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

项目摘要/摘要 红细胞生成性原红细胞增多症(EPP)和X连锁原红细胞增多症(XLP)是血红素的一种遗传缺陷 生物合成会导致皮肤对光的敏感度终生痛苦。EPP和XLP，统称为 原卟啉，导致光敏分子原卟啉IX(PPIX)在 红细胞，其次是血浆和肝脏。除了光敏性，原卟啉还可以 会导致贫血、胆结石和慢性肝病，在2%-5%的病例中会导致快速进展 胆汁淤积性肝功能衰竭，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，防晒霜在EPP中是无效的。增加皮肤黑色素的阿法那糖脂， 最近被FDA批准用于预防EPP中的光敏反应。除此之外的其他治疗方法 之所以有必要，是因为它不会改变PPIX水平，因此不会 预防EPP危及生命的并发症。西咪替丁作为一种可能的治疗方法引起了人们的关注 由于抑制血红素的第一种酶--碱性磷酸酶的潜在非靶标效应而导致的人类卟啉病 生物合成。这种抑制作用首次在体外被描述。后来的病例报告表明，西咪替丁是 有益于治疗急性间歇性卟啉病和迟发性皮肤卟啉病。随后，Case 报告还描述了EPP的一个潜在影响。然而，这些报道都是轶事，不受控制。一些人 患者也有先前存在的EPP肝损害，这使药物疗效的观察复杂化。 EPP。卟啉症社区的通讯表明，包括儿童在内的大量患者， 在没有监督和没有系统记录剂量或症状的情况下使用西咪替丁 进步。对更大的卟啉症社区相当感兴趣，以谨慎地评估其可能性 因此，作为一种治疗方法的益处既没有得到解决，也没有得到满足。因此，它的目标是 本研究旨在探讨口服西咪替丁治疗原卟啉中毒的疗效和安全性。这个 研究设计是一项多中心、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。如果结果是 都是阳性的，这将是第一项为作为疾病改良剂的制剂提供优质证据的研究 原卟啉症的治疗。

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.