대한소화기학회지 2000;35:23 - 31
4)
Received July. 10, 1999; revision accepted Oct. 15, 1999.
Corresponding Author: Sooheon Park, M.D., Catholic Uni versity of Korea, Division of Gastroenterology, Department of Internal Medicine, 62 Youido-dong, Youngdeungpo-gu, Seoul, Korea, 150-713
Tel: (02) 3779-1328, Fax: (02) 3779-1331
Introduction
Antibiotic therapy is commonly used to treat Helicobacter pylori (H. pylori) infection in patients with peptic ulcers. With antibiotic treatment alone,
E f f e c t o f S in g le - D o s e v s . D iv id e d - D o s e D r u g Adminis tr ation on Eradication of Helicobacter py lori
in P a t ien t s w it h P ep t ic U lce r s
Soohe on P ark, M.D., Se Hyu n Cho, M.D., Gyu Yong Choi, M.D., In Sik Chung, M.D., Gyu Won Ch u n g , M.D., H e e S i k S u n , M.D. a n d D o o H o P a rk , M.D.
St. Mary' s Hospital, Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
소화성 궤양 환자의 제균요법에서 약제 투여 방법이 제균율에 미치는 효과
가톨릭대학교 의과대학 내과학교실
박수헌・조세현・최규용・정인식・정규원・선희석・박두호
배경 및 목적: Helicobacter pylori (H. pylori)에 감염된 소화성 궤양 환자의 치료에 제균요법으로
항생제가 흔히 사용된다. 대부분 항생제의 흡수율은 위내 산도에 많은 영향을 받는데 제균약제의 투여 방법에 따른 제균요법의 결과가 차이가 있는지 알려져 있지 않다. 본 연구에서는 제균약제의 투여 방법에 따라 제균효과에 차이가 있는지를 알아보았다. 대상 및 방법: H. pylori에 감염된 소화 성 궤양 환자에서 1군은 lansoprazole 60 mg, amoxicillin 2.0g, clarithromycin 1.0g을 하루 한 번에 투여하였고 2군은 2회 분복하여 각각 2주간 투여하였고 투약 후 1주일에 24시간 위내 산도를 측정 하였다. 결과: 1군에서 제균율은 65.5%였고 2군에서의 제균율은 85.7%로 1군에서 의의 있게 낮았 다(p<0.05). Lansoprazole 투여 방식에 따른 평균 위내산도는 1군에서 5.38, 2군에서 5.85로 차이가 없었다. H. pylori가 제균된 환자들의 평균 24시간 위내 산도는 5.67인 반면 제균되지 않았던 환자군 의 평균 24시간 위내 산도는 3.87로 제균된 환자의 위내 산도가 의의 있게 높았다(p<0.05). 결론H. pylori에 감염된 소화성 궤양 환자의 제균요법에서 분복요법이 제균에 더 효과적이며 혈중 내 항
생제의 농도 증가보다는 위내산도의 억제가 제균에 중요한 요소로 생각된다. (대한소화기학회지2000;35:23 - 31)
색인단어: Helicobacter pylori, Lansoprazole, Eradication, Intragastric pH.
24 대한소화기학회지 : 제 35 권 제 1 호 2000
the eradication rates for amoxicillin and clarithromy- cin are approximately 20% and 40%, respectively.1-3 Proton pump inhibitors (PPIs) markedly increase the efficacy of eradication therapy against H. pylori.
When amoxicillin or clarithromycin therapy is com- plemented with PPIs, eradication rates are approxi- mately 60% and 70%, respectively.2-6 PPIs have a direct antimicrobial effect that interferes with a number of H. pylori' s physiological mechanisms in vitro. In addition to proton pump inhibitors, H2 receptor antagonists that have no direct antimicrobial activity also enhance the eradication effect of antibiotics.7 The postantibiotic effect is now a well- established pharmacodynamic parameter manifest as an antibacterial effect that lasts longer than expected, given the active concentration at the infection site.8 The most significant factor is the specific com- bination of antimicrobial drugs, followed by the concentration and the duration of exposure to the drugs.8 Other factors that influence the postantibiotic effect are pH, hyperbaric oxygen, and temperature.
