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Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas., (© 2014, The American College of Clinical Pharmacology.)

Background: Genital warts are common and usually are harmless but can be painful and psychologically burdensome. Several local treatments can be used, including topical 5-Fluorouracil (5-FU)., Objectives: To determine the effectiveness and safety of 5-FU topical treatment for genital warts in nonimmunocompromised individuals., Search Strategy: Databases searched were Cochrane Central Register of Controlled Trials (The Cochrane Library 2009 Issue 3), MEDLINE (1966 to August 2009), EMBASE (until August 2009), LILACS (1982 to August 2009). The search had no language or publication restrictions., Selection Criteria: The review included randomised controlled trials (RCTs) among women, men, or both sexes, aged 18 years and older, comparing: 5-FU versus placebo or no treatment; 5-FU in any dose versus other isolated treatment, topical or systemic; 5-FU in any dose associated with other treatment versus placebo; 5-FU in any dose associated with other treatment versus other isolated treatment, topical or systemic; 5-FU in any dose associated with other treatment versus other associated treatment, topical or systemic., Data Collection and Analysis: Two authors independently assessed trial quality and extracted data from the original publications., Main Results: Six trials involving 988 patients (645 women and 343 men) and reporting eight comparisons were found. Two studies reported withdrawals and dropouts, but none mentioned analysis by intention to treat (ITT). 5-FU presented better results for cure than placebo or no treatment (relative risk (RR) 0.39, 95% confidence interval (CI) 0.23 to 0.67), meta-cresol-sulfonic acid (MCSA) (RR 2.11, 95% CI 0.83 to 5.37), Podophylin 2%, 4% or 25% (RR 1.26, 95% CI 0.86 to 1.82). There were no statistical differences for treatment failure for 5-FU versus CO2 Laser (RR 0.69, 95% CI 0.43 to 1.11) versus 5-FU + INFalpha-2a (low dose) (RR 1.02, 95% CI 0.87 to 1.119). Worse results were found for 5-FU versus 5-FU + INFalpha-2a (high dose) (RR 10.78, 95% CI 1.50 to 77.36), and 5-FU + CO2 Laser INFalpha-2a (high dose) (RR 7.97, 95% CI 2.87 to 22.13)., Authors' Conclusions: The reviewed trials were highly variable in methods and quality, and the evidence provided by these studies was weak. Cure rates with several treatments were variable, and although 5-FU presents therapeutic results that are inferior to those seen with 5-FU + Inf alpha-2a (high dose) and 5-FU + CO2 Laser + Inf alpha-2a (high dose), the treatment should not be abandoned. Topical treatment with 5-FU has a therapeutic effect; however, the benefits and risks have not been determined clearly and further studies are needed.

Objective: The purpose of the present analysis was to analyze and compare the cost-effectiveness of solifenacin flexible dosing (5-10 mg) with tolterodine 4 mg sustained release (SR) or placebo (assumed to be comparable to no treatment) for patients with overactive bladder (OAB) symptoms., Design: A decision-analytic model was constructed., Methods: Costs and effects were evaluated for the three treatment options in a one-year timeframe. Costs included were treatment costs, cost of pad use, and patients productivity loss based on data from the Nordic countries., Sample: Results from two randomized controlled trials were used as input data in the cost-effectiveness analysis., Main Outcome Measures: Quality adjusted life years and incremental cost-effectiveness ratio., Results: Solifenacin flexible dosing was more effective with respect to reducing OAB symptoms compared to both placebo and tolterodine 4 mg. Treatment with both solifenacin and tolterodine was more costly compared to placebo, but treatment with solifenacin was a less costly alternative compared to tolterodine 4 mg SR. Sensitivity analyses revealed that the conclusions were robust., Conclusion: Solifenacin flexible dosing was a cost-effective treatment alternative compared to tolterodine 4 mg SR.

The objective of our study was to determine the QTc effects of tolterodine. A crossover-design thorough QT study of recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo was performed. Electrocardiograms (ECGs) and pharmacokinetic samples were obtained on days 1-4; time-matched baseline ECGs were taken on day 0. Mean placebo-subtracted change from baseline Fridericia-corrected QT (QTcF) during peak drug exposure on day 4 was the primary end point. Mean QTcF prolongation of moxifloxacin was 8.9 ms (machine-read) and 19.3 ms (manual-read). At recommended and supratherapeutic tolterodine doses, mean QTcF prolongation was 1.2 and 5.6 ms (machine-read), respectively, and 5.0 and 11.8 ms (manual-read), respectively. The QTc effect of tolterodine was lower than moxifloxacin. No subject receiving tolterodine exceeded the clinically relevant thresholds of 500 ms absolute QTc or 60 ms change from baseline. In conclusion, tolterodine does not have a clinically significant effect on QT interval.

