Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma
| Autor: | M C Allende, Juan Berenguer, Michael G. Rinaldi, Thomas J. Walsh, Phillip A. Pizzo, S Battaglia, Nasr M. Ali, Stephen C. Piscitelli, K Garrett, Jeannette Y. Lee |
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| Rok vydání: | 1994 |
| Předmět: |
Itraconazole
Biology Pharmacology Kidney Aspergillosis Aspergillus fumigatus Nephrotoxicity Amphotericin B Cyclosporin a medicine Animals Drug Interactions Pharmacology (medical) Mycosis Lung Diseases Fungal medicine.disease biology.organism_classification Infectious Diseases Pharmacodynamics Cyclosporine Female Rabbits Research Article medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 38:1303-1308 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.38.6.1303 |
| Popis: | Itraconazole and amphotericin B were compared by using a newly developed model of invasive pulmonary aspergillosis in rabbits immunosuppressed with methylprednisolone and cyclosporin A (CsA). Both itraconazole at 40 mg/kg (given orally) and amphotericin B at 1 mg/kg (given intravenously) had in vivo antifungal activity in comparison with controls. At these dosages, amphotericin B was more effective than itraconazole in reducing the tissue burden (log10 CFU per gram) of Aspergillus fumigatus (P < 0.05) and the number of pulmonary lesions (P < 0.01). However, there was considerable variation in the near-peak concentrations of itraconazole in plasma (median, 4.15 micrograms/ml; range, < 0.5 to 16.8 micrograms/ml) and a strong inverse correlation between concentrations of itraconazole in plasma and the tissue burden of A. fumigatus. An inhibitory sigmoid maximum-effect model predicted a significant pharmacodynamic relationship (r = 0.87, P < 0.001) between itraconazole concentrations in plasma and antifungal activity as a function of the tissue burden of A. fumigatus. This model demonstrated that levels in plasma of greater than 6 micrograms/ml were associated with a significantly greater antifungal effect. Levels in plasma of less than 6 micrograms/ml were associated with a rapid decline in the antifungal effect. Itraconazole, in comparison with amphotericin B, caused a twofold elevation of CsA levels (P < 0.01) but was less nephrotoxic (P < 0.01). This study of experimental pulmonary aspergillosis demonstrated that amphotericin B at 1 mg/kg/day was more active but more nephrotoxic than itraconazole at 40 mg/kg/day, that itraconazole increased concentrations of CsA in plasma, and that the antifungal activity of itraconazole strongly correlated with concentrations in plasma in an inhibitory sigmoid maximum-effect model. These findings further indicate the importance of monitoring concentrations of itraconazole in plasma as a guide to increasing dosage, improving bioavailability, and optimizing antifungal efficacy in the treatment of invasive pulmonary aspergillosis. |
| Databáze: | OpenAIRE |
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