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Safety Assessment of Newly MarketedHerbal Medicine s-Methodologic al

Approach (Ginkgo bilobaExample inBulgaria)

Ilko N. GetovAlexandra Tv. Tzenova

Mile S. RistoffToncho V TodorovGuenka I. Petrova

ABSTRACT. This study presents a proposal for the methodological ap-proach for postmarketing safety profile assessment based on sales dataand information for adverse drug reactions of newly introduced herbalmedicinal products in the market.

The study covers all herbal medicinal products containing dry extractof Ginkgo biloba leaves allowed for sale in Bulgaria.

The methodological approach we create should be used for the estab-lishment of the national herbal drugs policy complying with the recentEuropean regulatory changes and specificity ofthe therapeutic practicein the country.

KBYWORDS. Ginkgo biloba,herbal drugs, safety profile, surveillance,drug policy

The authors are affiliated to the Faculty of Pharmacy, Medical University, Sofia,Bulgaria.

Address correspondence to: Genka Petrova, DSc, Faculty of pharmacy, 2 DunavSt., Sofi a BG- I 000, Bulgaria @-mai I : gpetrova@pharmfac.net).

Journal of Herbal Pharmacotherapy, Vol. 7(34),200jAvailable online at http://www.haworthpress.com/web/JHp

O 2008 by Informa Healthcare USA, Inc. All rights reserved.doi: I 0. I 080/1 5228940802153040 239

240 J O U RN AL O F H ER BAL P LI ARM ACOTLI ERAPY

l. Is the literature evidence guaranteeing the safety and efficacy of ob-served products?

2. Did the marketing authorizationidence ensure the safety of themarket?

INTRODUCTION

A long-standing and widespread use of herbs combined with the activedevelopment of a variety of new products containing herbs,t-3 with dif-ferent regulatory status.a-6 poses a question not only for their regulatorydifferentiation but also for their safety and etficacy in the proposediosage.sand combinations.T.s

Recent legislation changes in the European Community (EC) and en-dorsement of Directive 2oo4l24lEc on rradirional herbal medicinal prod-ucts (HMPs) introduce the term "traditional use" that allows shortenedprocedure for marketing authorizatiorr of products used for at least 30years, 1,5 of which in anv EC countrv.e. l0

The term "traditionai use" could not be emproyed for the accessioncountries like Bulgaria and herbs for which the second requirement of theDirective is not applicable. The national regulatory authoiities remarn re-sponsible for rhe markering aurhorizarion oi tt Mps ihut ur. nor "rraditional"for the geographic region and local experiencer-\ In case of positive mar-keting authorization based on definition for "traditional use," resulatorvauthorities should establish a reliable approach for safety assessrn'ent anipostmarketing control of newly compounded medicines for the geographicregion and therapeutic practice.

This study presents the methodological approach for saf-ety profile as-sessment based on sales data and information for adverse drug reactions(4PRs) of newly introduced HMPs in Bulgaria conraining the dry exrracrof Ginkgo bitoha leaves.

G. biloba medicinal products have been selected for the current examplebecause the herb is not traditional for local flora. All G. hitoho medicinalproducts in the study have been allowed for sale in the country using thcnational shortened "bibliographic procedure" that requires only literatureevidence for safety and efficacy of the herbal medicine.

The main questions discussed in this srudv are the followins:

,i

procedure based on literature ev-herbal products in the Bulgariarr

3. Is the information provided to the patients consistent with the literaturcevidence and ensures peoples' safety?

Getov et ul. 74 r

EXPERIMENTAL

An observationar prospective (fbrtow-up) study of sares data and liter_ature information about ADRs *;r;;;;g""9. Th. srudy covers a, HMpsallowed for sale in Bulgaria """r"i"i"g iir" gry exrract of G. birobareaves.

