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Overactive bladder (OAB) is a medical syndrome defined by symptoms of urgency, with or without urge urinary incontinence (any involuntary loss of urine), usually with frequency and nocturia. Although anticholinergic agents have been the first-line treatment for OAB for many years, the efficacious pharmacologic management of this condition has been compromised by concerns regarding tolerability. Flavoxate was the first anticholinergic and antispasmodic agent approved by the Food and Drug Administration (FDA) to treat symptoms of OAB but is not routinely used today since newer agents are more effective. The more recent drugs, oxybutynin and tolterodine, have appeared to be equally efficacious in treating the symptoms of OAB in clinical trials; however, tolterodine has proven to be better tolerated with fewer adverse effects. In 2004, the FDA approved the three newest agents for the class: darifenacin, solifenacin, and trospium. Compared with oxybutynin and tolterodine, these agents have a more favorable side effect profile, which can enhance tolerability and patient compliance. Side effects are reduced in part because of the drugs' greater tissue selectivity for inhibiting the bladder muscle contraction over other anticholinergic receptors in the body. In recent clinical trials, darifenacin, solifenacin, and trospium have shown superiority to placebo and efficacy comparable to that of oxybutynin and tolterodine.
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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.
The effects of HY-770 on micturition reflexes in rats, dogs and cats and urethral pressure in dogs were compared with those of flavoxate.HC1 (flavoxate), terodiline.HCl (terodiline) and oxybutynin.HCl (oxybutynin). 1) HY-770, in intravenous (2 and 4 mg/kg) and intraduodenal (12.5 and 25 mg/kg) administrations, dose-dependently abolished the rhythmic bladder contractions in anesthetized rats. The activity of HY-770, in intravenous administration (i.v.), was almost equal to those of flavoxate, terodiline and oxybutynin; and the activity of HY-770, like terodiline, was more potent than that of flavoxate in intraduodenal administration (i.d.). 2) In the cystometrograms, HY-770 (3, 4 or 8 mg/kg, i.v.) dose-dependently increased the time to micturition (capacity of bladder) without decreasing the amplitude of micturition contraction in anesthetized rats, dogs and cats, and HY-770 (25 mg/kg, i.d.) also increased the capacity in anesthetized cats. 3) HY-770 (4 and 8 mg/kg, i.v.) dose-dependently increased the capacity of the bladder in the cystometrograms of pollakiuria induced by either transection of both the hypogastric nerves or chronic cannulation to the bladder in anesthetized or conscious rats, respectively. 4) HY-770 (25 mg/kg, i.d.) slightly decreased the urethral pressure in anesthetized dogs. These results suggest that HY-770 is a promising drug for the treatment of pollakiuria induced by a neurogenic bladder or unstable bladder, etc.
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We conclude that the minimal side effects and high tolerability of flavoxate make it worthy of consideration for the treatment of several clinical urogynecological conditions. It deserves more clinical studies to assess its efficacy as no randomized controlled trials have been performed with flavoxate during the last decade. More studies and novel drug formulations may reveal or improve its efficacy in daily practice.
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Mirabegron, darifenacin, fesoterodine, flavoxate, oxybutynin ER or immediate-release (IR), propiverine, solifenacin, tolterodine ER or IR, and trospium chloride.
Persistence and adherence were statistically significantly greater with mirabegron than with tolterodine ER and other antimuscarinics prescribed for OAB in the UK.
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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.
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Fourteen thousand six hundred thirty-eight subjects with a diagnosis of urinary incontinence made between January 1, 1991, and June 30, 1995; all were aged 65 and older and enrolled in Medicare and Medicaid or the Pharmacy Assistance for the Aged and Disabled programs of New Jersey.
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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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This study was designed to clarify the primary site of action of flavoxate, clinically used for the treatment of urinary frequency.
