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J. Med. Toxicol. (2010) 6:331336 DOI 10.1007/s13181-010-0025-6
FEATURE ARTICLE
Nanosuspension Formulation of Itraconazole Eliminates the Negative Inotropic Effect of SPORANOX in Dogs
Jeff McKee & Barrett Rabinow & Chyung Cook &
Jerry Gass
Published online: 18 March 2010# American College of Medical Toxicology 2010
Abstract Previously, it was observed that a nanosuspension formulation of itraconazole was more efficacious and yet less acutely toxic in rats as compared with the conventional solution formulation, SPORANOX (itraconazole) Injection. The present study compares the two formulations with respect to specifically myocardial contractility in conscious dogs. Motivation for doing so is highlighted by the black-box warning in the package insert for SPORANOX (itraconazole) Injection, which warns of negative inotropic effects. Conscious dogs, instrumented with a high-fidelity pressure transducer in the left ventricle, were placed in a sling for dosing and cardiac monitoring. Test and control articles were administered intravenously via a peripheral vein, and left ventricular parameters were measured continuously through 60 min from the start of dosing. As expected, SPORANOX (itraconazole) Injection caused a significant reduction in myocardial contractility as determined by the contractility index. In contrast, the itraconazole nanosuspension administered at twice the dose and at twice the rate of infusion did not result in significant changes in myocardial contractility. A novel formulation technology applied to itraconazole completely prevented the negative inotropic effect observed in conscious dogs as compared with SPORANOX (itraconazole) Injection.
Keywords Itraconazole . Ventricular contractility. Dog
Introduction
Opportunistic fungal infections have increased very significantly over the last 35 years, in both incidence and severity with associated mortality. This has occurred as patients immunological systems have become increasingly compromised, in response to disease states such as AIDS, cancer, and diabetes, as well as the use of more aggressive medical and surgical strategies, including life support systems, broad-spectrum antibiotics, high-dose cytotoxic chemotherapy, and organ transplantation [1].
To meet this challenge, an armamentarium of newer antifungal agents has been developed, accompanied by guidelines for their use that have become ever more specific [2]. This may have encouraged clinicians to proceed with dose-intensive anticancer chemotherapy even in patients having contracted invasive fungal disease (IFD) during previous cycles of treatment. However, these patients are at high risk of recurrent IFD, often with fatal outcome. Hence, efficacy of antifungal agents...