Duodenal ulcer healing drugs

infection. In the second experiment, a significant result was achieved by administration of either H felis or, more importantly, H pylori sonicate plus cholera toxin. The successfully treated mice in these experiments appeared well and suffered no obvious side-effects. Gastritis is minimal in SPF BALB/c mice and no significant differences between the groups were observed. Our results show that it is possible to eradicate active helicobacter infection of the gastric mucosa by administration or an oral vaccine. This raises the intriguing possibility that therapeutic immunisation might be a viable option in managing helicobacter-associated disease. If immunisation as a therapy for peptic ulcers were combined with short-term acid suppression, ulcers would heal, the possibility of reinfection would be eliminated, and so there would be no relapse.

Christopher Doidge, Ian Gust, Adrian Lee, Fiona Buck, Stuart Hazell, Upender Manne CSL Ltd, Parkville, Melbourne; and School of Microbiology and Immunology, of New South Wales, Sydney, New South Wales, 2052, Australia

University

1 Tytgat GNJ, Lee A, Graham DY, Dixon MF, Rokkas T. The role of infectious agents in peptic ulcer disease. Gastroenterol Int 1993; 6: 76-89. 2

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Glupczynski Y, Langenberg W, Dankert J, et al. Results of a multicentre European survey in 1991 of metronidazole resistance in Helicobacter pylori: European study group on antibiotic susceptibility of Helicobacter pylori. Eur J Clin Microbiol Infect Dis 1992; 11: 777-81. Chen M, Lee A, Hazell SL. Immunisation against gastric helicobacter infection in a mouse/Helicobacter felis model. Lancet 1992; i: 1120-21. Chen MH, Lee A, Hazell S, Hu PJ, Li YY. Immunisation against gastric infection with Helicobacter species: first step in the prophylaxis of gastric cancer? Int J Med Microbiol 1993; 280: 155-65. Czinn SJ, Cai A, Nedrud JG. Protection of germ-free mice from infection by Helicobacter felis after active oral or passive IgA immunization. Vaccine 1993; 11: 637-42.

Duodenal ulcer

healing drugs

SiR-Hosking and colleagues (Feb 26, p 508) achieved a 92% duodenal ulcer (DU) healing rate with a one-week course of Helicobacter pylori eradication therapy consisting of bismuth, tetracycline, and metronidazole. We disagree with their conclusion that healing was achieved without the use of anti-acid treatment: the administration of H pylori eradication therapy to patients with DU does constitute anti-acid therapy. DU patients with H pylori infection have a six-fold exaggerated gastric acid secretory response to stimulation with gastrin-releasing peptide (GRP) compared with H pylori negative healthy controls, and a two-fold exaggerated response compared with H pylori positive healthy volunteers.1 GRP stimulates the release of gastrin, which in turn stimulates acid secretion. The neuropeptide also stimulates the release of intestinal inhibitory hormones that suppress both gastrin release and the acid response to gastrin via local release of somatostatin.2 The exaggerated acid response to GRP in the DU patients is largely due to failure of this inhibitory control pathway,3 and this is likely to be a key factor in the pathogenesis of the ulcer disease. Studies in our unit show that the exaggerated acid response in DU is caused by H pylori and that eradicating the infection restores gastric secretory control to normal. A 3-week course of bismuth, metronidazole, and amoxycillin lowered GRPstimulated acid secretion by 66% at one month posteradication and by 84% at one year.1.4 The exaggerated gastric secretory response caused by Hpylori infection is likely to be an important mechanism by which the infection causes DU disease and the beneficial effects of eradication therapy can be explained by the correction of this disturbance in acidsecretory control.

Values are medians and ranges. *p < 0 005 versus pre-treatment. Table: Acid secretion In response to GRP (40 pmol/kg per h) In healthy volunteers with and without H pylori and DU patients before and after treatment with triple therapy or sucralfate

DU healing drugs are usually categorised as acid inhibitory drugs or as drugs that do not inhibit acid but act by "mucosal protection". The two major mucosa protecting agents are the bismuth drug De-nol and sucralfate. De-nol suppresses H pylori and, as described above, reduces the exaggerated acid secretory response caused by the infection in DU patients. Sucralfate also reduces the density of Hpylori colonisation, and this is accompanied by a 45% fall in GRP-stimulated acid secretion (table).5 It seems that all the major drugs effective in healing DU inhibit the exaggerated acid secretory response characteristic of DU disease, either directly (H2-receptor antagonists, protonpump inhibitors) or indirectly by suppressing or eradicating H pylori infection. K E L McColl, E El-Omar, S

