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Epidemiological data suggest that oestrogen contributes to the aetiology of colonic cancer. Furthermore, recent studies have suggested that local hormone metabolism may play a key role in determining colonic responsiveness to oestrogen. To further clarify this mechanism we have characterized the expression and regulation of isozymes of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in vitro and in situ. Immunohistochemistry was used to confirm expression of the type 2 and 4 isozymes of 17beta-HSD (17beta-HSD2 and 4) in normal colonic epithelial cells. Parallel studies suggested that both isozymes were abnormally expressed in colonic tumours and this was confirmed by Western blot analyses. Abnormal expression of 17beta-HSD2 and 4 proteins was also observed in Caco-2, HT-29 and SW620 colonic cancer cell lines, although the overall pattern of oestrogen metabolism in these cells was similar to that seen in primary colonic mucosal tissue. The predominant activity (conversion of oestradiol to oestrone) was highest in Caco-2>SW620>HT-29, which correlated inversely with the rate of proliferation of the cell lines. Regulatory studies using SW620 cells indicated that the most potent stimulator of oestradiol to oestrone inactivation was the antiproliferative agent 1,25-dihydroxyvitamin D3 (1,25D3), whilst oestradiol itself inhibited 17beta-HSD activity. Both oestradiol and 1,25D3 decreased mRNA for 17beta-HSD2 and 4. Data indicate that the high capacity for inactivation of oestrogens in the colon is associated with the presence of 17beta-HSD2 and 4 in epithelial cells. Abnormal expression of both isozymes in colonic cancer cells and the stimulation of oestrogen inactivation by the antiproliferative agent 1,25D3 highlights a possible role for 17beta-HSD isozymes as modulators of colonic cell proliferation.

1 Comparison of phenytoin clearance showed a marked increase in people over 65 years of age compared with people under 45 years of age. 2 This difference was apparent if phenytoin was given orally or intravenously. 3 Phenytoin clearance correlated inversely with phenytoin binding and plasma albumin, both of which were found to be reduced in the elderly. [ABSTRACT FROM AUTHOR]

Submaximal dose pentagastrin tests conducted in normal male volunteers with L-643.441, a novel histamine H2-receptor antagonist, indicate that it is a potent and long-acting inhibitor of gastric acid secretion. The effect appears dose-dependent and single doses of 50 mg are sufficient to reduce secretory potential by at least 50% when examined 24 h after drug administration. No adverse effects attributable to treatment were observed. [ABSTRACT FROM AUTHOR]

Omeprazole, a substituted benzimidazole, and a potent inhibitor of gastric parietal cell H+/K+ ATPase, was tested for drug interactions at two dose levels (30 mg and 60 mg/day) in man using the model drugs [14C]-aminopyrine and antipyrine. Elimination of both models was assessed before and after 15 days treatment with omeprazole. In addition [14C]-aminopyrine metabolism was assessed on day 2 of treatment to investigate the rapidity of onset of any effect. In 10 healthy male volunteers omeprazole 60 mg/day for 14 days prolonged aminopyrine 14CO2 half life (t1/2), measured on the 15th day, by 21% (P less than 0.05), and reduced percent dose demethylated in 2 h (ABT2) by 19% (P less than 0.005). No effect was seen on day 2 of therapy. After 14 days treatment antipyrine half-life was prolonged by 10% (P less than 0.025) and clearance was reduced by 14% (P = 0.063). In nine healthy male volunteers omeprazole 30 mg/day for 14 days prolonged aminopyrine 14CO2 by 13% and reduced ABT2 by 11%. Both changes just failed to reach statistical significance. At this dose antipyrine metabolism was unaltered. As the dose of omeprazole used in clinical practice may be less than 30 mg/day it is unlikely that metabolic inhibition will occur during routine use, although it will be necessary to test for interactions with therapeutically more important compounds. Interactions should be looked for when large doses of omeprazole are being used to treat hypersecretory states. [ABSTRACT FROM AUTHOR]

1. In a double-blind crossover study 10 healthy males received either placebo or omeprazole (40 mg day-1) for 9 days, a single dose of phenytoin (300 mg) being taken on the seventh day. 2. Omeprazole significantly increased the area under the curve (0 to 72 h) of phenytoin (mean +/- s.e. mean) from 121.6 +/- 14.0 to 151.4 +/- 13.6 micrograms ml-1 h) (P less than 0.01). 3. The peak concentration, and apparent elimination half-life of phenytoin also tended to be increased though not significantly. 4. The omeprazole-phenytoin interaction observed may be clinically important because of the low therapeutic index associated with phenytoin. [ABSTRACT FROM AUTHOR]

The possible influence of sucralfate on phenytoin absorption was investigated in a double-blind, placebo controlled study. Concomitant administration of 1 g sucralfate reduced the absorption of 300 mg phenytoin capsules by 20% as measured by the area under the curve from 0-48 h. This could be of significance in epileptic patients stabilised on phenytoin in whom sucralfate is used in ulcer treatment. [ABSTRACT FROM AUTHOR]

