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Two simple, accurate, sensitive and precise conductometric methods were developed for determination of trospium chloride in pure form and in pharmaceutical formulations. It is based on using two precipitating reagents; Phosphomolybdic acid (PMA) and Silver nitrate (AgNO3). The mean recovery for Silver nitrate is in the range (98-100.95%) and for Phosphomolybdic acid in the range (98-101.69%). A molar ratio has been determined conductometrically for the two reagents, revealed (1/1) for (drug/reagent). The proposed methods were validated and successfully applied for the determination of the studied drug in pure form and in its pharmaceutical preparation. The results of the proposed methods were compared to the results of reported method with no significant difference between them.

Objective To evaluate the effects of solifenacin, darifenacin, and propiverine on nasal-, subfoveal-, temporal choroidal thicknesses (NCT, SFCT, TCT), intraocular pressure (IOP) and pupil diameter (PD). Materials and Methods Patients with overactive bladder (OAB) diagnosed according to The International Continence Society were administered with solifenacin, darifenacin or propiverine on a daily basis between November 2017 and May 2018. NCT, SFCT, TCT, IOP, and PD of these patients were measured and compared as initial, fourth and twelfth weeks. Results A total of 165 patients (330 eyes) with OAB were evaluated. Solifenacin (n=140) significantly reduced IOP from 17.30±2.72 mmHg to 16.67±2.56 mmHg (p=0.006) and 16.57±2.41 mmHg (p=0.002), at the fourth and twelfth weeks, respectively. Darifenacin (n=110) significantly reduced NCT from 258.70±23.96 μm to 257.51±22.66 μm (p=0.002) and 255.36±19.69 μm (p=0.038), at the fourth and twelfth weeks, respectively. Propiverine (n=80) significantly increased PD from 4.04±0.48 mm to 4.08±0.44 mm (p=0.009) and 4.09±0.45 mm (p=0.001), at the fourth and twelfth weeks, respectively. Conclusion These findings can help to decide appropriate anticholinergic drug choice in OAB patients. We finally suggest further well-designed randomized prospective studies with a larger population to evaluate the anticholinergic-related complications in eyes.

Objective This analysis was conducted to investigate the cardiovascular (CV) safety outcomes from the MILAI II study. MILAI II was conducted to evaluate the long‐term safety and efficacy of antimuscarinic add‐on therapy to mirabegron over 52 weeks in patients with overactive bladder (OAB) symptoms. Methods MILAI II consisted of a 2‐week screening period (patients received mirabegron 50 mg once daily) plus a 52‐week treatment period (patients were randomized to receive a combination of mirabegron 50 mg/d plus solifenacin 5 mg/d, propiverine 20 mg/d, imidafenacin 0.2 mg/d, or tolterodine 4 mg/d). CV safety was assessed using treatment‐emergent adverse events (TEAEs), vital signs, and 12‐lead electrocardiograms (ECGs). Vital signs and ECG data were evaluated for each patient using worst post‐baseline values reported. Results Of 647 patients, 570 (88.1%) were female with a mean age of 65 years. CV history at baseline and CV‐related concomitant medication use throughout the study were balanced between groups. The incidences of overall and drug‐related CV TEAEs were ≤8.1% and ≤6.2%, respectively, for all groups. The most common TEAEs were ECG T wave amplitude decreased, ECG QT prolonged, and ventricular extrasystoles. Overall, 36 TEAEs of interest related to the CV system that were possibly/probably related to treatment were reported with similar incidences for each group. For the worst post‐baseline vital signs and ECGs, no relationships were noted in terms of either timing or treatment group. Conclusion A favorable CV safety profile was observed following long‐term combination treatment with mirabegron and an antimuscarinic in patients with OAB symptoms.

We investigated the mechanisms by which propiverine hydrochloride influenced bladder activity in rats with pelvic venous congestion (PC) and urinary frequency. To create PC rats, female rats were anesthetized with isoflurane and the bilateral common iliac veins and bilateral uterine veins were ligated. At 4 weeks after ligation, we assessed voiding behaviour, locomotor activity, and urinary 8-hydroxydeoxyguanosine (8-OHdG) and nitric oxide metabolites (NOx). We also performed cystometry and measured mRNAs for nitric oxide synthase (NOS) and several receptors in the bladder wall. PC rats showed a decrease in locomotor activity and an increased frequency of urination. There was a decrease in endothelial NOS (eNOS), M3, and TRPV1 mRNA expression in the bladder wall, as well as an increase in inducible NOS (iNOS) mRNA. Administration of propiverine to PC rats increased locomotor activity to the level in sham rats, improved bladder function, decreased urinary 8-OHdG excretion, and increased urinary NOx excretion. In addition, propiverine increased neuronal NOS (nNOS) mRNA expression, and decreased expression of iNOS, M3 and TRPV1 mRNA in the bladder wall. Therefore, propiverine not only improved bladder dysfunction through its previously reported actions (anti-muscarinic effect, Ca antagonist effect, and inhibition of noradrenaline re-uptake), but also by reducing inflammation.

To compare the heart rate increase side effect of different antimuscarinic drugs used in overactive bladder (OAB). Overall 341 patients were consecutively randomized to take seven different antimuscarinic drugs between January 2014 and June 2016 at three institutions, and 250 patients who completed the follow-up visits were accepted into this study. Ninety-one patients who never came to visits were excluded. Drugs were classified into two groups as selective (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride) and non-selective (fesoterodine fumarate, tolterodine tartrate, trospium chloride and propiverine hydrochloride) antimuscarinic drugs. The cardiac pulse rates and the blood pressures were recorded during the baseline, first visit (1 week) and second visit (1 month). Data were compared for drugs and two groups (selective versus non-selective) by using ANOVA test. Baseline characteristics were similar among the patients using different antimuscarinic drugs. Statistically significant increase in heart rate occurred in patients treated with non-selective antimuscarinic drugs compared to those treated with selective drugs (p

To introduce a new protocol for patients with primary nocturnal enuresis to increase efficacy of treatment and decrease relapse rate.A prospective study was done on 185 children diagnosed with nocturnal enuresis between the years 2007 and 2014. Inclusion criteria consisted of age5 years, monosymptomatic enuresis or non-monosymptomatic enuresis, strict abidance by the protocol, and follow-up24 months. Exclusion criteria consisted of secondary enuresis, poor compliance to protocol, and neurogenic bladder. Participants were started on combination therapy of desmopressin 120 µg (MELT formula) once per day and propiverine 7.5 mg twice per day, which were then adjusted as per their response to therapy and our designed protocol. Outcome was defined as per the International Children Continence Society (ICCS) latest definitions.One hundred twenty-two patients satisfied the inclusion criteria and were included in the study with a median age of 9 years (range 5-19 years). The mean follow-up time was 62 months (range 25-114 months). Our protocol showed an overall complete success of 87% with failure and relapse of 13%. The success rate of patients needing 120 µg desmopressin as maintenance therapy to achieve dryness was 92.7% as compared to 65% success in patients needing a higher dose of desmopressin to achieve dryness (P.05). Age, gender, and type of primary nocturnal enuresis had no effect over success (all P.05).Adopting combination therapy along with structured withdrawal as per our protocol showed higher success rates and lower relapses in primary nocturnal enuretic children.

AIM To carry out a network meta-analysis of randomised controlled trials (RCTs) of anticholinergic drug treatment for people with overactive bladders. METHODS Comprehensive searches for relevant RCTs were carried out starting with RCTs included in previous systematic reviews with the last search in February 2017. Searches included terms for the anticholinergic drugs tolterodine, oxybutynin, trospium, propiverine, solifenacin, darifenacin, imidafenacin, and fesoterodine. Data was extracted from the systematic reviews or reports of studies for cure or improvement, voids per 24 hr, leakage episodes per 24 hr and dry mouth. Data was analysed using frequentist network meta-analysis. RESULTS 128 studies were found. There was no clearly best treatment for cure or improvement. The differences between treatments for voids and leakages were small and unlikely to be of clinical importance. Transdermally delivered oxybutynin was clearly the best treatment for dry mouth but was still worse than placebo. CONCLUSIONS All the anticholinergic drugs were better than placebo but apart from dry mouth were similar in effect. Transdermal oxybutynin caused less dry mouth than the other treatments, so may be worth considering as the first treatment.

