Foukaridis, G.N., Osuch, E., Mathibe, L. and Tsipa, P. (1995). The Ethnopharmacology and Toxicology of Urginea sanguinea in the Pretoria Area, J. EthnopharmacoL, 49, 77-79. Galey, F.D., Holstege, D.M., Pluralee, K.H., Tor, E., Johnson, B., Anderson, M.L., Blanchard, P.C. and Brown, F. (1996). Diagnosis of Oleander Poisoning in Livestock, /. Vet. Diagn Invest., 8, 358-364. Mansoor, O., Gonzalez, D., Aquilina, C., Laurant, E., Guelon, D., Dissait, F., Meyrieux, J., Lamaison, D. and Schocffler, P. (1992). Intoxication grave au laurier rose traitee par anti-corps antidigoxine, JEUR, 5, 228-230. 1. Introduction.................................................................................................................7^2 2. Other Steroids..............................................................................................................752 A. Steroid-containing Drugs...............................................................................752 Myrrh tree........................................................................................752 Condurango......................................................................................754 Chaste tree........................................................................................754 B. Drugs with Activity Due Entirely, or in Part, to Phytosterols........................755 Nettle................................................................................................756 Sitosterol..........................................................................................758 Pollen extracts..................................................................................758 Pumpkin...........................................................................................7^S 3. Other Triterpenes.........................................................................................................759 A. Cucurbitacins, Bryony...................................................................................759 B. Miscellaneous Triterpenes..............................................................................760 Birch.................................................................................................760 Black Cohosh...................................................................................761 Salai Guggal - Boswellic Acids.......................................................763 C. Modified Triterpenes......................................................................................763 Limonoids........................................................................................763 Rutaceae....................................................................................7°4 Meliaceae (764), Neem.............................................................765 Quassinoids......................................................................................765 4. Bibliography................................................................................................................766 752 TERPENOIDS OTHER STEROIDS 1. INTRODUCTION Few plant steroids, except for the sapogenins and cardiac glycosides, have established therapeutical applications. From a strictly phytochemical point of view, ecdysteroids deserve to be mentioned here. These compounds, related to ecdysone (= 2p,3P,14a,22i?,25-pentahydroxy-5P-cholest-7-en-6-one), are characterized by a 7-en-6-one and multiple hydroxyl functions. Nearly one hundred structures have been described in plants, particularly in the Podocarpaceae. In the Arthropods, ecdysone and its metabolites are hormones involved in the regulation of ecdysis and other vital processes (e.g., reproduction, metamorphosis). The occurrence of structural analogs of the ecdysis hormone in plants is a surprise: they may play a defensive role against predators, or a role in the physiology of the plant, or both. Some of these compounds are potential insecticides; various other pharmacological and biological activities are also beginning to be recognized. o Ajugalactone Here we shall describe in one group, by arbitrary choice, drugs whose activity is certainly or probably linked to steroids, phytosterols, or related compounds. 