L Locally the latex is used as a rubber adulterant and is applied to carious teeth (Oliver, 1960).
C Since 1955 this plant has aroused considerable interest and has been the subject of numerous publications. From the bark of the stem and the root many alkaloids have been isolated (4-5% total alkaloids from the stembark and 5-10% from the rootbark). These include voacamine (the main alkaloid), voacangine, voacristine (= voacangarine), voacorine, vobasine, voacamidine (an isomer of voacamine) and many others. Most of these alkaloids have also been found in Voacanga thouarsi Roem. & Schult. and some in other species of Voacanga, Tabemaemontana and even Alstonia. In the leaves of V. africana voaphylline and vobtusine are found, and tabersonine is found in the seeds (Blanpin et al., 1961; Puisieux et al., 1965; Oliver-Bever, 1967).
P Voacamine and voacangine act on the heart in a similar way to the cardiac glycosides but their toxicity is very low in comparison with that of other alkaloids with a cardiostimulant action such as the Erythrophleum alkaloids. A dose of 100 /¿g of voacamine sulphate has a cardiotonic action equivalent to that of a dose of 0.25 units of digitalis standard (in isolated rabbit auricles) (Oliver-Bever, 1967). Voacamine does not bind to the cardiac proteins and has no cumulative action, but it has a direct myotonic effect on the cardiac fibre (Quevauviller and Blanpin, 1957a). Lethal doses for guinea pigs (by instillation in the jugular vein) are 313 mg/kg for voacamine sulphate and 348 mg/kg for voacangine sulphate, compared to 2.5 mg/kg for digitalin and 0.9 mg/kg for strophanthin. In mice the LDS0 of voacangine, given intravenously, is 41-42 mg/kg (La Barre and Gillo, 1955; Vogel and Uebel, 1961). Therapeutic doses (1-3 mg daily) are well tolerated, act rapidly and are quickly
Fig. 2.5. Voacanga africana Stapf.
Fig. 2.5. Voacanga africana Stapf.
eliminated without any cumulative effect. Voacamine, voacangine and voacorine also have a hypotensive action and are simultaneously mildly parasympatholytic and sympatholytic. Voacangine, which is also said to have analgesic and local anaesthetic action, and vobtusine increase the hypnotic effect of barbiturates. Voacorine is also cardiotonic through direct action on the heart muscle and on the coronary perfusion and seems to contribute considerably to the action of the total alkaloids of Voacanga (Quevauviller and Blanpin, 1957b). Its minimum LD50 in guinea pigs (by slow intravenous injection) is 228 mg/kg (Blanpin et al., 1961).
For the leaf alkaloid vobtusine, given intravenously, the LD50 is 33.75 mg/kg. Vobtusine has a depressive action on the heart and has hypotensive and sedative properties (Quevauviller et al., 1965). Tabersonine from the seeds has a hypotensive action which is equivalent to 25% of that of reserpine (Zetler, 1964).
(b) Cardiac depressants: anti-arrhythmic agents
Argemone mexicana L. (naturalized) (Fig. 2.6) PAPAVERACEAE
Mexican poppy, prickly pepper, prickly poppy L The plant is used in Nigeria and Senegal mainly for its diuretic, sedative, cholagogic and cicatrizing properties (Oliver, 1960; Kerharo and Adam, 1974). The seeds have a cannabis-like effect and in many countries the herb, juice and flowers are reputed to be narcotic (Watt, 1967).
Fig. 2.6. Argemone mexicana L.
Fig. 2.6. Argemone mexicana L.
C Numerous alkaloids have been reported to be present in all parts of the plant. Thus, leaves, stems and seeds contain berberine and protopine and the roots contain coptisine, a-allocryptopine, chelerythrine and dihydrochelerythrine. In the oil of the seeds sanguinarine and dihydrosanguinarine are found (Chakravarti et al., 1954; Bose et al., 1963). Argemonine was isolated from the leaves and capsules and identified as (—)A/-methy lpavine (Martell et al., 1963).
P a-Allocryptopine, (which represents 0.099%) of the roots of the plant in Czechoslovakia, is identical to a-fagarine. It slows down the heart rate and prolongs systole in rats and frogs. In doses of 10-20 mg/kg it also slows down the heartbeat of cats and rabbits. The action is a direct one on the myocardium and is also antifibrillatory, and a-allocryptopine has found clinical applications in this field. Thus it is considered more active than quinidine in cases of arrhythmias with fibrillation and auricular flutter (Alles, 1952; Dhar et al., 1968; Manske and Holmes, 1950-71, vol. 5, pp. 90-91).
Protopine was isolated from the total alkaloid fraction by Bose. He reported that it stimulated the heart, blood pressure and respiration, as well as the striated and smooth muscles on which it appears to act specifically (Manske and Holmes, 1950-71, vol. 5, pp. 92 and 138).
The seed oil is highly toxic due to sanguinarine (when given subcutaneously, the LD50 for mice is 1.8 mg/100 g). Sanguinarine can produce experimental glaucomas (Hakim, 1954).
