Low Doses of Traditional Nanophytomedicines for Clinical Treatment: Manufacturing Processes and...

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Copyright copy 2015 American Scientific PublishersAll rights reservedPrinted in the United States of America

ReviewJournal of

Nanoscience and NanotechnologyVol 15 4021ndash4038 2015

wwwaspbscomjnn

Low Doses of Traditional Nanophytomedicines for

Clinical Treatment Manufacturing Processes and

Nonlinear Response Patterns

Iris R Bell12lowast MD PhD Barbara Sarter34 PhD APRN FNP-C Leanna J Standish5 ND PhDPrasanta Banerji6 FMIH and Pratip Banerji6 MD(Hom)

1Department of Family and Community Medicine The University of Arizona College of Medicine

1450 N Cherry Avenue MS 245052 Tucson AZ 85719 USA2College of Nursing The University of Arizona 1305 N Martin Tucson AZ 85721 USA

3Hahn School of Nursing and Health Sciences University of San Diego

5998 Alcala Park San Diego CA 92110 USA4Bastyr UniversitymdashCalifornia 4106 Sorrento Valley Blvd San Diego CA 92121 USA

5Bastyr University 14500 Juanita Drive NE Kenmore WA 98028 USA6PBH Research Foundation 1031 Elgin Road (Lala Lajpat Rai Sarant) Kolkata 700020 West Bengal India

The purpose of the present paper is to (a) summarize evidence for the nanoparticle nature and bio-logical effects of traditional homeopathically-prepared medicines at low and ultralow doses (b) pro-vide details of historically-based homeopathic green manufacturing materials and methods relatingthem to top-down mechanical attrition and plant-based biosynthetic processes in modern nanotech-nology (c) outline the potential roles of nonlinear dose-responses and dynamical interactions withcomplex adaptive systems in generating endogenous amplification processes during low dose treat-ment Possible mechanisms of low dose effects for which there is evidence involving nanoparticlesandor homeopathically-manufactured medicines include hormesis time-dependent sensitizationand stochastic resonance All of the proposed mechanisms depend upon endogenous nonlinearamplification processes in the recipient organism in interaction with the salient albeit weak signalproperties of the medicine Conventional ligand-receptor mechanisms relevant to higher doses areless likely involved Effects especially for homeopathically-prepared nanophytomedicines includebidirectional host state-dependent changes in function Homeopathic clinicians report successfultreatment of serious infections and cancers Preclinical biological evidence is consistent with suchclaims Controlled biological data on homeopathically-prepared medicines indicate modulation ofgene expression and biological signaling pathways regulating cell cycles immune reactions andcentral nervous system function from studies on cells animals and human subjects As a 200-year old system of traditional medicine used by millions of people worldwide homeopathy offers apulsed low dose treatment strategy and strong safety record to facilitate progress in translationalnanomedicine with plants and other natural products In turn modern nanotechnology methodscan improve homeopathic manufacturing procedures characterize nanoparticle end-products anddescribe interactions of homeopathic nanophytomedicines with living systems at the nanoparticleand even individual organism level of detection Faster progress toward safe and effective person-alized nanophytomedicine treatments can result

Keywords Nanomedicine Nanoparticle Low Dose Phytomedicine Green ManufacturingHomeopathy Hormesis Time-Dependent Sensitization Stochastic ResonanceNonlinear Dynamics Complex Adaptive System Silica Self Assembly AdjuvantCancer Treatment

lowastAuthor to whom correspondence should be addressed

J Nanosci Nanotechnol 2015 Vol 15 No 6 1533-48802015154021018 doi101166jnn20159481 4021



Low Dose Traditional Nanophytomedicines Bell et al

CONTENTS1 Introduction 4022

2 Homeopathic Manufacturing Procedures for

Natural Nanomedicines 4024

21 Overview of Traditional Homeopathic

Medicine Manufacturing 4024

22 The Debate Over ldquoDilutionrdquo versus Homeopathic

Manufacturing Procedures 4026

3 Pulsed Dosing and Nonlinear Dose-Responses 4031

31 Dosing Homeopathic Nanoparticles 4031

32 Nonlinear Dose-Response Mechanisms 4032

4 Conclusions 4033

Acknowledgment 4034

References and Notes 4034

1 INTRODUCTIONThe purpose of the present paper is to (a) summarize evi-

dence for the nanoparticle nature and biological effects of

traditional homeopathically-prepared medicines at low and

ultralow doses (b) provide details of historically-based

homeopathic manufacturing materials and methods relat-

ing them to top-down mechanical attrition doping and

templating of nanosilica and plant-based biosynthetic pro-

cesses in modern nanotechnology (c) outline the potential

roles of nonlinear dose-responses of hormesis stochastic

resonance and nonlinear dynamical interactions with com-

plex adaptive systems in generating endogenous amplifi-

cation processes during low dose treatment

Many cultures worldwide have relied on bulk form

plant-based natural medicines for hundreds to thousands

of years for treating acute and chronic health problems

Traditional Chinese medicine Ayurvedic medicine and

Western herbalism are all examples of highly-developed

historical approaches to natural product-based treatment

for conditions ranging from infections to cancers1ndash6

Herbalists argue for use of the whole plant or traditionally-

used intact plant parts (eg roots stem bark leaves)

