, based on

comparisons of the initial values from the bSFI and the Urolife QoL-9 sex in our trial

with epidemiological data.

O'Leary (2003) observed an average total bSFI score of 27.7 in a population of 1883,

>50-year-old men in the United States (449), whereas in our study the same age group

had a lower initial value of 20.1. In another study the patients with ages of 36.9 ± 12.0

years displayed an average total bSFI of 33.5 ± 2.2 (458) compared to the total initial

bSFI of 26.3 ± 6.6 observed in our 21-50-year-old patients. A large study of 2829 LUTS

patients with an average age of 65.9 years evaluated Urolife QoL-9 scores and found an

for the Urolife QoL-9 sex an initial total value of 8.8 ± 0.1 (scale 0-30) (448), while in our

study an initial score of 130.0 ± 47.0 (scale 0-300) was recorded for the 51-80 year

patient group.

Andy Suter 170

Saw palmetto showed a significant improvement of SDys in this study population. Both

scores for SDys changed significantly, the bSFI by 41% and the Urolife QoL-9 sex by

42.0%.

Looking at the sub scores "sexual drive" and "erectile function", almost the same

degree of improvement was seen for both scores, with 35.3% and 37% in the bSFI and

35.7% and 44.9% in the Urolife QoL-9 sex, respectively. The major difference between

these two scores is caused by the more weighted problem assessment domain of the

bSFI. It has been shown that both questionnaires are equally sensitive in assessing

sexual dysfunctions, which was also substantiated by the correlation analysis.

Interestingly, we observed that it was almost impossible for patients to fill out the bSFI

without a doctor's help, whereas the Urolife QoL-9 sex was quite easy for patients to fill

out alone.

In summary, we have shown for the first time that a saw palmetto intervention in

patients with BPH and SDys had a beneficial influence on both BPH symptoms and on

SDys.

Our efficacy results are of further importance when considering the other available

options for simultaneous treatment of LUTS and SDys. It is currently debated whether

alpha blockers or phosphodiesterase (PDE) inhibitors may be beneficial for treating

symptoms of both disorders. Experimental models showed that al-adrenergic agents

may improve erectile dysfunctions by influencing the balance between contraction and

relaxation of the corpus cavernosum smooth muscle, of which, relaxation leads to an

erection (459). On the other hand, experimental data also indicates that NO synthase

and NO could play important roles in tissue from the urethra, corpus cavernosum,

prostate, vas deferens, and bladder neck (460). Reduced concentrations of NOS/NO in

the prostate and bladder increase smooth muscle tone and may improve prostatic cell

proliferation (461), indicating that PDE-5-inhibitors, which increase the NO

concentration, may have positive effects on LUTS.

Andy Suter 171

C/7Qpfe'' 4'

Initial clinical trials were carried out with alpha blockers or PDE-5-inhibitors (462).

Clinical data with alpha blockers, however, showed a good treatment effect on BPH

symptoms but only a small positive influence on SDys. In a clinical trial where patients

with moderate to severe BPH symptoms took lOmg alfuzosin for six months, the IPSS

decreased from 18.93 to 9.59 points and the Male Sexual Health Questionnaire MSHQ

ejaculation sub score improved from 23.09 to 21.54; this was statistically significant,

but the clinical relevance remains doubtful with an improvement only of about 7%. The

overall number of patients with moderate to severe erectile dysfunctions decreased

from 35% to 22% (434).

These results were not confirmed in another trial where patients with BPH symptoms

took lOmg alfuzosin daily for 12 weeks. Results of this trial showed that IPSS decreased

significantly from 17.92 to 12.07, but the MSHQ ejaculatory subdomain worsened

significantly from 24.9 to 27.14 and subdomains for erection and satisfaction did not

change significantly (463).

In a large open trial with 839 enrolled patients suffering from LUTS caused by BPH,

lOmg alfuzosin was taken daily for two years. The initial IPSS of 15.5 was reduced by 7

points, while the total initial bSFI value of 21.5 improved only slightly during the

treatment period, leading to the assessment by the authors that the treatment at least

"did not have any deleterious effect on sexual functions" (435).

A further open clinical trial with lOmg alfuzosin showed, besides a significant

improvement of the IPSS after 1 year of treatment, a significant improvement of the

bother score of the Danish Prostatic Symptom Score questionnaire for sexual

dysfunction (DAN-PSSsex) (464) while a study comparing tamsulosin/solifenacin either

alone or in combination in patients with LUTS also saw improved IPSS, but observed no

significant changes in the IIEF (465).

The IPSS reductions of about 6 to 7 points found in these studies with alpha-blockers

were similar to those observed in placebo-controlled trials (466,467). This is in line with

the trials of Debruyne (2004) and Zlotta (2005), which showed similar IPSS reductions

following treatment with a saw palmetto preparation and tamsulosin (468,469).

It also remains doubtful whether PDE-5 inhibitors are a good treatment for both LUTS

and SDys together. Clinical data for PDE-5 inhibitors showed a good improvement on

An CIV Suter 172

Chapter 4: Ciinicai pi lot stud}.

erectile dysfunctions, but a small effect on BPH symptoms.

McVary (2007) saw a significant decrease in the IPSS following 12 weeks of treatment

with lOOmg sildenafil, with an IPSS change of -6.3 vs. -1 .9 with placebo, as well as a

significant improvement of the IIEF erectile function domain (470).

In the trial of Roehrborn et al. (2008), the application of different dosages of tadalafil

demonstrated that an increased dosage correlated with increased IPSS improvement,

from +3.9 at 2.5mg to +5.2 at 20mg, with a dose of Smg showing the best benefit/risk

ratio. After a treatment period of 12 weeks, improvement was also seen in the IIEF

erectile function subdomain (471).

Vardenafil (20mg) taken twice daily for 8 weeks improved the IPSS by 5.9 points,

compared to placebo with 3.6 points; significant changes were also seen in the IIEF-ED,

and the Urolife QoL-9 sex improved by 62.6% compared to 17.2% under placebo (472).

While IPSS was improved in these trials, interestingly, changes in flow rates were never

reported.

In total, clinical data for PDE-5-inhibitors showed a moderate improvement in LUTS

from 2.3 to 4.4 IPSS-points compared to placebo even though sildenafil and vardenafil

were used at the highest applicable daily dosage, meanwhile the SDys improved in all

studies significantly.

One solution discussed in the literature for concomitant reduction of BPH symptoms

and ED is the combination of an alpha blocker with a PDE-5-inhibitor. Data from three

such clinical studies are presently available.

One small trial investigated alfuzosin, sildenafil, or the combination on LUTS and

erectile dysfunctions. After 12 weeks of treatment, initial values of IPSS, which were

between 16.9 and 17.8, were reduced significantly in all treatment groups with the

largest reduction (24.1%) in the combination group. The IIEF erectile function score was

significantly improved by the combination and sildenafil, but not in the alfuzosin group

(473).

Another combination trial with sildenafil or tamsulosin showed comparable results,

with the largest IPSS improvement observed with the combination (-40.1%), followed

by tamsulosin (-36.2%), and sildenafil (-28.2%); the IIEF improved significantly with

sildenafil and the combination but not with tamsulosin (474).

Andy Suter 173

In a further trial, lOOmg udenafil was added to a stable alpha-blocking therapy in

patients with BPH and erectile dysfunction for 8 weeks. The IPSS was reduced by 2.8

points and the IIEF-5 improved by more than 5 points, indicating that a combination or

add-on therapy of udenafil may be beneficial (475).

PDE-5-inhibitors are expensive treatments; therefore, a cost-benefit assessment is

warranted for a further extensive PDE-prescription. In the USA, a single dose of 25mg

sildenafil costs about 8 times as much as an alpha-blocking agent like Im g doxazosin

(476) or 30 times more than 0.4mg tamsulosin in Germany (477), whereas the cost for a

daily dosage of Prostasan® is in the lower range of an alpha blocker. These differences

in price, in addition to the only moderate efficacy, make it doubtful if PDE-5-inhibitors

should be advocated as a standard treatments for BPH symptoms.