Berberine is relatively non-toxic (when given intravenously, the LD50 in cats and dogs is 0.025 mg/100 g). In doses of 2 mg/kg, berberine has a depressant and vasodilating action on the heart. It also depresses breathing but stimulates the smooth muscles of different organs (intestine, uterus, bronchi). Moreover, berberine has marked antibiotic properties on Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Eberth typhosa and Shigella dysenteriae, and it also acts at concentrations of 1:80000, on Leishmania tropica (Lambin and Bernard, 1953). An alcohol-water extract of the fruits deprived of the seeds proved to be an excellent hypnotic and sedative for convulsions and spasmodic conditions (Martinez, 1959, p. 110). Antifibrillatory action has also been reported for oleandrin from Nerium oleander, described earlier under cardiotonics (Fauconnet and Pouly, 1962).
Zanthoxylum zanthoxyloides (Lam.) Watson syn. (Fagara zanthoxyloides Lam., F. senegalense (DC) Chev., Z. polyganum Schum.) RUTACEAE
Prickly ash, candlewood, toothache bark
L The aromatic rootbark is used in Ghana and Nigeria as a decoction, or in application, for its alleged antiseptic and analgesic properties, for example in the treatment of painful conditions, in childbirth, for toothache, etc., sometimes mixed with other ingredients. The decoction is also used as a vermifuge and in Guinea the bark is used to stupefy fish. The fixed oil contained in the rootbark causes salivation, a numbing action on the tongue and paralysis (Pobeguin, 1912; Irvine, 1930; Dalziel, 1937; Oliver, 1960).
C An amorphous alkaloid was isolated from the roots as early as 1887 and called artarine. (Later this was found to be identical with ethoxychelerythrine (Torto et al., 1969.) In 1911 a pungent principle which produced salivation was extracted from the rootbark (Thorns and Thumen, 1911). It was called fagaramide, and proved to be an N-isobutylamide of piperonylacrylic acid.
Since 1947 a number of tertiary and quaternary alkaloids have been identified in the bark and rootbark of Z. zanthoxyloides. These are, in addition to artarine, /3-fagarine (= skimmianine, a dimethoxydictamnine), fagaridine (= erythro-fagarine), angoline, angolinine, chelerythrine, dihydrochelerythrine, tembetarine, magnoflorine, N-methylcorydine. No a-fagarine (also called aegeline (from Aegle marmelos) = allocryptopine) was reported in West African species (Paris and Moyse-Mignon, 1947; Calderwood and Fish, 1966; Torto etal., 1969). The rootbark also contains fagarol (a lignan) and pseudofagarol, and in the fruits two coumarins, xanthotoxin and bergapten, were reported by Paris and Moyse-Mignon (1947). The leaves contain traces of alkaloids and a flavone heteroside.
P a-Fagarine is mainly extracted for pharmaceutical use from the leaves of the Argentinian Z. coco as it has proved to be a useful substitute for quinidine in auricular fibrillation. In some cases it has been found to normalize the sinus rhythm within 30 min and is so far the only Fagara base to be exploited in medical science. (Aegeline was considered to be a weak vasoconstrictor and in large doses a cardiac depressant (Paris and Moyse, 1967, p. 304).)
Xanthotoxin is ichthyotoxic in concentrations of only 0.1 p.p.m. and the pungent fagaramide has weak local anaesthetic action (Paris and Moyse-Mignon, 1947; Bowden and Ross, 1963).
An aqueous extract of the rootbark has further been reported to bring about a reversal of sickling and crenation in erythrocytes (Sofowora and Isaac-Sodeye, 1971; Murayama and Makyo, 1972). Later the antisickling compound was isolated and identified as 2-hydroxymethylbenzoic acid. On further investigation it was found that the greatest amounts of this acid were contained in the leaves, then in the stembark and lastly in the roots. Also the antisickling fractions varied among six different Nigerian Zanthoxylum spp. and also varied amongst parts of the same species (Isaac-Sodeye etal., 1975;Rumen, 1975; Sofowora et al., 1975).
From the roots of the Ghanaian species a new crystalline alkaloid was isolated in 1972 by Messmer et al. and called fagaronine. This benzophenanthridine alkaloid has a cytotoxic action, and is believed to be an inhibitor of RNA-directed activity in avian nucleoblastosis and in cases of infection by Rauscher leukaemia virus and Simian sarcoma virus, probably by preventing the elongation reaction (Messmer et al., 1972).
Fagara leprieuri (Guill. & Perr.) Engl., Zanthoxylum gillettii (de Wild.) Watson syn. (F. macrophylla Engl.) and Zanthoxylum rubescens (Planch, ex Hook, f.) Watson syn. (F. rubescens (Planch, ex Hook, f.) Engl.) are used in similar ways to Z. zanthoxyloides in local medicine. They also contain /3-fagarine (skimmianine), fagaridine, xanthofagarine, angoline, angolidine and a few other bases but so far no a-fagarine has been reported (Fish and Waterman, 1971, 1972).
Cinchona spp. (cultivated in the Cameroons and Guinea) RUBIACEAE
P One of the alkaloids of the Cinchona bark is used in cardiology. It is a dextrorotary stereoisomer of quinine, quinidine, which is used preferably as the sulphate, in the treatment of auricular arrhythmias as it has a specific depressant effect on the auricular muscle. It should, however, be reserved for the treatment of early persistent fibrillation as it is cumulative in action. Overdoses may cause extrasystole, paroxysmal ventricular tachycardia, ventricular fibrillation, intraventricular block and cardiac arrest (Martindale, 1969).
