Pharmacologic management of overactive bladder

Overactive bladder (OAB) is a prevalent and costly condition that can affect any age group. Typical symptoms include urinary urgency, frequency, incontinence and nocturia. OAB occurs as a result of abnormal contractions of the bladder detrusor muscle caused by the stimulation of certain muscarinic receptors. Therefore, antimuscarinic agents have long been considered the mainstay of pharmacologic treatment for OAB. Currently, there are five such agents approved for the management of OAB in the United States: oxybutynin, tolterodine, trospium, solifenacin and darifenacin. This article summarizes the efficacy, contraindications, precautions, dosing and common side effects of these agents. All available clinical trials on trospium, solifenacin and darifenacin were reviewed to determine its place in therapy.     

Antimuscarinic effect of tiquizium bromide in vitro and in vivo

Objective: We studied the bronchodilatory effect of tiquizium bromide [3-(di-2-thienylmethylene)-5-methyl-trans-quinolizidinium bromide; TQZ], an antimuscarinic agent, on airway smooth muscle in vitro, and also in patients with chronic obstructive pulmonary disease (COPD). Methods: In the first experiment, canine tracheal smooth muscle was used to measure the pA2 of TQZ in vitro. The selectivity of TQZ for muscarinic receptor subtypes was also examined with a radioligand binding assay. Results: The pA2 value of TQZ was 8.75. The pK _i values of TQZ for M1, M2, and M3 were 8.70, 8.94, and 9.11, respectively. In an open pilot experiment, the effects of TQZ inhalation were studied in seven patients with COPD (seven men, mean age 68.5 years). TQZ significantly increased forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV₁) in a dose-dependent manner. The mean maximum increases in FVC and FEV₁ caused by inhaled TQZ (2.0 mg) were 24% and 29%, respectively, and they were measured 1 h after the drug had been inhaled. The FVC and FEV₁ were still significantly higher than the control values even 8 h after the drug had been inhaled. No adverse effects were observed after inhalation of TQZ. Conclusion: These data suggest that TQZ is an effective antimuscarinic agent, and that it causes significant bronchodilation in patients with COPD. Received: 3 April 1995/Accepted in revised form: 27 November 1995     

Antimuscarinic Effects of (R)- and (S)-Oxyphencyclimine Hydrochloride

The (R)-( + )- and (S)-( – )-enantiomers of the anticholinergic compound, oxyphencyclimine, were synthesized from (R)-( – )- and (S)-( + )-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid, respectively. The potencies of the enantiomers were compared using a cholinergic receptor binding assay. The (R)-( + )-enantiomer inhibited binding 29 times more potently than the (S)-( – )-enantiomer.     

Fistula Secondary to Unoperated Benign Gastroduodenal Ulcer

The physician must be prepared to recognize bizarre fistulas complicating benign gastroduodenal ulcer and occurring without previous gastric surgery. A benign, often subclinical ulcer crater may suddenly perforate any hollow structure in the upper abdomen or lower chest. The consequences may be remarkably benign or immediately calamitous, depending on the anatomy of the resulting fistula.     

Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

AIMS

To confirm the lack of an interaction of fesoterodine 8 mg with warfarin pharmacokinetics and pharmacodynamics in healthy adults.

METHODS

In this open-label, two-treatment, crossover study, subjects (n = 14) aged 20–41 years with normal prothrombin time (PT) and International Normalized Ratio (INR) were randomized to receive a single dose of warfarin 25 mg alone in one period and fesoterodine 8 mg once daily on days 1–9 with a single dose of warfarin 25 mg co-administered on day 3 in the other period. There was a 10-day washout between treatments. Pharmacokinetic endpoints were area under the plasma concentration–time curve from time 0 to infinity (AUC(0,∞)), maximum plasma concentration (C_max), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to C_max (t_max), and half-life (t_1/2) for S- and R-warfarin. Pharmacodynamic endpoints were area under the INR-time curve (AUC_INR), maximum INR (INR_max), area under the PT-time curve (AUC_PT) and maximum PT (PT_max).

RESULTS

Across all pharmacokinetic and pharmacodynamic comparisons, the point estimates of treatment ratio (warfarin co-administered with fesoterodine vs. warfarin alone) were 92–100%. The 90% confidence intervals for the ratios of the adjusted geometric means were contained within (80%, 125%). There were no clinically relevant changes in laboratory tests, vital signs or ECG recordings.

CONCLUSIONS

The pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg. Concomitant administration of fesoterodine and warfarin was well tolerated.     

Comparison of fesoterodine and tolterodine in patients with overactive bladder

OBJECTIVE

To compare, in a post hoc analysis of a phase III trial, the maximum recommended doses of fesoterodine (8 mg) and tolterodine (4 mg) for improving overactive bladder (OAB) symptoms and health‐related quality of life (HRQoL), as fesoterodine effectively reduces OAB symptoms vs placebo.

PATIENTS AND METHODS

Eligible patients with frequency (≥eight voids/24 h) and either urgency (≥six episodes over 3 days) or urgency urinary incontinence (UUI; ≥three episodes over 3 days) were randomized to placebo, fesoterodine 4 or 8 mg, or tolterodine extended‐release (ER) 4 mg for 12 weeks; fesoterodine 4 mg data were published elsewhere. Patients completed a 3‐day bladder diary in which they recorded the time of each void, voided volume (VV), and the severity of urgency. A post hoc inferential analysis was conducted on the primary endpoint (voids/24 h), the two co‐primary endpoints (UUI episodes/24 h and treatment response), several secondary endpoints (severe urgency plus UUI per 24 h, mean VV (MVV)/void, and continent days/week), HRQoL, using the King’s Health Questionnaire (KHQ) and the International Consultation on Incontinence Questionnaire‐Short Form (ICIQ‐SF), and self‐reported bladder‐related problems. A subanalysis also assessed all endpoints for patients who were incontinent at baseline. Tolerability and safety were assessed by evaluating adverse events, residual urine volume, laboratory variables and treatment withdrawals.

RESULTS

By week 12, patients with OAB in both active‐treatment groups showed significant improvements in most bladder diary variables and treatment response rates compared with placebo. Fesoterodine 8 mg was statistically significantly better than tolterodine ER 4 mg for improving UUI episodes, severe urgency plus UUI, mean VV, and number of continent days/week. In addition, the fesoterodine and tolterodine ER groups showed significantly greater improvements in HRQoL than the placebo group, with positive changes in most domains of the KHQ and an improvement in ICIQ‐SF score. The fesoterodine 8‐mg group had statistically significant improvements over placebo in eight of nine KHQ domains. A major improvement in the severity of bladder‐related problems was reported by 39% of the fesoterodine 8 mg and 34% of the tolterodine ER groups vs 25% of those on placebo (P ≤ 0.01). Results for the subgroup of incontinent patients at baseline were similar to the overall results. Adverse events reported most commonly with active treatment included dry mouth, constipation, dry eye, dry throat, and nausea.

CONCLUSIONS

Both fesoterodine and tolterodine ER significantly improved OAB symptoms and HRQoL, with statistically significant advantages for fesoterodine 8 mg compared with tolterodine ER on several important endpoints.