Aliment. Pharmacol. Therap. (1990) 4, 49-54.
Dosage of colloidal bismuth subcifrate in duodenal ulcer healing and clearance of Campylobacter pylori
J. C O G H L A N , L. H U T C H I N S O N , D. GILLIGAN, D. McKENNA, C. KEANE, E. SWEENEY & C. O ’ M O R A I N Deparfmenf of Gasfroenferology, Meafh and Adelaide Hospifals, Dublin 8, and Deparfmenfs of Microbiology and Pathology, Sf James’ Hospital, James’ Sfreet, Dublin 2, Republic of Ireland Accepted for publication 12 September 1989
SUMMARY
Sixty consecutive patients with endoscopically proven duodenal ulcers were given colloidal bismuth subcitrate tablets either as 120 mg q.d.s. or 240 mg b.d., in a randomized single-blind study. The efficacy of each regimen was determined by endoscopic examination and antral biopsy at 4 weeks; if the ulcer remained unhealed, treatment was continued and endoscopy repeated at 8 weeks. The ulcer-healing efficacy of the two regimens was identical; however, in the four times daily group only 27% remained Campylobacfer pylovi positive after 8 weeks of treatment compared with 58 % of the twice-daily group. Similarly, only 21 % of twice daily patients were free of histological gastritis compared with 42 % of the four times daily patients, INTRODUCTION Colloidal bismuth subcitrate has been established as an effectiveanti-ulcer treatment of similar therapeutic efficacy to H,-antagonists in several well-designed double~~
~
~~
Correspondence to: Dr J. G. Coghlan, Harefield Hospital, Middlesex UB9 6JY, UK. 49 4- 2
50
J. C O G H L A N et al.
bind trials. The results of these trials have recently been summarized by Wagstaff et al.' More importantly perhaps, patients treated acutely with colloidal bismuth subcitrate are less likely than those treated with H,-antagonists to suffer ulcer relapse in the year after treatment.'" While many theories have been put forward to explain this difference, including the suggestion that H,-antagonists induce early relapse, most theories do not withstand more than superficial scrutiny.' The bactericidal effect of colloidal bismuth subcitrate on C. pylori is well established, and several long-term follow-up studies suggest that eradication of C. pylori is the key to prevention of ulcer relapse.2~6~1G1z Two double-blind studies have also demonstrated that colloidal bismuth subcitrate administered twice daily is as effective as a four times daily dosage in respect of ulcer healing.'3~14 It cannot, however, be inferred from these results that twice daily dosage will be as effective in eradicating C. pylori, or will cause a similar reduction in ulcer relapse rate. This single-blind randomized study was therefore undertaken to assess not only the ulcer-healing efficacy of these regimens but also specifically to evaluate their respective efficacy in the eradication of C. pylori. STUDY P O P U L A T I O N A N D M E T H O D Sixty consecutive patients referred from the Gastroenterology Out-patients Departments of the Meath and Adelaide Hospitals, and subsequently found to have duodenal ulceration at endoscopy, were entered to the study. Written consent was obtained from all patients prior to admission to the study and the study was approved by the Federated Dublin Voluntary Hospitals ethics committee. O n entry to the study each patient was allocated to twice-daily or four-times-daily treatment by our pharmacist in accordance with a randomization order (provided by Gist Brocades). There was no significant difference between the study groups in respect of age, sex, smoking habits, and duration of ulcer history. All the patients received colloidal bismuth subcitrate (De-No1swallow) tablets either 240 mg b.d. or 120 mg q.d.s. for 4 weeks and repeat endoscopy was undertaken. Ulcer healing was deemed to have occurred only where a macroscopically normal mucosa (with/without scarring) was found. Patients in whom complete healing had not occurred were continued on the same treatment regimen for a further 4 weeks, before a final endoscopy was carried out to assess the treatment efficacy. Two antral biopsies were taken from within 2 cm of the pylorus at each endoscopy. One biopsy was placed in formalin, sectioned and stained with Warthin Starry silver stain and evaluated for the presence of C. pylori; a second section of this biopsy was stained with haematoxylin and eosin and assessed for gastritis. The second biopsy specimen was placed in Carnpylobacter transport medium and processed within 1 h: a smear of the biopsy was made for Gram staining and the remainder of the second specimen was inoculated on a blood agar medium, to be incubated for up to 5 days in a micro-aerophilic environment. Translucent colonies,
