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C R Chapple

Publications and source records attributed to C R Chapple.

At least 73 records · Page 4Linked to original sources
PubMed1999

Signal transduction pathways associated with alpha1-adrenoceptor subtypes in cells and tissues including human prostate.

The complexity of the signal transduction pathways linked to alpha1A-adrenoceptors are becoming clearer. At one time it was thought that the alpha1A-subtype was linked to the influx of extracellular Ca2+ while the alpha1B-subtype was linked via inositol phosphate formation to the release of intracellular Ca2. However the coupling of the alpha1-adrenoceptors to G-proteins leads to the activation of a number of different effector enzymes which produce intracellular second messengers and alterations in biological activity. One area of diversity is in the many forms of the Galpha, beta, gamma heterotrimeric G-proteins which confer specificity towards certain effectors. All alpha1-adrenoceptor subtypes have been shown to couple to phospholipase C in many cells and tissues leading to the breakdown of PiP2 to give IP3, which releases intracellular Ca2+, and diacylglycerol, which stimulates protein kinase C. Additional effectors which can couple to alpha1-adrenoceptors include phospholipase D, adenylate cyclase and the mitogen-activated protein kinase pathway. The latter involves a longer term response and causes increased cell growth and may be important in, for example, the prostate as well as in vascular smooth muscle and the heart. In human prostate alpha1-adrenoceptor activation leads to the release of intracellular Ca2+ from ryanodine-sensitive store followed by an influx of extracellular Ca2+, a mechanism different from that linked to the same receptor subtype in several other smooth muscles. Therefore a given alpha1-subtype may be coupled to a variety of different signal transduction mechanisms in different systems. Further, there may be different effector mechanisms linked to alpha1-subtypes in a given cell or tissue e.g. phospholipase C and mitogen-activated protein kinase. An increased understanding of the complexity of signal transduction mechanisms and the elucidation of the details in a particular tissue will open up new possibilities for therapeutic interventions.

Animals↗
PubMed1998

Surgery for detrusor overactivity.

Intractable detrusor overactivity can result in considerable morbidity and, in the case of neurogenic bladder dysfunction, can put the upper tracts at risk. Once conservative treatments have been exhausted the aim of surgery is to increase functional bladder capacity and decrease the maximal detrusor pressure at this capacity. The mainstay of contemporary therapy has been augmentation cystoplasty; the different techniques and recent literature are reviewed herein. Bladder autoaugmentation is compared and contrasted with augmentation cystoplasty and its role is discussed, as is the less invasive technique of sacral neuromodulation with reference to their role within the range of surgical treatments for detrusor activity.

Animals↗
PubMed1998

Alpha1A-adrenoceptor mediated contraction of rat prostatic vas deferens and the involvement of ryanodine stores and Ca2+ influx stimulated by diacylglycerol and PKC.

1 The present study has investigated the alpha1-adrenoceptor subtype mediating contraction of the rat isolated prostatic vas deferens and the possible effector mechanisms involved in this response by use of functional experiments. 2 Contractions to noradrenaline in the rat isolated prostatic vas deferens were antagonized by prazosin (9.4, 1.04+/-0.19, pA2 and Schild plot slope), 5-methyl urapidil (8.9, 1.10+/-0.13), BMY 7378 (6.4, 1.53+/-0.07) and RS 17053 (8.3, 1.13+/-0.18). These affinities are consistent with the response being mediated by the alpha1A-adrenoceptor subtype. 3 The contraction to noradrenaline at 37 degrees C consisted of an initial phasic response, composed of many rhythmic contractile spikes and a more slowly developing tonic contraction. When the temperature was lowered to 25 degrees C the phasic contraction became a smooth single response which was increased in magnitude. 4 In Ca2+-free Krebs solution the tonic contraction to noradrenaline (10(-4) M) was abolished, suggesting that this response was dependent on influx of extracellular Ca2+. After 2 min in Ca2+-free Krebs solution at 37 degrees C and 25 degrees C the phasic response to noradrenaline (10(-4) M) was 38+/-2% and 91+/-4%, respectively, compared with the phasic contraction to noradrenaline (10(-4) M in normal Krebs solution) and after 30 min it was abolished at 37 degrees C and was 7+/-1% at 25 degrees C. Ryanodine abolished the noradrenaline response in Ca2+-free Krebs solution for 2 min at 25 degrees C, while cyclopiazonic acid reduced it to 36+/-2%. 5 In normal Krebs solution at 25 degrees C the protein kinase C inhibitor calphostin C reduced the tonic contraction to noradrenaline (10(-5) M) from 36+/-8% to 14+/-3% compared with the phasic contraction to noradrenaline (10(-4) M). The DAG kinase inhibitor R 59022 increased the contraction following the initial phasic response to a maximum of 107+/-17% after 35 s, before dropping down to a well maintained contraction which was still greater in magnitude compared with the control. Nifedipine (3x10(-7) M) reduced the tonic contraction from 49+/-6% to 7+/-1% but did not reduce the phasic response. Ryanodine (10(-4) M) reduced the phasic contraction from 50+/-2% to 7+/-1% and the tonic response from 47+/-5% to 27+/-5%. 6 The phorbol ester phorbol-12,13-dibutyrate at 25 degrees C produced a transient contraction of the rat prostatic vas deferens, maximum response (10(-5) M) 48+/-4%, compared with the maximum tonic response to noradrenaline. The contraction to PDBu (10(-5) M) was reduced to 23+/-2% by calphostin C (10(-6) M) and to 15+/-1% by nifedipine (3x10(-7) M) and was abolished after 2 min in Ca2+-free Krebs solution. 7 In conclusion, the alpha1A-adrenoceptor mediated contraction to noradrenaline of the rat prostatic vas deferens appears to consist of an initial phasic component due to the release of intracellular Ca2+ from ryanodine-sensitive stores. These stores are depleted in the absence of extracellular Ca2+ and this depletion is slower at 25 degrees C than at 37 degrees C. The phasic contraction is followed by a tonic contraction involving activation of protein kinase C by diacylglycerol and influx of Ca2+ through nifedipine-sensitive channels.

