TNF-alpha, including other proinflammatory cytokines alone or in combination, induces iNOS expression and upregulates inflammatory responses. We evaluated the relationship between TNF-alpha and iNOS expression in indomethacin-induced jejunoileitis in male Sprague-Dawley rats. Rats were fed a daily dose of a phosphodiesterase inhibitor-either theophylline or pentoxifylline-for 2 days. Jejunoileitis was induced with two subcutaneous injections of indomethacin (7.5 mg/kg) 24 hr apart and theophylline or pentoxifylline continued for 12 hr or 4 days. Other rats received a single intraperitoneal injection of anti-TNF-alpha monoclonal antibody (TNF-Ab) 30-min before indomethacin. At 4 days TNF-Ab, theophylline, or pentoxifylline treatment significantly decreased indomethacin-induced ulceration, myeloperoxidase activity, and disease activity index. Although indomethacin significantly increased serum TNF-alpha and nitrate/nitrite levels over the control value as early as 12 hr, iNOS expression was detected only after 4 days. Serum IL-1beta level did not change at 12 hr but increased fourfold at 4 days. Treatment with TNF-Ab, theophylline, or pentoxifylline significantly reduced serum/tissue TNF-alpha, IL-1beta, nitrate/nitrite, and iNOS expression. The downregulation of nitrate/nitrite by these inhibitors suggests that TNF-alpha modulates iNOS expression.

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Clinical Pharmacology & Therapeutics (2003) 73, P85–P85; doi:

Pharmacokinetic studies demonstrate that propoxyphene is a potent inhibitor of cytochrome P450 (CYP) 2D6. Clinically significant sequelae have not been previously reported. We report a case of this inhibition manifested by life-threatening bradycardia in a patient receiving a CYP2D6 substrate, metoprolol. A 48-year-old man came to the emergency department complaining of dizziness 3 hours after ingesting metoprolol, at his usual dose, and 2 tablets of propoxyphene, newly begun postoperatively. Four hours after ingestion of both drugs, the patient was noted to have a ventricular rate of about 30 beats/min with underlying atrial fibrillation. The patient's ventricular response returned to normal within 11 hours of ingestion. We have demonstrated the clinical importance of the interaction between propoxyphene and metoprolol likely resulting from inhibition of hepatic clearance of metoprolol by propoxyphene. Underscoring the clinical relevance of CYP2D6 inhibition by an analgesic of questionable efficacy should proscribe its use.