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NEAL J. BENEDICT, PHARM.D., is Assistant Professor, Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh (UP), and Clinical Pharmacist, UP Medical Center, 302 Scaife Hall, 200 Lothrop Street, Pittsburgh, PA 15213 (benedictnj{at}upmc.edu).

Purpose. The pharmacology, pharmacokinetics, clinical trials, adverse effects, drug interactions, and dosing and administration of the endothelin receptor antagonist, sitaxsentan, and its role in the treatment of pulmonary arterial hypertension (PAH) are reviewed. Summary. PAH is a serious and potentially devastating chronic disorder of the pulmonary circulation. Bosentan is the first and only approved endothelin receptor antagonist for the treatment of PAH. Endothelin-1, a potent endogenous vasoconstrictor and smooth-muscle mitogen, has been shown to be overexpressed in the plasma and lung tissue of patients with PAH; the reduction or blockade of entothelin-1 may aid in disease symptomatology and progression. Activation of ETA leads to vasoconstriction and vascular smooth-muscle-cell proliferation. Sitaxsentan is an orally active, organic nonpeptide that binds competitively to the ETA receptor. Sitaxsentan, unlike bosentan, has a high affinity for the ETA receptor. In one trial, sitaxsentan was compared with placebo, and the results suggested that sitaxsentan was more effective than placebo. A 12-week, open-label trial demonstrated the safety and efficacy of sitaxsentan in 20 patients. The Sitaxsentan to Relieve Impaired Exercise (STRIDE-1) trial randomized patients to receive placebo, sitaxsentan 100 mg orally once daily, or sitaxsentan 300 mg orally once daily. Significant improvements in exercise capacity and cardiopulmonary hemodynamics were demonstrated. The results of STRIDE-2, the second randomized sitaxsentan trial, demonstrated the efficacy and safety of 100 mg sitaxsentan and the unacceptable safety profile of 300 mg sitaxsentan. Conclusion. Sitaxsentan is an orally administered endothelin receptor blocker that offers the effective and safe treatment of patients with mild to moderate PAH. Index terms: Binding; Dosage; Drug administration; Drug interactions; Hypertension; Hypotensive agents; Mechanism of action; Pharmacokinetics; Sitaxsentan; Toxicity