Hormones of the adrenal cortex

I Introduction :theactionof plants on hormone secretion in Man

A number of plant constituents can act as a substitute for natural hormones in cases of hormone deficiency. Some of these constituents have been found to be chemically identical with the natural hormone (e.g. oestrone in the kernels of date and oil palm). Other plant components have a structural similarity to the hormone (e.g. Funtumia and Holarrhena alkaloids and corticosteroids). Others again have an entirely different chemical structure (e.g. coumestans and isoflavones with oes-trogenic action). All these constituents can act as a substitute for hormones and replace them in their biological functions.

Plant components often have an indirect action on the secretion of certain hormones by stimulating or inhibiting other areas like the hypothalamus and the pituitary gland which can control the function of most other glands (e.g. gonado-trophic, thyrotrophic and corticotrophic action). (For more details see Plants acting on sex hormones.) However, great precaution should be taken in using the hypothalamus-pituitary axis as a narrow interrelationship exists and often hormonal or pharmacological actions other than those desired can be obtained (Bianchi, 1962; Goodman and Gilman, 1976). Thus stimulation of lactation has been obtained with dried thyroid gland or thyroxine (Robinson, 1947; Naish, 1954), no doubt through indirect action via the pituitary gland and an impairment of the pituitary adrenal response to acute stress is observed in alloxan diabetes (Kraus, 1949).

Plant constituents capable of influencing hormone-controlled metabolic actions may also act by removing hormone-inactivating compounds such as enzymes (thus plant constituents can inhibit insulinase in hypoglycaemic plants or certain enzymes in antifertility plants). Also, certain plant substances can antagonize hormone-controlled action (thiocyanates can inhibit the secretions of the thyroid gland). As the future will no doubt reveal, there are many more ways in which the secretion of the hormones can be stimulated or inhibited.

Those plants already described in Chapter 2 as acting on the cardiovascular system are indicated hereunder by CV in both tables and text. Similarly, the plants already described as acting on the nervous system (Chapter 3) are indicated by N and those with an anti-infectious (antibiotic or antiparasitic action (Chapter 4)) are indicated by I.

The plants marked by an asterisk (*) in the enumeration of the constituents are described in this text, the others can be found in the corresponding tables.

II Plants acting like hormones of the adrenal cortex

The internal fasciculated zone of the adrenal cortex produces Cortisol, hydrocortisone and corticosterone under the control of the pituitary corticotrophin adrenocorticotrophic hormone (ACTH) which is in turn controlled by the cortico-trophin-releasing factor (CRF) of the hypothalamus. The external glomerulated zone of the cortex produces aldosterone. Cortisol is mainly used for its anti-inflammatory action and its effect on the glucides, whilst corticosterone and aldosterone mainly act on sodium retention. Cortisol can also act on the electrolyte balance; it is the prototype of the glucocorticoids or glucocorticosteroids. Besides their antiinflammatory and immuno-depressive actions these substances can act on diuresis, intercranial hypertension and asthma. Plant equivalents of these compounds should thus be examined for each action separately. The role played by the pituitary-hypothalamus axis makes this examination still more complicated. For example, inflammatory action can be controlled not only by corticosteroids but also by other anti-inflammatory agents which often have analgesic and antipyretic properties as well (e.g. salicylates and phenylbutazone). In many cases it is difficult to decide whether the action of a constituent of a given plant depends on its action on the adrenal-pituitary axis if no indication has been given by the authors. In a few rare cases the general action of a plant on both the adrenals and the pituitary has been reported. Two examples of this are for the actions of Funtumia africana* and Holarrhena floribunda*, where the anti-inflammatory action is mentioned as part of the many other effects of the different constituents. The anti-inflammatory constituents in Funtumia are glucofuntamine and funtumine and those in Holarrhena are holamine and holaphylline. They are all steroid alkaloids.

For the reasons mentioned above the other plants with anti-inflammatory action will be described under the heading Anti-inflammatory plants.

Two non West-African plants known to act on the adrenal cortex are Panax ginseng and Eleutherococcus. Equivalent plants have not been reported in the area.

