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Folklore herbal contraceptives and remedies
Trends in Pharmacological Sciences April 1986
Folklore herbal contraceptives ar remedies THE SPANISH MONK Fray Bernadino de Salgun in his 'Historica General de Las Cosa de las Nueve Espana' written in 1529 referred to the use of the plant zoapatle in Mexico as a plant being used by the Mexicans as a contraceptive. It took us about 450 years before this plant, botanicaUy known as Montanoa tomentosa, was first clinically evaluated in the human as a luteolytic agent and potential contraceptive. It is today one of the few plants being clinically tested for use as a contraceptive I. In the village of Wang in the Nanching province of the People's Republic of China there was great consternation in the 1940s because no babies were born in that village. It is fortunate that in this instance it did not need four hundred years for scientists to discover why this happened. It is known today that gossypol, present in the cotton seed oil used for cooking in that village at that time was responsible for the contraceptive effect acting through the men. Today gossypol is being evaluated in several parts of the world as a potential male contraceptive and over 12 000 men, in the People's Republic of China alone, have been administered this substance. In the village of Sukhodeora in the Bihar state of India, Paro Devi, an elderly woman of the village distributes a herbal powder prepared from the whole plant Vicoa indica to women who do not want to have any more children 2. This is administered to women immediately after delivery of the baby and the substance is reported to induce permanent irreversible effect. Clinical evaluation of this interesting plant is being carried out now. However, it is ethically not
possible to administer the plant substance to lactating women and so, after appropriate toxicological studies, the plant is being administered to non-lactating, non-parturient women and not therefore at the postpartum stage, but cyclically. This is of course not the way it is being used in Sukhodeora village.
( ~ 1986, Elsevier Science Publishers B.V., A m s t e r d a m
0165 - 61471861502.00
122 In the m o u n t a i n o u s interior of the state of Orissa the freshly prepared juice of the roots of the plant Plumbago rosea k n o w n locally as Rakta Chitraka is mixed with the freshly prepared alcoholic b r e w of the petals of Madhu Iongifolia and taken b y the tribal population as an early abortifacient agent - the type of contraceptive the developing countries are looking for. Yet, due to difficulties in simulating in clinical trials the conditions of actual use of the plant, no clinical trial of this very interesting plant has been undertaken 3. These four examples taken from herbal contraceptive clinical pharmacology, the area of specialization of the writer, illustrates in ~ c t , the problems, constraints and challenges in scientific evaluation and eventual use of age-old folklore and traditional remedies being used, even today, in most countries of the world. There is no w a y to know today whether there are good and effective folklore and herbal remedies which are not being investigated, like Plumbago rosea, because of the difficulties in organizing and carrying out preclinical and clinical studies u n d e r conditions similar to those u n d e r which the plant is actually b e i n g used. It is also very possible that some plants have been tested and found not effective b u t that the testing, like that of the plant Vicoa indica, was carried out on an inappropriate model (with the design feasible and possible b u t not as it should have been). It is certainly possible, as h a p p e n e d in the case of the cottonseed substance, gossypol, that chance will bring to our notice a very effective pharmacological agent. A scientific investigator testing cottonseed for its effect on bronchitis in 1970, found ozoospermia in four of the five men administered the drug 4 thereby bringing to our attention the earlier observations of a chronichler of the village of Wang. This would otherwise have r e m a i n e d buried in the archives of the province of Nanching where it had been faithfully recorded that babies again started appearing in the village of W a n g w h e n the economic conditions of the villagers had improved and they began using soya bean oil as their cooking media instead of cottonseed oil. It is also very likely that,
TIPS - April 1986
like the history ofMontanoa tomentosa, there are folklore remedies being used today, which will not see the light of day for another four h u n d r e d years because these will not be tested. This lack of a systematic scientific methodology, the absence of a framework which folklore remedies and medicinal plants could be fitted into and the elusive, fragile, unpredictable behaviour of the plants makes it a frustrating and yet challenging task for the investigator. The pharmaceutical houses, with all the scientific and financial resources backing them up, entered this area in the 1970s b u t quickly w i t h d r e w without perhaps appreciating that for proper testing of plants already being used by humans, the design has to be tailored for every single plant individually. In the highly organized, battery-like screening programmes set up b y pharmaceutical houses there was no easy w a y for the system to be modified or altered for the particular plant to be tested. Another possible reason for their withdrawal was the realization that the therapeutic activity does not always reside in neatly patentable chemically extractable form making the prospects of financial returns uncertain. Investigators in universities or research centres carried out chemical or pharmacological studies with individual plant extracts but, b y and large, had neither the interest nor the k n o w - h o w or the resources for developing an interesting plant extract into a drug. In m a n y instances chemists in developing countries, where the plants are in fact being used, have isolated the pure substances residing in the plants. However, since the facilities for pharmacological screening of these substances are not available, these substances are even today lining the offices and laboratories of these scientists - untested. The remaining part of this p a p e r will deal with approaches towards trying to obtain, as rapidly as possible, answers as to which of the m a n y folklore remedies b e i n g used today throughout the world, are effective and h o w these effective remedies could be used in therapeutics. The traditional approach to the evaluation of plants has recently been described in this journal s. The steps compris-
