Related Experiment Videos
Treatment of murine cryptococcal meningitis with UR-9751 and UR-9746
M I Restrepo1, L K Najvar, F Barchiesi
1University of Texas Health Science Center at San Antonio, 78284, USA.
Abstract:
In these studies, we compare the efficacy of two new azole antifungals with fluconazole in a murine model of cryptococcal meningitis. Mice were infected intracranially. Beginning one day later, groups of 7-10 mice were treated through to day 10 orally with UR-9751 or UR-9746 at 0.1, 0.25, 0.5, 1 or 10 mg kg(-1) day(-1) or fluconazole at 10 mg kg(-1) day(-1). At 10 mg kg(-1) day(-1), all three drugs prolonged survival over controls, but at 1 mg kg(-1) day(-1) only UR-9746 prolonged survival. Tissue counts were more varied on mice sacrificed 8 days after infection. In general, both UR drugs were equal or more potent than fluconazole, and UR-9751 was more effective than UR-9746.
Insights
Two new azole antifungals, UR-9751 and UR-9746, show promise against cryptococcal meningitis in mice. UR-9751 demonstrated superior efficacy compared to UR-9746 and fluconazole in this preclinical model.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Cryptococcal meningitis remains a significant threat, particularly in immunocompromised individuals.
- Fluconazole is a standard treatment, but resistance and efficacy limitations necessitate new therapeutic options.
- Azole antifungals are a key class of drugs for treating fungal infections.
Purpose of the Study:
- To evaluate the efficacy of two novel azole antifungals, UR-9751 and UR-9746, against cryptococcal meningitis.
- To compare the therapeutic potential of UR-9751 and UR-9746 with fluconazole, a current standard of care.
- To assess the impact of these agents on survival rates and fungal burden in a murine model.
Main Methods:
- A murine model of cryptococcal meningitis was established via intracranial infection.
- Groups of mice (7-10 per group) received oral administration of UR-9751, UR-9746, or fluconazole at varying doses (0.1-10 mg kg(-1) day(-1)).
- Treatment duration was from day 1 to day 10 post-infection, with survival and tissue fungal burden assessed.
Main Results:
- All three tested antifungals (UR-9751, UR-9746, fluconazole) significantly prolonged survival at a high dose (10 mg kg(-1) day(-1)).
- At a lower dose (1 mg kg(-1) day(-1)), only UR-9746 demonstrated a survival benefit over controls.
- Both UR drugs exhibited comparable or greater potency than fluconazole, with UR-9751 showing higher efficacy than UR-9746.
Conclusions:
- Novel azole antifungals UR-9751 and UR-9746 exhibit significant potential in treating cryptococcal meningitis.
- UR-9751 appears to be more effective than UR-9746 and fluconazole in this preclinical model.
- These findings support further investigation of UR-9751 and UR-9746 as alternative therapies for cryptococcal meningitis.