The stimulating action of ginseng on glucocorticoid production is believed to be of neurogenic origin. Ginseng appears to facilitate the adaptation of the adrenocor-ticol function to the need of the organism under changing conditions. Its effect is also manifested after hypophysectomy so it seems to act upon the peripheral site of the stress mechanism. Anti-inflammatory and anti-exudative as well as cardiovascular effects of the drug have also been reported (Brekhman and Dardymon, 1969; Chul Kim etal., 1970).

Funtumia africana (Benth.) Stapf syn. (Kicksia africana Benth., K. latifolia Stapf, F. latifolia (Stapf) Schlechter, K. zenkeri Schum.) APOCYNACEAE

False rubber tree

L In Ghana the roots are mixed with palm wine and given to patients suffering from incontinence. The dried pulverized leaves are applied as a dressing to burns (Dalziel, 1937). The latex of F. elastica Stapf has been used as a source of rubber. Its bitter bark is used as a remedy for haemorrhoids.

C The leaves of F. africana contain up to 4% of total alkaloids. The main alkaloid, funtumine, is 3-a-aminopregnane-20-one, funtumidine is 20a-hydroxy-3-a-aminopregnane. The presence of glucofuntamine has also been reported (Quevauvil-ler and Blanpin, 1960).

P Funtumine has hypotensive, antipyretic and local anaesthetic properties and the Funtumia alkaloids are similar in action and constitution to those of a related Apocynaceae, Holarrhena floribunda (see CV) (Fig. 5.1). This similarity is also confirmed in the hormonal activity of these alkaloids. Funtumine and holamine (3a-amino-5-pregnen-20-one) were observed to antagonize the effects of oestrogens. Holaphyllamine (3/3-aminopregnen-20-one) enhanced the activity of oestrogens and testosterone in female and male animals. Funtumine, funtumidine, glucoholamine, holaphyllamine and holaphylline (3/3-methylamino-5-pregnen-20-one) showed anti-gonadotrophin action as well as corticotrophic activity. Funtumine antagonized the release of corticotrophin like cortisone. All of the above-mentioned steroid alkaloids had anti-inflammatory properties, holamine and holaphylline being the most effective, followed by glucofuntamine and funtumine. The steroids increased liver glycogen and decreased the weight of the thymus. Holamine and holaphylline cause sodium retention and all three holarrhena alkaloids act as diuretics in rats. Holamine was found to decrease the protein and water content of the liver indicating an anti-anabolic action, and funtumine and funtumidine lowered the serum cholesterol and raised the phospholipid levels and may have anti-atherogenic properties. The six steroids appear to share the neurotrophic effects of steroids; all potentiated the narcotic action of pentobarbital and their toxic effect appears to be confined to the CNS. On intravenous injection in mice their LD50 values vary from 28 to 31 mg/kg, holamine being slightly less toxic (the LD50 is 37 mg/kg). All of them caused depletion of adrenal ascorbic acid (Blanpin and Quevauviller, 1960a, b; Quevauviller and Blanpin, 1960).

Funtumidine, holaphyllamine and to a lesser extent holamine have been found on subcutaneous injection of 5 mg/kg to exert antipyretic effects in rabbits made hyperthermic by injection of bacterial vaccine. An analgesic effect to thermal or mechanical stimuli in mice has been observed only with funtumidine (25 mg/kg given intraperitoneally). Glucofuntamine was more effective as a local anaesthetic on rabbit skin than cocaine; funtumidine and the holarrhena alkaloids were less effective. Funtumidine had the most consistent tranquillizing effect and was also hypotensive in rabbits (0.2 mg/kg). Funtumine had a spasmolytic action in particular against acetylcholine (Blanpin and Quevauviller, 1960a, b).

Corticosteroids are frequently prepared by hemisynthesis from plant sources such as diosgenin (see Dioscora spp. (Chapters 2 and 3)). Many other sources are found in West Africa, for example sarmentogenin (see Strophanthus samientosus (Chapter 2)), diosgenin plus yamogenin from the fruit of Balanites aegyptiaca (Chapters 2 and 4) (Hardman and Sofowora, 1971) and solasodine (from Solanum torvum). Another West African source might be costugenin (3% in Costus afer (Iwu, 1982)). Some of these constituents have oestrogenic activity themselves.

