Differential Effects of 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitors on the Development of Myopathy in Young Rats

Reijneveld, Jaap C.; Koot, Radboud W.; Bredman, J.J.; Joles, Jaap A.; Bär, P.R.

doi:10.1203/00006450-199606000-00016

Cited by 55 publications

(36 citation statements)

References 45 publications

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“…In this study, we examined the effects of Cer on Ca 2+ release in skinned skeletal muscle fibers mainly from the mouse, which we used in our previous experiments. In some experiments, however, we also used rat skinned muscle fibers because statin-induced myopathy was reported in the rat (8,9). Our results demonstrated that Cer, a lipophilic type of statin, also had an ability to cause Ca 2+ release from the SR.…”

Section: +mentioning

confidence: 68%

Ca2+-Releasing Effect of Cerivastatin on the Sarcoplasmic Reticulum of Mouse and Rat Skeletal Muscle Fibers

et al. 2003

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Abstract. We analyzed the effect of HMG-CoA reductase inhibitors on Ca 2+ release from the sarcoplasmic reticulum (SR) using chemically skinned skeletal muscle fibers from the mouse and the rat. Cerivastatin (>20 m M) released Ca 2+ from the SR, while pravastatin showed only a little effect. The rates of Ca 2+ release were increased by cerivastatin at all Ca 2+ concentrations tested. Cerivastatin-induced Ca 2+ release in the presence of Ca 2+ was affected by adenosine monophosphate, Mg 2+, and procaine in essentially the same way as for caffeine-induced Ca 2+release. The Ca 2+-uptake capacity of the SR was reduced after co-treatment with ryanodine and cerivastatin at pCa 6.0 to a much greater extent than with ryanodine alone. Thus, cerivastatininduced Ca 2+ release in the presence of Ca 2+ must be a result of the activation of the Ca 2+-induced Ca 2+ release (CICR) mechanism of the ryanodine receptor. However, even when CICR was maximally inhibited by Mg 2+ and procaine, or in the practical absence of Ca 2+ (pCa >8), cerivastatin still caused Ca 2+ release. These results indicate that cerivastatin causes Ca 2+ release also by activating some other mechanism(s) in addition to the activation of CICR. Either or both of these effects might be related to its adverse effect, rhabdomyolysis.

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Section: +mentioning

confidence: 68%

Ca2+-Releasing Effect of Cerivastatin on the Sarcoplasmic Reticulum of Mouse and Rat Skeletal Muscle Fibers

et al. 2003

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“…Several reports have shown that statins may induce apoptosis in cultures of cortical neurons of both humans and rat glioma cells 18 -20 and myopathy in young rats. 21 However, a recent prospective study in humans found no relationship between exposure to Sim during pregnancy and adverse pregnancy outcome. 22 In our experiments, the neuroprotective effect of Sim occurred without significant toxic effects, because the reduction of body weight observed during treatment and at weaning was completely recovered in adults, and both spontaneous activity and cognitive abilities in Sim-treated control animals did not differ from those of control animals.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Protects Against Long-Lasting Behavioral and Morphological Consequences of Neonatal Hypoxic/Ischemic Brain Injury

