Werelwijd bestaan er zowat 350.000 hogere planten, waarvan ik er zelf zowat 1000 in meer of mindere mate ken. Veel van die planten om niet te zeggen allemaal hebben een of andere gebruikswaarde, Ze bezitten zo wie zo stoffen die een bepaalde fysiologische werking hebben op mens, dier of plant. Een geneeskrachtige, giftige, stimulerend of hallucinerende werking. Ze worden ook gebruikt als kleurstof, dakbedekking, kleding en natuurlijk ook als voedsel. Sommigen zijn wereldwijd bekend (hennep, koffie, thee) anderen zijn zeer plaatselijk in gebruik. Een aantal van die minder bekende, soms curieuze planten, wil ik toch informatie over geven, zonder dat ik daar al zelf een artikel overgeschreven heb. Bij deze een interessant artikel over een bijzondere Afrikaanse anti-malariaplant.
Cryptolepis: An African Traditional Medicine that Provides Hope for Malaria Victims
HerbalGram. 2003;60:54-59,67 © American Botanical Council
The root of the plant cryptolepis (Cryptolepis sanguinolenta (Lindl.) Schlecter, Asclepiadaceae or Periplocaceae) is used in traditional African medicine to treat a variety of diseases, including malaria.1-6 Scientific investigations have indicated a number of biological/pharmacological effects of compounds isolated from the plant material, including anti-bacterial, anti-hyperglycemic, anti-inflammatory, anti-plasmodial/anti-malarial, and anti-viral effects.7-19 Some of these effects have been demonstrated in the crude extract as well as its fractions, including a dose-dependent inhibitory effect on the classical pathway of complement fixation.*11 During the past few years, cryptolepis has received additional attention by the phytomedicine division of a pharmaceutical company in Ghana, which developed an herbal tea based on this traditional medicinal herb and recently demonstrated the clinical efficacy of a tea-bag formulation in the treatment of malaria.20 A preliminary clinical study in 1989 conducted with an aqueous extract of cryptolepis, prepared by boiling powdered cryptolepis roots in water, also suggested the efficacy of the plant material against malaria.21Unlike most other plant-derived malaria medications on the market (i.e., the drug quinine, a pure compound extracted from the bark of Cinchona spp. of the family Rubiaceae, and the recently developed pure compound artemisinin and semi-synthetic derivatives from the Chinese herb quin hao or sweet wormwood, Artemisia annua L., Asteraceae), the herbal tea based on cryptolepis is a true herbal remedy containing the naturally occurring complex mixture of phytochemicals in a traditional dosage form, with a long-established history of use, just like the old remedies from which the two aforementioned malaria drugs were derived.
Malaria kills more than 1 million people every year, mostly young children under 5 years of age. Due to high levels of drug-resistance, typical pharmaceuticals are losing their ability to treat the infection effectively. Since malaria is most prevalent in developing countries that cannot afford novel patented drugs, there is little commercial incentive for multinational drug companies to focus research money on malaria. The work of organizations such as Medicine for Malaria Ventures (MMV) , an independent foundation committed to the sustainable discovery and development of affordable antimalarial chemotherapies, is therefore all the more important, in this author’s opinion.
Nomenclature and Taxonomy
Cryptolepis is derived from the root of Cryptolepis sanguinolenta; syn. C. triangularis N.E. Br., and Pergularia sanguinolenta Lindl. Its common name among the various tribes of Ghana include nibima (among the Twi speaking people), kadze (among the Ewe), and gangamau (among the Hausa). It is also known as Ghana quinine or yellow-dye root. Although the aqueous extract has a bitter taste, this name is probably based on the common use of the plant as a substitute for the anti-malarial alkaloid quinine, and should not be confused with it. Some decades ago, quinine was the drug of choice for the treatment of malaria, and is still in use in areas where there is resistance to chloroquine malaria drugs. In keeping with common practice with popular medicinal botanicals that do not have accepted common names in English, the common name cryptolepis, based on its Latin generic name, will be used throughout this paper.
