Dichlorphenamide vs Acetazolamide for Periodic Paralysis

描述（由申请人提供）：这两种碳酸酐酶抑制剂在周期性瘫痪中的多中心临床试验的修订申请已在计划拨款R21 NS 39939-01A1的帮助下准备。由于碳酸酐酶抑制剂（CAI）乙酰唑胺（ACZ）和二氯苯酰胺（DCP）已用于周期性瘫痪（PP）多年，但尚不确定治疗是否能预防慢性进行性虚弱，这种虚弱折磨PP患者。此外，尚不清楚ACZ或DCP哪种代理更适合用于攻击预防和治疗/预防弱点。只有10%的患者维持DCP，这可能是首选的治疗方法。在过去的十年中，许多PP的分子缺陷已经被发现，使得研究分子定义的PP患者的治疗成为可能。我们提出了14个中心的随机对照试验来验证以下假设：1)DCP和ACZ将降低高钾血症PP （HYP）和低钾血症PP （HOP）的虚弱发作频率；(2)与ACZ或安慰剂相比，DCP对两种PP的强度都有更大的提高；(3) DCP和ACZ将改善两种类型PP的生活质量。试验还将检验特定离子通道突变将：(1)预测不同表型的解释性假设；(2)预测对ACZ和DCP的不同反应；(3)ACZ/DCP对电解质和酸碱状态的影响与处理反应有关。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的监管审批提供数据，这是临床使用所必需的；(4)为更广泛地了解PP通道功能障碍以及大量神经肌肉和中枢神经系统通道病变奠定基础；(5)为合作基础科学实验室提供临床资源，在体内和体外研究通道病的病理机制。

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.