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Objectives Overactive bladder syndrome (OAB) is a urinary condition that often exerts detrimental effects on an individual's quality of life (QoL). A once-daily, extended-release (ER) formulation of the quaternary amine trospium chloride has recently been developed for the treatment of OAB. The pooled health-related QoL (HRQoL) data from two multicenter, parallel-group, double-blind Phase III studies with trospium chloride ER 60 mg were analyzed. Methods Subjects aged ≥18 years with urinary urgency, frequency, and an average of ≥1 urge urinary incontinence episode per day on a 3-day bladder diary were randomized (1:1) to receive once-daily trospium 60 mg ER or placebo for 12 weeks. HRQoL was assessed at baseline and at Week 12 using the King's Health Questionnaire (KHQ) and the OAB questionnaire (OAB-q). Results Overall, 1165 subjects were randomized (trospium ER, n=578; placebo, n=587). Trospium ER produced significantly greater improvements from baseline than placebo in seven of the nine KHQ domains. At Week 12, the improvement in mean OAB-q HRQoL total score (from approximately 52 at baseline) was significantly greater with trospium ER than with placebo (+25.8 vs. +20.7; P = 0.0003). Improvements from baseline were seen with trospium ER on all eight of the OAB-q symptom bother scales. Conclusions Once-daily trospium 60 mg ER improved the QoL of subjects with OAB, as assessed using the KHQ and the OAB-q, in two large Phase III clinical trials.

Summary Background: Trospium chloride is an antimuscarinic agent with a hydrophilic polar quaternary amine structure that is minimally metabolised by hepatic cytochrome P450 and is actively excreted in the urine, each of which confers a potential benefit with regard to efficacy and tolerability. Purpose: We analysed pooled data from two identically designed phase III trials of a once-daily, extended-release (XR) formulation of trospium chloride (trospium XR 60-mg capsules) in subjects with overactive bladder syndrome (OAB). Methods: Adults with OAB of ≥ 6 months’ duration with urinary urgency, frequency and ≥ 1 urge urinary incontinence (UUI) episode/day were enrolled in these multicentre, parallel-group, double-blind trials. Participants were randomised (1 : 1) to receive trospium XR 60 mg or placebo for 12 weeks. Primary efficacy variables were changes in urinary frequency and the number of UUI episodes/day. Adverse events (AEs) were recorded throughout. Results: In total, 1165 subjects were randomised (trospium XR, 578; placebo, 587). At baseline, subjects averaged 12.8 toilet voids/day and 4.1 UUI episodes/day. Compared with placebo, subjects treated with trospium XR had significantly greater reductions from baseline in the mean number of toilet voids/day (−1.9 vs. −2.7; p

Cholinesterase inhibitors for the treatment of Alzheimer's Disease (AD) and antimuscarinic agents for the treatment of urge urinary incontinence (UUI) may reduce the potential effect of each other in the patients with both diseases. Trospium has a relatively low lipophilicity and low CNS penetration, and galantamine, a cholinesterase inhibitors, has also allosterically modulates nicotinic cholinergic receptors. This study was designed to evaluate the effects of dual use of trospium and galantamine for 6 months in the elderly patients with AD and UUI.One hundred and seventy eight elderly patients: 99 UUI patients (Group I, treated with trospium), 43 AD patients (Group II, treated with galantamine) and 36 AD and UUI patients (Group III, treated with galantamine and trospium) were evaluated by geriatric assessments, the Global Perception Index (GPI), Patients' Satisfaction Question (PSQ), Estimated Patients' Improvement (EPI), nocturia and pads/day at baseline and in the 6th month.Trospium increased the satisfaction of the patients in Groups I and III according to the EPI, PSQ, GPI, number of nocturia and pads/day. Decreasing in the GDS score was significant in the Group I and III (p0.05). Decreasing in the ADL score was significant in the Group III (p0.05). The MMSE scores were not significantly changed in the all groups during the 6 months.Consequently, we have thought that a combination of trospium and galantamine could be recommended for the management of the elderly patients with UUI and AD, which are common problems in the elderly.

To confirm the efficacy and tolerability of extended release (ER) trospium chloride in women with overactive bladder syndrome (OAB), data from two identical phase III studies were analyzed. Adults (aged ≥ 18 years) who had OAB with urinary urgency, frequency, and urge urinary incontinence (UUI) were randomized to trospium ER 60 mg or placebo once daily for 12 weeks. The analysis included 989 women (trospium ER, n = 484; placebo, n = 505). Endpoints examined included changes from baseline in number of toilet voids and UUI episodes/day at week 12. Continuous data were analyzed using rank analysis of variance. At week 12, significantly greater mean reductions in numbers of toilet voids and UUI episodes/day occurred with trospium ER versus placebo (P

It has been assumed that a patient's underlying baseline overactive bladder (OAB) incontinence severity is predictive of the resulting efficacy of pharmacological treatment. The objective of this study was to stratify and analyse the effects of baseline incontinence disease severity on the treatment outcome of the percentage of patients continent (PPC) during treatment with once-daily trospium chloride 60 mg extended release (XR).A post hoc analysis was conducted on pooled data from two 12-week, randomised, double-blind phase III studies in the USA in which 1165 patients with baseline urgency, and an average ofor= 1 urge urinary incontinence (UUI) episode/day andor= 10 toilet voids/day on a 3-day bladder diary, received once-daily trospium chloride 60 mg XR (n = 578) or placebo (n = 587). Patients were stratified by the mean number of UUIs/day (1.0,1.0-2.0,2.0-5.0 or5.0) at baseline. The efficacy parameter that was analysed was complete continence (defined as no UUIs on a 3-day bladder diary collected at week 12 of treatment).Baseline UUI levels were inversely correlated with the week 12 PPC (p0.0001). Post-treatment PPCs were higher with trospium chloride XR vs. placebo at all degrees of severity. Complete continence was achieved in 75% of trospium chloride XR recipients with 1.0 UUI/day at baseline and 48% of those with1.0-2.0 UUIs/day at baseline.These findings support the assumption that baseline incontinence severity affects the likelihood of achieving continence from OAB therapy, and that patients with less severe OAB (e.g. 1 UUI/day) can expect higher 'dry rates' following treatment (e.g. up to 75%) than those with more severe OAB. This information can provide a useful tool for the physician and patient in establishing expectations during therapy.

We assessed the suitability of 4beta-hydroxycholesterol (4betaOH-C) as an endogenous cytochrome P450 3A (CYP3A) phenotyping metric. 4betaOH-C and its ratio to cholesterol (4betaOH-C/C) were determined in five cocktail phenotyping studies, with and without co-medication with a potential CYP3A inhibitor. These parameters were compared with established midazolam-based CYP3A metrics: clearance after intravenous (i.v.) administration (M-Cl) and apparent clearance after oral administration (M-Cl/F), reflecting hepatic and overall activity, respectively. In a common evaluation of periods without co-medication, there was a slight positive correlation of 4betaOH-C and 4betaOH-C/C with midazolam metrics: M-Cl (r = 0.239 and 0.348, respectively) and M-Cl/F (r = 0.267 and 0.353, respectively); P (one-sided) < 0.05. Co-medication with lopinavir/ritonavir caused a strong decrease in midazolam metrics and a mild decrease in cholesterol metrics. However, the intake of propiverine resulted in opposite trends for midazolam-based and cholesterol-based metrics. The information currently available does not justify the use of 4betaOH-C for estimation of basal CYP3A activity. Further studies to address the temporal variations in local CYP3A activity are needed to assess its role as a biomarker during CYP3A inhibition.

