Outcome of 12-month surveillance colonoscopy in high-risk patients in the National Health Service Bowel Cancer Screening Programme.

AIM: Current British guidelines recommend surveillance colonoscopy at 12 months for individuals found to have five or more adenomas, or three or more adenomas of which at least one is ≥ 1 cm in size. This study describes the yield of surveillance colonoscopy in this group and explores patient and clinical factors that may be associated with the presence of advanced adenomas or cancer at surveillance. METHOD: Data were retrieved from the national database of the National Health Service Bowel Cancer Screening Programme. The detection of advanced colonic neoplasia (ACN, cancer or advanced adenoma) was used as the main outcome variable. Multivariable analysis was used to analyse relationships between patient factors (age, gender, body mass index, smoking and alcohol use) and clinical findings (number, size and nature of adenomas detected during index colonoscopy) with the outcome variable. RESULTS: One-thousand, seven-hundred and sixty individuals were included in the study. The yield of ACN at 12-month surveillance was 6.6% (116/1760), of which 14/1760 (0.8%) had colorectal cancer. Nine (64.3%) of these 14 cancers were Dukes A at diagnosis. The presence of a villous adenoma or a right-sided adenoma at screening colonoscopy was associated with ORs of 1.98 (95% CI: 1.11-3.53, P = 0.012) and 1.76 (95% CI: 1.13-2.74, P = 0.020), respectively, for detection of ACN at surveillance. CONCLUSION: Twelve-month surveillance colonoscopy is necessary in this group of patients. The presence of villous or proximal lesions at baseline is associated with increased risk of ACN at surveillance. Site and histological type of baseline lesions may be relevant for determining the surveillance interval.

Longer mean colonoscopy withdrawal time is associated with increased adenoma detection: evidence from the Bowel Cancer Screening Programme in England.

BACKGROUND AND STUDY AIMS: Increasing colonoscopy withdrawal time (CWT) is thought to be associated with increasing adenoma detection rate (ADR). Current English guidelines recommend a minimum CWT of 6 minutes. It is known that in the Bowel Cancer Screening Programme (BCSP) in England there is wide variation in CWT. The aim of this observational study was to examine the relationship between CWT and ADR. PATIENTS AND METHODS: The study examined data from 31 088 colonoscopies by 147 screening program colonoscopists. Colonoscopists were grouped in four levels of mean CWT ( < 7, 7 - 8.9, 9 - 10.9, and ≥ 11 minutes). Univariable and multivariable analysis (binary logistic and negative binomial regression) were used to explore the relationship between CWT, ADR, mean number of adenomas and number of right-sided and advanced adenomas. RESULTS: In colonoscopists with a mean CWT < 7 minutes, the mean ADR was 42.5 % compared with 47.1 % in the ≥ 11-minute group (P < 0.001). The mean number of adenomas detected per procedure increased from 0.77 to 0.94, respectively (P < 0.001). The increase in adenoma detection was mainly of subcentimeter or proximal adenomas; there was no increase in the detection of advanced adenomas. Regression models showed an increase in ADR from 43 % to 46.5 % for mean CWT times ranging from 6 to 10 minutes. CONCLUSIONS: This study demonstrates that longer mean withdrawal times are associated with increasing adenoma detection, mainly of small or right-sided adenomas. However, beyond 10 minutes the increase in ADR is minimal. Mean withdrawal times longer than 6 minutes are not associated with increased detection of advanced adenomas. Withdrawal time remains an important quality metric of colonoscopy.

The misuse of the faecal occult blood test under the lower gastrointestinal two week wait rule.

AIM: To find the proportion of patients with a faecal occult blood (FOB) performed as part of the referral for the lower gastrointestinal two week wait (2WW) referral system, and whether this correlates with the cancer status. METHOD: All patients referred to the colorectal cancer service using the 2WW referral criteria, between August 2005 and August 2007, were identified using the hospital's cancer audit database. Faecal occult bloods and cancer status were recorded for each patient. RESULTS: Two thousand one hundred and fifty-nine patients (1177 female: 903 male; median age 58; age range 18-98) were referred by general practitioners. The FOBT was only performed on three samples in all cases. In total, 172 of 2159 patients (7.9%) had an FOB performed prior to their referral, with 55 of 172 patients (31.9%) as part of the referral for 2WW. Sixteen of 172 patients (9.3%) had an FOB performed in the presence of overt rectal bleeding. In only 2 of 172 patients (1.1%) the FOB correlated with a colorectal cancer. Unnecessary testing for FOB costs has cost pound4072.96 in total. DISCUSSION: A significant number of faecal occult bloods are being performed and the detection rate, even in this symptomatic group of patients, is very low. It is evident that the test is being performed in the community on three samples and not six. This, combined with the high false positive rate, leads to patients not only undergoing unnecessary psycho-social consequences but could potentially lead to significant risks from unnecessary invasive investigation as well as the added financial burden of test itself.