Fig. 5.1. Holarrhenafloribunda (Don) Diir. & Schinz.

Fig. 5.1. Holarrhenafloribunda (Don) Diir. & Schinz.

Estenosis Uretral

Anti-inflammatory plants The inflammatory reaction

Inflammation, whatever its origin (which may be infectious, chemical or physical), generally occurs in three consecutive phases:

( 1 ) an increase in capillary permeability with hyperaemia and oedemas ;

(2) cellular infiltration (phagocytosis by polynuclear cells and interference of lymphocytes);

(3) proliferation of fibroblasts and synthesis of collagen fibres and mucopolysaccharides, forming new conjunctive tissue.

If the new conjunctive tissue is attacked in turn by phagocytes and lymphocytes, a chronic inflammation results. Rheumatoid arthritis is a classic example of these conditions (Lechat et al., 1978).

Some of the anti-inflammatory drugs are more active in the initial stages of the inflammation (e.g. salicylates and Curcuma). Others tend to act in later stages (glucocorticosteroids and Phytolacca) whilst others again are active in both stages (<Commiphora, Crateva, Terminalia and Withania).

Several pharmacological tests have been devised to measure anti-inflammatory activity, most being based on experiments with inflammation in rats. These are:

(1) carrageenan and kaolin-induced hind-paw oedema (or rat pedal oedema), formalin-induced arthritis of ankle joint in rats; yeast-induced paw oedema, croton oil-induced granuloma, cotton-pellet granuloma (Winter etal., 1962; Benitz and Hall, 1963; van Armaneia/., 1965);

(2) adjuvant-arthritis, where injection of Mycobacterium butyricum in one hind-paw produces inflammation in the other paws and granulations in the ears ;

(3) graft-versus-host reaction in chicks (against lymphocytes of hens), which is usedtotest immune reaction.

It has been noticed that drugs which block inflammatory- and arthritis-like syndromes in animals are also effective against rheumatic diseases in Man. Inflammation in patients with rheumatoid arthritis implies the combination of an antigen (gamma-globulin) with an antibody (the rheumatoid factor) and a complement, resulting in phagocytosis by leucocytes and release of lysosomal enzymes. These enzymes damage cartilage and other tissues and enhance the inflammation (Woodbury and Fingl, in Goodman and Gilman, 1975). Prostaglandins are also formed by leucocytes during phagocytosis. Local injection of prostaglandin E, or E2 causes definite vasodilatation and hyperaemia and increases the permeability of cell membranes, and it is believed that inhibition of prostaglandin synthesis is one effect of anti-inflammatory drugs (Ferreira and Vane, 1974; Awouters et al., 1978; Oriowo, 1982). Other effects are stabilization of the lysosome membranes by prevention of loss of enzymes from the lysosomal envelope, uncoupling of oxidative phosphorylation (Whitehouse, 1965; Whitehouse etal., 1967) and inhibition of the synthesis of mucopolysaccharides (which constitute the fundamental substance of conjunctive tissue and cartilage (Paulus and Whitehouse, 1973; Lechat etal., 1978). Various mechanisms interfering with antigen-antibody aggregation have also been considered, including inhibition of antigen-induced release of histamine.

Interference with prostaglandin synthesis has been observed in the case of Zanthoxylum zanthoxyloides and Terminalia ivorensis. Immuno-depressive action has been reported for Allium and Withania somnífera, and Solanum spp.

Chemical mediators in inflammation processes are histamine, 5-hydroxy try p-tamine (serotonin), vitexin and bradykinin (Prabhakar et al., 1981; Saxena et al., 1982). Antihistamine action has been reported for Anthocleista, Amebia, Callo-phyllum, Citrus, Crateva, Cryptolepis, Curcuma and Ipomoea.

In some cases the anti-inflammatory action seems to be independent of the pituitary-adrenal axis (e.g. that of Cyperus rotundus and Commiphora) whilst in other cases the drugs are said to have a direct action on the adrenal cortex (e.g. curcumin (Chandra and Gupta, 1972) and glycyrrhetic acid (Gibson, 1978)).

