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.     

全膝关节置换术后的骨溶解：胫骨盘表面的修饰及聚乙烯衬垫灭菌方法对其的影响术 后5至10年的报告

背景：从关节和胫骨假体聚乙烯衬垫后表面转移磨损碎屑，是全膝关节置换术后假体周围骨溶解的主要原因。全膝人工关节假体设计随时问而发生变化，例如对胫骨盘近端表面的粗糙度和聚乙烯衬垫的灭菌方法。我们假设胫骨盘表面抛光和采用空气中γ射线照射之外的其他方法对衬垫灭菌，可降低骨溶解的发生率。方法：从1987年至1998年，我们采用后十字韧带保留型的解剖型组配式全膝人工关节假体系列。对300名患者施行365例全膝关节置换术。术后5至10年，对这些患者的膝关节摄正、侧位X线片。由两位关节置换专家对X线片上的骨溶解状况进行单独评定（骨溶解的界定标准为假体周围存在边缘清晰的非线性松质骨丢失区）。结果：在粗糙表面的胫骨盘的242例膝关节中，使用空气中γ射线照射灭菌的衬垫固定，有34％（82例）骨溶解阳性。用惰性气体中γ射线照射或没有照射的衬垫与抛光表面连接的98例膝关节中，有9％（9例）骨溶解阳性。骨溶解与六项因素相关，这些因素为：一项与患者（男性）相关、一项与胫骨盘（近端表面抛光）相关、三项与聚乙烯衬垫（加工的原材料、灭菌方法及存放时间）相关及一项与手术技术（股骨假体与胫骨假体间的过伸）相关。结论：在这类假体设计中，胫骨盘近端表面采用抛光及衬垫采用更为先进的灭菌方法（不用空气中γ射线照射灭菌）能显著减少骨溶解的发生率，但不能避免骨溶解。     

Use of CO2 to move structures as an aid to percutaneous procedures

By injecting small amounts of CO2 through a needle, one can move bowel or bladder from the intended path of instruments during interventional procedures. The technique worked well in six of seven cases in the pelvis and retroperitoneum; it was not effective in the mediastinum or midabdomen (n = 6).     

Primary tuberculous nasal polypi—A case report

Primary tuberculous pathology in nasolpolypi is a rare condition. A case of bilateral ethmoidal polypi with tubercular lesion diagnosed on histopathologlcal examination is being reported and the available relevant literature has been reviewed.