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Two facile spectroscopic methodologies were designed for estimating trospium chloride (TPM) in raw material and tablets with high operational reliability and selectivity. The methods were based on using erythrosine B (EB) as a spectroscopic tool for ion-pair complex formation with the drug. In a mild acidic medium of Britton Robinson buffer (pH 4.0), the ionized hydroxyl group in the reagent interacted with the ionized amine in the studied drug. Method I was based on the spectrophotometric measuring of the absorbance of the reaction product at 557 nm. Method II was based on spectrofluorimetric measurement of the quenching effect of TPM on the inherent fluorescence of EB at 550 nm (λ

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.

Unmet expectations are a major cause of perceived treatment failure and discontinuation of treatment. To enable evidence-based counselling of patients on realistic expectations, we determined the chance of patients with overactive bladder becoming free of a given symptom upon treatment with a muscarinic antagonist in a non-interventional setting.Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. They were monitored for becoming free of urgency, urinary incontinence, frequency, or nocturia. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. Categorical data are shown as a percentage of the respective population. Continuous data are expressed as means or as median depending on whether the variability was considered to exhibit a normal distribution.The probability of becoming symptom-free was largest for incontinence and frequency (about 50%), but lesser for urgency (about 20%) and nocturia (about 10%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These findings are in line with those of a limited number of randomized controlled trials.These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence.Unmet expectations are a major reason why patients with overactive bladder syndrome discontinue treatment. To enable evidence-based counselling of patients on realistic expectations, we have determined the chance that patients with overactive bladder become free of urgency, incontinence, voiding frequency, and nocturia. Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. The probability of becoming symptom-free was largest for incontinence and voiding frequency (about 50%), but lesser for urgency and nocturia (about 20%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence.

An overactive bladder and cognitive impairment are two medical and social problems, which have an outmost importance, affecting the quality of life. Both disorders are common in the practice of a urologist, neurologist, internist, and other physicians. Parkinsons disease and multiple sclerosis are the most common neurological diseases, which often manifest by pelvic dysfunction and cognitive dysfunction. The clinician needs to understand the pathogenesis of the underlying disease and the pharmacologic properties of drugs, which can be used both in neurology and urology, as well as in other related specialties.To evaluate cognitive functions in patients with neurogenic overactive bladder treated with trospium chloride.A total of 45 patients with neurological disease (28 with Parkinsons disease [group 1] and 17 with multiple sclerosis [group 2]) were included in the study. All patients had symptoms of an overactive bladder. Trospium chloride was administered in an individually adjusted dose for 12 weeks. Cognitive functions were assessed using the international Montreal Cognitive Assessment (MoCA) before and after the therapy. A change of total scores over time was assessed using the paired Wilcoxon test. The level of significance of0.05 was used (confidence level of 95%).A significant decrease in all studied parameters of an overactive bladder in both groups was seen. The baseline evaluation of the total score on the MoCA scale prior to the start of taking trospium chloride revealed the presence of moderate cognitive impairment (21.3+/-2.9 points) in patients of the group 1. After 12 weeks of therapy, no significant change in cognitive functions was observed (21.7+/-3.1 points; p0.05). In group 2, moderate cognitive impairment (MoCA 22.5+/-3.7 points) was found at baseline. After taking trospium chloride, no significant changes were noted (MoCA 22.9+/-4.1 points) (p0.05). No central nervous system side effects were reported in any group.Trospium chloride is an effective drug, which does not affect cognitive functions in patients with neurogenic overactive bladder. This drug is safe to use in both Parkinsons disease and multiple sclerosis, considering the low risk of cognitive impairment in polypharmacy.

