Efficacy of triple therapy with rabeprazole for Helicobacter pylori infection and CYP2C19 genetic polymorphism

BACKGROUND: Rabeprazole is a new, potent, proton pump inhibitor. The metabolism of rabeprazole is less dependent on CYP2C19 genetic polymorphism. METHODS: A total of 102 Helicobacter pylori-positive patients with gastric ulcer were randomly allocated to three groups: rabeprazole 10 mg (RAC10), rabeprazole 20 mg (RAC20) or rabeprazole 40 mg (RAC40) plus amoxicillin 750 mg and clarithromycin 200 mg twice daily for 7 days. CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: All-patients-treated-based eradication rates in patients treated with RAC10, RAC20 and RAC40 were 83%, 77% and 90%, respectively, and per protocol-based eradication rates were 83%, 80% and 90%, respectively. The eradication rates in the three groups were not significantly different. There was also no significant difference between the all-patients-treated-based eradication rate in CYP2C19 extensive metabolizers and that in poor metabolizers (86% vs. 77%). Adverse events were 12% in extensive metabolizers and 23% in poor metabolizers, and the difference in these incidence rates was also not statistically significant. CONCLUSIONS: Triple therapy with 10 mg of rabeprazole combined with amoxicillin/clarithromycin is effective for Japanese patients with H. pylori infection, and the H. pylori eradication rate is not affected by CYP2C19 genetic polymorphism.     

Eradication rates of clarithromycin-resistant Helicobacter pylori using either rabeprazole or lansoprazole plus amoxicillin and clarithromycin

BACKGROUND: The resistance of Helicobacter pylori to clarithromycin has become one of the primary reasons for eradication failure. AIM: To compare the eradication rates of triple therapy using amoxicillin (A), clarithromycin (C) and rabeprazole (R) or lansoprazole (L) against clarithromycin-sensitive and clarithromycin-resistant strains. METHODS: Two hundred and ninety-five patients were randomly divided into four groups and treated for 1 week: 147 cases were treated with RAC, i.e. 49 cases with R20C400 (10 mg R + 750 mg A + 200 mg C, twice daily), 48 cases with R40C400 (20 mg R + 750 mg A + 200 mg C, twice daily) and 50 cases with R40C800 (20 mg R + 750 mg A + 400 mg C, twice daily); 148 cases with treated with LAC (30 mg L + 750 mg A + 200 mg C, twice daily). RESULTS: According to intention-to-treat and per protocol analyses, the eradication rates were 88% and 91% with RAC and 78% and 81% with LAC; the eradication rates with R20C400, R40C400 and R40C800 were 94%, 81% and 86%, respectively, in the intention-to-treat analysis. In addition, the eradication rates for clarithromycin-sensitive strains with RAC and LAC were 98% and 89%, respectively, and for clarithromycin-resistant strains with RAC and LAC were 8.1% and 0%, respectively. CONCLUSIONS: The eradication rate was significantly higher with RAC than LAC. The eradication rate for clarithromycin-resistant strains was low in both groups, and an improved eradication rate could not be achieved by changing the dose of clarithromycin or proton pump inhibitor.     

Concomitant dosing of famotidine with a triple therapy increases the cure rates of Helicobacter pylori infections in patients with the homozygous extensive metabolizer genotype of CYP2C19

BACKGROUND: Proton-pump inhibitors, such as lansoprazole, are metabolized in the liver by CYP2C19 and cannot inhibit acid sufficiently in homozygous extensive metabolizers of CYP2C19. AIM: To examine whether famotidine would increase the cure rates of Helicobacter pylori infection by a standard triple therapy. METHODS: A total of 177 H. pylori-positive patients were randomly assigned to either lansoprazole 30 mg b.d., clarithromycin 200 mg b.d. and amoxicillin 750 mg b.d. for 1 week (LCA group; n = 89) or famotidine 20 mg b.d., lansoprazole 30 mg b.d., clarithromycin 200 mg b.d. and amoxicillin 750 mg b.d. for 1 week (FLCA group; n = 88). Famotidine was administered after lunch and before sleep, and the others were after breakfast and dinner. CYP2C19 genotypes were determined by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: In the LCA group, the eradication rates for homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers were 63%, 87%, and 100%, respectively (P = 0.014). Those in the FLCA group were 85%, 85%, and 100%, respectively (N.S.). The cure rate for homozygous extensive metabolizers in the FLCA group was significantly higher than that in the LCA group (P = 0.035). CONCLUSION: Famotidine improves the cure rate of H. pylori infection by a triple therapy in CYP2C19 homozygous extensive metabolizers patients.     