Banerjee

Department of Medicine and Therapeutics, University of Glasgow, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, UK

1

2

3

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El-Omar E, Penman I, Dorrian CA, Ardill JES, McColl KEL. Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer. Gut 1993; 34: 1060-65. Ghatei MA, Jung RT, Stevenson JC, et al. Bombesin: action on gut hormones and calcium in man. J Clin Endocrinol Metab 1981; 54: 980-85. El-Omar E, Banerjee S, Penman ID, Ardill JES, McColl KEL. H pylori impairs the inhibitory control of acid secretion in duodenal ulcer patients. Gastroenterology (in press). El-Omar E, Penman I, Ardill JES, McColl KEL. The exaggerated acid response to GRP in DU patients completely resolves following eradication of H pylori. Gut 1993; 34 (suppl 4): S49. Banerjee S, El-Omar E, Mowat A, et al. Sucralfate suppresses H pylori infection and reduces gastric acid secretion by 50% in DU patients.

Gastroenterology (in press).

SiR-Hosking and colleagues found that one week of triple therapy achieved DU healing and Helicobacter pylori eradication rates as high as those seen with the same three drugs plus omeprazole. They conclude that the only advantage of omeprazole lies in the more rapid relief of pain and that this antisecretory compound is not necessary for ulcer healing. This group does not provide information about an important clinical feature (first attack or relapse) so we assume that these were ordinary, not aggressive, ulcers. On average more than 40% of DUs heal with placebo,! and the patients on triple therapy in Hosking’s study were given antacids, which might have further favoured healing. Moreover, to be sure of eradication biopsy specimens should have been taken not only from the antrum but also from more proximal areas of the stomach, or breath testing should have been done.2 It would be interesting to know the numbers of patients with ulcer relapse or H pylori recrudescence after the first 6 months of therapy in both groups.

Efforts in H pylori eradication are aimed at reducing the daily number of tablets, improving compliance, reducing costs, and lessening the risk of side-effects. The combination of omeprazole plus amoxycillin has been proposed as an

915

alternative to triple therapy. Hosking et al note that eradication seems to be proportional to the dose of omeprazole, and the highest rates have been observed with daily doses of 80 mg.4 The mechanism of the omeprazole/amoxycillin interaction is not clear, but the achievement of high pH levels for most of the circadian cycle may decrease the minimum inhibitory concentration for amoxycillin or other antibiotics against H pylori.s This hypothesis has led to the progressive increase in omeprazole dosage in an attempt to reach gastric pH values as close as possible to neutrality. Using 24 hour pH recordings in a crossover controlled investigation of 12 DU patients in clinical remission we demonstrated that omeprazole 20 mg and 40 mg twice daily was highly effective in raising gastric pH with respect to placebo, but there was no significant difference between the two doses (mean pH 54 and 57, respectively vs 1 -4). This means that the reported efficacy of omeprazole 40 mg twice daily plus amoxycillin in eradicating H pylori depends not on the attainment of pH levels higher than those with half that dose, but on other factors not yet fully elucidated. These factors seem to affect the omeprazole/amoxycillin interaction to the point where this simple combination ensures H pylori eradication in DU disease with better compliance and fewer side-effects than triple therapy. If so, the relevance of omeprazole cannot be reduced to the quicker relief of pain. Vincenzo Savarino, Sergio Vigneri, Giuseppe Sandro Mela, Rosanna Termini, Guido Celle Department of Gastroenterology, University of Genoa, 16132 Genoa, Italy; and Institute of Internal Medicine and

1

2

3

Geriatrics, University of Palermo

Jones DB, Howard OM, Burget DW, Kerr GD, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987; 28: 1120-27. Logan RPH, Baron JH, Misiewicz JJ. Eradicating Helicobacter pylori in patients with duodenal ulcer. BMJ 1992; 305: 1094. Labenz J, Gyenes E, Rühl GH, Börsch G. Amoxicillin plus omeprazole versus triple therapy for eradication of Helicobacter pylori in duodenal ulcer disease: a prospective, randomized, and controlled study. Gut 1993; 34: 1167-70.

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Bayerdörffer E, Marines GA, Sommer A, et al. High dose omeprazole treatment combined with amoxicillin eradicates Helicobacter pylori. Eur J Gastroenterol Hepatol 1992; 4: 697-702. Goodwin CS, McNulty CAM. Bacteriological and pharmacological basis for the treatment of Helicobacter pylori infection. In: Rathbone BJ, Heatley RV, eds. Helicobacter pylori and gastroduodenal disease. London: Blackwell Scientific, 1992: 224-31.

