Itraconazole Induced Changes In Cardiac Function

Ref ID: 18756

Author:

J. D. Cleary, Pharm.D. – Professor, K. Stover, Pharm.D. – Assistant Professor, J. Farley, Ph.D. – Professor;

Author address:

Univ. of Mississippi Med. Ctr., Jackson, MS.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: The azole antifungals are rarely associated with severe adverse events. However, recent literature has identified cardiovascular toxicity at therapeutic doses of itraconazole (ITZ). Our purpose was to evaluate antifungal cardiac toxicity, modeling peripheral venous or oral administration at steady state serum concentrations. Methods: Ex vivo live-heart (Langendorff) studies were performed using Harlan Sprague-Dawley rats. Itraconazole, at therapeutic concentrations (0.25-2ug/mL), was compared to negative control Krebs-Henseleit solution (KHS) or negative antifungal control (fluconazole (FCZ)) in dose ranging time studies. Agents were administered to stabilized hearts at rates to achieve reported therapeutic serum concentrations. Myocardial activity (contractility), coronary filling pressure, heart rate, & arrhythmic activity were measured during medication infusion. Primary endpoints were defined as the time to reach a 50% and 80% reduction in contractility. All studies were performed in at least triplicate. Means (time to event) for median antifungal dose were compared to the matched media control and assessed by Student t-test. Results: ITZ was associated with a > 50% reduction in contractility that progressed from 129 + 135 minutes at 0.2ug/mL to 6.5 + 1 minutes at 2.5 ug/mL. We observed a > 80% reduction in contractility that progressed from 175 + 140 minutes at 0.2ug/mL to 8.5 + 1.1 minutes at 2.5ug/mL. The time to events for 50% and 80% reductions were significant (p < 0.05) when compared to control KHS. KHS buffer controls or FCZ were associated with no change in contractility (-5.8 ± 21.3%) during the longest period of exposure (4200 minutes). Conclusions: ITZ was associated with substantial reductions in contractility that occurred significantly sooner than controls. Concurrent studies elucidating ITZ’s mechanism of toxicity suggests mitochondrial dysfunction. Patient care studies will need to be performed to correlate these observations with clinical measures.

Abstract Number: M-991

Conference Year: 2012

Link to conference website: NULL

New link: NULL

Conference abstracts, posters & presentations

Showing 10 posts of 17325 posts found.

  • Title

    Author

    Year

    Number

    Poster