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• W2810179690 abstract "Annual global deaths from cryptococcal meningitis (CM) are estimated at 180 000 and mortality is as high as 30%, even with optimal therapy. VT-1598 is a novel fungal CYP51 inhibitor with potent intrinsic antifungal activity against Cryptococcus. We report here VT-1598’s in vivo antifungal activity in a murine model of CM. Single-dose plasma and brain pharmacokinetics in mice and MIC for Cryptococcus neoformans H99 were determined prior to efficacy studies. Short-course monotherapy and combination doses were explored with the endpoint of brain fungal burden. A survival study was also conducted using monotherapy treatment with fungal burden measured after a 6 day drug washout. Oral doses of VT-1598 had good plasma and brain exposure and resulted in significant (P < 0.0001) and dose-dependent reductions in brain fungal burden, reaching a 6 log10 reduction. Unlike either positive drug control (fluconazole or liposomal amphotericin B), both mid and high doses of VT-1598 reduced fungal burden to below levels measured at the start of treatment. When VT-1598 was dosed in the survival study, no VT-1598-treated animal succumbed to the infection. Whereas fluconazole showed a 2.5 log10 increase in fungal burden after the 6 day washout, the VT-1598 mid- and high-dose animals showed almost no regrowth (<0.5 log10). In a separate fungal burden study using suboptimal doses of VT-1598 and liposomal amphotericin B to probe for combination effects, each combination had a positive effect relative to corresponding monotherapies. These pre-clinical in vivo data strongly support clinical investigation of VT-1598 as a novel therapy for this lethal infection." @default.
• W2810179690 created "2018-07-10" @default.
• W2810179690 creator A5036927344 @default.
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• W2810179690 date "2018-06-26" @default.
• W2810179690 modified "2023-09-27" @default.
• W2810179690 title "The novel fungal CYP51 inhibitor VT-1598 is efficacious alone and in combination with liposomal amphotericin B in a murine model of cryptococcal meningitis" @default.
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• W2810179690 doi "https://doi.org/10.1093/jac/dky242" @default.
• W2810179690 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29947783" @default.
• W2810179690 hasPublicationYear "2018" @default.
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