In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction

Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field.     

Endodontic treatment of a hypertaurodontic mandibular left second molar in a patient with many taurodonts combined with multiple pulp stones

Taurodontism is a rare embryologic anomaly of teeth, defined by an apical displacement of the furcation of roots and enlarged pulp chambers. Taurodontism has been classified as hypo‐, meso‐ or hypertaurodontism according to the severity of the anomaly. The aim of this case report was to illustrate a clinical case with multiple bilateral taurodonts and to describe the endodontic management of the hypertaurodontic mandibular left second molar with a C‐shaped canal and extensive dental pulp calcifications. A healthy 20‐year‐old male patient was referred for the endodontic treatment of his lower left second molar. Cone beam computed tomography revealed a C‐shaped root canal configuration and several dental pulp calcifications in this tooth. The endodontic treatment was performed in two appointments under an operating dental microscope. A panoramic radiograph, made during the 18 months follow‐up appointment, revealed nine other taurodontic molars, most of them associated with dental pulp calcifications.     

Ligustrazine inhibits high voltage-gated Ca~(2+) and TTX-resistant Na~+ channels of primary sensory neuron and thermal nociception in the rat:a study on peripheral mechanism

Objective Ligustrazine, also named as tetramethylpyrazine, is a compound purified from Ligusticum chuanxiong hort and has ever been testified to be a calcium antagonist. The present investigation was to determine the antinoci-ceptive effect of ligustrazine and, if any, the peripheral ionic mechanism involved. Methods Paw withdrawal Latency ( PWL) to noxious heating was measured in vivo and whole-cell patch recording was performed on small dorsal root ganglion (DRG) neurons. Results Intraplantar injection of ligustrazine (0.5 mg in 25μl) significantly prolonged the withdrawal latency of ipsilateral hindpaw to noxious heating in the rat. Ligustrazine not only reversibly inhibited high-voltage gated calcium current of dorsal root ganglion (DRG) neuron in dose-dependent manner with IC50 of 1.89 mmol/L, but also decreased tetrodotoxin (TTX) -resistant sodium current in relatively selective and dose-dependent manner with IC50 of 2.49 mmol/L. Conclusion The results suggested that ligustrazine could elevate the threshold of thermal nociception through inhibiting the high-voltage gated calcium current and TTX-resistant sodium current of DRG neuron in the rat.     

环化酶激活剂对大鼠感觉神经元保护作用的实验研究

目的探讨环化酶激活剂（前列腺素E1、腺苷及Zn^2＋离子）对周围神经损伤后感觉神经元的保护作用.方法在大鼠坐骨神经夹毁模型术后21 d,取背根节用图像分析法观测前列腺素E1（PGE1）、腺苷（Ade）和高Zn^2＋饲料（Zn^2＋）对背根节细胞数、核偏心率及核等圆径的影响,并与人胎盘神经生长因子（hNGF）的作用相比较.结果NGF及环化酶激活剂组与夹毁对照组相比都能增进背根节细胞的存活和减轻核偏移（P＜0.05）;NGF组和高Zn^2＋饲料组在背根节细胞存活数、核偏心率及核等圆径方面与假手术组无差别（P＞0.05）.结论PEG1、Ade及Zn^2＋离子等环化酶激活剂对DRG神经元均有保护作用,其中Zn^2＋离子的保护效应与NGF无差别.     

大鼠骶髂关节传入神经通路的实验研究

目的:通过逆行神经追踪法研究大鼠骶髂关节的传入神经通路。方法:30只雄性Sprague-Dawley大鼠随机分成非交感神经切除组(A组)和交感神经切除组(B组),每组15只,交感神经切除组切除左侧L1以下椎旁交感干。两组左侧骶髂关节注入30%的辣根过氧化物酶(HRP)20μl,72h后取出双侧的L1-S1背根神经节(DRG),TMB法染色后在光学显微镜下观察HRP阳性神经元细胞并计数。结果:两组左侧L1、L2背根神经节内HRP阳性神经元差异有显著性意义(P<0·05),B组HRP阳性神经元明显减少;左侧L3-S1背根神经节内HRP阳性神经元差异无显著性意义(P>0·05)。结论:L1-S1神经节含有支配同侧骶髂关节的传入神经元,同侧椎旁交感干可能是骶髂关节到L1-L2神经节重要的传入神经旁路,而不是到L3-L5神经节的传入旁路或重要的传入旁路。     

术中电生理动态监护下显微手术切除椎管神经鞘瘤（附65例报告）

目的 探讨术中电生理监护对椎管神经鞘瘤显微手术中的作用及意义，提高对椎管内神经鞘瘤的治疗水平。方法 回顾性分析65例术中电生理动态监护下，显微手术切除椎管内神经鞘瘤。结果 治愈60例（占92．3％），好转5例（占7．7％），无死亡；肿瘤全切62例，次全切除3例，全切率95．4％。结论 常规动态电生理监测下显微手术切除椎管神经鞘瘤，能保全脊髓神经的功能，减少副损伤，提高手术安全性；显微手术有助于提高肿瘤全切率，可有效减少术后复发。对影响脊柱稳定性的行脊柱融合内固定。     

颈椎后纵韧带骨化症后路术后C5神经根麻痹

目的：探讨颈椎后纵韧带骨化症（OPLL）术后C5神经根麻痹的临床特点、治疗及预后。方法：2000年3月至2005年1月．采用后路减压手术治疗OPLL患者157例．其中9例术后卅现C5神经根麻痹。回顾性分析9例患者的临床资料，所有患者术后均进行功能康复训练，其中5例患者给予高压氧辅助治疗，随访观察预后情况。结果：本组C5神经根麻痹的发生率为5．7％．包括单开门椎管成形术2例、全椎板切除减压术7例。其临床表现为三角肌、肱二头肌肌力下降至1～2级，肩部及上臂外侧感觉障碍，肱二头肌腱反射减弱或消失。随访1～4年，9例患者的肌力均恢复至3～4级，7例感觉恢复正常。结论：C5神经根麻痹是颈椎后路手术治疗OPLL的并发症之一，经过功能康复训练等保守治疗后肌力、感觉均可获得一定恢复。