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Biomedical subjects

C R Chapple

Publications and source records attributed to C R Chapple.

At least 19 recordsLinked to original sources
PubMed2003

The acute effect of magnetic stimulation of the pelvic floor on involuntary detrusor activity during natural filling and overactive bladder symptoms.

OBJECTIVE: To evaluate the effect of magnetic stimulation of the pelvic floor (MSPF) on involuntary detrusor activity observed during natural filling, and on the overactive bladder symptom complex. PATIENTS AND METHODS: Eighteen women with detrusor overactivity on conventional cystometry underwent ambulatory urodynamic monitoring over two filling cycles. Fluid intake was standardized, provocative manoeuvres applied at regular intervals and symptoms documented contemporaneously. During the second filling cycle MSPF was delivered whenever the detrusor pressure increased by > 5 cmH2O. The women were subsequently treated with MSPF for 6 weeks; their lower urinary tract symptoms were assessed before and after treatment. RESULTS: Comparing the second (stimulated) cycle with the first (unstimulated) cycle, cystometric capacity was higher (373 vs 224 mL, P < 0.03). and involuntary detrusor activity of shorter duration (370 vs 427 s, P < 0.82) and lower amplitude (53 vs 63 cmH2O, P < or = 0.05). All women tolerated the procedure comfortably, but nine found it too time-consuming and withdrew. In the nine women who completed treatment there was no consistent change in overactive bladder symptoms. CONCLUSIONS: In this pilot study, MSPF during natural filling was associated with a decrease in the amplitude of involuntary detrusor contractions and a significant increase in cystometric capacity. However, MSPF had a variable effect on sensations of urgency, both acutely and after treatment, and currently there is no evidence to suggest that MSPF has an enduring effect on symptoms of the overactive bladder.

Electric Stimulation Therapy↗
PubMed2002

Future drugs for the treatment of benign prostatic hyperplasia.

For at least a decade, no new drug principles have been added to the therapeutic armamentarium for the treatment of lower urinary tract symptoms (LUTS) associated with or suggestive of benign prostatic hyperplasia (BPH). Theoretically, there seem to be several possibilities to improve the current treatment, which is based mainly on alpha1-adrenoceptor (AR) antagonists, 5alpha-reductase inhibitors and phytotherapy. It cannot be dismissed that subtype selective alpha1-AR antagonists can further improve treatment, but convincing evidence is still lacking. Muscarinic receptor antagonists are currently evaluated in BPH patients, but their eventual place in therapy, as a single treatment or in combination with alpha1-AR antagonists, has to be established. Endothelin receptor antagonists, alone or together with alpha1-AR antagonists, seem to offer a new attractive approach; however, proof of concept studies are lacking. The L-arginine/NO/cGMP pathway awaits further exploration; nitric oxide (NO) donors or phosphodiesterase (PDE) inhibitors may be clinically useful. Purinoceptors are currently the focus of interest as treatment targets in the lower urinary tract and inhibitors of P2X3 (and P2X1) subtypes may offer new opportunities. If a treatment based on desensitising C-fibres in the bladder and urethra is effective, not only in neurogenic bladders, but also for treating LUTS, it would be a viable option. For new treatments of LUTS, targets within the central nervous system (CNS) may offer exciting opportunities.

Adrenergic alpha-Antagonists↗
PubMed2002

Urothelium derived inhibitory factor and cross-talk among receptors in the trigone of the bladder of the pig.

PURPOSE: In the dome of the bladder of the pig muscarinic receptor stimulation has been shown to release a factor from the urothelium that exerts an inhibitory effect on the underlying smooth muscle. We examined whether the urothelium in the trigone of the bladder also releases this factor, identified which receptors stimulate its release and investigated possible cross-talk among these receptor systems in the trigone. MATERIALS AND METHODS: Paired longitudinal strips of pig bladder were isolated, the urothelium was removed from 1 strip per pair and tissues were set up in gassed Krebs solution at 37C. Cumulative concentration-response curves to carbachol, phenylephrine or histamine were constructed. In some tissues a second phenylephrine curve was constructed in the presence of 1 microM. carbachol or 1 microM. histamine. In a further group of tissues the second phenylephrine curve was constructed in the presence of 1 microM. carbachol and 1 microM. atropine or 1 microM. histamine and 100 nM. mepyramine. RESULTS: In the presence of an intact urothelium contractile responses to carbachol and histamine but not to phenylephrine were depressed. In the presence of 1 microM. carbachol or 1 microM. histamine the responses of intact urothelium strips to phenylephrine were significantly depressed. This effect was absent in the presence of atropine and mepyramine, respectively. CONCLUSIONS: Carbachol and histamine induce the release of a urothelium derived inhibitory factor in the bladder trigone. The factor appears to mediate cross-talk between these systems and the alpha-adrenoceptor system in this region of the bladder.