,r"fi t methodological ipproach *"

"a?p*a incl uaea n ve iuJ"".riu" rtuoy

l. Clarifying the registrarion status of -r!:r,produc.ts_Bulgarian DrugAgency (BDA) database f*.**.UaulU^g),, and drug referees fbr rhemedicines registered during ZOOO_iOfjg were review"4 r2, r 3 .2' corteuing tlok, a"to;iroriitill"uuout ;h"-JL, was gatheredvia manufacturers" int"*i"*ing "as wet as observing four ma-

l::J*:f *rers and 60,;;;;ry-,"r""t". -;6;,;;;;'?harmacies,

3' AnaryzinR safetv.data. in patient information reaflets (prLsFTheteaflets oi ar"HMps wirh G1 iii"'ir'iu.*ed for sare in Burgaria werereviewed for ADRs, safety, _O pr*r"rion info*uiion, ""..4. Analysis of literature sources assessing, t!r. 9ffirqry and soJbty_MEDLINE and Medscap" ;il ilr'*"rd, C inkgo bi[oba; saJ.ety andefficacy were searched.^6r, og3gial+i publications found, 2lra_3a that.tirfy the followrng requlrements were selected:I. Randomizedauthorization?controlled

trials (RCTs) before or after marketing

ta |^::;j:g.#th

medicinal products based on the srandardized pure

"t' lri:'rtttd during phase II, III, and IVa of the drug development

t" i;h"i:X#fjt'ution'

were svstem atizedaccording to the foilowingI' Disease for which the effectiveness andlor safety were evaruated;

-II. Author(s) and year of .tuOy; ----"

II- fyp" and lengtlh of ,tuay;lnO

^ IV. Analysed dosage fo._, _a."gimens.

flX'ilillrl:,'rt'ffi"i"r?:ild;ri#;;swerereassessedusingspss5. Applications of rhe phorygrorniarmiological methods(WHo CIOMSY:tll* Group rv and B""i;h;;;Jui">r,.. determination of thesenousness and outcome of ADRs report

porated in the pIL,s adverse reactions.44, led in the literature and incor-

242 .I O U RN AL O F H ER BAL PH ARM ACOTH ERAPY

RESULTS

Regulatory Status

The Bulgarian drug law endorses the marketing authorization proce-dures of medicinal products. The Ministry of Health specifies with Regu-lation 17 l2O0l the rules and necessary documentation for marketing autho-rization and with Regulation 712000 the requirements toward informationincluded in the PILs.a6-48

The HMPs' marketing authorization is granted according to three possi-ble subprocedures. In case of manufacturers' pretension for new therapeu-tic area or new medicinal product, the procedure based on full registrationdossier is applicable. The so-called "bibliographic procedure" requires thepresentation of administrative part of the dossier, chemical pharmaceuticalparts and bibliographic evidences on scientific publications on pharmaco-logical posology, as well as summarized and actualized literature evidenceon the clinical application of the active substances. In case of newly de-veloped combinations, products are requireb to fumish evidence for theadvantages of combination regarding risklbenefit ratio.

According to Regulationll20ffi, the information that is included in thePIL should comply with the summary of product characteristics and mustbe previously approved by the BDA. The data in the PILs of essentiallysimilar products should correspond with the originator. It is logical that thesafety data for all essentially similar products should be identical in thePlLs.

At the end of 2003, on the local market, four trade names in five dosageforms (four solid forms and one solution) approved after the "bibliographicprocedure" were found authorized for sale (Table l).

All products are containing standardized, regarding the quantity ofheterozides and bilobalides, dry extract of G. biloba (EGb 761). Out ofthem one is a combination and three are mono products Q7125 containing40 mg dry extract for a single-dose unit. In addition, one is a combinationand three are mono products containing 40 mg dry extract for a single-doseunit. The combination contains l4 mg G. biloba,300 mg troxerutin, and300 mg heptaminol.