Cryptolepis is a thin-stemmed twining and scrambling shrub. The leaves are petiolate, glabrous, elliptic or oblong-elliptic, up to 7 cm long and 3 cm wide. The blades have an acute apex and a symmetrical base. The inflorescence cymes, lateral on branch shoots, are few flowered, with a yellow corolla tube up to 5 mm long. The fruits are paired in linear follicles and are horn-like. The seeds are oblong in shape, small (averaging, 7.4 mm in length and 1.8 mm in the middle), and pinkish, embedded in long silky hairs. Photos on these pages show the root and other plant parts of cryptolepis.
Dried cryptolepis has a sweet fragrance. The root, the plant part used for the treatment of malaria, varies from 0.4—6.6. cm long and 0.31—1.4 cm wide and has a bitter taste. The root surface is light to medium brown in color. The texture is hard and brittle, longitudinally rigid with occasional cracks and striations. Rootlets are not present. Cut roots show a bright yellow surface, as seen in the photo on this page.
Range and Habitat
Cryptolepis grows wild, but can be cultivated. Indigenous to Africa, the plant is found as a climbing liana in Central, Eastern, and West Africa.1,4-6,22-24 The plant is found in forest clearings as it grows commonly in dispersed open areas.25
Traditional Ethnobotanical Use
The plant has been shown to be important in West African traditional medicine.4,26 Aqueous extract of cryptolepis is used by the Fulani traditional healers in Guinea-Bissau to treat jaundice and hepatitis.1 In Zaire and the Casamance district of Senegal, infusions of the roots are used in the treatment of stomach and intestinal disorders.2,27 In Ghana, dried root decoctions of the herb, prepared by boiling the powdered roots in water, are used in traditional medicine to treat various forms of fevers, including malaria, urinary and upper respiratory tract infections, rheumatism, and venereal diseases.3,19,28 Cryptolepis is used in Congolese traditional medicine for the treatment of amoebiasis. An aqueous decoction of the root bark of cryptolepis is used in Congo for this treatment.5
The major alkaloid, cryptolepine, was first isolated from C. sanguinolenta in Nigeria29 and later in Ghana by Dwuma-Badu and his co-workers.22 According to Ablordeppey et al.,30 and Tackie et al.,31 this indoloquinoline alkaloid was isolated from the roots of C. triangularis, a plant native to the Belgian Congo and synonymous with C. sanguinolenta. Curiously, cryptolepine was first artificially synthesized in 1906 by Fichter et al., but naturally-occurring cryptolepine from C. triangularis isolated by Clinquart was reported 23 years later in 1929.7
In addition to cryptolepine, several related minor alkaloids and their salts have been isolated from C. sanguinolenta. These include the hydrochloride (although the hydrochloride salt of a chemical compound is usually not considered a distinct compound) and the 11-hydroxy derivatives of cryptolepine, cryptoheptine, iso- and neo-cryptolepine, quindoline, and the dimers biscryptolepine, cryptoquindoline, and cryptospirolepine.23,31,32 The dimers have been found to be less active than the monomers, and they include cryptosanguinolentine, cryptotakienine, and cryptomisrine.33,34
Cryptolepine, the major alkaloid in cryptolepis, is not the only alkaloid with biological/pharmacological activity. Almost all the minor alkaloids also have anti-plasmodial activity. However, the activities of these, based on the inhibition of the chloroquine-sensitive strain of the malaria parasite Plasmodium falciparum, are less than the activity of cryptolepine.35 Samples of cryptolepis contain cryptolepine at varying concentrations, and since the minor alkaloids also have biological activity, using the content of cryptolepine alone for standardization is questionable. Total alkaloidal content or high performance thin-layer chromatography (HPTLC) with densitometry would be the preferred analytical methods for standardization.