Adrenergic alpha-Agonists↗
PubMed1998

Morning vs evening dosing with doxazosin in benign prostatic hyperplasia: efficacy and safety.

Three hundred and fifty-three patients with symptomatic benign prostatic hyperplasia were randomized to doxazosin or placebo, with morning or evening dosing, to compare the effect of dosing time on the efficacy and safety of doxazosin treatment. After 24 weeks of treatment, the mean International Prostate Symptom Score had decreased by 6.8 units in the doxazosin group compared with 4.5 units in the placebo group (P=0.003). Improvements in Q(max) of 2.03 ml/s and 0.30 ml/s were seen for the doxazosin and the placebo groups, respectively (P<0.001). No differences in efficacy or safety between the morning- and evening-dosed subgroups were observed. Doxazosin was significantly more effective than placebo at improving symptoms of BPH and urinary flow rates at endpoint, and was well tolerated. The time of dosing did not appear to influence the efficacy or safety of doxazosin, suggesting that there is no need to restrict administration of doxazosin to the evening in BPH patients.

Journal Article↗
PubMed1998

The value of prostate specific antigen (PSA) density and free: total PSA ratio in selecting patients with a normal digital rectal examination and intermediate total PSA levels for further investigation.

OBJECTIVES: To examine the use of prostate-specific antigen (PSA) density (PSAD) and free to total PSA ratio (f/tPSA) in enhancing the specificity of PSA in the diagnosis of prostate cancer in patients with a total PSA (tPSA) of 4-10 ng/mL and with a normal digital rectal examination (DRE). PATIENTS AND METHODS: The study comprised 77 consecutive men in whom the fPSA and tPSA levels were obtained before DRE and transrectal ultrasonography-guided sextant prostate biopsy. Prostate cancer was found in 39 patients and the histology was benign in 38. Receiver operator characteristic curves, obtained from all 77 patients, were used to determine the optimal thresholds for PSAD and f/tPSA in detecting cancer. A subset of 28 patients, including seven with prostate cancer, was identified who had a normal DRE and a tPSA of 4-10 ng/mL; PSAD and f/tPSA values were applied at the optimal thresholds to assess their use in identifying those patients with cancer. RESULTS: When applied to the selected group of 28 patients, the PSAD (threshold 0.15) failed to identify any with prostate cancer. The f/tPSA (threshold 0.12) yielded a sensitivity of 65% and a specificity of 38%, identifying only three of seven patients with cancer. By increasing the threshold to 0.25, six patients were correctly identified, giving a sensitivity of 86%, with a lower specificity of 14%. CONCLUSIONS: These findings suggest that the neither PSAD nor f/tPSA either significantly reduce the negative biopsy rate or identify patients at greater risk of prostate cancer, particularly when the tPSA is equivocal at 4-10 ng/mL.

Aged↗
PubMed1998

Giant hydronephrosis--a diagnostic dilemma.