As the plant triterpenoids often turned out to be active anti-inflammatory constituents, their anti-inflammatory and anticonvulsant properties were evaluated in rodents by Chaturvedi et al. (1974, 1976). For a number of natural plant triterpenoids the protection afforded against carrageenan-induced rat-paw oedema ranged from 9-48% when they were given intraperitoneally in doses of 40 mg/kg. Good correlation has been observed between the anti-inflammatory and antipro-teolytic properties of these plant products. The latter activity was demonstrated by in vitro "inhibition of trypsin-induced hydrolysis of bovine serum-albumin and casein. All the tested triterpenoids except friedelinoxime and acetylmethylursulate provided 10-40% protection against pentylene-tetrazol-induced convulsions in mice.

Active constituents of anti-inttammatory plants in West Africa In West Africa the most effective anti-inflammatory plants seem to be those which have the following active constituents.

Steroid or triterpene glycosides. Steroids or their heterosides are found in Commiphora indica*, Costus afer*, Cyperus rotundus*, Leptadenia pyrotechnica, Solanum torvum * and other Solanum spp. and Withania somnífera *. The triterpenic glycosides involved are the glycyrrhetic heterosides in Lonchocarpus cyanescens * and Terminalia ivorensis* or the oleanolic heterosides found in Boerhavia diffusa, Gymnema sylvestra, Securidaca longepedunculata, Tetrapleura tetraptera and probably Phytolacca dodecandra*. Triterpenoids are also present in Alstonia boonei (bark), which is applied topically in the treatment of rheumatic pains.

Terpenes (and their heterosides). These are found in Azadirachta indica, Atractylis gummifera c., Crateva religiosa, Xylopia aethiopica and Vemonia colorata.

Alkaloids and amides. These seem to be responsible for the anti-inflammatory action in Anthocleista procera, Capsicum frutescens*, C. Annuum*, Cryptolepis sanguinolenta* and Zanthoxylum zanthoxyloides*. Pungent amides are also found in Piper guineense and P. umbellatum (chavicine and piperine) as well as in Capsicum spp. The latter may also act through their flavonosides.

Flavonosides. Flavonosides, of which a number contain coumarins, are found in Afraegle paniculata*, Amebia hispidissima*, Calophyllum inophyllum*, Canscora decussata, Citrus nobilis, Dalbergia sissoo and Hibiscus vitifolius. Few of the above-

mentioned plants belong to the same family; there are, however, three Solanaceae and three Rutaceae, of which two have anti-inflammatory constituents belonging to the same chemical group.

Sulphur heterosides. Many of the plants used in local medicine in the treatment of rheumatic diseases are found in this group. Their constituents or scission products often contain pungent mustard oils or amides which act as counter-irritants or rubefacients, diverting hyperaemia by irritation of the skin or intestine, and these have been used, mostly locally, in the treatment of arthritis, lumbago, rheumatism bronchitis, congestion of the lungs, etc. In West Africa they are found in Cap-paridaceae, namely glucocapparin in Capparis decidua, Crateva religiosa and Gynan-dropsis gynandra; tropaeolin in Carica papaya seeds, glucotropaeolin (spirochine) in Moringa oleifera and alliin in Allium sativa and A. cepa.

Other constituents. Other active constituents are reported to be tetrahydrocannabinol in Cannabis sativa (the resin of which has also been found to contain coumarin glycosides), the dyes haematoxylin and brasilin in Haematoxylum cam-pechianum, tertiary phenylethylamines in Desmodium gangeticum and curcumine in Curcuma domestica*. The active fraction in Salvadora persica * could be /¡¡-sitosterol; in Ipomoea spp.* it has not yet been identified.

Many of these plants also have an antibiotic action, which in some cases may contribute to their effectiveness.

A number of these plants (those marked with an asterisk (*)) are described in more detail to give a better understanding of their possible therapeutic interest and modes of action. The others are listed in Table 5.1 (p. 211).

Plants with steroid or triterpene glycosides as active constituents.

