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.

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.

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.

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.

Effectiveness of Solifenacin and Trospium for Managing of Severe Symptoms of Overactive Bladder in Patients With Benign Prostatic Hyperplasia.

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

Adherence to Oral Therapy for Urgency Urinary Incontinence: Results from the Anticholinergic Versus Botox Comparison (ABC) Trial.

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.

In vitro and in vivo evaluation under finite conditions of a transdermal oil-in-water type emulsified formulation of propiverine hydrochloride.

A transdermal oil-in-water type emulsified formulation containing propiverine hydrochloride, used for treatment of an overactive bladder (OAB), was evaluated for in vitro skin permeation under finite conditions and in vivo transdermal absorption. Propiverine hydrochloride solubility was determined using 1,3-butyleneglycol, polyoxyethylene (2) oleylether, isostearyl alcohol, and lauryl alcohol. The solubility increased as the solubility parameter value increased. In vitro skin permeation in hairless mouse skin and in vivo transdermal absorption in rats were measured using propiverine hydrochloride dissolved in a simple solution containing these solvents. Dependent on the increase in in vitro flux, the in vivo area under the curve up to 72 h (AUC0-72) was increased. Therefore, the emulsified formulation was prepared containing these ingredients using polyoxyethylene (20) stearylether for optimization. The emulsified formulation was used to conduct in vivo single- and repeated-dose absorption studies in rats. After single-dose transdermal administration of the emulsified formulation, the AUC0-72 was equivalent to that of the simple solution. Furthermore, results using the emulsified formulation indicated an increase in AUC0-72 and significant extension of the elimination half-life, in comparison with oral administration. After repeated-dose administration, a significant minimum plasma concentration was observed compared with oral administration. These results demonstrate that the emulsified formulation is a good option for transdermal delivery of propiverine hydrochloride.

[Trospium chloride once daily for overactive bladder syndrome: results of a multicenter observational study]. / Trospiumchlorid als Einmalgabe bei überaktiver Blase: Ergebnisse einer multizentrischen Beobachtungsstudie.

BACKGROUND: An extended release form of trospium chloride (Urivesc 60 mg® slow release capsules) was recently approved for the treatment of overactive bladder syndrome (OAB). A multicentric, prospective observational study was conducted under routine private practice conditions to assess the safety and efficacy of this treatment in this indication, as well as the effect on quality of life parameters. PATIENTS AND METHODS: A total of 305 patients with OAB syndrome (mean age 60 years, 79% females) were evaluated in this prospective, non-interventional observation study. All patients received trospium chloride once daily (Urivesc® 60 mg extended release capsules) in accordance with the approved prescribing instructions. At the start of therapy and after a treatment period of 4 and 13 weeks (median) the patient urological endpoints and quality of life parameters were assessed. Safety and tolerability were evaluated from the documentation of all adverse events occurring during the entire observation period. RESULTS: Mean daily frequency of micturition decreased over the treatment period with once daily trospium chloride from 11.7 ± 4.3 to 7.7 ± 2.9 per 24 h (p<0.0001). In parallel the mean individual urine volume voided increased from 169.3 ± 79.8 ml to 238.4 ± 122.0 ml (p<0.0001). The proportion of patients with incontinence fell from 36.7% at the initiation of therapy to 20.3% at the end of therapy. Furthermore, the mean number of incontinence pads used declined from 3 per day to 1 per day. More than one third of initially incontinent patients (39.3%) needed no incontinence pads at the end of the treatment period. Quality of life parameters improved significantly in all five subsections recorded (i.e. daily life, family life, sleep quality, self esteem and ability to travel). The safety and tolerability of Urivesc 60 mg extended release was good, with a particularly low incidence of mouth dryness (1% of patients) reported. No central nervous system (CNS) associated adverse events and no serious adverse events occurred. CONCLUSION: As a once daily formulation prescribed under normal private practice conditions, the new trospium chloride extended-release formulation consistently demonstrated efficacy and tolerability for treatment of OBS. Treatment with once daily trospium chloride 60 mg extended release capsules significantly improved the frequency of micturition and nocturia, as well as incontinence episodes and use of absorptive pads in this patient population, accompanied by an improvement in quality of life. The reason for the good tolerability, in particular the relatively low incidence of mouth dryness, is probably due to the lower peak plasma concentration of trospium (cmax) enabled by the modified-release galenical form employed by the 60 mg extended release formulation. Once daily administration enabled enhanced compliance for the modified release formulation and associated improved tolerability. The limited access of trospium to the CNS afforded by the intact blood-brain barrier and absence of metabolic interaction potential via cytochrome P450 are established characteristics of trospium chloride. This infers a lower potential to impair cognitive function and a lower potential for metabolic interactions with concomitant medications. In the context of elderly patients and multimorbid and polypharmacy scenarios, the sum of these characteristics may afford distinct advantages in treating OAB patients.

