Short-Term Flavoxate Treatment Alters Detrusor Contractility Characteristics: Renewed Interest in Clinical Use?

OBJECTIVES: Flavoxate has had a long history of use in the treatment of overactive bladder, despite the lack of documentation on its clinical efficacy and mechanism(s) of action. This study was conducted to understand how contractility characteristics of the detrusor are affected after a short period of flavoxate treatment. METHODS: 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. RESULTS: K(+) -Krebs'-induced contraction developed more slowly while 64 Hz electrical field stimulation-induced contraction developed faster in flavoxate-treated strips when compared to control. Amplitudes of maximal and steady-state contraction induced by 3 µmol/L carbachol were also larger after flavoxate treatment. Control strips showed an overall greater dependence on stimulus strength in eliciting the responses. CONCLUSIONS: These findings provided new information of how short-term flavoxate treatment altered contractility characteristics at the bladder level, which may instill new interest in investigating the use of this drug in bladder disorders not responding well to conventional treatments.

Intravenous or local injections of flavoxate in the rostral pontine reticular formation inhibit urinary frequency induced by activation of medial frontal lobe neurons in rats.

PURPOSE: The rostral pontine reticular formation has a strong inhibitory effect on micturition by facilitating lumbosacral glycinergic neurons. We assessed the influence of the rostral pontine reticular formation on the micturition reflex after noradrenaline injection in the medial frontal lobe. We also examined the relation between the medial frontal lobe and the rostral pontine reticular formation. MATERIALS AND METHODS: Continuous cystometry was performed in 28 female rats. After the interval between bladder contractions was shortened by noradrenaline injection in the medial frontal lobe we injected glutamate or flavoxate hydrochloride in the rostral pontine reticular formation or intravenously injected flavoxate or propiverine. The change in bladder activity was examined. RESULTS: Noradrenaline injection in the medial frontal lobe shortened the interval between bladder contractions. In contrast to the bladder contraction interval before and after noradrenaline injection in the medial frontal lobe, the interval was prolonged after noradrenaline injection when glutamate or flavoxate was injected in the rostral pontine reticular formation, or flavoxate was injected intravenously. Noradrenaline injection in the medial frontal lobe plus intravenous propiverine injection also prolonged the interval compared to that after noradrenaline injection alone. However, the interval after noradrenaline injection in the medial frontal lobe plus intravenous injection of propiverine was shorter than that before noradrenaline injection only. CONCLUSIONS: 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.

Clarifying the mechanism of aggregation of particles in high-shear granulation based on their surface properties by using micro-spectroscopy.

The present study aimed to clarify, by means of micro-spectroscopy, the mechanism of aggregation of particles into granules during high-shear granulation. We used two types of pharmaceutical granules prepared by high-shear granulator, one containing mefenamic acid and the other containing flavoxate hydrochloride as poorly soluble active pharmaceutical ingredients (APIs). Lactose, cornstarch, and microcrystalline cellulose were used as excipients; and hydroxypropyl cellulose (HPC) was used as the binding agent. The distributions of components in granules were visualized by mapping cross-sections of individual granules with techniques utilizing mid-infrared spectroscopy at the SPring-8 synchrotron radiation facility and micro-Raman spectroscopy. In the distribution maps of mefenamic acid granules, distributions of mefenamic acid, cornstarch, and microcrystalline cellulose overlapped; in flavoxate hydrochloride granules, on the other hand, distributions of flavoxate hydrochloride and lactose overlapped. Assessment of the surface free energy of each component found that ingredients with overlapping distribution had similar surface properties. Therefore, it was revealed that in high-shear granulation, in addition to the granulator operating conditions and general properties of the formulation itself (such as the solubility and particle size of each ingredient), the surface properties of the ingredients and their interrelationships were also factors that determined the aggregation behavior of the particles.

[Clinical evaluation of supplemental administration of flavoxate hydrochloride in benign prostatic hyperplasia patients with nocturia resistant to an alpha1-adrenoceptor blocker].

We examined the effectiveness of supplemental administration of flavoxate hydrochloride in patients with benign prostatic hyperplasia (BPH) whose nocturia was not adequately relieved by an alpha1-adrenoceptor blocker. Fifty-two patients who had two or more nocturnal micturition after administration of tamsulosin hydrochloride or naftopidil for 4 weeks or more received 400-600 mg of flavoxate hydrochloride in addition to an alpha1-adrenoceptor blocker for another 8-12 weeks. With supplemental administration of flavoxate hydrochloride, significant improvement was observed in the number of nocturnal micturition, total International Prostate Sympton Score, quality of life score and BPH impact index. No significant change was observed in the voided volume, Qmax, voiding time and residual urine volume. Supplemental administration of flavoxate hydrochloride is therefore effective for the improvement of nocturia and QOL in BPH patients resistant to an alpha1-adrenoceptor blocker.

