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Eighteen patients treated with oxybutynin chloride are presented. The effect of the drug on the hyperactive detrusor is shown and discussed. Side effects and limitations are described and related to treatment.
The occurrence of spinal cord lesions in children has been reported to be rare. In the literature, there is little information about the management of the neurovesical dysfunction. We report our experience in the treatment of the neuropathic bladder in 18 children with spinal cord injury. The long-term follow-up shows that there is a good recovery and the complication rate is low.
Verapamil, a calcium channel blocker, was tested alone and in combination with oxybutynin chloride for its clinical effectiveness in the treatment of detrusor hyperreflexia in a spinal cord injured population. Fourteen patients with detrusor hyperreflexia were included. All patients were treated with oxybutynin chloride alone and with the combination of oxybutynin chloride and verapamil. Six of the patients were also studied on no medication and verapamil alone. Cystometric and clinical comparisons were made with each change in drug dosage. Verapamil 240SL, when used alone, produced a delay in the first detrusor contraction as compared to no medication in 5 of the 6 patients but clinical improvement was insignificant. Clinical improvement with tolerable side effects was noted in 13 of the 14 patients treated with the combination of oxybutynin chloride and verapamil over oxybutynin alone. Our early experience with verapamil suggests that it may be a valuable adjunct in the treatment of detrusor hyperreflexia.
This report deals with the control of detrusor hyperreflexia by the intravesical instillation of oxybutynin hydrochloride (OH) in 10 male and 3 female patients with complete suprasacral spinal cord lesions having clean intermittent catheterisation (CIC) because of unbalanced voiding. The indication for intravesical OH application was persisting urinary incontinence despite CIC in 11 patients and in 2 patients detrusor hypercontractility. One 5 mg tablet of OH was dissolved in distilled water and the solution was instilled into the bladder through the catheter, which has been used for urodynamics and which was then removed. Six hours later cystometry was repeated and the clinical effects were studied especially with regard to continence/incontinence and side-effects. The differences in the cystometric bladder capacity and maximum detrusor pressure before and after instillation of OH are statistically highly significant. Clinically, from those 10 patients who were incontinent between CIC before, 9 remained dry during the 6-hour period. None of the patients reported any side-effect after intravesical application of OH. However, with subsequent oral medication 8 out of 12 patients complained of typical anticholinergic side-effects. These results indicate that treatment with topical OH is an effective alternative to treating detrusor hyperreflexia, especially in patients already on CIC because of unbalanced voiding, but with persisting urinary incontinence due to detrusor hyperreflexia. OH is well absorbed from the bladder, however absorption seems to be protracted compared to oral intake.
Intravesical oxybutynin hydrochloride was administered to 17 patients with a neuropathic bladder (myelomeningocele in 15 and spinal cord tumour in two) and urinary incontinence refractory to intermittent catheterisation. Therapy consisted of instillation of a 10 ml solution containing 5 mg oxybutynin hydrochloride twice daily. The cystometric bladder capacity before and after 1 hour of intravesical oxybutynin hydrochloride was 132 +/- 45 ml and 193 +/- 71 ml (mean +/- 1 standard deviation, p < 0.01) in all 17 patients. In 13 patients with low compliant bladders, the mean bladder compliance before and after 1 hour of instillation was 4.2 +/- 2.4 ml/cmH2O and 8.5 +/- 6.4 ml/cmH2O respectively (p < 0.01). The period of the intravesical oxybutynin hydrochloride treatment ranged from 2 to 16 months (mean 11.1 months). The improvement rate of 'moderately improved' and better response was 76.5% in all 17 patients. One patient complained of slight lower abdominal pain, which receded as treatment continued. Since the pH value of the solution appeared to be so low as to irritate the vesical mucosa, the value was adjusted to 5.85. No local or systemic side effects were observed thereafter. These encouraging results suggest that intravesical instillation of oxybutynin hydrochloride is an attractive alternative in patients with a neuropathic bladder, who are either unresponsive to or have intolerable side effects from oral medications.
