作者: Philip B. Inskeep ; Charles E. Chandler ; Heidi A. Woody ; Lawrence M. Zaccaro ; Faan-Wen Bangerter ; Michael P. DeNinno ; Judith L. Pettini ; Eliot D. Sugarman ; Robert W. Wilkins ; Theresa C. Wilson ; Yvette E. Savoy ; Peter A. McCarthy ; Lee A. Morehouse

The hypocholesterolemic activities of pamaqueside and tiqueside, two structurally similar saponins, were evaluated in cholesterol-fed rabbits. The pharmacological profiles of the saponins were virtually identical: both dose-dependently decreased the intestinal absorption of labeled cholesterol 25-75%, increased fecal neutral sterol excretion up to 2.5-fold, and decreased hepatic cholesterol content 10-55%. High doses of pamaqueside (>5 mg/kg) or tiqueside (>125 mg/kg) completely prevented hypercholesterolemia. Decreases in plasma and hepatic cholesterol levels were strongly correlated with increased neutral sterol excretion. Ratios of neutral sterol excreted to pamaqueside administered were greater than 1:1 at all doses, in opposition to the formation of a stoichiometric complex previously suggested for tiqueside and other saponins. Ratios in tiqueside-treated rabbits were less than unity, a reflection of its lower potency. Pamaqueside-treated rabbits exhibited a more rapid decline in plasma cholesterol concentrations than control animals fed a cholesterol-free diet, indicating that the compound also inhibited the absorption of biliary cholesterol. Intravenous administration of pamaqueside had no effect on plasma cholesterol levels despite plasma levels twice those observed in rabbits given pamaqueside orally. These data indicate that pamaqueside and tiqueside induce hypocholesterolemia by blocking lumenal cholesterol absorption via a mechanism that apparently differs from the stoichiometric complexation of cholesterol hypothesized for other saponins.

1997-07-01·Journal of Cardiovascular Pharmacology4区 · 医学

Inhibiting Cholesterol Absorption with CP-88,818 (β-Tigogenin Cellobioside; Tiqueside): Studies in Normal and Hyperlipidemic Subjects

4区 · 医学

Article

作者: Sheryl L. Windsor ; William S. Harris ; Carlos A. Dujovne ; Fran A. Newton ; Linda L. Colle Gerrond ; Robert A. Gelfand

CP-88,818 (beta-tigogenin cellobioside; tiqueside) is a synthetic saponin developed to treat hypercholesterolemia by inhibiting the absorption of biliary and dietary cholesterol. Two studies are reported here: one in patients to assess safety and efficacy, and one in normal volunteers to explore the mechanism of action. The former included 15 hypercholesterolemic outpatients [low-density lipoprotein cholesterol (LDL-C) > or = 160 mg/dl] treated with 1, 2, and 3 g of tiqueside daily (b.i.d.) in a crossover design for three 2-week treatment periods, each separated by a 3-week placebo period. The mechanistic study was conducted with 24 healthy male subjects who were randomized in a parallel group design to either placebo (n = 6) or tiqueside (2 or 4 g/day; n = 9 each) once daily for 3 weeks. All subjects in this study were fed a low-fat, low-cholesterol diet [National Cholesterol Education Program (NCEP) Step 1]. Fecal steroid excretion rates and plasma lipid levels were determined at baseline and after 3 weeks of treatment. Fractional cholesterol absorption was measured before and after treatment by the continuous feeding, dual-isotope method. Tiqueside produced a dose-dependent reduction in plasma LDL cholesterol levels in the hypercholesterolemic patients. In the mechanistic study, it decreased fractional cholesterol absorption rates and increased fecal neutral sterol excretion rates, changes associated with trends toward lower LDL cholesterol levels. Other lipoprotein levels were unaffected, as were fecal fat and bile acid excretion and fat-soluble vitamin absorption. Thus tiqueside dose-dependently inhibits cholesterol absorption in humans, resulting in a reduction in serum LDL cholesterol levels.

1996-01-01·Journal of Medicinal Chemistry1区 · 医学

11-Ketotigogenin Cellobioside (Pamaqueside): A Potent Cholesterol Absorption Inhibitor in the Hamster

1区 · 医学

Article

作者: Fowler, Michael A. ; Watson, Harry A. ; Zaccaro, Lawrence M. ; Wilkins, Robert W. ; Pezzullo, Susan L. ; Cosgrove, Patricia G. ; Walinsky, Stanley W. ; Bangerter, Faan Wen ; Chandler, Charles E. ; Urban, Frank J. ; Lambert, John F. ; McCarthy, Peter A. ; Etienne, John B. ; Duplantier, Kimberly ; O'Donnell, John P. ; DeNinno, Michael P. ; Morehouse, Lee A. ; Wilson, Theresa C. ; Zawistoski, Michael P.

Plant saponins have been shown to inhibit cholesterol absorption in several species.For example, tiqueside (CP-88,818, tigogenin cellobioside) (I), a synthetic compound structurally-related to plant saponins, has been shown to inhibit cholesterol absorption and/or lower plasma cholesterol in eight species.Our objective was to identify a compound with increased potency relative to I.Literature data on plant saponins led us to investigate modification of the spirostane backbone of I.Ultimately, we discovered the greatly enhanced potency of C-ring oxygenated spirostane glycosides typified by 11-ketotigogenin cellobioside, pamaqueside (CP-148,623) (II).In cholesterol-fed male golden Syrian hamsters, II was 10-30-fold more potent than tiqueside with regard to effects on cholesterol absorption inhibition, plasma cholesterol lowering and hepatic cholesterol lowering.Pharmacokinetic studies in the dog showed II to have a substantially lower bioavailability than I.Since compounds in this class are believed to operate via a nonsystemic mechanism of action, the pharmacokinetic profile of II provides a further advantage over I.

100 项与 Tiqueside 相关的药物交易

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