We present the case of an 80-year-old lady known to be sensitive to chlorocresol (4-chloro-3-methyl phenol) who developed severe erythrodermic exfoliative dermatitis with atypical features 2 weeks after commencing subcutaneous insulin. All medications except insulin were stopped, without major improvement. It was noted that the insulin contained m-cresol (m-methyl phenol) so a parabens-based insulin was substituted. There was a significant improvement in her clinical condition within 72 hr. Further patch and intradermal testing to the insulin and m-cresol was planned, but she developed a nosocomial infection and died. We hypothesize that the adverse cutaneous reaction was a systemic manifestation of cresol sensitivity, given the rapid clinical resolution on changing insulins and the previously demonstrated sensitivity to chlorocresol, particularly as cross-reactivity between different low molecular weight methyl phenols is documented. Local injection site reactions and systemic side-effects including nausea, diarrhoea and vomiting have previously been reported with cresol-containing insulins, although to our knowledge, this is the first reported case of a severe cutaneous reaction. It is important to be aware of m-cresol as a potential allergen, as it is contained in most commercially available insulins.

This study assessed the effect of the proton pump inhibitor omeprazole on the bioavailability of the extended-release formulations of oxybutynin and tolterodine. Forty-four healthy volunteers received each of 4 treatments in a 4-period crossover design. The treatments consisted of osmotically controlled extended-release oxybutynin chloride tablets at 10 mg/d or extended-release tolterodine tartrate capsules at 4 mg/d, with and without preceding treatment with 20 mg omeprazole daily for 4 days. Blood samples collected predose and at scheduled time points for 36 hours postdose were analyzed for oxybutynin and its active metabolite, N-desethyloxybutynin, or tolterodine and its active 5-hydroxymethyl metabolite, as appropriate. The AUCinfinity ratios for oxybutynin and its metabolite with and without prior omeprazole fell within the 80% to 125% range (accepted as the criterion for bioequivalence), as did those for tolterodine and its active moiety. The peak concentration ratios for oxybutynin and metabolite also conformed to this range; those for tolterodine did not. Increasing gastric pH with omeprazole does not substantially alter the pharmacokinetic properties of extended-release oxybutynin but may alter those of extended-release tolterodine.

Clinicians often encounter patients with dementia and urge incontinence who might benefit from both an anticholinergic medication and a cholinesterase inhibitor. At first glance, this combination would seem to violate basic principles of geriatric pharmacology, as the drugs appear to be working at cross-purposes and anticholinergic medications are notorious for worsening cognitive function in susceptible patients. A case is presented and discussed in which this combination was clinically effective and pharmacologically sound.

Chlorocresol is a biocide with widespread use in industry and pharmaceutical products. It is an occasional human contact sensitizer. The sensitizing potential of chlorocresol was judged strong using the guinea pig maximization test (GPMT) and doubtful in the less sensitive open epicutaneous test (OET). When different induction concentrations were used, the results indicated an optimal sensitizing concentration above which no further increase in the sensitization rate occurred. Rechallenge 2 weeks later showed a marked decrease in sensitivity. Consecutive human patch tests with chlorocresol 2% in pet. showed 11 reactions among 1462 patients tested, but none were explainable and reproducible during re-tests and provocative use tests, indicating that the GPMT overestimated the sensitization potential. The results from guinea pig allergy tests cannot stand alone but have to be validated by other sources of information.

A patient with contact dermatitis from nickel and cobalt developed sensitivity to chlorocresol contained in topical steroid creams. The use of chlorocresol in aqueous creams and topical steroids is reviewed.

1 The effects of tolamolol on haemodynamics and myocardial contractility were investigated in two groups of six patients undergoing diagnostic cardiac catheterization.2 The intravenous administration of tolamolol (0.15 mg/kg) produced a significant fall in heart rate from a control value (87 +/- 7 to 62 +/- 3 beats/min) 5 min after administration and a concomitant fall in cardiac output from 4.7 +/- 0.9 to 3.5 +/- 0.8 litres/minute. There was no significant change in systemic blood pressure, pulmonary artery blood pressure or stroke volume.3 There was no change in left ventricular end diastolic pressure after tolamolol. There was a fall in the maximum rate of rise of the left ventricular pressure (LV dp/dt(max)) and the derived index of the left ventricular contractile state (V(max)).4 These results suggest that tolamolol has a predominantly negative chronotropic but also a lesser negative inotropic action on the heart.