Commiphora africana (Rich.) Engl. syn. (Heudelotia africana Rich., Balsamoden-dron africanum (Rich.) Arn.) BURSERACEAE

African bdellium or African myrrh L In Niger country a maceration of the stembark of C. africana is given perorally in the treatment of rheumatic diseases (Adjanohoun, 1980). In West Africa the gum-resin is boiled for treatment of inflammation of the eyes by holding the face over the steaming pot. For scorpion-bite the bark is applied after it has been chewed with natron (Dalziel, 1937). C The gum-resin contains 70% alcohol-soluble resin and 30% water soluble gum. The resin contains 7-9% of essential oil (Dalziel, 1937; Kerharo, 1968) and is composed of free terpenoids and terpenoid glycosides and the gums are composed of polyholosides (Boiteau et al., 1964).

In the Indian Commiphora mukul Hook, ex Stocks the essential oil has been found to contain 4-6% of myrcene, 11% of dimyrcene and some polymyrcene. The petroleum ether extract of the gum-resin has yielded sesamin, cholesterol and a few other steroids (Indian Council, 1976, p. 271). A number of steroids have been isolated and identified and the diterpenoid constituents cembrene A and mubulol as well as some fatty tetrols have been reported (Patil et al., 1972).

P The oleo-resin fraction from C. mukul has shown significant anti-arthritic and anti-inflammatory activity (minimum effective dose 12.5 mg/100 g in albino rats). This activity has been localized in the acidic fraction of the oleo-resin and has been shown to occur even in adrenalectomized animals (Santhakumari et al., 1964).

The aqueous extract of the oleo-gum-resin of C. mukul had suppressive action on carrageenan-induced acute rat paw oedema and in the granuloma pouch test as well. In adjuvant arthritis the secondary lesions were very effectively suppressed without any significant action on the primary phase. Side-effects were negligible as compared to those occurring in beta methasone-treated animals (Gujral et al., 1960; Satyavati et al, 1969).

A steroidal compound isolated from the petroleum ether extract of C. mukul showed a dose-dependent anti-inflammatory activity on rat paw oedema which was much more potent than that of the resin fraction. The steroid fraction had a pronounced effect on primary and secondary inflammation induced by Freund's adjuvant; it was less effective than hydrocortisone acetate in the primary phase but more effective in reducing the severity of secondary lesions (Arora et al., 1972). Furthermore, C. mukul was also found to lower the serum cholesterol in hyper-cholesterolaemic rabbits and to protect the animals against cholesterol-induced atherosclerosis (Satyavati et al., 1969; Nityanand et al., 1973). Long-term experimental studies of its effectiveness as a hypolipaedemic agent gave satisfactory results and showed that the effect could be attributed to (a) an increase in the rate of removal/excretion of cholesterol, (b) a decrease in the input/synthesis of cholesterol and (c) mobilization of cholesterol from tissues (Indian Council, 1976, pp. 272-5).

In view of the interesting results obtained with Indian myrrh, African myrrh might be examined chemically and pharmacologically for similar properties.

Costus afer Ker-Gawl. syn. (C. obliterans Schum., C. anomocalyx Schum, C. in-sularis Chev., C. lucanuscianus Chev.) (Fig. 5.2) ZINGIBERACEAE

Ginger lily

L C. afer is widely used as a cough medicine, either as a decoction of the stems or the pounded fruit, or by chewing the succulent stem itself. The boiled root is applied to cuts and sores and a soothing fomentation for rheumatic pains is prepared with the boiled leaves (Dalziel, 1937, p. 472).

C The abundant juice of the leaves (69.7%) (Odutola and Ekong, 1968) contains 0.4% oxalate, furan derivatives and starches.

Thin-layer chromatography of extracts of the tubers with petroleum ether and chloroform yielded three compounds which were identical with lanosterol, tigonenin and diosgenin. Iwu (1982) could isolate from the chloroform extract 3% costugenin, the most abundant sapogenin (closely related to sarmentogenin), 1.5% stigmasterol and 0.8% diosgenin. Similar sterols had been reported to be present in C. speciosus (Bhattacharya et al., 1973; Gupta et al., 1980, 1981).

