Advances in the pharmacological control of the bladder.
To effectively control bladder activity, and to treat urinary incontinence caused by bladder overactivity, identification of suitable targets for pharmacological intervention is necessary. Such targets may be found in the central nervous system (CNS) or peripherally. The causes of bladder overactivity are not known, but theoretically increased afferent activity, decreased inhibitory control in the CNS and/or peripheral ganglia, and increased sensitivity of the detrusor to efferent stimulation may be involved. Several CNS transmitters may modulate voiding, but few drugs with a defined CNS site of action have been developed for treatment of voiding disorders. Potentially, drugs affecting GABA, opioid, 5-HT, noradrenaline, dopamine, or glutamatergic receptors and mechanisms can be developed, but a selective action on the lower urinary tract may be difficult to obtain. Traditionally, drugs used for treatment of bladder overactivity have had a peripheral site of action, mainly the efferent neurotransmission or the detrusor muscle itself. Antimuscarinic drugs, beta-adrenoceptor agonists, alpha-adrenoceptor antagonists, drugs affecting membrane channels, prostaglandin synthetase inhibitors and several other agents have been used. However, none of them has been developed specifically for treatment of bladder disorders, and their efficacy, as judged from controlled clinical trials (where performed), is often limited. Recent information on the alpha-adrenoceptor, beta-adrenoceptor (beta 3), and muscarinic receptor subtypes of the human detrusor and outflow region can be the basis for the development of compounds with effect on bladder overactivity and with improved tolerance. New ways of decreasing acetylcholine release may represent a promising way of controlling bladder contraction. Potassium channel (KATP) openers are theoretically attractive, but the drugs available so far have targeted vascular rather than bladder smooth muscle, which has limited their clinical use. However, new drugs belonging to these groups with an interesting profile of action have been developed. Drugs decreasing afferent activity represent an attractive therapeutic approach and transmitters of afferent nerves and their receptors are possible targets for pharmacological interventions. Tachykinins, such as substance P, neurokinins A and B, and other neuropeptides have been demonstrated in nerves of the lower urinary tract and have been shown to influence bladder function. Agents affecting these nerves by causing release of tachykinins, such as capsaicin and resiniferatoxin, given intravesically can be effective in some cases of bladder overactivity, and agents antagonizing tachykinin receptors may also be of therapeutic interest. New drugs specifically directed for control of bladder activity are under development and will hopefully lead to improved treatment of urinary incontinence. (+info)
Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole.
AIM: To investigate the in vivo effect of treatment with tolterodine on debrisoquine 4-hydroxylation (an index of CYP2D6 activity), omeprazole 5-hydroxylation (CYP2C19), omeprazole sulphoxidation (CYP3A4) and caffeine N3-demethylation (CYP1A2). METHODS: Twelve healthy male volunteers (eight extensive metabolisers [EMs] and four poor metabolisers [PMs] with respect to CYP2D6) received 4 mg tolterodine L-tartrate orally twice daily for 6 days. All subjects were EMs with respect to CYP2C19. The subjects received single oral doses of debrisoquine (10 mg), omeprazole (20 mg) and caffeine (100 mg) for determination of the appropriate metabolic ratios (MR). The drugs were given on separate consecutive days, before, during and after the co-administration of tolterodine. RESULTS: Mean serum tolterodine concentrations were 5-10 times higher in PMs than in EMs. Serum concentrations of the active 5-hydroxymethyl metabolite of tolterodine, 5-HM, were not quantifiable in PMs. The mean MR of debrisoquine (95% confidence interval) during tolterodine treatment was 0.50 (0.25-0.99) and did not differ statistically from the values before [0.49 (0.20-1.2)] and after tolterodine administration [0.46 (0.14-1.6)] in EMs. The mean MR of omeprazole hydroxylation and sulphoxidation or caffeine metabolism were not changed in the presence of tolterodine in either EMs or PMs. Debrisoquine and caffeine had no significant effect on the AUC(1,3 h) of either tolterodine or 5-HM, but during omeprazole administration small decreases (13-19%) in these parameters were seen. CONCLUSIONS: Tolterodine, administered at twice the expected therapeutic dosage, did not change the disposition of the probe drugs debrisoquine, omeprazole and caffeine and thus had no detectable effect on the activities of CYPs 2D6, 2C19, 3A4 and 1A2. Alteration of the metabolism of substrates of these enzymes by tolterodine is unlikely to occur. (+info)
Predictors of outcome in cauda equina syndrome.
This retrospective review examined the cause, level of pathology, onset of symptoms, time taken to treatment, and outcome of 19 patients with cauda equina syndrome (CES). The minimum time to follow up was 22 months. Logistical regression analysis was used to determine how these factors influenced the eventual outcome. Out of 19 patients, 14 had satisfactory recovery at 2 years post-decompression; 5 patients were left with some residual dysfunction. The mean time to decompression in the group with a satisfactory outcome was 14 h (range 6-24 h) whilst that of the group with the poor outcome was 30 h (range 20-72 h). There was a clear correlation between delayed decompression and a poor outcome (P = 0.023). Saddle hypoaesthesia was evident in all patients. In addition complete perineal anaesthesia was evident in 7/19 patients, 5 of whom developed a poor outcome. Bladder dysfunction was observed in 19/19 patients, with 12/19 regarded as having significant impairment. Of the five patients identified as having a poor overall outcome, all five presented with a significant sphincter disturbance and 4/5 were left with residual sphincter dysfunction. There was a clear correlation between the presence of complete perineal anaesthesia and significant sphincter dysfunction as both univariate and multivariate predictors of a poor overall outcome. The association between a slower onset of CES and a more favourable outcome did not reach statistical significance (P = 0.052). No correlation could be found between initial motor function loss, bilateral sciatica, level or cause of injury as predictors of a poor outcome (P>0.05). CES can be diagnosed early by judicious physical examination, with particular attention to perineal sensation and a history of urinary dysfunction. The most important factors identified in this series as predictors of a favourable outcome in CES were early diagnosis and early decompression. (+info)
Long-term suppression of adult bladder morbidity and severe hydronephrosis following selective population chemotherapy for Schistosoma haematobium.
