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Biomedical subjects

C J Hawkey

Publications and source records attributed to C J Hawkey.

At least 217 records · Page 12Linked to original sources
PubMed1989

Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine.

1. We evaluated injury to the human gastric mucosa caused by low doses of aspirin and its prophylaxis by ranitidine. On two separate occasions, 30 subjects took aspirin 300 mg daily for 12 days either with or without ranitidine 150 mg, 30 min before aspirin. This dose of aspirin caused more than a 5 fold increase in gastric bleeding, from control values of 0.5 microliters 10 min-1 (95% confidence limits 0.3-0.8 microliters 10 min-1) to 2.8 microliters 10 min-1 (1.9-4.1 microliters 10 min-1, P less than 0.01) after 5 days of aspirin. Adaptation did not occur and the gastric bleeding rates remained elevated at 3.4 microliters 10 min-1 (1.9-6.1 microliters 10 min-1) after 12 days of aspirin consumption (P less than 0.01). 2. Coadministration of ranitidine significantly raised intragastric pH and reduced aspirin induced bleeding to 1.5 microliters 10 min-1 (1.0-2.3 microliters 10 min-1) after 5 days and 1.6 (1.0-2.5 microliters 10 min-1) after 12 days (P less than 0.05). 3. Although these values were higher than control levels our results raise the possibility that coadministration of ranitidine may reduce the incidence of peptic ulceration and gastrointestinal haemorrhage which is increasingly reported in some subjects taking low dose aspirin for vascular prophylaxis.

Adult↗
PubMed1989

Effect of information leaflets on knowledge in patients with gastrointestinal diseases.

Twelve patient information leaflets concerning common gastrointestinal diseases were produced by the British Digestive Foundation and evaluated to determine whether patients knew more about their disease if they received a leaflet. Eleven hundred and fifty patients attending gastroenterology clinics in the United Kingdom were assessed by postal questionnaire of whom half had received a leaflet relevant to their diagnosis six weeks before assessment. Seven hundred and fifty one replied (398 leafleted, 353 non-leafleted). Most patients found the leaflets helpful and easy to understand; few found them worrying. They were regarded as a better source of information than doctors, particularly for information about the characteristics of the illness and side effects of treatment. In all diagnostic groups assessed the patients' knowledge of their disease was significantly greater if they had received a leaflet than if they had not. Individual responses by patients without leaflets showed that fundamental misconceptions persisted about digestive diseases. The British Digestive Foundation leaflets are an effective means of imparting disease related information to patients.

Female↗
PubMed1989

Aspirin and gastroduodenal injury.

Aspirin almost invariably causes acute mucosal injury to the stomach or duodenum as evidenced by erosions seen endoscopically, extensive surface cell disruption on histology, reduced mucosal potential difference and increased gastric bleeding. This injury is usually minor and transient, and not associated with symptoms. However, in the elderly recent aspirin intake may be associated with bleeding peptic ulcer, and along with other NSAIDs, may be causal in a third of cases. Regular chronic aspirin intake may also be associated with gastric ulceration. Such ulceration, however, although seemingly capable of healing despite continued aspirin or other NSAID use, may take longer to do so. Although aspirin and other NSAIDs have a strong connection with gastroduodenal problems the risk in an individual needs to be balanced by the likelihood of such events. Given their widespread use, the serious side effects of these drugs occur in only a small proportion of users. This, however, does not mitigate against careful prescription.

Aspirin↗
PubMed1989

Treatment of reflux oesophagitis with trimoprostil.

Forty-four patients with symptomatic endoscopically proven mild to moderate reflux oesophagitis were enrolled in a single-centre, double-blind, clinical trial comparing trimoprostil 750 micrograms taken 4 times daily with placebo. Patients treated with trimoprostil but not placebo experienced a significant reduction in the frequency (p less than 0.005) and duration (p less than 0.02) of heartburn. Both groups reported a reduction in the severity of heartburn and resulting sleep disturbance during the trial, but differences between them in these respects at the end of the trial did not reach statistical significance. There was a significant reduction in the severity of oesophagitis seen at endoscopy after treatment with trimoprostil (p less than 0.01) but not placebo. Trimoprostil was well tolerated and appears to be more effective than placebo in the treatment of mild to moderate symptomatic reflux oesophagitis. Although this agent's mode of action was not investigated, we speculate that it may be protective to human squamous oesophageal mucosa.

