Preclinical evaluation of lovastatin

Macdonald, J. S.; Gerson, Ronald J.; Kornbrust, Douglas J.; Kloss, Michelle W.; Prahalada, S.; Berry, Peter H.; Alberts, Alfred W.; Bokelman, Delwin L.

doi:10.1016/0002-9149(88)90003-3

Cited by 194 publications

(108 citation statements)

References 15 publications

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“…Simvastatin administered at a dose about 250-times higher than the dose normally used to hypercholesterolemia treatment induced thyroid hypertophy and follicular cell adenomas in rats (Smith et al 1991). Similarly, lovastatin administration at high doses was associated with higher incidence of hepatocellular and pulmonary cancers in animal models (MacDonald et al 1988). In another study, an association between fluvastatin and higher risk of thyroid neoplasms and forestomach papillomas in rodents was found (Robison et al 1994).…”

Section: Discussionmentioning

confidence: 96%

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

et al. 2011

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Epidemiological studies indicate that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, play a role in inhibition of several human neoplasia including breast cancer. In this study, chemopreventive effects of atorvastatin in N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. Atorvastatin was administered in the diet at two concentrations: 10 mg/kg (ATOR 10) and 100 mg/kg (ATOR 100). Atorvastatin treatment began 8 days prior to carcinogen administration and subsequently continued for 15 weeks till the end of the experiment. Atorvastatin at a higher dose suppressed tumor frequency by 80.5% (P = 0.0008) and tumor incidence by 49.5% (P = 0.015), and extended latency period by 14 days (P = 0.076) when compared to the control group. Atorvastatin at a lower dose did not significantly alter tumor parameters in comparison with the control group. In the specimens of mammary tumors, atorvastatin (in the ATOR 100 group) significantly decreased mRNA expression of Bcl-2 gene but non-significantly increased Bax mRNA expression compared to control group. Atorvastatin administration did not alter serum concentration of triacylglycerols, total cholesterol, and LDL cholesterol in comparison with controls. This study is the first report on tumor suppressive effect of atorvastatin in rat mammary carcinogenesis.

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Section: Discussionmentioning

confidence: 96%

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

et al. 2011

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“…In one study included in this review, a patient experienced confusion after receiving 120 mg of atorvastatin, a dose that is 40 mg higher than the recommended daily dose for treating hyperlipidemia. 50 Neurotoxic effects associated with high dose statins have been reported in laboratory animals [67][68][69] and a phase 1 study in humans. 70 In the less controlled environment of home use, it is possible that some individuals reporting cognitive adverse events may have unintentionally overdosed.…”

Section: Discussionmentioning

confidence: 99%

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

et al. 2015

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BACKGROUND:In 2012, the United States Food and Drug Administration (FDA) issued a warning regarding potential adverse effects of HMG-CoA reductase inhibitors (statins) on cognition, based on the Adverse Events Reporting System and a review of the medical literature. We aimed to synthesize randomized clinical trial (RCTs) evidence on the association between statin therapy and cognitive outcomes. METHODS: We searched MEDLINE, EMBASE, and Cochrane CENTRAL through December 2012, and reviewed published systematic reviews of statin treatment. We sought RCTs that compared statin treatment versus placebo or standard care, and reported at least one cognitive outcome (frequency of adverse cognitive events or measurements using standard neuropsychological cognitive test scores). Studies reporting sufficient information to calculate effect sizes were included in metaanalyses. Standardized and unstandardized mean differences were calculated for continuous outcomes for global cognition and for pre-specified cognitive domains. The main outcome was change in cognition measured by neuropsychological tests; an outcome of secondary interest was the frequency of adverse cognitive events observed during follow-up. RESULTS: We identified 25 RCTs (all placebo-controlled) reporting cognitive outcomes in 46,836 subjects, of which 23 RCTs reported cognitive test results in 29,012 participants. Adverse cognitive outcomes attributable to statins were rarely reported in trials involving cognitively normal or impaired subjects. Furthermore, meta-analysis of cognitive test data (14 studies; 27,643 participants) failed to show significant adverse effects of statins on all tests of cognition in either cognitively normal subjects (standardized mean difference 0.01, 95 % confidence interval, CI, −0.01 to 0.03, p=0.42) or Alzheimer's disease subjects (standardized mean difference −0.05, 95 % CI −0.19 to 0.10, p=0.38). CONCLUSIONS: Statin therapy was not associated with cognitive impairment in RCTs. These results raise questions regarding the continued merit of the FDA warning about potential adverse effects of statins on cognition.

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“…CoQ10 is an essential co-factor in the generation of metabolic energy and may be important in liver function. MacDonald et al (23) have reported that co-administration of mevalonate with lovastatin in rabbits, rats and dogs, prevents the increases in transaminases levels. This result demonstrates that the transminase increase produced by statins is a direct consequence of inhibition of mevalonate synthesis.…”

Section: Statin Coq10 and Rhabdomyolysis And Liver Dysfunctionmentioning

confidence: 99%

Reduction of Serum Ubiquinol-10 and Ubiquinone-10 Levels by Atorvastatin in Hypercholesterolemic Patients

Mabuchi

Higashikata

Kawashiri

et al. 2005

JAT

107

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Reduction of serum cholesterol levels with statin therapy decreases the risk of coronary heart disease. Inhibition of HMG-CoA reductase by statin results in decreased synthesis of cholesterol and other products downstream of mevalonate, which may produce adverse effects in statin therapy. We studied the reductions of serum ubiquinol-10 and ubiquinone-10 levels in hypercholesterolemic patients treated with atorvastatin. Fourteen patients were treated with 10 mg/day of atorvastatin, and serum lipid, ubiquinol-10 and ubiquinone-10 levels were measured before and after 8 weeks of treatment. Serum total cholesterol and LDL-cholesterol levels decreased significantly. All patients showed definite reductions of serum ubiquinol-10 and ubiquinone-10 levels, and mean levels of serum ubiquinol-10 and ubiquinone-10 levels decreased significantly from 0.81 ± ± ± ± ± 0.21 to 0.46 ± ± ± ± ± 0.10 µ µ µ µ µg/ml (p < 0.0001), and from 0.10 ± ± ± ± ± 0.06 to 0.06 ± ± ± ± ± 0.02 µ µ µ µ µg/ml (p = 0.0008), respectively. Percent reductions of ubiquinol-10 and those of total cholesterol showed a positive correlation (r = 0.627, p = 0.0165). As atorvastatin reduces serum ubiquinol-10 as well as serum cholesterol levels in all patients, it is imperative that physicians are forewarned about the risks associated with ubiquinol-10 depletion. J Atheroscler Thromb, 2005; 12: 111-119.

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Preclinical evaluation of lovastatin

Cited by 194 publications

References 15 publications

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Reduction of Serum Ubiquinol-10 and Ubiquinone-10 Levels by Atorvastatin in Hypercholesterolemic Patients

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