Therapeutic Use of Heme Analogs: Absorption in Intestine

血红素类似物的治疗用途：肠道吸收

基本信息

批准号：
7565892
负责人：
DAVID K STEVENSON
金额：
$ 23.57万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-15 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7565892
关键词：
Address Adult Affect Age Bilirubin Biological Assay Brain Cell Culture Techniques Clinical Clinical Research Disease Dose Enzymes Evaluation Event Excretory function Failure Funding Genes Genetic Transcription Glycols Heme Hemolytic Jaundices Human Hyperbilirubinemia In Vitro Infant Intestines Kidney Light Liver Long-Term Effects Mediating Messenger RNA Metalloporphyrins Metals Modeling Monitor Mus Neonatal Neonatal Jaundice Newborn Animals Newborn Infant Oral Oral Administration Oxygenases Pattern Phase Porphyrins Post-Translational Protein Processing Prevention Prevention approach Production Proteins Rattus Regulation Rh Isoimmunization Rodent Model Safety Spleen Therapeutic Therapeutic Agents Therapeutic Uses Tissues Work Zinc absorption analog azalanstat brain tissue chromium mesoporphyrin design enzyme activity heme a heme oxygenase-1 heme oxygenase-2 in vivo inhibitor/antagonist mouse model neonate response therapeutic target tin mesoporphyrin

项目摘要

DESCRIPTION (provided by applicant): Neonatal jaundice occurs in 60-70% of all newborn infants. It is due to hyperbilirubinemia caused not only by an overproduction of bilirubin, but also by a transient failure to excrete this metabolite. Hyperbilirubinemia is exacerbated by hemolytic diseases, such as Rhesus isoimmunization and ABO incompatibility, which result in increased bilirubin production, as well as diseases that result in decreased bilirubin excretion. The rate- limiting enzyme in the production of bilirubin is heme oxygenase (HO), and as such is a key therapeutic target. Inhibition of HO activity has been shown to protect newborns from excessive hyperbilirubinemia. Heme analogs, metalloporphyrins (Mps), are potent competitive inhibitors of HO enzyme activity. The use of Mps as oral therapeutic agents may be an effective approach for the prevention and treatment of hyperbilirubinemia. In this competing renewal, we propose to logically extend our findings from the previous funded proposal to investigate the efficacy of the oral administration of tin mesoporphyrin (SnMP), other selected heme analogs, and non-porphyrin inhibitors of HO to the heme-loaded newborn mouse, a model analogous to the human infant with increased bilirubin production. In this evaluation, we will assess their accessibility to the brain, their short- and long-term effects, response following another heme load, and the mechanisms by which this response is mediated. In the previous funding period, we have continued to develop and validate assays to monitor both in vivo bilirubin production and HO-1 transcriptional patterns and in vitro enzymatic activity of HO so that we can evaluate regulation and expression at these levels. Application of these approaches to the newborn mouse model is a natural extension of our previous work with the adult rodent models. The results of this project will assist in the design of clinical studies for these and related compounds by providing both spatial and temporal information pertaining to direct effects on the enzymatic target, its expression, and subsequent short- and long-term effects on the newborn animal. The specific aims of this application are still directed at evaluating the efficacy and safety of the oral administration of selected Mps, a class of heme analogs, for their therapeutic value to neonatal jaundice through inhibition of HO activity. We will further expand these studies to an overall evaluation of selected Mps, which we have shown to be orally absorbed, and non-porphyrin inhibitors of HO, but with particular emphasis on the study of their accessibility to the brain and other non-target tissues as well as their short- and long-term effects in the heme-loaded newborn mouse.

描述（由申请人提供）：新生儿黄疸发生在60-70％的新生婴儿中。这是由于高胆红素血症不仅是由于胆红素过量产生而引起的，而且还由于瞬时无法排泄这种代谢产物而引起的。高胆红素血症因溶血疾病（例如恒河神异源免疫化和ABO的不相容性）加剧，这导致胆红素产生增加，以及导致胆红素排泄降低的疾病。胆红素生产中的速率限制酶是血红素氧酶（HO），因此是关键的治疗靶标。抑制HO活性已显示可保护新生儿免受过度高胆红素血症的侵害。血红素类似物（MPS）是HO酶活性的有效竞争抑制剂。使用MP作为口服治疗剂可能是预防和治疗高胆红素血症的有效方法。在这种竞争的更新中，我们建议从逻辑上将我们的发现从先前的资金提案中扩展出来，以调查口服锡中核酸（SNMP），其他选定的血红素类似物和HO的非孢子蛋白抑制剂对血红素新生小鼠对人类类似物的类似物的疗效，并增加了biliruubirubirubirubin。在此评估中，我们将评估它们对大脑的可及性，它们的短期和长期效果，另一个血红素负荷后的反应以及该反应介导的机制。在上一个资金期间，我们继续开发和验证测定法，以监测HO的体内胆红素产生和HO-1转录模式以及体外酶促活性，以便我们可以评估这些水平的调节和表达。这些方法在新生小鼠模型中的应用是我们以前使用成人啮齿动物模型的工作的自然扩展。该项目的结果将通过提供有关直接对酶促靶标，其表达以及随后对纽出生动物的短期和长期影响的直接影响的空间和时间信息来帮助设计这些和相关化合物的临床研究。该应用的具体目的仍然旨在评估所选MPS（一类血红素类似物）口服的功效和安全性，以通过抑制HO活性来对新生儿黄疸的治疗价值。我们将进一步将这些研究扩展到对选定的MP的总体评估，我们已证明其被口服吸收和非孢子虫的HO抑制剂，但特别强调了其对大脑和其他非目标组织的可及性以及在血红素载有新生儿小鼠中的短期和长期影响。