Can ethnopharmacology contribute to the development of anti-fertility drugs?

Journal qf Ethnophurmucology,

Elsevier Scientific

Publishers

32

167

( I99 I ) 167-117

Ireland

Ltd.

Can ethnopharmacology contribute to the development of anti-fertility drugs? Xiao Pei-Gena and Wang Nai-Gongb ‘Instituie

of Medicinal

Plant

Developmeni.

100094 Medical

Beging and hlnstitute Sciences (People’s

of Materia

Medica,

100050

Beging Chinese Academy

of

Republic of China)

China, one of the developing countries with approx. one-fifth of the world population. has been making great efforts in controlling her population size. One of the efforts being stressed is to look into the practicability of employing Chinese herbal medicine for fertility control. The rich ethnopharmacological descriptions in the ancient books of herbal remedy and those scattered in the folklore medicine contribute the possibility of this approach. After a discussion concerning the facets of antifertility drugs linked with male or female fertility regulation, several selected examples are presented, which include yuehchukene (isolated from Murrctw puniculuto). pseudolarix acids A and B (from Pseudolarix kaempferi). mardekoside A (from Mardenia koi). gardenic acid and gardenodic acid A (from Gardenia jasminoides) as early pregnancy terminating agent, for fertility regulation in females; whereas gossypol (from cottonseed oil) and total glycosides of Tripterygium wi&rdii (GTW) as antispermatogenic agent for fertility regulation in males. Further research and development strategies of antifertility drugs from herbal medicines have also been discussed based on a collective research data in this field worldwide.

Introduction

macological descriptions recorded in ancient books of herbal remedy and those scattered in the folklore medicine. In the Compedium of Chinese Muteria Medicu (Ben Cao Gang Mu) there are found a total of 228 drugs described with applications associated with fertility control, of which 27 as abortifacient, 97 as emmenagogue, 44 as uterine stimulant and 60 as contraindicated in pregnancy (But, 1988). Recently, a collection of ethnopharmacological data from Chinese traditional medicine (Kong et al., 1986; Wu et al., 1988) revealed that 817 species and varieties of Chinese medicinal plants are ascribed to indications related to fertility control (Fig. 1). These existing favorable leads need, of course, to be further clarified before they can provide the lead in developing new antifertility drugs from natural products. Similarly, the World Health Organization has set up a Task Force on plants for fertility regulation, the strategic plan of which is to identify novel drug prototypes found in plants which have been alleged to have fertility regulating properties. Compounds that are being sought in particular are

In recent years, the human race has been facing many seriously worrying problems, viz. population explosion, enviromental pollution, resources deficiency, food shortage and energy crisis. To this end, much attention has been paid by many international bodies to one of the key measures: birth control. China, one of the developing countries with 22% of the world population, has been making great efforts in controlling her population size. One of the efforts being stressed is to look into the praticability of employing Chinese herbal medicine for fertility control. The strategies adopted

The possibility of the above mentioned approach emerged in China from the rich ethnopharPresented macology,

at the First International Congress Strasbourg. 5-9 June, 1990.

on Ethnophar-

Correspondence to: Xiao Pei-Gen,

Development,

100094 Beijing,

Institute of Medicinal Plant People’s Republic of China.

0378-8741/$03.50 0 1991 Elsevier Scientific Published and Printed in Ireland

Publishers

Ireland

Ltd

-+---c Fabif

loras

e

2in__ V &bee

Fig. 1. Chinese medicinal plants contributing

to indications

related to fertility control expressed by the Dahlgren system (each dot

represents five plants).

those orally active, non-steroidal, non-estrogenic, safe and effective for the prevention or disruption of implanation in women and those that will inhibit spermatogenesis or interfere with sperm maturation in men (Griffin, 1988). The Task Force has classified those plants claimed to possess fertility regulating properties into several categories according to their physiological function (Table 1). It can be seen that plants falling into categories A, C and N would be interested for female fertility regulation, and that of category B for male fertility regulation. The routes toward the finding of an antifertility drug could be summarized as shown in Fig. 2.

regulation in females

f. 1. Acts-implantation

WHO TASK REGULATING

agent

Yuehchukene (I, Fig. 3) is a dimeric indole alkaloid isolated from the root of Murraya

FORCE CODES FOR FERTILITY AGENTS OF PLANT ORIGIN

Code

Traditional use and proposed activity

A

Used one per month by the female, just prior to menstruation

B c

Male antifertility agent, used by the male Used by the female after one missed menses Used by the female post-coitally (interceptive, anti-implantation) at post mid-cycle (postovulatory) Used continuously by the female (may be postcoital but not used only post-ovulation) Unable to categorize into a specific group Male antifertility agent, used by the female Used by the female after more than one missed