Objectives To evaluate the long-term safety (primary objective) and efficacy (secondary objective) of antimuscarinic add-on therapy in patients receiving mirabegron. Methods During a 2-week screening period, patients (aged ≥20 years, mirabegron treatment for ≥6 weeks, residual overactive bladder symptoms) received mirabegron 50 mg once daily. These patients were subsequently randomized to 52 weeks' treatment with mirabegron 50 mg/day plus an antimuscarinic (solifenacin 5 mg, propiverine 20 mg, imidafenacin 0.2 mg, or tolterodine 4 mg) with the potential to double the antimuscarinic dose (except for tolterodine) at week 8. Safety assessments included treatment-emergent adverse events, vital signs, 12-lead electrocardiograms, post-void residual volume, and laboratory evaluations. Efficacy was assessed using changes from baseline in overactive bladder symptom score total score; overactive bladder questionnaire short form score; micturitions, urgency episodes, urinary incontinence episodes, and urgency urinary incontinence episodes/24 h; mean volume voided per micturition; and number of night-time micturitions. Results Overall, 80.2% of patients (88.1% women, mean age 65 years) experienced at least one treatment-emergent adverse event, with similar rates for all treatments. The adverse events most commonly reported were dry mouth, nasopharyngitis, and constipation. No marked change was observed in systolic or diastolic blood pressure for any treatment, although pulse rate increased slightly in the mirabegron and propiverine, and mirabegron and tolterodine groups. For all treatments, significant improvements were observed in all efficacy parameters, including overactive bladder symptom score total and questionnaire short form scores. Conclusions Antimuscarinic add-on therapy is well tolerated and effective after initial treatment with mirabegron in patients with overactive bladder symptoms.

Glial fibrillary acidic protein expressing (GFAP+) glia modulate nociceptive neuronal activity in both the peripheral nervous system (PNS) and the central nervous system (CNS). Resident GFAP+ glia in dorsal root ganglia (DRG) known as satellite glial cells (SGCs) potentiate neuronal activity by releasing pro-inflammatory cytokines and neuroactive compounds. In this study, we tested the hypothesis that SGC Gq-coupled receptor (Gq-GPCR) signaling modulates pain sensitivity in vivo using Gfap-hM3Dq mice. Complete Freund’s adjuvant (CFA) was used to induce inflammatory pain, and mechanical sensitivity and thermal sensitivity were used to assess the neuromodulatory effect of glial Gq-GPCR activation in awake mice. Pharmacogenetic activation of Gq-GPCR signaling in sensory SGCs decreased heat-induced nociceptive responses and reversed inflammation-induced mechanical allodynia via peripheral adenosine A1 receptor activation. These data reveal a previously unexplored role of sensory SGCs in decreasing afferent excitability. The identified molecular mechanism underlying the analgesic role of SGCs offers new approaches for reversing peripheral nociceptive sensitization.

Background Elderly people are representative for the patients most likely to be treated with anticholinergics for overactive bladder (OAB). They often receive further drugs with anticholinergic properties for concomitant conditions. This increases the risk for side effects, including central nervous system disorders. Data on comorbidities and baseline anticholinergic burden of OAB patients seen in urological practice is scarce. Therefore, we included an epidemiological survey on these issues in our study which assessed the effectiveness and tolerability of trospium chloride (TC) in established dosages under routine conditions. Methods Outpatients (≥ 65 years of age), for whom treatment with TC was indicated, were eligible to participate in this non-interventional, prospective study performed in 162 urological practices in Germany. Epidemiological questions were evaluated by the Anticholinergic Burden (ACB) scale and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) at baseline. Efficacy was assessed by changes in symptom-related variables of OAB after treatment. Dosage regimen, duration of treatment, adverse events, withdrawals, and ease of subdivision of the prescribed SNAP-TAB tablet were documented. Patients and physicians rated efficacy and tolerability of treatment. Statistics were descriptive. Results Four hundred fourty-five out of 986 (47.54%) patients in the epidemiological population had a baseline ACB scale score > 0, 100 (24.72%) of whom a score ≥ 3. The median CIRS-G comorbidity index score for all patients was 5. 78.55% (608/774) of patients in the efficacy population received a daily dose of 45 mg TC. 60.03% (365/608) of them took this dose by dividing the SNAP-TAB tablet in three equal parts. Before-after-comparisons of the core symptoms of OAB showed clear improvements. An influence of the dosage scheme (1 × 45 mg TC/d vs 3 × 15 mg TC/d) on clinical outcome could not be observed. Most urologists and patients rated TC treatment as effective and well tolerated. 44 (4.37%) out of 1007 patients in the safety collective ended their treatment prematurely, while 75 patients (7.45%) experienced adverse events. Conclusions Anticholinergic burden and comorbidities in elderly OAB patients are frequent. The acceptance of the SNAP-TAB tablet, which facilitates flexible dosing with TC, was high, which is supportive in ensuring adherence in therapy. Trial registration This non-interventional study was registered on October 29, 2014 with the number DRKS00007109 at the German Register of Clinical Studies (DRKS).

Aims To compare efficacy and tolerability of solifenacin 5 mg/day versus other oral antimuscarinic agents for the treatment of overactive bladder (OAB). Methods Literature searches of MEDLINE, Embase, and the Cochrane Library were undertaken to identify randomized controlled trials in OAB (2000-2015) for antimuscarinic agents. A network meta-analysis (NMA) was performed to estimate efficacy and tolerability outcomes for solifenacin 5 mg/day relative to other antimuscarinics. Results The NMA included 53 eligible trials (published, n = 48; unpublished on search date, n = 5). Solifenacin 5 mg/day was significantly more effective than tolterodine 4 mg/day for reducing incontinence and urgency urinary incontinence (UUI) episodes, but significantly less effective than solifenacin 10 mg/day for micturition; no other statistically significant differences were noted for efficacy. Solifenacin 5 mg/day had a statistically significant lower risk of dry mouth compared with darifenacin 15 mg/day, fesoterodine 8 mg/day, oxybutynin extended-release 10 mg/day, oxybutynin immediate-release (IR) 9-15 mg/day, tolterodine IR 4 mg/day, propiverine 20 mg/day, and solifenacin 10 mg/day. There were no significant differences between solifenacin 5 mg/day and other antimuscarinics for risk of blurred vision, or for 11 of 17 active comparators for risk of constipation. Conclusions This NMA suggests that the efficacy of solifenacin 5 mg/day is at least similar to other common antimuscarinics across the spectrum of OAB symptoms analyzed, and is more effective than tolterodine 4 mg/day in reducing incontinence and UUI episodes. Solifenacin 5 mg/day has a lower risk of dry mouth compared with several agents.

To compare the efficacy of combination therapy with an alpha-blocker and an anticholinergic to monotherapy with an alpha blocker on lower urinary tract symptoms (LUTS) following brachytherapy in prostate cancer patients. A total of 124 patients that had been clinically diagnosed with localized prostate cancer and underwent prostate brachytherapy were enrolled in the present study. Patients were randomized and allocated to two groups, including 60 to the combination group (tamsulosin 0.2 mg/day and trospium chloride 20 mg twice daily) and 64 to the monotherapy group (tamsulosin 0.2 mg/day). Treatment began 1 day after brachytherapy and continued for 6 months. LUTS were compared between the two groups using the total International Prostate Symptom Score (IPSS), storage and voiding IPSS subscores, quality of life (QoL) scores, maximum flow rate (Qmax), and postvoid residual (PVR) urine volume at 1, 3, 6, and 12 months after implantation. In all, 111 patients were ultimately analyzed in the study. Compared with pretreatment scores, a significant increase in total IPSS was found at 1, 3, and 6 months in both groups, but no statistically significant differences were observed between the two groups. The combination therapy group showed a greater decrease in the IPSS storage score compared with the monotherapy group at 1, 3, and 6 months (p = 0.031, 0.030 and 0.042, respectively). Patients receiving tamsulosin plus trospium chloride also showed significant improvements in QoL at 1 and 3 months compared with tamsulosin alone (P = 0.039, P = 0.047). Between the two groups, there was no significant difference in IPSS voiding score, Qmax, and PVR from baseline to each point of the study period. Combination therapy with tamsulosin and trospium chloride helped to improve IPSS storage symptoms and Qol scores in prostate brachytherapy patients with LUTS compared with tamsulosin monotherapy.

