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PubMed2004

Behavioral and drug therapy for urinary incontinence.

In a randomized, controlled trial comparing biofeedback-assisted behavioral therapy and drug therapy with oxybutynin, both types of therapy were superior to placebo in older, community-dwelling women with urge or mixed incontinence. Behavioral therapy significantly reduced incontinence compared with oxybutynin therapy (80.7% vs 68.5%, P = 0.04). Patients expressed high levels of satisfaction with behavioral therapy, and 97% were willing to continue this therapy indefinitely, compared with 55% receiving drug therapy. Results of recent studies suggest that behavioral therapy without biofeedback or pelvic floor electrical stimulation also results in significant clinical benefits, which should make behavioral therapy a more practical approach in the general practice setting. Statistical analysis showed no significant relationship between posttreatment urodynamic changes and clinical outcomes, and thus, the mechanisms by which behavioral and drug therapies work remain unidentified. In a small trial of combination therapy, patients who received both drug and behavioral therapy experienced significant clinical improvements compared with the effects of monotherapy with either treatment.

Aged↗
PubMed2004

Bilateral spontaneous perinephric urinomas: case report and review of the literature.

Urinoma is defined as an encapsulated collection of extravasated urine in the perirenal or paraureteral space. Urinomas in childhood are rare and usually either secondary to obstructive uropathies or due to blunt or penetrating trauma leading to injuries of the collecting system and/or ureter. Spontaneous perinephric urinomas are rare. We report the case of an 8-year-old boy with bilateral spontaneous perinephric urinomas secondary to an abnormally elevated voiding pressure with detrusor sphincter dyssynergia. The available literature on this subject is reviewed, and clinical features, pathophysiology, and treatment of this entity are discussed.

Child↗
PubMed2005

Should we switch over to tolterodine in every child with non-neurogenic daytime urinary incontinence in whom oxybutynin failed?

OBJECTIVES: To assess the clinical efficacy of tolterodine prescribed to children with non-neurogenic daytime urinary incontinence secondary to overactive bladder who had previously failed to improve with oral oxybutynin treatment and its relation to the side-effect profile and compliance status. METHODS: We evaluated 92 children presenting with daytime wetting, with or without nocturnal enuresis, who were receiving oral oxybutynin treatment. Children with chronic urinary tract infections, a neurologic lesion, an anatomic abnormality of lower urinary tract, voiding abnormality, and less than 1 year of oxybutynin treatment were excluded. Of the remaining 41 children (mean age 7.2 years, range 5 to 14 years), 30 agreed to switch to tolterodine and 11 continued receiving oxybutynin. Anticholinergic side effects, compliance, and clinical efficacy were assessed in the follow-up. RESULTS: Of the 30 patients who switched to tolterodine, a complete response was in 18 patients (60%), partial improvement in 11 (37%), and no improvement in 1 (3%) after a mean of 14.4 months (range 12 to 16 months) of oxybutynin treatment. The anticholinergic side-effect score was 7.2, 9.3, and 11, respectively, for those with a complete response, partial improvement, and no improvement in the compliant group. The noncompliant group had the greatest side-effect score (16.9). The fairly compliant group had a side-effect score of 12.3. After a mean of 7.1 months (range 6 to 9 months) of tolterodine use, a complete response was reported in 24 patients and partial improvement in 5 (17%). In 1 patient, treatment failed completely. However, his side-effect score decreased from 11 to 2. All tolterodine users were compliant with treatment. CONCLUSIONS: The results of this study in children with non-neurogenic daytime urinary incontinence have shown that tolterodine may increase the efficacy of pharmacotherapy, particularly in patients noncompliant to oxybutynin. Additional investigation of the anticholinergic side-effect scores and compliance tables is required to improve the clinical results of pharmacotherapy in incontinence due to overactive bladder in children.

Adolescent↗
PubMed2005

Influence of estradiol pretreatment on antimuscarinic action of oxybutynin in rat detrusor muscle.

