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.     

单孔加一孔联合ERAS在高位直肠及乙状结肠癌中的应用

目的 探讨单孔加一孔腹腔镜手术联合 ERAS 治疗高位直肠及乙状结肠癌的近期疗效。方法 回顾性分析 2017 年 11 月至2018 年 10 月在福建省肿瘤医院胃肠肿瘤外科进行加速康复外科干预的 92 例高位直肠及乙状结肠癌患者资料，根 据手术方式的不同，分为单孔加一孔手术联合快速康复外科组39 例及常规腹腔镜手术联合ERAS 组 53 例，对比两组围术 期情况。结果 两组患者基线资料无明显统计学差异（P ＞ 0.05），且在手术时间、出血量、上下切缘、清扫淋巴结数量及 并发症方面无明显统计学差异（P ＞ 0.05）。但单孔加一孔手术联合ERAS 组较常规手术联合ERAS 组，总切口长度更短 [（6.7±1.1）cm 比（8.5±1.3）cm，P=0.000]，术后首次下床时间更早 [（22.2±5.2）h 比（27.1±7.9）h，P=0.001]，首次排便 时间更早[（70.2±19.8）h比（83.1±20.4）h，P=0.005]，术后第一天C反应蛋白值更低[（43.5±28.6）mg/L比（57.2±33.2） mg/L，P=0.038]，术后住院时间更短 [（7.0±1.7）d 比（8.1±2.1）d，P=0.010]，且术后 2~4 天疼痛评分更低（P ＜ 0.05）。 结论 经验丰富的腔镜医师采用单孔加一孔手术治疗高位直肠及乙状结肠癌并联合 ERAS 干预是安全可行的，且单孔加一孔 手术可减低操作难度，具有疼痛轻、术后恢复快等优势，值得临床推广。     

Postoperative development of sarcopenia is a strong predictor of a poor prognosis in patients with adenocarcinoma of the esophagogastric junction and upper gastric cancer

Background

There were few studies assessed the postoperative sarcopenia in patients with cancers. The objective of present study was to assess whether postoperative development of sarcopenia could predict a poor prognosis in patients with adenocarcinoma of esophagogastric junction, (AEG) and upper gastric cancer (UGC).

Major hepatectomy for intrahepatic cholangiocarcinoma or colorectal liver metastases. Are we talking about the same story?

IntroductionMajor hepatectomy (MH) is often needed in the curative management of intrahepatic cholangiocarcinoma (IHCC) and colorectal liver metastases (CRLM). While similar outcomes could be expected after MH for IHCC and CRLM, outcomes seem worse after MH for IHCC. A better understanding of such differences might help improving perioperative outcomes but comprehensive analysis are lacking.MethodsAll patients undergoing curative intent MH for IHCC or CRLM from 2003 to 2009 were included from two dedicated multi-institutional datasets. Preoperative management and short-term outcomes after MH were first compared. Independent predictors of postoperative mortality and morbidity were identified.ResultsAmong 827 patients, 333 and 494 patients underwent MH for IHCC and CRLM, respectively. Preoperative portal vein embolization was more frequently performed in the CRLM group (p < 0.001). MH in the IHCC group required more extended resection (p < 0.001). Postoperative mortality and severe morbidity rates were significantly higher in the IHCC group (7.2% vs. 1.2% and 29.7% vs. 11.1%, p < 0.001, respectively). Main causes for mortality were postoperative liver failure and deep surgical site infection. MH for IHCC was an independent risk factor for mortality (p < 0.001) and severe morbidity (p < 0.001). After propensity score matching (212 patients in each group), the aforementioned differences regarding outcomes remained statistically significant.ConclusionThis study suggests that IHCC patients are inherently more at risk after MH as compared to CRLM patients. Considering that postoperative liver failure was the most frequent cause of death, preoperative planning might have been inadequate in the setting of IHCC while more complex/extended resections should be expected.     

