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PubMed1999

Pharmacological effects of tolterodine on human isolated urinary bladder.

Tolterodine, (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine+ ++, is an antimuscarinic drug developed for the treatment of overactive bladder with symptoms of frequency, urgency and urge incontinence. We investigated the effects of tolterodine and its major active metabolite, DD 01 (PNU-200577), (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropa namine, on the contractions induced by carbachol, KCl, CaCl2 and electrical field stimulation in human isolated urinary bladder smooth muscles, using the muscle bath technique. Specimens of human urinary bladder were obtained from 20 patients who underwent total cystectomy due to malignant bladder tumor. The detrusor preparations were taken from the intact part of the dome region of the bladder. Carbachol (10(-9)-10(-2) M) caused concentration-dependent contraction of human detrusor smooth muscles. Tolterodine (10(-9)-10(-6) M), DD 01 (10(-9)-10(-6) M), oxybutynin (10(-8)-10(-6) M), propiverine (10(-8)-10(-6) M), atropine (10(-9)-10(-6) M), pirenzepine (10(-8)-10(-5) M), methoctramine (10(-8)-10(-5) M) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) (10(-9)-10(-6) M) caused typical shifts to the right of the concentration-response curves for carbachol, except for higher concentrations (10(-5) M) of oxybutynin and propiverine, which caused a decrease of about 30% of the maximum contractile responses to carbachol. All the slopes of the regression lines of Schild plots were close to unity, and the rank order of pA2 values was: atropine = DD 01 = tolterodine = 4-DAMP = oxybutynin > propiverine = pirenzepine > methoctramine. Tolterodine (10(-9)-10(-6) M) and DD 01 (10(-9)-10(-6) M) did not inhibit the KCl-induced (80 mM) and CaCl2-induced (5 mM) contractions, while oxybutynin (10(-8)-10(-5) M) and propiverine (10(-8)-10(-5) M) significantly inhibited the contractions. Electrical field stimulation (2-60 Hz) caused frequency-dependent contraction of human detrusor smooth muscles, which were significantly inhibited by various drugs. In the presence of 10(-6) M atropine, tolterodine and DD 01 did not inhibit the residual contractions induced by electrical field stimulation at any of the frequencies, while oxybutynin (10(-5) M) and propiverine (10(-5) M) significantly inhibited the atropine-resistant part of the contractions. The results suggest that the inhibitory effects of tolterodine and DD 01 are mediated only by their antimuscarinic action, which is equal to that of oxybutynin and significantly greater than that of propiverine, and that tolterodine and DD 01 have neither Ca2+ channel antagonist action nor inhibitory effect on the atropine-resistant part of the contractions in human detrusor smooth muscles. These findings support the usefulness of tolterodine as a therapeutic drug for overactive bladder with symptoms of frequency, urgency and urge incontinence.

Aged↗
PubMed1988

Determination of oxybutinin chloride in pharmaceuticals by reversed-phase ion-pair liquid chromatography with two counter-ions in the eluent.

A reliable stability-indicating method using reversed-phase ion-pair high-performance liquid chromatography for the determination of the anticholinergic drug oxybutinin chloride in pharmaceuticals is reported. Sample extraction is easy and fairly rapid and recovery and precision of the method are excellent. Due to the simultaneous use of an organic amine and of an alkanesulphonate in the mobile phase, good selectivity towards related (quaternary ammonium) anticholinergic drugs was obtained.

Chromatography, High Pressure Liquid↗
PubMed1998

Oxybutynin decreases renal pelvic pressures in normal and infected rat urinary tract.

Since abnormally elevated renal pelvic pressures may contribute to renal damage, we examined whether an anticholinergic agent could decrease elevated renal pelvic pressures. We have previously demonstrated in a rat model that renal pelvic pressures rise physiologically during normal bladder filling and high urinary flows; these pressures rise to abnormal levels during acute urinary tract infection (UTI). In these studies we investigated the effects of oxybutynin on the in vivo rat urinary tract. Simultaneous bladder and renal pelvic pressures were measured with and without oxybutynin at low (<2 ml./kg./hr.), moderate (2-10), high (10-20), and very high (>20) urinary flows while the rat bladder filled and emptied spontaneously. Although minimal differences were found between bladder filling pressures with and without oxybutynin, at higher urinary flows the renal pelvic pressure in oxybutynin treated rats was significantly lower than in nontreated animals. Indeed, when rats with urinary tract infection were treated with oxybutynin, their renal pelvic pressures were lower than those in uninfected rats. We conclude that oxybutynin affects rat upper urinary collecting system pressures, and is capable of decreasing abnormally elevated renal pelvic pressures due to urinary tract infection to normal or subnormal levels.

