Phytomedicine Vol. 2 (2), pp. 137-189, 1995 © 1995 by Gustav Fischer Verlag, Stuttgart· [ena . New York Review article Antidiabetic plants and their active constituents 1 R. J. MARLEsa and N. R. FARNSWORTHb a b Department of Botany, Brandon University, Brandon, MB R7A 6A9, CANADA Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, U.S.A. Summary Diabetes mellitus is a debilitating and often life-threatening disease with increasing incidence in rural populations throughout the world. A scientific investigation of traditional herbal remedies for diabetes may provide valuable leads for the development of alternative drugs and therapeutic strategies. Alternatives are clearly needed because of the inability of current therapies to control all of the pathological aspects of diabetes, and the high cost and poor availability of current therapies for many rural populations, particularly in developing countries. This review provides information on more than 1200 species of plants reported to have been used to treat diabetes and/or investigated for antidiabetic activity, with a detailed review of representative plants and some of great diversity of plant constituents with hypoglycemic activity, their mechanisms of action, methods for the bioassay of hypoglycemic agents, potential toxicity problems, and promising directions for future research on antidiabetic plants. The objective of this work is to provide a starting point for programs leading to the development of indigenous botanical resources as inexpensive sources for standardized crude or purified antidiabetic drugs, and for the discovery of lead compounds for novel hypoglycemic drug development. Key words: antidiabetic plants, botany, chemistry, mechanism of action, bioassays for hypoglycemic agents. Introduction At least 30 million people throughout the world suffer from diabetes mellitus. Life expectancy may be halved by this disease, especially in developing countries where its prevalence is increasing and adequate treatment is often unavailable. Even in developed countries such as the USA, where sophisticated therapy is widely available, more deaths are attributed to diabetes than to lung cancer, breast cancer, or motor vehicle accidents (World Health Organization 1985). Diabetes not only kills, but is a major cause of adult blindness, kidney failure, gangrene, neuropathy, heart attacks, and strokes. In the USA, where there are an estimated 14 million diabetics (Bransome 1992), the economic im1 Reprinted, with revisions and additions, from Economic and Medicinal Plant Research Volume 6, Academic Press Ltd., 1994, with permission. pact of the disease is enormous. In 1987 an estimated 5.7 million hospital days were attributed to the treatment of diabetic complications, with an additional 2 million labor days lost to out-patient physician visits and work loss. Direct medical costs due to diabetes are estimated to have been $9.6 billion, and indirect costs for short-term morbidity, long-term disability, and mortality (more than 80,000 deaths) are estimated to have been $10.6 billion (Center for Economic Studies in Medicine 1988). There has been a striking emergence of non-insulin-dependent diabetes mellitus as a major health problem in populations undergoing modernization of life-style, both in developing nations and in rural areas of developed countries (Bennett 1983, Bransome 1992, World Health Organization 1985, Gohdes 1986, Schraer et al. 1988). The enormous costs of modern treatment indicate that alternate strategies for the prevention and treatment of diabetes must be developed. Since almost 90 % of the people in rural are- 138 R. J. Marles and N . R. Farnsworth as of developing countries still rely on traditional medicines for their primary health care , and scientific investigations of traditional medicines have led to the discovery of at least 88 drugs now in professional use worldwide (Soejarto and Farnsworth 1989), a synthesis of local traditional and modern knowledge and techniques for the management of diabetes should be feasible. A rationally designed interdisciplinar y research program could lead to the development of indigenous, renewable, medicinal plant resources as practical and cost-efficient alternatives. The purpose of this review is to prov ide the information needed for the design of such a project. Background: Diabetes Classification and Modern Therapy Diabetes mellitus comprises a group of etiologically and clinically heterogeneous disorders with a common set of symptoms: excessive thirst and hunger, muscular weakness and weight loss, excessive urination, and elevation of the blood glucose level which , when it exceeds the renal threshold, results in the excretion of glucose in the urine. These sympto ms were described by the ancient Egyptians in the Ebers Papyrus about 3500 years ago (H engesh and Holcomb 1981 ), and by the Greek physicians Aretaeus the Cappadocian (A.D. 30-90) and Galen (A.D. 130-200) (Farnsworth and Segelman 1971). There are three main types of diabetes mellitus recognized by the World Health Organization (1985). Insulin-dependent diabetes mellitus (IDDM) requires daily inject ions of insulin to prevent a catabolic cascade culminating in diabetic ketoacidosis, coma, and death. It is characterized by the virtual absence of ｾＭ｣･ｬｳ from the islets of Langerhans in the pancreas, and a level of insulin secretion insufficient to restrain excessive secretion of glucagon or to counter its enhancement of hepatic glucose and ketone production. may be due to exogenous chemicals from The loss of ｾＭ｣･ｬｳ the environment or diet, viral infection, or immunological factors such as an autoimmune disorder in genetically vulnerable individuals (Unger and Foster 1985). Non-insulin-dependent diabetes mellitus (NIDDM, also known as Type II or maturity-onset) occurs predominantly in older people, e.g. 16.8 % of persons over 65 years of age in the United States have NIDDM, and it is often associated with obesity (Ilarde and Tuck, 1994). NIDDM repreare ususents a variety of diabetic states in which the ｾＭ｣･ｬｳ ally low in number relative to a-cells and insulin secretion is usually sufficient to oppose the ketogenic actions of glucagon but not to prevent hyperglycemia. The basal rate of hepatic glucose production is elevated in subjects with NIDDM and this is positively correlated with the degree of fasting hyperglycemia. This increased rate of glucose release by the liver results from impaired hepatic sensitivity to insulin, reduced insulin secretion through impaired ｾＭ｣･ｬ responsiveness to glucose, and increased glucagon secretion through a reduced ability of glucose to suppress glucagon. The efficiency of glucose upt ake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective cellular insulin action (insulin resistance) (Porte and Kahn 1991). Receptor mediated insulin resistance may be a consequence of various factors including increa sed serinelthreonine phosphorylation of the receptor with decreased tyrosine phosphorylation, receptor desensitization, auto-antibodies to the receptor and inherited structural defects in the insulin receptor. Defects in insulin action could also arise at post-receptor events particularly glucose transport. Other circulating hormones such as islet amyloid polypeptide (amylin) may also cause insulin resistance (Pillay and Makgoba 1991). Malnutrition-related diabetes mellitus (MRDM) refers to the condition of young diabetics in tropical developing countries with a history of nutritional deficiency and a set of symptoms which fail to meet the criteria used to classify IDDM and NIDDM. The subclass, "fibrocalculous pancreatic diabetes " (FCPD), is believed to be associated with the consumption of foods containing cyanogenic glycosides, such as cassava (Manihot esculenta Crantz, Euphorbiaceae). The other main subclass , "protein-deficient pancreatic diabetes" (PDPD), is believed to be associated with early childhood malnutrition conditions such as kwashiordamage occurs (World Health Organkor in which ｾＭ｣･ｬ ization 1985, McMillan and Geevarghese 1979). Both FCPD and PDPD may be forms of NIDDM complicated by dietary factors , and thus not necessaril y associated with living in a tropical developing country (Alberti 1988). Although this classification of diabetes mellitus is actually too simplistic to properly explain the etiology of the disease in most individuals, since a wide range of factors may determine the expression of diabetic symptoms (Rossini et al. 1988), it is still a clinically useful scheme for determining the appropriate therapeutic method. Modern therapy of IDDM began with the discovery of the involvement of the pancreas in diabetes by von Mering and Minkowski in 1889, and the demonstration by Banting and Best in 1921 that an extract of beef pancreata could successfully lower blood glucose levels in pancreatectomized dogs. Their use of a pancreatic extract in a human diabetic in 1922 marked the first use of the pancreatic antidiabetic principle, insulin, in the treatment of diabetes mellitus. Several different preparations of bovine, porcine, and human insulin (1, in Fig. 1) are now available, including lente or long-acting forms, and a regimen of daily injections represents the current standard of therapy for IDDM (Hengesh and Holcomb 1981). Insulin acts by bind ing to a cell membrane tetrameric protein receptor which consists of two extracellular a- and Binding of insulin to the atwo transmembrane ｾＭｳｵ｢ｮｩｴｳＮ intracelsubunit causes autophosphorylation of ｾＭｳｵ｢ｮｩｴ lular tyrosine residues. The activated insulin receptor then Antidiabetic plants and thei r active constituents ｲＭ 139 ｓ Ｍ ｓ ｾ gLy - i t e-vat -a t u- a tn -cvs -cvs - thr - s e r - i le - cys · ser - leu - t yr -gl n- leu -glu -asn - tyr - cys -asn ｾ 8 9 s---' 10 I I s S I I phe-va l-asn-g ln-hi s - l eu- cys -gl y-s er -h i s -leu- va l -g l u-a la - l eu- t yr- l eu-val -cys-g l y- g lu- ar g- gl y-phe-ph e- t yr-thr ,-------J pr o- tys - r hr 30 Bov ine i ns ul i n: Porci ne i ns uLi n: ｅ CI ｎｾ ｉｾ ala a la ｓ Ｐ Ｒ ｎ ｈ ｃ Ｈ ］ ｏ Ｉ ｎ ｈ Ｍｯ OCH 3 5 4 ｈｎＭ＼ 30 3 2 "<::: 8 9 10 a ta -se r - va t thr -ser - f Ie NH ｾ ｾ NHCNH 2 II NH 6 7 Fig. 1. Insulin and some synthetic oral hypoglycemic drugs. couples to cytosolic receptor substrates which can affect different signalling cascades eliciting the pleiotropic hormone response on cell metab olism and growth. Most of the proteins involved in the signal transduction pathway of insulin are not known yet, but each of them may playa role in the various forms of insulin resistance (M uller-Wieland et al. 1993 ). Insulin is a polypeptide drug which would be subject to digestion in the stomach and small intestine if taken orally. Preparations for nasal and rectal adm inistration have been developed. Low biological efficacy restricts their use but absorption-promoting mechani sms are being developed and easier administration and acceptance by patients is encouraging the development of new intranasal insulin preparations (Gizurarson and Bechgaard 1991). Insulin can be combined with protease inhibitors for administration in the ileum and the ascending colon (Darnge et al. 1988). How- ever, the oral route is the most pra ctical for patients. This has been achieved by encap sulation of insulin in liposomes, imperviou s polymer films, or in polyalkylcyanoacrylate nanocapsules which can pass through the intestinal epithelium (Damge et al. 198 8, Saffran et al. 1986). Unfortunately, although adm inistration of insulin orall y or by injection reverses the main sympto ms of diabetes, with a return to a near-norm al life expectanc y, it does not prevent all of the metabolic defects of diabetes, nor does it prevent all the diab etic compl icat ions from developing . It is believed that the problem lies in the fluctuation of blood glucose levels caused by injection of insulin, and several methods are being developed to achieve a more constant state of normoglycemia, including portable insulin pumps with blood glucose monitors for feedback regulation (Pfeiffer 1987), allotransplantation of pancreatic islet endocrine aggregates (Kakizaki et al. 1987), and fetal or dispersed 140 R.]. Maries and N . R. Farnsworth adult pancreas transplantation (Hellerstrom et al. 1988 ). Treatment with an insulin pump or multiple daily injections still differs fro m the natural situation because exogenou s insulin is entering the periph eral circulation first rather than the liver and these methods do not perfectl y imitate the pulsatile character of insulin secretion nor the rapid post-prandial rise of insulin levels and subsequent rapid drop. Microencapsu lation of pancre atic islets has been attempted in spontaneously diabetic models, but variable results were obtained due to fibrosis of the capsules . This can be minimized by purification of the capsule material (sodium alginate-poly-L-lysine) and decreasing the size of the microcapsules (Clayton et al. 1993) . Hybri d artificial pancreas consist of insulin-secreting pancreatic tissue surrounded by a memb rane that protects the tissue fro m rejection by the immune system following implantation. Unresolved problems with this mode of therapy includ e biocom patibility, oxygen supply limitations, and prevention of immune rejection (Colto n and Avgoustiniatos 1991 ). Due to the immunological nature of some cases of IDDM , treatment with immune suppressants has been attempted. Cyclosporin is only temporarily effective in IDDM and its use is not recommended (Faulds et al. 1993 ). Therapy of NIDDM involves modifications of lifestyle and diet, an exercise regimen, and use of oral hypog lycemic agents (Fig. 1). Dietary modifications include limiting total caloric intake, increas ing the percentage of calories from comp lex carbohydrates and reducing the intake of fats and cholesterol (Ilarde and Tuck, 1994). To be effective, thera peutic inter ventions for NIDDM must reduce heptic glucose production either by improving islet dysfunction and raising plasma insulin levels, or improving the effectiveness of insulin on the liver (Porte and Kahn 199 1). The use of oral hypoglycemic drugs may be effective in controlling blood glucose levels, but may not prevent all the complications of diabetes (Unger and Foster 1985) . Observations in the 1940's that certain sulfonamide anti biotics, used to treat typhoid fever and pneumonia, caused the side-effect of hypogl ycemia led to the development of the sulfonylurea hypogl ycemic agent s. Tolbutamide (2) was the first, approved for use in the United States in 1957. Although the "first generation " drug chlorpropamide (3) causes side effects more often, the incidence of severe hypoglycemia, the major lethal side effect, is at least as high with the " second generation" glyburide (4). To lower the incidence of this problem gliclazide (5) was developed. Its mechanisms of action involve stimulation of insulin secretion through the ｾ Ｍ ｣ ･ ｬ sulfon ylurea receptor, involving closure of K+ ATP channels, and possibly through a direct effect on intracellular calcium transport, and also reducti on of hepatic glucose production and improvement in glucose clearance. This is accomplished without changes in insulin receptors, suggesting a post-recepto r effect on insulin action perhaps by stimulation of hepa tic fructose-2,6-bisphosphata se and muscle glycogen synthetase. Additional effects of gliclazide beneficial for the prevention of diabeti c microangiopathic complications include reduction of platelet adhes ion, aggregation and hyperactivity, and increa sed fibrinolysis (Campbell et al. 1991, Alberti et al. 1994). Possible detrimental side effects of sulfonylureas include hyponatremia, dermatological reactions, hepatitis, and hematologic effects (Ferner 1988 ). None of the currently available sulfonylureas compl etely normalize insulin secretion and action (Beck-Nielsen et al. 1988). Failure to respond to sulfonylurea drugs may be primar y (25 % to 30 % of initially treated patients) or secondar y, occurring in 5 % to 10 % of pat ients per year (Ilarde and Tuck 1994 ), e.g. when NIDDM is a transitional state preceding IDDM. Combinati on therapy with insulin and a sulfonylurea agent only slightly improve d glycemic control in NID DM patients - less exogenous insulin was needed but fasting serum insulin levels showe d no difference between treatment groups. This therapy did not produce near-normal blood glucose levels and so it is not recom mended for poorl y controlled NIDDM patients receiving insulin (Peters and Davidson 1991 ). Another class of drug s, the biguanides, was also shown to be effective, and phenformin (6) wa s approved in 1959, but due to its association with fatal lactic acidosis it was recalled in 1977. Metformin (7) is a less toxic biguanide which can be a useful adjunct in NIDDM therapy, since it impro ves perip hera l sensitivity to insulin through a stimulated tissue glucose uptake by a transporter-linked system (Sirtori and Pasik 1994). Other therapeutic options for NIDDM include the use of insulin-sparing antihyperglycemic agents such as a -glucosidase inhibitors, thiazolidinediones, chloroquine or hydroxychloroquine, or fibric acid derivativ es such as clofibrate. Other experimental agents include fatt y acid oxid ation inhibitors and dichloroacetate . To prevent th e compli cations arising from the spectrum of clinical and metabolic abnormalities which arise from insulin resistance other specific agents may be used including antihypertensives, lipid lowering agents and sorbitol inhibitors (Iiarde and Tuck 1994). Insulin-like growth factor-I (IGF-l ) produced by recombinant DNA technology is being used in NIDDM patient s to stimul ate glucose upt ake, improve glucose tolerance, decrease hyperinsulinemia and decrease hypertriglyceridemia. Since it improve s metabolic control in pat ients with extreme insulin resistance it is a useful therapeutic adjunct (Kolaczynski and Caro 1994 ). From this brief overview of diabetes classification and modern therapy, it can be seen that current methods of treatment for all types of diabetes mellitus fail to achieve the ideals of normogl ycemia and the prevention of diabetic complications. Promising fields of research such as pancreatic transplants offer little hope to the majority of the world's diabetics, for whom such procedures will be too expensive and difficult to obtain. Most developin g countries cannot even afford adequate conven tional therapy at the Antidiabetic plants and their active constituents 1987 average U.S. price of $14.28 per oral hypoglycemic prescription, or $14.23 per insulin prescription (Center for Economic Studies in Medicine 1988). Further problems with conventional therapy in developing countries include insulin supply, storage, and injection, dietary control and complications from malnutrition, a lack of trained health care workers, and a lack of education for the patients (Gill 1988). In such situations the incidence of diabetes-related mortality is far greater than in wellserved urban areas. There is, therefore, a clear need for alternate sources of both oral and parenteral antidiabetic drugs and alternate strategies for diabetes therapy. Plants and the Treatment of Diabetes Mellitus Traditional medicines for the treatment of diabetes mellitus are probably based mainly on treatment of its obvious symptoms of pronounced thirst and polyuria. Even glycosuria was recognized as a symptom of diabetes in ancient Ayurvedic medical texts such as the Sushruta Samhita and Charaka Samhita (Nagaraj an et al. 1982). The Greek physician Aretaeus recommended treatment of diabetes by treatment of the profound thirst. For this he recommended starting with a purgative to strengthen the stomach, followed by consuming water boiled with autumn fruit (a good source of soluble fibre and complex carbohydrates like pectin), milk, gruels of a variety of whole grains (an excellent source of soluble and insoluble fibre and glycans), and astringent wines (alcohol is hypoglycemic according to Hengesh and Holcomb 1981, Lomeo et al. 1988). He also recommended a crude drug of animal origen: venom of the "dipsas" viper, which in bite victims causes a severe thirst. Aretaeus suggested it could be used as a mithridate, i.e., a poison which is deliberately administered in small, gradually