rather than chemically-isolated individual nutraceutical

ingredients in order to obtain gentler and synergistic

effects of multiple natural constituents7 interacting with

the individual as an integrated complex adaptive system8

However as modern researchers have taken a closer

look at the strengths and limitations of traditional phy-

tomedicines they often identify poor absorption lower

bioavailability and limited patient tolerability as barri-

ers to more widespread adoption of herbs for clinical

care

Nanotechnologists are currently beginning to exploit the

ability of nanoparticulate (NP) forms of traditional botan-

ical agents to dramatically improve absorption bioavail-

ability and reduce side effects9ndash17 Because of their tiny

size (eg a log unit smaller than the wavelength of vis-

ible light) many NPs can readily cross cell membranes

including blood-brain barrier1819 The therapeutic dose

ranges for nanoscale forms of many agents are lower by

orders of magnitude compared with their respective bulk

forms20ndash26 Modern NPs offer additional therapeutic advan-

tages over bulk forms such as better intracellular access22

and targeting of cancerous cells while sparing healthy cells

in the organism27ndash32 Nanoparticles made from botanical

and nutraceutical agents have particularly low toxicity and

favorable side effect profiles1633ndash35

At the same time translation from bench to bedside has

been slow36 Concerns about uncertain toxicity profiles of

manufactured NPs persist37 Plants and fungi are among

the natural products used to biosynthesize potentially safer

forms of certain NPs eg silver or gold38ndash42 Plant biosyn-

thesis helps avoid toxic reagents during green manufac-

turing of nanomedicines43 Similarly reducing and coating

the surface of otherwise more toxic NPs with benign sug-

ars such as lactose sucrose maltose or glucose appears

to attenuate toxicity for nanomedicine use44ndash46 This strat-

egy is important because of the ability of nanoparticles

to adsorb onto other materials involved in their produc-

tion given their highly reactive surfaces NP adsorbants

such as plants or sugars can not only modify the sur-

face charge and physicochemical properties of the resultant

NPs but also enhance the beneficial biological effects of

the nanoscale agent4047ndash49 Still widespread clinical appli-

cation of plant-synthesized NPs and nanophytomedicines

does not appear imminent Many practical and regulatory

hurdles lie ahead

Nanophytomedicines might otherwise appear to be new

and relatively untested forms of treatment However inves-

tigators have begun to identify specific nanoscale materials

in certain Chinese herbs5051 and Ayurvedic medicines52

In addition recent studies have demonstrated that the his-

torical manufacturing procedures for making homeopathic

medicines another traditional system of natural medicine

also generate polydisperse source nanoparticles of differ-

ent sizes from quantum dot (1ndash10 nm) to larger nanoscale

structures (Fig 1) Convergent evidence indicates that

homeopathic manufacturing methods mechanically gener-

ate top-down nanoscale particles of the original source

material1753ndash56 as well as silicasilicon from the inside

walls of the glass containers5557ndash61 Previous nanoscience

research suggests that interactions of homeopathic plant

mother tinctures with silica precursors and silicon-derived

materials in solution might also generate plant-modified

(coated doped or imprinted) andor plant self-assembled

silica NPs404362ndash65

The unique green top-down and bottom-up biosynthetic

manufacturing and pulsed low dosing methods of homeo-

pathic medicine combined with the large pharmacopoeias

for hundreds of natural medicines and already established

regulatory standards for these agents provide a possi-

ble foundation for accelerating progress in translational

nanophytomedicine Homeopaths have had over 200 years

of real-world experience and an estimated more than

500 million patients worldwide66 in the safe and effective

use of thousands of their nanoscale natural products ie

homeopathic medicines6768111ndash113117

4022 J Nanosci Nanotechnol 15 4021ndash4038 2015



Bell et al Low Dose Traditional Nanophytomedicines

Iris R Bell received her AB in Biology from Harvard University and completed her

PhD in Neuro- and Biobehavioral Sciences and MD (Medicine) from Stanford Univer-

sity She is Professor Emeritus in the Department of Family and Community Medicine at

the University of Arizona College of Medicine and Research Professor at the University of

Arizona College of Nursing Her main research interests supported by both National Insti-

tutes of health (NIH) and private foundation grants have focused on nonlinear complex

adaptive systems psychophysiological processes and basic science of complementary and

alternative medicine interventions in chronic disease She has more than 140 publications

and 30 book chapters Most recently she received competitive grant support to examine

the nanoparticle nature of classical homeopathic medicines and related natural products in

the treatment of cancer

Barbara Sarter is currently Professor in the School of Naturopathic Medicine at Bastyr

University California Previously she was Associate Professor at the University of South-

ern California Keck School of Medicine Dr Sarter organized the International Research

Consortium on the Banerji Protocols which is attempting to advance research on the

nano pharmacological approach using natural substances that is practiced at the PBH

Research Foundation in Kolkata India Her research background includes studies on nutri-

tional approaches for health promotion and natural substances for cancer treatment and

prevention

Leanna J Standish received her PhD in NeuroscienceBiopsychology from the Univer-

sity of Massachusetts and her ND (Naturopathic Medicine) from Bastyr University Dr

Standish is Research Professor for the School of Naturopathic Medicine at Bastyr Clinical

Professor for the School of Public Health at the University of Washington and Affili-

ate Research Professor in the University of Washingtonrsquos School of Medicinersquos radiology

department She is Board-certified in naturopathic oncology Dr Standish has also been

the medical director of the Bastyr Integrative Oncology Research Center (BIORC) and

a clinical research professor at the Bastyr University Research Institute She has served

as principal investigator on several National Institutes of Health (NIH) research grants

since 1994 Currently her research is focused on the Asian medicinal mushroom Tram-

etes versicolor in the treatment of breast and prostate cancer functional brain imaging in

the treatment of brain cancer and the development of integrative oncology outcomes studies New projects using IV

Resveratrol and IV Curcumin to treat cancer are being developed

Prasanta Banerji is Founder and Managing Trustee of the PBH Research Foundation

Fellow of the Mihijam Institute of Homeopathy and well known for establishing the

Banerji Protocols of treatment using Homeopathic Medicines internationally Research

areas include the treatment of every type of cancer and other serious illnesses which have

ensured replicability and helped produce vast amounts of data for meaningful research

which in turn has led to the acceptance at the Best Case Series program of the National

Cancer Institute (NCI) of USA He has been disseminating the protocols by lectures and

teaching seminars and has a number of published papers book chapters and books on the

subject

Pratip Banerji is Co-founder and Dy Managing Trustee of the Dr Prasanta Banerji

Homoeopathic Research Foundation (PBHRF) a consultant physician since 1991 with a

Bachelors Degree-BHMS from the Calcutta University He is also a Doctor of Medicine

MD(Hom) from the JRN Rajasthan Vidyapeeth (Deemed University) Udaipur in India

has played an important role in conducting research on the efficacy of treatment under the

Banerji Protocols The process of data accrual and documentation according to the highest

international standards was introduced by him This has made their research acceptable to

the international scientific community He has been disseminating the protocols by lectures

and teaching seminars and has a number of published papers book chapters and books on

the subject

J Nanosci Nanotechnol 15 4021ndash4038 2015 4023




Figure 1 Polydisperse size distribution of zinc metal nanoparticles of

homeopathically-prepared Zincum metallicum at 30C and 200C potencies

from two different manufacturers (SBL and WSI) Reprinted with per-

mission from [54] P S Chikramane et al Homeopathy 99 231 (2010)copy 2010 Churchill Livingstone

2 HOMEOPATHIC MANUFACTURINGPROCEDURES FOR NATURALNANOMEDICINES

21 Overview of Traditional Homeopathic MedicineManufacturing

Many skeptics globally reject homeopathy on the basis

of a concern about one aspect in the preparation of its

medicines without understanding specifics of what the

manufacturing procedures or rest of the field encompasses

Simplistic dismissal of an entire field risks missing the

relevance of this traditional approach to nanomedicine

in terms of actual manufacturing procedures range of

medicine doses used in treatment and 200 years of clin-

ical experience Homeopathic dosing methods are unique

and potentially informative for developing safer methods

for administering nanomedicines to patients in general

At the same time understanding homeopathic medicines

as crudely-made natural nanomedicines can also help clar-

ify the documented variability of basic preclinical and

clinical research findings69

The impact of integrating information from nan-

otechnology with homeopathy should lead to improved

consistency of data going forward The most controver-

sial principle of homeopathic medicine is the assertion

that serial dilutions of the bulk form of a natural prod-

uct to concentrations that are the reciprocal of Avogadrorsquos

number (110)minus23 nonetheless leave an active agent Until

the discovery of persistent source nanoparticles and silica

despite bulk form dilution53ndash55575960 there has been no

plausible physical mechanism to support such a claim

Homeopathic manufacturing methods are inherently

simple green and natural in their reagents with an

emphasis on mechanical attrition techniques andor plant

biosynthetic methods for generating nanoparticles in aque-

ous solutions at room temperature In nanotechnology it is

known that nanoparticles from mechanical attrition are pro-

duced by a top-down process using a mechanical device

generically described as a mill70ndash73 Notably extended peri-

ods of agitation by high energy ultrasonication of plant

starch in water alone can produce starch nanoparticles74

Samuel Hahnemann MD a physician-chemist and

founder of homeopathy originally designed his mechani-

cal techniques in the early 1800rsquos and refined them in his

writings until his death in 184375 His words (translated

from German) were75 ldquo This remarkable alterationin the properties of natural bodies is achieved throughmechanical action on their smallest particles by tritura-tion grinding in milk sugar and succussion agitation inethanol-distilled water solutions while these particles areseparated from one another by means of an interveningindifferent substance that is either dry or liquid rdquo