Referral of patients with iron deficiency anaemia under the lower gastrointestinal two-week wait rule.

OBJECTIVE: One of the 2-week wait (2WW) criteria for suspected lower gastrointestinal cancer states that patients should be referred who have iron deficiency anaemia (IDA) without obvious cause [Haemoglobin (Hb) <11 g/dl men, <10 g/dl postmenopausal women]. AIM: Our aim was to find the proportion of patients referred as a 2WW not meeting the criteria, and the cost accrued by unnecessary referral. METHOD: Patients referred over 1 year were identified using the hospitals cancer database. Haematology, haematinics, coeliac serology and cancer status were recorded for each patient. RESULTS: A total of 204 patients were referred. In total, only 22/204 patients (10.8%) met all the necessary criteria for diagnosis and investigation of IDA prior to referral. As only 43/204 (21.1%) had been assessed for coeliac serology, this accounted for the majority of incomplete referrals. Excluding coeliac serology, only 127 (62.3%) met 2WW criteria for IDA. Of the remaining 77 patients, 57 (74%) patients did not meet the 2WW criteria on Hb alone and 35/77 were referred with no evidence of IDA. 12/127 (9.4%) patients were diagnosed with colorectal cancer. No cancers were detected in patients without BSG evidence of IDA, although one patient did not meet the criteria on Hb level alone. CONCLUSION: Although iron deficiency is a good marker for gastrointestinal cancer, it is evident that 2WW referral guidelines are not being followed. 89.2% of referrals are inappropriate according to guidelines. This not only has considerable workload and financial implications but could be potentially detrimental to patient health.

Diagnostic methods for Helicobacter pylori detection and eradication.

Helicobacter pylori is the principal cause of peptic ulcer disease and an important risk factor for the development of gastric cancer. The efficacy of 1 week triple therapies, which often have eradication rates of>90%, is undermined by poor patient compliance and bacterial antimicrobial resistance. The development of new anti-H. pylori therapies presents enormous challenges to clinical pharmacologists, not only in the identification of novel targets, but also in ensuring adequate drug delivery to the unique gastric mucus niche of H. pylori. Animal models of H. pylori infection have been developed but their clinical validity has yet to be established. Vaccination, to prevent or treat infection, has been demonstrated in animal models, but human studies have not been so encouraging.

Low-dose misoprostol for the prevention of low-dose aspirin-induced gastroduodenal injury.

INTRODUCTION: The harmful effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastric mucosa and the prophylactic effects of misoprostol are both dose-dependent. AIM: To investigate whether a low-dose of misoprostol is sufficient to prevent gastric mucosal injury caused by low-dose aspirin. METHODS: We conducted a double-blind placebo controlled parallel group endoscopic study in 32 evaluable volunteers. The main outcome measure was erosive injury (ulcers and superficial erosions) in the gastric mucosa over 28 days. RESULTS: Most subjects developed erosions on aspirin 300 mg daily. This was significantly reduced by misoprostol 100 microg daily. (Odds ratio 0.18, 95% CI: 0.07-0.48). There were no drug-related or gastrointestinal adverse events in subjects receiving misoprostol. CONCLUSION: Misoprostol 100 microg daily can prevent low-dose aspirin induced gastric mucosal injury without causing identifiable adverse effects.

Randomized controlled comparison of nitroimidazoles for the eradication of Helicobacter pylori and relief of ulcer-associated and non-ulcer dyspepsia.

