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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43AI078537-01A1
Agency Tracking Number: AI078537
Amount: $197,522.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: N/A
Solicitation Number: PHS2007-2
Timeline
Solicitation Year: 2008
Award Year: 2008
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
THERASOURCE, LLC 59 HIGHLAND AVE
ROSLYN, NY 11576
United States
DUNS: 144994972
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 () -
Business Contact
Phone: (516) 562-1017
Email: pwang@nshs.edu
Research Institution
N/A
Abstract

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.

* Information listed above is at the time of submission. *

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