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Biomedical subjects

M P Williams

Publications and source records attributed to M P Williams.

At least 19 recordsLinked to original sources
PubMed2003

Eradication of Helicobacter pylori increases nocturnal intragastric acidity during dosing with rabeprazole, omeprazole, lansoprazole and placebo.

BACKGROUND: The eradication of Helicobacter pylori decreases the antisecretory activity of omeprazole and lansoprazole. Rabeprazole is a potent proton pump inhibitor that may not be affected as greatly by H. pylori status. AIM: To compare the effect of H. pylori eradication on intragastric acidity and plasma gastrin during dosing with lansoprazole, omeprazole, rabeprazole and placebo. METHODS: Twenty-four healthy H. pylori-infected volunteers were studied on day 7 of dosing with placebo, lansoprazole 30 mg, omeprazole 20 mg and rabeprazole 20 mg, before and at least 5 weeks after H. pylori eradication. On each occasion, the 24-h intragastric acidity was measured by gastric aspiration. Plasma gastrin concentrations were measured hourly from 08.00 to 13.00 h. RESULTS: Sixteen subjects completed the study. For all three drugs and placebo, H. pylori eradication increased intragastric acidity, particularly nocturnal acidity, and decreased plasma gastrin. There were no differences between the three drugs with respect to 24-h acidity, percentage of time pH > 4 or 5-h plasma gastrin, either before or after H. pylori eradication. Before eradication, the percentage nocturnal time at pH > 3 was significantly greater during rabeprazole than during lanso-prazole dosing. CONCLUSIONS: The increase in intragastric acidity seen after H. pylori eradication during dosing with proton pump inhibitors is a drug-class effect, particularly affecting nocturnal acid control. This is related to increased spontaneous intragastric acidity after H. pylori eradication.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2002

Objective assessment of bladder neck elevation and urethral compression at colposuspension.

OBJECTIVES: 1. To assess whether magnetic resonance imaging and intra-operative measurements are useful in assessing bladder neck elevation and urethral compression at colposuspension; 2. to see if intra-operative measurements could be a substitute for magnetic resonance scan measurements. DESIGN: Prospective, observational study. SETTING: Urogynaecology Unit, NHS Trust hospital. POPULATION: Seventy-seven women undergoing colposuspension. METHODS: Bladder neck elevation was assessed using magnetic resonance imaging and measuring the amount of suture bow-stringing intra-operatively. Urethral compression was assessed using magnetic resonance imaging and by two intra-operative measurements: the distance between the medial sutures (with a ruler) and the distance between the urethra and the pubic bone (using paired Hegar dilators). RESULTS: The assessment of bladder neck elevation and compression against the pubic bone using magnetic resonance imaging was reliable (95% limits of agreement: -7.1mm to +7.1mm and -1.7mm to +3.8mm, correlation coefficient 0.92 and 0.87, respectively). The intra-operative assessment of urethral compression with a ruler was also reproducible at both paravaginal and pectineal sites (95% limits of agreement -2.6mm to +2mm and -2.1mm to +2.4mm, respectively; correlation coefficient 0.99 for both distances). Other intra-operative measurements of bladder neck elevation (suture bow-stringing) and urethral compression (Hegars) did not correlate with equivalent magnetic resonance scan measurements (kappa =-0.046, P = 0.31; kappa = 0.052, P = 0.41, respectively). CONCLUSIONS: Measurements have been found that can reliably assess bladder neck elevation and urethral compression at colposuspension. These measurements should be suitable for investigating morbidity following colposuspension.

Adult↗
PubMed2002

Why do women have voiding dysfunction and de novo detrusor instability after colposuspension?