Animals↗
PubMed1998

Oxybutynin lowers elevated renal pelvic pressures in a rat congenital unilateral hydronephrosis.

We investigated whether oxybutynin could lower elevated renal pelvic pressures measured in a rat with an inbred unilateral congenital hydronephrosis. Simultaneous renal pelvic and bladder pressures were measured in 8 hydronephrotic rats and compared to those of 10 hydronephrotic rats treated with intravenous injection of 1.6 mg./kg. oxybutynin. Pressures were recorded at different urinary flow rates and during bladder filling and emptying. Hydronephrotic rats not given oxybutynin showed significantly higher renal pelvic pressures (e.g. p-bladder at 50% capacity = 8.9 +/- 3.1 cm. H2O, corresponding p-pelvis = 20.8 +/- 2.1 at very high urinary flow rates) than rats treated with oxybutynin. The latter had renal pelvic pressures similar to rats with normal non-hydronephrotic kidneys (e.g. p-bladder at 50% capacity = 10.1 +/- 3.5 cm. H2O, corresponding p-pelvis = 6.3 +/- 1.1 at very high urinary flow rates). Renal pelvic pressures were, moreover, lower than corresponding bladder pressures in contrast to the untreated hydronephrotic pelvic pressure that exceeded bladder pressure. This effect of oxybutynin in lowering elevated renal pelvic pressures in the obstructed kidney has not been described before and suggests a possible role for oxybutynin in this condition.

Animals↗
PubMed1998

Intravesical oxybutynin for neurogenic bladder dysfunction: less systemic side effects due to reduced first pass metabolism.

PURPOSE: To unravel why intravesical oxybutynin is more effective and causes significantly fewer systemic side effects than oral oxybutynin in the treatment of neurogenic bladder dysfunction, we tested the hypothesis that the absorption and metabolism of oxybutynin are changed after intravesical instillation. MATERIALS AND METHODS: A high-performance liquid chromatography assay was developed for both oxybutynin and its active metabolite, N-desethyl-oxybutynin. Plasma concentrations were quantified after intravesical (n = 11) and oral (n = 5) administration of oxybutynin in children under steady-state conditions. Pharmacokinetic parameters were calculated. RESULTS: Oral administration of oxybutynin (0.2 mg./kg./dose) resulted in peak plasma concentrations for N-desethyl-oxybutynin which were 7.4 +/- 1.3 times higher than corresponding values for oxybutynin (n = 5). Also the AUC (area under the plasma concentration time curve) values were higher for N-desethyl-oxybutynin compared with those of oxybutynin, the ratio being 10.8 +/- 1.0 (n = 5). Intravesical instillation (0.2 mg./kg./dose), on the other hand, resulted in reduced metabolite generation and peak plasma concentrations for N-desethyl-oxybutynin which were in the same range as those for oxybutynin, the ratio being 1.2 +/- 0.1 (n = 11). The ratio for the AUC values for N-desethyl-oxybutynin and oxybutynin was 2.1 +/- 0.2 (n = 11). CONCLUSIONS: The significantly lower AUC ratio of the N-desethyl metabolite over the mother compound, due to a reduced first pass metabolism, may explain the clinically relevant reduction of side effects that characterizes intravesical compared with oral oxybutynin therapy.

Administration, Intravesical↗
PubMed1999

Improved bladder function after prophylactic treatment of the high risk neurogenic bladder in newborns with myelomentingocele.