To investigate the effect of trospium chloride, which has an anticholinergic effect, used in overactive bladder (OAB) treatment on the intraocular pressure (IOP) and tear secretion after 12 weeks of treatment.This prospective study was performed at a single center between October 2014 and January 2016. A detailed history was obtained from the female OAB patients at the eye outpatient department. After checking the exclusion criteria, oral trospium chloride 30 mg bd was started. The patients were followed-up in terms of drug effectiveness and ophthalmic and other side effects at the 4th and 12th weeks. All procedures were repeated at both of these time-points.The mean age of the patients was 48.98 ± 11.98 years (range 19-75). The data of 80 OAB patients were evaluated in the study. Trospium chloride did not cause any significant change in the OAB patients regarding their 4th week and 12th week IOP measurements (p = 0.251, p = 0.340, respectively). It was found to decrease tear secretion significantly at both time-points (p = 0.020, p = 0.001, respectively). Trospium chloride treatment of one patient (1.25%) was discontinued due to dry eye.Trospium chloride decreases the symptoms in female OAB patients. Trospium chloride can be safely used in female OAB patients with normal IOP and no comorbidity as regards IOP changes as it did not cause a significant change in IOP in these patients. Pre-treatment and post-treatment dry eye symptoms of OAB patients about to start using trospium chloride should be queried beforehand as it can cause a statistically significant decrease in tear secretion. We concluded that it would be appropriate to refer the patients to an ophthalmologist before starting the drug if relevant symptoms are present.

Objectives This study aimed to investigate the effect of trospium chloride on cognitive function in postmenopausal women treated for overactive bladder (OAB). Methods Randomized double-blind placebo-controlled trial conducted from April 2013 to April 2015. Women aged 50 years or older seeking treatment for OAB were randomized to either trospium chloride XR 60 mg daily or placebo. Baseline cognitive function was assessed via Hopkins Verbal Learning Test-Revised (HVLT-R), Mini Mental Status Exam, Mini Mental Status X, Digit Span, Trails A, Trails B, and Epworth Sleepiness Scale. Cognitive function was reassessed at week 1 and week 4. A priori power analysis determined that 21 subjects were needed per group. Results Although 59 women were enrolled and randomized (28 trospium and 31 placebo), 45 completed assessment (21 trospium and 24 placebo). Mean age was 68 years, 78% were white, and 44% had previously taken OAB medication. For the primary outcome, there was no difference in HVLT-R total score between trospium and placebo groups at week 4 (P = 0.29). There were also no differences based on the other cognitive tests. There was a correlation between age and the following week-4 tests: HVLT-R total score (r = -0.3, P = 0.02), HVLT-R total recall subscale (r = -0.4, P = 0.007), Trails A (r = 0.4, P = 0.002), and Trails B (r = 0.4, P = 0.004). A linear regression model found that HVLT-R total score decreased by 0.372 points for each increased year of age. Conclusions In women aged 50 years and older, there were no changes in cognitive function between those taking trospium and placebo. Cognitive function was correlated with age.

We aimed to compare the safety and efficacy of solifenacin versus trospium chloride and compare each drug versus placebo regarding the relief of stent-related symptoms following uncomplicated ureteroscopic lithotripsy (URSL). In a prospective, randomized, double-blind study, 210 eligible patients who underwent URSL with double-J stent insertion were recruited and randomly assigned to either the first group, receiving solifenacin (10 mg), second group, receiving trospium chloride (60 mg), or the third group, receiving placebo (one tablet). All patients were kept on study medication once daily during the entire 2-week postoperative period. All subjects were asked to complete a brief-form questionnaire to assess the lower urinary symptoms, stent-related body pain and hematuria, preoperatively and 2 weeks postoperatively. There were no statistically significant differences among the study groups in terms of mean age, gender, anthropometric measurements, stone and stent criteria. The overall symptom score, urgency, urge incontinence, flank pain, urethral pain and gross hematuria scores were significantly lower in solifenacin group compared to trospium chloride and placebo groups (p

Background Propiverine hydrochloride (P4) is an antimuscarinic drug used in overactive bladder syndrome. Methods Two studies were performed: one in 24 patients with open-angle glaucoma (OAG) treated with topical β-blockers, one in 24 patients with narrow-angle glaucoma (NAG) treated with pilocarpine ± topical β-blockers. Patients were treated in randomized, placebo-controlled, double-blind parallel-group fashion (15 : 9 attribution to P4 vs. placebo (PL)). Treatments Single-blind PL dose in the morning of day 1 for baseline; double-blind 15 mg P4 or matched placebo t.i.d. from the afternoon of day 1 until the morning of day 7. Results In the morning of day 7, trough mean serum P4 concentrations were 169.4 ng/mL (CV (coefficient of variation): 0.55) and 140.7 ng/mL (CV: 0.56) in OAG and NAG; at 3:15 hours after dosing: 237.4 ng/mL (CV: 0.47) and 212.4 ng/mL P4 (CV: 0.38), respectively. P4-treatment led to a prompt (OAG) or more gradient (NAG) increase in pupil diameter (PUD), with a maximum difference from PL of 0.97 mm (95% confidence interval (CI): 0.67 - 1.27) and 0.87 mm (95% CI: 0.36 - 1.39) in OAG and NAG, respectively. However, there was no average increase in intraocular pressure (IOP) or increase in noteworthy safety-relevant individual IOP values (or changes thereof). There was no effect on visual acuity or accommodation. Conclusions 1-week treatment with P4 appeared to be safe 1) in OAG patients treated with topical β-blockers and 2) in NAG patients treated with topical pilocarpine ± β-blockers, irrespective of whether the eyes had previously been treated with glaucoma surgery or laser therapy. .

Trospium chloride, a muscarinic receptor blocker, is poorly absorbed with different rates from areas in the jejunum and the cecum/ascending colon. To evaluate whether organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion (MATE) 1 and MATE2-K are involved in pharmacokinetics, competitions with ranitidine, a probe inhibitor of the cation transporters, were evaluated in transfected HEK293 cells. Furthermore, a drug interaction study with trospium chloride after intravenous (2 mg) and oral dosing (30 mg) plus ranitidine (300 mg) was performed in 12 healthy subjects and evaluated by noncompartmental analysis and population pharmacokinetic modeling. Ranitidine inhibited OCT1, OCT2, MATE1, and MATE2-K with half maximal inhibitory concentration values of 186 ± 25 µM, 482 ± 105 µM, 134 ± 37 µM, and 35 ± 11 µM, respectively. In contrast to our hypothesis, coadministration of ranitidine did not significantly decrease oral absorption of trospium. Instead, renal clearance was lowered by ∼15% (530 ± 99 vs 460 ± 120 mL/min; P < .05). It is possible that ranitidine was not available in competitive concentrations at the major colonic absorption site, as the inhibitor is absorbed in the small intestine and undergoes degradation by microbiota. The renal effects apparently result from inhibition of MATE1 and/or MATE2-K by ranitidine as predicted by in vitro to in vivo extrapolation. However, all pharmacokinetic changes were not of clinical relevance for the drug with highly variable pharmacokinetics. Intravenous trospium significantly lowered mean absorption time and relative bioavailability of ranitidine, which was most likely caused by muscarinic receptor blocking effects on intestinal motility and water turnover.

The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.

The quaternary ammonium compound trospium chloride is poorly absorbed from 2 "absorption windows" in the jejunum and cecum/ascending colon, respectively. To confirm whether intestinal P-glycoprotein (P-gp) is involved, a 4-period, crossover drug interaction study with trospium chloride after intravenous (2 mg) and oral administration (30 mg) without and after comedication of clarithromycin (500 mg), an inhibitor for P-gp, was initiated in 12 healthy subjects. Pharmacokinetics of trospium was evaluated using gas chromatography-mass spectrometry, noncompartmental evaluation, and pharmacokinetic modeling. Trospium chloride was poorly absorbed after oral administration (absolute bioavailability, ∼8%-10%). About 30% of the bioavailable dose fraction was absorbed from the "narrow window". Comedication with clarithromycin increased steady-state distribution volumes by ∼27% (P

Aims We evaluated long-term efficacy and safety of a combination therapy (CT) with an anticholinergic agent and an α1-blocker for patients with benign prostatic enlargement (BPE) complaining of voiding and overactive bladder (OAB) symptoms, in comparison with those of α1-blocker monotherapy (MT), by conducting a urodynamic study (UDS). Methods This was a randomized prospective study involving 120 outpatients with untreated BPE associated with urinary urgency at least once per week and OABSS of ≥3. The patients were randomly assigned to receive MT with silodosin at 8 mg/day or CT with silodosin at 8 mg/day and propiverine at 20 mg/day. Changes in parameters from baseline to 12 weeks and 1 year after administration were assessed based on IPSS, IPSS-QOL, OABSS, and voiding and storage functions as measured by UDS. Results In efficacy analysis, 53 patients with MT and 51 with CT were included. Although mean IPSS and OABSS significantly improved in both groups, the CT group showed statistically significant improvement in OABSS (−3.4 in CT, −2.4 in MT, P = 0.04), IPSS-QOL (−1.9, −1.2, P = 0.01), and OAB-urgency score (−1.8, −1.2, P