Adult↗
PubMed1989

Immunosuppressive drugs in inflammatory bowel disease. A review of their mechanisms of efficacy and place in therapy.

Immune effector mechanisms are central to the disease process in inflammatory bowel disease, but it is not clear whether the mucosal or systemic immunological abnormalities are primary phenomena, or are secondary to disease activity. Corticosteroid drugs remain the most effective treatment for active disease, but there is no evidence that they are useful for maintenance therapy. Some patients, however, are dependent on low-dose corticosteroids, and relapse when the drug is withdrawn. These drugs have widespread actions on the immune response, and monocytes are particularly sensitive to corticosteroids. In contrast, sulphasalazine and 5-aminosalicylic acid are effective in maintenance therapy, but do not act primarily by immunosuppressive mechanisms. They are effective in maintenance therapy of ulcerative colitis, and mild relapses of ulcerative colitis and colonic Crohn's disease. New preparations of 5-aminosalicylic acid have reduced side effects, many of which are due to sulphapyridine. Azathioprine and 6-mercaptopurine are used less widely: in Crohn's disease there is reasonable evidence for benefit in chronic active disease unresponsive to corticosteroids, and maintenance of remission. In ulcerative colitis, the position is less clearcut. Overall, trials favour an effect in chronic active disease, and there are pointers to an effect in maintenance of remission. Because of their side effects, in particular marrow suppression, these drugs should be reserved for second-line therapy. Similarly, other cytotoxic drugs are not used because of their side effects. More recently, cyclosporin A, with its selective action on interleukin-2 release and/or synthesis, and inhibition of helper T cell function, has been shown to be helpful in Crohn's disease. At present it should only be used in controlled trials, for patients with unresponsive disease in whom surgery is contraindicated. Renal toxicity may limit long term use. There is little data for cyclosporin A in ulcerative colitis. On the basis that there may be an underlying immune defect in Crohn's disease leading to mucosal inflammation, immunostimulant therapy has been used, but there is no evidence for benefit from treatment with BCG or levamisole in active disease or in maintenance therapy. 7S-Immunoglobulin, plasmapheresis or T-lymphocyte apheresis have been used in acute relapse, but evidence is anecdotal, and does not support their use except as a desperate measure to avoid surgery. Further well-designed controlled trials are needed to define the role of all these drugs, and further research into the mechanism of action on the immune response may shed light on the pathogenesis of inflammatory bowel disease.

Clinical Trials as Topic↗
PubMed1989

Discrimination between normal and malignant hepatocytes in man by the monoclonal antibody RL23/36: comparison with the Ca1 and 791T/36 monoclonal antibodies.

The monoclonal antibody RL23/36 has been shown to discriminate normal from malignant hepatocytes in man. In frozen sections of liver tissue from 25 Thai patients without hepatocellular carcinomas, the antibody reacted strongly and preferentially with hepatocytes. Reactivity with 7 hepatocellular carcinomas was invariably abnormal, being totally absent in 5 and partially lost in 2. This discrimination was superior to that achieved with Ca1 and 791T/36 monoclonal antibodies. In 2 cases of hepatocellular carcinoma, binding of RL23/36 to associated apparently non-malignant hepatocytes was abnormal, being absent in one and partially lost in the other. These data show that RL23/36 detects an antigenic determinant which is lost during malignant transformation of human hepatocytes, sometimes before the development of frank malignancy.

Animals↗
PubMed1989

Prostaglandins: mucosal protection and peptic ulceration.

Endogenous and exogenous prostaglandins mobilize gastroduodenal mucosal defenses which are compromised by inhibition of prostaglandin synthesis with non-steroidal anti-inflammatory drugs (NSAIDS). There is some evidence, conversely, that stimulation of endogenous prostaglandin synthesis by increasing precursor availability by dietary enrichment or by provoking its release may increase mucosal integrity. However, there are also non-prostaglandin defense mechanisms which can be elicited even when prostaglandin synthesis is profoundly depressed. Most (but not all) evidence suggests that gastric ulcer patients have deficient prostaglandin synthesis, though it is not clear whether this is a primary or secondary defect and the evidence on duodenal ulcer patients is incoherent. Prostaglandin analogues heal both gastric ulcers and duodenal ulcers, mainly as a result of acid inhibition. There is suggestive, but not conclusive, evidence that subsequent relapse may be retarded. Misoprostol has obtained a licensed indication for the prevention of NSAID-induced peptic ulcer on the basis of studies showing a reduced development of peptic ulcers and erosions over 4-8 weeks, implying that deficient endogenous prostaglandin levels can be replaced by exogenous administration.