Purpose: Laboratory and case-control studies suggest a pivotal role for the cyclooxygenase-2 (COX-2) pathway in colorectal carcinogenesis. The purpose of this study was to test whether the COX-2 inhibitor rofecoxib could reduce recurrence and improve survival when administered in the adjuvant setting of colorectal cancer (CRC)., Patients and Methods: Patients who had undergone potentially curative surgery and completion of adjuvant therapy for stage II and III CRC were randomly assigned to receive rofecoxib (20 mg daily) or placebo. The primary end point was overall survival (OS). Where formalin-fixed paraffin-embedded tumor tissue samples were available, COX-2 expression was evaluated by immunohistochemistry and correlated with clinical outcome., Results: Two thousand four hundred thirty-four patients were entered onto the study. The trial was terminated early because of the worldwide withdrawal of rofecoxib. At this point, 1,167 patients had received rofecoxib and 1,160 patients had received placebo for median treatment durations of 7.4 and 8.2 months, respectively. For the rofecoxib and placebo arms, median follow-up times were 4.84 and 4.85 years, with 241 and 246 deaths and 297 and 329 recurrences, respectively. No difference was demonstrated in OS (hazard ratio [HR] = 0.97; 95% CI, 0.81 to 1.16; P = .75) or recurrence (HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) comparing the two groups. Tumor COX-2 expression by immunohistochemistry was assessed for 871 patients, but neither prognostic nor predictive effects were observed., Conclusion: In this study of abbreviated therapy in the adjuvant setting of CRC, rofecoxib did not improve OS or protect from recurrence in unselected patients. In addition, COX-2 expression did not correlate with prognosis overall or predict effectiveness of COX-2 inhibitors.

Aims: To examine risks of sudden death in the community associated with drugs grouped by their risk of causing torsades de pointes (TdP) and to explore the risks for individual drugs., Methods: Case-control study comparing prior drug intakes and morbidities, using the Arizona classification of drugs causing TdP. Participants included 1010 patients dying suddenly where post-mortem examination did not identify a clear cause of death, and 3030 matched living controls from primary care., Results: Noncardiac drug risk was posed by antipsychotics and antidepressants. Significantly raised odds ratios (ORs) were found for takers of typical and atypical antipsychotics, ORs [95% confidence interval] 3.94 (2.05, 7.55) and 4.36 (2.54, 7.51), and of selective serotonin reuptake inhibitors [SSRIs] rather than tricyclic antidepressants, ORs 2.21 (1.61, 3.05) and 1.44 (0.96, 2.13). No significant risk was associated with other, noncardiac or psychiatric drugs, OR 1.09 (0.85, 1.41). Arizona classified drugs considered to raise risk of TdP were associated with raised risk of sudden death, as were those only weakly associated with TdP and not considered to pose a risk in normal use, ORs 2.08 (1.45, 3.00) and 1.74 (1.33, 2.28), respectively., Conclusions: Atypical and typical antipsychotic drug use were both strongly associated with raised risks, as were SSRIs. Tricyclic antidepressants were not associated with raised risks. The Arizona classification of risk of TdP was a poor predictor of likelihood of noncardiac drug-associated sudden death.

Impaired butyrate oxidation and raised counts of sulfate-reducing bacteria in the colon of patients with ulcerative colitis (UC) indicate that the disease may be induced or aggravated by hydrogen sulfide toxicity. We aimed to examine enzymatic removal of H(2)S in erythrocytes and colonic mucosa from controls and patients with UC and Crohn's disease (CD). Rhodanese (RHOD) and thiol methyltransferase (TMT) activities were measured in rectal mucosa and erythrocytes, and plasma thiocyanate was determined. Four groups were analyzed: patients with UC, patients with CD, hospital controls (patients with dyspepsia or IBS), and a group of healthy volunteers. RHOD and TMT activity in rectal biopsies did not differ significantly between controls and patients with UC or CD (n=56). Control levels of RHOD were significantly higher in men than in women (212+/-25 and 132+/-14 nmol/mg/min, respectively; P<0.01). In erythrocytes (n=128) RHOD activity was significantly higher in UC patients than in hospital or volunteer controls (1.15+/-0.12 compared with 0.88+/-0.12 and 0.66+/-0.02 nmol/mg/min; P<0.05 and P<0.02, respectively). TMT activity was also significantly higher in erythrocytes from UC patients and hospital controls than volunteer controls (2.02+/-0.13 pmol/mg/min [P<0.001], 1.51+/-0.21 pmol/mg/min [P<0.05], and 1.17+/-0.18 pmol/mg/min, respectively). We found no evidence of defective enzymic detoxication of sulfide by RHOD or TMT in patients with UC or CD.

Objective: Angiotensin-converting enzyme (ACE) inhibitors and diuretics have been associated with acute pancreatitis. We quantified the risk of acute pancreatitis associated with the use of antihypertensive medication in the European study on drug-induced acute pancreatitis (EDIP)., Material and Methods: The EDIP study is a multicenter population-based European case-control investigation of the association between drug use and acute pancreatitis. Patients between 40 and 85 years of age hospitalized for acute pancreatitis were included in the study between 1 October 1994 and 31 December 1998. For each case, age- and gender-matched community controls were recruited. Detailed information on drug use and potential confounders (e.g. comorbidity, alcohol use) was obtained through a structured interview., Results: In all, 724 patients with acute pancreatitis and 1791 community controls were identified and interviewed. Use of ACE inhibitors in the week prior to the index date was associated with an increased risk of acute pancreatitis (adjusted odds ratio 1.5; 95% CI: 1.1-2.2). The risk of acute pancreatitis associated with ACE inhibitors increased with higher daily doses and was highest in the first 6 months of therapy. Calcium channel blockers increased the risk of acute pancreatitis (adjusted odds ratio 1.5; 95% CI: 1.1-2.1) without an apparent dose- or response relationship. Loop and thiazide diuretic use was not associated with an increased risk of acute pancreatitis. Potassium-sparing diuretics elevated the risk of acute pancreatitis, albeit non-significantly., Conclusion: Use of ACE inhibitors is associated with a modest increase in the risk of acute pancreatitis during the first months of treatment.