PURPOSE: High pressure dyssynergic voiding may result in irreversible damage to the urinary tract. Prophylactic therapy in the form of clean intermittent catheterization and anticholinergic medication may significantly decrease the incidence of upper urinary tract deterioration. Whether prophylactic therapy in the high risk bladder may also lead to improved long-term bladder dynamics prompted us to study the effect of early versus late treatment of bladder hypertonicity and detrusor-sphincter dyssynergia on the ultimate need for bladder augmentation. MATERIALS AND METHODS: We retrospectively reviewed urological outcomes in patients with myelodysplasia who were at risk for urological deterioration within year 1 of life based on bladder sphincter dyssynergia and/or high filling or voiding pressure. We recorded the dates when high risk voiding dynamics were initially observed, and when intermittent catheterization and anticholinergic therapy were initiated. Patients in whom treatment began at the time a high risk profile was noted (prophylactic group seen between 1985 and 1990) were compared to controls with the same high risk voiding parameters who did not receive early therapy (observation group seen between 1978 and 1984 with therapy instituted 1 year or longer after high risk was noted). The number of augmentations performed in each group was indexed to the total number of years of followup in the 2 populations, respectively. Patients with less than 2 years of followup were excluded from further analysis. RESULTS: Of the 45 patients at risk clean intermittent catheterization and anticholinergic medication were immediately initiated in 18, while 27 were treated expectantly. Patients in the observation group were followed an average of 4.1 years (range 1.1 to 14) before clean intermittent catheterization and anticholinergic medication were started. Of the 27 children treated expectantly 11 (41%) required augmentation, whereas only 3 of the 18 (17%) treated prophylactically required enterocystoplasty. When the number of augmentations was indexed to total years of followup in each of the 2 groups (296 versus 156 years) patients in the expectant group were nearly twice as likely to require augmentation. CONCLUSIONS: Identification and early proactive treatment of the high pressure, dyssynergic lower urinary tract significantly decreases the need for bladder augmentation as children with neurogenic bladder secondary to myelomeningocele mature.

Adolescent↗
PubMed1997

The role of oxybutynin in spinal cord injured patients with indwelling catheters.

PURPOSE: The long-term benefits of oral oxybutynin in spinal cord injured patients with indwelling catheters is unknown. We reviewed our experience with this population of men and present the results of our analysis. MATERIALS AND METHODS: A total of 109 male spinal cord injured patients at the Houston Veterans Affairs Medical Center have been treated with chronic indwelling catheters (80 transurethral and 29 suprapubic). Thirty-eight patients (35%) were identified as using oxybutynin on a regular basis. These patients were compared to those not using oxybutynin with regard to urodynamic parameters and upper tract deterioration. Specifically examined were bladder compliance, bladder leak point pressure, vesicoureteral reflux, hydronephrosis, urolithiasis, febrile urinary tract infections and serum creatinine greater than 2 mg./dl. RESULTS: The mean duration of indwelling catheter use was 11.9 years (12.4 without oxybutynin and 10.9 on oral oxybutynin). Of the 31 patients with normal compliance (greater than 20 ml./cm. water), 24 (77%) were using oxybutynin (p = 0.001). Bladder leak point pressures were abnormal (greater than 35 cm. water) in 5 of 32 patients (16%) on oxybutynin versus 34 of 60 (57%) without it (p <0.001). Hydronephrosis was present in 15 of 66 patients (23%) without oxybutynin versus 1 of 36 (3%) with oxybutynin (p = 0.009). Febrile urinary tract infections occurred in 4 of 35 patients (11%) versus 17 of 62 patients (27%) with or without oxybutynin, respectively (p = 0.077). No significant differences were found between the 2 groups with regard to reflux, renal scars, stones or elevated serum creatinine. CONCLUSIONS: It appears that regular use of oxybutynin may be beneficial in spinal cord injured patients who require chronic indwelling catheters for bladder management. Our analysis reveals that patients who take oxybutynin regularly have better bladder compliance, lower bladder leak point pressures and less hydronephrosis. Until a prospective, randomized trial reveals contradicting outcomes, empiric use of oxybutynin in all spinal cord injured patients requiring chronic indwelling catheters seems justified.

Adult↗
PubMed2003

Therapeutic efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with diurnal urinary incontinence.

PURPOSE: We compare the tolerability and efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with nonneurogenic diurnal urinary incontinence and symptoms of overactive bladder. MATERIALS AND METHODS: Children with a history of diurnal urinary incontinence were arbitrarily assigned to extended release oxybutynin, immediate release tolterodine or long acting tolterodine. The dose was titrated until effective (onset of complete diurnal urinary continence), maximal recommended dosage was achieved or bothersome anticholinergic side effects developed. An independent observer recorded the dose used, anticholinergic side effects and efficacy of therapy (incidence of urinary frequency, urgency, posturing and urinary incontinence). RESULTS: The study included 86 girls and 46 boys. There were no statistically significant differences among the 3 treatment groups regarding the presence of peripheral or central nervous system anticholinergic side effects. Extended release oxybutynin and long acting tolterodine were significantly more effective at reducing daytime urinary incontinence than immediate release tolterodine (p <0.01 and 0 <0.05, respectively). Extended release oxybutynin was significantly more effective then long acting tolterodine for complete resolution of diurnal incontinence (p <0.05). CONCLUSIONS: Extended release oxybutynin and long acting tolterodine are more effective than immediate release tolterodine in decreasing diurnal urinary incontinence. Extended release oxybutynin chloride is more effective than either immediate or long acting tolterodine for control of daytime urinary incontinence and urinary frequency.

