Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral NLRP3 Inflammasome Inhibitor ZYIL1: First-in-Human Phase 1 Studies (Single Ascending Dose and Multiple Ascending Dose).

ZYIL1 is a nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome inhibitor, which prevents NLRP3-induced apoptosis-associated speck-like protein containing a caspase activation and recruitment domain oligomerization, thus inhibiting NLRP3 inflammasome pathway. We investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ZYIL1 after single and multiple doses in healthy subjects. The subjects aged 18-55 years were enrolled in 2 different studies: single and multiple ascending dose. Blood/urine samples were collected at designated time points for pharmacokinetic and pharmacodynamic analysis. In the single-ascending-dose study, 30 subjects were enrolled (6 subjects each in 5 dose groups). One adverse event was reported during the study. ZYIL1 was well absorbed with median time to maximum plasma concentration at 1-1.5 hours. The exposures were dose proportional across the dose ranges. ZYIL1 is excreted as an unchanged form via the renal route. The mean elimination half-life was 6-7 hours. In the multiple-ascending-dose study, 18 subjects were enrolled (6 subjects each in 3 dose groups). Eleven adverse events were reported by 6 subjects during the study. The accumulation index at steady state for area under the plasma concentration-time curve indicated that ZYIL1 has a marginal accumulation upon repeated dosing. Dose-proportional exposure was observed across the dose ranges. All subjects showed >90% interleukin (IL)-1ß inhibition in all dose groups for both studies. Inhibition in IL-1ß and IL-18 was observed throughout the 14 days of treatment in the multiple-dose study. The safety profile, rapid absorption, marginal accumulation, and significant inhibition of IL-1ß and IL-18 level support its development for the management of inflammatory disorders.

Evaluation of treatment outcome and adverse drug reaction of directly observed treatment (DOT) plus regimen in multidrug-resistant tuberculosis (MDR-TB) patients at district tuberculosis centre Rajkot.

BACKGROUND: The emergence of drug-resistant mycobacteria becomes a significant public health problem globally creating an obstacle to effective tuberculosis (TB) control. Gujarat, Maharashtra, and Andhra Pradesh DRS survey estimated that the proportion of multidrug-resistant TB (MDR-TB) is 2.1% (in new TB cases) and 15% (in previously treated cases). Programmatic management of MDR-TB implemented under Revised National Tuberculosis Control Programme in India in 2007. OBJECTIVES: The objective of this study is to evaluate treatment outcome and adverse drug reactions (ADRs) of category IV. MATERIALS AND METHODS: A total of 108 MDR-TB patients were analyzed retrospectively who registered and received treatment during the year of 2014 and 2015 at district TB centre, Rajkot. MDR patients who died or transferred out or defaulter before completion of intensive phase were excluded from the analysis. RESULTS: Of total 108 patients majority patients (64.81%) were in young (20-39 years) with m:f: 2:1. All MDR-TB patients were retreated cases and 69.44% were "undernutrition category". Culture conversion rate was 86.91% at 4 months of treatment. Cure rate was 50.93% while defaulter rate and died rate was same (17.59%). Failure rate was 18.51%. Weight improvement was significantly associated with cure rate. The incidence of ADR was 32.71%. Most frequent ADRs were related to gastrointestinal system (34.42%), ototoxicity (13.11%), and central nervous system (8.1%). Aminoglycosides, cycloserine, and ethambutol were discontinued due to ADR. Majority ADRs (77.04%) were "possible" category by causality assessment and "mild" in severity assessment. Ototoxicity was only severe ADRs observed. CONCLUSION: Cure rate was improved than previous years at same center. Attention should be paid for defaulters.