Biology and Pharmacology
Numerous biological/pharmacological activities have been demonstrated in extracts from the roots of C. sanguinolenta, as well as for the alkaloids isolated from these extracts. They include anti-plasmodial (both chloroquine-sensitive and chloroquine-resistant strains of the malaria parasite), anti-bacterial, anti-viral, anti-inflammatory, anti-diabetic and hypotensive effects, as discussed below and in the accompanying sidebar on Pharmacology. Aqueous extracts, which are normally used by traditional medical practitioners, have been shown to be less effective compared to ethanolic extracts in some of the studies showing activity against the malaria parasite35 and bacteria.26,36 The significance of these findings is presented in the sidebar on pharmacology.
In a preliminary study aimed at comparing efficacy of an aqueous extract of cryptolepis with that of chloroquine, G.L. Boye, of the University of Ghana, used the WHO extended seven-day in vivo test43 to measure P. falciparum response in a number of patients attending the outpatient clinic of the Centre for Scientific Research into Plant Medicine, a facility in Ghana where orthodox medical practitioners collaborate with traditional medical practitioners. Malarial patients with parasitemia of 1,000 to 100,000 P. falciparum parasites per 8,000 white blood cells, and negative for urinary chloroquine and sulphonamide were recruited into the study. The patients were given either aqueous extract of cryptolepis roots obtained by boiling root powder of the plant in hot water, in a dose as that prescribed by the local herbalist, or chloroquine according to the prescribed dose. After 7 days, the subjects were observed weekly for 3 weeks. The results of this open, randomized, comparative study indicated that the efficacy of cryptolepis in the treatment of malaria was comparable to that of chloroquine.21 All 22 patients in the study responded clinically and asexual parasitemia was cleared within 7 days. There was no recurrence of parasitemia during the follow-up period. The mean parasite clearance time in the 12 patients on cryptolepis extract was 3.3 days compared to 2.3 days in the 10 patients on chloroquine. Of significance in this trial is that the author states that the efficacy of the extract in this study was similar to that of chloroquine. The mean fever clearance time in the cryptolepis extract-treated group was 36 hours, compared to 48 hours for the chloroquine-treated group. Unlike patients in the chloroquine group, patients in the cryptolepis group did not require anti-pyretics (fever-reducing drugs).
More recently, another open label, uncontrolled clinical trial was conducted by Boye, which demonstrated the clinical efficacy of Phyto-laria®, a product of cryptolepis roots formulated as a tea for use in the treatment of acute uncomplicated malaria (Phyto-Riker Pharmaceuticals, Phytomedicine Division, Accra, Ghana).20 Phyto-laria is approved by Ghana’s drug regulatory agency, the Food and Drugs Board, and is packaged with instructions on the volume of boiling water to use per tea bag. A volume of approximately 150mls (one cup) of boiling water is to be added to one tea bag, which contains 2.5 g of cryptolepis root powder plus flavorings. The bag is to steep for 5—10 minutes to ensure adequate dosage. The product is also standardized using total content of alkaloids. Forty-six adult patients with simple uncomplicated malaria, confirmed by microscopy, were recruited for the study. Each patient was given one tea bag, for consumption 3 times a day for 5 days of treatment. The dose administered was based on that calculated from the decoctions prescribed by traditional healers. The results of this study indicated a mean parasite clearance time of 82.3 hours (24—144 hours). The mean fever clearance time was 25.4 hours (12—96 hours). These figures are comparable to those obtained with chloroquine in Ghana and elsewhere in West Africa.
Safety is one of the most important considerations for the assessment of any agent administered for treatment of a disease. Assessment of toxicity is therefore critical in research and development of phytomedicines. Cryptolepine is believed to interact with DNA13 and this could result in toxicity.
