Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin

BACKGROUND: Proton pump inhibitors such as omeprazole and lansoprazole are mainly metabolized by CYP2C19 in the liver. The therapeutic effects of proton pump inhibitors are assumed to depend on CYP2C19 genotype status. OBJECTIVE: We investigated whether CYP2C19 genotype status was related to eradication rates of H pylori by triple proton pump inhibitor-clarithromycin-amoxicillin (INN, amoxicilline) therapy and attempted to establish a strategy for treatment after failure to eradicate H pylori. METHODS: A total of 261 patients infected with H pylori completed initial treatment with 20 mg of omeprazole or 30 mg of lansoprazole twice a day, 200 mg of clarithromycin three times a day, and 500 mg of amoxicillin three times a day for 1 week. CYP2C19 genotypes of patients were determined with polymerase chain reaction-restriction fragment length polymorphism analysis. Patients without eradication after initial treatment were retreated with 30 mg of lansoprazole four times daily and 500 mg of amoxicillin four times daily for 2 weeks. RESULTS: Eradication rates for H pylori were 72.7% (95% confidence interval, 64.4%-81.8%), 92.1% (confidence interval, 86.4%-97.3%), and 97.8% (confidence interval, 88.5%-99.9%) in the homozygous extensive, heterozygous extensive, and poor metabolizer groups, respectively. Thirty-four of 35 patients without eradication had an extensive metabolizer genotype of CYP2C19. Nineteen of those patients were infected with clarithromycin-resistant strains of H pylori. However, there were no amoxicillin-resistant strains of H pylori. Re-treatment of H pylori infection with dual high-dose lansoprazole-amoxicillin therapy succeeded in 30 of 31 patients with extensive metabolizer genotype of CYP2C19. CONCLUSION: The majority of patients without initial eradication of H pylori had an extensive metabolizer CYP2C19 genotype but were successfully re-treated with high doses of lansoprazole and an antibiotic to which H pylori was sensitive, such as amoxicillin, even when the patients were infected with clarithromycin-resistant strains of H pylori.     

CYP2C19 genotype-related efficacy of omeprazole for the treatment of infection caused by Helicobacter pylori

OBJECTIVES: Omeprazole is used for the treatment of infection caused by Helicobacter pylori, and it is metabolized by the polymorphic cytochrome P4502C19 (CYP2C19). We have found that the anti-H pylori efficacy by the combination of omeprazole and antibiotics is related to the CYP2C19 genotype. METHODS: One hundred eight patients with cultured H pylori-positive gastritis or peptic ulcer were treated with three regimens: quadruple treatment without proton pump inhibitors (n = 25), dual treatment with omeprazole and amoxicillin (INN, amoxicilline) (n = 26), and triple treatment with omeprazole, amoxicillin, and clarithromycin (n = 57). The CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and the assessment of the eradication of H pylori was based on all negative examinations, including culture, histology, and 13C-urea breath test. RESULTS: The eradication rates for the extensive metabolizers were 50% and 86% for the dual and triple treatments, respectively. In contrast, all of the poor metabolizers treated with omeprazole and antibiotics (n = 15) showed an eradication of H pylori. CONCLUSION: The anti-H pylori effect of dual treatment is highly efficient for CYP2C19 poor metabolizers, which suggests that clarithromycin is not necessary as a first line of therapy for this type of patients. Genotyping can provide a choice for the optimal regimen based on individual CYP2C19 genotype.     

Cure of refractory duodenal ulcer and infection caused by Helicobacter pylori by high doses of omeprazole and amoxicillin in a homozygous CYP2C19 extensive metabolizer patient

