Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability.

INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors are indicated for the treatment of erectile dysfunction (ED); however, they can also inhibit other PDE isozymes, affecting their target tissues (e.g., PDE1: heart; PDE6: retina; and PDE11: skeletal muscle), which in some cases can cause unwanted side effects and therapy discontinuation. Data from in vitro studies showed that avanafil, a PDE5 inhibitor for the treatment of ED, exhibited strong selectivity toward PDE5 and against all other PDE isozymes. AIM: To review the inhibitory effects of avanafil for PDE isozymes compared with those of sildenafil, tadalafil, and vardenafil and to discuss these results within the context of clinical trial safety observations. METHODS: Review of in vitro selectivity data for avanafil (published primary data from a peer-reviewed journal and scientific congress abstracts); PubMed search for pertinent publications on PDE5 inhibitor safety data; and review of published articles and abstracts from avanafil phase 1, 2, and 3 clinical trials. MAIN OUTCOME MEASURES: A low incidence of some PDE-related adverse events may be reflected by the high selectivity of avanafil against non-PDE5 isozymes. RESULTS: Avanafil is highly selective toward PDE5 and against all other PDE isozymes tested. Lower selectivity against PDE1, PDE6, and PDE11 is consistent with results from randomized, placebo-controlled, phase 3 trials in which musculoskeletal and hemodynamic adverse events were reported in <2% of patients and no color vision-related abnormalities were reported with avanafil doses up to 200 mg once daily. CONCLUSIONS: Data suggest that avanafil may confer a safety benefit, in terms of a lower incidence of specific adverse events, by virtue of its high specificity to PDE5 and its overall selectivity against other PDE isozymes.

Phase III efficacy and safety study of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis.

OBJECTIVE: To compare the clinical and antimicrobial efficacy of besifloxacin ophthalmic suspension 0.6% with that of vehicle in the treatment of bacterial conjunctivitis. RESEARCH DESIGN AND METHODS: This was a randomized, multicenter, double-masked, vehicle-controlled study. A total of 957 patients aged 1 year and older with bacterial conjunctivitis were randomized to treatment with besifloxacin ophthalmic suspension 0.6% or vehicle applied topically three times daily for 5 days. MAIN OUTCOME MEASURES: Primary endpoints were clinical resolution and microbial eradication of baseline bacterial infection at Visit 2 (Day 5 +/- 1). Secondary endpoints included clinical resolution and microbial eradication at Visit 3 (Day 8 or 9), individual clinical outcomes at follow-up visits, and safety. CLINICAL TRIAL REGISTRATION: NCT number, NCT00347932. RESULTS: Three hundred and ninety patients had culture-confirmed bacterial conjunctivitis. Clinical resolution and microbial eradication were significantly greater with besifloxacin ophthalmic suspension than with vehicle at Visit 2 (45.2% vs. 33.0%, p = 0.0084; and 91.5% vs. 59.7%, p < 0.0001, respectively) and Visit 3 (84.4% vs. 69.1%, p = 0.0011; and 88.4% vs. 71.7%, p < 0.0001, respectively). Results for secondary endpoints of individual clinical outcomes were consistent with primary endpoints. Fewer eyes receiving besifloxacin ophthalmic suspension experienced adverse events than those receiving vehicle (9.2% vs. 13.9%; p = 0.0047). CONCLUSIONS: Besifloxacin ophthalmic suspension produces clinical resolution and microbial eradication rates significantly better than vehicle and is safe for the treatment of bacterial conjunctivitis. LIMITATIONS: A limitation of this study is the lack of a non-treatment control group.