Cantil is reported as a new-found organ specific to the model plant Arabidopsis thaliana that is prominent only in short-day-grown wild-type accessions or long-day-grown genetic mutants with delayed vegetative to reproductive transition. Here, we show that cantils (previously known as nubbins) arise as one of the many phenotypic consequences of aneuploidy resulting from chromosome dosage imbalances in Arabidopsis polyaneuploids despite normal reproductive transition in long-day photoperiods. Without a demonstrated function or adaptive significance, we view cantils as a morphological oddity rather than a separate organ, and as a manifestation of physiological perturbations triggered by genetic and environmental factors. We also note a striking phenotypic resemblance between 'cantil' and 'gynophore', a floral morphological structure that is naturally present in the allopolyploid Arabidopsis suecica.

Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. This manuscript is part of a broader publication from the IQ Consortium's food effect physiologically based pharmacokinetic model (PBPK) modeling working group and complements previous publications by focusing on cases where the food effect was predicted with low confidence. Pazopanib-HCl, trospium-Cl, and ziprasidone-HCl served as model compounds to provide insights into why several food effect predictions failed in the first instance. Furthermore, the manuscript depicts approaches whereby PBPK-based food effect predictions may be improved. These improvements should focus on the PBPK model functionality, especially better reflecting fasted- and fed-state gastric solubility, gastric re-acidification, and complex mechanisms related to gastric emptying of drugs. For improvement of in vitro methodologies, the focus should be on the development of more predictive solubility, supersaturation, and precipitation assays. With regards to the general PBPK modeling methodology, modelers should account for the full solubility profile when modeling ionizable compounds, including common ion effects, and apply a straightforward strategy to account for drug precipitation.

To clarify the efficacy and safety of propiverine hydrochloride for incontinence after robot-assisted laparoscopic prostatectomy (RALP)/laparoscopic radical prostatectomy (LRP), along with changes in the urethral pressure profile (UPP) and quality of life in patients treated with propiverine hydrochloride.In this randomized, comparative study, 104 patients who were aware of urinary incontinence after RALP or LRP were assigned to receive propiverine hydrochloride (treatment group) or not (controls). Pad test results, International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) scores, and UPP results [including maximum urethral closure pressure (MUCP) and functional urethral length (FUL)], were recorded immediately and at 6 months postoperatively.No serious intraoperative complications or adverse events were caused by propiverine hydrochloride. The pad-test negative rate was significantly greater in the treatment group than in controls (89.1% vs. 73.2%, p = 0.044). Changes in ICIQ-SF scores and MUCP were significantly greater in the treatment group than in controls [-6.5 vs. -4.5 points (p = 0.021), and +49.5 vs. +28.7 mmHg (p = 0.038), respectively]. FUL change did not significantly differ between groups [+4.5 vs. +3.8 mm (p = 0.091)]. In univariate logistic regression analyses, body mass index (BMI), MUCP, and treatment with propiverine hydrochloride were significantly associated with continence status. In multivariate analyses, BMI and MUCP were independently associated with continence status [odds ratio (OR), 1.266; 95% confidence interval (CI), 1.047-1.530 (p = 0.015), and OR, 0.986; 95% CI, 0.973-0.999 (p = 0.042), respectively].Treatment with propiverine hydrochloride alleviated urinary incontinence while improving patient symptoms and quality of life after RALP or LRP.

We describe a previously unreported macroscopic Arabidopsis organ, the cantil, named for its ‘cantilever’ function of holding the pedicel at a distance from the stem. Cantil development is strongest at the first nodes after the vegetative to reproductive inflorescence transition; cantil magnitude and frequency decrease acropetally. Cantils develop in wild-type Arabidopsis accessions (e.g. Col-0, Ws and Di-G) as a consequence of delayed flowering in short days; cantil formation is observed in long days when flowering is delayed by null mutation of the floral regulator FLOWERING LOCUS T. The receptor-like kinase ERECTA is a global positive regulator of cantil formation; therefore, cantils never form in the Arabidopsis strain Ler. ERECTA functions genetically upstream of heterotrimeric G proteins. Cantil expressivity is repressed by the specific heterotrimeric complex subunits GPA1, AGB1 and AGG3, which also play independent roles: GPA1 suppresses distal spurs at cantil termini, while AGB1 and AGG3 suppress ectopic epidermal rippling. These G protein mutant traits are recapitulated in long-day flowering gpa1-3 ft-10 plants, demonstrating that cantils, spurs and ectopic rippling occur as a function of delayed phase transition, rather than as a function of photoperiod per se.