Oral doses of Pronethalol and Poldine were given to six subjects as blocking drugs for not less than one week. A hemodynamic study was then repeated 1–3 hours after the last dose. Heart rate, intra-arterial pressures, right atrial pressure, cardiac output, pulmonary ventilation, oxygen consumption and respiratory exchange ratio were measured with the subject at rest, in a recumbent and a sitting position, and during exercise sitting on a bicycle ergometer. The mean values at rest were unchanged during blockade, but the reactions of the variables when the patient was sitting up, were changed for systolic and diastolic pressure, oxygen consumption and arteriovenous oxygen difference. The responses of heart rate and arteriovenous oxygen difference, when the subjects changed from the recumbent to the seated position, had lower variabilities during treatment. The left ventricular work and stroke work in the seated position had also lower variabilities during treatment than before. During exercise, the mean values for heart rate, arterial pressures, pulmonary ventilation and oxygen consumption were lower during blockade. The variabilities of cardiac output, stroke volume, left ventricular work and stroke work and arteriovenous oxygen difference were also lower. The changes in mean values from rest to exercise were reduced, during treatment, for heart rate, arterial pressures, left ventricular work, pulmonary ventilation and oxygen consumption; and the variability of reaction during treatment was higher for right atrial pressure, but lower for left ventricular work. Similar studies which were made in each case with Pronethalol and Poldine, respectively, indicated that the present blockade was essentially additive. Thus, the most obvious effects were produced by Pronethalol, but many of the “orthostatic reactions” were influenced by Poldine. The exercise adaptation was well maintained during the present autonomic blockade.

The aim of the present study was to characterize the role of the drug-efflux transporter P-glycoprotein (P-gp) for the disposition of trospium chloride, a widely used anticholinergic drug for the treatment of overactive bladder. P-gp-deficient mdr1a,b(-/-) knockout mice were given either 1 mg/kg trospium chloride orally or 1 mg/kg intravenously to analyze brain penetration, intestinal secretion, and hepatobiliary excretion of the drug. The concentrations of trospium chloride in the brain were up to 7 times higher in the mdr1a,b(-/-) knockout mice compared with wild-type mice (p < 0.05), making P-gp a limiting factor for the blood-brain barrier penetration of this drug. Moreover, the residence time of the drug in the central nervous system was significantly prolonged in mdr1a,b(-/-) knockout mice. Apart from the blood-brain barrier, P-gp also had significant effects on the overall pharmacokinetics of trospium chloride. In the mdr1a,b(-/-) knockout mice, hepatobiliary excretion and intestinal secretion were significantly reduced compared with the wild-type mice. Our study indicates that the multidrug resistance transporter P-gp is a major determinant for the distribution of trospium chloride in the body and highly restricts its entry into the brain.

The uptake of 3H-piribenzil (2-hydroxymethyl)-1,1-dimethylpiperidinium (-3H) benzilate, an anticholinergic agent, into rat liver slices was found to be concentration and time dependent. At a medium concentration of 10−5 M the slice to medium (S/M) ratio was about 4 after 60 minutes incubation. The uptake was decreased by metabolic inhibitors (iodoacetic acid and 2,4-dinitrophenol) and by incubation in N2-atmosphere. Structurally similar compounds (cations) also decreased the uptake of piribenzil but organic anions did not influence the uptake process. Chromatographic studies revealed unchanged piribenzil in the slices. Binding of piribenzil to liver homogenate occurred. Moreover efflux of piribenzil from liver slices was decreased by iodoacetic acid. These in vitro experiments may reflect processes responsible for the biliary excretion of organic cations.

The biliary excretion of some isotopically labelled quaternary ammonium compounds and tertiary amines have been studied in rats after intravenous administration. The elimination of radioactivity into the bile was followed 4–6 hours. The amount of radioactivity eliminated ranged from 0.0–54% of the given doses of activity. Chromatographic studies indicated that only a small fraction of the activity eliminated into the bile was attributable to the original compound in most of the cases in which extensive excretion of radioactivity was noted. Metabolites were formed which seemed to be more polar than the original compounds. Molecular properties for biliary excretion are discussed.

Background Until now no confirmatory clinical trial in children suffering from nonneurogenic overactive bladder (OAB) and urinary incontinence could demonstrate superiority for antimuscarinics over placebo. Objectives The following study was conducted to prove efficacy and tolerability of propiverine compared to placebo. Design, Setting, and Participants A randomized, double-blind, placebo-controlled phase 3 trial with parallel-group design in children aged 5–10 yr was performed. Prior to the 8-wk medical therapy urologic baseline diagnostics, a 3-wk lifestyle advice (urotherapy) was established. Intervention After re-evaluation of in- and exclusion criteria and uroflowmetry, only children fulfilling the requested criteria were allocated to a body-weight-adjusted therapy (10 or 15mg propiverine twice daily or corresponding placebo). Measurements Efficacy parameters derived from bladder diary and a micturition volume protocol. Decrease in voiding frequency per day was chosen as primary efficacy parameter; secondary endpoints included voided volume and incontinence episodes. A safety assessment was conducted. Results and Limitations Of 171 randomized children, 87 were treated with propiverine and 84 with placebo. The primary efficacy parameter showed a decrease in voiding frequency (−2.0 episodes for propiverine versus −1.2 for placebo; p =0.0007). Superiority could also be demonstrated for voided volume (31.4 vs. 5.1ml; p p =0.0005). The trial design did not allow for separate evaluation of the effect of urotherapy prior to medical treatment. Propiverine was well-tolerated in children. Altogether 23% of side-effects were reported for propiverine and 20% for placebo. Conclusions This clinical trial showed superior efficacy of propiverine over placebo and good tolerability for the treatment of children suffering from OAB and urinary incontinence. An important additional factor for the success of the trial was a modified trial design with previous urotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT00603343.

Objective: To review the pharmacology, pharmacokinetics, safety, and clinical application of trospium chloride for the management of overactive bladder (OAB). Data Sources: Clinical literature including both primary sources and review articles was accessed through MEDLINE, International Pharmaceutical Abstracts, and Cochrane databases from 1980 through January 8, 2009. Search terms included overactive bladder, urge urinary incontinence, muscarinic receptor antagonists, and urinary frequency. Further data sources were identified from bibliographies of selected articles. Study Selection and Data Extraction: Basic pharmacology data were extracted from animal studies and pharmacokinetic data were gathered from human studies. Multicenter, parallel, randomized, double-blind, placebo-controlled studies were included to describe the efficacy and adverse effects of trospium. Data Synthesis: Trospium chloride is an antimuscarinic agent indicated for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency. Trospium has 3 chemical and pharmacokinetic properties unique among antimuscarinic agents: it is a positively charged quaternary ammonium compound with minimal central nervous system penetration; it is not metabolized by the cytochrome P450 system, resulting in a lower tendency for drug interactions; and it is excreted mainly unchanged in the urine as the active parent compound, providing local activity to achieve early onset of clinical effect and prolonged efficacy. In two 12-week, randomized, placebo-controlled clinical studies in adults with OAB, trospium 20 mg twice daily was more effective than placebo in reducing the number of micturitions per 24 hours, reducing the number of urge incontinence episodes per week, and increasing the volume of urine voided per micturition. Placebo-controlled trials report efficacy with trospium in treatment of OAB; comparative trials with other anticholinergic agents are limited. Current therapy of OAB consists primarily of anticholinergic drugs such as oxybutynin, which are associated with therapy-limiting adverse effects. Because the prevalence of OAB is greatest among the elderly, safety considerations regarding renal function must be noted, with dosage adjustment required in patients with severe renal impairment. Conclusions: Whether the pharmacodynamic properties of trospium make it superior to other therapies will require considerable additional experience with the drug. For now, it appears to be a feasible alternative for patients who cannot tolerate oxybutynin.

We investigated whether the improvement of lower urinary tract symptoms (LUTS) and urinary adenosine triphosphate (ATP) level were related. Fifty-seven patients and 13 normal controls were enrolled in this study. All of the male patients had benign prostatic hyperplasia (BPH), and all of the female patients had overactive bladder (OAB). We administered an alpha-1 adrenergic receptor antagonist (tamsulosin hydrochloride) for BPH, while OAB patients received an anti-muscarinic agent (propiverine hydrochloride). Before and after treatment, we examined LUTS and urinary ATP/creatinine ratio. The urinary ATP/creatinine ratio was lower in males than females in both controls and patients. In the BPH patients, administration of the alpha-1 receptor antagonist decreased LUTS and urinary ATP/creatinine ratio, and improvement of LUTS was greater in patients with a high baseline urinary ATP level. In the OAB patients, administration of the anti-muscarinic agent decreased LUTS and urinary ATP/creatinine ratio, and improvement of LUTS was greater in patients with a high baseline urinary ATP level. Improvement of LUTS by treatment with the alpha-1 receptor antagonist or the anti-muscarinic agent was related to the decrease of urinary ATP/creatinine ratio in patients with BPH or OAB. Measurement of urinary ATP can be used as a marker of pathologic bladder function.

