Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone

Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d₉-methadone.The pharmacokinetic profiles of d₉-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d₉-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD₅₀ value for a single intravenous dose of d₉-methadone was 2.1-fold higher than that for methadone. Moreover, d₉-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy.     

靶向测序诊断黑棘皮病1家系

【摘要】 报道临床症状不典型的家族性黑棘皮病1家系。先证者女，4岁，自1周岁时，颈部、腹部出现黑色斑片，近年来逐渐扩大至唇周、躯干前部。腹部皮肤全反式共聚焦显微镜检查可见乳头环下延扭曲及沟壑结构，乳头环内可见中高折光颗粒结构。先证者父亲及祖母既往有类似病史，但随着年龄增长色素沉着自发性消退，仅有局部皮纹增粗。采集先证者及父母、祖母外周血，对先证者外周血DNA行Panel靶向测序，结果显示，先证者存在FGFR3基因14号外显子c.1949A>C（p.Lys650Thr）错义突变，Sanger测序验证证实先证者及其父亲和祖母均存在此突变。诊断：家族性黑棘皮病。     

Effects of synthetic and biological disease modifying antirheumatic drugs on lipid and lipoprotein parameters in patients with rheumatoid arthritis

BackgroundDyslipidemia in rheumatoid arthritis (RA) patients is frequently observed, and treatment with anti-rheumatic drugs has an impact on lipid profiles. Pathophysiologically, inflammation leads to decreased blood lipids and lipoproteins; RA treatment reduces inflammation and therefore may increase lipids and lipoproteins. Whether the lipid changes with RA treatment confer an increased risk of cardiovascular disease or just reflect their potentially atheroprotective anti-inflammatory effect is currently unclear due to limited and conflicting data.ObjectiveThe aim of this review is to summarize the current knowledge on the effects of synthetic and biological disease modifying antirheumatic drugs for the treatment of RA on lipid and lipoprotein parameters.ResultsRecent studies on methotrexate emphasize its anti-atherogenic effect. Golimumab combined with methotrexate revealed a trend towards an anti-atherogenic potential. The known pro-atherogenic lipid-spectrum alterations caused by tofacitinib can be effectively treated with atorvastatin. Tocilizumab signals a favorable impact on the extent of lipid modifications when combined with methotrexate. Abatacept indicated a trend towards an anti-atherogenic lipid profile demonstrated by favorable effects on HDL-C and on the TC/HDL-C ratio. Rituximab has beneficial effects on HDL-C and ApoA1, as well as on the ApoB/ApoA1 ratio.Clinical implicationsAnti-rheumatic drugs have various effects on lipid parameters, which in part appear pro-atherogenic. However, because many of these lipid changes may well reflect their potentially atheroprotective anti-inflammatory action the cardiovascular impact of these changes remains unclear. Whatsoever, cardiovascular safety trials for antirheumatic drugs would be valuable.     

Smad2 increases the apoptosis of activated human hepatic stellate cells induced by TRAIL

The activation of hepatic stellate cells (HSCs) plays a critical role in the development of liver fibrosis. The induction of apoptosis in activated HSCs during the recovery phase of hepatic fibrosis represents a potential anti-fibrotic therapy. We have previously shown that Smad2 protects against hepatic fibrogenesis; however, the role of Smad2 in the regulation of activated HSC apoptosis remains unknown. We hypothesized that Smad2 regulates the apoptosis of activated HSCs, leading to the resolution of liver fibrosis. To test this hypothesis, the livers of rats were harvested at 0 and 4 weeks after hepatic fibrosis was established by CCl₄ injection. Furthermore, TGF-β1-activated HSCs were treated with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following the silencing or overexpression of Smad2. Both the phosphorylation of Smad2 and TRAIL were detected in fibrotic liver tissues. The results of TUNEL and α-SMA double-staining showed an increase in the apoptosis of activated HSCs during the spontaneous recovery phase. The knockdown of Smad2 reduced TRAIL-induced apoptosis in TGF-β1-activated human LX-2 cells and resulted in an increased expression of α-SMA and collagen I (Col. I). In contrast, the overexpression of Smad2 increased TRAIL-induced HSC apoptosis and reduced the expression of α-SMA and Col. I. The mechanisms underlying these findings were associated with the Smad2-mediated down-regulation of X-linked inhibitor of apoptosis protein (XIAP), resulting in enhanced caspase-3 activity and apoptosis. In conclusion, Smad2 enhances TRAIL-induced apoptosis in activated HSCs, which facilitates the resolution of hepatic fibrosis.     

贝那普利降压疗效与校正QT间期的关系

目的探讨原发性高血压患者心电图心率校正QT间期(QTc)和贝那普利降压疗效之间的关系.方法采用前瞻性队列研究方法调查安徽A县899名高血压病患者的基线心电图、治疗15 d前后的血压变化及相关临床和流行病学特点等情况.结果 QTc和血压下降呈负相关.QTc每增加0.1秒1/2,收缩压和舒张压的下降值分别减少3.6 mmHg和3.3 mmHg,且差异均有显著性(P＜0.05).将QTc三等分后,随着QTc等分的增加,收缩压和舒张压的下降值均逐渐减少,且差异具有显著性(P＜0.05);将QTc等分后的变量放入方程中进行趋势性分析,发现在收缩压和舒张压组中的负相关关系具有显著性(P＜0.05).随着QTc等级的增加,舒张压有效率逐渐降低,且有显著性差异(P＜0.05),收缩压的效应关系不如舒张压明显.结论 QTc和贝那普利降压疗效呈负相关,对贝那普利短期降压疗效具有重要的预测价值.     

