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: 10487494
• 负责人: KARL ELMO ANDERSON
• 金额: $ 40.35万
• 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/10487494
• 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.

项目摘要/摘要 红细胞原质畸形（EPP）和X连锁原生质（XLP）是血红素的遗传缺陷 生物合成会引起对光的终身，痛苦的皮肤敏感性。 EPP和XLP，统称为 原磷脂，导致光敏分子原源性IX（PPIX）的积累 红细胞，其次在血浆和肝脏中。除了光敏性外，原畸形也可以 导致贫血，胆结石和慢性肝病，在2-5％的情况下，它导致了迅速进行的 胆固性肝衰竭是致命的，没有肝移植。因为患者对可见光敏感 而且不是紫外线，防晒霜在EPP中无效。增加皮肤黑色素的afamelanotide是 最近，FDA批准了EPP预防光敏性的批准。此外，其他疗法 afamelanotide是必要的 防止EPP威胁生命的并发症。西米替丁引起了人们的关注，作为可能的治疗方法 人卟啉症是由于抑制Alas的潜在脱靶效应，这是血红素的第一种酶 生物合成。首先在体外描述了这种抑制作用。后来的病例报告表明cimetidine是 有益于治疗急性间歇性卟啉症和卟啉症cutanea tarda。随后，案件 报告还描述了EPP的潜在影响。但是，这些报告是轶事和不受控制的。一些 患者还受到EPP的肝损害，这使对药物作用的观察变得复杂 epp。卟啉症社区中的通讯表明，包括儿童在内的大量患者 已经使用了没有监督的甲甲依丁，并且没有系统的剂量或有症状记录 改进。对较大的斑岩社区的极大兴趣，以谨慎评估 因此，作为治疗方法的好处既没有被解决，也没有满足。因此，目的 这项研究是为了确定口服西米替丁在原磷酸中的疗效和安全性。这 研究设计是一个多中心，前瞻性，随机，双盲，安慰剂对照，跨界试验和 功效将基于原源性磷灰蛋白水平，光敏性和生活质量问卷。如果结果 是积极的，这将是第一个为疾病改良的特工提供质量证据的研究 原化治疗。