H2S is highly toxic and selectively inhibits butyrate oxidation in colonocytes. Ineffective detoxification may result in mucosal insult, inflammation, and ultimately in colorectal cancer (CRC). Rhodanese can detoxify H2S and is comprised of two isoenzymes: thiosulfate sulfurtransferase (TST) and mercaptopyruvate sulfurtransferase (MST). Using specific antisera to discriminate TST from MST, we found that only TST could detoxify H2S. In sections of normal colon, both enzymes were located on the luminal mucosal surface, and they were expressed in the colonocytes but not in the mucin-secreting goblet cells. Expression of both enzymes was focally lost in ulcerative colitis and markedly reduced in advanced colon cancer, the disease progression correlating with the decreased expression of MST and TST. In HT-29 cells, a human colon cancer cell line, TST activity and expression were significantly increased by butyrate and by histone deacetylase inhibition, agents that promote HT-29 cell differentiation. Sulfide (0.1 mM) also increased TST activity, but higher sulfide concentrations (0.3-3 mM) were toxic. Preincubation in butyrate to increase TST expression, decreased sensitivity of the cells to sulfide toxicity. We conclude that decreased expression of TST (or MST) is a tumor marker for CRC. TST expression is increased in colonocyte differentiation. Dysregulation of TST expression and activity resulting in inability to effectively detoxify could be a factor in the cell loss and inflammation that accompany ulcerative colitis and ultimately then in CRC.

Aims: To determine whether systemic hypertension and glaucoma might coexist more often than expected, with possible implications for treatment., Methods: Case-control study using general practitioner database of patients with glaucoma matched with controls for age and sex., Results: Hypertension was significantly more common in the 27,080 patients with glaucoma (odds ratio 1.29, 95% confidence intervals 1.23 to 1.36, p<0.001) than in controls. Treatment by oral beta blockade appeared to protect from risk (odds ratio 0.77, 95% CI 0.73 to 0.83, p<0.0001), but oral calcium channel antagonists or angiotensin converting enzyme (ACE) inhibitors did not (odds ratios 1.34, 1.24 to 1.44 and 1.16 1.09-1.24, respectively, p<0.0001 in each case). Oral corticosteroid treatment was associated with enhanced risk (odds ratio 1.78, 1.61 to 1.96)., Conclusion: Common pathogenetic mechanisms in ciliary and renal tubular epithelia may explain coincidence of glaucoma and systemic hypertension. The choice of cardiovascular treatment, could substantially influence glaucoma incidence, with beta blockade protecting and ACE inhibitors or calcium channel blockers not affecting underlying risk.

Activation of protein kinase C delta (PKCdelta) is believed to be pro-apoptotic. PKCdelta is reported to be reduced in colon cancers. Using a colon cancer cell line, COLO 205, we have examined the roles of PKCdelta in apoptosis and of caspase-3 in the activation and inhibition of PKCdelta. PKCdelta activation with bistratene A and its inhibition with rottlerin induced apoptosis. Effects of PKC activators and inhibitors were additive, suggesting that PKCdelta down-regulation was responsible for the effects on apoptosis. Different apoptotic pathways induced PKCdelta cleavage, but the fragment produced was inactive in kinase assays. Caspase-3 inhibition did not block DNA fragmentation or PKCdelta proteolysis despite blocking intracellular caspase-3 activity. Calpain inhibition with calpeptin did not prevent TPA-induced PKCdelta cleavage. We conclude that in colonocytes, inhibition of PKCdelta is sufficient to lead to caspase-3-independent apoptosis. Caspase-3 does not cleave PKCdelta to an active form, nor does caspase-3 inhibition block apoptosis.

Background: The comparative effects of cyclooxygenase-2- (COX-2) selective inhibitors and nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) on blood pressure are debated. Clinicians have been concerned about the need for antihypertensive treatment following therapy with these agents., Objective: To compare initiation of antihypertensive treatment among new users of the COX-2-selective inhibitor rofecoxib and of nonselective NSAIDs in clinical practice., Methods: Retrospective cohort study using the MediPlus (UK) database that covers 1.8 million patients throughout the UK. Patients included were at least 50 years of age, had at least 1 prescription for either diclofenac, ibuprofen, naproxen or rofecoxib (drugs of interest, DOIs), and had no prescription for any NSAID, COX-2 inhibitor, or antihypertensive treatment during the 6 months prior to their first/index prescription date. A subset of patients, classified as chronic and persistent new users, had at least 3 prescriptions of the index prescription DOI and did not switch to another DOI during the 6-month follow-up period. Logistic regression analysis, adjusted for potential predictors, was used to assess initiation of new antihypertensive treatment., Results: 18,737 suitable patients were identified (diclofenac 7,861, ibuprofen 8,423, naproxen 1,556 and rofecoxib 897). Those using rofecoxib were older and more likely to be female than those using NSAIDs. During the 6 months following the index prescription, 7.0% of all new users and 11.5% of chronic and persistent new users initiated antihypertensive treatment. After adjusting for potential predictors there were no statistically significant differences in the risk of initiating antihypertensive treatment between new or chronic and persistent new users of rofecoxib, diclofenac, ibuprofen and naproxen (p > 0.05)., Conclusion: The results of this study did not indicate any significant differences in the initiation of antihypertensive therapy among patients who were prescribed rofecoxib and NSAIDs, even after multiple prescriptions.