OBJECTIVES: To investigate the antimuscarinic effect of oxybutynin in the rat detrusor muscle after estrogen pretreatment because, to our knowledge, no study has been done on the interaction of estrogen with antimuscarinic drugs. Estrogen has been shown to affect muscarinic receptors in the detrusor muscle of animals. In addition, oxybutynin has been shown to block muscarinic receptors in the bladder. METHODS: Estradiol benzoate (150 microg/kg) or saline was given subcutaneously to virgin female Wistar albino rats (n = 6, each group) for 10 consecutive days. On the 11th day, isolated detrusor muscle strips were taken, and acetylcholine (ACh)-induced contractions were evaluated in the absence or presence of oxybutynin (10 and 100 nM). RESULTS: ACh induced concentration-dependent contractions in the detrusor muscle. In the estradiol-pretreated group, the maximum of the ACh-induced contractions was diminished compared with that in the control group (P < 0.05). Oxybutynin (10 and 100 nM) inhibited ACh-induced contractions competitively (pK(B) 8.85). In the estradiol-pretreated group, the concentration-response curve to ACh was shifted further to the right in the presence of oxybutynin (100 nM). CONCLUSIONS: We have demonstrated for the first time that oxybutynin further inhibits ACh-induced and muscarinic receptor-mediated contractions in rat detrusor muscle after pretreatment with estrogen.

Animals↗
PubMed2004

Update on nocturia: the best of rest is sleep.

Adequate sleep is a basic requirement for good health. Adults generally require 7 to 8 hours of sleep per night. Sleep deprivation is associated with a decreased ability to perform tasks controlled by the frontal lobe, such as planning, concentration, motor performance, and high-level intellectual skills. Constant poor-quality sleep can also cause excessive daytime sleepiness, depression, and immune function compromise. In addition, continued sleep disruption has been associated with an increased risk for mortality.

Behavior Therapy↗
PubMed2005

Antimuscarinic agents exhibit local inhibitory effects on muscarinic receptors in bladder-afferent pathways.

OBJECTIVES: To investigate the potential of antimuscarinic agents for sensory mechanisms in overactive bladder using intravesical instillation. METHODS: Antimuscarinic agents were instilled intravesically in rats using two protocols. In the high-dose protocol, 5 mg atropine, oxybutynin, and dimethindene (M2-selective muscarinic receptor antagonist) were instilled into the bladder, and cystometric parameters, such as bladder capacity, intercontraction interval, pressure threshold, and maximal voiding pressure were monitored. In the low-dose protocol, 0.1 and 0.5 mug/mL oxybutynin, trospium, tolterodine, and dimethindene were continuously infused into the bladder. The doses chosen were based on the calculated urine-excreted concentrations of trospium typically achieved from human oral treatment of 40 mg/day. The effect of carbachol with and without the low-dose agents was then assessed. RESULTS: With the high-dose protocol, bladder capacity, intercontraction interval, and pressure threshold were increased when atropine and oxybutynin were instilled, but not when dimethindene was used. The maximal voiding pressure was not affected by any of the agents tested. In the low-dose protocol, none of the cystometric parameters were altered with antimuscarinic agents alone. The intercontraction interval decreased with intravesical carbachol (65% +/- 0.1% compared with baseline), but this was prevented with concomitant antimuscarinic agents. CONCLUSIONS: We have separated the local inhibitory effects of antimuscarinic agents during the storage phase from a decrease in voiding pressure. Intravesical instillation of antimuscarinic agents at clinically meaningful concentrations also suppressed carbachol-induced bladder overactivity. Antimuscarinic agents may be effective in treating overactive bladder, not only by suppression of muscarinic receptor-mediated detrusor muscle contractions, but also by blocking muscarinic receptors in bladder-afferent pathways.

Acetylcholine↗
PubMed2006

Frequency of wetting is predictive of response to anticholinergic treatment in children with overactive bladder.

