Sepsis-induced acute lung injury is a major cause of morbidity and mortality after trauma and infection. Sepsis is often complicated by pulmonary hypertension, a life-threatening condition that produces hypoxemia and heart failure. Treatment of sepsis with inhaled gaseous nitric oxide (NO) produces dramatic benefits in an """"""""NO-responder"""""""" subset of patients. Current treatment regimens to provide gaseous inhaled NO are cumbersome, expensive and involve potential toxic exposure to health care personnel. Inotek is developing a novel class of soluble nitrovasodilators (diazeniumdiolate pro-drugs), which are selective for the pulmonary circulation when administered by an aerosol route. Diazeniumdiolates are impermeant to the epithelial tight junction due to electrostatic considerations (charged at physiologic pH) and steric hindrance (MW=160 kDa). NO, being lipophilic, is released from the parent compound and traverses the mucosal epithelium, thus acting as a vasodilator in the vascular smooth muscle of the pulmonary vascular bed. NO which crosses further into the circulation is immediately inactivated by hemoglobin; thus, no systemic vasodilation occurs. In a Phase I SBIR scope of work, Inotek validated that three diazeniumdiolates (DMAEP/NO, DMDE/NO, and CBC-NO) were highly effective in increasing oxygenation and decreasing pulmonary vascular resistance, without any effect on systemic blood pressure, in clinically-relevant large animal models of pulmonary hypertension induced by oleic-acid infusion, bacterial sepsis, and combined smoke inhalation and thermal injury. CBC-NO (N-carboxybutyl chitosan diazeniumdiolate) is a derivative of chitosan, a naturally occurring polymer that is non-toxic and readily biodegradable. The duration of action of CBC-NO in vivo was 18 h, allowing for the convenience of bid dosing. Inotek now proposes to accelerate innovation of the CBC-NO technology, to include: 1) synthesis of gram-scale batches and characterization of the specific activity and release profile of NO, 2) characterization of the chemical stability and degradation products, 3) pharmacodynamic profile, defining pulmonary shunt, vascular resistance, and oxygenation in an experimental large animal model of pseudomonas-induced acute lung injury, and 4) toxicologic profile, to include genotoxicology and histopathology studies of sub-acute aerosol exposure in three species. This scope of work will form the basis for clinical trials of CBC-NO for treatment of sepsis-induced pulmonary hypertension, scheduled to begin in Q1 2001.
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