We report a complex case in which the left kidney had undergone giant hydronephrotic change after chronic obstruction at the vesicoureteric junction. Minor blunt abdominal trauma caused rupture of the parenchyma of this expanded and dilated kidney, with bleeding into its collecting system. The mixture of blood and urine remained contained within the kidney's structural layers, so producing a tense, cystic, fluid-filled mass arising from the left hypochondrium. Pathogenesis, differential diagnosis and investigation of giant hydronephrosis and its rupture are discussed. The observation is made that gross distortion of the renal parenchyma by rupture or hydronephrosis impairs arterial inflow to the kidney.

Abdominal Injuries↗
PubMed1998

Medical therapy and quality of life.

The risk of mortality and long-term morbidity, including loss of sexual function, associated with surgical procedures for symptomatic benign prostatic hyperplasia (BPH) has prompted research into alternative medical therapies. Phytotherapy involves the use of herbal formulations, where the mechanisms of action are usually obscure and although studies have confirmed their effectiveness in symptom relief and improving quality of life (QOL), few placebo-controlled trials exist. Both the 5 alpha-reductase inhibitor finasteride and alpha 1-adrenoceptor antagonists (e.g. alfuzosin, doxazosin, prazosin, tamsulosin and terazosin) have been recommended as appropriate treatment options for patients with lower urinary tract symptoms (LUTS) associated with benign prostatic obstruction (BPO), and their efficacy has been proven in several placebo-controlled trials. Finasteride reduces the static component of BPO--by reducing the size of the prostate--and, as a result, symptom relief is slow (6-12 months) and is predominantly restricted to patients with large prostates (> 40 g). The alpha 1-adrenoceptor antagonists, on the other hand, reduce the dynamic component of obstruction--relaxation of smooth muscle in the prostate, urethra and bladder neck--and provide rapid symptom relief after only a few doses, relieving LUTS more effectively than finasteride and irrespective of prostate size. All of the various alpha 1-adrenoceptor antagonists provide effective and comparable relief of LUTS, and an improvement in bothersomeness and symptom-related QOL. However, it is also important that the therapy is fast acting and acceptable to the patient, in that it does not interfere with other medication or produce unpleasant side effects. These documented properties of the alpha 1A-adrenoceptor antagonists make them an ideal choice for the medical treatment of symptomatic BPH.

5-alpha Reductase Inhibitors↗
PubMed1997

The effects of tamsulosin, a high affinity antagonist at functional alpha 1A- and alpha 1D-adrenoceptor subtypes.

1. The actions of the alpha 1-adrenoceptor antagonist tamsulosin have been examined at functional alpha 1-adrenoceptor subtypes and compared with those at the human prostate receptor. 2. At the alpha 1D-adrenoceptors of the rat aorta, tamsulosin acted as a competitive antagonist with a high affinity (pKB = 10.1). 3. At the alpha 1B-adrenoceptor of the rat spleen and rabbit corpus cavernosum penis, tamsulosin again acted as a competitive antagonist but with a significantly lower affinity (pKB = 8.9-9.2). 4. Tamsulosin acted as an unsurmountable antagonist of the alpha 1A-adrenoceptor-mediated responses of the rat and human vas deferens, reducing maximal responses to phenylephrine by 20% and 50%, respectively, at an antagonist concentration of 1 nM. Responses of depolarized (100 mM KCl) rat vas deferens preparations were unaffected by 10 nM tamsulosin but this concentration reduced maximal responses to 5-hydroxytryptamine (5-HT) in this tissue. 5. When longer antagonist incubation periods (> or = 60 min) were used, tamsulosin behaved as a competitive antagonist on the human prostate with a significantly higher affinity (pKB = 10.0) than obtained at the alpha 1B-adrenoceptor. 6. The data demonstrate that tamsulosin is a high affinity antagonist at functional alpha 1-adrenoceptors with a selectivity alpha 1D > or = alpha 1A > alpha 1B. In some tissues the compound exhibits an additional unsurmountable antagonist action, the clinical significance of which is unknown.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1997

Relaxant effects of potassium-channel openers on normal and hyper-reflexic detrusor muscle.