Solifenacin is an antimuscarinic agent used to treat symptoms of overactive bladder. Pharmacologically significant amounts of solifenacin were excreted in the urine of humans taking a clinical dose of this drug. The aim of this study is to measure muscarinic receptor binding in the bladder urothelium and detrusor muscles of rats following the intravesical instillation of solifenacin. Muscarinic receptors were measured by radioreceptor assay using [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS), a selective radioligand of muscarinic receptors. Solifenacin showed concentration-dependent inhibition of specific [(3)H]NMS binding in the bladder urothelium and detrusor muscle of rats, with no significant difference in Ki values or Hill coefficients between these tissues. Following the intravesical instillation of solifenacin, there was significant muscarinic receptor binding (increase in Kd for specific [(3)H]NMS binding) in the bladder urothelium and detrusor muscle of rats. Similar bladder muscarinic receptor binding was observed by the intravesical instillation of oxybutynin, but not with trospium. In conclusion, the present study has demonstrated that solifenacin binds muscarinic receptors not only in the detrusor muscle but also in the bladder urothelium with high affinity. These bladder muscarinic receptors may be significantly affected by solifenacin excreted in the urine.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common condition in ageing men that may cause lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and prevent disease‐related complications. Naftopidil is an alpha‐blocker (AB) that has a high affinity for the A1d receptor that may have advantages in treating LUTS in this setting. This is an update of a Cochrane Review first published in 2009. Since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant. OBJECTIVES: To evaluate the effects of naftopidil for the treatment of LUTS associated with BPH. SEARCH METHODS: We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, LILAC, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up to 31 May 2018 SELECTION CRITERIA: We included all parallel RCTs. We also included cross‐over design trials. DATA COLLECTION AND ANALYSIS: Two review authors independently classified and abstracted data from the included studies. We performed statistical analyses using a random‐effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. Primary outcomes were urological symptom scores, quality of life (QoL) and treatment withdrawals for any reason; secondary outcomes were treatment withdrawals due to adverse events, acute urinary retention, surgical intervention for BPH, and cardiovascular and sexual adverse events. We considered outcomes measured up to 12 months after randomisation as short term, and later than 12 months as long term. We rated the certainty of the evidence according to the GRADE approach. MAIN RESULTS: We included 22 RCTs with 2223 randomised participants across four comparisons for short‐term follow‐up. This abstract focuses on only two of four comparisons for which we found data since two comparators (i.e. propiverine and Eviprostat (phytotherapy)) are rarely used. One study comparing naftopidil to placebo did not report any relevant outcomes and was therefore excluded. There were no trials that compared to combination therapy with naftopidil or any 5‐alpha reductase inhibitors (5‐ARIs) to combination therapy with other ABs and any 5‐ARIs. All included studies were conducted in Asian countries. Study duration ranged from four to 12 weeks. Mean age was 67.8 years, prostate volume was 35.4 mL, and International Prostate Symptom Score was 18.3. We were unable to perform any of the preplanned subgroup analyses based on age and baseline symptom score. Naftopidil versus tamsulosin Based on 12 studies with 965 randomised participants, naftopidil may have resulted in little or no difference in urological symptom score (mean difference (MD) 0.47, 95% confidence interval (CI) –0.09 to 1.04 measured on a scale from 0 to 35 with higher score representing increased symptoms), QoL (MD 0.11, 95% CI –0.09 to 0.30; measured on a scale from 0 to 6 with higher scores representing worse QoL), and treatment withdrawals for any reason (risk ratio (RR) 0.92, 95% CI 0.64 to 1.34; corresponding to 7 fewer per 1000 participants, 95% CI 32 fewer to 31 more). Naftopidil may have resulted in little to no difference in sexual adverse events (RR 0.54, 95% CI 0.24 to 1.22); this would result in 26 fewer sexual adverse events per 1000 participants (95% CI 43 fewer to 13 more). We rated the certainty of evidence as moderate for urological symptom score and low for the other outcomes. Naftopidil versus silodosin Based on five studies with 652 randomised participants, naftopidil may have resulted in little or no difference in the urological symptom scores (MD 1.04, 95% CI –0.78 to 2.85), QoL (MD 0.21, 95% CI –0.23 to 0.66), and treatment withdrawals for any reason (RR 0.80, 95% CI 0.52 to 1.23; corresponding to 26 fewer per 1000 participants, 95% CI 62 fewer to 32 more). We rated the certainty of evidence as low for all these outcomes. Naftopidil likely reduced sexual adverse events (RR 0.15, 95% CI 0.06 to 0.42; corresponding to 126 fewer sexual adverse events per 1000 participants, 95% CI 139 fewer to 86 fewer). We rated the certainty of evidence as moderate for sexual adverse events. AUTHORS' CONCLUSIONS: Naftopidil appears to have similar effects in the urological symptom scores and QoL compared to tamsulosin and silodosin. Naftopidil has similar sexual adverse events compared to tamsulosin but has fewer compared to silodosin.

Objective To investigate whether propiverine has a noradrenaline re-uptake inhibitor and whether it acts on the lumbosacral cord or the urethral wall. In addition, we aimed to examine the effect of propiverine on leak point pressure in rats. Methods A total of 72 female and 30 male rats were used to examine the following: (i) the change of leak point pressure caused by intravenous agents in rats with vaginal distention; (ii) the change of leak point pressure caused by intrathecal agents in rats with vaginal distention; (iii) the noradrenaline re-uptake inhibitor action of propiverine; and (iv) catecholamine levels in the bladder wall, urethral wall, cerebrospinal fluid and plasma after oral administration of propiverine. Results Intravenous injection of propiverine, imipramine and duloxetine increased the leak point pressure in rats with vaginal distention. Intrathecal naftopidil decreased the leak point pressure, whereas subsequent intravenous propiverine restored the leak point pressure to the level before intrathecal naftopidil in rats with vaginal distention. Propiverine acted like a noradrenaline re-uptake inhibitor, increasing noradrenaline and/or dopamine levels in the plasma, cerebrospinal fluid, and urethral wall perfusion fluid. Conclusion Propiverine inhibits noradrenaline re-uptake, as well as having antimuscarinic and Ca-antagonist actions. The inhibition of noradrenaline re-uptake by propiverine mainly occurs at the urethral level and partially in the central nervous system, and might stimulate the smooth muscle of the bladder neck and proximal urethra through α1-adrenergic receptors, as well as stimulating the striated muscle of the urethra and pelvic floor by activation of spinal motoneurons. Therefore, propiverine might be effective for both stress and urge incontinence.

Antimuscarinics are the first-line choice of treatment for overactive bladder (OAB). Imidafenacin distributes in the bladder more selectively than in the submaxillary gland and colon, and hence, this drug is considered more useful for OAB than other antimuscarinics. However, the examination of imidafenacin selectivity to bladder over colon using in vivo models is limited. Thus, the author examined whether imidafenacin could induce more selective blockade of the bladder over colon in conscious rats using two pharmacological indices (colonic transit and neostigmine-induced fecal pellet output) and compared its bladder selectivity with propiverine. In the bladder study, the inhibitory doses of antimuscarinics were calculated using the area under the curve of the distension-induced rhythmic contraction in conscious rats. The relative bladder selectivity of imidafenacin to propiverine was 50-fold and 61-fold, respectively, in a dye marker colonic transit model and in a neostigmine-induced fecal pellet output model. This comparative study shows that the functional bladder selectivity of imidafenacin is higher than that of propiverine tested under the present conditions in conscious rats.

