Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain

AimsThe aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight.MethodsIndividual concentration–time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post‐dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme‐linked immunosorbent assay.ResultsA two compartment model with parallel linear and non‐linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V ₁), peripheral volume (V ₂), inter‐compartmental clearance, maximum elimination capacity (VM) and concentration at half‐maximum elimination capacity were 0.135 l day^–1, 2.71 l, 1.98 l, 0.371 l day^–1, 8.03 μg day^–1 and 27.7 ng ml^–1, respectively. Inter‐individual variability (IIV) was included on CL, V ₁, V ₂ and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V ₁ and V ₂ significantly reduced IIV.ConclusionsThe small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.     

Severe lumbar spinal stenosis combined with Guillain-Barré syndrome: A case report

BACKGROUNDGuillain-Barré syndrome (GBS) is a rare disorder that typically presents with ascending weakness, pain, paraesthesias, and numbness, which mimic the findings in lumbar spinal stenosis. Here, we report a case of severe lumbar spinal stenosis combined with GBS.CASE SUMMARYA 70-year-old man with a history of lumbar spinal stenosis presented to our emergency department with severe lower back pain and lower extremity numbness. Magnetic resonance imaging confirmed the diagnosis of severe lumbar spinal stenosis. However, his symptoms did not improve postoperatively and he developed dysphagia and upper extremity numbness. An electromyogram was performed. Based on his symptoms, physical examination, and electromyogram, he was diagnosed with GBS. After 5 d of intravenous immunoglobulin (0.4 g/kg/d for 5 d) therapy, he gained 4/5 of strength in his upper and lower extremities and denied paraesthesias. He had regained 5/5 of strength in his extremities when he was discharged and had no symptoms during follow-up.CONCLUSIONGBS should be considered in the differential diagnosis of spinal disorder, even though magnetic resonance imaging shows severe lumbar spinal stenosis. This case highlights the importance of a careful diagnosis when a patient has a history of a disease and comes to the hospital with the same or similar symptoms.     

平心复脉合剂联合琥珀酸美托洛尔缓释片治疗频发室性早搏临床研究

目的：观察平心复脉合剂联合琥珀酸美托洛尔缓释片对频发室性早搏的疗效及对心率变异性的影响。方法：纳入气阴两虚型频发室性早搏患者 80 例，采用随机数字表法分为治疗组和对照组各 40 例。对照组予琥珀酸美托洛尔缓释片治疗，治疗组在对照组基础上加用平心复脉合剂，共治疗 4 周。比较 2 组治疗前后心率变异性指标、临床疗效及不良反应发生率。结果：总有效率治疗组为 90.0%，对照组为 72.5%，2 组比较，差异有统计学意义（P＜0.05）。治疗前，2 组心率变异性指标比较，差异均无统计学意义 （P＞0.05）。治疗后，2 组间期标准差 （SDNN）、连续正常间距差的均方根 （rMSSD）、高频功率 （HF） 均较治疗前增大（P＜0.05），低频功率（LF）较治疗前减小（P＜0.05）；治疗组 SDNN、rMSSD、HF 均大于对照组，LF 小于对照组（P＜ 0.05）。2 组不良反应发生率均为 2.50%，组间比较，差异无统计学意义（P＞0.05）。结论：平心复脉合剂联合琥珀酸美托洛尔缓释片治疗频发室性早搏，能改善患者心率变异性，安全有效。     

层面递进法激光腔内剜除高危前列腺增生的治疗体会

目的探讨1 470 nm激光剜除治疗高危前列腺增生的手术技巧及临床效果。 方法回顾分析2018年6月至2018年9月中山大学附属第三医院泌尿外科采用1 470 nm激光治疗共89例高危前列腺增生患者的临床资料，年龄平均（68±3）岁，前列腺体积（57.4±2.6）ml。所有患者均采用"寻找层面，先易后难，剜切结合"的层面递进法思路行激光腔内前列腺剜除术，比较患者术中及术后情况。 结果89例均顺利完成手术，与术前相比，术后3个月患者最大尿流率明显增加，[（6.9±2.1） ml/s vs（19.8±3.6） ml/s]。国际前列腺症状评分显著好转，[（24.6±1.7） vs（8.0±1.2）]。术中无输血、无电切综合征、无直肠和膀胱穿孔病例，无输尿管损伤、大出血、心脑血管意外等严重并发症发生。 结论层面递进法激光剜除技术构想对于高危前列腺增生外科包膜层面的寻找、减少术后并发症有独到优势，且易于掌握，或可为业界同行提供一个新的思路。     

A randomized study on the effect of modified behavioral activation treatment for depressive symptoms in rural left-behind elderly

Objective: To evaluate the effectiveness of a modified behavioral activation treatment (MBAT) intervention on reducing depressive symptoms in rural left-behind elderly.

Method: This is a randomized study registered in Chinese Clinical Trial Registry (ChiCTR-IOR-17011289). Eighty rural left-behind elderly people who had a Geriatric Depression Scale (GDS) score between 11 and 25 were randomly assigned to the intervention (n?=?40) and control group (n?=?40). The intervention group received both MBAT and regular treatment for 8 weeks while the control group received regular treatment. Both groups were assessed with the GDS, Beck Anxiety Inventory (BAI), and Oxford Happiness Questionnaire (OHQ) at baseline, immediately post-intervention, and at 3 months post-intervention.

Results: There were a total of 73 participants that completed the intervention. The scores of GDS and BAI decreased significantly, but the scores of OHQ increased significantly in the intervention group after 8 sessions of MBAT (P?<?.01). The reduction in depression symptoms after the intervention was maintained at the 3-month follow-up. Significant differences in GDS, BAI, and OHQ scores were observed between the intervention group and the control group (P?<?.01).

Conclusion: MBAT produced a significantly greater reduction in depressive symptoms than regular care in rural left-behind elderly.

Clinical or methodological significance of this article: A modified behavioral activation (BA) psychotherapy can significantly reduce the recurrence and seriousness of depression symptoms in the left-behind elderly with mild to moderate depression. This study also suggests that further study of the MBAT as an intervention will provide a direction for the management of mental health in rural left-behind elders.     

Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

Dying is the Most Grown-Up Thing We Ever Do: But Do Health Care Professionals Prevent Us from Taking It Seriously?

This paper takes a somewhat slant perspective on flourishing and care in the context of suffering, death and dying, arguing that care in this context consists principally of ‘acts of work and courage that enable flourishing’. Starting with the perception that individuals, society and health care professionals have become dulled to death and the process of dying in Western advanced health systems, it suggests that for flourishing to occur, both of these aspects of life need to be faced more directly. The last days of life need to be ‘undulled’. Reflections upon the experiences of the author as carer and daughter in the face of her mother’s experience of death are used as basis for making suggestions about how care systems and professionals might better assist people in dealing with ‘the most grown up thing’ humans ever do, which is to die.