Use of Physiologically Based Pharmacokinetic Modeling for Predicting Drug-Food Interactions: Recommendations for Improving Predictive Performance of Low Confidence Food Effect Models.

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.

Effect of desmopressin lyophilisate (MELT) plus anticholinergics combination on functional bladder capacity and therapeutic outcome as the first-line treatment for primary monosymptomatic nocturnal enuresis: A randomized clinical trial.

PURPOSE: To assess the efficacy of desmopressin plus anticholinergic combination therapy as first-line treatment for children with primary monosymptomatic nocturnal enuresis (PMNE) and to analyze this combination's effect on functional bladder capacity (FBC). MATERIALS AND METHODS: A total of 99 children with PMNE were prospectively enrolled from 2015 to 2019 and randomly allocated to a monotherapy group (n=49), with oral desmopressin lyophilisate (MELT) only; and a combination group (n=50), with desmopressin plus an anticholinergic (propiverine 5 mg). Efficacy and FBC were evaluated at 1 and 3 months after treatment initiation; the relapse rate was assessed at 6 months after treatment cessation. RESULTS: The combination therapy group showed a higher rate of complete response than the monotherapy group after 3 months of treatment (44.0% vs. 22.4%, p=0.002). A significant increase in mean FBC was observed only in the combination group, from 88.72±26.34 mL at baseline to 115.52±42.23 mL at 3 months of treatment (p=0.024). Combination therapy was significantly associated with treatment success at 3 months after treatment initiation (odds ratio [OR], 3.527; 95% confidence interval [CI], 1.203-6.983; p=0.011) and decreased risk of relapse at 6 months after treatment cessation (OR, 0.306; 95% CI, 0.213-0.894; p=0.021), by multivariable analysis. CONCLUSIONS: This study represents the first prospective, randomized controlled trial showing higher response rates and lower relapse rates with desmopressin plus anticholinergic combination therapy compared with desmopressin monotherapy as first-line treatment for children with PMNE.

Comparision effects of solifenacin, darifenacin, propiverine on ocular parameters in eyes: A prospective study

ABSTRACT 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.

Comparision effects of solifenacin, darifenacin, propiverine on ocular parameters in eyes: A prospective study.

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) signifi cantly 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) signifi cantly 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) signifi cantly 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.

Pharmacokinetic Drug-Drug Interactions Between Trospium Chloride and Ranitidine Substrates of Organic Cation Transporters in Healthy Human Subjects.

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.

Cardiovascular safety of antimuscarinic add-on therapy in patients with overactive bladder who had a suboptimal response to mirabegron monotherapy: A post hoc analysis from the Japanese MILAI II study.

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.

Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity.

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.

Overactive bladder - pharmacological treatment.

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.

Overactive bladder - pharmacological treatment

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.

Designing robust immediate release tablet formulations avoiding food effects for BCS class 3 drugs.

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.

Long-term safety and efficacy of antimuscarinic add-on therapy in patients with overactive bladder who had a suboptimal response to mirabegron monotherapy: A multicenter, randomized study in Japan (MILAI II study).

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.

Primary Nocturnal Enuresis: A Novel Therapeutic Strategy With Higher Efficacy.

OBJECTIVE: To introduce a new protocol for patients with primary nocturnal enuresis to increase efficacy of treatment and decrease relapse rate. METHODS: A prospective study was done on 185 children diagnosed with nocturnal enuresis between the years 2007 and 2014. Inclusion criteria consisted of age >5 years, monosymptomatic enuresis or non-monosymptomatic enuresis, strict abidance by the protocol, and follow-up >24 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. RESULTS: 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). CONCLUSION: Adopting combination therapy along with structured withdrawal as per our protocol showed higher success rates and lower relapses in primary nocturnal enuretic children.

Anticholinergic burden and comorbidities in patients attending treatment with trospium chloride for overactive bladder in a real-life setting: results of a prospective non-interventional study.

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).

Effect of denaverine hydrochloride application to heifers on the APGAR score and lactate concentration in newborn calves.

OBJECTIVE: The aim of this study was to evaluate the influence of Denaverine hydrochloride (DNH) in heifers on calf vitality. MATERIAL AND METHODS: 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). RESULTS: No effect of treatment was observed on APGAR score and lactate concentration. CLINICAL RELEVANCE: 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.