We carried out a systematic review and meta-analysis to assess the efficacy and safety of imidafenacin for treating overactive bladder in adult. A literature review was performed to identify all published randomized placebo-controlled trials of imidafenacin for the treatment of OAB. The search included the following databases: MEDLINE, EMBASE. The reference lists of retrieved studies were also investigated. Five publications involving a total of 1,428 patients were used in the analysis, which compared imidafenacin with propiverine and solifenacin. We found that imidafenacin was effective in treating OAB in our meta-analysis, which was similar to propiverine in its efficacy. The mean number of UI per week (the standardized mean difference (SMD) = 1.23, 95 % CI −0.19 to 2.65, p = 0.09), the mean number of urgency episodes per day (SMD = 0.26, 95 % CI −0.11 to 0.63, p = 0.17), the mean number of micturitions per day (SMD = 0.01, 95 % CI −0.30 to 0.31, p = 0.96), and the mean urine volume (ml) per micturition (SMD = −13.04, 95 % CI −20.45 to −5.62, p = 0.0006) indicated that imidafenacin was similar to propiverine in its efficacy. Mean OABSS (SMD = 0.48, 95 % CI −0.08 to 1.03, p = 0.09) indicated that imidafenacin was also similar to solifenacin in its efficacy. Besides, imidafenacin was better tolerated than propiverine in the safety, indicated by dry mouth (OR 0.73, 95 % CI 0.54–0.98, p = 0.04) and any adverse events (OR 0.63, 95 % CI 0.46–0.88, p = 0.006). Moreover, imidafenacin was also better tolerated than solifenacin in the safety, indicated by constipation (OR 0.21, 95 % CI 0.08–0.53, p = 0.001) and any adverse events (OR 0.33, 95 % CI 0.15–0.71, p = 0.004). This meta-analysis indicates that imidafenacin was similar to propiverine or solifenacin in its efficacy for OAB and was better tolerated than propiverine or solifenacin in the safety for OAB. We conclude that imidafenacin is preferable to propiverine or solifenacin from a perspective of safety.

Incidences of overactive bladder (OAB) and cognitive dysfunction increase with aging. Treatment of OAB with antimuscarinic agents may result in cognitive decline, especially in patients with Alzheimer's disease (AD). The aim of this study is to evaluate the effect of antimuscarinic treatment on cognitive functions, depression, and quality of life (QOL) of patients with OAB.This non-interventional prospective observational study was conducted in a geriatric medicine outpatient clinic. Overall, 168 OAB patients were enrolled. Patients were followed up in five groups: oxybutynin, darifenacin, tolterodine, trospium, and control groups. Follow-up visits were done at second, third, and sixth months. Comprehensive geriatric assessment, cognitive and mood assessment, QOL scales (IIQ-7, UDI-6) were performed.Mean age of the patients was 73.5 ± 6.1. Of the 168 patients, 92.3% were female, 83.3% benefited from the treatment, and 37.1% discontinued the medication. Discontinuation rate and frequency of side effects were more frequent in the oxybutynin group. Mini Mental State Examination scores did not decline after treatment, even in AD patients. Geriatric Depression Scale scores, Activities of Daily Living scores, and QOL scores significantly improved after treatment.Antimuscarinic agents are effective in OAB treatment. They have a positive impact on daily life activities, depression, and QOL indices. Furthermore, they do not have a negative effect on cognitive function in older adults with or without AD.

Orally disintegrating tablets (ODTs) containing propiverine hydrochloride (which is extremely bitter and leaves a feeling of numbness in the mouth) were prepared with a combined use of physical and organoleptic taste masking. Propiverine-loaded masking particles (PLMPs) were prepared with different amounts of gastric-soluble coatings as physical masking. ODTs without organoleptic masking were prepared by mixing each group of PLMPs with Ludiflash®, crospovidone, and magnesium stearate. ODTs with organoleptic masking were also prepared by addition of L-menthol, aspartame, thaumatin, and cinnamon. Fifteen-minute dissolution of propiverine in solutions with pH 1.2 was ≥ 85% for all ODTs, whereas that in pH 6.8 solutions was ≤ 85% and increased with physical masking. A single blind randomized crossover trial was conducted. Ten healthy volunteers were asked to quantify the bitterness, numbness, and overall palatability using a 100-mm visual analog scale (VAS) at the period of disintegration as well as 1 and 5 min later. VAS scores of bitterness, numbness, and overall palatability improved along with increasing amounts of physical masking, and the effects persisted for 5 min. VAS scores for numbness increased over time regardless of the amount of physical masking. Bitterness, numbness, and overall palatability were significantly improved by organoleptic masking if the amount of physical masking was small. Combined use of physical and organoleptic masking is useful for improving palatability of ODTs containing propiverine.

The cationic, water-soluble quaternary trospium chloride (TC) is incompletely absorbed from the gut and undergoes wide distribution but does not pass the blood-brain barrier. It is secreted by the kidneys, liver, and intestine. To evaluate potential transport mechanisms for TC, we measured affinity of the drug to the human uptake and efflux transporters known to be of pharmacokinetic relevance. Affinity of TC to the uptake transporters OATP1A2, -1B1, -1B3, -2B1, OCT1, -2, -3, OCTN2, NTCP, and ASBT and the efflux carriers P-gp, MRP2 and MRP3 transfected in HEK293 and MDCK2 cells was measured. To identify relevant pharmacokinetic mechanisms in the bladder urothelium, mRNA expression of multidrug transporters, drug metabolizing enzymes, and nuclear receptors, and the uptake of TC into primary human bladder urothelium (HBU) cells were measured. TC was shown to be a substrate of OATP1A2 (Km = 6.9 ± 1.3 μmol/L; Vmax = 41.6 ± 1.8 pmol/mg·min), OCT1 (Km = 106 ± 16 μmol/L; Vmax = 269 ± 18 pmol/mg·min), and P-gp (Km = 34.9 ± 7.5 μmol/L; Vmax = 105 ± 9.1 pmol/mg·min, lipovesicle assay). The genetic OATP1A2 variants *2 and *3 were loss-of-function transporters for TC. The mRNA expression analysis identified the following transporter proteins in the human urothelium: ABCB1 (P-gp), ABCC1-5 (MRP1-5), ABCG2 (BCRP), SLCO2B1 (OATP2B1), SLCO4A1 (OATP4A1), SLC22A1 (OCT1), SLC22A3 (OCT3), SLC22A4 (OCTN1), SLC22A5 (OCTN2), and SLC47A1 (MATE1). Immuno-reactive P-gp and OATP1A2 were localized to the apical cell layers. Drug metabolizing enzymes CYP3A5, -2B6, -2B7 -2E1, SULT1A1-4, UGT1A1-10, and UGT2B15, and nuclear receptors NR1H3 and NR1H4 were also expressed on mRNA level. TC was taken up into HBU cells (Km = 18.5 ± 4.8 μmol/L; Vmax = 106 ± 11.3 pmol/mg·min) by mechanisms that could be synergistically inhibited by naringin (IC50 = 10.8 (8.4; 13.8) μmol/L) and verapamil (IC50 = 4.6 (2.8; 7.5) μmol/L), inhibitors of OATP1A2 and OCT1, respectively. Affinity of TC to OCT1 and P-glycoprotein may be the reason for incomplete oral absorption, wide distribution into liver and kidneys, and substantial intestinal and renal secretions. Absence of brain distribution may result from affinity to P-gp and a low affinity to OATP1A2. The human urothelium expresses many drug transporters and drug metabolizing enzymes that may interact with TC and other drugs eliminated into the urine.

Background Despite enormous progresses in understanding pathophysiology of the lower urinary tract, antimuscarinics remain the chief clinically well-established approach for improving symptoms of overactive bladder (OAB). Dry mouth on the other hand remains one of the most untolerated systemic side effects of these drugs that limits their uses and results in high discontinuation rate. Three novel drugs have been recently approved by US Food and Drug Administration for treatment of OAB: trospium, darifenacin, and solifenacin. Aims This study has been conducted to provide clear head to head comparative studying of histological and ultrastructural effect of those newly emerging drugs on parotid and submandibular salivary glands and to demonstrate the differential expression of CXCL10 to make a cogent structural and molecular assessment of the relative tolerability of these drugs and the potential mechanisms of occurrence of dry mouth. Methods Fifty male Sprague Dawley rats were equally divided into five groups: Group I (control), Group II (oxybutynin-treated), Group III (trospium-treated), Group IV (darifenacin-treated) and Group V (solifenacin-treated). Histological and ultrastructural studies were performed on parotid and submandibular glands. Measurement of salivary flow, PCR analysis and immunohistochemical assessment of CXCL10 expression have been carried-out. Results Muscarinic receptor antagonists led to various histological, morphometric and ultrastructural changes together with diminished salivary secretion and up-regulation of CXCL10 expression with the mildest alterations observed with solifenacin. Conclusions Solifenacin has shown the least adverse effects to salivary glands. CXCL10 is involved in degenerative changes of salivary glands induced by muscarinic antagonists.