Chemotherapeutic effects of different paclitaxel plus poldine combination methods for treatment of ovarian carcinoma.

The study aimed to evaluate the curative effects and toxicity of different paclitaxel (PTX) plus poldine chemotherapeutic combination methods for treatment of advanced ovarian carcinoma. A total of 27 patients with ovarian epithelial carcinoma were divided into four groups: A1, taxotere plus poldine intravenous chemotherapy (n=5); A2, taxotere intravenous chemotherapy combined with poldine intraperitoneal chemotherapy (n=7); B1, paclitaxel plus poldine intravenous chemotherapy (n=6); B2, paclitaxel intravenous chemotherapy combined with poldine intraperitoneal chemotherapy (n=9). Toxic side effects were observed after chemotherapy, and the short-term effects were assessed. Some 25 (25/27) cases completed a four-course treatment, the remaining two stopping halfway due to anaphylactic shock. The total effective rate for the A1 Group was 60% (3/5) and that of A2 group was 71.4% (5/7), Figuires for the B1 and B2 groups were 50% (3/6) and 66.7% (6/9), respectively. In comparisons of toxic side reactions, there were significant differences between taxotere groups and paclitaxel groups, and between intravenous chemotherapy alone groups and intravenous plus intraperitoneal combination chemotherapy groups (p<0.05). Chemotherapy of toxol plus poldine was effective in treatment of advanced ovarian cancer, the toxicities of intravenous plus intraperitoneal combination chemotherapy was lower than that of intravenous chemotherapy alone, and the heart toxicity with taxoere was lower than with paclitexal.

[Additional effect of propiverine for naftopidil-resistant nocturia in the patient with benign prostate hypertrophy].

The efficacy and safety of additional administration of propiverine were prospectively studied for naftopidil-resistant nocturia in patients with benign prostatic hypertrophy (BPH). Patients of 50 years and over with BPH who experienced nocturia twice a night or more and an overall International Prostate Symptom Score (IPSS) of 8 or more were first administered naftopidil (50 or 75 mg/day) for 4 weeks. Thirty subjects who did not show improvement in nocturia and requested further treatment were enrolled in the present study. Propiverine was then administered concomitantly 10 mg/day for 8 weeks. Significant improvement was observed with additional propiverine in the frequency of nocturia on voiding diary, total IPSS, voiding symptom, storage symptom and nocturnal voiding scores. No significant change was observed in the peak urinary flow rate (Qmax), mean urinary flow rate (Qave), voided urine volume, or residual urine volume. Adverse events were dysuria (2 cases), increased residual urine (6 cases), weak urine flow (1 case), thirsty (2 cases), angular cheilitis (1 case). Administration of propiverine was suspended in 7 subjects, 1 following dysuria and 6 following increased residual urine volume. The suspension of propiverine following increased residual urine volume was significantly more prevalent in subjects with pretreatment Qmax values of less than 10 ml/second or in subjects whose prostate specific antigen (PSA) levels were 2 ng/ml or more. In conclusion, the results indicate that additional administration of propiverine may be useful for the patients with BPH who have naftopidil-resistant nocturia. However, caution must be exercised regarding Qmax and PSA levels.