Repeated selective population chemotherapy of school age children reduces infection and morbidity associated with Schistosoma haematobium infection. To examine the long-term effect of this treatment on susceptibility to re-infection and late disease, a cohort of Kenyans (n = 194) were re-examined for infection and urinary tract morbidity 7-13 years after they underwent annual ultrasonography and treatment for an average of 5 years beginning in 1984 as children. Controls were previously untreated age-matched individuals residing in the same or adjacent villages. The overall prevalence and intensity of infection were equivalent between the 2 groups. In contrast, the prevalence of bladder wall pathology was 11-fold lower in previously treated (1.5%) versus untreated subjects (17%). Severe hydronephrosis was completely reversed. These data demonstrate that treatment significantly reduced urinary tract morbidity despite re-infection, and suggest that the important risk factors for urinary tract morbidity in adulthood are cumulative intensity and duration of infection during early adolescence. (+info)
Intravesical rhGM-CSF for the treatment of late onset hemorrhagic cystitis after bone marrow transplant.
In the present study, we assessed the clinical effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in the treatment of refractory, grade III-IV hemorrhagic cystitis (HC) in six patients who underwent bone marrow transplantation (BMT). These were four males and two females, aged 24-40 years (median age 30.5 years). All received allogeneic BMT from HLA-identical siblings after preparation with busulfan-cyclophosphamide. HC was evident 24. 5 days (range 15-33 days) after BMT. Median duration of HC before treatment was 5 days (range 4-9 days). Treatment consisted of intravesical instillation of rhGM-CSF (400 microg) for 3 consecutive days. A complete response was observed in three patients, the other three showed a partial response. Median time to achieve response was 36 h (range 0.2-72 h). Hematuria was controlled after the first (two patients), second (two patients) or third (two patients) dose of intravesical rhGM-CSF. Patients were discharged from the hospital 10. 5 days (range 3-41 days) after treatment. All patients have been followed for up to 10 months and none have required further treatment. No systemic or bladder side-effects have been observed. Although our results indicate that intravesical instillation of rhGM-CSF is effective in the treatment of HC, a phase II clinical trial, including a larger series of patients, is needed. (+info)
Urinary catheter management.
The use of urinary catheters should be avoided whenever possible. Clean intermittent catheterization, when practical, is preferable to long-term catheterization. Suprapubic catheters offer some advantages, and condom catheters may be appropriate for some men. While clean handling of catheters is important, routine perineal cleaning and catheter irrigation or changing are ineffective in eliminating bacteriuria. Bacteriuria is inevitable in patients requiring long-term catheterization, but only symptomatic infections should be treated. Infections are usually polymicrobial, and seriously ill patients require therapy with two antibiotics. Patients with spinal cord injuries and those using catheters for more than 10 years are at greater risk of bladder cancer and renal complications; periodic renal scans, urine cytology and cystoscopy may be indicated in these patients. (+info)
Quantitative assessment of eosinophiluria in Schistosoma haematobium infections: a new marker of infection and bladder morbidity.
Eosinophiluria, as quantified by measuring eosinophil cationic protein (ECP) in urinary extracts, microhematuria, egg excretion, and ultrasound-detectable bladder pathology were recorded in Schistosoma haematobium-infected Tanzanian school children at a baseline survey and during an 18-month post-treatment follow-up study. Significant correlations were seen between urinary ECP levels, intensity of infection, and bladder pathology. Treatment resulted in a marked reduction in prevalence and intensity of infection, in a delayed and less marked reduction in ECP levels, and in a resolution of pathology. The overall diagnostic efficiency of the ECP test (cut-off value for the ECP > or =5 ng/ml) in relation to infection was comparable with that of egg count and microhematuria, but with a better sensitivity than a single egg count. In relation to bladder pathology, the diagnostic performance of the ECP test (cut-off value for the ECP > or =25 ng/ml) exceeded that of a single egg count. In addition, the ECP was better in discriminating between different grades of bladder pathology. The present study points to the ECP as a useful marker of both S. haematobium infection and of associated bladder morbidity reflecting the inflammatory status of the bladder wall. (+info)
Inflammatory pseudotumor of urinary bladder.
A previously healthy 44-year-old male was admitted with the chief complaint of intermittent gross hematuria. On initial ultrasonographic and CT examination, a grossly protruding intravesical tumor was noted and, under the impression of a malignant bladder tumor, transurethral resection was performed. The histological findings were spindle cells with elongated cytoplasm with rare mitotic figures distributed in myxoid stroma, consistent with diagnosis of inflammatory pseudotumor of the bladder. The benign nature of this tumor warrants conservative surgical management, usually consisting of transurethral resection or partial cystectomy. No reports of metastasis have been reported following complete excision. Therefore, any suspicion and recognition of this entity is imperative to avoid performing an irreversible radical procedure. (+info)