INVESTIGATIONS OF NEW THERAPIES IN SEPTIC SHOCK

感染性休克新疗法的研究

• 批准号: 3896256
• 负责人: C 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/3896256
• 关键词: antireceptor antibody; colony stimulating factor; disease /disorder model; dogs; endotoxins; ibuprofen; immunotherapy; monoclonal antibody; nonhuman therapy evaluation; plasmapheresis; platelet activating factor; protein C; shock; tumor necrosis factor alpha

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 and young adults with trauma or cancer, and elderly patients with pneumonia or gall bladder disease. Half of all children and adults who acquire 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 a great financial burden on society. Surprisingly, little is known about the pathophysiology of this disease. Available data indicate that septic shock is caused by a highly complex interaction of factors related to the 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 the 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 (TNF) 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. As these therapies are potentially toxic and might worsen a patient's condition, they must be tested in an animal model that closely simulates the human disease. 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. We are evaluating or have planned to evaluate the following therapies of septic shock in the canine model; Lipid X; Plasmapheresis, Ibuprofen; Monoclonal Antibodies to Endotoxin; Antibody to Tumor Necrosis Factor; Pentoxyphylline; Granulocyte Stimulating Factor; Antibodies to Platelet Activating Factor; Antibodies to Protein C; Antibodies to Receptors on White Blood Cells.

感染性休克和相关感染后遗症（例如多器官系统 失败）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中，在所有情况下 年龄组以及各种常见的临床环境。 一些常见的 诱发因素是： 早产儿、既往健康 患有获得性感染（例如脑膜炎、肺炎、上呼吸道感染）的儿童 呼吸道感染）、患有创伤或癌症的青少年和年轻人， 以及患有肺炎或胆囊疾病的老年患者。 全部一半 感染性休克的儿童和成人死于该综合征。 因此， 感染性休克，影响幼儿和老年人（甚至 那些没有诱发疾病的人），是临床上常见且重要的 造成大量死亡的问题，并给人们带来沉重的经济负担 社会。 令人惊讶的是，人们对这种疾病的病理生理学知之甚少。 疾病。 现有数据表明，感染性休克是由高度 与感染相关的因素之间复杂的相互作用（生物体毒力 因素和毒素）以及与宿主反应相关的因素（内源性 影响和调节炎症反应的分子）。 因此， 成功治疗感染性休克综合征，降低发病率 治愈感染并中断病毒传播将导致死亡 这些生物体和宿主介质的影响。 使用专门饲养的比格犬， 感染性休克的犬模型已成功提供以下信息 人类疾病的病理生理学和治疗。 这个模型， 急慢性感染，模拟病程和心血管 脓毒性休克儿童和成人中常见的变化。 事先的 使用该模型的实验已经确定了特定细菌的作用 （革兰氏阳性和革兰氏阴性）、细菌毒素（内毒素）和宿主 介质（TNF）产生感染性休克。 因此，犬类模型已 在模拟人类疾病和指导治疗方面非常成功 人类。 有几种疗法正在研究中，可能会 对人类感染性休克有效。 由于这些疗法具有潜在毒性 并且可能会使患者的病情恶化，因此必须在动物身上进行测试 密切模拟人类疾病的模型。 犬类模型， 模拟儿童和成年人的心血管变化 感染性休克，非常适合这些新药物的临床前试验 疗法。 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，并不总是 在人类研究中是可能的。 我们正在评估或计划评估 犬模型中感染性休克的以下治疗方法；脂质X； 血浆置换术，布洛芬；内毒素单克隆抗体；抗体 肿瘤坏死因子；己茶碱；粒细胞刺激因子； 血小板激活因子抗体；蛋白 C 抗体； 白细胞受体抗体。