阿西马朵林性质、用途与生产工艺
易激综合征是一种以腹痛或腹部不适伴排便习惯改变为特点的功能性肠病。目前其病因、发病机制并未完全明确，可能与肠道功能紊乱、内脏感觉异常、肠黏膜屏障功能障碍、肠道免疫异常激活、精神心理等多种因素有关。其治疗并不是针对病因，而是以减轻主要症状为目的。除了一些传统的治疗，如解痉药、三环类抗抑郁药等，还出现了许多新的潜在的药物，包括益生菌、氯离子通道，鸟苷酸环化酶-C受体激动剂等。
阿西马朵林是K-阿片受体激动剂，可升高肠易激综合征（IBS）患者的敏感阈值，几乎不通过血脑屏障，耐受性良好。阿西马朵林是一种胃肠道的选择性κ新型阿片受体激动剂，被认为能显著降低IBS患者的腹痛感；实验显示阿西马朵林虽然不能明显改善患者的疼痛阈值，能显著降低疼痛强度。在腹痛改善方面阿西马朵林跟安慰剂无显著差别。
Asimadoline (EMD-61753) 是一种口服有效的，选择性的，具有周边活性的 κ-opioid 激动剂，对豚鼠和人重组 κ-opioid 的 IC50s 分别为 5.6 nM 和 1.2 nM。Asimadoline 对血脑屏障的渗透性低，具有外周抗炎作用。Asimadoline 可改善糖尿病大鼠的异常性疼痛，并具有用于肠易激综合征 (IBS) 研究的潜力。
IC50: 5.6 nM (guinea pig κ opioid), 1.2 nM (human recombinant κ opioid)
Asimadoline (EMD-61753) has high selectively in κ: μ: δ opioid binding ratios of 1:501:498 in human recombinant receptors. The IC
50
for Asimadoline binding to μ-opioid receptors is 3 µM and to δ-opioid receptors is 0.7 µM. The IC
50
values for D1, D2, kainate, σ, PCP/NMDA, H1, α1, α2, M1/M2, glycine, 5HT1A, 5HT1C, 5HT1D, 5HT2, 5HT3, AMPA and kainate/AMPA receptors are all >10 µM.
Asimadoline has affinity to sodium and L type Ca
2+
ion channels at IC
50
concentrations 150 to 800 fold the IC
50
for the κ receptors.
At high concentrations, Asimadoline demonstrates spasmolytic action against 400 µM barium chloride in the rat duodenum (IC
50
=4.2 µM), suggesting that Asimadoline may block the direct stimulant effects of barium on smooth muscle through mechanisms that are not identified.
Asimadoline (EMD-61753; 1, 5, 15 mg/kg; s.c.) acutely ameliorates both formalin-evoked hyperalgesia and tactile allodynia in diabetic rats.
The absorption rate following oral administration is 80% in rats and >90% in dogs and monkeys. The metabolism of Asimadoline is rapid and appears similar in animals and man. Asimadoline has peripheral anti-inflammatory actions that are partly mediated through increase in joint fluid substance P levels.
Treatment with Asimadoline (5 mg/kg/day; i.p.) produces marked (and sustained) attenuation of the disease with all three time regimes.
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Animal Model:
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Adult female Sprague-Dawley rats
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Dosage:
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1, 5, 15 mg/kg
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Administration:
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SC; single dose
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Result:
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Acutely ameliorated both formalin-evoked hyperalgesia and tactile allodynia in diabetic rats.
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阿西马朵林
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