Thousands of different medicines each made with simi-

lar procedures from specific members of the plant mineral

and animal kingdoms contribute to the overall contempo-

rary homeopathic materia medica worldwide76ndash79 Homeo-

pathic manufacturing methods overlap crudely with those

of modern top-down nanoparticle mechanical attrition

manufacturing techniques and plant-based biosynthetic

bottom-up methods40627080 Plants are among the various

biological materials that can synthesize nanoparticles of

metals or silica from their precursors in solution However

neither homeopathic researchers nor commercial clinical

suppliers have usually provided the types of details neces-

sary to reliably replicate production of specific nanoparti-

cles of a given size shape distribution surface charge or

other properties relevant to their biological effects8182

Indeed homeopathic basic research reveals objectively-

measurable differences between verum medicines and

succussed controls8384 but variability of specific find-

ings from study to study85ndash88 UV-vis and Raman

spectroscopy8489 as well as thermoluminescence83 are

among the technologies that show differences between

verums and controls All three of these technologies are

also used to study properties of various modern manufac-

tured NPs90ndash92 Like nanoparticles93 at least three studies

on homeopathic medicines have shown aging effects of liq-

uid samples stored in glass619495 However aging status

of test solutions is rarely assessed or reported in homeo-

pathic studies

Variations in manufacturing methods and materials with

resultant variability of the test medicines could contribute

substantially to the situation of inconsistent research

findings96 Top down mechanical methods for NP produc-

tion are well-known to cause variable defects in the final

products7097 Homeopathic medicine research test mate-

rials are typically liquids which would be susceptible to

nonlinear NP aggregation processes that change their sur-

face chemistry reactivity98ndash101 On the other hand many





commercial homeopathic clinical products are dried onto

lactose or lactose-sucrose pellets immediately after manu-

facturing a step that could stabilize and retain nanostruc-

tural integrity46102ndash106

Integrating modern nanoparticle manufacturing and

characterization methods107 and relevant bioassays108ndash110

could guide homeopathic manufacturers and researchers

to generate more reproducible products and experimental

findings Still some NP suspensions eg fullerene C60

NPs produced top-down by extended mixing in water and

sonication (agitation) can exhibit inherently uncontrolled

variability in batch-to-batch properties such as average par-

ticle sizes size distribution and ultraviolet visual spectro-

scopic patterns101 Mere dilution of fullerene C60 NPs can

also by itself introduce variability of colloidal properties

compared with a more concentrated parent suspension111

The fundamental steps for making all plant- and

most other natural source material derived homeopathic

medicines are

bull Preparation of an ethanolic herbal extract of the origi-

nal plant source or grinding and milling fresh raw plant or

mineral materials then added directly into ethanolic solu-

tions (manufacturers can differ on how homeopathic plant

medicines are prepared from raw materials)

bull For insoluble inorganic and organic source materials

such as metals and some mineral salts as well as cer-

tain plant and animal parts initial grinding and milling of

the natural raw source material in dry lactose for many

hours (termed ldquotriturationrdquo) Notably in nanotechnology

mechanical milling of lactose generates a variety of differ-

ent sized nanoparticles and nanocrystals of lactose itself112

Ball milling plant material for hours can generate silica

NPs71

bull Serial dilutions and multiple succussions per dilution

step (intense up and down agitation inside a glass con-

tainer) in liquid diluent typically ethanol-water or distilled

water

Common dilution ratios include 110 or 11001 part

source material to 9 parts diluent (X or D dose series) or

1 part source material to 99 parts diluent (C dose series)

Every insoluble source for a homeopathically-

prepared medicine begins by being ground up in lactose

for hours to make low potency dry dilutions (bulk mate-

rial diluted but not exceeding the reciprocal of Avogadrorsquos

number ie less than 24X or 12C potency)

Every dose of homeopathic medicines prepared past

the lowest dilutions is made by placing source material

into a glass container of ethanol-water solvent (typically

up to 90 vv ethanol but sometimes 0 20 43

or 70 ethanol) for making high potency dilutions (bulk

material diluted and exceeding the reciprocal of Avo-

gadrorsquos number ie higher than 24X or 12C potency) and

succussing (violently agitating) the flask or container 10

or more times after each ldquodilutionrdquo step53

From nanotechnology variations in ethanol con-

centration113ndash117 andor variations in dilution factors100111

can alter the resultant NP properties especially zeta poten-

tials and surface reactivity with other materials

Potentially parallel to the effects of multiple suc-

cussions in homeopathy a recent nanotechnology study

has shown that longer periods of ultrasound agitation of

plant starch granules in water can produce 30ndash100 nm sized

starch nanoparticles mechanically without any toxic chem-

ical treatment74 Longer periods of ultrasound agitation led

to progressively smaller sized starch NPs as small as 30 nm

after 90 minutes Notably increased numbers of succus-

sions can reportedly heighten the biological effects of a

given homeopathic medicine potency in an experimental

plant development model118

Moreover the extensive mechanical agitation of

liquid forms of the medicines (succussions) likely facil-

itates dispersion of any nanoparticle agglomerates or

aggregates that might form after initial production119

Homeopathic manufacturers may use manual pounding of

the glass container on a hard elastic surface vortexing or

sonication to perform their multiple agitations120

bull Final commercial products in ethanol-water solutions

are sprayed or poured and dried onto dry lactose (or

lactose-sucrose) pellets for ease of transport and dis-

pensing In homeopathic manufacturing only lactose and

sucrose are used Nanotechnologists have found that not

only lactose and sucrose but also fructose maltose glu-

cose and honey can all serve as biochemical reducing and

nanoparticle capping agents49121ndash124 as well as biological

carriers for nano-proteins105 and other NPs112

Modern homeopathic manufacturers each use variations

of the same original procedures and natural materials that

Hahnemann used However instead of manual mortar and

pestle grinding and agitation of subsequent ethanol-water

solutions within the glassware some homeopathic com-

panies utilize ball milling or similar methods to accom-

plish the grinding in lactose The methods for agitating the

ethanol-water solutions (succussions) also vary between

manufacturers Some perform manual succussions against

a hard elastic surface eg a book or even the palm of the

opposite hand Others have developed proprietary mechan-

ical arms to mimic the action of a human arm pounding the

glass container against a hard rubberized or elastic surface

with a relatively consistent arc and force Still others uti-

lize modern vortexing or sonication procedures to agitate

the solutions120125

For lower potencies manufacturers often use the Hah-

nemannian dilution method of removing one part of the

powder or solution from the previous triturated or suc-

cussed container placing it into a new container of 9 parts

or 99 parts either dry lactose (at the lowest potencies)

