Tim Schneider

Does gender or age affect the efficacy and safety of tolterodine

PURPOSE We compared the importance of patient age and gender relative to the intensity of baseline symptoms of overactive bladder in the therapeutic response to the muscarinic receptor antagonist tolterodine. MATERIALS AND METHODS Data from an open label, observational study of 2,250 patients with overactive bladder treated for 12 weeks with tolterodine were analyzed for alterations in frequency, urgency and urge incontinence, and for global efficacy and tolerability using logistic regression analysis, stratifying for gender, age, baseline symptom intensity and tolterodine dose. RESULTS Gender or tolterodine dose were not consistently associated with altered treatment efficacy. Greater age was associated with a slight but statistically significant decrease in treatment efficacy. Patients with great baseline symptom intensity had greater treatment associated improvement but a lesser chance to become symptom-free. Even with a large number of patients no statistically significant gender or age associated alterations in the tolerability of tolterodine treatment were detected. CONCLUSIONS The extent of the therapeutic response to tolterodine is largely determined by the extent of baseline symptoms. While gender does not affect the efficacy or tolerability of tolterodine in a clinically relevant manner, advanced age is associated with a slight decrease in efficacy but not in tolerability.

Solifenacin Plus Tamsulosin Combination Treatment in Men With Lower Urinary Tract Symptoms and Bladder Outlet Obstruction: A Randomized Controlled Trial

BACKGROUND Alpha blockers are prescribed to manage lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Antimuscarinics are prescribed to treat overactive bladder (OAB). OBJECTIVE To investigate the safety of a combination of solifenacin (SOLI) and tamsulosin oral controlled absorption system (TOCAS) in men with LUTS and bladder outlet obstruction (BOO). DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, parallel-group, placebo-controlled study in men aged >45 yr with LUTS and BOO for ≥3 mo, total International Prostate Symptom Score (IPSS) ≥8, BOO index ≥20, maximum urinary flow rate (Q(max)) ≤12 ml/s, and voided volume ≥120 ml. INTERVENTIONS Once-daily coadministration of TOCAS 0.4 mg plus SOLI 6 mg, TOCAS 0.4 mg plus SOLI 9 mg, or placebo for 12 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary (safety) measurements: Q(max) and detrusor pressure at Q(max) (P(det)Q(max)). Other safety assessments included postvoid residual (PVR) volume. Secondary end points included bladder contractile index (BCI) score and percent bladder voiding efficiency (BVE). An analysis of covariance model compared each TOCAS plus SOLI combination with placebo. RESULTS AND LIMITATIONS Both active treatment groups were noninferior to placebo at end of treatment (EOT) for P(det)Q(max) and Q(max). Mean change from baseline PVR was significantly higher at all time points for TOCAS 0.4 mg plus SOLI 6 mg, and at weeks 2, 12, and EOT for TOCAS 0.4 mg plus SOLI 9 mg versus placebo. Both treatment groups were similar to placebo for BCI and BVE. Urinary retention was seen in only one patient receiving TOCAS 0.4 mg plus SOLI 6 mg. Limitations of the study were that prostate size and prostate-specific antigen level were not measured. CONCLUSIONS TOCAS 0.4 mg plus SOLI 6 mg or 9 mg was noninferior to placebo at EOT for P(det)Q(max) and Q(max) in men with LUTS and BOO, and there was no clinical or statistical evidence of increased risk of urinary retention.

Functional investigation of β-adrenoceptors in human isolated detrusor focusing on the novel selective β3-adrenoceptor agonist KUC-7322

This study aimed to characterize the β-adrenoceptor (β-AR) subtype mediating relaxation of isolated human bladder strips and to explore relaxation by the novel β3-AR-selective agonist KUC-7322 for its relaxant effect on the human isolated detrusor and for its effect on the carbachol (CCh)-induced contractile response. In two parallel studies, relaxation of isolated human bladder strips was tested for the β-AR agonists isoproterenol, clenbuterol, BRL 37344, and KUC-7322. For the isoproterenol and KUC-7322 responses, antagonism by CGP 20712A, ICI 118551, and SR59230A was determined. The potency and efficacy of the reference agonists for detrusor relaxation was in line with their known β3-AR activity. KUC-7322 relative to isoproterenol was a full agonist with a pEC50 of 5.95 ± 0.09 and 5.92 ± 0.11 in the two studies. SR59230A exhibited antagonism of the expected potency against isoproterenol (apparent pKB 7.2) but not against KUC-7322. Neither isoproterenol nor KUC-7322 nor forskolin significantly attenuated CCh-induced contraction. These results suggest that KUC-7322 displays full agonistic activity in relaxing the human detrusor without inhibiting the contraction induced by cholinergic stimulation. These characteristics, if proven in vivo, may be beneficial for the treatment of overactive bladder, as increased bladder capacity with a negligible effect on voiding contractions may be anticipated.