Rauvolfia vomitoria Afzel. syn. (R. senegambiae DC., Hylacium owariense P. Beauv.) (Fig. 2.7) APOCYNACEAE
P Ajmaline, one of the sympatholytic alkaloids of this plant (the others are discussed below under hypotensives), is chemically and pharmacologically closely related to quinidine. It is used in the treatment of arrhythmias as it slows down the rhythm and decreases myocardial excitability in doses of mg/kg without influencing the blood pressure. In clinical trials it produced a return to normal sinus rhythm in a high percentage of patients with multiple extrasystole and sinus tachycardia, but results
Fig. 2.7. Rauvolfia vomitoria Afzel.
Fig. 2.7. Rauvolfia vomitoria Afzel.
have been more uncertain for atrial fibrillation (Knipel et al., 1971; Lampertico,
1971). The maximum single dose should not exceed 50 mg and constant cardio-graphic control is required. The action of 10 mg of ajmaline (given intravenously) is approximately equivalent to that of 100 mg of prominamide (Puech et al., 1964).
Rauvanine (also in R. vomitoria) has an effect on the cardiovascular system similar to that of ajmaline (antifibrillatory, coronary dilating and slowing down the heartbeat), but it is non-sympatholytic and also has hypotensive action. It is only half as toxic as reserpine and is not ulcer producing (Quevauviller et al., 1963, 1971,
(c) Vascular agents
These can be divided into three groups:
(A) Hypotensive and some hypertensive plants. Some of the plants discussed in the sections on cardiotonics and cardiac depressants (above) were shown to act on the blood pressure. Haemodynamically the blood pressure depends on (i) the cardiac output and (ii) the peripheral resistance in the capillaries. The sympathetic system controls hypertension through the action of noradrenaline: stimulation of the a-receptors of the small arteries produces vasoconstriction while stimulation of the /3-receptors causes vasodilatation. In normal conditions the action on the a-receptors predominates over the action on the /3-receptors and a state of semi-contraction is maintained.
Hypotensive treatment can include a depletion of catecholamines in the postganglionic fibres of the sympathetic system as well as in the CNS. This is the case e.g. of reserpine. As an increase in blood pressure entails adaptation of glomerular filtration and maximum reabsorption of sodium, requiring an increase in sodium excretion, hypotensive treatment often includes administration of diuretics to produce sodium depletion.
(B) Plants containing compounds that are capable of increasing resistance and decreasing the permeability of capillaries and veins. These compounds are widely distributed in fruit and green leaves and are used on a large scale in capillary and venous insufficiencies. Their action, discovered by Szent Gyorgyi in 1936, was at first attributed to a compound called vitamin P, or sometimes vitamin C2. This consists of several constituents, also called bioflavonoids, which mainly belong to three groups:
(i) the coumarin or a-benzopyrone group, which includes aesculetol and its glycoside aesculoside;
(ii) the chromane group, including polyhydroxylated derivatives of phenyl-chromane or flavane (catechins, anthocyanins, leucoanthocyanins;
(in) the chromone or -y-benzopyrone group, comprising flavanone, flavanol, flavonol and their (polyhydroxylated) derivatives like the flavone derivatives quercitin (3, 3', 4', 5,7-pentahydroxyflavone), kaempferol (3,4', 5, 7-tetrahydroxyflavone), or the flavanones eryodictyol, naringetol and hesperetol.
These flavonoids increase the capillary resistance, have an antihistamine and antihyaluronidase action and can protect against radiation, the leucopenic effect of cytostatics and disorders due to an atherogenic diet. They have also been called citroflavonoids as they are found in the pericarp of citrus fruits and are extracted in large quantities from different plants (Sophora, Vaccinium leaves, Eucalyptus macror-rhyncha) for use in pharmacy. They appear to be well tolerated, no serious side-effects having been reported (Paris, 1971; 1977). A few of the plants reported to heal oedemas and piles in indigenous medicine may be found to contain bioflavonoids.
(C) Plants containing constituents which act more specifically on blood coagulation and formation. Some plants promote coagulation and are reputed to have a haemostatic action (group C,). Amongst the constituents responsible for this action there are some naphthoquinones closely related to vitamin K. In West Africa these are found in, for example, Lawsonia inermis and Diospyros mespiliformis. Vitamins K and K, (phytylnaphthoquinone) improve prothrombin formation and as a result hasten blood coagulation. Vitamin K is very easily prepared synthetically. Other plants are anticoagulants (group C2), inhibiting prothrombin formation, an action which could be attributed to dicoumarin in the case of dried Melilotus sativa in Europe, which produces a haemorrhagic syndrome in cattle. Yet other plants have an anti-anaemic action (group C3).
Most of the West African plants having a haemolytic action contain saponosides. Coumarin derivatives (calophyllide and inophyllide) are found in a plant introduced into West Africa, Calophyllum inophyllum Guttiferae, which increases capillary permeability and has anticoagulant properties (see Chapter 5).
Group Aj: hypotensives
Plants containing hypotensive alkaloids. Amongst these many indole and indoline alkaloids are found. Many of them act through the ANS or through the CNS and, as we will see, most of them are not only hypotensive but are also sympatholytic (yohimbine, akuammidine and corynanthine), sympathomimetic (eserine and Mit-ragyna and Hunteria alkaloids), local anaesthetic (Mitragyna alkaloids) or sedative (reserpine).