or ethanol-water solvent (for some low and all higher

potencies) For making higher potencies many manu-

facturers revert to the Korsakovian dilution method of

pouring off 9 parts (X potencies) or 99 parts (C poten-

cies) of the previously-succussed solution and repeatedly





refilling the same glass tube or container with fresh

solvent before resuming the next set of succussions

Thus certain lower homeopathic medicine potencies will

entail use of a new glass container for each prepara-

tion step whereas higher potencies often involve only a

single reused glass container for later preparation steps

Manufacturers may or may not specify their dilution

methods and materials for a given potency on their web-

sites Few commercial producers specify their glassware

sources despite its increasingly likely role in homeopathic

medicine production555759126127

The importance of these procedural details is that

at least 6 different laboratories have replicated evidence

for silica derivatives andor silicon in borosilicate or

soda lime glass-succussed but not plastic-succussed

liquid homeopathic medicines and succussed solvent

controls5557596189120128 Given recent evidence that spe-

cific glass materials from different manufacturers can

release different amounts of nanosilica and its precursors

into solution129 the sources sizes shapes and inner

surfaces of the glass containers themselves may con-

tribute indeterminate variables and variability to the

final products130 Any adsorption or binding of plant or

other nanomedicine source materials might adsorb to the

inside container walls andor coat some of the nanosil-

ica (or vice versa) in solution and modify the biological

effects106131ndash133 Silica NPs can also serve as carriers with

organosilanes as possible building blocks for synthetic

nanomaterials templated around the specific medicine

source65134ndash136 Rough versus smooth NP surfaces137 and

different shapes138ndash140 as well as particle defects and sur-

face charge variations may contribute another source of

variability to the homeopathically-manufactured materials

The ability of silica crystals and nanoparticles to stim-

ulate vigorous immune system adjuvant activation is

well-documented in the nanomedicine literature30141ndash143

Thus the presence of variable amounts of nanosilica

and silicon-based strtuctures could amplify biological

effects of even a small amount of source materials141

but in a correspondingly variable manner144 Ethanol

itself can dope nanosilica to change its optical fluores-

cence properties116 Silica and some metal NPs can also

self-assemble larger nanostructures from 3-dimensional

structural and electromagnetic information from epitaxial

templates such as viruses proteins DNA plant steroids

cells or calcium phosphate nanoparticles in solution with

the silica65134145ndash152 No homeopathic studies to date have

examined the inside walls of the succussed glass containers

as a silicate-rich adsorptive and adhesive area for source

nanoparticles133153 nanobubbles from succusions53 and

their possible release with agitation

All homeopathic medicine preparation occurs at room

temperature though the specific ambient temperature

may vary between manufacturers in terms of indoor

room air conditioning or heating Homeopathic pharma-

copoeia regulatory standards in various countries spec-

ify the medicine sources lactose and ethanol reagents

and preparation steps at room temperature although no

pharmacopoeias currently dictate in their documentation

any specific particle sizes or characterization methods for

the final products Unlike Hahnemann some contempo-

rary homeopathic manufacturers use container materials

such as polypropylene or polyethylene rather than glass in

which to succuss their products59120 materials likely to

generate different types of nanostructures154ndash157 Nanotech-

nology research has repeatedly documented the ability of

variations of manufacturing parameters such as solvent

type and concentration reducing and capping agents pH

temperature sonication force and duration to modify the

resultant nanoparticles made4874112ndash114158159 Seemingly

trivial differences such as lactose on the surface of silver

NPs for instance increases their rate of uptake into cancer

cells48

22 The Debate Over ldquoDilutionrdquo versus HomeopathicManufacturing Procedures

The debate over the validity of homeopathy as a clini-

cal treatment stems primarily from the serial dilution steps

during manufacturing The claim of skeptics is that for

high potencies that is serial bulk form ldquoultra-dilutionsrdquo

past the reciprocal of Avogadrorsquos number (6times 1023mdashie

24X or 12C potencies and higher) homeopathic medicines

could only serve as biologically inert placebos They

rarely address the facts that (a) homeopaths also use

low potencies that are not ultra-diluted or (b) the objec-

tive laboratory data using different technologies show that

homeopathic medicines at low and high potencies dif-

fer from control materials with unique physico-chemical

patterns838489160161 Animal plant and cell culture stud-

ies also show biological activity of low and high potency

homeopathic medicines69 There are many scientific lim-

itations to such a globally dismissive assumption that all

homeopathic medicines are merely biologically inert plain

solvent (Table I)

First the simplistic negative argument might be rel-

evant if homeopathic medicines were only bulk form

drugs andor prepared by simple dilution On the con-

trary the objective empirical evidence suggests that

both low and high potencies of homeopathically-

prepared metal (gold silver copper zinc tin plat-

inum) plant (Pulsatilla Belladonna Colchicum) and

conventional medicines (Phenazepam Panovir) contain

source nanoparticles1754ndash56 Quantities of source NPs

across different manufacturers and batches are variable

and low but nevertheless present54 Other investiga-

tors have also identified reproducible differences at the

nanoscale between homeopathically-prepared medicines

and homeopathically-prepared solvent controls60 Low

doses of NPs are biologically much more active than are

low doses of the ldquosamerdquo source material in bulk form2226





Table I Biological effects of exemplar homeopathically-manufactured (nano)phytomedicines at homeopathically-manufactured potencies on cells

animals and human subjects including control groups

Homeopathic phytomedicine Biological effects

Aconitum napellus In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen

species and nitric oxide production217

In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and

differential expression of 147 genes in mouse macrophages218

In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts

micronucleus and DNA damage in non-human primates219

4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human

viruses220

4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and

anti-inflammatory cytokines by human white blood cells221

Aloe vera 3X 6X 12X 30X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated

release of pro- and anti-inflammatory cytokines by human white blood cells221

Arnica montana 30C potency reduced genotoxicity of sonication stress in mice222

Combination homeopathic product including Arnica 3X potency blocked experimentally-induced edema in rat paws223

Combination homeopathic product including Arnica 4X potency stimulated fibroblast migration and promoted

experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on

cell migration224

30C potency upregulated DNA repair genes compared with controls in E coli bacterial model exposed to ultraviolet

irradiation225

Asclepias vincetoxicum 6X 10X 30X potencies as part of a combination homeopathic product demonstrated antiviral activity independent of

activation of the cellular interferon system226



Bryonia alba In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen







viruses220

Calendula officinalis Combination homeopathic product including Calendula 4X potency stimulated fibroblast migration and promoted


cell migration224

Chelidonium majus 30C and 200C potencies caused significant amelioration of p-DAB induced hepatocarcinogenesis227

Coffea cruda 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on

electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229

30C potency caused increased power in slow wave delta sleep of rats compared with controls230 effect was similar to

that of bulk form caffeine 200C potency affected only electroencephalographic synchronization231

Conium maculatum 30X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and


Eupatorium perfoliatum 3X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human

viruses220



30C potency caused a maximum 60 inhibition of parasitemia in a rodent model for malaria infection232

Euphorbium officinarum 6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and


Gelsemium sempervirens Reduced anxiety-related behaviors in open field testing at 5C 9C and 30C potencies comparable to conventional

anxiolytic drug buspirone in mice186 233

Anti-cancer effects of 2C potency on HeLa cells120



Hydrastis canadensis 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos

Lymphoma Ascites induced-tumors by 694 and 1 M (1000C) potency reduced metastases of melanoma-affected

mice234 235

Hypericum perforatum Combination homeopathic product including Hypericum 4X potency stimulated fibroblast migration and promoted


cell migration224





Table I Continued


Lycopodium clavatum 1 M (1000C) potency reduced metastases of melanoma-affected mice234

200C potency reduces cytogenetic damage from exposure to chemical carcinogens in mice236

Nux vomica 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on


30C 200C and 1000C potencies restored righting reflex sooner than untreated controls in mice injected with ethanol

4gkg challenge237

30C potency caused transient reduced coherence of electroencephalographic signals in otherwise healthy rats238