D

E

Examples from China I. Fertility

TABLE 1

F G H

menses

I

Used by the female immediately after menstruation

169

FERTILITY REGULATION IN FEMALE

FERTILITY REGULATION IN MALE

0 Inhibition genesis

of spermato-

l

Inhibit sperm maturation in epididymis

l

Spermatocide, the enzyme of sperm

or destroy system

l

Inhibit oval growth and ovulation

l

Disrupt transfer of fertilized egg

l

Anti-implantation

. Terminate early pregnancy l

,

Trrn

abortificient

ANTI-FERTILITY EFFECT Fig. 2. Facets of antifertility

drug effects linked with male or female fertility

regulation.

0

2

I

HoocdQ H3C' I

Yuehchukene

II

Pseudolaric

acid

A

:

R = CH

III

Pseudolaric

acid

B

:

R = COOCH3

0 3HCd

bH

IV

marsdekoiside

A:R=H

3

170

:cc!! HoHoi \ 0

COOH

H- -CH2 )_Ay (=3

CH20H V

gardenic

COOH acid

VI

gardenolic

acid B

OH OH OH

R1

R2

X

Wilforidine

H

OH

w

Wilforine

C6H5C0

H

XII

Wilfordine

c6n5co

OH

VIII

triptolide:

IX

tripdlolide

R=H :

R =

on

~ff~icu~~tu (Fam. Rutaceae). Ethnopha~acolo~tally, the plant has ben used as an oxytocic in women for delivery at full term (Kong et al., 1985). Yuehchukene was reportedly 100% active at the dosage of 2.5 mg/kg po. on pregnancy days 1-2 The single dose/single day (PD,_J or PD,, schedule demonstrated that yuehchukene was 100% active in rats when administered at 3 mg/kg on PD, after successful mating (Kong et al., 1985; Griffin, 1988). The Allen-Doisy test showed that yuehchukene had obvious estrogenic activity. Treatment of immature mice with yuehchukene at the dosage of 2 or 4 mg/kg per day for 3 days caused an increase of uterine weight. Experiments showed that the estrogenic activity of (I) was weaker than that of estriol (Wang et al., 1990). Yuehchukene was synthesized from indole through several steps, and the synthetic samlJle was administered to rats at 2 mg/kg and found to be 100% active for preventing implatation (Xie et al., 1988).

171

Yuehchukene could potentially be further developed as an orally-active postcoital contraceptive by semi-synthetic means in order to eliminate the estrogenic activity.

acid B showed strong cytotoxic activities against several cancer cell lines in vitro. It might elicit problems with undesirable side effects when used as an antifertility agent (Zhou et al., 1989).

1.2. Early pregnancy terminating agents

1.2.2. Marsdekoside A From the result of a WHO joint project of screening, eight plants demonstrated the activity of termination of early pregnancy by antiimplanation in animals (Ding et al., 1989). Subsequently, steroidal two new glycosides marsdckoside (IV) A and B were isolated from ~arsdenja koi (Fam. Asclepediaceae). Marsdekoiside A was able to terminate early pregnancy in animals without any estrogenic effects (Yuan et al., 1989; Zhou et al., 1989).

1.2.1. Pseudolaric acids A and B Pseudolaric acids A (II) and B (III) were isolated from the root bark of Pseudolarix kaempferi (P. amabi~is) (Zhou et al., 1983), which is a traditiona Chinese drug recorded in the Chinese Pharmacopoeia for the treatment of ringworm. Pseudolaric acid B in a dilute bicarbonate solution injected S.C. at 15-40 mg/kg in rats on of early PI&_.9 could result in termination pregnancy. Administration of the compound by the i.g., S.C. or i.m. routes had the same effectiveness but with increasing dose levels in that order. Given in 1% carboxymethyl cellulose suspension i.g. to rats, rabbits and dogs, pseudolaric acid B produced effective termination of early pregnancy at the dosages of 5 mglkg, 40 mgikg and 1 mglkg, respectively. However, the compound did not exhibit any anti-implantation activity. Pseudolaric acid B showed no uterotrophic effect in immature rats, but caused severe decidual hemorrhage and necrosis. It lowered the plasma progesterone level after 5 days of administration at anti-fertility dose levels. Progesterone did not antagonize the effects of pseudolaric acid B on early pregnancy in rats (Wang et al., 1982). Pseudoiaric acid A when suspended in 1% carboxymethyl cellulose and given p.o. at the daily doses of 7.5 mgikg, 60 mg/kg and 0.5 mg/kg on PDT-9 to rats, hamsters and dogs respectively, caused pregnancy termination in all treated animals. Subcutaneous injection or vaginal administration of pseudolaric acid A to rats and hamsters also showed effectiveness in terminating early pregnancies. In toxicity studies on dogs, pseudolaric acid A showed mainly gastrointestinal side effects; viz. vomiting, diarrhea and bloody stools (Wang et al., 1989). According to a latest report, although pseudolaric acid A and B could terminate early pregnancy in all treated animals without any estrogenic effect, it was found that pseudolaric