The treatment of choice for the failure to restore neurogenic bladder dysfunction, managed with clean intermittent catheterization program with incontinence, is anticholinergic medication. The goal is to increase bladder capacity, and decrease intravesical pressure in order to maintain continence between catheterizations. The most commonly used anticholinergic medication in the United States is Oxybutynin. Previous clinical studies have shown that 61% of the patients on oral Oxybutynin report adverse systemic side effects and are noncompliant in taking it. In 48% of the patients, possibly due to their noncompliance, oral Oxybutynin Hydrochloride is ineffective. In this study, 13 spinal cord injured patients with a failure to restore bladder dysfunction were treated with intravesical Oxybutynin. Nine patients improved on the regimen while one patient underwent surgical bladder augmentation. Postoperatively, this patient continued to be incontinent between catheterizations. Reinstitution of intravesical Oxybutynin stabilized the patient's bladder with clean intermittent catheterization without further intervention. After 3 months post instillation in the urodynamic studies, the mean bladder capacity increased, the mean volume at first contraction increased and the leak point pressure decreased. The decrease in leak point pressure was statistically significant. Leak point pressure is one of the most important parameters we monitor to preserve upper urinary tract function. We recommend the trial of intravesical Oxybutynin for patients who fit the criteria of the protocol prior to surgical bladder augmentation.
1. Affinity estimates were obtained for several muscarinic antagonists against carbachol-stimulated [3H]-inositol phosphates accumulation in Chinese hamster ovary (CHO-KI) cells stably expressing either human muscarinic M3 or M5 receptor subtypes. The rationale for these studies was to generate a functional antagonist affinity profile for the M5 receptor subtype and compare this with that of the M3 receptor, in order to identify compounds which discriminate between these two subtypes. 2. The rank order of antagonist apparent affinities (pK(B)) at the muscarinic M5 receptor was atropine (8.7) > or =tolterodine (8.6) = 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, 8.6)> darifenacin (7.7) > or =zamifenacin (7.6)>oxybutynin (6.6)= para-fluorohexahydrosiladifenidol (p-F-HHSiD, 6.6)>pirenzepine (6.4) > or = methoctramine (6.3)=himbacine (6.3)>AQ-RA 741 (6.1). 3. Antagonist apparent affinities for both receptor subtypes compare well with published binding affinity estimates. No antagonist displayed greater selectivity for the muscarinic M5 subtype over the M3 subtype, but himbacine, AQ-RA 741, p-F-HHSiD, darifenacin and oxybutynin displayed between 9- and 60 fold greater selectivity for the muscarinic M3 over the M5 subtype. 4. This study highlights the similarity in pharmacological profiles of M3 and M5 receptor subtypes and identifies five antagonists that may represent useful tools for discriminating between these two subtypes. Collectively, these data show that in the absence of a high affinity M5 selective antagonist, affinity data for a large range of antagonists is critical to define operationally the M5 receptor subtype.
1. The cardiac electrophysiological effects of S-oxybutynin, a single-enantiomer drug under evaluation for the management of urinary incontinence, have been investigated and compared with those of terodiline, an incontinence agent withdrawn following reports of QT lengthening and ventricular tachyarrhythmia. Membrane currents were recorded from whole-cell configured guinea-pig and rabbit ventricular myocytes, and action potentials were recorded from guinea-pig and rabbit papillary muscles. 2. L-type Ca(2+) current (I:(Ca,L)), rapidly-activating K(+) current (I:(Kr)) and slowly-activating K(+) current (I:(Ks)) were unaffected by submicromolar S-oxybutynin and inhibited by higher concentrations; IC(50) values were 17.8 microM for I:(Ca,L), 12 microM for I:(Kr), and 41 microM for I:(Ks). Terodiline IC(50) values were somewhat lower for I:(Ca,L) (15.2 microM) and I:(Ks) (30 microM), but 24 fold lower in the case of I:(Kr) (0.5 microM). 3. The durations of action potentials in guinea-pig and rabbit papillary muscles driven at 1 Hz were unaffected or moderately shortened by 0.1 - 100 microM S-oxybutynin, but lengthened by terodiline. Terodiline (< or =10 microM) also depressed maximal upstroke velocity. 4. The action potential plateau shortened by an average of 23% when control rabbit papillary muscles were driven at 0.4 Hz instead of 1 Hz. Plateau shortening was significantly smaller in the presence of drugs (30 microM S-oxybutynin, 3 and 30 microM terodiline), suggesting that they suppress the transient outward current (I:(to)) involved in rate-dependent shortening. In experiments on rabbit ventricular myocytes, 3 and 30 microM S-oxybutynin inhibited I:(to) by 9+/-2% and 35+/-3%, respectively, whereas 3 and 30 microM terodiline inhibited the current by 31+/-3% and 87+/-3%, respectively. 5. The results indicate that S-oxybutynin has relatively weak non-specific effects on cardiac ion channels, and that clinically relevant submicromolar concentrations are unlikely to have terodiline-like proarrhythmic actions on the myocardium.