BACKGROUND: A combination of omeprazole, clarithromycin and either metronidazole or tinidazole is commonly used for Helicobacter pylori eradication. Metronidazole is considerably cheaper than tinidazole but the two have not previously been compared in a randomized trial. METHODS: One hundred and twenty dyspeptic H. pylori-positive patients with endoscopically defined peptic ulcer [DU (n = 65), GU (n = 12)] or non-ulcer dyspepsia (NUD, n = 43) were randomized to receive a 1-week course of twice daily omeprazole 20 mg, clarithromycin 250 mg and either metronidazole 400 mg (OCM) or tinidazole 500 mg (OCT) in a double-blind fashion. Eradication of H. pylori, safety and side-effects of treatment, dyspeptic symptom score and consumption of antisecretory drugs were assessed at 6 weeks and 1 year after treatment. RESULTS: H. pylori eradication was successfully achieved in 57/60 (95%, ITT analysis) of patients receiving OCT and 58/60 (97%, ITT analysis) receiving OCM. Both regimens had similar side-effect profiles, which accounted for only one patient withdrawal. All patients remained uninfected (as assessed by 14C-urea breath test) at 1-year follow-up, but major symptom improvements and decreased antisecretory drug use were only seen in patients with DU (P<0.0001). CONCLUSIONS: Treatment with OCM is as effective as the more expensive OCT at eradicating H. pylori. H. pylori eradication results in long-term relief of dyspeptic symptoms and reduced antisecretory consumption only in patients with DU, and not in those with NUD.

The effect of protein binding and lipophilicity of penicillins on their in-vitro flux across gastric mucosa.

Delivery of amoxycillin across the human gastric mucosa to Helicobacter pylori is poor compared with that of metronidazole and clarithromycin, limiting the clinical effectiveness of this penicillin. To investigate the physicochemical properties of penicillins that influence their flux across gastric mucosa, the fluxes of metronidazole and eight penicillins were measured in vitro across rat gastric mucosa. The lipophilicity of these drugs was also measured using potentiometric titration. The mean fluxes of monobasic penicillins (range 0.66-0.89 nmol/cm2/h) were significantly lower than those of the aminopenicillins (range 1.94-2.80 nmol/cm2/h) (P < 0.005). Penicillin flux was not significantly correlated with lipophilicity as measured, but was significantly correlated with published protein binding data (rs = 0.9048, P < 0.002). Metronidazole flux was significantly higher than that of any penicillin at 22.6 (+/-0.9) nmol/cm2/h (P < 0.001). Therefore, the in-vitro gastric delivery of penicillins can be predicted from protein binding which may in turn predict activity against H. pylori in vivo.

Review article: factors influencing antibiotic transfer across the gastric mucosa.

The delivery of antimicrobial drugs to Helicobacter pylori within the stomach is poorly understood. The gastric environment represents a unique pharmacokinetic compartment, into which drug can be delivered directly following oral administration, or indirectly following intestinal absorption and transfer from the blood into the stomach across the gastric mucosa. Several methods have been used to study drug disposition across the gastric mucosa, including endoscopic biopsy studies, nasogastric intubation studies and animal models. Direct, or topical, delivery is limited by luminal drug degradation, drug formulation and the permeability of the mucus layer. Indirect, or systemic, delivery is limited by factors affecting the concentration gradient across the gastric mucosa and the permeability of the mucosa. These factors include intragastric pH, plasma protein binding, drug lipophilicity, the presence of active transport mechanisms, drugs that damage the gastric mucosa and inflammation secondary to H. pylori infection. Little is known about the last of these, and further research in this area should help in the rational approach to development of treatments against H. pylori.

The effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in human plasma, saliva and gastric juice.