When looking at safety and tolerability, our data was in accordance with previous

findings and indicated that saw palmetto was very well tolerated, in contrast to the

standard treatments for LUTS. A major problem for patients taking an alpha blocker

and/or a 5-alpha-reductase inhibitor is the occurrence of sexual adverse effects that

cause many men to discontinue treatment (478).

Study data show that 2-16% of all patients under alpha reductase inhibitor therapy

experience erectile dysfunctions, decreased libido, and decreased volume of ejaculate

(twice the frequency seen with placebo), whereas alpha-blocking agents, particularly

tamsulosin, have been frequently linked with ejaculatory disorders in around 10% of all

patients (479).

In daily practice, the incidence rates may even be higher than in clinical trials. In a large

epidemiological study carried out with urologists and internal medicine physicians in

the United States, doctors estimated that 18-27% of the patients taking an alpha-

blocking medication suffer from ejaculatory disorders and 16-22% of men taking a

5-alpha-reductase-inhibitor suffer from erectile dysfunctions (480). Nevertheless, the

latest American Urology Association guideline for treatment of BPH symptoms also

advocates using a combination of alpha-blockers and 5-alpha-reductase inhibitors

(197), a protocol designed to achieve better efficacy, but without fully considering the

additive side effect rates of these two drugs as shown in combination trials (461).

Andy S'j 1er 174

O'lopte/'4; C/.n.To/ p/'/o::' iTL/c'y

This trial has some limitations; it was designed as an uncontrolled pilot trial to elucidate

if an effect of a saw palmetto treatment could be observed. Consequently, the size of

the placebo effect can only be estimated.

A review on the placebo effect in studies with alpha blockers and 5-alpha-reductase

inhibitors in BPH found a reduction in LUTS under placebo ranging from 9-34% (481).

Considering this effect size, that the reductions in IPSS seen in our trial were similar to

those of other controlled saw palmetto trials it can be assumed that our Sabal

treatment was probably efficacious in reducing BPH symptoms.

To assess the placebo effect in reducing SDys in this trial is more difficult and no clear

statement can be made as our observed improvement of SDys was about 40%.

A review on treatments for erectile dysfunction showed an average placebo effect

when looking at improvement of erectile function in nine clinical trials of 28.0% (482),

another review taking the intercourse success rate as main measure found a placebo

effect of 31.4% as mean from 19 sildenafil trials, 32% from twelve tadalafil studies, and

35.1% from eleven vardenafil trials (483).

Furthermore, there was a strong centre effect in our trial, as one centre recruited

substantially more patients than the others and these other centres did have fewer

responders than the main centre. Subgroup analysis did not unveil any significant

differences in patient characteristics between these centres; however, these analyses

were limited by the low number of patients in the other five centres together.

Nevertheless, a strong influence by the treating physician on the outcome of SDys could

not be confirmed with the data available as there was a positive correlation between

the bSFI which was filled out by the investigator and the Urolife sex QoL-9 score which

was completed by patients. Further, during the treatment-free run in period the values

for SDys and IPSS remained in the majority stable.

Nevertheless, the results of this uncontrolled pilot trial showed that the applied saw

palmetto treatment exerted a good benefit/risk ratio in reducing BPH symptoms and at

least not negatively affecting SDys at the same time. When considering also the low

treatment costs, the very good acceptance and compliance by the patients it can be

nonetheless assumed that this trial showed promising results for the effectiveness,

which describes the degree of a beneficial effect in a real world clinical settings (484) of

saw palmetto in treating BPH symptoms and concomitant SDys.

A ndy Su te i 175

Based on our findings here, a further placebo-controlled clinical trial with a more

balanced patient distribution in the centres would be the next step to prove the

efficacy.

Conclusions

This is the first trial ever to observe that a saw palmetto treatment could have a

positive effect in reducing BPH symptoms and in concomitant SDys. The applied

medication was very well tolerated, safe, highly accepted and the compliance was very

good. Further, the cost of daily treatment with saw palmetto is much cheaper than with

many other medications, for example, in Switzerland the cost would be 0.75 Swiss

franks for saw palmetto vs. 22.30 Swiss franks for lOOmg sildenafil (485).

The results from our pilot trial let assume that due to the positive benefit/risk ratio of

saw palmetto in treating BPH symptoms and at least not deteriorating SDys, there is a

good chance for a good effectiveness of this treatment.

Based on these promising results, a further, larger placebo-controlled clinical trial

should be carried out to confirm the findings and answer questions on the efficacy of

saw palmetto in treating BPH symptoms and SDys.

An dy Suter 176

Chapter 5General discussion and conciusion

Andy Suter 177

5/ Gene'-o,' cc.'?dL/F,r'

5 Chapter 5: General discussion and conclusion

5.1 General discussion

In the last 150 years saw palmetto has made a fascinating journey as a medical plant:

Starting with the first use by the Indians of Florida, then discovered by white settlers

and made popular within 20 years in the United States, soon after in Europe to become

today's world favourite herbal treatment for BPH with a turnover of an estimated 700

million dollars (163) which is equivalent to the worldwide annual combined sales of the

5-alpha-reductase inhibitor top brands Proscar® (486) and Avodart® (487).

This thesis followed important aspects of this path and gained new data on the past,

present and future of saw palmetto as a medical therapy.

In terms of the past the aim was to show who first made medical use of saw palmetto

among the U.S. American physicians and how the plant became popular in the United

States and later in Germany.

I identified the first written record of saw palmetto as a medical treatment in 1877 by

J.B. Read of Savannah, Georgia (208). One can speculate that his description of the use

of the plant was lead by commercial interests as Dr. Read was to become president of

the Georgia Medical Society (210) and a large manufacturer of medical products, the

A.A. Solomons Drug Co. was situated in his hometown (488). It was the time of the so

called 'Gilded Age' in the United States, an exciting era of economic growth - also for

venturers in the medical field and quacks. This is well documented in the 1880's, for

example, in case of Echinacea - made popular in the U.S.A. also as a product called

'Meyer's Blood Purifier'. Its producer, H.C.F. Meyer proposed to a medical board to

prove the efficacy of his product by letting himself bite by a rattlesnake and then take

the 'Blood Purifier' as a treatment (489).

But saw palmetto was more than quackery - it proved to be a good remedy which is

demonstrated by the broad acceptance and use firstly among the eclectic physicians,

followed soon by homeopathic doctors. A comprehensive collection of various sources

documenting the wide spread use of the plant indicate that the first experiences with

Andy Suter 178

C f Gene' of r/fCL/ss/cn ono' conc/L/s.'c.'-

Sabal were gathered in respiratory tract infections (208) but soon after in genito

urinary problems and as a sexual stimulant (253). The important medical role of eclectic

medicine in this period contributed to the plant becoming a popular therapy. The 'gold

standards' of available therapies for BPH symptoms in the second half 19 century like

catheterisations or use of mercury, iodine, and bromine were generally harmful.

Consequently, saw palmetto could fill a gap as a safe and also efficacious new therapy

which proved to be best for prostatic problems.

To show how saw palmetto was introduced as a medical treatment in Europe, I chose

Germany as a model. In this country mainly the homeopaths were the first to use saw

palmetto and they had strong ties to the American homeopathic society (265). Soon

afterwards the pharmacists, too and then food scientists and chemists became

interested in the plant and until the beginning of the Second World War the species

must have been known and also used at least by a certain group of practitioners in

Germany.

Further botanico-historical studies especially in archives need to focus on

How the plant became popular in Germany,

Who were its main promoters and

Which were the main brands being used.