Rauvolfia vomitoria Afzel. (for synonyms see above) APOCYNACEAE
L Ghanaian and Nigerian healers use the rootbark, which in high doses is a powerful purgative and emetic, in cases of infantile convulsions, jaundice and gastrointestinal troubles. The latex or a decoction of the leaves is used in the treatment of parasitic skin diseases, head lice, etc. (Dalziel, 1937).
C Although a decoction of the root was used in 1936 by Shapara as a sedative in cases of maniacal symptoms, inducing several hours of sleep (see Dalziel, 1937), it was only in 1952 that the Rauvolfia species raised any considerable interest. This was after the isolation of reserpine, with its sedative and hypotensive action, from the Indian R. serpentina Benth. (Müller et al., 1952). Since then numerous alkaloids have been isolated from different Rauvolfia spp. and their pharmacological properties tested. From R. vomitoria rootbark, 4-8% of total alkaloids have been isolated, containing up to 1.7% of reserpine (which has to be separated from accompanying resins). The plant thus contains more reserpine than the Indian R. serpentina and is indicated in the 1968 British Pharmaceutical Codex and the 1968 British Pharmacopoeia as a source of reserpine. Harvesting is done by periodically cutting small pieces of root without uprooting the tree. Many other Rauvolfia alkaloids have now been isolated; they appear to belong to four main groups. In the first, the yohimbane group, m addition to reserpine, rescinnamine, seredine and yohimbine have been reported. In the second, the heteroyohimbane group, have been found reserpiline, raumitorine, alstonine (also in Alstonia), rauvanine and ajmalicine. In the third, the ajmaline group, ajmaline is the main alkaloid, and in the fourth, the oxindole group, rauvoxine. All these alkaloids are accompanied by a number of secondary alkaloids (Woodson et al., 1957; Patel etal., 1964; Delaveau, 1966). A complete and clear table of the numerous Rauvolfia alkaloids can be found in Kerharo and Adam (1974, p. 182). Mainly reserpine, rescinnamine, ajmaline, ajmalicine and reserpiline are extracted from the rootbark for therapeutic use by pharmaceutical firms.
From the seeds 2,6-dimethoxybenzoquinone, and from the leaves two flavone heterosides, 3-rhamnoglucoside and the 3-glucoside of kaempferol, have been isolated (Patel et al., 1964; Paris and Etchepare, 1967; Paris and Moyse, 1971).
P Reserpine has a hypotensive action in cases of hypertension and slows down the heartbeat. The alkaloid also has sedative and tranquillizing effects but is not hypnotic. It acts through the CNS and is active only in the presence of the hypothalamus and diencephalon and seems to act as an antimetabolite of serotonin and catecholamines, decreasing considerably the serotonin content of the nerve centres. This explains why, next to its use as a hypotensive agent in arterial hypertension, reserpine (given orally in 0.1-0.25 nig tablets) is currently used as a tranquillizer in anxiety states and in psychoses with hallucinations and delirium. Although it is not very toxic, the action of reserpine is cumulative and after prolonged administration side-effects like nasal congestion, bradycardia, oedema, stimulation of intestinal peristalsis and even ulceration are noticed (Woodson et al., 1957; Smith, 1963; Delaveau, 1966; Fattorusso and Ritter, 1967).
Rescinnamine and, in particular, reserpiline also have a hypotensive action. Reserpiline, representing up to 75% of the remaining alkaloids, produces, in contrast to reserpine, no digestive troubles or ulcers in rats, even in doses of 2 mg/kg. It has, however, no tranquillizing or hypnotic effects (La Barre and Gillo, 1958).
Ajmalicine, which also acts through the central nervous system, is a coronary and peripheral vasodilator and is used in angina pectoris and Raynaud's disease (Fattorusso and Ritter, 1967).
Raumitorine has a hypotensive action similar to that of reserpiline (La Barre and Hans, 1958) and does not act on the digestive tract. It has, however, to a certain extent, the tranquillizing effect of reserpine (La Barre and Demarez, 1958; La Barre and Gillo, 1958; La Barre et al., 1958). Rauvolfia macrophylla Stapf, R. caffra Sond. and R. mannili Stapf also contain alkaloids but are less common than R. vomitoria in tropical West Africa. Reserpine and ajmalicine (= vincaine = S-yohimbine) are also found in Catharanthus roseus, now mainly used for the extraction of antileukaemia principles (Oliver-Bever, 1971).
Picralima nítida (Stapf) Th. & H. Dur. syn. (P. macrocarpa Chev., Tabemae montana nítida Stapf, P. klaineana Pierre) APOCYNACEAE
L The seeds are eaten locally as a tonic and excitant and are used in the treatment of malaria and jaundice (Irvine, 1930; Dalziel, 1937). C They contain 3-5% of total alkaloids many of which have been identified. The main alkaloids are akuammine, akuammidine, and akuammigine, an isomer of ajmalicine. Some further alkaloids reported are pseudoakuammidine and akuammiline (indoline derivatives), akuammicine (indole derivative), etc. (Olivier et al., 1965; Pousset et al., 1965). From the leaves picraphylline and from the roots picracine and melinosiine have been isolated (Le Double et al., 1964). P Akuammine, the main alkaloid, has been found to be inactive in malaria both in pharmacological and clinical trials, but it is a powerful sympathomimetic and has a local anaesthetic action almost equal to that of cocaine (Raymond-Hamet, 1951; Paris and Moyse, 1971, p. 94).