Animals↗
PubMed1988

Evidence that adaptive cytoprotection in rats is not mediated by prostaglandins.

We investigated the proposition that adaptive cytoprotection (enhanced gastric mucosal integrity) caused by exposure to 20% ethanol in rats is mediated by endogenous prostaglandin synthesis. Experiments were performed both without and with indomethacin sufficient to inhibit ex vivo release of prostaglandin E2 by 56% +/- 9% (2.5 mg/kg) or 86% +/- 4% (10 mg/kg). Twenty percent ethanol significantly reduced both macroscopic and histologic signs of injury caused by subsequent exposure to 100% ethanol whether or not the rats were pretreated with indomethacin. Twenty percent ethanol itself caused extensive superficial disruption of the surface epithelium, so that about half of the mucosa was covered by desquamated debris, but did not stimulate prostaglandin release. We conclude that adaptive cytoprotection still occurs after doses of indomethacin sufficient to cause a profound depression of prostaglandin E2 release. The possibility that it could be due to formation of a protective covering of surface debris is worth further investigation.

Animals↗
PubMed1988

Prophylaxis of aspirin-induced gastric mucosal bleeding with ranitidine.

The ability of ranitidine to protect the human gastric mucosa against aspirin-induced damage was investigated by timed measurements of blood loss collected by gastric washing. Ranitidine (150 mg) 1 h or 5 h before 900 mg aspirin (5 doses of each) over 48 h reduced subsequent mean bleeding from 7.7 microliters/10 min to 2.6 microliters/10 min or 3.4 microliters/10 min, respectively. Both regimens were antisecretory at the time of aspirin administration, as judged by a rise in the pH of the aspirated washings. The prolonged protection against aspirin-induced bleeding achieved with twice daily dosing with ranitidine has clinical potential in the management of patients taking anti-inflammatory drugs.

Adult↗
PubMed1988

Non-steroidal anti-inflammatory drugs and the gastric mucosa: mechanisms of damage and protection.

Prostaglandins have numerous mucosal protective properties, impairment of which contribute to NSAID injury. It is not clear which is the most important injurious factor affecting patients taking NSAIDs. Is it the NSAID itself, either by topical toxicity and/or production of toxic mediators or does the patient become more sensitive to NSAIDs as a result of some other luminal component, such as acid or bile acids, food (by physical or chemical mechanisms) or accompanying alcohol? Intrinsic irritancy/toxicity probably accounts for the greater mucosal toxicity of aspirin, although it is not clear whether this is due to a direct (non-prostaglandin-dependent) effect on mucus or bicarbonate secretion, membrane integrity, interference with intermediary metabolism or the production of toxic products. Similarly, the relationship of irritancy to the symptom of dyspepsia, to which patients on aspirin are prone, is as yet not well understood. While strategies for short-term protection of experimental animals and humans are well established, protection against important, but relatively rare clinical events, is more difficult to study and much less well understood. In particular, the importance of the ability of NSAIDs to exacerbate bleeding, independent of injury, has been largely neglected in the context of presentation with haematemesis and melaena.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Effect in man of aspirin, standard indomethacin, and sustained release indomethacin preparations on gastric bleeding.

