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Eight-week-old mice were treated with flavoxate for 5 days and detrusor contractile responses were examined ex vivo under different pharmacological and electrical stimuli.
42 patients with 'unstable bladder' were treated with flavoxate hydrochloride. A previous treatment with parasympathicolytic drugs (propantheline bromide and/or emepronium bromide) was unsuccessful. The instability of the detrusor was proven by a urodynamical investigation. Flavoxate hydrochloride is a papaverine-like smooth muscle relaxant. The results and the complications of the treatment are discussed.
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Four polyvinyl chloride (PVC) matrix membrane electrodes responsive to 2 drugs affecting the urogenital system--oxybutynin hydrochloride (OX) and flavoxate hydrochloride (FX)--were developed, described, and characterized. A precipitation-based technique with tungstophosphate (TP) and ammonium reineckate (R) anions as electroactive materials in a PVC matrix with an OX cation was used for electrode 1 and 2 fabrication, respectively. Electrode 3 and 4 fabrication was based on use of the precipitation technique of FX cation with tetrakis (4-chlorophenyl) borate and R anions as electroactive materials. Fast and stable Nernstian responses in the range 1 x 10(-2)-1 x 10(-6) M for the 2 drugs over the pH range 5-8 revealed the performance characteristics of these electrodes, which were evaluated according to International Union of Pure and Applied Chemistry recommendations. The method was applied to FX and OX in their pharmaceutical formulations and in human plasma samples. The 4 proposed sensors were found to be specific for the drugs in the presence of up to 60% of their degradation products. Validation of the method according to the quality assurance standards showed suitability of the proposed electrodes for use in the quality control assessment of these drugs. The recoveries for determination of the drugs by the 4 proposed selective electrodes were 99.5 +/- 0.5, 100.0 +/- 0.4, 99.9 +/- 0.4, and 100.1 +/- 0.4% for sensors 1-4, respectively. Statistical comparison between the results obtained by this method and the official method of the drugs was done, and no significant difference found.
Flavoxate suppressed carbachol- and calcium ion (Ca2+)-induced contractions of isolated detrusor strips in a noncompetitive and a competitive manner, respectively. Intravenous flavoxate suppressed both initial phasic, and later tonic, bladder contractions induced by electrical stimulation of the distal end of the pelvic nerve. It abolished isovolumetric rhythmic bladder contractions and the associated efferent pelvic nerve activity, without affecting baseline vesical pressure and afferent pelvic nerve activity. When administered intracerebroventricularly or intrathecally, it abolished isovolumetric rhythmic bladder contractions. Flavoxate microinjected into the nucleus reticularis pontis oralis (PoO; pontine micturition inhibitory region) of decerebrated cats inhibited the reflex micturition, but had no effect when microinjected into the locus coeruleus alpha (pontine micturition center) or locus subcoeruleus (pontine urine storage center).
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The effects on urodynamic parameters of i.v. administration of different drugs utilized in the therapy of detrusor instability, have been studied in conscious catheterized rats. Emepronium bromide, oxybutynin and nifedipine affected in a dose-dependent way the micturition pressure (MP), with sporadic changes in bladder volume capacity (BVC). Terodiline induced significant increases in BVC values in a wide range of doses. These changes, however, were always not dose-dependent. The drug significantly reduced MP only at the higher administered dose (10 mg/kg). Flavoxate induced increases of bladder capacity (BVC) not dependent on the administered doses, with no changes in micturition pressure (MP). Indomethacin significantly increased BVC and weakly reduced MP, but the effects were not dose-related. The effects of drugs on BVC were unrelated with the basal value of this parameter, whereas the decrease of MP seems to be related to high basal values before treatment. From a quantitative point of view, cystometrographic recordings in conscious normal rats can provide comparative data among drugs acting on bladder contractility (MP) such as anticholinergics and strong calcium antagonists.
To evaluate what type of patient received tolterodine compared with the spasmolytic drugs previously marketed (oxybutynin, flavoxate, emepronium).