Phytolacca decandra Homeopathic mother tincture reduces proliferation activates caspase-mediated signaling and reactive oxygen species

generation with DNA damage in A375 cancer cells but not healthy lymphocytes239

200C potency exhibited inhibitory effects on 2 different breast cancer cell lines compared with solvent controls with

no difference in survival of healthy breast tissue cells from solvent controls240

3X 11X 19X 27X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated


Pulsatilla nigricans 3X potency produced greater anxiolytic effects than 6X potency or bulk diazepam drug in mice on a common measure

of anxiety (elevated plus maze and open field test)241

6C 12C and 30C potencies by olfactory sniff administration produced significant effects on waking spectral alpha

electroencephalographic magnitudes in healthy young adults with constitutional traits of Pulsatilla patients controlled

for placebo sniffs242

Ruta graveolens 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos

Lymphoma Ascites induced-tumors by 497234 243

Ruta 6C in combination with Calcarea phosphorica 3X induced survival-signaling pathways in normal lymphocytes but

apoptosis-signaling pathways in human brain cancer cells194

Secale cornutum 30C potency induced changes in histological cytogenetical signal and pro-apoptotic proteins and other biomarkers of

skin papilloma in mice244

Symphytum officinale 6C potency enhanced bone formation around titanium implants in rats compared with controls245

Combination homeopathic product including Symphytum 6X potency stimulated fibroblast migration and promoted


cell migration224

Taraxacum officinalis 1X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and


Thuja occidentalis Potency induced apoptosis in Daltonrsquos Lymphoma Ascites cells235 and 1 M (1000C) potency reduced metastases of

melanoma-affected mice234

In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen








Viscum album 8X 16X 24X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated release

of pro- and anti-inflammatory cytokines by human white blood cells221

Moreover in a recent paper from Langmuir Chikra-mane et al53 used manufactured gold nanoparticles to

demonstrate that applying Hahnemannian homeopathic

manufacturing methods makes the difference Performing

serial dilution after trituration in lactose and succussion

in 90 vv ethanol solvent of modern manufactured gold

nanoparticles causes a heterogeneous distribution and lay-

ering of the nanoparticles in part because of nanobub-

bles surrounding the NPs and rising toward the liquid-air

interface Consequently the nanoparticles are then trans-

ferred from container to container over the course of bulk

form dilutions albeit in variable amounts (Fig 2) Bulk

form materials were removed during homeopathic serial

ldquodilutionsrdquo but the nanoparticles triturated in lactose and

succussed in ethanolic solutions persisted across serial

container transfers

Korsakovian homeopathic manufacturing methods

within the same glassware container also may involve

source NP- and silica-related interactions For instance

separate from homeopathic research Kiel et al have

shown that agitation of salt solutions can concomitantly

generate and embed salt nanoparticles on glass or poly-

mer surfaces133 Furthermore the repeated agitation and

pouring of solvent solutions in and out of the same con-

tainer during homeopathic Korsakovian steps would add

capillary forces for charged particle attachment to some

silicate surfaces117 Such inner silica surfaces would be

progressively roughened and partially worn down by the





Figure 2 Retention and transfer of gold source nanoparticles from container to container during homeopathic manufacturing procedures Lactose

trituration and succussion together offset serial ldquodilutionrdquo effect for NPs but not bulk form materials Reprinted with permission from [53] P S

Chikramane et al Langmuir 28 15864 (2012) copy 2012 American Chemical Society TL = Top layer ML =Middle layer ICP-MS = Inductively-

coupled plasma-mass spectroscopy

Notes This study found that nanobubbles formed during succussions can contribute to heterogeneous accumulation of the nanoparticles toward the

top layer of solution (froth flotation) if the metal nanoparticles were first mechanically ground in lactose per homeopathic manufacturing procedures

Middle layers in solution and bulk material contained lower and much less consistent quantities of the original gold nanoparticles

effects of the many cumulative succussions of the liquids

within the same glass container117162ndash164

At this point three different research groups have pre-

sented either electron microscopic evidence or dynamic

light scattering (DLS) data documenting persistent

nanoparticle forms of source materials in homeopathically-

manufactured medicines54ndash56 A fourth research group has

demonstrated that homeopathic ethanolic plant mother

tinctures of Gelsemium Hydrastis Phytolacca and Thujacan each biosynthesize well-characterized silver nanopar-

