Gregory D. Sides

Retinal Effects of 6 Months of Daily Use of Tadalafil or Sildenafil

OBJECTIVE To assess changes in electroretinography (ERG) and other retinal function parameters during 6 months of daily use of tadalafil, sildenafil citrate, or placebo. METHODS Subjects were randomized to use of a placebo (n=82), 5 mg of tadalafil (n=85), or 50 mg of sildenafil (n=77) daily for 6 months. Electroretinographs were recorded using the International Society for Clinical Electrophysiology of Vision (ISCEV) protocol and standardized ERG equipment at all 15 study sites. Other tests of ocular anatomy and visual function were performed at each assessment. MAIN OUTCOME MEASURES The primary outcome was the average mean change for both eyes from baseline to endpoint in ERG b-wave amplitude using dark-adapted combined standard response to a bright ISCEV standard flash. Secondary endpoints were other ERG parameter changes, visual acuity, number of errors in color discrimination testing, mean deviation in automated visual field testing, and intraocular pressure (IOP). RESULTS No significant differences were found between treatment/placebo groups for the primary outcome, most other ERG variables, visual function, IOP, or anatomic assessments. The medications were well tolerated. CONCLUSIONS No abnormalities in ERG or visual function and no treatment-related findings suggestive of drug toxicity are associated with daily administration of tadalafil or sildenafil for 6 months. APPLICATION TO CLINICAL PRACTICE Assessed visual safety of tadalafil/sildenafil administered daily over a prolonged period. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00333281.

A phase 2 dose-ranging study of subcutaneous tabalumab for the treatment of patients with active rheumatoid arthritis and an inadequate response to methotrexate

Objectives To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX). Methods In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ≥50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified α=0.10). Results At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50–69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only. Conclusions A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. Clinical Trial # NCT00785928.

Electrocardiogram reference ranges derived from a standardized clinical trial population

Accurate assessment of electrocardiographic intervals is crucial for routine patient care and clinical research. This assessment requires well-characterized reference ranges. This article provides a complete set of reference ranges for numerical electrocardiogram (ECG) parameters (PR, QRS, QTc intervals, and heart rate). The reference ranges are derived from a large clinical trial patient population using a standardized ECG acquisition and analysis system (N = 15,039). The reference ranges are stratified by important prognostic factors: age, sex, and overall ECG evaluation at baseline (normal or abnormal). The proposed reference ranges may be useful for patient management and data analyses in clinical drug development. In addition, the article provides a QT correction formula to correct the QT interval for heart rate. This QT correction formula was shown to be superior to the Bazett and Fridericia corrections in a clinical trial population in the ability to minimize the correlation between QT and RR.

QT Interval Prolongation as a Biomarker for Torsades de Pointes and Sudden Death in Drug Development

Prolongation of the QT interval on the surface 12-lead electrocardiogram is widely accepted as a biomarker for the potential of a drug to produce torsades de pointes and/or sudden death. Detection of drug-induced prolongation of the QT interval in animals and man is frequently confounded by extrinsic and intrinsic factors that limit the ability to detect a true drug effect. In particular drugs that increase heart rate show an apparent increase in QT interval that confounds assessment of a true drug effect on cardiac ventricular repolarization. The basis for the use of the QT interval as a biomarker will be examined.

The efficacy of tadalafil in improving sexual satisfaction and overall satisfaction in men with mild, moderate, and severe erectile dysfunction: a retrospective pooled analysis of data from randomized, placebo-controlled clinical trials

