C Oxindole and bis-indole alkaloids have been reported in S. usambarensis. Alkaloids of this type were formerly known in certain species of Rubiaceae and Apocynaceae but their presence has now been detected in Loganiaceae. The alkaloids found in the bark and leaves of 5. usambarensis in the Congo have been identified as harmine, strychnofoline, 2-isostrychnofoline, strychnophylline and isostrychnophylline. In addition, the presence of 18,19-dihydro-usambarine, usambaridine and their dihydro-derivatives strychnobaridine, strychnopentamine and isomers has been reported (Angenot, 1978; Angenot etal., 1970,1973,1975,1978a, b). Usambarine, usambaridine and strychnambarine have been isolated from the leaves, the two former are indole alkaloids biogenetically derived from two tryptamines and one monoterpene (Koch et al., 1973).
P The indole alkaloids showed both convulsant and curarizing muscle relaxant activity (Angenot etal., 1970,1975).
Strychnos dolichothyrsa (Gilg) Onochi & Hepper LOGANIACEAE
C In the stembark of this climber, the following alkaloids were found: bisnordihydro-toxiferine, bis-nor-C-curarine, bis-nordihydrotoxiferine-N-oxide, and bis-nordihydrotoxiferine-di-iV-oxide (Verpoorte and Svendsen, 1976; Verpoorte, 1980, 1981). In the stems and leaves only traces of alkaloids were found (Bouquet, 1970).
P From the stembark of Strychnos decussata, a tertiary alkaloid has ben isolated which has a pronounced muscle relaxant activity both in vivo and in vitro. The blockade effect of this alkaloid, decussine, is not antagonized by synstigamine (Bisset and Phillipson, 1970, 1973; Olaniji and Rolfsen, 1980; Rolfsen et al., 1980a, b).
Strychnos spinosa Lam. syn. (5. lokua A. Rich., 5. laxa Solered., 5 buettneri Gilg, 5. spinosa var pubescens Bak., 5. djalonensis Chev.) LOGANIACEAE
L Locally this species is used mainly in colitis, entero-colitis and diarrhoea (roots and bark); the root powder is sold in the markets in Senegal as a stomachic (Oguakwa et al., 1980).
C Lofgren and Kinsley (1942) found no alkaloids in the seeds, stems and leaves and the different parts of the plant were found to be non-toxic to mice and guinea pigs. More recently, Mathis and Duquenois (1963) found, by using two-dimensional thin-layer chromatography, 0.009% of alkaloids in the pericarp and 0.012% in the fruit plus seed. In 1980, Oguakwa et al. reported the presence of akagerine and 10-hydro-
xyakagerine in the leaves. Akagerine had already been reported in S. panamensis (Marini Bettolo etal., 1970). P The toxicity of the plant appears to be very low. Verpoorte and Bohhn (1976) report only weak muscle relaxant effect.
L The plant, which is found in Liberia, Ghana, Guinea and the Ivory Coast, is used in local medicine in the treatment of diseases of the mouth, the kidneys and the heart (Oguakwa et al., 1980). C Traces of alkaloids have been found in the leaves but they are more abundant in the bark. In the stembark, ellipticine has been found as the main alkaloid. It is the first time that a non-corynane, strychnine-type of alkaloid has been isolated from a Strychnos sp. (Michel et al., 1980). Akagerine and derivatives were also found in S. dinklagei (Oguakwa etal., 1980). P Ellipticine had been shown to have slight convulsive properties (Sandberg et al., 1971; Verpoorte and Svendsen, 1976). Fractionation led to the discovery of five alkaloids with a convulsive action. In addition to the already known akagerine, four new indole alkaloids were isolated including O-methylakagerine, which produced strychnine-like convulsions but which is less potent than akagerine (Verpoorte and Bohlin, 1976; Oguakwa et al., 1980).