Fístulas posquirúrgicas de líquido cefalorraquídeo tras cirugía transesfenoidal de adenomas hipofisarios: análisis de una serie de 302 intervenciones

IntroductionTranssphenoidal surgical removal is the preferred treatment of most pituitary adenomas. Postoperative cerebrospinal fluid (CSF) leakage is the leading cause of morbidity after this procedure, with an incidence rate that varies from 0,5-15% in the main published series.ObjectivesThe primary objective of this study was to establish the incidence of postoperative CSF leakage in a sample of surgeries performed at the University Hospital of La Ribera by the same surgical team. The secondary objectives were to: ascertain the distinctive features between patients with and without postoperative CSF leakage, identify risk factors for their development, evaluate the relationship between the surgical technique for closing the sella turcica and the onset of postoperative CSF leakage and evaluate different treatment regimens for this complication.MethodsThe data of 302 consecutive transsphenoidal surgical procedures for pituitary adenoma removal which were performed between 1999 and 2017 were retrospectively reviewed.Results and conclusionsThe incidence of postoperative CSF leakage in our series was 2,3% (in accordance with similar published studies). It was possible to correlate intraoperative CSF leakage with two variables: pituitary macroadenoma and tumors with suprasellar extension (P < .005). This correlation did not exist for postoperative CSF leakage. We found a statistically significant correlation between intraoperative and postoperative CSF leakage (P < .005). Due to the low incidence of postoperative CSF leakage in our series, it was not possible to identify risk factors for its development.     

T1~T2期乳腺癌保乳术后化疗后程同步大分割放疗前瞻性Ⅰ期临床研究

目的 前瞻性评估T1~T2期乳腺癌保乳术后化疗后程大分割放疗的不良反应和耐受性，以及在缩短治疗时间、减轻患者经济负担等方面的价值。方法 共入组20例T1~T2期乳腺癌保乳术后患者，所有患者于末次多西他赛化疗前开始大分割放疗。观察急性放射反应、治疗完成率及无病生存率、住院时间及住院费用等。结果 治疗完成率100%。主要不良反应为血液学毒性（白细胞减少）及皮肤反应，患者均可耐受。中位随访时间为30.1个月，随访率100%。美容效果良好率100%。平均总治疗时间为4周，总住院治疗费用节省约1万元。21个月无病生存率为100%。结论 T1~T2期乳腺癌保乳术后可耐受同步大分割放化疗，局部控制好，美容效果佳，且具有较高的卫生经济学价值。     

电针复合TCI靶控输注在单肺通气食管癌开胸手术麻醉中的应用与安全性＊

目的 探讨电针复合靶控输注（Target Controlled Infusion， TCI）在单肺通气食管癌开胸手术麻醉中的应用价值。方法 选取于我院拟行单肺通气食管癌开胸切除手术患者60例作为研究对象。随机将其分为试验组与对照组，对照组30例采取气管插管全麻及TCI靶控输注维持麻醉深度，试验组30例则在对照组方案基础上辅助电针麻醉，记录两组患者手术麻醉时间、药物用量、苏醒时间、并发症；以及术前（T_Ⅰ）、插管前即刻（T_Ⅱ）、插管后1 min（T_Ⅲ）、切皮即刻（T_Ⅳ）、去骨时（T_Ⅴ）、拔管即刻（T_Ⅵ）时平均动脉压（MAP）、平均心率（HR）、BIS值；术前、术后1天、术后3天简易智能精神状态检查量表（MMSE）；并于麻醉诱导前（T₀）、手术开始2 h（T₁）、术后1天（T₂）、术后3天（T₃）时抽取患者外周静脉血检测IL-1β、IL-6、IL-10、TNF-α浓度。结果 试验组手术用时、麻醉时间略低于对照组，但差异无统计学意义（P>0.05），试验组异丙酚、舒芬太尼用量以及苏醒时间均明显低于对照组（P<0.05）；T_Ⅱ时两组平均动脉压（Mean Arterial Pressure， MAP）、心率（Heartrate， HR）较术前明显降低，且试验组MAP明显低于对照组（P<0.05），但两组T_Ⅱ时HR比较无显著差异（P>0.05）；T_Ⅲ、T_Ⅵ时对照组MAP、HR明显高于T_Ⅰ时，而试验组MAP、HR与T_Ⅰ比较无显著差异（P>0.05）。术后1天、3天试验组简易智能精神状态检查量表（Mini-Mental State Examination， MMSE）评分低于对照组，有显著性差异（P<0.05）。T₁、T₂、T₃时试验组白介素-1β（IL-1β）、白介素-6（IL-6）、肿瘤坏死因子（Tumor Necrosis Factor-α， TNF-α）水平明显低于对照组（P<0.05），白介素-10（IL-10）水平明显高于对照组（P<0.05）。结论 采用电针复合TCI靶控输注麻醉方案可有效提升单肺通气食管癌开胸手术麻醉效果，能够降低患者术后认知功能障碍发生风险。