Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias. We evaluated the cardiac effect of azole antifungals, specifically ITZ, and possible mechanisms of toxicity. Ex vivo live-heart studies were performed utilizing Sprague Dawley rats. Short exposure (<5 minutes), random crossover, dose ranging studies were performed with each pharmacologic agent. ITZ focused trials also included dose ranging utilizing a non-crossover design. The only azole found to have significant toxicity was ITZ. At ITZ ~ ED25 (2 - 2.5 ug/mL) exposures, contractility decreased by 22.2% ± 15.7% and amplitude of left ventricular pressure decreased by 11% ± 0.17%. Electron micrograph and alterations in mitochondrial respiration suggest mitochondrial toxicity as an underlying mechanism. In conclusion, ITZ was associated with reductions in contractility, possibly secondary to mitochondrial dysfunction and dilated cardiomyopathy.
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机译:Structure Determination and Mechanistic Insights of: I.Cyanobacteriochrome NpR6012g4 Light Sensor Protein in Phototaxis II.Retinal Degeneration 3 (RD3) Protein in Vision III.Ryanodine Receptor 2 (RyR2) Regulation by Calmodulin (CaM) in Cardiac Function =结构测定和机理洞悉:I.趋光性中的蓝细菌色素NpR6012g4光敏蛋白 II.视觉作用中的视网膜退化蛋白3 III.心脏功能中的钙调蛋白调控兰诺定受体2