ing this approach could be broadly divided as: (1) identification of the plant: (2) collection, transport and storage of the plant before testing; (3) preparation of the extracts; (4) pharmacological screening in animal models; (5) identification of the most active extracts; (6) further fractionization of the active principle; (7) identification of the chemical structure; (8) synthesis of the active structure; (9) toxicological assessment of the active principle or synthetic c o m p o u n d - acute and subacute studies; (10) clinical pharmacology evaluation of the substance on normal subjects; (11) clinical evaluation for therapeutic efficacy. This approach has, in the past, yielded results and should certainly be continued b y those organizations which have the necessary resources and the time n e e d e d for this scheme of things. However, there are scientific uncertainties and constraints inherent in this approach which make the discovery of newer therapeutic agents unlikely. These have been described in detail elsewhere 6 and will only be mentioned here in brief. These constraints relate to dangers of incorrect identification and variability in activity during transport and storage. Another p r o b l e m to be overcome is that several plants m a y be acting together and the traditional approach is not appropriate for evaluating this type of 'combination therapy' for several reasons. It has been repeatedly stated b y practitioners of the traditional systems of medicine that some plants are included to reduce the toxicity of the other more therapeutically effective plants in the combination. It has also been observed that, with certain plants, the activity present in the total plant extract is reduced in all fractions after extraction instead of the activity being increased in one fraction 7. This type of activity also cannot be tested b y the traditional approach. Finally, the animal model selected for testing the plant m a y be inappropriate. In an attempt to overcome some
123
TIPS - April 1986
of these constraints the writer and his group at the Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh developed a complementing model 8 for evaluating plants and folklore remedies already in use and actually being used today. This complementing model consists of the following steps only: (1) identification and collection of the total sample to be used for all studies at one time; (2) modified shorter toxicology studies; (3) clinical evaluation after ethical review of animal toxicology studies. In this complementing approach no chemical extraction of the plant is carried out and it is administered to the patients in a form as similar as possible to that used in folklore medicine. No efficacy studies are carried out on animal models since the substance is already being used in h u m a n s and preliminary surveys have indicated that the plant extract may be effective. Only shorter acute and subacute toxicity studies are carried out on two species of animals. The modified shorter toxicity studies need to be carried out only for six weeks. The toxicology studies have to be designed specifically for the particular plant or combination of plants to be tested. (The toxicity profile used for testing two plants, Vicoa indica and Semecarpus anacardium can be obtained from the writer.) The rationale b e h i n d the shorter toxicity study is that the plant is already being used b y persons in the country and a longer detailed toxicity study is neither relevant nor necessary unless indicated b y the results of the six-week study. The results of all toxicity studies need to be assessed and the plant cleared for administration to h u m a n s b y the Ethical Committees of the Institute and the Indian Council of Research before clinical evaluation is initiated. It is felt b y the author and his colleagues that this approach,
complementary in nature, is more appropriate for evaluating folklore remedies which are already in use. Further, it permits evaluation of combination of plants because toxicity of all plants together would be evaluated on the animal models and all plants will be administered together, as is done in folklore and traditional medicine, during clinical evaluation. Conclusions regarding clinical efficacy can be reached more rapidly of the plant and certainly needs less material resources. The Council for Research in Ayurvedic Medicine have set up a ward at the Nehru Hospital for clinical evaluation of plants by this approach and both the Indian Council of Medical Research and the Family Planning Foundation are supporting studies with this approach. Several plants are being tested b y this complementing model. The toxicity results obtained with the plant Semecarpus anacardium clearly indicated that the plant induced haematological effects which made it unwise to administer the plant to humans. The results were therefore not placed before the Ethical Committees and work has been stopped with this plant. The toxicological results obtained with the plant Vicoa indica were reviewed by the two Ethical Committees and the plant is n o w being clinically evaluated for efficacy with, however, the constraints mentioned above. Adequate plant material for the total toxicological and clinical pharmacological studies with Hibiscus rosasinensis, could not be collected at one time which is a prerequisite to rule out variability of the active extracts in different samples collected at different times. Studies with this plant have remained in abeyance for the time being. []
[]
[]
The experience gained with the complementing approach has identified other problems e.g. standardization of plant material, ethical constraints and difficulty in
obtaining adequate material without cultivation of the plants. The experience gathered so far indicates that this modified complementary approach is one step closer to the real-life situation than the traditional approach, but that there are still considerable problems to be overcome. Perhaps the next approach would be to conduct trials at the spot where the folklore medicines are actually being used. There would then be no probMms of availability of material, even if it is used and required in the fresh state. There would be no need for developing complicated logistics for collection, transport and storage of plant material. Ethical problems will need to be viewed from a different perspective, since the plants are already being used and will continue to be used irrespective of whether or not a clinical pharmacological study is carried out. Results could be richly rewarding. RANJIT ROY CHAUDHURY
Regional Adviser, Pharmaceutical, Diagnostic and Therapeutic Substances, Eastern Mediterranean Regional Office, World Health Organization, Alexandria 21511, Egypt. Former Chairman, Dept of Pharmacology and Dean, Postgraduate Medical Institute, Chandigarth, India. This article has been written by the author in a personal capacity.
