In vivo pharmacological interactions between a type II positive allosteric modulator of α7 nicotinic ACh receptors and nicotinic agonists in a murine tonic pain model

Background and Purpose

The α7 nicotinic ACh receptor subtype is abundantly expressed in the CNS and in the periphery. Recent evidence suggests that α7 nicotinic ACh receptor (nAChR) subtypes, which can be activated by an endogenous cholinergic tone comprising ACh and the α7 agonist choline, play an important role in chronic pain and inflammation. In this study, we evaluated whether type II α7 positive allosteric modulator PNU-120596 induces antinociception on its own and in combination with choline in the formalin pain model.

Experimental Approach

We assessed the effects of PNU-120596 and choline and the nature of their interactions in the formalin test using an isobolographic analysis. In addition, we evaluated the interaction of PNU-120596 with PHA-54613, an exogenous selective α7 nAChR agonist, in the formalin test. Finally, we assessed the interaction between PNU-120596 and nicotine using acute thermal pain, locomotor activity, body temperature and convulsing activity tests in mice.

Key Results

We found that PNU-120596 dose-dependently attenuated nociceptive behaviour in the formalin test after systemic administration in mice. In addition, mixtures of PNU-120596 and choline synergistically reduced formalin-induced pain. PNU-120596 enhanced the effects of nicotine and α7 agonist PHA-543613 in the same test. In contrast, PNU-120596 failed to enhance nicotine-induced convulsions, hypomotility and antinociception in acute pain models. Surprisingly, it enhanced nicotine-induced hypothermia via activation of α7 nAChRs.

Conclusions and Implications

Our results demonstrate that type II α7 positive allosteric modulators produce antinociceptive effects in the formalin test through a synergistic interaction with the endogenous α7 agonist choline.     

咖啡因5种主要代谢物的反相高效液相色谱法测定

为保证应用咖啡因代谢探针的正确性,建立了反相高效液相色谱测定尿中咖啡因代谢物的方法。采用日本岛津 Shim Pack CLC-ODS柱(5μm),以甲醇—乙腈—0.05%醋酸(12∶1∶87)为流动相,咖啡因和它的13种代谢物及内标均能良好分离。重点对其中5个主要代谢物AFMU,1U,1X,17U,17X进行了测定。结果表明这5种代谢物回收率均在87%以上,日内和日间误差均小于3%,显示了方法的稳定性。并对120例志愿者尿中5种主要代谢物浓度进行了测定,为进一步评价多种药物代谢酶活性创造条件。     

Adjuncts to transcatheter aortic valve implantation

Introduction: The appreciable rise in percutaneous valve procedures has been pursued by a wave of development in advanced technology to help guide straightforward, streamlined and safe intervention. This review article aims to highlight the adjunctive devices, tools and techniques currently used in transcatheter aortic valve implantation procedures to avoid potential pitfalls.

Areas covered: The software and devices featured here are at the forefront of technological advances, most of which are not yet in widespread use. These products have been discussed in national and international structural intervention conferences and the authors felt it important to showcase particularly well designed adjuncts that improve procedural efficacy and safety. Whilst vascular pre-closure systems are used routinely and are an integral part of these complex cardiovascular procedures, these have been well summarised elsewhere and are beyond the scope of this article.

Expert commentary: The rising volume of patients with aortic stenosis who are treatable with TAVI means that this exponential increase in procedures must be accompanied by a steady decline in procedural complications. This section provides an overview of our current perspective, and what we feel the direction of travel will be.     

胶原蛋白膜对人牙周膜细胞增殖能力量效分析的影响

目的:观察不同质量浓度胶原蛋白膜对人牙周膜细胞增殖能力的影响,寻求牙周组织工程中胶原蛋白膜载体的最佳浓度。方法:实验于2006-02/11在辽宁医学院实验中心完成。实验材料:选取因正畸需要拔除的新鲜第一前磨牙,患者知情同意并自愿捐献。实验分组:通过热烘干法制备胶原蛋白膜(胶原质量浓度分别为3,6,9g/L)。将细胞浓度为5×107L-1的第3～8代的人牙周膜细胞接种到3,6,9g/L胶原蛋白膜上,每种薄膜设立3个样本。分别将负载细胞的薄膜移至24孔板中,对照组为细胞直接接种于24孔板中。实验评估:①复合培养第7天对人牙周膜细胞进行细胞记数。②利用扫描电镜观察人牙周膜细胞在胶原蛋白膜上的生长情况。结果:①复合培养第7天人牙周膜细胞记数:随着培养时间的增长,3,6,9g/L胶原蛋白膜上的细胞数量逐渐增加[分别为(3.63±0.59)×104,(3.92±0.10)×104,(4.26±0.24)×104个],9g/L胶原蛋白膜上的细胞生长最旺盛,均高于对照组(2.51±0.11)×104个,4组之间比较差异均有显著性意义(t=3.263,17.099,11.611,P<0.05)。②扫描电镜下人牙周膜细胞在胶原蛋白膜上的生长情况:复合培养1周,胶原蛋白膜具有较好的多孔状结构;人牙周膜细胞伸出多个伪足样突起,紧密贴附在材料表面,细胞沿材料的孔隙边缘生长。结论:9g/L胶原蛋白膜最适合人牙周膜细胞生长增殖。