OBJECTIVE: To investigate the causes of voiding dysfunction and new detrusor instability after colposuspension. DESIGN: Prospective, observational study. SETTING: Urogynaecology unit, district general hospital. POPULATION: Seventy-seven women undergoing colposuspension for genuine stress incontinence. METHODS: The following factors were investigated: 1. bladder neck elevation by magnetic resonance imaging before and after surgery; 2. urethral compression by measuring bladder neck approximation to the pubis with magnetic resonance imaging after surgery (anterior compression) and the distance between the medial stitches during surgery (lateral compression); 3. clinical and urodynamic factors. MAIN OUTCOME MEASURES: 1. Post-operative voiding function (i.e. first day of voiding and day of catheter removal); 2. objective evidence of detrusor instability three months post-operatively. RESULTS: Pre-operative peak flow rate (P = 0.004), straining during voiding (P = 0.005), increasing age (P < 0.001), operative elevation (P < 0.001) and anterior urethral compression (P = 0.001) were associated with the number of days of post-operative catheterisation. Increasing age (P = 0.02), previous bladder neck surgery (P = 0.04), operative elevation (P = 0.049) and anterior urethral compression (P < 0.001) were associated with detrusor instability at three months. CONCLUSION: Surgical factors (bladder neck elevation and compression) are associated with voiding dysfunction and detrusor instability after colposuspension. These findings have implications for prevention.

Adult↗
PubMed2000

A placebo-controlled study to assess the effects of 7-day dosing with 10, 20 and 40 mg rabeprazole on 24-h intragastric acidity and plasma gastrin in healthy male subjects.

AIM: To compare the effects of rabeprazole 10, 20 and 40 mg o.d. on 24-h intragastric acidity and plasma gastrin concentration in a randomized, double-blind placebo-controlled trial. METHODS: Twenty-four healthy male volunteers were studied on the 7th day of morning dosing with either placebo or rabeprazole 10, 20 or 40 mg in a crossover fashion. On day 7, hourly intragastric acidity was measured for 24 h from 08.00 hours by gastric aspiration. Plasma gastrin concentrations were also measured hourly from 08.00 to 24.00 hours, and 2-hourly thereafter. RESULTS: Compared with placebo, rabeprazole 10, 20 and 40 mg produced significant dose-related decreases in intragastric acidity (median 24-h integrated acidity=697, 186, 129 and 82 mmol h/L, respectively). This was associated with significant elevation of plasma gastrin concentration (median 24-h integrated gastrin=141, 1184, 1484 and 1763 pmol.h/L, respectively). Rabeprazole 40 mg resulted in significantly decreased acidity compared with both 10 and 20 mg, and in longer times for which intragastric pH was maintained at > 3 (19. 2 h vs. 17.3 h and 17.5 h) and > 4 (17 h vs. 14.2 h and 15.2 h), but was accompanied by significantly increased plasma gastrin. There was a consistent trend for greater antisecretory activity for 20 mg compared with 10 mg, but these differences did not reach statistical significance. The interindividual variability in antisecretory response was greatest with 10 mg. CONCLUSIONS: Rabeprazole 10, 20 and 40 mg produce significant, profound dose-related inhibition of gastric acid secretion. Taking into account reciprocal increases in plasma gastrin and the interindividual variation in antisecretory response, 20 mg appears to be the preferred dose for routine clinical use.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

A molecular mechanism of integrin crosstalk: alphavbeta3 suppression of calcium/calmodulin-dependent protein kinase II regulates alpha5beta1 function.

Many cells express more than one integrin receptor for extracellular matrix, and in vivo these receptors may be simultaneously engaged. Ligation of one integrin may influence the behavior of others on the cell, a phenomenon we have called integrin crosstalk. Ligation of the integrin alphavbeta3 inhibits both phagocytosis and migration mediated by alpha5beta1 on the same cell, and the beta3 cytoplasmic tail is necessary and sufficient for this regulation of alpha5beta1. Ligation of alpha5beta1 activates the calcium- and calmodulin-dependent protein kinase II (CamKII). This activation is required for alpha5beta1-mediated phagocytosis and migration. Simultaneous ligation of alphavbeta3 or expression of a chimeric molecule with a free beta3 cytoplasmic tail prevents alpha5beta1-mediated activation of CamKII. Expression of a constitutively active CamKII restores alpha5beta1 functions blocked by alphavbeta3-initiated integrin crosstalk. Thus, alphavbeta3 inhibition of alpha5beta1 activation of CamKII is required for its role in integrin crosstalk. Structure-function analysis of the beta3 cytoplasmic tail demonstrates a requirement for Ser752 in beta3-mediated suppression of CamKII activation, while crosstalk is independent of Tyr747 and Tyr759, implicating Ser752, but not beta3 tyrosine phosphorylation in initiation of the alphavbeta3 signal for integrin crosstalk.