The acidic environment of the stomach has a profound effect on antibiotic action. The intragastric pH is already known to be an important predictor of the success of H. pylori eradication.9 In a recent in vitro study,10 omeprazole, lansoprazole, and erythro- mycin demonstrated concentration-dependent eradica- tion of H. pylori. However, it remains unclear whether high peak serum drug levels or prolonged exposure to antimicrobials given with PPI in patients with peptic ulcers results in the most effective eradication of H. pylori.
We designed the current study to determine whether there are any differential effects on H. pylori eradication when treatment is administered as one dose as opposed to a divided dose. The primary hypothesis tested in this study is that antibiotics and lansoprazole administered to peptic ulcer patients once per day cause a higher serum peak level, leading to a higher H. pylori eradication rate, than
treatment administered as a divided dose, increasing the duration of exposure to antimicrobials. We have also studied whether there is a difference in the intragastric pH of patients in the single-dose group as compared to patients in the divided-dose group, and whether the intragastic pH affects the eradication rate of H. pylori in patients with peptic ulcers.
Me thods
1. S t u dy popula t ion s
Fifty-six patients previously diagnosed with peptic ulcers were enrolled into this randomized study according to two inclusion criteria: a history of endoscopically-confirmed peptic ulcer disease, and H.
pylori infection confirmed by histological analysis and a rapid urease test. Patients were excluded from the study if they were over 70 years of age and if they exhibited any of the following: a history of ulcer surgery, coexisting pyloric stenosis, cirrhosis of the liver, renal failure, alcoholism, pregnancy, or lactation. Patients who had taken NSAIDs, proton pump inhibitors, bismuth salts, or antibiotic treatment during the two months prior to initiation of the study, or who showed a hypersensitivity to one of the study drugs, were also excluded from the study. All patients provided written informed consent. The protocol for the study was approved by the Insti- tutional Review Board of Human Research at the Catholic University of Korea.
2. S t u dy de s ig n
Before eradication treatment was initiated, and after four weeks of treatment, an upper gastroin- testinal endoscopy was performed on each patient. H.
pylori infection was confirmed with a rapid urease test (CLOtestTM, Delta West, Australia) and histo- logical assessment (Wharthin Starry silver stain). The rapid urease test was performed on two biopsy specimens from each patient (one from the antrum,
박수헌 외 6인. 소화성궤양 환자의 제균요법에서 약제 투여방법이 제균율에 미치는 효과 25
and the second from the corpus). Histological assess ment of H. pylori infection was performed using an additional three biopsy specimens (two from the antrum, and one from the gastric body).
Patients were randomized into two groups to receive two-week treatment, either lansoprazole (60 mg o.d.), clarithromycin (1.0g o.d.), and amoxycillin (2.0g o.d.) before breakfast (Group 1), or lanso- prazole (30 mg b.i.d.), clarithromycin (500 mg b.i.d.), and amoxycillin (1.0g b.i.d.) before breakfast and dinner (Group 2). For four weeks following the initial two-week treatment period, treatment was continued with lansoprazole (30 mg) before break- fast. After one week of combined lansoprazole, amoxycillin, and clarithromycin treatment, 24-hour intragastric pH measurements were performed on all patients. Patient compliance was checked by mea- suring returned drugs and by direct questioning on the day that treatment concluded. Four weeks fol- lowing antimicrobial treatment, the status of H. pylori infection was determined. Eradication of infection was defined as an absence of infection as determined by both the rapid urease test and histological assessment by endoscopy, as at entry.
3. 24- hour in t r a g a s t r ic pH m on it or in g Seven days after administration of eradication agents, 24-hour intragastric pH recordings were performed on all patients. The intragastric pH was recorded with an antimony electrode connected to a digital recorder (Digitrapper MKIII, Synetics) that registered the pH every four seconds. Electrodes and digital loggers were calibrated in vitro at room temperature using commercial buffer solutions of pH 1.07 (Synetics 5002) and pH 7.01 (Synetics 5001) at the start and conclusion of each recording. An elec trode drift of 0.1 pH unit was considered acceptable.
