Citations

Background Atogepant is an oral, small-molecule, calcitonin gene–related peptide receptor antagonist for the preventive treatment of migraine. Methods In the double-blind, phase 3 ADVANCE trial, participants with 4–14 migraine days/month were randomized to atogepant 10 mg, 30 mg, 60 mg, or placebo once daily for 12 weeks. We evaluated the time course of efficacy of atogepant for the preventive treatment of migraine. Analyses included change from baseline in mean monthly migraine days during each of the three 4-week treatment periods, change in weekly migraine days during weeks 1–4, and proportion of participants with a migraine on each day during the first week. Results We analyzed 873 participants (n = 214 atogepant 10 mg, n = 223 atogepant 30 mg, n = 222 atogepant 60 mg, n = 214 placebo). For weeks 1–4, mean change from baseline in mean monthly migraine days ranged from −3.1 to −3.9 across atogepant doses vs −1.6 for placebo ( p < 0.0001). For weeks 5–8 and 9–12, reductions in mean monthly migraine days ranged from −3.7 to −4.2 for atogepant vs −2.9 for placebo ( p ≤ 0.012) and −4.2 to −4.4 for atogepant vs −3.0 for placebo ( p < 0.0002), respectively. Mean change from baseline in weekly migraine days in week 1 ranged from −0.77 to −1.03 for atogepant vs −0.29 with placebo ( p < 0.0001). Percentages of participants reporting a migraine on post-dose day 1 ranged from 10.8% to 14.1% for atogepant vs 25.2% with placebo ( p ≤ 0.0071). Conclusion Atogepant demonstrated treatment benefits as early as the first full day after treatment initiation, and sustained efficacy across each 4-week interval during the 12-week treatment period. Clinical trial registration: ClinicalTrials.gov identifier: NCT03777059

AbstractCisplatin nephrotoxicity has been considered as serious side effect caused by cisplatin‐based chemotherapy. Recent evidence indicates that renal tubular cell apoptosis and inflammation contribute to the progression of cisplatin‐induced acute kidney injury (AKI). Hepatocyte nuclear factor 1β (HNF1β) has been reported to regulate the development of kidney cystogenesis, diabetic nephrotoxicity, etc However, the regulatory mechanism of HNF1β in cisplatin nephrotoxicity is largely unknown. In the present study, we examined the effects of HNF1β deficiency on the development of cisplatin‐induced AKI in vitro and in vivo. HNF1β down‐regulation exacerbated cisplatin‐induced RPTC apoptosis by indirectly inducing NF‐κB p65 phosphorylation and nuclear translocation. HNF1β knockdown C57BL/6 mice were constructed by injecting intravenously with HNF1β‐interfering shRNA and PEI. The HNF1β scramble and knockdown mice were treated with 30 mg/kg cisplatin for 3 days to induce acute kidney injury. Cisplatin treatment caused increased caspase 3 cleavage and p65 phosphorylation, elevated serum urea nitrogen and creatinine, and obvious histological damage of kidney such as fractured tubules in control mice, which were enhanced in HNF1β knockdown mice. These results suggest that HNF1β may ameliorate cisplatin nephrotoxicity in vitro and in vivo, probably through regulating NF‐κB signalling pathway.