Effect of Oral Cimetidine in the Protoporphyrias (IND 153247 submitted 9/2/2020)

口服西咪替丁对原卟啉症的作用（IND 153247 于 2020 年 9 月 2 日提交）

• 批准号: 10275566
• 负责人: KARL ELMO ANDERSON
• 金额: $ 49.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10275566
• 关键词: Effect; Oral; Cimetidine; Protoporphyrias; IND

PROJECT SUMMARY/ABSTRACT Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are a genetic defects of heme biosynthesis that cause life-long, painful cutaneous sensitivity to light. EPP and XLP, collectively called the protoporphyrias, result in the accumulation of the light-sensitive molecule protoporphyrin IX (PPIX) in erythrocytes and secondarily in the plasma and the liver. In addition to photosensitivity, protoporphyria can also result in anemia, gallstones, and chronic liver disease, and in 2-5% of cases it results in rapidly progressive cholestatic liver failure that is fatal without liver transplantation. Because patients are sensitive to visible light and not UV light, sunscreen is not effective in EPP. Afamelanotide, which increases cutaneous melanin, was recently approved by the FDA for the prevention of photosensitivity in EPP. Additional therapies besides afamelanotide are necessary because afamelanotide is does not change PPIX level and therefore does not prevent the life-threatening complications of EPP. Cimetidine has gained attention as a possible treatment for human porphyrias because of a potential off-target effect of inhibition of ALAS, the first enzyme of heme biosynthesis. This inhibition was first described in vitro. Later case reports suggested that cimetidine was beneficial for the treatment of acute intermittent porphyria and porphyria cutanea tarda. Subsequently, case reports also described a potential effect in EPP. However, these reports are anecdotal and uncontrolled. Some patients also had pre-existing hepatic damage from EPP, which complicates the observations of drug effects in EPP. Communications in the porphyria community indicate that a large number of patients, including children, have used cimetidine without oversight and without a systematic record of dosage or symptomatic improvement. The considerable interest in the larger porphyria community to assess with care its possible benefit as a treatment approach has therefore neither been addressed nor satisfied. Therefore, the objective of this study is to determine the efficacy and safety of oral cimetidine administration in the protoporphyrias. The study design is a multicenter, prospective, randomized, double-blind, placebo-controlled, crossover trial, and efficacy will be based on protoporphyrin levels, photosensitivity, and quality of life questionnaires. If the results are positive, this would be the first study providing quality evidence for an agent acting as a disease-modifying therapy for protoporphyria.

项目总结/摘要 红细胞生成性原卟啉症（EPP）和X连锁原卟啉症（XLP）是一种血红素遗传缺陷 导致终生疼痛的皮肤对光敏感的生物合成。EPP和XLP，统称为 原卟啉症，导致光敏分子原卟啉IX（PPIX）的积累， 红细胞，其次是血浆和肝脏。除了光敏性，原卟啉症还可以 导致贫血、胆结石和慢性肝病，并且在2-5%的病例中，它导致快速进行性 胆汁淤积性肝衰竭，如果不进行肝移植是致命的。因为病人对可见光很敏感 而不是紫外线，防晒霜对EPP无效。阿法黑素肽，增加皮肤黑色素， 最近被FDA批准用于预防EPP的光敏性。除此之外的其他治疗 因为阿法黑浪肽不改变PPIX水平，因此不 预防EPP危及生命的并发症。西咪替丁作为一种可能治疗 由于血红素的第一种酶ALAS的抑制作用的潜在脱靶效应， 生物合成这种抑制作用首次在体外描述。后来的病例报告表明，西咪替丁是 有益于急性间歇性卟啉症和迟发性皮肤卟啉症的治疗。随后，案件 报告还描述了EPP的潜在影响。然而，这些报告是轶事和不受控制的。一些 患者也有预先存在的肝损害，从EPP，这使得观察药物的影响， EPP.卟啉症社区的交流表明，包括儿童在内的大量患者， 使用西咪替丁没有监督，没有剂量或症状的系统记录 改进.在更大的卟啉症社区的相当大的兴趣，以评估与照顾其可能的 因此，作为一种治疗方法的好处既没有得到解决，也没有得到满足。因此， 本研究旨在确定口服西咪替丁治疗原卟啉病的有效性和安全性。的 研究设计为多中心、前瞻性、随机、双盲、安慰剂对照、交叉试验， 疗效将基于原卟啉水平、光敏性和生活质量问卷。如果结果 这将是第一项为作为疾病修饰剂的药物提供质量证据的研究。 治疗原卟啉症