OBJECTIVES: To examine the variables relative to the response of oxybutynin treatment in children with daytime urinary incontinence. METHODS: The records of patients seen for voiding problems between 1999 and 2003 were reviewed. Patients taking oxybutynin for 3 months or longer were included in the study. Patients with structural or neurologic bladder abnormalities and those taking oxybutynin at the initial visit were excluded. Age, sex, uroflowmetry findings, postvoid residual urine volume, duration and severity of symptoms before oxybutynin, urinary tract infection history, constipation, and the duration, dosage, and adverse effects of oxybutynin treatment were evaluated. Data were analyzed using Fisher's exact test for categorical variables, the two-sample t test or Wilcoxon rank-sum test for continuous and ordinal variables, and the linear mixed model analysis for uroflow data. RESULTS: Eighty-one patients met the inclusion criteria. After an average follow-up of 1.2 years, 31 (38.3%) were dry, 25 (30.9%) had experienced significant improvement, 19 (23.5%) had experienced slight improvement, and 6 (7.4%) were unchanged. No significant differences were detected between those who became dry and those with little to no improvement with respect to age, sex, duration of symptoms, follow-up, uroflow pattern, postvoid residual urine volume, or bladder capacity. Those children presenting with decreased frequency of wetting episodes were significantly more likely to obtain daytime continence. The most common side effects were constipation (18.5%), dry mouth (17.3%), and flushing (13.6%). CONCLUSIONS: Children with daytime incontinence presenting with the lowest frequency of wetting were most likely to achieve continence. The frequency of wetting should be considered a significant prognostic variable when assessing the results of therapeutic intervention trials.

Adolescent↗
PubMed2006

Improved efficacy of extended release oxybutynin in children with persistent daytime urinary incontinence converted from regular oxybutynin.

OBJECTIVES: To examine the response to conversion from regular oxybutynin (Ditropan) to an extended-release form (Ditropan XL) in children with persistent daytime urinary incontinence. METHODS: A retrospective review of patients with daytime wetting who switched from Ditropan to Ditropan XL included patient age, sex, reason for the change in medication, uroflowmetry findings before and after the change, side effects, and duration and dosage of the medication. The data were analyzed using a paired, two-tailed t test, with P <0.05 considered significant. RESULTS: Twenty-seven patients were followed up for an average of 35.8 months. A lack of improvement (n = 11), convenience (n = 6), side effects (n = 2), and a dislike of the taste (n = 2) were identified as reasons for changing to the extended release form. The mean dosage of Ditropan and Ditropan XL did not differ significantly (0.40 and 0.38 mg/kg/day, respectively). After the change to Ditropan XL, 6 patients had a resolution of side effects and 7 developed new side effects. Of the 27 patients, 13 became dry or had significant improvement by the first visit after the change to Ditropan XL. Significant increases in voided volume (38% versus 53%; P <0.01) and total bladder capacity (55% versus 70%; P = 0.03), normalized for age-expected bladder capacity, occurred by the first clinic visit after beginning Ditropan XL. No significant changes in the postvoid residual urine volume occurred. CONCLUSIONS: The frequency of wetting decreased and the voided volume and bladder capacity increased after a change to Ditropan XL in children with persistent wetting when taking Ditropan.

Child↗
PubMed2006

Comparison of electric stimulation and oxybutynin chloride in management of overactive bladder with special reference to urinary urgency: a randomized placebo-controlled trial.

OBJECTIVES: To compare the efficacy of electric stimulation (ES), oxybutynin, and placebo in managing the symptom complex of overactive bladder (OAB), particularly urgency. METHODS: A randomized placebo-controlled trial was conducted for 68 patients with OAB, placing emphasis on urinary urgency. The interventions for the 12-week treatment period, conducted by the physiotherapist, who was unaware of the progress and outcome, included a vaginal ES program using biphasic symmetric, pulsed current with a 10-Hz frequency, 400-micros pulse width, 10/5 duty cycle, and varying intensity; and oxybutynin (2.5 mg) or placebo three times per day. Identical preintervention and postintervention assessments included the measurement of warning time, urodynamics, voiding diaries, and King's Health Questionnaire. RESULTS: Of the 68 women who completed this study, 24 were in the ES, 23 in the oxybutynin, and 21 in the placebo group. The between-group comparison showed that significant improvements in daily voided volume, pad count, number of urgency and nocturia episodes, and the domain 2 score and total score of the King's Health Questionnaire existed between the ES and the other groups (all P < or = 0.050). The changes in warning time, maximal voided volume, number of urgency episodes, and frequency were significantly improved between oxybutynin and placebo (all P < 0.013). Additionally, a comparison of the voided volume in uroflowmetry between the ES and placebo groups revealed a greater difference after treatment (P = 0.013). The reduction rate of OAB was 58.4% for the ES, 39.1% for the oxybutynin, and 9.5% for the placebo group (P = 0.036). CONCLUSIONS: ES had the greatest subjective outcome for OAB and was the most effective of the three treatments. Oxybutynin was more effective than placebo.