Nevertheless, this is at the time the most comprehensive medico-historical evaluation

of the first use on saw palmetto in the U.S.A. and Germany from publicly available

sources.

Regarding the present, the largest phytochemical analysis so far of 46 products from

nine different countries containing Sabal was carried out. The advantage of saw

palmetto is that in clinical trials 320mg berry extract with 70-95% fatty acids proved to

be efficacious and safe in treating BPH symptoms demonstrating that the fatty acids are

most probably one of the main active constituent of saw palmetto preparations (17,

A n d v S i J t c r 179

n .'jp r fr 5; Gf/ifro.' n.no' (onr/û/s/o/

151). Like this a good reference standard is given to measure the product quality of saw

palmetto preparations.

There was an unexpectedly large difference in the amount of fatty acids per daily dose

among saw palmetto mono preparations: The highest dosed product contained 177

times more fatty acids than the lowest dosed. When compared to the proposed dosage

of the monographs of 320mg extract (17, 40, 146, 147), unregistered Sabal

preparations contained in the majority either too low or too high daily amounts of fatty

acids and these were further often wrongly declared, casting serious doubts on the

usefulness of these products as therapeutic agents, especially since extensive

preclinical and clinical research with more than 90 publicly available clinical trials

provided sound evidence for this dose range (151). The analysis also showed that on

average registered products contained an amount of 320mg lipophilic saw palmetto

extract and the declarations were correct. The capsule sizes of unregistered

preparations were in average also bigger than those of registered products, indicating

that manufacturers wanted to profit from the fact that patients regard larger capsules

as more efficacious than smaller ones (490).

Additionally, the ethanolic mono-extracts showed a characteristic pattern in their

composition of nine fatty acids and, consequently, a saw palmetto extract can be

distinguished easily from other herbal extracts containing fatty acids. Based on this

study the proposed amount of 20% lauric acid for a saw palmetto extract proposed by

the European Pharmacopoeia (336) may not be sufficient to characterise the quality of

a Sabal extract; in the future minimum concentrations of oleic or myristic acids should

be recommended as well.

Even though fatty acids are an important marker, further investigations should focus

also on other active constituents as well. This could be phytosterols like ^-sitosterol,

cam peste ro I or stigmasterol which showed to have a positive effect on mechanisms

associated with the BPH pathology (385, 387, 388). These compounds were also shown

to be efficacious in improving BPH symptoms (127). However, they had to be taken in

dosages at least 60 times higher than generally found in saw palmetto mono

preparations (127, 340).

A n d y S u te r 180

C/7(7prer5; Gerem/ nVsci'fs-o.'i nrn ronc/ur.'c.':

To assess the characteristics of the different test samples, we used a different method

than just to determine a further marker substance. For the first time a metabolomic

approach to characterise saw palmetto preparations using proton-NMR was carried out

in the MSc-thesis of Anthony Booker (341). His results emphasise that in the future this

could become the method of choice for a characterisation of saw palmetto products. It

is fast and reliable, straightforward to set up a library of products and their

characteristics and with PCA a good statistical method is available to analyse the

different preparations. With the applied clustering, preparations which are similar in

their characteristics could be grouped together and outliers can well be identified.

In general, this phytochemical analysis showed that what is sold on the markets under

the label 'saw palmetto' varies widely in its amount of active constituents highlighting

that the registration of herbal medicinal products would be the best measure for

quality assurance on the markets.

The last part of my thesis addressed the future of saw palmetto with a clinical pilot trial

in patients with BPH and concomitant SDys.

I stated in the discussion of the historical part that being a BPH patient at the end of the

19 *’ century was a miserable thing. At the begin of the 21® century, the situation looks

brighter for a patient but it is far from being shiny.

The disease is better understood but why it evolves is still unclear; the latest hypothesis

that BPH could be caused by a venous insufficiency in the testicular veins (97) still

needs to be substantiated. There are only two classes of medication available for

treatment of BPH symptoms, alpha-blockers and 5-alpha-reductase inhibitors but both

cause frequently side effects like ejaculatory disorders (426) or erectile problems (428).

The last treatment option is surgery and the golden standard, TURP is a surgical method

which is about hundred years old (175) and also causes a lot of side effects (139).

It is also known today that a BPH patient is at a greater risk of experiencing SDys. Large

epidemiological studies carried out about 10 years ago corrected the existing paradigm

that SDys in the elderly male population were simply age related. The results of these

Andy Suter 181

oVscL fS'cn cndconc/us,'o.'

trials showed that BPH is besides age the most important factor causing SDys - which

could be worsened significantly with the mentioned therapy options to treat BPH.

Therefore, additional treatment solutions are intensively sought which are efficacious

and safe in treating BPH and SDys together (411).

Saw palmetto with its clinically proven efficacy in BPH and the traditional use as a

therapy for SDys was predestined to be a good treatment for these disorders. Our

clinical pilot trial which was designed to be a pragmatic study (491) showed a tendency

that after a treatment duration of eight weeks, saw palmetto could reduce BPH

symptoms and at the same time improve SDys.

Our results are of considerable interest in particular in the context of improved

compliance, good acceptance, the low treatment costs of the saw palmetto treatment,

and the good benefit/risk ratio for one patient. Consequently, a good effectiveness of

saw palmetto in treating BPH symptoms and concomitant SDys can be assumed.

Nevertheless, the study has several limitations and its level of evidence is ll-b according

to the rating in Evidence Based Medicine where level I stands for a well designed

randomised clinical trial and level III are case reports or opinions from expert

authorities (492). There was no placebo control involved in our study and the amount

of the placebo effect could only be estimated. Further, a strong centre effect was noted

as one centre recruited the majority of the patients and since this study was designed

as a pilot study to generate hypotheses for a further controlled study, the sample size

was also rather small with 69 analysable patients.

To confirm the promising findings from our pilot trial, next a placebo controlled study

needs to be carried out. The results from our trial can be taken to estimate the effect

size of the saw palmetto treatment and the needed sample size.

Probably even better results could be obtained when combining Sabal with another

plant which proved to be efficacious in SDys like Panax ginseng where a review on six

placebo controlled trials reported efficacy in treating ED (493) or maca (Lepidium

meyenii) which in two placebo controlled studies improved SDys (494). Existing

combinations of saw palmetto with an additional herbal extract were mainly developed

182

rrn'conc/cvs/o'

to improve uroflow or BPH symptoms like with Urtica dioica (150) but none to improve

concomitant SDys.

A further topic of interest relates to the mechanisms underlying these effects. It could

be that in our trial the reduction of BPH symptoms leads to the improvement of SDys or

that saw palmetto itself has aphrodisiac properties. A trial with BPH-free patients

suffering from SDys could answer this question.

In summary, our trial gave interesting hints that saw palmetto has also a positive effect

on concomitant SDys. Given, this the plant has now even more the potential to become

the first line treatment for mild to moderate BPH symptoms.

5.2 Final conclusion

Saw palmetto is one of the best known and investigated herbal treatments worldwide.

This thesis contributes new historical, analytical and clinical knowledge on the plant.

Overall, good quality products which are manufactured in accordance with the existing

monographs on saw palmetto have a bright future - they could become a well

tolerated and cost effective therapeutic option for patients suffering from mild to

moderate BPH symptoms with concomitant SDys. More clinical research and maybe a

combination with another plant which is efficacious in improving SDys is warranted to

secure saw palmetto its place as a more widely recognised treatment for BPH and other

urogenital conditions.

183

L i te ra t u rc

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468. Debruyne F, Boyle P, Calais Da Silva F, Gillenwater JG, Hamdy FC, Perrin P, et al. Evaluation of the clinical benefit of permixon and tamsulosin in severe BPH patients-PERMAL study subset analysis. Eur Urol. 2004;45(6):773-9; disucssion 9-80.

