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Experimental Studies on Thevetia Neriifolia Juss-A Review Indian Journal of Chemistry Vol. 398, November 2000, pp. 808-812 Review Article Experimental studies on Thevetia neriifolia Juss-A review Anarnika Gulati*t, S K Jain & P S Srivastava Department of Biotechnology, Hamdard University, New Delhi II 0062, India Received 18 August 1999; accepted (revised) 16 August 2000 'fhis review article provides a comprehensive description of various studies, carried out on Thevetia neriifoiia which is a source of several cardioactive glycosides, since early 20th century. The article provides an overview of various other medicinal herbs containing cardiac glycosides and discusses in depth various com[pounds isolated so far from this medicinal herb and their pharmacology. Additionally, various in vitro and biotransformation studies carried out on Thevetia and yield of glycosides in cultures is also detailed. 1 2 Heart failure is one of the most common causes of and Roxpellina boivini ' .The compounds are found in death and disability and is among the syndromes most almost all parts of the plant, but the total amount or commonly encountered in clinical practice. Despite relative distrilbution in any given plant varies with important advances in the pharmacotherapy of heart ecological factors, stage of development, time of failure over the past decade, the mortality rate still harvest and mode of drying etc. approaches 50%. In the 1990s, digoxin has become by far the most The cardiac glycosides have been used for centuries commonly prescribed cardiac glycoside because of its as therapeutic agents. Compounds containing the convenient pharmacokinetics, alternative routes of molecular motifs common to these agents- a steroid administration, and the widespread availability of nucleus containing an unsaturated lactone at the C-17 techniques for its measurement. position a~d one or more glycosidic residues at C-3 are A number of cardiac glycosides have been isolated found in many plants and several toad species, usually from Thevetia neriifolia, one of which, the peruvoside acting as venoms or toxins that serve as protection is more potent than digoxin. against predators. The steroidal cardenolides comprise one of the most interesting group of naturally occurring Pharmacological Evaluation substances which are efficacious in the treatment of Thevetia neriifolia Juss was used in ancient India heart diseases. As components of arrow poisons, (I 000 BC) in various skin diseases by Charak. It was primitive people had used these substances from time classified under poisons by Sushruta in 1000 BC and immemorial. was known to be a horse poison, hence named The first comprehensive description of Digitalis Ashwamarak or Ashwahan- the horse killer in glycosides in the treatment of congestive heart failure, Sanskrie. It was only in 1863 that its cardiotonic as well as other ailments, are recorded in William activity was discovered. Subsequently, the ouabain­ Withering's 1785 monograph on the therapeutic like action of glycoside present in the kernels of this 4 efficacy and toxicities of the leaves of the common plant was noticed . The kernels are very bitter and foxglove plant, Digitalis purpurea. Eversince, a dozen when chewed produce numbness in the tongue. A families of cardenolide- bearing plants have been decoction of the seeds acts as a violent emetic, hinders recognised which include Digitalis lanata, respiration and causes paralysis of the heart. However, Strophanthus gratus, S. divaricatus, S. sarmentosus, S. with caution it can be used for the treatment of thollonii, Nerium oleander, Thevetia neriifolia, haemorrhoids. The seeds are also employed in criminal Cerbera j1oribunda, C. dilatata, Beaumontia poisoning of ~ he cattle. The animals fed with it, show 5 grandiflora, Acocanthera longiflora, A. oppositifolia salivation, expectoration and drowsiness . Kernels are 6 also used as an insecticide, mashed with soap solution · 8 *BECPRG, National Physical Laboratory, New Delhi, 11001 2, . Bactericidal activity has also been detected in seed 9 1 India oil distillates -~ . Antifungal principle was detected in GULA TI el a/.: EXPERIMENTAL STUDIES ON THE VET/A NERIJFOUA JUSS- A REVIEW 809 12 . l . 13 E 31 t h e fl oral extracts aga.tnst 8tpo ans oryzae . vans major component of the seeds • It was subsequently and Kaleysa8 reported larvicidal activity and Qamar et found to be a mixture of two triosides, cerberoside al. 14 nematicidal activity. Recently Vohora and (thevetin-B) and thevetin A. A small proportion of Mishra15 reported its utility in skin diseases. All parts another trioside, 2'-0-acetyl cerberoside is also 35 of the plant produce latex, which is used for healing associated with thevetin • The separation of thevetin sores and too_thache. into pure components, thevetin A and cerberoside was Every part of the plant, however, is· poisonous, the achieved by partial chromatographic and counter kernels being the most toxic. The toxic manifestations current techniques by several workers. By the counter of yellow oleander- poisoning mainly involve the current technique, thevetin-A and cerberoside were 4 36 7 card wva. scu I ar system an d t he gastromte. stma. 1 tract ·!