BISMUTH DOSAGE A N D C. PYLORI
51
positive for urease, were identified as being C. pylori. Demonstration of the presence of the organism by any of these three methods was accepted as evidence of infection. The endoscopist, microbiologist and pathologist were unaware of a patient’s treatment regimen and previous C.pylori status. Chi-squared analysis with Yates’ correction for continuity was used for statistical analysis. RESULTS Four patients (two from each group) did not complete the first 4 weeks of treatment because of gastrointestinal side-effects, and ,a further four (two from each group) refused to continue the trial, having failed to heal at 4 weeks. Both treatment regimens were found equally effective at each stage of treatment with respect to ulcer healing. After 4 weeks, 50% (14/28) of those who received four times daily colloidal bismuth subcitrate therapy had healed, as had 46% (13/28) of the twice-daily group. At 8 weeks of treatment the healing rates were identical; 69% (18/26) of each group were ulcer-free. Anfi-bacterial efficacy C. pylori was isolated from 90 % of the four-times-daily group at entry, in 43 % after 4 weeks and in only 27% at completion of the study. In patients whose ulcers healed, C. pylori was identified in 38%at 4 weeks and in 28% at 8 weeks. In patients randomized to twice-daily therapy, C. pylori was identified in 93 % at entry, 64% at 4 weeks and 58% at 8 weeks. Patients whose ulcers healed on twice-daily therapy tended to remain positive for C. pylori: 77% at 4 weeks and 67% at 8 weeks. Four-times-daily treatment with colloidal bismuth subcitrate was significantly more effective than twice-daily treatment in rendering patients culture-negative (Fig. I). The difference between the treatment regimens’ efficacy in suppressing C. pylori was significant at 4 weeks of treatment ( P < 0.02,) and remained significant with the same P value at 8 weeks. Hislological gastritis Evidence of histological gastritis was found in 94 % of C. pylori-positive patients at entry and 40% (2/5) of C.pylori-negative patients. In patients who were C. pyloripositive and had gastritis at entry, the gastritis score was reduced by two or more grades in 77% of those rendered culture-negative, and in 50% of those in whom C. pylori persisted ( P < 0.05). The gastric mucosa was normalized in 46 % of those in whom C. pylori was suppressed and only 19% of those who remained C. pyloripositive. Normalization of the gastric mucosa occurred in 21 % of those randomized to twice-daily therapy, and 42% of the four-times-daily group; this difference does not achieve statistical significance.
52
J. C O G H L A N et al.
I 00
° 4
F 0
Weeks of treatment
Figure 1.Effect of treatment regimen with bismuth subcitrate on C. pylori status.
DISCUSSION The main finding of this study is that twice-daily administration of colloidal bismuth subcitrate is relatively ineffective against C. pylori, despite being adequate for ulcerhealing purposes. This is entirely consistent with the findings of Skoglund & WattersI5 in dogs, and LamberP in human subjects, both of whom found that bismuth concentrations in the gastric mucus fell to below the minimum inhibitory concentration for C. pylon’ 6 h after administration. The degree of C. pylori clearance achieved by four-times-daily treatment in this study is considerably higher than is normally quoted. In more recent studies, repeat endoscopic biopsy is delayed for between 1week and 1month after discontinuing therapy with colloidal bismuth subcitrate, in an attempt to obtain an assessment of true eradication. In this study repeat endoscopy was undertaken the day after cessation of therapy as patients with healed ulcers were subsequently entered to a colloidal bismuth subcitrate maintenance study. Thus our suppression figures will include a considerable proportion of patients who would relapse to C. pylori positive if re-examined 1 month later. As any bias favours both the twice-daily and fourtimes-daily groups equally, it seems most unlikely that re-biopsy would alter the outcome of this study except in the magnitude of the reduction of culture positively in both groups. Furthermore, evidence that the difference in C. pylori suppression rates reflects a real difference between the groups comes from the differential effects of both
BISMUTH DOSAGE A N D C. PYLORI
53
