Application of sequential multimodal analgesia before and after impacted mandibular third molar extraction: Protocol for a randomized controlled trial.

Background: Several analgesics have been applied under various protocols to control the moderate-to-severe postoperative pain caused by the surgical extraction of an impacted mandibular third molar. However, a consensus on optimal pain management while minimizing side effects is yet to be reached. Methods: This multi-center, prospective, double-blind, randomized controlled trial aims to evaluate the efficacy and safety of sequential multimodal analgesia combined with postoperative zaltoprofen along with multiple preemptive analgesics. A total of 80 participants with bilateral impacted mandibular third molar from two hospitals were randomized into two groups. Two surgical extractions were performed at one-month intervals, and in a crossover design, celecoxib or tramadol/acetaminophen was administered before one extraction and placebo before the other extraction. Following extraction, all subjects took zaltoprofen for 5 days. The outcome measures included pain at specific times, time and intensity of the first pain onset after extraction, need of rescue drugs, and occurrence and frequency of side effects. Conclusions: This ongoing clinical trial was designed to provide evidence regarding a new protocol for effective postoperative pain management of a commonly performed surgical extraction. The results of this study will provide guidance to clinicians regarding the timing and combination of oral analgesics in various oral surgeries performed under local anesthesia. Trial registration: KCT0005450, registered on October 7, 2020.

A novel NLRP3 inhibitor as a therapeutic agent against monosodium urate-induced gout.

Background: Since NEK7 is critical for NLRP3 inflammasome activation, NEK7 inhibitors could be employed as therapeutic agents against gout, a representative disease caused by NLRP3 inflammasome. Methods: We designed NEK7 inhibitors based on biochemical kinome profiling of 2,7-substituted thieno[3,2-d]pyrimidine derivatives (SLC3031~3035 and SLC3037). Inflammasome activation was assessed by ELISA of IL-1b and immunoblotting of IL-1b maturation after treatment of bone marrow-derived macrophages with LPS+monosodium urate (MSU). NLPR3 binding to NEK7 and oligomerization were examined using immunoprecipitation and Blue Native gel electrophoresis, respectively. In vivo effect was investigated by studying gross and histopathological changes of food pad tissue of MSU-injected mice, together with assays of maturation of IL-1b and ASC speck in the tissue. Results: SLC3037 inhibited inflammasome by MSU and other inflammasome activators through blockade of NLRP3 binding to NEK7 or oligomerization, and subsequent ASC oligomerization/phosphorylation. SLC3037 significantly reduced foot pad thickness and inflammation by MSU, which was superior to the effects of colchicine. SLC3037 significantly reduced content or maturation of IL-1b and ASC speck in the food pad. The number and height of intestinal villi were decreased by colchicine but not by SLC3037. Conclusion: SLC3037, a NLRP3 inhibitor blocking NEK7 binding to NLRP3, could be a novel agent against diseases associated with NLRP3 inflammasome activation such as gout, cardiovascular diseases, metabolic syndrome or neurodegenerative diseases.