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Biomedical subjects

I Eardley

Publications and source records attributed to I Eardley.

At least 37 records · Page 2Linked to original sources
PubMed2001

Efficacy and safety of sildenafil citrate in the treatment of men with mild to moderate erectile dysfunction.

BACKGROUND: Erectile dysfunction is a common, multi-factorial disorder. AIMS: To evaluate the efficacy, tolerability and frequency of use of sildenafil citrate in men with mild to moderate erectile dysfunction of no established organic cause. METHOD: This double-blind, randomised, placebo-controlled, flexible-dose, two-way crossover study was conducted at four centres in the UK in 44 men with mild to moderate erectile dysfunction of no clinically obvious organic cause. The study included two 28-day treatment periods, during which time sildenafil or placebo (25-75 mg, based on efficacy) was taken as required. RESULTS: Compared with placebo, sildenafil was associated with increases in frequency of use, erections adequate for sexual intercourse and level of sexual satisfaction (P:<0.0001). More patients receiving sildenafil stated they would use the treatment again compared with those receiving placebo (P:<0.0001). There were no discontinuations due to sildenafil treatment. CONCLUSIONS: Sildenafil is effective and well tolerated in men with mild to moderate erectile dysfunction of no clinically identifiable organic cause.

Adolescent↗
PubMed2001

The role of nitric oxide in penile erection.

The functional state of the penis, flaccid or erect is governed by smooth muscle tone. Sympathetic contractile factors maintain flaccidity whilst parasympathetic factors induce smooth muscle relaxation and erection. It is generally accepted that nitric oxide (NO) is the principal agent responsible for relaxation of penile smooth muscle. NO is derived from two principal sources: directly from non-adrenergic non-cholinergic parasympathetic nerves and indirectly from the endothelium lining cavernosal sinusoids and blood vessels in response to cholinergic stimulation. The generation of NO from L-arginine is catalysed by nitric oxide synthase (NOS). There has been controversy over the relative prevalence of endothelial or neuronal NOS within the penis of different animal species. This review examines the role of NO in the penis in detail. Established and new treatments for erectile dysfunction whose effects are mediated via manipulation of the NO pathway are also described.

Animals↗
PubMed2001

The pathophysiological role of prostaglandins in penile erection.

Penile erection is a complex haemodynamic event and relaxation of the vascular smooth muscle of the penis is fundamental to this process. This is primarily mediated by nitric oxide (NO) produced from non-adrenergic non-cholinergic (NANC) nerves and the endothelium surrounding the corporal sinusoids. However, corporal tissue has been shown to produce a number of other vasoactive factors, including prostaglandins (PGs), which appear to not only have diverse physiological effects, but are also able to modulate the effects of other neurotransmitters, including NO.

Collagen↗
PubMed2000

Endothelial and neuronal-derived nitric oxide mediated relaxation of corpus cavernosal smooth muscle in a rat, in vitro, model of erectile function.

We set out to establish a simple, reproducible, rat in vitro model of erectile function and to use this to demonstrate the functional importance of both neuronal- and endothelial-derived nitric oxide within this animal. Two corpora cavernosal smooth muscle strips were harvested from sexually mature male Wistar rats and mounted in an organ bath for measurement of isometric tension. Following contraction with noradrenaline the strips were relaxed by the addition of either acetylcholine or sodium nitroprusside. Electrical field stimulation was performed in the presence of atropine and guanethidine. Relaxation responses were repeated in the presence of methylene blue, L-arginine, L-NNA and haemoglobin +/- L-arginine. Methylene blue abolishes the relaxation to acetylcholine and EFS; L-NNA and haemoglobin cause a significant impairment in the relaxation response. L-arginine reverses the effect of haemoglobin. In conclusion, the inhibitory, relaxant stimulus of rat corpora cavernosa is due to both neuronal nitric oxide and endothelial-derived nitric oxide released in response to cholinergic stimulation.