AIMS: To evaluate the effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in plasma, gastric juice and saliva following intravenous infusion or oral dosing of metronidazole. METHODS: Eight volunteers received single doses of metronidazole (400 mg) intravenously and orally, whilst taking placebo or omeprazole (40 mg, twice daily for 5 days) in a randomized 4-way crossover study. Metronidazole and hydroxymetronidazole concentrations in plasma, saliva and gastric juice samples were determined by h.p.l.c. Pharmacokinetic parameters for metronidazole and hydroxymetronidazole were calculated, and the significance of the mean differences in parameters between omeprazole and placebo co-administration was assessed using a two-tailed, paired t-test. RESULTS: There were no significant differences (P < 0.05) in any of the plasma or saliva pharmacokinetic parameter values for metronidazole between volunteers receiving omeprazole or placebo when metronidazole was administered either as an intravenous infusion or orally. Following intravenous administration of metronidazole to the placebo group and omeprazole treated group respectively, the gastric transfer of metronidazole was significantly reduced from 15.5 +/- 10.4% to 2.6 +/- 1.0% of the dose (P = 0.007; 95% CI of difference 4.8 to 21.0) with concomitant changes in the metronidazole AUC (from 77.5 +/- 18.0 mumol l-1 h to 352.6 +/- 182.1 mumol l-1 h; P = 0.0003; 95% CI of difference 127.6 to 422.7), Cmax (from 61.4 +/- 26.5 mumol l-1 to 271.8 +/- 104.3 mumol l-1; p = 0.0001; 95% CI of difference 118.6 to 302.1). Similarly, the gastric juice AUC of hydroxymetronidazole was significantly reduced from 3.2 +/- 1.9 mumol l-1 h to 1.5 +/- 0.8 mumol l-1 h of the dose (P = 0.0043; 95% CI of difference 0.4 to 3.0) with a concomitant change in Cmax (from 5.0 +/- 2.5 mumol l-1 to 3.0 +/- 1.2 mumol l-1; P = 0.0007; 95% CI of difference 0.7 to 3.4). CONCLUSIONS: Omeprazole had little effect on the plasma and salivary pharmacokinetics of metronidazole (or its hydroxymetabolite) after intravenous or oral administration, but it did have a substantial effect on the pharmacokinetics of metronidazole and hydroxymetronidazole in gastric juice.

Review article: urea breath tests for detecting Helicobacter pylori.

The urea breath test (UBT) is the most sensitive and specific non-invasive test for the detection of Helicobacter pylori infection both before and after treatment. Labelling of the urea with either 13C or 14C has relative advantages and disadvantages. 13C-UBTs are both safe and well-validated, and have the additional advantage that they can be used in children. However, the initial capital costs of 13CO2 analysis are large compared to those for 14CO2. The protocol details for use of the 13C-UBT are variable: a test meal is important if urea solution is to be used and a single sample time point at 30 min is adequate. The recent development of novel formulations of 13C urea and new analytical techniques for the measurement of 13CO2 should allow reduction in the length of the test and its cost: they may herald a more widespread clinical application of this useful test.

In vitro assessment of gastric mucosal transfer of anti-Helicobacter therapeutic agents.

A novel animal model for studying antibiotic transfer across gastric mucosa was developed by using adult rats. Gastric corpus mucosa was mounted in an Ussing chamber system and bathed in oxygenated Krebs solution. Metronidazole flux from serosa to mucosa (J(S-->M)) was measured over 60 min under basal conditions and compared with mucosa-to-serosa flux (J(M-->S)). The effects of varying the chamber cross-sectional diameter and of stimulation by histamine and carbachol were assessed. Metronidazole J(M-->S) was measured with the mucosal pH at 2.2, 2.7, 3.2, and 7.4. Amoxicillin J(S-->M) under basal conditions was also measured and compared with metronidazole J(S-->M). Metronidazole J(S-->M) was proportional to serosal concentration (P < 0.001) under basal conditions, being 3.98 nmol x h(-1) x cm(-2) with a serosal concentration of 0.2 mmol/liter. Amoxicillin J(S-->M) was significantly lower under similar conditions at 0.50 nmol x h(-1) x cm(-2) (P < 0.01). Metronidazole J(S-->M) was not significantly different from J(M-->S), between chambers of different sizes, or following stimulation. When the mucosal pH was changed, J(M-->S) was proportional to the un-ionized concentration on the mucosal side (P < 0.001). Therefore, this model shows properties analogous to those of human gastric mucosa in vivo, with partitioning of metronidazole on the mucosal side according to pH, diffusion of metronidazole across the mucosa in both directions, and selectivity for different antibiotics, and it will be useful for the study of other therapeutic agents in the treatment of Helicobacter pylori.

The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection.