Sales Data Analvsis

During period 2000-2003, sales data witnessed 2o/o-llolo steady in-crease depending on brand name. In 2003, on the local market, 125,000

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TABLE2.ADRandSaletyinformationforGinkgobi|obaproductsinPlLs

Description of ADR and warnlngs

Number of Products in which

the PIL inlormation is mentioned

Skin reactions (erythema, edema, itching)

Gl disorders (abdominal pain, diarrhea, and nausea)

HeadacheHypersensitivitY reactions

Caution while used during pregnancy

Contraindication for patients with thyrotoxicosls

Abbreviations:ADR,adversedrugreaction;PlL'patienrinformationleaflet;Gl'gastrointestinal

21

1

'I

packages of G. biloba products with proportion 5:l among solid dosage

forms and solution, resiectively, werc soid' More than 907o of the whole

rehil market possesse; two of the authorized medicinal products. In the

observed pharmacies, ihe sales data of alllroducts show an increase that

^r* a"p"ios on the uruna nu-".It varies b-etween 2vo andSvo for 2001 in

"ornpuiiron with 2000 and between 4Vo and llvo for 2002 in comparison

with200l.Theleadingbrandshavegreaterincreaseintheirrelativemarket,ir";*

"sr*riur1"na"n|i.s are obserJed also in the wholesaling companies

*tt"t" leading products haveg5o/o share (Table l)'

Safety Information in the PILs

ThesafetyinfbrmationinthePlLsissummarizedinTable2.EightADRs affecting three physiological systems' one precautiol 3nd

one con-

traindication *"r" o"riri'u"d irithe pit-s. tt should be noted that not all of

listed items are included in all leaflets'

The ADRs' O.t.tiftion und precaution were incomplete' Information for

tVp"t."t.irivereactions,aswellasprecautionandcontraindication'was-found in one leaflet

^nJ'*L.mg in all others. Neither all possible effects

nor interactions during the common use of the medicines and measures

that should be taken in*case if they appear were pointed out'

Safety Information in Selected Studies

The literature search carried out in MEDLINE and Medscape for three

f."V *oti*t Ginkgo biloba, safety' fficacy revealed the following:

Getov et al. 245

TABLE 3. t-Test parameters for the observed patients and duration of clinicaltrials.

No. ofvariables Mean SEM

One-sample statisticsPatientsMonths

21

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'124,48

15,81199,861 1,56

43,6 t

2,52

95% Cl of the difference

df Significance (two{ailed) Mean difference Lower Upper

Patients 2,854Months 6,2

One-sample test (test value : 0)202A

0.010.00 3,59

16,76 33,49 215,4510,55 21,07

There are a total of 21 published studies satisfying the criteria for RCTin phase II, III,. or IVa in-cruding dosage from onry ih" pu." extract (Ap-pendix 1) .t+-:a The studies eniornpais the period lggb-20o2, which isthe requested l5-year period by the Directiv e-20M/24lEC. They include atotal of 2614 patients (Thble 3; MD : L24).Thirteen studies inciude a toralof 1300 patients with cerebral insufficiency (Alzheimer's, multi-infarctiondementia, mild-to-moderate forms of dementia and age-dependent memoryirretention).14-26 1*o studies include in all lg_5 prii"nt, with peripheralarterial insufficiency (limping intermittently).zt-2a, Among the other sixstudies, two studies analyse the effects of Ginkgo bitobain iinnitus aurium(noise in the ears) and acute cochlear deafness with a total of 976patients,two studies focus on the prevention of acute mountain sickness in 7b volun-teers,.and one study in sexual disorders due to serotonin selective reuptakeinhibitor and depression in 63 and 20 patients, respectively.zs-r+ Studyduration is between I and l3 months (19% for I month, l}vo for 2 months,33vo for 3 months, and 29vo for 6 months). Detailed /-test parameters ofboth variables are presented in Thble 3 (95Vo CI).

In three of the studies, patienrs use liquid forms (solution) and the other18 use solid forms. All HMPs contain the extract of Ginkgo biloba (EGb761). The daily dosages vary among 80 and 240 mg (most frequentlyless than 200 mg). Among all studies, 18 are placebo-controlled, one iscontrolled versus nicergolin,32 and one is an.open-label uncontrolled.33

As presented in Table 4, most of the studies (glvo) found that the G.biloba is more effective in comparison with placebo in the treatment of

246 JOIJRNALOF HERBAL PHARMACOTHERAPY

TABLE4'Systemat|Zationofthestudiesaccordingthediseasestreatedandsafety/eff icacY results.