Genitourinary problems, including neurogenic dysfunction, impotence, prostatism, urinary tract infections, and prostate cancer, are common in the elderly, and most of the symptoms can be alleviated through pharmacological management. Patients with neurogenic dysfunction who present with symptoms such as incontinence and urinary retention can be appropriately managed with bladder and sphincter relaxants or stimulants. Anticholinergic agents in the form of oxybutynin, flavoxate, and propantheline are effective bladder relaxants, and phenoxybenzamine, prazosin, and terazosin are commonly used as sphincter relaxants. Bethanechol chloride is the agent most commonly used to stimulate bladder contraction, but physicians should be careful when prescribing it for elderly patients with cardiovascular problems. Organic and psychogenic causes of impotence usually overlap, and oral agents have limited use in the treatment process. The use of yohimbine has increased recently, but its value and rate of success remains questionable. Testosterone is being used widely to treat impotence, but it is only helpful to patients with hypogonadism and should be used with discretion in the elderly, who have a high incidence of prostate cancer. Vasoactive intracavernous pharmacotherapy, on the other hand, is a recently discovered alternative to testosterone with promising results. Although the treatment of choice for benign prostatic hypertrophy is surgery, there have been important pharmacological advances in treating this disorder. alpha-Adrenergic antagonists and anti-androgenic agents have been found to relieve the symptoms of prostatic enlargement. The use of chemotherapeutic and antibiotic agents to treat and suppress acute and chronic urinary tract infections is reviewed; these are second only to pulmonary infections as the most frequent cause of febrile episodes in patients over the age of 65. Lower urinary tract infections can be treated with almost any antibacterial agent. Upper urinary tract infections require full genitourinary evaluation and appropriate antibiotics should be used according to the urine culture sensitivity studies. With the advent of new hormonal agents, more choices are now available for the management of prostate cancer, which is the second most common malignancy in men. Diethylstilbestrol (stilboestrol), an oral estrogen, remains a commonly used agent to achieve castrate levels of androgens in advanced prostatic carcinoma. Agonist analogues, such as goserelin and leuprorelin, of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH); or gonadorelin] achieve the same results as diethylstilbestrol but without the cardiovascular side effects. Antiandrogens are also being used in combination with GnRH agonists to produce complete androgen blockage, with mixed results.
As part of study, among 500 patients evaluated, three most common diagnosis were upper respiratory infections (URIs; 18%), acute gastroenteritis including water-borne diseases (15.8%), and anemia (10.4%). Treatment given to these patients comprised of mostly of antipyretic, analgesic, and antimicrobial agents. Most common drug prescribed was paracetamol for fever. Other common drugs prescribed were amoxicillin/clavulanic acid, chloroquine, artemisin derivative, doxycycline, co-trimoxazole, miltefosine, cephalexin, ceftriaxone sodium, cefixime, oral rehydration salts, ranitidine, omeprazole, pantoprazole, metronidazole, albendazole, ondansetron, diclofenac sodium, piroxicam, ibuprofen, diphenhydramine, codeine-sulfate, amlodipine, ramipril, hydrochlorothiazide, atenolol, salbutamol, etophyline, metformin, glimepiride, fluoxetine, flavoxate, tamsulosin, iron-folic acid, etc. The fact that three or more drugs are given in most of the prescriptions, can be justified due to multiple morbidity and the severity of disease than to irresponsible prescribing.
We assessed 73 reports of 36 potentially relevant trials; 28 reports of ten trials were eligible for inclusion with a total of 1366, predominantly female, participants. Not all participants' with overactive bladder, in five trials had urinary incontinence. Data from five trials with 467 participants, all female, are therefore included in the review. The quality of trials was variable. Few data describing long term follow up are available.Is bladder training better than no bladder training? Data were available for 149 women from two trials comparing bladder training with no bladder training. These described only a limited number of prespecified outcomes, which varied across the two trials. Point estimates of effect favoured bladder training however confidence intervals were wide and no statistically significant differences were found for primary outcome variables.Is bladder training better than other treatments? Only two trials including 125 women compared bladder training with drugs: one with oxybutynin and one with imipramine plus flavoxate. In the former trial the only outcomes demonstrating a statistically significant difference were participant's perception of cure at six months (RR 1.69; 95% CI 1.21 to 2.34) and adverse events (RR 0.03; 95% CI 0.00 to 0.44), both favouring bladder training. In the latter trial participant's perception of cure immediately after treatment just achieved statistical significance (RR 1.50; 95% CI 1.02 to 2.21) favouring bladder training, and this difference was maintained at approximately two months post treatment. One comparison of bladder training with pelvic floor muscle training plus biofeedback included 132 women: none of the differences in the primary outcomes achieved statistical significance.Is combining bladder training with another treatment better than that other treatment alone? One trial compared pelvic floor muscle training plus biofeedback supplemented with bladder training versus pelvic floor muscle training plus biofeedback alone and included 125 women. Of the primary outcomes both participants' perception of improvement and quality of life, both immediately after treatment, achieved statistical significance, favouring the bladder training combined with pelvic floor muscle training and biofeedback group (perception of improvement: RR 1.18; 95% CI 1.01 to 1.39; quality of life: MD -47.20; 95% CI -87.03 to -7.37), this was not sustained at three months.
