Fudosteine

The bioequivalence of a generic fudosteine tablet vs a brand‐named fudosteine tablet under fasting and fed conditions was evaluated in this study. This randomized, open‐label, single‐dose, 4‐way replicate, crossover, bioequivalence study included 64 healthy Chinese subjects (fasting cohort, n = 32; fed cohort, n = 32) who were assigned to receive a single 200‐mg dose of generic or brand‐named fudosteine. Blood samples were collected before dosing and up to 24 hours after dosing. The plasma concentrations of fudosteine were analyzed by high‐performance liquid chromatography–tandem mass spectrometry. Safety was monitored. There were no significant differences in maximum plasma concentration (Cmax), area under the plasma concentration–time curve (AUC) from time 0 to time t (AUC0‐t), or AUC from time 0 to infinity (AUC0‐∞) between the test and reference formulations. However, food showed a significant effect on Cmax, AUC0‐t, and AUC0‐∞ for both generic and brand‐named fudosteine. The 90%CIs of the test/reference ratios of Cmax, AUC0‐t, and AUC0‐∞ were within the range of 80% to 125% under both fasting and fed conditions. No serious adverse events were reported. The bioequivalence between generic and brand‐named fudosteine under fasting and fed conditions was demonstrated. Both of them had good tolerance for healthy Chinese volunteers. In addition, food delayed the absorption of fudosteine, so taking this medicine before meals might be an optimized option.

There is a dearth of effective pharmacotherapies for sepsis-induced acute lung injury/acute respiratory distress syndrome (ALI/ARDS) to which oxidative stress and excessive inflammation are major contributors. We hypothesized that fudosteine, a cysteine derivative, may protect against sepsis-induced ALI/ARDS given its anti-oxidant capacity. This study aimed to investigate the effects and mechanisms of fudosteine in a mouse model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP). The intragastrical administration of fudosteine (25 mg/kg, 50 mg/kg, and 100 mg/kg) dose-dependently decreased proinflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) and serum and reduced BALF/serum albumin and lung wet/dry weight ratios in septic mice. The lung injury score was significantly lowered by fudosteine [e.g., 0.18 ± 0.03 (100 mg/kg) vs. 0.42 ± 0.03 (CLP), P < 0.0001]. Fudosteine also reduced the biomarkers of lung epithelial injury in BALF and markedly improved oxidative stress indicators in lung tissues [e.g., malondialdehyde: 337.70 ± 23.78 (100 mg/kg) vs. 686.40 ± 28.36 (CLP) nmol/mg protein, P < 0.0001]. Lung tissue transcriptomics analyses revealed suppressed inflammatory responses and oxidative stress with fudosteine and the involvement of the inflammasome and pyroptosis pathways. Western blot analyses indicated that fudosteine inhibited the sepsis-induced activation of gasdermin D (GSDMD) and caspase-1 and the upregulation of thioredoxin-interacting protein (TXNIP), nucleotide-binding domain, leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3), and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). Fudosteine therefore protects against sepsis-induced ALI in mice, and the inhibition of pyroptosis via the TXNIP/NLRP3/GSDMD pathway may be an underlying mechanism.