Issue: 60 Page: 54-59,67
Cryptolepis: An African Traditional Medicine that Provides Hope for Malaria Victims
by Marian Addy
HerbalGram. 2003; 60:54-59,67 American Botanical Council
Cryptolepis: An African Traditional Medicine that Provides Hope for Malaria Victims
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.21
Unlike 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.
Description
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
Chemistry
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.
Clinical Trials
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
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
Concluding Remarks
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.
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