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Zinc compound is a novel, highly effective triple therapy for eradication of Helicobacter pylori
April 1995
•
Esophageal, Gastric, and Duodenal Disorders
CANENDOSCOPICAPPEAR/%NCE OF HELICOBRCTER PYLORI?
OF T~m-STOMACHPREDICTTHEPRESE~CE
H a j i m e K u w a y a m a , Noriko Nakajima, and Y a s u y u k i Arakawa. Department of Medicine, Nihon University School of Medicine, Tokyo, Japan. INTRODUCTION~ A new classification system for gastritis, The Sydney System, recognizes 2 distinct approaches to classifying gastritis: endoscopic and histologic gastritis. It is now widely accepted that Helicobacter pylori (H. pylori) i s a causal pathogen in most cases of chronic gastritis. It is unclear whether endoscopic appearance can reliably predict histologic gastritis. Nevertheless, physicians often make their initial diagnosis of gastritis using endoscopic findings. We t h e r e f o r e s o u g h t to determine the relationship between endoscopic appearance of gastritis and diagnosis of H. pylori-associated gastritis. One hundred and forty-five consecutive patients undergoing endoscopy for symptoms of dyspepsia were enrolled in this s t u d y . The endoscopic appearance was recorded by the endoscopiet after the exam. H. pylori status was confirmed by culture, histology, and rapid urease test at the time of endoscopy using 6 biopsies taken from antral and gastric body mucosae. H. pylori was considered present if any one of the 3 tests was positive. Patients with a history of nonsteroidal anti-inflammatory drug use were excluded. METHODS:
RESULTS: The endoscopic "diagnoses" in the 145 patients were 57 erythematous gastritis, 22 erosive gastritis, 32 hemorrhagic gastritis, 19 atrophic gastritis, 5 hyperplastic gastritis, and i0 normal subjects. Overall, H. pylori was present i n 71 patients (49%). H. pylori was present in all endoscopic diagnoses - erythematous gastritis 40%; erosive gastritis 68%; hemorrhagic gastritis 41%; atrophic gastritis 74%; hyperplastic g a s t r i t i s 4 0 % , normal 40%. The endoscopic appearance of erosive gastritis or atrophic gastritis was associated with a significantly higher frequency of H. pylori than all other endoscopic appearances (71% vs 40%, p<0.05 by Fisher' s exact test). CONCLUSION: The endoscopic appearance of erosive gastritis or atrophic gastritis is m o r e l i k e l y t o be associated with the presence of H. pylori, but the positive and negative predictive values are only moderate.
ZINC C O M P O U N D IS A N O V E L , H I G H L Y E F F E C T I V E T R I P L E T H E R A P ¥ FOR ERADICATION OF HELICOBACTER PYLORI. Ha~ime KuwaTama. Department of Medicine, Nihon Hospital at Tachikawa, and Nihoo University School of Medicine, Tokyo, Japan. INTRODUCTION~ Helicobacter pylori (H. pylori) infection causes gastritis and predisposes to peptic ulcer disease. At present the most effective regimen in eradicating H. pylori is a s o - c a l l e d t r i p l e therapy consisting of bismuth compound, metronidazole, and either tetracycline or amoxicillin, yielding an eradication rate of about 80%. Unfortunately, neither colloidal bismuth subcitrate nor bismuth aubsalicylate is available in Japan. An alternative therapy is urgently needed. Heavy metals are known to be bacteridical, and our previous in vitro studies found a significant inhibitory effect of zinc compound on the growth as well as ureaee activity of H. pylori. Based on these observations, we conducted a double-blind placebo-controlled trial of zinc compound in eradicating S. pylori in patients with and without duodenal ulcer. METHODS: H. pylori status was confirmed by culture, histology, and rapid urease test at the time of endoscopy. A total of 64 H. pylori positive patients were enrolled in this clinical trial and randomly assigned to receive a 2 week course of triple agent therapy consisting of either Z-103 zinc compound, 75 mg, orally b.i.d. (Zeria Pharmaceutical Co., Ltd., Tokyo), metronidazole 250 mg, and amoxicillin 250 mg t.i.d., or placebo, metronidazole a n d amoxicillin. Endoscopy was repeated immediately after completion of therapy, at least 4 weeks and again a year after cessation of therapy. RESULTS: All patients tolerated treatment and completed the 2-week course. Eight patients did not return for reendoscopy. Thus, 26 patients in the zinc compound group and 30 patients and in the placebo (antibiotic only)-group were available for evaluation of H. pylorl eradication. None of 26 zinc-treated patients were positive for H. pylori Whereas 6 placebo-treated patients were positive, corresponding to a 100% eradication rate for zinc compound treatment and 76% eradication for antibiotics only in evaluable patients. CONCLUSION: Triple therapy with zinc compound in combination with low dose metronidazole and amoxicillin is well tolerated, with an N. pylori eradication rate approaching 100%. This zinc compound triple therapy may be an effective alternative to standard triple therapy. * This research was funded in part by Zeria Pharmaceutical Co., Ltd., Tokyo, Japan.