To assess the efficacy and safety of propiverine hydrochloride (antimuscarinic), naftopidil (alpha(1)-adrenoceptor antagonist) or both in patients with male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia and concomitant overactive bladder (OAB).Men aged at least 50 years who had a total International Prostate Symptom Score (IPSS) of 8 or higher and bladder dairy documenting micturition frequency (more than eight micturitions/24 h) and urgency (more than one episode/24 h), with or without urgency urinary incontinence were randomized into three groups: group N, naftopidil (50 mg once daily) only; group P, propiverine hydrochloride (20 mg once daily); and group NP, naftopidil (50 mg once daily) plus propiverine hydrochloride (20 mg once daily) for a 4-week treatment regimen.A total of 66 men, including 20 in group N, 23 in group P and 23 in group NP, were treated and 58 (87.9%) completed the 4 weeks of treatment. IPSS improved significantly in groups N and NP. Urinary frequency improved significantly in groups P and NP. Postvoid residual urine volume increased significantly in groups P and NP. Significant improvements in urgency episodes were noted in each group. One patient in group P required catheterization owing to acute urinary retention and another stopped medication because of difficulty in voiding.These results suggest that each treatment showed effectiveness for male LUTS with OAB. However, there are some possibilities of adverse effects with propiverine hydrochloride monotherapy.

This paper reports for the first time the development of an immunoassay for the analysis of the miticide bromopropylate (BP). The chemical structure of the immunizing haptens was designed to maximize the recognition of the bis-bromophenyl group of BP. Thus, the assay uses polyclonal antibodies raised against 2,2-bis(4-bromophenyl)-N-2-hydroxyacetamide-butanoic acid (hapten 2) conjugated to keyhole limpet hemocyanin from horseshoe crab. A heterologous indirect competitive enzyme-linked immunosorbent assay (ELISA) has been developed that can detect BP down to 0.14 microg L(-1). The assay has been proven to tolerate a wide range of ionic strengths and pH values. Studies on the selectivity of this immunoassay have demonstrated a high recognition of related pesticides that contain a bis-halophenyl group in their structure. Other pesticides do not interfere in the analysis of BP using this immunochemical technique. Preliminary experiments have shown that BP can be directly analyzed in white wine samples down to 0.16 microg L(-1) without the necessity of a cleanup procedure prior to the ELISA.

Male and female F344 rats but not B6C3F1 mice exposed for 104 weeks to propiverine hydrochloride (1-methylpiperid-4-yl 2,2-diphenyl-2-(1-propoxy)acetate hydrochloride), used for treatment of patients with neurogenic detrusor overactivity (NDO) and overactive bladder (OAB), presented with an accumulation of proteins in the cytosol and nuclei of renal proximal tubule epithelial cells, yet despite this, no increased renal tumor incidence was observed. In order to provide an improved interpretation of these findings and a better basis for human health risk assessment, male and female F344 rats were exposed for 16 weeks to 1000 ppm propiverine in the diet, the accumulating protein was isolated from the kidneys via cytosolic and nuclear preparations or laser-capture microdissection and analyzed using molecular weight determination and mass spectrometry. The accumulating protein was found to be d-amino acid oxidase (DAAO), an enzyme involved in amino and fatty acid metabolism. Subsequent reanalysis of kidney homogenate and nuclear samples as well as tissue sections using western blot and DAAO-immunohistochemistry, confirmed the presence and localization of DAAO in propiverine-treated male and female F344 rats. The accumulation of DAAO only in rats, and the limited similarity of rat DAAO with other species, including humans, suggests a rat-specific mechanism underlying the drug-induced renal DAAO accumulation with little relevance for patients chronically treated with propiverine.

The superacid-promoted reactions of alpha-hydroxy and alpha-ketoamides have been studied. Ionization of these compounds leads to varied aryl-substituted oxyindole products. In some cases, electrocyclization can lead to substituted fluorene products. Dicationic, superelectrophilic intermediates are proposed as intermediates leading to the products from alpha-hydroxy and alpha-ketoamides.

The muscarine receptor antagonist propiverine in immediate release tablet form (IR) undergoes presystemic elimination mediated by CYP450 enzymes and intestinal efflux transporters. The aim of our study with propiverine IR and extended release (ER) was to determine whether propiverine disposition is dose linear, to compare the pharmacokinetics of propiverine in oral solution with IR and ER and to show how absorption rate is associated with bioavailability.The pharmacokinetics of propiverine administered as intravenous propiverine (15 mg), 10, 15, and 30 mg propiverine IR, an oral propiverine solution (15 mg) and 10, 15, 30, and 45 mg propiverine ER were measured in two randomized, controlled, single-dose, five-period, cross-over studies, with each case involving a study cohort of ten healthy Caucasian subjects.Disposition of propiverine IR and ER was not dose-related. The bioavailability of ER was 64.5 +/- 16.1% compared to 50.3 +/- 13.4% (non-significant) after administration of the IR and propiverine solution (42.6 +/- 14.8%, p0.05). The mean absorption time (MAT) of ER (14.2 +/- 4.79 h) was significantly longer than that of the solution and IR (3.94 +/- 4.14 and 0.38 +/- 3.79 h, respectively; both p0.05). The bioavailability of propiverine was significantly correlated to the MAT (r = 0.521, p0.001). Renal excretion of the metabolite M-23 after propiverine ER administration (6.7 +/- 2.7%) was significantly lower than that after administration of the oral solution (10 +/- 2.2%) and of IR (9.8 +/- 2.7%; both p0.05).The bioavailability of propiverine appears to be dependent on the intestinal site of dissolution and, consequently, on the extent of presystemic intestinal elimination.

A liquid chromatography–tandem mass spectrometric (LC–MS–MS) method was developed for the determination of the neurotropic–musculotropic spasmolytic agent denaverine and five of its metabolites in urine. In a first step β-glucuronidase was used to cleave glucuronides in the human urine. After that samples containing denaverine and its phase I metabolites were extracted and cleaned up using an automated solid phase extraction method. An external calibration was used. The analytes were measured employing the multiple reaction-monitoring mode (MRM). The linear dynamic range for denaverine and its five metabolites determination was demonstrated from lower limit of quantification (8.0 ng/ml) to at least 500 ng/ml. The presented method is suitable for pharmacokinetic or toxicokinetic studies. With the help of reference substances some additional potential metabolites could be excluded in the urine samples. To look for additional unknown metabolites the LC–MS–MS system operated on one hand in the precursor ion mode using typical product ions of denaverine and of its metabolites and on the other hand in the product ion mode using postulated protonated molecules [ M + H] + . With the help of the chromatographic behaviour and typical fragment ions of the unknown metabolites it was possible to elucidate their structures. Nine until now unknown metabolites were found in the urine samples. However, without reference substances a quantification of these analytes was not possible.

Propiverine extended release is expected to be better tolerated compared to immediate release tablets because of slower drug release and reduced formation of active metabolites in the colon. CYP3A4 and ABCC2, the major variables in pharmacokinetics of propiverine, are less expressed in the colon. Therefore, disposition and pharmacodynamics of propiverine were measured in a double-blind, double-dummy, crossover study with administration of 15 mg immediate release 3 times daily for 7 days compared to 45 mg extended release once daily for 7 days in 24 healthy subjects. Twelve subjects also received 15 mg propiverine intravenously. Serum and urine propiverine levels were measured repeatedly following oral administration on day 7 for up to 72 hours and correlated to duodenal expression of CYP3A4, ABCB1, and ABCC2. Propiverine immediate release 3 times daily was not different to extended release once daily in areas under the serum concentration-time curve (0-24 hours) and peak-trough fluctuation. The areas under the serum concentration-time curve of propiverine immediate release was circadian-time-dependent, with the lowest values during the night. Disposition of intravenous propiverine and propiverine immediate release administered in the night was influenced by intestinal expression of ABCC2. We concluded that oral absorption of propiverine is site-dependent and influenced by dosage form and circadian-time-dependent elimination processes.