Calcium-Calmodulin-Dependent Protein Kinase Type 2↗
PubMed1999

Helicobacter pylori: from the benign to the malignant.

Half of the world's population is infected with Helicobacter pylori, making it a pathogen of potentially great significance. Although in the majority of cases, infection is harmless, many infected individuals develop peptic ulcer disease or gastric cancer. In developed countries, the prevalence of infection has decreased along with the incidences of duodenal and gastric ulcer and distal gastric cancer. In developing countries, H. pylori infection rates remain high, and, as life expectancy increases, the incidence of gastric cancer will increase. Recently, a working party of the World Health Organization designated H. pylori a class I carcinogen. This designation, along with the description of an H. pylori-infected animal model of gastric cancer, has strengthened the case for H. pylori eradication to prevent gastric cancer. However, concerns are growing that H. pylori eradication itself may cause harm. And, in developed countries, an increase in the rate of cancers arising near the gastroesophageal junction might be linked to the disappearance of H. pylori. Therefore, we are faced with a dilemma: Should we eradicate H. pylori to prevent cancer of the distal stomach, or should we leave it and hence avoid cancer of the proximal stomach or distal esophagus? The need for more reliable treatments further complicates the issue. So far, we cannot assume that current treatment regimens provide adequate eradication rates to justify widespread screening. Further research is needed to determine in whom, when, and how to eradicate H. pylori infection.

Drug Therapy, Combination↗
PubMed1999

Review article: the pharmacology of rabeprazole.

Rabeprazole sodium is a new substituted benzimidazole proton pump inhibitor with several differences compared with existing proton pump inhibitors. In vitro and animal studies have demonstrated that rabeprazole is a more potent inhibitor of H+,K(+)-ATPase and acid secretion than omeprazole, and is a more rapid inhibitor of proton pumps than omeprazole, lansoprazole, or pantoprazole. This probably reflects rabeprazole's faster activation in the parietal cell canaliculus. In human studies, once-daily doses of 5-40 mg of rabeprazole inhibit gastric acid secretion in a dose-dependent fashion. A once-daily dose of 20 mg has consistently achieved profound decreases in 24-h intragastric acidity in single and repeat dosing studies, in healthy volunteers and patients with either peptic ulcer disease or gastro-oesophageal reflux disease. Significantly greater decreases in intragastric acidity are achieved on day 1 of dosing with rabeprazole 20 mg than with omeprazole 20 mg. As with other proton pump inhibitors, rabeprazole has in vitro antibacterial activity against Helicobacter pylori, with greater activity against this organism than either lansoprazole or omeprazole. In addition to inhibiting bacterial urease activity, rabeprazole binds to several molecules on H. pylori. Clinical trials are needed to assess the clinical importance of these findings, as well as to assess whether the potential advantages of rabeprazole result in clinical benefit for patients with acid-related diseases.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

The effect of omeprazole dosing on the isolation of Helicobacter pylori from gastric aspirates.