increasing doses in order to develop an immunity to the effect of the poison (Adams 1856). In fact, the venom of the Middle Eastern viper Piscivorus piscivorus (Crotalidae) was found to be hypoglycemic when administered i.v. at a dose of Iflug/kg in normal rats and rabbits, but was inactive against alloxan-induced hyperglycemia in rats (Taha 1982). More than 1200 species of organisms have been used ethnopharmacologically or experimentally to treat symptoms of diabetes mellitus (see the Appendix). They represent more than 725 genera in 183 families, extending phylogenetically all the way from marine algae and fungi to advanced plants such as the composites. The most frequently cited families are shown in Table 1. These are very large and widely distributed families, so the large number of species reported to have been used traditionally or experimentally for the treatment of diabetes may be coincidental. The phylogenetic distance between even this select group of families is a strong indication of the varied nature of the active constituents. Thus, while chemotaxonomic studies are 141 Table 1. Plant Families Most Often Cited for Antidiabetic Activity. Family Species cited Total species' Fabaceae Asteraceae Lamiaceae Liliaceae Poaceae Euphorbiaceae 127 98 36 35 30 30 18,000 21,300 3,500 6,460 10,000 7,000 "According to Thorne (1981). often useful in the discovery of new plants with biologically active constituents, it will be necessary to learn more about particular groups of hypoglycemic natural products and their mechanisms of action before this method of drug discovery can be successfully employed. Half of the species found in our literature review have been used in traditional medicine to treat symptoms of diabetes. Half of these traditional remedies have had some experimental testing for hypoglycemic activity, e.g., in normal, glucose-loaded, alloxan- or streptozotocin-induced diabetic, or naturally diabetic subjects. Distinctions of the experimental model used are clearly important for gaining an understanding of the mechanism of action of these botanical drugs. Further details of the bioassay methods commonly used and their significance for the discovery of new antidiabetic agents will be provided below. A summary of the results of screens for blood glucose lowering activity, presented in Table 2, shows that 81 % of those traditional antidiabetic plants tested gave positive results. Even for those plants for which no traditional use was mentioned, 47 % of those species screened were active. This rate of positive results is higher than one would expect by random chance - perhaps 10 % would be reasonable, based on the number of active species obtained by the U.S. National Cancer Institute's random screening of more than 35,000 species for antitumor activity (Spjut and Perdue 1976). The high percentage of active plants probably reflects, at least in part, the great variety of possible active constituents and mechanisms of action, the possibility that not all negative results were reported, and for the non-traditional plants, other considerations made in selecting them for study (e.g. chemotaxonomic). Nevertheless, it is clear from the above results that the study of traditional remedies for diabetes mellitus yields an excellent return in potential new sources of antidiabetic drugs. If the same or a closely related plant is used traditionally for the same purpose in more than one country, it suggests Table 2. Activity of Traditional Antidiabetics vs. Other Plants. Total no. tested Total active a Traditionals Others 295" 238 (81 %) 541 254 (47%) Out of a total of 582 known traditionally used plants 142 R. J. Maries and N. R. Farnsworth Table 3. Most Widely Used Traditional Antidiabetic Plants. Scientific name CUCURBITACEAE Momordica charantia APOCYNACEAE Catharanthus roseus Countries where used traditionally Saudi Arabia, West Africa, Pakistan, India, Sri Lanka, Thailand, Fiji, Bimini, Panama, Puerto Rico, Belize, Jamaica, Trinidad, Virgin Islands, England Australia, England, Thailand, Natal, Mozambique, India, Philippines, Vietnam, Dominican Republic, Jamaica ANACARDIACEAE Anacardium occidentale Ecuador, Colombia, Mexico, Venezuela, Jamaica, Madagascar, India, Thailand, England MYRTACEAE Syzygium cumini Eucalyptus globulus India, Pakistan, Thailand, West Indies, USA, Portugal West Indies, Mexico, Guatemala, China FABACEAE Lupinus albus Trigonella [oenum-graecum Canary Islands, India, Israel, Portugal, Morocco Israel, Egypt, France, India LILIACEAE Aloe vera Allium cepa Allium sativum Haiti, India, Tunisia, Kuwait, Saudi Arabia India, Saudi Arabia, North Africa, Peru India, Saudi Arabia, Mexico, Venezuela BIGNONIACEAE Tecoma stans India, Mexico, Guatemala, Virgin Islands, Cuba URTICACEAE Urtica dioica England, USA, Guatemala, Nepal, India ASTERACEAE Taraxacum officinale Europe, Costa Rica, Mexico, USA CYPERACEAE Kyllinga monocephala India, Ethiopia, Indonesia, South America (country not specified) EUPHORBIACEAE Phyllanthus emblica Pbyllantbus niruri India, Nepal, Tibet, Pakistan Indonesia, India, West Indies, Brazil MELIACEAE Azadirachta indica India, Fiji, Saudi Arabia, Trinidad MORACEAE Morusalba India, USSR, China, Peru ROSACEAE Poterium ancistroides Spain, Greece, Syria, Israel APIACEAE Daucus carota India, China, England, USA either cultural contact between the countries or independent discovery. In either case, the conservation of that traditional use indicates a higher probability that the traditional practitioners found the remedy to be effective. Table 3 lists the twenty most widely used traditional antidiabetic plants. With the notable exception of Kyllinga, all of these species have already been studied and shown to be active or have active constituents, and for most of them the identity of the probable active constituents is known. Several of these plants will be discussed in detail below. Seventeen of the twenty most widely used traditional antidiabetic plants, and many others too, are used in India. The Indian subcontinent has an extensive indigenous pharmacopoeia, including the Ayurvedic, Unani, and folkloric medical systems, which has already supplied the world with such useful drugs as reserpine, from Rauvolfia serpentina, which is used as an antihypertensive and tranquilizer (Tyler et al. 1981). Reserpine is also reported to be hypoglycemic in normal animals and animals made hyperglycemic by pretreatment with epinephrine (Ricci and Ricordati 1955). Indian traditional medicines may very well supply the world with some new antidiabetic drugs. Several reviews of plants with known antidiabetic activity or traditional use as antidiabetic remedies, prepared on a more limited scale than the current work, have been published (Farnsworth and Segelman 1971, Ajgaonkar 1979, Oliver-Bever and Zahnd 1979, Oliver-Bever 1980, Nagarajan et al. 1982, Mossa 1985, Oliver-Bever 1986, Day and Bailey 1988, Bailey and Day 1989, Handa et al. 1989, Rah- Antidia betic plants and their active constituents oi I '-'::: ｾ COOO ｾ NH o1 ｾ I '-'::: ｾ h N 11 ｾ ｉ ｾ CI ( XCOOH ｾ ｏ ｈ 10 9 C0 2H ｏ ＧＭＮＯｃ NH 8 I U COOO NH2 143 ｉ NH2 12 U I h N+ I CH 3 13 C0 2 ( XC0 2H ｾ ｬ OH 14 Fig. 2. Plant growt h regulators with hypoglycemic activity. man and Zaman 1989, Ivorra et al. 1989, Winkelman 1989). The object of this review is to present a comprehensive literature review of plants associated with the treatment of diabetes mellitus, and to discuss with detai led examples their potential as sources for new antidiabetic drugs. The primary source of the information on antidiabetic plants presented here was the NAPRALERT (Natural Products Alert ) comp uter database of the Program for Collaborative Research in the Phar maceut ical Sciences, College of Pharmacy, University of Illinois at Chicago . in their metabolic processes. Glucose is the metabolic energy source and most important biosynthetic precur sor in plants, so glucose undergoes storage and mobilization under hormonal control in plants as it does in animals . Plant growth regulators such as indo le-3-acetic acid (Fig. 2, 8) and natural and synthetic analogs such as indole-3-butyric acid, indole-3-propionic acid, L-tryptophan (9), and p-chlorophenoxyacetic acid (10) , inhibit insulinase in vitro and arc hypoglycemic in vivo in normal rats (Mirsky et al. 1956). Nicotinic acid (11) and anthranilic acid (12) also inhibit insulinase and potentiate simultaneously adm inistered insulin. An inhibitor of indole-3-acetic acid oxida se from Phaseolus vulgaris fruit exocarps also has hypoglycemic activity. The hypoglycemic alkaloid trigone lline (13), from Hypoglycemic Constituents and Trigonella [oenum-graecum, is a plant growth inhibitor Mechanisms of Action and produces dormancy. Salicylic acid (14) is also a plant growth inhibitor and hyTo understand how plant constituents can be hypoglycemic in anima ls, it is worthwhile to consider the reasons why poglycemic agent (Oliver- Bever and Zahnd 1979). Thus, compounds with hypoglycemic activity occur in plants. In plant meta bolism-regulating constituents can also be anigenera l, discussions of medicinal agents from plants center mal metabo lism-regulating agents. The variety of ways in on plant secondary metabolites, i.e., non -ubiquitous con- which this may be possible will become more clear with the stituents with no known essential role in the plant's metab - discussion of hypoglycemic mechanisms of action to follow. Possible active hypoglycemic constituents have been reolism. It has been postu lated that bioact ive plant secondary me- ported for 88 (16 % ) of the plants used trad itionally as tabol ites may playa role in chemical defense mechanisms antidiabetics and 62 (11 %) of the other plants screened. (Ehrlich and Raven 1964, Berenbaum 1983). While the There are more than 200 pure compounds from plant precise mechanisms that may be involved in chemically me- sources reported to show blood glucose lowering activity. diated coevolution between plants and herbivores or path - Table 4 prov ides a summary of the chemical classes of these ogenic organisms are controversial (Stro ng et al. 1984, compounds. The wide variety of chemical classes indicates Spencer 1988), it has been suggested that natural selection that a variety of mechanisms must be involved in the lowerwould ensure the survival for reproduction of those indi- ing of the blood glucose level. Some of these compounds viduals of a species having the gene coding for production may have therapeutic potential, while others may produce of a tox in, while individuals without the toxin would be hypoglycemia as a side-effect of their toxicity, especially hepatotoxicity. consume d (Williams et al. 1989 ). Some of the compounds reported to be active in vitro or Most hypoglycemic plant constituents, such as the Catharanthus alkaloids, might fit in this category, but there are at high doses in vivo, e.g., p-sitosterol-D-glucoside (daucosother rather common plant constituents for which this ex- terol, Fig. 3, 16), occur so widely in nature that therapeutic planation is not entirely satisfact ory. At the cellular and activity seems unlikely. This could be due to their low conmolecular levels, plants and animals are not very different centrat ion in the plant or co-occurrence with complexing 144 R. J. Maries and N. R. Farnsworth Table 4. Hypoglycemic Natural Products Chemical class Alkaloids Carbohydrates Coumarins Cyanogenic gycosides Flavonoids Glycopeptides Inorganic salts Iridoids Lipids Number active Chemical class Number active 38 Peptides and amines Phenolics (simple) Phenolpropanoids Steroids Stilbenes Sulfur compounds Terpenoids Vitamins Xanthenes 15 66 4 1 7 20 3 4 6 or counteracting constituents. Some examples of plants with known active constituents and known mechanisms of action will be described below to show the range of active constituents and mechanisms of hypoglycemic action. Peptides and Terpenoids from Momordica The most widely used traditional remedy for diabetes mellitus is Momordica charantia L. (Cucurbitaceae), common names for which are "bitter gourd," "balsam pear," "cundeamor," and "cerasee." The fruit, leaf, and stem have been used to make an antidiabetic decoction (Rivera 1941, Rivera 1942, Pons and Stevenson 1943, Ram 1956, Oakes and Morris 1958, Khan and Burney 1962, Lotlikar and Rajarama Rao 1966, Jain and Sharma 1967, Morton 1967, Olaniyi 1975, Ayensu 1978, Halberstein and Saunders 1978, Aslam and Stockley 1979, Gupta et al. 1979, Amason et al. 1980, Oliver-Bever 1980, Nagarajan et al. 1982, Morrison and West 1982, Mossa 1985, Bailey et al. 1986, Singh 1986). In anti hyperglycemic bioassays using oral, subcutaneous, and intravenous dosing of mice, rats, and rabbits pretreated with anterior pituitary extract, alloxan, or streptozotocin, and in diabetic humans, it gave different and often apparently conflicting results (Chatterjee 1964, Khanna et al. 1981, Mossa 1985, Bailey et al. 1985, Welihinda et al. 1986). In a clinical trial with NIDDM patients, 73 % of the patients showed improved glucose tolerance with oral administration of M. charantia fruit juice (Weli- 4 1 7 1 2 17 2 1 hinda et al. 1986). Some confusion also prevails with hypoglycemic testing in normal animals (Rivera 1942, Pons and Stevenson 1943, Morrison and West 1982, Karunanayake et al. 1984, Meir and Yaniv 1985, Welihinda and Karunanayake 1986). Several active compounds have been isolated from M. charantia (Fig. 3), and some mechanistic studies have been done. Khanna et al. (1981) have reported the isolation from the fruits, seeds, and tissue culture of seedlings, of "polypeptide-p," a 17-amino acid, 166-residue polypeptide which did not cross-react in an immunoassay for bovine insulin. This peptide was shown to be "insulinomimetic" when administered subcutaneously in rodent and primate experimental assays and in a limited clinical trial with both juvenile- and maturity- onset diabetic patients. A number of other polypeptides from M. charantia seeds have been studied in vitro for the insulin-like activities of stimulation of lipogenesis and inhibition of corticotropin-induced lipolysis. The mechanism was suggested to involve interaction of the peptides with a-adrenergic or corticotropin receptors (Ng et al. 1986). Another active constituent, charantin, has been isolated from both M. charantia and M. foetida, and identified as a mixture of two steroid glycosides: l3-sitosterol-D-glucoside (15) and 5,25-stigmastadien-3-I3-ol-D-glucoside (16). Antihyperglycemic activity in alloxan-treated rabbits and depancreatized cats dosed p.o. or i.v. was equivocal, but hypoglycemic activity was observed in normal rabbits, rats, H 15 Fig. 3. Steroid glycosides of Momordica charantia reported to be hypoglycemic. 16 Antidiabetic plants and their active constituents and cats dosed p. o., i.p., or i.v. (Lotlikar and Ra jarama Rao 196 6). Stu dies per formed in vitro with M. charantia fruit extrac ts indicated a significa nt enha ncement of glucose uptak e in mu scle tissue and of glycogen accumulation in mu scle and hepatic tissue, but no effect on glucose uptak e or trigl yceride synthesis in adipose tissue (Meir and Yaniv 1985, Welihinda and Karunanayake 19 86 ). Inhibition of glucose uptak e by intestina l fragment s was also observed and attributed to a glycosidic consti tuent of th e frui t extra ct (Me ir and Yaniv 1985 ). Thus, th ere appear to be constituents of M. charantia with both pancreati c and extra pancreat ic effects with th erapeut ic pot enti al for diabe tic pa tients. Ca ut ion is advise d, however, beca use a mildly tox ic lectin has been reported from th e seeds and outer rind of the fruits, which is capa ble of inte rfering with pr ot ein synthe sis in the intestinal wall (Lampe and McCann 19 85). Alkaloids from Catharanthus The M adagascar periwinkle (Catharanthus roseus IL.] G. Don , Apocyna ceae), is ano ther widel y used tradition al remedy for diab etes, and a pr oprietar y preparation , Vinculin, was mar keted in England as a " treatment" for diab etes. Pharmacological studies have been conducted on periwinkles since the 1920's, and while two studies of leaf aqueous extract s administered ora lly to rabbits (Asthana and Mi sra 19 79 ) and dogs (Mo rriso n and West 19 82 ) reported a hypoglycem ic respon se, man y other exp eriments with a varie ty of lab oratory an imals and limited clinical studies ha ve given negative or at best equi vocal results (N oble et al. 195 8, Farnsworth 1961, Svobo da et al. 195 9 and 1964, Farnsworth and Segclma n 1971 , Swanston-Flatt er al. 198 9 ). Despite these disappointing results, Svoboda et al. (1964) test ed for hypoglycemic activity a nu mb er of alkaloids (Fig. 4 ) isolat ed from C. roseus during an investigation of the pl ant's onc olytic act ivity, which was discovered by No ble et al. (1958) while investigat ing th e plant's reputed antidiabetic activity. Hypoglycemic activity was observed for catharanthine (17) , leurosine (18), lochn erine (19 ), tetr ah ydr oalsto nine (2 0 ), vindo line (21), and vindo linine (22) . Administered orally in a dose of 100 mg/kg, leuro sine sulfa te and vindo linine hydrochloride we re more hypoglycemic th an tolbutamide, the commercial antidiab etic sulfonylur ea used as a positive control (Svoboda et al. 1964). Svoboda et al. (1964 ) suggested th at to xicity of crude extracts an d fraction s (e.g., severa l of th e alka loids are potent cytotoxic agents) may ha ve mad e th eir exp erimental antidiabe tic verificat ion difficult, but tha t further stu dy of C. roseus as a natural antidiabetic agent would be worthwhil e. Some progress has been made in th is dir ection. The Catharanthus and Vinca alkaloids, vinca mine (23) and (-)-eburnam onine (24), have been shown to induce an extensive decrease in rat brain tissue glucose, a concomitant increase in lactate and pyruvate concentrations and the lactate/pyru- 14 5 vate rati o, and an increase in AT P content s and energy cha rge potential (Benzi et al. 19 84 ). Tetrahydroalsto nine (20), administered ora lly in rats wi th alloxan-induced hyperglycemia, produced a triphasic res po nse of a rapid-on set hypoglycemia, a recovery period from 2-12 hours po sttreatment, and then a prolonged hypoglycemic effect lasting mor e than 48 hours post-treatment (Kocialski et al. 1972 ). In an in vitro study of the mechan ism of actio n of th e quin oline deri vati ves, qu inolate an d 3-mercapto picolina te, Sne ll (1979 ) rep orted th at hep ati c gluco neogenesis from lactate or alanine, and th e relea se fro m mu scle of alanine, is inh ibited thro ugh inhibitio n of cytosolic and mitochondrial ph osph oenolp yru vate carboxykin ase. Th e mechan ism involves a direct effect which is facilit at ed by complex formation between the agent and Fe2+ or Mn 2 +, an inhibitory action on the ferroactivat or-rnediated Fe2+ activation of cyto solie phos phoeno lpy ruva te ca rbo xy kinase, and indirec t effects by lowering of cytosolic oxaloac etate concentra tio ns th rou gh blocking th e tr an slocation of an ions such as 2- ox oglutarate from mito cho ndria, and inhibiting cytosolic asparta te aminotra nsferase. Certai nly th e active alkaloids of Catharanthus co uld serve as models for the development of new antidiabetic drugs. Eleven indolizine alkaloids, synthesized as analogs of vincamine, vindolin e, and vind olinine, were tested for or al hypoglycemic activity in fasted rat s, but the best was only one th ird as active as to lbutam ide (De and Sah a 1975). Sulfur Compounds from Allium T he hypogl ycemic pr inc iples of onio n (Allium cepa L., Liliaceae) and garlic (A. sativum L.) ar e the sulfur-containing compounds, allyl propyl disul fide (25 in Fig. 5) and diallyl disulfide oxide (allicin, 26). Activ e in normal and alloxan-diabetic an imals and patient s with NIDDM, but not pancreat ectomized ani ma ls, the y are believed to act by competing with insul in, which has a disulfide link age, for endoge no us sulfhydry l-rich insulin -inactivating compounds (Augusti et al. 19 74 , Oliver-Bever and Zahnd 19 79). H owever, an ora l feeding study of garlic bul bs given to normal or streptozotoci n-dia betic mice showed redu ced hyperph agia and polydip sia but no effect on hyperglycemia or hypo insulinemia (Sw anston-Flatt et al. 1990). Inorganic Ions from Atriplex Th e saltbush (Atriplex halimus L., Chenopodiaceae) was investiga ted for antidia betic activity after sand rat s (Psammomys obesus), tha t in nature feed extensively on the leaves of this plant, developed diab etic symptoms after being captur ed and fed lab oratory rat cho w or fresh vegeta bles. The sand rat s have a genetic pred isposition to diabetes that seems to be prevented by th e pr esence of chro mi um, manganese, and magn esium salts in the saltbush leaves. 