1. Muscarinic cholinoceptors (MChR) in freshly dispersed rat salivary gland (RSG) cells were characterized using microphysiometry to measure changes in acidification rates. Several non-selective and selective muscarinic antagonists were used to elucidate the nature of the subtypes mediating the response to carbachol. 2. The effects of carbachol (pEC(50) = 5.74 +/- 0.02 s.e.mean; n = 53) were highly reproducible and most antagonists acted in a surmountable, reversible fashion. The following antagonist rank order, with apparent affinity constants in parentheses, was noted: 4-DAMP (8.9)= atropine (8.9) > tolterodine (8.5) > oxybutynin (7.9) > S-secoverine (7.2) > pirenzepine (6.9) > himbacine (6.8) > AQ-RA 741 (6.6) > methoctramine (5.9). 3. These studies validate the use of primary isolated RSG cells in microphysiometry for pharmacological analysis. These data are consistent with, and extend, previous studies using alternative functional methods, which reported a lack of differential receptor pharmacology between bladder and salivary gland tissue. 4. The antagonist affinity profile significantly correlated with the profile at human recombinant muscarinic M(3) and M(5) receptors. Given a lack of antagonists that discriminate between M(3) and M(5), definitive conclusion of which subtype(s) is present within RSG cells cannot be determined.
1 A novel muscarinic receptor antagonist, solifenacin succinate, inhibited specific binding of [N-methyl-(3)H]-scopolamine ([(3)H]-NMS) in the mouse bladder, submaxillary gland and heart in a concentration-dependent manner. This inhibitory effect was greatest in the submaxillary gland, followed by the bladder and heart. 2 After oral administration of oxybutynin (76.1 micromol kg(-1)) or solifenacin (62.4, 208 micromol kg(-1)), a significant dose- and time-dependent increase in K(D) values for specific [(3)H]-NMS binding was seen in the bladder, prostate, submaxillary gland, heart, colon and lung, compared with control values. The increase in K(D) induced by oxybutynin in each tissue reached a maximum 0.5 h after oral administration and then rapidly declined, while that induced by solifenacin was greatest 2 h after administration and was maintained for at least 6 or 12 h, depending on the dose. The muscarinic receptor binding of oral solifenacin was slower in onset and of a longer duration than that of oxybutynin. 3 Plasma concentrations of oxybutynin and its active metabolite (N-desethyl-oxybutynin, DEOB) were maximum 0.5 h after its oral administration and then declined rapidly. Oral solifenacin persisted in the blood for longer than oxybutynin. 4 Pilocarpine-induced salivary secretion in mice was significantly reduced by oral administration of solifenacin and was completely abolished 0.5 h after oral oxybutynin. Although the suppression induced by solifenacin was more persistent than that due to oxybutynin, the antagonistic effect of solifenacin on the dose-response curves to pilocarpine was significantly weaker than that of oxybutynin. It is concluded that oral solifenacin persistently binds to muscarinic receptors in tissues expressing the M(3) subtype, such as the bladder.
Evidence suggests that compounds that increase the synaptic availability of more than one neurotransmitter have greater efficacy in the treatment of depression than single-acting drugs. Preclinical studies indicate that duloxetine acts to inhibit serotonin (5-HT) and norepinephrine (NE) transporters. The ability of duloxetine to alter 5-HT and NE reuptake was tested in 12 healthy male subjects. Placebo, desipramine 50 mg b.i.d., and duloxetine (80 mg q.d. or 60 mg b.i.d.) were compared in a randomized, double-blind, three-period crossover study in 12 healthy male subjects. Whole-blood 5-HT, urinary excretion of NE and major metabolites, and TYR PD30 (IV tyramine pressor dose needed to increase systolic blood pressure by 30 mmHg) were measured at steady state. Vital signs were measured periodically. Duloxetine affected 5-HT reuptake, with whole-blood 5-HT depletion vs placebo (80 mg q.d.: p=0.07; 60 mg b.i.d.: p=0.02; combined regimens: p=0.01). Cardiovascular changes reflecting increased sympathetic tone were observed with both duloxetine and desipramine, and both treatments significantly decreased whole body NE turnover (p<0.01). Duloxetine and desipramine were associated with similar mean increases in fractional extraneuronal NE concentration, although these changes did not reach statistical significance. TYR PD30 increased significantly with desipramine dosing (p<0.01). In conclusion, whole-blood measurements confirm that duloxetine inhibits platelet 5-HT uptake in vivo. Urinary and cardiovascular measurements suggest that duloxetine has an effect on NE synthesis and turnover, indicative of NE reuptake inhibition. The lack of a detectable impact of duloxetine on TYR PD30 suggests that this may not be the most sensitive indirect measure of NE reuptake when assessing dual reuptake inhibitors.