Adolescent↗
PubMed2006

Patient-reported outcomes in overactive bladder: importance for determining clinical effectiveness of treatment.

Overactive bladder (OAB) is a condition defined by its symptoms--urinary urgency with or without urgency urinary incontinence and often with frequency and nocturia. As such, determining the efficacy of OAB treatments using objective measures, such as urodynamic testing, can be difficult. A better means of gauging treatment efficacy for symptom-based conditions is through the use of patient-reported outcomes (PROs). With PROs, clinicians can gain insight into how a treatment affects a patient's symptoms and whether improvement in symptoms has a positive effect from the patient's perspective. PROs are increasingly being included as end points in clinical trials, including those of antimuscarinic drugs for OAB. Consequently, clinicians should become familiar with the most commonly used instruments. We provide an overview of instruments used to assess symptoms, health-related quality of life, and treatment satisfaction in patients with OAB and discuss how PROs can be incorporated into clinical trial protocols.

Benzhydryl Compounds↗
PubMed2006

An approach to daytime wetting in children.

Daytime wetting is a common problem with various causes that can usually be identified through a careful history, thorough physical examination, and urinalysis. Conservative approaches to therapy have a successful outcome in most children. Invasive diagnostic imaging studies and pharmacologic or surgical intervention are necessary only for carefully selected children.

Arousal↗
PubMed2005

[Development of an intravesial oxybutynin chloride solution: from formulation to quality control].

Intravesical oxybutynin chloride has demonstrated its efficacy in children with neurogenic bladder and urinary incontinence refractory to oral anticholinergic agents. We developed a 205 microg/ml oxybutynin chloride solution in accordance with the specifications of the European Pharmacopeae. To guarantee quality, we assessed and validated formulation, the preparation process, and packaging. The solution was obtained by disolving oxybutynin chloride in 0.9% saline and sterile filtration. The solution was then packaged in syringes. Physical properies for intravesical instillation were met: pH 5.76 +/- 0.03, osmolality 281 mosmol/kg. The unit dose package guarantees sterility of the solution until use. The medication is given by adapting the syringe on the Luer Lock exteremity of the urinary catheter. The solution remains stable up to one month at 4 degrees C.

Chemistry, Pharmaceutical↗
PubMed1999

Quantitative characterization of therapeutic index: application of mixed-effects modeling to evaluate oxybutynin dose-efficacy and dose-side effect relationships.

BACKGROUND: Describing a therapeutic index for a drug is important for evaluating safe and effective dosage regimens. Therapeutic index can be evaluated as the relative position of the dose-efficacy and the dose-side effect curves. Oxybutynin XL (Ditropan XL), a once-daily oral controlled-release formulation for oxybutynin chloride, is being developed. Oxybutynin XL efficacy and side-effect data obtained from two parallel-group, randomized, controlled clinical trials were modeled to evaluate the therapeutic index. METHODS: A nonlinear mixed-effects model was used to characterize the oxybutynin dose-efficacy and dose-dry mouth relationship. Weekly urge urinary incontinence episodes, the primary efficacy variable, is a discrete variable (counts) with only non-negative integer values and was therefore modeled as a Poisson variable. The probability of dry mouth severity (the most frequently reported side effect), assessed on a categorical four-point scale, was modeled with a proportional odds model. In the modeling process, it was assumed that the time effect was the same for the active and placebo treatments and that the drug effect was additive. RESULTS AND CONCLUSIONS: The urge urinary incontinence episodes declined log-linearly, and no significant difference was observed between the two formulations. However, there was a trend toward higher efficacy with oxybutynin XL than with immediate-release oxybutynin at the same dose in one study. Dose-dry mouth analysis showed that the probability of dry mouth with an increasing dose was significantly lower with oxybutynin XL than with immediate-release oxybutynin in the second study, and a similar trend was observed in the first study. By combining the dose-urge urinary incontinence and dose-dry mouth relationship, a wider therapeutic index was predicted for oxybutynin XL than for immediate-release oxybutynin.