Rabeprazole-based eradication therapy for Helicobacter pylori: a large-scale study in Japan

BACKGROUND: Large-scale studies of rabeprazole-based Helicobacter pylori eradication therapy have not been reported in Japan. AIMS: To evaluate H. pylori eradication by rabeprazole-based therapy with reference to antibiotic susceptibility, CYP2C19 genotype, and rabeprazole and clarithromycin dosages. METHODS: From 35 centres 479 H. pylori-positive patients with gastric or duodenal ulcer were randomized to four treatment groups: Group 1 (10 mg rabeprazole + 750 mg amoxicillin + 200 mg clarithromycin twice daily for 7 days); Group 2 (10 mg, 750 mg, 400 mg); Group 3 (20 mg, 750 mg, 200 mg) and Group 4 (20 mg, 750 mg, 400 mg). RESULTS: Eradication rates were 86% (102 of 119), 89% (97 of 109), 91% (106 of 116) and 90% (104 of 115) for Groups 1-4, respectively. The eradication rate was 95% (360 of 379) for clarithromycin-susceptible strains, and 50% (30 of 60) for clarithromycin-resistant strains. The eradication rates were 88% (332 of 379) and 96% (77 of 80) in extensive metabolizers and poor metabolizers, respectively. CONCLUSIONS: Rabeprazole-based therapies achieved 50% eradication of clarithromycin-resistant H. pylori, and even achieved good rates in extensive metabolizers. Accordingly, rabeprazole can be recommended as part of a first-line proton pump inhibitor-based triple therapy for H. pylori.     

CYP2C19 polymorphism and proton pump inhibitors

Proton pump inhibitors such as omeprazole (esomeprazole), lansoprazole, pantoprazole and rabeprazole are eliminated by the hepatic route and the polymorphic CYP2C19 is mainly involved in their metabolism. In different populations three phenotypes have been identified: extensive metabolizers, poor metabolizers and individuals carrying one wild type and one mutant allele (het extensive metabolizers). Systemic exposure to the proton pump inhibitors as expressed by the AUC (area under the plasma level time profiles) is 5-12-times higher in poor metabolizers than in extensive metabolizers. As the pharmacodynamic response (elevation of intragastric pH) to the proton pump inhibitors is related directly to their AUC, a much higher pH can be monitored over 24 hr in poor metabolizers than in extensive metabolizers. Furthermore, clinical efficacy of all proton pump inhibitors depend on maintaining intragastric pH above certain threshold levels and significantly higher eradication rates of Helicobacter pylori have been observed in patients of the poor metabolizers and het extensive metabolizers phenotype if compared to extensive metabolizers. Likewise, limited data suggest that proton pump inhibitors-induced healing rates in gastro-oesophageal reflux disease are apparently higher in poor metabolizers/het extensive metabolizers than in extensive metabolizers of CYP2C19. Therefore initial genotyping for this enzyme and higher dosage in extensive metabolizers is likely to improve the clinical efficacy of proton pump inhibitors.     

Studies on drug interactions between esomeprazole, amoxicillin and clarithromycin in healthy subjects

OBJECTIVE: A combination of esomeprazole, amoxicillin and clarithromycin may be used for Helicobacter pylori eradication. We explored the potential for interactions between these drugs. METHODS: In 2 randomized, 4-way crossover studies, healthy CYP2C19 extensive metabolizers (EMs) received esomeprazole 40 mg once daily (n = 20) or 20 mg twice daily (b.i.d.) (n = 20), clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d. or the combination of the 3 drugs for 7 days. In a third randomized, 2-way, crossover study, 6 healthy CYP2C 19 poor metabolizers (PMs) received esomeprazole 40 mg once daily with and without clarithromycin 500 mg b.i.d. for 1 week. RESULTS: Triple therapy with esomeprazole 40 mg increased the area under the plasma concentration-time curve during the dosing interval (AUCtau) from 13.31 micromol x h/l (11.12-15.93) for esomeprazole alone to 22.69 micromol x h/l (18.94-27.17) for triple treatment. Respective AUCtau values with esomeprazole 20 mg b.i.d. were 4.97 micromol.h/l (3.97-6.21) and 11.29 micromol x h/l (9.03-14.12). Clarithromycin and amoxicillin plasma levels were largely unchanged by combination therapy. In PMs, the esomeprazole AUC also approximately doubled when administered in combination with clarithromycin. All treatments were well tolerated. CONCLUSION: Clarithromycin decreases the metabolism rate of esomeprazole, leading to approximately doubled AUC values, both in EMs and PMs.     