Evidence of DNA being the direct target of cryptolepine has been provided by Bonjean and his co-workers.42 Their work has shown that cryptolepine binds tightly to DNA. As is well known, DNA in the nucleus of living organisms exists as a double helix, two intertwined coils or helices. Some chemical compounds can insert themselves, or intercalate, between the two helices, thereby interfering with the functions of the DNA that depend on this unique double helical structure. One such function is cell division, preceded by replication of the nuclear material and separation of the two sets of nuclear material resulting from the replication. DNA replication occurs through nucleic acid synthesis, using one uncoiled strand of DNA as a template. The reactions responsible for replicating the nuclear material, must therefore involve uncoiling and recoiling of DNA, and are catalyzed by a set of enzymes including those responsible for the unwinding and relaxation of the DNA to remove the tightly coiled helices. One of these enzymes is known as topoisomerase, responsible for the interconversion between the relaxed and coiled forms of DNA. For this interconversion to take place, the DNA must be cut and then rejoined. Topoisomerase I cuts only one strand of the double-stranded DNA and topoisomerase II cuts both strands. When topoisomerases are inhibited, DNA replication ceases to occur. Cryptolepine has been shown to be a potent inhibitor of topoisomerase II. Its effect is to stop the cell from dividing and is probably the basis for its effect on microorganisms, including the malaria parasite. It is also the basis for it being regarded as a promising anti-tumor agent.42
There have been reports of toxicity of the aqueous extracts of cryptolepis and compounds isolated from the plant material when cell lines usually used to assess anti-tumor activity or in vitro methods of risk assessment were used.43 Cytotoxicity in anti-viral test systems has also been reported.44 In one study, cytotoxicity, measured as anti-tumor activity (against B16 melanoma cells) did not correlate with toxicity in the in vivo mouse model for malaria used in the same study.37 Phyto-laria, the cryptolepis product formulated as a tea, was evaluated in vivo by administering it orally to mice, rats, and rabbits and using the conventional acute toxicity and clinical chemistry tests. This tea bag formulation, which represents an aqueous preparation, was shown to be safe.45 The LD50 (lethal dose in which 50 percent of test animals died) obtained was above 2,000mg/kg, more than two orders of magnitude higher than the effective dose. It is noteworthy that Luo et al. report the use of cryptolepis extract as a tonic, often taken daily for years without evidence of side effects or toxicity.25
In new drug discovery from medicinal botanical preparations, most pharmaceutical companies would use an approach that relies on random, mostly in vitro, mechanism-based, high throughput screening, especially in the initial phases. This approach leads to the formulation of a drug based on a pure chemical compound isolated from a medicinal plant or a derivative of such a compound. An alternative pathway is based on ethnomedical information obtained mainly from traditional medical practitioners (TMPs) and unequivocal biological/pharmacological research results of a number of scientists and clinicians working on the products used by these TMPs. The latter approach is the one used by the Phytomedicine Division of Phyto-Riker, coupled with toxicity as well as clinical confirmatory tests. The scientific research that ought to be an important part of this alternative pathway is not merely to inject science into the art of healing that is practiced by indigenous people using medicinal plants, but also to make this art better serve the indigenous and other people.
As demonstrated in some of the research work on the biology/pharmacology of cryptolepis, the alcoholic extract is more effective compared to the aqueous extract that the people normally use. It would be worthwhile to carry out appropriate toxicity tests to ensure that the more effective ethanolic extract is just as safe as the aqueous extract, and that it does not extract from the plant compounds that are toxic to humans in addition to extracting more of the effective and safe compounds. When this has been done and the safety of the ethanolic extract assured, a better product could be formulated.
As shown in the accompanying Pharmacology article, cryptolepis, or compounds extracted from it, has antimicrobial properties, affecting a number of different microorganisms. In West Africa, where the plant originates, infections from microorganisms are rampant. Malaria is endemic in the sub-region as well. A phytomedicine that is capable of treating malarial and other infections could provide an excellent remedy for a whole host of diseases which afflict the majority of the people. It is for this reason that many local health professionals are keen on promoting scientific research efforts required for the development of such a remedy. Quality, safety, and efficacy are obviously key issues. Evaluation of these parameters should be conducted on the plant extract so that standardized remedies of plant materials can be produced without requiring processes that would make the remedy extremely expensive and unaffordable to a large number of people.
Marian Addy, PhD, is a Professor of Biochemistry at the University of Ghana and a Research Consultant for the Phytomedicine Division of Phyto-Riker.