469. Zlotta AR, Teillac P, Raynaud JP, Schulman CC. Evaluation of male sexual function in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) treated with a phytotherapeutic agent (Permixon), tamsulosin or finasteride. Eur Urol. 2005;48(2):269-76.

470. McVary KT, Monnig W, Camps JL, Jr., Young JM, Tseng U, van den Ende G. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol. 2007; 177(3): 1071-7.

471. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008;180(4):1228-34.

472. Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. 2008;53(6):1236-44.

473. Kaplan SA, Gonzalez RR, Te AE. Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol. 2007;51(6):1717-23.

474. Tuncel A, Nalcacioglu V, Ener K, Aslan V, Aydin 0, Atan A. Sildenafil citrate and tamsulosin combination is not superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. World J Urol. 2010;28(l):17-22.

475. Chung BH, Lee JY, Lee SH, Yoo SJ, Lee SW, Oh CY. Safety and efficacy of the simultaneous administration of udenafil and an alpha-blocker in men with erectile dysfunction concomitant with BPH/LUTS. Int J Impôt Res. 2009;21(2):122-8.

476. Stafford RS, Radley DC. The potential of pill splitting to achieve cost savings. Am J Manag Care. 2002;8(8):706-12.

477. Schneider D RF. Checkliste Arzneimittel. Stuttgart: Georg Thieme Verlag; 2008.

478. Roehrborn CG. Lower urinary tract symptoms, benign prostatic hyperplasia, erectile dysfunction, and phosphodiesterase-5 inhibitors. Rev Urol. 2004;6(3):121-7.

479. Gacci M, Eardley I, Giuliano F, Hatzichristou D, Kaplan SA, Maggi M, et al. Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2011;60(4):809-25.

480. Seftel A, Rosen R, Kuritzky L. Physician perceptions of sexual dysfunction related to benign prostatic hyperplasia (BPH) symptoms and sexual side effects related to BPH medications. Int J Impôt Res. 2007;19(4):386-92.

481. van Leeuwen JH, Castro R, Busse M, Bemelmans BL. The placebo effect in the pharmacologic treatment of patients with lower urinary tract symptoms. Eur Urol. 2006;50(3):440-52; discussion 53.

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482. Campbell HE. Clinical monograph for drug formulary review: erectile dysfunction agents. J Manag Care Pharm. 2005;11(2):151-71.

483. Eardley I. Oral therapy for erectile dysfunction. Arch Esp Urol. 2010;63(8):703-14.

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485. Stebler T. Viagra® (Sildenafil). Goldene Engel Apotheke Basel; 2009 [cited 2011 12nd of November]; Available from: http://www.engelapo.ch/medis/viagra.htm.

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488. Wilson RC. Drugs and pharmacy in the life of Georgia, 1733-1959. Athens, Georgia: University of Georgia Press; 2010.

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493. Jang DJ, Lee MS, Shin BC, Lee YC, Ernst E. Red ginseng for treating erectile dysfunction: a systematic review. Br J Clin Pharmacol. 2008;66(4):444-50.

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http://www.engelapo.ch/medis/viagra.htm

http://en.wikipedia.org/wiki/Annual

http://www.drugpatentwatch.com/ultimate/preview/tradename/index.php7querv

7 Appendix

7.1 Appendix 1

Data on reference samples for analytic investigations including sample number, country

of origin, brand name, producer, galenic form, tablet or capsule weight, amount of saw

palmetto per unit, daily dosage, drug extractant ratio DER, active constituents, and

batch numbers

Andy Suter 215

Appendix

Sample nr. (SP)

Country Brand name Producer

Regulatory status

Registered (R ) Food

supplement |FS)

mono or combination

Tablet or capsuleTablet or

capsule weight[mg]

Amount of saw palmetto per unit [mg] as given on

package


DER and extractant of saw palmetto

extract

active constituents Batch Nr.

1 CAN Prostate PerformNew Roots Herbal

R combi soft gel capsule 1800 160 2x1: 4 :1 , (95% oil extract)

sterols and sterolins, 5P ,Pyg, rye flower pollen, vit E, P5, pau d'arco, Zn, lyc, 5e, borage oil, olive oil, cranberry, vit 86, 1- alanine, l-glycine, 1- glutamic acid

691

7 UKSaw Palmetto Berry

Viridian FS combi hard capsule 450ISOmg SP

extract, 132mg SP berry powder

1x1For extract : 45- 50% free fatty

acids

5P extract, 5P powder, bilberry extract, alfalfa, spirulina

492411

8 ESP Sereprostat Robapharm ESP FS mono tablet 450 80 4x1 - 5P C04

11 UK Saw Palmetto Holland&Barrett FS mono hard capsule 450 450 2x2 - 5P243314-05

12 ESP Permixon Pierre Favre SA FS mono hard capsule 410 160 2x1 6-12:1 , Hexane 5P DOI

13 CANSaw Palmetto Berries

Natural Factors R mono hard capsule 500 500 3x1 - 5P 598045

14 UKSaw Palmetto Berries

Solgar FS mono hard capsule 520 300 1-3x1 -5P powder extract, 5P powder

04023EN05OA

15 UKSaw Palmetto & Pygeum Bark

Higher Nature FS combi hard capsule 400 120 1-3x1 45% fatty acids5P, Pyg, urt root, rice bran

18342

16 Korea CJ Nutra CJ Nutra FS combi soft gel capsule 750 500 1x1 - 5P, Zn, P5

17 USA Prostate HealthSchiff Nutrition Group Inc.

FS combi hard capsule 550 333.5 2x1 vit D, Zn, 5e, Cu, 5P, Ca- d-gluCarate, lyc

128152A

18 KoreaChung WaePharmaCorporation

Chung Wae Pharma

FS combi soft gel capsule 800 500 1x15P, Zn,soybean oil, tom ato extract powder

Andy Siitcr 216

Appendix

Sample nr. (SP)


Regulatory status


supplement (FS)

mono or combination


capsule weight [mg]


package



extract


19 CAN Frost - Force Prairie Naturals R combi soft gel capsule 1362 80 1-2x2 -vit B6, Zn, SP, Pyg, lyc, urt, PS, lecithin

20907146

20 USA Life ExtensionQualitySupplements and Vitamins Inc.

FS combi soft gel capsule 1800 160 2x1

CO2, Standardized to

85-95% fatty acids

SP, flower pollen extract, boswellia serrata extract, urt, Pyg, lyc, phytosterols, enterolactone,B, rosemary

2410110

21 NL Prostavit Forte Bional FS combi soft gel capsule 1400 160 1x1 -PS oil, urt, SP, Zn, Se, yeast, tomatoes extract, vitE

09E0404

22 ESP BiprostatDietéticos Intersa S.A.

FS combi hard capsule 365 365 2x1 -SP, PS, Pyg, bearberry, Zn, vit B6

9HE7

23 UKSaw Palmetto Complex

Natures aid FS combi tablet 1200 160 1-2x1 1 :10, 72mg fatty acids per tab!.

SP, PS211D0117

24 NLProstaFleur Extra Forte

BloemNatuurprodukte n Winschoten bv

FS combi hard capsule 500 40 2-3x1 4 :1SP, PS, Epilobium

p a rv iflo ru m , b-sit. Se, Zn, vit E, lyc

80S1447S

27 SW! Prostagutt UnoSchwabe Pharma AG

R mono soft gel capsule 500 320 1x110-14.3 :1,

ethanol 90% m /m

SP 1470S10

29 KoreaCJ Nutra Saw Palmetto

CJ Nutra FS mono soft gel capsule 500 320 1x1 - SP

30 SW! Prosta UrgeninMax Zeller AG

( Schwabe Pharma AG)

R mono soft gel capsule 480 320 1x1 8-9.52 :1, ethanol 90% V /V

SPB090168S

31 SW! SabCaps Vifor SA R mono soft gel capsule 480 320 1x1 9 -1 1 :1, ethanol 96% V /V

SP6S4760100

ndy Suter 217

Sample nr. (SP)


Regulatory status

Registered (R I Food

supplement (FS)

mono or combination


capsule weight [mg]


package



extract


32 KoreaChong Kun Dang HealthSaw Palmetto

Chong Kun Dang Health

FS mono soft gel capsule soo 320 1x1 - 5P

33 FIN Curbisal Pharbio R mono soft gel capsule 480 320 1x1 9 -1 1 :1, ethanol 5P 220181

34 USASaw Palmetto Extract

Now Foods FS mono soft gel capsule 600 160 1x2standardized to

85-95% fatty acids

5P12147060239

35 SWI ProstasanA. Vogel Bioforce AG

R mono soft gel capsule 48S 320 1x19 ,0 -12 ,0 :1 ,

ethanol 96% (V/V).