Animals↗
PubMed2000

Single dose methodology to assess the influence of an alpha1-adrenoceptor antagonist on uroflowmetric parameters in patients with benign prostatic hyperplasia.

AIMS: To establish methodology which rapidly and reliably assesses the effect of an alpha1-adrenoceptor antagonist on peak urine flow rates in men with benign prostatic hyperplasia (BPH). This methodology could then be applied to screening new drugs to treat BPH. METHODS: Twenty-five patients with BPH enrolled in a double-blind, placebo-controlled, two-period crossover study. Patients were either withdrawn from their current alpha1-adrenoceptor antagonist therapy (n = 22) or were untreated prestudy (n = 3) and all met prespecified uroflowmetric criteria including: (1) a peak urine flow rate (Qmax) < 12 ml s-1 off therapy (or < 10 ml s-1 if untreated prestudy) and (2) a decrease in peak urine flow rate (Qmax) of > 2 ml s-1 after withdrawal from therapy. Study treatment consisted of tamsulosin 0.4 mg (or matching placebo) once daily for 8 days in a two-period crossover. Uroflowmetry was performed predose and once postdose (4.5-5.5 h postdose) on day 1, and once postdose (4.5-5.5 h postdose) on day 8 of each treatment period. RESULTS: After a single dose of tamsulosin, the least-square mean difference between tamsulosin and placebo in the change from baseline Qmax was 2.8 ml s-1 (P = 0.017 vs placebo). After 8 days dosing of tamsulosin, the least-square mean difference between tamsulosin and placebo in the change from baseline Qmax was also 2.8 ml s-1 (P = 0.044 vs placebo). Additionally, there was no significant difference observed between the single and multiple dose results (P > 0.200 for between group difference). CONCLUSIONS: Both single and multiple doses of tamsulosin 0.4 mg increased Qmax in men with BPH. A single dose produced a comparable response to multiple dose administration. The magnitude of the effect was greater than the effect generally seen in longer term clinical trials, but this difference may be explained by the patient population in this study which was preselected for 'responsiveness' to an alpha1-adrenoceptor antagonist. These results support the utility of single dose uroflowmetric measurements in rapidly providing preliminary data on new investigational agents, specifically agents which act to increase urine flow in men with BPH. However, clinical efficacy would still need to be confirmed with longer term clinical trials.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2000

A randomized double-blind placebo-controlled crossover trial of the efficacy of L-arginine in the treatment of interstitial cystitis.

OBJECTIVES: To determine, in a double-blind placebo-controlled crossover study, whether L-arginine improves the symptoms of interstitial cystitis (IC), a chronic condition in which nitric oxide (NO) may be important, as previous open pilot studies suggested that L-arginine reduced the pain and frequency associated with IC. PATIENTS AND METHODS: Patients fulfilling the standard diagnostic criteria for IC were randomized to receive L-arginine (2.4 g/day) or placebo for one month. After a 2-week 'washout' period they received the other medication. Patients were assessed at each stage using a validated symptom index, a voiding diary, urine analysis and records of adverse events. Patients were asked about overall efficacy at the close of the study. The results were compared using a t-test, with significance indicated at P<0.05. RESULTS: Sixteen (16) patients (mean age 51.3 years) were enrolled; the mean duration of IC was 5.4 years, the IC symptom index score 29.1, their nocturnal frequency 3.5 (voided volume 182 mL) and daytime frequency 12.7 (124 mL). Patients on placebo showed no differences in any recorded variable over the baseline values. L-arginine caused a statistically significant reduction in the overall symptom score of 2.2 over baseline, but there was no difference in voided volume, frequency or nocturia. As there was no significant difference for any variable between L-arginine and placebo, this reduction in score should be regarded with caution. Three patients withdrew because of side-effects (severe headaches, night sweats and flushing). CONCLUSION: Oral L-arginine produces a statistically significant improvement in the IC symptom index in patients with IC, but the effect is small. This effect may not be clinically significant as there were no improvements in the other variables assessed and no significant difference between the response to L-arginine and placebo. From these results the use of L-arginine cannot be recommended for treating IC.