1.2.3. Gardenic acid and gardenolic acid B The flowers of Gardenia jasminoides (Fam. Rubiaceae) has been used in Chinese folk medicine for birth control. It was found that the ethyl acetate extract of the flowers had a significant action of pregnancy termination in rats. Soon after, two cycloartene triterpenoids, gardenic acid (V) and gardenolic acid B (VI) were isolated and identified as the active ingredients (Xu et al., 1987a,b). Gardenic acid possessed a potential activity to damage decidual cells of early pregnant women at a concentration of 5 r&ml in vitro, which was lower than the effective dose of Ru 486 (10 pg/ml) (Zhou et al., 1989). 2, Fertility regulation in males 2.2. Gossy~ol (VII) In the 1950s it was found in China that several rural communities in Henan and Hubei provinces suffered from a subnormal fertility which was due to the use of crude cottenseed oil in food. Subsequently, gossypol was confirmed as the constituent causing male infertility (National Research Group on Male Contraceptives, 1978). (i)-Gossypol has been tested in more than 8800 healthy men, and the overall efficacy was 99.89% (National Research Group on Male Contraceptives, 1985). As there are already so many papers reporting on the properties and mechanism of action of this compound, I would like here to mention only very briefly:

172

RESEARCH

ACTIVE

CANDIDATES

PRINCIPLE(S)

NEW DRUG

RATIFICATION Clinic

Detailed pharmacologic and toxicologic studies

experiences

Folklore

usages

Ancient herbal records

Isolation of active principle Screening

ETHNOPHARMACOLOGIC DATA

Fig.

3.The strategic

methodology

tests

LABORATORY EXPERIMENTS

towards

getting

an antifertility

The antifertility activity of gossypol was confirmed mainly due to the destruction of the seminiferous tubules of men (Lei, 1982); (*)-Gossypol can be resolved into optical isomers, only the (-)enantiomer possesses antifertility effect while (+)-gossypol does not (Wang et al., 1984). Unfortunately, several undesirable side effects have rendered the use of gossypol as an antifitility agent impracticable. For instance, hypokalemia was found in 0.75% of the cases, gastrointestinal disorder about 4%, fatigue about 12% and change in libibo about 5%. Irreversible infertility could develop on prolonged administration (National Research Group on Male Contraceptives, 1985). In order to overcome the adverse effects of gossypol, several measures have been undertaken:

Efficacy,toxicity and sideeffects studies Clinic pharmacologic studies CLINICAL

TRIALS

drug based on ethnopharmacologic

research.

2.2. GTW* and total alkaloids of Tripterygium wilfordii

The debarked root of Tripterygium wilfordii (common tree wingnut) is a traditional Chinese medicine used for the treatment of several diseases, including rheumatoid arthritis, chronic nephritis and skin diseases. In a toxicological study of this drug, it was found that its decoction, the alkaloid fraction or the GTW extract given in feeds at a dose equal to one-third of their corresponding LD,, over a period of 4.5 months, effectively reduced the fertility of male mice. The GTW also inhibited spermatogenesis in dogs, rats and mice in a manner somewhat similar to that of gossypol (Zheng et al., 1983). The total alkaloids of Tripterygium wilfordii were given through a gastric gavage at doses of 1500 mg/kg, 1000 mg/kg and 500 mg/kg for 60 days

(1) A number of gossypol derivatives and metal chelates have been synthesized. However, none of the derivatives works better than gossypol. (2) A lower dosage (e.g. 15 mg daily) of gossypol is now under re-evaluation. Combined use of gossypol with the total (3) glycosides (GTW) of Tripterygium wilfordii (cf. next subtopic item).