Purpose: The objective of this study was to evaluate the influence of propiverine-HCl (P4) and propiverine-N-oxide (P4NO), one of the major metabolites of P4, on bladder contraction in a standardized in vivo model. Additionally, salivary flow measurements enabled the evaluation of hyposalivation, one of the most predominant anticholinergic side effects. Materials and Methods: Ten male mini pigs were anesthetized. P4 (0.4 mg/kg b.w.) and P4NO (0.422 mg/kg b.w.) were administered intravenously. Bladder contractions were induced through sacral anterior root stimulation and cystometrogram evaluation was performed. For stimulation-induced salivary flow measurements, the lingual nerve was exposed for neurostimulation. The effects of P4 and P4NO on stimulation-induced bladder contraction and salivation were evaluated in 5 mini pigs, respectively. Results: In all experiments, for each animal reproducible intravesical pressure values (Pves) were elicited during sacral anterior root stimulation before administration of the study drug. After administration of P4, Pves decreased by 64% whereas P4NO decreased Pves by 28%. Inhibition of salivary flow with P4 and P4NO was 71 and 32%, respectively. Directly following intravenous administration of P4, a short-term and reversible period of mild fluctuations in heart rate was observed. Administration of P4NO revealed no changes in either heart rate, or blood pressure. Conclusion: All of the investigated parameters revealed less anticholinergic effects for P4NO compared to P4. Under the experimental conditions described above, it may be assumed that P4NO behaves as a substance with poor anticholinergic effects with respect to side effects. As expected, P4 showed anticholinergic effects on bladder contraction and salivation.

Urinary bladder function is known to mature during fetal and postnatal development, including changes in neurotransmitter regulation of detrusor contraction. However, only few experimental data are available about muscarinic receptor antagonist function in the urinary bladder from young animals. In the present study, we compare the muscarinic receptor-mediated contractions in juvenile and adult porcine detrusor and the effects of antimuscarinic compounds. Urinary bladders from young (8–12 weeks; 12- to 35-kg body weight) and mature pigs (>40 weeks; >100 kg) were compared. Muscarinic receptor expression was assessed by real time polymerase chain reaction and radioligand binding. Muscle contraction was measured with a force transducer; L-type Ca2+ currents (I Ca,L) of isolated detrusor myocytes were recorded with standard voltage clamp technique. Juvenile and adult detrusor expressed similar quantities of the messenger RNA of M2 and M3 receptors. The number of [3H]QNB-binding sites and their affinity for the radioligand were also similar between juvenile and adult detrusor. In contrast, maximum contractile responses to the muscarinic receptor agonist carbachol were slightly larger in juvenile than adult bladders. On the other hand, carbachol was slightly less potent in juvenile than in adult tissue. The M3 antagonist DAU 5884 and the spasmolytic drug propiverine inhibited contractile responses with comparable efficacies and potencies in juvenile and adult tissue. I Ca,L was somewhat smaller in juvenile than in adult cells. Taken together, these data suggest that expression and function of M2 and M3 receptors are similar in the detrusor of juvenile and mature pigs. Therefore, similar responses to antimuscarinic compounds could be expected in young and adult patients.

Drugs that prolong the QT interval by blocking human ether-a-go-go (HERG) channels may enhance the risk of ventricular arrhythmia. The spasmolytic drug propiverine is widely used for the therapy of overactive bladder (OAB). Here, we have investigated the effects of propiverine on cardiac ion channels and action potentials as well as on contractile properties of cardiac tissue, in order to estimate its cardiac safety profile, because other drugs used in this indication had to be withdrawn due to safety reasons. Whole-cell patch clamp technique was used to record the following cardiac ion currents: rapidly and slowly activating delayed rectifier K+ current (I(Kr), I(Ks)), ultra rapidly activating delayed rectifier K+ current (I(Kur)), inwardly rectifying K+ current I(K1), transient outward K+ current (I(to)), and L-type Ca2+ current (I(Ca,L)). Action potentials in cardiac tissue biopsies were recorded with conventional microelectrodes. The torsade de pointes screening assay (TDPScreen) was used for drug scoring. Propiverine blocked in a concentration-dependent manner HERG channels expressed in HEK293 cells, as well as native I(Kr) current in ventricular myocytes of guinea pig (IC50 values: 10 microM and 1.8 microM respectively). At high concentrations (100 microM), propiverine suppressed I(Ks). I(K1) and the transient outward current I(to) and I(Kur) were not affected. In guinea-pig ventricular and human atrial myocytes, propiverine also blocked I(Ca,L) (IC50 values: 34.7 microM and 41.7 microM, respectively) and reduced force of contraction. Despite block of I(Kr), action potential duration was not prolonged in guinea-pig and human ventricular tissue, but decreased progressively until excitation failed altogether. Similar effects were observed in dog Purkinje fibers. Propiverine obtained a low score in the TDPScreen. In conclusion, in vitro and in vivo studies of propiverine do not provide evidence for an enhanced cardiovascular safety risk. We propose that lack of torsadogenic risk of propiverine is related to enhancement of repolarization reserve by block of I(Ca,L).

The anticholinergic propiverine (1-methyl-4-piperidyl diphenylpropoxyacetate), which is used for the treatment of overactive bladder syndrome, has functionally active metabolites [M-1 (1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide) and M-2 (1-methyl-4-piperidyl benzilate N-oxide)], but the site of actions of these metabolites is uncertain. Propiverine is rapidly absorbed after oral administration and is extensively biotransformed in the liver, giving rise to several active metabolites (M-1 and M-2). This study determines the effect of M-1 and M-2 on voltage-dependent nifedipine-sensitive inward Ca(2+) currents (I(Ca)) using patch-clamp techniques and fluorescent Ca(2+) imaging [after electrical field stimulation (EFS) and acetylcholine (ACh)] in the murine urinary bladder. In conventional whole-cell recording, propiverine and M-1 but not M-2 inhibited the peak amplitude of I(Ca) in a concentration-dependent manner at a holding potential of -60 mV (propiverine, K(i) = 10 microM; M-1, K(i) = 118 microM). M-1 shifted the steady-state inactivation curve of I(Ca) to the left at -90 mV by 7 mV. Carbachol (CCh) reversibly inhibited I(Ca). This inhibition probably occurred through muscarinic type 3 receptors, coupling with G-proteins, because nanomolar concentrations of 4-diphenylacetoxy-N-methyl-piperidine greatly reduced this inhibition, whereas pirenzepine or 11-([2-[(diethylamino)methyl]-1-piperdinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) at concentrations up to 1 microM was almost ineffective. In the presence of M-2, the CCh-induced inhibition of I(Ca) was blocked. In fluorescent Ca(2+) imaging, M-2 inhibited EFS-induced and ACh-induced Ca(2+) transients. These results suggest that M-1 acts, at least in part, as a Ca(2+) channel antagonist (as it inhibited I(Ca)), whereas M-2 has more direct antimuscarinic actions.