• AUGMENTATION OF THE ANTACID EFFECT OF OMEPRAZOLE BY HELICOBACTER PYLORI INFECTION IN DUODENAL ULCER DISEASE. l.Labenz, A,L.Blum, J.P.IdstrSm, E.Verdu, M.Stolte, B.Tiilenburg, l~I.SolibShmer, G.BSrsch. Dept. of Medicine, Elisabeth Hospital Essen, Germany.
CORRELATION OF 13CO2 EXCESS WITH HELICOBACTER PYLORI DENSITY, GRADE AND ACTIVITY OF GASTRITIS. ~ S.Aygen, O.Hennemann, M.Stolte, T.Becker, U.Peitz, G.B6rsch. Dept. of Medicine, Elisabeth Hospital Essen, INFAI GmbH Bochum, Germany.
We habe previously observed higher pH-values during omeprazole (OME) treatment of Helicobacter pylori (Hp)-positive subjects as compared to Hp-negative subjects. We therefore have tested the hypotheses that this effect is due to Hp infection and that it is also present in duodenal ulcer (DU) patients. Methods: In 17 patients presenting with Hp positive DU, the infection was cured by omeprazole 60 mg bid and amoxicillin 1 g bid given over two weeks. Eradication wa s assessed by urease test, culture, histology, and urea breath test. Before eradication and 4 to 6 weeks (wash out period) after cessation of the eradication therapy, a standardized (time and meals) 24-hour gastric pH measurement (Ingold glas electrode 5 cm below the eardia) was performed after one-week treatment with 20 mg omeprazole od. Results: Cure of bacterial infection resulted in a statistically significant decrease of the gastric pH obtained by OME 20 mg od. Table: Group median pH (95%-confidence intervals)
The density of Helicobacter pylori (H.pylori) determines the grade and activity of gastritis and the amount ~ urease. Therefore, it is tempting to speculate that the CO 2 excess after ingestion of labelled urea correlates with the d6nsity of H.pylori as well as with the grade and activity of gastritis. Methods: 70 patients with dyspeptic symptoms, u n k n o w n H.pylori status, and without treatment with potentially H.pylori suppressive drugs during the last four weeks were enrolled to the study. All patients were investigated clinically and endocopically with taking of 4 antrum and 4 body biopsies, which were assessed for H.pylori infection by means of an urease test (HUT test), culture and histologyt(,l-IE and Warthin&Starry st4~ns). In addition, a simplifiedXaC ~ e a breath test (75 mg xaC labelled urea, measurement of the CO2/ CO2ratio in the exhalated air before and 30 minutes after urea qntake by isotope massspectrometry) was performed. Results: 47 patients proved to be H.pylori positive as judged ~stology. In 46 patients, H.pylori infection was also detected w i t h t h e urease test, culture and urea b r a t h test (sensitivity: 97.9%). In one female patient with focal and minimal colonization of H.pylori on histology, all the other methods failed to detect bacterial colonization. In 33 patients all four methods did not indicate bacterial colon~z,0tion (specifity: 100%). The semiquantitatively catagorized ~°CO~ excess was statistically highly significantly correlated witE the histologically visible degree of H.pylori colonization (r=0.88) as well as with grade (r=0.69) and activity of gastritis (r=0.71) (p<0.0001). Conclusions: The simplified urea breath test used in this ~ l y sensitive and specific with regard to diagnosis of H.pylori infection. In addition, the lOCO~ excess allows a rough prediction of the grade and activity of gastritis.
Hp positive
Hp negative
p
Total 5.5 (3.9-5.7) 3.0 (2.4-3.9) <0.002 Daytime 5.7 (3.8-5.9) 3.1 (2.4-4.1) <0.005 Postprandial 5.2 (3.5-5.5) 4.2 (3.1-4.4) <0.03 Nighttime 6.4 (4.6-6.4) 2.1 (1.8-3.8) <0.001 Conclusions: Intragastric pH during OME treatment markedly decreases after successful Hp treatment of DU patients. Thus, omeprazole appears to lose its effectiveness after Hp treatment, and this despite of many previous reports describing decreased acid output after cure of this infection. The most likely explanation for our observation is the production of buffer substances by Hp which cease after treatment. As a consequence of our study, previous analyses relating drug induced changes of gastric acidity and ulcer healing must be performed separately for Hp positive and negative subjects. The study was supported by a grant form AB Astra H~ssle.