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OBJECTIVES: A comparative assessment of (i) urinary continence status, (ii) quality of life, and (iii) sexuality in spinal cord injury patients prior to, and during intermittent catheterization with adjunctive intravesical oxybutynin therapy (Cystin: manufactured by Leiras Oy. Helsinki, Finland). SETTING: A hospital, and community-based study of selected adult, male, spinal cord injury patients registered with the Regional Spinal Injuries Centre, Southport. PATIENTS: Seven patients (mean age: 44.3 years) suffering from neuropathic bladder due to suprasacral spinal cord lesion of traumatic aetiology, and well settled in the community in the north-west of England were the subjects of this study. Before commencing the intermittent catheterization regime, these patients were on penile sheath drainage. INTERVENTION: Intermittent urethral catheterization was performed with sterile, single-use Nelaton catheters 5-6 times a day with intravesical instillation of oxybutynin 5 mg in 30 ml. 1-3 times a day for periods ranging from 14 to 30 months. OUTCOME MEASURES: Assessment of urinary continence, sexuality, and quality of life was made (i) at the outset before any intervention, (ii) during intermittent catheterization regime, and (iii) when the patients were using the oxybutynin bladder instillation along with intermittent catheterization. RESULTS: Initially all the seven patients were constantly wearing penile sheaths and leg bags. When these patients performed intermittent catheterization 5-6 times in 24 h, they attempted to discard the penile sheath during the day but they were experiencing mild to moderate urine leak between catheterization. They were compelled to wear penile sheaths during night. Subsequently, five patients took oxybutynin by mouth, but developed an unacceptable degree of side-effects necessitating discontinuation of the medication. Following commencement of intravesical oxybutynin therapy, all of them were able to discard the penile sheaths and leg bags during the day as well as during the night. However, on waking-up after a full night's sleep, three patients found dampness of their undergarments 1-2 times per week. None of the patients experienced side-effects attributable either to the intermittent catheterization procedure, or to the intravesical oxybutynin therapy. The number of episodes of urinary infection requiring antibiotic therapy was 0.08/patient/month. All the seven patients noticed a remarkable improvement in the quality of life because they had achieved a high degree of continence. All the seven patients commented on the improved sense of their own sexuality which was attributed to (i) absence of incontinence episodes, (ii) improved self-image, and (iii) not wearing penile sheaths and leg bags. CONCLUSION: These seven spinal cord injury patients achieved socially acceptable continence with improved quality of life, and enhanced sexuality with the intermittent urethral catheterization regime and intravesical oxybutynin therapy.
OBJECTIVE: To further investigate mechanisms of airway hyperreactivity among subjects with chronic cervical spinal cord injury (SCI), we assessed airway responsiveness to aerosolized methacholine and histamine in subjects receiving chronic oxybutynin chloride therapy, and compared the findings with those not receiving the agent. METHODS: Twenty-five male subjects with cervical SCI participated in this study; 12 were maintained on oral oxybutynin chloride and 13 served as age-matched controls. Six of the 12 subjects receiving oxybutynin were challenged with aerosolized methacholine, and six with histamine; seven of the 13 control subjects were challenged with aerosolized methacholine and the remaining six with histamine. RESULTS: All 13 control subjects and all six oxybutynin/histamine subjects exhibited a significant bronchoconstrictor response (PC20 < 8 mg/ml), whereas mean PC20 values for the oxybutynin/methacholine group were > or =25 mg/ml. CONCLUSION: Our finding that the bronchoconstrictor effects of methacholine were blocked by oxybutynin chloride while those of histamine were not suggests that oxybutynin acts primarily through anticholinergic pathways rather than by causing generalized airway smooth muscle relaxation.
