Mechanism-driven phase I translational study of trifluoperazine in adults with sickle cell disease.
Mechanism-driven phase I translational study of trifluoperazine in adults with sickle cell disease.
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三氟拉嗪治疗镰状细胞病成人的机制驱动 I 期转化研究。
DOI：
10.1016/j.ejphar.2013.10.062
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发表时间：
2014
影响因子：
5
通讯作者：
Wang,ZaijieJ
中科院分区：
文献类型：
--
作者：
Molokie,RobertE;Wilkie,DianaJ;Wittert,Harriett;Suarez,MarieL;Yao,Yingwei;Zhao,Zhongsheng;He,Ying;Wang,ZaijieJ
最近有证据表明，患有镰状细胞病(SCD)的成人患者存在神经病理性疼痛，需要对这些患者进行辅助止痛治疗。钙/钙调素蛋白激酶IIα(CaMKIIα)在神经病理性疼痛中起重要作用，三氟拉嗪是一种有效的CaMKIIα抑制剂。本研究的目的是确定三氟拉嗪对成人SCD患者的急性作用，主要是不良反应，其次是减轻疼痛强度。在一项I期开放研究中，我们对6剂三氟拉嗪(0.5、1、2、5、7.5、10 mg)进行了7小时和24小时的重复测量，对18名SCD成人患者(18名血红蛋白SS病，15名女性，平均35.8±8.9岁，范围23-53岁)进行了不良反应、疼痛强度和补充阿片类止痛药的重复测量。数据采用描述性统计方法进行分析。受试者分别报告了7.5 mg和10 mg剂量的中到重度镇静效果。8名受试者报告称，在没有严重镇静或补充阿片类止痛剂的情况下，慢性疼痛减轻了50%；其中一名受试者在服用10毫克后24.5小时出现肌张力障碍。3例受试者的止痛作用持续时间至少为24小时。镇静用咖啡因缓解，肌张力障碍用苯海拉明缓解。患有SCD的成年人在10毫克以下的剂量下体验到最小的不良反应。在这项分子机制驱动的翻译研究中，三氟拉嗪显示出作为一种止痛药的前景，值得在一项针对成年SCD患者的随机对照研究中进一步测试，该研究始于1 mg的重复剂量，以确定长期的不良反应和止痛效果。
Recent evidence of neuropathic pain among adults with sickle cell disease (SCD) reveals a need for adjuvant analgesic treatments for these patients. Ca2+/calmodulin protein kinase IIα (CaMKIIα) has a known role in neuropathic pain and trifluoperazine is a potent CaMKIIα inhibitor. The study aim was to determine trifluoperazine's acute effects, primarily on adverse effects and secondarily on pain intensity reduction, in adults with SCD. In a phase I, open-label study of 6 doses of trifluoperazine (0.5, 1, 2, 5, 7.5, 10 mg), we obtained 7-hourly and 24-h repeated measures of adverse effects, pain intensity, and supplemental opioid analgesics in 18 adults with SCD (18 hemoglobin SS disease, 15 women, average age 35.8±8.9 years, ranged 23–53) each of whom received a single dose. Data were analyzed with descriptive statistics. Subjects reported moderate to severe sedative effects at 7.5 and 10 mg doses, respectively. Eight subjects reported 50% reduction in chronic pain without severe sedation or supplemental opioid analgesics; one of these subjects had dystonia 24.5 h after the 10 mg dose. The analgesic effect lasted for at least 24 h in 3 subjects. Sedation resolved with caffeine and dystonia resolved with diphenhydramine. Adults with SCD experienced minimal adverse effects at doses under 10 mg. In this molecular mechanism-driven translational study, trifluoperazine shows promise as an analgesic drug that is worthy of further testing in a randomized controlled study of adults with SCD starting at a dose of 1 mg in repeated doses to determine long-term adverse and analgesic effects.