An extended release formulation of trospium chloride was recently developed for the once daily treatment of overactive bladder. We investigated the safety, efficacy and tolerability of 60 mg trospium chloride once daily.Subjects with overactive bladder were randomized 1:1 to receive 60 mg trospium chloride once daily or placebo in this 12-week multicenter, parallel, double-blind, placebo controlled trial. Primary end points were calculated changes in diary recorded daily urinary frequency and daily urgency urinary incontinence episodes. Secondary end points were urgency severity, volume voided per void and the number of urgency voids per day. Safety was assessed by clinical examination, adverse event monitoring, clinical laboratory values and resting electrocardiograms.Overall 601 subjects were prescribed trospium once daily (298) or placebo (303). Trospium once daily treatment resulted in significant improvements over placebo in all primary and key secondary efficacy outcomes at weeks 1 through 12. The most common adverse events were dry mouth (trospium 8.7% vs placebo 3%) and constipation (trospium 9.4% vs placebo 1.3%). Central nervous system adverse events were rare (headache with trospium 1.0% vs placebo 2.6%). No clinically meaningful changes in laboratory, physical examination or electrocardiogram parameters were noted.Trospium once daily provided significant improvements in overactive bladder symptoms (frequency, urgency urinary incontinence and urgency). Efficacy was similar to that seen previously with trospium chloride twice daily, while class effect anticholinergic adverse events occurred at comparatively low levels. Dry mouth was elicited at the lowest reported rate in the oral antimuscarinic drug class.

The present study was undertaken to characterize the binding activities of propiverine and its N-oxide metabolites (1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide: P-4(N--O), 1-methyl-4-piperidyl benzilate N-oxide: DPr-P-4(N--O)) toward L-type calcium channel antagonist receptors in the rat bladder and brain. Propiverine and P-4(N--O) inhibited specific (+)-[(3)H]PN 200-110 binding in the rat bladder in a concentration-dependent manner. Compared with that for propiverine, the K(i) value for P-4(N--O) in the bladder was significantly greater. Scatchard analysis has revealed that propiverine increased significantly K(d) values for bladder (+)-[(3)H]PN 200-110 binding. DPr-P-4(N--O) had little inhibitory effects on the bladder (+)-[(3)H]PN 200-110 binding. Oxybutynin and N-desethyl-oxybutynin (DEOB) also inhibited specific (+)-[(3)H]PN 200-110 binding in the rat bladder. Propiverine, oxybutynin and their metabolites inhibited specific [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) binding in the rat bladder. The ratios of K(i) values for (+)-[(3)H]PN 200-110 to [(3)H]NMS were markedly smaller for propiverine and P-4(N--O) than oxybutynin and DEOB. Propiverine and P-4(N--O) inhibited specific binding of (+)-[(3)H]PN 200-110, [(3)H]diltiazem and [(3)H]verapamil in the rat cerebral cortex in a concentration-dependent manner. The K(i) values of propiverine and P-4(N--O) for [(3)H]diltiazem were significantly smaller than those for (+)-[(3)H]PN 200-110 and [(3)H]verapamil. Further, their K(i) values for [(3)H]verapamil were significantly smaller than those for (+)-[(3)H]PN 200-110. The K(i) values of propiverine for each radioligand in the cerebral cortex were significantly (P0.05) smaller than those of P-4(N--O). In conclusion, the present study has shown that propiverine and P-4(N--O) exert a significant binding activity of L-type calcium channel antagonist receptors in the bladder and these effects may be pharmacologically relevant in the treatment of overactive bladder after oral administration of propiverine.

Purpose The objective was to validate an in vivo model for evaluation of pharmacological effects on bladder function taking the most predominant anticholinergic side effect (hyposalivation) into account. Therefore, two anticholinergic properties (propiverine hydrochloride and tolterodine- l (+)-tartrate) were used to test the in vivo model. Sacral anterior root stimulation (SARS) was performed to induce reproducible and standardized bladder contractions. To evaluate hyposalivation standardised salivavary flow measurements by stimulating the lingual nerve was performed in addition to SARS. Materials and methods 10 male mini pigs were anaesthetised. The carotid artery was cannulated for blood pressure measurement and the jugular vein for administration of propiverine 0.4 mg kg −1 b.w. and tolterodine 0.06 mg kg −1 b.w. For stimulation-induced salivary flow measurements both lingual nerves were exposed and a cuff electrode was placed around the nerves. The bladder was exposed and a cystostomy catheter was inserted to performed cystometrographic measurements during SARS. Results In all experiments, for each animal reproducible intravesical pressure values (pves) and salivary flow rates were elicited during electrostimulation before administration of the drug. Bladder pressure : After administration of propiverine , neurostimulation-induced rise in pves had fallen by 60% from the initial value. After administration of tolterodine pves had fallen by about 50%. After additional administration of atropine pves decreased to about 15% of the initial value for both drugs. Salivation : After propiverine salivary flow had fallen by 61%. Inhibition of salivary flow under tolterodine was about 56%. Additional administration of atropine led in both drugs to a nearly complete blockade of salivation. Heart rate (HR) and blood pressure (BP) : Directly following intravenous administration of both drugs, a short-term and reversible period of mild but significant fluctuations in HR was observed. There was also a slight but non-significant rise in blood pressure. Conclusions This model allows comparative investigations of various drugs with bladder inhibitory properties in terms of acute efficacy and side effects.

This research is aimed to study the possibility of management of severe symptoms of overactive bladder (OAB) with solifenacin and trospium in patients who receive treatment with tamsulosin due to benign prostatic hyperplasia (BPH). The 338 men more than 50 years old (average age 58.4 years) diagnosed with BPH and severe symptoms of OAB were enrolled in the study. Over three episodes of urinary incontinence per day (registration according to bladder diaries), International Prostate Symptom Score over 19, OAB-V8 questionnaire score over 32, and urodynamic disorders diagnosed using cystometry and uroflowmetry were taken as a criterion of severe symptoms of OAB. Patients of the main group during 2 months received treatment with daily combination of solifenacin 5 mg and trospium 5 mg simultaneously with tamsulosin 0.4 mg. Patients of the control group were treated only with tamsulosin. First endpoint is a quantitative assessment of patients with BPH having severe symptoms of OAB. Second endpoint is a state of the patients’ lower urinary tract after the treatment. In the main group, most of urodynamic indices normalized significantly. Number of episodes of incontinence reduced from middle level 3.4 (0.8) per day to 0.9 (0.7) per day. In the control group changes of urodynamic indices were not significant. Quantity of side effects did not exceed the level which is common for antimuscarinic monotherapy. Therefore, percentage of patients with severe symptoms of OAB is not less than 44% of all cases of prostatic hyperplasia accompanied by OAB symptoms. Combination of trospium and solifenacin in standard doses is an efficient and safe method of management of severe symptoms of OAB in the course of the treatment of with tamsulosin in patients more than 50 years of age.

Anticholinergic treatment combined with intermittent catheterisation is the cornerstone of the conservative treatment strategy in children with neurogenic detrusor overactivity, which in most cases is due to congenital causes. Efficacy, tolerability and safety of propiverine hydrochloride were evaluated retrospectively in these children.At four specialized outpatient clinics, all children's records were scrutinized for first-line propiverine hydrochloride treatment, or second- or third-line treatment after failure of a non-selective alpha-blocker (phenoxybenzamine) and/or other anticholinergics (oxybutynin, trospium chloride). The primary efficacy outcomes were urodynamic parameters, with clinical symptoms as secondary outcomes. Statistical analysis was performed by paired t-tests (significance level p0.05).Altogether 74 children and adolescents (40 boys, 34 girls; age range 11 months-19 years) were treated with propiverine hydrochloride (average duration 2 years and approximately 4 months; individual dose range 5-75 mg). The primary efficacy outcome parameters improved significantly: maximum cystometric capacity 161.2 [standard deviation (SD) 97.3] to 252.2 ml (SD 117.2), p0.001; maximum detrusor pressure 43.8 (SD 39.2) to 27.1 cm H(2)O (SD 26.4), p = 0.002; bladder compliance 7.6 (SD 6.4) to 17.0 ml/cm H(2)O (SD 16.2), p0.001. Phasic detrusor overactivity was abolished by 63%; incontinence resolved by 54%. One patient spontaneously reported a typical anticholinergic adverse event, which resolved after dose reduction. No safety concerns were documented.Propiverine hydrochloride is effective in neurogenic detrusor overactivity in children and adolescents, even in some of those cases unresponsive to other anticholinergics. The low incidence rate (1.5%) of adverse events evidences a favourable risk-benefit profile of propiverine hydrochloride, considering in particular the total documented treatment and surveillance period of 171 patient years and nine months.