Akuammidine has a sympatholytic action and a hypotensive effect which is weaker but longer lasting than that of yohimbine. Akuammidine also has a strong local anaesthetic action (three times that of cocaine hydrochloride) (Raymond-Hamet, 1944).
Holarrhena floribunda (Don) Dur. & Schinz var .floribunda syn. (H. africana DC., H. Wulfsbergii Stapf, Rondeletia floribunda Don) APOCYNACEAE
L Used in Ghana and Nigeria as an antipyretic and antidysenteric (Dalziel, 1937). C The stembark and rootbark of this small tree have been found to contain 1.2-2.44% and 2.5-3.8% of total alkaloids, respectively. Of these alkaloids at least 50% is
conessine, used mainly for its antibiotic action, which is not relevant here. Most of the main alkaloids of the bark are steroid alkaloids derived from conamine, whilst in the leaves alkaloids derived from pregnane (Janot et al., 1959) plus 0.6% of a non-steroid alkaloid, triacanthine (an adenine derivative), are found (Janot et al., 1959, 1960). Further acid phenols (p-hydroxybenzoic, protocatechuic and p-coumaric acids) are found in the leaves of Holarrhena and quercetol and kaempferol flavonols are found in the leaves and seeds (Paris and Duret, 1973).
P Many of the steroid alkaloids derived from conamine, holarrhenine (Fig. 2.8a) or pregnane (Fig. 2.8Z>), like holarrimine, holaphyllamine and holaphylline, have a hypotensive action and are simultaneously local anaesthetic and spasmolytic. Triacanthine also has a hypotensive action, but while conessine, holarrhenine, etc., are cardiotoxic, triacanthine has a cardiotonic action on the heart of the rabbit in doses of 1/30 of the LD50. It produces an important and long-lasting vasodilatation of the coronary arteries and is, in addition, antispasmodic and respiratory analeptic (Quevauviller and Blanpin, 1961). For this reason Foussard-Blanpin et al. (1969) considered the possibility of its clinical use for cardiovascular disorders.
In addition, triacanthine appears to stimulate erythropoiesis and has been observed to act on experimental anaemia in rabbits (Foussard-Blanpin et al., 1969) (see also under plants with antibiotic and antiparasitic action).
Hunteria eburnea Pichon syn. (Picralima gracilis Chev.) APOCYNACEAE
Hunteria elliotii (Stapf) Pichon syn. (Picralima elliotii (Stapf) Stapf, Polyadoa elliotii (Stapf) Pichon)
Hunteria umbellata (Schum.) Hallier syn. (Carpodinus umbellatus Schum., Picralima umbellata (Schum.) Stapf, Polyadoa umbellata (Schum.) Stapf)
L The bark of H. umbellata is used in Sierra Leone and the Ivory Coast as a bitter tonic and febrifuge (Dalziel, 1937).
C The stembark and rootbark of all three species have a closely related chemical composition. They mostly contain indole alkaloids with cardiovascular effects. In 1978 Le Men and Olivier identified 34 alkaloids in H. eburnea of which 18 were in the bark, 9 in the leaves and 7 in the seeds. In H. elliotii the authors reported 26 alkaloids of which 7 were in the bark, 12 in the leaves and 7 in the rootbark. Amongst the bark alkaloids eburnamonine, eburnamine, hunterine, vincadifformine, isobur-namine and eburnamenine were found, whilst in the leaves of both species corymine and acetylcorymine, were reported. The leaves of H. elliotii also contain tetra-hydroalstonine (Morfaux et al., 1978). Eburnamonine and eburnine are also found in the seeds (Bartlett and Taylor, 1963; Bartlett et al., 1959, 1963; Renner, 1963).
P Eburnamonine, eburnamine and hunterine are sympathomimetic and have a strong and lasting hypotensive action (Raymond-Hamet, 1955). Morfaux et al. (1969) suggest that the hypotensive properties are mainly due to hunteramine (a quaternary ammonium compound) and that eburnamonine seems to have a favourable effect on the circulation in general. Vincamonine, which is less toxic than its antipode eburnamonine, has recently been introduced in pharmacy (Le Men and Olivier, 1978).
Pausinystalia johimbe (Schum.) Pierre ex Beille syn. (P. macroceras Kenn., Corynanthe johimbe Schum.) RUBIACEAE
L The longitudinally fissured bark of the trunk of this tall forest tree is considered in the Cameroons to be an aphrodisiac and stimulant (Dalziel, 1937).
C The bark of the tree contains the alkaloids yohimbine, mesoyohimbine and yohim-binine as well as corynanthine (closely related to yohimbine but less toxic and more active as a sympatholytic agent), alloyohimbine and ajmalicine (which has a vasodilating effect on the coronary arteries, as mentioned earlier). The bark is used to extract yohimbine; the main stem gives the best material but is not rich in alkaloids until the tree is 15-20 years of age when it can contain 2-15% (Holland, 1929; Paris and Letouzey, 1960; Poisson, 1964).
P Yohimbine is sympatholytic and hypotensive and has a local anaesthetic action similar to that of cocaine but it is not mydriatic (see Oliver, 1960). It is given in cases of atherosclerosis as it dilates the walls of the small peripheral arteries, thereby increasing the flow of blood and decreasing the blood pressure. It is interesting to note that its action differs from that of reserpine, which is also hypotensive but not sympatholytic.