OBJECTIVE: To compare the effects of the potassium-channel openers, levcromakalim and YM934, in isolated human detrusor muscle from normal and hyper-reflexic bladders. MATERIALS AND METHODS: Strips of human detrusor muscle from normal and hyper-reflexic bladder were pre-contracted with carbachol and the potassium-channel openers (0.1-0.3 mumol/L) were added cumulatively to the organ baths. Other strips were field-stimulated at frequencies producing 25% and 75% of the maximum response to field stimulation. Contractions could be abolished by atropine (10 mumol/L) and tetrodotoxin (1 mumol/L). RESULTS: The hyper-reflexic bladder was significantly more sensitive to carbachol than the normal bladder but the maximum response was significantly lower in the hyper-reflexic tissue. There was no significant difference between the potency of the potassium-channel openers in normal and hyper-reflexic detrusor muscle. Hyper-reflexic bladder was significantly more sensitive to electrical field stimulation than was normal bladder: maximum responses to field stimulation were not significantly different. Concentration-response curves for the potassium-channel openers were displaced to the left in hyper-reflexic bladder at both 25% and 75% maximum frequencies: however, only with levcromakalim at 75% of the maximum frequency was the shift significant. CONCLUSION: The greater sensitivity of hyper-reflexic bladder to carbachol and field stimulation supports existing evidence for post-junctional supersensitivity in detrusor instability. The results of this study also suggest that there are no appreciable changes in KATP channel function in the unstable bladder.

Benzopyrans↗
PubMed1997

Safety and efficacy of transurethral needle ablation of the prostate for symptomatic outlet obstruction.

OBJECTIVES: To examine, in an observational study, the safety and efficacy of transurethral needle ablation (TUNA) of the prostate as a treatment for symptomatic benign prostatic enlargement. PATIENTS AND METHODS: This prospective study included 71 symptomatic men with unequivocal obstruction on pressure-flow urodynamics. The variables measured at baseline and up to 12 months after treatment included the American Urological Association (AUA)-7 symptom index and an added quality-of-life question, the AUA BPH-Impact Index, a sexual function score, transrectal ultrasonography of the prostate, a frequency-volume chart, free-flow uroflowmetry, post-void residual urine volume (PVR) and pressure-flow urodynamics. Transurethral resection of the prostate (TURP) was offered if the symptoms failed to resolve at any time during the follow-up period. TUNA was performed under local anaesthetic and sedation in 63 (89%) men and as a day-case procedure in 10 (14%). Five patients were on warfarin which was not discontinued. RESULTS: There were no serious treatment-related adverse events. Eight of the initial nine patients who were not routinely catheterized after treatment with TUNA developed acute urinary retention. Although some haematuria occurred in all patients, only one (1.4%) developed catheter blockage by clot. There were no problems with bleeding in those patients on warfarin at the time of treatment. The mean (95% confidence interval, CI) AUA-7 index fell from 23 (1.7) to 10.6 (1.8) (P < 0.001, Mann-Whitney U-test) at 12 months, 29 men (41%) had an AUA-7 index of < or = 7. The maximum (95% CI) urinary flow rate increased from 9.0 (0.8) to 11.3 (1.1) mL/s (P < 0.001) and this was accompanied by a small but significant reduction in PVR of 70 (14) mL to 35 (8) mL (P < 0.001 Mann-Whitney U-test). There was a significant reduction in both maximal voiding pressure and detrusor pressure at peak flow at 3 months (Mann-Whitney U-test, both P < 0.001) and at 12 months (P < 0.001, Wilcoxon matched-pairs signed-ranks test). However, 78% of the 45 men undergoing repeat pressure-flow studies at 12 months were unequivocally obstructed according to the Abrams-Griffiths nomogram. The mean (95% CI) prostatic volume fell from 49.0 (4.8) mL at baseline to 40.8 (4.9) mL at 3 months, but this change was not statistically significant (P = 0.011, Mann-Whitney U-test). Two men reported erectile dysfunction, one experienced ejaculatory problems and seven reported an improvement in erectile function after TUNA. During the study, 22 men (31%) underwent TURP. CONCLUSIONS: TUNA is a safe treatment which can be performed as an out-patient procedure under local anaesthesia and sedation in the vast majority of patients. There was no evidence of serious adverse events and no significant adverse effect on sexual function. The symptomatic improvement was sustained at 12 months in most (54%) patients, with modest improvements in peak flow rate, PVR and voiding pressures, indicating that TUNA may result in prolonged symptomatic improvement in a proportion of patients suffering from bladder outlet obstruction. A randomized controlled study against established therapies is now essential to clearly delineate its place in the management of such patients.

Aged↗
PubMed1997

Bulbar elongation anastomotic meatoplasty (BEAM) for subterminal and hypospadiac urethroplasty.

