Potential for developing purinergic drugs for gastrointestinal diseases.
Potential for developing purinergic drugs for gastrointestinal diseases.
复制标题
DOI：
10.1097/mib.0000000000000047
复制
发表时间：
2014-07
影响因子：
4.9
通讯作者：
Christofi FL
中科院分区：
文献类型：
--
作者：
Ochoa-Cortes F;Liñán-Rico A;Jacobson KA;Christofi FL
治疗IBD，IBS，FD或运动障碍是不够的，嘌呤能药物提供了令人兴奋的新的可能性。可以作为治疗目标的GI症状包括内脏痛、炎性疼痛、运动障碍、便秘和腹泻。本次审查的重点是潜在的开发嘌呤能药物的临床试验，以治疗胃肠道症状。嘌呤能受体分为腺苷P1（A1、A2 A、A2 B、A3）、亲离子型ATP门控P2 X离子通道（P2 X1 -7）或亲代谢型P2 Y1、2、4、6、11-14受体。靶向A2 A、A2 B、A3、P2 X7、P2 X3受体或增加内源性腺苷水平以治疗IBD、炎性疼痛、IBS/内脏痛、炎性腹泻和运动障碍有良好的实验证据。嘌呤基因也是疾病的潜在生物标志物。药物化学的进步加速了临床试验的步伐：用于治疗IBD的甲氨蝶呤和柳氮磺胺吡啶通过刺激CD 73依赖性腺苷的产生而起作用。ATP可防止NSAID诱导的肠病，并具有缓解人类疼痛的特性。P2 X7 R拮抗剂AZD 9056正在进行CD的临床试验。A3 AR药物针对炎症性疾病（例如CF 101; CF 102）。双嘧达莫是一种核苷摄取抑制剂，正在进行内毒素血症的试验。临床试验中的疼痛药物包括P2 X3/P2 X2/3（AF-219）和P2 X7（GSK 1482160）拮抗剂和A1（GW 493838）或A2 A（BVT. 115959）激动剂。IberogastR是一种靶向嘌呤机制的植物药物，对IBS和FD有效。嘌呤能药物在IBD、IBS、FD和炎性腹泻的前瞻性临床试验中具有良好的安全性/有效性。遗传多态性和咖啡因摄入量可能会影响对治疗的敏感性。进一步的动物研究可以阐明机制并测试新一代药物。最后，我们对嘌呤能信号的人类病理生理学的认识仍然存在巨大的差距。
Treatments for IBD, IBS, FD or motility disorders are not adequate, and purinergic drugs offer exciting new possibilities. GI symptoms that could be targeted for therapy include visceral pain, inflammatory pain, dysmotility, constipation and diarrhea. The focus of this review is on potential for developing purinergic drugs for clinical trials to treat GI symptoms. Purinergic receptors are divided into adenosine P1 (A1,A2A,A2B,A3), ionotropic ATP-gated P2X ion channel (P2X1–7) or metabotropic P2Y1,2,4,6,11–14 receptors. There is good experimental evidence for targeting A2A, A2B, A3, P2X7, P2X3 receptors or increasing endogenous adenosine levels to treat IBD, inflammatory pain, IBS/visceral pain, inflammatory-diarrhea and motility disorders. Purine genes are also potential biomarkers of disease. Advances in medicinal-chemistry have an accelerated pace toward clinical trials: Methotrexate and sulfasalazine, used to treat IBD, act by stimulating CD73-dependent adenosine production. ATP protects against NSAID-induced enteropathy and has pain-relieving properties in humans. A P2X7R antagonist AZD9056 is in clinical trials for CD. A3 AR drugs target inflammatory diseases (e.g. CF101; CF102). Dipyridamole, a nucleoside uptake-inhibitor, is in trials for endotoxemia. Drugs for pain in clinical-trials include P2X3/P2X2/3(AF-219) and P2X7(GSK1482160) antagonists and A1(GW493838) or A2A(BVT.115959) agonists. IberogastR is a phytopharmacon targeting purine-mechanisms with efficacy in IBS and FD. Purinergic drugs have excellent safety/efficacy profile for prospective clinical trials in IBD, IBS, FD and inflammatory-diarrhea. Genetic polymorphisms and caffeine consumption may affect susceptibility to treatment. Further studies in animals can clarify mechanisms and test new-generation drugs. Finally, there is still a huge gap in our knowledge of human pathophysiology of purinergic signaling.