EB病毒在结外NK/T细胞淋巴瘤中的预后价值：一项淮海淋巴瘤协作组的多中心回顾性研究

目的 基于倾向性评分逆处理概率加权(IPTW)法评估EB病毒(EBV)在结外NK/T细胞淋巴瘤患者中的预后价值。方法 收集2012年10月—2021年4月淮海淋巴瘤协作组中8家医疗机构初诊为结外NK/T细胞淋巴瘤且具有全血EBV-DNA数据的468例患者的临床资料。采用IPTW法分析EBV载量对结外NK/T细胞淋巴瘤患者生存期的影响;采用Cox比例风险模型进行多因素分析;绘制Kaplan-Meier曲线,组间比较采用Log rank χ²检验。结果 468例结外NK/T细胞淋巴瘤患者中,EBV-DNA阳性266例,EBV-DNA阴性202例。EBV-DNA阳性组和阴性组患者的5年OS分别为62.5%和89.2%,两组比较,经Log rank χ²检验,差异有统计学意义(χ²=42.900,P=0.000)。IPTW前,两组的美国东部肿瘤协作组(ECOG)活动状态(PS)评分(ECOG PS评分)、原发部位、CA分期、Ann Arbor分期、白蛋白、乳酸脱氢酶、治疗方案比较,差异均有统计学意义(P<0.05)。IPT...     

急性缺血性脑卒中病人医院感染与卒中复发风险研究

目的研究急性缺血性脑卒中(acute ischemic stroke, AIS)病人医院感染与脑卒中复发之间的关系。方法采用队列研究, 收集121例AIS病人基本资料, 随访收集病人卒中复发情况。Cox回归分析医院感染是否为脑卒中复发的独立危险因素。结果121例AIS病人中医院感染的发生率为19.8%(95%CI: 0.127~0.269), 卒中复发率为26.4%(95%CI: 0.185~0.343), 医院感染导致卒中复发的HR为6.485(95%CI: 2.984~14.091)。结论AIS病人医院感染可能是卒中复发的一个独立风险因素。     

成人髌内侧滑膜皱襞的形态和症状性皱襞的诊治

目的关节镜术中比较成人膝关节髌内侧滑膜皱襞和症状性皱襞的形态学特点，探讨滑膜皱襞综合征的诊治。方法210例成人患者施行关节镜术，155例膝关节存在髌内侧滑膜皱襞，其中38例确诊为髌内侧滑膜皱襞综合征，髌内侧滑膜皱襞的形态依照Sakakibara分型法分成A、B、C、D等4型，比较分析髌内侧滑膜皱襞形态特点和发生率，症状性皱襞采用关节镜下滑膜皱襞切除术。结果非症状髌内侧滑膜性皱襞以A型和B型皱襞多见，症状髌内侧滑膜性皱襞以B、C、D型皱襞多见。症状性髌内侧滑膜性皱襞各型髌内侧滑膜皱襞的发生率在性别和别侧差异无显著性（P〉0．05），36例髌内侧滑膜皱襞综合征随访6～19个月，2例失访，疗效优良率86．1％。结论成人髌内侧滑膜皱襞形态具有多样性，各种类型的滑膜皱襞都可能产生症状，其中B、C和D型皱襞易于产生症状；关节镜技术是诊治症状性皱襞的重要手段，症状性皱襞经行关节镜下皱襞切除术疗效确切。     

呼吸机相关性肺炎病原学与细菌耐药性变迁的临床研究

目的调查安徽省铜陵市人民医院近10年来呼吸机相关性肺炎（VAP）病原学构成与细菌耐药性的变迁。方法比较两个不同时间段（1996年6月～2001年6月和2001年7月～2006年6月）病原学分布特点及细菌耐药性的变迁。结果10年间，有完整病历资料、接受有创机械通气的患者共1236例，VAP发生率为44．34％（538／1236）；在538例VAP中，2种及2种以上致病菌感染占56．51％；革兰阴性细菌中，铜绿假单胞菌和不动杆菌属为VAP的主要致病菌（68．63％）（385／561）；表皮葡萄球菌感染为VAP的主要革兰阳性致病菌（75．40％）（95／126）；真菌占20．98％（183／872）；铜绿假单胞菌在两个时间段所占比例无明显变化，不动杆菌属的检出率呈上升趋势（8．23％～15．23％）；铜绿假单胞菌和不动杆菌属对亚胺培南、头孢他啶的敏感性明显下降，耐苯唑西林表皮葡萄球菌的检出率显著升高（18．75％～71．43％）。结论铜绿假单胞菌和不动杆菌属是我院VAP的主要革兰阴性致病菌，10年间，致病菌的分布及细菌耐药菌性已经发生了明显的变化，临床初始经验性治疗面临更大的难度。