The vasodilating action of yohimbine is particularly strong on the sex organs, hence its aphrodisiac action. It is mainly used in the form of the hydrochloride, which was in the British Pharmaceutical Codex in 1949, in the French Codex 1949 Table A, and in the Pharmacopoeia Helvetica, 1949 (5-20 mg daily) (Raymond-Hamet and Goutarel, 1965).
Corynanthe pachyceras Schum. syn. (Pausinystaliapachyceras (Schum.) de Wild., Pseudocinchona africana Chev. ex Perrot) RUBIACEAE
C The bark of the tree is used on the Ivory Coast as an aphrodisiac and antipyretic. It contains corynanthine, the closely related corynanthidine and corynantheidine and several other alkaloids (Poisson, 1964).
P Corynanthine is 4-5 times less toxic than yohimbine whilst its sympatholytic effects are twice as strong (Steinmetz, 1976). It has mild local anaesthetic action, inferior to that of cocaine.
Mitragyna inermis (Willd.) Ktze. syn. (M. africana (Willd.) Korth, Uncaria inermis Willd., Nauclea africana Willd.) RUBIACEAE
Mitragyna stipulosa (DC.) Ktze. syn. (Nauclea stipulosa DC., M. macrophylla Hiern)
L The bark and leaves of both species are used in Nigeria, Guinea and the Ivory Coast for fever and diarrhoea and also as a diuretic and analgesic (Pobeguin, 1912; Raymond-Hamet and Millat, 1934; Kerharo and Bouquet, 1950). The wood is used in Nigeria for carving small objects as it is easy to work (Dalziel, 1937).
C The oxindole alkaloids rhynchophylline and rotundifoline have been reported to be present in the leaves and in the bark of the stem and roots of both M. inermis and M. stipulosa (Ongley, 1953; Shellard and Alam, 1968). At first Raymond-Hamet and Millat (1934) had named an alkaloid they isolated from M. inermis 'mitrinermine', but it could be shown by Badger et al. (1950) that this alkaloid, when purified, was identical with rhynchophylline, isolated earlier by these authors from M. stipulosa. From M. stipulosa another oxindole alkaloid, mitraphylline, has also been obtained whilst in M. inermis speciophylline was also found (Beckett et al., 1963; Shellard and Sarpong, 1969; Shellard et al., 1976). A bitter heteroside, quinovin, which can be split into quinovic acid and quinovose has been isolated from M. inermis as well (Badger et al., 1950; Beckett et al., 1963).
In order to try to understand the biogenesis and translocation of these alkaloids, the alkaloid distribution of three West African Mitragyna spp. was studied by Shellard and Sarpong (1969; 1970). In the above-mentioned species as well as in M. ciliata Aubrev. and Pellegr., the main stembark and rootbark alkaloid is rhynchophylline and in M. stipulosa and M. ciliata the principal leaf alkaloid is rotundifoline while in M. inermis it is isorhynchophylline. The authors conclude that it would appear that the alkaloids are synthetized in the leaves and that conversion of the leaf oxindoles (by dehydroxylation of rotundifoline to rhynchophylline) takes place in the leaves before translocation to the root (Shellard and Sarpong, 1970). The leaves of an Asian species of Mitragyna, M. speciosa, contain in addition to other alkaloids mitragynine (methoxycorynantheidine), a hallucinogenic agent (Tyler, 1966).
P Already in 1932 Blaise had reported the occurrence of a hypotensive alkaloid in Mitragyna spp. It was confirmed later that rhynchophylline, mitraversine and mitraphylline lower the blood pressure by decreasing the rhythm of the heart (Xiao, 1983), and that they also have a local anaesthetic action. Further, these alkaloids strongly stimulate intestinal and uterine contractions and are toxic to protozoa (Massion, 1934; Caiment-Leblond, 1957; Ansa-Asamoa, 1967).
Cryptolepis sanguinolenta (Lindl.) Schltr. syn. (Pergularia sanguinolenta Lindl., C. triangularis N.E.Br.) PERIPLOCACEAE
L In Nigeria the macerated roots are used for gripe (colic) as a tonic and sometimes in rheumatism and urogenital infections (Boakiji Yiadom, 1979).
C The roots contain a quinoline-derived indole alkaloid, cryptolepine, which is violet in colour, producing yellow salts (Gellert etal., 1951).
P Cryptolepine has a marked hypothermic effect; it also induces prolonged and important vasodilatation, causing marked and durable hypotension (Raymond-Hamet, 1937, 1938). It has a low toxicity (120 mg/kg produce death in guinea pigs about 12 h after administration). An aqueous extract of the root has antimicrobial activity against three urogenital pathogens (Boakiji Yiadom, 1979).
Physostigma venenosum Balfour FABACEAE
L The poisonous effect of the Calabar bean in trials is caused by its strong sedative action on the spinal cord which results in paralysis of the lower limbs and death by asphyxia, and, in large doses, in paralysis of the heart. It is used by the Bakwiris with other drugs in the local treatment of articular rheumatism (Dalziel, 1937).
C From the seeds an alkaloid, physostigmine or eserine, is obtained (0.15%); in addition, the beans contain geneserine or eseridine and several other alkaloids like eseramine and physovenine (which is also myotic) (Robinson and Spitteler, 1964).