Propiverine, a frequently-prescribed pharmaceutical for the treatment of symptoms associated with overactive bladder syndrome, provoked massive intranuclear and cytosolic protein inclusions in rat proximal tubule epithelium, primarily consisting of the peroxisomal targeting signal 1 (PTS1) containing protein d -amino acid oxidase (DAAO). As this type of nephropathy was also observed for other drugs, the aim was to determine whether propiverine interferes with trafficking and/or import of peroxisomal proteins. To elucidate this, DAAO- and propiverine-specific interaction partners from human HEK293 and rat WKPT cell lines and rat kidney and liver homogenate were determined using co-immunoprecipitation with subsequent nano-ESI-LC-MS/MS analyses. Corroboration of the role of DAAO- and/or propiverine-specific interaction partners in the drug-induced DAAO accumulation was sought via specific immunofluorescence staining of rat kidney sections from control and propiverine-treated rats. Above analyses demonstrated the interaction of propiverine with several protein classes, foremost peroxisomal proteins (DAAO, MFE2, HAOX2) and proteins of the protein quality control system, i.e. chaperones (HSP70 and DnaJ co-chaperones), proteases and proteasomal proteins (regulatory subunits of the 26S proteasome; Rpn1/2). The immunofluorescence analysis revealed mislocalization of many PTS1-proteins (DAAO, CAT, MFE2, ACOX1, EHHADH) in rat renal sections, strongly suggesting that propiverine primarily binds to PTS1 proteins resulting in the formation of PTS1 but not PTS2 or peroxisomal membrane protein (PMP) accumulations. Moreover, chaperones involved in peroxisomal trafficking (HSC70, DnaJB1) and peroxisomal biogenesis factor proteins (PEX3, PEX5, PEX7), also presented with distinct mislocalization patterns. Concomitantly, an increased number of peroxisomes was observed, suggestive of a compensatory mechanism for the presumably suboptimally functioning peroxisomes. Overall, the data presented suggested that propiverine interacts exclusively with DAAO or with a selected number of PTS1 proteins. The consequence of this interaction is the abrogated trafficking and peroxisomal import of PTS1 proteins concomitant with their nuclear and cytosolic accumulation due to inhibited degradation and imbalanced protein homeostasis.

Two simple and accurate chemometric-assisted spectrophotometric models were developed and validated for the simultaneous determination of chlordiazepoxide (CDZ) and clidinium bromide (CDB) in the presence of an alkali-induced degradation product of CDB in their pure and pharmaceutical formulation. Resolution was accomplished by using two multivariate calibration models, including principal component regression (PCR) and partial least-squares (PLS), applied to the UV spectra of the mixtures. Great improvement in the predictive abilities of these multivariate calibrations was observed. A calibration set was constructed and the best model used to predict the concentrations of the studied drugs. CDZ and CDB were analyzed with mean accuracies of 99.84 ± 1.41 and 99.81 ± 0.89% for CDZ and 99.56 ± 1.43 and 99.44 ± 1.41% for CDB using PLS and PCR models, respectively. The proposed models were validated and applied for the analysis of a commercial formulation and laboratory-prepared mixtures. The developed models were statistically compared with those of the official and reported methods with no significant differences observed. The models can be used for the routine analysis of both drugs in QC laboratories.

Aim To evaluate the effect of adding low dose trospium chloride with transcutaneous posterior tibial nerve stimulation (TPTNS) in the treatment of overactive bladder (OAB) in females after failure of behavioral therapy. Methods We randomized 30 women with OAB, in two groups: G I received 30 min TPTNS, three times a week; GII received TPTNS plus 20 mg trospium chloride daily. OAB Symptom Score questionnaire (OABSS), Incontinence Impact Questionnaire-short form 7 (IIQ-7), 3 day voiding diary and urodynamics at weeks 0 and 8 were evaluated. Results The groups were similar before treatment. Eight weeks after treatment, the mean OABSS decreased significantly to 8.53 ± 1.30 for group II vs 10.0 ± 2.0 for GI (P

Study of validity of the Medication Adherence Self-Report Inventory (MASRI) for use in clinical practice to treat patients with benign prostatic obstruction (BPO) accompanied with overactive bladder (OAB) symptoms.During 12 weeks of the randomized study, 452 patients with BPO and OAB symptoms (mean age of 61.3 (12.7)) were studied for adherence to the treatment with Tamsulosin, Solifenacin and Trospium using the MASRI. External monitoring instruments included the Brief Medication Questionnaire (BMQ) and the visual remaining pill count. The state of the prostate gland and the lower urinary tract was monitored using questionnaires I-PSS, OAB Awareness Tool, uroflowmetry and voiding diaries.Correlation between the percentage of men non-adherent to treatment (MASRI) and the percentage of patients having a belief barrier on the screen of the BMQ was r = 0.89, p ≤0.05, r = 0.92, p ≤0.01, r = 0.85, p ≤0.05, a number of missed doses on the Regimen Screen of the BMQ was r = 0.79; p ≤0.05; r = 0.81; p ≤0.05; r = 0.75, p ≤0.05, a number of non-adherent patients according to the BMQ was r = 0.83 (p ≤0.05), r = 0.88 (p ≤0.05), r = 0.79, p ≤0.05, the results of the pill count were r = 0.65-0.76; p ≤0.05-0.01. These data confirm high validity of the MASRI.The MASRI is a valid tool for rapid assessment of adherence to treatment of patients with BPO and OAB receiving Tamsulosin and antimuscarinic drugs and may be recommended for use in clinical practice.

To study the effectiveness and safety of combined standard-dosed Solifenacin and Trospium for management of symptoms of overactive bladder (OAB) in elderly patients after the treatment with Tamsulosin.A total of 417 men over 50 years of age (average age 57.9 (8.3)) with diagnosed prostatic obstruction (score 8-19 according to I-PSS), who had not taken Tamsulosin before, were enrolled in the study. I-PSS questionnaire (from 8 to 19 - moderate) and Awareness Tool questionnaire for evaluating OAB symptoms (total score for OAB symptoms over 8) were used at the beginning and at the end of the observation. Also, urodynamic parameters were examined.Percentage of patients with prevalent symptoms of obstruction of urethra decreases after the treatment with Tamsulosin and then rises again (36.2%), but absolute number of patients remains smaller than initial data. Percentage of patients with relative prevalence of symptoms of overactive bladder slightly increases against administration of Tamsulosin and reaches initial values at the time of administration of anti-muscarinic drugs with absolute decrease in number of such patients.Combination of Trospium and Solifenacin is an effective way to manage residual symptoms of hyperactive bladder during treatment of early obstruction of urinary bladder.

To evaluate the efficacy of anticholinergic agents in the treatment of neurogenic overactive bladder (NOAB) and neurogenic detrusor overactivity (NDO) in spinal cord injury (SCI) patients on clean intermittent catheterisation (CIC). Chronic suprasacral SCI patients on CIC presenting with at least one urinary leakage a day were included. Urodynamics and voiding diaries were performed at baseline and 1 month follow-up. In case of NDO at baseline, an anticholinergic drug was prescribed. The 231 SCI patients presented with one to five urinary leakages per day (mean 2.1). Urodynamics showed NDO in all patients. A new anticholinergic treatment was started in all, either in monotherapy (134 patients) or in association with the existing anticholinergic drug (oxybutynin+trospium bitherapy, 97 patients). The mean maximum bladder capacity significantly increased from 225 to 441 ml, and the mean involuntary detrusor contractions (IDC) significantly decreased from 67 to 41 cm H2O. Only 75 SCI patients (32%) were fully continent. However, 25 out of these 75 patients showed persistent NDO, with amplitudes of IDC above 40 cm H2O in 12 patients. Incontinence was still found in 156 SCI patients (67%), with an average of 1,2 leakages a day. In 100 patients, amplitudes of IDC remained above 40 cm H2O. There was no statistical difference between patients on anticholinergic monotherapy or bitherapy at follow-up. Anticholinergic treatment is not always satisfactory in terms of control of NDO and rarely allows full continence. Urodynamic follow-up is mandatory in all patients, even in those showing clinical continence.

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist mepenzolate bromide (mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-mepenzolate. In vivo, the bronchodilatory activity of (R)-mepenzolate was superior to that of (S)-mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-mepenzolate may have superior properties to (S)-mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.

Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-β1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that mepenzolate bromide (mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO2). Intratracheal administration of mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO2 compared with control. Furthermore, mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of mepenzolate also prevented bleomycin-induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-β1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-β1 activities and its stimulatory effect on GST.