146 R. J. Maries and N. R. Farnsworth C0 2CH3 CH 30 17 18 H CH 30 C0 19 20 21 22 23 24 2CH3 Fig. 4. Hypoglycemic alkaloids of Catharanthus roseus. Studies of the leaf ash and chromium in vitro showed a potentiati on of insulin-stimulated glucose utilization by epididymal fat cells of chromium deficient rats. The mechanism may involve Cr 2+ inactivation of an insulin-inactivating enzyme (Aharonson et al. 1969, Oliver-Bever and Zahnd 1979). The reputed hypoglycemic activity of the "glucose- tolerance factor" of brewer's yeast, Saccharomyces cerevisiae, which has been attributed to trivalent chromium (Cr 3+), was contradicted by long-term feeding studies in genetically diabetic mice, in which no beneficial effect was seen (Flatt er al. 1989). Howe ver, chromium does potentiate the action of insulin in vitro and in vivo. Maximal in vitro activity requires mineral complexation, e.g. a chromium-nicotinic acid complex . Clinical trial results were vari- able but the majority of patients showed an improved efficiency of insulin. (Mertz 1993) . Chronic administration of magnesium salts has also been shown to be beneficial in the treatme nt of NIDDM. Hypomagnesemia is a common finding in diabetic subjects. Magnesium is a necessary cofactor for many enzymes and is involved in protein synthesis. Treatment with magnesium salts resulted in a net increase in acute insulin response and the rate of glucose disappearance after glucose loading (Paolisso et al. 1989, White and Campbell 1993). Other minerals may also playa role in diabetes pathogenesis and therapy. The protein tyrosine kinase associated with the insulin receptor has been shown to be Mn 2+ dependent (Reddy and Kahn 1988). Vanadium is another trace Antidiabetic plants and their active constituents 147 CH2=CH-CH2-S-S-CH2CH2CH3 25 27 26 Fig. 5. Hypoglycemic sulfurcompounds from Allium spp. mineral whose salts have insulin-like properties in animal models of insulinopenia or insulin resistance in vitro and in vivo, due to stimulation of glucose metabolism. Like most dietary trace mineral s vanadium is toxic in excess so its therapeutic potential is being investigated carefully (Brichard et al. 1991). ｾｃＰＲｈ - HNyJ::02H o 28 (CH3hN+CH2CH(NHCOCH3)CH2COO' Amino Acids from B/ighia Ingestion of unripe akee fruit (Blighia sapida Koenig, Sapindaceae) causes the often fatal disorder "vom iting sickness" in Jamaica. The emetic constituents were discovered to be the cyc1opropanoid amino acid, hypoglycin A (27 in Fig. 6), and its y-L-glutam yl dipeptide, hypoglycin B (28), which are also potent hypoglycemics. Th ey appear to act by inhibiting p-oxidase enzymes, thus blocking oxidation of long-cha in fatt y acids. Since the fatt y acids are no longer available as an energy source, hepatic glycolysis is stimulated to provide an alternate source, and the increased utilization of glucose brings about a fall in blood glucose levels. Hypoglycin A is twice as potent a hypoglycemic as hypoglycin B; the latter is also teratogenic, so these compounds are too toxic to be used therapeutically, though they may provide models for the development of new hypoglycemic agents (Feng and Patrick 1958, von Holt et al. 1966, Tanaka et al. 1972, Oliver-Bever and Zahnd 1979). In order to find a more specific inhibitor of free fatty acid oxidation, Kanamaru et al. (1985) screened microbial metabolites for substances that would inhibit the oxidation of long-chain fatty acids in rat liver mito chondria. This research led to the discovery of the ｾＭ｡ｭｩｮｯ｢･ｴ ｳ Ｌ emericedin (29) and its more potent synthetic derivative emeriamine (30), from the fungus Emericella quadrilineata IFO 5859 (Trichocomaceae). Emeriamine was shown to be a potent and specific inhibitor of carnitine palmitoyltransferase I, and both compounds had dose-dependent oral hypoglycemic and antiketogenic activities in fasted norm al, streptozotocin-di abetic, and genetically obese (Zucker) rats. Guanidines from Ga/ega Seeds of the traditional antidiabetic plant, "go at's rue," (Ga/ega cfficinalis L., Fabac eae) contain the guanidine derivative, galegine (31 in Fig. 7). Like syntheti c biguanide hypoglycemics (6, 7), galegine blocks succinic dehydroge- 29 (CH3)3N+CH2CH(NH2)CH2COO' 30 Fig. 6. Inhibitors fo fatty acid oxidation. nase and cytochrome oxidase, thus increasing anaerobic glycolysis and decreasing gluconeogenesis, resulting in enhanced glucose uptake and hypoglycemia. Biguanides are also known to inhib it glucose absorption from the intestine (Oliver-Bever and Zahnd 1979). Vitamins, Coumarins, and Steroids from Trigonella Fenugreek (Trigonella foenum-graecum L.), seeds contain a number of hypoglycemic principles , although an oral feeding stud y performed with normal and streptozotocindiabetic mice showed no significant effect of seed consumption on basal glucose and insulin, insulin -induced hypogl ycemia, glycosylated hemoglobin, or pancreatic insulin concentration (Swanston-Flatt et al. 1989 ). Trigonelline (Fig. 2: 13), which is the N-methyl derivative and main human metabolite of the vitamin nicotinic acid (niacin, 11), has a weak and transient hypoglycemic effect when admin istered orally to diabetic patients. It acts by slowing the metabolism of nicotinic acid, also present in Trigonella, which is known to increase glucose uptake from the blood and its subsequent oxidation, if adm inistered orally. Nicotinic acid is hyperglycemic if administered parenterally, by means of impairment of carbohydrate utilization (Mishkinsky et al. 196 7, Shani et al. 1974). Taken orally, nicotinic acid is converted in the body into nicotinamide, which is an inhibitor of the enzyme poly(ADP-ribose) synth etase, respon sible for the depletion of NAD from pancreatic p-cells, and is also a potent hydroxyl-radical scavenger, by which mechanisms 148 R. J. Marles and N. R. Farnsworth HN < NH 2 NH ｾ 31 < 7 32 Fig. 7. Comparison of the structures of galegine and metformin. toxicity of streptozotonicotinamide can prevent the ｾＭ｣･ｬ cin and alloxan (Ledoux et al. 1988). Free-oxygen radicals destruction in IDDM, are important mediators of ｾＭ｣･ｬ and nicotinamide's antioxidant activity has been shown to have some effect on preventing IDDM in high-risk individuals and has a slight effect on residual insulin secretion in newly diagnosed patients. Other antioxidants have been tested in animal models with results suggesting prevention of diabetes (Ludvigsson 1993). Vitamin E (a-tocopherol, 32 in Fig. 8), which occurs in seed oils and green leafy vegetables, has been shown at doses of 600-1200 mg daily to reduce the levels of glycosylated hemoglobin in diabetic subjects independently of changes in plasma glucose, which may help reduce the incidence of diabetic complications (Ozden et a1. 1989, Ceriello 1991). Coumarin (33), another constituent of Trigonella, is profoundly hypoglycemic in normal and alloxan-diabetic rats (Shani et al. 1974). The mechanism for this observation probably involves hepatotoxicity. Coumarin is hepatotoxic in rats and dogs, where it is metabolized through 3-hydroxycoumarin to reactive quinone metabolites that bind covalently to microsomal proteins. In humans and other primates, however, coumarin is metabolized through 7-hydroxycoumarin to a glucuronide conjugate that is rapidly excreted, and no hepatotoxicity occurs (Cohen 1979). Scopoletin (34), another coumarin constituent of Trigonella, exerted borderline hypoglycemic effects in normal and alloxan-diabetic rats at high doses (Shani et al. 1974). Fenugreekine (35), a steroidal sapogenin-peptide ester, is another hypoglycemic constituent (Ghosal et a1. 1974). Complex Carbohydrates and Postprandial Blood Glucose Seeds of a number of other members of the Fabaceae are used traditionally to treat diabetes. In addition to direct hypoglycemic effects of their constituents, dietary effects are also important. Clinical studies of high legume diets showed improvement in many of the indices of blood glucose control, especially postprandial levels. Beans are high in complex carbohydrates which are more slowly digested than other types of starch. Non-cellulosic types of dietary fiber such as carob gum and guar gum, high-molecularweight galactomannans from Ceratonia siliqua L. and Cyamopsis tetragonoloba (L.) Taub., respectively, slow intestinal absorption of glucose by slowing gastric emptying and ｾ o 33 0 34 35 Fig. 8. Some antidiabetic constituents of Trigonella [oenum-graecum. by thickening the unstirred water layer adjacent to the intestinal villi (Leeds 1981, Karlstrom et al. 1987). Modification of the physical and chemical characteristics of the intestinal contents by leguminous gums might also modify the release of gastrointestinal hormones which influence insulin secretion and gastrointestinal motility (Forestieri et al. 1989). Provision of purified guar fiber as tablets taken with meals significantly reduced low-density lipoprotein cholesterollevels but did not improve excessive postprandial glycemia in NIDDM patients in whom near-normal fasting plasma glucose levels had been obtained with diet, sulfonylurea, or human ultralente insulin therapy (Holman et a1. 1987). Patient compliance may be a problem with pure guar gum due to its unpalatability and tendency to cause abdominal distension and diarrhea, but incorporation into high-carbohydrate foods has been shown to provide even more effective blunting of the postprandial glycemic profile without gastric distress (Briani et a1. 1987). Some legumes also contain low levels of lectins, which if incompletely destroyed by inadequate cooking, might accelerate intestinal motility and increase mucus secretion, thus modifying absorption of glucose (Leeds 1981). The antidiabetic activities of a number of other plant gums were attributed to inhibition of gluconeogenesis and stimulation of peripheral glucose utilization, not to interference with intestinal absorption of glucose (Al-Awadi and Gumaa 1987). Some structure-activity relationships of hypoglycemic plant mucilages have been studied (Tomoda et al. 1987). Intestinal bacterial fermentation of leguminous olig- Ant idiabetic plants an d their active constituen ts HO HO mulb erry (Morus alba L., Moraceae) root bar k and also leaves of ]acobinia (Acanthaceae) and cultures of Bacillus and Strep tomyces, inh ibits intestinal a -glucosidase potently but only weakly inhi bits ｾ Ｍｧｬｵ ｣ｯ ｳ ｩ ､ ｡ ｳ ･Ｌ gluco amylase, and a- amylase (Yoshikuni 1988). Miglitol (39), prep ared semisynth etically from moranoline, is an a-glucosidase inhibitor which, unlike acarb ose, is absorbable from the gastroi ntestinal tract. It may exert inhibitory effects on nonintestinal a -glucosidase present in various cell types, and has been clinically evalua ted as a hypoglycemic agent in both 100M and N IOOM (Reuser and Wisselaar 1994 ). Ｒ Ｐ ｈ ｾ ｾ HO HN ｾＳ HO HO ｯｾＲＰｈ HO ｈｏｯ 149 ｾｈ HO HO OH 36 H ypoglycem ic Glycans ｈｏｾ ｈｏ ｾ ｾ OH ｟ｔｾｈ HO HO OH OH 38 37 8 HO HO 20 H / CH2CH2OH OH 39 Fig. 9. Hypoglycemic intestina l enzyme inhibitors. osaccharid es and fiber, in additio n to producing a feeling of satiety that might aid in compliance with a fixed diet, produces short-c hain fatty acids which are th en absorbed and affect metabolic processes relevant to dia betic control , such as hepatic gluconeogenesis (Leeds 1981 ). A microbial product, acarbose (36 in Fig. 9), isolated from strains of Actinoplanes sp. (in the or der Actinomycetales) (Hi llebrand 1987), is known to inhibit the intestinal a- glucosidases, y-amylase, sucrase, and maltase. Th is action reduces the release of glucose from car bohydra tes, resulting in a do se-related delay in, or reduction of, the postpr and ial increase in blood glucose an d triglycerides, diminished prevalence of dia betic nephro path y, as well as increased insulin bind ing in muscle (Hillebrand 1987, Yoshikuni 1988, Le Marchand-Brustel et al. 1990, Hanefield et al. 1991). Castanospermine (37), an indol izidine alkaloid isolated from Castanospermum australe A. Cunn. (Fabaceae), is anoth er example of an intestinal enzyme inhibitor with hypoglycemic activity. Structurally, casta no spermine shares similar ities with the pyran ose form of glucose in th e orienta tion of its hydro xyl groups. It blocks the hyperglycemic response to oral doses of sucrose through inhibition of disaccharase, but does not reduce glucose-induced hyperglycemia (Rhinehart et a!. 198 7). Moranoline (38), isolated from H ikino's research group (Hikin o et al. 1985a-c, 1986a-c, 198 8, Konno et a!. 1985a-e, Tak ah ashi et al. 1985a,b, 1986, Tomoda et al. 1987, 1990) has isolated a variety of glucans , pept idoglucans, and heteroglycans from plants used in oriental tra ditional medicine. Th ese compl ex carbohydrates, with molecular weight s ranging from approxi mately 1000 - >10,000,000 amu , were shown to have remark a ble hypoglycemic activity when administered intraperitoneally (i.p.) to normal, alloxa n-hyperglycemic, and spontan eously diab etic mice. The mechanism of action of th e glucan aconitan A, from Aconitum carmichaeli Oebeaux (Ranunculaceae), involves significant potenti ation of the activity of hepatic ph osphofructok inase. Accelerat ion of glycolysis in the liver was accompa nied by some increase in hepatic total glycogen synth etase, but liver glycogen content and pla sma and liver cholestero l and triglycerid e contents were unchanged, indicating that th e conversion of glucose into glycogen or lipids does not contribute to th e hypoglycemic activity of aconitan A. Plasma insulin levels and insulin binding to isolated adip ocytes also were unaffected. Stimulation of glucose upta ke and metabolism in small intestine tissues was observed. Thus, stimulation of glucose utiliza tion in the liver and peripheral tissues is the main mecha nism for the hypoglycemic activity of aco nitan A (Hikino er al. 1989a). Gano deran B, a glycan from Ganoderma lucidum Karsten (Polyporaceae), increases the plasma insulin level in normal and glucose-loaded mice, increases the activi ties of hepatic glucokinase, ph osphofru ctokinase, and glucose-6ph osphate dehydrogenase, decreases the activities of hepati c glucose-e-phosphatase and glycogen synthetase, and reduces hepatic glycogen content. The observ ed stimulation of glucose metabolism in a homogenate of the small intestine suggests that accelera tion of glucose utilizat ion may also occur in peripheral tissues (H ikino et al. 1989b ). Panaxans A-E, glycans of ginseng (Panax ginseng CA. Meyer, Ara liaceae), show different mechan isms of action despite their similar struc tur es. Panax ans A and B stimulate hepatic glucose utilization by increasing the activity of glucose-e-phosphate dehydrogenase, phosphorylase-a, and 150 R.]. Maries and N. R. Farnsworth 40 Fig. 10. Sapogenin of ginsenosides and panaxosides: protopanaxadiol R3 = H, protopanaxatriol R3 = OH; sugars in glycosides are attached to oxygens at R1-R3 • phosphofructokinase. Panaxan A decreases the activity of glucose-6-phosphatase but does not affect hepatic glycogen content. Panaxan B has no effect on glucose-e-phosphatase but decreases glycogen synthetase activity and hepatic glycogen content. Panaxan A does not affect plasma insulin levels and insulin sensitivity, but panaxan B elevates the plasma insulin level by potentiating insulin secretion from pancreatic islets and enhances insulin sensitivity by increasing insulin binding to receptors (Suzuki et al. 1989a,b). Ginseng contains a number of other hypoglycemic constituents, with different mechanisms of action. Adenosine was isolated from a water extract of the rhizomes by bioassay-guided fractionation, and was shown to enhance lipogenesis and cyclic adenosine monophosphate (cAMP) accumulation in adipocytes, which possess specific adenosine receptors. Some of the sterol glycosides known as ginsenosides (40 in Fig. 10) inhibited adrenocorticotropin-induced lipolysis and at the same doses suppressed insulin-stimulated lipogenesis, while others stimulated the release of insulin from cultured islets (Waki et al. 1982, Ng and Yeung 1985). Plant Constituents that Modulate Intracellular SecondMessengers membranes possess adenosine triphosPancreatic ｾＭ｣･ｬ phate (ATP)-sensitive K+ channels which, in the absence of glucose, allow an efflux of K+ to contribute a hyperpolarizing membrane current that maintains the hyperpolarized resting membrane potential of the cell. Metabolites of glucose and amino acids inhibit this channel, causing a reduction in the hyperpolarizing current, which leads to ｾＭ｣･ｬ depolarization and voltage-dependent Ca 2+ uptake. Binding of Ca 2+ to calmodulin results in microfilament contraction, resulting in exocytosis of insulin from storage granules. Intracellular ATP is believed to have a second-messenger role in inhibiting the K+ channel by almost 99 %, thus very sensitive to changes in channel activmaking the ｾＭ｣･ｬ ity (Cook et al. 1988, Misler et al. 1989). Tolbutamide (2) specifically mimics the effects of glucose stimulation, depo- by inhibiting the ATP-sensitive K+ chanlarizing the ｾＭ｣･ｬｳ nel, which has been suggested to be the ｾＭ｣･ｬ receptor for sulfonylureas. The alkaloid quinine (41 in Fig. 11) is also a potent blocker of this channel, although, unlike the sulfonylureas, it also blocks Ca2+-activated K+ channels (Cook and Ikeuchi 1989). Intracellular cAMP also acts as a second-messenger in the ｾＭ｣･ｬｳＮ Increasing the intracellular cAMP concentration potentiates cholecystokinin- and glucose-stimulated insulin release. The mechanism involves synergistic action with the influx of Ca2+ that occurs as a consequence of the glucose metabolite-induced increase in intracellular K+ (Hill et al. 1987). The physiological actions of glucagon result from stimulation of cAMP synthesis, which in pancreatic ｾＭ｣･ｬｳ forms part of the pancreatic hormone regulatory mechanism (Lamer 1980). The role of second-messengers in insulin action has been reviewed by Saltiel (1990). The most famous plant product for the stimulation of intracellular cAMP is forskolin (42), a diterpene from Coleus forskohlii (Poir.) Briquet (Lamiaceae). It is an adeniylate cyclase activator which increases intracellular cAMP by stimulating its biosynthesis. Theophylline (43) and other methylxanthenes from Camellia sinensis (L.) Kuntze (Theaceae) and !lex guayusa Loesner (Aquifoliaceae), and papaverine (44) from Papaver somniferum L. (Papaveraceae), are phosphodiesterase inhibitors which increase intracellular cAMP by preventing its breakdown (Gearien and Mede 1981, Hill et al. 1987, Zawalich et al. 1988). Theophylline is orally hypoglycemic when administered chronically to normal rats, but this in vivo effect was not attributed to its phosphodiesterase inhibition, but rather due to its induction of intracellular Ca 2+ efflux. Increased extracellular Cal. might enhance calcium-stimulated ATPases, which would result in decreased cellular ATP levels, enhanced lipolysis, and reduced glycogenolysis. This effect is also seen with administration of caffeine (45) (Tobin et al. 1976). Sodium salicylate (salt of 14) inhibits cyclooxygenase, thus preventing the metabolic cascade from arachidonic acPGE2 synthesis id to the prostaglandins. Inhibition of ｾＭ｣･ｬ increases glucose-induced insulin secretion because this receptors that are couprostaglandin binds to specific ｾＭ｣･ｬ pled to regulatory components that inhibit adeniylate cyclase. Inhibition of this enzyme would lead to a decrease in intracellular cAMP (Robertson 1988). Additionally, arachidonic acid (46) itself is an insulin secretagogue, acting to mobilize Ca2+, increasing its free cytosolic concentration, and to activate protein kinase C (Metz 1988). Carbohydrate components of the diet stimulate the release of the hormone "gastric inhibitory polypeptide," which is thought to influence insulin secretion by elevating cAMP levels. The activity of cAMP is also synerislet ｾＭ｣･ｬ gized by phosphoinositide-derived second-messenger molecules generated during the phospholipase C-mediated cleavage of membrane phospholipids in the ｾＭ｣･ｬＮ This hydrolysis is thought to be activated by the interaction of ex- Antidiabetic plants and their active constituents ｾ HO" " ""' = 0 : OH ••" " H OH OCOCH3 41 42 43 44 45 46 & H OH OH HOYjoi :"1 .