Antimuscarinic drug inhibits detrusor overactivity induced by topical application of prostaglandin E2 to the urethra with a decrease in urethral pressure.

PURPOSE: Antimuscarinic drugs increase bladder capacity without prominent side effects such as urinary retention even when administered to patients with mild to moderate bladder outlet obstruction. Some mechanisms might exist in the urethra to compensate for the emptying function of the detrusor after the administration of antimuscarinic drugs. We investigated the influence of the antimuscarinic drug propiverine (Taiho Pharmaceutical, Tokyo, Japan) on urethral function. MATERIALS AND METHODS: Urethral pressure and rhythmic bladder pressure were simultaneously monitored in urethane anesthetized female Sprague-Dawley rats. Prostaglandin E(2) was continuously administered intravesically or intraurethrally to induce detrusor overactivity. To eliminate the influence of bladder activity and monitor urethral baseline pressure isovolumetric pressure of the urethra was then recorded after cystectomy and ligation of the external urethral meatus. Furthermore, in vitro contractile responses of the urethral circular smooth muscle to field stimulation were examined in the presence of propiverine, tamsulosin (Taiho Pharmaceutical), verapamil, omega-conotoxin and atropine (Sigma). RESULTS: Intravesical or intraurethral administration of prostaglandin E(2) significantly decreased the bladder contraction interval by 10.7% and 36.0%, respectively. Intra-arterial administration of 2 x 10(2) nM/kg propiverine significantly increased the bladder contraction interval in rats receiving intraurethral prostaglandin E(2) by 81.8% but it had no marked effect on rats receiving intravesical prostaglandin E(2). Significant decreases in urethral baseline pressure were found after propiverine administration. Field stimulation induced contraction was inhibited by propiverine and verapamil but not by tamsulosin, omega-conotoxin or atropine. CONCLUSIONS: These results suggest that the inhibitory effects of propiverine are more prominent in rats with detrusor overactivity induced by intraurethral prostaglandin E(2) than by intravesical prostaglandin E(2). Propiverine may compensate for detrusor function by decreasing urethral resistance in the voiding phase.

The overactive bladder: review of current pharmacotherapy in adults. Part 1: pathophysiology and anticholinergic therapy.

Overactive bladder is a syndrome characterised by urinary urgency, with or without urge incontinence, and usually with frequency and nocturia. It affects millions of people of all ages worldwide and causes significant morbidity, especially in terms of health-related quality of life. It poses a huge economic burden on health resources. Managing such patients involves a thorough history, physical examination and the use of pertinent investigations before the initiation of treatment. Therapy consists of lifestyle changes, bladder training, anticholinergics, second-line agents such as resiniferatoxin instillation or botulinum toxin injections into the bladder in refractory cases and, finally, in intractable cases, surgery. In the first part of this review of pharmacotherapy for the treatment of this condition, the focus is on the pathophysiological factors potentially involved in overactive bladder and covers the wide range of currently available first-line anticholinergic agents. Treatment algorithms are suggested on the basis of current literature.

A placebo-controlled, multicentre study comparing the tolerability and efficacy of propiverine and oxybutynin in patients with urgency and urge incontinence.