ticles from aqueous silver nitrate precursor40 The resul-

tant plant-modified silver NPs had different and distinct

patterns of sizes on electron microscopy dynamic light

scattering characteristics zeta potentials and biological

activity against E Coli bacteria and melanoma cancer cells

on in vitro testing40

Such findings follow repeated evidence involving mul-

tiple different types of spectroscopy thermoluminescence

and other technology that homeopathically-prepared mate-

rials in potencies differ objectively from plain or succussed

solvent controls838494160165 These verum medicines

also retain the unique ldquofingerprintsrdquo of their original

source materials on thermoluminescence testing83 Simi-

larly in nanoscience research specific metal nanoparticles

eg iron or copper NPs can enhance their thermolumi-

nescence response compared with pure silica samples92

Second the empirical evidence from multiple inde-

pendent laboratories has shown not only clinical ben-

efits but also objective changes in biological markers

in cells animals and human subjects at both low and

high potencies compared with controls166167 Table I

summarizes exemplar controlled studies using objec-

tive biomarkers of homeopathic phytomedicine effects

Skeptics rarely address the controlled cellular animal

or physiological evidence showing biological effects of

homeopathic medicines167ndash169 They also fail to distinguish

between lower and higher potencies in terms of the plausi-

bility argument Variability in findings from study to study

would be expected based on the crude traditional manu-

facturing procedures However negative findings in some

studies would not exclude the presence of NPs with bio-

logical activity in other positive studies on homeopathic

medicines The issue becomes an empirical question for

objective characterization of NPs and biological activity of

the same materials in a given study

Third numerous randomized clinical trials and asso-

ciated meta-analyses have many methodological flaws

including the obviously-inappropriate application of meta-

analysis to validate or invalidate an entire system of

medicine by combining only 8 studies across all pos-

sible diagnoses homeopathic medicines and providers

let alone study designs170 External and model validity

of study designs are also often overlooked in RCTs of





homeopathy171 The scientific answers obtained to date

are that homeopathic medicines are not and do not

act like conventional bulk form drugs The reader is

referred to other resources for a more detailed discus-

sion of the debates over the validity and plausibility of

homeopathy167169172173

It is no longer sufficient however to use the circular

argument that any study demonstrating positive biological

or clinical effects is a fluke because of the lack of any plau-

sible active agent in homeopathically-prepared medicines

Plausible active and measurable NPs of source and silica

are present53ndash5659120165 Because of their heightened bio-

logical reactivity doses of nano-forms of plants drugs and

antigens can be far lower than for bulk forms of the same

materials to achieve comparable effects2026143 Thus low

Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous

adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose

effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological

ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur

doses of homeopathically-manufactured NPs per se do not

preclude the potential for significant biological effects

The more interesting questions are currently at the

basic science and preclinical phasesmdashhow are the

homeopathically-prepared nanophytomedicines and other

NPs biologically active (Table I)174 How might they work

to stimulate systemic healing in an organism175 Then

how could additional research optimize the benefits for

clinical care What factors can inactivate homeopathically-

prepared medicines (eg heating direct sunlight certain

electromagnetic fields)95176 Despite its past controversial

history homeopathic medicine is positioned to contribute

valuable insights and guidance into how to make and use

nanophytomedicines and other natural NPs for safe and

effective care including in infections and cancer





Homeopaths have spent over 200 years using thousands

of these different natural nanoscale medicines many of

them plant-derived to treat a full range of acute and

chronic conditions in millions of patients The short- and

long-term safety data and patient acceptability of these

medicines are very favorable67177 The data suggest that

the doses of the homeopathically-made nanoparticles are

low and clinicians typically use each dose in a care-

fully timed and pulsed manner The goal of homeopathic

treatment is to stimulate innate healing processes systemi-

cally in the organism not to enforce local ligand-receptor

effects for local symptom suppression (Fig 3) Looking

for simple ligand-receptor mechanisms for isolated symp-

toms may not be productive

Conversely modern nanotechnology and particle char-

acterization and testing tools offer essential methods

for updating the 200-year-old manufacturing techniques

standardizing products and optimizing therapeutic effec-

tiveness of homeopathic medicines The absence of a way

to detect characterize and measure the active constituents

in homeopathic medicines has historically stymied high

quality clinical research The translation of NP technol-

ogy to homeopathic medicine will improve homeopathic

medicine research Conversely the translation of homeo-

pathic principles and practices will hasten important dis-

coveries in the emerging field of nanomedicine

3 PULSED DOSING AND NONLINEARDOSE-RESPONSES

31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several

laboratories that source NPs and silicate nanostructures

are present in homeopathically-manufactured medicines

Other independent properly controlled studies using state-

of-the-science technologies such as transmission electron

microscopy dynamic light scattering zeta potentials and

nanoparticle tracking analysis will offer additional data on

identifying and characterizing the NPs40107 when present

assuming that future studies support the already accumu-

lating evidence for the presence of different sizes and

quantities of nanoparticles in homeopathically-prepared

medicines dosing regimens and safety are key issues Here

the extensive clinical experience of homeopaths comes

into play and could facilitate progress on NP dosing in

nanomedicine overall

While homeopathic NP sizes may be polydisperse

homeopathic medicine source NP doses are low and very

low mostly likely in the picograms up to 4 nanogram

milliliter range5354 In different studies silicon mea-

surements in homeopathically-prepared medicines have

ranged from 24 parts per million55 to 19ndash23 parts per

million59 and 1ndash4 mgmL57 No studies to date have

examined the potential amplification or interaction of

the source NPs with silica and silicon NPs in these

medicines Evidence from nanotechnology research sug-

gests that ensembles or multiple sizes of the same

material may contribute self-similar178 self-amplifying

effects179180 Silica and silicon nanostructures will also

add non-specific amplifying capabilities30143181 but may

also serve as drug delivery vehicles modified or imprinted

by the natural source materials for the specific medicine

Some homeopathically-prepared materials can emit mea-

surable unique electromagnetic signals165

Overall the convergent evidence suggests that phys-

ical chemistry and electron microscopic methods used

to detect nanoparticles can also distinguish specific

homeopathically-prepared medicines from solvent con-

trols Thus from nanomedicine we learn that Raman

and UV-vis spectroscopy182 and thermoluminescence92

together with other composition and particle charac-

terization techniques54 might translate ultimately into

quality control standards for homeopathic manufacturing

procedures

Moreover homeopaths emphasize the pulsed spac-

ing of repeat doses Patients typically take homeopathic

medicines by dissolving the sugar pellets under the tongue

but olfactory and dermal routes of administration are also

possible75 A subset of homeopathic clinicians favor dis-

pensing the medicine in liquid form or redissolving the

pellets in water and succussing the material immediately

prior to oral administration The latter strategy likely redis-

perses any nanostructures into smaller sizes119129

The frequency of repeat dosing is inversely related

to the homeopathic potency Thus in an acute illness

or many cancers a patient might take a homeopathic

medicine at a 6C potency every 2ndash4 hours whereas

they might take a 30C potency of the same medicine

every 8ndash12 hours If they were taking the medicine for a

slower-paced chronic disease at a higher potency such as

200C dosing might occur as infrequently as once every

few months or longer One animal study of four dif-

ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-

tion of their effects on restraint stress-induced catalepsy

was longer at the 200C potency than the 30C potency183

This type of prolonged action is reminiscent of reduced

doses and widely-spaced dosing regimens possible with

nano-forms of conventional drugs eg in tuberculosis ani-

mal models25184 in a transplant graft survival drug26 or

an autoimmune type 1 diabetes animal model185

Although cell plant and animal studies suggest the

likelihood that consecutive potencies exhibit a highly

nonlinear sometimes sinusoidal dose-response pattern

(Fig 4)56186ndash191 most clinicians rely on certain potencies

eg 6C 12C 30C 200C and employ their own empir-

ical systems for determining the choice of a low or high

potency for a given patient One protocol-based system

for cancer treatment reports a systematic determination of





Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to

homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving

a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and

ethanol control solutions were also succussed

Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution

a diagnosis-based low or high potency selection approach

for each medicine192ndash194 but clinical studies to evaluate

these potency selection issues are as yet not published

Given the evidence that different nanoparticle and clus-

ter sizes of the ldquosamerdquo composition material can lead to

differential nonlinear effect patterns30158195ndash197 it will be

crucial for future homeopathic research studies to test con-

currently (a) the nanoparticle characteristics and (b) bio-

logical effects of consecutive potencies

Finding source and silica NPs in homeopathic medicines

is an important advance in bringing this traditional sys-

tem of medicine into better scientific focus A body

of research already shows objective biological effects of

homeopathically-prepared plant-based medicines in cells

animals and human subjects at both lower and higher

potencies (Table I) However despite the enhanced bio-

logical reactivity of nanoparticle forms of natural mate-

rials such as plants the question of low dose effects

remains The next research challenge for the field is to

relate the available data to nonlinear endogenous ampli-

fication mechanisms underlying low dose effects of both

NPs and homeopathic medicines175198ndash200

32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of

homeopathic nanomedicines might restore health focuses

on the endogenous amplification capacity of the organ-

ism as a complex adaptive system175200 Complex adaptive

systems exhibit nonlinear dynamics self-organization and

emergent properties201 Disease and aging lead to a loss

of dynamical complexity202 Properly timed low intensity

stimuli can initiate a cascade of nonlinear adaptive bio-

logical events to restore systemic complexity especially in

the stress response networks of the body203

Various investigators have proposed three specific per-

haps overlapping mechanisms175 These all depend upon

interactions of a low dose of the salient homeopathic

nanomedicine with the history and state of the organism

(Table II) Endogenous amplification occurs as an inher-

ent aspect of the organismrsquos adaptive response capacity

The mechanisms include hormesis time-dependent sensi-

tization and stochastic resonance All three mechanisms

include the potential to reverse the direction of the sys-

temrsquos dynamics from a diseased pattern back toward a

healthier pattern It is beyond the scope of the present

paper to address the relevant issues and data in detail

However Table II provides a summary of definitions and

relevant citations for further reading The reader is referred

to the additional papers to consider this important topic in

greater depth200203

Nonlinear dose-response relationships involve both

enhanced magnitude and reversed direction of effects that

are disproportionate to the size and nature of the input

signal A unique aspect of nanoscale forms of herbs and

medicines compared with their respective bulk forms is

the multiple perhaps interacting ways in which response

amplification can occur Below is an overall summary of

possibilities175

Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface

area and altered surface charge properties





Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms

require interaction of low doses with the organism as a complex adaptive system

Proposed mechanism Definition

Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function

Nanoparticles can cause hormesis206

Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated

(pulsed) doses of the same or a cross-sensitized drug stressor or other agent

Relies on the passage of time between doses for the organism to amplify biological and behavioral

