Niclosamide ethanolamine

Coccidioidomycosis or valley fever is a treatment-limited fungal infection endemic to the alkaline deserts of North and South America for which two classes of antifungals are typically used: the polyenes and the triazoles. In light of the limited usefulness of the echinocandins and a growing trend of azole resistance, it is essential that we identify novel antifungals. In this study, we have developed and optimized a screening methodology for identifying potential antifungals effective against Coccidioides spherule initials using a metabolic assay, used it to screen four diverse drug libraries with limited drug overlap, and established safety and efficacy data for a majority of the compounds, including the Broad Repurposing Hub, Prestwick Chemicals 1520, Selleck L8200 Anti-parasitic, and MedChemExpress CNS Penetrants libraries. Hits were defined as compounds with strong metabolic inhibition (≥70%), which were significantly different compared to the median plate readout (B-scores ≤ −3). We identified 30 promising hits and found 12 compounds exhibiting half-maximal inhibitory concentrations below 6 µM. Among these, oxethazaine, niclosamide ethanolamine, 10058-F4, niclosamide (NIC), and pentamidine isethionate showed synergy with amphotericin B, suggesting their potential use in combination therapy. Further assessment of lead compounds’ effects on spherules was conducted by image flow cytometry. Additionally, we explored the potential to use an attenuated, Biosafety Level 2 containment mutant, C. posadasii ∆ cts2 /∆ ard1 /∆ cts3 (∆T), as a surrogate model for drug screening. Overall, our findings provide a foundation for future research focused on screening and developing novel coccidioidomycosis treatments.

The antifungal treatment arsenal is especially limited against Coccidioides . Due to toxicity concerns, amphotericin B is generally reserved for triazole-recalcitrant infections. Recent laboratory susceptibility tests show an increase in fluconazole resistance, highlighting a need for new treatments. We have developed a large-scale metabolic screening assay under Biosafety Level 3 containment to identify existing drugs with novel activity against Coccidioides spherules. This drug-repurposing approach represents a convenient and cost-effective strategy to increase the available antifungals effective against these infections.

Functional constipation (FC) is a prevalent disorder with large disease burden and high associated cost. Noninvasive electrical neuromodulation (NEN) has been studied for treatment of FC, but its overall efficacy and safety remain unclear. This meta-analysis evaluates the efficacy and safety of NEN for treatment of FC.

A search of PubMed, Cochrane Library, Embase, and Web of Science data bases was completed for randomized controlled studies assessing the efficacy and safety of NEN in patients with FC through June 2024. We performed a meta-analysis using risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with 95% CIs.

The analysis included eight randomized controlled trials with 1465 participants. Compared with sham interventions, NEN significantly increased the proportion of patients having ≥three spontaneous bowel movements per week (RR [95% CI] = 2.47 [1.79, 3.40], p < 0.00001), decreased the number of patients using laxative for FC (RR [95% CI] = 0.81 [0.69, 0.95], p = 0.01), decreased the overall constipation severity (MD [95% CI] = -0.58 [-0.81, -0.35], p < 0.00001), and improved the constipation-specific quality of life (MD [95% CI] = -0.24 [-0.32, -0.16], p < 0.00001). There was no significant difference in the frequency of adverse events between NEN and sham interventions (RR [95% CI] = 1.30 [0.77, 2.19], p = 0.32), and participant drop-out rate with NEN was lower (RR [95% CI] = 0.38 [0.17, 0.84], p = 0.02). Mechanistically, NEN was found to modulate the autonomic function (p < 0.00001) and improve the rectal sensation (p = 0.03).

NEN relieves constipation symptoms, improves quality of life, and reduces use of pharmacologic remedies in adults with FC. These effects seem to be modulated through improved autonomic function and rectal sensation. NEN is safe, well-tolerated, and has a high level of patient compliance.