Polymeric matrix membrane sensors for stability-indicating potentiometric determination of oxybutynin hydrochloride and flavoxate hydrochloride urogenital system drugs.

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.

[Comparative studies of the effect of mictonorm (propiverin hydrochloride) and Spasuret (flavoxate hydrochloride) on the bladder detrusor muscle]. / Vergleichende Untersuchungen zur Wirkung von Mictonorm (Propiverin hydrochlorid) und Spasuret (Flavoxat hydrochlorid) auf den Detrusor vesicae.

46 patients suffering from urgency/urge incontinency were treated with Mictonorm and Spasuret in a crossing-over study. In consideration of the placebo effect in this disease both agents were tested versus a non-verum. The application period was 4 weeks and the dosage was 45 mg/d Mictonorm and 300 mg/d Spasuret, respectively. Both with Mictonorm and with Spasuret a significant reduction of micturition frequency and an increase of the compliance could be observed, whereas the placebo was ineffective. A markedly growth of the maximal bladder capacity (16.9%) was obtained only by Mictonorm. Both agents keep likewise to an improvement of the symptoms or urgency/urge incontinency. Side effects could observed in a small size without a breaking-off of the treatment.

Comparison of flavoxate hydrochloride in daily dosages of 600 versus 1200 mg for the treatment of urgency and urge incontinence.

Flavoxate hydrochloride at a daily dosage of 600 mg was compared to a daily dosage of 1200 mg for the treatment of unstable bladder. Twenty-seven patients were treated for 4 weeks in a double-blind, randomized, parallel-group trial. Clinically, both schedules were equally successful. In urodynamic terms, however, particularly with respect to uninhibited detrusor contractions, 1200 mg/day was significantly superior to 600 mg/day. Tolerability was excellent for both regimens. The side-effect free treatment of urgency and urge incontinence is of paramount importance for a patient's quality of life.

Flavoxate hydrochloride for urinary urgency after pelvic radiotherapy: comparison of 600 mg versus 1200 mg daily dosages.

This preliminary communication reports on a non-randomized pilot type trial of 34 females with urgency after pelvic radiotherapy who were treated with flavoxate hydrochloride for 4 weeks. A dosage of 600 mg/day was given to 21 patients and 1200 mg/day to 13 patients. Clinically, both regimens achieved comparable results. Urodynamically (first desire volume, bladder capacity and pressure at capacity) treatment with 1200 mg/day was significantly superior to 600 mg/day. Both schedules were equally well tolerated by patients and no treatment interruption occurred. A randomized double-blind trial comparing 600 and 1200 mg/day flavoxate hydrochloride is currently underway the results of which will be reported in due course.

A comparison between the combination emepronium bromide/flavoxate and emepronium bromide in the treatment of detrusor instability.

Emepronium bromide and flavoxate have both and separately been used with success in the treatment of detrusor instability. In this study we have combined the two drugs emepronium bromide and flavoxate and compared the results with emepronium bromide. 20 consecutive patients with an uninhibited bladder, 12 men and 8 women, were randomly allocated to treatment with either emepronium bromide/flavoxate or emepronium bromide. In this trial we found that treatment with the combination is significantly better than treatment with emepronium bromide only.

The effect of flavoxate on uninhibited detrusor contractions and urinary incontinence in the elderly.

The effect of flavoxate, a smooth muscle relaxant, was investigated in 6 elderly patients with uninhibited detrusor contractions associated with urinary incontinence. Cystometry was done initially to confirm the diagnosis, immediately after an intravenous injection of 100 mg. flavoxate and after 200 mg. flavoxate orally 4 times daily for 7 days. No consistent drug effect could be detected cystometrically and incontinence was unchanged clinically.

An objective comparison of the effects of parenterally administered drugs in patients suffering from detrusor instability.

Cystometric changes produced by 3 parenterally administered drugs, flavoxate hydrochloride, emepronium bromide and imipramine hydrochloride, have been evaluated in 15 female patients with detrusor instability. Each patient was given 2 of the 3 drugs and cystometric recordings were done 10 and 30 minutes after the administration of each drug. Emepronium bromide was found to be the only drug to cause a significant improvement in bladder capacity and reduction in detrusor pressure.

Flavoxate hydrochloride in the treatment of detrusor instability.

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.