References 1 GaUegos, A. J. (1983) Contraception 27, 211-221 2 Chaudhury, R. R. (1985) Advances in Maternal and Child Health (Jenife, D. B. and Jellife, E. F., eds), pp. 20-26, Oxford University Press 3 Chaudhury, R. R. (1982) J. Vivekananda Inst. Med. Sci. 2, II, 6-12 4 Qian, S. Z., Hu, J. H., Ho, L.X., Sun, M. X., Huang, Y. Z and Fang, J. H. (1980) Clinical Pharmacology and Therapeutics (Turner, P., ed.), pp. 489-492, MacmiUan, London 5 Dohadwalla, A. N. (1985) Trends Pharmacol. Sci. 6, 2, 49-53 6 Chaudhury, R. R. (1980) Clinical Pharmacology and Therapeutics (Turner, P. ed.), pp. 474-482, Macmillan, London 7 Chaudhury, R. R., Mathur, V.S. and Garg, S. K. (1978) Indian. J. Exp. Biol. 16, 1077 8 Chaudhury, R. R. Mathur, V.S. and Shankarnarayanan, A. Proceedings Asian Congress of Pharmacology held at New Delhi January 1985, (in press)
Folklore herbal contraceptives ar remedies THE SPANISH MONK Fray Bernadino de Salgun in his 'Historica General de Las Cosa de las Nueve Espana' written in 1529 referred to the use of the plant zoapatle in Mexico as a plant being used by the Mexicans as a contraceptive. It took us about 450 years before this plant, botanicaUy known as Montanoa tomentosa, was first clinically evaluated in the human as a luteolytic agent and potential contraceptive. It is today one of the few plants being clinically tested for use as a contraceptive I. In the village of Wang in the Nanching province of the People's Republic of China there was great consternation in the 1940s because no babies were born in that village. It is fortunate that in this instance it did not need four hundred years for scientists to discover why this happened. It is known today that gossypol, present in the cotton seed oil used for cooking in that village at that time was responsible for the contraceptive effect acting through the men. Today gossypol is being evaluated in several parts of the world as a potential male contraceptive and over 12 000 men, in the People's Republic of China alone, have been administered this substance. In the village of Sukhodeora in the Bihar state of India, Paro Devi, an elderly woman of the village distributes a herbal powder prepared from the whole plant Vicoa indica to women who do not want to have any more children 2. This is administered to women immediately after delivery of the baby and the substance is reported to induce permanent irreversible effect. Clinical evaluation of this interesting plant is being carried out now. However, it is ethically not
possible to administer the plant substance to lactating women and so, after appropriate toxicological studies, the plant is being administered to non-lactating, non-parturient women and not therefore at the postpartum stage, but cyclically. This is of course not the way it is being used in Sukhodeora village.