*CiTWhas been widely cited as total glycosides or multiglycosides of Tripterygium wilfordii. Thepreparation hasbeenused for the treatment of rheumatoid arthritis etc. In the process of GTW production the quality is controlled by the determination of two active fractions, namely the total lactonic alcohols (VIII, 1X etc.) and the total alkaloids (X., XI, XII etc.) (Xia et al.. 1990). Detailed.ptudy of the active principle going on (Qian et al.. 1989).

from GTW is still

173

TABLE

2

PLANTS

TESTED

WITH

Kong et al., 1986; Bhargawa,

VARIOUS

ANTIFERTILITY

ACTIVITIES”

1988; But, 1988; Griffin,

1988; Zhou

and Su, 1988: Zhou

and Yu. 1990)

Species

Part used

Activity

Ahtomu ungustu~u

rt rt sd rt rt oleanolic acid alk. songorine

Al AI AF TEP. AB AB AF AI S S A0

Abtus pteculotius Achytuwhes

aspetu

A. bidenmm A. long$oliu Aconitum polyschistum Aeschynomenu indicu

Allium surivum

Pl rt sd. saponins bulb, garlicin

Aloe butbudensis

I

Anunus comosus

fr. juice

Andtogtuphis puniculuto

Pl triterpene rhz

Albixiu

lebbeck

Andtosuce septenrtionulis Atuchniodes exilis Atdisiu neti$oliu Atgemone e.uilis Atgemone mexicunu Atecu curechu Atisrolochiu

indicu

A. mollissimu A. vetsicolot Atnebiu euchtomu Anisomules mulubaticu Annonu squumosu Atrubottys

odotutissimus

glycosides

Pl rhz sd, protopine, berberine nut rt pl. aristolochic acid A aristolochic acids rt Pl sd I

Atremisiu ahsinrhium

Pl I

A. scoputiu

pl. scoparone fr

Aretthou

bilimbi

Axdituchru

indicu

Bethetis chittiu Bolbos~emmu paniculutum Bureu monospetmu Culoltopis gigunrw Cultho pulusttis Cuticu papu.w Celosiu ctislutu Citrus hysttix Cichotium

inrybus

Clemutis chinensis Cletodendton

settulum

C0t.wlali.s sheuteti Ctolulutio

junceu

Cuminum c:wlinum Curlw11u rrtomuricu

c. longu C. :edoatiu

I rt tuber. saponin sd. butin latex Pl fr, papain inflorescence fr Pl rt Pl rt. protopine sd sd rhz rhz tuber

A. D

S AI. AI AI. AF PI. S PI. IS

A0 AB AB AB

PI Al TEP. AB S PI AF AF. AE AI AF PI. s AF s. IS Al AB AI. S AB AB Al. AB AB. IS Al. TEP. AB S TEP AF PI PI PI AI. TEP

174

TABLE

2 (continued) Activity

Part used Duphne genkwo

rt. yuanhuacine

Duphne tunguticu

rt. bk

etc.

AB AB

Duiuru yuercifdiu

fr. daturalacetone

Duucus curotu

sd

AE.

P-bisabolene

AB

Desmodium gungeticum

gangetin

Al

Dictumnus ulhus

rt. bk. fraxinellone

AB. AF

Diefliwhuchiu

I

Al

Pl sd

AB

umoenu

Dimeriu grucilis Discoglypremnu Dryopteris

culoneuru

crussirrhix~mu

s

rhz. lilixic acids

TEP

Emheliu rihes

fr. embelin

AF.

Ensete superhum

sd

AI

Euphorhiu kunsu

rt

AB

Ferulu uxwfbetidu

resin

TEP.