responses247 Homeopathic medicines can cause TDS248

Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the

system249

In the case of disease the dysfunctions that characterize the unique manifestations of the emergent

system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo

The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175

bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of

polypropylene or polyethylene if succussed in plastic)120

bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor

nanosilicasilicon functionalized by plant or animal DNA

and proteins in a single homeopathically-prepared nat-

ural medicine Homeopathically-prepared nanomedicines

use the whole plant not purified single components and

generate multiple different sized NPs54

Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low

doses in a complex adaptive system206

bull Time-dependent sensitizationmdashfor elicitation of an

endogenously amplified response after initiation by the

same or another cross-sensitized agent or stressor reversal

of direction can occur with overly frequent dosing203207

bull Stochastic resonancemdashfor salience of the low dose as

a meaningful weak signal embedded in the larger back-

ground biological noise of the disease dysfunctions with

emergent properties across the organism as a complex

adaptive system208209

4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-

pathicallyndashprepared medicines is promising but

admittedly limited to date Other nanotechnology lab-

oratories have the necessary equipment to replicate

extend or refute the studies already published Highly

sensitive detection methods for low and very low con-

centrations of NPs but high levels of nonlinear biological

amplification are needed However the overlaps between

mechanical attrition methods for generating NPs and

manufacturing homeopathic medicines in their initial

steps are obvious Some homeopathic manufacturers even

use the same modern ball andor cylinder milling equip-

ment that contemporary nanotechnologists themselves

use to make contemporary nanomaterials from insoluble

sources (httphahnemannlabscompreparationhtml

accessed 051513)7173112 Thus triturated lower potency

homeopathically-prepared medicines most certainly con-

tain top-down NPs and perhaps micro-sized particles

coated with lactose55 Traditionally-made succussed

higher potency homeopathically-prepared liquid medicines

contain not only natural source NPs5455 but also sili-

cates from the glassware in amounts not seen in plastic

containers55575961

Why should nanoscientists invest time and effort to

understand homeopathic NPs and their mechanisms of

action in living systems We return to the fact that these

types of natural nanomedicines have had extensive field-

testing for safety across millions of patients in real-world

clinical practice for over 200 years Official pharma-

copoeias in many countries already contain monograph

documentation for the manufacture of well over 1000

different natural agents including hundreds of nanophy-

tomedicines all made with green manufacturing methods

Homeopaths have additionally field tested several thou-

sand more custom-prepared agents from the plant min-

eral and animal kingdoms7778210 In short homeopathy

like other traditional systems of medicine has already

been in phase 4-like post-marketing real-world use for

hundreds of years This status existed long before contem-

porary Western medicine formalized ldquonewrdquo drug develop-

ment phases for their own clinical agents211

Homeopathic NP doses are very low usually far below

the recognized cut-offs for toxic effects The pulsed

spaced infrequent repetitions of doses are another time-

tested clinical strategy that ensures little risk for

cumulative toxicity over time67 Nonlinear endogenous

amplification mechanisms are likely involved in the clini-

cal response These are vitally important considerations as

modern nanomedicine experts attempt to translate promis-

ing nanomedicines into clinical practice in a more expedi-

tious manner

The present discussion raises many questions but ones

that are amenable to experimental testing and verifica-

tion For example in addition to state-dependent nonlinear

responses in the recipient organism do variations in





nanoparticle quantities sizes shapes structural defects

and surface charges of these top-down homeopathic

nanoparticles and particle dynamics in solution98212ndash214

account for some replication problems in previous home-

opathic research as they can in other nanoscience

studies100101111

Also is the serial dilution process even necessary

to make homeopathically-effective nanophytomedicines

Perhaps Hahnemann needed to introduce ldquodilutionrdquo for

mechanical separation of the nanoparticles with lac-

tose or ethanol-water diluents simply to reduce the risk

of agglomeration and aggregation but the ideal is for

the higher potencies to contain a very low but mea-

surable and consistent quantity of polydisperse NPs

Repeated succussions would likely parallel extended peri-

ods of sonication in modern NP manufacturing proce-

dures for dispersion of larger nanostructures of different

sizes74119 potentially adding more nanosilica and nanosil-

icon as carriers134 surface imprinted structures134136 and

biological amplifiers141 Are there alternative green tech-

niques for accomplishing this same goal more reliably in

the era of contemporary nanotechnology

In conclusion the identification of nanoscale struc-

tures in traditional phytomedicine systems from tradi-

tional Chinese medicine to Ayurveda to homeopathy

opens the door to important advances in integrative health-

care The extensive histories of real-world clinical appli-

cations in these traditional fields especially homeopathy

can contribute a wealth of practical insights for guid-

ing translation of numerous natural nanophytomedicines

from bench to bedside58210215 Of the traditional sys-

tems of medicine homeopathy previously one of the

most controversial brings the most extensive experience

in manufacturing top-down and possibly biosynthesized

nanophytomedicines from members of many different

plant families77210 Modern nanotechnology can add great

sophistication to nanoparticle generation characterization

and biological testing techniques for homeopathically-

prepared nanomedicines107109216 In turn homeopathy

stands ready to point toward potential strategies and mech-

anisms for safe and effective use of pulsed low dose

nanomedicines in therapeutic contexts

Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands

Inc a US-based manufacturer of homeopathic medicines

Acknowledgment This study was supported in part

by National Center for Complementary and Alternative

Medicine grant T32 AT01287 (PI IRB)

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of serially diluted and agitated solutions Preliminary results

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(2011)136 R Zhu W Zhao M Zhai F Wei Z Cai N Sheng and Q Hu

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Chem 391 2469 (2008)139 S Pandey M Thakur R Shah G Oza A Mewada and

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(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D

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Imbeloni J A Muniz G R Pinto A Smith Mde and R R

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Received 25 June 2013 Accepted 12 November 2013





CONTENTS1 Introduction 4022

2 Homeopathic Manufacturing Procedures for

Natural Nanomedicines 4024

21 Overview of Traditional Homeopathic

Medicine Manufacturing 4024

22 The Debate Over ldquoDilutionrdquo versus Homeopathic

Manufacturing Procedures 4026

3 Pulsed Dosing and Nonlinear Dose-Responses 4031

31 Dosing Homeopathic Nanoparticles 4031

32 Nonlinear Dose-Response Mechanisms 4032

4 Conclusions 4033

Acknowledgment 4034

References and Notes 4034

1 INTRODUCTIONThe purpose of the present paper is to (a) summarize evi-

dence for the nanoparticle nature and biological effects of

traditional homeopathically-prepared medicines at low and

ultralow doses (b) provide details of historically-based

homeopathic manufacturing materials and methods relat-

ing them to top-down mechanical attrition doping and

templating of nanosilica and plant-based biosynthetic pro-

cesses in modern nanotechnology (c) outline the potential

roles of nonlinear dose-responses of hormesis stochastic

resonance and nonlinear dynamical interactions with com-

plex adaptive systems in generating endogenous amplifi-

cation processes during low dose treatment

Many cultures worldwide have relied on bulk form

plant-based natural medicines for hundreds to thousands

of years for treating acute and chronic health problems

Traditional Chinese medicine Ayurvedic medicine and

Western herbalism are all examples of highly-developed

historical approaches to natural product-based treatment

for conditions ranging from infections to cancers1ndash6

Herbalists argue for use of the whole plant or traditionally-

used intact plant parts (eg roots stem bark leaves)