Summary Purpose The efficacy and safety of treatment with alfuzosin 10 mg plus propiverine 10 or 20 mg in men with lower urinary tract symptoms (LUTS) and an overactive bladder were investigated. Materials and methods In this parallel-arm, prospective, multicentre, single-blind study, men who were ≥ 40 years old, had an International Prostate Symptom Score (IPSS) of ≥ 8, an Overactive Bladder Symptom Score (OABSS) of ≥ 3 and an OABSS urgency item score of ≥ 2 were randomised in a 1 : 1 :1 ratio to receive alfuzosin 10 mg alone (Group A) or with propiverine 10 mg (Group B) or 20 mg (Group C) for 8 weeks. Four and 8 weeks after commencing treatment, OABSS was measured along with IPSS, maximal urinary flow rate (Qmax) and postvoid residual volume (PVR). Adverse events were recorded. Results A total of 135 men, including 43 in Group A, 48 in Group B and 44 in Group C, completed the study. Relative to baseline, all groups demonstrated significant reductions in OABSS and the IPSS after eight treatment weeks (p

Aim To assess the efficacy and safety of imidafenacin compared with propiverine for treatment of overactive bladder (OAB) in Korean patients. Materials and methods Patients with OAB symptoms were randomised to double-blind treatment with 0.1 mg of imidafenacin twice daily (group A) or propiverine 20 mg once daily (group B) for 12-week regimen, and assessed for efficacy and safety. The primary efficacy outcome was per cent change of weekly urgency urinary incontinence (UUI) episodes at week 12. The secondary efficacy outcomes were changes in the micturitions per day, urine volume voided per micturition, urgency episodes per day, complete disappearance of incontinence episodes and severity of urgency from baseline to week 12. Quality of life and safety profiles were also compared. Results Of 162 patients randomised, 140 completed the study protocol. The per cent change of weekly UUI episodes at week 12 was −69.1% in group A and −70.4% in group B (both p

The objective of this study was to investigate the potential of λ-carrageenan to work as an absorption modifying excipient in combination with formulations of BCS class 3 substances. Trospium chloride was used as a model BCS class 3 substance. Polyelectrolyte complexes of trospium and λ-carrageenan were produced by layer-by-layer complexation. A λ-carrageenan-containing formulation was administered either in capsules size 9 to rats by gavage or directly into ligated intestinal loops of rats. Exceptionally strong variations were observed in the plasma concentrations of the rats that received λ-carrageenan compared to the control group, but enhanced plasma concentrations were observed only in some of the rats. In vitro permeability studies were performed across Caco2-monolayers and across excised segments of rat jejunum in a modified Ussing chamber to learn more about the mechanism of absorption enhancement. The complex did not show any effect in Caco2-cells, but led to a major enhancement of permeability across excised segments in modified Ussing chambers. Carrageenan did not lead to alterations of tight junctions. The bioavailability enhancing effect thus was most likely due to an interaction of the polyelectrolyte-drug complex with the mucus, which provided an intimate contact between the drug and the absorbing surface. A similar effect was also achievable with other types of carrageenan and was also transferable to other compounds. In conclusion, λ-carrageenan-drug complexes show interesting excipient-drug-epithelium interactions - however, for full utilization of the permeation enhancing potential, an intimate and reproducible contact between absorbing epithelia and the complex is needed.

In the current study the involvement of ion pair formation between bile salts and trospium chloride (TC), a positively charged Biopharmaceutical Classification System (BCS) class III substance, showing a decrease in bioavailability upon coadministration with food (negative food effect) was investigated. Isothermal titration calorimetry provided evidence of a reaction between TC and bile acids. An effect of ion pair formation on the apparent partition coefficient (APC) was examined using (3)H-trospium. The addition of bovine bile and bile extract porcine led to a significant increase of the APC. In vitro permeability studies of trospium were performed across Caco-2-monolayers and excised segments of rat jejunum in a modified Ussing chamber. The addition of bile acids led to an increase of trospium permeation across Caco-2-monolayers and rat excised segments by approximately a factor of 1.5. The addition of glycochenodeoxycholate (GCDC) was less effective than taurodeoxycholate (TDOC). In the presence of an olive oil emulsion, a complete extinction of the permeation increasing effects of bile salts was observed. Thus, although there are more bile acids in the intestine in the fed state compared to the fasted state, these are not able to form ion pairs with trospium in fed state, because they are involved in the emulsification of dietary fats. In conclusion, the formation of ion pairs between trospium and bile acids can partially explain its negative food effect. Our results are presumably transferable to other organic cations showing a negative food effect.

Patient compliance can be reduced when bitter-tasting compounds, such as propiverine hydrochloride, are administered orally. Propiverine hydrochloride is an example of a drug with a bitter taste, used for the treatment of overactive bladders.This study tested whether propiverine free base palatability and aqueous solubility could be improved by crystalline complex formation.We used 42 compounds, and found 9 new propiverine crystalline complexes. The properties and solubility of these complexes were studied using a range of techniques. A taste perception study was carried out using a taste sensor to evaluate the taste masking ability of the crystalline complex formation.The melting points of the crystalline complexes were higher than that of propiverine. The dissolution rates of the crystalline complexes in aqueous buffer solution (pH 6.8) and in purified water were much faster than that of propiverine. Propiverine salicylic acid crystalline complex had substantially less bitterness than propiverine hydrochloride, which was extremely bitter.The present findings indicated that crystalline complex formation provided an effective approach to enhancing propiverine solubility, and to masking its bitter taste.Crystalline complex formation represents a useful and valuable technique for the preparation of orally disintegrating tablets and improving patient compliance, even for substances with bitter tastes.

Background Overactive bladder (OAB) is often associated with a number of co-morbid medical conditions, including diabetes mellitus. This may necessitate several concomitant treatments, thus creating the potential for drug–drug interactions (DDIs). Trospium is renally eliminated, not metabolized via cytochrome P450; therefore, cytochrome P450 DDIs are unlikely. However, coadministration with another renally eliminated drug (e.g., metformin) may theoretically result in a DDI. Objective The objective of this study was to evaluate the pharmacokinetics (plasma and urine) and safety/tolerability of the coadministration of trospium chloride extended release (XR) and metformin under steady-state conditions in healthy male and female subjects. Methods In a single-centre, randomized, open-label, two-group, two-period study in healthy males and females aged 18–45 years, 44 subjects received oral metformin 500 mg twice daily for 3.5 days during one period, and oral trospium chloride XR 60 mg once daily for 10 days, followed by trospium chloride XR 60 mg once daily for 4 days plus metformin 500 mg twice daily for 3.5 days during the other period. The two periods occurred in a crossover fashion, separated by a 3-day washout period. Results Trospium chloride XR coadministration did not alter metformin steady-state pharmacokinetics. Metformin coadministration reduced trospium steady-state maximum plasma concentration (by 34 %) and area under the concentration–time curve from 0–24 hours (by 29 %). Neither drug’s renal clearance was affected. No safety/tolerability issues of concern were observed with coadministration. Conclusion No dosage adjustment is necessary for metformin when coadministered with trospium chloride XR.

Intestinal P-glycoprotein is regio-selectively expressed and is a high affinity, low capacity efflux carrier for the cationic, poorly permeable trospium. Organic cation transporter 1 (OCT1) provides lower affinity but higher capacity for trospium uptake. To evaluate regional intestinal permeability, absorption profiles after gastric infusion of trospium chloride (30 mg/250 ml = [I]2) for 6 h and after swallowing 30 mg immediate-release tablets in fasted and fed healthy subjects, were evaluated using an inverse Gaussian density function to model input rate and mean absorption time (MAT). Trospium chloride was slowly absorbed (MAT ∼10 h) after gastric infusion involving two processes with different input rates, peaking at about 3 h and 7 h. Input rates and MAT were influenced by dosage form and meal. In conclusion, trospium is absorbed from two “windows” located in the jejunum and cecum/ascending colon, whose uptake capacity might result from local abundance and functional interplay of P-glycoprotein and OCT1.

