Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.

To prospectively assess the incidence and clinical significance of thromboembolic complications in patients with multiple (> or = 3) noninfected transvenous leads; 48 consecutive patients were evaluated. Half of the patients had two ventricular leads and one atrial lead, 15 patients had two atrial leads and one ventricular lead, while 9 patients had two ventricular and two atrial leads. No additional care was provided except for aspirin (80 mg bid) and annually performed echo-Doppler studies. Clinical follow-up included signs and symptoms of subclavian and/or axillary vein thrombosis, the presence of right congestive heart failure, the number of hospital admissions, and death. Echo-Doppler studies assessed the presence of an enlarged right atrium or ventricle, right atrial or ventricular spontaneous contrast, and the presence of tricuspid regurgitation. During a total follow-up of 7.4 +/- 2.2 years there were no differences in the incidence of clinical variables as compared to age-matched controls with DDD pacemakers. The most common complication was transient venous thrombosis (mostly presenting as venous prominence 1-2 weeks after implantation), which was seen in 17% of the study group versus 15% in controls (NS). Cumulative mortality was not different in both groups (13% in the study group vs 15% in controls). No differences were present with respect to hospital admissions (1.1 +/- 0.27/year in the study group vs 1.2 +/- 0.30/year in the controls). In patients with multiple ventricular leads, tricuspid regurgitation on echo-Doppler studies was more frequent (24%) as compared to controls (4%); however, clinical signs of right heart failure were equally distributed. Thus, patients with multiple (> or = 3) noninfected leads have no clinical adverse outcome during long-term follow-up.