Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease
Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease
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DOI：
10.1172/jci118537
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发表时间：
1996-03-01
影响因子：
15.9
通讯作者：
Platt, OS
中科院分区：
文献类型：
--
作者：
Brugnara, C;Gee, B;Platt, OS
镰状红细胞的病理性失水使异常血红蛋白集中，促进镰状红细胞的形成。Ca2+激活的K+通道（Gardos通道）在体外有助于这种有害的脱水，通过该通道阻断K+和水分流失可能是一种潜在的体内治疗方法。我们用口服氯霉唑（一种特异性Gardos通道抑制剂）治疗了5名患有镰状细胞性贫血的患者。患者开始服用10mg氯曲霉唑/kg/d，持续一周。方案设计允许每日剂量每周递增10mg /kg，直到红细胞密度和K+转运发生显著变化。每周取血3次，进行血液学和化学分析、红细胞密度、阳离子含量和K+转运。在氯霉唑20mg /kg/d剂量下，所有受试者均表现出Gardos通道抑制，红细胞脱水减少，细胞K+含量增加，血红蛋白水平有所升高，所有受试者的不良反应仅限于轻度/中度排尿困难。两名服用30mg /kg/d氯霉唑的受试者血浆丙氨酸转氨酶和天冬氨酸转氨酶水平出现可逆性升高。这是第一个证明Gardos通道导致镰状红细胞脱水的体内证据，其药理学抑制提供了一种现实的抗镰状红细胞策略。
Pathologic water loss from sickle erythrocytes concentrates the abnormal hemoglobin and promotes sickling. The Ca2+-activated K+ channel (Gardos channel) contributes to this deleterious dehydration in vitro, and blockade of K+ and water loss via this channel could be a potential therapy in vivo. We treated five subjects who have sickle cell anemia with oral clotrimazole, a specific Gardos channel inhibitor. Patients were started on a dose of 10 mg clotrimazole/kg/d for one week. Protocol design allowed the daily dose to be escalated by 10 mg/kg each week until significant changes in erythrocyte density and K+ transport were achieved. Blood was sampled three times a week for hematological and chemical assays, erythrocyte density, cation content, and K+ transport, At dosages of 20 mg clotrimazole/kg/d, all subjects showed Gardos channel inhibition, reduced erythrocyte dehydration, increased cell K+ content, and somewhat increased hemoglobin levels, Adverse effects were limited to mild/moderate dysuria in all subjects, and a reversible increase in plasma alanine transaminase and aspartic transaminase levels in two subjects treated with 30 mg clotrimazole/kg/d. This is the first in vivo evidence that the Gardos channel causes dehydration of sickle erythrocytes, and that its pharmacologic inhibition provides a realistic antisickling strategy.