A 53-year old female patient with duodenal ulcer and Helicobacter pylori infection was treated three times with a proton pump inhibitor-based triple therapy, such as lansoprazole-clarithromycin-amoxicillin (INN, amoxicilline) and lansoprazole-minocycline-cefaclor. However, the H pylori infection was not cured. A culture test revealed that her infection was a clarithromycin-resistant but amoxicillin-sensitive strain of H pylori. Moreover, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis revealed that she was a homozygous extensive metabolizer of cytochrome P450 (CYP) 2C19 (wt/wt). The usual dose of the proton pump inhibitor was therefore assumed to be insufficient for her and then she was treated with a high dose of omeprazole (120 mg/day) and amoxicillin (2,250 mg/day) for 2 weeks. The H pylori infection and the ulcer lesion were then cured. One of the factors associated with success or failure of cure of H pylori infection by the proton pump inhibitor-based triple therapy appeared to be CYP2C19 genotype status. Dual treatment with a sufficient dose of a proton pump inhibitor plus amoxicillin could cure H pylori infection even after the failure to cure H pylori infection by a usual proton pump inhibitor-based triple therapy in patients with the wt/wt homozygous extensive metabolizer genotype of CYP2C19.     

Influences of proinflammatory and anti-inflammatory cytokine polymorphisms on eradication rates of clarithromycin-sensitive strains of Helicobacter pylori by triple therapy

BACKGROUNDS AND AIMS: Polymorphisms of proinflammatory cytokines, such as interleukin (IL) 1beta and tumor necrosis factor (TNF) alpha, are associated with individual differences in gastric mucosal inflammation and acid inhibition in response to Helicobacter pylori infection. We investigated whether inflammation-related cytokine polymorphisms would influence the eradication rates of H pylori by a triple-therapy regimen. METHODS: Three hundred sixty patients infected with clarithromycin-sensitive strains of H pylori were genotyped for IL1B -511, IL1RN, TNFA -857/-863/-1,031, IL10 -1,082/-819/-592, and CYP2C19 and underwent triple therapy for 1 week with a proton pump inhibitor (20 mg omeprazole, 30 mg lansoprazole, or 10 mg rabeprazole) twice daily, 400 mg clarithromycin twice daily, and 750 mg amoxicillin (INN, amoxicilline) twice daily. The influences of the previously mentioned polymorphisms on the eradication rates were analyzed. RESULTS: The intention-to-treat-based total eradication rate was 83.6% (301/360). The logistic regression analysis revealed that polymorphisms of CYP2C19 and IL1B -511 were independently associated with the eradication rates, but other cytokine polymorphisms were not associated with these rates. The eradication rates in patients with IL1B -511 C/C, C/T, and T/T genotypes were 72.2% (70/97), 87.7% (164/187), and 88.2% (67/76), respectively (P = .0017). When patients were stratified by CYP2C19 genotype status, IL1B -511 genotype-dependent differences in eradication rates were observed in homozygous extensive metabolizers (EMs) but not in heterozygous EMs and poor metabolizers of CYP2C19. The eradication rate in homozygous EM patients with the IL1B -511 C/C genotype was quite low (51.1% [22/43]). CONCLUSIONS: IL1B -511 polymorphism, but not IL1RN, TNFA, or IL10 polymorphism, is one of the determinants of triple therapy for clarithromycin-sensitive strains of H pylori in CYP2C19 homozygous EMs.     

The effect of cytochrome P2C19 and interleukin-1 polymorphisms on H. pylori eradication rate of 1-week triple therapy with omeprazole or rabeprazole, amoxycillin and clarithromycin in Chinese people

What is known and objective: Genetic polymorphism of interleukin (IL)–1β and IL‐1 receptor antagonist (IL‐1rα) are associated with efficacy of acid suppression, whereas cytochrome P (CYP) 2C19 polymorphism influences the metabolism of proton pump inhibitor family. Thus, CYP2C19 and IL‐1 polymorphisms may affect the efficacy of H. pylori eradication therapy. We compared the efficacies of omeprazole and rabeprazole on eradication of H. pylori in relation to CYP2C19, IL‐1B and IL‐1RN genotypes in Chinese people. Methods: Two hundred and forty Chinese with peptic ulcer disease were randomly assigned to the following regimens: amoxicillin and clarithromycin together with omeprazole (OAC) or rabeprazole (RAC). CYP2C19*2 and *3, IL1B‐511, IL1B‐31, IL1B+ 3954 and intron 2 of the IL‐1RN genotypes were analyzed by polymerase chain reaction‐restriction fragment length polymorphism. Results: The intention‐to‐treat‐based cure rate of the OAC regimen was significantly lower than that of the RAC regimen in the CYP2C19 wild‐type homozygotes (P = 0·014). No significant differences in the cure rates were observed among the IL‐1RN and the IL‐1B genotype groups. What is new and conclusions: The rabeprazole‐based triple regimen was better than the omeprazole in Chinese patients with the CYP2C19 extensive metabolizer genotype. The effectiveness of the PPI/AC regimen is unrelated to IL‐1B and IL1‐RN genetic polymorphism.     

