Preclinical Testing of Human Ghrelin and Growth Hormone for Sepsis in the Elderly

人类生长素释放肽和生长激素治疗老年人脓毒症的临床前测试

• 批准号: 9199963
• 负责人: Weng-Lang Yang
• 金额: $ 54.04万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199963
• 关键词: Aftercare; Age; Anatomy; Animals; Area Under Curve; Attenuated; Bacterial Translocation; Blood; Cardiac Output; Cause of Death; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Creatinine; Data; Dose; Drug Kinetics; Elderly; FDA approved; Failure; Functional disorder; Funding; Future; Goals; Heart; Heart Rate; Hepatic; Hormones; Human; Inbred F344 Rats; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Interleukin-6; Kidney; Lethal Dose 50; Ligation; Liver; Lung; Maximum Tolerated Dose; Modeling; Monitor; Nerve; Normal saline; Organ; Outcome; Patients; Perfusion; Peripheral Resistance; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Preclinical Testing; Pseudomonas aeruginosa; Puncture procedure; Rattus; Safety; Sepsis; Septic Shock; Sheep; Small Business Innovation Research Grant; Small Intestines; Smoke Inhalation Injury; Somatotropin; Somatropin; Stroke Volume; Survival Rate; TNF gene; Testing; Therapeutic; Time; Tissues; Toxic effect; United States; aged; base; cytokine; drug candidate; effective therapy; ghrelin; hemodynamics; hormone therapy; human old age (65+); improved; intravenous injection; juvenile animal; male; novel; older patient; phase 1 study; preclinical evaluation; pressure; public health relevance; receptor; respiratory; response; septic

PROJECT DESCRIPTION: This SBIR Phase II proposal is intended to further develop human ghrelin (hGhr) and human growth hormone (hGH) as a combination therapy for elderly patients with sepsis and septic shock. In the US, more than one million people develop sepsis every year, and nearly 80% of septic deaths occur in patients older than 65 years of age. Currently, no effective pharmacotherapy exists for the treatment of sepsis. One of the reasons for sepsis clinical trial failures is that the preclinical evaluation of anti-sepsis drug candidates has been conducted exclusively in young animals. Rat Ghr, for example, ameliorates sepsis in young, but not aged, rats. We have discovered that administration of GH upregulates the expression of the Ghr receptor and restores Ghr’s responsiveness in aged animals with sepsis. In our completed SBIR Phase I project, co-administration of hGhr and hGH (hGhr-hGH) significantly ameliorated sepsis-associated lung, liver, and kidney injury in septic aged animals. We further demonstrated that the combination therapy nearly doubled the survival rate of septic aged rats. Moreover, both hGhr and hGH have been clinically tested and used for other indications with an excellent safety profile. Based on our Phase I results, we hypothesize that hGhr-hGH can be further developed as an effective therapy for sepsis in the elderly. To advance hGhr-hGH therapy towards its clinical use against sepsis in the elderly, we plan to determine the combination therapy’s most effective dose and therapeutic window to attenuate tissue injury and improve survival. We will also study hGhr-hGH’s combination effects on safety and pharmacokinetics (PK). Finally, we will conduct an exploratory study in an ovine model of sepsis to evaluate hGhr-hGH’s effects on hemodynamic parameters and organ injury. These proposed studies should provide crucial information for the future filing of an IND application to further develop hGhr-hGH in clinical trials. Our ultimate goal is to obtain FDA approval for the use of hGhr-hGH as a safe and effective treatment for elderly patients with sepsis and septic shock.

项目描述：该SBIR II期提案旨在进一步发展人类ghrelin （HGHR）和人类生长马（HGH）作为败血症患者和 败血性冲击。在美国，每年有超过100万人出现败血症，近80％的化粪池 65岁以上的患者死亡。目前，没有有效的药物治疗 败血症的治疗。败血症临床试验失败的原因之一是对 抗盐候选药物仅在年轻动物中进行。例如，大鼠GHR， 改善年轻人（但不老龄）大鼠的败血症。我们发现GH的给药上调 GHR接收器的表达并恢复了败血症老年动物的GHR反应性。在我们的 完成的SBIR I期项目，HGHR和HGH（HGHR-HGH）的共同管理已显着改善 败血症衰老动物中与败血症相关的肺，肝脏和肾损伤。我们进一步证明了 联合疗法几乎使化粪池老鼠的存活率翻了一番。而且，HGHR和HGH都 已通过临床测试并用于具有出色安全性的其他指示。基于我们 第一阶段的结果，我们假设HGHR-HGH可以作为败血症的有效疗法进一步开发 在过去。为了将HGHR-HGH疗法推向对败血症的临床用途，我们计划 确定组合疗法最有效的剂量和治疗窗口以减弱组织 受伤并提高生存率。我们还将研究HGHR-HGH对安全性和 药代动力学（PK）。最后，我们将在败血症的卵巢模型中进行探索性研究以评估 HGHR-HGH对血液动力学参数和器官损伤的影响。这些提出的研究应提供 未来提交IND应用程序的关键信息，以进一步发展临床试验中的HGHR-HGH。 我们的最终目标是获得FDA的批准，用于使用HGHR-HGH作为安全有效的治疗方法 败血症和败血性休克的老年患者。