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.

Food induced viscosity in the gastrointestinal tract is reported to reduce the bioavailability of tablets containing BCS class 3 drugs, mainly by retarding their disintegration and dissolution of the active pharmaceutical ingredient. The role of formulation factors in minimizing this negative food effect is largely unknown. Combinations of disintegrants were studied together with soluble and insoluble fillers and trospium chloride as model drug substance. Different batches of tablets were compressed at 10 kN and 30 kN, by incorporating different combinations of croscarmellose sodium (CSS), cross-linked (CPD) and sodium starch glycolate (SSG) at low level i.e, 2% + 2% and high level i.e, 4% + 4% of compressional weight, while taking lactose as a soluble filler and dibasic calcium phosphate (DCP) and microcrystalline cellulose (MCC) as insoluble fillers. Under low viscous conditions, disintegration of DCP based tablets was faster compared to lactose based tablets, but under high viscous conditions, simulating the effect of an ingested FDA meal, the disintegration behavior was reverted. Increased compressional force prolonged the disintegration of lactose and DCP based formulations under fasted conditions. However, when evaluated under food viscosity conditions, DCP based tablets compressed at higher force showed rapid disintegration while no effect of increased compressional force in lactose based tablets was observed. MCC based tablets in particular showed largely prolonged disintegration times in viscous media irrespective of the disintegrant type and levels investigated. Disintegrant combinations possessing wicking ability with minimum or no gelling were found to reduce disintegration times. The disintegrant combination of CPD + CCS was effective in reducing disintegration and enhancing dissolution besides not being affected by changes in compressional force and their total proportion in the tablet. In conclusion, it is recommended to evaluate formulations under increased viscosity conditions during the development phase of tablets with an objective to minimize the negative effect of food viscosity on disintegration and dissolution.

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.

The anticholinergic drug trospium is secreted into urine and, to a smaller extent, into bile. Chemically, it is an organic cation, and it is a substrate of the uptake transporters OCT1 and OCT2 as well as for the export proteins MATE1 and MATE2-K as determined in uptake studies using HEK293 cells. So far, neither MATE-mediated export nor the interplay of OCT-mediated uptake and MATE-mediated export have been investigated. Therefore, we used polarized monolayers of single- and double-transfected MDCKII cells (MDCK-OCT1, MDCK-OCT2, MDCK-MATE1, MDCK-OCT1-MATE1, and MDCK-OCT2-MATE1) and the respective control cells (MDCK-Co) for transcellular transport assays. We demonstrate that the transcellular, basal-to-apical transport of trospium is significantly higher in all cell lines compared to control cells over nearly the complete concentration range tested. The transcellular transport mediated by double-transfected MDCK-OCT1-MATE1 and MDCK-OCT2-MATE1 exceeded that in the single-transfected cells (MDCK-OCT1-MATE1 vs MDCK-OCT1: 2.2-fold; MDCK-OCT1-MATE1 vs MDCK-MATE1: 1.7-fold; MDCK-OCT2-MATE1 vs MDCK-OCT2: 6.1-fold; MDCK-OCT2-MATE1 vs MDCK-MATE1: 1.8-fold at a trospium concentration of 1.0 μM; p0.001 each). Thus, we show that MATE1 does not only mediate the uptake of trospium into HEK293 cells but also the efflux of trospium out of polarized MDCKII-cells. Furthermore, our results indicate that OCT1 or OCT2 as uptake transporters and MATE1 as an export protein contribute to the transcellular transport of trospium at concentrations normally reached during trospium therapy. These data suggest that both, OCT-mediated uptake as well as MATE1-mediated efflux may contribute to trospium renal and biliary elimination.