Enhancing apoptosis to remove abnormal cells has potential in reversing cancerous processes. Caspase-3 activation generally accompanies apoptosis and its substrates include enzymes responsible for DNA fragmentation and isozymes of protein kinase C (PKC). Recent data, however, question its obligatory role in apoptosis. We have examined whether modulation of PKC activity induces apoptosis in COLO 205 cells and the role of caspase-3. Proliferation ([3H]thymidine) and apoptosis (DNA fragmentation and FACS) of COLO 205 cells were measured in response to PKC activation and inhibition. Caspase-3 activity was assayed and the effects of its inhibition with Ac-DEVD-cmk, and the effect of other protease inhibitors, on apoptosis were determined. PKC activation and inhibition both reduced DNA synthesis and induced DNA fragmentation. As PKC inhibitors induced DNA fragmentation more rapidly than PKC activators and failed to block activator effects, we conclude that it is PKC down-regulation (i.e., inhibition) after activator exposure that mediates apoptosis. Increases in caspase-3 activity occurred during apoptosis but apoptosis was not blocked by caspase inhibition. By contrast, the cysteine protease inhibitor, E-64d, blocked apoptosis. Cysteine proteases not of the caspase family may either act more closely to the apoptotic process than caspases or lie on an alternative, more active pathway.

This article reviews the clinical and epidemiological features of conventional non-steroidal anti-inflammatory drug (NSAID) related peptic ulcer complications, and the associated risk factors. The degree of gastrointestinal toxicity varies widely between the available drugs and with dose of each. The risk of ulcer complications can however be reduced, and perhaps completely removed, by using the lowest dose of the least toxic member of the class. Enteric coating and other delayed release formulations have not been shown to reduce risk. Estimates of the imposed disease burden have varied widely, in part through assuming that risks in selected patient groups will necessarily translate to the general population. Nevertheless, the imposed disease burden is one of the largest associated with current drug treatment. Associated risk factors such as prior ulcer, corticosteroid use and concurrent aspirin as well as general cardiovascular disease will raise the likelihood of an ulcer complication in NSAID takers and non-takers. Therefore, strategies dependent on substituting COX-selective drugs will then be only partially successful.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well recognised as causing peptic ulceration and ulcer complications. However, several critical issues, including the amount of both gastrointestinal and non-gastrointestinal disease affected by NSAIDs, their interaction with ancillary risk factors, and how to optimise management in subgroups, remain poorly understood. In this article, strategies for subgroups that take account of non-specific gastrointestinal risks, minimisation of residual risk, and the importance of non-gastrointestinal toxicity are suggested, and areas for research identified.

Background: Many drugs are believed, clinically, to cause acute pancreatitis. We used information held on the UK General Practitioner Research Database to compare risks for drugs for which reports of pancreatitis were common or uncommon., Methods: Drug prescriptions were examined in 3673 patients with acute pancreatitis and in matched controls. Odds ratios were calculated for recent (1-90 days before the episode), past (91-360 days before the episode) or continuing (prescription in both periods) use., Results: Odds ratios were markedly increased for recent antisecretory use in non-ulcer patients only [all H2-antagonists, 12.4 (9.5-16.4); all proton pump antagonists, 9.3 (6.6-13.0)], with smaller increases for past [3.1 (2.5-3.7) and 3.5 (2.6-4.6), respectively] and continuing [2.6 (2.2-3.1) and 3.7 (2.9-4.7), respectively] use in patients without ulcer. Recent users of mesalazine showed a markedly increased risk [9.0 (1.8-44.6)], with smaller increases in past and continuing users [4.5 (1.3-16.0) and 2.5 (1.2-5.0), respectively]. Odds ratios for other drugs, suspect or not, were modestly increased, irrespective of whether the use was recent, past or continuing. The presence of gall-stones was not associated with a modified risk., Conclusions: Mesalazine, azathioprine and antisecretory drugs in non-ulcer subjects may increase the risk of pancreatitis, but warnings of drug-induced pancreatitis are generally not accompanied by increased population risks.