Although omeprazole is an important component in anti-Helicobacter pylori therapeutic regimes using clarithromycin, amoxycillin and metronidazole, the mechanism by which it enhances antimicrobial action is unknown. One potential explanation for this effect is increased antibiotic chemical stability resulting from gastric pH changes induced by co-administration of omeprazole. The chemical stability of clarithromycin, amoxycillin and metronidazole was investigated in aqueous solutions and in human gastric juice collected before and after a 7-day course of omeprazole. Amoxycillin, clarithromycin and metronidazole were prepared in buffered aqueous solutions of pH 1.0 to 8.0 and in gastric juice of pH 2.0 and 7.0. The gastric juice samples were obtained from fasted H. pylori-negative volunteers before and after they had received a 7-day course of omeprazole. All the samples were incubated at 37 degrees C and analysed at intervals by HPLC. Amoxycillin, clarithromycin and metronidazole were stable in aqueous solutions of pH 4.0-7.0, pH 5.0-8.0 and pH 2.0-7.0, respectively. At pH 2.0, the degradation half-lives were 19.0 +/- 0.2 h, 1.3 +/- 0.05 h and 2200 +/- 1100 h, respectively. In gastric juice samples of pH 2.0, the degradation half-lives were 15.2 +/- 0.3 h, 1.0 +/- 0.04 h and > or = 800 h, respectively. The half-lives of the drugs in the gastric juice samples of pH 7.0 were all > 68 h. The co-administration of omeprazole with amoxycillin or clarithromycin is likely to increase the chemical stability of amoxycillin and clarithromycin in gastric juice. Clarithromycin degrades rapidly at normal gastric pH (1.0-2.0) but amoxycillin and metronidazole are sufficiently stable at this pH to maintain an antibacterial concentration in the stomach.

Helicobacter pylori eradication in clinical practice: one-week low-dose triple therapy is preferable to classical bismuth based triple therapy.

BACKGROUND: Both classical 2-week bismuth based triple therapy and the newer 1-week low-dose omeprazole based triple therapies achieve high Helicobacter pylori eradication rates in controlled clinical trials and are in widespread use in routine clinical practice. However, their efficacy and acceptability in this setting is unproved. METHODS: Over a 1-year period, the notes for patients attending a dedicated H. pylori treatment clinic were audited. Assessments were made of patient demographics, diagnosis, smoking habits, use of H2-antagonists, regimen used, efficacy of treatment, compliance and side-effects experienced. RESULTS: 223 sets of notes were audited. 89 patients received bismuth, tetracycline and metronidazole for two weeks and 111 patients received omeprazole, clarithromycin and either metronidazole (63 patients) or tinidazole (48 patients) for 1 week. Successful eradication was achieved in 75/89 (84.3%), 56/63 (89%) and 42/48 (88%), respectively, (P = N.S.). Severe side-effects occurred in 11 (12%) of patients receiving bismuth based treatment compared to 1 (0.9%) patient receiving omeprazole based regimens (P < 0.02). Treatment failure in patients receiving omeprazole based treatment was associated with smoking (P < 0.05). CONCLUSIONS: Outside the context of clinical trials, both regimens achieved acceptable eradication rates. However, 1-week low-dose therapy is preferable due to the lower incidence of severe side-effects.

Effect of omeprazole on the distribution of metronidazole, amoxicillin, and clarithromycin in human gastric juice.

BACKGROUND & AIMS: The mechanism by which antimicrobial therapy against Helicobacter pylori is enhanced by acid suppression is unknown. The aim of this study was to investigate the effect of omeprazole on gastric juice, plasma, and saliva concentrations of metronidazole, amoxicillin, and clarithromycin. METHODS: Single doses of antibiotic were administered intravenously to 24 healthy men (each antibiotic to 8 subjects) while taking placebo or omeprazole. Antibiotic concentrations were measured in gastric juice, plasma, and saliva. The pharmacokinetic parameters gastric clearance and gastric transfer fraction were calculated for each antibiotic. RESULTS: In the omeprazole group compared with the placebo group, mean maximum antibiotic gastric juice concentrations (in milligram per liter) of metronidazole decreased from 33.6 to 8.3 (P = 0.0001), whereas those of clarithromycin were unchanged, and those of amoxicillin increased from 0.13 to 0.68 (P = 0.02). Omeprazole increased salivary concentrations of metronidazole (P = 0.02) but had no effect on clarithromycin concentrations (no amoxicillin was detectable in saliva). CONCLUSIONS: Omeprazole decreases the intragastric concentrations of metronidazole by reducing acid secretion and increases intragastric concentrations of amoxicillin partly by reducing gastric juice volume. Novel pharmacokinetic parameters have been described that provide an insight into the mechanisms underlying drug transfer across the blood-stomach barrier.