2. OTHER STEROIDS A. Steroid-containing Drugs • Myrrh Tree, Commiphora mukul (Hook, ex Stocks) Engl., Burseraceae The oleo-gum-resin secreted by this plant from the desert areas of India is a drug used in Ayurvedic medicine to treat, among other ailments, rheumatism, obesity, and miscellaneous disorders of lipid metabolism. The Plant, the Drug. The myrrh tree is a bushy shrub with thorny branches, with ash-colored bark that peels into thin rolls, 1,3-foliolate leaves, flowers with a fuzzy calyx and a brownish-red corolla, and ovoid drupes that turn red when ripe. The Species 2TOWS in the ariH arpac nf tho 1,............ Tndto^fPVri v»f Mr. J Can .a .-.'I I - --^iit I as in Pakistan (Baluchistan). The drug is collected at regular intervals for some weeks, following the superficial incision of the bark of the trunk and main branches. Good quality myrrh occurs in vermiculated, translucent, pale yellow or greenish fragments, of aromatic or bitter taste, and of balsamic odor. Chemical Composition. The constituent polysaccharide of the gummy fraction of myrrh is a highly ramified molecule comprising D-galactose, L-arabinose, and the 4-methyl ether of D-glucuronic acid. The volatile fraction of the oleoresin is chiefly composed of monoterpenes (myrcene). The resinous fraction per se contains diarylfuranofuranoid lignans (sesamin and related compounds), macrocyclic diterpenes (cembranes), esters of ferulic acid, and of C1S, C19, and C2q polyhydro-xylated saturated hydrocarbons (the "guggultetrols"), and steroids derived from pregnane and cholestane. The compounds of greatest pharmacological interest axe the E- and Z-guggulsterones, which are geometrical isomers of pregna-4,17(20)-dien-3,16-dione. They occur alongside guggulslerols, which are Cj\ pregnane-type and C27 cholestane-type di- or trihydroxylated derivatives. Z-Guggulsterone E-Guggulsterone Pharmacological Properties and Uses. "Guggulipid" (that is, the standardized product of the extraction of the oleo-gum-resin by ethyl acetate) lowers blood cholesterol and lipids in animals. The activity is linked to the guggulsterones and potentiated by the other constituents in the extract. These ketones, like guggulipid and clofibrate, lower blood cholesterol and triglycerides in various animals; they decrease LDL- and VLDL-cholesterol, and increase the HDL-cholesterol/total cholesterol ratio. The guggulsterones are thought to act by stimulation of thyroid function, probably by a direct effect; they are also thought to activate the hepatic membrane receptors that bind LDL, thereby increasing their metabolism. These ketones also induce an increase in the activity of dopamine-j3-D-hydroxylase. The purified product seems devoid of acute, subacute, or chronic toxicity (in rats, dogs, and monkeys); it is neither a mutagen nor a teratogen. Several double blind clinical trials using methodology of uneven quality have been conducted in humans and in India: they demonstrate the efficacy, comparable to that of clofibrate, of the prolonged administration of guggulipid in the treatment of certain types of hyperlipidemia (decrease in blood cholesterol and triglycerides). These trials resulted in the marketing of guggulipid in India (500-mg tablets containing 25 mg of guggulsterones). The indications are the treatment of mixed hyperlipidemia, h^ttr^aWrtnAfjfKiay- , 1-7 anti-inflammatory, but what could be the biological activity of the sterols? What about their metabolites? The possibility of an action via aromatase inhibition by the hydroxylated fatty acid has been considered, but deemed unlikely (and no change in prostate volume was observed). Another hypothesis is that the nettle extract would interact with the serum globulin that binds testosterone. This interaction is weak (1-10 mg/mL) and was observed in vitro; it is due to the hydrophilic fraction, not to the lectin. The extract does not inhibit 5cc-reductase nor the binding of dihydrotestosterone to its receptors in the prostate. Recently, German authors came up with the hypothesis that polysaccharides and the lectin (Urtica dioica agglutinin = UDA) are responsible for the activity: the polar fractions are thought to inhibit the growth of prostatic tissue and the lectin is thought to block the binding of the epidermal growth factor secreted by the prostatic tissue onto its receptor. In tiiat case, what is the bioavailability of these polar compounds? The question was not addressed. The results of several clinical trials, published between 1980 and 1990, strongly indicate a rather positive impact of long-term treatment with the alcoholic extract of nettle root on the urinary symptoms associated with prostatic adenoma (improvement of bladder outlet obstruction symptoms and decrease in post-voiding residual urine), but experts find that the methodology used in these trials