( ~ 1986, Elsevier Science Publishers B.V., A m s t e r d a m
0165 - 61471861502.00
122 In the m o u n t a i n o u s interior of the state of Orissa the freshly prepared juice of the roots of the plant Plumbago rosea k n o w n locally as Rakta Chitraka is mixed with the freshly prepared alcoholic b r e w of the petals of Madhu Iongifolia and taken b y the tribal population as an early abortifacient agent - the type of contraceptive the developing countries are looking for. Yet, due to difficulties in simulating in clinical trials the conditions of actual use of the plant, no clinical trial of this very interesting plant has been undertaken 3. These four examples taken from herbal contraceptive clinical pharmacology, the area of specialization of the writer, illustrates in ~ c t , the problems, constraints and challenges in scientific evaluation and eventual use of age-old folklore and traditional remedies being used, even today, in most countries of the world. There is no w a y to know today whether there are good and effective folklore and herbal remedies which are not being investigated, like Plumbago rosea, because of the difficulties in organizing and carrying out preclinical and clinical studies u n d e r conditions similar to those u n d e r which the plant is actually b e i n g used. It is also very possible that some plants have been tested and found not effective b u t that the testing, like that of the plant Vicoa indica, was carried out on an inappropriate model (with the design feasible and possible b u t not as it should have been). It is certainly possible, as h a p p e n e d in the case of the cottonseed substance, gossypol, that chance will bring to our notice a very effective pharmacological agent. A scientific investigator testing cottonseed for its effect on bronchitis in 1970, found ozoospermia in four of the five men administered the drug 4 thereby bringing to our attention the earlier observations of a chronichler of the village of Wang. This would otherwise have r e m a i n e d buried in the archives of the province of Nanching where it had been faithfully recorded that babies again started appearing in the village of W a n g w h e n the economic conditions of the villagers had improved and they began using soya bean oil as their cooking media instead of cottonseed oil. It is also very likely that,
TIPS - April 1986
like the history ofMontanoa tomentosa, there are folklore remedies being used today, which will not see the light of day for another four h u n d r e d years because these will not be tested. This lack of a systematic scientific methodology, the absence of a framework which folklore remedies and medicinal plants could be fitted into and the elusive, fragile, unpredictable behaviour of the plants makes it a frustrating and yet challenging task for the investigator. The pharmaceutical houses, with all the scientific and financial resources backing them up, entered this area in the 1970s b u t quickly w i t h d r e w without perhaps appreciating that for proper testing of plants already being used by humans, the design has to be tailored for every single plant individually. In the highly organized, battery-like screening programmes set up b y pharmaceutical houses there was no easy w a y for the system to be modified or altered for the particular plant to be tested. Another possible reason for their withdrawal was the realization that the therapeutic activity does not always reside in neatly patentable chemically extractable form making the prospects of financial returns uncertain. Investigators in universities or research centres carried out chemical or pharmacological studies with individual plant extracts but, b y and large, had neither the interest nor the k n o w - h o w or the resources for developing an interesting plant extract into a drug. In m a n y instances chemists in developing countries, where the plants are in fact being used, have isolated the pure substances residing in the plants. However, since the facilities for pharmacological screening of these substances are not available, these substances are even today lining the offices and laboratories of these scientists - untested. The remaining part of this p a p e r will deal with approaches towards trying to obtain, as rapidly as possible, answers as to which of the m a n y folklore remedies b e i n g used today throughout the world, are effective and h o w these effective remedies could be used in therapeutics. The traditional approach to the evaluation of plants has recently been described in this journal s. The steps compris-
ing this approach could be broadly divided as: (1) identification of the plant: (2) collection, transport and storage of the plant before testing; (3) preparation of the extracts; (4) pharmacological screening in animal models; (5) identification of the most active extracts; (6) further fractionization of the active principle; (7) identification of the chemical structure; (8) synthesis of the active structure; (9) toxicological assessment of the active principle or synthetic c o m p o u n d - acute and subacute studies; (10) clinical pharmacology evaluation of the substance on normal subjects; (11) clinical evaluation for therapeutic efficacy. This approach has, in the past, yielded results and should certainly be continued b y those organizations which have the necessary resources and the time n e e d e d for this scheme of things. However, there are scientific uncertainties and constraints inherent in this approach which make the discovery of newer therapeutic agents unlikely. These have been described in detail elsewhere 6 and will only be mentioned here in brief. These constraints relate to dangers of incorrect identification and variability in activity during transport and storage. Another p r o b l e m to be overcome is that several plants m a y be acting together and the traditional approach is not appropriate for evaluating this type of 'combination therapy' for several reasons. It has been repeatedly stated b y practitioners of the traditional systems of medicine that some plants are included to reduce the toxicity of the other more therapeutically effective plants in the combination. It has also been observed that, with certain plants, the activity present in the total plant extract is reduced in all fractions after extraction instead of the activity being increased in one fraction 7. This type of activity also cannot be tested b y the traditional approach. Finally, the animal model selected for testing the plant m a y be inappropriate. In an attempt to overcome some