Treated disease

No- of Etfectiveness

studies results

Safetyresults

Cerebral insufficiencY

Peripheral arterialinsufficiencY

Respiratorydisease-acutemountain sickness

Tinnitus and acutecochlear deafness

Other (sexual disordersand depression)

12 positive 1 negatlve

2 positve

2 positlve

1 inconclusive 1 Positive

2 inconcluslve

Well tolerated in fourproducts and safe in one

N/A

N/A

N/A

N/A

t3

11

above-mentioned symptoms. The study of Van Dongen'.conducted on

puri"n,t with dementia and age-dependent memory retention' concludes

ivith negatiue opinion. Three iudies (patients with tinnitus, sexual disor-

ders, an"cl depreision) were inconclusive because they neither confirm nor

reject product effi cacY.

Table 4 also shows that safety prolile of G' bitoba products is rarely

assessedincomparisonwithefticacy.onlylivestudiesfocusonproduct#iljiro.zi.;i'[l-oirt.-, four itudies state that the product is well

iot"ru,"O and one study, in addition' proves its safety'

Safety Assessment

Assessment tor seriousness (as per CIOMS Working group IV) and

ou,**" (as per Benichou scalejof itre ADRs are presented in Table 5'

By definition, hypersensitivity reactions are a typical time pattern related

tothedrugexposure.Theyhavedifferentseriousnessandoutcomes.Acuteanaphylactic reactions to G' nibna are rare and do not have systemic

.tuluo"r. In the published studies, we found one such reaction but its

relation with product use was not proved; thus we can conclude that it is

no real serious hypersensitivity reaction'

The most common skin reactions reported in the PILs are rash arrtl

itching(80o/o).Theyarecharacterizedbylowseverity,donotaffectvitalfunctions, and the outcome is not related to hospitalization or other com-

plications. Therefore their seriousness is low'

Cctov at ul. 247

IABLE 5. Seriousness (as per CIOMS Working group lV) and outcome (asper Benichou scale) of ADRs.

Adverse drug reactionSeriousness Outcome(CIOMS lV) (Benichou scate)

Hypersensitivity reactions tr

1Skin reactions (erythema, edema, and itching)Gastrointestinal disorders including the following:

Abdominal painDiarrheaNauseaHeadache

I

1

1

1

l. CIOMS lV: 7.51 very serious; 5-7.5 serious; 2.5-5 fairly serious; <2.5 least serious.ll. Benichou: Category 6: Death in more than 107" of the cases. Category 5: Death in 1./-10% of all casesof hepatocellular impairment, agranulocytosis, and anaphylactic shock. Category 4: Death in less than1% of the cases or permanent disablement. Category 3: Hospitalization for more than 2 days, incapacityfor more than 7 days. Category 2: Hospitalization tor not more than 2 days or incapacity up to 7 days.Calegory 1: Any other outcome

Diarrhea is a least serious adverse reaction and does not suggest hos-pitalization and development of complications. stomach pain related todiarrhea and nausea does not present a safety problem. Headache has thelowest grade for seriousness and outcome; it does not affect vital functionsand has a subjective character to a large extent.

Thus all outcome-related ADRs toward G. biloba products are placedin the lowest category although seriousness values are in a large rangeof 1.09-7.5. This is a confirmation that both more rare and single ADRscan have moderate-to-high seriousness and should be included in pILs ofHMPs.

The mean annual G. biloba consumers were found to be approximately2 million, and no ADR case reports were received via the spontaneousreporting system in Drug Safety Unit at BDA. From safety requirementspoint of view, the ADRs could be characterized as predominantly mild,with low occurrence, and presenting permissible (acceptable) risk.