1. We have compared acute gastric bleeding caused by a new slow release preparation of indomethacin (indomethacin Continus) with that caused by aspirin and other indomethacin preparations. 2. In a randomized crossover study, blood loss into timed gastric aspirates was determined in 20 healthy volunteers after receiving, over 96 h, either placebo, aspirin (600 mg four times daily; 17 doses) indomethacin BP (50 mg three times daily; 13 doses), Indocid-R (75 mg twice daily; 9 doses) or indomethacin Continus (75 mg twice daily; 9 doses). A venous blood sample was also taken during each treatment period for subsequent determination of alpha 1-glycoprotein, and for drug assay. 3. Gastric bleeding on placebo was 1.4 (0.7-2.8) microliters 10 min-1 (mean, 95% confidence interval). Both aspirin and the indomethacin preparations caused significantly more bleeding (P less than 0.05). Rates of bleeding after aspirin, indomethacin BP, Indocid-R, and indomethacin Continus were respectively 22.0 (10.7-47.2) microliters 10 min-1, 4.4 (2.2-9.1) microliters 10 min-1, 10.8 (5.3-22.3) microliters 10 min-1, and 5.1 (3.0-10.6) microliters 10 min-1. 4. Rates of bleeding after indomethacin BP and indomethacin Continus, but not Indocid-R, were significantly less than after aspirin (P less than 0.01). 5. Salicylate or indomethacin was detectable in the plasma of all subjects after the active treatment periods, except for one instance involving a subject allocated indomethacin BP. Indomethacin levels were significantly higher 2 h after Indocid-R than with indomethacin BP or indomethacin Continus. 6. alpha 1-acid glycoprotein levels were not significantly affected by prior treatment with aspirin or indomethacin.

Adolescent↗
PubMed1988

Medical treatment of ulcerative colitis: scoring the advances.

Recently, oenological prejudices were challenged by the use of a points scoring system (from 50 to 100) to evaluate wine in a book now widely regarded as one of the most authoritative. On this scale, a 1981 Chateau Citran described as 'emaciated' scored 65, a 1983 Chateau Kirwan scored 85, and a 1982 Petrus 100. If the same approach were used for drugs used in ulcerative colitis to quantify an advance over conditions existing at the time of its introduction how would they score? Because they were the first available drugs in their class and clearly constituted major advances, corticosteroids and sulphasalazine both score 95, the score being limited by a high level of side effects. The new salicylates score 75, because they extend the benefits of sulphasalazine to a minority of patients but they have the potential to score 90 if increased dosing and greater effectiveness over sulphasalazine can be achieved. Salicylate enemas score 80, because they advance treatment over topical corticosteroids for patients with resistant distal disease, but the mode of delivery needs improvement. Steroid foams also score 80, particularly if the patient's vote is taken into account. Azathioprine's score cannot be calculated because there is doubt over its efficacy, but it is potentially 88 if it saves patients with difficult disease from colectomy. We can only guess what an oral non-absorbed steroid would score, but if response rates for relapse were substantially improved, or if corticosteroids could be used as effective maintenance treatment, it could be as high as 95. There are indications that we should 'watch this space'.

Adrenal Cortex Hormones↗
PubMed1988

Devastating diarrhoea caused by azathioprine: management difficulty in inflammatory bowel disease.

Azathioprine toxicity complicated the management of four patients with inflammatory bowel disease. All patients received the drug as adjunctive therapy to steroids when responses to the latter were poor. After a variable sensitising period the patients developed severe diarrhoea and abdominal pain and this was believed at first to be a manifestation of their underlying diseases but rechallenge with azathioprine reproduced the problem. During three episodes described emergency admission to hospital and resuscitation with intravenous fluids was required. The cases illustrate the difficulty clinicians have in recognising drug induced effects which mimic the underlying disease. When a patient suspects a reaction to azathioprine we believe any rechallenge should only be undertaken in the controlled hospital environment.

Adolescent↗
PubMed1987

Twenty-four-hour intragastric acidity and clinical trial of bedtime enprostil 70 micrograms compared with ranitidine 300 mg in duodenal ulcer.

The effects of bedtime 70 micrograms and twice daily 35 micrograms doses of enprostil on 24-hour intragastric acidity were investigated in nine duodenal ulcer patients in remission. Median nocturnal acidity decreased significantly by 30% with 35 micrograms twice daily, and by 48% with 70 micrograms at bedtime. In a clinical trial using bedtime dosing, 102 duodenal ulcer patients randomly received either ranitidine 300 mg or enprostil 70 micrograms. More ulcers healed after 4 and 8 weeks treatment with ranitidine than with enprostil (76% ranitidine vs 52% enprostil, at 4 weeks p = 0.0065 and 94% vs 68%, respectively at 8 weeks, P = 0.0007). However, 6 months after cessation of treatment there was no material difference in overall outcome. Despite combining mucosal protection with acid inhibition enprostil treatment conferred no advantage over simple acid inhibition.

Adult↗