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The effects of FL-155, which was synthesized to develop a new orally-active anti-pollakiuria agent, on the rhythmic bladder contractions were studied in anesthetized rats. At a pressure exceeding 10 cm H2O in the bladder, a rhythmic bladder contraction was observed up to at least 120 min. This response was abolished by a spinal (C1 level) cut, cuts of both pelvic nerves, thiopental (3.0 mg/kg, i.v.) or lidocaine (1.0 mg/kg, i.v.); and atropine (0.01 mg/kg, i.v.) strongly inhibited the amplitude of the response. FL-155 and flavoxate, in intravenous (0.3-3.0 mg/kg and 1.0-3.0 mg/kg, respectively) and intraduodenal (12.5-100 mg/kg and 200-400 mg/kg, respectively) administrations, dose-dependently abolished the rhythmic bladder contractions, and FL-155 was 8-16 times more potent than flavoxate in intraduodenal administrations. These results suggest that the rhythmic bladder contraction in anesthetized rat may be a polysynaptic reflex through pelvic nerves and the central nervous system (supraspinal level), and FL-155 appears to be a candidate for an orally active anti-pollakiuria agent.
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Following a mandate of the Canadian Urological Association, six Canadian urologists collaborated to produce these guidelines after having extensively reviewed existing foreign guidelines and literature from 1966 to June 2005.
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The effects of clenbuterol, a selective beta 2-agonist, on isolated smooth muscle preparations from the rabbit bladder body, bladder base and proximal urethra have been investigated. The inhibitory effects on resting tension and acetylcholine- and field stimulation-induced contractions in the bladder body were compared with those of flavoxate, atropine, and verapamil. Clenbuterol (10(-10)-10(-7) M) had a strong, concentration-dependent relaxant effect on resting tension of the bladder body, and the relaxant effect was antagonized by propranolol. However, clenbuterol had little effect on the bladder base or proximal urethra. Isoproterenol, a non-selective beta agonist, gave a similar result, but was less potent than clenbuterol. Flavoxate failed to reduce the resting tension, but rather enhanced the spontaneous rhythmic contraction in a concentration-dependent manner. Atropine had little effect. Verapamil produced a concentration-dependent relaxation in the bladder body. Acetylcholine-induced contraction in the bladder body was completely inhibited by pretreatment with atropine (10(-7) M). Clenbuterol, flavoxate, and verapamil concentration-dependently inhibited acetylcholine-induced contraction. Field stimulation-induced contraction in the bladder body was not completely inhibited by atropine. However, the residual contraction was completely inhibited by tetrodotoxin. Clenbuterol, flavoxate, and verapamil concentration-dependently inhibited field stimulation-induced contraction. The inhibitory effects of clenbuterol and verapamil were antagonized by an application of propranolol and an increase in external Ca, respectively. The data suggest that the selective relaxant effect of clenbuterol on the bladder body is due to beta 2-antagonistic action, resulting in the inhibition of the contractile response to acetylcholine or field stimulation. Also, its response was different from that of the other drugs used.
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Medial frontal lobe neurons excited by noradrenaline may facilitate the micturition reflex via activation of inhibitory interneurons, which inhibit descending rostral pontine reticular formation neurons that innervate the lumbosacral glycinergic inhibitory neurons. Therefore, the mechanism of micturition reflex facilitation by the activation of medial frontal lobe neurons involves the rostral pontine reticular formation.
A prospective study was done in pediatric out-patient department of a tertiary care hospital to evaluate the role of urodynamics in the management of primary enuresis in the 5-14-year-old children and to compare the effectiveness of multidimensional behavioral therapy with pharmacological therapy. Hundred and nineteen children between 5-14 years with primary enuresis were evaluated clinically and investigated. Three patients with obvious organic causes were then excluded. The remaining patients were given either behavioral or pharmacological treatment on the basis of urodynamic assessment. Urodynamic abnormalities were seen in 80/116 (68.9%) patients namely uninhibited bladder contraction 50/116 (43.1%), small bladder capacity 20/116 (17.2%), large bladder capacity 4/116 (3.4%), decreased bladder compliance 3/116 (2.5%) and detrusor sphincter dyssenergia 3/116 (2.5%). Combination of abnormal micturition history stating daytime urgency or frequency or dysfunctional voiding symptoms like squatting and/or abnormal voiding charts could predict abnormal results of urodynamics correctly with sensitivity of 81% and specificity of 86.2%. Ultrasound identified only 38/80 enuretics with urodynamic abnormalities although it was 100% specific. Additionally one patient who was identified as having a small bladder capacity on voiding chart was seen to have mild pelvicalyceal dilatation on ultrasound and subsequently on urodynamic assessment was found to have Detrusor sphincter dyssenergia (DSD). Behavioral therapy as compared to drug therapy produced more complete remission (17/18 vs. 14/18) and lesser relapse rate (2/17 vs. 5/14) in monosymptomatic enuretics with normal urodynamics. In patients with urodynamic abnormality, response rates with behavioral therapy, imipramine, oxybutynin and flavoxate were 73.9% (CI 56-91.8%), 89.4% (CI 75.7-100%), 94.2% (CI 84.7-100%) and 89.4% (CI 75.7-100%), respectively. Specific drug therapy as per the urodynamic abnormality was significantly more effective 49/57 [86% (CI 77-95%)] vs 17/23 [73.9% (CI 56.1-91.9%)] at P < 0.05 than behavioral therapy in patients with underlying abnormal urodynamics. Micturition history and voiding chart can be used as screening tool for enuretics. Behavioral therapy should be the first line treatment for mono symptomatic and drug therapy for polysymptomatic enuretics. Urodynamic testing may be reserved for polysymptomatic enuretics with abnormal ultrasound or those who fail to respond to first line treatment.