P In clinical trials, 25 patients, 17 of whom were suffering from rheumatoid arthritis and 5 from osteo-arthrosis, received, in groups of seven, differential solvent extracts (prepared according to traditional methods by native doctors) of C. afer (30 ml doses twice daily) for four days and, after an interruption of three days, the same treatment for ten days. Two further groups of seven patients received the same treatment with extracts of Lonchocarpus cyanescens and Terminalia ivoretisis (see below for these plants). All the patients suffering from rheumatoid arthritis were relieved of their symptoms (Iwu and Anyanwu, 1982a, b). Three of the patients who received Lonchocarpus and one each of those receiving Costus and Terminalia reported complete recovery. Only two of five patients suffering from osteo-arthrosis showed some improvement (no results with Costus).

In pharmacological tests with the same three plants the extracts reduced car-rageenan-induced oedema in the rat paw, checked diarrhoea due to arachidonic acid and castor-oil (Awouters et al., 1978) and ameliorated all signs associated with adjuvant-induced polyarthritis in rats. The extracts were well tolerated in daily doses of 100-300 mg/kg except for the chloroform extract of C. afer, which caused the death of four out of ten experimental animals at that dose regimen.

Further chemical and pharmacological tests are planned by the authors (Iwu and Anyanwu, 1982b).

Fig. 5.2. Costus afer Ker-Gawl.

Fig. 5.2. Costus afer Ker-Gawl.

Cyperus rotundus L. CYPERACEAE


L The rhizomes are slighdy fragrant and the essential oil they yield is used in Asia as a perfume for clothes and to repel insects. In Nigeria the plant is used as cattle fodder and the tuberous rhizomes as a cough medicine for children. In the Congo Brazzaville the pulp of the roots is used in frictions for oedema and rheumatism (Dalziel, 1937; Bouquet, 1969). In India the tubers are reputed to be diuretic, emmanagogic and anthelmintic and are used for treating disorders of the digestive tract (Chopra etal., 1956, p. 88; Hegnauer, 1964, Vol. Ill, p. 285).

C The tubers contain a fatty oil, which is chiefly made up of glycerides of oleic, palmitic and linolic acids with small quantities of essential oils. The crude volatile oil has been noted to contain about 40% of a sesquiterpenic ketone, a-cyperone (McQuillin, 1951). In tubers collected in India, the essential oil fraction is reported to be composed of pinene, traces of cineol, sesquiterpenoids, monoterpenic and aliphatic alcohols and ^-sitosterol (Kalsi etal., 1969). The sesquiterpenoids were identified by Kapadia et al. (1967). In C. esculentus cholesterol has also been found (Abu-Mustafa etal., 1960).

P The anti-inflammatory action has been studied in India on oedema induced in the rat paw by carrageenan or by cotton-pellet implantation and was first attributed to the petroleum ether extract of the roots. Then a triterpenoid obtained from this extract by chromatographic separation was shown to possess an anti-inflammatory activity which was eight times greater than that of cortisone; the fraction also had antipyretic properties (in pyrexia induced by brewer's yeast) plus an analgesic action. On intraperitoneal administration the LD50 of the extract was 50 mg/kg; the ED50 was 1.6 mg/kg (Gupta et al., 1970). Later, /3-sitosterol isolated from tubers grown in India was found to be a powerful agent against inflammation in the above-mentioned tests (Bach, 1978). When it was administered intraperitoneally the effect was similar to that of hydrocortisone and oxyphenbutazone and the substance was also effective against carrageenan-induced oedema when given perorally. Its action proved to be independent of the pituitary-adrenal axis and to be similar to that of acetylsalicyclic acid. /3-sitosterol showed a broad safety margin as in intraperitoneal administration the LD50 was more than 3 g/kg in mice and the minimum ulcerogenic dose was 600 mg/kg in rats (Gupta et al., 1980). The essential oil was reported to have oestrogenic activity which could be attributed to cyperene I, a hydrocarbon fraction (Indira et al., 1956).

Solanum torvum Sw. including 5. torvum var. compactum Wright syn. (S. mannii Wright including var. compactum Wright) SOLANACEAE

L The small orange-red berries are eaten cooked or sometimes raw. In Sierra Leone a decoction of the fruit is used as a cough medicine for children (Dalziel, 1937, p. 435).