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.

BACKGROUND: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor–blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown. METHODS: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline–trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression–Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. RESULTS: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline–trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline–trospium group and 96.6 in the placebo group. The change from baseline to week 5 was −17.4 points with xanomeline–trospium and −5.9 points with placebo (least-squares mean difference, −11.6 points; 95% confidence interval, −16.1 to −7.1; P

Background: The muscarinic receptor antagonist trospium chloride (TCl) is used for pharmacotherapy of the overactive bladder syndrome. TCl is a hydrophilic positively charged drug. Therefore, it has low permeability through biomembranes and requires drug transporters for distribution and excretion. In humans, the organic cation transporters OCT1 and OCT2 and the multidrug and toxin extrusion MATE1 and MATE2-K carriers showed TCl transport. However, their individual role for distribution and excretion of TCl is unclear. Knockout mouse models lacking mOct1/mOct2 or mMate1 might help to clarify their role for the overall pharmacokinetics of TCl. Method: In preparation of such experiments, TCl transport was analyzed in HEK293 cells stably transfected with the mouse carriers mOct1, mOct2, mMate1, and mMate2, respectively. Results: Mouse mOct1, mOct2, and mMate1 showed significant TCl transport with Km values of 58.7, 78.5, and 29.3 &micro, M, respectively. In contrast, mMate2 did not transport TCl but showed MPP+ transport with Km of 60.0 &micro, M that was inhibited by the drugs topotecan, acyclovir, and levofloxacin. Conclusion: TCl transport behavior as well as expression pattern were quite similar for the mouse carriers mOct1, mOct2, and mMate1 compared to their human counterparts.

Overactive bladder syndrome (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology. The mainstay of treatment of OAB is anticholinergic/antimuscarinic medication. These drugs block muscarinic receptors throughout the body, not only the bladder, including in the brain, which may lead to cognitive side effects. Anticholinergic load or burden is the cumulative effect of taking drugs that are capable of producing anticholinergic adverse effects. The elderly are more susceptible to these effects, especially as there is increased permeability of the blood brain barrier. The anticholinergic drugs for OAB are able to enter the central nervous system and lead to central side effects. There is increasing evidence that a high anticholinergic load is linked to the development of cognitive impairment and even dementia. Some studies have found an increased risk of mortality. In view of this, care is needed when treating OAB in the elderly. Trospium chloride is a quaternary amine anticholinergic, which has a molecular structure, which theoretically means it is less likely to cross the blood brain barrier and exert central side effects. Alternatively, mirabegron can be used, which is a beta-3 adrenoceptor agonist, which does not add to the anticholinergic load or exert central nervous system side effects. Conservative therapy can be used as an alternative to pharmacological treatment in the form of behavioral modification, fluid management and bladder retraining. Neuromodulation or the use of botox can also be alternatives, but success may be less in the older adult and will require increased hospital attendances.

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).

Objectives To show the efficacy of propiverine hydrochloride in the management of symptoms of stress urinary incontinence in female patients with mixed-type urinary incontinence. Methods The study was carried out as a multicenter single-arm clinical trial at 64 institutions in Japan. The participants were female patients aged ≥20 years with mixed-type urinary incontinence. The frequency of stress urinary incontinence and urgency urinary incontinence was evaluated at baseline and 4, 8 and 12 weeks after treatment with propiverine hydrochloride. Subjective symptoms were evaluated using the Overactive Bladder Symptom Score and the International Consultation on Incontinence Questionnaire-Short Form. Functional urethral length and maximum urethral closing pressure were also measured at baseline and 12 weeks after treatment at the institutions where the urethral pressure profile was taken. Results In total, 49 mixed-type urinary incontinence patients were enrolled in the present study. The number of cases of urgency urinary incontinence was reduced time-dependently, which showed statistically significant differences between baseline and 4, 8 and 12 weeks after treatment. A similar statistically different reduction was also observed for stress urinary incontinence. The mean reduction rates of urgency urinary incontinence and stress urinary incontinence at 12 weeks after treatment were 63.9% and 44.3%, respectively. The total scores of International Consultation on Incontinence Questionnaire-Short Form and Overactive Bladder Symptom Score were gradually reduced, and the differences were statistically significant. Functional urethral length and maximum urethral closing pressure at 12 weeks after treatment did not show any statistical differences compared with those at baseline. Conclusions Propiverine hydrochloride can be an effective therapeutic option for stress urinary incontinence in patients with mixed-type urinary incontinence.