DISCUSSION

Analysis of the HMPs authorized for sale reveal that the shortened"bibliographic procedure" was preferred by the regulatory body in spiteof the fact that the herb is not with "traditional use" on the local market.It is necessary to point out rhat the Bulgarian legislation did not include

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this term and the shortened proceclure relies on the understanding fbr thegeneral safety of natural products proved by the literature evidence thatcould not always be the case. In such a situation, it is reaily necessary toestablish transparent and reliable approach fbr literature ,orr.., ,"u..hingand evaluating. Afier the launch in the market, the authorization holdersex.tensively rrse all possible approaches to increase products' sares oftenrelying on saf-ety messages. The analysis of the market activities supportedsuch a conclusion, but in case of HMps with over-the-counter (orc)starus, patients and pharmacists should expect complete and consistentinformation in the PILs.ae

. unfortunately, the analysis of the plls reveals their inconsistency andi.accuracy in comparison with the literature studies. Not all known ADRswere included in all leaflets. Generally information in the leaflets corncidedwith the literature, but it is necessary to include all possible ADRs in caseof correct usage and measures, which have to be undertaken if they appear.

The analysis of the published studies on efficacy and safety providedenough evidence on the efficacy for copcrete diseises, but inconclusivetrials as well as one negative still remairi. The safety profile could not beconsidered as well evident by the published studies beciusejust one quarrerof the studies focus on safety and prove mainly tolerability. There is reallythe-need for strong postmarketing surveillance of the newly introducedHMPs.

Assessment of the ADRs' information mentioned in the pll-s and stud_ies raises a serious issue for the reguratory authority requirements andprocedure. Seriousness and outcome assessment r"u.ois thai the prevailingpart of ADRs is of low occurrence and acceptable risk.

It does not release the responsibility of the regulatory bodies to ensurethe unification of the wamings and ADRs in the pILs.

All such measures should be in the frame of previously created Na-tional Polic'y on Alternatit,e Medic.ine ancl H erbat drags thatis still lackingin Bulgaria.siFsl 15" suggested methodologicar appioach shourd supporrgood practice in this process in connection with the recent European reg-ulatory changes and the specificity of the locar therapeutic practice.

REFERENCES

ill Blumenthal M. Market report: herbal market levels after five years of boorrr.HerbalGram. 1999' 4l :64-5.

[2] Eisenberg DM, Kessler RC, Foster c, Norlock FE, Carkins DR, Derbanco l.t_.unconventional medicine in the United states: prevalence, costs and parterns oruse. N Engl J Med. 1993328246-52.

Getov et ul,249

[3] Eisenberg OV, Oa.llfe, Frtner,r,", 1l,.Jl:.!ds in alremative medicine use inrhe united Stares, I99o_igsl. jeuti.lruo,rru,

ts6g_75.tt' WilB",fiir;'ito.rn

stuution ""i"i'"r'or'

rnedicines: r worrdwide review.[5] WgO. Legal status of traditional medilnq^yd complemenrary/altemativemedicines: a worldwide review. Wff Oni4n, ZOOf .

", Hl Guiderines for the

";r;r;;;;;; of heruai medicines. wHo/TMR/91.4,[7] EMEA. Herbal Medicinal producrs Worlassociaredwiththerse_oih;;i;;#{:r,^.#x;r::,,,:,,::#$.TJ.H;T

we bsite : www.eudra.org/emea.html. Ocrober 200 I .[8] Bames J' Milrs sv- art iNi,;;ffi;;r M,.Ernsr E. Different standards ror

iT^',[T.t"l ?ff:.liBl!#. di"' ;;l-;;"ven riona r orc "' "ai"

ms. B r r cr in[9] Sirano M, De vincenzi M, De Vincenzi A, Sitano v. The new European regisration

;3r[,1i8:ill",'::' medicines: 'nuin-r"u,u.", and perspectiulr. nitot.rupru.