The electrode was placed by passing it trans- nasally into the stomach cavity, where it was positioned 5 cm below the manometrically-deter-
mined lower margin of the lower esophageal sphincter; positioning was confirmed by fluoroscopy.
The patients took usual meals at 12:30 h and 18:00 h, and kept diaries. After the 24-hour monitoring period, the pH data on the data logger were trans ferred to an IBM computer and stored using the Gastrograph program (Version 5.0, 1987, Gastrosoft, Inc.).
4. S t a t is t ics
Statistical comparisons were performed on the demographic parameters, the treatment results in the study groups, and the 24-hour intragastric pH parameter, using the Mann-Whitney rank sum test and the unpaired t test. A p value of <0.05 was considered significant.
Re s ults
There were no significant differences between the two study groups in any demographic variables (Table 1). Six of the 62 patients did not return for follow-up endoscopy, and, as compliance less than 90%, the final analysis was carried out on 56 patients.
1. H . p y lori e r a dic a t ion
Eradication was achieved in 19 out of 29 patients (65.5%) in Group 1, and in 23 out of 27 patients (85.2%) in Group 2 (Table 2). Eradication rates were significantly higher in Group 2 (p<0.05). Overall, H.
pylori was eradicated in 42 out of 56 patients (75%) There were no serious adverse effects reported in either group of patients (Table 3).
2. In t r a g a s t r ic pH m on it or in g
There was no significant difference between the mean intragastric pH for Group 1 and that for Group 2 (5.38 vs. 5.85, p=0.8467). In Group 1, the mean intragastric pH of the group in which H. pylori had
26 The Korean Journal of Gastroenterology : Vol. 35, No. 1, 2000
been eradicated was 5.47, while the mean intragastric pH was 4.03 in the group in which H. pylori
persisted (p=0.0315). In Group 2, the mean intragas tric pH in the H. pylori eradication group was 6.09 as compared to 3.48 in the group in which H. pylor persisted (p=0.0024). In both Group 1 and Group 2 patients showing H. pylori eradication, the mean intragastric pH was higher during the entire 24-hour period than in patients in whom H. pylori persisted (5.67 vs 3.87, p=0.0023)(Table 4).
Dis cus s ion
Benzimidazole proton pump inhibitors have been shown to exert a specific antibacterial activity against H. pylori in vitro.11-14 However, when the compound was administered at more than 100 times the thera peutic dose, it failed to eradicate Helicobacter felis in rats.15 At therapeutic doses, the plasma concentration Table 1. Demographic Characteristics of Two Ran-
domized Groups
Group 1 Group 2 Number
Mean age (range) Sex (M:F) GU DU
29 40.4 (18-69)
24:5 13 16
27 44.6 (28-69)
20:7 14 13 GU, gastric ulcer; DU, duodenal ulcer; Group 1:
lansoprazole 60 mg o.d.+ clarithromycin 1.0g o.d+ amoxycillin 2.0g o.d before breakfast; Group 2: lansoprazole 30 mg b.i.d.+ clarithromycin 500 mg b.i.d.+ amoxycillin 1.0 g b.i.d before breakfast and dinner for two weeks.
Table 2. Helicobacter Pylori Eradication Results in Groups 1 and 2
H. pylori eradication
Group 1 Group 2
Yes No Yes No
Absence of H. pylori Age*
Mean pH*
Fraction time pH below 4 (%)*
19/29 (65.5%) 43.6 5.47±0.31†
24.7±5.9
10/29 (34.5%) 34.5 4.03±0.66 53.3±11.6
23/27 (85.2%) 45.6 6.09±0.20 9.42±3.50§
4/27 (14.8%) 39.0 3.48±0.17 60.15±5.05
* Value represents mean±SE.
†p=0.0315 vs. H. pylori persistence in Group 1.
p=0.0024 vs. H. pylori persistence in Group 2.
§p=0.0037 vs. H. pylori persistence in Group 2.
