Agents and mechanisms of toxic myopathy.

Ralph W Kuncl

University of Rochester, Rochester, New York 14627, USA.

Current opinion in neurology 2009 Oct

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Mechanistic-based research has made possible a more pathophysiologic approach to certain drug-induced muscle disorders, especially those caused by the lipid-lowering statin family of drugs, but also myopathies caused by antimicrotubule drugs, mitochondrial toxins, foods, and purported nutriceutical remedies. This is a critical review of those syndromes that are most well founded on evidence of challenge/de-challenge/re-challenge, case-controls, or experimental controls. Statins are well tolerated drugs with very high safety windows in skeletal muscle, and third-generation statins now under development offer the hope of even less risk of toxic myopathy. Toxicity is dose-related and time-related, and is due to intramyofiber cascades downstream from 3-hydroxy-3-methylglutaryl-coenzyme A (HMG Co-A) reductase inhibition. A robust pathophysiologic animal model shows that statins decrease strength and increase cytosolic Ca2+ by increasing both mitochondrial Ca2+ permeability and Ca2+ release from sarcoplasmic reticulum. As a result, the earliest pathologic change in statin myotoxicity is compatible with simple necrosis and intracellular membrane accumulation. Genome-wide searching has yielded a single nucleotide polymorphism in the SLCO1B1 gene for the organic anion-transporting polypeptide that regulates statin uptake. Drug-drug interactions dominate recent reports of all toxic myopathies. The peculiar mitochondrial pathology of zidovudine-induced mitochondrial DNA depletion, cytochrome oxidase depletion, and mitochondrial proliferation has been confirmed in a rigorous animal model. Finally, recent interest has been piqued by putative lipid-lowering neutraceuticals like red yeast rice (Monascus purpureus) and edible mushrooms that can clearly cause toxic myopathy. A principled approach to the diagnosis of toxic myopathies, based on the consideration of currently known pathophysiologic mechanisms, biopsy pathology, the characteristic clearance properties of creatine kinase, the time course of muscle fiber regeneration, drug challenge/de-challenge/re-challenge, and differential diagnoses, rather than on mere temporal association, will reduce the healthcare costs of common diagnostic error.