I l0] European Commission. Directive 2M4/24 of theEuropean parliament and of thecouncir amending Direcrive iootTai/E;^s regards traditionar herbar medicinal.. . _ products. otr J Eir Urior. a0 l;;;i;;^:t t t t

3#iiff Drug Agencv. tnro.,nuiion ro, the ricensed for sare medicinar products.ttzt r**:,ttf,fi|"" I. Pharmacorherapeuticat handbook. 5th ed. sofia, Butgaria:

:l:] i'1!i"JJ;HtH:"iS'Konstantinov S' et ar' pharmacorogv (second part).

r | +J van l,ongen MCMJ, van Rossurn E, Kessels AGH, Sierhorst HJG. The efficacy ofGinkgo fot elderly people wittr o"-l"ii" "riage-associared memory impairmenr:new resurts of a randomised crinicar rriui.-ia"- c"ri;;s;;Od;'ori , ol, , ,rr_

[15] Kanowski s' Herrmann-wM, wierich w. proof of efficacy of the Ginkgo biroba

ffii "."?"T:::,i":'. Ji:"LT?:;ffi :,*'i "

g r-"' -;,

io',J i. #;,u,. o,i -1997;a(1:T13. mer rype or MlD. Phytomedicine.

[16] t-eBars pL' Katz MM, Berman N, Freedman AM. A pracebo-controred, doubre_iiii:r1ti1lT:r1;, or un

""t u"-ili\i*r, oi"o" ii, i";;;,;" rAMA.

'71 Hofferbenh B. The efficacy of EGb 76 r in pati.ents with senire dementia of rhel]'.i:ltl oryr a doubte-blind,;;;; ;,i,."red studies on different revels ofrnvesrrgation. Hum psychopharmacol.

1994g:21 5_22.[18] vesper J' Hanseen K-D, tidil '"i-6,i*et bitoba in 90 outpatientswith cerebral iniufficiency .uur"d Uy otO age. phyromedicine.

1994;l:9_[19] Grassef E. Effect of Ginkgo biroba extract on mental performance. Double_blind study using comp_uterir"o -"urur"mJit conditions in patients with cerebrarinsuffi ciency. Fortschi Med. r s92, i ioG;j_6.

250 .I O U RN,4L O F H E R RAL P Tt ARM ACOT H ERA P Y

t26l

t27l

[20] tsrLrchert E. Heinrich SE. Ruf-Kohrer p. E,fficacy of EGb 76r in order parrenrswirh cerebral insufticiency. Munch Med Wschr. 199 l;ll3(l):9 I4.[2 lJ tlalama P. Judgnrent of welr bein-g ancr psychonietric test in p.tients fionr aneurorogicar pra*ice treated wirh Ginkgo. Munch Med wschr. iolt;t::lsuppt

| ):S I9-22.[22] Rai cS, shovfin c, wesnes KA. A doubre-brincr, pracebo-controlled srudy of.Cinkgo biloba extract^(Tanakan) in elderly outparienrs wirh rnild ro moderaremenrory rmpairment. Curr. Med Res Opin. 199 I ; | 2(6): j j0_-5.[23f Schmidt U, Rabinovici K, Lande S. Efiect of aGinkgi. hir.hu specialexrracr onwell being in cerebrar insutticiency. Manch Med Wschr. | 99 l, ri:i ii, i5-s.[24i Ecknrann VF. cerebral

-insufficieircy-rreatnrent with Ginkeo hirobu exrracr.Time of onset of the effect in a doubre brind study invorving oo inpo,,.n,r.Forrcshr Med. I 990; | 0g(29):557_60.[25] Hofferberth B. The effecr of cinkg, biroha extracr on neurophysiological

and psychometric me.asurement resurts in patients *ith cereb.olo.-*ur,,. ,yn-dronre. A doubre-blind study versus pracebo in Gernrany. n-n-i*itt"liorr.nrng.1989;39(8):9 t8-22.Vorberg G, Schenk N, schimdr u. The efricacy of a new ()inkgo birrbtt extractin 100 patienrs wirh cerebral insufliciency. Hez Gefabe. l9g9;9:396-401.Schweizer J, Hautmann c. cor'parison ot'rwo dosages ot-Ginkg, birohu extractEGb 761 in patients with peripherar arterialocclusive crisease nontain".r rtu-e. ilu.A randomized, doubre-brind, rnurticentric crinical triar. Arzneimitt.rforr.irr,g.1999:49(lIJ:90O-4.

[28] Pete's H, Kieser M, Horscher U. Dernonstrarion of efticacy of the cinkgo birobospecial extract EGb 76r on intermittent craudication-u ptu..uo-*ntroiled,double-blind, mulricenrric trial. VASA. l99g;27 (2):105_10.

