In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization.
In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization.
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追求P2X3拮抗剂：用于慢性疼痛和传入敏化的新型治疗学。
DOI：
10.1007/s11302-011-9271-6
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发表时间：
2012-02
影响因子：
3.5
通讯作者：
Ford, Anthony P.
中科院分区：
文献类型：
--
作者：
Ford, Anthony P.
关键词：
通过抑制含P2 X3受体的ATP激活来治疗疼痛预示着一种令人兴奋的疼痛管理新方法，而Afferent的计划标志着一类新药物的先锋，这些药物准备探索这种方法以满足疼痛管理中未满足的重大需求。P2 X3受体亚基主要和选择性地在大多数组织和器官系统（包括皮肤、关节和中空器官）中的所谓C-和Aδ-纤维初级传入神经元中表达，表明对人体中的疼痛感测系统具有高度特异性。P2 X3拮抗剂阻断ATP对这些纤维的激活，并为疼痛和不适的管理提供了另一种方法。此外，P2 X3在C-纤维传入神经元的中央末端突触前表达，其中ATP进一步使疼痛信号的传递敏感。由于P2 X3表达的选择性，对大脑、胃肠道或心血管组织产生不良反应的可能性较低，这些影响仍然是许多现有疼痛治疗方法的限制因素。在外周，ATP（触发P2 X3受体激活的因子）可以由于组织炎症、损伤或应激以及内脏器官扩张而从各种细胞释放，并刺激这些局部伤害感受器。P2 X3受体的基本原理引起了大量的研究，产生了许多报告，阐明了ATP作为疼痛介质的潜在作用，特别是在慢性致敏状态下，并引起了制药公司的兴趣。P2 X受体介导的传入激活与炎症、内脏和神经性疼痛状态以及气道高反应性、偏头痛、瘙痒和癌症疼痛有关。人们很好地认识到，新的机制往往很难从模型转化为临床疗效和有效性;然而，从模型中的P2 X3抑制中看到的活性广度提供了一个现实的机会，即这种抑制传入神经敏化的新机制可能会在阳光下找到自己的位置，并为持续的不适和疼痛带来一些仁慈的缓解。Afferent的开发理念是进行概念验证患者研究，并最好地确定可能从这种新干预中受益的目标患者群体。
Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention.
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影响因子：
3.4
作者：
Beijer, Sandra;Gielisse, Eric A. R.;Hupperets, Pierre S.;van den Borne, Ben E. E. M.;van den Beuken-van Everdingen, Marieke;Nijziel, Marten R.;van Henten, Arjen M. J.;Dagnelie, Pieter C.
通讯作者：
Dagnelie, Pieter C.
影响因子：
7.4
作者：
Ambalavanar, R;Moritani, M;Dessem, D
通讯作者：
Dessem, D
DOI：
10.1165/ajrcmb.23.1.3936
发表时间：
2000-07-01
影响因子：
6.4
作者：
Brouns, I;Adriaensen, D;Timmermans, JP
通讯作者：
Timmermans, JP
DOI：
10.1007/bf01931108
发表时间：
1995-03-15
期刊：
EXPERIENTIA
影响因子：
--
作者：
BODIN, P;BURNSTOCK, G
通讯作者：
BURNSTOCK, G
影响因子：
2.7
作者：
Brotherton-Pleiss, Christine E.;Dillon, Michael P.;Zhai, Yansheng
通讯作者：
Zhai, Yansheng