Adolescent↗
PubMed2001

Oxybutynin, desmopressin and enuresis.

PURPOSE: A review of the scarce literature concerning oxybutynin treatment for nocturnal enuresis reveals that its success is greatest when enuresis is combined with daytime incontinence. The renal and bladder related characteristics of children with monosymptomatic enuresis responsive to oxybutynin were evaluated. MATERIALS AND METHODS: Renal concentrating capacity and functional bladder capacity were compared between 55 dry children who served as controls, and children with monosymptomatic enuresis who responded to desmopressin only (group 1, 27), oxybutynin only (group 2, 11), combination desmopressin and oxybutynin (group 3, 7) or were resistant to all treatment alternatives (group 4, 23). RESULTS: Renal concentrating capacity was lowest in groups 1 and 3 (939 +/- 147 mOsm./kg. controls, 856 +/- 158 group 1, 1,073 +/- 71 group 2, 762 +/- 119 group 3 and 970 +/- 146 group 4; p <0.01), whereas they had high urinary output (15.4 +/- 73.4 ml./kg. per hour controls, 22.2 +/- 10.2 group 1, 13.5 +/- 4.3 group 2, 21.5 +/- 11.2 group 3 and 15.0 +/- 6.9 group 4; p <0.01). Forced functional bladder capacity of that expected for age was lowest in groups 2 to 4 (107 +/- 43% controls, 88 +/- 43 group 1, 71 +/- 25 group 2, 68 +/- 22 group 3 and 59 +/- 22 group 4; p <0.01). CONCLUSIONS: Children responding to oxybutynin have small bladders and probably hyperactive detrusors, whereas those responding to desmopressin or who need both drugs to achieve dryness have polyuria.

Child↗
PubMed2000

Interstitial cystitis: bladder training with intravesical oxybutynin.

PURPOSE: We assess the efficacy of intravesical administration of oxybutynin chloride in patients with interstitial cystitis. MATERIALS AND METHODS: The study included 36 women with a mean age of 45 years with a diagnosis of interstitial cystitis. Patients were treated with gradual intravesical instillation of saline oxybutynin solution (oxybutynin group) or gradual filling of simple saline (control group). Evaluation parameters consisted of symptom problem index, voids per day, volume per void, functional bladder capacity, volume at first sensation, cystometric bladder capacity and cystometric volume at first sensation. RESULTS: Statistically significant improvement of all evaluated parameters was found in both groups. When comparing the outcomes statistically significant improvement of parameters favored the oxybutynin group. CONCLUSIONS: Bladder training alone produces a satisfactory result by gradually expanding the bladder, and an additional statistically significant improvement is evident with intravesical oxybutynin.

Administration, Intravesical↗
PubMed2006

Prediction of Medicare drug formulary drugs for treatment of overactive bladder.

PURPOSE: With the establishment and signing into law the Medicare and Prescription Drug Improvement and Modernization Act of 2003, also known as Medicare Part D, medical costs are expected to soar. In fact, the program is expected to cost more than a trillion dollars through 2015. Establishment of the Medicare Part D drug formulary will allow cost containment but still absorb patient and physician preferences as well as a consideration of efficacy and safety data. MATERIALS AND METHODS: Potential Medicare formulary choices were examined in the anticholinergic class, as commonly used by urologists, and small in number of available drugs. Formulary selection parties and issues were individually analyzed, including the government in respect to cost containment, patients in relation to efficacy and cost, physicians in relation to preferences and influence and drug companies in relation to lobbying power, country of base of operations and market shares. Costs to Medicare and patients were calculated using discount Internet sites for pricing and simulated using Medicare Part D benefits. RESULTS: Generic oxybutynin is likely to be included because it is the least expensive to patients and Medicare, but it has the lowest efficacy. Detrol LA is likely to be the long acting choice due to efficacy, cost and manufacture by a United States based company. CONCLUSIONS: A simulation of cost analysis of anticholinergics for treatment of overactive bladder would help urologists better understand the Medicare formulary selection process.

