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 二期提案旨在进一步开发人类生长素释放肽 (hGhr) 和人生长激素 (hGH) 联合治疗脓毒症老年患者 败血性休克。在美国，每年有超过一百万人患上脓毒症，其中近 80% 的脓毒症患者 死亡发生在65岁以上的患者中。目前尚无有效的药物治疗方法 治疗败血症。脓毒症临床试验失败的原因之一是临床前评估 候选抗败血症药物仅在幼年动物中进行。以大鼠 Ghr 为例， 改善年轻大鼠的败血症，但不能改善老年大鼠的败血症。我们发现 GH 的施用会上调 Ghr 受体的表达并恢复患有败血症的老年动物的 Ghr 反应能力。在我们的 完成SBIR第一期项目，hGhr和hGH（hGhr-hGH）联合给药显着改善 败血症老年动物中败血症相关的肺、肝和肾损伤。我们进一步证明了 联合治疗使脓毒症老年大鼠的存活率几乎翻倍。此外，hGhr 和 hGH 已经过临床测试并用于其他适应症，具有出色的安全性。基于我们的 I 期结果，我们假设 hGhr-hGH 可以进一步开发为脓毒症的有效疗法 在老年人中。为了推进 hGhr-hGH 疗法在临床上用于治疗老年人脓毒症，我们计划 确定联合疗法最有效的剂量和治疗窗以削弱组织 伤害并提高生存率。我们还将研究 hGhr-hGH 的组合对安全性和 药代动力学（PK）。最后，我们将在败血症绵羊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 为未来提交 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 脓毒症和脓毒性休克的老年患者。