Animals↗
PubMed2001

Role of endogenous transforming growth factor beta (TGFbeta)1 in prostatic stromal cells.

BACKGROUND: In this study, defined culture conditions were used to examine the effects of recombinant TGFbeta1 on prostatic stromal cells and to determine the role of endogenous TGFbeta produced by these cells. METHODS: Cells were grown +/- recombinant TGFbeta1 and cell population sizes in replicate cultures determined. In other experiments, TGFbeta1 production by prostatic stromal cells was examined and the effects of neutralization of this activity on cell population sizes and apoptosis evaluated. RESULTS: At > 1 ng/ml, TGFbeta1 reduced cell population sizes while at 0.01 ng/ml cell numbers were increased cf. controls. Stromal cells produced up to 10 ng/ml/48 hr of latent TGFbeta1 of which < 0.2% was biologically active. When cells were treated with anti-TGFbeta1 antibodies, cell numbers decreased cf. controls and the proportion of apoptotic cells increased. CONCLUSIONS: These observations suggest that TGFbeta1 is an autocrine factor made by prostatic stromal cells in which it inhibits apoptosis at the activity levels produced.

Antibodies↗
PubMed2001

Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, double-blind crossover study.

The aim of the study was to evaluate the potential role for a selective alpha1-adrenoceptor agonist in the treatment of urinary stress incontinence. A randomised, double-blind, placebo-controlled, crossover study design was employed. Half log incremental doses of intravenous methoxamine or placebo (saline) were administered to a group of women with genuine stress incontinence while measuring maximum urethral pressure (MUP), blood pressure, heart rate, and symptomatic side effects. Methoxamine evoked non-significant increases in MUP and diastolic blood pressure but caused a significant rise in systolic blood pressure and significant fall in heart rate at maximum dosage. Systemic side effects including piloerection, headache, and cold extremities were experienced in all subjects. The results indicate that the clinical usefulness of direct, peripherally acting sub-type-selective alpha1-adrenoceptor agonists in the medical treatment of stress incontinence may be limited by associated piloerection and cardiovascular side effects.

Adrenergic alpha-Agonists↗
PubMed2001

Potential therapeutic targets for treatment of the overactive bladder.

Muscarinic receptor antagonists remain the main therapy for the treatment of the overactive bladder yet severe adverse effects make them unsuitable for a large number of patients. The development of new drugs with novel mechanisms of action for the treatment of this condition is therefore essential. This article considers some of the targets currently under investigation for the development of such compounds. Beta-adrenoceptor agonists and KATP channel openers inhibit detrusor muscle activity and remain targets for drug development. There is also evidence that alpha-adrenoceptor antagonists may be effective in the overactive bladder, but the mechanism involved in this action is unclear. Finally the role of tachykinins in regulating bladder function through both the sensory and the motor innervation make them a potential target for drug development, but as with the the others, a selective action on the bladder must remain the goal of drug development.

Adrenergic alpha-Agonists↗
PubMed2001

Oxybutynin and the overactive bladder.

Oxybutynin is a tertiary amine, which undergoes an extensive first-pass metabolism. It has an active metabolite, N-desethyl oxybutynin, and the effect of oral oxybutynin is to a large extent exerted by this metabolite. Oxybutynin has both an antimuscarinic and a direct muscle relaxant effect, and, in addition, local anesthetic actions. Most probably, oral oxybutynin exerts its effects on the overactive bladder (OAB) by an antimuscarinic action. Several studies have shown that oral oxybutynin is effective in controlling OAB. Admininistred intravesically, it can increase bladder capacity and produce clinical improvement both in patients with hypereflexia and in other types of OAB with few side effects. Adverse effects related to the antimuscarinic activity occur frequently and can necessitate treatment discontinuation in up to 25% of patients, depending on the dosage. A controlled-release preparation has recently been introduced. Oxybutynin has a well-documented efficacy in the treatment of detrusor overactivity, and is a drug of first choice in patients with this disorder.

Humans↗
PubMed2001

Which muscarinic receptor is important in the bladder?