Table 3. Adverse Effects in Patient Population for Analysis
Adverse effects Group 1 (n=29) Group 2 (n=27)
Sore mouth or throat Diarrhea
Increased bowel movement*
Bitter taste Headache
6 (20.7%) 2 ( 6.9%) 17 (58.6%) 11 (37.9%) 1 ( 3.4%)
5 (18.5%) 3 (11.1%) 15 (55.6%) 9 (33.3%) 0 ( 0 %)
* “Increased bowel movement” is defined as increased forquency of bowel movement, two fold move than usval.
Park, et al. Type of drug Administration affects Helicobacter pylori Eradication 27
of omeprazole is well below the level required for antibacterial action in vitro. But it is difficult to rule out completely the possibility that omeprazole exerts a direct antibacterial effect in vivo.16 In this study, we used same overall dosage of lansoprazole per day to patients in both groups because of its possible antibacterial action in vivo and the effects of intra gastric pH.
The intragastric pH also influences the rate of H.
pylori eradication by various mechanisms.9 It is still uncertain whether there is a difference in the mean intragastric pH between patients who received a divided dose of lansoprazole at 60 mg per day, and those who received a single dose of lansoprazole.
PPIs are systematically active for about an hour after ingestion. During this period, only the mature wor- king proton pumps are inactivated, and they rege- nerate over the next 17 hours. A twice-daily dosage of a PPI will inhibit a greater number of pumps than a once-daily dosage.17 But in our study, there was no difference in the mean intragastric pH of patients who received a single dose of lansoprazole and those who received a divided dose of lansoprazole. The eradication rate in the divided-dose group was significantly higher than that in the single-dose group. In the MACH 1 study, which employed a combination of PPI, amoxicillin and clarithromycin b.d. over a seven-day period, eradication rates were 83.8-96.4%.18 The eradication rate in Group 2 of our study and in the MACH I study were similar, and
higher than the rate in Group 1 in our study. Under similar intragastric pH conditions, our results suggest that the duration of exposure to antibiotics is more important for eradication of H. pylori than peak serum drug level.
We did not assess resistance of H. pylori to clarithromycin and amoxicillin, because our cultures of H. pylori were not always successful. Whereas H.
pylori does not appear to develop resistance to amoxicillin, resistance to macrolides has been well established; in Western countries, resistance rates of 9-11% have been recorded.19 Where clarithromycin was administered as the only antibiotic, at a high dose (1.5g/day) over a 14-day period, in association with an antisecretory drug, the rate of eradication was only in the 20% range in patients harbouring clarithromycin-resistant strains, as compared to 60%
in patients with clarithromycin-susceptible strains.20,21 In a recent European multicenter trial, the rate of H pylori eradication was 50% in patients infected with clarithromycin-resistant strains who were treated with a combination of clarithromycin and amoxicillin.22 The explanation is that amoxicillin can cure infection in up to 50% of cases when it is administered with PPI. In Korea, however, the resistance rate to clarithromycin is lower than 3.5% (paper in press).
The difference in the H. pylori eradication rates between the two groups in our study (85.7% vs 65.5%) suggests that baseline clarithromycin resis- tance may not be an important limiting factor in the Table 4. Patient Characteristics by Treatment Results
Eradication of H. pylori Persistence of H. pylori Number
Mean intragastric pH*
Fraction of time pH below 4 (%)*
42 5.67±0.24†
16.34±3.48
14 3.87±0.47 55.26±8.31
* Value represents mean±SE.
†p=0.0023 vs. H. pylori persistence group.
p<0.0001 vs. H. pylori persistence group.
28 대한소화기학회지 : 제 35 권 제 1 호 2000
success of treatment.