SP L030S618

36 SW! Prostadyn Dr. Diinner AG R mono soft gel capsule 260 160 2x110-14 :1, ethanol

90% m /mSP E090276

37 CAN Saw PalmettoSwiss Herbal Remedies Ltd

R mono soft gel capsule 400 80 2x110:1 extract,

85%-95% fatty acids

SP 34426

38 NL Prostaat Phital FS combi tablet 14S0 100 2x1 -

lyc, Pyg, phytosterols, urt, SP, provit A, vit A, vit E, 81, vit 82, vit 83, vit 85, vit 86, vit 88, vit 811, vit 812, vit C, vit D3, vit K, choline, inositol, paba, lutein, b- sit, Ca, Cr, Fe, 1, Na, Cu, Mg, Mn, Se, Mo, Se, Si, Zn, g rap e seed, ginseng, ginkgo b ilo b a , green tea

07J08C

40 SWI Prostagutt FSchwabe Pharma AG

R combi soft gel capsule 67S 160 2x110-14.3 :1,

ethanol 90% m /m

SP, urt 6760910

41 NL ProstalifeBloemNatuurprodukte n Winschoten bv

FS combi hard capsule SSO 320 2-3x1 4 :1SP, urt root, Epim ed ium ,

M u ira p u a m a , b-sit. Se, Zn, vit 86, vit E, lyc

91019829

!y Sut" : 218

Appendix

Sample nr. (SP)


Regulatory status


supplement (FS)

mono or combination


capsule weight [mg]


package



extract


42 NL Prosta TotaalDistributie care bv

FS combi tablet 1450 100 1-2x1

lyc, Pyg, phytosterols, urt, 5P, provit A, vit A, vit E, 81, vit 82, vit 83, vit 85, vit 86, vit 88, vit 811, vit 812, vit C, vit D3, vit K, choline, inositol, paba, lutein, b- sit, Ca, Cr, Fe, 1, Na, Cu, Mg, Mn, 5e, Mo, 5e, 5i, Zn, g ra p e seed, ginseng,

ginkgo b iloba, green tea

08818E

43 NL Prostalan Forte VSM FS combi soft gel capsule 666 160 2x1 -SP, urt, saturated fatty acids

71221

44 NL Prostavit Bional FS combi soft gel capsule 1400 2.5 1-3x1SP, PS oil, urt, echinacea pallida, b-sit. Mg, vit E, Zn

0910202

45 CAN Saw Palmetto Homeocan R mono hard capsule 350 350 04. Jun12:1,

standardised to 25% fatty acids

5P 0 0034

46 UK Prostavital Health Aid FS combi soft gel capsule 2000 30 1x1 12 :1

vit E, vit C, vit 86, Mg, Zn, Cr, Cu, Se, lyc, 1- alanine, l-glutamic acid, wheat germ oil, PS oil, lecithin, urt, SP, Pyg

710

47 USASaw Palmetto & Pygeum Extract

Country Life FS combi soft gel capsule 600 160 2x1

9 :1 , standardised to

45% fatty acids=72mg/caps

SP, Pyg, plant sterol complex, soy phosphatides (soy lecithin), lipase

10A996A

48 CANSaw Palmetto & Pygeum

PreferredNutrition

R combi soft gel capsule 1800 80 2-4x1 85% fatty acids

b-sit, PS oil, flower pollen extract, SP, urt, Pyg, Zn, hydrangea root, lyc, Cu SP

616880

49 USA ProstActiveNature's Way

(Schwabe Pharma AG)

FS mono soft gel capsule 480 320 1x1 12:01SP, Se, probiotic nutrients, green tea , PS, ginger, urt, rosemary

589696

50 USA Prostate 5LX New Chapter Inc. FS combi soft gel capsule 750 160 2x1 Supercritical extract, 136mg

SP, Se, probiotic nutrients, green tea , PS,

40503009A

Andy Siit'-r 219

Appendix

Sample nr. (SP)


Regulatory status

Registered (R I Food

supplement (FS)

mono or combination


capsule weight [mg]


package



extract


fatty acids/caps (=85%)

ginger, urt, rosemary SP, P5, Pyg

51 USAProstateAdvantage

Enzymatic Therapy Inc.

FS combi soft gel capsule 555 80 2x1Standardised to

85-95% fatty acids

SP, PS, Pyg vit 86, 5P, Pyg

103392

52 USASaw Palmetto & Pygeum

Nature's Way FS combi soft gel capsule 850 350 1x1Standardised to

85-95% fatty acids

5P 589422

53 USASaw Palmetto Berry Extract

Solaray FS mono soft gel capsule 570 160 1x1-2 85% fatty acids and sterols

SP 132812

54 USASaw Palmetto Extract

Source Naturals FS mono soft gel capsule 700 320 1x285-95% fatty

acids and sterolsSP, urt, Pyg 1001807

55 ESP Prosta - Fort

GSN Compania General Suplementos Nutricionales

FS combi tablet 600 160 2x1 10 ;1

vit A, vit C, vit D, vit 81, vit 82, vit 86, Ca, Zn Cu glycine l-glutamic acid 1- alanine plant sterol complex, b-sis, SP, Pyg, urt, lyc

8317

56 USA Prosta - Max Country Life FS combi tablet 1600 50 2x1SP, echinacea angustifolia

10A321A

57 ESPSpasmoUrgenin

Madaus FS combi tablet 450 25 2x3 Z-04

Abbreviations: SP = saw palmetto extract, PS = pumpkin Seed extract, Pyg = Pygeum ofricanum extract, Urt = Urtica dioica (stinging nettle), b-sit = beta-

sitosterol, lyc = lycopene

An ‘y '-L't- 2 2 0

7.2 Appendix 2

Total fatty acid content per capsule or tablet of each tested preparation and of the single fatty acids lauric acid, capric acid, caprylic acid, myristic acid,

palmitic acid, linolenic acid, oleic/linoleic acid and stearic acid

Andy Suter 221

Appendix

Mono or

combin

ation

Brand name Producer Country SP Nr.