1. The pharmacological properties of an antispasmodic drug, tiropramide, were studied in isolated smooth muscle preparations. 2. Tiropramide at concentrations of 10(-6) to 10(-4) M relaxed various smooth muscles contracted spontaneously and by smooth muscle stimulants or electrical stimulation. Tiropramide did not interact with all drug-receptors examined, suggesting a pure musculotropic smooth muscle relaxant activity. 3. Tiropramide was found to inhibit both Ca uptake and Ca release in the guinea pig urinary bladder. 4. Tiropramide is considered to be useful to inhibit the contractile response of the urinary bladder, as this organ is mainly innervated by noncholinergic excitatory neurons.
The effects and the possible mode of action of some drugs were studied in isolated preparations of the human upper urinary tract. Norepinephrine, histamine and serotonin had excitatory effects, whereas isoprenaline had inhibitory effects on smooth muscle activity. Norepinephrine induced different types of mechanical activity in different tissues of the human upper urinary tract suggesting different and separate coupling mechanism between the receptors involved and the calcium pools responsible for initiation of contraction. Acetylcholine had only little effects on smooth muscle activity even in high concentrations. Contractions which were triggered by action potentials or depolarizing extracellular potassium concentrations were highly sensitive to calcium channel blockers. Other drugs with relaxing properties such as papaverine, bencyclane, flavoxate or pitofenone seem to have effects on different calcium activation or calcium storing mechanisms.
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A simple, sensitive and selective spectrofluorimetric method has been developed for the determination of 3-methylflavone-8-carboxylic acid as the main active metabolite of flavoxate hydrochloride in human urine. The proposed method was based on the measurement of the native fluorescence of the metabolite in methanol at an emission wavelength 390 nm, upon excitation at 338 nm. Moreover, the urinary excretion pattern has been calculated using the proposed method. Taking the advantage that 3-methylflavone-8-carboxylic acid is also the alkaline degradate, the proposed method was applied to in vitro determination of flavoxate hydrochloride in tablets dosage form via the measurement of its corresponding degradate. The method was validated in accordance with the ICH requirements and statistically compared to the official method with no significant difference in performance.
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The objective of this study was to develop simple, precise, accurate and sensitive UV spectrophotometric methods for the simultaneous determination of ofloxacin (OFX) and flavoxate HCl (FLX) in pharmaceutical formulations. The first method is based on absorption ratio method, by formation of Q absorbance equation at 289 nm (λmax of OFX) and 322.4 nm (isoabsorptive point). The linearity range was found to be 1 to 30 μg/ml for FLX and OFX. In the method-II second derivative absorption at 311.4 nm for OFX (zero crossing for FLX) and at 246.2 nm for FLX (zero crossing for OFX) was used for the determination of the drugs and the linearity range was found to be 2 to 30 μg/ml for OFX and 2-75 μg /ml for FLX. The accuracy and precision of the methods were determined and validated statistically. Both the methods showed good reproducibility and recovery with % RSD less than 1.5%. Both the methods were found to be rapid, specific, precise and accurate and can be successfully applied for the routine analysis of OFX and FLX in combined dosage form.