regimens on the severity of histological gastritis, and more specifically the significant reduction in gastritis scores in those rendered C. pylori-negative. C. pylori eradication has been shown to be a central factor in the prevention of duodenal ulcer relapse in four long-term studies.2,6110,1Z However, eradication rates in excess of 30% have proved very difficult to achieve, thus tempting some investigators to use triple therapy (bismuth, amoxycillin and metronidazole), with potentially lethal side-effects (CI. diffcile diarrhoea) in two patients."~17Adequate bismuth therapy remains the cornerstone of anti-C. pylori therapy, particularly as it has been shown to retard the development of antibiotic resistance by C. pylori." Thus it is clearly essential, if one believes that C. pylori eradication is beneficial, that an effective regimen of colloidal bismuth subcitrate must be prescribed. This study clearly shows that four-times-daily therapy is superior to twice-daily colloidal bismuth subcitrate in the suppression of C. pylori. ACKNOWLEDGEMENT
No financial support was received for the study of Campylobactev in the gastric mucosa; however, the study of the relative ulcer-healing efficacy of each regimen was supported by Gist Brocades. REFERENCES 1 Wagstaff A J, Benfield P, Monk J P. Colloidal bismuth subcitrate: a review of its
2
3
4
5
pharmacodynamic and pharmacokinetic properties, and its therapeutic use in peptic ulcer disease. Drugs 1988; 36: 132-57. Smith A C, Price A B, Borriello P, Levi A J. A comparison of ranitidine and tripotassium dicitrato bismuthate (TDB) in relapse rates of duodenal ulcer: the role of Campylobacfer pylori (CP). Gastroenterology 1988; 431. (Abstract.) Martin D F, Hollanders D, May S J, Ravenscroft M M, Tweedle D E F, Miller J P. Difference in relapse rates of duodenal ulcer after healing with cimetidine or tripotassium dicitrato bismuthate. Lancet 1981; i: 7-10. Hamilton I, OConnor H J, Wood N C, Bradbury I, Axon A T R. Healing and recurrence of duodenal ulcer after treatment with tripotassium dicitrato bismuthate (TDB) tablets or cimetidine. Gut 1986;27: 106-10. Lee F I, Samlof I M, Hardman M. Comparison of tripotassium dicitrato bismuthate tablets with ranitidine in healing and relapse of duodenal ulcers. Lancet 1985; i: 1299-1301.
6 Coghlan J G, Gilligan D, Humphries H,
McKenna D, Dooley C, Sweeney E, Keane C, O'Morain C. Campylobacter pylori and recurrence of duodenal ulcers-12 months follow-up study. Lancet 1987; ii: 1109-11. 7 Kang J Y, Piper D W. Cimetidine and colloidal bismuth subcitrate in the treatment of chronic duodenal ulcer, comparison of initial healing and recurrence after healing. Digestion 1982; 2 3 : 73-9. 8 Schreeve D R, Klass H J, Jones P E. Comparison of cimetidine and, tripotassium dicitrato bismuthate in healing and relapse of duodenal ulcers. Digestion 1983; 38: 96-101. 9 Dobrilla G, Vallaperta P, Amplatz S. Influence of ulcer healing agents in ulcer relapse after discontinuation of acute treatment: a pooled estimate of controlled clinical trials. Gut 1988; 29: 181-7. 10 Lambert J R , Borromeo M, Korman M C , Hansky J, Eaves E R. Effect of colloidal bismuth subcitrate (De-nol) on healing and reof lapse of duodenal ulcers-role Campylobacfer pyloridis. Gastroenterology 1987; 92: 1489. (Abstract.) 11 Borody T, Cole P, Noonan A, Morgan A, Ossip-G, Masey J, Brand L. L o n i term
54
J. C O G H L A N et al.
Cumpylobucter pylori recurrence post eradication. Gastroenterology 1988; 94: 43. (Abstract.) I2 Goodwin C S, Marshall B J, Blincow E D, Wilson D H, Blackboum S, Phillips M. Prevention of notomidazole resistance in Cumpylobucter pylori by co-administration of colloidal bismuth subcitrate: clinical and in vitro studies. J Clin Pathol 1988; 41: 207-10. 13 Hollanders D. Twice daily tripotassium dicitrato bismuthate in the treatment of duodenal ulceration. Post Grad Med J 1986; 62: 19-21. 14 Lazzaroni M, Parante F, Prada A, Bianchi-
Porro G. Colloidal bismuth subcitrate coated
tablets, four times daily versus twice daily dosage in duodenal ulcer. Scand J Gastroenterol 1986; 21 (Suppl. 122): 51-3. 15 Skoglund M, Watters K. Bismuth concentration at the site of Cumpylobucter pylori colonisation. Gastroenterology 1988; 94: 430. (Abstract.) 16 Lambert J R, Way D J, King R G, Eaves E R, Hansky J. Bismuth pharmacokinetics in the human gastric mucosa. Gastroenterology 1988; 94: 248. (Abstract.) 17 Borsch G, Mai U, Opperkuch W. Oral triple therapy may effectively eradicate Cumpylobucter pylori (CP) in man: a pilot study. Gastroenterology 1988; 94: 44. (Abstract.)