was not without bias. Uses Nettle Root. In the absence of undebatable clinical trial results, nettle root is traditionally used orally in France [French Expl. Note, 1998] as adjunctive treatment for bladder outlet obstruction symptoms of prostatic origin and to enhance the renal elimination of water. The German Commission E monograph describes that nettle root increases urinary volume and flow rate, and decrease the post-voiding residual urine. Therefore, it is used for the urination difficulties linked to stages I and II benign prostatic hyperplasia. The monograph specifies that since the use of the drug does not decrease the actual hypertrophy, a physician should be consulted on a regular basis. In some medicines marketed in Germany, nettle root extract is combined with the extract of Prunus africana (see p. 161). Nettle Leaf. The nettle leaf is rich in minerals, proteins, vitamins, and phenolics, and it is said to be edible. It was formerly traditionally used as poultry feed. It is an industrial source of chlorophyll. In some European countries, it is recommended for asthenia and anemia. In France, it is now permitted for phyto-pharmaceuticals based on dioecious nettle leaf to claim the following indications for oral and topical administration [French Expl. Note, 1998]: traditionally used for seborrhea, and traditionally used for the symptomatic treatment of minor pain in the joints. The German Commission E monograph describes nettle herb (leafy stem) as used for the adjunctive treatment of rheumatism pain, for the preventive treatment of renal lithiasis, and for irrigation in case of inflammation of the urinary tract. Also in Germany, nettle fruit is used in folk medicine (tonic, "hepatic stimulant"). 758 TERPENOIDS OTHER STEROIDS '59 » P-SlTOSTEROL Phytomedicines consisting primarily of P-sitosterol have been commercially available in Germany for several years. They are prescribed to improve the symptoms of benign prostate hyperplasia. Faced with the fact that international experts were not taking into account this type ot treatment, the manufacturers of these products began to provide support for clinical trials. The results of randomized double-blind studies indicate that prolonged treatment induces a regression of symptoms that were quantified using a normalized questionnaire (I-PSS), an improvement of the quality of life, and an increase in urinary flow rate. These effects are significantly superior to those of a placebo. No side effects were observed, even at the highest doses (130 mg/day for 6 months). • Pollen Extracts In some countries, an extract is marketed that is obtained from the pollen of various plant species from the south of Sweden. Two fractions from this extract are responsible for the biological activity: one is water-soluble, and the other is soluble in acetone and contains sterols. The water-soluble fraction inhibits the growth of prostatic tumor cells and normal cells in vitro. Fractionation monitored by checking the biological activity has led to the isolation of a cyclic hydroxamic acid, 2,4-dihydroxy-2/f-l,4-benzoxazin-3(4//)-one, which has the same inhibitory properties. The total extract decreases prostatic hypertrophy in rats. When it is administered to humans, it does not change the blood levels of luteinizing hormone (= LH), follicle stimulating hormone {- FSH), testosterone, or dihydrotestosterone. In view of the results of trials conducted on patients with prostate adenoma, the total pollen extract is presented as capable of improving nocturia, significantly decreasing the post-voiding residual urine, and in the long run, decreasing the anterio-posterior diameter of the prostate. Its effects on the other common symptoms affecting the prostate are not statistically significant. It does not affect the urinary flow rate. • Pumpkin, Cucurbita pepo L., Cucurbitaceae Pumpkin seeds were official until the beginning of the twentieth century. They have long been used for their vermifuge properties (a taenicide proprietary product based on pumpkin seeds used to be marketed in France until the early 1980s). For a few years now, some European countries have been marketing the oil of pumpkin seeds as a drug treatment for benign prostate hypertrophy. This large annual plant with procumbent stems is characterized by large leaves covered with stiff hairs, ramified tendrils, large (5-10 cm), pentamerous, unisexual ¥■ Pi.:''-' flowers, and by a humongous berry containing a large number of seeds within a spongy pulp. The seed is flattened (15-20 x 8-10 x 2-3 mm) and whitish. It is tapered at one end and has a rounded rim. Pumpkin seeds are rich (30-50%) in unsaturated oil (43-55% linoleic acid). The vermifuge properties of the seed are attributed to a cyclic amino acid: 3-amino-3-carboxypyrrolidine (0.4-0.8%). But it is the sterol composition of the unsaponifiable matter that has retained the attention of chemists. The chief constituents are, as in many other Cucurbitaceae, A7-sterols and their glycosides: spinasterol glucoside, 24p-ethyl-5a-cholesta-7,25(27)-dien-3|3-ol 3-0-((3-D-glucopyranoside), and the corresponding 7,22£,25(27)-trien-3(3-ol; they occur alongside A5-sterols (clerosterol, isofucosterol, stigmasterol, campesterol), squalene, and others. The activity of pumpkin seeds on the symptoms linked to benign prostate hypertrophy is attributed to the A7-sterols, but its mechanism is not known and there are few published clinical studies. The use of pumpkin oil is an ancient and current practice in Germany, and in other countries of central Europe, and Commission E approves the use of the seed, while specifying that is is merely a symptomatic remedy. Pumpkin seed extract is sometimes combined with Serenoa repens extract (see p. 162). 3. OTHER TRITERPENES A. Cucurbitacins Cucurbitacins are tetracyclic triterpenes arising from a rearrangement of the protostane cation (see p. 665). They are unsaturated and polyfunctionalized—they may include up to nine oxygen atoms—occur most often as glycosides, and are characteristic of several genera in the family Cucurbitaceae. They are particularly toxic substances (ld50 near 1 mg/kg in mice by IP administration), are bitter and cytotoxic, and impart to the drugs that contain them drastic purgative properties: colocynth seeds (Citrullus colocynthis [L.] Schrad.), the juice of the fruit of the squirting or wild cucumber (Ecballium elaterium [L.] A. Rich.), and the bryony root (Bryonia cretica and other species) were formerly used as purgatives. Although these drugs have long been abandoned * by allopathy and phytotherapy, some, like the bryony, are still used in homeopathy. Cucurbitacins have also been isolated from plants such as the gratiola (Gratiola officinalis L., Scrophulariaceae); their presence explains the purgative and emetic action of this old folk remedy which, fortunately, is now obsolete. (TWO nairc nf f]ijg^ f^ßTT?gac 4 Ärft= ihvfC »fjnb * In some cases, they are still used, either on purpose or by error, and with serious consequences, including death. See: 1° Galvez Contreras, M. del C, Lopez Gallardo, A„ Diez Garcia, F. and Yelamos Rodriguez, F. (1996). Intoxicaoion por coloqufntida, una causa poco frecuente de sindrome diarreico agudo, Med. Clin., (Barcelone), 106, 599 ; 2° Vlachos, P., Kanitsakis. N.N. and Kokonas, N. (1994). Fatal Cardiac and Renal Failure Due to Ecballium 760 TERPENOIDS • Bryony, Bryonia cretica L. subsp. dioica (Jacq.) Tutin, Cucurbitaceae This toxic plant is a perennial dioecious species whose long (5 m) stems bear palmatilobate leaves covered with rough hairs, and tendrils which allow it to climb on nearby supports. The fruit is a berry which is red when ripe and may attract children. The roots, formerly prized for their purgative properties, contain cucurbitacin glycosides, including bryodulcoside, bryoside, bryonoside, cucurbitacin L, bryoamaride, and bryodiosides A-C. All parts of the plant are toxic, however, their composition is not as well known as that of the roots. Upon contact with the skin, the fresh roots cause redness, irritation, and the formation of vesicles. The ingestion of a few fruits (<10 in children) induces vomiting, abdominal pains, diarrhea, and in rare cases, agitation. Bryony appears in the French Pharmacopoeia (10th Ed., IV.7.b), but on liste B, which means that it is a species "for which the evaluation of the benefit-to-risk ratio is negative". Currently, the sole use of the drug is in homeopathy. In Armenia, the root of a closely related species, the white bryony, {Bryonia alba L.) is considered to be a tonic and an adaptogen. OCOCH3 Betulinic acid Cucurbitacin E B. Miscellaneous Triterpenes • Birch, Betula spp., Betulaceae The drug (Eur. Ph., 3rd Ed., add. 1998) consists of the dried leaves, entire or fragmented, of Betula pendula Roth, or B. pubescens Ehrh, or both, or hybrids of the two species. The leaf of B. pendula ends in a long acuminate point and is glabrous; that of B. pubescens is slightly hairy, and it is neither elongated nor acuminate. The drug contains not less