*Complement is a group of proteins in the blood that, when fixed (i.e., combined with antibodies bound to the surfaces of foreign cells, including bacteria), triggers a precisely regulated cascade of reactions leading to destruction of these foreign cells or the antigen.
Pharmacology of Cryptolepis
In vitro anti-plasmodial activities, which are indicative of anti-malarial activity, have been carried out using inhibition of the incorporation of the malaria parasite into red blood cells.12,13,15,19,35,37 In one study in which both the chloroquine-sensitive D6 strain and the chloroquine-resistant K-1 and W-2 strains of the malaria parasite were used, the anti-plasmodial activity was measured using the incorporation of 3H-hypoxanthine into red blood cells infected with P. falciparum, the standard anti-plasmodial assay. Aqueous, alcoholic, and total alkaloidal extracts, and compounds isolated from the plant material were found to be effective against all three strains of parasite to varying degrees. Of the extracts, the total alkaloid was the most active with mean IC50 values of 47, 42, and 54 micromolar for the three strains, respectively, compared to values of 2.3, 72, and 68 micromolar, for chloroquine. The aqueous extract was the least active. Of the isolated compounds, cryptolepine was the most effective, with mean IC50 values of 27, 33 and 41 micromolar for the D6 chloroquine-sensitive and K-1 and W-2 chloroquine-resistant strains, respectively. Hydroxy-cryptolepine was the next best compound with IC50 values of 31, 45, and 59 micromolar, respectively, followed by neocryptolepine. Quindoline, or nor-cryptolepine, without the methyl group, was the least active anti-plasmodial of the isolated compounds.35 This is an indication that the methyl group contributes to anti-malarial activity, at least in part. The result of this study with respect to the K-1 strain is in agreement with the work of Noamesi and coworkers,15 as well as Kirby and coworkers,13 who reported the anti-plasmodial activity of cryptolepine against the multi-drug resistant K-1 strain of P. falciparum.
In another study, Wright et al., using multi-drug resistant K1 strain of P. falciparum and a method of assessing inhibition of parasite growth based on measurement of lactate dehydrogenase activity, showed that among a number of anhydronium bases, only cryptolepine, the major alkaloid in cryptolepis, had anti-plasmodial activity similar to that of chloroquine.19 The mean IC50 value, determined from linear regression analysis of dose-response curves, was 0.114 micromolar for cryptolepine, compared to a mean value of 0.2 micromolar for chloroquine diphosphate.
Inhibition of beta-hematin formation in a cell-free system is another in vitro test for anti-plasmodial activity. Reduction or elimination of the characteristic peaks of beta-hematin at 1663 and 1210 cm-1 in an infrared spectrum indicates efficacy. Cryptolepine has been shown to be effective in this model, the peaks disappearing when the reaction mixture was pre-incubated with the alkaloid,37 suggesting that cryptolepine’s anti-plasmodial effect depended, at least in part, on a quinine-like mode of action. A relatively simple method of measuring beta-hematin, using absorbance in a simple spectrophotometer, is currently being used in the Department of Biochemistry of the University of Ghana, and could be adopted for assessing the efficacy of extracts of cryptolepis and compounds isolated from them in a research and development effort to develop this particular phytomedicine.
Studies have been carried out to evaluate the anti-microbial properties of cryptolepis extracts and compounds isolated from them. In a program of biological evaluation to justify traditional uses of herbal remedies, cryptolepis was studied because of its successful use in treating diarrhea caused by intestinal amoebiasis, and found to be effective in vitro against Entamoeba histolytica.5 Diarrheal diseases are very common in West Africa and therefore, any anti-diarrheal remedy is of great interest. Over 100 strains of Campylobacter species, which are causative agents for gastroenteritis, have been used to study the effect of cryptolepis and compounds isolated from it on diarrheal bacteria.17 The finding that cryptolepine was more effective than co-trimoxazole and sulfamethoxazole, just as effective as ampicillin and less effective than erythromycin and streptomycin, the antibiotics usually used against diarrheal diseases, indicates that cryptolepis may be a potential remedy for diarrhea. The ethanolic extract, not the aqueous one, had activity but not as good as that of the isolated alkaloid. The effect of the plant material was not so dramatic when Vibrio cholerae, the causative agent for enteric infections, was used as the test organism. Obviously, cryptolepis could be used as therapy for gastroenteritis although it is not known as such in the region where it is used to manage a number of infections.
