CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species

Tsujita, Yasuyuki; Kuroda, Masao; Shimada, Yôko; Tanzawa, Kazuhiko; Arai, Mamoru; Kaneko, Isao; Tanaka, Minoru; Masuda, Hiroshi; Tarumi, Chitoshi; Watanabe, Yoshio; Fujii, Satoshi

doi:10.1016/0005-2760(86)90117-7

Cited by 366 publications

(112 citation statements)

References 30 publications

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“…Previously, we reported that HMG-CoA reductase activity and protein content, as well as cholesterol biosynthesis, were increased in human HCC tissues (Kawata et al, 1990). The liver has a high affinity for pravastatin (Tsujita et al, 1986). Prior to this study, we observed that pravastatin at a daily dose of 40 mg led to a significant decrease in serum concentrations of cholesterol and AFP in 3 patients with hypercholesterolaemia associated with HCC as a paraneoplastic syndrome (data not shown).…”

Section: Discussionmentioning

confidence: 75%

Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

et al. 2001

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Summary Chemotherapy is not effective for hepatocellular carcinoma (HCC). HMG-CoA redutase inhibitors have cytostatic activity for cancer cells, but their clinical usefulness is unknown. To investigate whether pravastatin, a potent HMG-CoA reductase inhibitor, prolongs survival in patients with advanced HCC, this randomized controlled trial was conducted between February 1990 and February 1998 at Osaka University Hospital. 91 consecutive patients <71 years old (mean age 62) with unresectable HCC were enroled in this study. 8 patients were withdrawn because of progressive liver dysfunction; 83 patients were randomized to standard treatment with or without pravastatin. All patients underwent transcatheter arterial embolization (TAE) followed by oral 5-FU 200 mg -1 d for 2 months. Patients were then randomly assigned to control (n = 42) and pravastatin (n = 41) groups. Pravastatin was administered at a daily dose of 40 mg. The effect of pravastatin on tumour growth was assessed by ultrasonography. Primary endpoint was death due to progression of HCC. The duration of pravastatin administration was 16.5 ± 9.8 months (mean ± SD). No patients in either group were lost to follow-up. Median survival was 18 months in the pravastatin group versus 9 months in controls (P = 0.006). The Cox proportional hazards model showed that pravastatin was a significant factor contributing to survival. Pravastatin prolonged the survival of patients with advanced HCC, suggesting its value for adjuvant treatment.

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Section: Discussionmentioning

confidence: 75%

Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

et al. 2001

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“…Clinical trials have demonstrated that pravastatin sodium (hereafter referred to as pravastatin) is a safe and potent orally effective cholesterollowering agent (Nakaya et al, 1987;Yoshino et al, 1986). Animal studies have demonstrated that pravastatin is a tissue-selective inhibitor of HMG-CoA reductase (Tsujita et al, 1986). Since the major site of cholesterol synthesis is the liver, this tissue-selective property of pravastatin may be a desirable clinical feature.…”

Section: Introductionmentioning

confidence: 99%

Disposition of pravastatin sodium, a tissue‐selective HMG‐CoA reductase inhibitor, in healthy subjects.

Singhvi¹,

Pan²,

Morrison³

et al. 1990

Brit J Clinical Pharma

159

126

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Pravastatin sodium, a competitive inhibitor of HMG-CoA reductase, is a new orally effective hypocholesterolaemic agent. In a two-way crossover study, eight healthy male subjects each received an intravenous and an oral dose of [14C]-pravastatin sodium. The oral absorption of [14C] activity from pravastatin sodium was about 34% and the oral bioavailability was about 18%, suggesting first-pass metabolism of pravastatin. After the intravenous dose, the recovery of radioactivity averaged 60% and 34% in urine and faeces, respectively. Corresponding values were 20% (urine) and 71% (faeces) for the oral dose. The estimated average plasma elimination half-life of pravastatin was 0.8 and 1.8 h for the intravenous and oral routes, respectively. The average values for total and renal clearances were 13.5 and 6.3 ml min-' kg-', respectively, and the steady-state volume of distribution averaged 0.51 kg-1. These results suggest that both kidney and liver are important sites of elimination for pravastatin.

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“…Previous studies of patients with heterozygous FH have shown the reduction of plasma LDL cholesterol levels by such drugs,7-9 and the additive effects of bile acid sequestrant resins were observed. [10][11][12] In this study, we used the heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbit as an animal model for heterozygous FH to investigate the hepatic LDL receptor activity.313, 14 We administered to heterozygous WHHL rabbits, CS-514, 15 an inhibitor of HMG-CoA reductase alone and in combination with cholestyramine, and we studied the induction of hepatic LDL receptor protein and mRNA for LDL receptors.…”

mentioning

confidence: 99%

Induction of mRNA for low-density lipoprotein receptors in heterozygous Watanabe heritable hyperlipidemic rabbits treated with CS-514 (Pravastatin) and cholestyramine.

et al. 1989

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We administered CS-514, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, alone and in combination with cholestyramine to heterozygous Watanabe heritable hyperlipidemic rabbits. This rabbit model for heterozygous familial hypercholesterolemia has hepatic low-density lipoprotein receptors that are assumed to be half as many as in normal rabbits. CS-514 alone lowered plasma low-density lipoprotein cholesterol levels by 50%, and in combination with cholestyramine, it lowered levels by 80%. The membrane-binding assay showed these drugs caused 1.5-and 1.8-fold increases in the number of hepatic low-density lipoprotein receptors, respectively. We also measured the amount of mRNA for low-density lipoprotein receptor by S1 nuclease protection assay in the same livers as above. These drugs induced mutant mRNA for the low-density lipoprotein receptor, which has an in-flame deletion of 12 nucleotides, as well as normal receptor mRNA. CS-514 alone produced a 1.8-fold increase in the amount of mRNA for the normal receptor and a 2.3-fold increase for the mutant mRNA, whereas CS-514 in combination with cholestyramine produced 1.9-and 3.1-fold increases, respectively. We conclude that CS-514 induces mRNA for the low-density lipoprotein receptor, subsequently increasing the receptor protein in the liver, and then reduces the levels of plasma cholesterol, and that the induction is augmented when the drug is administered in combination with cholestyramine. (Circulation 1989;79:1084-1090 P atients with hypercholesterolemia, especially with high levels of plasma low-density lipoprotein (LDL) cholesterol, are known to be at increased risk for coronary heart disease. LDL carries the bulk of cholesterol in plasma and is mostly catabolized through a hepatic LDL receptor.1 The decrease in the number of hepatic LDL receptors raises the level of LDL cholesterol in blood, causing both the overproduction and the underca-

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CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species

Cited by 366 publications

References 30 publications

Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

Disposition of pravastatin sodium, a tissue‐selective HMG‐CoA reductase inhibitor, in healthy subjects.

Induction of mRNA for low-density lipoprotein receptors in heterozygous Watanabe heritable hyperlipidemic rabbits treated with CS-514 (Pravastatin) and cholestyramine.

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