Abstract
D0870 is a novel azole antifungal compound. It was compared with conventional amphotericin B and itraconazole therapy in two murine models of invasive aspergillosis, one a systemic nonimmunocompromised mouse model and the other a temporarily neutropenic mouse respiratory model. D0870 was given orally and achieved measurable concentrations in serum approximately proportional to the daily dose with accumulation over time if it was given twice daily. Amphotericin B at 3.3 mg/kg of body weight was given intraperitoneally for four to six doses, and itraconazole was given orally in a cyclodextrin suspension at 5 to 50 mg/kg daily or twice daily (BID). The duration of therapy varied from 7 to 14 days. In the nonimmunocompromised mouse model, D0870 at 25 mg/kg BID was slightly inferior to amphotericin B and itraconazole with regard to mortality, with a median survival of 20 days for the three groups (P = 0.03 compared with amphotericin B). However, D0870 at 25 mg/kg BID was inferior to amphotericin B (but not itraconazole) with respect to renal culture (P = 0.01) and brain culture (P = 0.0001) results. Only amphotericin B was statistically superior to controls with regard to mortality. In the neutropenic mouse respiratory model, D0870 at 50 mg/kg/day was superior to amphotericin B, itraconazole, and controls with regard to mortality. D0870 at both 25 and 50 mg/kg/day was statistically superior to controls with regard to lung culture results (P = 0.004 to 0.04). A second experiment with a higher inoculum showed that no drug regimen was effective in that model. In all models low doses and concentrations of D0870 in serum were ineffective. D0870 has some efficacy for the treatment of invasive aspergillosis when it is given at modest doses.
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- Clemons K. V., Stevens D. A. Utility of the triazole D0870 in the treatment of experimental systemic coccidioidomycosis. J Med Vet Mycol. 1994;32(4):323–326. doi: 10.1080/02681219480000411. [DOI] [PubMed] [Google Scholar]
- Denning D. W., Follansbee S. E., Scolaro M., Norris S., Edelstein H., Stevens D. A. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med. 1991 Mar 7;324(10):654–662. doi: 10.1056/NEJM199103073241003. [DOI] [PubMed] [Google Scholar]
- Denning D. W., Stevens D. A. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis. 1990 Nov-Dec;12(6):1147–1201. doi: 10.1093/clinids/12.6.1147. [DOI] [PubMed] [Google Scholar]
- Denning D. W., Stevens D. A. Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis. Antimicrob Agents Chemother. 1991 Jul;35(7):1329–1333. doi: 10.1128/aac.35.7.1329. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Denning D. W., Tucker R. M., Hanson L. H., Stevens D. A. Treatment of invasive aspergillosis with itraconazole. Am J Med. 1989 Jun;86(6 Pt 2):791–800. doi: 10.1016/0002-9343(89)90475-0. [DOI] [PubMed] [Google Scholar]
- Meunier F. Alternative modalities of administering amphotericin B: current issues. J Infect. 1994 May;28 (Suppl 1):51–56. doi: 10.1016/s0163-4453(94)95986-2. [DOI] [PubMed] [Google Scholar]
- Moore C. B., Law D., Denning D. W. In-vitro activity of the new triazole D0870 compared with amphotericin B and itraconazole against Aspergillus spp. J Antimicrob Chemother. 1993 Dec;32(6):831–836. doi: 10.1093/jac/32.6.831. [DOI] [PubMed] [Google Scholar]
- Peng T., Galgiani J. N. In vitro studies of a new antifungal triazole, D0870, against Candida albicans, Cryptococcus neoformans, and other pathogenic yeasts. Antimicrob Agents Chemother. 1993 Oct;37(10):2126–2131. doi: 10.1128/aac.37.10.2126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tucker R. M., Hanson L. H., Brummer E., Stevens D. A. Activity of ICI 195,739, a new oral triazole, compared with that of ketoconazole in the therapy of experimental murine blastomycosis. Antimicrob Agents Chemother. 1989 Apr;33(4):573–575. doi: 10.1128/aac.33.4.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yamada H., Tsuda T., Watanabe T., Ohashi M., Murakami K., Mochizuki H. In vitro and in vivo antifungal activities of D0870, a new triazole agent. Antimicrob Agents Chemother. 1993 Nov;37(11):2412–2417. doi: 10.1128/aac.37.11.2412. [DOI] [PMC free article] [PubMed] [Google Scholar]