Out of 12 plants used in Guinea-Bissau traditional remedies to treat infectious diseases, only cryptolepis was found effective against Escherichia coli and nine out of 10 microbial test organisms used; only Pseudomonas aeruginosa was not susceptible.1 Ineffectiveness against P. aeruginosa was also reported in another anti-microbial screening study in vitro, using extracts as well as five alkaloids isolated from cryptolepis.26
Of all the isolated alkaloids, cryptolepine is the most active anti-bacterial agent, and it is more active against Gram-positive bacteria than the Gram-negative ones.28,38 Some of the minor alkaloids are also effective as anti-bacterial agents, including the hydrochloride,9 cryptoheptine, neocryptolepine, and biscryptolepine; cryptoquindoline was not active.38 The anti-bacterial actions of neocryptolepine appear to mirror those of the major alkaloid, cryptolepine.39 Cryptolepine also has some anti-fungal activity against Saccharomyces cerevisiae but not the Candida species.18 Its anti-fungal activity seems to be limited compared to its anti-bacterial activities.
Some pharmacological effects of cryptolepis, quite unrelated to the use of the plant in folkloric medicine, are its anti-inflammatory and anti-hyperglycemic properties. It has been more than two decades since the anti-inflammatory properties were established, as indicated by inhibition of carageenan-induced edema and that of platelet aggregation.8,16 (Carageenan-induced edema is a typical pharmacological test for antiinflammatory drugs; carageenan, a gelatinous preparation made from seaweed, is injected into parts, often the paw, of test animals to produce a localized inflammation – usually, the type characterized by accumulated fluids, i.e., edema. The tested agent is then measured for its ability to inhibit the resulting inflammation.) The anti-hyperglycemic property has been shown as enhanced insulin-mediated glucose disposal in a mouse model of diabetes and in an in vitro system using the 3T3-L1 glucose transport assay, indicating an effect on Type 2 diabetes.7,25 Hypotensive properties have also been reported, including effects on cholinergic nerve transmission, alpha-adrenoceptors, and muscarinic receptors.40,41 Malaria and other infectious diseases are more prevalent in the West African sub-region and therefore the anti-plasmodial and anti-bacterial properties of cryptolepis are more exciting. However, one should not underestimate the potential of cryptolepis in treating some of these other diseases.
1. Silva O, Duarte A., Cabrita J, Pimentel M, Diniz A, Gomes E. Antimicrobial activity of Guinea-Bissau traditional remedies. J Ethnopharmacol 1996;50:55-59.
2. Sofowora A. Medicinal Plants and Traditional Medicine in Africa. John Wiley and Sons. Chichester; 1982. p 221-3.
3. Boye GL, Ampofo O. Medicinal Plants in Ghana. In: Wagner and Farnsworth NR, editors. Economic and Medicinal Plants Research. Vol. 4. Plants and Traditional Medicine. London: Academic Press; 1990. p 32-3.
4. Oliver-Bever BEP. Medicinal Plants in Tropical West Africa. Cambridge: Cambridge University Press; 1986. p. 18, 41, 131, 205.
5. Tona L, Kambu K, Ngimbi N, Cimanga K, Vlietinck AJ. Antiamoebic and phytochemical screening of some Congolese medicinal plants. J. Ethnopharmacol 1998;61:57-65.