PURPOSE: All urethral reconstruction that involves substitution has an inherent ongoing incidence of restenosis with time. Anastomotic restoration of urethral continuity naturally obviates these complications but to achieve its potential of a long-term stricture-free success rate that approaches 100% circumstances must be ideal and the reconstructive surgical technique must be meticulous. If the critical indications for anastomotic reconstruction are overextended, complications inevitably increase. Considerable additional urethral length is required to overcome the terminal atretic deficiency associated with hypospadias and create a tension-free anastomotic neomeatoplasty. Mobilization and advancement of the penile urethra alone are rarely sufficient to achieve this without causing penile chordee. We describe the details of bulbar elongation anastomotic meatoplasty (BEAM) that we have been using for approximately the last 8 years. MATERIALS AND METHODS: The only part of the urethra that can be mobilized to provide extra length for anastomotic urethroplasty without creating penile curvature chordee is the bulbar urethra. Full length mobilization of the whole length of the bulbar urethra through a perineal incision provides 2 to 2.5 cm. of tension-free lengthening in children and 4 to 5 cm. in adults. Thus, many subterminal urethral deficiencies can be resolved by bulbar elongation anastomotic meatoplasty when the total extent of the urethral deficiency is not disproportionally long. We performed bulbar elongation anastomotic meatoplasty in 12 patients 2 to 25 years old. RESULTS: At a followup of 2 to 7 years the neomeatus is functionally and cosmetically satisfactory in all cases with no long-term complications or chordee. CONCLUSIONS: When circumstances are appropriate, bulbar elongation anastomotic meatoplasty is a preferable alternative to some of the current substitution procedures. Once established, anastomotic reconstructions are generally stable in the long term.

Adolescent↗
PubMed1997

Tamsulosin 0.4 mg once daily: tolerability in older and younger patients with lower urinary tract symptoms suggestive of benign prostatic obstruction (symptomatic BPH). The European Tamsulosin Study Group.

OBJECTIVES: To compare the safety and tolerability of tamsulosin 0.4 mg once daily in younger (< 65 years) and older (> or = 65 years) patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO). METHODS: In a retrospective analysis of two European double-blind, randomized, placebo-controlled trials, safety was assessed in 574 younger or older patients treated with tamsulosin or placebo for 12 weeks. RESULTS: The incidence of adverse events, drug-related adverse events, serious adverse events and discontinuations due to adverse events was similar in older and younger tamsulosin-treated patients and was not significantly different from placebo. Although abnormal ejaculation was slightly more common in younger than older men receiving tamsulosin, the difference was not statistically significant from the placebo groups in both age groups. The incidence of adverse events possibly associated with vasodilation in tamsulosin-treated younger and older patients was 8.4 and 4.2%, respectively; these were comparable with the values for placebo-treated patients: 7.5 and 6%, respectively. Baseline systolic blood pressure was higher in older than younger patients, but there were minimal changes in blood pressure or pulse rate in tamsulosin- or placebo-treated patients in either age group. CONCLUSIONS: Tamsulosin is well tolerated and suitable for use in older and younger patients with LUTS suggestive of BPO (symptomatic BPH).

Adrenergic alpha-Antagonists↗
PubMed1996

A prospective audit of the use of a prostate clinic.

OBJECTIVE: To assess the efficiency of a prostate clinic and to determine the treatment outcomes and the proportion of patients who could potentially be managed by their General Practitioners (GPs). PATIENTS AND METHODS: Referral letters from GPs were screened by the consultant urologists and appropriate patients seen in the next available prostate clinic. The initial assessment consisted of an International Prostate Symptom Score and a medical history, uroflowmetry, ultrasonographically determined post-void urine volumes, renal function tests and measurement of prostate specific antigen, in addition to a physical examination and a digital rectal examination. Further investigations were requested as required. RESULTS: Over a period of 18 months, 403 patients were seen, 90% of them within 12 weeks from the time of referral. Uroflowmetry was performed in 96% of patients and further urodynamics in 22%. Bladder outlet obstruction was diagnosed in 246 (61%) patients and primary detrusor instability was detected in 20 (5%) patients. Fourteen per cent of patients were returned to the care of the GP following their first visit. The audit identified a potential group of patients (52%) who could be managed by their GP. Seven per cent underwent prostate surgery for the relief of bladder outlet obstruction. CONCLUSION: The prostate clinic significantly reduced the delay for patients to be seen at the hospital and facilitated rapid assessment and investigation, much of which was carried out by a nurse practitioner during the first visit (in most cases). Several patients were identified who could be managed in the community.

Aged↗