C The fruits contain sitosterol D-glucoside and 0.1% of the glucoalkaloid solasonine (solasodine-glycoside), from which solasodine is obtained. Solasodine is used as a starting product in the hemisynthesis of cortisone and sex hormones (Chopra etal., 1956, p. 230). The glycoalkaloid contents vary considerably during growth (Paris and Moyse, 1971, Vol. III, p. 148). Furthermore, S. torvum yields a rare sterol, first reported from S. cerasiferum Dun. syn. (S. xanthocarpum) (Sayed and Kanga, 1936), which has been shown to have the structure of (22R)22 hydroxy-6-oxo-4a-methyl-5a-stigma-7-en-3/3-yl benzoate (Beisler and Sato, 1971). S. torvum contains as much as 0.04% of carpestrol (Bhattacharya et al., 1980).

P The steroidal alkaloid solasodine has been shown to cause thymolysis in rats and to have antiphlogistic properties in experimental arthritis in rats and in experimental burns in rabbit ears. Investigation of the immunomodulating properties of solasodine (isolated from 5. nigrum) and of withanolide D from Withania somnífera showed that both substances had an immunodepressive action in vitro (Bär and Hänsel, 1982).

Carpestrol has also been reported to produce a dose-dependent inhibition of carrageenan-induced paw oedema in albino mice. As compared to withaferine A and hydrocortisone it showed the highest potency, being active in doses of 0.9 mg/kg when given intraperitoneally, whilst the LD50 for mice of carpestrol given intra-peritoneally is 500 mg (±8 mg)/kg and that of withaferine A is 110 mg (±5 mg)/kg. Carpestrol has certain structural similarities to hydrocortisone and withaferine A, both of which also have anti-inflammatory activity (Bhattacharya et al., 1980).

Withania somnífera L. SOLANACEAE

Winter cherry

The roots of this plant, already reported to have sedative and antibiotic properties (N and I), have been used for centuries in folk medicine to treat rheumatism, ulcers and skin diseases (Menssen and Stapel, 1973). The roots contain withaferine A and several other steroidal lactones and withanolides, and these were also isolated as minor constituents of the leaves (Abraham et al., 1975). Withaferine A is also a tumor inhibitor (Kupchan et al., 1965).

Withaferine A and withanolide D (isolated by Menssen and Stapel, 1973) have been shown to be active against inflammation. Six intraperitoneal doses of withaferine A of 25 mg/kg every second day in one series of tests, and twelve doses of 12.5 mg/kg every second day in a second series of tests, have been shown to delay the onset of adjuvant arthritis in rats and strongly to inhibit swelling and inflammation of the diseased area and of the secondary lesions (Fuegner, 1973; Roshchin and Geraschenko, 1973). Withaferine A has also been observed to inhibit the xenogenic graft-versus-host reaction in chicks to a great extent (Fuegner, 1973; Bär and Hänsel, 1982). The mode of action of withaferine appeared to be similar to that of prednisolone and azathioprin (purine antagonist). The similarity of their structures and actions to those of glucocorticosteroids had already suggested that withaferine and withanolide D might have, besides their antiproliferative effect, a complex influence on inflammation and immune responses (Bär and Hänsel, 1982). Shohat et al. (1978) also observed that in concentrations of 1 /xg/ml withaferine A and withanolide E showed immuno-depressive action in cultures stimulated by 1 /xg ml and 0.3 /xg/ml phytohaemaglutinin and in those without mitagenic stimulation. The functional activity of normal human T lymphocytes as assessed by local xenogenic graft via host reaction was also affected by these two steroidal lactones. Apparently, withanolide E had a specific effect on T lymphocytes whereas withaferine A affects both T and B lymphocytes. The authors believe that rheumatism, asthma and certain skin diseases all have an immuno-pharmacological basis.

Lonchocarpus cyanescens (Schum. & Thonn.) Benth. syn. (Robinia cyanescens Schum. & Thonn., Philenoptera cyanescens (Schum. & Thonn.) Roberty)

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