6. Irvine FR. Woody Plants of Ghana. London: Oxford University Press; 1961.
7. Bierer DE, Fort DM, Mendez CD, et al. Ethnobotanical-directed discovery of the antihyperglycaemic properties of cryptolepine: its isolation from Cryptolepis sanguinolenta, synthesis, and in vitro and in vivo activities. J Med Chem 1998;41: 894-901.
8. Bamgbose SOA, Noamesi, BK. Studies on cryptolepine II: Inhibition of carrageenan-induced oedema by cryptolepine. Planta Med 1981;41:392-6.
9. Boakye-Yiadom K, Herman Ackah SM. Cryptolepine hydrochloride: Effect on Staphylococcus aureus. J Pharmaceut Sci 1979;68:1510-4
10. Boye GL, Ampofo O. Clinical uses of Cryptolepis sanguinolenta (Asclepiadaceae). In: Boakye-Yiadom K, Bamgbose SOA, editors. Proceedings of the First International Symposium on Cryptolepine; 1983 University of Science and Technology. Kumasi, Ghana.
11. Cimanga K, De Bruyne T, Lasure A, Van Poel B, Pieters L, Claeys M, Vanden Berghe D, Kambu K, Tona L, Vlietinck AJ. In vitro biological activities of alkaloids from Cryptolepis sanguinolenta. Planta Med 1996;62: 22-7.
12. Grellier P, Ramiaramanana L, Milleriox V, Deharo E, Shrevel J, Frappier F. Antimalarial activity of cryptolepine and isocryptolepine, alkaloids isolated from Cryptolepis sanguinolenta. Phytother Res 1996;10:317-321.
13. Kirby GC, Paine A, Warhurst DC, Noamesi BK, Phillipson JD. In vitro and in vivo antimalarial activity of cryptolepine, a plant-derived indoquinoline. Phytother Res 1995;9:359-363.
14. Noamesi BK, Bamgbose SOA. Studies on cryptolepine: Effect of cryptolepine on smooth muscle contraction and cholinergic nerve transmission of isolated guinea pig ileum. Planta Med 1983;48: 48-51.
15. Noamesi BK, Paine A, Kirby GC, Warhurst DC, Phillipson JD. In vitro antimalarial activity of cryptolepine, an indoquinoline. Trans Roy Soc Trop Med Hyg 1991;85:315.
16. Oyekan AO, Botting JH, Noamesi BK. Cryptolepine inhibits platelets aggregation in vitro and in vivo and stimulates fibrinolysis ex vivo. Gen Pharmacol 1988;19:233-7.
17. Paulo A, Pimentel M, Viegas S, Pires I, Duarte A, Cabrita J, Gomes ET Cryptolepis sanguinolenta activity against diarrhoeal bacteria. J Ethnopharmacol 1994;44:73-77.
18. Sawer IK, Berry MI, Brown MW, Ford JL. (1995). The effect of cryptolepine on the morphology and survival of Escherichia coli, Candida albicans and Saccharomyces cerevisiae. J Appl Bact 1995;79:314-321.
19. Wright CW, Phillipson JD, Awe SO, Kirby GC, Warhurst DC, Quertin-Leclerq J, Angenot L. Antimalarial activity of cryptolepine and some other anhydronium bases. Phytother Res 1996;10:361-3.
20. Boye GL. Clinical efficacy of Phyto-Laria®: a formulation of Cryptolepis sanguinolenta - in uncomplicated malaria in Ghana (2002). An unpublished report of a study carried out to obtain clinical evidence of anti-malarial efficacy of the tea bag formulation of cryptolepis for registration with Ghana’s drug regulatory body, The Food and Drugs Board (FDB). FDB requires clinical studies on a product before registration.
21. Boye GL. Studies on antimalarial action of Cryptolepis sanguinolenta extract. Proceedings of the International Symposium on East-West Medicine;1989 October 10-11; Seoul, Korea. p. 243-51.
22. Dwuma-Badu D, Ayim JSK, Fiagbe NYI, Knapp PhE, Schiff Jr. PL, Slatkin DJ. Constituents of West African medicinal plants XX: Quindoline from Cryptolepis sanguinolenta. J Pharm Sci 1978;67:4339-434.