P Eserine is mainly used in ophthalmic medicine for its myotic action (1-2 drops of a 1:1000 physiological solution: British Pharmacopoeia, 1934, British Pharmaceutical Codex, Italian Pharmacopoeia, French Pharmacopoeia, 1949, Pharmacopoeia Helvetica, etc.), but it also dilates peripheral blood vessels and slows the pulse. The alkaloid acts by inhibition of cholinesterase, thus allowing acetylcholine to exert its full effect on the smooth muscles, glands and heart. Being antidotal to strychnine, nicotine, curare and atropine, it was used in myasthenia gravis to improve peristalsis in post-operative intestinal atony, but has been replaced by synthetic neostigmine (Martindale, 1969).
Eseridine is used in dyspepsia and as eye drops in glaucoma (Oliver, 1960; Paris and Moyse, 1967, Vol. 2). The solutions must be protected from air, light and moisture; their oxidation can be delayed for some time by adding ascorbic acid (Swallow, 1951).
Thalictrum rhynchocarpum Dill. & Rich. RANUNCULACEAE
C The roots of most Thalictrum spp. contain alkaloids of the berberine group with an aporphine nucleus, such as thalictrine (= magnoflorine), as well as flavonoids.
P Some Thalictrum alkaloids like thaliadine, adiantifoline and thaliadanine from T. minus and an alkaloid fraction from T. revolutum DC. have a powerful and prolonged hypotensive effect (at 2 mg/kg) in dogs, cats and rabbits. Further, thaliadanine is antimicrobial to Mycobacterium smegmatis (Patel et al., 1963; Wan Tra Liao et al., 1978).
Thalicmine (ocoteme) hydrochloride is also hypotensive in dogs and cats (1-2 mg/ kg given intravenously) and inhibits the blood pressure response to adrenaline at 1-3 mg/kg. Detailed information about the constitution of the West African species was not available in 1976 (Farnsworth and Cordell, 1976); none seems to have become available since then.
Carica papaya L. CARICACEAE
L Originating from Tropical America, this tree is extensively grown for its fruit. In West Africa the plant is mainly used as a diuretic (roots and leaves), anthelmintic (leaves and seeds) and to treat bilious conditions (fruit) (Dalziel, 1937).
C The milky sap of the unripe fruit yields a complex proteolytic enzyme, papain, which is not destroyed by heating. The crude papain consists of two crystallized enzymes, papain and chymopapain, as well as tryptophan, tyrosine and cysteine, which all seem to be part of the crude enzyme preparation. The enzyme has peptidase, coagulase (acting on milk casein), amylase, pectase and lipase action (Kerharo and Adam, 1974). Vitamins and traces of an alkaloid have also been found in the latex. This alkaloid from the pyridine group, called carpaine, has also been reported in other parts of the plant and particularly in young leaves (0.28%) (Bevan and Ogan, 1964). The seeds contain, apart from fixed oils, carbohydrates, etc., carpasemine (a benzylthiourea), benzyl senevol and a glucoside (Manske and Holmes, 1950-71, vol. 11, p. 491; Watt and Breyer-Brandwijk, 1962). Papain has an anticoagulant effect. Intravenous injection of a purified extract in the dog (2 mg/kg) increases prothrombin and coagulation time threefold; an anticoagulant action has also been noticed in rabbits, rats and mice, the maximum effect being achieved half an hour after the injection (Chandrasekhar et al., 1961). Standardization of the enzyme has been suggested (International Commission for the Standardization of Pharmaceutical Enzymes, 1965). The maximum dose tolerated by rats and mice was found to be 50 mg/kg, while a therapeutic action was observed with doses of 1-2 mg/kg. Acute toxic effects at higher doses were similar to those observed with heparin (Chandrasekhar et al., 1961).
The enzyme is also used as a digestive enzyme in dyspepsia and digestive troubles (British Pharmaceutical Codex, 1950, French Pharmacopoeia, 1949, Indian Pharmacopoeia) and has also been used successfully in peritoneal instillation to avoid adherences. In addition, it is claimed to eliminate necrotic tissues in chronic wounds, burns and ulcers (Ravina and Wenger, 1957; Rigaud et al., 1956).
(Crude papain is of considerable commercial importance. In addition to its pharmaceutical applications, great quantities are used in the brewing industry (chill-proofing beer), in the food industry (in pre-cooked foods and in meat-tenderizing preparations), and in the manufacture of chewing gum. It also finds application in the textile industry (shrinkage resistance and other treatment of wool and wool-containing materials), and in the rubber industry to season latex (Oliver, I960).)
In small doses carpaine slows down the heart and thus reduces the blood pressure. Higher doses produce vasoconstriction. In addition the alkaloid has a spasmolytic action on the smooth muscles (Henry, 1949).
In humans, carpaine hydrochloride, given orally in doses of 0.01-0.02 mg/day or given subcutaneously in doses of 0.006-0.01 mg/day has a digitalis-like action and Noble (1947) recommends its use in hypertension.
Anthelmintic and amoebicide actions of the alkaloid have been reported (Kerharo and Bouquet, 1950; Kerharo and Adam, 1974), and the seeds are also considered to be anthelmintic and carminative (Dar et al., 1965).