A139
•
Esophageal, Gastric, and Duodenal Disorders
CANENDOSCOPICAPPEAR/%NCE OF HELICOBRCTER PYLORI?
OF T~m-STOMACHPREDICTTHEPRESE~CE
H a j i m e K u w a y a m a , Noriko Nakajima, and Y a s u y u k i Arakawa. Department of Medicine, Nihon University School of Medicine, Tokyo, Japan. INTRODUCTION~ A new classification system for gastritis, The Sydney System, recognizes 2 distinct approaches to classifying gastritis: endoscopic and histologic gastritis. It is now widely accepted that Helicobacter pylori (H. pylori) i s a causal pathogen in most cases of chronic gastritis. It is unclear whether endoscopic appearance can reliably predict histologic gastritis. Nevertheless, physicians often make their initial diagnosis of gastritis using endoscopic findings. We t h e r e f o r e s o u g h t to determine the relationship between endoscopic appearance of gastritis and diagnosis of H. pylori-associated gastritis. One hundred and forty-five consecutive patients undergoing endoscopy for symptoms of dyspepsia were enrolled in this s t u d y . The endoscopic appearance was recorded by the endoscopiet after the exam. H. pylori status was confirmed by culture, histology, and rapid urease test at the time of endoscopy using 6 biopsies taken from antral and gastric body mucosae. H. pylori was considered present if any one of the 3 tests was positive. Patients with a history of nonsteroidal anti-inflammatory drug use were excluded. METHODS:
RESULTS: The endoscopic "diagnoses" in the 145 patients were 57 erythematous gastritis, 22 erosive gastritis, 32 hemorrhagic gastritis, 19 atrophic gastritis, 5 hyperplastic gastritis, and i0 normal subjects. Overall, H. pylori was present i n 71 patients (49%). H. pylori was present in all endoscopic diagnoses - erythematous gastritis 40%; erosive gastritis 68%; hemorrhagic gastritis 41%; atrophic gastritis 74%; hyperplastic g a s t r i t i s 4 0 % , normal 40%. The endoscopic appearance of erosive gastritis or atrophic gastritis was associated with a significantly higher frequency of H. pylori than all other endoscopic appearances (71% vs 40%, p<0.05 by Fisher' s exact test). CONCLUSION: The endoscopic appearance of erosive gastritis or atrophic gastritis is m o r e l i k e l y t o be associated with the presence of H. pylori, but the positive and negative predictive values are only moderate.
ZINC C O M P O U N D IS A N O V E L , H I G H L Y E F F E C T I V E T R I P L E T H E R A P ¥ FOR ERADICATION OF HELICOBACTER PYLORI. Ha~ime KuwaTama. Department of Medicine, Nihon Hospital at Tachikawa, and Nihoo University School of Medicine, Tokyo, Japan. INTRODUCTION~ Helicobacter pylori (H. pylori) infection causes gastritis and predisposes to peptic ulcer disease. At present the most effective regimen in eradicating H. pylori is a s o - c a l l e d t r i p l e therapy consisting of bismuth compound, metronidazole, and either tetracycline or amoxicillin, yielding an eradication rate of about 80%. Unfortunately, neither colloidal bismuth subcitrate nor bismuth aubsalicylate is available in Japan. An alternative therapy is urgently needed. Heavy metals are known to be bacteridical, and our previous in vitro studies found a significant inhibitory effect of zinc compound on the growth as well as ureaee activity of H. pylori. Based on these observations, we conducted a double-blind placebo-controlled trial of zinc compound in eradicating S. pylori in patients with and without duodenal ulcer. METHODS: H. pylori status was confirmed by culture, histology, and rapid urease test at the time of endoscopy. A total of 64 H. pylori positive patients were enrolled in this clinical trial and randomly assigned to receive a 2 week course of triple agent therapy consisting of either Z-103 zinc compound, 75 mg, orally b.i.d. (Zeria Pharmaceutical Co., Ltd., Tokyo), metronidazole 250 mg, and amoxicillin 250 mg t.i.d., or placebo, metronidazole a n d amoxicillin. Endoscopy was repeated immediately after completion of therapy, at least 4 weeks and again a year after cessation of therapy. RESULTS: All patients tolerated treatment and completed the 2-week course. Eight patients did not return for reendoscopy. Thus, 26 patients in the zinc compound group and 30 patients and in the placebo (antibiotic only)-group were available for evaluation of H. pylorl eradication. None of 26 zinc-treated patients were positive for H. pylori Whereas 6 placebo-treated patients were positive, corresponding to a 100% eradication rate for zinc compound treatment and 76% eradication for antibiotics only in evaluable patients. CONCLUSION: Triple therapy with zinc compound in combination with low dose metronidazole and amoxicillin is well tolerated, with an N. pylori eradication rate approaching 100%. This zinc compound triple therapy may be an effective alternative to standard triple therapy. * This research was funded in part by Zeria Pharmaceutical Co., Ltd., Tokyo, Japan.
