Dichlorphenamide vs Acetazolamide for Periodic Paralysis

描述（由申请人提供）：在计划补助金R21 NS 39939- 01 A1的帮助下，编写了两种碳酸酐酶抑制剂治疗周期性麻痹的多中心临床试验的修订申请。 授予该补助金是因为碳酸酐酶抑制剂（CAI）乙酰唑胺（ACZ）和双氯芬酰胺（DCP）已用于周期性麻痹（PP）多年，但不确定治疗是否会预防慢性进行性虚弱，折磨PP患者。 此外，尚不清楚ACZ或DCP哪种药剂优选用于预防发作和治疗/预防虚弱。 只有10%的患者维持DCP，这可能是首选治疗。 在过去的十年中，许多PP的分子缺陷已被确定，使分子定义的PP患者的治疗研究成为可能。 我们提出了14个中心的随机对照试验，以检验实用的假设，即（1）DCP和ACZ将减少高钾PP（HYP）和低钾PP（HOP）的虚弱发作的频率;（2）DCP将改善力量-在更大程度上比ACZ或安慰剂在两个PP的;和（3）DCP和ACZ将改善两种类型的PP的生活质量。 这些试验还将检验解释性假设，即特定离子通道突变将：（1）预测不同的表型;（2）预测对ACZ和DCP的不同反应，以及（3）ACZ/DCP对电解质和酸/碱状态的影响与治疗反应相关。 计划中的HYP-HOP试验将：（1）开发PP的标准治疗方法;（2）为PP的长期治疗建议辩护;（3）为DCP的监管批准提供数据，这对于临床使用至关重要;（4）为更广泛地了解PP中的通道功能障碍以及大量神经肌肉和CNS通道病变奠定基础;（5）为合作的基础科学实验室提供临床资源，以研究体内和体外通道病变的病理机制。

DESCRIPTION (provided by the applicant): This revised application for multicenter clinical trials of two carbonic anhydrase inhibitors in the periodic paralyses has been prepared with the help of planning grant R21 NS 39939-01A1. This grant was awarded because the carbonic anhydrase inhibitors (CAI) acetazolamide (ACZ) and dichlorphenamide (DCP) have been used in the periodic paralyses (PP) for many years but there is uncertainty whether treatment will prevent the chronic, progressive weakness that afflicts PP patients. Moreover, it is not known which agent, ACZ or DCP is preferable for attack prevention and treatment/prevention of weakness. Only 10% of patients are maintained on DCP, which may be preferred treatment. In the past decade, the molecular defects of many of the PP's have been identified, making possible the study of treatment in molecularly-defined patients with PP. We propose 14-center randomized controlled trials to test the pragmatic hypotheses that (1) DCP and ACZ will decrease the frequency of attacks of weakness in hyperkalemic PP (HYP) and in hypokalemic PP (HOP); (2) DCP will improve strength-to a greater extent than ACZ or placebo in both PP's; and (3) that DCP and ACZ will improve quality of life in both types of PP. The trials will also test the explanatory hypotheses that specific ion channel mutations will: (1) predict differing phenotypes; and (2) predict differing responses to ACZ and DCP and that (3) ACZ/DCP effects on electrolyte and acid/base status are related to treatment responses. The planned HYP-HOP trials will: (1) develop standard treatments for the PP; (2) defend recommendations for long-term treatments in PP; (3) provide data for regulatory approval of DCP, which is essential to have it available for clinical use; (4) lay the groundwork for broader insight into channel dysfunction in the PP and a large number of neuromuscular and CNS channelopathies; (5) provide clinical resources for collaborating basic science laboratories to study pathomechanisms of channelopathies in vivo and vitro.