Cholinergic Antagonists↗
PubMed2006

The role of bladder capacity in antidiuretic and anticholinergic treatment for nocturnal enuresis.

PURPOSE: We evaluated combination treatment with desmopressin and oxybutynin in patients with enuresis who did not respond to desmopressin monotherapy. Furthermore, we compared 2 methods of estimating bladder capacity and evaluated the ability of these methods to predict the response to desmopressin and oxybutynin. MATERIALS AND METHODS: A total of 60 children with a mean age +/- SD of 10.6 +/- 3.0 years who had monosymptomatic nocturnal enuresis completed the study. After a 2-week observation period maximal voided volume during free access to fluid intake was determined by a 2-day frequency-volume chart and maximal voided volume after water load was determined on a separate day. Patients then received 20 mug desmopressin intranasally at bedtime during 2 weeks. In nonresponders to desmopressin with less than a 50% decrease in wet nights 5 mg oxybutynin twice daily was added for another 2 weeks. RESULTS: Of the patients 41 (68%) showed more than 50% decrease in wet nights during the 2-week desmopressin treatment period (4.6 +/- 1.6 to 0.7 +/- 0.8, p <0.001). In desmopressin nonresponders combined treatment with desmopressin and oxybutynin resulted in a further decrease in wet nights (4.0 +/- 1.2 to 1.7 +/- 1.4, p <0.001). Maximal voided volume during free access to fluid intake was significantly higher in desmopressin responders than in nonresponders (244 +/- 111 vs 160 +/- 65 ml, p <0.001). In contrast, maximal voided volume after water load was not significantly different between desmopressin responders and nonresponders. CONCLUSIONS: The study indicates a role for oxybutynin in combination with desmopressin in children who are not responding to desmopressin monotherapy. Maximal voided volume during free access to fluid intake is a clinically useful predictor of the response to desmopressin but not to oxybutynin.

Antidiuretic Agents↗
PubMed1994

Nonsurgical management of threatened upper urinary tracts and incontinence in children with myelomeningocele.

The 2 major urological objectives in treating the child with myelomeningocele are to preserve renal function and achieve continence. We report our success in managing these cases with nonsurgical therapy. From 1981 to 1991, 45 patients with myelomeningocele 1 to 15 years old were evaluated urodynamically before and after initiating nonsurgical treatment. Pretreatment urodynamics identified 2 groups. Group 1 consisted of 31 patients with leak point pressure of 40 cm. water or more of whom 10 had grades II to V/V vesicoureteral reflux and 4 had moderate or severe hydronephrosis. Group 2 consisted of 14 incontinent patients with leak point pressure of less than 40 cm. water and no reflux or hydronephrosis. Both groups were treated with intermittent catheterization, anticholinergic medications and fluid restriction. Within a mean followup of 5.5 years nonsurgical intervention resulted in lowering maximum detrusor pressure at maximum cystometric capacity to less than 40 cm. water in 22 of 31 group 1 patients (71%), and in resolving vesicoureteral reflux in 7 of 10 (70%) and hydronephrosis in 3 of 4 (75%) group 1 patients. Of 4 patients in group 1 with persistent high grade vesicoureteral reflux or severe hydronephrosis 3 (10%) required augmentation cystoplasty. With nonsurgical management 18 patients (40%) were completely continent, 18 (40%) required 2 or less pads daily and 9 (20%) required more than 2 pads daily. Nonsurgical management alone was effective in preserving the upper urinary tract in 90% of patients and it provided satisfactory continence in 80%. Surgical management should be reserved for the minority of patients whose upper tract changes do not resolve and for those whose degree of continence is not satisfactory with nonsurgical management.

Adolescent↗
PubMed1994

The use of intravesical oxybutynin chloride in patients with detrusor hypertonicity and detrusor hyperreflexia.

Intravesical oxybutynin chloride was administered to 11 children and 7 adults with upper motor neuron bladder dysfunction who were refractory to oral use or who had intolerable side effects from the medication. This therapy was combined with clean intermittent catheterization to ensure complete emptying of the bladder. Five children and 5 adults discontinued therapy due to side effects or the inconvenience of the procedure. The remaining 6 children and 2 adults continue the medication successfully and have shown on followup urodynamic studies that bladder volumes are greater and intravesical pressures are lower than before medication. Intravesical oxybutynin chloride seems to be an effective modality to treat some of these patients but it is not without significant side effects.

Administration, Intravesical↗