Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects

Cancer Chemotherapy and Pharmacology - Zanubrutinib (BGB-3111) is a potent Bruton’s tyrosine kinase inhibitor with promising clinical activity in B-cell malignancies. Zanubrutinib was shown...     

CDC42 promotes vascular calcification in chronic kidney disease

Vascular calcification is prevalent in patients with chronic kidney disease (CKD) and a major risk factor of cardiovascular disease. Vascular calcification is now recognised as a biological process similar to bone formation involving osteogenic differentiation of vascular smooth muscle cells (VSMCs). Cell division cycle 42 (CDC42), a Rac1 family member GTPase, is essential for cartilage development during endochondral bone formation. However, whether CDC42 affects osteogenic differentiation of VSMCs and vascular calcification remains unknown. In the present study, we observed a significant increase in the expression of CDC42 both in rat VSMCs and in calcified arteries during vascular calcification. Alizarin red staining and calcium content assay revealed that adenovirus-mediated CDC42 overexpression led to an apparent VSMC calcification in the presence of calcifying medium, accompanied with up-regulation of bone-related molecules including RUNX2 and BMP2. By contrast, inhibition of CDC42 by ML141 significantly blocked calcification of VSMCs in vitro and aortic rings ex vivo. Moreover, ML141 markedly attenuated vascular calcification in rats with CKD. Furthermore, pharmacological inhibition of AKT signal was shown to block CDC42-induced VSMC calcification. These findings demonstrate for the first time that CDC42 contributes to vascular calcification through a mechanism involving AKT signalling; this uncovered a new function of CDC42 in regulating vascular calcification. This may provide a potential therapeutic target for the treatment of vascular calcification in the context of CKD. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

腹腔镜胆囊切除术后右美托咪定滴鼻镇痛的效果观察

目的观察右美托咪定滴鼻用于腹腔镜胆囊切除术后镇痛的有效性和安全性。 方法选择2021年10月至2022年1月于邛崃市医疗中心医院收治并择期行全身麻醉下腹腔镜胆囊切除术的患者64例，其中男性17例，女性47例；年龄18~65岁，平均(44.03±10.97)岁；体重指数(BMI)<35kg/m²；美国麻醉医师协会(ASA)分级Ⅰ或Ⅱ级。采用随机数字表法将患者分为两组，试验组(D组，31例)于术毕清醒拔除喉罩后给予右美托咪定2 μg/kg滴鼻，对照组(C组，33例)于术毕清醒拔除喉罩后给予等容量0.9%等渗盐水滴鼻。记录两组患者一般情况及术中情况；记录术后2、8、12、24 h静息和运动时视觉模拟评分(visual analogue scale，VAS)；记录术后24 h内补救镇痛的例数以及初次补救镇痛的间隔时间；记录术后24 h内恶心、呕吐的发生例数及严重程度；记录24 h内最满意镇痛且最轻呕吐(satisfactory analgesia with minimal emesis，SAME)的达标比例；记录术后24 h内严重心动过缓、呼吸抑制、循环不稳、镇静过度等不良反应的发生情况。 结果与C组比较，D组2、8 h静息和运动VAS评分及12 h运动VAS评分明显降低(P<0.05)，两组术后补救镇痛的次数差异无统计学意义(P>0.05)，但D组初次补救镇痛的间隔时间明显延长(P<0.05)。与C组比较，D组术后恶心呕吐的发生率及严重程度明显降低(P<0.05)。D组SAME达标率明显高于C组(P<0.05)。两组患者术后均未出现严重心动过缓、呼吸抑制(SPO₂低于95%)、循环不稳(需要药物干预)、镇静过度等不良反应。 结论腹腔镜胆囊切除术后右美托咪定2 μg/kg滴鼻能在不辅助其他术后镇痛药的情况下，改善患者术后疼痛及恶心呕吐，延长初次补救镇痛的间隔时间，且无明显不良反应。     

香萱益神方对血管性痴呆模型大鼠神经元凋亡机制研究

目的:探讨香萱益神方治疗血管性痴呆(VD)模型大鼠认知功能作用及其对神经元凋亡机制的研究。方法:两血管阻断法建立VD大鼠模型,给予中药方香萱益神方灌胃治疗6周,分别于造模后、中药喂养6周后进行Morris水迷宫行为学检测,测试大鼠认知行为能力改变,行为学测试结束后,检测VD模型大鼠海马中海马组织脑源性神经营养因子(BDNF)表达水平的变化。结果:香萱益神方治疗6周后,血管性痴呆大鼠模型学习记忆能力得到改善,上调脑内海马组织神经营养因子水平,海马神经元凋亡率下降。结论:香萱益神方是治疗血管性痴呆的有效方剂,可以有效改善VD大鼠模型认知行为功能的障碍情况,起到减少海马神经元细胞凋亡,诱导海马神经元细胞修复的作用。香萱益神方可能是通过激活BDNF相关通路,起到保护海马神经元的作用。     

