The novel fungal CYP51 inhibitor VT-1598 is efficacious alone and in combination with liposomal amphotericin B in a murine model of cryptococcal meningitis.
Objectives: 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 antifunga...
| Publicado en: | Journal of Antimicrobial Chemotherapy (JAC) Vol. 73; no. 10; pp. 2815 - 2823 |
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| Autores principales: | , , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Oxford University Press / USA
Oct2018
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=131920674&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 131920674 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 03057453 N5O jtl: Journal of Antimicrobial Chemotherapy (JAC) issn: 03057453 maglogo: N pubinfo: dt: Oct2018 vid: 73 iid: 10 pid: 622 pub: Oxford University Press / USA artinfo: ui: 131920674 131920674 NLM29947783 131920674 10.1093/jac/dky242 NLM29947783 131920674 ppf: 2815 ppct: 8 formats: tig: atl: The novel fungal CYP51 inhibitor VT-1598 is efficacious alone and in combination with liposomal amphotericin B in a murine model of cryptococcal meningitis. aug: au: Garvey, E P Sharp, A D Warn, P A Yates, C M Schotzinger, R J affil: Viamet Pharmaceuticals, Inc., Durham, NC, USA sug: subj: Antifungal Agents Administration and Dosage Enzyme Inhibitors Administration and Dosage Meningitis, Cryptococcal Drug Therapy Amphotericin B Administration and Dosage Amphotericin B Pharmacodynamics Administration, Oral Antifungal Agents Pharmacodynamics Models, Biological Cryptococcus Colony Count, Microbial Animal Studies Treatment Outcomes Microbial Culture and Sensitivity Tests Survival Analysis Drug Therapy, Combination Methods Cryptococcus Drug Effects Enzyme Inhibitors Pharmacodynamics Mice Validation Studies Comparative Studies Evaluation Research Multicenter Studies ab: Objectives: 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.Methods: 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.Results: 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.Conclusions: These pre-clinical in vivo data strongly support clinical investigation of VT-1598 as a novel therapy for this lethal infection. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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