[29] certsch JH' Basnyat B, Johnson EW, onopa J, Horck pS. Randomised, doubleblind, placebo controiled comparison of Ginkgo biroba and acetazoramide forprevention of acute mounrain-sickness among Hinrarayan r..kk.;r, ;;;revenrro'of high alritude illness triat(pHAtT). BMJ.1U)4;32A(7qqr,lgl_g. '

[30] Roncin JP, Schwartz F. EGb 761 in contror of acute mountain sickness and vas_cular reactivity to cold exposure . Aviation space Environ Med. r996:67(5):445-52.

f 3lJ Drew S, Davies E. Effecriveness of cirit3o bilobu in rreating rinnirus: doubleblind, placebo_controlled triat. BMJ. 2(nt'322e21g):73_g.[32] Dubreuil c. Therapeutic trial in acure cochlear deafness. Cornparativc srucrywith Gink,go hiroba, extract and nicer-9orine. presse rr,'ea. s.ften-'ber 25,

I 986; I 5(3 I ): | 559-6 I

[33] cohen AJ, Barrrik B. Ginkg, hiroha for antidepressant-inducecr sexual dys_function. I L)L)B;24(2): | 3943.l34l Halama P what does rhe speciar exrrac do (ECb 76 l ).r rreatrnent with Grnrgr,,bilrba in patients with cerebr.ar insufliciency and refr-actory crepressiv. rf ,np,orr.

R^esults of a pracebo-conrroilecl randomiied DB pirot .r,riy. ir,"ruiiewoche.| 990;40(5 l /52):3160-5 .

[35] DeFe.ud s F. cinkgo biloba Extracr (ECb 76 l): Frorn Chemist to rhe criricWiesbaden. U I lstein Med ical Ver.lagsgesel lschafi; Cerrlanv. I 99g.

l

(ietttt't'! ttl251

[36J DeFeudis F. Cinkgo,biloba Exrra'f]C;f, ZOI): .pharnracological Acriviries and150 crirrical Aooricarions. Ersevier. Edirit_,rrs Scientifiques; piaris, France r99r.

:ll] iH:i.: : ^E :k7!i::i,:;;ii'

-uli"l'' "' Book,ei N-. :rii A u s,in (rX) :

[38] Fowrer JS, wang cl, vortow'No, ., ..r. Evidence that G^inkgo biroba extract doesnot inhibit Meo,+an{ n i" ri","g irrrrfn'uruln. Life Sci. )ooo;ooist,t Lt+t_0.

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:1] ff|ofl''Jff:.l,T: axrff:i:g;J5;:Dts: Evaruaring sarerv Signa,s, Reporr[45] Benichou Ch. Adverse*oiug n.u.tionr-pru.ti"ur Guide to Diagnosis and Man_-. __ agemenr. lst ed. paris: Rousiel Uclaf; 199a.[46] National Peoples ay,e.mbrv. r-u* on orrgr'and^pharmacies in human medicine.. . __ 99fi u, Governmentar N.*rpup". r Uioot," {r,r*,:ill {"",l,,:,'.11,11111J1'z#i:t''fffi#'^l'1l1Yi;ordrugregisrrarionSona,[48] MoH Reguration ltzcinrot'tr," oorigutory information printed on rhe packages

$irff|.,, of the medicin"t pr.a*,rlliolu, oou.rnrn.ntal newspaper 54/2000,

*n' R:';uE #,\T,l;,;r^cists

should know abour herbar remedies? r Am pharm

[50] Ernst E, Dixon A. Alternative medicines in Europe. In: Mossiaros E, MrazekM, walley T, eds. Reguta,tng pt,ur*u"",iicats in Europe, ;ril;;.;;."fficiency,eq u i ty a nd q u a I i t v. London : "d; u;;;i,],'"r"rr, 2004 :3 0j _2i[51] wHo Tradirronar medicines rrr"i.gv'iotiilz005. wHo/DAp, Geneva; 2002.

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