Impact of rabeprazole, a new proton pump inhibitor, in triple therapy for Helicobacter pylori infection—comparison with omeprazole and lansoprazole

BACKGROUND: A recent trend in curative therapy for Helicobacter pylori infection is the so-called triple therapy, which consists of a proton pump inhibitor (PPI) and two different antimicrobials. Various regimens employing this triple therapy have been reported. However, little is known about the effectiveness of rabeprazole, a recently developed proton pump inhibitor, when used in the triple therapy. AIM: To validate its usefulness by comparing rabeprazole with omeprazole and lansoprazole, in combination with amoxycillin and clarithromycin. PATIENTS AND METHODS: 221 H. pylori-positive patients with peptic ulcer disease were randomized to receive one of three different proton pump inhibitor/amoxycillin-clarithromycin (PPI/AC) regimens for 7 days. (i) OAC regimen (n = 75): omeprazole 20 mg b.d., amoxycillin (AMOX) 500 mg t.d.s. and clarithromycin (CAM) 200 mg b.d.; (ii) LAC regimen (n = 74): lansoprazole 30 mg b.d. , AMOX 500 mg t.d.s. and CAM 200 mg b.d.; and (iii) RAC regimen (n = 72): rabeprazole 20 mg b.d., AMOX 500 mg t.d.s. and CAM 200 mg b.d. Cure of the infection was determined by the 13C urea breath test 1 month after completion of the treatment. RESULTS: Intention-to-treat based cure rates for OAC, LAC and RAC regimens were 85% (95% CI, 75-92), 84% (95%, CI 73-91) and 88% (95% CI, 78-94), respectively, and per protocol based cure rates of these regimens were 88% (95% CI, 78-94), 91% (95%, CI 82-99) and 93% (95% CI, 84-98), respectively. Adverse effects in the entire study population, which included diarrhoea, glossitis or skin rash, were reported by 15% of the patients, and complete compliance was achieved in 95% of these patients. CONCLUSION: 1-week proton pump inhibitor/AC regimens for H. pylori infection were effective in the Japanese population. Rabeprazole can be considered as equivalent to omeprazole and lansoprazole in the PPI/AC triple therapy.     

The importance of clarithromycin dose in the management of Helicobacter pylori infection: a meta-analysis of triple therapies with a proton pump inhibitor, clarithromycin and amoxycillin or metronidazole

BACKGROUND: It is not clear which dose of clarithromycin (500 mg b.d. or 250 mg b.d.) is more effective for Helicobacter pylori eradication in proton pump inhibitor-based triple therapies. METHODS: We undertook a meta-analysis of the effect of 7-day triple therapies consisting of a proton pump inhibitor (P), and clarithromycin (C) and amoxycillin (A) or metronidazole (M). A meta-analysis of all clinical trials performed in an adult population and published in English up to March 1998 was undertaken. Studies with doses of clarithromycin 500 mg b.d. or 250 mg b.d. only were included. RESULTS: A total of 82 studies (31 papers and 51 abstracts) involving 110 treatment arms and 6123 patients were analysed that met the predetermined inclusion and exclusion criteria. In the PAC combination, the pooled eradication rate in patients treated with clarithromycin 500 mg b.d. was 89.5% (95% CI: 86.9-92. 0%) by per protocol analysis and 86.6% (95% CI: 81.0-89.3%) by intention-to-treat analysis. These rates are significantly higher than those achieved with clarithromycin 250 mg b.d. (83.3% by per protocol and 78.2% by intention-to-treat analysis, both P < 0.0001). This difference was confirmed in head-to-head comparative studies. In the PMC regimen, clarithromycin 500 mg b.d. eradicated 90.8% (95% CI: 87.0-94.5%) of the infections compared to 88.5% (95% CI: 85.5-91. 5%) in patients treated with clarithromycin 250 mg b.d. by per protocol analysis (P = 0.082). The corresponding rates by intention-to-treat analysis for clarithromycin 500 mg b.d. and 250 mg b.d. was 88.3% and 86.7%, respectively (P = 0.259). CONCLUSIONS: Seven-day triple therapies with a proton pump inhibitor, clarithromycin and amoxycillin or metronidazole are highly effective treatments for the eradication of H. pylori. Clarithromycin 500 mg b. d. should be used in these combinations to achieve the best first treatment results, which can minimize the subsequent development of bacterial resistance to clarithromycin and metronidazole.     