BACKGROUND: Animal experiments suggest that omeprazole dosing increases shedding of Helicobacter into the gastric lumen, and hence into gastric juice. AIM: To assess the effect of omeprazole dosing on the yield of H. pylori from gastric aspirates of infected volunteers. METHODS: Six serial nasogastric aspirates, three before and three during dosing with omeprazole 40 mg b.d., were obtained for culture from 10 H. pylori infected volunteers and one uninfected volunteer. To reduce contamination, samples were diluted 1:10 with Maximum Recovery Diluent (MRD; pH 7.0) or HCl-KCl buffer (pH 2.2) prior to culture on Columbia and Dent's agar. RESULTS: Undiluted gastric juice cultures were rapidly overgrown by upper respiratory tract flora. HCl-KCl dilution resulted in isolation of H. pylori from 77% of infected subject aspirates before, and 67% of aspirates during dosing with omeprazole. The yields were significantly lower with MRD dilution, 47% and 10%, respectively. Omeprazole dosing significantly decreased the yield after MRD dilution, but not after HCl-KCl dilution. CONCLUSIONS: Decreasing intragastric acidity, by dosing with omeprazole, decreases the isolation of H. pylori from routinely processed gastric aspirates. In vitro acidification of gastric aspirates, by HCl-KCl dilution, increases the isolation of H. pylori both before and during omeprazole dosing.

Adult↗
PubMed1998

A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects.

BACKGROUND: Rabeprazole (LY307640, E3810) is a new, potent, proton pump inhibitor. A single daily 20 mg dose significantly decreases 24-h intragastric acidity. There are no data currently available directly comparing the effect of rabeprazole on 24-h acidity with established proton pump inhibitors. AIM: To compare the effects of rabeprazole 20 mg o.m. and omeprazole 20 mg o.m. on 24-h intragastric acidity and plasma gastrin concentration in a randomized, double-blind, placebo-controlled trial, in healthy H. pylori-negative subjects. METHODS: Twenty-four healthy male volunteers, negative for H. pylori infection by serology and 13C-urea breath test, were studied on the 1st and 8th day of dosing with either placebo, rabeprazole 20 mg or omeprazole 20 mg, once each morning, in a crossover fashion. On days 1 and 8, hourly intragastric acidity was measured by gastric aspiration for 24 h from 08.00 hours. On day 8, plasma gastrin concentrations were also measured hourly from 08.00 to 24.00 hours, then every 2 h thereafter. RESULTS: A single dose of both rabeprazole and omeprazole significantly decreased 24-h intragastric acidity compared with placebo. The 24-h acidity on day 1 was significantly decreased for rabeprazole compared with omeprazole (331 vs. 640 mmol.h/L, P < 0.001), resulting in a significantly higher median 24-h intragastric pH and longer times at which intragastric pH was > 3 and > 4. On day 8 of dosing, the decrease in 24-h intragastric acidity was greater with rabeprazole than with omeprazole, but the difference was not statistically significant (160 vs. 218 mmol.h/L, P = 0.1). However, 24-h plasma gastrin concentration (1687 vs. 1085 pmol.h/L. P < 0.01) and percentage time that intragastric pH was > 3 (69 vs. 59%, P = 0.008) and > 4 (60 vs. 51%, P = 0.03) were significantly greater. CONCLUSIONS: Rabeprazole 20 mg once daily has a significantly faster onset of antisecretory activity than omeprazole 20 mg once daily. After 8 days the differences in intragastric pH > 3 and > 4 holding times persisted, but there was no significant difference in 24-h acidity.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

What are appropriate end-points for Helicobacter pylori eradication in the treatment of duodenal ulcer?

The end-point of Helicobacter pylori eradication trials in peptic ulcer disease should be the presence or absence of continuing H. pylori infection, and not ulcer healing or recurrence. This is not to suggest that ulcer healing or prevention of recurrence is not the desired clinical end-point. It is to allow large trials to be conducted in a 'patient-friendly' manner and in a shorter time-scale, both of which reduce patient withdrawals, protocol violations and cost. For the same reasons, diagnosis of cure should be made by noninvasive means whenever possible. It is currently impossible to make anything other than generalisations regarding the relative efficacies of modern eradication regiments. As it seems unlikely that definitive head-to-head studies will be performed, the conduct and reporting of current trials needs to be improved and standardised, to allow meaningful comparisons. In particular, the course of each and every patient through the trial should be fully and clearly reported, especially withdrawals and dropouts. The primary efficacy analysis should be the intention-to-treat analysis, with per protocol and modified intention-to-treat analyses also reported, where appropriate.

Clinical Trials as Topic↗