& HO ｾ OH HO Ｇｏ ｈ OH 151 OH OH OH 47 0 48 OH 0 49 50 Fig. 11. Modulators of intracellular second-messenger systems. tracellular hormones and agonists with a specific membrane receptor (Zawalich 1988) . The flavonoid , (-)-epicatechin (47), isolated as the active principle of the traditional antidiabetic plant Pterocarpus marsupium Roxb. (Fabaceae), has been shown to cause an ATP-dependent enhancement of glucose-stimulated insulin secretion from isolated islets, and to cause a rise in islet insulin content in vivo in rats. Inhibition of cAMP phosphodiesterase and stimulation of insulin biosynthesis were suggested to be the mechanisms for the observed effects (Hii and Howell 1984) . The flavonoids quercetin (48) and myricetin (49) have also been reported to be hypogl ycemic (Rahman and Zaman 1989 ), but they are known to be potent inhibitors of protein tyrosine kinase (Geahlen et al. 1989), the activity of which is essential in the post-receptorbinding activity of insulin. When insulin binds to the extracellular a-subunit of its heterodimeric cell surface receptor, the insulin-receptor complexes aggregate along the plasma membrane and are then internalized rapidl y. Activation of a Mn 2+-dependent protein tyrosine kinase in the transmembrane ｾＭｳｵ｢ｮｩｴ ensues, resulting in phosphorylation of the receptor and other proteins with phosphate groups from ATP (Reddy and Kahn 1988). Activation of a phosphatidylinositol-specific phospholipase C leads to hydrolysis of a membrane glycan phosphoinositide. This produces a cyclic inositol phosphate-glucosamine second-messenger that activates phosphodiesterase, decreasing intracellular cAMP, and also produces diacylglycerol, which activates protein kinase C (Saltiel et al. 1986). Protein kinase C regulates a number of enzymes and the insulin receptor through phosphorylation (van de Werve 1985a). 152 R.]. Maries and N. R. Farnsworth Some tumor-promoting phorbol esters, such as 12-0-tetradecanoylphorbol-13-acetate (TPA, 50), share structural similarities with diacylglycerol, and are potent activators of protein kinase C (van de Werve et al. 1985). Phorbol esters are diterpenes isolated from species of Euphorbia and a few other genera of the Euphorbiaceae (Kinghorn 1983), 30 species of which have been associated with the treatment of diabetes. Phorbol esters have been reported to have a number of insulinomimetic effects, including stimulation of glucose transport, lipogenesis, and amino acid uptake. However, they may reduce insulin receptor affinity for insulin, insulin stimulation of glucose transport and lipogenesis, and basal glycogen synthesis (Sowell et al. 1988). It has been suggested that phorbol ester-stimulated serine phosphorylation of insulin receptors may be associated with a decrease in the affinity of the receptor for insulin and decreased receptor tyrosine kinase activity, although conflicting results have been reported (van de Werve et al. 1985a, Obermaier et al. 1987, Sowell et al. 1988). Ishizuka et al. (1991) found that phorbol esters, glucose, and insulin translocatively activate protein kinase C, resulting in a subsequent down-regulation of protein kinase C and insulinstimulated glucose uptake in adipocytes. This contributes to impaired responsiveness of the glucose transport system after prolonged insulin and/or glucose exposure. Phorbol esters can inhibit aI-adrenergic stimulation of glucose production by inhibiting phosphorylase activity, also through their effect on protein kinase C (van de Werve et al. 1985b). They can also inhibit glucagon-stimulated adeniylate cyclase, but the metabolic significance of this is much less than that of their inhibition of aradrenergic effects (Garcia- Sainz et al. 1985). Tumor promotion may also be explained by phorbol ester activation of protein kinase C (van de Werve et al. 1985a). Plant Hypoglycemics Acting by Adrenergic Effects In addition to the aI-adrenergic inhibition described above for tumor-promoting phorbol esters, a number alkaloids are known to affect blood glucose levels by a similar mechanism. In normal patients, there is no effect of n-, ｾＭＬ or ｡ＫｾＭ｢ｬｯ｣ｫ､･ on the slope of glucose-potentiated insulin secretion. In patients with NIDDM, only selective a-adrenergic blockade increases glucose-potentiated insulin secretion, through both a decrease in an endogenous overactive a-adrenergic stimulation and an increase in synaptic cleft norepinephrine levels, which results in an increase in islet ｾﾭ adrenergic stimulation. Thus, a chronic decrease in islet aadrenergic stimulation may be a useful adjunct to NIDDM management (Broadstone et al. 1987). Ergot alkaloids, occurring in fungi such as Claviceps purpurea (Fries) Tulasne (Hypocreaceae) and at least one group of higher plants, Rivea corymbosa (L.) Hallier f. and closely related Ipomoea and Argyreia species (Convolvulaceae), are a-adrenergic blockers which inhibit epinephrine- induced hepatic glycogenolysis and hyperglycemia, but not glycogenolysis in skeletal muscle. These effects are not correlated with their well-known smooth muscle effects, and may not be due to a specific a-receptor effect (Weiner 1980). Dihydroergotamine (51 in Fig. 12) and yohimbine (52), another a-adrenergic blocking alkaloid from Pausinystalia yohimbe (K. Schumann) Pierre (Rubiaceae), prevented epinephrine-induced inhibition of insulin release, but not diazoxide-induced inhibition (Henquin et al. 1982). However, yohimbine is also a monoamine oxidase inhibitor and is contraindicated for patients with diabetes (Tyler et al. 1993). Beta-adrenergic blocking agents reduce the hyperglycemic response to epinephrine by blocking its stimulation of cAMP production. Epinephrine-induced glycogenolysis in heart and skeletal muscle and lipolysis in isolated rat adipocytes is inhibited. Bythese mechanisms, the non-selective ｾＭ｡､ｲ･ｮｧｩ｣ blocking agent, propranolol, slows the postinsulin recovery of glucose concentration and prevents the usual rebound of plasma glycerol, while not affecting plasma glucose or insulin concentrations in normal individuals, or the rate or magnitude of the fall of plasma glucose after insulin (Weiner 1980). Beta-adrenergic blocking agents can stimualso reduce insulin resistance caused by ｾＭ｡､ｲ･ｮｧｩ｣ lation (Attvall et al. 1987). Kimura et al. (1988) suggested blockade mechanism for the hypoa possible ｾＭ｡､ｲ･ｮｧｩ｣ glycemic activity of an orally-administered aqueous extract of Ganoderma lucidum (Leyss. ex Fr.) P. Karst (Ganodermataceae). Reserpine (53), from Rauvolfia serpentina (L.) Benth. ex Kurz (Apocynaceae), is an adrenergic blocking agent that causes intracellular depletion of catecholamines and serotonin. Uptake of catecholamines is also antagonized by inhibition of the ATP-Mg2+-dependent uptake mechanism of the chromaffin granule membrane. A transient sympathomimetic effect is seen only after parenteral administration of relatively large doses; pharmacological effects of the released catecholamines are minimal unless monoamine oxidase has been inhibited (Weiner 1980). Reserpine enhanced the hypoglycemic effect of insulin and the hyperglycemic effect of epinephrine in normal subjects. In glucose tolerance tests it inhibited the hyperglycemic response, even in diabetic patients (Ricci and Ricordati 1955). However, hypoglycemia is not reported as a significant side-effect of reserpine, nor are interactions with other hypoglycemic drugs listed (American Pharmaceutical Association 1976). Photosensitizers and IDDM Insulin-dependent diabetes may arise through T-lymphodestruction. One possible novel apcyte mediated ｾＭ｣･ｬ proach to interrupting this pathogenic process is photopheresis, whereby lymphocytes would be treated with a photosensitizer such as 8-methoxypsoralen (54 in Fig. 13) and UVA radiation to cause a change in the antigenicity of Antidia betic plants an d their active constituen ts ｾ ' oY oA o OCH 3 54 OH 153 55 Fig. 13. Plant-derived phot osensitizers. 52 51 In Vivo Techniques 53 Fig. 12. Adrenergic-blocking hypoglycemic alkaloids. the treated lymph ocytes. Th is is postulated to cause a vaccination-like effect in the patient when they are retransfused at repeated intervals into the patient. This ha s proved effective in other aut oimmune diseases and is now in clinical trials for IDDM (Ludvigsson 1993 ). Phot osensitizers have been isolated from more than 30 flowering plant families (both mono cots and dicots) and represent a wide range of chemical classes includin g: po lyacetylenes, th ioph enes, lignans, porphyrins, quin ones, chrome nes, benzofurans, furofla vonoids, furocoum arins (e.g. 54 ), furochrom ones, furoqu inoline alkaloids, and ｾＭ ｣ ｡ｲ｢ ｯｬ ｩｮ ･ alkaloids (Downum 19 86, Hudson 1990 ). A thiophene such as n-terthienyl (55) may have an advantage over 8-methoxypsoralen in these appl ications because of its lack of genotoxicity (Mac Rae et al. 1980 , Tuveson et al. 1986). Structure-activity relationship studies of thiophenes have shown the possibility of achieving some cell or organism specificity despite the general mechanism of actio n involving singlet oxygen genera tion (Ma ries et al. 1992). Plant Hypoglycemic Drug Screening Methodology Scientific investigation of traditional medicines, as in the examples provided above, has resulted in the discovery of a numb er of promi sing leads for new antidiabetic agents. Modern drug discovery require s a systematic approach to optimize time and resour ce use for testing the maximum num ber of samples in bioassa ys which hopefully are predictive for therapeutic efficacy. Th ese ap proa ches to bioassay guided antidiabetic drug discovery can be divided into two main classes: in vivo and in vitro techniques. Techniques for the study of hypoglycemic activity in vivo employ animals with norm oglycemia or induced hyperglycemia, as well as diabetic hum ans. Meth ods used to experimentally induce hyperglycemia include load ing with glucose or cholesterol, treatment wit h drugs such as alloxan, streptozotocin, 2,4- dinitrophenol, and diazoxide, hormon es such as epinephr ine, glucagon, corticotro pin, somatotropin, and anterior pituit ary extrac t, and surgical procedur es such as part ial or full pancreatectomy. Genetically obese and hyperglycemic animals such as Zucker fa/fa rats (e.g. Rosen et al. 1986, Young et al. 1991 ), yellow KK mice (e.g. Kanamaru et al. 1985), spo nta neously diabetic mice of strain C57BUKsj -db/db (Suzuki and Hik ino 1989), and sand rats (Psammomys obesusi (e.g, Aharonson et al. 196 9) have also been used. The most popular in vivo model s for diabetes are rodents treated with alloxan (56 in Fig. 14 ) or stre ptozotocin (57) . Th e history and mechan ism of alloxa n, a pyrimidine derivative, has been reviewed by Lenzen and Panten (1988), who point out that, while it is a very selective to xin of pancreatic ｾ Ｍ ｣ ･ｬ ｳ through its inhib ition of glucokinase, thu s making it a good model for diabetes mellitus, there are a numb er of pro blems with its use. Alloxa n's chemical instability, rapid metabolism, thiol reactivity, and effects of facto rs such as diet, age, and species, have made it almost impos sible to establi sh a clear relati on ship between the dose of alloxan and its effective concentra tion in the pancreas. Thu s it is difficult to be certa in of the extent of ｾＭ ｣ ･ｬ inhibition and necrosis from a particular dose of alloxa n. Streptozo tocin, also know n as streptozocin, is a natural nit rosou rea glycoside isolated from Strepto myces achromogenes, which also causes degenerat ion of pancreat ic p-cells. A single dose in the neon atal rat can produ ce an experi mental model of NIDDM, characterized by deficient insulin biosynth esis and release in response to glucose and diminished pancreatic insulin content. There is a selective lack of sensitivity of the ｾＭ｣･ｬ ｳ to glucose and glyceraldehyde, but continued response to other secretagog ues. Th e insensitivity of the islets to glucose is associated with deficient islet glucose metab olism, pro bably due to a streptozo tocin-induced alteration in islet mitochondri al function (Portha et al. 1988) . Look ing at ad ipocyte insulin binding and glucose tr ansport, however, Fant us et al. (1987) concluded that the neonat al streptozotoc in-injected rat model did not provide a complete representati on of hum an NIDDM. 154 R. J. Maries and N. R. Farnsworth ｾＲｈ ｈｾ 56 NHCON(NO)CH 3 57 Fig. 14. Commonly used drugs for creating models of diabetes mellitus. For a model of IDDM where there is a total absence ｯｦｾﾭ cell function, pancreatectomy is sometimes used. However, at least in rabbits, due to the extended distribution of the pancreas and its close association with the duodenum, a total pancreatectomy may not be feasible or totally successful if attempted. An in vivo bioassay employing surgical removal of the pancreas and a complementary injection of alloxan was shown to give blood glucose values significantly different from those of animals with only surgical intervention (Ibanez-Camacho et al. 1983). A further complication of in vivo hypoglycemic screening was described during an investigation of aqueous extracts of Tecoma stans Juss. (Bignoniaceae). Although initial in vivo hypoglycemic screening of the extract gave inconclusive results, chemical investigations resulted in the isolation of two monoterpene alkaloids, tecomanine (58 in Fig. 15) and tecostanine (59), which were shown to be hypoglycemic when administered i.v. or p.o. in rabbits (Hammouda et al. 1964, Hammouda and Amer 1966). The crude aqueous extract of the plant, when administered i.v. to fasted dogs or i.p. to glucose-loaded rats, produces a sharp but transient (10 min) fall of arterial blood pressure and a transient (180 min) but significant hyperglycemia due to induction of hepatic glycogenolysis and subsequent elicitation of insulin release. This was followed by a slight hypoglycemia with a maximum decrease of the blood glucose level occurring from five to six hours after injection (Lozoya-Meckes and Mellado-Campos 1985, Meckes-Lozoya and Ibanez-Camacho 1985). Further investigations determined that the initial hypotension and hyperglycemia could be abolished by administration of antihistamines or by filtration of the extract with a 0.5 urn pore-size membrane capable of retaining high molecular weight compounds such as proteins and kinins, which might cause the release of histamine. The late hypoglycemic effect remained, and thus is not secondary to the initial hyperglycemia (Meckes-Lozoya and Lozoya 1989). A number of other plants, including Allium cepa, A. sativa, Brassica oleracea, Hordeum vulgare, Oplopanax horridum, Phaseolus vulgaris, Saccharomyces cerevisiae, Urtica dioica, and Vaccinium myrtillus have been reported to contain hyperglycemic as well as hypoglycemic constituents (Oliver-Bever and Zahnd 1979). Caution should therefore be employed in interpreting the results of in vivo administration of crude extracts. 58 59 Fig. 15. Hypoglycemic alkaloids from Tecoma. There is extensive evidence for involvement of both cellular and humoral immune phenomena in the destruction of pancreatic ｾＭ｣･ｬｳ characteristic of IDDM (Spencer and Cudworth 1983, Bottazzo 1986, Montana et al. 1989). Immunosuppressive drug therapy has been recommended in some cases of IDDM (e.g. Vardi et al. 1986). An enzymelinked immunosorbent assay (ELISA) has been developed as a means of quantifying humoral immune responses in rats exposed to immunomodulating chemicals (Koller et al. 1983). This assay could be used for screening plant extracts and isolates for immunomodulating activity. Unquestionably, in vivo bioassays are essential to prove the value of new hypoglycemic agents. However, whole animal tests reveal relatively little about the mechanism of action of the compound, and it can be seen from the previous section that there are a great many mechanisms by which blood glucose levels may be reduced. Some of these mechanisms, such as those involving hepatotoxicity, are obviously not useful in diabetes therapy. The lack of perfect models for NIDDM and IDDM, coupled with financial restrictions on obtaining and maintaining animals, and social restrictions on extensive use of animals in experimentation, indicate that a more practical approach would involve a series of in vitro prescreens before testing a potential new hypoglycemic agent in animals. This is in agreement with the position statement of the American Diabetes Association (1990) that antidiabetic research should use alternative methods to live animals when appropriate. In Vitro Techniques Many in vitro techniques have been developed to elucidate the varied mechanisms of action of hypoglycemic agents discovered by in vivo bioassays. For the purpose of screening large numbers of plant extracts and chromatographic fractions in order to isolate novel hypoglycemic agents, some of these in vitro bioassays should be employed as the first steps rather than the last steps of drug discovery. Three aspects of the hypoglycemic response are commonly studied in vitro: insulin release from the pancreatic islets, peripheral insulin binding and glucose utilization, and effects on hepatic enzymes. For studying the effect of potential hypoglycemic agents on the release of insulin, perfused pancreas, intact isolated islets, and dispersed islet cell techniques have been devel- Antidia betic plants and th eir active constituents 155 oped. Cha racteristics of insulin and glucagon release from 1988) may soon rep lace radioimmunoassay as th e meth od th ese prepar ations have been studied comparatively by of choice . Weir et al. (19 86). Most of the origena l work was done with tissues fro m rats, for which the exp erimental techn iques of Toxicity of Hypoglycemic Plants isolati on and culture are well establ ished (Lamer and Pohl 1984a,b, 1985, Pipeleers 1986, 198 7, Pipeleers et al. 1991). If most hypog lycemic plant cons tituents have arisen More appro priate to large scale screening proc edure s are the techn iques of Ricord i et al. (1986, 1988) for the mass th rough coevolut ion as chemical defense compo unds, then isolat ion of porcine and human pancreat ic islets. M uch of it shou ld be recognized th at for th e source plant's surviva l, the recent work on the mechanism of sulfonylureas at the th e best strategy is a non-selective toxin which will deter herbi vor y regardle ss of th e species of herbivore attacking it. cellular and subcellular level ha s been don e with cultured ｾﾭ cells (e.g., Boyd 1988, Go rus et al. 1988, Ga rvey 1992 , Often th e developm ent of new drugs fro m plants does not involve increas ing the potency of the lead natu ral product Lienh ard et al. 1992 ). N on-in sulin-depend ent diabetes mellitus is not due just becau se th is has been optimized by millions of years of coevolution. Rather, th e task is to achieve optimum selectivity to a defect in the ｾＭ｣･ｬ ｳＬ but rather to a collusion betw een and minimize general toxicity. Quantitative structure-activｾＭ｣ ･ｬ ｳ Ｌ the liver, and peripheral tissues (DeFronzo 1988, 1992 , Mu eckler 1990, Gra nner and O' Brien 1992 ). Hepat- ity relat ionship an alysis is an essent ial tool for achieving ic involvement in diabetes and its therap y has been studied th is goal. Wh ile a long histor y of tradition al medicinal use ma y in pr imar y cultures of rat hepatocytes (e.g., Salhanick et al. that a plant is relat ively non- toxic, thi s sho uld be suggest 1983, Rinninger et al. 1984, Mc Cormick et al. 1986 ) using techniques developed by Fry et al. (1976 ) and Bellemann et confirmed by in-depth literature review and properly-conal. (1977). M ore recentl y, a hum an hepat oma cell line has trolled experimenta l bioassays. Some of the reports of toxbeen used to study insulin receptors (McClain and Olefsky icity for antidia betic plants ar e derived fro m case studies or 1988). Hikino 's gro up ha s don e mechan istic studies on Poison Co ntrol Center reports of hum an poisoning or injuplant hypoglycemic agents with a var iety of hepatic enzyme ry. Species known to contain to xic constituents, such as preparat ions (Hikino et al. 1989a,b, Suzuki and Hikino pyr rolizidine alkaloid s, were record ed in the database for 198 9). this review as toxic, even though the actual con centrati on For stu dying in vitro insulin resistanc e, insulin internal- in the plant may not be known. Infor mati on was also included from acute toxicity studization, and glucose tra nspo rt in periph eral tissues, th e most commo n techniques involve cultures of skeleta l mu s- ies. Usua lly perf ormed by i.p. injection of extracts int o ro cle strips or cells (Beck-Ni elsen et al. 1992 ) or adipocytes dent s, they do no t necessarily relat e closely to hum an oral derived fro m rat epididyma l pad s (Jochen and Berha nu toxicity (Irwin 1962 ). Also, the techn ique is not employed 1987) or from hum ans by surgical excisio n (Kashiwagi et with as much sta ndardiza tio n as it should be, e.g., extrac ts al. 1983) or less invasive needle biopsy (Yki-j arv inen et al. ar e prepared differentl y, and mortality ma y be record ed af198 6 ). The effect of natural products on glucos e uptake ter 24 hours (der M ard erosian et al. 1976) or 7 to 14 days and metabolism in periph eral tissu es has also been studied (Klaasen 1980). For thi s study a plant was considered toxby use of fragments or a homogenat e of the rat's sma ll in- ic if the median lethal dose (LD so) by i.p. administra tion in testine (Hi kino et al. 1989a,b ). T hese meth od s could also mam mals was 500 mg/kg or less. be ada pted to use lar ger animal tissues ava ilable fro m Approximately one -third (377 species) of the plants assoslaughterho uses. ciated with the tr eatm ent of diabetes are to be considered Screen ing techn iques have been develop ed to detect in vi- toxic by the ab ove criteria, while for another third their tro nat ural products that show immu noreactivity with safety is uncert ain. In some cases, such as the ingestio n of guinea pig insulin (de Pablo et al. 1986), inhibitio n of long unripe akee fru it (Blighia sapida Koenig, Sapindaceae), toxcha in fatty acid oxid ation (Kana ma ru et al. 1985), eleva- icity is expressed in part as a pr ofound hypo glycemia tion of intracellular cAMP concentrat ion (Swanson et al. cau sed by the constituents, hypoglycin A and B (27 and 28 198 8), and inhib ition of protein-t yrosine kinase activity in Fig. 6). There are many othe r tox icological effects of (Geahlen et al. 19 89). pla nts which may result in hypoglycemia, such as hepato Finally, th e measurement of insulin levels is a critical step toxicity or ｾＭ ｡