Laurence Stewart

Antimuscarinic drugs in detrusor overactivity and the overactive bladder syndrome: motor or sensory actions?

Antimuscarinic drugs are generally thought to exert their therapeutic action on detrusor overactivity by reducing the ability of the detrusor muscle to contract. We review currently available published data to establish whether there is any evidence to support this contention. Using a PubMed data search, only 14 original articles (including two abstracts) were found that contained cystometric data for both filling and voiding phases and where the actions of antimuscarinic drugs have been reported in detail. These articles were separated into three groups dealing with neuropathic patients (three papers), patients with idiopathic overactive bladder (four papers) and a group whose aetiology was unclear (seven papers). Variables relating to bladder function during the filling phase (time of first desire to void, time to first unstable contraction, and bladder capacity) were identified. Similarly, variables relating to voiding were identified and compared (e.g. maximum detrusor pressure and detrusor pressure at maximum flow rate). The antimuscarinic drugs have a clearly significant effect on sensations of urge, time to first sensation to void, maximum bladder capacity, decrease in voiding frequency and reduction in incontinence episodes. However, only one article (studying neuropaths) reported a significant reduction of the variables associated with detrusor contraction. The remaining four studies (idiopaths/not stated), reported no change in bladder contractility with antimuscarinic drugs. Thus the available data do not support the conclusion that antimuscarinic drugs at doses used in current clinical practice exert their therapeutic action by inhibiting detrusor contractility, but they suggest effects on variables associated with sensation.

Oral complications after buccal mucosal graft harvest for urethroplasty

To report long‐term oral complications after buccal mucosal graft (BMG) harvesting for urethroplasty.

5α-Reductase Type 1 Modulates Insulin Sensitivity in Men

Context: 5α-Reductase (5αR) types 1 and 2 catalyze the A-ring reduction of steroids, including androgens and glucocorticoids. 5α-R inhibitors lower dihydrotestosterone in benign prostatic hyperplasia; finasteride inhibits 5αR2, and dutasteride inhibits both 5αR2 and 5αR1. In rodents, loss of 5αR1 promotes fatty liver. Objective: Our objective was to test the hypothesis that inhibition of 5αR1 causes metabolic dysfunction in humans. Design, Setting, and Participants: This double-blind randomized controlled parallel group study at a clinical research facility included 46 men (20–85 years) studied before and after intervention. Intervention: Oral dutasteride (0.5 mg daily; n = 16), finasteride (5 mg daily; n = 16), or control (tamsulosin; 0.4 mg daily; n = 14) was administered for 3 months. Main Outcome Measure: Glucose disposal was measured during a stepwise hyperinsulinemic-euglycemic clamp. Data are mean (SEM). Results: Dutasteride and finasteride had similar effects on steroid profiles, with reduced urinary androgen and glucocorticoid metabolites and reduced circulating DHT but no change in plasma or salivary cortisol. Dutasteride, but not finasteride, reduced stimulation of glucose disposal by high-dose insulin (dutasteride by −5.7 [3.2] μmol/kg fat-free mass/min, versus finasteride +7.2 [3.0], and tamsulosin +7.0 [2.0]). Dutasteride also reduced suppression of nonesterified fatty acids by insulin and increased body fat (by 1.6% [0.6%]). Glucose production and glycerol turnover were unchanged. Consistent with metabolic effects of dutasteride being mediated in peripheral tissues, mRNA for 5αR1 but not 5αR2 was detected in human adipose tissue. Conclusion: Dual inhibition of 5αRs, but not inhibition of 5αR2 alone, modulates insulin sensitivity in human peripheral tissues rather than liver. This may have important implications for patients prescribed dutasteride for prostatic disease.

Cholinergic activation of phasic activity in the isolated bladder: possible evidence for M3‐ and M2‐dependent components of a motor/sensory system

To analyse pressure changes induced by muscarinic agonists on the isolated bladder in order to examine whether there are different responses representing different components of a motor/sensory system within the bladder wall.

Nocturia, nocturia indices and variables from frequency-volume charts are significantly different in Asian and Caucasian men with lower urinary tract symptoms: a prospective comparison study.