基因多态性对质子泵抑制剂联合阿莫西林与克拉霉素三联疗法根除幽门螺杆菌效果的影响

目的探讨CYP2C19基因多态性对质子泵抑制剂联合阿莫西林与克拉霉素三联疗法根除幽门螺杆菌（Hp）的影响。方法选择90例Hp阳性的消化性溃疡患者，随机分成观察组与对照组，每组45例，所有患者均于治疗前测定cYP2C19基因型，分为EM、IM及PM型。观察组给予雷贝拉唑＋阿莫西林＋克拉霉素口服，对照组给予奥美拉唑＋阿莫西林＋克拉霉素口服，两组均治疗1周。停药4周后检测Hp根除情况。结果观察组与对照组HP根除率分别为85：7％和77．8％，差异无统计学意义（P〉0．05）；观察组EM、IM、PM型HP根除率及各基因分型比较，差异无统计学意义（P〉0．05）；对照组EM与IM、EM与PM之间HP根除率差异有统计学意义（P〈O．01），IM与PM间差异无统计学意义（P〉0．05）。结论CYP2C19基因多态性对雷贝拉唑联合阿莫西林与克拉霉素三联疗法Hp根除率无明显影响，对奥美拉唑联合阿莫西林与克拉霉素三联疗法的Hp根除率影响较大。     

Progress of tailor-made treatment of peptic ulcer]

We previously reported that a comparative pharmacokinetic study with each PPI was designed as an open, randomized, and crossover study of 18 Japanese healthy volunteers who were classified into the homozygous, heterozygous extensive metabolizer and the poor metabolizer based on the CYP2C19 genotype. With at least 1 week washout period between treatments. Plasma concentrations of PPIs and their metabolites were monitored until 12 h after medication. Pharmacokinetic profiles of omeprazole and lansoprazole were well correlated with the CYP2C19 genotype. The heterozygous extensive metabolizer was slightly different from the homozygote, but there was no statistically significant difference. The CYP2C19 genotype dependence found for lansoprazole was not obvious compared with omeprazole. As for rabeprazole, the pharmacokinetic profile was independent of the CYP2C19 genotype. CYP2C19 genotyping can provide a new strategy to choose an optimal regimen, and this genotyping is especially useful for Japanese, as the frequency of poor metabolizers is five times greater than that found among Caucasians.     

Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19.

BACKGROUNDS AND AIM: Lansoprazole is mainly metabolized by cytochrome P4502C19 (CYP2C19) in the liver. The effect of lansoprazole is assumed to be insufficient in subjects who are homozygous extensive metabolizers of CYP2C19. This study aimed to examine whether the CYP2C19 genotype status affected the acid-inhibitory effects of lansoprazole and to develop a strategy to overcome this pharmacogenetic problem. METHODS: Eighteen Helicobacter pylori-negative healthy volunteers, whose CYP2C19 genotypic status had been assessed, participated in the study. They consisted of 7 subjects who were homozygous extensive metabolizers, 7 subjects who were heterozygous extensive metabolizers, and 4 subjects who were poor metabolizers of CYP2C19, who took a placebo or lansoprazole 30 mg once daily in the morning for 8 days. On day 8 of dosing, 24-hour intragastric pH values were recorded. Five of the homozygous extensive metabolizer subjects underwent the 24-hour intragastric pH monitoring on day 8 of dosing of lansoprazole 30 mg 4 times daily. RESULTS: When lansoprazole 30 mg was given once daily, the mean 24-hour intragastric pH values in the subjects who were homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers were 4.5, 4.9, and 5.5, respectively (P <.005). On day 8 of dosing of lansoprazole 30 mg 4 times daily in subjects who were homozygous extensive metabolizers, the mean 24-hour intragastric pH value was 7.4. CONCLUSION: The effect of lansoprazole on intragastric pH depended significantly on CYP2C19 genotype status. Complete acid inhibition could be achieved by the frequent administration of lansoprazole (eg, 30 mg 4 times daily) in subjects who were homozygous extensive metabolizers. A genotyping test of CYP2C19 status appears useful for prescribing an optimal dosing scheme of lansoprazole.     