Rabeprazole, amoxycillin and low- or high-dose clarithromycin for cure of Helicobacter pylori infection

BACKGROUND: Rabeprazole sodium is a proton pump inhibitor. AIM: To evaluate the efficacy and safety of 1-week triple therapy with rabeprazole, amoxycillin and clarithromycin for the eradication of Helicobacter pylori. METHODS: A total of 100 subjects with H. pylori were randomly divided into two groups of 1-week triple therapy with rabeprazole 10 mg b.d., amoxycillin 750 mg b.d. and either clarithromycin 200 mg b.d. (RAC400, n=50) or clarithromycin 400 mg b. d. (RAC800, n=50). Endoscopic examination with four biopsies (two specimens from the antrum and two from the gastric body) was performed. The status of H. pylori infection was determined using culture and histology (Giemsa stain) of the biopsy specimens. Sensitivity to clarithromycin was determined using the E-test: MIC > 8 g/mL was considered to be resistant, whereas MIC < 2 g/mL was considered to be sensitive. Cure was defined as no evidence of H. pylori infection 1 month after completion of treatment. RESULTS: There were no significant differences in the clinical characteristics of the two groups. Eradication rates (intention-to-treat and per protocol, respectively) were: RAC400: 86% (95% CI: 76-95%) and 89% (95% CI: 80-97%); RAC800: 94% (95% CI: 87-100%) and 97% (95% CI: 94-100%). There was no significant difference between the eradication rates of either regimen. Three subjects with failed eradication in the RAC400 group were all infected with a clarithromycin-resistant strain before beginning the therapy. Haemorrhagic colitis was the only severe adverse event, which was observed in one patient in the RAC800 group. CONCLUSION: One-week triple therapy with rabeprazole, amoxycillin and low-dose clarithromycin is effective for the eradication of H. pylori infection.     

Helicobacter pylori eradication with proton pump inhibitor-based triple therapies and re-treatment with ranitidine bismuth citrate-based triple therapy

BACKGROUND: It has been suggested that short-term triple therapy comprising a proton pump inhibitor, plus clarithromycin and amoxycillin be used as first choice in treating H. pylori infection, while eradication failure patients should be further treated with a quadruple therapy. Nevertheless, conflicting results have been reported using these treatment regimens in different countries. METHODS: A total of 278 patients with H. pylori infection were randomised to receive one-week triple therapy, comprising clarithromycin 500 mg b.d., amoxycillin 1 g b.d., and either omeprazole 20 mg b.d. (OAC; 90 patients), or pantoprazole 40 mg b.d. (PAC; 95 patients), or lansoprazole 30 mg b.d. (LAC; 93 patients). H. pylori infection at entry, and eradication 4-6 weeks after therapy had ended, were assessed by rapid urease test and histology on biopsies from the antrum and the corpus. When eradication did not occur, patients were given a 2-week treatment comprising ranitidine bismuth citrate 400 mg b.d., tetracycline 500 mg t.d.s. and tinidazole 500 mg b.d. (RBTT). Eradication in these patients was assessed 4-6 weeks after conclusion of treatment by a further endoscopy. RESULTS: Six patients were lost to the follow-up. At the end of the first course of treatment, the overall H. pylori eradication rate was 78% (95% CI: 73-83) and 79% (95% CI: 75-84) at 'intention-to-treat' (ITT) and 'per protocol' (PP) analysis, respectively, without any statistically significant difference between treatment regimens, although a trend for better results with the omeprazole combination was observed. Moreover, H. pylori eradication was achieved in 82% (95% CI: 75-97) (ITT) and 86% (95% CI: 69-94) (PP) of 38 patients re-treated with RBTT regimen. CONCLUSIONS: Our data found that this short-term triple therapy is not a satisfactory treatment (< 80% eradication rate) for H. pylori infection. The 2-week triple therapy used as re-treatment in eradication failure patients yielded more promising results.     