rather than chemically-isolated individual nutraceutical

ingredients in order to obtain gentler and synergistic

effects of multiple natural constituents7 interacting with

the individual as an integrated complex adaptive system8

However as modern researchers have taken a closer

look at the strengths and limitations of traditional phy-

tomedicines they often identify poor absorption lower

bioavailability and limited patient tolerability as barri-

ers to more widespread adoption of herbs for clinical

care

Nanotechnologists are currently beginning to exploit the

ability of nanoparticulate (NP) forms of traditional botan-

ical agents to dramatically improve absorption bioavail-

ability and reduce side effects9ndash17 Because of their tiny

size (eg a log unit smaller than the wavelength of vis-

ible light) many NPs can readily cross cell membranes

including blood-brain barrier1819 The therapeutic dose

ranges for nanoscale forms of many agents are lower by

orders of magnitude compared with their respective bulk

forms20ndash26 Modern NPs offer additional therapeutic advan-

tages over bulk forms such as better intracellular access22

and targeting of cancerous cells while sparing healthy cells

in the organism27ndash32 Nanoparticles made from botanical

and nutraceutical agents have particularly low toxicity and

favorable side effect profiles1633ndash35

At the same time translation from bench to bedside has

been slow36 Concerns about uncertain toxicity profiles of

manufactured NPs persist37 Plants and fungi are among

the natural products used to biosynthesize potentially safer

forms of certain NPs eg silver or gold38ndash42 Plant biosyn-

thesis helps avoid toxic reagents during green manufac-

turing of nanomedicines43 Similarly reducing and coating

the surface of otherwise more toxic NPs with benign sug-

ars such as lactose sucrose maltose or glucose appears

to attenuate toxicity for nanomedicine use44ndash46 This strat-

egy is important because of the ability of nanoparticles

to adsorb onto other materials involved in their produc-

tion given their highly reactive surfaces NP adsorbants

such as plants or sugars can not only modify the sur-

face charge and physicochemical properties of the resultant

NPs but also enhance the beneficial biological effects of

the nanoscale agent4047ndash49 Still widespread clinical appli-

cation of plant-synthesized NPs and nanophytomedicines

does not appear imminent Many practical and regulatory

hurdles lie ahead

Nanophytomedicines might otherwise appear to be new

and relatively untested forms of treatment However inves-

tigators have begun to identify specific nanoscale materials

in certain Chinese herbs5051 and Ayurvedic medicines52

In addition recent studies have demonstrated that the his-

torical manufacturing procedures for making homeopathic

medicines another traditional system of natural medicine

also generate polydisperse source nanoparticles of differ-

ent sizes from quantum dot (1ndash10 nm) to larger nanoscale

structures (Fig 1) Convergent evidence indicates that

homeopathic manufacturing methods mechanically gener-

ate top-down nanoscale particles of the original source

material1753ndash56 as well as silicasilicon from the inside

walls of the glass containers5557ndash61 Previous nanoscience

research suggests that interactions of homeopathic plant

mother tinctures with silica precursors and silicon-derived

materials in solution might also generate plant-modified

(coated doped or imprinted) andor plant self-assembled

silica NPs404362ndash65

The unique green top-down and bottom-up biosynthetic

manufacturing and pulsed low dosing methods of homeo-

pathic medicine combined with the large pharmacopoeias

for hundreds of natural medicines and already established

regulatory standards for these agents provide a possi-

ble foundation for accelerating progress in translational

nanophytomedicine Homeopaths have had over 200 years

of real-world experience and an estimated more than

500 million patients worldwide66 in the safe and effective

use of thousands of their nanoscale natural products ie

homeopathic medicines6768111ndash113117























prevention






















subject










the subject














































































pathic studies
































medicines are














NPs71




water
































































the solutions120125























































































cells48



















solvent (Table I)































viruses220









cell migration224


irradiation225












viruses220



cell migration224









viruses220













mice234 235



cell migration224





Table I Continued







4gkg challenge237






















cell migration224





























container transfers



























































































































































































procedures



























































































greater depth200203








possibilities175

















system249













































containers55575961




























tious manner














studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)












































































































































































































prevention






















subject










the subject














































































pathic studies
































medicines are














NPs71




water
































































the solutions120125























































































cells48



















solvent (Table I)































viruses220









cell migration224


irradiation225












viruses220



cell migration224









viruses220













mice234 235



cell migration224





Table I Continued







4gkg challenge237






















cell migration224





























container transfers



























































































































































































procedures



























































































greater depth200203








possibilities175

















system249













































containers55575961




























tious manner














studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)



































































































































































































































































pathic studies
































medicines are














NPs71




water
































































the solutions120125























































































cells48



















solvent (Table I)































viruses220









cell migration224


irradiation225












viruses220



cell migration224









viruses220













mice234 235



cell migration224





Table I Continued







4gkg challenge237






















cell migration224





























container transfers



























































































































































































procedures



























































































greater depth200203








possibilities175

















system249













































containers55575961




























tious manner














studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)












































































































































































































medicines are














NPs71




water
































































the solutions120125























































































cells48



















solvent (Table I)































viruses220









cell migration224


irradiation225












viruses220



cell migration224









viruses220













mice234 235



cell migration224





Table I Continued







4gkg challenge237






















cell migration224





























container transfers



























































































































































































procedures



























































































greater depth200203








possibilities175

















system249













































containers55575961




























tious manner














studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)


































































































































































































































































cells48



















solvent (Table I)































viruses220









cell migration224


irradiation225












viruses220



cell migration224









viruses220













mice234 235



cell migration224





Table I Continued







4gkg challenge237






















cell migration224





























container transfers



























































































































































































procedures



























































































greater depth200203








possibilities175

















system249













































containers55575961




























tious manner














studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)




































































































































































































viruses220









cell migration224


irradiation225












viruses220



cell migration224









viruses220













mice234 235



cell migration224





Table I Continued







4gkg challenge237






















cell migration224





























container transfers



























































































































































































procedures



























































































greater depth200203








possibilities175

















system249













































containers55575961




























tious manner














studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)


























































































































































































Table I Continued







4gkg challenge237






















cell migration224





























container transfers



























































































































































































procedures



























































































greater depth200203








possibilities175

















system249













































containers55575961




























tious manner














studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)




































































































































































































































































































































































procedures



























































































greater depth200203








possibilities175

















system249













































containers55575961




























tious manner














studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)














































































































































































































































greater depth200203








possibilities175

















system249













































containers55575961




























tious manner














studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)




































































































































































































system249













































containers55575961




























tious manner














studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)































































































































































































studies100101111












































Med 2013 456747 (2013)









































































matogr A 1216 2254 (2009)





































(2011)



























































































































































































































matogr A 1216 2254 (2009)





































(2011)























































































































































































Low Doses of Traditional Nanophytomedicines for Clinical Treatment: Manufacturing Processes and...

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Transcript of Low Doses of Traditional Nanophytomedicines for Clinical Treatment: Manufacturing Processes and...