Antimuscarinic agents are the most widely used therapy for urge incontinence, but have side effects such as constipation, tachycardia and dry mouth, resulting from a lack of selectivity for the bladder. M2 receptors are the predominant cholinoceptors present in urinary bladder, but mainly the minor population of M3 receptors mediate its contraction. M2 receptors modulate detrusor contraction by several mechanisms, and may contribute more to contraction of the bladder in pathological states such as bladder denervation or spinal cord injury. Prejunctional inhibitory M2 or M4 receptors and prejunctional facilitatory muscarinic Ml receptors in the bladder have all been reported. In clinical studies, tolterodine, a non-selective muscarinic antagonist, has been reported to be as effective as oxybutynin but inducing less dry mouth. Thus, although it is not certain which antimuscarinic drugs have the better efficacy and tolerability, the non-selective antimuscarinic drugs seem to be better than M3-selective antagonists in their clinical efficacies. However, controlled release, or intravesical, intravaginal, or rectal administrations of oxybutynin have been reported to cause fewer side effects. Darifenacin, a new M3 selective antagonist, has been reported to have selectivity for the bladder over the salivary gland in vivo. To verify which antimuscarinic drugs selective for the muscarinic subtypes have the best efficacy and tolerability, comparative clinical trials between M3 selective antagonists and non-selective compounds, such as olterodine, are required in the future.

Humans↗
PubMed2001

Alpha adrenoceptor antagonists in the year 2000: is there anything new?

Selective alpha1-adrenergic blockade is now a well accepted and widely used therapeutic treatment for patients presenting with symptomatic bladder outlet obstruction thought to be associated with benign prostatic hyperplasia. This review summarizes the recent developments in this field relating to the subject of receptor subtype selectivity and the potential relevance of this to clinical usefulness of existing drug therapy. Whilst a number of unanswered questions remain as to the exact mechanisms of both drug action and side-effect profile, nevertheless it is clear that existing clinically available alpha1-antagonists provide a safe, effective and generally well tolerated therapy for patients with lower urinary tract symptoms thought to be associated with benign prostatic obstruction. The implications of the ALLHAT study are discussed.

Adrenergic alpha-Antagonists↗
PubMed2001

Transurethral implantation of macroplastique for the treatment of female stress urinary incontinence secondary to urethral sphincter deficiency.

OBJECTIVE: To assess the results of transurethral implantation of Macroplastique in women with stress incontinence secondary to urethral sphincter deficiency using subjective and objective outcome measures. METHODS: A total of 60 women with genuine stress incontinence secondary to intrinsic urethral sphincter deficiency were treated with transurethral implantation of Macroplastique. The patients had undergone a mean of 1.9 (range 0-7) previous episodes of continence surgery. Up to three treatment episodes were used, if necessary. The outcome was assessed by telephone interview (56 patients, mean follow-up period 19 months) and videocystometry (41 patients, mean follow-up period 16 months). Transurethral ultrasound scanning was performed in a further 9 patients. RESULTS: Symptomatically, 19.6% of the women interviewed by telephone considered themselves cured of their incontinence or were no longer using pads. A further 41.1% said their symptoms had significantly improved. Pad usage was reduced from a median of five to three pads per day (p < 0.001). Videocystometry in 41 women (mean follow-up period 16 months) was normal in 16 patients (39%) and showed genuine stress incontinence in 18 (43.9%) and detrusor instability in 12 patients (29.3%). Overall, 71.4% stated that they would undergo the procedure again under the same circumstances, and 80.4% would recommend this form of treatment to a friend with the same condition. Transurethral ultrasound scanning was performed in 9 patients (5 subjectively improved or cured, 1 patient with persistent symptoms but normal cystometry, and 3 patients with persistent genuine stress incontinence). Hyperechoic foci were seen surrounding the proximal urethra, consistent with implanted Macroplastique boluses. When completely encircling the urethra, the outcome was generally good. A total of 10 patients have undergone or are awaiting open surgery, and 3 are awaiting repeat implantation. CONCLUSION: Sustained improvement or cure of genuine stress incontinence has been achieved using Macroplastique in a large proportion of women with intrinsic sphincter deficiency, often following previous unsuccessful continence surgery. Transurethral ultrasound may prove to be a clinically useful imaging technique for the assessment and subsequent management of treatment failure following Macroplastique implantation.

Adult↗
PubMed2001

Lower urinary tract symptoms suggestive of benign prostatic obstruction--Triumph: design and implementation.

Lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO) are likely to become an increasing burden for health care budgets in the future due to the high prevalence of this condition in the elderly and the ageing of the population. Data on the cost-effectiveness of the available treatment options in order to promote rational management will therefore be crucial. As this information is currently largely lacking, the European Association of Urology (EAU) has endorsed the formation of a Pan-European Expert Panel that has developed the Triumph (TransEuropean Research Into the Use of Management Policies for LUTS suggestive of BPH in Primary Healthcare) project. The Triumph project will evaluate how LUTS suggestive of BPO is currently managed in real life practice in initially 6 European countries (France, Germany, Italy, Poland, Spain and the UK) and how this condition progresses over time in relation to an initial treatment choice. In other words, how many patients remain on their initial therapy, how many switch to another therapy (including surgery) and within which time frame and how many develop serious complications related to BPO such as acute urinary retention. The clinical data will be retrieved from continuous analysis of large computer-based patient files such as the General Practice Research Database (GPRD) in the UK and the Integrated Primary Care Information (IPCI) database in The Netherlands. Furthermore, a cross-sectional, observational survey will gather similar data in a prospective fashion for at least 1 year from approximately 13,000 patients managed by more than 1,000 primary care physicians in all 6 countries. Both newly diagnosed (around 7,500) and existing (around 5,500) LUTS patients will be enrolled. For the existing patients in whom the diagnosis was made in the past (from January 1997 onwards), the relevant retrospective data (up to 3.5 years) on disease progression will also be collected. Finally, the costs associated with these treatments will be investigated by the development of a national costing database for each participating country that will detail costs related to visits, investigations, prescriptions, surgical interventions, etc. The last patient is anticipated to come out of the initial prospective survey by the end of 2002/beginning of 2003 and the results will hopefully contribute to improved cost-effective management of LUTS suggestive of BPO in the future.

Europe↗
PubMed2001

Conventional and ambulatory urodynamic findings in women with symptoms suggestive of bladder overactivity.

PURPOSE: We compared ambulatory urodynamics and conventional video cystometry findings in women with symptoms of bladder overactivity. MATERIALS AND METHODS: In a prospective randomized crossover study 106 women with symptoms of urinary urgency with or without incontinence were comprehensively investigated by video cystometry and ambulatory urodynamics in random order. In addition, all women completed a validated symptoms questionnaire and voiding diary. RESULTS: Involuntary detrusor activity was detected in 32 and 70 cases on video cystometry and ambulatory urodynamics, respectively (p <0.001). Video cystometry done according to International Continence Society standards diagnosed detrusor instability in 4 women with no involuntary detrusor activity on ambulatory urodynamics. Involuntary detrusor activity resulting in incontinence was observed in 39 cases on ambulatory urodynamics, including 20 (51%) with stable video cystometry results. Stress incontinence was diagnosed in 42 cases on video cystometry and in 34 on ambulatory urodynamics (p = 0.629). Increasingly severe urge and stress incontinence reported in the symptoms questionnaire correlated positively with the subsequent detection of detrusor overactivity and stress incontinence, respectively, on the 2 urodynamic tests. CONCLUSIONS: In contrast to video cystometry, ambulatory urodynamics provides objective evidence of clinically important bladder overactivity in the majority of women with symptoms suggestive of bladder overactivity. The correlation of symptoms with ambulatory urodynamic findings implies that greater reliance may be placed on symptomatic diagnosis of bladder overactivity. Improved objective assessment of detrusor function provided by ambulatory urodynamics has implications for the definition of bladder overactivity and relevance of conventional cystometry in this context. In women who complain of urgency stable conventional cystometrography findings should be interpreted with caution.

Adult↗
PubMed2000

Muscarinic receptor antagonists in the treatment of overactive bladder.

A wealth of clinical evidence supports the view that muscarinic receptor antagonists are effective in the treatment of overactive bladder. However, treatment-limiting adverse effects such as dry mouth, constipation, and blurred vision have restricted the usefulness of previously available agents, such as oxybutynin. A real need therefore existed for effective and well-tolerated agents for the long-term management of the troublesome symptoms of overactive bladder. This review outlines the various approaches that have been used in attempts to overcome the tolerability problems of oxybutynin. It also describes how advances in our understanding of muscarinic receptors and bladder function has led to the potential development of either tissue- or subtype-selective antimuscarinic agents with improved tolerability. Drugs that have been developed in this way include tolterodine and darifenacin, each of which shows some bladder selectivity in animal models. Unlike darifenacin, however, the bladder selectivity of tolterodine has been confirmed by numerous clinical studies. Tolterodine's improved tolerability compared with oxybutynin, along with its equivalent therapeutic efficacy at recommended dosages, permits patients to experience the beneficial effects of long-term treatment. Tolterodine therefore represents a real alternative for the long-term management of overactive bladder. The results of ongoing clinical studies with darifenacin are awaited before it can be concluded that selective antagonism of M(3) receptors leads to improved tolerability over existing agents in the treatment of overactive bladder. Similarly, the potential improvements in tolerability associated with different dosage formulations of oxybutynin, and the clinical utility of S-oxybutynin, are yet to be conclusively demonstrated.