Dosage of colloidal bismuth subcifrate in duodenal ulcer healing and clearance of Campylobacter pylori
J. C O G H L A N , L. H U T C H I N S O N , D. GILLIGAN, D. McKENNA, C. KEANE, E. SWEENEY & C. O ’ M O R A I N Deparfmenf of Gasfroenferology, Meafh and Adelaide Hospifals, Dublin 8, and Deparfmenfs of Microbiology and Pathology, Sf James’ Hospital, James’ Sfreet, Dublin 2, Republic of Ireland Accepted for publication 12 September 1989
SUMMARY
Sixty consecutive patients with endoscopically proven duodenal ulcers were given colloidal bismuth subcitrate tablets either as 120 mg q.d.s. or 240 mg b.d., in a randomized single-blind study. The efficacy of each regimen was determined by endoscopic examination and antral biopsy at 4 weeks; if the ulcer remained unhealed, treatment was continued and endoscopy repeated at 8 weeks. The ulcer-healing efficacy of the two regimens was identical; however, in the four times daily group only 27% remained Campylobacfer pylovi positive after 8 weeks of treatment compared with 58 % of the twice-daily group. Similarly, only 21 % of twice daily patients were free of histological gastritis compared with 42 % of the four times daily patients, INTRODUCTION Colloidal bismuth subcitrate has been established as an effectiveanti-ulcer treatment of similar therapeutic efficacy to H,-antagonists in several well-designed double~~
~
~~
Correspondence to: Dr J. G. Coghlan, Harefield Hospital, Middlesex UB9 6JY, UK. 49 4- 2
50
J. C O G H L A N et al.
bind trials. The results of these trials have recently been summarized by Wagstaff et al.' More importantly perhaps, patients treated acutely with colloidal bismuth subcitrate are less likely than those treated with H,-antagonists to suffer ulcer relapse in the year after treatment.'" While many theories have been put forward to explain this difference, including the suggestion that H,-antagonists induce early relapse, most theories do not withstand more than superficial scrutiny.' The bactericidal effect of colloidal bismuth subcitrate on C. pylori is well established, and several long-term follow-up studies suggest that eradication of C. pylori is the key to prevention of ulcer relapse.2~6~1G1z Two double-blind studies have also demonstrated that colloidal bismuth subcitrate administered twice daily is as effective as a four times daily dosage in respect of ulcer healing.'3~14 It cannot, however, be inferred from these results that twice daily dosage will be as effective in eradicating C. pylori, or will cause a similar reduction in ulcer relapse rate. This single-blind randomized study was therefore undertaken to assess not only the ulcer-healing efficacy of these regimens but also specifically to evaluate their respective efficacy in the eradication of C. pylori. STUDY P O P U L A T I O N A N D M E T H O D Sixty consecutive patients referred from the Gastroenterology Out-patients Departments of the Meath and Adelaide Hospitals, and subsequently found to have duodenal ulceration at endoscopy, were entered to the study. Written consent was obtained from all patients prior to admission to the study and the study was approved by the Federated Dublin Voluntary Hospitals ethics committee. O n entry to the study each patient was allocated to twice-daily or four-times-daily treatment by our pharmacist in accordance with a randomization order (provided by Gist Brocades). There was no significant difference between the study groups in respect of age, sex, smoking habits, and duration of ulcer history. All the patients received colloidal bismuth subcitrate (De-No1swallow) tablets either 240 mg b.d. or 120 mg q.d.s. for 4 weeks and repeat endoscopy was undertaken. Ulcer healing was deemed to have occurred only where a macroscopically normal mucosa (with/without scarring) was found. Patients in whom complete healing had not occurred were continued on the same treatment regimen for a further 4 weeks, before a final endoscopy was carried out to assess the treatment efficacy. Two antral biopsies were taken from within 2 cm of the pylorus at each endoscopy. One biopsy was placed in formalin, sectioned and stained with Warthin Starry silver stain and evaluated for the presence of C. pylori; a second section of this biopsy was stained with haematoxylin and eosin and assessed for gastritis. The second biopsy specimen was placed in Carnpylobacter transport medium and processed within 1 h: a smear of the biopsy was made for Gram staining and the remainder of the second specimen was inoculated on a blood agar medium, to be incubated for up to 5 days in a micro-aerophilic environment. Translucent colonies,