Adult↗
PubMed2000

Impairment of corpus cavernosal smooth muscle relaxation by glycosylated human haemoglobin.

OBJECTIVE: To examine the effect of HbA1c, an isoform of glycosylated haemoglobin (GHb, a product of non-enzymatic reactions between elevated blood glucose and haemoglobin), on nitric oxide-mediated corpus cavernosal smooth muscle relaxation, and to categorize the mechanisms involved. MATERIALS AND METHODS: Corpus cavernosal tissue from Wistar rats (300-350 g body weight) was prepared for the measurement of isometric tension. After equilibration in Krebs solution gassed with 95% O2/5% CO2 at 37 degrees C for 90 min, optimal resting tension was applied. Tissue was precontracted with 1 micromol/L noradrenaline (NAd) and either relaxed with incremental doses of acetylcholine (ACh) or sodium nitroprusside (SNP). After washout, strips were again precontracted with NAd and then incubated with pyrogallol (100 micromol/L), 100 microL of haemoglobin or 100 microL of GHb in the presence of either L-arginine (100 micromol/L), indomethacin (10 micromol/L), allopurinol (100 micromol/L), deferoxamine (100 micromol/L), catalase (600 IU/mL), or superoxide dismutase (SOD) (120 IU/mL) before ACh- or SNP-induced relaxation responses were repeated. RESULTS: Haemoglobin and GHb significantly impaired the relaxation of rat corpus cavernosum to ACh in a dose-dependent manner. L-arginine reversed the impairment caused by Hb, but not GHb. A donor of superoxide anions, pyrogallol, mimicked this impairment to ACh when added to control strips. Catalase, deferoxamine, indomethacin and allopurinol had no significant effect on the impaired relaxation response to ACh, whilst L-arginine partially reversed it. SOD completely reversed the GHb-induced impaired relaxation; GHb did not alter the relaxation response to SNP. CONCLUSION: GHb significantly impairs endothelial NO-mediated corpus cavernosal relaxation in the rat, in vitro. This effect is caused partly by the generation of superoxide anions and the extracellular inactivation of NO.

Acetylcholine↗
PubMed2000

The role of prostaglandins in penile erection.

The balance of penile smooth muscle tone is finely controlled, with contractile factors acting in opposition to relaxant factors. The principal agents in this process are undoubtedly noradrenaline and nitric oxide. Prostaglandins probably have a crucial role in the 'fine tuning' of corporal smooth muscle tone. Their effects on control mechanisms in the healthy penis are more likely to be modulatory rather than direct.

Endothelium↗
PubMed2000

The effect of cyclic GMP on rabbit corporal smooth muscle tone and its modulation by cyclo-oxygenase products.

Corporal smooth muscle (CSM) tone is maintained by a finite balance between relaxant and contractile neurotransmitters. The aim of these experiments was to ascertain the degree to which cyclic GMP is involved in these interactions. We also sought to elucidate the pharmacological mechanism of action of MB in rabbit corpus cavernosum (RCC), an important tool in nitric oxide research. Using an organ chamber technique, strips of RCC were treated with the guanylate cyclase inhibitors Methylene Blue (MB) and LY83583; 100 microM MB led to increases in resting tension which were antagonized by indomethacin, nifedipine, phentolamine, but not superoxide dismutase (SOD). Contractile responses to noradrenaline (NA) were increased and relaxation to ACh was impaired by both MB and LY83583 and reversed with indomethacin, but not SOD. Pyrogallol had no effect on agonist-induced responses. The pharmacological action of MB in RCC does not depend on the generation of superoxide anions. Endothelium-dependent relaxation in RCC results in activation of soluble guanylate cyclase and release of a stable endothelium derived contracting factor(s), which is likely to be a constrictor prostanoid(s). Tonic production of cGMP in RCC inhibits the presynaptic release and contractile effects of NA and can be modulated by cyclo-oxygenase inhibition, demonstrating the important interaction and functional antagonism between cGMP and prostaglandins in the control of CSM tone.

