CHELATION THERAPY OF IRON OVERLOAD WITH PIH

PIH 铁过载的螯合疗法

• 批准号: 3361125
• 负责人: Gary M Brittenham
• 金额: $ 21.12万
• 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/3361125
• 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 口服吡哆醛异烟酰的安全性和有效性 腙（PIH）用于铁过载的慢性治疗。 吡哆 异烟酰腙（PIH）是一种容易由席夫碱生成的化合物 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 一种有效的铁螯合剂。 在第一次人体试验中， 我们最近在健康对照组中进行的低剂量妊高征的I期研究， 铁过量的志愿者没有发现毒性的证据， 产生一定量的铁排泄，这在临床上是有用的， 铁负荷治疗非输血依赖患者 贫血 积累的数据表明，妊高征可能是一个几乎理想的铁 螯合剂;一种高度选择性的试剂，（i）几乎完全吸收 从胃肠道，（ii）直接通过门静脉递送 血液进入肝脏，其中药物具有高的肝脏提取率， 固有清除率，（iii）由肝细胞吸收，其主要的 作用，其中药物螯合铁并在胆汁中排泄，或 会被代谢和消除 肝外部位的过量铁可以 通过生理手段被动员并运输到肝脏， 随后螯合和排泄。 建议的具体目标 II期临床试验旨在证明其安全性和有效性 （1）降低机体铁负荷至接近正常水平， 铁负荷性贫血的输血依赖患者（需要螯合物- 诱导铁排泄至少0.10 - 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 谁以前有良好的螯合与慢性皮下或 静脉注射去铁胺（需要螯合物诱导的铁排泄， 至少0.25至0.40 mg Fe/kg/天）;（3）降低体内铁负荷， 在铁负荷的输血依赖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）。 的 开发一种安全有效的PIH口服给药方案， 治疗铁超载的一个重大进展， 改善受影响患者的生活质量和寿命， 美国，并在全球范围内提供重要的公共卫生福利。