Evaluation of Usefulness of Propiverine Hydrochloride in Poor Responders to Previous Anticholinergics.

OBJECTIVES: In recent years, some patients have been unresponsive to anticholinergics used in the treatment of pollakisuria/urinary incontinence. It has been suggested that propiverine hydrochloride, which has not only anticholinergic activity, but also calcium antagonistic activity, may be useful in poor responders to other anticholinergics. In this study, a specific drug use-results survey was conducted in poor responders to other anticholinergics to evaluate the usefulness of propiverine hydrochloride. METHODS: In this survey, propiverine hydrochloride was administered for 12 weeks to poor responders to previous anticholinergics, and its usefulness was evaluated by the overactive bladder symptom score (OABSS). RESULTS: A total of 3851 subjects at 680 institutions were enrolled in the survey. Of the 3624 subjects included in the safety evaluation (male 1899, female 1725, mean age 73.4 years), 2932 were included in the efficacy evaluation (male 1610, female 1322, mean age 73.8 years). Propiverine hydrochloride significantly improved the OABSS without any safety concerns in poor responders to previous anticholinergics (OABSS, 8.22 at baseline, 6.50 at Week 4, 5.87 at Week 8, and 5.57 at Week 12, P < 0.001). CONCLUSIONS: The present findings indicate that propiverine hydrochloride may be a useful therapeutic option for poor responders to previous anticholinergics.

Transcutaneous posterior tibial nerve electrostimulation with low dose trospium chloride: Could it be used as a second line treatment of overactive bladder in females.

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 < 0.024). The mean IIQ-7 score decreased significantly to 51.86 ± 17.26 in group I vs 31.99 ± 9.26 in group II (P < 0.001). Before treatment, 11 (73.3%) and 4 (26.7%) patients in each group had moderate and poor quality of life (QoL), respectively. After treatment, 6 (40%) and 14 (93.3%) had good QoL, 7 (46.7%) and 1 (6.7%) had moderate QoL in GI and GII, respectively. Two (13.3%) patients in GI had poor QoL. The mean frequency was reduced to 8.60 ± 0.83 vs 10.60 ± 2.32 for GII and GI respectively (P = 0.006). The cystometric capacity increased from 263.40 ± 50.45 to 377.80 ± 112.92 mL (P = 0.001) for GII vs 250.13 ± 56.24 to 296.40 ± 99.0 mL (P = 0.026) for GI. CONCLUSION: TPTNS combined with low dose trospium chloride proved to be more effective than TPTNS alone in the treatment of OAB in females.

Effect of Trospium Chloride on Cognitive Function in Women Aged 50 and Older: A Randomized Trial.

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.

Results of a randomized, double-blind, active-controlled clinical trial with propiverine extended release 30 mg in patients with overactive bladder.

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.

Novel insights into renal D-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo.

Chronic exposure to propiverine, a frequently prescribed pharmaceutical for treatment of overactive bladder and incontinence, provokes massive protein accumulation in the cytosol and nucleus of renal proximal tubule epithelial cells in rats. Previously, the accumulating protein was identified as D-amino acid oxidase (DAAO), a peroxisomal flavoenzyme expressed in kidney, liver and brain. The cellular mechanism of propiverine-induced DAAO accumulation, however, remains unexplained and poorly characterized. Therefore, to further increase the understanding of DAAO accumulation in rat kidney, this study aimed to characterize DAAO accumulations using differential immunofluorescent staining of rat kidney sections as well as in vitro binding analyses and proteasomal activity studies. We demonstrated that propiverine is neither a ligand of DAAO nor an inhibitor of the proteasome in vitro. However, propiverine treatment resulted in a significant decrease of peroxisomal size in rat proximal tubule epithelial cells. Moreover, peroxisomal catalase also accumulated in the cytosol and nuclei of propiverine-treated rats concurrently with DAAO. Taken together, our study indicates that propiverine treatment affects the trafficking and/or degradation of peroxisomal proteins such as DAAO and catalase by a so far unique and unknown mechanism.

Combined low-dose antimuscarinics for refractory detrusor overactivity in children.

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. 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.