Pharmacogenetics of esomeprazole or rabeprazole‐based triple therapy in Helicobacter pylori eradication in Hong Kong non‐ulcer dyspepsia Chinese subjects

Objective: Our study aimed to assess the effectiveness of esomeprazole or rabeprazole in combination with amoxicillin and clarithromycin for the eradication of Helicobacter pylori in Hong Kong non‐ulcer dyspepsia (NUD) patients. Methods: A prospective clinical trial was conducted at the Alice Ho Miu ling Nethersole Hospital outpatient endoscopy center from June 2004 to December 2005. Participants received amoxicillin 1 g, clarithromycin 500 mg, and, esomeprazole 20 mg (EAC) or rabeprazole 20 mg (RAC), all given twice daily for 1 week. The H. pylori status was determined by the [¹³C] urea breath test at least 4 weeks after completion of the treatment. Mutation status of CYP2C19 in exon 4 and exon 5 associated with the poor metabolizer phenotype was determined. Results: The intention‐to‐treat eradication rates in patients treated with RAC and EAC were 77% and 84·6% respectively, and per protocol‐based eradication rates were 83·7% and 88·9% respectively. The eradication rates did not vary with CYP2C19 phenotype found. For clarithromycin‐sensitive strains, the cure rates were statistically significant regardless of CYP2C19 polymorphism (P < 0·0001). Conclusion: Triple therapy with either EAC or RAC is effective for Hong Kong Chinese NUD patients with H. pylori infection. Success eradication was related to clarithromycin resistance and not CYP2C19 genotype.     

Effects of CYP2C19 genetic polymorphism on the pharmacokinetics and pharmacodynamics of omeprazole in Chinese people

BACKGROUND: To investigate whether the pharmacodynamics and pharmacokinetics of omeprazole (OPZ) are dependent of the CYP2C19 genotype status in Chinese people. METHODS: Eighteen healthy subjects were voluntary to participate in the study, whose CYP2C19 genotype status were determined by polymerase chain reaction-restriction fragment length polymorphism method. There were six homozygous extensive metabolizers, six heterozygous extensive metabolizers and six poor metabolizers (PMs). All subjects were Helicobacter pylori-negative, determined by serology method and (13)C-urea breath test. After d1 and d8 orally received OPZ 20 mg once daily in the morning, intragastric pH values were monitored for 24 h by Digitrapper pH. Meanwhile, blood samples were collected at various time-points until 24 h after administration. The serum concentrations of OPZ were measured by liquid chromatography. RESULTS: After single or repeated doses, the PMs showed a significantly higher mean area under the serum concentration-time curves (AUC) values than that observed in the homozygous extensive metabolizers or the heterozygous extensive metabolizers, with a relative ratio of 1.0 : 1.1 : 4.2 and 1.0 : 1.3 : 3.3 (homozygous extensive metabolizers:heterozygous extensive metabolizers:poor metabolizers), respectively. After a single dose of OPZ, significant differences in intragastric pH median, pH > 3 holding time and pH > 4 holding time were observed among the three groups. After repeated doses, the PMs showed a significantly higher intragastric pH values than that observed in the homozygous extensive metabolizers or the heterozygous extensive metabolizers. CONCLUSION: The pharmacodynamic effects of OPZ and its pharmacokinetics depend on the CYP2C19 genotype status in Chinese people.     

Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. pylori

Helicobacter pylori eradication rates by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin at standard doses depend on bacterial susceptibility to clarithromycin and patient CYP2C19 genotypes. We examined the usefulness of a personalized therapy for H. pylori infection based on these factors as determined by genetic testing. First, optimal lansoprazole dosing schedules that would achieve sufficient acid inhibition to allow H. pylori eradication therapy in each of different CYP2C19 genotype groups were determined by a 24-h intragastric pH monitoring. Next, 300 H. pylori-positive patients were randomly assigned to the standard regimen group (lansoprazole 30 mg twice daily (b.i.d.)), clarithromycin 400 mg b.i.d., and amoxicillin 750 mg b.i.d. for 1 week) or the tailored regimen group based on CYP2C19 status and bacterial susceptibility to clarithromycin assessed by genetic testing. Patients with failure of eradication underwent the second-line regimen. The per-patient cost required for successful eradication was calculated for each of the groups. In the first-line therapy, the intention-to-treat eradication rate in the tailored regimen group was 96.0% (95% CI=91.5-98.2%, 144/150), significantly higher than that in the standard regimen group (70.0%: 95% CI=62.2-77.2%, 105/150) (P<0.001). Final costs per successful eradication in the tailored and standard regimen groups were $669 and $657, respectively. In conclusion, the pharmacogenomics-based tailored treatment for H. pylori infection allowed a higher eradication rate by the initial treatment without an increase of the final per-patient cost for successful eradication. However, the precise cost-effectiveness of this strategy remains to be determined.     

Relationship between the acid-inhibitory effects of two proton pump inhibitors and CYP2C19 genotype in Japanese subjects: a randomized two-way crossover study

This two-way crossover study investigated possible differences between the proton pump inhibitors, omeprazole and rabeprazole, in their effect on gastric acid secretion in Japanese subjects with differing cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) genotypes. A total of 23 Helicobacter pylori-negative healthy volunteers received omeprazole 20 mg/day and rabeprazole 10 mg/day. Each drug treatment was given for a continuous 7-day period allocated in random order, with an interval of at least 1 week between drug treatment periods to allow for wash-out. Intragastric pH was measured on days 1 and 7. Overall median intragastric pH levels at 7 and 8 h after the first administration were significantly higher with omeprazole. There was no significant difference in intragastric pH in homozygous extensive metabolizers, whereas intragastric pH was significantly higher with omeprazole in combined data from heterozygous extensive metabolizers and poor metabolizers at 6, 7 and 8 h after the first drug administration. There were no significant differences in intragastric pH between omeprazole and rabeprazole irrespective of genotype on day 7 of administration. In conclusion, on day 1 the time to onset of the antisecretory action of 20 mg/day omeprazole was more rapid than that of 10 mg/day rabeprazole in Japanese individuals who have a higher incidence of the CYP2C19 poor metabolizer genotype, however by day 7 no difference in antisecretory effect was found, regardless of genotype.     

Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole

BACKGROUND AND OBJECTIVES: The acid-inhibitory effect of lansoprazole depends on differences in cytochrome P450 (CYP) 2C19 genotypes. We assessed whether therapeutic effects of lansoprazole on gastroesophageal reflux disease (GERD) depended on the CYP2C19 genotype status in relation to the grade of GERD. METHODS: A total of 65 patients with GERD (grades A-D) completed treatment with lansoprazole, by taking 30 mg orally once a day for 8 weeks. The CYP2C19 genotype status of patients was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Before and after treatment, esophageal endoscopy was performed. GERD was considered to be cured on the basis of endoscopic findings at the end of treatment. Plasma lansoprazole levels could be determined at 3 hours after the last 30-mg dose of lansoprazole in the 27 genotyped patients. RESULTS: Cure rates for GERD depended significantly on the CYP2C19 genotype status, as well as the grade of GERD before treatment. Cure rates in the homozygous extensive, heterozygous extensive, and poor metabolizer groups were 45.8%, 67.9%, and 84.6%, respectively. Cure rates in the groups with GERD grade A, grade B, and grade C or D were 85.0%, 60.0%, and 45.0%, respectively. The cure rate in patients with the homozygous extensive metabolizer genotype of CYP2C19 with a GERD grade of C or D was very low (16.7%). Plasma lansoprazole levels in patients with the homozygous extensive metabolizer genotype were the lowest of the 3 groups. CONCLUSIONS: CYP2C19 genotype status, as well as the grade of GERD before treatment, is one of the determinants for the success or failure of treatment of GERD with lansoprazole. The low cure rate in patients with the homozygous extensive metabolizer genotype appeared to be a result of these patients having the lowest plasma lansoprazole levels among the 3 genotype groups.     