For chronic OAB/UI patients identified in this study, both persistence and adherence with medication treatment were suboptimal. These results suggest that persistence and treatment discontinuation remains problematic for the OAB/UI population.
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Retrospective, longitudinal, observational study of anonymised data from the UK Clinical Practice Research Datalink GOLD database. Eligibility: age ≥18 yr, ≥1 prescription for target OAB drug (between May 1, 2013 and June 29, 2014), and 12-mo continuous enrolment before and after the index prescription date.
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Canadian guidelines on incontinence have been completed in 2005 reflecting the Canadian health environment. This field of UI is in constant progression and, when of proven efficacy, new medications and devices have to be included in the proposed algorithm of care.
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To investigate the effect of flavoxate (Urispadol) treatment on patients with symptomatic benign prostatic hypertrophy (BPH), with the main weight on the irritative symptoms, a randomized, double-blind, parallel-group, placebo-controlled and multicenter investigation was carried out. Seventy patients entered the study, 37 were allocated to flavoxate treatment on a daily dose of 1,200 mg (400 mg t.i.d.) for 12 weeks, and 33 patients were allocated to placebo treatment. In spite of a sufficient power, the study did not discriminate the two treatment groups in a statistically significant way (p > 0.05), when considering the main endpoints: the irritative symptom score and the global patient evaluation. Conservative treatment of micturition disorders accompanying BPH with flavoxate in doses of 1,200 mg/day cannot be recommended for clinical use.
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An observational, follow-up study.
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Tolterodine was often used as a second-line and even as a third-line treatment, and was prescribed to a "polluted" population in terms of concomitant psychotropic medication. Tolterodine users were 7.5 times more likely to have received another spasmolytic drug (RR 7.5, 95% CI 4.8 to 11.9). In addition, these patients more frequently used antiparkinsonian drugs (RR 4.1, 95% CI 1.6 to 10.4) as well as antipsychotic drugs (RR 2.9, 95% CI 1.4 to 6.2). There was a small difference in concomitant use of antidepressants and benzodiazepines between patients receiving tolterodine versus those taking other spasmolytic drugs.
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To investigate persistence and adherence of medication treatment in chronic overactive bladder/urinary incontinence (OAB/UI) patients, and to evaluate OAB/UI-related comorbidity events associated with persistence.
A model for in vivo screening of spasmolytic compounds of the rat urinary bladder has been developed. It is physiological, specific, and adaptable. A filling volume of the bladder of 0.6-1 ml proved to be optimal. Agonists such as acetylcholine, KCl and BaCl2 exerted almost identical spasmogenic effects on both the in vivo and the in vitro model (isolated rat bladder strip). Moreover, the antagonistic effects of atropine, N-butylscopolammonium bromide, or flavoxate hydrochloride were directly comparable between the two models. Intravenously administered atropine was shown to be effective immediately; after intragastric application the maximum effect can not be observed until after 9 min. The in vivo rat bladder model presented is proposed to be a suitable method for advanced screening of spasmolytic compounds to include their absorption, biotransformation, and excretion.
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Agents which exert their effect on the lower urinary tract by stimulating or depressing the activity of smooth muscle directly are discussed. Many of these drugs also exert other actions on the urinary tract mediated via the autonomic nervous system.
Flavoxate hydrochloride is an antispasmodic agent which exerts an inhibition of the phosphodiesterases, a moderate calcium antagonistic activity, and a local anesthetic effect. Results from preclinical and clinical studies show that flavoxate significantly increases bladder volume capacity (BVC), with greater results if compared to other drugs such as emepronium bromide and propantheline. Moreover in clinical trials, both versus placebo or versus active comparators, flavoxate treatment was associated with a significant improvement in different low urinary tract symptoms, such as diurnal and night frequency, urgency and urinary incontinence, suprapubic pain, dysuria, hesitancy and burning. In addition flavoxate was associated with an overall more favourable safety profile than competitors.