Background: 5-aminosalicylates are extensively prescribed for the treatment of ulcerative colitis but have a wide range of described adverse effects., Aims: To determine whether serious adverse effect profiles differ for sulphasalazine and mesalazine., Methods: Analysis of suspected serious adverse reactions reported to the Committee on Safety of Medicines of the UK in 1991-1998. Adverse effect profiles were categorised for interstitial nephritis, pancreatitis, serious skin reactions, hepatitis and hepatic failure, and blood dyscrasias. Report rates were calculated using prescribing data from the Department of Health and compared for mesalazine and sulphasalazine. Further analysis was undertaken for sulphasalazine according to disease indication of inflammatory bowel disease or rheumatoid arthritis., Results: A total of 4.7 million prescriptions were dispensed for sulphasalazine compared with 2.8 million for mesalazine. Interstitial nephritis was only described for mesalazine, with 11.1 reports per million prescriptions. Pancreatitis was reported seven times as frequently for mesalazine (7.5 per million prescriptions) compared with sulphasalazine (1.1 per million prescriptions) (odds ratio (OR) 7.0; 95% confidence interval (CI) 2.6-18.6; p<0.001). There were no reports of serious skin disorders in patients prescribed sulphasalazine for inflammatory bowel disease. Blood dyscrasias were reported significantly more often in patients receiving sulphasalazine for rheumatoid arthritis than for inflammatory bowel disease (OR 5.31; 95% CI 2.6-11.0; p<0.001), and there was a similar trend for hepatic disorders., Conclusions: Spontaneous reports suggest that within the five sets of disorders considered, there is no evidence to indicate a safety advantage of mesalazine over sulphasalazine in the treatment of inflammatory bowel disease. Pancreatitis and interstitial nephritis appear significantly more common with mesalazine, and advice on renal monitoring in patients who receive mesalazine may need reinforcing.

Aims: To define by amalgamation of data obtained in contemporaneous case-control studies, the risks associated with individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) according to doses used., Methods: Meta-analysis of individual patient data from three retrospective case-control studies using similar data collection protocols was carried out in hospitals in Catalonia, England, Scotland and Sweden. 2472 cases of upper gastrointestinal bleeding and 5877 controls were studied. Main outcome measures were risks associated with individual NANSAIDs according to dose used and the period of time for which they were given., Results: Ibuprofen showed the lowest odds ratio (OR = 1.7; 95% confidence interval 1.1, 2.5), followed by diclofenac (4.9; 3.3, 7.1), indomethacin (6.0; 3.6, 10.0), naproxen (9.1; 6.0-13.7), piroxicam (13.1; 7.9-21.8) and ketoprofen (34.9; 12.7, 96.5). Striking dose-response relationships were seen with four to eight-fold increases in risk within conventionally used dose ranges for all except ketoprofen, where numbers were too few to allow dose analysis. Across the class, risk was highest during the first week of use (11.7; 6.5, 21.0), decreased thereafter with continuing use (5.6; 4.6, 7.0), and fell to 3.2 (2.1, 5.1) 1 week after discontinuing use. Concurrent use of more than one NANSAID substantially increased risk., Conclusions: The risk of upper gastrointestinal bleeding with NANSAIDs varies twenty-fold depending on the drug, and by three to seven-fold depending on the dose chosen. Risk is maximal during the first week and decreases thereafter. Paracetamol (acetaminophen) is not associated with upper gastrointestinal bleeding at any dose and should be the first-line analgesic wherever possible.

Background: Hydrogen sulphide (H(2)S) is a potent toxin normally present in the colonic lumen which may play a role in ulcerative colitis (UC). Two enzymes, thiol methyltransferase (TMT) and rhodanese (RHOD), are thought to be responsible for sulphide removal but supportive evidence is lacking., Aims: To determine the distribution of TMT and RHOD in different sites throughout the gastrointestinal tract and their efficacy as detoxifiers of H(2)S., Methods: Enzyme activities were measured in normal tissue resected from patients with cancer. TMT and RHOD activities were determined using their conventional substrates, 2-mercaptoethanol and sodium thiosulphate, respectively. For measurement of H(2)S metabolism, sodium sulphide was used in the absence of dithiothreitol. Thiopurine methyltransferase (TPMT), which in common with TMT methylates sulphydryl groups but is not thought to act on H(2)S, was also examined., Results: TMT, RHOD, and TPMT activities using their conventional substrates were found throughout the gastrointestinal tract with highest activity in the colonic mucosa. When H(2)S was given as substrate, no reaction product was found with TMT or TPMT but RHOD was extremely active (Km 8.8 mM, Vmax 14.6 nmol/mg/min). Incubation of colonic homogenates with a specific RHOD antibody prevented the metabolism of H(2)S, indicating that RHOD is responsible for detoxifying H(2)S. A purified preparation of RHOD also detoxified H(2)S., Conclusions: RHOD, located in the submucosa and crypts of the colon, is the principal enzyme involved in H(2)S detoxication. TMT does not participate in the detoxication of H(2)S.