OBJECTIVE: We prospectively analyzed the dose dependent outcome and side effects of neurogenic bladder patients with intravesical application of oxybutynin at our centre. MATERIALS AND METHODS: We examined the data of 32 patients with neurogenic bladders and detrusor hyperreflexia. We registered clinical outcome, continence situation, side effects and urodynamic data of patients with (A) standard dosages of intravesical oxybutynin (0.3 mg/kg bodyweight per day) and (B) with increasing dosages in steps of 0.2 mg/kg bodyweight per day up to 0.9 mg/kg bodyweight per day. RESULTS: We examined 32 patients aged 1 to 34 years, mean age 12 years. 21/32 patients became totally continent with the dosage (A). They showed a significant (P<0.01) decrease in the median max detrusor pressure (MDP) and a significant (P<0.01) increase in the median compliance and the median age adjusted bladder capacity (AABC). Eleven out of 32 patients remained incontinent under this dosage (A). Their median MDP, their median compliance and their median AABC remained nearly unchanged. Seven out of 11 incontinent patients under dosage (A) were treated efficiently with the higher dosages (B). Their median necessary dosage escalation to achieve treatment success was 0.7 mg/kg bodyweight per day (range 0.5 to 0.9 mg/kg bodyweight per day). Their median MDP was significantly (P<0.05) decreased and their median compliance and median AABC were significantly (P<0.05) increased. Four out of 11 patients remained incontinent and showed only little improvement in urodynamic data. Two out of 11 patients with the dosage escalation (B) showed side effects at a dosage of 0. 9 mg/kg bodyweight per day. CONCLUSIONS: The intravesical application of oxybutynin was a well tolerated and efficacious therapy. The topical oxybutynin therapy dosage (A) was efficient in 66% of our selected patients, the escalating dosage titration (B) could increase the efficiency to 87%.
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STUDY DESIGN: Prospective investigation using serial urodynamic studies. OBJECTIVE: To evaluate type of neurogenic bladder and to observe changes of autonomous detrusor contraction (ADC) after the normalization of the compliance and capacity of the bladder in cauda equina injury. SETTING: Spinal Cord Injury Unit, Yonsei Rehabilitation Hospital, Seoul, Korea. METHODS: Urodynamic studies were performed in 50 patients with complete cauda equina injury from trauma with an infusion ratio of 30 ml/min. Findings of urodynamic studies and clinical features of patients with low compliance were compared with those of the normal compliant patients. Fourteen patients with low compliance received oral administration of oxybutynin and propiverine and intravesical instillation of oxybutynin to increase the compliance and capacity of the bladder, and follow-up urodynamic studies to monitor the change were undertaken. RESULTS: Bladder compliance was decreased in 14 (28%) patients and normal in 36 (72%) patients. There was a significantly long time interval between the onset of injury and the initiation of rehabilitative treatment in the neurogenic bladder group with low compliance when compared to those of the normal compliance group (P < 0.05). Clean intermittent catheterization was used as the voiding method, significantly less than the normal compliance group (P < 0.05). ADC was observed in six out of fourteen patients with low compliance neurogenic bladder, but none in the normal compliance group. Upon the completion of conservative treatment, ADC disappeared in four patients whose compliance and capacity of the bladder were normalized on follow-up urodynamic studies. CONCLUSION: ADC was only observed in the low compliant bladder and as ADC disappeared when compliance and capacity of the bladder was normalized; low compliance appeared to be the main cause of ADC. In addition, this study supports that the maintenance of compliance of the bladder may be the most important factor in the management of neurogenic bladder.
OBJECTIVE: To report a case of Carbamazepine toxicity following the administration of Oxybutynin and Dantrolene. STUDY DESIGN: A case report. SETTING: The Spinal Rehabilitation Department, Loewenstein Hospital, Raanana, Israel. METHODS: A patient with C6D tetraplegia who sustained intoxication because of drug interaction is presented. She had been treated by Carbamazepine 1000 mg/day for neuropathic pain for 2 years without clinical or laboratory signs of toxicity. After administration of Oxybutynin concomitantly with an increase in the dose of Dantrolene, she presented the clinical symptoms and laboratory finding of Carbamazepine intoxication. Trying to adjust the treatment to the patient's requirements, Carbamazepine together with Oxybutynin and Dantrolene was readministrated in lower doses. RESULTS: The combination of these drugs, even small doses, caused toxicity. Adding Dantrolene and Oxybutynin elevated the blood level of Carbamazepine, possibly by inhibition of cytochrome P450. CONCLUSION: A possible pharmacokinetic interaction between Dantrolene and Oxybutynin should be borne in mind when considering Carbamazepine medication for a patient with a spinal cord lesion.