than 1.5% flavonoids, expressed as hyperin (colorimetry after reaction with AICI3), Birch leaf contains many flavonoids (2-3%): rutin, quercitrin, hyperin, and other glycosides of quercetin (3-O-glucuronyl, 3-O-arabinosyl), glycosides of kaempferol and of myricetin, methylated flavones, and more, as well as phenolic acids and triterpenes derived from lupane and dammarane (free or esterified by malonic acid). OTHER TRITERPENES In the' absence of pharmacological or clinical data, in France the drug is traditionally used orally [French Expl. Note, 1998]: 1. to enhance urinary and digestive elimination functions, and 2. to enhance the renal elimination of water *. The German Commission E attributes a diuretic effect to birch leaf; the monograph specifies that it is used for inflammation and infection of the urinary tract and for urinary lithiasis *. It is also used for the adjunctive treatment of rheumatism pain, although this use is not mentioned on package inserts. Birch bark contains very large quantities of lupane-type derivatives (lupeol and hydroxylated derivatives, betulinol, betulinic acid) as well as dammaranes, often esterified through the hydroxyl group at C-3 by malonic acid (papyriferic acid). The bark also contains arylbutanoids and glycosidic diarylheptanoids. Like birch leaf, it passes for a diuretic. Betulinic acid is cytotoxic in vitro and in vivo; it inhibits the growth of human melanoma in mice selectively, by inducing apoptosis. Certain amides of betulinic acid (amide of 11-amino-undecanoic acid and RPR 103611) are potent and selective inhibitors of HIV-1 replication. Their IC50 on some strains is on the order of 10 nM. They are inactive on the viral enzymes (protease, reverse transcriptase), but they prevent the formation of the syncytium and block the entry of the virus into the cells. (Note that the initial experiments that allowed die discovery of these properties were conducted with betulinic acid isolated from plane tree bark, " Platanus hybrida Brot.", Platanaceae). • Black Cohosh, Cimicijuga racemosa (L.) Nutí, (=Aáea racemosa L.), Ranunculaceae This North American herb, also known as black snakeroot or rattleroot, has a reputation as an anti-inflammatory, diuretic, sedative, and antitussive. The rhizome and roots (BHP 1990) are presented as having an estrogenic activity, and traditionally proposed to relieve various minor gynecological problems. Chemically, the subterranean parts contain formononetin, which may be the basis of the estrogenic activity, since this isoflavone binds competitively to estrogen receptors (ovariectomized female rat uterus). They also contain tetracyclic triterpenes derived from cycloartanol, whose side chain is oxidized and cyclized by ketalization (actein, cimifugoside). In animals, the drug extract is a hypotensive agent, a vasodilator, a spasmolytic, and an anti-inflammatory. In France, the drug is virtually not used any more (except in homeopathy); it is still used in Germany (neurovegetative problems of the menopause, premenstrual syndrome). * The same traditional indications may be claimed by cammock root in France and Germany. This European Fabaceae also known as rest-harrow {Ononis spinosa L.) contains a triterpene arising from a «double» cyclization of squalene, namely onocerin. There is no proof that onocerin contributes to the activity, which itself remains to be verified. Ononis root also contains isoflavonoids (isoflavones, [glycosides of formononetin and of biochanin A], ^J)ff./.p 1 "iT IVcy nf ooc^nticil nil OTHER TRITERPENES Cimicifugoside 3-O-Acetyl-11-ketoboswellic acid • SALA1 GUGGAL - BOSWELLIC ACIDS Boswellic acid (3a-hydroxy-urs-12-en-23-oic acid), 3-O-acetyl-l 1-ketoboswellic acid (= AKBA), and closely related derivatives are the biologically active principles of salai guggal, in other words the oleo-gum-resin produced by Boswellia serrata Roxb. ex Colebr. (= B.glabra Roxb., Burseraceae). A traditional remedy in Ayurvedic medicine, this product is used in India to treat various inflammatory disorders, particularly as an alcoholic extract (Sallaki ®). These boswellic acids are also found in olibanum (frankincense), the oleo-gum-resin secreted by Boswellia carterl Birdw. (see p. 580). The anti-inflammatory activity of the boswellic acids has been studied on different animal models (induced arthritis and edema). It has been established that AKBA, and to a lesser extent, boswellic acid, are specific inhibitors of 5-lipoxy-genase in vitro, therefore they are inhibitors of leukotriene