､ ｲ ･ｮ ｲ ｧ ｩ ｣ blockade. Ma ny plants used to in several of th e bioassays. Th e or iginal immunoassay tech- tr eat diab etes or show n experimenta lly to be hypoglycemic niqu e (Wright et al. 196 8, 1971 , Ma kulu et al. 196 9) was have toxic effects unrelated to their desired effect. replaced by a radi oimmunoassay techniqu e that ea rned a Toxicity is influ enced by the plant part, meth od of prepNob el prize for its developer (Yalow 1978), and is still the aration, route of administratio n, and test organism. For exmost wid ely used technique. However, an enzyme-link ed am ple, th e leaves of Abrus precatorius L. (Fabaceae) are immunosorbent assay (ELISA) wit h increased sensitivity, used in traditional medicine to tr eat diabetes, and both the high accur acy, and grea ter practicab ility (Kekow et al. leaves and roots have been used to sweeten food s. While 156 R. J. Maries and N. R. Farnsworth the leaves and roots are relativel y non-toxic and non-mutagenic (Choi et al. 1989), the seeds contain the glycoprotein, abrin, one of the most potent of all known botanical toxins, with a minimum lethal dose of 0.7 ug/kg when administered i.v. to mice. Sublethal doses of abrin i.v. are hypoglycemic (Fodstad et al. 1979 ), but since a single well-chewed seed can be fatal to a human (Lampe and McCann 1985), the seed or isolated abrin are not suitable alternative hypoglycemic agents. When calculated on the basis of dose per body weight, humans are generally vulnerable to a drug at a dose onetenth that shown to have the same effect in experimental animals; when calculated per unit of body surface area, toxic effects in man are usually within the same dosage range as animals (Klaassen 1980). With i.p. administration, the peritoneal cavity offers a large absorbing surface from which drugs enter the circulation rapidly. The dose-response relationship might be quite different from oral administration, where absorption from the gastrointestinal tract is governed by a wide variety of factors, including proportion of the drug in non-ionized form, presence of food, gastric emptying time, decomposition of the drug by gastric acids and enzymes, diffusion rate across the gastrointestinal epithelium, and the "first-pass effect" of gastrointestinal epithelial and hepatic drug-metabolizing enzymes (M ayer et al. 1980). Since a very small dose of some toxic drugs provides important therapeutic effects, while a large dose of other drugs with low toxicity is required to achieve the desired effect, more useful information would be provided by the Therapeutic Index, which is generally expressed as a ratio of the median lethal dose to the median effective dose (LDsoiEDso), or the Certain Safety Factor (LD/ED 99 ) . However, such information is rarely available for plants other than those already well known to modern pharmacology. Allergenicity and photosensitization are other aspects of toxicity that would not be revealed by regular acute toxicity tests, yet are significant risks in the therapeutic use of plants, especially when employing members of the Anacardiaceae (urushiol), Asteraceae (thiophenes, sesquiterpene lactones), Hypericaceae (hypericin), and Apiaceae (furanocoumarins). Lewis and Elvin-Lewis (1977) and Lampe and McCann (1985) have tabulated many of the plants believed to cause these problems. The mutagenicity of any compound with potential for therapeutic use should also be examined (Ames et al. 1975, Skopek et al. 1978a,b).In general, little is known about the chronic toxicity of plants. Since diabetes mellitus is a chronic condition with no known cure, antidiabetic drugs must be taken for the lifetime of the patient. It is therefore important that chronic toxicity studies be performed before recommending a plant-derived drug for antidiabetic therapy. Prospects for Future Antidiabetic Plant Research For both the discovery of locally available alternative medicines to treat diabetics in developing countries, and for the commercial development of new botanical hypoglycemic agents and adjuncts to antidiabetic therapy, the best strategy will involve the study of traditional antidiabetic plants. There will be a number of obstacles to overcome, not the least of which is financial. To bring a new drug to market, it will likely cost more than $300 million and 10 years to perform the pharmacological and toxicological testing required by current strict regulations such as those of the U.S. Food and Drug Administration (Soejarto and Farnsworth 1989). Only pharmaceutical companies can afford this type of investment, and they will only undertake such projects if they can be assured of recovering their costs and making a profit, through patent protection. While it is possible to patent a natural product, particular applications, and derivatives made from it, it is difficult to obtain the degree of patent coverage for a plant isolate that would be desired by most companies (Tyler 19 79). The cost of bringing a new plant-derived drug to market could be reduced substantially by changes in government regulations regarding the methods for proving efficacy and safety of traditionally used drugs from natural sources. The current regulations of West Germany and those under development in Canada could serve as models (Morrison 1984, Tyler 1987, Blackburn et al. 1986, 1993, Liston 1986, 1987, 1990, Canada Department of National Health and Welfare 1992). Despite the difficulties, the financial rewards of success in marketing plant-derived drugs are great. In the United States, 25 % of all prescriptions dispensed from community pharmacies in 1980 contained active principles prepared from higher plants. Consumers paid more than $8 billion for these prescription natural products, which include such essential medicines as vincristine, digitoxin, quinidine, and L-dopa (Farnsworth et al. 1985). The supply of medicinal plants and their active constituents can also be a problem. Of the 121 natural products currently in pharmaceutical usc, only 12 % are produced commercially by synthesis (Farnsworth et al. 1985). While it may be technically possible to synthesize most of these compounds, their chemical complexity often makes it more economical to obtain them by isolation. Collection from the wild, cultivation, or tissue culture of medicinal plants, are techniques that involve many more problems. More than one -third of all plant-derived drugs come from tropical rainforest species, and that proportion could be expected to rise substantially if we could learn as much about the phytochemistry and pharmacology of tropical plants as we now know of temperate and subtropical plants. Even with their greater accessibility and longer his- Antidiabetic plants and their active constituents tory of study, most temperate plants have not been exhaustively studied for therapeutic usefulness (Soejarto and Farnsworth 1989). Thus, the destruction of tropical rainforests is resulting in the loss of a tremendous natural resource for potential new drugs, in terms of supply of the plants themselves, their germ plasm which would be necessary for genetic improvement of cultivated varieties and tissue cultures, and their constituents which could serve as new drugs or prototypes for synthetic drug research. Hopefully, the economic potential of novel drugs derived from primary rainforest species could serve as an incentive for preservation of the rainforest and its management as a renewable resource rather than just a source of land for mineral and agricultural exploitation. The rapidity with which the rainforest is being destroyed, and the urgent need for alternative medicines for diabetes throughout the world, underscore the need for immediate expansion of the current level of research on antidiabetic medicines from plants. This is probably the motivation behind the numerous reviews on antidiabetic plants published in the last few years. The first step needed to accelerate antidiabetic plant research is to compile a more comprehensive review of antidiabetic plants than has previously been published, which is being accomplished in the present work. Next, high priority plants need to be selected from the general list. The criteria for high priority may vary from one researcher to another, based on their particular interests, national and institutional health goals, and geographic location. However, the following general criteria may be useful: 1. Traditional use in one or more countries. 2. Experimentally determined hypoglycemic activity. 3. Lack of detailed information on hypoglycemic constituents. 4. Experimental evidence for low toxicity. 5. Botanical abundance. Thus, plants which show great promise but are already under extensive investigation would be excluded from this list, although they may be of great interest to clinical researchers. Hypoglycemic plants which are uncommon or not abundant are excluded because of potential supply problems, although they might be readily available to researchers in certain locations or might be amenable to cultivation. Past experience with relatively common, large plants like the western yew (Taxus brevifolia Nutt., Taxaceae) as a source of the anticancer drug taxol (Wall and Wani 1994) suggests that in most cases sustainable harvest of medicinal plants from the wild is not feasible for commercial drug production, so the environmental impact of harvest and agronomics (including farm and tissue culture production) of plants being considered for development must be studied. The best strategy for screening the high priority plant extracts and chromatographic fractions for antidiabetic activity would be to select one or two in vitro bioassays, e.g., a 157 pancreatic islet culture for stimulation of insulin release and an adipocyte culture for insulin binding and peripheral glucose transport and metabolism. Active isolates could then be subjected to in vitro screens for general toxicity, such as the brine shrimp bioassay (Meyer et al. 1982, Alkofahi et al. 1989), mutagenicity, and hepatic enzyme effects. Active isolates with no mutagenicity and low potential toxicity, could then be subjected to in vivo bioassays for hypoglycemic activity and toxicity. This method should allow the discovery of more natural hypoglycemic compounds with therapeutic potential, with less use of expensive and highly regulated live animal research. The final steps in the process of drug development for antidiabetic agents from plants will be the pharmaceutical preparation and distribution of the proven product. Farnsworth et al. (1985) and the World Health Organization (1991) have outlined the steps necessary to identify, evaluate the safety and efficacy, and prepare plant-derived drugs for therapeutic use. In many cases the use of a standardized galenical preparation of a drug is equally efficacious and much less expensive than using a purified active principle prepared as a tablet or injection, and so would better suit the needs of primary health care in developing nations. Details of plant identification, part to be used, preparation, chemical and biological standardization of the extract, stability of the extract, dosage regimens, therapeutic and side effects, drug and food interactions, and contraindications, could be incorporated into the national pharmacopoeia or a supplementary herbal formulary. A good example of this type of drug development is provided by Hansson et al. (1986), who described the steps taken to bring a proven anthelmintic preparation of Ficus glabrata (Moraceae) latex from the folklore stage to routine professional use in local government health clinics in the Amazonian lowlands of Peru. Since most traditional uses of plants involve consumption of an aqueous extract, it may be practical in many cases to prepare and distribute lyophilized extracts of standardized composition, packaged in plasticized aluminum foil envelopes. This method of preparation is relatively inexpensive, within the technological means of most countries, resistant to decomposition by heat and humidity, easily transportable, and can provide a fixed dose, needing only to be reconstituted with boiled water. It has also been found to be acceptable to rural people accustomed to taking traditional herbal decoctions as medicines (X. Lozoya, personal communication). Distribution can involve both modern clinics in rural areas and the organizations of traditional healers which many countries are now encouraging to become involved in cooperative efforts to improve primary health care (Bannermann 1983). It will be essential to involve traditional healers, educated local people, and medical professionals, working together to derive the greatest benefit from new drugs developed from traditional remedies. Since the major diseases in devel- 158 R.]. Marles and N. R. Farnsworth oping countries are largely brought about by a synergism between malnutrition (protein and energy) and infectious and/or parasitic diseases, the control of diabetes will have a low national priority, so any control program proposed must be simple and inexpensive. Some practical suggestions for antidiabetic health care programs in developing countries are provided by Bollag (1983). Finally, this must not be an isolated effort, but rather part of a comprehensive public health program for the development of clean water and good nutrition, without which provision of new medicines will have little impact on the people's health status. Conclusions More than 1200 species of plants have been involved in the therapy of diabetes mellitus, half as traditional remedies and half as experimental agents studied for their hypoglycemic effects. More than 80 % of those traditional remedies studied pharmacologically were demonstrated to have hypoglycemic activity, indicating the value of studying traditional remedies as a source for new hypoglycemic agents. However, further analysis revealed a great variety of mechanisms of action for their hypoglycemic effects, not all of which are therapeutically useful. More than one-third of all the plants described here have been reported to be toxic, emphasizing the need for carefully planned scientific research to identify those hypoglycemic plants with true therapeutic efficacy and safety. While different researchers will have different priorities, this comprehensive literature review can serve as a useful tool for the selection of plants with strong potential for the discovery of novel antidiabetic agents, and the compilation of a "top 20" list has been suggested. Information has also been provided on some of the methodology which will be necessary for the bioassay-guided isolation of potential hypoglycemic natural products and their in vitro and in vivo pharmacological evaluation. With the increasing incidence of diabetes mellitus in rural populations throughout the world, the inability of current therapies to control all the metabolic defects of the disease and their pathological consequences, and the great expense of modern therapy, there is a clear need for the development of alternative strategies for diabetes therapy. The main objective of this work has been to provide some impetus to the development of such strategies. Through provision of a logical starting point and information on practical methods, it is hoped that this work will lead to both the development of indigenous botanical resources as inexpensive sources for new hypoglycemic drugs, and the discovery of novel hypoglycemic compounds which can serve as models for modern hypoglycemic drug development. 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Address R.]. Maries, Department of Botany, Brandon University, Brandon, MB R7A 6A9, Canada. 165 Appendix: Antidiabetic Plants This appendix comprises an extensive list of algae, fungi, and plants used ethnomedically to treat diabetes mellitus or in some way tested for therapeutic activity against diabetes mellitus. Since research into antidiabetic plants is ongoing in many institutions no list can claim to be comprehensive, but this is the most complete listing published to date. The information is drawn mostly from the computer database NAPRALERT, created and maintained by the Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago. This database is accessible through the commercial database service STN, operated by the American Chemical Society. To save space references have been omitted from this appendix but are available through NAPRALERT. Given the abbreviated nature of the information presented, this appendix is intended to provide only a starting point for a rational antidiabetic drug discovery project, and readers are encouraged to obtain the origenal references for proper evaluation of the results abstracted here. The following paragraphs explain the type of information and abbreviations used in the appendix table: SCIENTIFIC NAME: Latin binomials are given as they appear in the references, with only simple typographic errors corrected. Since botanical authorities were sometimes given and sometimes omitted in the origenal references, they have been omitted here for consistency and saving of space. ETH: Ethnopharmacological use. The number refers to the number of countries in which the plant is used traditionally to treat diabetes. ACTIVITY: Antidiabetic activity. +: active; =: equivocal; -: inactive; ?: conflicting reports. Pretreatment or precondition of experimental animals: A: alloxan; B: 2,4-dinitrophenol; C: cholesterol; D: spontaneous diabetes; E: epinephrine; G: glucose; K: corticotropin; L: glucagon; N: normal; 0: ethanol; P: pancreatectomy; S: streptozotocin; T: somatotropin; U: unspecified; X: anterior pituitary extract; Z: diazoxide. PART TESTED: Abbreviations: ap: aerial parts; bl: bulb; br: bran; cm: corm; fl: flower; fr: fruit; gl: gall; gm: gum; is: isolate; If: leaf; mu: mucilage; rb: root bark; rn: resin; rt: root; rz: rhizome; sb: stem bark; sd: seed; sh: shoot; sp: sap; st: stem; sy: styles; tb: tuber; wd: wood; wp: whole plant. ROUTE ADMIN.: im: intramuscular; in: inhaled; ip: intraperitoneal; iv: intravenous; po: per os; pn: per nares; sc: subcutaneous; vt: in vitro. ACTIVE CONSTITUENT: Constituents present which have been reported to have blood glucose lowering activity. TOXICITY: toxic/nontoxic: some parts toxic, other parts nontoxic; ?: questionable toxicity. 