Adult↗
PubMed2000

Effects of TAK-637, a tachykinin receptor antagonist, on the micturition reflex in guinea pigs.

The effects of a new tachykinin NK(1) receptor antagonist, (aR, 9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10, 11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1, 7]naphthyridine-6,13-dione (TAK-637), on the micturition reflex were compared with those of drugs used for abnormally frequent micturition or incontinence. TAK-637 showed a characteristic effect on the distension-induced rhythmic bladder contractions in guinea pigs. The systemic administration of TAK-637 decreased the number but not the amplitude of the distension-induced rhythmic bladder contractions. A similar effect was observed in animals in which the spinal cord had been severed. TAK-637 also inhibited the micturition reflex induced by topical application of capsaicin onto the surface of bladder dome. From these results, it is concluded that TAK-637 inhibits sensory transmissions from the bladder evoked by both physiological and nociceptive stimuli by blocking tachykinin NK(1) receptors, possibly at the level of the spinal cord. On the other hand, the other drugs such as oxybutynin, tolterodine, propiverine, and inaperisone showed no effects on the frequency of the distension-induced rhythmic bladder contractions but decreased the contraction amplitude. Therefore, TAK-637 may represent a new class of drugs, which would be effective for abnormally frequent micturition without causing voiding difficulties due to decreased voiding pressure.

Animals↗
PubMed2000

Possible site of action of TAK-637, a tachykinin NK(1) receptor antagonist, on the micturition reflex in guinea pigs.

TAK-637((aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10, 11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1,7]naphthyridine-6,13-dione) is a novel tachykinin NK(1) receptor antagonist that has been shown to inhibit the micturition reflex in guinea pigs. The aim of this study was to clarify its mechanism of action in guinea pigs. TAK-637 inhibited the spinal vesico-vesical reflex induced by electrical stimulation of the proximal cut end of the pelvic nerve in spinal animals, but not bladder contractions induced by electrical stimulation of the distal cut end of the nerve. Furthermore, TAK-637 had no effect on carbachol- or electrical field stimulation-induced contractions of isolated bladder muscle strips in an organ bath, whereas drugs used for abnormally frequent micturition inhibited both contractions. These results suggest that TAK-637 inhibits the micturition reflex by acting, at least in part, on the spinal cord, and its mechanism of action clearly differs from those of antimuscarinics or spasmolytics.

Animals↗
PubMed2001

Pharmacological actions of AH-9700 on micturition reflex in anesthetized rats.

In radioligand binding assays, AH-9700 (1-[2-(3,4-dihydro-6,7-dimethyl-2-naphthalenyl)ethyl]pyrrolidine fumarate) had high affinity for sigma receptors and moderate affinity for muscarinic receptors. The affinity of AH-9700 for sigma(1) receptors was significantly reduced in the presence of 5'-guanylyl-imidodiphosphate (GppNHp). In isolated bladder strips of rats, AH-9700 inhibited carbachol-induced contractions. In anesthetized rats, i.v. administration of AH-9700 and typical sigma receptor ligands, (+)-pentazocine and 1,3-di-o-tolylguanidine (DTG), but not oxybutynin, dose-dependently inhibited rhythmic isovolumetric reflex bladder contractions. AH-9700 and oxybutynin suppressed the amplitude of rhythmic bladder contractions. On the other hand, at doses lower than used i.v., the i.c.v. administration of AH-9700 or the sigma receptor ligands inhibited rhythmic bladder contractions without suppressing the amplitude. This inhibitory effect of AH-9700 was markedly reduced by pretreatment with i.c.v. pertussis toxin. These results suggest that AH-9700 exerts a marked anti-micturition reflex effect through central sigma receptors possibly related to pertussis toxin-sensitive Gi/o-proteins and a moderate spasmolytic effect based on its peripheral anti-muscarinic activity.

Anesthesia↗
PubMed2002

Different responses to drugs against overactive bladder in detrusor muscle of pig, guinea pig and mouse.