Acetylcholine↗
PubMed1999

Minimally invasive treatment of urinary tract calculi in children.

OBJECTIVE: To report experience of a broad multimodality approach to the treatment of calculi in children using extracorporeal shock wave lithotripsy (ESWL), ureteroscopy/laser lithotripsy, lithoclast and percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: The treatment and outcome were reviewed in 43 children managed by a range of minimally invasive modalities, either singly or in combination, between 1990 and 1997. These patients represent a selected group deemed suitable for minimally invasive management during a period of developing experience with these techniques. Of this cohort, six children had previously undergone open stone surgery and contributory metabolic abnormalities were identified in seven. ESWL was the sole treatment modality in 24 children (56%). In five children (12%) ureteroscopy/laser lithotripsy was combined with ESWL, eight (18%) underwent ureteroscopy/laser lithotripsy alone, whilst three with bladder stones were treated with the lithoclast. Combined therapy including PCNL was required in three patients. RESULTS: Of the 43 children treated, 38 (88%) were rendered stone-free. Metabolic disorders accounted for three of the five cases of residual calculi. Complications requiring intervention occurred in two children (7%) and three subsequently underwent open pyelolithotomy or ureterolithotomy after unsuccessful minimally invasive treatment. CONCLUSIONS: Used selectively, the range of minimally invasive procedures available for adults, including ureteroscopy and PCNL, can be safely and effectively extended to the treatment of urinary tract calculi in children. The role of open surgery will diminish further with the availability of specialized instruments for paediatric PCNL.

Adolescent↗
PubMed1999

Purinergic sensory neurotransmission in the urinary bladder: an in vitro study in the rat.

OBJECTIVES: To determine the response of mechanosensitive pelvic nerve afferents, arising from the rat urinary bladder, to the purinergic agonist alpha,beta-methylene ATP and to the purinergic antagonist suramin. MATERIALS AND METHODS: Using a newly developed in vitro bladder-pelvic nerve afferent model, multiunit recordings were taken from mechanosensitive pelvic nerve afferents arising from the rat urinary bladder, in response to bladder distension. Control experiments were performed by distending the bladder with saline at 0.04 mL/min, and recording the total afferent nerve activity and the bladder pressure response to the distension. Bladder distensions were then repeated using a solution of the stable purinergic agonist alpha,beta-methylene ATP (10 micromol/L), which is known to desensitize P2X-purinoceptors after prolonged exposure, and the total afferent activity and bladder pressure response were again measured. In a separate series of experiments the afferent nerve activity and bladder pressure response to bladder distension with saline was determined in the presence of the purinergic antagonist suramin (10 micromol/L) and repeated after washout of the drug. In both series of experiments, afferent nerve responses were compared with control using the paired t-test, whilst the bladder pressure responses were compared using one-way analysis of variance. RESULTS: Bladder distension with alpha,beta-methylene-ATP produced a statistically significant reduction in afferent nerve activity, by up to 75% compared with the control, whilst having no significant effect on the bladder pressure response. Bladder distension with saline in the presence of suramin (10 micromol/L) produced a significant reduction in the resultant afferent nerve activity, by 50%, which returned to normal after washout of the drug. CONCLUSION: These findings are consistent with the notion that ATP is released endogenously during bladder distension in the rat and is involved significantly in the activation of pelvic nerve afferents arising from the rat urinary bladder.

Adenosine Triphosphate↗
PubMed1999

The stability of free and bound prostate-specific antigen.