Objective To compare the efficacy and safety of the 30 mg extended release (ER) formulation of propiverine hydrochloride with the 4 mg ER formulation of tolterodine tartrate in patients with overactive bladder (OAB) in a non-inferiority trial. Patients and methods Eligible patients, aged 18-75 years and with symptoms of OAB, were enrolled in this multicentre, randomized, double-blind, parallel-group, active-controlled study. After a 2-week screening period, patients were randomized at a 1:1 ratio to receive either propiverine ER 30 mg or tolterodine ER 4 mg daily during the 8-week treatment period. Efficacy was assessed using a 3-day voiding diary and patient's self-reported assessment of treatment effect. Safety assessment included recording of adverse events, laboratory test results, measurement of post-void residual urine and electrocardiograms. Results A total of 324 patients (244 female and 80 male) were included in the study. Both active treatments improved the variables included in the voiding diary and in the patient's self-reported assessment. The change from baseline in the number of voidings per 24 h was significantly greater in the propiverine ER 30 mg group compared with the tolterodine ER 4 mg group after 8 weeks of treatment (full analysis set [FAS] -4.6 ± 4.1 vs -3.8 ± 5.1; P = 0.005). Significant improvements were also observed for the change of urgency incontinence episodes after 2 weeks (P = 0.026) and 8 weeks (P = 0.028) of treatment when comparing propiverine ER 30 mg with tolterodine ER 4 mg. Both treatments were well tolerated, with a similar frequency of adverse drug reactions in both the propiverine ER 30 mg and tolterodine ER 4 mg groups (FAS 40.7 vs 39.5%; P = 0.8). More patients treated with tolterodine ER 4 mg discontinued the treatment because of adverse drug reactions compared with propiverine ER 30 mg (7.4 vs 3.1%). Conclusions Propiverine ER 30 mg was confirmed to be an effective and well-tolerated treatment option for patients with OAB symptoms. This first head-to-head study showed non-inferiority of propiverine ER 30 mg compared with tolterodine ER 4 mg.

Summary Introduction and aims Behavioral therapy and bowel management are the initial and mainstay treatments for overactive bladder (OAB). Antimuscarinic agents are initiated if these measures fail or symptoms are severe. This study reported the results of treatment with a high dosage of a single drug in children with refractory detrusor overactivity (DO). After the children maintained their previous antimuscarinic medication, a second antimuscarinic drug (trospium chloride) was added as a combination therapy. Materials and method Seventy-two children with DO were enrolled in this prospective study (Figure). They had persistent urgency and urgency urinary incontinence (UUI), even with behavioral bowel therapy, and used an optimized dosage of oxybutynine. All patients demonstrated DO at urodynamic study and started on oxybutynin and trospium chloride at the lowest weight-adjusted dose (10–20 mg/day for trospium chloride). A bladder diary was recorded for 3 days, and urodynamic studies were repeated at 3 and 6 months. Results Sixteen children (22.2%) became dry. Thirty-three children (45.8%) attained a significant decrease in incontinence from an average of 5 to 1.3 episodes per day. A statistically significant increase of mean cystometeric bladder capacity (P = 0.006) was also observed at the 6-month follow-up. The overall success rate was 68%, since 23 children (32%) discontinued combined treatment due to persistent symptoms and/or intolerable side effects. A total of 41 children (57%) reported no side effects, 25 (34.7%) reported mild side effects, six (8.3%) reported moderate side effects, and two withdrew from the study due to their side effects. Download : Download high-res image (282KB) Download : Download full-size image Figure . Flow chart showing clinical response to combined low-dose antimuscarinic treatment. Conclusions The addition of low-dose trospium chloride to oxybutynine seemed to be an effective and safe treatment approach for children with DO who were refractory to high-dosage monotherapy. Different combinations with different antimuscarinics drugs could be evaluated in the future.

Anticholinergics are used to treat overactive bladder. Anticholinergic agents such as propiverine hydrochloride reportedly increase plasma catecholamine levels in rats. It is also known that active urethral closure mechanisms prevents stress urinary incontinence (SUI), which is enhanced by central and peripheral noradrenergic system activation. Therefore, we examined the influence of propiverine hydrochloride on urethral anti-incontinence function in rats. Adult female rats were divided into propiverine and vehicle-treated groups. The propiverine group was given propiverine orally once a day for 2 weeks, after which urethral function and plasma concentrations of catecholamine (dopamine, norepinephrine, epinephrine) were tested. Urethral baseline pressure measured by a microtransducer-tipped urethral catheter and leak-point pressure during passive intravesical pressure elevation were significantly increased in the propiverine group compared with the vehicle group. Plasma norepinephrine and epinephrine levels in the propiverine group were also significantly increased. Propiverine treatment that increases plasma catecholamine levels could contribute to improvement of SUI conditions by increasing urethral resistance.

Objective To evaluate prospectively the efficacy and tolerability of propiverine for long-term treatment of neurogenic detrusor overactivity (NDO) in children. Materials and methods 17 children and adolescents with NDO (10 female, 7 male; average age at last consultation 13.0 years) were evaluated during long-term treatment with propiverine (0.8 mg/kg body weight/day). Outcome measurements included urodynamic parameters, continence, hydronephrosis and tolerability of propiverine. Results Average follow-up was 3.6 years (range 2.0–5.9). The average maximum detrusor pressure was 33.2 ± 4.8 cmH2O and bladder compliance was 20.0 ± 5.4 ml/cmH2O at the last follow-up visit. Maximum cystometric bladder capacity (MCBC) within the normal range was attained in 11 patients; it was still reduced (average of 61% of expected MCBC) in the remaining 6. Incontinence occurred on average once per day. Hydronephrosis was classified for each renal unit separately: grade 0 was measured in 26 and 22 cases, grade 1 or 2 in 6 and 8 cases, grade 3 or 4 in 2 and 4 cases pre and post treatment, respectively. In 6/17 patients adjuvant intravesical oxybutynin was applied, in 4 out of these 6 patients more invasive procedures, such as untethering, augmentation cystoplasty or botulinum toxin injections, were necessitated. Propiverine monotherapy was well tolerated in 11/17 patients. No serious adverse events were encountered during the study period. Conclusion Long-term efficacy and tolerability of propiverine for NDO in children and adolescents is promising: clinically relevant improvements in key urodynamic outcomes were paralleled by improvements in incontinence score.

The muscarinic receptor antagonist propiverine is unique insofar as extended-release (ER) tablets are of higher bioavailability than immediate-release (IR) tablets; this is caused by lower "first-pass" elimination of propiverine via CYP3A4 and efflux transporters in the distal small intestine and colon. Food may influence gastrointestinal transiting and, in turn, may affect regional absorption of propiverine IR and ER. Therefore, food effects on disposition of 30 mg IR and 45 mg ER were measured in a randomized, open, 4-period interaction study in 24 healthy participants. In fasting participants, ER had higher bioavailability than IR (F(rel) = 169%, P = .03). Fat-rich meal did not change the disposition of ER markedly (AUC(0-∞) ratio, 1.00 [90% confidence interval (CI), 0.90-1.11], C(max) ratio, 0.97 [0.87-1.09]). However, C(max) and renal A(e) of the major N-oxidized metabolite (M-5) significantly increased, whereas t(1/2) decreased. By eating a fat-rich meal before administration, the differences in absorption of IR and ER were nearly abolished (AUC(0-∞) ratio for propiverine, 1.12 [90% CI, 0.95-1.33]; AUC(0-∞) ratio for M-5, 0.89 [0.82-0.95]). In conclusion, propiverine ER has higher bioavailability than IR and no positive food effect because it reaches, independently of food, intestinal absorption areas with lower metabolism and efflux transport, which results in constant absorption rates.

The study aimed to compare and evaluate the bioequivalence of a new generic preparation of trospium chloride (CAS NO:10405-02-4) capsule (20 mg, test) and the available import tablet (20 mg , reference) for the requirement of state regulatory criteria in China. A randomized- sequence, 2-period crossover study was conducted in 20 healthy Chinese male volunteers in the fasted state. Blood samples were collected before and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60 h after administration of a single oral dose of 40 mg trospium chloride capsules or tablets, followed by a 7-day washout period. The concentration of trospium chloride was determined by a LC-MS/MS method. Drug And Statistical-Version 2.0 was used to caculate the pharmacokinetics parameters and assess bioequivalence of the two preparations. It was considered bioequivalent if the 90% CIs of the mean ratios (test: reference) for C max , AUC 0–t and AUC 0–∞ were within the range from 80% to 125%, respectively. The main pharmacokinetics parameters of test and reference were as follows: t 1/2 was (15.11±3.24) h and (16.00±3.96) h; T max was (4.0±1.2) h and (4.1±0.9) h; C max was (3.76±1.87) ng·mL − 1 and (3.70±1.89) ng·mL − 1 ; AUC 0–t was (33.51±14.39) ng·mL − 1 ·h and (33.33±14.88) ng·mL − 1 ·h, and the AUC 0–∞ was (35.20±14.88) ng·mL − 1 ·h and (35.16±15.17) ng·mL − 1 ·h. The ratios (test: reference) for C max , AUC 0–t , and AUC 0–∞ were 94.0%~111.7%, 96.4%~106.8%, and 96.1%~105.3%, respectively. No significant differences in pharmacokinetic parameters were found between preparations and periods ( p >0.05). No obvious adverse events were monitored throughout the study based on clinical parameters and patient reports.