123
TIPS - April 1986
of these constraints the writer and his group at the Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh developed a complementing model 8 for evaluating plants and folklore remedies already in use and actually being used today. This complementing model consists of the following steps only: (1) identification and collection of the total sample to be used for all studies at one time; (2) modified shorter toxicology studies; (3) clinical evaluation after ethical review of animal toxicology studies. In this complementing approach no chemical extraction of the plant is carried out and it is administered to the patients in a form as similar as possible to that used in folklore medicine. No efficacy studies are carried out on animal models since the substance is already being used in h u m a n s and preliminary surveys have indicated that the plant extract may be effective. Only shorter acute and subacute toxicity studies are carried out on two species of animals. The modified shorter toxicity studies need to be carried out only for six weeks. The toxicology studies have to be designed specifically for the particular plant or combination of plants to be tested. (The toxicity profile used for testing two plants, Vicoa indica and Semecarpus anacardium can be obtained from the writer.) The rationale b e h i n d the shorter toxicity study is that the plant is already being used b y persons in the country and a longer detailed toxicity study is neither relevant nor necessary unless indicated b y the results of the six-week study. The results of all toxicity studies need to be assessed and the plant cleared for administration to h u m a n s b y the Ethical Committees of the Institute and the Indian Council of Research before clinical evaluation is initiated. It is felt b y the author and his colleagues that this approach,
complementary in nature, is more appropriate for evaluating folklore remedies which are already in use. Further, it permits evaluation of combination of plants because toxicity of all plants together would be evaluated on the animal models and all plants will be administered together, as is done in folklore and traditional medicine, during clinical evaluation. Conclusions regarding clinical efficacy can be reached more rapidly of the plant and certainly needs less material resources. The Council for Research in Ayurvedic Medicine have set up a ward at the Nehru Hospital for clinical evaluation of plants by this approach and both the Indian Council of Medical Research and the Family Planning Foundation are supporting studies with this approach. Several plants are being tested b y this complementing model. The toxicity results obtained with the plant Semecarpus anacardium clearly indicated that the plant induced haematological effects which made it unwise to administer the plant to humans. The results were therefore not placed before the Ethical Committees and work has been stopped with this plant. The toxicological results obtained with the plant Vicoa indica were reviewed by the two Ethical Committees and the plant is n o w being clinically evaluated for efficacy with, however, the constraints mentioned above. Adequate plant material for the total toxicological and clinical pharmacological studies with Hibiscus rosasinensis, could not be collected at one time which is a prerequisite to rule out variability of the active extracts in different samples collected at different times. Studies with this plant have remained in abeyance for the time being. []
[]
[]
The experience gained with the complementing approach has identified other problems e.g. standardization of plant material, ethical constraints and difficulty in
obtaining adequate material without cultivation of the plants. The experience gathered so far indicates that this modified complementary approach is one step closer to the real-life situation than the traditional approach, but that there are still considerable problems to be overcome. Perhaps the next approach would be to conduct trials at the spot where the folklore medicines are actually being used. There would then be no probMms of availability of material, even if it is used and required in the fresh state. There would be no need for developing complicated logistics for collection, transport and storage of plant material. Ethical problems will need to be viewed from a different perspective, since the plants are already being used and will continue to be used irrespective of whether or not a clinical pharmacological study is carried out. Results could be richly rewarding. RANJIT ROY CHAUDHURY
Regional Adviser, Pharmaceutical, Diagnostic and Therapeutic Substances, Eastern Mediterranean Regional Office, World Health Organization, Alexandria 21511, Egypt. Former Chairman, Dept of Pharmacology and Dean, Postgraduate Medical Institute, Chandigarth, India. This article has been written by the author in a personal capacity.
References 1 GaUegos, A. J. (1983) Contraception 27, 211-221 2 Chaudhury, R. R. (1985) Advances in Maternal and Child Health (Jenife, D. B. and Jellife, E. F., eds), pp. 20-26, Oxford University Press 3 Chaudhury, R. R. (1982) J. Vivekananda Inst. Med. Sci. 2, II, 6-12 4 Qian, S. Z., Hu, J. H., Ho, L.X., Sun, M. X., Huang, Y. Z and Fang, J. H. (1980) Clinical Pharmacology and Therapeutics (Turner, P., ed.), pp. 489-492, MacmiUan, London 5 Dohadwalla, A. N. (1985) Trends Pharmacol. Sci. 6, 2, 49-53 6 Chaudhury, R. R. (1980) Clinical Pharmacology and Therapeutics (Turner, P. ed.), pp. 474-482, Macmillan, London 7 Chaudhury, R. R., Mathur, V.S. and Garg, S. K. (1978) Indian. J. Exp. Biol. 16, 1077 8 Chaudhury, R. R. Mathur, V.S. and Shankarnarayanan, A. Proceedings Asian Congress of Pharmacology held at New Delhi January 1985, (in press)