Cholesterol synthesisenzyme inhibitors

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Pharmacology and toxicology

The lipophylic statins atorvastatin.fluvastatin, lovastatin (mevinolinic acid), pitavastatin, simvastatin, and hydrophilic statins pravastatin and rosuvastatin, are used to treat hyperlipidemia and hypercholesterolemia. These agents reduce the biosynthesis of cholesterol through a competitive inhibition of the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase.

The proliferation-inhibiting properties of some of these agents ('-statin -induced apoptosis) with respect to tumors/malignant diseases are an ongoing topic of discussion.

A case study (Ghidin 1992) described a newborn with birth defects (VATER-association) following maternal treatment with lovastatin in the first trimester: the mother had taken dexampheta-mine at the same time. Another case report described the occurrence of a neural tube defect in a fetus exposed to lovastatin (Hayes 1995).

A collection of human malformations - including the aforementioned cases, holoprocencephaly, other CNS malformations, and limb anomalies - involving first-trimester exposure to the lipophylic HMG-CoA reductase inhibitors atorvastatin, cerivastatin, lovastatin, and simvastatin has been published. The authors suggest a possible link to abnormal Sonic Hedgehog signaling. Cholesterol binding to Sonic Hedgehog protein is required for this protein to play a signaling role in embryonic development. The same authors hypothesized that statins may affect fetal development by lowering in utero cholesterol biosynthesis. No malformations were reported after exposure to hydrophilic statins (Edison 2005A, 2004). In this collection, a cardiac malformation was misclassified as holoprosencephaly (Edison 2005B). These cases were based upon spontaneous uncontrolled reports, and are not proof of a causal association.

On the other hand, experience of the manufacturers involving prospectively collected data on pregnancy exposure to simvastatine (191 cases) and lovastatin (34 cases), and retrospectively collected cases, did not demonstrate an increase in adverse pregnancy outcome compared to general population rates obtained from the US CDC. No specific pattern of anomalies was identified in either the prospective or the retrospective reports. The authors report that a case with hydrocephalus was misclassified as holoprosencephaly in their earlier study by Manson (Pollack 2005, Manson 1996). However, data are still insufficient to exclude a teratogenic risk.

There are no published studies on use of atorvastatin, cerivastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin in human pregnancy. To date, the only case of holoprosencephaly in a fetus, involving exposure to statins during pregnancy, was exposed to cerivastatin (withdrawn from clinical use in 2001).

Experimental animal studies with these agents do not indicate a substantial teratogenic risk; only very high-dose lovastatin exposure of pregnant rats resulted in abnormalities of the skeleton and gas-troschisis in the offspring. Holoprosencephaly as a marker of Sonic Hedgehog dysfunction due to impaired cholesterol biosynthesis has been supported by rat studies; however, the exact relation remains to be clarified. It is clear, however, that the role of cholesterol in embryonic development must be taken into account (Roux 2000).

Recommendation. Atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin should not be prescribed during pregnancy; discontinuing this medication would not significantly impair the long-term treatment of hyperlipidemia, and their safety has not been proven. In addition, theoretical considerations concerning the role of cholesterol in embryo development argue against the intentional use of statins during pregnancy. Nevertheless, inadvertent treatment with these drugs does not require termination of the pregnancy, but a detailed fetal ultrasound to confirm normal morphologic development may be considered.

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