23. Paulo A, Gomes ET, Houghton PJ. New alkaloids from Cryptolepis sanguinolenta. J Nat Prod 1995;58:1485-91.
24. Watt JM, Breyer-Brandwijk MG. The Medicinal and Poisonous Plants of Southern and Eastern Africa. 2nd Edition. 1962.
25. Luo J, Fort DM, Carlson TJ, et al. Cryptolepis sanguinolenta: an ethnobotanical approach to drug discovery and the isolation of a potentially useful new antihyperglycaemic agent. Diab Med 1998;15:367-74.
26. Paulo A, Duarte A, Gomes ET. In vitro antibacterial screening of Cryptolepis sanguinolenta alkaloids. J Ethnopharmacol 1994;44:127
27. Kerharo J, Adam JG. La pharmacopee Senegalaise traditionnelle. Plantes medicinal et toxiques. Paris: Vigot et Freres; 1974. pp 632-3.
28. Boakye-Yiadom K. Antimicrobial properties of some West African medicinal plants. II. Antimicrobial activity of aqueous extracts of Cryptolepis sanguinolenta (Lindl.) Schlechter. Quart J Crude Drug Res 1979;17:78-80.
29. Gellert E, Raymond-Hamet, Schlittler E. Die Konstitution des Alkaloids Cryptolepin. (The structure of the alkaloid cryptolepine) Helv Chim Acta 1951;34:642-51.
30. Ablordeppey SY, Hufford CD, Borne RF, Dwuma-Badu D. 1H-NMR and 13C-NMR assignments of cryptolepine, a 3:4 benzo-d-carboline derivative isolated from Cryptolepis sanguinolenta. Planta Med 1990;56: 416-7.
31. Tackie AN, Boye GL, Sharaf MHM, et al. Cryptospirolepine, an unique spiro-nonacyclic alkaloid isolated from Cryptolepis sanguinolenta. J Nat Prod 1993;56:653-70.
32. Pousset JL, Martin MT, Jossang A, Bodo B. Isocryptolepine from Cryptolepis sanguinolenta. Phytochem 1995;39:735-6.
33. Sharaf MHM, Schiff Jr. PL, Tackie AN, Phoebe Jr. CH, Martin GE. Two new indoloquinoline alkaloids from Cryptolepis sanguinolenta: cryptosanguinolentine and cryptotackieine. J Heterocyclic Chem 1996;33:239-43.
34. Sharaf MHM, Schiff Jr. PL, Tackie AN, Phoebe Jr. CH, Johnson RL, Minick D. The isolation and structure determination of cryptomisrine, a novel indolo[3,2-b] dimeric alkaloid from Cryptolepis sanguinolenta. J Heterocyclic Chem 1996;33:789-97.
35. Cimanga K, De Bruyne T, Pieters L, Vlietinck AJ. In vitro and in vivo antiplasmodial activity of cryptolepine and related alkaloids from Cryptolepis sanguinolenta. J Nat Prod 1997;60:688-91.
36. Paulo A, Pimentel M, Viegas S, et al. Cryptolepis sanguinolenta activity against diarrhoeal bacteria. J Ethnopharmacol 1994;44:73-7.
37. Wright CW, Addae-Kyereme J, Breen AG, et al. Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents. J Med Chem 2001;44:3187-94.
38. Sawer IK, Berry MI, Brown MW, Ford JL. Antimicrobial activity of cryptolepine. J Pharm Pharmacol 1993;45:1108-11.
39. Cimanga K, De Bruyne T, Pieters L, et al. Antibacterial and antifungal activities of neocryptolepine, biscryptolepine and cryptoquindoline, alkaloids isolated from Cryptolepis sanguinolenta. Phytomed 1998;5:209-14.
40. Noamesi BK, Bamgbose SOA. The a-adrenoceptor blocking properties of cryptolepine on the rat isolated vas deferens: studies on cryptolepine. Part I. Planta Med 1980;39:51-6.
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