PARP inhibitor therapy for septic shock

PARP 抑制剂治疗感染性休克

基本信息

项目摘要

DESCRIPTION (provided by applicant): Progression of septic shock to multiple organ failure (MOF) is mediated by the activation of poly(ADP-ribose) polymerase ("PARP"), a nuclear cell death enzyme that catalyzes intracellular energetic failure and necrosis. Genetic deletion or pharmacologic inhibition of PARP is profoundly protective in models of endotoxinemia and sepsis. PARP activation also plays a key role in mediating the pathologic overexpression of pro-inflammatory cytokines, chemokines, and cell adhesion molecules that initiate the cell death cascade, via its effects on NF-kappaB activation and AP-1 expression. PARP inhibition is dramatically protective when therapy is begun after the onset of shock. Inotek is developing an ultrapotent PARP inhibitor (Ki = 15 nM) that reduces mortality by 50% in an LD100 porcine model of E. coli-induced peritonitis and septic shock, when administered AFTER the initiation of infection and onset of hemodynamic instability. In healthy human volunteers, INO-1001 is well-tolerated and safe. In a Phase 1 SBIR, we propose a pilot single-center study in 8 subjects focused on the safety and PK profile of INO-1001. Enrollment will include patients with: 1) septic shock < 24 h duration, 2) fever, 3) hypotension requiring vasoactive support, 4) evidence of intra-abdominal infection, and 5) no surgery within 24 h. Administration of INO-1001 will be provided for 5 days, the critical period of sepsis-induced MOF. In a Phase 2 SBIR, we will demonstrate the role of PARP activation in clinical septic shock by carrying out a prospective, randomized, double-blind, placebo-controlled, Phase IIb study of PARP inhibition in 200 patients meeting the same criteria as in the pilot study. The primary clinical endpoints will be: 1) safety, 2) PK of INO-1001, and reductions in: 3) PARP activation in peripheral blood, 4) plasma inflammatory response (TNF, IL-6, IL-8), and 5) development and duration of MOF, as reflected by: (a) metabolic acidosis, (b) cardiovascular instability (MAP and vasoporessor/inotrope requirement) and cardiac index, (c) hepatic insufficiency (PT, albumin, total protein), (d) renal insufficiency (BUN/Cr, CVVH, oliguria), and (e) respiratory insufficiency (PaO2/FiO2 ratio, days of mechanical ventilation). Secondary clinical endpoints will be reductions in 1) 28-day all cause mortality, 2) duration of ICU stay, 3) APACHE II index. Based on pre-clinical porcine shock models and clinical safety studies, we expect INO-1001 to be a safe, well-tolerated and effective therapeutic in patients with septic shock.
描述(由申请人提供):

项目成果

期刊论文数量(0)
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ANDREW Lurie SALZMAN其他文献

ANDREW Lurie SALZMAN的其他文献

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{{ truncateString('ANDREW Lurie SALZMAN', 18)}}的其他基金

Treatment of congenital heart disease associated pulmonary hypertension
先天性心脏病相关肺动脉高压的治疗
  • 批准号:
    8831801
  • 财政年份:
    2015
  • 资助金额:
    $ 21.02万
  • 项目类别:
A Novel Immunotolerizing Therapy for Autoimmune Vitiligo
一种治疗自身免疫性白癜风的新型免疫耐受疗法
  • 批准号:
    8713488
  • 财政年份:
    2014
  • 资助金额:
    $ 21.02万
  • 项目类别:
Restoration of free radical homeostasis: novel therapy of septic shock
恢复自由基稳态:感染性休克的新疗法
  • 批准号:
    9342949
  • 财政年份:
    2012
  • 资助金额:
    $ 21.02万
  • 项目类别:
Resuscitation of smoke inhalation and burn injury with a thioredoxin mimetic
用硫氧还蛋白模拟物复苏烟雾吸入和烧伤
  • 批准号:
    8338756
  • 财政年份:
    2012
  • 资助金额:
    $ 21.02万
  • 项目类别:
A Redox-active PARP Inhibitor for Lung Transplantation
用于肺移植的氧化还原活性 PARP 抑制剂
  • 批准号:
    8391286
  • 财政年份:
    2012
  • 资助金额:
    $ 21.02万
  • 项目类别:
Restoration of free radical homeostasis: novel therapy of septic shock
恢复自由基稳态:感染性休克的新疗法
  • 批准号:
    9140177
  • 财政年份:
    2012
  • 资助金额:
    $ 21.02万
  • 项目类别:
Bifunctional Redox Catalyst & Organic Nitrate for Limb Reperfusion
双功能氧化还原催化剂
  • 批准号:
    8522327
  • 财政年份:
    2011
  • 资助金额:
    $ 21.02万
  • 项目类别:
PARP inhibition for thoraco-abdominal aneurysm surgery
PARP 抑制在胸腹动脉瘤手术中的应用
  • 批准号:
    6933563
  • 财政年份:
    2005
  • 资助金额:
    $ 21.02万
  • 项目类别:
PARP inhibitory therapy of acute ischemic stroke
PARP抑制治疗急性缺血性脑卒中
  • 批准号:
    6785744
  • 财政年份:
    2004
  • 资助金额:
    $ 21.02万
  • 项目类别:
Inosine pro-drug: novel therapy for arthritis
肌苷前药:关节炎的新疗法
  • 批准号:
    6867616
  • 财政年份:
    2003
  • 资助金额:
    $ 21.02万
  • 项目类别:

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