CHELATION THERAPY OF IRON OVERLOAD WITH PIH

PIH 铁过载的螯合疗法

• 批准号: 3361124
• 负责人: Gary M Brittenham
• 金额: $ 20.31万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-06-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3361124
• 关键词: Schiff bases; blood transfusion; chelation therapy; clinical trials; deferoxamine; dosage; drug administration rate /duration; drug administration routes; drug adverse effect; drug design /synthesis /production; excretion; gastrointestinal drug absorption; human subject; human therapy evaluation; iron metabolism; iron storage disorder; isoniazid

The proposed Phase II clinical trials are designed to demonstrate the safety and effectiveness of orally administered pyridoxal isonicotinoyl hydrazone (PIH) for the chronic treatment of iron overload. Pyridoxal isonicotinoyl hydrazone (PIH) is easily produced by the Schiff base condensation of two widely used, inexpensive drugs, vitamin B-6 (pyridoxal) and the antituberculous agent isoniazid (INH). PIH was first recognized as an effective iron chelator in vitro in 1979. In the first human trials, our recent Phase I studies of low-dose PIH in healthy controls and volunteers with iron overload have found no evidence of toxicity while producing an amount of iron excretion that would be clinically useful in the treatment of non-transfusion-dependent patients with iron-loading anemias. The accumulated data suggest that PIH may be an almost ideal iron chelator; a highly selective agent that is (i) almost completely absorbed from the gastrointestinal tract, (ii) delivered directly via the portal blood to the liver, where the drug has a high hepatic extraction ratio and intrinsic clearance, (iii) taken up by the hepatocyte, its major site of action, where the drug either chelates iron and is excreted in the bile or is metabolized and eliminated. Excess iron at extra-hepatic sites can then be mobilized and transported by physiologic means to the liver for subsequent chelation and excretion. The specific aims of the proposed Phase II clinical trials are to demonstrate the safety and effectiveness of PIH in: (1) reducing the body iron burden to near-normal levels in non- transfusion-dependent patients with iron-loading anemias (requires chelate- induced iron excretion of at least 0.10 to 0.20 mg Fe/kg/day); (2) maintaining near-normal body iron stores in transfusion-dependent patients who have previously been well-chelated with chronic subcutaneous or intravenous desferrioxamine (requires chelate-induced iron excretion of at least 0.25 to 0.40 mg Fe/kg/day); (3) reducing the body iron burden to near-normal levels in iron-loaded, transfusion-dependent patients (requires chelate-induced iron excretion greater than 0.40 mg Fe/kg/day). The development of a safe and effective oral dosage regimen for PIH would be a major advance in the treatment of iron overload that could substantially improve both the quality and length of life of affected patients in the United States and provide important public health benefit worldwide.

拟议的 II 期临床试验旨在证明 口服异烟酰吡哆醛的安全性和有效性 腙（PIH）用于慢性治疗铁过载。 吡哆醛 希夫碱很容易产生异烟酰腙（PIH） 两种广泛使用的廉价药物维生素 B-6（吡哆醛）的缩合物 和抗结核药异烟肼（INH）。 PIH 最初被认为是 1979 年，一种有效的体外铁螯合剂。在第一次人体试验中， 我们最近对健康对照者进行低剂量 PIH 的 I 期研究 铁超载的志愿者没有发现毒性证据，而 产生一定量的铁排泄物，在临床上有用 非输血依赖性铁负荷患者的治疗 贫血。 积累的数据表明 PIH 可能是一种近乎理想的铁 螯合剂；一种高度选择性的试剂，(i) 几乎完全被吸收 来自胃肠道，(ii) 直接通过门户输送 血液进入肝脏，药物具有较高的肝提取率 内在清除率，（iii）被肝细胞吸收，其主要部位 作用，药物要么螯合铁并在胆汁中排泄，要么 被代谢和消除。 肝外部位过量的铁可以 通过生理手段动员并转运至肝脏 随后进行螯合和排泄。 拟议的具体目标 II期临床试验旨在证明安全性和有效性 妊娠高血压综合征 (PIH) 的治疗效果体现在：(1) 将非妊娠期患者的体内铁负荷降低至接近正常水平。 患有铁负荷性贫血的输血依赖性患者（需要螯合剂） 诱导铁排泄至少 0.10 至 0.20 mg Fe/kg/天）； (2) 维持输血依赖患者体内接近正常的铁储备 以前曾患有慢性皮下或 静脉注射去铁胺（需要螯合物诱导铁排泄） 至少 0.25 至 0.40 毫克铁/公斤/天）； (3)降低体内铁负荷 在铁负荷、输血依赖的患者中接近正常水平（需要 螯合物诱导的铁排泄大于 0.40 mg Fe/kg/天）。 这 开发一种安全有效的口服 PIH 剂量方案 治疗铁超负荷的一项重大进展，可以显着 提高受影响患者的生活质量和寿命 美国并为全球提供重要的公共卫生益处。