Plants containing hypotensive non-alkaloidal constituents.
Anacardium occidentale L. ANACARDIACEAE
The cashew tree, native of tropical America, is widely cultivated, its kernels and fruit being much appreciated. In Nigerian local medicine the astringent infusion of the bark and leaves is used as a lotion and mouthwash to relieve toothache and sore gums and is given internally in dysentery (Dalziel, 1937).
C The gum exuding from the bark is a mixture of bassorin and true gum (Dispensary of USA, 1955). Cashew 'balsam' is composed of anacardic acid and its decarboxy-lated derivates, anacardol, cardol and gingkol, which are aromatic phenols.
In the leaves, polyphenols (chiefly hydroxybenzoic acid) and flavonoids which are heteromonosides (glucoside, rhamnoside, arabinoside or xyloside) of kaempferol and in particular quercetin were found by Laurens and Paris (1976) and by Attanasi and Caglioti (1970).
P Ingestion of extracts of the leaves and bark has been found to reduce hypertension and hyperglycaemia to normal values. The effects are believed to be due to peripheral vasodilatation. The hypotensive effect was observed first in rats with three different forms of experimental hypertension (Giono et al., 1971) (see also under plants with antibiotic and antiparasitic action).
Morinda lucida Benth. syn. (Morinda citrifolia Chev.) RUBIACEAE
L Stem, bark, roots and leaves are bitter and astringent and are used in Nigeria in the treatment of fever, malaria, yellow fever, jaundice and dysentery (Dalziel, 1937; Oliver, 1960).
C Tannins, methylanthraquinones and a heteroside, morindin, have been reported in M. lucida and allied species (M. geminata DC.) in varying amounts according to the species and the geographical origin of the plant (Caiment-Leblond, 1957).
P The use of a total extract of leaves and stembark of M. lucida is recommended by Dang Van Ho (1955) for the treatment and prevention of hypertension and its cerebral complications. Purified extracts produced a strong hypotensive action which, however, when compared to the action of Rauvolfia vomitoria, proved to be of shorter duration. Further, the extract showed a distinct diuretic and a slight tranquillizing effect. In view of the complete absence of toxic side-effects, permitting the use of strong and frequent doses, La Barre and Wirtheimer (1962) consider that M. lucida may be very useful when strong doses are required to initiate the treatment of hypertension. M. lucida bark and leaves have been proved to be effective in the treatment of jaundice, thus justifying one of its local uses (Guedel, 1955).
L Garlic is widely cultivated and finds broad applications in northern Nigeria (respiratory and infectious diseases, worms, skin diseases, etc.) (Oliver, 1960).
C The strong-smelling juice of the bulbs contains a mixture of mono- and polysul-phides. The main compound of these is allicin (diallyl disulphide oxide) which is the result of spontaneous enzymatic degradation of alliin (S-allylcysteine sulphoxide). Allicin is unstable and decomposes into polysulphides (Schulz and Mohrman, 1965; Augusti, 1974, 1975, 1976a, b).
P The hypotensive effect in arterial hypertension of a tincture of garlic (20-25 drops daily) is attributed to allicin. This constituent is also antidiabetic and bacteriostatic (Bhandari and Mukerjee, 1959; Jain and Vyas, 1974). For more details on Allium see Oliver-Bever and Zahnd (1979).
Sapindus trifoliatus L. SAPINDACEAE
L A native of tropical Asia, the plant is naturalized in many areas of West Africa. It is used as a fish poison in India (Singh et al., 1978).
C The fruit of S. trifoliatus contains saponins. Hederagenin-heterosides have been identified by Takagi etal. (1980).
P Alcoholic extracts showed, when injected intravenously in cats in doses of 10-20 mg/ kg, a dose-dependent decrease in blood pressure and heart rate. Tests demonstrate the direct action of the drug on the vascular smooth muscles to produce a hypotensive effect (Singh etal., 1978).
Mostuea hirsuta (Anders, ex Benth.) Baill. ex Bak. LOGANIACEAE
C The roots of related M. stimulans and M. buchholzii Engl, contain indole alkaloids identical to, or closely related to sempervirine and probably gelsemine. The alkaloid content of M. hirsuta seems poor (0.2%) in the roots (Bouquet, 1975). The LD50 of these alkaloids in guinea pigs is 15.4 mg and 250 mg, respectively (Paris and Moyse-Mignon, 1949b; Gellertand Schwartz, 1951).
P In mice 600 mg of alkaloids per kg of body weight, given subcutaneously, produced agitation and convulsions followed by death. The alkaloids were found to be analgesic and cardiac depressant, stimulating respiration in small doses. They can cause death through respiratory paralysis in higher doses, sempervirine being the most toxic of the two. In the chloralosed dog a dose of 0.1-0.2 g of an extract of the root of M. stimulans produces a prolonged fall in blood pressure and after a short spell of tachycardia, cardiac and respiratory depressant effects (Chevalier, 1947).
It appears that the Mostuea spp. that were investigated, and no doubt also M. hirsuta, have similar properties to Gelsemium and are used for the same indications as this (Paris and Moyse, 1971, Vol. 3; Kerharo and Adam, 1974).
Adenia cissampeloides (Planch, ex Benth.) Harms syn. (Modecca cissampeloides Planch, ex Benth., Ophiocaulon cissampeloides (Planch, ex Benth.) Mast)
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