Five-day proton pump inhibitor-based quadruple therapy regimen is more effective than 7-day triple therapy regimen for Helicobacter pylori infection

BACKGROUND: There have been no reports that describe whether 5-day quadruple therapy (rabeprazole + amoxicillin + clarithromycin + metronidazole; RACM) could substitute for standard 7-day triple therapy as a first-line therapy for Helicobacter pylori. PATIENTS AND METHODS: This study was designed as a randomized prospective single centre study. A total of 160 H. pylori-positive patients who had not received therapy were given either a 5-day RACM regimen (n=80, rabeprazole 20 mg b.d., amoxicillin 750 mg b.d., clarithromycin 200 mg b.d. and metronidazole 250 mg b.d.) or a 7-day RAC regimen (n=80, rabeprazole 20 mg b.d., amoxicillin 750 mg b.d. and clarithromycin 200 mg b.d.). Cure of the infection was assessed by a (13)C urea breath test 1 month after the completion of therapy. RESULTS: The eradication rates of the 5-day RACM regimen and the 7-day RAC regimen were 93% (95% CI: 84--97%) and 81% (95% CI: 71--89%) by intention-to-treat analysis, 94% (95% CI: 86--98%) and 83% (95% CI: 73--91%) by all-patients-treated analysis analysis and 95% (95% CI: 87--98%; P < 0.05) and 82% (95% CI: 72--90%) by per protocol analysis, respectively. No serious adverse effect was observed, and 99% of the patients reported complete compliance. CONCLUSIONS: The cure rate of the 5-day RACM regimen was more effective than the 7-day RAC regimen, suggesting that this regimen could be preferable as a first-line therapy for H. pylori infection.     

Treatment options for Helicobacter pylori infection when proton pump inhibitor-based triple therapy fails in clinical practice

BACKGROUND: The effectiveness of Helicobacter pylori eradication regimens has not been extensively investigated in the clinical practice setting. The optimal treatment choice after an initial failed eradication attempt has not been determined. AIMS: To evaluate proton pump inhibitor-based triple therapies as first-line eradication regimens in clinical practice, and to establish the efficacy of second-line regimens in the context of an initial failed eradication attempt. METHODS: Three hundred and eight patients with dyspepsia and evidence of H. pylori at endoscopy were recruited. As first-line therapy, 116 patients received omeprazole 20 mg b.d. in combination with amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. (OAC) while 192 patients received omeprazole 20 mg b.d. in combination with metronidazole 400 mg b.d. and clarithromycin 250 mg b.d. (OMC). H. pylori status was reassessed at least 4 weeks after therapy (25 patients failed to attend for further testing). Of 52 patients with an initial failed eradication attempt, 20 patients received a 1 week quadruple therapy regimen incorporating omeprazole 20 mg b.d., tripotassium dicitrato bismuthate 120 mg q.d.s., tetracycline 500 mg q.d.s. and metronidazole 400 mg t.d.s., 20 patients received a 2-week proton pump inhibitor-based triple therapy regimen as described, and 12 patients received a further 1-week proton pump inhibitor-based triple therapy regimen. RESULTS: Including 308 patients, the intention-to-treat (ITT) eradication rates for OAC and OMC as first-line regimens were 72% (95% CI: 63-80%) and 73% (95% CI: 67-79%) respectively. A per protocol (PP) analysis on the 283 patients who completed follow-up gives an initial eradication rate of 78% (95% CI: 69-86%) for OAC and 79% (95% CI: 73-85%) for OMC. There were 60 patients (21%; 95% CI: 17-26%) in whom the initial eradication attempt was unsuccessful. With second-line therapy, H. pylori was successfully eradicated in a further 35/52 (67%; 95% CI: 58-73%) patients. The eradication rates with the quadruple regimen and 2-week triple therapy regimens were 75% (95% CI: 56-94%) and 80% (95% CI: 63-98%) respectively (P = 0. 71). The eradication rate with a repeat 1-week regimen was 33% (95% CI: 7-60%). CONCLUSIONS: The eradication rates achieved in this 'in practice' study with recommended first-line 1-week proton pump inhibitor-based triple therapy regimens were lower than the rates achieved with similar regimens in the clinical trial setting. A repeat 1-week proton pump inhibitor-based triple therapy regimen was not successful as a salvage therapy. Both the 2-week proton pump inhibitor-based triple therapy regimen and the 1-week quadruple therapy regimen were successful second-line treatments in >/=75% of patients.     