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.

Proper subcellular trafficking is essential to prevent protein mislocalization and aggregation. Transport of the peroxisomal enzyme d-amino acid oxidase (DAAO) appears dysregulated by specific pharmaceuticals, e.g., the anti-overactive bladder drug propiverine or a norepinephrine/serotonin reuptake inhibitor (NSRI), resulting in massive cytosolic and nuclear accumulations in rat kidney. To assess the underlying molecular mechanism of the latter, we aimed to characterize the nature of peroxisomal and cyto-nuclear shuttling of human and rat DAAO overexpressed in three cell lines using confocal microscopy. Indeed, interference with peroxisomal transport via deletion of the PTS1 signal or PEX5 knockdown resulted in induced nuclear DAAO localization. Having demonstrated the absence of active nuclear import and employing variably sized mCherry- and/or EYFP-fusion proteins of DAAO and catalase, we showed that peroxisomal proteins ≤134 kDa can passively diffuse into mammalian cell nuclei—thereby contradicting the often-cited 40 kDa diffusion limit. Moreover, their inherent nuclear presence and nuclear accumulation subsequent to proteasome inhibition or abrogated peroxisomal transport suggests that nuclear localization is a characteristic in the lifecycle of peroxisomal proteins. Based on this molecular trafficking analysis, we suggest that pharmaceuticals like propiverine or an NSRI may interfere with peroxisomal protein targeting and import, consequently resulting in massive nuclear protein accumulation in vivo. published

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 Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

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

Pelvic venous congestion (PC) is thought to be related to several diseases of the lower urinary tract (LUT). We examined the characteristics of the LUT in rats with PC. To create PC, female rats were anesthetized with isoflurane, and the bilateral common iliac veins and bilateral uterine veins were ligated. At 1-8 weeks after either ligation or sham surgery, we performed cystometry with or without administration of carbazochrome sodium sulfonate hydrate or propiverine hydrochloride, histologic examination of the bladder, blood flow imaging, assessment of locomotor activity, measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) and nitric oxide metabolites (NOx), and the Evans blue dye extravasation test. PC elevated frequency of urination after 2-6 weeks, and caused a decrease of spontaneous locomotor activity. In addition, there was a decrease of bladder blood flow, an increase of bladder vascular permeability, an increase of urinary 8-OHdG, a decrease of urinary NOx, and mild inflammatory changes of the bladder. In rats with PC, frequency of urination was normalized by administration of propiverine or carbazochrome. Rats with PC may be used as a model of PC associated with high frequency of urination, and this model may be useful when developing treatment for LUT symptoms associated with PC.

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

An iron-oxygen intermediate species generated in situ in the reductive activation of dioxygen by an iron(II)-benzilate complex of a monoanionic facial N3 ligand, promoted the halogenation of aliphatic C-H bonds in the presence of a protic acid and a halide anion. An electrophilic iron(IV)-oxo oxidant with a coordinated halide is proposed as the active oxidant. The halogenation reaction with dioxygen and the iron complex mimics the activity of non-heme iron halogenases.

A highly efficient two-step asymmetric synthesis of 1H-pyrrol-3(2H)-one derivatives from conveniently accessed 2,3-diketoesters. Aldol products are obtained with up to 89/11 d.r. and 99% ee. Benzilic acid rearrangement produces 1H-pyrrol-3(2H)-ones in good yields without loss of enantioselectivity.

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.