F. ,jueschkeunu

ferujoi

PI

Gurdeniu ,jusmsinoides

fl

TEP

Gerunium lucidum

PI

Al

Gypsophilu ceru.stioides

s

Hibiscus rosu-sinensis

PI fl

H. svriurus

fl

AF

Hwlrocot.vle podunthu

Pl sd. irisquinonc

S

Iris pullusii Juniperus communis

PI

IS

AF

AF

Al Al. AB

Luccurdiu luccu

pl. fr resinous deposit

AF Al

Lugenuriu hrev~floru

fr

Lurreu tridentutu

I & twig. st

AF

Lepidium cupitutum

Al

Litho.~permum erythrorrhi~on

Pl rt

Loniceru ,juponicu

fl, bud

PI. AB

Pl sd

S

.f lerosum

Lygodium

Mudhucu hutyuceu Mulvuviscus conxttii

fl, malvidin

Mursdeniu koi

marsdckoside

AF At; AF A

TEP

Menthu urwn.sis

sd

Al A0

Momordicu

Pl sd. proteins fresh juice

IS AF

M. cochinchinensi.~

Pl sd. proteins

Montunou ,frutescens

I

Al

churuntiu

M. ungustisepulu

Montunou leucunthu ssp. Ieucunthu

AB

AB AF

M. tomentosu

I

AI. TEP

Muwuendu

I. twig

TEP

Moringu ptergospermum

rt

AB

Murruyu

rt. yuehchukcnc

Al

puhescens

puniculutu

Ocimum sunctum

I

Al

Pueoniu s~ffiiuticosu

rt. bk

TEP

Puri.\ polyphyllu

rhz. saponins

S

Pegunum hurmulu

pl. vasicinc

AB

Perillu ,frutescens

Al

Phu.seolu.r wIguris

PI sd. proteins

Phytoluccu doclecundru

rt, sdpononin

S

Pinellu ternutu

rt. pinellin

Al. TEP

Piper niRrum

rt

AB

AI. TEP.

AB

175

TABLE

2 (continued)

Species Piper sp. Plumbago

xylenicu

Podophyllum

peliutum

Polygonum

hydropiper

P. juponicum Porfulucu

oleruceo

Pseudolurix

Part used

Activity

pl, piperine

Al.

rt, plumbagin

AB

rt. podophyilotoxin

AF

rt

PI. A0

Ql sd

PI IS

rt. pseudoiaric

kuempjkri

acid A & B

TEP

rt

Al

Ql rt

S

sd. oleanic acid 3 P-glucoside

Al

Rheum moorcro~iiunum

rhz

S

Ruhus ellipricus

Ql

Al

Ruru gruveolens

Ql corm. protease inhibitor

AB

Ql fr

S

sd

PI

PI rt

Al

Psi&urn

guuvu

Pterolohium Pueruriu

inclicum

iuherosu

Run&u

dumetorum

Sugilleriu

.wgiltiJoliu

Sumuneu

sumun

Supindus

mukorosii

S. ir~fdiulus Sd~ej‘eru

tupiluru

Srhuhrrtiu

multifloru

Suussureu Scnecio

me&u

vu&iris

AB

Al

IS S S

pl, polysaccharide

TEP

pl. senecionine,

AF

senecionine

N-oxide Solunum

uunihocurpum

fr, solasodine

IS

fr. genistein. kaempferol

Al

sd

PI

Ql rt. coronaridine

S

St

AB

Thespepesiupopulneu

(+)-gOSS)‘QOl

Al

Truchycurpu.~ fortunei

rt

PI

Trichosunthes

rt. trichosanthin

AB

sd

S

rt. GTW

IS

Sophoru juponicuu Stryphnodendron Symplocos

polyphyllum

gurdneriunu

Tuhernuc,montunu Turus

var. hehenuchrri

hcyneunu

Al

hu(.(.utu

Tcrminuliu

PI

urjunu

Trigonellu

kirilowii

,ftienum-gruecum

Tripterygium

wi&rdii

T. hypogluucum

rt

PI. IS

l)phu

pollen

AB

rt

AF

PI sd

AF

ungustulu

Uncuriu

tomeniosu

Vicou indicu Wikstroemiu

chunrueduphne

AB

W. in&u

rt

AB

Vilc~r ncgunclo

sd. tri-hydroxyttrimethoxyflavone

Al.

Ql

A0

“Ahhreviutiuns: ty; AI.

bk. bark; fl. flowers; fr, fruits: I. leaves: pl. plants. rhz. rhizome: rt. root: sd. seeds; AB. abortifacient;

antiimplantation;

pregnancy

IS

inhibitory;

AO,

antiovulatory

S. spermicidal

activity;

TEP.

terminating

early

pregnancy:

IS. inhibition

AF. antifertili-

of spermatogenesis:

PI.

activity.

to observe the pathologic changes in the rats testis. The results indicated that the total alkaloids caused various degree of damage on spermatids and spermatocytes, while spermatogonia were not af-

fected. No morphological changes could be observed in interstitial cells of the testis and epididymis. No morphological changes in the liver and kidney was discernible either (Sun, 1989).

176

A retrospective clinic study was carried out on 22 patients suffering from rheumatoid arthritis. They were 2240 years of age and were divided into three groups:

the effects of GTW and gossypol on the fertility of male rats are additive and reversible and may offer a potential chance of further pratical use (Xu et al., 1987).

treated:

Concluding remark

recovery:

control:

11 cases who had taken GTW for 1.5-4 months or a low dose regime, i.e. 2@--30 m&d; 2 cases had taken the above dose of GTW for 2-2.5 months and had ceased to take it for 2-4 months; 9 cases who had not taken GTW.