Direct comparison of experimental data for drugs commonly used in the treatment of overactive bladder is difficult because of possible species differences. In this study, we compare the effects of atropine, propiverine, oxybutynin and tolterodine in strips of pig, guinea pig and mouse detrusor muscle. In the three species, we observed slight differences in potency of carbachol-induced biphasic contractile responses between the species (guinea pig>pig>mouse). Cumulative concentration-response curves for carbachol were shifted to the right by atropine, propiverine, oxybutynin and tolterodine. However, at higher concentrations of the latter three antagonists, the maximum response to carbachol was also reduced. Therefore, propiverine, oxybutynin and tolterodine must have additional pharmacological actions beyond competitive antagonism at muscarinic receptors. Electric field stimulation (30 Hz) of detrusor strips led to contraction amplitudes, which remained constant over time (210 min) in pig, decreased by 17+/-5% in guinea pig, and increased by 28+/-9% in mouse detrusor muscle. Electric field stimulation-evoked contractions were suppressed to 18% of pre-drug control by high concentrations of atropine (10 microM) in pig, but to a much lesser extent in guinea pig and mouse (to 46% and 70%, respectively). In all three species, a myogenic component of contraction was observed in the presence of tetrodotoxin (1 microM). Compared to atropine, the bladder spasmolytic agents propiverine, oxybutynin and tolterodine also reduced electrically evoked contractions in the three species, though higher concentrations were required. The differences in the reported effects of the spasmolytic agents commonly used for treating overactive bladder suggest that drug action is strongly dependent on the species. Thus, a comparison of drug effects is only feasible in the same animal model and the results cannot easily be transferred to humans.

Animals↗
PubMed1997

Tolterodine--a new bladder-selective antimuscarinic agent.

Tolterodine is a new muscarinic receptor antagonist intended for the treatment of urinary urge incontinence and other symptoms related to an overactive bladder. The aim of the present study was to compare the antimuscarinic properties of tolterodine with those of oxybutynin, in vitro and in vivo. Tolterodine effectively inhibited carbachol-induced contractions of isolated strips of urinary bladder from guinea pigs (K(B) 3.0 nM; pA2 8.6; Schild slope 0.97) and humans (K(B) 4.0 nM; pA2 8.4; Schild slope 1.04) in a concentration-dependent, competitive manner. The affinity of tolterodine was similar to that derived for oxybutynin (K(B) 4.4 nM; pA2 8.5; Schild slope 0.89) in the guinea-pig bladder. Tolterodine (21-2103 nmol/kg (0.01-1 mg/kg); intravenous infusion) was significantly more potent in inhibiting acetylcholine-induced urinary bladder contraction than electrically-induced salivation in the anaesthetised cat. In contrast, oxybutynin displayed the opposite tissue selectivity. Radioligand binding data showed that tolterodine bound with high affinity to muscarinic receptors in urinary bladder (K(i) 2.7 nM), heart (K(i) 1.6 nM), cerebral cortex (K(i) 0.75 nM) and parotid gland (K(i) 4.8 nM) from guinea pigs and in urinary bladder from humans (K(i) 3.3 nM). Tolterodine and oxybutynin were equipotent, except in the parotid gland, where oxybutynin bound with 8-times higher affinity (K(i) 0.62 nM). Binding data on human muscarinic m1-m5 receptors expressed in Chinese hamster ovary cells showed that oxybutynin, in contrast to tolterodine, exhibits selectivity (10-fold) for muscarinic m3 over m2 receptors. The K(B) value determined for oxybutynin (4.4 nM) in functional studies on guinea-pig bladder correlated better with the binding affinity at muscarinic M2/m2 receptors (K(i) 2.8 and 6.7 nM) than at muscarinic M3/m3 receptors (K(i) 0.62 and 0.67 nM). The tissue selectivity demonstrated for tolterodine in vivo cannot be attributed to selectivity for a single muscarinic receptor subtype. However, the combined in vitro and in vivo data on tolterodine and oxybutynin may indicate either that muscarinic M3/m3 receptors in glands are more sensitive to blockade than those in bladder smooth muscle, or that muscarinic M2/m2 receptors contribute to bladder contraction.

Adult↗