Total fatty

acid

[m g /ta b le t o r

capsule]

Lauric acid

[m g /ta b le t o r

capsule]

Caprylic acid

[m g /ta b le t o r

capsule]

Capric acid

[m g /ta b le t o r

capsule]

Myristic

acid

[m g /ta b le t o r

capsule]

Palmitic acid

[m g /ta b le t o r

capsule]

Linolenic

acid

[m g /ta b le t o r

capsule]

Oleic+/

Linoleic acid

[m g /ta b le t o r

capsule]

Stearic acid

[m g /ta b le t o r

capsule]

m o n oSaw Palmetto

ExtractSource

Naturals Inc.USA SP 5 4 4 4 4 .3 1 9 7 .7 8 7 .8 8 7 .0 5 3 9 .1 5 4 6 .9 9 2 1 .2 1 2 1 2 .9 6 1 1 .2 7

m o n o Curbisal Pharbio F in land S P 3 3 2 9 0 .2 4 9 2 .9 4 6 8 .6 1 34 2 7 .6 2 6 .6 7 8 9 .6 4 .8

m o n oSawpalmetto

Mono Product 2 (HFS)

Chong Kun

Dang HealthKorea SP32 2 7 1 .9 8 8 .1 6 6 .5 6 8 .2 1 3 3 .1 7 2 5 .2 5 14 .1 9 0 .0 2 6 .4 5

m o n o Prosta UrgeninM ax Zeller

Sohne AGS w itzerlan d S P 3 0 2 7 1 .8 2 8 7 .4 1 5 .7 8 7 .7 6 3 3 .5 7 2 5 .4 7 1 4 .1 9 2 .5 3 5 .2

m o n o Prostagutt UnoSchwabe

Phram a AGS w itzerlan d S P 2 7 2 7 4 .5 3 8 4 .4 2 4 .6 4 5 .6 3 6 .6 4 2 7 .1 5 9 .6 1 0 1 .9 7 4 .5 1

m o n o Prostasan Bioforce S w itzerlan d S P 3 5 2 8 1 .3 4 8 3 .0 1 5 .7 4 .7 3 8 .1 2 8 .1 1 7 .5 1 1 0 .4 3 .8 7

m o n o ProstActive Nature 's W ay USA S P 4 9 2 8 5 .6 8 8 1 .3 6 4 .8 6 5 .6 3 6 .0 2 2 8 .3 5 1 3 .3 6 1 1 1 .5 7 4 .5 8

m o n o SabCaps V ifo r SA S w itzerlan d S P 3 1 2 7 4 .4 5 8 1 .2 5 5 .0 6 7 .1 4 3 0 .8 6 2 7 .1 2 2 8 .2 7 8 9 .3 4 5 .4 1

m o n oSawpalmetto

Mono Product 1 (HFS)

CJ Nutra Korea SP 29 2 3 7 .7 4 7 9 .8 1 5 .3 9 7 .1 4 2 9 .9 8 2 2 .5 9 1 2 .1 6 7 5 .3 1 5 .3 9

m o n oSaw Palmetto

ExtractN ow Foods USA S P 3 4 3 7 8 .2 6 6 .4 5 4 .3 6 .0 4 2 3 .4 8 3 6 .7 5 2 0 .9 9 2 1 1 .3 5 8 .8 3

m o n oSaw Palmetto Berry Extract

Solaray USA S P 5 3 3 5 4 .6 1 5 7 .8 3 3 .8 9 4 .4 9 2 3 .2 3 5 .3 4 2 3 .3 7 1 9 8 .7 5 7 .7 5

m o n o SereoprostatRobapharm

Espana S.A.Spain S P 8 3 6 8 .3 5 0 .2 1 .9 4 4 .3 7 1 4 .3 8 1 9 .0 4 3 3 .8 2 2 4 0 .1 2 4 .4 8

m o n o ProstadynDr. D iinner

AGS w itzerlan d SP 3 6 1 5 1 .5 6 4 5 .9 7 3 .1 1 4 .0 7 1 7 .8 5 1 4 .8 1 1 2 .7 6 5 0 .4 1 2 .5 8

Andy Suter 222

Aro ! -/

Mono or

combin

ation


Total fatty

acid

[m g /ta b le t o r

capsule]

Lauric acid

[m g /ta b le t o r

capsule]

Caprylic acid

[m g /ta b le t o r

capsule]

Capric acid

[m g /ta b le t o r

capsule]

Myristic

acid

[m g /ta b le t o r

capsule]

Palmitic acid

[m g /ta b le t o r

capsule]

Linolenic

acid

[m g /ta b le t o r

capsule]

Oleic+/

Linoleic acid

(m g /ta b le t o r

capsule]

Stearic acid

[m g /ta b le t o r

capsule]

m o n o Saw PalmettoSwiss Herbal Rem edies Ltd

C anada S P 3 7 2 S 3 .0 6 2S .94 2 .9 7 2 .8 lO.OS 2 S .7 9 9 6 .9 4 7 9 .1 3 9 .4S

m o n oSaw Palmetto

BerriesNaturalFactors

C anada S P 1 3 S 6.8 17.9S 0 .9 l.S S 6 .6 8 S .7 8 3 .6 3 1 8 .0 3 2 .2S

m o n o PermixonPierre Fabre

Iberica S.A.Spain SP 12 S S.68 1 7 .8 4 1 .11 1 .4 4 7 .2 2 S .37 2 .3 4 1 9 .4 8 0 .9 4

m o n o Saw PalmettoHolland &

BarretUK SP 11 4 4 .S 7 I S . 17 0 .S 4 1 .1 7 S .S 6 4 .4 1 3 .2 13.SS 0 .9 S

m o n o Saw Palmetto Hom eocan C anada SP 4 5 S l.O l 1 3 .2 1 0 .8 9 1 .S9 4.S 3 6 .4 6 2 .6 4 IS .O S 6 .6

m o n oSaw Palmetto

Berries

Solgar

V itam in and Herb

UK SP 14 34.S 1 1 .9 6 0 .6 0 .9 6 4.S 4 .6 3 1 .2 8 .S 8 2 .1 1

com bi Life ExtensionQuality

Supplements and Vitamins

USA SP 20 402 .S S S .94 6 .7 7 S 8 .9 8 2 1 .2 1 4 4 .4 9 1 4 0 .3 1 0 9 .3 6 IS .S

com bi Prost - ForcePrairie

NaturalsC anada SP 19 S 86.S1 6.S 2 6 .3 4 2 4 .4 1 9.7S 6 8 .7 3 2 1 7 .9 2 2 2 S .7 4 2 7 .0 1

com bi Prosta - FortGSN Compania

General Suplementos

Spain SPS S 1 7 6 .3 1 2 .0 1 4 .8 4 6 .6 2 1 4 .8 2 1 1 .6 1 1 0 .7 1 80.SS S .16

com bi Prosta - Max Country Life USA S P S 6 4 4 .8 8 0 0 0 .1 6 0 .4 2 S .6 8 0 .8 8 0 .7 2 1 7 .0 4

com bi Prosta TotaalD istributie

care bvN e th e rla n d SP 4 2 S 9 .2 3 0 .7 3 0 .7 3 6 .0 2 2 .6 8 1 4 .2 8 1 .3 1 7 .1 8 2 6 .3 2

com bi Prostaat Phital N e th e rla n d SP 38 S 2 .9 3 O .S l 0 .S 8 4 .2 1 1 .8 9 1 6 .1 7 0 .S 8 4 .4 2 24.S 1

com biProstaFleur Extra

Forte

Bloem

N atuurprodukten

N e th e rla n d SP 24 2 8 .6 3 0 .3 3 0 .S 3 7.4S 2 .6 8 3 .1 8 S .18 8 .S 3 0 .7 S

com bi Prostalan Forte VSM N e th e rla n d S P 4 3 2 3 9 .3 3 1 .0 6 2 2 .6 7 3 8 .6 3 17.S 4 3 3 .3 6 S.S3 4 6 .8 4 3 .6 8

ndv Su'T 223

App en d i x

Mono or

combin

ation


Total fatty

acid

[m g /ta b le t o r

capsule]

Lauric acid

[m g /ta b le t or

capsule]

Caprylic acid

[m g /ta b le t or

capsule]

Capric acid

[m g /ta b le t o r

capsule]

Myristic

acid

[m g /ta b le t o r

capsule]

Palmitic acid

[m g /ta b le t o r

capsule]

Linolenic

acid

(m g /ta b le t o r

capsule]

Oleic+/

Linoleic acid

(m g /ta b le t o r

capsule]

