CHELATION THERAPY OF IRON OVERLOAD WITH PIH

PIH 铁过载的螯合疗法

基本信息

  • 批准号:
    2220695
  • 负责人:
  • 金额:
    $ 21.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1989
  • 资助国家:
    美国
  • 起止时间:
    1989-06-01 至 1995-03-31
  • 项目状态:
    已结题

项目摘要

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.
拟议的第二阶段临床试验旨在证明 口服异烟酰吡哆醛的安全性和有效性 肼(PIH)用于慢性铁超载的治疗。吡哆醛 异烟酰肼(PIH)很容易由席夫碱生成 两种广泛使用的廉价药物--维生素B-6(吡哆醛)的缩合 和抗结核药物异烟肼(INH)。妊高征最初被认为是 1979年,一种有效的体外铁络合剂。在第一次人体试验中, 我们最近对健康对照和低剂量妊高征患者进行的I期研究 铁负荷过重的志愿者没有发现中毒的证据,而 产生一定量的铁排泄量,这将在临床上用于 铁负荷治疗非输血依赖患者的临床研究 贫血。积累的数据表明,妊高征可能是一种近乎理想的铁 一种几乎完全被吸收的高选择性试剂 来自胃肠道,(Ii)直接通过门户递送 血液到肝脏,在那里药物有很高的肝脏萃取率和 内源性清除,(Iii)由肝细胞占据,其主要部位为 作用,药物要么螯合铁并在胆汁中排泄,要么 会被新陈代谢和消除。肝脏外部位的过量铁可以 通过生理手段动员并输送到肝脏,用于 随后的螯合和排泄。建议的具体目标 第二阶段临床试验将证明其安全性和有效性。 在以下方面:(1)将非妊娠期高血压疾病患者的体内铁负荷降至接近正常水平 铁负荷贫血的输血依赖患者(需要螯合- 诱导的铁排泄量至少为0.10至0.20毫克铁/公斤/天); 输血依赖患者维持接近正常的体内铁储存 以前患有慢性皮下或 静脉注射去铁胺(需要螯合物诱导的AT的铁排泄 至少0.25至0.40毫克铁/公斤/天);(3)将体内铁负荷减少到 铁负荷、输血依赖患者的接近正常水平(需要 螯合诱导的铁排泄大于0.40毫克铁/公斤/天)。这个 开发一种安全有效的妊高征口服给药方案将是 铁超载治疗方面的重大进展可能会显著 改善受影响患者的生活质量和生命长度 在美国,并在全球范围内提供重要的公共卫生福利。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Iron chelation with desferrioxamine B in adults with asymptomatic Plasmodium falciparum parasitemia.
  • DOI:
    10.1182/blood.v79.2.308.bloodjournal792308
  • 发表时间:
    1992-01
  • 期刊:
  • 影响因子:
    20.3
  • 作者:
    V. Gordeuk;P. Thuma;G. Brittenham;S. Zulu;G. Simwanza;A. Mhangu;G. Flesch;D. Parry
  • 通讯作者:
    V. Gordeuk;P. Thuma;G. Brittenham;S. Zulu;G. Simwanza;A. Mhangu;G. Flesch;D. Parry
Pyridoxal isonicotinoyl hydrazone: an effective iron-chelator after oral administration.
吡哆醛异烟酰腙:口服后有效的铁螯合剂。
  • DOI:
  • 发表时间:
    1990
  • 期刊:
  • 影响因子:
    3.6
  • 作者:
    Brittenham,GM
  • 通讯作者:
    Brittenham,GM
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Gary M Brittenham其他文献

LOW PREVALENCE OF ANEMIA AMONG NAVAJO CHILDREN
纳瓦霍族儿童贫血患病率低
  • DOI:
    10.1203/00006450-197704000-00458
  • 发表时间:
    1977-04-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Betsy Lozoff;Gary M Brittenham;Mahmoud Y Einajjar;M Klaus
  • 通讯作者:
    M Klaus
56 INFANT CARE-CACHE OR CARRY?
  • DOI:
    10.1203/00006450-197804001-00061
  • 发表时间:
    1978-04-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Betsy Lozoff;Gary M Brittenham;M Klaus
  • 通讯作者:
    M Klaus
Physiologically based serum ferritin thresholds for iron deficiency among women and children from Africa, Asia, Europe, and central America: a multinational comparative study
基于生理学的非洲、亚洲、欧洲和中美洲妇女及儿童缺铁的血清铁蛋白阈值:一项多国比较研究
  • DOI:
    10.1016/s2214-109x(25)00009-9
  • 发表时间:
    2025-05-01
  • 期刊:
  • 影响因子:
    18.000
  • 作者:
    O Yaw Addo;Zuguo Mei;Maria Elena D Jefferds;Mica Jenkins;Rafael Flores-Ayala;Anne M Williams;Melissa Fox Young;Hanqi Luo;Yi-An Ko;Ioannis Papassotiriou;Mireya Palmieri;Karla Mesarina;Zulfiqar Bhutta;Parminder S Suchdev;Gary M Brittenham
  • 通讯作者:
    Gary M Brittenham