BISMUTH DOSAGE A N D C. PYLORI
51
positive for urease, were identified as being C. pylori. Demonstration of the presence of the organism by any of these three methods was accepted as evidence of infection. The endoscopist, microbiologist and pathologist were unaware of a patient’s treatment regimen and previous C.pylori status. Chi-squared analysis with Yates’ correction for continuity was used for statistical analysis. RESULTS Four patients (two from each group) did not complete the first 4 weeks of treatment because of gastrointestinal side-effects, and ,a further four (two from each group) refused to continue the trial, having failed to heal at 4 weeks. Both treatment regimens were found equally effective at each stage of treatment with respect to ulcer healing. After 4 weeks, 50% (14/28) of those who received four times daily colloidal bismuth subcitrate therapy had healed, as had 46% (13/28) of the twice-daily group. At 8 weeks of treatment the healing rates were identical; 69% (18/26) of each group were ulcer-free. Anfi-bacterial efficacy C. pylori was isolated from 90 % of the four-times-daily group at entry, in 43 % after 4 weeks and in only 27% at completion of the study. In patients whose ulcers healed, C. pylori was identified in 38%at 4 weeks and in 28% at 8 weeks. In patients randomized to twice-daily therapy, C. pylori was identified in 93 % at entry, 64% at 4 weeks and 58% at 8 weeks. Patients whose ulcers healed on twice-daily therapy tended to remain positive for C. pylori: 77% at 4 weeks and 67% at 8 weeks. Four-times-daily treatment with colloidal bismuth subcitrate was significantly more effective than twice-daily treatment in rendering patients culture-negative (Fig. I). The difference between the treatment regimens’ efficacy in suppressing C. pylori was significant at 4 weeks of treatment ( P < 0.02,) and remained significant with the same P value at 8 weeks. Hislological gastritis Evidence of histological gastritis was found in 94 % of C. pylori-positive patients at entry and 40% (2/5) of C.pylori-negative patients. In patients who were C. pyloripositive and had gastritis at entry, the gastritis score was reduced by two or more grades in 77% of those rendered culture-negative, and in 50% of those in whom C. pylori persisted ( P < 0.05). The gastric mucosa was normalized in 46 % of those in whom C. pylori was suppressed and only 19% of those who remained C. pyloripositive. Normalization of the gastric mucosa occurred in 21 % of those randomized to twice-daily therapy, and 42% of the four-times-daily group; this difference does not achieve statistical significance.
52
J. C O G H L A N et al.
I 00
° 4
F 0
Weeks of treatment
Figure 1.Effect of treatment regimen with bismuth subcitrate on C. pylori status.
DISCUSSION The main finding of this study is that twice-daily administration of colloidal bismuth subcitrate is relatively ineffective against C. pylori, despite being adequate for ulcerhealing purposes. This is entirely consistent with the findings of Skoglund & WattersI5 in dogs, and LamberP in human subjects, both of whom found that bismuth concentrations in the gastric mucus fell to below the minimum inhibitory concentration for C. pylon’ 6 h after administration. The degree of C. pylori clearance achieved by four-times-daily treatment in this study is considerably higher than is normally quoted. In more recent studies, repeat endoscopic biopsy is delayed for between 1week and 1month after discontinuing therapy with colloidal bismuth subcitrate, in an attempt to obtain an assessment of true eradication. In this study repeat endoscopy was undertaken the day after cessation of therapy as patients with healed ulcers were subsequently entered to a colloidal bismuth subcitrate maintenance study. Thus our suppression figures will include a considerable proportion of patients who would relapse to C. pylori positive if re-examined 1 month later. As any bias favours both the twice-daily and fourtimes-daily groups equally, it seems most unlikely that re-biopsy would alter the outcome of this study except in the magnitude of the reduction of culture positively in both groups. Furthermore, evidence that the difference in C. pylori suppression rates reflects a real difference between the groups comes from the differential effects of both
BISMUTH DOSAGE A N D C. PYLORI
53