Dioscorea dumetorum (Kunth) Pax. syn. (Helmia dumetorum Kunth, Dioscorea buchholziana Engl.) DIOSCOREACEAE
Bitter yam or cluster yam L The tuber is used as a food only in cases of scarcity and requires to be sliced and steeped long before use to eliminate the poisonous alkaloid dioscorine, which produces CNS paralysis. It is said to have caused death when eaten during famine in the Sudan. In Senegal, the tuber is sometimes used externally as a rubefacient. C The dried tubers contain, besides dioscin, the genin of which is diosgenin, small quantities of other steroid sapogenins and a convulsant alkaloid, dihydrodioscorine (Bevan et al., 1956; Bevan and Hirst, 1958). Nigerian yams also contain 83.3% of glucides and 9.9% of proteins. Diosgenin has been much used as a starting compound in the synthesis of hormones, corticosteroids, etc. (Oliver-Bever, 1972). P The LD50 in mice of a water-soluble extract of the tubers from the Congo (containing 6.2% of dihydrodioscorine) is 15.5 mg/20 g, and the convulsant dose ED50 is 12.5 mg/20 g. In the cat, the extract produces a long-lasting hypotension when injected intravenously in doses of 100 mg/kg. The total extract produces a contraction of the smooth muscle fibres of the intestine both in vivo and in vitro (Bevan et al., 1956). In small doses (30 mg/kg) in the cat or monkey, Schlag et al. (1959) have noted a desynchronization of the cortical electrical record lasting over 0.5 h. With higher doses (200 mg/kg) there are progessive convulsive impulses preceded each time by an increase in the arterial pressure and of the intestinal peristalsis which, according to the authors, indicates an excitant action of the drug on the cerebral cortex. In mice the LD50 of dioscorine is 65 mg/kg. Dioscorine produces first clonic then tonic convulsions and in concentrations of 10~5 M it reduces the response to acetylcholine of the isolated intestine of the cat and of the duodenum of the rabbit (Bevan et al., 1956). Dioscin is less toxic; the LD50 is 100 mg/kg in mice. It has a picrotoxin-like convulsive action and the effect on the blood pressure of the cat and on the isolated ileum of the guinea pig is distinct although less pronounced than that of dioscorine (Broadbent and Schnieden, 1958; Correia da Silva et al., 1962).
Afrormosia laxiflora (Benth. ex Bak.) Harms syn. (Ormosia laxiflora Benth. ex Bak.) FABACEAE
L The local medicinal uses of the leaves, bark and roots of Afrormosia are based on their analgesic and antipyretic actions. The root is said to increase the intoxicating effect of palm wine, and to be slightly intoxicating if taken by itself. The plant was formerly used in arrow poisons and as an ingredient in a complex prescription taken to impart strength or stimulus 'when undertaking a journey or other enterprise' (Dalziel, 1937).
C The stembark of the Nigerian plant contains 6.7% of total bases including six alkaloids. The three main alkaloids are non-quaternary; the main constituent of these is Af-methylcytisine (a quinolizidine derivative), a second is probably ammodendrine. Three minor alkaloids are also non-quaternary and a quaternary fraction is almost entirely composed of choline (Bevan and Ogun, 1964). In the heartwood of the related A. elata, afrormosine (a dimethoxyhydroxyflavone) has been reported, and in the bark catechuic tannins (Caiment-Leblond, 1957). The related Ormosia dasycarpa Jacks, and O. coccinea Jacks, contain two alkaloids, ormosine and ormosinine, which have a physiological action smaller than that of morphine (Caiment-Leblond, 1957).
P AT-Methylcytisine is very toxic to mice, which can only tolerate a dose of 1 mg, producing long-lasting sedation. Higher doses (4 mg) produce severe ataxia and convulsions followed by death within 5 min. In anaesthetized rabbits doses of 2 mg produce a prolonged increase in blood pressure (Raymond-Hamet, 1954; Bevan and Ogun, 1964). The constituent appears to have a cytisine-like action, paralysing the ganglia after a short stimulation.
Tinctures of the rootbark and the isolated total alkaloids show a distinct hypertensive action when injected intravenously to the chloralosed dog (Kerharo and Bouquet, 1950; Caiment-Leblond, 1957). Tests on cytotoxicity were negative but a certain insecticidal effect was observed and the toxicity for mice (10 g/kg killed 40%) is high. The extracts are much less toxic to daphnia and fish (Kerharo and Bouquet, 1950).
For those plants with a stimulant action on the CNS already described in Chapter 2 see Table 3.3
(b) Antidepressants and hallucinogens
The drugs with these properties have been treated by Burgen and Mitchell (1972) under CNS stimulants. It should, however, be stressed that antidepressant and MAOI action is usually related to anticholinergic activity and it is not possible
Table 3.3. Plants with stimulant action on the nervous system which are described in Chapter 2
Action on nervous system References
Achyranthes aspera Amaranthaceae
Holarrhena floribunda Apocynaceae
Mostua hirsuta Loganiaceae
Erythrophleum guineense Fabaceae
Physostigma venenosum Fabaceae
Alkaloid closely related to sempervirine
Roots Bark, seeds
Respiratory analeptic Respiratory analeptic
Convulsant, sedative and analgesic
Convulsant, medulla stimulant, treatment of dental and facial neuralgia
Stimulant in myasthenia gravis
CNS. Chapter 2 and Massion (1934)
CNS. Chapter 2 and
Quevauviller and Blanpin (1961)
CNS. Chapter 2 and Chevalier (1947)
Inhibits Cholinesterase, see Chapter 2
to make a rigorous distinction between ANS and CNS activities. However, a number of these drugs may prove useful in the treatment of certain forms of mental illness. Unfortunately, these effects can be accompanied by secondary effects, by visual or other hallucinations, and may be followed by depression.