SiR-Omeprazole monotherapy clears, but does not eradicate, Helicobacter pylori from the gastric antrum. This invalidates any diagnostic test for eradication where there has been recent omeprazole therapy. Eradication should be claimed only at least four weeks after cessation of omeprazole treatment.’ Hosking and colleagues state that omeprazole was given for 4 weeks to one group and that all patients had endosopy after 5 weeks. This would imply that omeprazole had been stopped for only a week, thus invalidating any conclusions about eradication in this arm of the study. The effect of omeprazole dosage on eradication rates with omeprazole/amoxycillin combination remains unclear. The studies cited were of different sizes and involved differing doses of amoxycillin. Comparative trials have been published in abstract--one showing an effect,2 the other not. Acid output probably varies between patients infected with H pylori,, depending on the duration of infection. If omeprazole augments amoxycillin treatment by raising gastric pH, it is likely that different patients will require different doses to achieve this. Increasing pH has been shown to reduce the in vitro minimum inhibitory concentrations of ampicillin and penicillin, but not amoxycillin, though it seems reasonable to 916

extrapolate this effect to that agent. However, those experiments were done with planktonic H pylori. Experiments with sessile organisms (attached to HEp-2 cells), probably more akin to the in vivo situation, have shown no such effect of pH.4 Hosking’s study confirms that H pylori eradication is important in the treatment of duodenal ulcers associated with this organism. How this is best achieved, though, remains a tantalising question. A F Goddard Division of Therapeutics and Gastroenterology, Nottingham NG7 2UH, UK

University Hospital,

GD, Powell KU. Eradication of Helicobacter pylori and its effect in

1

Bell

2

peptic ulcer disease. Scand J Gastroenterol 1993; 28 (suppl 196): 7-11. Mannes GA, Bayerdorffer E, Hele C, Ruckdeschel G, Stolte M. An increasing dose of omeprazole combined with amoxicillin increases the eradication rate of Helicobacter pylori. Gastroenterology 1993; 104:

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A140. Labenz J, Ruhl GH, Bertrams J, Borsch G. Efficiency of three amoxicillin/omeprazole schedules for eradication of HP in DU disease. Acta Gastro-Enterol Bel 1993; 56: 138 (abstr). Megraud F, Trimoulet P, Lamouliatte H, Boyanova L. Bactericidal effect of amoxycillin on Helicobacter pylori in an in vitro model using epithelial cells. Antimicrob Agents Chemother 1991; 35: 869-72.

Treatment of erythropoletin resistance with

cyclosporin SIR—The therapeutic response in patients with chronic renal failure (CRF) to erythropoietin (EPO) is dose dependent but, for various poorly understood reasons, variable. Factors recognised to reduce the effectiveness of EPO in these patients include chronic inflammation, high serum aluminium, haematinic deficiency, hyperparathyroidism with marrow fibrosis, and occult bleeding. The reasons for the variation in response and the biochemical basis for the inhibition of the action of EPO in many of these states are unknown. We report the use of cyclosporin in the treatment of a patient with CRF and erythroid hypoplasia resistant to EPO. A 25-year-old man reached end-stage renal failure at the age of 17 as a consequence of a neuropathic bladder. He received a cadaveric transplant when aged 18 but returned to haemodialysis at age 23 when the graft failed as a further consequence of his neuropathic bladder despite the use of intermittent catheterisation and a caecocytoplasty. A biopsy specimen of the graft was not taken. The graft was left in situ and all immunosuppressive therapy withdrawn. Shortly after that he was started on EPO for symptomatic anaemia but his haemoglobin (Hb) remained low (60 g/L). Despite progressively increasing doses of EPO he became transfusion dependent (see figure). Extensive investigation failed to identify any of the accepted causes of failure to respond to EPO. As part of his investigations a bone marrow biopsy specimen was taken that showed active myeloid maturation but reduced erythroid activity. Iron stains were normal and there was no evidence of megaloblastic change or infiltration. The impression was of EPO-resistant erythroid hypoplasia; at this time the patient was receiving 18 000 units of EPO

weekly. We hypothesised that chronic rejection and/or inflammation in the retained graft was contributing to his poor response to EPO and began immunosuppressive treatment with cyclosporin. Serum concentrations (detected by radioimmunoassay) were maintained between 100-200 ng/mL. He rapidly became transfusion independent and his EPO requirements fell to 4000 units weekly while his Hb rose to above 100 g/L (figure). The patient’s C-reactive protein was