regimens on the severity of histological gastritis, and more specifically the significant reduction in gastritis scores in those rendered C. pylori-negative. C. pylori eradication has been shown to be a central factor in the prevention of duodenal ulcer relapse in four long-term studies.2,6110,1Z However, eradication rates in excess of 30% have proved very difficult to achieve, thus tempting some investigators to use triple therapy (bismuth, amoxycillin and metronidazole), with potentially lethal side-effects (CI. diffcile diarrhoea) in two patients."~17Adequate bismuth therapy remains the cornerstone of anti-C. pylori therapy, particularly as it has been shown to retard the development of antibiotic resistance by C. pylori." Thus it is clearly essential, if one believes that C. pylori eradication is beneficial, that an effective regimen of colloidal bismuth subcitrate must be prescribed. This study clearly shows that four-times-daily therapy is superior to twice-daily colloidal bismuth subcitrate in the suppression of C. pylori. ACKNOWLEDGEMENT
No financial support was received for the study of Campylobactev in the gastric mucosa; however, the study of the relative ulcer-healing efficacy of each regimen was supported by Gist Brocades. REFERENCES 1 Wagstaff A J, Benfield P, Monk J P. Colloidal bismuth subcitrate: a review of its
2
3
4
5
pharmacodynamic and pharmacokinetic properties, and its therapeutic use in peptic ulcer disease. Drugs 1988; 36: 132-57. Smith A C, Price A B, Borriello P, Levi A J. A comparison of ranitidine and tripotassium dicitrato bismuthate (TDB) in relapse rates of duodenal ulcer: the role of Campylobacfer pylori (CP). Gastroenterology 1988; 431. (Abstract.) Martin D F, Hollanders D, May S J, Ravenscroft M M, Tweedle D E F, Miller J P. Difference in relapse rates of duodenal ulcer after healing with cimetidine or tripotassium dicitrato bismuthate. Lancet 1981; i: 7-10. Hamilton I, OConnor H J, Wood N C, Bradbury I, Axon A T R. Healing and recurrence of duodenal ulcer after treatment with tripotassium dicitrato bismuthate (TDB) tablets or cimetidine. Gut 1986;27: 106-10. Lee F I, Samlof I M, Hardman M. Comparison of tripotassium dicitrato bismuthate tablets with ranitidine in healing and relapse of duodenal ulcers. Lancet 1985; i: 1299-1301.
6 Coghlan J G, Gilligan D, Humphries H,
McKenna D, Dooley C, Sweeney E, Keane C, O'Morain C. Campylobacter pylori and recurrence of duodenal ulcers-12 months follow-up study. Lancet 1987; ii: 1109-11. 7 Kang J Y, Piper D W. Cimetidine and colloidal bismuth subcitrate in the treatment of chronic duodenal ulcer, comparison of initial healing and recurrence after healing. Digestion 1982; 2 3 : 73-9. 8 Schreeve D R, Klass H J, Jones P E. Comparison of cimetidine and, tripotassium dicitrato bismuthate in healing and relapse of duodenal ulcers. Digestion 1983; 38: 96-101. 9 Dobrilla G, Vallaperta P, Amplatz S. Influence of ulcer healing agents in ulcer relapse after discontinuation of acute treatment: a pooled estimate of controlled clinical trials. Gut 1988; 29: 181-7. 10 Lambert J R , Borromeo M, Korman M C , Hansky J, Eaves E R. Effect of colloidal bismuth subcitrate (De-nol) on healing and reof lapse of duodenal ulcers-role Campylobacfer pyloridis. Gastroenterology 1987; 92: 1489. (Abstract.) 11 Borody T, Cole P, Noonan A, Morgan A, Ossip-G, Masey J, Brand L. L o n i term
54
J. C O G H L A N et al.
Cumpylobucter pylori recurrence post eradication. Gastroenterology 1988; 94: 43. (Abstract.) I2 Goodwin C S, Marshall B J, Blincow E D, Wilson D H, Blackboum S, Phillips M. Prevention of notomidazole resistance in Cumpylobucter pylori by co-administration of colloidal bismuth subcitrate: clinical and in vitro studies. J Clin Pathol 1988; 41: 207-10. 13 Hollanders D. Twice daily tripotassium dicitrato bismuthate in the treatment of duodenal ulceration. Post Grad Med J 1986; 62: 19-21. 14 Lazzaroni M, Parante F, Prada A, Bianchi-
Porro G. Colloidal bismuth subcitrate coated
tablets, four times daily versus twice daily dosage in duodenal ulcer. Scand J Gastroenterol 1986; 21 (Suppl. 122): 51-3. 15 Skoglund M, Watters K. Bismuth concentration at the site of Cumpylobucter pylori colonisation. Gastroenterology 1988; 94: 430. (Abstract.) 16 Lambert J R, Way D J, King R G, Eaves E R, Hansky J. Bismuth pharmacokinetics in the human gastric mucosa. Gastroenterology 1988; 94: 248. (Abstract.) 17 Borsch G, Mai U, Opperkuch W. Oral triple therapy may effectively eradicate Cumpylobucter pylori (CP) in man: a pilot study. Gastroenterology 1988; 94: 44. (Abstract.)