Stearic acid

[m g /ta b le t o r

capsule]

com bi ProstalifeBloem

N atuurprodu N e th e rla n d S P 4 1 3 1 .1 1 .1 6 1 .1 9 .7 4 3 .6 9 3 .8 8 3 .8 8 6 .7 1 0 .9 9

com bi Prostate 5LXN ew Chapter

Inc.USA SP 5 0 2 4 5 .2 2 3 .5 6 4 .8 5 3 .7 8 2 0 .8 6 2 9 .7 7 3 9 .6 7 8 5 .1 9 7 .5 7

com biProstate

AdvantageEnzym athic

Therapy Inc.USA S P 5 1 3 2 2 .6 8 1 .7 4 2 .4 7 2 7 .8 3 1 0 .4 7 4 0 .2 4 1 3 0 .3 9 7 .2 8 1 2 .3 3

com bi Prostate HealthSchiff Nutrition

Group Inc. USA SP 17 5 9 .6 8 1 .2 7 1 .2 7 1 2 .6 5 4 .2 9 3 .0 3 3 .4 7 3 2 .6 2 1.1

com bi Prostate PerformN ew Roots

HerbalC anada SP 1 3 7 9 .3 9 4 6 .8 7 2 2 .5 7 3 6 .1 7 1 3 .6 6 4 8 .5 3 6 8 .8 4 1 3 3 .3 5 9 .3 9

com bi Prostavit Bional N e th e rla n d SP 4 4 8 2 3 .8 8 3 .1 6 2 .3 9 0 .4 8 1 1 .2 1 0 5 .0 8 1 .9 1 6 6 3 .6 8 3 6 .1 7

com bi Prostavit Forte Bional N e th e rla n d SP 21 5 2 9 .5 9 4 .2 5 4 .9 9 4 6 .5 7 1 7 .4 2 7 2 .7 7 2 0 8 .5 5 1 4 0 .1 7 3 4 .8 3

com bi Prostavital Health Aid UK SP 4 6 8 6 0 .9 7 4 .7 5 3 .7 6 7 .3 3 3 .9 6 1 4 9 .2 9 3 .4 3 6 3 9 .2 8 4 9 .1 7

com biSaw Palmetto &

PygeumPreferredN utrition

C anada SP 4 8 5 4 6 .1 8 3 .6 8 2 .4 9 1 5 .4 4 5 .9 4 6 1 .4 8 2 6 0 .1 7 1 7 0 .5 4 2 6 .3 7


PygeumNature 's W ay USA S P 5 2 4 0 6 .9 8 6 .8 2 10 .1 1 1 1 .8 6 4 0 .2 4 0 .3 4 5 9 .9 1 1 2 8 .7 2 9


Pygeum BarkHigher

N atureUK SP 15 6 8 .3 2 1 .1 2 1 .5 6 1 7 .3 6 6 .3 6 8 .1 8 8 .1 8 2 4 .2 2 1 .3 4

com biSaw Palmetto & Pygeum Extract

Country Life USA SP 4 7 4 5 .4 2 0 .5 7 0 .7 2 6 .6 2 .4 1 2 .6 3 .9 6 1 0 .0 5 8 .4 6

com biSaw Palmetto

BarryViridian UK S P 7 3 0 .8 9 0 .2 9 0 .7 9 .8 3 3 .6 3 .5 1 2 .7 5 9 .5 9 0 .6 3

com biSaw Palmetto

ComplexNatures Aid

Ltd.UK S P 2 3 1 0 8 .6 6 1 .5 2 .1 6 2 1 .6 6 7 .7 4 3 0 .0 6 3 .7 8 2 1 .1 2 2 0 .5 2

Andy Sutrr 224

Appi ndix

Mono or

combin

ation


Total fatty

acid

[mg/tablet or

capsule]

Laurie acid

[mg/tablet or

capsule]

Caprylic acid

[mg/tablet or

capsule]

Capric acid

[mg/tablet or

capsule]

Myristic

acid

(mg/tablet or

capsule]

Palmitic acid

[mg/tablet or

capsule]

Linolenic

acid

[mg/tablet or

capsule]

Olelc+/

Linoleic acid

[mg/tablet or

capsule]

Stearic acid

(mg/tablet or

capsule]

c om biSawpatmetto Combination

Product 1 (HFS)CJ Nutra Korea SP 16 4 0 1 .8 7 8 .0 9 8 .9 3 8 7 .4 4 3 3 .7 8 4 1 .9 6 6 .2 1 1 4 0 .4 1 1 5 .0 5

c om biSawpatmetto Combination

Product 2 (HFS)

Chung Wae Pharma

CorporationKorea SP 18 3 1 5 .4 5 6 .7 6 5 .5 4 5 4 .7 3 2 0 .4 9 3 1 .2 3 8 1 .1 5 1 0 3 .9 9 1 1 .5 1

c om bi Prostagutt FSchwabe

Phram a AGSwitzerlancJ SP 27 2 6 5 .5 9 3 8 .1 3 2 5 .2 9 4 3 .5 7 1 9 .2 7 3 6 .6 2 5 .6 2 4 8 .7 7 4 8 .3 2

c om biSpasmo - Urgenin

IVladaus Spain S P 5 7 1 .3 9 0 0 .0 2 0 .2 9 0 .0 9 0 .2 3 0 .0 9 0 .4 7 0 .2

Andy buter 225

7.3 Appendix 3

Chromatograms of GC analytic of each investigated preparation from chapter 2

And /S u te r 226

1000

798-

596

192-

3,8 7,6 (min) 11,4 15,2 19,0

SP22 Biprostat, Dietéticos Intersa S.A., Spain

596

nVo«)

15,20,0 3,8 7,6 (mm) 11,4 19,0

SP12 Permixon, Pierre Fabre Iberica S.A., Spain

596

mVoK)

394

- r -0,0 3,8 7,6 (min) 11,4 15,2

SP47: Saw Palmetto, Homeocan, Canada

596-

mVol)

394

192-

-100,0

I ‘ I 3,8

1----------1----------1----------r15,27,6 (min) 11,4

SP13 Saw Palmetto Berries, Natural Factors, Canada

'■ - .^y Sul. 227

Appendix

596

nVoH)

394-1

Ja-0,0 3,8 7,6 (tnin) 11,4 15,2 19,0

S P ll Saw Palmetto, Holland & Barret, UK

596

mVol)

394

0,0=F

3,8 7,6 (min) 11,4 15,2 19,0

SP15 Saw Palmetto & Pygeum Bark, Higher Nature, UK

596

mVol)

394-

.10-t=J =*Tl----1 * 1 ' »‘l"“0,0 3,8 7,6 (mh) 11,4 15,2

SP7 Saw Palmetto Berry, Viridian, UK19,0

596-

nVo«)

394-

0,0J___ L

3,8 7,6 (min) 11,4 15,2 19,0

SP14 Saw Palmetto Berries, Solgar Vitamin and Herb, UK

Andy Suter 228

•P/

mVoft)

1.0,0 3,8 7,6 (min) 11,4 15,2 19,0

SP41 Prostaiife, Bloem Natuurprodukten Winschoten bv, Netherland

1 0 0 0 a

596-

nVolt)

394-1

0,0— t—

3,8 7.6 (min) 11,4 15,2 19,0

SP24 ProstaFleur Extra Forte, Bloem Natuurprodukten Winschoten bv, Netherland

1000

798

596

iVol)

394-

192

-107,6 (min) 11,4 15,2 19,00,0 3,8

SP17 Prostate Health, Schiff Nutrition Group, USA

596

;mVol)

394

Li0,0

i .3,8 7,6 (min) 11,4 15,2 19,0

SP47 Saw Palmetto & Pygeum Extract, Country Life, USA

Andv Su:6! 229

1000^

798

596-

mVolt)

394

-100,0 3,8 7,6 (min) 11,4 15,2 19,0

SP55 Prosta - Fort, GSN Compania General Suplementos Nutricionales, Spain

1000

795

590

385

180

-253,8 7,8 (min) 11,4 15,2 19,00,0

SP8 Sereprostat, Robapharm Espana S.A., Spain

1000 a

798-

596

nVo«)