OBJECTIVE: To assess the tolerability and efficacy of propiverine and oxybutynin in patients with urgency and urge incontinence in a randomized, double-blind placebo-controlled clinical trial. PATIENTS AND METHODS: In all, 366 patients (149 on propiverine, 145 oxybutynin and 72 placebo, ratio 2:2:1) with urgency and urge incontinence were recruited in 32 study centres. Propiverine (group 1, 15 mg three times daily), oxybutynin (group 2, 5 mg twice daily) or placebo (group 3) were administered for 4 weeks, using the double-dummy technique. The dosages were selected specifically to compare the tolerability profile of propiverine with the commonly used therapeutic dosage of oxybutynin. Tolerability was assessed by directly questioning the patients about adverse events at four visits (V-1 before and V0 after a 1-week 'washout' period, V1 after 1 week and V4 after 4 weeks of treatment) during a 5-week surveillance period, and by tolerability ratings of the physicians. Efficacy was assessed using urodynamics at V0 and V4, evaluating the cystometric bladder capacity at maximal and first desire to void, and postvoid residual urine, according to the criteria of the International Continence Society. Additionally, a voiding protocol, overall assessment of clinical symptomatology and efficacy ratings by the physicians were documented. RESULTS: A remarkably high percentage of adverse events was reported in the washout period (VO: 13%, 16% and 18% in groups 1-3, respectively). At V4, the clinically most relevant symptom (dry mouth) occurred in 53% of patients in group 1, in 67% of group 2 and in 28% of group 3. Furthermore, dry mouth was less severe in group 1 than group 2. In contrast to groups 2 and 3, only patients in group 1 showed increasing tolerability during the treatment (from V1 to V4). These tolerability results were further supported by the overall tolerability assessment ('very good' or 'good' tolerability in 67% of group 1, in 59% of group 2 and in 83% of group 3). The urodynamic assessment of efficacy (comparing V0 and V4) showed a statistically significant increase in the mean (sd) maximal cystometric bladder capacity in group 1, being 222 (77) mL at V0 and 311 (125) mL at V4, an increase of 89 (108) mL, and in group 2, at 226 (75) mL and 322 (123) mL, an increase of 96 (106) mL, compared with group 3, at 211 (77) mL and 263 (93) mL, an increase of only 52 (92) mL. The cystometric bladder capacity at first desire to void also increased in group 1 (93 to 160 mL) and group 2 (89 to 160 mL), whereas in group 3 there were only minor changes (93 to 120 mL). Changes in the residual urine volume within and between the treatment groups were minimal and clinically irrelevant. The overall assessment of efficacy showed significant differences between the drugs when compared with placebo. CONCLUSION: Propiverine is a safe and effective drug in the treatment of urgency and urge incontinence; it is as effective as oxybutynin, but the incidence of dry mouth and its severity is less with propiverine than with oxybutynin. The availability of alternative pharmacotherapeutics such as propiverine should reduce the therapeutic failure rate and improves the success rate in the treatment of patients suffering from urgency and urge incontinence.

Efficacy and safety of propiverine in SCI-patients suffering from detrusor hyperreflexia--a double-blind, placebo-controlled clinical trial.

AIMS OF THE STUDY: The aim of this double-blind, randomised, prospective, multicentre trial was to evaluate the efficacy of propiverine in patients suffering from detrusor hyperreflexia caused by spinal cord injury in comparison to placebo. STUDY DESIGN: The treatment period of 14 days comprised visits at baseline (V1) and after 14 days treatment (V2). Fifteen mg propiverine t.i.d. or placebo t.i.d. were administered as medication. The following efficacy parameters were adopted: the urodynamic parameters maximal cystometric bladder capacity, bladder volume on onset of the first as well as duration and amplitude of the maximum detrusor contraction, bladder compliance and residual urine, and subjective assessment of efficacy by physicians. For the evaluation of the safety of propiverine the incidence rate of adverse events by directly questioning as well as laboratory parameters were investigated. For biometrical evaluation t-test for independent groups was applied. RESULTS: One hundred and thirteen patients were investigated. The maximal cystometric bladder capacity increased significantly in the propiverine group, on average by 104 ml (V1: 262+/-132 ml. V2: 366+/-143 ml, P<0.001). The changes in bladder capacity during the first contraction and the maximum detrusor contraction in the verum group were both statistically significant. The bladder compliance documented a more pronounced increase under propiverine in comparison to placebo. Residual urine increased by 37+/-71 ml in the propiverine group, significantly more than in the placebo group (P=0.01). Sixty-three per cent of the patients expressed subjectively an improvement under propiverine in comparison with 23% of the placebo group. Expected anticholinergic adverse events occurred: dryness of the mouth (37% in the verum and 8% in the placebo group), accommodation disorders (28% and 2% respectively). Nausea, constipation, headache, dizziness, tiredness and palpitations were reported in almost comparable incidence rates between 3 and 13% in both treatment groups. Eight drop-outs were registered in the propiverine group (five due to adverse events) and three in the placebo group (one due to adverse events). The laboratory parameters revealed no changes. CONCLUSION: Propiverine proved its efficacy in detrusor hyperreflexia with regard to the urodynamic parameters of the maximal cystometric bladder capacity and detrusor contractility. Anticholinergic adverse events such as dryness of the mouth and accommodation disorders were considered being tolerable. The increase in residual urine reflects the therapeutically desired effect of detrusor relaxation because the majority of patients normally practise intermittent catheterisation for bladder emptying.

