Irritable Bowel Syndrome neuropharmacology - A review of approved and investigational compounds
Irritable Bowel Syndrome neuropharmacology - A review of approved and investigational compounds
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DOI：
10.1097/00004836-200207001-00011
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发表时间：
2002-07-01
影响因子：
2.9
通讯作者：
Callahan, MJ
中科院分区：
文献类型：
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作者：
Callahan, MJ
抗胆碱能药物和促动力剂是肠易激综合征（IBS）患者治疗的主要药物，尽管其疗效有限且副作用严重。这些药物的临床局限性是它们与各种受体的相对广泛和非特异性药理学相互作用的结果。肠道生理学的最新进展已经鉴定出可能在IBS发病机制中起关键作用的各种受体靶点。寻求安全有效的IBS疗法的药物化学家现在正在开发针对许多这些特定受体的化合物。最新一代的抗胆碱能药物，如扎米那新、达非那新和YM-905，提供毒蕈碱3型受体的选择性拮抗作用。替加色罗是一种选择性5-HT 4部分激动剂，在多项临床试验中进行了测试，可有效减轻腹痛、腹胀和便秘的症状。Ezlopitant和nepadudant分别是1型和2型神经激肽受体的选择性拮抗剂，在减少肠道运动和疼痛方面显示出前景。洛哌丁胺是一种μ阿片受体激动剂，对以腹泻（IBS-D）为主要肠道综合征的IBS患者安全有效。非多托嗪是一种κ（kappa）阿片受体激动剂，已在各种临床试验中尝试作为内脏镇痛剂，结果相互矛盾。阿洛司琼是一种5-HT 3受体拮抗剂，已证明对IBS-D患者有效，但在上市后随访中观察到的缺血性结肠炎事件导致其从市场上撤下。化合物的目标胆囊收缩素A，N-甲基-D-天冬氨酸，α（2）-肾上腺素能，和促肾上腺皮质激素释放因子受体也检查在这篇评论。
Anticholinergics and prokinetics are mainstays of therapy for Irritable Bowel Syndrome (IBS) patients despite their limited efficacy and troublesome side-effect profile. The clinical limitations of these drugs are a result of their relative broad and nonspecific pharmacologic interaction with various receptors. Recent advances in gut physiology have led to the identification of various receptor targets that may play a pivotal role in the pathogenesis of IBS. Medicinal chemists searching for safe and effective IBS therapies are now developing compounds targeting many of these specific receptors. The latest generation of anticholinergics, such as zamifenacin, darifenacin, and YM-905, provide selective antagonism of the muscarinic type-3 receptor. Tegaserod, a selective 5-HT4 partial agonist, tested in multiple clinical trials, is effective in reducing the symptoms of abdominal pain, bloating, and constipation. Ezlopitant and nepadudant, selective antagonists for neurokinin receptors type 1 and type 2, respectively, show promise in reducing gut motility and pain. Loperamide, a mu (mu) opioid receptor agonist, is safe and effective for IBS patients with diarrhea (IBS-D) as the predominant bowel syndrome. Fedotozine, a kappa (kappa) opioid receptor agonist, has been tried as a visceral analgesic in various clinical trials with conflicting results. Alosetron, a 5-HT3 receptor antagonist, has demonstrated efficacy in IBS-D patients but incidents of ischemic colitis seen in post-marketing follow-up resulted its removal from the market. Compounds that target cholecystokinin A, N-methyl-D-aspartate, alpha(2)-adrenergic, and corticotropin-releasing factor receptors are also examined in this review.