Gary M Brittenham的其他文献

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{{ truncateString('Gary M Brittenham', 18)}}的其他基金

QSM to Guide Iron Chelating Therapy in Transfusional Iron Overload
QSM 指导铁螯合疗法治疗输血铁过量
  • 批准号:
    10558645
  • 财政年份:
    2019
  • 资助金额:
    $ 21.81万
  • 项目类别:
Daily vitamin D for sickle-cell respiratory complications: Phase 2: IND107584 - 11/14/17
每日维生素 D 治疗镰状细胞呼吸道并发症:第 2 阶段:IND107584 - 11/14/2017
  • 批准号:
    10364602
  • 财政年份:
    2019
  • 资助金额:
    $ 21.81万
  • 项目类别:
Daily vitamin D for sickle-cell respiratory complications: Phase 2: IND107584 - 11/14/17
每日维生素 D 治疗镰状细胞呼吸道并发症:第 2 阶段:IND107584 - 11/14/2017
  • 批准号:
    10004019
  • 财政年份:
    2019
  • 资助金额:
    $ 21.81万
  • 项目类别:
Daily vitamin D for sickle-cell respiratory complications: Phase 2: IND107584 - 11/14/17
每日维生素 D 治疗镰状细胞呼吸道并发症:第 2 阶段:IND107584 - 11/14/2017
  • 批准号:
    10577417
  • 财政年份:
    2019
  • 资助金额:
    $ 21.81万
  • 项目类别:
QSM to Guide Iron Chelating Therapy in Transfusional Iron Overload
QSM 指导铁螯合疗法治疗输血铁过量
  • 批准号:
    10337227
  • 财政年份:
    2019
  • 资助金额:
    $ 21.81万
  • 项目类别:
QSM to Guide Iron Chelating Therapy in Transfusional Iron Overload
QSM 指导铁螯合疗法治疗输血铁过量
  • 批准号:
    10808000
  • 财政年份:
    2019
  • 资助金额:
    $ 21.81万
  • 项目类别:
Prebiotic GOS and lactoferrin for beneficial gut microbiota with iron supplements
益生元 GOS 和乳铁蛋白通过铁补充剂有益肠道微生物群
  • 批准号:
    10388259
  • 财政年份:
    2018
  • 资助金额:
    $ 21.81万
  • 项目类别:
Prebiotic GOS and lactoferrin for beneficial gut microbiota with iron supplements
益生元 GOS 和乳铁蛋白通过铁补充剂有益肠道微生物群
  • 批准号:
    9918916
  • 财政年份:
    2018
  • 资助金额:
    $ 21.81万
  • 项目类别:
Prebiotic GOS and lactoferrin for beneficial gut microbiota with iron supplements
益生元 GOS 和乳铁蛋白通过铁补充剂有益肠道微生物群
  • 批准号:
    9753231
  • 财政年份:
    2018
  • 资助金额:
    $ 21.81万
  • 项目类别:
Prebiotic GOS and lactoferrin for beneficial gut microbiota with iron supplements
益生元 GOS 和乳铁蛋白通过铁补充剂有益肠道微生物群
  • 批准号:
    10163166
  • 财政年份:
    2018
  • 资助金额:
    $ 21.81万
  • 项目类别:

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Novel Strategies to Improve Blood Transfusion Practice
改善输血实践的新策略
  • 批准号:
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    2022
  • 资助金额:
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使用光声成像评估心肺搭桥和输血后的血脑屏障渗透性和脑损伤
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描述一氧化氮在确定输红血减轻缺血性脑损伤功效中的作用
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揭示脐带血在脑瘫输注治疗机制中的调节功能
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