OBJECTIVES Medication adherence with urgency urinary incontinence (UUI) treatment is challenging and the best assessment methodology is uncertain. We sought to describe adherence with anticholinergic (AC) versus placebo (P) by comparing pill counts and MEMSCAP event data and to identify factors associated with adherence. METHODS The randomized controlled AC versus Botox Comparison trial of women with moderate to severe idiopathic UUI included 126 participants initiating AC plus P bladder injection and 121 receiving P pills plus Botox injection. Adherence data on 243 participants (124 AC and 119 P) were calculated by pill count and MEMSCAP data for each 2-month interval during the 6-month study that allowed for dose escalation/drug change. Overall composite adherence estimates were calculated using the average of both methods and weighted by the duration of each 2-month interval. RESULTS Treatment groups had no significant differences in dosing duration (P = 0.76) or mean adherence (AC, 83.3% [16.8] vs. P, 84.8% [13.8]). Only 53% of women met the dichotomous outcome of more than 80% adherence during all intervals. Correlation between adherence by pill counts versus MEMSCAP decreased over time with pill counts demonstrating higher adherence than MEMSCAP (r = 0.53, 0.50, and 0.36 for each 2-month interval). Lower adherence was associated with higher baseline incontinence severity and better UUI quality of life for the AC group and with current smoking status in both groups. CONCLUSIONS Adherence using pill counts and MEMSCAP was reasonably correlated and similar in both the AC and P groups. In the AC group, higher baseline incontinence severity and better UUI Quality of Life were associated with decreased adherence. Smokers were less adherent.

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.

Summary: Stem cell-based therapies have been proposed as a strategy to replace damaged tissues, especially in the nervous system. A primary sensory modality, olfaction, is impaired in 12% of the US population, but lacks treatment options. We report here the development of a novel mouse model of inducible hyposmia and demonstrate that purified tissue-specific stem cells delivered intranasally engraft to produce olfactory neurons, achieving recovery of function. Adult mice were rendered hyposmic by conditional deletion of the ciliopathy-related IFT88 gene in the olfactory sensory neuron lineage and following experimentally induced olfactory injury, received either vehicle or stem cell infusion intranasally. Engraftment-derived olfactory neurons were identified histologically, and functional improvements were measured via electrophysiology and behavioral assay. We further explored mechanisms in culture that promote expansion of engraftment-competent adult olfactory basal progenitor cells. These findings provide a basis for translational research on propagating adult tissue-specific sensory progenitor cells and testing their therapeutic potential. : Olfactory sensory losses lack treatment options. The corresponding author and colleagues report the testing of a cellular therapy for olfactory loss. Inducible hyposmia was produced by targeting ciliopathy to the olfactory lineage in mice, and wild-type adult stem cells engrafted to produce functional neurons, assessed using histology, electrophysiology, and behavioral assay. Keywords: olfaction, anosmia, stem cells, neuron, ciliopathy

A mononuclear iron(II)-α-hydroxy acid complex [(TpPh,Me)FeII(benzilate)] (TpPh,Me = hydrotris(3-phenyl-5-methylpyrazol-1-yl)borate) of a facial tridentate ligand has been isolated and characterized to explore its catalytic efficiency for aerial oxidation of organic substrates. In the reaction between the iron(II)-benzilate complex and O2, the metal-coordinated benzilate is stoichiometrically converted to benzophenone with concomitant reduction of dioxygen on the iron center. Based on the results from interception experiments and labeling studies, different iron-oxygen oxidants are proposed to generate in situ in the reaction pathway depending upon the absence or presence of an external additive (such as protic acid or Lewis acid). The five-coordinate iron(II) complex catalytically cis-dihydroxylates olefins and oxygenates the C–H bonds of aliphatic substrates using O2 as the terminal oxidant. The iron(II) complex exhibits better catalytic activity in the presence of a Lewis acid.