Background: In ulcerative colitis, hydrogen sulphide is postulated to impair colonocyte butyrate metabolism, leading to cellular energy deficiency and dysfunction., Aims: To determine the effects of sulphide exposure on butyrate metabolism and adenosine triphosphate levels of HT29 colonic epithelial cancer cells, and to establish whether energy deficiency can be prevented by increased butyrate concentrations or the presence of glucose., Methods: HT29 cells were maintained in medium containing 3 mM butyrate, 5 mM glucose, or both substrates. Oxidation rates were measured by 14CO2 release from 14C-labelled substrates. Cellular adenosine triphosphate was assayed using the luciferin/luciferase chemiluminescent method. The effects of sulphide (0-5 mM) on substrate oxidation and adenosine triphosphate levels and of increasing butyrate concentration (0-30 mM) with sulphide were observed., Results: HT29 cells showed similar energy substrate usage to primary colonocyte cultures. Sulphide exposure inhibited butyrate oxidation and led to a reduction in cellular adenosine triphosphate. This fall was prevented by co-incubation with glucose, but not by increasing concentrations of butyrate., Conclusions: HT29 cells utilize butyrate as an energy substrate and represent a useful in vitro model of the effects of sulphide on colonocytes. Sulphide inhibits butyrate oxidation and leads to demonstrable energy deficiency, prevented by the presence of glucose but not by increased butyrate concentrations.

Background: Ketorolac is approved for the relief of postoperative pain but concerns have been raised over a possible risk of serious adverse effects and death. Two regulatory reviews in Europe on the safety of ketorolac found the data were inconclusive and lacked comparison with other non-steroidal anti-inflammatory drugs. The aim of this study was to compare the risk of serious adverse effects with ketorolac vs diclofenac or ketoprofen in adult patients after elective major surgery., Methods: This prospective, randomized multicentre trial evaluated the risks of death, increased surgical site bleeding, gastrointestinal bleeding, acute renal failure, and allergic reactions, with ketorolac vs diclofenac or ketoprofen administered according to their approved parenteral and oral dose and duration of treatment. Patients were followed for 30 days after surgery., Results: A total of 11,245 patients completed the trial at 49 European hospitals. Of these, 5634 patients received ketorolac and 5611 patients received one of the comparators. 155 patients (1.38%) had a serious adverse outcome, with 19 deaths (0. 17%), 117 patients with surgical site bleeding (1.04%), 12 patients with allergic reactions (0.12%), 10 patients with acute renal failure (0.09%), and four patients with gastrointestinal bleeding (0.04%). There were no differences between ketorolac and ketoprofen or diclofenac. Postoperative anticoagulants increased the risk of surgical site bleeding equally with ketorolac (odds ratio=2.65, 95% CI=1.51-4.67) and the comparators (odds ratio=3.58, 95% CI=1.93-6.70). Other risk factors for serious adverse outcomes were age, ASA score, and some types of surgery (plastic/ear, nose and throat, gynaecology, and urology)., Conclusion: We conclude that ketorolac is as safe as ketoprofen and diclofenac for the treatment of pain after major surgery.

Numerous studies report the relationship between aspirin and other nonsteroidal anti-inflammatories (NSAIDs) and cancer incidence, in particular for colorectal cancer. This paper systematically reviews the evidence of the effect of aspirin and other NSAIDs on the primary prevention of colorectal and other gastrointestinal cancers in the general population. In 25 investigations of NSAIDs and colorectal cancer, 23 observational studies reported a relative risk reduction but estimates vary widely. Cohort studies generally indicate lesser reductions than case-control studies suggesting possible biases in the latter. Clear evidence of a dose relationship generally appears lacking but data do not indicate useful effects of aspirin in cardioprophylactic doses. Differences have otherwise not been detected between aspirin and other NSAIDs, nor between non-aspirin NSAIDs. There is some evidence that the risk of colorectal cancer reduces with increased duration of NSAID use. The lower incidence of oesophageal and gastric cancers results in smaller numbers of cases in the studies reporting these cancers, particularly in the cohort studies. The trend is for a risk reduction for oesophageal and gastric cancers in people taking NSAIDs, which is more likely to be statistically significant in the case-control studies. A very small number of observational studies have reported the relationship between NSAIDs and the incidence of pancreatic, gallbladder and liver cancers. These show no consistent relationship. In view of the inadequate information about optimal dose and duration of NSAIDs for colorectal cancer reduction, and the adverse effects of NSAIDs, we are not yet in a position to recommend NSAIDs for the primary prevention of colorectal cancer in the general population.

Despite intensive medical treatment with steroids and immunosuppressants, acute colitis is still associated with a colectomy rate of up to 15%. Following the observation that a patient with severe steroid-resistant colitis went into remission when treated with heparin for a deep vein thrombosis, there have been a number of reports on the use of heparin in acute ulcerative colitis. Although small and uncontrolled, these studies consistently demonstrate the beneficial effects of heparin, with surprisingly few side-effects in a disease characterized by mucosal haemorrhage. The mechanisms by which heparin may ameliorate ulcerative colitis remain unclear. A simple anticoagulant effect may be responsible, but similar effects are not seen with warfarin. As a result of their intense negative charge, the glycosaminoglycans that constitute heparin have diverse biological effects. These include potent anti-inflammatory actions, in vitro and in vivo, and the potentiation of the activity of the peptide growth factors necessary for mucosal regeneration and repair. This review summarizes the clinical reports on heparin treatment for ulcerative colitis and explores the mechanisms by which this novel form of treatment may exert its effects.

