The acute hepatotoxicity of acetaminophen is a major health concern since this analgesic is one of the most commonly used drugs in intentional overdose. The clinical presentation of acetaminophen toxicity is characterized by rapid and progressive liver injury that may result in death. A critical aspect of the pathogenesis of acetaminophen toxicity is the activation of inflammatory cells to produce nitric oxide and superoxide radical, and their reaction product, the potent oxidant peroxynitrite. Current anti-inflammatory treatment regimens for acetaminophen-induced hepatotoxicity have limited efficacy. Inotek Corporation is developing a unique anti-inflammatory pyrazolopyrimidine derivative, 4- Amino.6.hydroxypyrazolo[3,4-d] pyrimidine (AHPP), which selectively inhibits xanthine oxidase (XO) activity. Given the critical role that superoxide radical production and XO activation play in the generation of hepatic inflammatory injury, we hypothesize that AHPP represents an innovative therapeutic candidate with significant commercial potential. AHPP requires demonstration of efficacy in a clinically relevant and stringent experimental model of acetaminophen intoxication in order to justify its commercialization as a novel anti-inflammatory agent for the prevention of liver failure.
In Specific Aim #1, we will test this hypothesis in a well-established rodent model of acetaminophen intoxication.
In Specific Aim #2, we will establish that AHPP is not genotoxic. The demonstration that AHPP is not mutagenic and effectively prevents histologic injury, tissue lipid peroxidation, and serum transaminasemia would represent a breakthrough in the design of novel regimens for the treatment of acetaminophen intoxication and would justify its further commercial development.
The domestic market for a novel, effective therapy for acetaminophen intoxication is estimated at $250 million per annum. Global markets are estimated at $800 million. Current market entrants are marginally effective: massive acetaminophen intoxication frequently results in fulminant liver failure necessitating orthotopic liver transplantation. AHPP may represent the first highly potent and successful adjunct to the current therapeutic regimen; funding of SBIR Phases I and II will allow for market entry in 4 years.