OBJECTIVE To evaluate the time to onset of statistically significant and clinically meaningful effects of trospium chloride in patients with an overactive bladder (OAB). PATIENTS AND METHODS Data from a recent Phase III clinical study of trospium chloride were obtained, in which 658 patients with OAB were randomized (1 : 1) to placebo or trospium chloride 20 mg twice daily for 12 weeks. Original study safety endpoints consisting of adverse events, vital signs, electrocardiograms, and laboratory changes were collected, while original efficacy endpoints included number of toilet voids/day, urgency severity per toilet void, urge urinary incontinence (UUI), and volume voided per toilet void at weeks 1, 4, and 12. Results were also analysed using the OAB Symptom Composite Score (OAB-SCS). The efficacy analysis focused on changes from baseline in these endpoints from 1 to 7 days of treatment to establish the earliest point at which there was statistical significance or clinical efficacy. RESULTS There were statistically significant improvements in efficacy over placebo in endpoints (toilet voids, urgency severity/void, UUI episodes, OAB-SCS) within a few days of treatment, with improvements in symptoms continuing to 7 days of treatment. There were clinically meaningful improvements in most endpoints by the end of the first week. CONCLUSIONS The time to onset of the clinical effect should be studied more extensively to identify when patients might expect a clinically meaningful improvement in their OAB-related symptoms.

Benzilic ester derivatives with a basic moiety like N-methyl-4-piperidyl benzilates are potential drugs for the treatment of urinary incontinence, duodenal and gastric ulcers and Parkinson's disease. The effect of structural variations of chiral N-methyl-4-piperidyl benzilates was investigated using radioligand binding studies on muscarinic receptors (M1-M3). The results of the binding studies demonstrate that the absolute configuration and the aromatic substituent of benzilates have an influence on muscarinic affinity and selectivity. In this regard, (S)-configuration of benzilates and hydrophilic aromatic substituents seems to enhance muscarinic affinity. A model of the receptor ligand complex for N-methyl-4-piperidyl benzilates was obtained by molecular modelling. Both the affinity of enantiomeric benzilic esters and the subtype selectivity for muscarinic receptors are comprehensively explained by this model.

Objectives To study the efficacy and safety of trospium chloride in treating overactive bladder. Trospium chloride is an anticholinergic agent with predominantly peripheral nonselective antimuscarinic activity and thus has potential therapeutic value in treating patients with overactive bladder. Methods Patients with overactive bladder were randomized on a 1:1 basis to either placebo or trospium chloride 20 mg twice daily in this 12-week, multicenter, parallel, double-blind, placebo-controlled study. The primary endpoint was the change in the average number of toilet voids per 24 hours. The secondary efficacy variables were changes in the average void urgency severity, volume per toilet void, urge frequency, number of daily urge urinary incontinence episodes, and daytime sleepiness. Results A total of 658 patients were randomized at 52 sites. Trospium chloride significantly decreased the average number of daily toilet voids, average urgency severity, urge frequency, and urge urinary incontinence episodes and increased the average volume per void at weeks 1, 4, and 12. All effects occurred by the end of week 1 and all improved and were sustained throughout the 12-week study. Adverse events included dry mouth and constipation. Conclusions Trospium chloride had significant and sustained effectiveness beginning at the end of week 1 and continuing through 12 weeks of treatment. Trospium chloride was also safe and generally well tolerated.

The management of stones in children is often controversial; extracorporeal shock wave lithotripsy appears to be very successful, with excellent clearance rates, and probably better than in adults. For this reason, many maintain that percutaneous nephrolithotripsy might not be required in children. Authors from Pakistan retrospectively assessed their use of percutaneous nephrolithotripsy, finding that it too yields satisfactory results. OBJECTIVES To evaluate prospectively the efficacy and tolerability of propiverine for treating neurogenic detrusor overactivity (NDO) in children. PATIENTS AND METHODS Twenty children (mean age 8.9 years; median 5.6) with NDO due to an upper motor neurone lesion were enrolled (17 had myelomeningocele). In the urodynamic examination, reflex volume (RV), maximum detrusor pressure (MDP), maximum cystometric bladder capacity (MCBC) and bladder compliance (BC) before and after a twice-daily propiverine hydrochloride regimen were determined. The urodynamic follow-up was after 3–6 months. Incontinence was assessed by an incontinence score. RESULTS The mean (sem) RV increased from 103.8 (21.3) to 174.5 (33.7) mL (P

Multidrug resistance (MDR) of cancer cells remains to be an important cause of chemotherapy failure. Search for the new MDR reversal agents is still an unceasing challenge for the scientists. In an attempt to find clinically useful modulators of MDR, a series of 19 N(10)-substituted-2-bromoacridones has been synthesized. Parent compound 1, prepared by the Ullmann condensation of o-chlorobenzoic acid and p-bromoaniline, undergoes N-alkylation in the presence of a phase transfer catalyst. N-(omega-Chloroalkyl) analogues were subjected to iodide catalyzed nucleophilic substitution reaction with various secondary amines to get the products 3-10 and 12-19, which increased the uptake of vinblastine (VLB) in MDR KBCh(R)-8-5 cells to a greater extent (1.25 to 1.9-fold) than did a similar concentration of the standard modulator, verapamil (VRP). Results of the efflux experiment showed that each modulator significantly inhibited the efflux of VLB, suggesting that they may be competitors for P-gp. All the compounds effectively compete with [(3)H] azidopine for binding to P-gp, pointed out this transport membrane protein as their likely site of action. Compounds at IC(10) were evaluated for their efficacy to modulate the cytotoxicity of VLB in KBCh(R)-8-5 cells and found that the modulators enhanced the cytotoxicity of VLB by 3.8 to 34-fold. The study on the structure-activity relationship revealed that substitution of hydrogen atom at position C-2 in acridone nucleus by a bromine atom increased the cytotoxic and anti-MDR activities. The ability of acridones to inhibit calmodulin-dependent cyclic AMP phosphodiesterase has been determined and the results have shown a strong positive correlation between anti-calmodulin activity and cytotoxicity in KBCh(R)-8-5 cells or anti-MDR activity.

Introduction: This study aims to compare the efficacy of propiverine hydrochloride immediate release (IR), propiverine hydrochloride extended release (ER) and placebo for the treatment of overactive bladder syndrome. The primary outcome measure is incontinence episode frequency, with secondary outcome measures including mean volume per void and quality of life as assessed on King’s Health Questionnaire. Material and Methods: The double-blind, double-dummy, randomized study compared IR 15 mg twice daily, ER 30 mg once daily and placebo in 3 parallel groups. After a run-in period of 7 days, the patients were treated for 32 days. Nine hundred and eighty-eight patients were randomized, and 910 patients completed the protocol without major violations. Results: The number of incontinence episodes/24 h decreased by 2.26 in the IR group (p < 0.001 vs. placebo), by 2.46 in the ER group (p < 0.0001 vs. placebo) and by 1.75 in the placebo group. The most frequent adverse event was dry mouth with 22.8% of the patients in the IR group, 21.7% in the ER group and 6.4% in the placebo group. The overall tolerability was rated ‘very good’ or ‘good’ by more than 80% of the investigators and patients in all 3 groups. Conclusions: Propiverine ER 30 mg once daily and propiverine IR 15 mg twice daily significantly reduce the number of incontinence episodes/24h within a treatment period of 32 days. Both formulations are safe and well tolerated. The extended release formulation of propiverine is a suitable new option for the treatment of the overactive bladder.