Information on the intake of non-steroidal anti-inflammatory drugs (NSAIDs) and on aspirin taken regularly by patients with peptic ulcer bleeding aged 60 years and over was used in conjunction with data measuring the overall frequency of hospital admissions with ulcer bleeding in England and Wales to determine the annual burden of disease imposed by particular treatment strategies. Over 40% of the calculated 8528 episodes of ulcer bleeding in those aged 60 years and over, and over 40% of the estimated 981 deaths each year would seem to be causally related to the treatments. Substitution of the NSAID with the lowest associated risk would be expected to reduce the frequency of non-aspirin NSAID-associated episodes of ulcer bleeding, and deaths, each by over 70%. Use of the lowest conventional dose of regular prophylactic aspirin (75 mg) would also be expected to reduce the frequency of treatment-related episodes, and deaths, by nearly 30%. Both strategies employed together would be expected to reduce NSAID and regular aspirin-related bleeding ulcer admissions from 4121 to less than 2184, and deaths from 523 to less than 250. Substitution of completely safe anti-inflammatory analgesics and anti-platelet drugs would be expected to reduce admissions from 4121 to 1072, and deaths from 523 to 123.

Objective: To examine whether anti-inflammatory drug treatment protects against the commoner cancers in the United Kingdom., Design: Case-control study using the general practice research database., Setting: Practices throughout United Kingdom providing data to the database., Subjects: Patients who had a first diagnosis of five gastrointestinal (oesophagus, stomach, colon, rectum, and pancreas) cancers and four non-gastrointestinal (bladder, breast, lung, and prostate) cancers in 1993-5 for whom prescription data were available for the at least the previous 36 months. Each case was matched for age, sex, and general practice with three controls., Main Outcome Measure: Risk of cancer., Results: In 12 174 cancer cases and 34 934 controls overall risk of the nine cancers was not significantly reduced among those who had received at least seven prescriptions in the 13-36 months before cancer diagnosis (odds ratio 0.98, 95% confidence interval 0.89 to 1.07). Findings were nevertheless compatible with protective effects from anti-inflammatory drugs against cancers of the oesophagus (0.64, 0. 41 to 0.98), stomach (0.51, 0.33 to 0.79), colon (0.76, 0.58 to 1. 00), and rectum (0.75, 0.49 to 1.14) with dose related trends. The risk of pancreatic cancer (1.49, 1.02 to 2.18) and prostatic cancer (1.33, 1.07 to1.64) was increased among patients who had received at least seven prescriptions, but the trend was dose related for only pancreatic cancer., Conclusions: Anti-inflammatory drugs may protect against oesophageal and gastric cancer as well as colon and rectal cancer. The increased risks of pancreatic and prostatic cancer could be due to chance or to undetected biases and warrant further investigation.

Despite many clinical investigations, proof is lacking that pharmacological treatments significantly influence the outcome in non-variceal upper gastrointestinal bleeding. Reaching conclusions has been hindered by the small size of many studies in a situation in which a large number of patients must be included if confident conclusions are to be reached. In addition, many studies, by comparing two potentially active treatments without a placebo group, have been unable to determine whether an equivalence of the active treatments represents equivalent but active or equivalent but inactive therapy., (Copyright 2000 Harcourt Publishers Ltd.)

Aims: To determine risk factors for peptic ulcer bleeding other than non-steroidal anti-inflammatory drugs (NSAIDs). Methods-Data on possible antecedent risk factors obtained in a large case control study of 1121 patients admitted to hospitals in Glasgow, Newcastle, Nottingham, Oxford, and Portsmouth with bleeding peptic ulcers were compared with the same information obtained in 989 population controls. Data were analysed by logistic regression with the calculation of odds ratios (OR) and 95% confidence intervals (CI)., Results: From a logistic regression model, oral anticoagulants (OR 7. 8; 95% CI 2.8-21.5), previous peptic ulcer (3.8; 2.6-4.9), treatment for heart failure (5.9; 2.3-13.1), oral corticosteroid use (2.7; 1. 3-4.5), treatment for diabetes (3.1; 1.2-4.3), and current smoking (1.6; 1.2-2.0) were all independent risk factors. No association was found with use of calcium channel antagonists. Odds ratios for concomitant NSAID usage were multiplicative with the exception of current smoking., Conclusions: Some 45% of admissions for peptic ulcer bleeding in England and Wales in those aged 60 or more are calculated to be attributable to, or associated with, these accessory risk factors, which, together with those associated with aspirin or other NSAID use will account for over 80% of predisposing factors to ulcer bleeding.

Cimetidine is thought to inhibit suppressor T-lymphocyte function and preliminary evidence from a randomized trial indicated that it might prolong survival for patients with operable and inoperable gastric cancer. The British Stomach Cancer Group conducted a randomized, double-blind, placebo-controlled trial examining the effects of cimetidine (400 mg or 800 mg twice a day) on the survival of patients with early (stages I, II and III: n = 229) and advanced (stages IVa and IVb: n = 201) gastric cancer. The primary end point was death. A total of 442 patients were randomized by 59 consultants in 39 hospitals between February 1990 and March 1995. Log-rank survival analysis was used to assess differences between the groups. Three hundred and forty patients died during the study: 166 (49%) in the cimetidine treatment groups and 174 (51%) in the placebo groups. Median survival for patients receiving cimetidine was 13 months (95% confidence interval (CI) 9-16 months) and 11 months in the placebo arm (95% CI 9-14 months). There was no significant difference in survival between the two treatment groups (P = 0.42) or between different doses of cimetidine tablets (P = 0.46). Five-year survival of those patients randomized to cimetidine was 21% compared to 18% for those patients randomized to placebo. Cimetidine at a dose of 400 mg or 800 mg twice a day does not have a significant influence on the survival of patients with gastric cancer compared to placebo.

