Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis (original) (raw)

Abstract

The in vivo activity of the Merck antifungal echinocandin drug candidate MK-0991 (L-743,872) was evaluated in mouse models of disseminated candidiasis, aspergillosis, and cryptococcosis. The echinocandins are potent inhibitors of 1,3-beta-D-glucan synthase. Two models of disseminated candidiasis were used. In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED50s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 21 days after challenge, respectively. In a C. albicans target organ assay (TOA) with DBA/2N mice, MK-0991 at levels of > or =0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mice from 1 to 28 days after challenge. Even when given as a single intraperitoneal dose either 30 min or 24 h after challenge, MK-0991 was effective and significantly reduced the numbers of C. albicans CFU/g of kidney compared to those in the controls. MK-0991 was >300-fold less active when it was administered orally than when it was administered parenterally. MK-0991 was efficacious in mouse TOAs against other C. albicans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococcus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of > or =0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respectively, at 28 days after challenge. MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.

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Selected References

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  1. Abruzzo G. K., Flattery A. M., Gill C. J., Kong L., Smith J. G., Krupa D., Pikounis V. B., Kropp H., Bartizal K. Evaluation of water-soluble pneumocandin analogs L-733560, L-705589, and L-731373 with mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis. Antimicrob Agents Chemother. 1995 May;39(5):1077–1081. doi: 10.1128/aac.39.5.1077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bartizal K., Gill C. J., Abruzzo G. K., Flattery A. M., Kong L., Scott P. M., Smith J. G., Leighton C. E., Bouffard A., Dropinski J. F. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicrob Agents Chemother. 1997 Nov;41(11):2326–2332. doi: 10.1128/aac.41.11.2326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bartizal K., Scott T., Abruzzo G. K., Gill C. J., Pacholok C., Lynch L., Kropp H. In vitro evaluation of the pneumocandin antifungal agent L-733560, a new water-soluble hybrid of L-705589 and L-731373. Antimicrob Agents Chemother. 1995 May;39(5):1070–1076. doi: 10.1128/aac.39.5.1070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bouffard F. A., Zambias R. A., Dropinski J. F., Balkovec J. M., Hammond M. L., Abruzzo G. K., Bartizal K. F., Marrinan J. A., Kurtz M. B., McFadden D. C. Synthesis and antifungal activity of novel cationic pneumocandin B(o) derivatives. J Med Chem. 1994 Jan 21;37(2):222–225. doi: 10.1021/jm00028a003. [DOI] [PubMed] [Google Scholar]
  5. Hajdu R., Thompson R., Sundelof J. G., Pelak B. A., Bouffard F. A., Dropinski J. F., Kropp H. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872). Antimicrob Agents Chemother. 1997 Nov;41(11):2339–2344. doi: 10.1128/aac.41.11.2339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kurtz M. B., Douglas C., Marrinan J., Nollstadt K., Onishi J., Dreikorn S., Milligan J., Mandala S., Thompson J., Balkovec J. M. Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis. Antimicrob Agents Chemother. 1994 Dec;38(12):2750–2757. doi: 10.1128/aac.38.12.2750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kurtz M. B., Heath I. B., Marrinan J., Dreikorn S., Onishi J., Douglas C. Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)-beta-D-glucan synthase. Antimicrob Agents Chemother. 1994 Jul;38(7):1480–1489. doi: 10.1128/aac.38.7.1480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Pregibon D. Resistant fits for some commonly used logistic models with medical application. Biometrics. 1982 Jun;38(2):485–498. [PubMed] [Google Scholar]
  9. Schmatz D. M., Abruzzo G., Powles M. A., McFadden D. C., Balkovec J. M., Black R. M., Nollstadt K., Bartizal K. Pneumocandins from Zalerion arboricola. IV. Biological evaluation of natural and semisynthetic pneumocandins for activity against Pneumocystis carinii and Candida species. J Antibiot (Tokyo) 1992 Dec;45(12):1886–1891. doi: 10.7164/antibiotics.45.1886. [DOI] [PubMed] [Google Scholar]