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Sun S, Chowdhury S, Hemeon I, Hasan A, Wilson MS , et al.
Bioorganic & medicinal chemistry letters •
Discovery efforts leading to the identification of cyclopentane carboxylic acid 31, a potent inhibitor of Na1.7 that showed high selectivity over Na1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein. Key design elements that culminated in the discovery of 31 include exploration of proline substituents, replacement of the proline warhead with cyclopentane carboxylic acid, that led to significantly boosted Na1.7 potency, and replacement of the metabolically labile adamantane motif with the 2,6-dichlorobenzyl substituted piperidine system, that addressed metabolic instability and led to a significant improvement in PK.
Cold hypersensitivity in the hands and feet is a common clinical symptom in Asian women. Currently, treatment of cold hypersensitivity in the hands and feet is still limited to traditional Chinese medicine, mainly herbal medicine. However, many patients with cold hypersensitivity in the hands and feet in China are not satisfied with the therapeutic effect of herbal medicine, and took medication for a longer time. Chemical lumbar sympathectomy is widely used in the treatment of plantar hyperhidrosis, diabetic foot, recalcitrant erythromelalgia, and other diseases. This study was conducted to evaluate the short-term as well as long-term efficacy, complications, and patient satisfaction of chemical lumbar sympathectomy during treatment cold hypersensitivity in the hands and feet. A retrospective, observational study. Department of Anesthesiology and Pain Medicine, Jiaxing, China. A retrospective study of 72 patients with cold hypersensitivity in the hands and feet who received chemical lumbar sympathectomy treatment in our hospital from January 2015 to October 2018 was conducted. The heart rate, non-invasive blood pressure, oxygen saturation, visual analog scale, perfusion index, and plantar temperature were monitored and recorded in before treatment (T1) and after treatment (T2) groups. The patients were followed up on day 1, at week 1, 1 month, 3 months, 6 months, one year, and 2 years after operation for satisfaction, complications, and recurrence. There were no significant differences in heart rate, non-invasive blood pressure, and oxygen saturation between T1 and T2 groups (P > 0.05). Perfusion index and plantar temperature in T2 group were remarkably higher than T1 group, and the difference was statistically significant (P < 0.01). The visual analog scale score of the T2 group was significantly reduced (P < 0.01). Of all the patients who underwent chemical lumbar sympathectomy, the postoperative therapeutic effect was effective in 63 cases (87.5%) and ineffective in 9 cases (12.5%). Among the effective patients, the postoperative curative effect was shown to be excellent in 47 cases and improved in 16 cases. According to the follow-up results at day 1, 1 week, 1 month, 3 months, 6 months, 1 year, and 2 years after operation, the satisfaction rate was 87.5%, 87.5%, 81.9%, 61.1%, 52.7%, 41.6%, and 34.7%, respectively. There were no serious complications observed and 23 patients relapsed after two years. Multivariate logistic regression analysis results showed that the effect of visual analog scale (OR = 7.312, 95% CI: 1.598 - 33.646, P = 0.011) and plantar temperature (OR = 0.470, 95% CI: 0.288 - 0.766, P = 0.002) on therapeutic effect showed has statistical significance; the effect of gender (OR = 0.654, 95% CI: 0.134 - 3.181, P = 0.599), age (OR = 0.975, 95% CI: 0.916 - 1.039, P = 0.441), perfusion index (OR = 0.710, 95% CI: 0.367 - 1.375, P = 0.310), and disease course (OR = 1.019, 95% CI: 0.997 - 1.042, P = 0.088) on therapeutic effect showed no statistical significance. The effect of gender (OR = 0.451, 95% CI 0.131 - 1.554, P = 0.207), age (OR = 0.961, 95% CI 0.912 - 1.013, P = 0.141), and course of disease (OR = 1.006, 95% CI 0.997 - 1.015, P = 0.203) on postoperative recurrence showed no statistical significance. The nonrandomized, single-center, small sample size, retrospective design is a major limitation of this study. Chemical lumbar sympathectomy is a valid treatment option for cold hypersensitivity in hands and feet, and computed tomography-guided percutaneous puncture chemical lumbar sympathectomy has the advantages of high success rate, less invasion, less complications, and repeatablity.