The inhibitory effects of flavoxate hydrochloride (piperidinoethyl-3-methylflavone-8-carboxylate; hereafter referred as flavoxate) on voltage-dependent nifedipine-sensitive inward Ba2+ currents (I Ba) in human detrusor myocytes were investigated at different temperatures using conventional whole-cell patch-clamp techniques. When the bath-solution temperature was increased from 22 degrees C to 30 degrees C, I Ba peak amplitude was enhanced by approximately twice at several test potentials. Neither the I Ba threshold nor the membrane potentials for the I Ba maximum peak amplitude was affected by the temperature change. The concentration-response curves of flavoxate at both 30 degrees C (Ki = 5.1 microM) and 37 degrees C (Ki = 4.6 microM) were slightly shifted to the left in comparison with that at 22 degrees C (Ki = 10.3 microM). Similar results were also obtained in the presence of nifedipine (Ki = 14 nM at 22 degrees C vs. Ki = 2.5 nM at 30 degrees C and Ki = 2.1 nM at 37 degrees C). Altering the bath-solution temperature from 22 degrees C to 30 degrees C shifted the steady-state inactivation curve of I Ba at -90 mV to the left. At 30 degrees C, the steady-state inactivation curve of I Ba in the presence of flavoxate was also shifted to the left in comparison with that in the absence of flavoxate. Either 3-isobutyl-1-methylxanthine (IBMX) or theophylline, a phosphodiesterase inhibitor, caused little effects on I Ba, although cyclic nucleotides (dibutyryl cAMP and 8-Br-cGMP) inhibited I Ba. These results suggest that the inhibitory actions of flavoxate on I Ba in human detrusor myocytes were slightly changed at different experimental temperatures and that flavoxate directly blocked voltage-dependent L-type Ca2+ channels, not through the inhibition of phosphodiesterase activity pathway.
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Forty patients, aged 51 to 79 years, with nocturia due to bladder instability, resorption of postural edema, or senile decay, were treated with rociverine or flavoxate to test the possibility of reducing or eliminating nocturnal voidings. After a two-day observation period, each patient received either 20 mg of rociverine or 200 mg of flavoxate in a single dose at 8 PM. The following were assessed before the trial and after 14 and 28 days of treatment: number of night voidings, interval between drug administration and first voiding, volume of first voiding, volume of urine voided during the night, volume of morning urine, and total volume of urine passed between 8 PM and 8 AM. Routine laboratory tests performed before and after the trial showed both drugs to be well tolerated. The results of the trial show that rociverine reduced the number of night voidings significantly more (P less than 0.05) than did flavoxate.
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Bladder instability provokes frequency, urgency, urge incontinence and enuresis in a great percentage of patients of both sexes, who undergo urodynamic examination when other clinical elements are not in evidence. The presence of bladder contractions of variable entity, even capable of inducing emptying, during filling are accompanied by a strong desire to micturate. Our study includes daily recordings of rhythm and quantity of micturitions and leaks, evaluation of urethral pressure, transurethral cystometry and uroflowmetry. The urethral pressure profile was performed with the technique of Brown and Wickham by infusing at 2 ml/min with 10-Ch catheter, withdrawn at a speed of 15 cm/min. Transurethral cystometry was performed by a continuous infusion at moderate speed (50 ml/min) of an isotonic solution at room temperature in a recumbent patient with two catheters in the bladder. When the contractions of the detrusor appear, we evaluate the pharmacological response to the filling with a myolitic agent (flavoxate) first, and with synthetic anticholinergic (emepronium bromide) after, with the purpose of discriminating the myogenic or neurogenic nature of the alteration and to propose suitable therapy.
Overactive bladder, very frequent in neurological disorders, leads to very distressing symptoms such as urgency, frequency and incontinence which may dramatically impair the patient's quality of life. The medical approach is essentially pharmacological but the management of the nociceptive factors must not be neglected. In the mild urinary dysfunctions, bladder training can be advised. The pharmacological treatment aims at reducing the parasympathetic activity or at deafferenting the bladder. The antimuscarinic agents are an essential part of the treatment. Oxybutynin is the most widely used medication but recent agents like tolterodin have a better tolerability. Other drugs can also be used such as desmopressin, flavoxate. New molecules are under experiment (darifenacin). In case of troublesome side-effects or resistance to oral medications, local treatments are considered. Intravesical oxybutynin has been tried but has a short-lived efficacy. Intravesical instillation of capsaicine or resiniferatoxin blocks C-fibres afferents and leads to clinical and urodynamic improvement. Recently, injections of botulinum-A toxin in the detrusor have been advocated aiming at blocking the transmission of parasympathetic impulse. The first studies report encouraging results. All these local treatments resulting in bladder paresis are recommended for patients performing self-catheterization. Should these treatments fail, other therapeutic approaches are considered such as intrathecal treatment, neuromodulation, before deciding on neurosurgical or urosurgical procedures.