synthesis. . Preliminary studies in rats indicate that these triterpenic acids have no toxicity, acute or chronic (1 g/kg/day x 6 months). Clinical observations in rheumatoid arthritis patients—but the methodology of these trials was not described—lead some authors to think that these compounds are well tolerated and could be used for adjunctive therapy. It is clear that further trials are necessary to determine if there are real benefits. C. Modified Triterpenes Many genera within families of the order Rutales (Rutaceae, Meliaceae, Simaroubaceae, Cneoraceae) are capable of achieving profound degradations of the triterpenoid skeleton. The chief modifications are a cyclization (limonoids), or an elimination of the C-17 side chain (in most quassinoids), as well as an opening with oxidation of the D ring (quassinoids), or of the A ring (limonoids), or of both (limonoids). In some cases, the modifications are deeper: opening of the B or C ring, sometimes followed by recyclization, and more. Limonoids Over 300 limonoids arising from the metabolism of a 4,4,8-trimethyl-17-- j----:u„j „„ tt-,!c TM-opnrcnr is fnrmp.fl from A'-tirucallol TERPENOIDS (or from A7-euphol): the opening of the 7,8-epoxide allows migration of the methyl group from C-14 to C-8, creates unsaturation at C-14, and always places a hydroxyl group at C-7. The oxidation of the A ring, or of the D ring, or of both, takes place according to a similar mechanism, for example oxidation at the a position relative to the unsaturation and Baeyer-Villiger reaction. Further rearrangements and oxidations are possible (see figure on next page and corresponding references). Obacunone "O-COCH3 Gedunin Rutaceae. Citrus limonoids are of no interest to pharmacy; they are responsible for the bitterness which gradually develops in fruit juices after their preparation. This delayed bitterness is common to all of the Citrus, unlike the immediate bitterness which is specific to certain species (grapefruit), and which is due to flavanone glycosides. In the fresh and intact fruit, monocarboxylic limonoic acid occurs as a salt which is not bitter. After the juice is squeezed, acidification leads to its lactonization to limonin, which is bitter. Commercially, this delayed bitterness could cause various problems and justify the biotechnological elimination of the principles responsible for it. Meliaceae. The chief economical interest of this family is that it produces the finest of woods: African mahoganies (Khaya grandifolia DC, K. ivorensis A. Chev., K. anthotheca (Welw.) DC, and more), Honduran mahogany (Swietenia macrophylla King), a west African timber of mahogany type (Entandophragma utile [Dawe & Sprague] Sprague) and various species of Turraeanthus, Guarea, and Cedrelus. The handling of these woods often causes allergic reactions: contact dermatitis or respiratory symptoms. In most cases, these effects are attributed to modified tri-terpenes (e.g., anthothecol). • Neem, Azadirachta indica A. Juss., Meliaceae A. indica is a tree common in India and acclimatized in tropical Africa. The bark, the leaves, and the oil from the seeds are widely used in folk medicine: the bark has a reputation for being a tonic, the leaves and the oil from die seeds are recommended as anthelmintics, antiseptics, and antiparasitic agents. Many terpenoid constituents have been isolated from the different drugs: diterpenes (abietane derivatives), and, most of all, more than fifty highly oxidized tetranortriterpenoids, including azadirachtin, nimbolide, nimbidinic acid, azadirone, and nimbin. Some of the activities attributed to this drug have been investigated (antimalarial, anti-inflammatory, CNS activity), but it is mostly the activity of azadirachtin that has been die focus of attention. This compound acts on insects as an antifeedant. In addition, at low doses, azadirachtin, _by a complex mechanism of action on the insect's neuro-hormonal regulation, interferes substantially with larval growth and insect development; it delays growth, inhibits ecdysis, and induces malformations, all of which make it an insecticide tiiat is all the more interesting because its environmental impact is much smaller tiian that of synthetic pesticides. Several products are now commercially available in the United States (e.g., Margosan-O, Azatin); they contain azadirachtin, and some contain Azadirachta seed oil, which is thought to potentiate die activity. Quassinoids (see formulas p. 766) Most of these bitter principles from the Simaroubaceae have a C20 (or a C19) skeleton; some of them retain part of the side chain from the common precursor, and therefore, have a C25 skeleton. All of the compounds in this group are highly oxidized and include lactones as part of their structure. Various quassinoid-containing drugs were formerly used for their tonic or insecticidal properties, for example the quassias. Surinam quassia (Quassia amara L.) and Jamaican quassia, two tall Caribbean trees, were formerly used for their wood, rich in quassin, itself considered bitter and aperitive*. The potential applications of the Simaroubaceae are linked to tire marked biological activities of a certain number of quassinoids. An example is that of the C2o quassinoids isolated from Brucea, Ailanthus, Simarouba, Castela, and Simaba, which have cytotoxic properties. This activity is due to compounds that are bridged (8,11 or 8,13), esterified (at C-15 or C-6), and have an unsaturated A ring and hydroxyl groups at C-l 1 and C-12, for example bruceantin. Several quassinoids, mostly with 20 carbon atoms and a bridge, are antimalarials in vitro and at very low doses (IC50<0.02 |j.g/mL). Some are also amebicides. * One of the rare proprietary drugs containing quassia wood (but also yellow gentian root, cinnamon bitter orange peel, cinchona bark, kola nuts, nux vomica extract, and calcium glycerophosphate) has been on the French market since 1910! Its brand name is Quintomne®. TERPENOIDS OTHER TRITERPENES COOH Origin of the quassinoids (main lines) CH3Ox OCH3 i í H I 1 ^ ' 0 ;0 í e Quassin Bruceantin 4. BIBLIOGRAPHY Ac-cr "o CH3O2C '-—4 Azadirachtin Myrrh Tree Chander, R., Khanna, A.K. and Kapoor, N.K. (1996). Lipid Lowering Activity of Guggul-sterone from Commiphora mukul in Hyperlipaemic Rats, Phytother. Res., 10, 508-511. Satyavati, G.V. (1991). Guggulipid: a Promising Hypolipidemic Agent from Gum Guggul (Commiphora wightii), in "Economic and Medicinal Plant Research", (Wagner, H. and Farnsworth, N.R., Eds.), vol. 5, p. 47-82, Academic Press, London. Singh, R.B., Niaz, M.A. and Ghosh, S. (1994). Hypolipidemic and Antioxidant Effects of Commiphora mukul as an Adjunct to Dietary Therapy in Patients with Hypercholesterolemia, Cardiovasc. Drugs Ther., 8, 659-664. Chaste Tree Jarry, H., Leonhardt, S., Wuttke, W., Behr, B. and Gorkow, C. (1991). Agnus castus als dopaminerges Wirkprinzip in Mastodynon® N, Z. Phytother., 12, 77-82. Lauritzen, C., Reuter, H.D., Repges, R., Bohnert, K.-J. and Schmidt, U. (1997). Treatment of Premenstrual Tension Syndrome with Vitex agnus-castus. Controlled, Double-blind study versus Pyridoxine, Phytomedicine, 4, 183-189. Neumann-Kühnelt, B., Stief, G., Schmiady, H. and Kentenich, H. (1993). Investigations of Possible Effects of the Phytotherapeutic Agent Agnus Castus on the Follicular and Corpus Luteum Phases, Human Reprod., 8, suppl. 1, 140. Nettle Chrubasik, S., Enderlein, W., Bauer, R. and Grabner, W. (1997). Evidence for Antirheumatic Effectiveness of Herba Urticae dioicae in Acute Arthritis: a Pilot Study, Phytomedicine, 4, 105-108. Hryb, D.J., Khan, M.S., Romas, N.A. and Rosner, W. (1995). The Effect of Extracts of die Roots of the Stinging Nettle (Urtica dioica) on the Interaction of SHBG with its Receptor on Human Prostatic Membranes, Planta Med., 61, 31-32. Wagner, H., Willer, F., Samtleben, R. and Boos, G. (1994). Search for the Antiprostatic Principle of Stinging Nettle (Urtica dioica) Roots, Phytomedicine, 1, 213-224. ß-Sitosterol Berges, R.R., Windeier, J., Trampisch, H.J. and Senge, T. (1995). Randomised, Placebo-controlled, Double-blind Clinical Trial of ß-Sitosterol in Patients with Benign Prostatic Hyperplasia, Lancet, 345, 1529-1532. Klippel, K.F., Hiltl, D.M. and Schipp, B. (1997). A Multicentric, Placebo-controlled, Double-blind Clinical Trial of ß-Sitosterol (Phytosterol) for the Treatment of Benign Prostatic Hyperplasia, Br. J. Urol, 80, 427-432. Pollen Habib, F.K., Ross, M., Lewenstein, A., Zhang, X. and Jaton, J.-C. (1995). Identification of a Prostate Inhibitory Substance in a Pollen Extract, Prostate, 26, 133-139; see also Zhang et al. (1995). J. Med. Chem., 38, 735-738. Rugendorff, EW., Weidner, W., Ebeling, L. and Buck, A.C. (1993). Results of Treatment with Pollen Extract (Cernilton ® N) in Chronic Prostatitis and Prostatodynia, Br. J. Urology, 71, 433-438. Cucurbitacins - Bryony Miro, M. (1995). Cucurbitacins and their Pharmacological Effects, Phytother. Res., 9, 159-168. Oobayashi, K, Yoshikawa, K. and Arihara, S. (1992). 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