Balduini

Angelis

Mazzoni

et al. 2001

Stroke

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Background and Purpose-Recent studies suggest that statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) not only reduce the incidence of stroke by lowering cholesterol levels but may also exert neuroprotective effects via a mechanism not related to their lipid-lowering effect. Despite the growing body of evidence, however, the neuroprotective effect of statins in stroke is still controversial. Herein, we studied whether a prophylactic administration of simvastatin (Sim) provides significant protection against brain damage, and we sought to determine its long-lasting behavioral consequences in a neonatal model of hypoxia/ischemia. Methods-Newborn male rats were injected daily from postnatal days 1 to 7 with activated Sim (20 mg/kg) or an equivalent volume of vehicle. On postnatal day 7, the rats were subjected to ligation of the right common carotid artery, followed by 3 hours of hypoxia or by sham operation. The neuroprotective effect of Sim was evaluated after the rats had achieved adulthood by using a battery of behavioral tests and histological analysis. Results-Sim-treated ischemic rats performed the circular water maze, the radial arm maze, and the multiple-choice water maze significantly better than did vehicle-treated ischemic rats. Furthermore, in contrast to the ischemic rats, hypoxia/ischemia-injured rats pretreated with Sim were not hyperactive at weaning and showed less behavioral asymmetry. Consistently, it was found that brain damage was significantly attenuated. Conclusions-These findings indicate that prophylactic administration of statins may provide a potential neuroprotective strategy leading to an improvement in functional outcome in ischemic stroke. However, toxicity concern must be addressed before these agents can be directed to the asphyxiated fetus or newborn. Key Words: cerebral ischemia Ⅲ HMG-CoA reductase inhibitors Ⅲ neuroprotection Ⅲ newborn Ⅲ rats I schemic stroke is one of the leading causes of permanent disabilities and death in the elderly. Stroke also commonly occurs in the perinatal period and can have severe consequences on motor, cognitive, and behavioral functions that span the infant's lifetime. The mechanisms of hypoxia/ischemia (HI)-induced brain damage, the behavioral outcome, and the effect of potential pharmacological treatments during development can be studied in 7-day-old rats subjected to unilateral carotid artery ligation and exposure to a hypoxic environment for 2 to 3 hours. [1][2][3][4] In terms of brain development, this age of the rat is similar to that of near-term human babies. 5 In a recent study, we characterized the long-lasting behavioral alterations occurring in this model of neonatal HI and found that these animals, when adults, show behavioral asymmetry and deficits in performing spatial learning tasks. 4 Therefore, these behavioral abnormalities can be used as an end point to evaluate the efficacy of potential pharmacological treatments that may improve the consequences of a perinatal HI insult.Recent clinical studies have reported ...

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“…Rats, especially juveniles, are susceptible to statin-induced myotoxicity (Reijneveld et al, 1996;Westwood et al, 2005). However, because the rat liver responds to statins by increasing hepatic cholesterol synthesis, use of plasma cholesterol as an indication of statin efficacy precludes the rat from being an optimal model for estimating therapeutic safety margins (Krause and Newton, 1995).…”

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confidence: 99%

The Guinea Pig as a Preclinical Model for Demonstrating the Efficacy and Safety of Statins

Madsen

Janovitz²,

Zhang³

et al. 2007

J Pharmacol Exp Ther

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Statins, because of their excellent efficacy and manageable safety profile, represent a key component in the current armamentarium for the treatment of hypercholesterolemia. Nonetheless, myopathy remains a safety concern for this important drug class. Cerivastatin was withdrawn from the market for myotoxicity safety concerns. BMS-423526 ,5-dihydroxy-heptenoic acid} sodium salt], similar to cerivastatin in potency and lipophilicity, was terminated in early clinical development due to an unacceptable myotoxicity profile. In this report, we describe the guinea pig as a model of statin-induced cholesterol lowering and myotoxicity and show that this model can distinguish statins with unacceptable myotoxicity profiles from statins with acceptable safety profiles. In our guinea pig model, both cerivastatin and BMS-423526 induced myotoxicity at doses near the ED 50 for total cholesterol (TC) lowering in plasma. In contrast, wide differences between myotoxic and TC-lowering doses were established for the currently marketed, more hydrophilic statins, pravastatin, rosuvastatin, and atorvastatin. This in vivo model compared favorably to an in vitro model, which used statin inhibition of cholesterol synthesis in rat hepatocytes and L6 myoblasts as surrogates of potential efficacy and toxicity, respectively. Our conclusion is that the guinea pig is a useful preclinical in vivo model for demonstrating whether a statin is likely to have an acceptable therapeutic safety margin.

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Differential Effects of 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitors on the Development of Myopathy in Young Rats

Cited by 55 publications

References 45 publications

Ca2+-Releasing Effect of Cerivastatin on the Sarcoplasmic Reticulum of Mouse and Rat Skeletal Muscle Fibers

Ca2+-Releasing Effect of Cerivastatin on the Sarcoplasmic Reticulum of Mouse and Rat Skeletal Muscle Fibers

Simvastatin Protects Against Long-Lasting Behavioral and Morphological Consequences of Neonatal Hypoxic/Ischemic Brain Injury

The Guinea Pig as a Preclinical Model for Demonstrating the Efficacy and Safety of Statins

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