Randomized trial of rifabutin-based triple therapy and high-dose dual therapy for rescue treatment of Helicobacter pylori resistant to both metronidazole and clarithromycin

BACKGROUND: The clinical management of Helicobacter pylori infected patients who failed standard eradication therapies remains a challenge. AIM: To investigate the efficacy of rifabutin-based triple therapy and high-dose dual therapy for rescue treatment of H. pylori, and the correlation between cytochrome P450 2C19 (CYP2C19) polymorphisms and treatment outcome. METHODS: Patients infected with H. pylori resistant to both metronidazole and clarithromycin (n = 145) were randomized to either esomeprazole 20 mg, rifabutin 150 mg and amoxicillin 1 g, each given b.d. for 7 days (ERA), or to omeprazole 40 mg and amoxicillin 1000 mg, each given t.d.s. for 14 days (OA). Crossover therapy was offered in cases of persistent infection. CYP2C19 polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphism. RESULTS: Intention-to-treat and per-protocol eradication rates were: ERA 74% (62.4-83.6) and 78% (66.7-87.3); high-dose OA 70% (57.5-79.7) and 75% (62.5-84.5). Crossover therapy was successful in seven of 10 patients with ERA and in eight of 10 patients with OA. Premature discontinuation of treatment occurred in 2% and 5% of patients, respectively. There was only a non-significant trend to lower eradication rates in homozygous extensive metabolizers. CONCLUSIONS: Triple therapy with esomeprazole, rifabutin and amoxicillin and high-dose omeprazole/amoxicillin are comparable and effective and safe for rescue therapy of H. pylori regardless of the patient's CYP2C19 genotype.     

Polaprezinc, a mucosal protective agent, in combination with lansoprazole, amoxycillin and clarithromycin increases the cure rate of Helicobacter pylori infection

AIM: To evaluate the efficacy of polaprezinc, a mucosal protective agent, in combination with a 7-day triple therapy containing lansoprazole, amoxycillin and clarithromycin, as a treatment for Helicobacter pylori. METHODS: Sixty-six consecutive patients suffering from dyspeptic symptoms with H. pylori infection were randomly allocated to one of two regimens: one group (LAC; n = 31) received lansoprazole 30 mg b.d., amoxycillin 500 mg b.d. and clarithromycin 400 mg b.d. for 7 days. The other group (LACP; n = 35) received the LAC regimen plus polaprezinc 150 mg b.d. for 7 days. H. pylori status was evaluated by rapid urease test, histology and culture at entry and 4 weeks after treatment. RESULTS: Five patients did not complete the treatment: no follow-up endoscopy was performed on two patients in the LAC group; one patient in the LAC group and two in the LACP group had their treatment stopped due to severe diarrhoea. By per protocol analysis, H. pylori eradication was achieved in 24 of the 28 evaluable patients (86%; 95% CI: 72-100%) after LAC therapy, and in 33 of the 33 evaluable patients (100%) after LACP therapy (P < 0.05). On intention-to-treat analysis, the rates of eradication were 24 of 31 patients (77%; 95% CI: 62-93%) in the LAC group, and 33 of 35 patients (94%; 95% CI: 86-100%) in the LACP group (P < 0.05). CONCLUSION: A 7-day triple therapy with lansoprazole, amoxycillin and clarithromycin is effective in H. pylori eradication, but this regimen is significantly improved by the addition of polaprezinc.     

Efficacy of triple therapy comprising rabeprazole,amoxicillin and metronidazole for second-line Helicobacter pylori eradication in Japan,and the influence of metronidazole resistance

BACKGROUND: The widespread use of eradication therapy for Helicobacter pylori in Japan has led to an increase in antibiotic-resistant strains and the problem of re-treatment in cases of eradication failure. AIM: To perform drug sensitivity testing for metronidazole in 92 H. pylori-positive patients who had failed eradication treatment with first-line triple therapy, consisting of a proton pump inhibitor, amoxicillin and clarithromycin, and were administered metronidazole-containing second-line therapy. METHODS: Second-line eradication therapy, consisting of rabeprazole (20 mg b.d.), amoxicillin (750 mg b.d.) and metronidazole (250 mg b.d.), was administered for 1 week and the eradication rates and influence of metronidazole resistance were determined. RESULTS: The eradication rates for rabeprazole-amoxicillin-metronidazole were 88% (81/92) using intention-to-treat analysis and 91% (81/89) using per protocol analysis. The eradication rates were 97% (61/63) for metronidazole-sensitive strains and 82% (18/22) for metronidazole-resistant strains. CONCLUSIONS: As second-line H. pylori eradication treatment in Japan, rabeprazole-amoxicillin-metronidazole triple therapy is effective, even with metronidazole-resistant strains.     