ABSTRACT Background: Satisfaction with the sexual experience is considered important when evaluating the impact of treatments for erectile dysfunction (ED), yet satisfaction has been infrequently assessed in clinical trials. Objective: To evaluate satisfaction with, and enjoyment of, the sexual experience in men with ED enrolled in 11 placebo-controlled clinical trials of tadalafil. Study design and methods: Retrospective pooled analysis of data from 11 randomized, double blind, placebo-controlled clinical trials of tadalafil. Men with mild (N = 838), moderate (N = 558), or severe (N = 703) ED who were randomized to tadalafil 10 mg or 20 mg or placebo taken as needed for 12 weeks were included in this analysis. Efficacy measures included the International Index of Erectile Function (IIEF). Reported herein are the scores on the IIEF overall satisfaction domain and individual IIEF questions (IIEF‐Q7, satisfaction with intercourse; and IIEF‐Q8, enjoyment of intercourse). Results: At least moderate satisfaction (IIEF overall satisfaction domain) was reported by 55% and 72% of patients with mild ED taking tadalafil 10 mg and 20 mg, respectively, compared with 33% taking placebo ( p < 0.002); 60% and 65% vs. 19% of patients with moderate ED ( p < 0.001); and 32% and 49% vs. 9% with severe ED ( p < 0.001). Satisfactory intercourse during most attempts or almost always/always (IIEF‐Q7) was reported by 59% and 79% of patients with mild ED taking tadalafil 10 mg and 20 mg vs. 32% taking placebo ( p < 0.001); 52% and 65% vs. 18% with moderate ED ( p < 0.001); and 28% and 49% vs. 5% with severe ED ( p < 0.001). Highly or very highly enjoyable intercourse (IIEF‐Q8) was reported by 45% and 63% of patients with mild ED taking tadalafil 10 mg and 20 mg vs. 21% taking placebo ( p < 0.001); 43% and 56% vs. 16% with moderate ED ( p < 0.001); and 19% and 44% vs. 5% with severe ED ( p < 0.001). Conclusions: Compared with placebo, tadalafil 10 mg and 20 mg improved overall satisfaction with the sexual experience, intercourse satisfaction, and intercourse enjoyment in men with mild, moderate, and severe ED.

Efficacy of Tadalafil in Men with Erectile Dysfunction Naïve to Phosphodiesterase 5 Inhibitor Therapy Compared with Prior Responders to Sildenafil Citrate

INTRODUCTION Tadalafil, an inhibitor of phosphodiesterase 5 (PDE5), is indicated for treatment of erectile dysfunction. Most tadalafil clinical trials excluded patients with unsuccessful prior treatment with sildenafil citrate (sildenafil). AIM This retrospective analysis of pooled data from 14 tadalafil clinical trials examines the effect of this exclusion by comparing efficacy results in 1,349 patients without prior sildenafil use (naïve, presumably a mixture of potential responders and nonresponders) with efficacy results in 1,440 patients previously responsive to sildenafil (prior responders). MAIN OUTCOME MEASURES Efficacy measures included the International Index of Erectile Function (IIEF) erectile function (EF) domain, overall satisfaction (OS), and intercourse satisfaction (IS) domain scores; Sexual Encounter Profile (SEP) diary questions 2 through 5 (SEP2 [successful penetration], SEP3 [successful intercourse], SEP4 (satisfaction with hardness of erection), and SEP5 [overall satisfaction with the sexual experience]); and a Global Assessment Question (GAQ1) (13/14 trials) about erection improvement. Efficacy was compared using analysis of covariance (IIEF and SEP) and logistic regression (GAQ1) models. METHODS After a 4-week, treatment-free, run-in period, patients in 14 double-blind, placebo-controlled, parallel-group trials were treated with tadalafil 10 mg, tadalafil 20 mg, or placebo for 12 weeks (dosed as needed before sexual activity, no more than once daily). RESULTS Tadalafil improved erectile function compared with placebo (P < 0.001) in naïve patients and sildenafil prior responders for all efficacy measures. For most efficacy outcomes, responses in the naïve group (probable mix of responders and nonresponders) were not statistically different from responses in the prior-responder group (P >or= 0.10). CONCLUSIONS The similar responses of these two patient groups observed in this post hoc analysis suggest, but do not confirm, that exclusion of sildenafil nonresponders in previously reported tadalafil clinical trials may not have substantially affected efficacy outcomes. Tadalafil improved erectile function in patients naïve to PDE5 inhibitor therapy and in patients who previously responded to sildenafil therapy.

Clinical efficacy of dirithromycin in patients with bacteremic pneumonia.