• AUGMENTATION OF THE ANTACID EFFECT OF OMEPRAZOLE BY HELICOBACTER PYLORI INFECTION IN DUODENAL ULCER DISEASE. l.Labenz, A,L.Blum, J.P.IdstrSm, E.Verdu, M.Stolte, B.Tiilenburg, l~I.SolibShmer, G.BSrsch. Dept. of Medicine, Elisabeth Hospital Essen, Germany.
CORRELATION OF 13CO2 EXCESS WITH HELICOBACTER PYLORI DENSITY, GRADE AND ACTIVITY OF GASTRITIS. ~ S.Aygen, O.Hennemann, M.Stolte, T.Becker, U.Peitz, G.B6rsch. Dept. of Medicine, Elisabeth Hospital Essen, INFAI GmbH Bochum, Germany.
We habe previously observed higher pH-values during omeprazole (OME) treatment of Helicobacter pylori (Hp)-positive subjects as compared to Hp-negative subjects. We therefore have tested the hypotheses that this effect is due to Hp infection and that it is also present in duodenal ulcer (DU) patients. Methods: In 17 patients presenting with Hp positive DU, the infection was cured by omeprazole 60 mg bid and amoxicillin 1 g bid given over two weeks. Eradication wa s assessed by urease test, culture, histology, and urea breath test. Before eradication and 4 to 6 weeks (wash out period) after cessation of the eradication therapy, a standardized (time and meals) 24-hour gastric pH measurement (Ingold glas electrode 5 cm below the eardia) was performed after one-week treatment with 20 mg omeprazole od. Results: Cure of bacterial infection resulted in a statistically significant decrease of the gastric pH obtained by OME 20 mg od. Table: Group median pH (95%-confidence intervals)
The density of Helicobacter pylori (H.pylori) determines the grade and activity of gastritis and the amount ~ urease. Therefore, it is tempting to speculate that the CO 2 excess after ingestion of labelled urea correlates with the d6nsity of H.pylori as well as with the grade and activity of gastritis. Methods: 70 patients with dyspeptic symptoms, u n k n o w n H.pylori status, and without treatment with potentially H.pylori suppressive drugs during the last four weeks were enrolled to the study. All patients were investigated clinically and endocopically with taking of 4 antrum and 4 body biopsies, which were assessed for H.pylori infection by means of an urease test (HUT test), culture and histologyt(,l-IE and Warthin&Starry st4~ns). In addition, a simplifiedXaC ~ e a breath test (75 mg xaC labelled urea, measurement of the CO2/ CO2ratio in the exhalated air before and 30 minutes after urea qntake by isotope massspectrometry) was performed. Results: 47 patients proved to be H.pylori positive as judged ~stology. In 46 patients, H.pylori infection was also detected w i t h t h e urease test, culture and urea b r a t h test (sensitivity: 97.9%). In one female patient with focal and minimal colonization of H.pylori on histology, all the other methods failed to detect bacterial colonization. In 33 patients all four methods did not indicate bacterial colon~z,0tion (specifity: 100%). The semiquantitatively catagorized ~°CO~ excess was statistically highly significantly correlated witE the histologically visible degree of H.pylori colonization (r=0.88) as well as with grade (r=0.69) and activity of gastritis (r=0.71) (p<0.0001). Conclusions: The simplified urea breath test used in this ~ l y sensitive and specific with regard to diagnosis of H.pylori infection. In addition, the lOCO~ excess allows a rough prediction of the grade and activity of gastritis.
Hp positive
Hp negative
p
Total 5.5 (3.9-5.7) 3.0 (2.4-3.9) <0.002 Daytime 5.7 (3.8-5.9) 3.1 (2.4-4.1) <0.005 Postprandial 5.2 (3.5-5.5) 4.2 (3.1-4.4) <0.03 Nighttime 6.4 (4.6-6.4) 2.1 (1.8-3.8) <0.001 Conclusions: Intragastric pH during OME treatment markedly decreases after successful Hp treatment of DU patients. Thus, omeprazole appears to lose its effectiveness after Hp treatment, and this despite of many previous reports describing decreased acid output after cure of this infection. The most likely explanation for our observation is the production of buffer substances by Hp which cease after treatment. As a consequence of our study, previous analyses relating drug induced changes of gastric acidity and ulcer healing must be performed separately for Hp positive and negative subjects. The study was supported by a grant form AB Astra H~ssle.
A139