In isolated detrusor strips, propiverine is known to be effective to decrease contractions elicited by electric field stimulation (EFS). Here we investigated whether the metabolites M-5, M-6 and M-14 of propiverine retain the pharmacological properties of the parent compound also in juvenile organisms. EFS-induced contractions of detrusor strips from juvenile pigs are more sensitive to atropine than strips from mature pigs. The atropine-resistant component of contraction is also significantly larger in juvenile pigs. Propiverine, its metabolites M-5, M-14 and also tolterodine completely reduced detrusor contraction in juvenile pigs. M-6 almost did not affect atropine-resistant contractions. We conclude that juvenile pig detrusors possess a higher atropine-resistant component of EFS-elicited contraction. Nevertheless order of potency and efficacy of propiverine and its metabolites M-5 and M-14 are similar in juvenile and mature pigs, while M-6 only reduces atropine-sensitive contractions in the juvenile organism.

The combination of an alpha1-blocker with an anticholinergic is a new and promising therapeutic approach for bladder outlet obstruction and detrusor overactivity. Both placebo-controlled and comparative studies have demonstrated that the addition of an anticholinergic in the conventional treatment of patients with bladder outlet obstruction is safe, as the likelihood of acute urinary retention is low. Although the pathophysiology of detrusor overactivity is unknown and most probably multifactorial, it is not expected that the voiding phase is influenced by regular doses of anticholinergics, although high doses may affect detrusor contraction. However, safety issues must be studied further. The combination of tamsulosin with propiverine or tolterodine, and of doxasosin with tolterodine has been shown to cause a significant improvement of lower urinary tract symptoms when compared with alpha1-blocker monotherapy. Indisputably, the existing literature provides clear evidence that the combination of an alpha1-blocker with an anticholinergic extends physicians ability to manage lower urinary tract symptoms caused by bladder outlet obstruction and overactive bladder syndrome.

Background: Urinary incontinence is caused by an overactive bladder, leading to symptoms of urgency, frequency, and incontinence. Urge incontinence occurs predominantly in women as they age. Objectives: This article reviews the current primary literature concerning the efficacy and tolerability of the anticholinergic agent trospium chloride (TC1) in the treatment of overactive bladder with symptoms of urge incontinence, urgency, and frequency. The pharmacokinetics of TC1 are also reviewed. Methods: Pertinent articles in English were identified through a search of MEDLINE (1966-present), EMBASE Drugs & Pharmacology (1980-third quarter 2004), Current Contents/Clinical Medicine (week 42, 2003-week 41, 2004), Cochrane Database of Systematic Reviews, MICROMEDEX Healthcare Series, and International Pharmaceutical Abstracts (1970-present). The search terms were overactive bladder urinary incontinence, trospium, randomized controlled clinical trial, oxybutynin, tolterodine, scopolamine, imipramine, desipramine, and propanthetine. Results: TCI, a quaternary amine, exhibits high solubility in water but low oral bioavailability (9.6%) and poor central nervous system penetration. Approximately 80% of the absorbed fraction is renally eliminated as unchanged drug via active tubular secretion, with -15% hepatically metabolized into a spiroalcohol and hydrolysis/oxidation products. In 3 placebocontrolled studies, patients who received TC1 had an increase in maximum bladder filling capacity and bladder compliance, with a reduction in maximum cystometric capacity (P < 0.005); however, only 1 of these studies showed an increase in bladder compliance, with reductions in maximum detrusor pressure (P < 0.001), number of voids/d (P < 0.001), and incontinence episodes/d (P < 0.001). In another placebo-controlled study, TCI reduced the number of voids/d and incontinence episodes/d (both, P < 0.001). In 2 double-blind studies, TCI and oxybutynin were similarly effective in significantly increasing maximum cystometric capacity and bladder compliance, and in significantly reducing maximum detrusor pressure compared with baseline (all, P < 0.001); there were no significant differences between the 2 treatments at end point. In a third doubleblind study comparing TCI and tolterodine with placebo, only TC1 significantly reduced the frequency of micturitions/d (P = 0.01). Commonly reported adverse effects in patients receiving TC1 included dry mouth, constipation, and headache. Conclusions: In the 7 studies reviewed, TC1 was effective and well tolerated in patients with urge incontinence caused by idiopathic detrusor muscle overactivity or neurogenic detrusor overactivity resulting from spinal cord injury. However, this agent was associated with anticholinergic adverse effects similar to those of other anticholinergic agents; careful monitoring of tolerability is required. (Ctin Tber. 2005;27:511-53 O) Copyright © 2005 Excerpta Medica, Inc.

Solifenacin succinate [YM905, (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate] is a novel muscarinic receptor antagonist. We examined the effects of solifenacin and two other muscarinic receptor antagonists, tolterodine and propiverine, on detrusor overactivity in cerebral infarcted rats. Evaluation was done under conscious conditions using cystometry 1 day after middle cerebral artery occlusion. The cerebral infarcted rats showed decreases in bladder capacity and voided volume and an increase in residual volume, but no change in micturition pressure. Solifenacin increased bladder capacity and voided volume at doses of 0.03 mg/kg i.v. or more. Tolterodine increased bladder capacity and voided volume at 0.03 and 0.1 mg/kg i.v., while propiverine increased bladder capacity and voided volume at 1 mg/kg i.v. and at 0.3 and 1 mg/kg i.v., respectively. In contrast, none of the three drugs affected residual volume or micturition pressure. These results suggest that solifenacin may improve detrusor overactivity without causing urinary retention and may be a promising drug in the treatment of patients with overactive bladder syndrome.

Anticholinergic medications and onabotulinumtoxinA are used to treat urgency urinary incontinence, but data directly comparing the two types of therapy are needed.We performed a double-blind, double-placebo-controlled, randomized trial involving women with idiopathic urgency urinary incontinence who had five or more episodes of urgency urinary incontinence per 3-day period, as recorded in a diary. For a 6-month period, participants were randomly assigned to daily oral anticholinergic medication (solifenacin, 5 mg initially, with possible escalation to 10 mg and, if necessary, subsequent switch to trospium XR, 60 mg) plus one intradetrusor injection of saline or one intradetrusor injection of 100 U of onabotulinumtoxinA plus daily oral placebo. The primary outcome was the reduction from baseline in mean episodes of urgency urinary incontinence per day over the 6-month period, as recorded in 3-day diaries submitted monthly. Secondary outcomes included complete resolution of urgency urinary incontinence, quality of life, use of catheters, and adverse events.Of 249 women who underwent randomization, 247 were treated, and 241 had data available for the primary outcome analyses. The mean reduction in episodes of urgency urinary incontinence per day over the course of 6 months, from a baseline average of 5.0 per day, was 3.4 in the anticholinergic group and 3.3 in the onabotulinumtoxinA group (P=0.81). Complete resolution of urgency urinary incontinence was reported by 13% and 27% of the women, respectively (P=0.003). Quality of life improved in both groups, without significant between-group differences. The anticholinergic group had a higher rate of dry mouth (46% vs. 31%, P=0.02) but lower rates of catheter use at 2 months (0% vs. 5%, P=0.01) and urinary tract infections (13% vs. 33%, P0.001).Oral anticholinergic therapy and onabotulinumtoxinA by injection were associated with similar reductions in the frequency of daily episodes of urgency urinary incontinence. The group receiving onabotulinumtoxinA was less likely to have dry mouth and more likely to have complete resolution of urgency urinary incontinence but had higher rates of transient urinary retention and urinary tract infections. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women's Health; ClinicalTrials.gov number, NCT01166438.).

An objective of a large US phase-3 study was to determine the effects of trospium chloride 20-mg tablets versus placebo, administered twice daily, on central nervous system (CNS) adverse events (eg, somnolence) and on daytime sleepiness using the validated Stanford Sleepiness Scale. The impact of age groups also was assessed. Trospium chloride did not increase daytime sleepiness or appear to produce CNS adverse effects, as measured by the Stanford Sleepiness Scale and the incidence of CNS adverse events. Furthermore, there was no difference in these findings across age groups.

The presence of degradation products of bromopropylate, trichlorphon, parathion-methyl and tebuconazole in white and red wines elaborated from musts spiked with commercial formulations of the pesticides was studied. Must and wine were subjected to solid-phase extraction followed by gas chromatography with electron ionization mass spectrometric detection. α-Bromophenylphenylmethanol, aminoparathion, acetylaminoparathion-oxon and dichlorvos have been identified as degradation products of bromopropylate, parathion-methyl and trichlorphon in wines, respectively. Moreover, the presence of additives and impurities of the formulations in elaborated wines has also been found. Copyright © 2004 John Wiley & Sons, Ltd.

