Recent advances in plant hepatoprotectives - CIMAP Staff - Central ...

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RECENT ADVANCES IN PLANT HEPATOPROTECTIVES * 757 C. Biological Activity Different in-vivo studies were done on animal models with hepatic damage induced by various agents to establish the hepatoprotective activity of picroliv. It showed potent dose-dependent (3–12 mg/kg p.o. for 1–2 weeks) activity by significant reversal in the serum and tissue biochemical parameters including histopathology. In these studies picroliv was found to be more active than silymarin. 100 The hepatoprotective activity data of picroliv has been depicted in Table II. The extract of P. kurroa showed hepatoprotective activity when given to patients suffering from jaundice. 114 Picroliv showed curative in-vitro activity in primary cultured rat hepatocytes against toxicity induced by thioacetamide, galactosamine, and CCl 4 . 103 It resulted in a concentrationdependent restoration of altered viability and biochemical parameters. Picroliv showed dosedependent choleretic effects in conscious rats and anaesthetized guinea pigs and cats. 109 Picroliv was found potent against viral hepatitis by showing a promising anti-HBsAg-like effect. It is also able to lower serum lipids (total VLDL and LDL cholesterol), triglycerides and phospolipids, in both normal and hyperlipidemic animals. 115 Picroliv has also showed a potent inhibition of hepatocarcinogenesis. 116 D. Mode of Action Picroliv antagonizes paracetamol-induced lowering in LDL receptor cell surface expression and increases conjugated dienes in hepatocytes. 117 Its antioxidant effect has been shown to be similar to that of superoxide dismutase, 118 metal-ion chelators, and xanthine oxidase inhibitors. Picroliv restored depleted glutathione levels in rats infected with P. berghei, thereby enhancing detoxification and antioxidation. Thus, picroliv maintains a normal oxidation-reduction balance, glutathione metabolism and reduce the increased levels of lipid peroxidation products in the liver. 119 Like silymarin, it showed liver regeneration in rats, possibly via stimulation of nucleic acid and protein synthesis. 120,121 Thus, its hepatoprotective effect appears to result from a combination of membranestabilizing, hypolipidemic and antioxidant properties. These properties may also be responsible for the effects on the immune system. E. Toxicity and Side Effects Picroliv showed LD 50 value 2026.9 mg/Kg when administered by the peritoneal route in mice. No mortality was found up to 2.5 g/kg dose in mice or rats through oral route. Long-term toxicity studies Table II. Hepatoprotective Activity of Picroliv Toxin Dosage/kg %Histopathological Changes Picroliv dose (mg/kg p.o.)Xdays % protection with picroliv Reference Paracetamol 2g p.o. 35-100 12x7 50-100 101, 102 Carbon 0.7mlx6i.p. 35-120 12x15 70-100 103, 104 tetrachloride Thioacetamide 100mg s.c. 35-170 25x7 50-90 105-107 d- 80mg i.p. 35-890 12x7 50-100 108, 109 Galactosamine Ethyl alcohol 20 ml 30-180 6x7 60-90 110-112 (40%)x21 p.o. Rifampicin 50mgx5 i.p. 15-60 12x6 45-100 113 Medicinal Research Reviews DOI 10.1002/med
758 * NEGI ET AL. done on histopathological parameters in rats showed picroliv was non-toxic. 122 A similar experiment done on adult rhesus monkeys showed no abnormality in food intake, daily activities, body weight, hematology, and blood biochemistry. F. Future Prospects Picroliv was found to be a safe drug with no reported side effects. 123 Picroliv has successfully completed phase I and phase II clinical trials and waiting for phase III clearance. Being a potent hepatoprotective, this may emerge as a potent hepatoprotective drug in a near future. 6. PHYLLANTHIN AND HYPOPHYLLANTHIN A. Introduction Phyllanthin (13) and hypophyllanthin (14) are potent hepatoprotective lignans found in Phyllanthus niruri Linn. (Family: Euphorbiacea). The genus includes more than 600 species of shrubs, trees, and annual/biennial herbs distributed throughout the globe, many of which are used medicinally in different countries such as P. emblica L., P. urinaria L., P. reticulates in Indo-China, P. niruri in Brazil and West Indies, P. elegans Wall, P. urinaria in the Philippines. The plant is commonly known as ‘‘Bhuiamliki’’ in India and ‘‘Look Tai Bai’’ in Thailand. P. niruri is a small, erect, annual herb that grows 30–60 cm in height mainly as a weed in both cultivated fields and wastelands. It is a wellknown Ayurvedic plant used in folk remedy for jaundice and other liver disorders. B. Chemistry Chemically, both phyllanthin (13) and hypophyllanthin (14) are lignans (Fig. 10). 124,125 Phyllanthin is linked through C8–C8 0 of phenyl propanoid units, while hypophyllanthin is additionally linked through C2–C7 0 to make a tetrahydronaphthalene ring system. The stereochemistry of phyllanthin was established as 8(S), 8 0 (R). 126 Phyllanthin and hypophyllanthin have been isolated from the hexane extracts of P. niruri. A complete spectral studies 127 including single crystal X-ray analysis 128 have left no doubt on the full 3-dimensional structural characterization of phyllanthin and hypophyllanthin. Being important markers of the medicinal plant, several HPTLC methods have also been developed for quantitative estimation of these molecules. 129 C. Biological Activity The plant has been effective against infective hepatitis 130,131 and other disorders of liver. 132–134 The hexane fraction of the ethanolic extract showed potent hepatoprotective activity. Its liver protective effects have been established by various in vitro and in vivo experiments in rats and mice. Human H 3 CO H 3 CO 3' 4' H 2' 7' 9' 1' 8' OCH 3 6' 8 OCH 3 7 5' 1 H 9 6 2 5 3 4 OCH 3 OCH 3 13 H 3 CO O O H H H OCH 3 OCH 3 14 OCH 3 OCH 3 Medicinal Research Reviews DOI 10.1002/med Figure 10. Structures of phyllanthin (13) and hypophyllanthin (14).
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