Lack of evidence that nebivolol is a β3-adrenoceptor agonist

Nebivolol is a selective β₁-adrenoceptor antagonist which, in addition, displays endothelium-dependent vasodilating properties in humans and other species. β₃-adrenoceptors have been proposed to be a molecular target of nebivolol-induced vasodilatation. Therefore, we have investigated possible β₃-adrenoceptor agonism by nebivolol for relaxation of the human and rat urinary bladder (prototypical β₃-adrenoceptor-mediated responses) as well as for cAMP accumulation in Chinese hamster ovary cells stably transfected with the human β-adrenoceptor subtypes. Nebivolol concentration-dependently relaxed both human and rat isolated urinary bladder strips but with low potency, similar to that reported for vasodilatation. However, nebivolol-induced bladder relaxation in either species was not inhibited by the β₃-adrenoceptor antagonist SR 59,230A (10μM), although this compound inhibited the isoprenaline-induced relaxation with the expected potency. In radioligand binding studies nebivolol had lower affinity for human β₃-adrenoceptors than the other two β-adrenoceptor subtypes, but this low affinity was in line with its potency to relax the bladder or isolated blood vessels. In functional studies nebivolol even in high concentrations did not stimulate cAMP formation via any of the three cloned human β-adrenoceptors or in rat bladder smooth muscle cells. Taken together these data demonstrate that nebivolol can relax not only vascular but also urinary bladder smooth muscle. However, they do not support the hypothesis that nebivolol is an agonist at cloned human β₃-adrenoceptors or in rat or human urinary bladder.

Human urinary bladder strip relaxation by the β-adrenoceptor agonist isoprenaline: methodological considerations and effects of gender and age

The present study was primarily designed to explore various methodological aspects related to organ bath experiments evaluating human detrusor relaxation by the β-adrenoceptor agonist isoprenaline. Data are based upon a series of 30 consecutive patients, and this cohort was also used to explore possible effects of gender and age. KCl-induced contraction was related to strip length but not weight or cross-sectional area, indicating that the former is most suitable for data normalization. Storage of detrusor strips in cold buffer for up to 2 days did not affect contractile responses to KCl or efficacy of isoprenaline to cause relaxation but significantly affected the isoprenaline potency. No such alterations were observed with up to 1 day of cold storage. The type (KCl vs. passive tension) or strength of contractile stimulus had only minor effects on isoprenaline responses although these differences reached statistical significance in some cases. Similarly, gender and age had only minor if any effects on KCl-induced contraction or isoprenaline-induced relaxation, but the current data are too limited for robust conclusions. In summary we have evaluated experimental conditions for the testing of human detrusor strip contraction and relaxation which should be useful for future larger studies.

Can [125I]-Iodocyanopindolol Label β3-Adrenoceptors in Rat Urinary Bladder?

β3-Adrenoceptors have been demonstrated to mediate urinary bladder smooth muscle relaxation but proof of their expression at the protein level has been missing because of lack of suitable antibodies or radioligands. As among various available radioligands [125I]-iodocyanopindolol ([125I]-ICYP) exhibited the smallest problems in labeling cloned human β3-adrenoceptors in previous studies, we have explored its suitability to label β3-adrenoceptors in rat urinary bladder in saturation and competition radioligand binding experiments. Rat lung was used as an internal control and exhibited all characteristics expected from this tissue with regard to β1/β2-adrenoceptor labeling. Saturation and competition binding studies with [125I]-ICYP in rat bladder yielded saturable binding sites with an affinity compatible with β3-adrenoceptors. In competition experiments various agonists and antagonists largely exhibited a profile compatible with a population consisting largely of β3-adrenoceptors. However, the binding competition properties of ICI 118,551 and SR 59,230A were not easily explained by the idea of labeling a homogeneous β3-adrenoceptor population but interpretation of the data was limited by a high degree of non-specific binding in [125I]-ICYP concentrations required to label the receptors. We conclude that [125I]-ICYP can be used to label tissue β3-adrenoceptors but results obtained with this ligand have to be interpreted with caution.