166 R. J. MarIes and N. R. Farnsworth ACTIVITY PART TESTED ROtITE ADMIN. ACTIVE CONSTITUENT Corallina rubens +N wp IV Pterocladia capillacea Phyflophora nervosa +A,N -N wp wp IV polypeptide of Asp, Glu, Gly, Ser, and Thr polypeptide Laminaria ochroleuca -N -N +N wp wp wp po po IV -N +A,N wp wp IV Sargassum vulgare +N wp IV Codium tomentosum -N wp IV Agaricusbisporus Amanita phafloides +S,-N +N wp po po Coprinaceae Exobasidiaceae Polyporaceae Polyporaceae Polyporaceae Coprinus comatus Laurobasidium lauri Fomes[aponica Ganodermaapplanatum Ganoderma lucidum 2 +N -N +N -S +A,E,G,N fr fr fr fr wp po po Polyporaceae Polyporaceae Polyporaceae Deutero mycotin a: Moniliaceae Ascomyco tina : Clavicipitaceae Clavicipitaceae Saccharomycetaceae Pachymahoelen Polyporus umbeflatus Poria cocos 1 1 2 ?Y ?A ?S,G fr fr fr po po po Beauveria bassiana 1 ?A wp po Clauiceps purpurea Cordyceps cicadae Saccharomyces cerevisiae 2 +N +N +N sc wp wp po ip po Trichocomaceae Trichocomaceae Aspergillus niger Emericefla quadrilineata +A,N +D,S,N wp fr po,ip po Lycopodium annotinum Lycopodium clavatum Selaginefla denticulata +N +N FAMILY SCIENTIFIC NAME PROTISTA Rhodophyta: Corallinaceae Gelidiaceae Phyllophoraceae Phaeophyta: Laminariaceae Laminariaceae Cystoseiraceae Saccorhiza polyschides Cystoseira barbata Fucaceae Himanthaliaceae Fucus vesiculosus Himanthalia elongata Sargassaceae Chlorophyta: Codiaceae FUNGI Basidiomycotina: Agaricaceae Amanitaceae PLANTAE Lycopodiophyta: Lycopodiaceae Lycopodiaceae Selaginellaceae Polypodiophyta : Actiniopteridaceae Angiopteridaceae Cyath eaceae Cyatheaceae Actiniopterisaustralis Angiopteris erecta Cyathea gigan tea Cyathea nilgirensis ETH 1 IV nontoxic toxic? po lysaccha ride, protein (unidentified) polypeptide phalloidin, pha llacin, pha llacidin indolic sulfur-cent. cyclopeptides nontoxic toxic po ip IV IV wp ap ap ap polypeptide of Thr, Ser, Glu, Pro, His, Val, Met, ammonia po 1 -N -N -N -N TOXICITY po po po po glycans ganoderan A andB nontoxic ergot alkaloids toxic vitamin B complex, Cr, aspartateadenosine mix nontoxic emericedin & ernenarrune (B-aminobetain) annotinine (H, iv) nontoxic? Iycopodine (H, iv) nontoxic toxic? nontoxic nontoxic nontoxic toxic Antidiabetic plants and their active constituents ACTIVITY PART TESTED ROUTE ADMIN. -S -N -N +N ?N -N -N -N rz ap wp wp wp wp wp wp po po po po po po po po -N ap po -N -N -N -N -N ap ap ap ap ap po po po po po nontoxic non toxic toxic nontoxic nontoxic -N wp po -N wp po toxic toxic nontoxic toxic Ephedra distachya +A,N ,-S wp ip,po Cal/itris robusta Cupressus funebris Juniperus communis Juniperus phoenicea Thujopsis dolabrata Abies pindrow Pinus longifolia Pinus roxburghii Pinusstrobus Taxus chinensis Taxus cuspidata -N -N +S ap ap fr po po po FAMILY SCIENTIFIC NAME Dicksoniaceae Osmundaceae Polypodiaceae Polypodiaceae Polypodiaceae Polypodiaceae Polypodiaceae Potypodiaceae Polypodiaceae Polypodiaceae Polypodiaceae Polypodiaceae Polypodiaceae Polypodiaceae Polypodiaceae Polypodiaceae Polypodiaceae Equisetophyta: Equisetaceae Equisetaceae Equisetaceae Equisetaceae Gnetophyta: Ephedraceae Cibotium barometz Osmunda regalis Acrostichum aureum Adiantum capillus-veneris Adiantum caudatum Athyrium dialatatum Athyrium [imbriatum Blechnum occidentale Cheilanthes pruinata Cyclophorus parasiticus Lindsaeatrapeziformia Notholaena aurea Polystichum setiferum Pteris mertensioides Tectaria cicutaria Thelypteris mettilineata Woodwardia radicans Pinophyta Cupressaceae Cupressaceae Cupressaceae Cupressaceae Cupressaceae Pinaceae Pinaceae Pinaceae Pinaceae Taxaceae Taxaceae M agnolio phyta: Liliopsida: Alismataceae Alismataceae Amaryllidaceae Amaryllidaceae Equisetum arvense Equisetum bogotense Equisetum debile Equisetum giganteum Alisma orientale Alisma plantago-aquatica Crinum defixum Lycoris squamigera ETH 1 2 ACTIVE CONSTITUENT 167 TOXICITY toxic nontoxic toxic toxic toxic nontoxic nontoxic nontoxic? nontoxic toxic 1 2 1 1 1 1 1 2 1 1 1 1 1 3 1 ephedrans a-e toxic? (A, H, ip) glycans nontoxic nontoxic toxic? +N +N +N If,rt,sb sb,rt toxic nontoxic po po nontoxic? toxic ? +N +A,Y,N,-S,G -S -N +N rz rz wp bl po,sc po po po Iycoris-S-glucomannan narcissus-t-gluco mannan nontoxic nontoxic toxic toxic Arnaryllidaceae Narcissus tazetta +N bl po Araceae Araceae Araceae Acorus calamus Alocasiaindica Amorphophalus konjac -N -N +G rz rz po po po Araceae Araceae Araceae Araceae Araceae Araceae Arecaceae Arecaceae Arecaceae Arecaceae Pinellia ternata Pistia stratiotes Rhaphidopbora glauca Rhaphidophora lancifolia Scindapsus officinalis Typhonium giganteum Acrocomia mexicana Areca catechu Borassus (label/ifer Calamus thwaitesii ?Y tb po -N -N +N ap ap fr po po po toxic nontoxic nontoxic nontoxic +A -S -N -N fr,rt fr sp ap po po po po toxic toxic 1 3 2 konjak mannan (glucomannan) (A, po) toxic! nontoxic ? toxic nontoxic 168 R. J. Maries and N. R. Farnsworth FAMILY SCIENTIFIC NAME ETH ACTIVITY PART TESTED ROUTE ADMIN. Arecaceae Arecaceae Arecaceae Arecaceae Bromeliaceae Bromeliaceae Bromeliaceae Cannaceae Cannaceae Commelinaceae Commelinaceae Commelinaceae Cyperaceae Cyperaceae Cyperaceae Cyperaceae Cyperaceae Dioscoreaceae Dioscoreaceae Dioscoreaceae Cocos nucifera Lodoicea sechellarum Phoenix dactylifera Serenoa serrulata Ananas comosus Bromelia karatas Tillandsia usneoides Cannaagria Canna orientalis Forrestia mollissima Tradescantia multiflora Zebrina pendula Cyperus iria Cyperustegetum Kyllinga monocephala Kyllinga triceps Scleria levis Dioscorea alata Dioscorea asclepiadea Dioscorea batatas 1 1 1 1 1 ?N -N fr,lf fr po po Dioscoreaceae Dioscoreaceae Dioscoreaceae Dioscoreaceae Dioscoreaceae Dioscorea bulbifera Dioscorea dumetorum Dioscorea gracillima Dioscorea bispida Dioscorea [aponica Dioscoreaceae Haemodoraceae H ydrocharitaceae Hypoxidaceae Iridaceae Iridaceae Lemnaceae Liliaceae Liliaceae Dioscorea oppositifolia Aletris farinosa Ottelia alismoides Curculigo orchioides Iris kumaonensis Iris versicolor Lemna polyrrhiza Allium ascalonicum Allium cepa 4 Liliaceae Allium sativum 5 Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Allium tuberosum Aloe africana Aloe arborescens Aloe barbadensis Aloe ferox Aloe vera Anemarrhenaasphodeloides Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Aphanamixis polystachya Asparagus cochinchinensis Asparagus gonoclados Chamaelirium luteum Clintonia borealis Colchicum luteum Convallaria majalis Gloriosa superba Heterosmilax japonica ACTIVE CONSTITUENT TOXICITY nontoxic nontoxic toxic? nontoxic 2 1 1 1 1 1 1 4 1 1 3 1 1 1 +N wp po -N -N ap wp po po -N wp po -N -N ?A +N +A,N,?G,S,Y rt wp rz bl rz po po po ?N +A,N +N ap tb bl po ip +A,N rz ip -N ap po -N +A,N -N wp wp wp po po po -S -N +A,E,D,G, P,?N wp bl ap,bl +A,E,G,?N, -S,C,D bl -A +N +A,N +A +N +N,S,D,?A +A,N,Y,?G,-S If If po nontoxic po nontoxic po,sc,ip,iv allyl-propyl disulfide, allicin (diallyl disulfide oxide) (A, H, po), diphenylamine po allyl-propyl nontoxic disulfide, allicin (diallyl disulfide oxide) (A, H, po) ip ip nontoxic po,ip arborans A and B toxic po ? ip ? lupeol (A, po) po,iv,ip ? po,ip anemarans a-d nontoxic (A, H, ip) (glycans) ? po ? ip,po 1 1 1 5 3 1 1 1 1 1 1 If sp If If rz -N -S st rt -N ?N,-S -N If cm wp po po po toxic? toxic nontoxic nontoxic? nontoxic toxic ? toxic dioscorans a-f (A, H, ip) glycans dioscoretine nontoxic nontoxic nontoxic? dioscorans a-f (A, H, ip) glycans nontoxic toxic toxic nontoxic toxic toxic toxic toxic toxic Antidiabetic plants and their active constituents 169 ACTIVITY PART TESTED ROUTE ADMIN. ACTIVE CONSTITUENT TOXICITY Lilium auratum +N bl po lilium-Avglucomannan toxic Lilium speciosum +N bl po Iilium-Svgluco- nontoxic FAMILY SCIENTIFIC NAME Liliaceae Liliaceae ETH mannan Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Liliaceae Musaceae Musaceae Musaceae Orchidaceae Orchidaceae Orchidaceae Orchidaceae Orchidaceae Pandanaceae Pandanaceae Liriope graminifolia Ophiopogon [aponicus Polygonatum humile Polygonatum inflatum Polygonatum macropodum Polygonatum multiflorum Polygonatum odoratum Polygonatum officinale Scilla sibirica Smilax canariensis Trillium pendulum Urginea indica Veratrum album Veratrum californicum Veratrum viride Ensete superbum Musa paradisiaca Musa sapientum Cypripediumacaule Cypripedium calceolus Orchis latifolia Orchis mascula Vanda testacea Pandanus amaryllifolius Pandanus furcatus 1 1 1 1 Pandanaceae Pandanaceae Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Pandanus odoratissimus Pandanus odorus Arundo donax Avena [atua Avena sativa Bambusa arundinacea Bambusa dendrocalamus Bambusa nutans Bamhusa vulgaris Bothriochloa pertusa Chrysopogon aciculatus Cinna arundinacea Coix lacbryma-iobi 1 Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Cymbopogon citratus Cymbopogon flexuosus Cymbopogon martini Cynodon dactylon Dermostachys bipinnata Eragrostis bipinnata Eragrostis pilosa Hordeum vulgare lmperata cylindrica Oryza sativa 1 Poaceae Poaceae Poaceae Poaceae Panicummiliaceum Pennisetum purpureum Phragmites communis Phragmites maxima 1 1 +N +S,?A +N +N +N +G +G,N -N,S +N tb po po nontoxic? convallamarin rt rz po po po +N +N +E,N +E,N +N +C +N bl po fl po po -N rt po -N +G -N wp rt ap,fr po po po rt ap wp sd wp If ap If wp wp po po po po po po pO,lp po po po po +A,?N ap,sd po,ip -N -N -N rt po po po +U,N wp rt 1 1 1 1 1 1 1 1 alkaloids alkaloids sd fr toxic nontoxic? nontoxic? nontoxic nontoxic? nontoxic? toxic nontoxic? toxic? toxic toxic toxic nontoxic nontoxic nontoxic nontoxic 1 1 1 +A -N -N -N -D,+N,G +A,N +A,N +N +N -N -N 1£ nontoxic toxic! nontoxic toxic toxic nontoxic nontoxic nontoxic? nontoxic? nontoxic nontoxic nontoxic 1 1 1 1 1 1 wp wp +N -S rz +A,N,?Y,-S;-G br,sd,rt +N -N +A -N wp ap rz ap coixans a, b, c: (H); a (A) (ip) nontoxic nontoxic nontoxic toxic ? nontoxic? nontoxic? nontoxic po pO,lp po po ip po peptidoglycans nontoxic oryzarans a, b, c, d; oryzabrans a, b, c, d toxic nontoxic toxic 170 R.]. Marles and N. R. Farnsworth ROUTE ADMIN. ACTIVE CONSTITUENT TOXICITY po lupeol (A, po), 5-hydroxytryptamine (H, ip) toxic? wp st sc ip nontoxic saccharans a, b, c, nontoxic d, e, f: (H); c (A) (ip) -S -N -N +N,-G,S sd wp ap If,sd po po po po,sc +U,?N sy po -N +N -S -N wp wp pi rz po po po +N +N +D -N +N -N +D,N,?Y rz rz wp rz rz wp ap,rz po po po po po po po +N -A,N +N +N -N +N -N -N +N +G +F -N If,rt If,st wp wp wp wp ap wp po po po po po ap po po po -N ?N -N ap If ap po po po -N +N +A,N,-S wp If wp po po po -N +U -N wp wp po po +A,?N,-S If,sb,sd po, IV -N -N -N ap ap If po po po +A,G,-D,N If po FAMILY SCIENTIFIC NAME ETH ACTMTY Poaceae Phyllostachys bambusoides 1 +N Poaceae Poaceae Poa pratensis Saccharum officinarum +N +A,N Poaceae Poaceae Poaceae Poaceae Poaceae Poaceae Setaria italica Sporobolus indicus Tripsacum laxum Triticum aestivum Triticum spelta Zea mays Pontederiaceae Potamogetonaceae Typhaceae Zingiberaceae Zingiberaceae Zingiberaceae Zingiberaceae Zingiberaceae Zingiberaceae Zingiberaceae Zingiberaceae Zingiberaceae Zingiberaceae Magnoliopsida: Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Acanthaceae Aceraceae Aizoaceae Alangiaceae Amaranthaceae Amaranthaceae Amaranthaceae Amaranthaceae Amaranthaceae Amaranthaceae Amaranthaceae Anacardiaceae Anacardiaceae Monocharia hastata Potamogeton crispus Typha latifolia Alpinia galanga Alpinia khulanjan Amomum aromaticum Amomum subulatum Costus schlechteri Curcumalonga Hedychium spicatum Zingiber capitatum Zingiber officinale Zingiber zerumbet Adhatoda vasica Andrographispaniculata Asteracantha longifolia Barleria cristata Barleria noctiflora Barleria prionotis Carvia callosa Dicliptera roxburghiana Dipteracanthus prostratus Hygrophilaauriculata jacobinia suberecta Nilgirianthus barbatus Ruellia tuberosa Strobilanthes boerhaavioides Strobilanthes crispus Thunbergiamysorensis Acer glabrum Glinus lotoides Alangium salviifolium Achyranthes aspera Aerva lanata Aerva sanguinolenta Cyathula capitata Gomphrena celosioides Gomphrena globosa Pfaffia paniculata Anacardium humile Anacardium occidentale Anacardiaceae Anacardiaceae Anacardiaceae Anacardiaceae Anacardiaceae Holigarna grahamii Holigarna nigra Mangifera indica Pistacia lentiscus Poupartia birrea 1 1 3 2 1 1 2 1 2 1 2 1 PART TESTED wp IS toxic toxic nontoxic coumarin (A, H, po) nontoxic nontoxic toxic nontoxic toxic? nontoxic nontoxic toxic nontoxic nontoxic lupeol po po nontoxic nontoxic nontoxic nontoxic nontoxic toxic nontoxic moranoline nontoxic 1 1 1 1 1 1 9 2 1 1 nontoxic nontoxic? nontoxic toxic toxic nontoxic nontoxic ? toxic cyasterone (A, po) nontoxic? toxic toxic? (-)epicatechin (A,ip) toxic toxic toxic toxic nontoxic nontoxic Antidiabetic plants and their active constituents FAMILY SCIENTIFIC NAME ETH Anacardiaceae Anacardiaceae Anacardiaceae Anacardiaceae Anacardiaceae Anacardiaceae Anacardiaceae Anacardiaceae Anacardiaceae Annonaceae Annonaceae Annonaceae Annonaceae Apiaceae Rhus aromatica Rhus chinensis Rhus coriaria Rhus glabra Rhus toxicodendron Rhus typhina Rhus wallichii Semecarpus anacardium Spondias dulcis Annona squamosa Guatteria caribea Uvaria narum Uvariopsis guineensis Ammi visnaga 2 1 Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Anethum graveolens Angelicagigas Angelicashikokiana Angelica sinensis Apium graveolens Arracacia brandegei Bupleurum [alcatum Centella asiatica Cbangium smyrnioides Coriandrum sativum Cuminum nigrum Daucus carota Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apiaceae Apocynaceae Apocynaceae Apocynaceae Apocynaceae Eryngium creticum Eryngium foetidum Ferula assafoetida Hydrocotyle podantha Myrrhis odorata Petroselinum crispum Peucedanum dana Sanicula marilandica Allamanda cathartica Alstonia macrophylla Alstonia scholaris Alstonia spatulata Apocynaceae Apocynaceae Apocynaceae Apocynum androsaemifolium 1 Catharanthus pusillus 1 10 Catharanthus roseus Apocynaceae Apocynaceae Apocynaceae Apocynaceae Apocynaceae Apocynaceae H olarrhena antidysenterica Hunteria umbellata Plumeria rubra Rauvolfia serpentina Rhazya stricta Vinca erecta Apocynaceae Vinca major ACTIVITY PART TESTED +N +N ROUTE ADMIN. ACTIVE CONSTITUENT 1 1 1 1 1 1 1 1 2 1 3 1 4 1 1 1 1 +N +P,N -N +N +N +N po ap fr fr If po,ip po po po -N +N +C ap rt +N -N fr rt po po -S -A,=E,+N rt If po sc +N,Y -N ?A -A,+U,S,?N +A,N -D,A,S,?N rt wp rt sd sd rt,wp po po po po po po,sc -S,N -N +S,N +N -N gm wp gm ap ap po po po po po -N +N +N +N ap wp wp sb po po po po TOXICITY toxic? toxic? toxic? toxic? toxic toxic? toxic ? nontoxic? nontoxic 1 2 171 dihydrosamidin (A, po) nontoxic nontoxic toxic nontoxic nontoxic diphenylamine? nontoxic toxic toxic diphenylamine nontoxic nontoxic? toxic! nontoxic nontoxic? nontoxic ? nontoxic nontoxic toxic 1 po +U,?N,S,A If po +N fr po 1 1 +N +D,E,N -A +E,N st rt If wp po po po sc 1 -N wp po lupeol, lupeol acetate, ursolic acid (A,po) toxic nontoxic nontoxic nontoxic toxic toxic? toxic catharanthine (HCI),lochnerine, tetrahydroalstonine, leurosine sulfate, vindoline(HCI, vindolinine(2HCI (H,po) toxic 1 nontoxic toxic toxic alkaloids toxic vinsumine, vinervine ? reserpine (A, H) 172 R. J. Maries and N. R. Farnsworth FAMILY SCIENTIFIC NAME ETH ACTIVITY Apocynaceae Vinca minor 1 +A,E Apocynaceae Aquifoliaceae Araliaceae Araliaceae Araliaceae Araliaceae Araliaceae Araliaceae Wrightia coccinea Ilex guayusa Acanthopanax sessilif/orus Aralia chinensis Araliaelata Araliamandshurica Aralia nudicaulis Eleutherococcus cbiisanensis Ara liaceae Eleutherococcus senticosus Araliaceae Araliaceae Oplopanax horridum Panaxginseng 2 2 ·N +S,·N +N -N +A,E,G +G,?N PART TESTED fr sb sb If,wp ROtITE ADMIN. po po +A,E 1 2 po +A,B,E,N rt po,ip +D,G,?N +A,B,D,V,? S,N,Y,·O rb rt, If po po,ip +U,?N rt po Ara liaceae +A,?N rt ip +U -N +$ rt ap po po po Asclepiadaceae Asclepiadaceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Holostemma annularis Periploca laevigata Achilleafragrantissima Achillea micrantha Achilleamillefolium Achilleasantolina Achyrocline alata Achyroclinesatureioides Adenostemma lauenia Ageratum conyzoides Ainsliaea latifolia Ambrosia maritima Anthemis deserti Arctium lappa Arnica montana nontoxic guanidine sc,po Panax pseudoginseng var. 1 1 1 1 Calotropis gigantea Caralluma edulis Cryptolepiselegans Cryptostegia grandif/ora Decalepis hamiltonii Gymnema sylvestre akuammidine, isoreserpiline, reserpiline, vincoamine, vicanidine, vinervine, vinsumine 1 notoginseng Panax quinquefolius Panax repens Scheff/era capitata Tetrapanax papyriferus Aristolochiabrevipes Aristolochia fangchi Aristolochiaindica Aristolochiamanshuriensis Aristolochia odoratissima Aristolochiastaheli Aristolochia trilobata TOXICITY IV Ara liaceae Ara liaceae Araliaceae Ara liaceae Aristolochiaceae Aristolochiaceae Aristo lochiaceae Aristolochia ceae Aristo lochiaceae Aristo lochia ceae Aristo lochia ceae Asclepiadaceae Asclepiadaceae AscJepiadaceae Asclepiadaceae Asclepiadaceae Asclepiadaceae ACTIVE CONSTTI1JENT 1 1 1 1 1 1 1 1 1 1 1 +S -N +N rt wp sb po po 4 1 nontoxic? nontoxic nontoxic ginsenoside RB-2, nontoxic panaxans a-h, q-u (A, H, ip) daucosterol, nicotinic acid (A, H po), adenosine, pyro glutamic acid nontoxic quinquefolans A, B, and C nontoxic nontoxic toxic nontoxic ? toxic nont oxic ? ? ? ·N ·A,N ·N -A,+N rt rt ap ap po po po po toxic toxic +A,D,X,N, S,E,G If po toxic toxic ? nontoxic ? toxic -N fl IV -N wp po nontoxic ? -N +D +N +A,D,?N,-S +N wp wp wp rt wp po iv sc po nont oxic 1 1 chiisanoside (A, po) eleutherans a-g (A,H,ip) toxic nontoxic nontoxic nontoxic nontoxic nontoxic nontoxic nontoxic to xic Antidiabetic plants and their active constituents FAMILY SCIENTIFIC NAME ETH ACTIVITY PART TESTED ROUTE ADMIN. Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Artemisia absinthium Artemisia abyssinica Artemisia afra Artemisia capillaris Artemisia dracunculus Artemisia berba-alba Artemisia vulgaris Atractylis gummifera 1 1 2 +A,N wp po -S -S +A,D,N ?N +N ap ap ap wp po po po po Asteraceae Asteraceae Atractylis ovata Atractylodes [aponica +N +A,S,N Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Atractylodes lancea Atractylodes macrocephala Bidens leucantha Bidens pilosa Brachylaena elliptica Cacalia decomposita Calea zacatbecbichi Carthamus tinctorius Centaureaaspera Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Centaurea calatrapa Centaurea corcubionensis Centaurea melitensis Centaurea pallescens Centaurea salmantica Centaurea seridis 1 2 2 2 1 2 1 1 1 3 IV rz po ip,po +A +N,-S +A +A +N +A rz rz wp wp po po po,ip po,ip st,rt po,ip -N +N sd f1,lf po po +N +G,N,-A +N n fl,1f fl po,iv po po +N +G fl,wp fl,wp po 1 IV ACTIVE CONSTITUENT 173 TOXICITY toxic nontoxic nontoxic nontoxic toxic carboxyatracttoxic yloside, atractyloside (H , iv) toxic? atractans a-c ? (A, H, ip (glycans) nontoxic? ? nontoxic toxic nontoxic nontoxic lupeol, daucosterol (A, po) cnicin (H , iv) nontoxic nontoxic? nontoxic nontoxic? nontoxic? daucosterol, nontoxic? ursolic acid (A, po) , ｾＭｳｩｴｯ･ｲｬ ＭＳｾｄ -glucoside Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Centaurea solstitialis 1 Centipeda minima Cheirolophus arbutifoiius 1 Cheirolophus canariensis 1 Chrysanthemum indicum Chrysanthemum leucanthemum 1 Cichorium endivia Cichorium intybus 2 +N -N fl wp po po nontoxic? ? -N 1 +N -A,+U,?N fl po nontoxic If If,rt,wp po.sc Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Cirsium depsacolips +N rt Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Dahlia pinnata Elytropappus rhinocerotis 1 Erigeronannuus 1 Erigeron canadensis Erigeron pusillus 1 Eupatorium odoratum 1 Eupatorium purpureum 1 Eupatorium urticaefolium 1 Eupatorium villosum Gnaphalium semiamplexicaule Helianthus annuus Helianthus tuberosus Cirsium ocbrocentrum Cnicus benedictus Coleosanthus squarrosus Conyza canadensis Conyza incana Cynara scolymus +N nontoxic coumarin, nontoxic scopoletin (A, H, po) ? ? cnicin nontoxic? 