Effect of ornidazole and clarithromycin resistance on eradication of Helicobacter pylori in peptic ulcer disease

BACKGROUND: Clarithromycin and nitroimidazoles such as metronidazole and ornidazole are among the most frequently used antibiotics for curing Helicobacter pylori infection. However, controversial data exist on whether their in vitro resistance has a negative impact on treatment outcome. METHODS: Patients with H. pylori positive active peptic ulcer disease were randomly assigned to receive lansoprazole 30 mg o.d., amoxycillin 1 g b.d. and ornidazole 500 mg b.d. (LAO) or lansoprazole 30 mg o.d., amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. (LAC) for 2 weeks. Pre-treatment resistance to ornidazole and clarithromycin was assessed by Epsilometer (E-) test. Four weeks after completion of treatment, patients underwent a 13C urea breath test to assess H. pylori status. RESULTS: Data from 80 patients with active peptic ulcer disease and positive H. pylori status were analysed. The prevalence of primary drug resistance was 25% for metronidazole and 7.5% for clarithromycin. In patients treated with LAO, effective treatment was achieved in 87% of metronidazole-susceptible, but only 30% of metronidazole-resistant strains (P < 0.01). In the LAC group, therapy was successful in 81% of clarithromycin-susceptible strains, whereas treatment failed in all patients with primary clarithromycin resistance (n = 3). CONCLUSION: Resistance against nitroimidazoles significantly affects treatment outcome in H. pylori eradication therapy.     

Helicobacter pylori-positive duodenal ulcer: three-day antibiotic eradication regimen

BACKGROUND: The most widely used treatments for ulcer healing and Helicobacter pylori eradication consist of a 1-2 week regimen of a proton pump inhibitor plus two or three antimicrobials. AIMS: To evaluate the efficacy, safety, cost, and tolerance of a three-day regimen with three antibiotics vs. a 10-day treatment with a proton pump inhibitor or vs. a ranitidine bismuth citrate triple therapy. METHODS: Two hundred and twenty-one patients with endoscopically-proven H. pylori-positive duodenal ulcers were recruited to the study. Recruited patients were assigned to one of the following four regimens: (I) omeprazole 40 mg o.m. plus amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. for 10 days (OAC: 55 patients); (ii) omeprazole 40 mg o.m. on days 1-5, plus amoxycillin 1 g b.d., clarithromycin 500 mg b.d. and metronidazole 500 mg b.d. on days 3-5 (OACM: 56 patients); (iii) ranitidine bismuth citrate 400 mg b.d. plus amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. for 10 days (RAC: 54 patients); (iv) ranitidine bismuth citrate 400 mg b.d. on days 1-5, plus amoxycillin 1 g b.d., clarithromycin 500 mg b.d. and metronidazole 500 mg b.d. on days 3-5 (RACM: 56 patients). Fisher's exact test was used to compare data regarding healing and eradication in the four groups. RESULTS: The intention-to-treat eradication and ulcer healing rates for the RACM regimen were 95% and 98%, respectively. Statistically significant differences were observed, relating to the eradication and healing of ulcers, between RACM and either the RAC or OAC regimens. CONCLUSION: The three-day antibiotic therapy with amoxycillin, clarithromycin and metronidazole in addition to ranitidine bismuth citrate is a very effective anti-H. pylori regimen.     

Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem

Proton pump inhibitors (e.g. omeprazole/esomeprazole, lansoprazole, pantoprazole, rabeprazole) have a prominent role in the short- and long-term management of acid-related intestinal disease. They are eliminated by the hepatic route and the polymorphic CYP2C19 is involved in their metabolism. Three phenotypes have been identified in various populations: extensive metabolizers (homEM), poor metabolizers (PM) and individuals carrying one wild type and one mutant allele (hetEM). Therefore, systemic drug exposure (AUC) varies widely between these three populations and the AUC for omeprazole, lansoprazole and rabeprazole are approximately 7.5-, 4.5- and 4-fold higher in PM than in homEM. Since the pharmacodynamic response to proton pump inhibitors (PPIs) is related to their AUC, intragastric pH is much more elevated in PM (median around 6) and hetEM (4 - 5) than in homEM (3 - 4). This genotype-dependent increase in AUC and intragastric pH has clinical consequences because the healing rate in peptic ulcer (PU, target pH > or = 3) and gastroesophageal reflux disease (GERD, target pH > or = 4) and the eradication of Helicobacter pylori (Hp) depend on a long-lasting (> or = 16 hours) and effective inhibition of acid secretion. Several clinical studies have shown that PM and hetEM benefit from an approximately 18% higher Hp eradication rate compared to homEM when standard dosages of PPIs are administered orally. In our own study with lansoprazole (+ amoxicillin, clarithromycin, metronidazole) the eradication rates were 100, 98 and 80% in PM, hetEM and homEM, respectively, and in patients with GERD treated with lansoprazole (30 mg/day) the healing rates after 8 weeks were much higher in PM (85 - 100%) and hetEM (68 - 95%) than in homEM (46 - 77%). In a further study with esomeprazole (40 mg/day) in 205 patients with GERD we were surprised to observe that the healing rate after 4 weeks was not dependent on the CYP2C19 genotype. In an accompanying pharmacokinetic trial in 10 patients with GERD, both esomeprazole and 5-OH-esomeprazole (formed by CYP2C19) plasma levels and those of omeprazole-sulfone (formed by CYP3A4) were determined. Based on the calculated metabolic ratios it could be shown that CYP3A4 plays a major role in kinetics of esomeprozale, particularly after multiple dosing when there is a metabolic shift in favor of the formation of the sulfone. In conclusion, for most PPIs the activity of CYP2C 19 determines the level of drug exposure (AUC), pharmacodynamic response (elevation of intragastric pH and serum levels of gastrin) and clinical outcome (Hp eradication, healing rates of PU and GERD). Thus, a genotype-adjusted dosage regimen will improve therapeutic efficacy of PPIs.     