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Urge incontinence (also known as overactive bladder) is a common form of urinary incontinence, occurring alone or as a component of mixed urinary incontinence, frequently together with stress incontinence. Because of the pathophysiology of urge incontinence, anticholinergic/antispasmodic agents form the cornerstone of therapy. Unfortunately, the pharmacological activity of these agents is not limited to the urinary tract, leading to systemic adverse effects that often promote nonadherence. Although the pharmacokinetics of flavoxate, propantheline, scopolamine, imipramine/desipramine, trospium chloride and propiverine are also reviewed here, only for oxybutynin and tolterodine are there adequate efficacy/tolerability data to support their use in urge incontinence. Oxybutynin is poorly absorbed orally (2-11% for the immediate-release tablet formulation). Controlled-release oral formulations significantly prolong the time to peak plasma concentration and reduce the degree of fluctuation around the average concentration. Significant absorption occurs after intravesical (bladder) and transdermal administration, although concentrations of the active N-desethyl metabolite are lower after transdermal compared with oral administration, possibly improving tolerability. Food has been found to significantly affect the absorption of one of the controlled-release formulations of oxybutynin, enhancing the rate of drug release. Oxybutynin is extensively metabolised, principally via N-demethylation mediated by the cytochrome P450 (CYP) 3A isozyme. The pharmacokinetics of tolterodine are dependent in large part on the pharmacogenomics of the CYP2D6 and 3A4 isozymes. In an unselected population, oral bioavailability of tolterodine ranges from 10% to 74% (mean 33%) whereas in CYP2D6 extensive metabolisers and poor metabolisers mean bioavailabilities are 26% and 91%, respectively. Tolterodine is metabolised via CYP2D6 to the active metabolite 5-hydroxymethyl-tolterodine and via CYP3A to N-dealkylated metabolites. Urinary excretion of parent compound plays a minor role in drug disposition. Drug effect is based upon the unbound concentration of the so-called 'active moiety' (sum of tolterodine + 5-hydroxymethyl-tolterodine). Terminal disposition half-lives of tolterodine and 5-hydroxymethyl-tolterodine (in CYP2D6 extensive metabolisers) are 2-3 and 3-4 hours, respectively. Coadministration of antacid essentially converts the extended-release formulation into an immediate-release formulation. Knowledge of the pharmacokinetics of these agents may improve the treatment of urge incontinence by allowing the identification of individuals at high risk for toxicity with 'usual' dosages. In addition, the use of alternative formulations (controlled-release oral, transdermal) may also facilitate adherence, not only by reducing the frequency of drug administration but also by enhancing tolerability by altering the proportions of parent compound and active metabolite in the blood.
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A 22-year-old man was referred to us complaining of enuresis. The excretory urogram and cystogram were almost normal. Spina bifida was not present. The results of the urodynamic examination including uroflowmetry, cystometry, urethral pressure profile, electromyogram and sensory threshold of external urethral sphincter were within normal limits. Amitriptyline hydrochloride and flavoxate hydrochloride showed no effects. Because we found a positive spike wave on the electroencephalogram, the patient was referred to a psychopathologist, and was diagnosed as being in the early stage of schizophrenia. He complained of enuresis as his olfactive hallucination of urine. Psychopathological treatment for 1 year and 2 months resulted in disappearance of his complaining of enuresis.
All four review authors independently assessed eligibility and trial quality, and extracted data. Data were processed as described in the Cochrane Handbook for Systematic Reviews of Interventions.
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Of 2496 eligible patients, 36.9% had only one OAB/UI prescription. The mean MPR was 0.34 (SD 0.21) and the median was 0.3, indicating that on average only about one-third of period of time since medication initiation was covered by the therapy. Only 122 patients exhibited > 80% adherence during the 6-month follow-up-period. Significant predictors of higher persistence included: white ethnicity, previous hospitalization length, starting with tolterodine or oxybutynin extended-release, and previous use of topical drugs or antipsychotics. Nevertheless, previous depression or urinary tract infection (UTI) diagnosis, polypharmacy, significantly increased the odds of early discontinuation. Treatment discontinuation increased the risk of UTI diagnosis by 37% in the post-treatment period (P = 0.03; OR 1.37; 95% CI 1.03-1.84), but had no significant effect on other OAB/UI-related comorbidities.
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To review the efficacy of drug therapy for urinary urge incontinence by examining the published literature.
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NS-21 is under development for the treatment of urinary frequency and urinary incontinence. The purpose of this study was to investigate the effects of NS-21 and its active metabolite, RCC-36, on lower urinary tract function in an experimental rat model of urinary frequency.