Patients in whom H. pylori infection was eradi- cated had a mean intragastric pH of 5.67, while patients in whom H. pylori infection persisted had a mean gastric pH of 3.87 during the period of lansoprazole administration. Obviously, a high intra- gastric pH may augment the effects of amoxicillin and clarithromycin by various mechanisms proposed by prior researchers. A high pH may lower the minimal inhibitory concentration value of these pH- dependent antibiotics, increase the stability of the antibiotics in gastric juice, increase their luminal concentration by slowing the emptying of the sto- mach, lowering the dilution volume, interfering with the adherence of H. pylori to the stomach lining, and creating an environment that permits overgrowth of bacterial competitors, and improving the stability of luminal immunoglobulins.23-28 On the basis of these observations, the efficacy of eradication therapy should be related to the intragastric pH, and the inhibition of acid secretion. But a question remains concerning the degree of gastric acid inhibition necessary for optimal function of antibiotics. Accor- ding to one research team, to heal peptic ulcers within three to four weeks, the optimal method of suppressing acid is to increase the intragastric pH to 3 and higher for a period of 18-20 hours per day.29 As far as omeprazole is concerned, some resear- chers,4,30 but not others,31,32 have observed a dif- ference in H. pylori eradication when infection is treated with a combination of antibiotics and sequentially increased doses of PPIs. However, there is little rationale for increasing the potency of antisecretory agents, because an acidity may be defined as any pH above 3 for the purpose of healing duodenal ulcers.29 Most antibiotics are acid-labile and can be protected from the intragastric environment by reducing the intragastric acidity.33-35 Some resear- chers36,37 have underscored the importance of raising the intragastric pH to obtain optimal antibiotic
function. In our own study, no clear pH cutoff poin existed for separating patients in whom H. pylori persisted from patients in whom H. pylori infection was eradicated. Also, we have another question about whether there is a difference in intragastric pH between the H. pylori eradication group and the group in which infection persisted, given adminis- tration of the same dose of PPI. It is unclear why H pylori infection produces different patterns of acid secretion in different individuals. The effect of H.
pylori on acid secretion depends on several variables, such as the strain of H. pylori, the enterochromaffin cell mass, and the degree of gastritis and atrophy.
This trial was not designed to evaluate the difference in intragastric pH between the group in which H.
pylori infection was eradicated and the group in which it persisted. Instead, this trial addressed the practical question of whether single dosing or divided dosing with eradication drugs was more successful in its clinical outcome. Additional studies on various other antibiotics used to eradicate H. pylori should investigate their different stabilities in gastric acid in vivo, and differences in intragastric pH during eradication therapy, and may provide new insights into treatment of H. pylori in patients with peptic ulcers.
In conclusion, our data show that divided dosing is more effective than single dosing in eradicating H.
pylori, and therefore suggest that the duration of antibiotic exposure is more important for eradicating H. pylori in patients given antibiotics and lanso- prazole. Intragastric pH is one of the factors that determines the success of H. pylori eradication.
S umma ry
Background/Aims: Antibiotic therapy is comm- only used to treat Helicobacter pylori (H. pylori) infection in patients with peptic ulcers. The aim of this study was to determine whether antibiotics in
박수헌 외 6인. 소화성궤양 환자의 제균요법에서 약제 투여방법이 제균율에 미치는 효과 29
combination with lansoprazole given once per day, causing a high serum peak level, would lead to a higher H. pylori eradication rate than would a divided dose, increasing exposure to antimicrobials, in peptic ulcer patients. Methods: A total of 56 patients with H. pylori-positive duodenal ulcers and/or gastric ulcers were randomized into two groups, and treated with a combination of lanso- prazole, clarithromycin and amoxycillin once per day before breakfast (Group 1), or divided dose before breakfast and dinner (Group 2) for two weeks. After one week of combined treatment, 24-hour measure- ments of intragastric pH were performed for all patients. Results: H. pylori eradication was achieved in 19 out of 29 patients (65.5%) in Group 1, and in 23 out of 27 patients (85.7%) in Group 2. The mean intragastric pH was significantly higher in patients in whom H. pylori was eradicated (5.67) than in patients in whom H. pylori persisted (3.87) during the entire 24-hour period (p=0.005). Conclusions: Our results confirm that prolonged exposure to drug treatment is important for eradication of H. pylori in patients with peptic ulcers.
Key Words: Helicobacter pylori, Lansoprazole, Era- dication, Intragastric pH
Acknowle dge me nt
The authors thank Ms Anne Chapple for her careful review of the manuscript.
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