Dirithromycin is a new macrolide antimicrobial drug with a long half-life (44 hours) that reaches high tissue concentrations, thus permitting once-daily oral dosing and shorter courses of therapy. Soon after absorption, dirithromycin enters the tissue so rapidly that serum concentrations are comparatively low. It could be hypothesized that these low serum levels could endanger the outcome in patients with bacteremic pneumonia. We reviewed the database on dirithromycin pneumonia (consisting of 1108 patients randomized to receive dirithromycin or erythromycin in two double-masked trials) to ascertain its efficacy in patients with community-acquired pneumonia and concomitant bacteremia. Fourteen (2.5%) of 555 dirithromycin-treated patients and 10 (1.8%) of 553 erythromycin-treated patients had bacteremia. A favorable clinical response posttherapy was observed in 92.3% and 88.9% of these patients with a response assigned, respectively. Overall, favorable response rates were comparable between the two groups in the bacteremic subsets: patients with pneumococcal bacteremia, patients with nonbacteremic pneumococcal pneumonia, and all patients enrolled with acute pneumonia who had a posttherapy clinical response. In the treatment of patients with mild or moderate community-acquired pneumonia, including those with unsuspected and incidental bacteremia, dirithromycin is an effective macrolide antimicrobial drug.

Effect of Dirithromycin on Human CYP3A In Vitro and on Pharmacokinetics and Pharmacodynamics of Terfenadine In Vivo

Terfenadine is metabolized by the cytochrome P‐450 3A subfamily of enzymes (CYP3A). Certain macrolide antibiotic agents inhibit CYP3A and, when coadministered with terfenadine, result in a drug interaction. The authors compared the abilities of dirithromycin (a new macrolide antibiotic agent), its major metabolite erythromycylamine, and the known CYP3A substrate terfenadine to inhibit CYP3A in vitro. The hydroxylation of midazolam in human liver microsomes was used as a probe for CYP3A activity. Dirithromycin and erythromycylamine were low affinity inhibitors of CYP3A (inhibitory binding affinities of 493 μmol/L and 701 μmol/L, respectively); conversely, terfenadine was a moderate affinity inhibitor (inhibitory binding affinity of 28 μmol/L). Based on these data, the authors tested the hypothesis that dirithromycin would not interact with terfenadine in humans. Six healthy men received terfenadine alone (60 mg twice daily) for 8 days, after which dirithromycin (500 mg once daily) was added to the terfenadine regimen for an additional 10 days. The pharmacokinetics of terfenadine (and its acid metabolite) and the QTc interval were measured during both treatments, and it was found that neither parameter was affected. In this study, dirithromycin was found to have low affinity for human CYP3A in vitro, which is in accordance with the studys finding that in vivo dirithromycin has no major effect on the metabolism of the CYP3A substrate terfenadine in humans.

Tonsillar Tissue Penetration of Dirithromycin after Multiple Doses

Dirithromycin is a new macrolide antibiotic that is effective against group A β‐hemolytic streptococcal pharyngotonsillitis. This prospective, multicenter, randomized study compared the serum and tonsil tissue concentrations of erythromycylamine (to which dirithromycin is rapidly converted by nonenzymatic hydrolysis during absorption) and erythromycin after 5‐ and 10‐day regimens of dirithromycin and erythromycin, respectively. Thirty‐nine patients undergoing elective tonsillectomy but without active tonsillitis were assigned in randomized fashion to receive dirithromycin 500 mg orally once daily (n = 22) or erythromycin base 250 mg orally four times daily (n = 17). Data from 12 patients receiving dirithromycin and 10 receiving erythromycin were eligible for analysis. Mean serum concentrations (± standard deviation) of erythromycylamine and erythromycin were 0.20 ± 0.07 μg/mL and 0.12 ± 0.25 μg/mL, respectively, after the 5‐day regimen and 0.17 ± 0.10 μg/mL and 1.57 ± 3.16 μg/mL, respectively, after the 10‐day regimen. The mean serum concentration of erythromycin after 10 days was skewed by the data for one of the six patients in the group (concentration of >8 μg/mL). Mean concentrations of erythromycylamine in tonsil tissue were 4.62 ± 0.97 μg/g after 5 days and 3.47 ± 2.84 μg/g after 10 days. Concentrations in tonsillar tissue were undetectable in all patients given erythromycin for 5 days and in 4 of the 6 patients given erythromycin for 10 days. The high concentrations of erythromycylamine in tonsillar tissue agree with the clinical efficacy seen in the treatment of group A β‐hemolytic streptococcal tonsillopharyngitis with dirithromycin.