To describe and compare the patterns of nocturia in Asian and Caucasian men presenting with lower urinary tract symptoms (LUTS), and to identify associations or correlations between LUTS and variables from a frequency‐volume chart (FVC), as nocturia is common among men with LUTS, and analysis of FVCs shows nocturnal polyuria and reduced nocturnal bladder capacity (NBC) as the predominant causes in Western patients, but there are few comparisons with other ethnic groups.

SIU/ICUD Consultation on Urethral Strictures: Anterior Urethra—Lichen Sclerosus

We reviewed the current literature on lichen sclerosus as it related to urethral stricture disease using MEDLINE and PubMed (U.S. National Library of Medicine, National Institutes of Health) up to the current time. We identified 65 reports, 40 of which were considered relevant and form the basis of this review. Lichen sclerosus is now the accepted term, and balanitis xerotica obliterans is no longer acceptable. This common chronic inflammatory skin condition, mainly affecting the genitalia, remains an enigma, with uncertain etiology, varied presentation, and multiple treatments. In the early stages of the condition, a short course of steroids may be beneficial for some patients. If persistent, patients need long-term surveillance because of the potential development of squamous cell carcinoma. If diagnosed early, lichen sclerosus can be controlled, preventing progression. But once the disease has progressed, it is very difficult to treat. Surgical treatment by circumcision can be curative if the disease is treated early when still localized. Once progression to urethral involvement has occurred, treatment is much more difficult. Meatal stenosis alone is likely to require meatotomy or meatoplasty. Treatment of the involved urethra requires urethroplasty. Single-stage and multiple-stage procedures using oral mucosa have both been reported to give acceptable results, but the use of skin, genital or nongenital, is not recommended, because being skin, it remains prone to lichen sclerosus. With extensive disease, affecting the full length of the urethra, consideration should be given to perineal urethrostomy. A significant number of patients may prefer this simpler option.

Simultaneous pharmacokinetic and pharmacodynamic analysis of 5α-reductase inhibitors and androgens by liquid chromatography tandem mass spectrometry

Benign prostatic hyperplasia and prostate cancer can be treated with the 5α-reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5α-reductases (testosterone, 5α-dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP® 5500, with a Waters Acquity™ UPLC. Analytes were extracted from serum (500 µL) via solid-phase extraction (Oasis® HLB), with 13C3-labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150×3 mm, 2.6 µm), using a gradient run of 19 min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289→97), DHT (m/z 291→255), androstenedione (m/z 287→97), dutasteride (m/z 529→461), finasteride (m/z 373→317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased.

Does Closure of the Buccal Mucosal Graft Bed Matter? Results From a Randomized Controlled Trial

OBJECTIVE To study the effects of closure vs nonclosure of buccal mucosal graft harvest site. MATERIALS AND METHODS Patients were randomized to either primary closure or nonclosure of buccal mucosal harvest site during urethroplasty. Graft widths were standardized to 2 cm. Prospective data were collected via patient visual analog scales (0-10) of 5 domains examining pain, numbness, tightness, drinking, and eating at postoperative day 1 and 3 and then at 3 weeks and 3 months until 1 year. RESULTS There were 34 patients who underwent randomization and completed the study. The preoperative demographics between both groups were comparable with no significant differences. The median age is 44 years. There were 16 patients in the closure group and 18 patients in the nonclosure group. The results show an improvement in the domains of pain (P = .08), drinking (P = .06), and eating (P = .03) in favor of the closure group at postoperative day 1 and 3. There are no significant differences in all 5 domains between both groups after 3 weeks postoperatively CONCLUSION This study shows that primary closure of buccal mucosal graft bed improves pain as well as oral intake in the immediate postoperative period. There are no long-term differences.

Measurement of tamsulosin in human serum by liquid chromatography–tandem mass spectrometry

Highlights • A method to quantify tamsulosin by liquid chromatography–tandem mass spectrometry.• Simple extraction method from serum, excellent recovery, linear range 0.2–50 ng/mL.• In-house synthesis of internal standard, d9-finasteride.• Validated method with acceptable reproducibility, precision, accuracy and stability.• Useful to assess compliance and pharmacokinetics in studies of benign prostatic hyperplasia.

Volume-induced responses in the isolated bladder: evidence for excitatory and inhibitory elements

To quantify changes in autonomous activity in response to alterations in intravesical volume, to explore the possible underlying regulatory mechanisms.