Fozivudine tidoxil (FZD) is a thioether lipid-zidovudine (ZDV) conjugate with anti-HIV activity demonstrated in vitro and in pilot phase I studies. To assess its safety, efficacy and pharmacokinetics, we conducted a multicenter, randomized, double-blind, placebo-controlled trial of FZD monotherapy in 72 HIV-infected patients who had not previously received antiretroviral therapy. In each dosage group (200 mg daily, 400 mg daily, 200 mg twice daily, 800 mg daily, 400 mg twice daily, and 600 mg twice daily), 12 patients were randomized to receive in a 10:2 ratio either FZD or a placebo for 4 weeks. Overall, FZD was well tolerated in all dosage groups; only 1 patient discontinued the drug, because of a moderate rise in aminotransaminase activity. HIV viral load fell in all the patients who were receiving FZD, except in the 200 mg daily group. The largest decrease (-0.67 log10) was observed in the 600 mg twice daily group. The plasma half-life was significantly longer (approximately 3.8 hours) than that of the parent drug ZDV. Exposure to ZDV, as reflected by the area under the time-concentration curve, was much lower after FZD than after ZDV administration. FZD thus appears to be as effective as and potentially better tolerated than ZDV during short-term administration and has the advantage of once daily intake.
Influenza virus infection accounts for significant morbidity, mortality, and healthcare expenditures among persons worldwide. Approximately 20,000 to 40,000 people in the US die each year as a result of influenza. Individuals most susceptible to adverse outcomes include the elderly and those with asthma, chronic obstructive pulmonary disease (COPD), heart disease, renal failure, malignancy, or immunosuppression. Prior to the AIDS epidemic, underlying respiratory disease was the greatest risk factor for influenza-related hospitalization ranking third to heart disease and malignancy for risk of mortality. Although the influenza vaccine can help prevent pneumonia and hospitalization, it is limited by less than ideal immunization rates and the possibility of viral antigenic shifts that render the vaccine ineffective. Pharmacologic interventions play an important role in the management of influenza virus infection by shortening the duration of symptoms. The advent of the neuraminidase inhibitors (NAIs) zanamivir and oseltamivir has significantly affected the treatment of influenza. Unlike NAIs, the older therapeutic options amantadine and rimantadine may cause significant central nervous system adverse effects. In addition, amantadine and rimantadine are not active against influenza B viruses, whereas NAIs are active against both influenza A and B. Post-marketing surveillance of the NAIs has revealed that bronchospasm may occur in patients with underlying respiratory disease treated with the NAI zanamivir. Recent data suggest zanamivir is effective in patients with underlying respiratory disease, but the data are insufficient to elucidate the true risk of bronchospasm. Based on post-marketing reports, zanamivir should be used with caution in patients with asthma or COPD. Although oseltamivir has not been associated with any significant respiratory adverse effects, no data exist on the safety and efficacy of this NAI in patients with underlying respiratory disease.
The records of 206 patients with advanced infection due to human immunodeficiency virus type 1 who were receiving prophylaxis with clindamycin/primaquine (C/P), trimethoprim-sulfamethoxazole (TMP-SMZ), or dapsone to prevent Pneumocystis carinii pneumonia (PCP) were retrospectively examined. Two hundred sixty-two patient-years of prophylaxis were accrued (176.2 of TMP-SMZ, 63.4 of dapsone, and 22.8 of C/P). The rates of PCP in the TMP-SMZ, dapsone, and C/P groups were 3.4, 11.0, and 30.7 per 100 patient-years, respectively. Pairwise comparisons showed C/P to be less effective than TMP-SMZ (relative risk [RR], 9.02; 95% confidence interval [CI], 3.03-26.83). A similar trend was apparent for C/P vs. dapsone (RR, 2.78; 95% CI, 0.98-7.93). When only those receiving primary prophylaxis were analyzed, C/P recipients remained at greater risk than TMP-SMZ recipients (RR, 13.19; 95% CI, 3.54-49.12) and dapsone recipients (RR, 3.85; 95% CI, 1.12-13.31). Failure of C/P prophylaxis could be due, at least in part, to underdosing (clindamycin, 300 mg/d; primaquine, 15 mg/d). C/P recipients had more nonspecific diarrhea than did TMP-SMZ recipients (RR, 2.99; 95% CI, 1.61-5.55).
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