Treatment of congenital heart disease associated pulmonary hypertension

DESCRIPTION provided by applicant Restoration of the balance of the free radicals nitric oxide NO and superoxide in the pulmonary vasculature may prevent life threatening perioperative pulmonary hypertension PH in children with congenital heart defects CHD undergoing surgical correction of a left to right shunt In rodent models of PH intratracheal IT administration of R a bifunctional NO donor and redox catalyst prodrug intended to correct free radical imbalance selectively and profoundly reduces mean pulmonary arterial pressure MPAP without impacting systemic mean arterial pressure MAP or heart rate HR R the metabolite of R inhibits vascular remodeling R is dephosphorylated in vivo to form an intermediate R which is then hydrolyzed to form para hydroxyphenylacetate PHPA and nitratoproxyl hydroxylamine The freed PHPA detoxifies peroxynitrite the reaction product of NO with superoxide anion while the liberated nitratoproxyl hydroxylamine oxidizes to form R a molecule serving as a a nitric oxide donor via its organic nitrate and b a broad spectrum catalyst of reactive oxygen species degradation via its nitroxide moiety The fusion of all the above functional domains into a single entity R assures that their multiple biologica activities are co localized The unique potency selectivity and sustained duration of effect justify development of R for perioperative prevention of PH in CHD Aim Establish the pharmacodynamic PD profile of R in a lamb model of PH induced by a thromboxane mimetic Juvenile lambs will undergo continuous infusion with the pulmonary selective vasoconstrictor U to achieve a MPAP mmHg R mg kg nebulized per IT will be compared to inhaled NO iNO for the amplitude and duration of its effect on SVR and PVR Blood will be collected for correlation of PVR and SVR with the plasma concentrations of R and its major metabolites Aim Determine the efficacy of R in a lamb model of perioperative pulmonary hypertension induced by cardiopulmonary bypass CPB and surgical correction of a congenital left t right shunt Juvenile lambs with PH MPAP mmHg induced by in utero placement of a pulmonary aortic window will undergo CPB and surgical closure of the arteriovenous connection Directly following CPB the effect of a single dose of nebulized IT R or vehicle control will be compared to iNO ppm for the amplitude and duration of its effect on SVR and PVR Aim Establish the acute safety stability and tolerance of the aerosolized R by IND enabling toxicology and safety pharmacology studies Lovelace Biomedical and Environmental Research Institute will carry out GLP grade in vivo dose range finding and day repeat dose toxicology investigations in juvenile rats and dogs with a day recovery period RTX will then prepare and submit a full IND application to the FDA for a Phase a clinical dose escalation study PUBLIC HEALTH RELEVANCE Perioperative pulmonary hypertension in the setting of surgical correction of congenital heart disease may be life threatening requiring urgent restoration of vascular tone in the pulmonary circulation Existing therapies provide marginal relief and are often ineffective We are developing a novel drug that targets the basic mechanisms of this condition and will test this agent in a clinically relevant animal model