Early hepatic changes induced in rats by two hepatocarcinogenic organohalogen pesticides: bromopropylate and DDT.

The aim of the present studies was to describe the effect of two organohalogen pesticides: DDT and bromopropylate, on early changes in rat liver, proposed in the literature to be useful endpoints in screening of non-genotoxic hepatocarcinogens and/or liver tumor promoters. We investigated the effects on the following endpoints: hepatomegaly, mitogenesis (DNA synthesis, mitotic activity, percentage of binuclear cells) and cytochrome CYP2B1-dependent monooxygenase induction. The histological and cytochemical changes in the liver were also recorded. Male Wistar rats received bromopropylate in one, three or five daily oral doses of 125, 250, and 500 mg/kg body wt. day-1. DDT was applied as one, three, and five daily oral doses of 24 mg/kg body wt. day-1 (this dose is close to the mean hepatocarcinogenic dose in male Wistar rats: 34.1 mg/kg body wt. day-1). In the case of both pesticides the early effects observed consisted of hepatomegaly accompanied by an increase in the p-nitroanisole O-demethylase activity and hepatocyte proliferation. Hepatocyte proliferation was elevated during the total experimental period. Vacuolated cytoplasm and evident focal necrosis may suggest that the maximal increase in hepatocyte proliferation, preceding hepatomegaly, is at least partly related to a regenerative liver response to pesticides. In addition to the above-mentioned early changes, the present findings provide new evidence for the occurrence of dose-dependent abnormal mitoses (and c-mitoses) in the hepatocytes of the bromopropylate and DDT treated rats.

Bromopropylate: induction of hepatic cytochromes P450 and absence of covalent binding to DNA in mouse liver.

Oral administration of benzilic acid ester-based acaricide bromopropylate at daily doses of 3, 15, 100, and 300 mg/kg body wt to young adult male Tif:MAGf mice for 14 days caused slightly increased liver weights in the high-dose group. A dose-dependent increase of the microsomal cytochrome P450 content was accompanied by elevated ethoxycoumarin O-deethylase, ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylase, and total testosterone hydroxylase activities. When compared with mice treated in parallel with the model compounds for hepatic xenobiotic metabolizing enzyme induction, phenobarbitone, and 3-methylcholanthrene, the enzyme activity changes observed with bromopropylate largely equalled those expressed in phenobarbitone-treated mice. Immunochemical studies with monoclonal antibodies against rat liver cytochrome P450 isoenzymes of the gene families 1A, 2B, 3A, and 4A confirmed that bromopropylate is a phenobarbitone-type inducer in the mouse liver. Titration of liver microsomal suspensions with bromopropylate yielded Type I substrate binding spectra. The specific amplitude was increased 1.5-fold when microsomes from bromopropylate-treated mice (300 mg/kg body wt) were used instead of control microsomes, indicating the induction of cytochromes P450 catalyzing the oxidative metabolism of the test compound. Single oral administration of 300 mg/kg body wt [14C]bromopropylate to male mice, without or following pretreatment for 14 days with 300 mg/kg body wt unlabeled bromopropylate, gave no indication for DNA binding of the test compound in the liver. This excludes a genotoxic potential via covalent DNA modification. The results suggest that, in analogy to phenobarbitone, bromopropylate acts as a tumor promotor rather than a tumor initiator in the mouse liver.

[Clinical and urodynamic effects of oral propiverine therapy in neurogenic urinary incontinence. A multicenter study for optimizing dosage]. / Klinische und urodynamische Effekte einer oralen Propiverintherapie bei neurogener Harninkontinenz. Eine multizentrische Studie zur Dosisoptimierung.