394

-100,0

■| ' I 3,8

I I---------------1---------------r7,6 (min) 11,4

Î ' I 15.2 19,0

SP57 Spasmo - Urgenin, Madaus, Spain

Andy Sut: 230

A p n r : . d :

596-

iVoK)

394-

4 : I ^0,0 3.8 7,8 (min) 11,4 18,2 19,0

SP23 Saw Palmetto Complex, Natures Aid Ltd. UK

596

mVo»)

394

L u0,0

SP42

—1—3,8 7,6 (min) 11,4 15,2 19,0

Prosta Totaal, Distributie care bv, Netherland

596

iVo«)

394

0,0 3,8 7,6 (min) 11,4

SP38 Prostaat, Phital, Netherland15,2 19,0

596

■nVoi)

394

0,0

SP56

-T-3,8 7,6 (min) 11,4 15,2

Prosta - Max, Country Life, USA19,0

Andy Suter 231

û n ; .-: Q

1000

798-

596-

394-

192-

-100,0 3,8 7,6 (tnin) 11,4 15,2 19,0

SP19 Prost - Force, Prairie Naturals, Canada

1000

798

596

192

-100,0 3,1,8 7,6 (min) 11,4 15,2 19,0

SPl Prostate Perform, New Roots Herbal, Canada

1000

798

596

nVolt)

394

192

-10 “1 r~0.0 3,8 7,6 (tnin) 11,4 15,2 19,0

SP37 Saw Palmetto, Swiss Herbal Remedies Ltd, Canada

1000^

798-

596 -

n V d )

394 -

192

-100,0

1 r3,8 7,6 (min) 11,4 15,2 19,0

232

SP48 Saw Palmetto & Pygeum, Preferred Nutrition, Canada

596-

nVolt)

394-

3,8 7,6 (min) 11,4 15,2 19 ,0

SP20 Life Extension, Quality Supplements and Vitamins Inc., USA

1 0 0 0 a

mVolt)

0,0 3,8 7,6 (tnin) 11,4 15,2

SP49 ProstActive, Nature's Way, USA

798-

596-

iVolt)

394-

0,0 3,8 7,6 (min) 11,4 15,2

SP50 Prostate 5LX, New Chapter Inc., USA19,0

Ar-' 233

Appendix

0,0 3,8 7,8 (min) 11,4 15,2 19,0

SP51 Prostate Advantage, Enzymatic Therapy Inc., USA

1 000.

596-

(mVo*)

394

f0,0 3,8 7,6 (min) 11,4 15,2 19,0

SP52 Saw Palmetto & Pygeum, Nature's Way, USA

596

mVo»)

394

-10 L L _ l0,0 3,8 7,6 (min) 11,4 15,2

SP53 Saw Palmetto Barry Extract, Solaray, USA

1000^

798

5961

nVo»)

394

-100,0 3,8 7,6 (min) 11,4

L15,2 19,0

Andy Suter 234

SP34 Saw Palmetto Extract, Now Foods, USA

798-

596-

(rnVoH)

394-

192-

0,01 r—

3,8 7,6 (min) 11,4 15,2 19,0

SP54 Saw Palmetto Extract, Source Naturals Inc., USA

1000

796-

596 -

(mVoK)

394-

J0.0 3.8 7,6 (min) 11,

SP33 Curbisal, Pharbio, Finland15,2 19,0

1000

798

596

;mVo»)

394

192

-100,0

-n—3,8

47,6 (min) 11,4 15,2 19,0

SP43 Prostalan Forte, VSM, Netherland

596-

(mVo«)

394-

0,0 3,8-V ^ — H7,6 (min) 11,4 15,2 19,0

235

ive'

SP44 Prostavit, Bional, Netherland

1000

798

596 4 (mVolt)

394 4

192

lJ0,0

I3,8 7,6 (min) 11,4 15,2

SP21 Prostavit Forte, Bional, Netherland

19,0

7981

598

mVol)

394

-10 —T"0,0 3,8 7,6 (min) 11,4

SP46 Prostavital, Health Aid, UK

15,2 19,0

798

596-

mVolt)

394

192-

-100,0 3,8 7,6 (mh) 11,4 15,2 19,0

SP16 Sawpalmetto Combination Product 1 (HFS), CJ Nutra, Korea

Andy Sutei 236

Appendix

1000

798-

596-

192-

-103,8 7,6 (min) 11,40,0 15.2 19,0

SP18 Saw palmetto Combination Product 2 (HFS), Chung Wae Pharma Corporation, Korea

1000 .

596 -

;mVo»)

394

1 92-

-100,0 3,8 7,6 (min) 11,4 15,2 19,0

SP29 Sawpalmetto Mono Product 1 (HFS), CJ Nutra, Korea

1000 *

596-

(mVo«)

394

0,0 3,8 7,6 (min) 11,4 15,2 19,0

SP32 Sawpalmetto Mono Product 2 (HFS), Chong Kun Dang Health, Korea

1000

798-

596

192-

-100,0 3,8 7,6 (tnin) 11,4 15,2 19,0

SP35 Prostasan, Bioforce AG, Switzerland

Andy Suter 237

5 3 0 -

(mVol)

385-

-25-0,0

SP30

-I 1--------------1--------------r3,8 7,6 (min) 11,4 15,2

Prosta Urgenin, Zeller, Switzerland19,0

590

(m V o l)

-250,0 3,8 7,6 (min) 11,4 15,2 19,0

SP31 SabCaps, Vifor, Switzerland

7 9 5 -

590-

180-

-250.0 3,8 7,6 Cmh) 11,4 15,2 19,0

SP27 Prostagutt Uno, Schwabe, Switzerland

795

590

(mva)

385 ■

180

0,0-| 1—

3,8 7,6 (min) 11,4— I---------- r

15,2

SP40 Prostagutt F, Schwabe, Switzerland

19,0

238

Anper

(mvol)

0,0 3,8 7,6 (min) 11,4 15,2

SP36 Prostadyn, Dr.Dünner, Switzerland19,0

Andy Suter 239

7.4 Publications

Publications

Suter A, Sailer R, Riedi E, Heinrich M. Improving BPH symptoms and sexual dysfunctions with a

saw palmetto preparation? Results from a pilot trial. Phytother Res. DOI: 10.1002/ptr.4696,

Published online, 23 * of April 2012

Poster presentations

Suter A, Sailer R, Heinrich M. A new View on Saw Palmetto - Results from an Analytical

Comparison and of a Clinical Pilot Trial. PhD Research Day, Internal Symposium at the School of

Pharmacy, 15.04.2011, London, United Kingdom.

Suter A, Sailer R, Riedi E, Heinrich M. Improving BPH symptoms and sexual dysfunctions with a

saw palmetto prepare

St. Petersburg, Russia.

saw palmetto preparation? XVI International Congress "PHYTOPHARM 2012" 9-11.07.2012,

Booker AJ, Zloh M, Said M, Suter A, Heinrich M. Metabolomic profiling of saw palmetto products

using proton-NMR spectroscopy and multi-variate analysis. 59 International Congress and

Annual Meeting of the Society for Medicinal Plant and Natural Product Research. 4-9.09.2011,

Antalya, Turkey.

Talks

Suter A, Sailer R, Riedi E, Heinrich M. The quality of different saw palmetto products on the

market and a pilot trial with saw palmetto in treatment of benign prostatic hyperplasia and

sexual dysfunctions. PhD Research Day, Internal Symposium at the School of Pharmacy,

29.09.2011, London, United Kingdom. Awarded with first price for best presentation.

Andy Suter 240

New perspectives on saw palmetto - UCL Discovery

Documents

Transcript of New perspectives on saw palmetto - UCL Discovery