&- obtained in a ratio of 1:2 .3 • 5-Methyl ether of 20 38 . Jaundice and renal failure is also reported in yellow apigenin is also reported from seeds . The monosides 2122 oleander poisoning ' . The toxic principles in yellow separated from the seeds include neriifolin, cerberin oleander are the cardiac glycosides; kernels contain (2'-0-acetyl neriifolin), peruvoside, theveneriin 39 nearly seven ti mes as much glycosides as the leaves, (ruvoside) and peruvosidic acid (perusitin) . These 23 stem, flowers or fruit pulp • A number of cardiac glycosides do not occur as such in the seeds and are glycosides have been isolated from this laticifer, some formed as a result of enzymic hydrolysis of the of which are thevetin cerberin, peruvoside and triosides. Peruvoside is obtained by partial hydrolysis 2425 nerrifoside · . A number of experiments conclude of thevetin A; upon reduction, peruvoside yields ouabain or digoxin-like action on heart muscles. theveneriin (ruvoside). Peruvoside and theveneriin are 40 Positive inotropic effect followed by cardiac arrest in related as aldehyde and alcohol to each other • isolated frog, guinea pig or albino rats26 and emesis and Peruvosidic acid is obtained upon oxidation of musculotropic activity was produced in cats and peruvoside by Cr03. pigeons. Perfusion of thevetin, peruvoside or ruvoside During the isolation of cerberoside (thevetin-B), part (Thevetia glycosides) produces positive inotropic effect of the trioside is partially hydrolyzed, losing two on hypodynamic myocardium and electrocardiographic molecules of glucose, yielding a mixture of 41 changes. It also exhibits marked cardiotonic effect in cerberoside, and neriifolin • The enzyme thevetinase is isolated denervated heart lung preparation of dog. All responsible for the hydrolysis. If incipient enzymic cardiac glycosides, thevetin, peruvoside, neriifolin are action is carefully prevented, as high as 4.5% trioside is as potent as Digitalis glycosides and appear to be obtained, with correspondingly insignificant amount of 27 30 promising drugs for congestive heart failure • • One of monoside. In contrast, if the enzymic action is these, peruvoside is even more potent than digoxin and deliberately promoted such as by fermenting the seeds, has been marketed in Germany under the trade name almost the entire quantity of the trioside disappears, 25 Encordin . concomttant. 1 y monost'd e becomes htg' h3436404243· · · · . Fermented seeds additionally yield acetyl glycosides Thevetia Glycosides (neriifolin monoacetate, peruvoside monoacetate). Thevetin was the first glycoside to be isolated31 Partial acetylation of neriifolin yields cerberin and 35 from kernels. Since then as many as 15 glycosides are isomeric neriifolin- 4"-monoacetate • 32 reported in the fresh seeds . The natural glycosides of Thevetia glycosides are chemically closely related to Thevetia are triosides as they contain an aglycone unit each other as represented in Chart 1. combined with three units of sugar. The aglycone of these glycosides is digitoxigenin (or the related The aglycones as well as the glycosides undergo cannogenin and cannogenol) which is one of the isomeric changes in the presence of bases. aglycones of the glycosides of Digitalis purpurea. A number of known and new glycosides have also Cannogenin is the 19-oxo form and cannogenol is the been isolated from various parts of this plant, albeit in 44 45 19-oxy form of digitoxigenin. The sugars are D-glucose small amounts . Abe et a/. isolated several new and L-thevetose (6-deoxy-3-0-methyl-L-arabinose). An cardiac glycosides from air dried leaves including analysis of thevetioside (a mixture of cardenolides) neriifolin (C:mll3404), solanoside, thevetioside (A-G). A showed presence of peruvoside, neriifolin and new cardenolide, neriifoside 3~-0-a.-L-enolide was 33 cerberin . isolated from fresh uncrushed leaves along with 34 46 Thevetin, the first trioside to be isolated , is the peruvoside . Besides, a steroid, 4,16-pregnadien-126- 810 INDIAN 1 CHEM, SEC B, -NOVEMBER 2000 Thevetin (Crude) J C erberos1de! . (ThevetinB) enzyme -2 mots enzymic -2 mols action glucose oct1on glucose Special reduction process oxidation Neriifolin _________:. ______ Peruvoside -----Peruvo acid Reduction acetylation Cerberin 4'-0-acetylneriifolin ---- Theveneriin(rlM>side) (2'-0-acetylneriifolin) Source: Wealth of India Chart 1 hydroxy-3,20-dione
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