Benzhydryl Compounds↗
PubMed2000

Urothelium-derived inhibitory factor(s) influences on detrusor muscle contractility in vitro.

The function of the bladder urothelium in modulating contractile responses of the underlying detrusor smooth muscle to muscarinic stimulation has been examined in the pig bladder. Saturation curves for [3H]-QNB binding demonstrated a greater muscarinic receptor density in the urothelium than in the detrusor smooth muscle. The presence of an intact urothelium on isolated bladder strips inhibited contractions induced by carbachol but not KCl. Contractions of a urothelium-denuded muscle strip were inhibited in the presence of a second bladder strip with an intact urothelium, but not if the second strip was denuded. The urothelium-induced inhibition of contractions was not prevented in the presence of L-NOARG, methylene blue, indomethacin, propranolol, suramin, TEA or apamin. The data suggest the presence of a diffusable, urothelium-derived inhibitory factor, which could not be identified but appears to be neither nitric oxide, a cyclo-oxygenase product, a catecholamine, adenosine, GABA nor an EDHF sensitive to apamin.

Animals↗
PubMed2000

The role of M(2)-muscarinic receptors in mediating contraction of the pig urinary bladder in vitro.

1. In urinary bladder, M(2)-muscarinic receptors predominate, but it is the smaller population of M(3)-receptors which mediate detrusor contraction. This study examines the M(2) : M(3) ratio and the role of M(2)-receptors in contraction of pig urinary bladder. 2. Competition experiments with [(3)H]-QNB determined the ratio of M(2) : M(3). In functional studies, affinity values (pK(B)) for 4-DAMP, darifenacin and methoctramine were calculated. Similar experiments were performed on tissues following selective M(3)-inactivation (incubation with 40 nM 4-DAMP mustard in the presence of 1 microM methoctramine to protect M(2)-receptors), precontraction with 50 mM KCl and relaxation with isoprenaline (30 microM) or forskolin (1 microM). 3. In competition binding, displacement of [(3)H]-QNB by 4-DAMP, darifenacin and methoctramine best fitted a two-site model suggesting a predominant (70 - 80%) population of M(2)-receptors. 4. On normal detrusor in vitro, 4-DAMP and methoctramine caused surmountable antagonism of responses to carbachol with pK(B) values of 9.37+/-0.07 and 6.05+/-0.05 respectively. Darifenacin caused unsurmountable antagonism, the apparent pK(B) value being 8.61+/-0.10. 5. In tissues where the M(3)-receptors had been inactivated and cyclic AMP levels elevated, 4-DAMP and darifenacin were less potent, with apparent pK(B) values of 8.72+/-0.08 and 6.74+/-0.07. In contrast, methoctramine was more potent, the apparent pK(B) value increasing significantly to 6.86+/-0.06. 6. se data suggest that the pig bladder possesses a similar muscarinic receptor population to the human bladder and that the M(3)-receptor subtype mediates contraction of the normal detrusor muscle. However an involvement of M(2)-receptors in contraction can be observed following pharmacological manipulation of the receptor population.

Animals↗
PubMed2000

M3 muscarinic receptors but not M2 mediate contraction of the porcine detrusor muscle in vitro.

1. The objective of the study was to determine the role of muscarinic receptor subtypes in mediating contraction of the porcine detrusor smooth muscle in vitro. 2. Strips of pig detrusor muscle were set up in physiological salt solution and the tensions developed by the tissues were recorded. Responses to carbachol were obtained in the absence and presence of a range of muscarinic antagonists (4-DAMP, methoctramine, darifenacin, oxybutynin, tolterodine and pirenzepine). Antagonist affinity values (pKB values) were calculated and compared with those quoted in the literature for these antagonists at each of the muscarinic receptor subtypes. 3. The M3-selective antagonists, 4-DAMP and darifenacin had high affinities (pKB values of 9.4 and 8.6, respectively). Oxybutynin, tolterodine and pirenzepine had affinities of 8.2, 8.1 and 6.8, respectively, whilst the M2-selective agent methoctramine had a relatively low affinity (pKB = 6.1). The rank order of affinities was, therefore, 4-DAMP > darifenacin > oxybutynin > tolterodine > pirenzepine > methoctramine for the pig detrusor. Correlation of the antagonist affinities obtained on the bladder with those published for these antagonists at the five muscarinic receptor subtypes identified the M3(m3)-receptor as the muscarinic subtype mediating detrusor contractile responses in vitro. 4. These data suggest that a small population of M3-muscarinic receptors must mediate direct contractile responses of the pig detrusor muscle to muscarinic receptor stimulation in vitro.

Animals↗