Securinine and phyllochrysine, alkaloids found in Securinega virosa and Phyllanthus discoideus (Euphorbiaceae), are mainly muscular stimulants which have been shown to be successful in re-establishing mobility in cases of paralysis and paresis and in mental patients. Indole alkylamines and MAOIs (/3-carbolines) have been reported in Pauridiantha viridiflora and other Rubiaceae which also act on the ANS, e.g. Nauclea diderichii and N. latifolia and Borreria verticillata. All of these plants have been found to have a stimulant effect in post-encephalitic conditions. Antidepressant action is also attributed to Justicia insularis (Acanthaceae).
Stimulating to the CNS in small doses but narcotic and hallucinogenic in large doses are Tabemaemontana crassa, through ibogaine; Cannabis sativa, through tetrahydrocannabinols and Myristica fragrans, through myristicin (also a MAOI). Datura metel and Datura spp. containing hyoscyamine and hyoscine are sedative in psychomotor agitation like the other hallucinogens, and the alkaloids are used as pre-anaesthetics. They mainly act, however, via the ANS (anticholinergic with blockade of muscarinic receptors).
Securinega virosa (Roxb. ex Willd.) Baill. syn. (Phyllanthus virosus (Roxb. ex Willd.), Fluggea microcarpa Blume, 5. microcarpa (Blume) Pax & Hoffm. ex Aubrev., F. virosa (Roxb. ex. Willd.) Baill.) EUPHORBIACEAE
L S. virosa is widely used in Senegalese local medicine. A decoction of the roots is given mainly for disorders of the liver, the gallbladder, the kidneys (including stones), the bladder and the genitals. It is also recommended in many tribes to Bilharzia patients (Kerharo and Adam, 1974). The Hakims in India use S. virosa as a cure for diabetes mellitus (Watt and Breyer-Brandwijk, 1962).
C Numerous alkaloids have been isolated from the leaves, rootbark and stembark of this and closely related species. Paris et al. (1955) isolated a crystalline alkaloid which they called fluggeine, together with choline. Fluggeine was later identified as hordenine by Iketubosin and Mathieson (1963), who also isolated norsecurinine from the Nigerian plants. Securinine, first isolated from S. suffruticosa in 1956 by Muraveva and Bankovski, was later also found in S. virosa. In addition, norsecurinine (1.6%), dihydrosecurinine (0.06%) and virosecurinine (1.14%) were isolated from the rootbark, viroallosecurinine from the leaves and virosine (dihydrosecurinine) from the roots (Kjaer and Friis, 1962). Considerable differences have been observed in the alkaloid content of the male and female plants, and in the different parts of the plants (Chatterjee and Bhattacharya, 1964; Saito etal., 1964a, b; Satoda et al., 1972). The presence of thioglycosides has been reported in several botanically allied species, e.g. in the Indian Putranjeva roxburghii Wall., glucocochlearin, glucoputranjevin and glucojeaputin were found, and later, glucoil-comin (Kjaer and Friis, 1962). The same glycosides of 5. virosa have been found in the fresh leaves, stems and roots and some may also exist in other Securinega spp. as the hypoglycaemic action appears to be related to the presence of thioglycosides (Chatterjee and Roy, 1965; Oliver-Bever and Zahnd, 1979). In S. virosa leaves rutin has also been reported.
P Securinine was found to have an action similar to strychnine (Quevauviller et al., 1967). In pharmacological and clinical trials, Tourova (1957) noted that the alkaloid stimulates the CNS, including the spinal cord. In clinical trials with the nitrate (200 cases), Tourova (1957) observed that a rapid re-establishment of motility was produced, and hence it seems indicated in paresis, paralysis in poliomyelitis and diphtheria, and in apoplectic paresis and paralysis. The use of securinine is also indicated for impotence, decrease of cardiac activity, functional amaurosis, asthenia consecutive to extenuating diseases and ocular nerve atrophy. The drug was administered either by mouth (10-20 drops daily of a 1:250 solution of securinine nitrate) or subcutaneously (1 ml of a 1:500 solution daily). With these doses, no secondary effects have been noticed but overdosage produces a painful tension in the nape of the neck, face muscles and other muscle groups. In China securinine is used in the treatment of facial paralysis and of neurasthenia (Xiao, 1983). It has also shown promising results in the treatment of multiple sclerosis in man (Chang, 1974). Chang compares it with strychnine with regard to toxicity and pharmacological activity and reports that although both are powerful stimulants of the CNS, the LD50 of securinine in rats following intravenous administration is 26-fold higher than that of strychnine (Chang, 1974).
Phyllanthus discoideus (Baill.) Müll. Arg. syn. (P. discoides Müll. Arg., Cicca discoidea Baill., Fluggea klaineana Pierre ex. Chev., F. obovata var. luxurious Beille)
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