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Overactive bladder syndrome is defined as "urgency with or without urge incontinence, usually with frequency and nocturia". It is a common condition with significant economic and quality of life implications. While the condition's pathophysiology remains to be fully elucidated, pharmacotherapy is the main treatment option. Despite uncertainty as to drug treatment of choice, anticholinergics are increasingly being used in primary and secondary care settings. This review compares anticholinergic drugs with other types or classes of drugs for treating overactive bladder syndromes.
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This article provides a review of the use of flavoxate hydrochloride in the treatment of urge incontinence. It outlines the pharmacology, mode of action, toxicology and pharmacokinetic studies which have been carried out, and then reviews the clinical studies, including those involving patients with benign prostatic hypertrophy. The effects of dosages of 600-1200 mg/day are compared, particularly regarding safety and tolerability factors. Finally, alternative therapies to flavoxate hydrochloride (alpha-adrenergic receptor blockers, oxybutinin chloride, terodiline hydrochloride, emepronium bromide and imipramine) are summarized. The article is written in the knowledge of recent evidence which indicates that flavoxate hydrochloride exhibits only weak anticholinergic activity on receptors involved in the control of the lower urinary tract.
Propiverine hydrochloride (P-4) is a new derivative of benzilic acid. The effect of P-4 on the vesico-detrusor reflex (corresponding to the first reflex of Barrington) in anesthetized or decerebrated dogs was studied to elucidate the mode of action of the drug. When bladder contraction was induced by electrical stimulation of the distal ending of the pelvic nerve under the bilateral pelvic nerve and hypogastric nerve transection, P-4 (2, 5 and 10 mg/kg, i.v.) significantly inhibited the contraction. A similar effect was also observed following intravenous administration of flavoxate (10 and 20 mg/kg), verapamil (1 mg/kg) or propantheline (2 mg/kg), while thiopental (4 mg/kg, i.v.) had no significant effect. When the bladder was filled under the bilateral pelvic nerve and hypogastric nerve transection, an increase of afferent impulses from the distal ending of a pelvic vesical branch was observed. P-4 (10 mg/kg, i.v.) had no effect on the afferent impulses. When the central endings of the pelvic vesical branches were electrically stimulated, reflex discharges were noted from a pelvic vesical branch on the contralateral side. Thiopental (2 and 4 mg/kg, i.v.) markedly decreased the reflex discharge, whereas P-4 (10 mg/kg, i.v.) caused no such inhibition. These findings suggest that the inhibition of the vesico-detrusor reflex by P-4 may result from its inhibitory action on the efferent terminal of the pelvic nerve.
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The aim of this paper was to evaluate the efficacy (0= none; 3= fully) of the treatment with nonsteroidal anti-inflammatory (NSAI) drugs on (a) gland post-inflammatory echopattern, by transrectal ultrasound (TRUS); (b) seminal cytologic (WBC concentration and spermiophagies) and (c) >2 physicochemical inflammatory parameters in patients with chronic amicrobial prostato-vesiculitis (PV).
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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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Key articles relating to the etiology, diagnosis, classification, economic burden, quality of life, and treatment of UI were retrieved, and this information formed the basis of the review.
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The objective of the study was to develop a high performance liquid chromatography (HPLC) method using ultra violet (UV) detection for the determination of flavoxate HCl in bulk and solid dosage forms by using ibuprofen as the internal standard. Eclipse C18 column (150 mm × 4.6 mm, 5 μm) was used as the stationary phase with a mixture of acetonitrile : 0.1% formic acid in water (75: 25 v/v) as the mobile phase. The response of the drug was linear in the concentration range of 1 - 250 μg/ml. Limit of detection and Limit of quantification were found to be 0.23 μg/ml and 0.69 μg/ml, respectively. The percentage of recovery ranged between 97.4 and 101.3%. The factors affecting column separation of the analyte were studied. The results demonstrated that this method is reliable, reproducible, and suitable for routine quantitative use.