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 II期提案旨在进一步开发人类饥饿素