Investigations Of New Therapies In Septic Shock

感染性休克新疗法的研究

• 批准号: 6690262
• 负责人: CHARLES NATANSON
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6690262
• 关键词: antibody; cardiovascular disorder; cardiovascular disorder therapy; chemotherapy; colony stimulating factor; cytokine receptors; dantrolene; disease /disorder model; dogs; gene therapy; ibuprofen; immunotherapy; nonhuman therapy evaluation; septic shock; superoxide dismutase

Septic shock and related sequelae of infection (e.g., multiple organ system failure) are the most common cause of death in intensive care units. Deaths due to sepsis can occur in previously healthy individuals, in all age groups, and in a variety of common clinical settings. Some common predisposing conditions are premature neonates, previously healthy children with acquired infections (e.g., meningitis, pneumonia, upper respiratory infections), teenagers or young adults with trauma or cancer, and elderly patients with pneumonia or gall bladder disease. Half of all children or adults who acquire this septic shock die from the syndrome. Thus septic shock, which affects young children and the elderly alike (even those without predisposing illness), is a common and important clinical problem with substantial mortality and produces an great financial burden on society. Surprisingly little is known about the pathophysiology of this disease infection (organism virulence factors and toxins) and factors related to the host response (endogenous molecules that affect and modulate the inflammatory response). Thus successful treatment of the septic shock syndrome which reduces morbidity and mortality will result from curing the infection and interrupting the effects of these organism and host mediators. Using purpose bred beagles, the canine model of septic shock has successfully provided information on the pathophysiology and treatment of human disease. This model of acute and chronic infection simulates the course and cardiovascular changes seen routinely in children and adults with septic shock. Prior experiments using the model have established the role of specific bacteria (gram positive and gram negative), bacterial toxins (endotoxin), and host mediators to produce septic shock. Thus, the canine model has been highly successful in simulating the human disease and guiding therapy for humans. There are several therapies under investigation that might be effective in human septic shock. The canine model, which simulates the cardiovascular changes seen in children and adult humans with septic shock is ideally suited for pre-clinical trials of these new therapies. The canine model allows properly controlled trials to evaluate therapeutic mechanisms and adverse effects of therapies; that is not always possible in human studies. This model is expected to be used in 2002 - 2004 to test the efficacy of intra-aortic balloon pumping, and to compare the effects of vasopressin vs. norepinephrine vs. the combination as a therapy for shock, other agents to be tested include AG556, Tyrosin kinase inhibitor adjusted to the severity of illness. Additionally, anti-inflammatory agents such as anti-TNF antibodies and interleukin 1 receptor antagonists adjusted for severity of illness will also be tested.

感染性休克和相关感染后遗症（例如多器官系统衰竭）是重症监护病房最常见的死亡原因。脓毒症导致的死亡可能发生在以前健康的个体、所有年龄组以及各种常见的临床环境中。一些常见的诱发因素是早产儿、先前健康的患有获得性感染（例如脑膜炎、肺炎、上呼吸道感染）的儿童、患有外伤或癌症的青少年或年轻人，以及患有肺炎或胆囊疾病的老年患者。患有感染性休克的儿童或成人中有一半死于该综合征。因此，败血性休克影响幼儿和老年人（甚至那些没有诱发疾病的人），是一种常见且重要的临床问题，死亡率很高，给社会带来巨大的经济负担。令人惊讶的是，人们对这种疾病感染的病理生理学（生物体毒力因子和毒素）以及与宿主反应相关的因素（影响和调节炎症反应的内源性分子）知之甚少。因此，通过治愈感染并中断这些生物体和宿主介质的作用，可以成功治疗败血性休克综合征，从而降低发病率和死亡率。使用专门饲养的比格犬，感染性休克的犬模型已成功提供有关人类疾病的病理生理学和治疗的信息。这种急性和慢性感染模型模拟了感染性休克儿童和成人中常见的病程和心血管变化。先前使用该模型的实验已经确定了特定细菌（革兰氏阳性和革兰氏阴性）、细菌毒素（内毒素）和宿主介质在产生感染性休克中的作用。因此，犬类模型在模拟人类疾病和指导人类治疗方面取得了巨大成功。有几种疗法正在研究中，可能对人类感染性休克有效。犬模型模拟了患有感染性休克的儿童和成年人的心血管变化，非常适合这些新疗法的临床前试验。犬模型允许进行适当的对照试验来评估治疗机制和治疗的副作用；这在人类研究中并不总是可能的。该模型预计将在 2002 - 2004 年用于测试主动脉内球囊反搏的功效，并比较加压素与去甲肾上腺素与联合用药治疗休克的效果，其他待测试药物包括 AG556、酪氨酸激酶抑制剂根据疾病的严重程度进行调整。此外，还将测试根据疾病严重程度调整的抗炎药物，例如抗 TNF 抗体和白细胞介素 1 受体拮抗剂。