The objective of the study was immunohistochemical evaluation of distribution of various NO synthase fractions in the structural elements of the bladder wall under stress urinary incontinence and its overactivity prior and post Mirabegron, Spasmex, Quercetin therapies and their combinations with Testosterone and Estradiol. Using the immunohistochemical method, we studied the expression of the main fractions of NO synthase in experimental models of hyperactive bladder (OAB) and stress urinary incontinence (SUI). We found that OAB and SUI were characterized by emergence of expression of the inducible fraction (iNOS) predominantly in the interstitial cells of the muscular layer of the bladder and reduced expression of endothelial (eNOS) and neuronal (nNOs) NO synthase fractions. In contrast to Spasmex, Mirabegron and Quercetin in combination with Testosterone and Estradiol contributed to stabilization of eNOS and nNOs expression already at early observation phases, and reduced the level of iNOS expression with its further disappearance in the later observation period.

The aim of this study was to evaluate the influence of Denaverine hydrochloride (DNH) in heifers on calf vitality.A total of 83 calvings with 38 female and 45 male calves were included in the study. Thirty minutes after onset of stage 2 of calving, 400 mg DNH or placebo (0.9% NaCl) were administered subcutaneously. If the calving procedure was not completed after 60 minutes, an extraction was conducted and pulling force was measured by using a digital force gauge. Directly after parturition, vitality of calves was evaluated using a modified APGAR score. Additionally, lactate concentration in blood from Vena auricularis was measured with a handheld measuring device (lactate scout).No effect of treatment was observed on APGAR score and lactate concentration.Denaverine hydrochloride is a regularly used substance in obstetrics in veterinary medicine in many European countries. We could not confirm our hypotheses that treating heifers with DNH has a positive effect on calf vitality evaluated by APGAR score and lactate concentration in blood.ZIEL:: der Studie war, den Effekt einer Behandlung von Färsen mit Denaverinhydrochlorid auf die Vitalität der geborenen Kälber zu testen.Die Auswertung umfasste 83 Färsengeburten, bei denen 38 weibliche und 45 männliche Kälber geboren wurden. Eine halbe Stunde nach Beginn der Aufweitungsphase wurden dem Muttertier randomisiert 400 mg Denaverinhydrochlorid oder ein Plazebo subkutan appliziert. War das Kalb nach 60 Minuten nicht geboren, erfolgte eine Zughilfe mit Messung der benötigten Zugkraft. Unmittelbar nach der Geburt wurde die Vitalität des Kalbes mit einem modifizierten APGAR-Score bewertet und in einer Blutprobe aus der Vena auricularis mit einem Handmessgerät die Laktatkonzentration bestimmt.Es wurde kein Effekt der Behand-lung auf APGAR-Score und Laktatkonzentration der Kälber im Blut festgestellt.Denaverinhydrochlorid ist eine in vielen Ländern der EU in der Geburtshilfe regelmäßig eingesetzte Substanz. Wir konnten die Hypothese, dass die Behandlung von Färsen mit DNH einen positiven Effekt auf die Vitalität der Kälber hat, gemessen am APGAR-Score und der Laktatkonzentration im Blut, nicht beweisen.

Calving is assumed to be an exhausting and painful event. A drug that eases the calving procedure and alleviates pain would help cows, especially those suffering from dystocia. In a randomized, controlled, and blinded trial, we measured the effect of denaverine hydrochloride on physical and physiological calving parameters. Eighty-three Holstein-Friesian heifers were included in the analysis. Pulling force was measured using a digital force gauge interposed between the calf and a mechanical calf puller. The concentration of cortisol was measured in serum before and after parturition. There was no effect of treatment group on calving modality (i.e., spontaneous vs. assisted calving), duration of calving, and cortisol concentration. The area under the curve of pulling force × time (n = 44), however, was significantly smaller in the treatment group compared with the placebo group. Also, duration of calving assistance was numerically shorter in the treatment group compared with the placebo group. The results provide evidence that calving ease can be influenced by denaverine hydrochloride during calving assistance.