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: 9346602
• 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/9346602
• 关键词: Aftercare; Age-Years; Anatomy; Animals; Antisepsis; 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; Histologic; Hormones; Human; Inbred F344 Rats; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Interleukin-1 beta; Interleukin-6; Intravenous; 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; 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第二阶段提案旨在进一步开发人生长激素释放肽 （hGhr）和人生长激素（hGH）作为脓毒症老年患者的联合治疗， 败血性休克在美国，每年有超过100万人患败血症，近80%的败血症患者 死亡发生在65岁以上的患者中。目前，没有有效的药物治疗存在 脓毒症的治疗脓毒症临床试验失败的原因之一是， 抗败血症药物候选物仅在幼小动物中进行。例如，Rat Ghr， 改善了年轻而非老年大鼠的脓毒症。我们已经发现，GH的管理上调， Ghr受体的表达，并恢复脓毒症老年动物Ghr的反应性。在我们 完成SBIR I期项目，hGhr和hGH联合给药（hGhr-hGH）显著改善 脓毒症老年动物中脓毒症相关的肺、肝和肾损伤。我们进一步证明， 联合治疗几乎使脓毒症老年大鼠的存活率加倍。此外，hGH和hGH 已经过临床测试，并用于其他适应症，具有良好的安全性。基于我们 I期结果，我们假设hGhr-hGH可以进一步发展为脓毒症的有效治疗方法 在老年人中。为了推进hGhr-hGH治疗在老年人脓毒症的临床应用，我们计划 以确定联合治疗的最有效剂量和治疗窗口， 伤害和提高生存率。我们还将研究hGhr-hGH对安全性和耐受性的联合作用。 药代动力学（PK）。最后，我们将在绵羊脓毒症模型中进行探索性研究，以评估 hGhr-hGH对血流动力学参数和器官损伤的影响。这些拟议的研究应提供 为今后提交IND申请以在临床试验中进一步开发hGhr-hGH提供重要信息。 我们的最终目标是获得FDA批准使用hGhr-hGH作为安全有效的治疗方法， 老年脓毒症和脓毒性休克患者。