It was found incidentally that the density of sperm in the treated group was far lower than that of the control group and the sperm of all the treated men was totally non-motile, while the sperm density and motility of the control and recovery groups were within the normal ranges. The serum levels of testosterone, luteinzing hormone, K+ and Na+ and the libido and potency of the treated patients were not signiftcantly affected. The results indicated that in men, GTW can induce infertility in relatively small doses (one third of the normal dose), and it seems to be reversible after cessation of the treatment (Qian et al., 1986a,b). Recently, a study was designed to investigate the effect of combined use of sub-threshold doses of gossypol and GTW to see if their effects could be additive. GTW and gossypol, S mg/kg each, daily were given to adult male SD rats by gastric gavage, 6 times a week, for 11 weeks. Groups taking the vehicle and the same dose of GTW or gossypol alone were set as the controls. The results indicated that all the rats of the GTW-gossypol group became infertile but the mating behavior still existed, and the density and motility of spermatoza in the cauda epididymis were dramatically decreased. In addition, no significant difference in morphological and biochemical parameters were observed between the GTW-gossypol groups and the vehicle controls. Both the fertility and the epididymal spermatozoa were found to be completely restored 6 weeks after cessation of treatment; while, in the remaining three groups fertility and epididymal spermatozoa were normal. Thus,

From the examples worked out in China as mentioned above and other results tested on plants for fertility regulation worldwide (Table 2), it is conceivable that ethnopharmacology as well as herbal products can contribute greatly to the development of natural antifertility drugs. Taking a birds-eye view of the information in this respect, it can be seen that the plants acting on fertility regulation are distributed widely in different taxa, and the active components isolated from them showed diverse chemical structures that could served as the prototype of synthetic antifertility drugs. Thus, we would like to suggest a strategic meth~oio~ towards getting an antifertility drug as shown in the scheme in Fig. 3. As a desirable anti-fertility drug, it has to be high in efficacy, low in toxicity and with few or no undesirable side effects, easy for use, without influence to the secondary generation, and, reversible after cessation of treatment. Acknowledgements My grateful thanks are due to Prof. Lei Haipeng and Prof. Sung Wei-liang for their valuable help in preparing this manuscript. References Bhargawa,

S.K. (1988) Anti-fertility

agents from plants.

Fitoterap~ LIX f3), 163-177.

But, P.P.H.

(1988) Chinese

medicine

for birth control.

Abstracts of Chinese Medicines 2(2), 247-269.

Ding. W.P., Shi, J.P., l-u, Z.B., Zhao, Z.E., Ma. B.X., Yuan, J.L., Chen, G.X. and Chang, C.F. (1989) Studies on active components isolated from plants for termination of early pregnancy or anti-impIanation. In: Y.T. Gong, J.X. Qu and L.X. Wang (Eds.), Inter~tioaai Symposium on Advanres in Fertility Regulation Research (Abstracts). Shanghai. China p. 46. Griffin, P.D. (1988) Plants for fertility regulation. Research in Human Reproduction, Biennial Report 1986-1987. World Health Organization. Geneva, 229-239.

177

Kong, Y.C., Ng, K.H., Wat,C.K.H., Wong, A., Saxena, LF., Cheng, K.F., But, P.P.H. and Chang, H.T. (1985) Yuehchukene - a novel anti-implantation indole alkaloid from Murraya panicuIata. Planta Medica 49, 304-307. Kong, Y.C., Xie, J.X. and But, P.P.H. (1986) Fertility regulating agents from traditional Chinese medicines. Journal of Ethnopharmacology 15. I-14. Ku, Y., Tong, J.S., Wi, A.P., Zhong, C.Q. and Qian, S.Z. (1987) The effect of combined use of gossypol and Tripterygium wiffordii on the fertility of male rats. Acfa Pharmaceutica

Sinica 22(

i I). 818-82 I.

National Research Group on Male Contraceptives (1985) Goss~pol Cfinical Studies Group. Reproduction and ConS(4) 5-l

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in

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Research

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Wang, N.G., Guan, M.Z. and Lei, H.P. (1990) Studies on antiimplanation and hormone activity of yuehchukene and alkaloid isolated from the root of Murraya paniculata. Acta Pharmaceutics

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