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
Full Text
The Full Text of this article is available as a PDF (149.8 KB).
Acknowledgements
We would like to thank Audrey Hutchcraft for her contributions which have helped to support the generation of this manuscript. This work was supported in full by Baxter Healthcare Corporation.
References
- 1.Pfaller M, Wenzel R. The epidemiology of fungal infections. In: Elias E, McGinnis M, Pfaller M, editors. Clinical mycology. New York: Elsevier Science; 2003. [Google Scholar]
- 2.Pappas P, Kauffman C, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503–535. doi: 10.1086/596757. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Vehreschild J, Sieniawski M, Reuter S, et al. Efficacy of caspofungin and itraconazole as secondary antifungal prophylaxis: analysis of data from a multinational registry. Int J Antimicrob Agents. 2009;34:446–450. doi: 10.1016/j.ijantimicag.2009.06.025. [DOI] [PubMed] [Google Scholar]
- 4.Pappas P, Rex J, Sobel J, et al. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38:161–189. doi: 10.1086/380796. [DOI] [PubMed] [Google Scholar]
- 5.Ohta K, Kosaka S, Nakao Y, et al. Efficacy and safety of intravenous itraconazole as empirical antifungal therapy for persistent fever in neutropenic patients with hematological malignancies in Japan. Int J Hematol. 2009;89:649–655. doi: 10.1007/s12185-009-0316-3. [DOI] [PubMed] [Google Scholar]
- 6.Walsh T, Anaissie E, Denning D, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–360. doi: 10.1086/525258. [DOI] [PubMed] [Google Scholar]
- 7.Hughes W, Armstrong D, Bodey G, et al. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis. 1997;25:551–573. doi: 10.1086/513764. [DOI] [PubMed] [Google Scholar]
- 8.Revankar S, Kirkpatrick W, McAtee R, et al. Detection and significance of fluconazole resistance in oropharyngeal candidiasis in human immunodeficiency virus-infected patients. J Infect Dis. 1996;174:821–827. doi: 10.1093/infdis/174.4.821. [DOI] [PubMed] [Google Scholar]
- 9.Wingard J, Merz W, Rinaldi M, et al. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. New Engl J Med. 1991;325:1274–1277. doi: 10.1056/NEJM199110313251803. [DOI] [PubMed] [Google Scholar]
- 10.Walsh T, Teppler H, Donowitz G, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. New Engl J Med. 2004;351:1391–1402. doi: 10.1056/NEJMoa040446. [DOI] [PubMed] [Google Scholar]
- 11.Boogaerts M, Winston D, Bow E, et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. Ann Intern Med. 2001;135:412–422. doi: 10.7326/0003-4819-135-6-200109180-00010. [DOI] [PubMed] [Google Scholar]
- 12.Rabinow B, Kipp J, Papadopoulos P, et al. Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat. Int J Pharm. 2007;339:251–260. doi: 10.1016/j.ijpharm.2007.02.030. [DOI] [PubMed] [Google Scholar]
- 13.Andes D. In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis. Antimicrob Agents Chemother. 2003;47:1179–1186. doi: 10.1128/AAC.47.4.1179-1186.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.SPORANOX® (itraconazole) Injection package insert. Revised March 2009
- 15.Ahmad S, Singer S, Leissa B. Congestive heart failure associated with itraconazole. The Lancet. 2001;357:1766–1767. doi: 10.1016/S0140-6736(00)04891-1. [DOI] [PubMed] [Google Scholar]
- 16.Kipp J, Wong J, Doty M et al (2003) Microprecipitation method for preparing submicron suspensions. US Patent No. 6607784 B2
- 17.Code of Federal Regulations (2009) Title 9: Animals and animal products. Chapter 1, subchapter A, parts 1, and 3: Animal welfare. Jan 1, 2009.
- 18.Guide for the care and use of laboratory animals. Bethesda: Public Health Service, US Dept. of Health and Human Services; 1996. [Google Scholar]
- 19.Patterson S, Piper H, Starling E. The regulation of the heartbeat. J Physiol. 1914;48(6):465–513. doi: 10.1113/jphysiol.1914.sp001676. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Moghimi M, Hunter C, Murray C. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev. 2001;53:283–318. [PubMed] [Google Scholar]