ERCC1在结直肠癌组织中的表达及预后价值

目的:探究核苷酸切除修复交叉互补基因1（excision repair cross-complementation gene 1，ERCC1）表达对结直肠癌（colorectal cancer，CRC）患者铂类辅助化疗的预后价值。方法:选取2011年01月至2013年01月安徽医科大学附属六安医院行CRC根治术后接受mFOLFOX6方案化疗的患者共84例，通过免疫组化方法评估ERCC1在CRC组织中表达情况，分析ERCC1表达与预后的关联。结果:ERCC1高表达30例（35.7%）。Kaplan-Meier曲线显示ERCC1高表达的CRC患者无病生存期（DFS）和总生存期（OS）均缩短（P均<0.001）。多因素COX分析显示ERCC1高表达（DFS HR=4.645，95%CI:2.045~10.548，P<0.001；OS HR=4.898，95%CI:1.971~12.170，P<0.001）是CRC患者预后的不良因素，分析各亚组患者中ERCC1表达与生存相关性得到相似的结果。复发患者中ERCC1高表达的肝肺转移占68.8%（11/16），低表达的腹腔转移为70.0%（7/10），ERCC1表达与首次复发模式显著相关（P=0.006）。结论:ERCC1表达可作为评价CRC患者预后的重要指标。ERCC1表达可能有助于预测CRC患者辅助化疗后首次复发模式。ERCC1表达的预后价值需进一步研究。     

Immunogenicity and protection efficacy of a Salmonella enterica serovar Typhimurium fnr,arcA and fliC mutant

Salmonella enterica serovar Typhimurium is a major food-borne pathogen that can cause self-limited gastroenteritis or life-threatening invasive diseases in humans. There is no licensed S. Typhimurium vaccine for humans to date. In this study, we attempted to construct a live attenuated vaccine strain of S. Typhimurium based on three genes, namely, the two global regulator genes fnr and arcA and the flagellin subunit gene fliC. The S. Typhimurium three-gene mutant, named SLT39 (ΔfnrΔarcAΔfliC), exhibited a high level of attenuation with a colonization defect in mouse tissues and approximately 10⁴-fold decreased virulence compared with that of the wild-type strain. To evaluate the immunogenicity and protection efficacy of STL39, mice were inoculated twice with a dose of 10⁷ CFU or 10⁸ CFU at a 28-day interval, and the immunized mice were challenged with a lethal dose of the wild-type S. Typhimurium strain one month post second immunization. Compared with mock immunization, SLT39 immunization with either dose elicited significant serum total IgG, IgG1 and IgG2a and faecal IgA responses against inactivated S. Typhimurium antigens at a comparable level post second immunization, whereas the 10⁸ CFU group induced higher levels of duodenal and caecal IgA than the 10⁷ CFU group. Furthermore, the bacterial loads in mouse tissues, including Peyer’s patches, spleen and liver, significantly decreased in the two SLT39 immunization groups compared to those in the control group post challenge. Additionally, all mice in the SLT39 (10⁸ CFU) group and 80% of the mice in the SLT39 (10⁷ CFU) group survived the lethal challenge, suggesting full protection and 80% protection efficacy, respectively. Thus, the S. Typhimurium fnr, arcA and fliC mutant proved to be a potential attenuated live vaccine candidate for prevention of homologous infection.     

拉莫三嗪与奥卡西平单药治疗成人新诊断局灶性癫痫的长期疗效及安全性比较

目的 比较拉莫三嗪(LTG)和奥卡西平(OXC)单药治疗成人新诊断局灶性癫痫的长期疗效、耐受性和安全性。方法 收集本院癫痫专病门诊新诊断的局灶性癫痫,随机分成OXC组和LTG组,根据临床情况调整剂量,OXC最大剂量1200 mg/d,LTG最大剂量300 mg/d,至少随访3年,评估二种药物单药治疗成人新诊断局灶性癫痫无发作率、保留率及不良反应。结果 2009年6月-2016年6月符合入组标准146例,其中OXC组74例,LTG组72例,2组1年无发作率分别为35.1%和51.3%(χ2=3.9,P=0.047),3年无发作率分别为21.6%和40.2%(χ2=5.96,P=0.015),LTG组总体无发作率高于OXC组(P<0.05); OXC组和LTG组1年保留率分别为59.5%和69.4%(χ2=1.59,P=0.208),3年保留率分别为44.6%和51.4%(χ2=0.68,P=0.411),LTG组总体保留率亦高于OXC组,但无明显差异(P>0.05)。OXC组和LTG组最常见的不良反应均为皮疹(6.8% vs. 8.3%)。结论 LTG单药治疗新诊断成人局灶性癫痫的长期无发作率高于OXC,两者不良反应较轻,有较好的安全性。