OBJECTIVE: To determine if the assay for free prostate specific antigen (fPSA) and the calculated ratio of fPSA to total PSA (f/tPSA) is stable in conditions likely to be met in routine clinical practice. MATERIALS AND METHODS: Two blood samples were obtained from 27 patients attending a routine urology clinic. Sample 1 was centrifuged immediately, assayed for fPSA and tPSA, and the f/tPSA calculated. This sample was then stored at 4 degrees C for 24 h, 48 h and 1 week, or at -20 degrees C for 24 h, 1 week and 1 month before the assays for fPSA and tPSA were repeated. The second sample was left at room temperature for 24 h before assay and processing, as for sample 1. RESULTS: tPSA is a highly stable analyte; if whole blood samples are processed immediately, fPSA is stable for 24 h at 4 degrees C and 1 month at -20 degrees C. There was a significant reduction in the calculated f/tPSA in samples stored for >/=24 h at 4 degrees C (P<0.01); if the sample was stored at -20 degrees C the calculated f/tPSA was stable. After 24 h storage at room temperature, fPSA decreased by 6.3% and f/tPSA by 6.4%. Subsequent storage of serum at 4 degrees C for 1 week resulted in a 25% decrease from the baseline value. After 1 month at -20 degrees C the fPSA value was 13% lower than the baseline value. CONCLUSION: These results indicate that if there is to be confidence in the accuracy of the f/tPSA value, then blood samples must be handled and processed correctly. Total PSA is sufficiently stable to permit whole blood samples to remain at room temperature for 24 h before serum is separated. If fPSA is to be determined accurately then the whole blood sample must be centrifuged promptly. As the fPSA values in blood samples left at room temperature for 24 h are up to 25% lower than those on immediate assay, and the subsequent f/tPSA 29% lower, then for the optimum use of this test, these samples should also be handled appropriately.

Humans↗
PubMed1999

Extra-anatomic stents in ureteric obstruction: experience and complications.

OBJECTIVE: To assess the role of extra-anatomic stents (EAS) as a means of urinary diversion in patients with ureteric obstruction secondary to malignancy. PATIENTS AND METHODS: The technique for inserting EAS in patients with ureteric obstruction was described previously; to date, 13 patients (seven women and six men, mean age 45.3 years, range 22-78) have been treated. All patients had ultrasonographic evidence of hydronephrosis and/or significant biochemical evidence of renal impairment. Patients had advanced malignancy and one patient an abdominal aortic aneurysm. RESULTS: Urinary diversion was successful in all patients; two survived for more than 1 year, with stent changes at 6-monthly intervals. In three patients the stents were replaced by percutaneous nephrostomies because of problems with leakage or infection. The remaining patients died with functioning EAS in situ. CONCLUSIONS: In patients with ureteric obstruction secondary to malignancy or medical conditions excluding them from more invasive surgery, EAS provide a further therapeutic option instead of a permanent nephrostomy, which has associated inherent problems. This technique is not without potential problems and careful selection of patients remains vital in this difficult area.

Adult↗
PubMed1999

Sildenafil.

Sildenafil (Viagra, Pfizer, Inc.) is a new orally effective therapy for the treatment of men with erectile dysfunction (ED). It is a specific and selective inhibitor of phosphodiesterase Type 5 (PDE5), an enzyme which is an important modulator of smooth muscle relaxation in the corpus cavernosum. In the presence of a sexual stimulus, inhibition of PDE5 results in improved smooth muscle relaxation within the sinusoids of the corpus cavernosum and the penile arteries. This results in improved erections in men with ED. In clinical trials, sildenafil has been found to be effective in improving the erections of large numbers of men with ED secondary to a range of causes. The presence of PDE5 in other tissues such as vascular smooth muscle results in side effects such as headache, flushing, indigestion and nasal congestion. These side effects are dose-dependent and well-tolerated. The introduction of sildenafil in many countries around the world has revolutionised the assessment and treatment of men with ED.

Animals↗