Context: Nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) toxic effects, such as upper GI tract perforations, symptomatic gastroduodenal ulcers, and upper GI tract bleeding (PUBs), are thought to be attributable to cyclooxygenase 1 (COX-1) inhibition. Rofecoxib specifically inhibits COX-2 and has demonstrated a low potential for causing upper GI injury., Objective: To compare the incidence of PUBs in patients with osteoarthritis treated with rofecoxib vs NSAIDs., Design: Prespecified analysis of all 8 double-blind, randomized phase 2b/3 rofecoxib osteoarthritis trials conducted from December 1996 through March 1998, including one 6-week dose-ranging study, two 6-week efficacy studies vs ibuprofen and placebo, two 1-year efficacy studies vs diclofenac, two 6-month endoscopy studies vs ibuprofen and placebo, and one 6-week efficacy study vs nabumetone and placebo., Setting: Multinational sites. Participants Osteoarthritis patients (N = 5435; mean age, 63 years [range, 38-94 years]; 72.9% women)., Interventions: Rofecoxib, 12.5, 25, or 50 mg/d (n = 1209, 1603, and 545, respectively, combined) vs ibuprofen, 800 mg 3 times per day (n = 847), diclofenac, 50 mg 3 times per day (n = 590); or nabumetone, 1500 mg/d (n = 127) (combined)., Main Outcome Measure: Cumulative incidence of PUBs for rofecoxib vs NSAIDs, based on survival analysis of time to first PUB diagnosis, using PUBs that met pre-specified criteria judged by a blinded, external adjudication committee., Results: The incidence of PUBs over 12 months was significantly lower with rofecoxib vs NSAIDs (12-month cumulative incidence, 1.3% vs 1.8%; P = .046; rate per 100 patient-years, 1.33 vs 2.60; relative risk, 0.51; 95% confidence interval, 0.26-1.00). The cumulative incidence of dyspeptic GI adverse experiences was also lower with rofecoxib vs NSAIDS over 6 months (23.5% vs 25.5%; P = .02), after which the incidence rates converged., Conclusion: In a combined analysis of 8 trials of patients with osteoarthritis, treatment with rofecoxib was associated with a significantly lower incidence of PUBs than treatment with NSAIDs.

Age and sex differences in the incidence of colonic cancer, together with epidemiological data on patients taking hormone replacement therapy, suggest the involvement of estrogens. Analogous to the role of aromatase in breast cancer, we postulated that steroid metabolism within the colon itself may be a crucial mechanism in regulating tissue exposure to estrogens. We have characterized expression of aromatase (responsible for converting C19 androgens to C18 estrogens) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) [responsible for interconversion of active estradiol (E2) to less potent estrone (E1)] in normal and neoplastic human colon from 24 patients undergoing tumor resection. Aromatase activity was similar in homogenates from normal mucosa, tissue adjacent to tumors, and the tumors themselves. Analysis of 17beta-HSD activity indicated that the predominant activity was oxidative (E2 to E1), and this conversion was significantly lower in colonic tumors [444 (90-1735); median (95% confidence interval) pmol/mg protein x h], compared with normal mucosa [1709 (415-13828), P < 0.001]. Northern blot analyses indicated expression of messenger RNAs (mRNAs) for the type 2 and 4 isozymes of 17beta-HSD in normal colon; messenger RNA for 17beta-HSD 4 was significantly lower in tumor tissue [0.75 +/- 0.22 (mean +/- SD) arbitrary U vs. 0.43 +/- 0.17, P < 0.01]. Studies in vitro, using three colonic cancer cell lines, indicated that there was an inverse correlation between 17beta-HSD oxidative activity and the rate of cell proliferation. In addition, E1, but not E2, was shown to significantly decrease proliferation when added exogenously to the colonic epithelial cell line, SW620 cells. Colonic mucosa can regulate estrogen hormone action in an intracrine fashion. The loss of estrogen inactivation may be an important mechanism in the pathogenesis of colonic cancer.

Non-steroidal anti-inflammatory drug toxicity to the upper gastrointestinal tract differs consistently and strongly between the individual agents. Exact measures of the difference are not yet available because meta-analyses combining individual data sets from a sufficiently large number of subjects and incorporating dosage information are not available. The importance of obtaining such information is emphasised by simple modelling based upon expected usage patterns and disease risks. The adverse effects of the non-steroidal anti-inflammatory drugs (NSAIDs) are, in terms of general population impact, the most common and important of all adverse effects of pharmaceuticals in any group. This is because they are widely used, and the adverse effects are common. Amongst these adverse effects, gastrointestinal problems, manifested by peptic ulceration and its complications, are by far the most frequent. Approaches to prevention can be of three general types. The first is the characterisation and mitigation of the circumstances under which the effects occur, the second the use of preventative treatments, and the third the introduction of selective agents by which therapeutic properties are retained and adverse effects minimised. This commentary concentrates on characterising the extent of risks. However, a good understanding will not be achieved without knowledge of the general epidemiology of peptic ulceration.