Therapeutic potential for transient inhibition of adenosine deaminase in systemic inflammatory response syndrome

• Published in: Critical care medicine Vol. 31; no. 5; p. 1475
• Main Authors: Law, William R, Valli, Victor E, Conlon, Beth A
• Format: Journal Article
• Language: English
• Published: United States 01.05.2003
• Subjects: Adenosine Deaminase - analysis; Adenosine Deaminase - immunology; Adenosine Deaminase Inhibitors; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Feces; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Infusions, Intravenous; Injections, Intraperitoneal; Leukocyte Count; Male; Pentostatin - pharmacology; Pentostatin - therapeutic use; Peritonitis - complications; Proportional Hazards Models; Prospective Studies; Random Allocation; Rats; Rats, Sprague-Dawley; Survival Analysis; Systemic Inflammatory Response Syndrome - drug therapy; Systemic Inflammatory Response Syndrome - enzymology; Systemic Inflammatory Response Syndrome - microbiology; Systemic Inflammatory Response Syndrome - mortality; Systemic Inflammatory Response Syndrome - prevention & control; Time Factors
• DOI: 10.1097/01.CCM.0000063259.09580.D8
• ISSN: 0090-3493

We sought to determine the potential usefulness of 2'-deoxycoformycin (pentostatin), an inhibitor of adenosine deaminase, as a postinsult, or prophylactic treatment for systemic inflammatory response syndrome resulting from fecal peritonitis. Prospective, randomized, controlled experiment. Small animal basic science laboratory. Male Spague-Dawley rats, weighing 300 to 350 g. Rats with fecal peritonitis (intraperitoneal cecal slurry) were treated with 1 mg/kg pentostatin intraperitoneally 24 hrs before, or intravenously when signs of illness presented (2 hrs after induction of peritonitis). Signs of illness included tachycardia, tachypnea, and leukopenia. All rats received 50 mL/kg 0.9% saline resuscitative fluid at 2 hrs. Survival to day 6 was 100% in nonseptic sham rats, but 33% in untreated septic rats. In rats given pentostatin either 2 hrs after the insult, or 24 hrs before the insult, 6-day survival improved to 81% and 78%, respectively. Histology revealed diffuse peritonitis, and evidence of systemic inflammatory response syndrome, including local and distant site vascular damage and leukocyte activation. These responses to the septic challenge were abrogated by pentostatin treatment. Return of significant amount of tissue adenosine deaminase activity by 24 hrs and later recovery of white blood cell counts argue against any potential for inappropriate immunosuppression by pentostatin. These data indicate that the novel use of pentostatin to prevent systemic inflammatory response syndrome secondary to fecal peritonitis shows uncommon promise as a therapeutic tool. All indices of systemic inflammatory response syndrome were abrogated and survival improved when pentostatin was not given until after signs of the illness became manifest. Because protection was afforded with treatment 24 hrs in advance of the inciting insult, pentostatin also has the unique potential for use as a true prophylactic agent.