High-dose rabeprazole-amoxicillin versus rabeprazole-amoxicillin-metronidazole as second-line treatment after failure of the Japanese standard regimen for Helicobacter pylori infection

BACKGROUND: There is currently no optimal second-line treatment after failure of Helicobacter pylori triple therapy. AIM: To determine effective salvage therapy after failure of lansoprazole-amoxicillin-clarithromycin. METHODS: After failure of lansoprazole-amoxicillin-clarithromycin 123 out-patients were randomized to receive either 2-week rabeprazole (20 mg b.d.) + amoxicillin (1000 mg b.d.) (RA group) or 1-week rabeprazole (10 mg b.d.) + amoxicillin (750 mg twice b.d.) + metronidazole (250 mg b.d.) (RAM group). Eradication was assessed by the 13C-urea breath test. We also evaluated cytochrome p450 (CYP) 2C19 genotype status, determined by polymerase chain reaction - restriction fragment length polymorphism, and susceptibility to clarithromycin and metronidazole. RESULTS: On an intention-to-treat basis, H. pylori infection cure was achieved in 37 of 63 (59%) patients in the RA group and in 49 of 60 (82%) patients in the RAM group. Per protocol-based eradication rates in the RA and RAM groups were 66% (37/56) and 88% (49/56), respectively. In both analytic sets there were significant differences between the treatment groups (P < 0.01 in each). Mild adverse events were observed in eight and five patients from the RA and RAM groups, respectively. Genetic predisposition of CYP2C19 and antibiotic resistance did not influence the treatment outcome either regimen. CONCLUSIONS: The rabeprazole + amoxicillin + metronidazole therapy yielded satisfactory results. In contrast, the cure rate in high-dose rabeprazole + amoxicillin was below an acceptable level.     

CYP2C19 Genotype Related Effect of Omeprazole on Intragastric pH and Antimicrobial Stability

PURPOSE: A combination of proton pump inhibitors and antimicrobials has been applied as an anti-Helicobacter pylori (H. pylori) therapy. Omeprazole, one of the proton pump inhibitors, is metabolized by CYP2C19. which exhibits genetic polymorphism. It was reported previously that the overall anti-H. pylori efficacy can be related to the CYP2C19 genotype. The main aim of the present study was to obtain a rational explanation for the relationship between the overall anti-H. pylori efficacy and the CYP2C19 genotype. METHODS: Six healthy volunteers were classified as extensive metabolizers and poor metabolizers, according to their CYP2C19 genotypes. Plasma concentrations and intragastric pH were monitored prior to and until 24 h after the administration of 20 mg omeprazole. The stability of amoxicillin, clarithromycin, and metronidazole was examined using buffer solutions with monitored intragastric pH, and their remaining percentage in the intragastric space was simulated. RESULTS: The poor metabolizers, classified by the CYP2C19 genotypes, showed the higher effectiveness in anti-H. pylori therapy, via the higher plasma concentration of omeprazole and the higher intragastric pH, and possibly the higher stability of antimicrobials in the higher intragastric pH. CONCLUSIONS: CYP2C19 genotyping is a very useful method to determine the effective and safe dosage regimen including the selection of the dual and triple therapy in anti-H. pylori therapy.