Background and objectives: The antimuscarinic drug trospium chloride is hydrophilic and therefore does not enter the CNS when used for the treatment of overactive bladder disturbances. However, the same property is the main reason for low and variable oral bioavailability. The present study was performed to assess the influence of intestinal site on absorption of the drug as the basis for the development of modified release preparations. Methods: In a change-over pilot study, 8 healthy male volunteers received single 20 mg doses of trospium chloride orally as a tablet (reference), as Eudragit-coated tablets dissolving at pH 6.0 (local administration into the small intestine), and rectally via a mini enema (corresponding to local administration into the large intestine). Plasma concentrations of trospium chloride were determined up to 36 hours after administration using GC/MS. Results: Extent and rate of trospium chloride absorption declined rapidly upon administration into more distal regions of the gastrointestinal tract. C m a x (median: 6.42 ng/ml) and AUC ( 0 - t l a s t ) (42.28 ng/ml x h) were highest and t m a x (3.5 h) was shortest after administration of the reference tablet. AUC ( 0 - t l a s t ) reached 78% (90% CI 43 - 139%) after small intestine administration and 2% (90% CI 1 - 9%) following rectal administration, respectively, relative to the values for the oral tablet. Conclusion: Trospium chloride is absorbed primarily in the upper gastrointestinal tract. Development of modified release preparations must balance prolonged apparent absorption rates of the drug against a decrease in bioavailability.

This year, the US Food and Drug Administration will approve four new drugs indicated for the treatment of lower urinary tract dysfunction. Darifenacin, solifenacin, and trospium are antimuscarinic agents aimed at relieving the symptoms of overactive bladder and urge incontinence in men and women. Duloxetine will be the first drug approved for the treatment of female stress urinary incontinence. This article presents current data on the efficacy and tolerability of these new agents and invites the reader to decide whether they offer any potential advantages over existing therapies.

Successful response rates of monotherapeutic strategies in urge incontinent children are limited. We evaluate whether adjuvant treatment improves outcomes.Incontinent children were evaluated according to International Consultation on Incontinence standards. Propiverine (0.4 mg/kg) was applied 2 times daily for 4 weeks (treatment period 1) before reevaluation. Primary outcome was achievement of continence and secondary outcome was improvement of functional bladder capacity. In partial responders an alternative adjuvant treatment was initiated for another 12 weeks (treatment period 2).Of 70 enrolled patients 29 achieved continence (responders) and 35 responded partially and were assigned to adjuvant treatment, which consisted of selective alpha-blocker for functional bladder outflow obstruction (6), desmopressin for excessive nocturnal urine production (19) and biofeedback for increased pelvic floor activity during micturition (10). Only 6 nonresponders (9%) were assigned to specialized management. After treatment 2, 20 of the 35 partial responders achieved continence, thus avoiding specialized management.Propiverine monotherapy for incontinent children is effective. However, applying adjuvant treatment modalities to partial responders increases overall efficacy rates.

Integration metabolic considerations into the drug-design process can allow safer pharmaceuticals to be designed. "Soft" drugs are designed to be deactivated in a predictable and controllable way after achieving their therapeutic role. They are designed to be metabolized rapidly and by avoiding oxidative pathways into inactive and nontoxic species. Successful application of such design principles has already resulted in a number of marketed drugs. The present article illustrates advantages inherent in avoiding the formation of oxidative metabolites, with examples that include soft bufuralol analogs and soft insecticides such as chlorobenzilate and malathion. Design principles for various soft drug classes are briefly summarized together with computerized tools intended to make the application of these principles more quantitative and more accessible.

We investigated postischemic alterations in benzodiazepine receptor, D1 dopamine receptor, and muscarinic acetylcholine receptor binding after transient middle cerebral artery (MCA) occlusion in rats using [3H]-flumazenil, [3H]-SCH23390, and [3H]-N-methyl-4-piperidyl benzilate ([3H]-NMPB), respectively, as radioligand. These ligand bindings were determined at 3 and 24 h and at 3 and 7 days after ischemia/reperfusion of MCA by using autoradiographic methods. Ischemic cell injury was clearly detected from 3 h after ischemia/reperfusion and progressively increased from 3–24 h after ischemia/reperfusion of MCA. The area of cell injury reached maximum at 24 h after ischemia/reperfusion of MCA. [3H]-SCH23390 binding was reduced to 47% of the contralateral side at 3 days after ischemia/reperfusion of MCA. After 7 days, [3H]-SCH23390 binding was further reduced by 20% in the striatum. [3H]-NMPB binding was slightly decreased in both the striatum and cerebral cortex at 3 days after ischemia/reperfusion of MCA, and [3H]-NMPB binding in the striatum and cerebral cortex were reduced to 42 and 62% of the contralateral side at 7 days after ischemia/reperfusion of MCA. [3H]-NMPB was also decreased at 24 h. In contrast, [3H]-flumazenil binding was not decreased in the striatum and cerebral cortex within 7 days after ischemia/reperfusion of MCA. These results suggest that [3H]-SCH23390 and [3H]-NMPB binding do not correlate with cell injury by ischemia/reperfusion, although vulnerability to ischemia/reperfusion was observed with these receptors. In addition, central benzodiazepine receptor imaging might be essentially stable to neuronal cell injury induced by transient focal cerebral ischemia in rats, in contrast to the results of PET studies. Synapse 53:234–239, 2004. © 2004 Wiley-Liss, Inc.

We assessed the efficacy and most appropriate dosage of trospium chloride (TCl) for managing bladder instability in children as compared with a placebo.A total of 58 patients with bladder instability were allocated at random to 1 of 5 groups-10, 15, 20 or 25 mg TCl, or placebo administered daily in a multicenter, randomized, single-blind clinical study. Patients were treated for 21 days, and current symptoms, voiding diary and urodynamic values were collected at the beginning and end of the treatment period. All adverse events were recorded at the last visit.Of 50 patients treated with TCl 41 (82%) had a positive therapeutic result (excellent, good or fair) versus only 3 of 8 patients with improvement in the placebo group (37.5%, p = 0.006). In all responding patients clinical symptoms either resolved or decreased markedly, and in 37 (74%) this improvement was accompanied by urodynamic improvement. In these 37 children the average number of uninhibited contractions decreased by 54.3% (p0.0001) and the volume at first contraction increased by 71.4% (p = 0.001). There were no statistically significant differences with regard to therapeutic efficacy between TCl dosages. Fourteen patients (9 with TCl, 5 with placebo) showed no clinical improvement, although some had improved urodynamic parameters. Furthermore, TCl was well tolerated with few patients (10%) experiencing adverse effects.Trospium chloride (10 to 25 mg total daily dosage, split into 2 doses) is an effective option for the management of detrusor instability in children.

Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.

The crystal structure of lithium benzilate hemihydrate (C14H11O_3^-Li+·0.5H2O) was solved from synchrotron powder diffraction data. This compound crystallizes in the monoclinic space group P21/a. The structure was solved via the direct space search for two benzilate fragments using the simulated-annealing program DASH, localization of the lithium ions and water molecule from a difference Fourier map, and a restrained Rietveld refinement (R wp = 0.0687). The structure is a coordination polymer of [Li2(C14H11O3)2·H2O]2 tetramers building helical fourfold one-dimensional channels parallel to [010]. Inside the channels the tetrahedral coordination spheres of the lithium ions contain hydroxyl and carbonyl groups, and water molecules. The water molecule functions as the cohesive entity forming extended hydrogen-bonded chains running along [010], and bifurcated donor hydrogen bonds with the two nearest carboxylates. At the outer edge of the channels, weaker intermolecular C—H...Ph hydrogen bonds along [100] and [001] contribute to the supramolecular aggregation of the structure.