Martin G R
Department of Molecular Pharmacology, Center for Biological Research, Roche Bioscience, Palo Alto, CA 94303, USA.
Cephalalgia. 1997 Oct;17 Suppl 18:4-14. doi: 10.1177/0333102497017S1802.
Zolmitriptan (Zomig; formerly 311C90) is a novel 5-hydroxytryptamine (5HT)1B/1D receptor agonist with proven efficacy in the acute treatment of migraine with or without preceding aura. The drug differs from presently available members of this drug class in that it combines 5HT1B/1D receptor partial agonist activity with robust oral pharmacokinetics and an ability to inhibit trigeminovascular activation centrally as well as peripherally in preclinical studies. Consistent with its selectivity for 5HT1B/1D receptors, zolmitriptan produces constriction of various isolated blood vessels, most notably cranial arteries. In anaesthetized animals, these vascular effects manifest as a selective constriction of cranial arterio-venous anastomoses resulting in a redistribution of carotid arterial blood flow. This effect is produced without significant effects on heart rate, blood pressure or blood flow to the brain, heart or lungs. Zolmitriptan also inhibits trigeminal-evoked increases in cerebral blood flow in anaesthetized cats and blocks trigeminal-evoked plasma protein extravasation in the dura of guinea-pigs. These actions are consistent with a pre-junctional inhibition of neuropeptide release from perivascular afferents of the trigeminal nerve, as confirmed by independent studies showing that zolmitriptan blocks elevations of calcitonin-gene-related peptide in jugular venous blood during electrical stimulation of the trigeminal ganglion. In all of these effects, zolmitriptan is three to four times more potent than sumatriptan, but produces the same maximum response. Zolmitriptan crosses the intact blood-brain barrier to inhibit trigeminovascular activation in the brainstem. This was shown initially by the ability of the drug to block a brainstem reflex provoking vasoactive intestinal peptide release from the VIIth cranial (facial) nerve during trigeminal stimulation. Subsequent ex vivo autoradiography confirmed that intravenously injected [3H]zolmitriptan labels a discrete population of cells in the trigeminal nucleus caudalis (TNC) and nucleus tractus solitarius. Direct evidence for a central neuromodulatory effect of zolmitriptan was provided by electrophysiological experiments which clearly demonstrated that the drug inhibits the excitability of cells in the TNC after systemic administration. This novel pre-clinical profile not only distinguishes zolmitriptan from sumatriptan, but raises intriguing questions about the clinical relevance of a dual action. Studies to date show that zolmitriptan indeed modulates cranial sensory processing in humans, yet central side-effects are no different from sumatriptan. This property may account for the remarkable consistency in clinical efficacy observed in clinical trials.
佐米曲坦（佐米格；原称311C90）是一种新型5-羟色胺（5HT）1B/1D受体激动剂，在急性治疗伴或不伴先兆的偏头痛方面已证实具有疗效。该药物与这一类现有药物的不同之处在于，在临床前研究中，它兼具5HT1B/1D受体部分激动剂活性、强大的口服药代动力学特性以及在中枢和外周抑制三叉神经血管系统激活的能力。与它对5HT1B/1D受体的选择性一致，佐米曲坦可使各种离体血管收缩，最显著的是颅动脉。在麻醉动物中，这些血管效应表现为颅动静脉吻合处的选择性收缩，导致颈动脉血流重新分布。产生这种效应时，对心率、血压或脑、心脏或肺部的血流没有显著影响。佐米曲坦还可抑制麻醉猫中三叉神经诱发的脑血流增加，并阻断豚鼠硬脑膜中三叉神经诱发的血浆蛋白外渗。这些作用与三叉神经血管周围传入神经的神经肽释放的突触前抑制一致，独立研究证实，在电刺激三叉神经节期间，佐米曲坦可阻断颈静脉血中降钙素基因相关肽的升高。在所有这些效应中，佐米曲坦的效力比舒马曲坦强三到四倍，但产生的最大反应相同。佐米曲坦可穿过完整的血脑屏障，抑制脑干中的三叉神经血管系统激活。最初通过该药物阻断三叉神经刺激期间诱发来自第VII对颅（面）神经的血管活性肠肽释放的脑干反射的能力得以证明。随后的离体放射自显影证实，静脉注射的[3H]佐米曲坦标记了三叉神经尾侧核（TNC）和孤束核中的离散细胞群。电生理实验提供了佐米曲坦具有中枢神经调节作用的直接证据，这些实验清楚地表明，该药物在全身给药后可抑制TNC中细胞的兴奋性。这种新的临床前特征不仅使佐米曲坦有别于舒马曲坦，还引发了关于双重作用临床相关性的有趣问题。迄今为止的研究表明，佐米曲坦确实可调节人类的颅感觉处理，但中枢副作用与舒马曲坦并无不同。这一特性可能解释了临床试验中观察到的临床疗效的显著一致性。
