Antagonism of Alpha2A-Adrenoceptor: A Novel Anti-Sepsis Therapy

DESCRIPTION (provided by applicant): This SBIR Phase I proposal is intended to demonstrate the feasibility of further development of a novel therapy for patients with sepsis through the modulation of cytokine production. Sepsis is a leading cause of death in non-cardiac intensive care units. Despite advances in the management of trauma victims, the incidence of sepsis has significantly increased. More than three quarters of a million patients develop sepsis each year in the US alone with an overall mortali ty rate of 28.6%. The global market potential for sepsis treatment is estimated at over 30 billion annually. Thus, successful development of a novel and effective anti-sepsis therapy will not only have a positive impact on health care, but will also have significant commercial benefits. A balanced inflammatory response is an essential element of a successful( host defense after injury. However, excessive production of proinflammatory cytokines [e.g., TNF-1, IL-1(, IL-6, and high mobility group box-1 (HMGB- 1)] may cause further tissue injury. Macrophages/Kupffer cells play important roles in producing proinflammatory cytokines during sepsis. The nervous system reflexively regulates the inflammatory response in real time. Our preliminary studies indicate that the release of the sympathetic neurotransmitter, norepinephrine (NE), from the gut is increased in sepsis, and that NE potentiates endotoxin-induced TNF-( upregulation via the A subtype of (2A-adrenoceptors (i.e., (2A-AR) expressed on the surface of Kupff er cells. Pre-treatment with a specific (2A antagonist, 2-[(4,5-dihydro-1H-imidazol-2-yl) methyl]-2,3-dihydro-1-methyl-1H-isoindole 2A maleate (BRL-44408 maleate), downregulates TNF-(, attenuates tissue injury, and improves survival in a rat model of polym icrobial sepsis induced by cecal ligation and puncture (CLP). However, it remains unknown whether the delayed administration of BRL-44408 maleate (which is more clinically relevant) reduces sepsis-induced mortality as well. We, therefore, hypothesize that the administration of BRL-44408 maleate late after the onset of sepsis attenuates tissue injury and improves survival. The primary objective of this project is targeted towards demonstrating the feasibility of the further development and commercialization of BRL-44408 maleate as a novel therapeutic agent in reducing mortality in sepsis. The optimal dosage(s) of BRL-44408 maleate (delayed treatment) will be determined by assessing 1) the dose- response effect of BRL-44408 maleate on proinflammatory cytokines and tissue injury in sepsis; and 2) the dose-response effect of BRL-44408 maleate on sepsis-induced mortality. Our ultimate goal (SBIR Phase II and beyond) is to obtain commercial utilization of BRL-44408 maleate as a safe and effective treatment for pati ents with sepsis or septic shock. PUBLIC HEALTH RELEVANCE: Sepsis is the second leading cause of death among patients in non-coronary intensive care units (ICU) and the 10th leading cause of death overall in this nation. Evidence indicates that in the US alone, more than 750,000 people develop sepsis each year with an overall mortality rate of 28.6%. Given the intensive and prolonged care necessary to treat patients with sepsis, the economic burden is profound. A recent report indicates that the average cost per septic patient is at least 22,100, with current annual total costs of more than 16 billion nationally. Thus, there is an urgent unmet medical need for an effective novel therapy for septic patients.