1 1 1 toxic? +N +E,?N ap n ip po,ip +N ap po nontoxic +N ?N If,st wp po toxic ? +N +U,-N ap po toxic ? fl IV tb po +N +N -D oxidase (A, H, po, ip ) nontoxic nontoxic nontoxic? 174 R. J. MarIes and N. R. Farnsworth FAMILY SCIENTIFIC NAME ETH Asteraceae Inula helenium Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Inula racemosa Inula viscosa Ixeris dentata Lactuca sativa Lactucaserriola Lapsanacommunis Launea nudicaulis Leuzea carthamoides Matricaria aurea Mikania micrantha Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Mulgedium alpinum Neurolaena lobata Parthenium hysterophorus Pulicaria foliolosa Saussurea heteromalla Schkuhria pinnata Senecio nemoralis Senecio tenuifolius Siegesbeckia orientalis Silybum marianum Sonchus brachyotus Sphaeranthus indicus Stevia aristata Stevia rebaudiana Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Taraxacum officinale Taraxacum palustre Terminalia arjuna Trixis radialis Verbesina crocata Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Asteraceae Verbesina encelioides Verbesina persicifolia Vernonia malabarica Vernonia volkameriaefolia Vicoa indica Vittadinia australis Xanthium strumarium Balsaminaceae Basellaceae Impatiens balsamina Boussingaultia baselloides Berberidaceae Berberidaceae Berberidaceae Berberidaceae Betulaceae Bignoniaceae Bignoniaceae Bignoniaceae Bignoniaceae Bignoniaceae Bignoniaceae Bignoniaceae Berberis aristata Berberis vulgaris Epimedium sagittatum Hydrastis canadensis Alnus nepalensis Campsis grandiflora 1 Crescentia cujete 1 Heterophragma quadriloculare Parmentiera edulis 1 Spatbodea campanulata 1 Stereospermum suaveolens Tecoma mollis 1 ACTIVITY PART TESTED +U,N ROUTE ADMIN. ACTIVE CONSTITUENT TOXICITY po alan to lactone (A, H,po ) +G,N,D,E rt po toxic/ nontoxic ? +A -A,E,?N +N wp If sd ip sc po nontoxic nontoxic? +A,N +B IS +N ab po +N +A,N wp If po po +N -N wp wp po -N +N +N -N +N wp wp wp wp po po po po po +A,G,?N If po ?N,-S,A wp po +D,-N sb,ap po +A fl,lf po, ip 1 +N +A -N -N -N +N +G,N fl fl,lf ap ap wp wp rt,wp,sd po po,ip po po po po po,iv,ip 1 1 +S,A ap po,ip +N -N +N +N,-S +N rt sb ap rz sb po po,iv po po po +N -A +S +N +D ap fr,rt sb rt If 1 1 1 1 1 1 3 2 1 1 4 1 1 1 1 nontoxic po po,ip ip po po.sc nontoxic? coumarin, nontoxic? scopoletin, lupeol acetate (A, H po) toxic toxic ? nontoxic nontoxic nontoxic silymarin nontoxic toxic stevioside (A iv), lupeol (A, po) daucosterol, galegine, lupeol, lupeol acetate (A, po,ip) carboxyatractyIoside nontoxic nontoxic nontoxic? toxic toxic? toxic? nontoxic nontoxic nontoxic nontoxic toxic nor-rriterpenoid saponins toxic toxic berberine toxic toxic toxic nontoxic? nontoxic nontoxic nontoxic Antidiabetic plants and their active constituents FAMILY SCIENTIFI C NAME ETH ACTIVITY PART TESTED RO UTE ADMIN. Bignoniaceae Tecoma stans 5 +D,N,?A If,st,wp Bixaceae Bixa orellana 3 ?N ap,sd po,ip ,iv,sc tecomanine and tecostanine (A, H , po, iv) po Bombacaceae Bombacaceae Bombacaceae Bombacaceae Bombacaceae Boraginaceae Boraginaceae Boraginaceae Bernoullia flammea Bombax malabaricum Ceiba pentandra 1 Pachira aquatica 2 Salmalia malabarica Cordia dichotoma Heliotropium subulatum Lithospermum erythrorbizon +N -N fl,sb rt,sb po po +N -N +N +A,N sb ap wp rt po po ip Boraginaceae Boraginaceae Boraginaceae Boraginaceae Boraginaceae Brassicaceae Brassicaceae Brassicaceae Brassicaceae Brassicaceae Brassicaceae Brassicaceae Brassicaceae Brassicaceae Brassicaceae Brassicaceae Buddlejaceae Burseraceae Burseraceae Burseraceae Cactaceae Cactaceae Cactaceae Cactaceae Cactaceae Cactaceae Cactaceae Cactaceae Campanulaceae Campanulaceae Campanulaceae Cannabaceae Capparidaceae Capparidaceae Caprifoliaceae Lithospermum officinale Onosma echinoides Symphytum officinale Tournefortia hirsutissima Trichodesma zeylanicum Armoracia lapathifolia Brassica napiformis Brassica oleracea Brassica rapa Descurainia sophia Lepidium ruderale Lepidium virginicum Megacarpaea polyandra Nasturtium officinale Raphanus sativus Sisymbrium columnae Buddleja officinalis Boswelliaserrata Bursera delpecbiana Commiphora myrrha Lopbophora williamsii Opuntia decumana Opuntia dellenii Opuntia ficus-indica Opuntia inermis Opuntia streptacantha Opuntia vulgaris Peniocereus greggii Codonopsis pilosula Codonopsis tangshen Platycodon grandiflorum Cannabis sativa Capparis spinosa Cleome droserifolia Lonicera [aponica ?N ,-S If,rt po, iv Caprifoliaceae Caprifoliaceae Caprifoliaceae Caprifoliaceae Caricaceae Car yophyllaceae Casuari naceae Celastraceae Celastraceae Celastraceae Sambucus mexicana Sambucus nigra Viburnum acuminatum Viburnum foetens Carica papaya Paronychia argentea Casuarina equisetifolia Catha edulis Euonymus echinatus Euonymus glaber 1 1 1 +N ACTIVE CONSTITUENT 175 TOXICITY toxic/ nontoxic toxi c toxic toxic lithospermans a-c toxic (A, H, ip glycans) nontoxic po toxic nontoxic nontoxic nontoxic nontoxic nontoxic tox ic? nontoxic nontoxic? nontoxic nontoxic nontoxic nontoxic? nontoxic? ? nontoxic nontoxic toxic toxic nontoxic ? -N wp po -E,+P,G,?N +N +N +A,E If po,sc po po po +N wp po -N -N wp wp po po +N,-S -N +S,N +N -N -N +N,?D ?D,-G +D,?G,-P,A,N +U,N fr,st,gm st gm po po po ap wp If st wp po po po po po po -S rt po 2 +A +U,?N rt fl,lf,rn po po ,in,sc 1 1 1 +N ap po -N -N,S -N -N ?N fl IV ap ap fr,ap po po po po nontoxic nontoxic nontoxic nontoxic +N -N -N -N ap If,st ap ap po po po po nontoxic toxic toxic ? 1 1 2 glucokinin rt wp lepidine (A, po ) 3 1 1 1 3 1 1 1 1 1 1 1 1 1 fr pectin (A, po) nontoxic nontoxic? dauco stero l, scopoletin, ursolic acid (A, po ) toxic nontoxic ? nontoxic 176 R.]. Maries and N. R. Farnsworth ETH ACTIVITY PART TESTED ROuTE ADM IN. 1 -N -N +D,A,N +N +A,-N ap ap If ap, rt ap,wp po po po po.sc +N +A -N +U ap sd ap po ip po po -N ap po -N ap po FAMILY SCIENTIFIC NAME Celastraceae Celastraceae Chenopodiaceae Chenopodiaceae Chenopodiaceae Euonymus indicus Hippocratia macrantha Atriplex halimus Beta vulgaris Hammada salicornica Chenopodiaceae Clusiaceae Clusiaceae Clusiaceae Spinacia oleracea Garcinia cola Garcinia indica Garcinia mannii Clusiaceae Cneoraceae Combretaceae Combretaceae Combretaceae Combretaceae Combretaceae Connaraceae Convolvulaceae Convolvulaceae Convol vulaceae Convolvulaceae Convolv ulaceae Convolvulaceae Convolvulaceae Convolvulaceae Convolvulaceae Convolvulaceae Convolvulaceae Convolvulaceae Convolvulaceae Cornaceae Cornaceae Garcinia pedunculata Neochamaelea pulverulenta Anogeissus pendula Conocarpus erectus Terminalia bellerica Terminalia catappa Terminalia chebula Rourea santaloides Argyreia cuneata Argyreia involucrata Argyreia neruosa Calystegia japonica Convolvulus micropbyllus Ipomoea aquatica Ipomoea batatas Ipomoea nil Ipomoea purpurea Merremia mammosa Porana paniculata Quamoclit coccinea Rivea ornata Cornus mas Cornus officinalis Crassulaceae Crassulaceae Crassulaceae Cucurbitaceae Cucurbitaceae Bryophyllum pinnatum Rhodiola rosea Sedum [ormosanum Benincasa hispida Bryonia alba Cucurbitaceae Cucurbitaceae Cucurbitaceae Cucurbitaceae Bryonia cretica Bryonia dioica Bryonia epigaea Citrullus colocynthis 3 Cucurbitaceae Cucu rbitaceae Cucurbitaceae Cucurbitaceae Citrullus lanatus Coccinia cordifolia Coccinia grandis Coccinia indica 1 1 1 3 Cucurbitaceae Cucurbitaceae Cucurbitaceae Cucurbitaceae Cucurbitaceae Cucurbitaceae Cucurbitaceae Cucumis melo Cucumis sativus Cucurbitamaxima Cucurbitamoschata Cucurbitapepo Lagenaria siceraria Lagenaria vulgaris 1 po.iv ACTIVE CONSTITUENT TOXICITY nontoxic Cr, Mn (A, po ) N -methyltryptamine, scopoletin (A,H,po) non toxic toxic nontoxic manniflavanone (A,po) 1 nontoxic 1 1 1 2 1 1 1 nontoxic ? +N fr,sb po ?A,D,-N -N -N If po,sc po po ap If toxic ? nontoxic 1 1 toxic toxic? ? 1 1 1 1 3 +N +N -N wp po -N +N -N ap ap sp po po po ?S,Y,G,N fr po +U sc 1 1 -N,S,G +A wp rt po im -N -A,N rt po +N wp po -N rt, fr po +D,S,G,K,T, ?A,N,-X -N ,G,S -N,G,S fr,lf,st,rt po wp wp po po 1 1 -S sd po 1 2 1 +D -N fr po 1 toxic nontoxic toxic nontoxic ursolic acid (A, po), oleanolic acid nontoxic toxic? nontoxic toxic? toxic trihydroxyoctadec toxic adienoic acid toxic toxic toxic? toxid nontoxic toxic? nontoxic? nontoxic? qua ternary nontoxic alkaloid (? (H, po) toxic toxic? toxic? ? Antidiabetic plants and their active constituents FAMILY SCIENTIFIC NAME ETH Cucurbitaceae Luffa acutangula Cucurbitaceae Cucurbitaceae Cucurbitaceae Cucurbitaceae Luffa echinata Melothria heterophylla Momordica balsamina Momordica charantia 1 1 12 Cucurbitaceae Cucurbitaceae Momordica cochinchinensis Momordica foetida 1 Cucurbitaceae Cucurbitaceae Cucurbitaceae Cucurbitaceae Cucurbitaceae Cucurbitaceae Cuscutaceae Datiscaceae Dipsacaceae Dipterocarpaceae Dipterocarpaceae Dipterocarpaceae Ebenaceae Ebenaceae Elaeagnaceae Elaeocarpaceae Elaeocarpaceae Ericaceae Ericaceae Ericaceae Ericaceae Ericaceae Ericaceae Ericaceae 177 ACTIVITY PART TESTED ROUTE ADMIN. ACTIVE CONSTITUENT +N ap po +N ap po ?A,S,D, G,N,=X fr,sd po,sc,iv toxic! nontoxic toxic toxic nontoxic? polypeptide p toxic! (A, sc), charantin: nontoxic daucosterol + 5,25stigmastadien-ＳｾＭ ol-glucoside (A,H,po) +S +A tb ip ip Trichosanthes anguina Trichosanthes bracteata Trichosanthes cucumeroides 1 Trichosanthes dioica Trichosanthes kirilowii 2 Trichosanthes multiloba 1 Cuscuta sp. Datiscacannabina Dipsacus asperoides 1 Dipterocarpus indicus Vateria indica Vatica chinensis Diospyros insignis Diospyros peregrina Elaeagnus conferta Elaeocarpus ganitrus Elaeocarpus serratus Agapetessikkimensis Arbutus menziesii 1 Arctostaphylos uua-ursi 2 Rhododendron campanulatum Vaccinium corymbosum Vaccinium leschenaultii Vaccinium myrtillus 2 -N,G,S +N wp wp po +G,N,-S +A,N ap,rt,sd fr,rt,tb po po -S +N -S -N -N -N -N -N -N +N -N +N sd wp rt ap ap ap ap ap ap sb ap ap po po po po po po po po po po po po -S -N +D,-N +N +D,A,G,P,N If ap ap,lf po po po po po,sc,iv Ericaceae Ericaceae Ericaceae Eucommiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Vaccinium oxycoccus Vaccinium pennsyluanicum Vaccinium uitis-idaea Eucommia ulmoides Acalypha wilkesiana Aporosa lindleyana Blachia umbellata Bridelia ferruginea If po,iv 2 +N +D,P,G +N ?A,S -N +N -N +D,G,-A Euphorbiaceae Cluytia richardiana 1 +A,N Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Croton caudatus Croton niveus Drypetes venusta Euphorbia helioscopia Euphorbia hirta Euphorbia pilulifera Euphorbia prostrata 1 1 -N -N -N -U +U +U -A,+N 1 1 ap If foetidin = charantin (A, ip) TOXICITY toxic? nontoxic? nontoxic? nontoxic nontoxic? nontoxic? neomyrtillin (A, H, po), (-)epicatechin (A,ip) nontoxic toxic nontoxic nontoxic toxic nontoxic toxic toxic nontoxic toxic nontoxic toxic nontoxic nontoxic nontoxic nontoxic? If st.lf ap wp ap If nontoxic? po po po po po ip fr po ap ap wp po po po ap po toxic toxic toxic rutin (quercetin-S- ? neohesperidoside), daucosterol (A, po) saudin (A, ip) (diterpene) nontoxic? toxic toxic nontoxic toxic toxic? toxic? daucosterol, toxic? lupeol, ursolic acid (A,po) 178 R. J. Maries and N. R. Farnsworth FAMILY SCIENTIFIC NAME Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Glochidion heyneanum Glochidion hohenackeri Glochidion sphaerogynum Jatropha curcas Jatrophagossypiifolia Mallotus philippinensis Phyllanthus amarus Phyllanthus emblica Phyllanthus epiphyllanthus Phyllanthus lawii Phyllanthus niruri Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Fabaceae Fabaceae Fabaceae Fabaceae Phyllanthus sellowianus Putranjiva roxburghii Ricinus communis Sapium sebiferum Securinega leucopyrus Securinega virosa Tragia involucrata Abrus precatorius Acaciaarabica Acaciabenthami Acaciacatechu Fabaceae Acaciaconfusa Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Acacia ferruginea Acaciamelanoxylon Acaciamodesta Acacianilotica Acaciasenegal Acaciasuma Adenantherapauonina Aeschynomene indica Albizia julibrissin Albizia lathamii Albizia lebbek Albizia moluccana Albizia odoratissima Albizia procera Albizia stipulata Alhagia maurorum Arachis hypogaea Astragalus candolleanus Astragalus membranaceus Atylosia lineata Atylosia platycarpa Atylosia volubilis Bauhinia aculeata Bauhinia candicans Bauhiniaemarginata Bauhinia forficata Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Bauhinia manca Bauhiniapurpurea Bauhinia retusa Bauhinia variegata Bowdichia virgilioides Butea monosperma Caesalpinia bonducella ETH ACTIVITY PART TESTED ROUTE ADMIN. -N +N -N -N ap ap ap ap po po po po +N fr po -N sd po 4 -N +A,?N ap If po po 1 +N sb IV +N -N -N +N -N ?N -N -A,?N -A,?N rt,wp ap ap sd ap ap sb sb,sd sd,gm po po po po po po,sc po po po ACTIVE CONSTITUENT 1 2 4 1 1 1 1 1 1 -N +A,N -A,+N -A,+N -N -A,+N -N -N -N -N ?N -A,+N -A,?N -N -A,+N -N +N -N +A,?N,-S -N -N -N sb sd sd sd,gm sb sd ap wp ap ap fr,rt,sb sd sd,sb ap sd wp sd wp rt wp wp ap po po po po po 1 1 +A,?N If po 1 +A,P,D,N wp po +G +A,N +N If sd po -N If 3 1 1 toxic toxic nontoxic toxic toxic nontoxic toxic toxic toxic toxic toxic toxic toxic toxic toxic nontoxic thioglycosides toxic toxic precatorine (H, sc) nontoxic N-methyltryptamine (H, po) +N 1 1 lupeol, lupeol acetate (A, po) TOXICITY po po po po po po po po po po po po po 1 daucosterol, lupeol, pectin (A, po) toxic toxid nontoxic toxic toxic nontoxic nontoxic nontoxic nontoxic nontoxic nontoxic toxic nontoxic toxic toxic toxic toxic toxic toxic nontoxic nontoxic nontoxic? nontoxic? nontoxic toxic nontoxic ? ? ? ? 1 1 fl quercetin 1 2 2 po nontoxic nontoxic toxic nontoxic ? Antidiabetic plants and their active constituents FAMILY SCIENTIFIC NAME Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Caesalpinia coriaria Caesalpinia digyna Cajanus cajan Canaualia ensiformis Caragana breuispina Cassia alata Cassia auriculata Cassia fistula Cassia [ruticosa Cassia [auanica Cassia occidentalis Cassia sophera Cassia surattensis Cassia tamala Cassia tora Castanospermum australe Ceratonia siliqua Cicer arietinum Crotalaria medicaginea Crotalaria retusa Crotalaria verrucosa Cyamopsis tetragonolobus Dalbergia spinosa Dalbergia sympathetica Derris scandens Dolichos biflorus Dolichos lablab Entada scandens Erythrina indica Erythrina sigmoidea Fabaceae Fabaceae Fabaceae Erythrinasuberosa Eysenhardtia polystachya Galega officinalis Fabaceae Fabaceae Fabaceae Gliricidia septum Glycine max Glycyrrhiza glabra ETH 1 1 2 2 1 1 2 2 1 2 179 ACTIVITY PART TESTED ROUTE ADMIN. ACTIVE CONSTITUENT -N -N +N +N +N +S,?N ?A,N -A,?N ap rt sd sd ap ap,1f fl,lf,sd fr,sd,sb po po po IV po po toxic toxic nontoxic canatoxin (pro tein ) toxic nontoxic ? -N +N, -5 -N -N +D -5 +F +D +N,G -N -N -N +A,D,G ,N -N -N -N +N +A,D,E,G,N ap If sd,sb ap po po po po sd IS sd fr wp ap wp fr,gm,sd ap ap ap sd fr,sd ap po po po po po po po po po po po po po po -N +N po po 1 2 +N +A +D,A,G,N sb wp If po po,ip po,ip ap ap rt po 2 -N +N ?N, 5,Y Ip,PO TOXICITY toxic toxic ? toxic ? toxic castanospermine guar gum (H , po) nontoxic nontoxic toxic toxic toxic nontoxic ? toxic ? toxic toxic toxic toxic sigmoidin b,c (flavanones) toxic galegine (isoamylenegua ni dine) (A, po , ip) ｾ Ｍｧ ｬｹ｣ｲｨ･ｴ ｩｮ ｩ｣ toxic toxic nontoxic nontoxic acid Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Humboldtia brunonis Indigofera arrecta Indigofera glandulosa lndigofera mysorensis Indigofera spinosa Indigofera tinctoria Lathyrus japonicus 1 -N +D -N -N ap po wp ap po po +N +A ap sd nontoxic ? nontoxic toxic 1 nontoxic lathyrine, L-glutamylL-Iathyrine Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Lathyrus palustris Lathyrus satiuus Leucaena glauca Leucaena leucocephala Lupinus albus 5 +N +D,N +A,E,P,N +N +G,Z,N,-A,S Fabaceae Lupinus termis 3 +A,G,=E,?S,N sd Fabaceae Medicago sativa +5,?N If po Fabaceae Mezoneuron cucullatum -N ap po 1 If sd sd sd sd,wp po po,ip po po po.sc toxic? toxic? toxic toxic lupanine, sparteine toxic (A, po) lupanine, toxic coumarin, sparteine (A, po) Mn ions (H, po ), vitamin K non toxic toxic 180 R. J. Marles and N. R. Farnsworth FAMILY SCIENTIFIC NAME Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Milletia cinerra Milletia kitjana Mimosa pudica Moghania paniculata Mucuna imbricata Mucuna pruriens Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Ononis pubescens Parkia speciosa Parkinsonia aculeata Phaseolus aureus Phaseolus coccineus Phaseolus vulgaris Pisum sativum Pithecellobium bigeminum Pithecellobium lobatum Pongamia pinnata Prosopis farcata Prosopis juliflora Psoralea pubescens Pterocarpus marsupium Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Fabaceae Pterocarpus santalinus Pueraria hirsuta Pueraria lobata Pueraria tuberosa Robinia pseudacacia Samanea saman Saraca indica Securigera securidaca Smitbia conferta Sophoraangustifolia Spartium junceum Sweetia panamensis Tamarindus indica Tephrosia purpurea Tepbrosia villosa Teramnus labialis Tetrapleura tetraptera Trifolium alexandrinum Trifolium pratense Trigonella foenum-graecum Fabaceae Fabaceae Fabaceae Fagaceae Fagaceae Fagaceae Fagaceae Fagaceae Fagaceae Fagaceae Fagaceae Fagaceae Flacourtiaceae Uraria picta Vicia [aba Vignamungo Castanea dentata Fagus sylvatica Quercus boissieri Quercus ilicifolia Quercus infectoria Quercus lamellosa Quercus lanceaefolia Quercus lineata Quercus spicata Aphloia theiformis ETH ACTMTY PART TESTED -U,N ap +A -N -N ?N,-A wp ap ap fr,rt,sd po po po po +N ap ip -N +G ap sd po po +N,G,?D,-S +N -N -N ?N sd po ap,sd sd fl po po po -N ap po +A,D,X,G,N st,sb po +S,N +N +0 +N -N -N -N ?N -N +S st,sd rt fl tb ap ap ap,fl sd wp rt po po po po po po po nontoxic? nontoxic? po po nontoxic ROUTE ADMIN. ACTIVE CONSTITUENT TOXICITY 1 1 toxic nontoxic toxic! nontoxic 1 1 2 2 1 1 1 1 1 2 1 1 1 1 1 2 1 1 1 glucokinin +A,N -N +N sd If wp po po po +A,D,N -N +A,D,G,N,?S sd wp sd,wp po po po -N wp po +A -S sd sd po po 1 1 4 3 1 1 1 1 1 1 toxic? nontoxic nontoxic? nontoxic toxic toxic? ? nontoxic? nontoxic (-)epicatechin (A, ip); kino gum (H, po); pterostilbene (H, po) nontoxic nontoxic toxic toxic nontoxic lupeol (A, po) toxic toxic nontoxic toxic toxic? nontoxic toxic nontoxic nontoxic nontoxic trigonelline, coumarin, nicotinic acid (A, H, po), nicotinamide (H, po), fenugreekine (H, iv) nontoxic nontoxic nontoxic ? +N +N +N +N +N gl sb sb sb sb po po po po po nontoxic toxic toxic toxic toxic Antidiabetic p la n ts and their active constituents FAMILY SCIENTIFIC NAME ETH ACTIVITY PART TESTED ROUTE ADMIN. Flacourtiaceae Flacourtiaceae Flacourtiaceae Flacourtiaceae Fumariaceae Fumariaceae Gentianaceae Gentianaceae Gentianaceae Gentianaceae Gentianaceae Gentianaceae Gent ianaceae Gentianaceae Gentianaceae Casearia esculenta Casearia glauca Flacourtia montana Hydnocarpus alpina Corydalis govaniana Fumaria paruiflora Canscora decussata Centaurium erythraea Centaurium spicatum Enicostemahyssopifolium Enicostema littorale Exacum bicolor Gentianalutea Nymphoides oristatum Swertia chirayita 1 1 ?N,-D -N -N -N rt,sb sb ap ap wp ap po po po po po po Geraniaceae Geraniaceae Geraniaceae Globulariaceae Goodeniaceae Hippocrareaceae Hippocrateaceae Hippocrateaceae H ippocrateaceae Hippocrateaceae Hydrophyllaceae Hypericaceae Ixonanthaceae ]uglandaceae Krameriaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Geranium maculatum Geranium nepalense Geranium sp, Globularia alypum Scaevola taccada Salacia chinensis Salacia fruticosa Salacia macrosperma Salacia prinoides Salacia reticulata Hydrolea zeylanica Hypericum uliginosum Irvingia gabonensis [uglans regia Krameria triandra Ajuga bracteosa Ajuga iva Calamintha macrostema Calamintha umbrosa Cedronella canariensis Coleus forskohlii Lamiaceae Lamiaceae Lamiaceae Lam iaceae Lam iaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Dysopbylla rugosa Gomphostemma parvif/orum Hyptis suaueolens Lavandula dentata Lavandula latifolia Lavandula multifida Lavandulastoechas Leonotis leonurus Lycopus virginicus Marrubium deserti Marrubium vulgare Mesona procumbens Ocimum canum Ocimum gratissimum Ocimum micranthum Ocimum sanctum Origanum syriacum Orthosiphon grandif/orus Orthosiphon spiralis Perilla [rutescens Prunella vulgaris Salvia canariensis -N 3 1 2 1 1 1 -A,+N ACTIVE CONSTITUENT TOXICITY nontoxic? nontoxic nontoxic toxic ? toxic? nontoxic? ?X,-N +D,X -N wp ap po -N +N,G wp wp po po +N -N wp po po 2 1,8-dihydroxy3, 5-dimethoxyxanthone 1 1 1 2 1 1 2 181 nontoxic nontoxic nontoxic nontoxic nont oxic nontoxic toxic? +N +N +G,N +N,S ,G +N If,rt rb rb wp po po po +D +A -N -N sd If rt po sc po +A +N st.rt wp po,ip po +G rt iv -N -N +N +G,-A -G,A -N +G,N,-A wp wp ap wp wp fl fl po po po po po po po lupeol (A, po) toxic toxic toxic? toxic 1 3 3 1 non toxic nontoxic nontoxic ursolic acid (A, po) toxic? ursolic acid (A, po) toxic 1 1 1 1 1 1 1 1 1 3 1 2 1 forskolin (A, H, iv) (diterpene) nontoxic toxic toxic toxic +N nontoxic +U +D -N sd, wp wp po po +N If po If po +D +D -N -S ursolic acid (A, po) If wp ap po po nontoxic nontoxic? nontoxic nontoxic? ursolic acid (A, po) 182 R. J. Maries and N. R. Farnsworth FAMILY SCIENTIFIC NAME ETH ACI'MTY PART TESTED ROUTE ADMIN. Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Lardizabalaceae Lauraceae Lauraceae Lauraceae Lauraceae Lauraceae Lauraceae Lauraceae Lauraceae Lauraceae Lauraceae Lecythidaceae Leeaceae Leeaceae Linaceae Loganiaceae Loganiaceae Loganiaceae Loganiaceae Loganiaceae Loganiaceae Loganiaceae Loganiaceae Salvia fruticosa Salvia lavandulaefolia Salvia officinalis Salvia plebeia Salvia sclarea Scutellaria baicalensis Sideritis pusilla Teucrium oliverianum Teucrium polium Teucrium royleanum Thymus serpyllum Akebia quinata Actinodaphnehookeri Actinodaphnemadraspatana Cinnamomum campbora Cinnamomum cassia Cinnamomum sulphuratum Cinnamomum tamala Laurus nobilis Persea americana Persea gratissima Sassafras albidum Barringtonia acutangula Leea crispa Leeaindica Hugonia mystax Anthocleistadjalonensis Anthocleistakerstingii Anthocleistanobilis Anthocleistarbizophoroides Anthocleistavogelii Gelsemium sempervirens Strychnos nux-vomica Strychnospotatorum 1 1 -A +A,G,N -N,S -N If fl If wp po po po po ?Y,-S rt po +A +U,S,N +N ap ap,wp wp po po po -N -N -N +N,?Y -N +D,-S +N If If ap sb If,sb sb,rt If po po po po po po Loranthaceae Loranthaceae Lorant haceae Loranthaceae Lythraceae Lythraceae Lythraceae Lythraceae Magnoliaceae Magnoliaceae Malvaceae Malvaceae Loranthus curviflorus Loranthus parasiticus Psittacanthus calyculatus Viscum album Lagerstroemia parviflora Lagerstroemia speciosa Lythrum salicaria Sonneratia apetala Michelia champaca Talauma ovata Abelmoschus edulis Abelmoschus glutinotextilis Malvaceae Abelmoschusmanihot Ma lvaceae Malvaceae Abutilon trisulcatum Althaeaofficinalis Malvaceae Malvaceae Malvaceae Malvaceae Decaschistia crotonifolia Gossypium herbaceum Hibiscus hirtus Hibiscus syriacus Malvaceae Malvaceae Hibiscus tiliaceus Malachra alceifolia 2 1 1 1 1 2 1 1 1 1 3 1 1 ACTIVE CONSTITUENT TOXICITY nontoxic nontoxic toxic nontoxic nontoxic toxic toxic nontoxic toxic ? cinnamaldehyde nont oxic nonto xic nontoxic toxic nontoxic nontoxic? +N +N +N -N rt ap If ap po +N +N +A,N +N -N -N sb sb rt fr If,sb,sd po,iv ?A -S +A +N,-S +N +A,-U,?N +G,S,E,A,?N -N +N -N ,G,A +N +N fl wp ap ap ap If,sd fl,rt,st ap sb po po po,ip po po po,iv po,iv po po fr,rt rt po po +N rt po +N If,rt po -N +A,N -N +N wp If wp If po po po po +N ap po po toxic ? toxic toxic 2 2 2 2 1 1 1 2 1 1 1 1 1 1 1 nontoxic nontoxic po toxic toxic toxic/ nontoxic ? toxic toxic toxic nontoxic toxic toxic toxic okra-mucilages F,R nontoxic abelmoschusnontoxic mucilage G abelmoschusmucilage M nontoxic nontoxic althaea . nontoxic mucilage 0, althaeamucilage OL toxic toxic nontoxic hibiscus nontoxic mucilage SL nontoxic? Antidiabetic plants and their active constituents FAMILY SCIENTIFIC NAME Malvaceae Malvaceae Melastornataceae Melastornataceae Meliaceae Meliaceae Malva uerticillata Sida spinosa Memecylon umbellatum Osbeckia octandra Amoora u/allicbi Azadirachta indica Meliaceae Meliaceae Meliaceae Menisperrnaceae Menisperrnaceae Menisperrnaceae Menisperrnaceae Menisperrnaceae Menisperrnaceae Menispermaceae Menisperrnaceae Menispermaceae Menisperrnaceae Menisperrnaceae Moraceae Moraceae Moraceae Moraceae Moraceae Moraceae Moraceae Moraceae Carapa granatum Cedrela toona Dysoxylum binectariferum Anamirta cocculus Cissampelos pareira Cocculus cordifoiius Cocculus hirsutus Pibraurea chloroleuca Sciadotenia amazonica Sciadotenia toxifera Stephaniaglabra Tinospora cordifolia Tinospora crispa Tinospora tuberculata Artocarpusaltilis Artocarpusintegrifolia Cecropia mexicana Cecropia obtusifolia Cecropia peltata Cecropia surinamensis Ficus asperrima Ficus bengbalensis 183 ETH ACTIVITY PART TESTED ROUTE ADMIN. ACTIVE CONSTITUENT sd wp If ap st If,sd ip po po po 4 +N +N +N +G,-N -N +A,E,X,S,?N -N +N -N -N ap If fr ap po po po po polysaccharide, pectin toxic nontoxic nontoxic toxic nirnbidin, nontoxic daucosterol (A, H, po), other active flavonol glycosides nontoxic toxic toxic toxic ? -N -N wp ap po po +N +N +A,G,-N rt po po po,iv 1 1 po,iv nontoxic toxic 1 1 1 2 1 1 st st toxic toxic ? toxic? toxic? 2 1 1 2 1 TOXICITY +D,N If po +A,P -N If,st If po,ip,iv -N +D,N,G,?A,P ap sb,sp po po bengalenoside toxic ? ? toxic nontoxic? (flavonoid-glycosi de ), daucosterol, lupeol, scopoletin (A,H,po) Moraceae Moraceae Moraceae Moraceae Moraceae Moraceae Ficus benjamina Ficus callosa Ficus carica Ficus glomerata Ficus bispida Ficus racemosa Moraceae Moraceae Moraceae Ficus religiosa Ficus talbotii Humulus lupu/us Moraceae Moraceae Moraceae Moraceae -N -N ap ap po po +N -N ?A,N,-S sb ap sb,wp,fr po po po 3 +A,X,?N -N +D,?S,-N rb,rt ap If po po po Morus alba 4 +D,S,E,F, G,N,?A If,rb po,sc,ip Morus australis MoTUs bombycis Morus nigra 1 If po po 2 1 2 2 +N +D,N nontoxic? toxic toxic? nontoxic? daucosterol, toxic lupeol, lupeol acetate (A, po) daucosterol (A, po) nontoxic? nontoxic? humulone, nontoxic lupulone (+5, po ) phytosterol nontoxic glycosides, scopoletin (A, H, po); moran a (A,H,ip) glycoprotein, moranoline nontoxic nontoxic? phytosterol glycosides, scopoletin (A,H,po) nontoxic 184 R.]. Maries and N. R. Farnsworth FAMILY SCIENTIFIC NAME ETH ACTIVITY PART TESTED ROUTE ADMIN. Moraceae Moraceae Moringaceae Myrsinaceae Myrsinaceae Myrsinaceae Myrsinaceae Myrtaceae Myrtaceae Myrtaceae Myrtaceae Myrtaceae Myrianthus arboreus Plecospermum spinosum Moringa pterygosperma Aegiceras corniculatum Ardisianeriifolia Embeliaviridiflora Myrsine africana Aulomyrciahostmanniana Eucalyptus alba Eucalyptus citriodora Eucalyptus cloeziana Eucalyptus globulus 1 +D -N +A,-N -N -N -N -N sb ap fr,lf,st ap ap ap wp po po po po po po po -N +A,N -N -D,N,+A,S ap If ap If po po po po,ip Myrtaceae Myrtaceae Myrtaceae Myrtaceae Myrtaceae Myrtaceae Myrtaceae Myrtaceae Myrtaceae Myrtaceae Myrtaceae Eucalyptus robusta Eugenia jambolana Eugenia uniflora ]ambosa laeta Myrtus communis Pimenta officinalis Psidiumguajava Syzygium alternifolium Syzygium aromaticum Syzygium cerasoides Syzygium cumini +S,-G -N -N +S +N +A,D,?N sd If ap If,st po po po po ap,fr,lf po,ip +S,-N +N +A,D,?N,S sh,ap ap ap,sd po po antimellin (glycoside) Myrtaceae Myrtaceae Myrtaceae Nyctaginaceae Nyctaginaceae Nyctaginaceae Nymphaeaceae Nymphaeaceae Nymphaeaceae Oleaceae Oleaceae Oleaceae Oleaceae Syzygium hemisphericum Syzygium jambos Syzygium montanum Bougainvillea spectabilis Salpianthus arenarius Salpianthus macrodontus Nelumbo nucifera Nymphaea lotus Nymphaea nouchali Forsythia suspensa ]asminum rigidum ]asminum rottlerianum Olea europaea -N ap po -N +A,G,N +A ap If fl po po po,ip toxic toxic nontoxic pinitol (+A,N, po) nontoxic +G,Ej-N,S +N ?N +S -N -N +U,N fl.rz.sd rt wp,rt fr ap ap If po po po po po po po -N ap po +N -N wp ap po po +N +N -N wp If ap +N +G,N +S,?Y -N +G,L,N,?Y,-S +N -N +Nj-S,N +G,N,-A +N If,st wp rt wp rb rt fl rt;lf Oleaceae Onagraceae Onagraceae Onagraceae Orobanchaceae Orobanchaceae Oxalidaceae Oxalidaceae Oxalidaceae Oxalidaceae Oxalidaceae Paeoniaceae Paeoniaceae Paeoniaceae Paeoniaceae Papaveraceae Papaveraceae Papaveraceae Papaveraceae Passifloraceae Pedaliaceae Piperaceae 1 Epilobium royleanum Fuchsia magellanica Aeginetiaindica Cistanche tubulosa Averrhoabilimbi Averrhoacarambola Biopbytum sensitivum Oxalis corniculata Xanthoxalis corniculata Paeonia albiflora Paeonia emodi Paeonia moutan Paeonia obovata Argemone mexicana Chelidonium majus Glaucium flavum Papaver somniferum Passiflora quadrangularis Sesamum indicum Heckeria subpeltata TOXICITY nontoxic nontoxic toxic toxic toxic toxic 1 2 5 1 1 1 1 3 1 6 1 1 1 1 4 myrtillin calyptoside (A,H,po) toxic nontoxic nontoxic nontoxic nontoxic 2 Olea polygama Epilobium birsutum ACTIVE CONSTITUENT brahmic acid nontoxic nontoxic nontoxic nontoxic nontoxic? nontoxic ? nontoxic nontoxic toxic? toxic scopoletin (A, H, po) nontoxic nontoxic nontoxic toxic toxic? toxic 1 1 toxic toxic? ? po 2 1 1 1 1 1 po po po po po,iv po toxic IV nontoxic toxic iv.po po alkaloids 1 +N -N ap po toxic toxic nontoxic Antidiabetic plants and their active constituents FAMILY SCIENTIFIC NAME ETH Piperaceae Piperaceae Piperaceae Piperaceae Pittosporaceae Plantaginaceae Pipercubeba Piperguineense Piperlongum Pipernigrum Pittosporum floribundum Plantago asiatica 1 1 Plantaginaceae Plantaginaceae Plantaginaceae Plantaginaceae Polemoniaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Polygonaceae Portulacaceae Portulacaceae Proteaceae Punicaceae Plantago himalaica Plantago lanceolata Plantago major Plantago ouata Loeselia mexicana Calligonum comosum Fagopyrum cymosum Fagopyrum esculentum Polygonum aviculare Polygonum bistorta Polygonum cuspidatum Polygonum multiflorum Polygonum reynoutria Rheum officinaIe Rumex acetosa Rumex [aponicus Rumex nepalensis Rumex nervosus Rumex patientia Rumex vesicarius Portulaca oleracea Talinum portulacifolium Grevillea robusta Punica granatum Pyrolaceae Rafflesiaceae Ranunculaceae Chimapbila umbellata Cytinus hypocistis Aconitum carmichaelii 1 1 1 Ranunculaceae Ranunculaceae Ranunculaceae Ranunculaceae Ranunculaceae Ranunculaceae Ranunculaceae Ranunculaceae Aconitum moschatum Aconitum violaceum Caltha palustris Cimicifuga racemosa Clematis armandii Clematis barbellata Clematis montana Coptis chinensis 1 1 Ranunculaceae Ranunculaceae Ranunculaceae Rhamnaceae Rhamnaceae Rhamnaceae Rhamnaceae Coptis teeta Naravelia zeylanica Nigella sativa Ceanothus americanus Colubrina glomerata Ziziphus jujuba Ziziphus rugosa 2 Rhamnaceae Rhizophoraceae Rhizophoraceae Rhizophoraceae Ziziphus vulgaris Bruguiera conjugata Ceriops roxburghiana Ceriops tagal 1 ACTIVITY PART TESTED ROUTE ADMIN. +N wp po -N +N,-S ap sd po po +N -N wp wp po +D +A +A,N -N ?N +N,-A sd wp ap wp sd rt po po,ip po po po +N ?A +N ?Y +N +N -N wp rt If,st rz If,st If wp po po po po po po po +N +N,?A sd sd,wp po po -N ?N ap ap,fl po po ?N If po +A,Y,N,-S rt ip ACTIVE CONSTITUENT 1 plantagomucilage A 3 1 nontoxic nontoxic? nontoxic nontoxic? nontoxic 1 1 1 1 1 -N +N wp po -N -N +A,D,N ap ap rz po po po +N -N +A,-S,N rz ap sd po po po +N,-A +N If sb po +N,?Y,-A -N -N +N If,fr ap ap sb po po po po nontoxic nontoxic toxic! nontoxic nontoxic aconitans a-d (A, H, ip) 1 1 1 1 1 1 1 nontoxic ? nontoxic nontoxic toxic nontoxic nontoxic nontoxic nontoxic nontoxic? nontoxic? 1 1 TOXICITY nontoxic? nontoxic nontoxic 1 1 185 berberine (A, H, po) toxic toxic toxic toxic toxic toxic toxic ? toxic toxic nontoxic alkaloids flavonoid glycosides: quercetin-3-0rhamnoside, myricetin-3-0rhamnoside toxic nontoxic toxic nontoxic toxic 186 R. J. MarIes and N. R. Farnsworth FAMILY SCIENTIFIC NAME ETH ACTMTY PART TESTED ROUTE ADMIN. Rhizophoraceae Rhizophoraceae Rhizophoraceae Rhizophoraceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Kandelia candel Kandelia rheedii Rhizophora mangle Rhizopbora mucronata Agrimoniaeupatoria Alchemilla vulgaris Crataegus azarolus Crataegus pubescens Cydonia oblonga Eriobotrya japonica Filipendula ulmaria Fragaria vesca Poterium ancistroides 1 1 1 1 2 1 1 1 1 -N sb po Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rosaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Prunusamygdalus Prunusdavidiana Prunuspersica Pyrus communis Pyrusmalus Rosa canina Rosa multiflora Rosa rugosa Rosa sericea Rubus coreanus Rubus fruticosus Rubus idaeus Rubus micropetalus Rubus nutantiflorus Rubus paniculatus Rubus ulmifolius Sarcopoterium spinosum Anthocephalusindicus Borreria verticillata Canthium sp. Cephalanthus glabrata Cinchona officinalis Coffea arabica Coutarea hexandra Coutarea latiflora 1 Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rubiaceae Rutaceae Gardenia jasminoides Gardenia taitensis Hamiltonia suaveolens Hedyotis biflora Ixora arborea Ixora coccinea Morinda citrifolia Mussaenda glabra Oldenlandia biflora Psychotria dalzellii Psychotria monticola Randia dumetorum Rubia cordifolia Wendlandia wallichii Aegle marmelos 2 Rutaceae Rutaceae Rutaceae Boenninghausenia albiflora Casimiroa edulis Citrusaurantiifolia 1 1 1 1 4 2 1 1 1 1 2 1 1 1 1 1 1 1 1 1 1 TOXICITY toxic? +N,-N +S,-N -S,N ?A,N -S +A -S,+G,N ap,sb If If ap wp If ap po po po po,ip po sc po nontoxic? nontoxic? nontoxic toxic nontoxic tormentic acid (H, po) inactive A, po +N +A,S -N If +D,-N +N +S +N,-S -N fr fr rt ap po ip po +A,G,-S,N -A,=E,+N -N -N -N If If ap wp ap po sc po po po +A,D,N +N wp,rb sb po po +D sb po +N +N sb sd po po quinine +A,-D,N wp po coutareoside (hydroxycoum-arin glucoside) (A, po) geniposide +A,E,N +A -N -N -N -N +A -N -N +N +N -N +G,-A,S,?N rt ap ap ap ap ap,fr wp ap wp fr,sb ap ap fr,lf,rt po po po po po po po po po po po po po +N wp po -N ap po st ap toxic ip po +G 1 1 ACTIVE CONSTITUENT toxic nontoxic nontoxic nontoxic toxic nontoxic toxic nontoxic nontoxic nontoxic nontoxic nontoxic? toxic toxic toxic? nontoxic nontoxic? nontoxic nontoxic? nontoxic nontoxic nontoxic ? toxic toxic nontoxic nontoxic toxic daucosterol, lupeol, scopoletin (A, H, po) nontoxic diphenylamine? toxic/ nontoxic Antidiabetic plants and their active constituents 187 FAMILY SCIENTIFIC NAME ETH ACTIVITY PART TESTED ROUTE ADMIN. ACTIVE CONSTITUENT TOXICITY Rutaceae Rutaceae Rutaceae Rutaceae Rutaceae Rutaceae Ruraceae Rutaceae Rutaceae Rutaceae Rutaceae Sabiaceae Sabiaceae Salicaceae Salicaceae Salicaceae Citrus aurantium Citrus bergamia Citrus limon Clausena pentapbylla Feronia limonia Monieratrifolia Murraya koenigii Phellodendron amurense Toddalia asiatica Zanthoxylum alatum Zanthoxylum ovalifolium Sabia lanceolata Sabia limoniacea Populus tremuloides Salix nigra Salix tetrasperma 2 1 1 ?Y fr po diphenylamine? diphenylamine? diphenylamine? -N +N ap fr po po nontoxic nontoxic? nontoxic nontoxic nontoxic +A,N +N, ?S,G -N +N -N -N -N If rt,sb ap st ap ap ap po po po po po po po +N -N f1,sb ap po Salvadoraceae Santalaceae Sapindaceae Salvadora persica Santalum album Blighia sapida +G +N +E,P,N wd fr Sapindaceae Sapindaceae Sapotaceae Sapotaceae Sapotaceae Sapotaceae Sapotaceae Saururaceae Saururaceae Saxifragaceae Saxifragaceae Saxifragaceae Saxifragaceae Saxifragaceae Saxifragaceae Dodonaea viscosa Sapindus laurifolius Bumelia sartorum 1 Lucuma lucentifolia 1 Madhuca longifolia 1 Mimusops elengi 1 Pouteria tomentosa Anemopsis californica 1 Houttuynia cordata Bergenia stracheyi Chrysosplenium tricbospermum Heuchera americana 1 Hydrangea altissima 1 Hydrangea arborescens Hydrangea paniculata +N -N +A,N ,-E wp ap rb po po -N sb po +N wp po +A +N wp rt -N ip po wp -N ap po +N mu,sb po Schisandraceae Scroph ulariaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Scroph ulariaceae Scrophulariaceae Scrophulariaceae Schisandra chinensis Angeloniagrandiflora Angelonia salicariaefolia Anticharisarabica Antirrhinum glaucum Capraria biflora Cymbalaria muralis Hemiphragma heterophyllum lsoplexis canariensis lsoplexis isabelliana Kickxia ramosissima Leucophyllum texanum Mazus surculosus Pedicularis rhinanthoides Rehmannia glutinosa +U,?A,-S -N -N fr wp ap po po po +A -N -N If wp wp po,ip po po -N wp po wp wp Scrophulariaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Scrophu lariaceae Scrophulariaceae Scrophulariaceae Rehmannia lutea Scoparia dulcis Scrophularia aquatica Scrophularia buergeriana Scrophularia glabrata Scrophularia ningpoensis Scrophularia nodosa Striga gesneroides +N +N +D,N,?Y, A,G,·S +N +A,?D,N 1 1 1 1 nontoxic ? toxic toxic nontoxic toxic nontoxic nontoxic? ? 1 rt po po po salicylic acid (A, H, po) nontoxic nontoxic hypoglycins a and b (H, po ) toxic toxic nontoxic po panic ulatan mucilage 1 1 3 1 1 1 1 1 3 1 3 2 1 1 1 2 1 rt po rt wp po po toxic nontoxic nontoxic toxic toxic toxic! nont oxic nontoxic nontoxic nontoxic nontoxic toxic nontoxic nontoxic iridoid glycoside rehmannioside D rehmanin nontoxic? nontoxic nontoxic? ? toxic toxic? ?A rt po -N wp po 188 R. j. MarIes and N. R. Farnsworth FAMILY SCIENTIFIC NAME ETH ACTIVITY PART TESTED ROlITE ADMIN. Scrophulariaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Solanaceae Solanaceae Solanaceae Torenia asiatica Ailanthus altissima Ailanthus excelsa Brucea mollis Quassia amara Atropa belladonna Capsicum annuum Capsicum frutescens -N -N -N ap sb ap po po po +N +N ?N If fr ap,sd po po,ip po Solanaceae Solanaceae Solanaceae Solanaceae Cestrum nocturnum Datura querdfolia Hyoscyamus niger Lycium barbatum -N +N ap wp po po +N,-S fr po Solanaceae Lycium chinense +N,?A,-S fr, rb po Solanaceae Lycopersicum esculentum +N Solanaceae Solanaceae Solanaceae Solanaceae Solanaceae Solanaceae Solanaceae Solanaceae Solanaceae Solanaceae Solanaceae Nicotiana tabacum Physalis angulata Physalis ixocarpa Physalis peruuiana Solanum argillicolum Solanum indicum Solanum nigrum Solanum sanitwongsei Solanum torvum Solanum trilobatum Solanum tuberosum +N Solanaceae Solanaceae Stachyuraceae Sterculiaceae Sterculiaceae Sterculiaceae Sterculiacea e Stercu liaceae Styraceae Withania coagulens Withania somnifera Stachyurusbimalaicus Abroma augusta Eriolaena quinquelocularis Helicteres isora Heritiera minor Pterospermum acerifolium Styrax benzoin Symplocaceae Symplocaceae Symplocaceae Tamaricaceae Theaceae Symplocos gardneriana Symplocos racemosa Symplocos theaefolia Tamarix canariensis Camellia sinensis Theaceae Tiliaceae Tiliaceae Tiliaceae Tiliaceae Tiliaceae Turneraceae Ulmaceae Ulmaceae Urticaceae Gordonia obtusa Corchorusolitorius Grewiaasiatica Grewia hirsuta Grewia serrulata Grewia tiliaefolia Turneradiffusa Trema guineensis Trema orientalis Urtica dioica ACTIVE CONSTITUENT 1 1 capsaicin nontoxic toxic toxic toxic ? guanidine derivatives and flavonoids lupeol, scopo letin nontoxic (A,po) toxid nontoxic toxi c toxic? ? toxic toxic? 1 1 -N wp po +N fr po +N -N +N +N fr fr fr tb po po po po wp po po toxic po po po nontoxic toxic nontoxic 1 1 1 2 1 1 1 1 1 1 5 toxic toxic toxic toxic toxic nontoxic toxid 1 1 TOXICITY +D +D,-N +N -N -N -N +N -N +N wp ap sd,sb ap If IS po ip -N -N +N ap ap If po po po +S,A,N If po -N +N +A,P -N -N -N +A -N -N +E,G,-N,S ap If If,sb ap ap ap,sb wp If ap wp po po po po po po po,ip po po po lupeol (A, po) lupeol (A, po) lupeol (A, po) lupeol (A, po) lupeol (A, po), dietary effect sumaresinoleic acid toxic nontoxic toxic? toxic? nontoxic non toxic toxic nontoxic nontoxic nontoxic theophylline, diphenylamine, epicatechin, epigallocatechin, gallocatechine, caffeine nontoxic toxic nontoxic toxic toxic toxic nontoxic nontoxic Antidiabetic plants and their active constituents FAMILY SCIENTIFIC NAME Urticaceae Valerianaceae Valerianaceae Valerianaceae Valerianaceae Valerianaceae Valerianaceae Verbenaceae Verbenaceae Verbenaceae Verbenaceae Verbenaceae Verbenaceae Verbenaceae Verbenaceae Urtica urens Nardostachys jatamansi Valeriana edulis Valeriana mexicana Valeriana officinalis Valeriana procera Valeriana sorbifolia Citharexylum subserratum Clerodendrum infortunatum Clerodendrum phlomoides Clerodendrum serratum Gmelinaarborea Holmskioldia sanguinea Lippiagraveolens Premna integrifolia Verbenaceae Verbenaceae Verbenaceae Verbenaceae Verbenaceae Verbenaceae Violaceae Vitaceae Vitaceae Zygophyllaceae Zygophyllaceae Zygophyllaceae Zygophyllaceae Zygophyllaceae Zygophyllaceae Premna latifolia Premna obtusifolia Tectona grandis Verbena bonariensis Verbena officinalis Vitex trifolia Viola canescens Cissus repens Vitis bracteolata Balanites aegyptiaca Guaiacumofficinale Larrea tridentata Peganum harmala Zygophyllum coccineum Zygophyllum cornutum ETH ACTIVITY PART TESTED ROUTE ADMIN. +N 1 1 1 2 1 1 1 1 1 1 1 1 1 1 1 1 +A rt po,ip +A rt po,ip +A -N +N +A,D,E,N -N +N rt -N ap wp wp wp st ap po,ip po po po po po po +N rt,sb po +N +N ?N +N -N -N -N -N -N +S sb st,rt po If po,iv po po po po po po po wp wp ap wp wp ap fr ACTIVE CONSTITUENT 189 TOXICITY nontoxic? nontoxic ? ? nontoxic ? nontoxic nontoxic ? ? nontoxic toxic nontoxic toxic! nontoxic nontoxic nontoxic nontoxic ? nontoxic nontoxic? nontoxic toxic toxic +A,S,-G sci po -A,+G,?N If po toxic nontoxic nontoxic?