The efficacy and tolerability of propiverine hydrochloride (in doses of 15, 30, 45 and 60 mg/day) were evaluated in the treatment of 66 patients suffering from neurogenic incontinence for 21 days in an open, randomized, multicentre, parallel-group trial. Evaluation of efficacy was based on changes in cystometry, flow measurements and micturition and that of safety on adverse reactions and blood chemistry. The bladder volume increased and bladder pressure decreased dose dependently; the ratio of the two increased by 0.6, 3.3, 3.8 and 8.1 ml/cm H2O after 15, 30, 45 and 60 mg/day respectively. Some 54% of patients had a decreased micturition frequency after 15 mg/day and about 80% after 30-60 mg/day. At the same time, 8, 35, 12 and 42% of patients had subjective anticholinergic symptoms after therapy with 15, 30, 45 and 60 mg/day, respectively. The results suggest that propiverine is a safe and effective drug for the treatment of neurogenic incontinence. A daily dose of 30 mg propiverine is recommended; individual adjustment of the maintenance dose to 15 or 45 mg/day may be necessary.

Pain after thoracic surgery.

In order to evaluate postoperative pain treatment following thoracic surgery, 214 medical records of patients who were operated during 1986-1988 were examined. Nurses' comments concerning pain and the amounts of analgesics given during the 2 postoperative days were recorded. The 150 patients who were still alive in December 1989 were sent a postal questionnaire which asked about the pain and the efficacy of pain relief they had received after their operation. They were also asked if they still had pain which they connected to the thoracotomy and if any attempts had been made to treat that pain. The mean consumption of intramuscular oxycodone was 38 mg during the 1st and 33 mg during the 2nd postoperative day. The administration of nonsteroidal anti-inflammatory drugs significantly reduced the opioid consumption on the second but not on the first postoperative day. In 30% of the patients' charts there were no remarks on pain, in 10% there was a mention of no pain, in 40% pain was mentioned and in 20% the patient was reported to have severe pain. During the first postoperative week little pain was experienced by 60% of the patients, considerable pain by 35% and excruciating pain by 5% of the patients being interviewed. The postoperative pain relief was rated as good in 60% of the answers, satisfactory in 38% and poor in 2%. Persistent post-thoracotomy pain lasting for more than 6 months was reported by 44% of the patients, of whom 66% had received treatment for the pain.

[Behavioral pharmacological properties of propiverine hydrochloride (P-4) in mice and rats].

Since propiverine hydrochloride (P-4), an anti-pollakiuria drug, increased the spontaneous motor activity of mice in general pharmacological experiments, behavioral pharmacological effects of P-4 were further studied by experiments for spontaneous motor activity, convulsion-inducing effect, and differential reinforcement of low rate (DRL) schedule in mice and rats. A high dose of P-4 (100 mg/kg, p.o.) increased slightly but significantly the spontaneous motor activity level in rats. P-4 (10, 20, and 50 mg/kg, p.o. for one week) did not affect the activity level in mice, whereas methamphetamine caused the reverse tolerance after being daily administered for one week at a dose of 1 mg/kg, s.c. P-4 (20, 50, and 100 mg/kg, p.o.) did not induce convulsive behaviors such as minimal full seisure (M.F.S.), clonic convulsion (C.C.) and tonic convulsion (T.C.) in combination with a dose (40 mg/kg, i.p.) of pentylenetetrazol, which is below the threshold in mice, whereas methamphetamine (8 mg/kg, s.c.) in combination with pentylenetetrazol induced M.F.S. Under a DRL schedule for food reinforcement in rats, P-4 (50 and 100 mg/kg, p.o.) lowered the reinforcement rate, but it did not affect other parameters. On the other hand, methamphetamine (0.5, 1, and 2 mg/kg, s.c.) facilitated DRL responses and lowered the reinforcement rate, mean of inter-response time, efficiency, respectively, in a dose-dependent manner. These results suggest that P-4 does not possess the methamphetamine-like CNS stimulating effect.