Tailor-made medicine in Helicobacter pylori eradication therapy

Pharmacokinetic profiles of omeprazole and lansoprazole were well correlated with the CYP2C19 genotype. The heterozygous extensive metabolizer was slightly different from the homozygote, but there was no statistically significant difference. The CYP2C19 genotype dependence found for lansoprazole was not obvious compared with omeprazole. As for rabeprazole, the pharmacokinetic profile was independent of the CYP2C19 genotype. CYP2C19 genotyping can provide a new strategy to choose an optimal regimen, and this genotyping is especially useful for Japanese, as the frequency of poor metabolizers is five times greater than that found among Caucasians. However, we should be aware that the increase of antimicrobial-resistant strains of H. pylori may force us to examine antimicrobial susceptibility of all patients in order to achieve a more than 80% eradication rate at first-line therapy in the near future. We should also have proper knowledge of the influence of the CYP2C19 genetic polymorphism on treatment efficacy according to the variety of PPI and the combination with other drugs.     

Dose-dependent inhibition of CYP3A activity by clarithromycin during Helicobacter pylori eradication therapy assessed by changes in plasma lansoprazole levels and partial cortisol clearance to 6beta-hydroxycortisol

OBJECTIVE: A 7-day triple therapy with lansoprazole, amoxicillin (INN, amoxicilline), and clarithromycin is widely used for eradication of Helicobacter pylori. Because clarithromycin is a potent inhibitor of cytochrome P450 (CYP) 3A, we investigated whether the standard triple therapy with clarithromycin would elicit clinically relevant CYP3A inhibition and alter CYP3A-mediated lansoprazole disposition in H pylori-positive patients. METHODS: Twenty H pylori-positive patients with peptic ulcer disease were randomly assigned to 2 groups: One group received 200 mg clarithromycin, 30 mg lansoprazole, and 750 mg amoxicillin at 8 am and 8 pm for 7 days; the other group received 400 mg clarithromycin, 30 mg lansoprazole, and 750 mg amoxicillin at 8 am and 8 pm for 7 days. Ten healthy control subjects received 30 mg lansoprazole and 750 mg amoxicillin at 8 am and 8 pm for 7 days but did not receive clarithromycin. Urine samples were collected for 3 hours (from 8 am to 11 am) for urinary 6beta-hydroxycortisol and cortisol assay, and midpoint (at 9:30 am) plasma samples for cortisol assay were obtained from all participants before the drug therapy (day 0) and on day 7. In vivo CYP3A activity was assessed by the partial cortisol clearance by means of the formation of 6beta-hydroxycortisol (CL(cortisol-->6beta-hydroxycortisol)) and the urinary 6beta-hydroxycortisol/cortisol ratio. Additional plasma samples for lansoprazole, 5-hydroxylansoprazole, and lansoprazole sulfone assay were obtained at 11 am on day 7. RESULTS: The groups of patients given 400 and 800 mg/day clarithromycin for H pylori eradication therapy showed 39% (from 2.20 +/- 1.29 to 1.35 +/- 0.88 mL/min [day 0 versus 7, mean +/- SD]; P <.05) and 68% (2.40 +/- 1.22 to 0.76 +/- 0.51 mL/min; P <.05) reductions in CL(cortisol-->6beta-hydroxycortisol), respectively. In contrast, the control subjects given lansoprazole and amoxicillin without clarithromycin showed no significant changes in CL(cortisol-->6beta-hydroxycortisol). The urinary 6beta-hydroxycortisol/cortisol ratio also decreased significantly (P <.05) in the patient groups but not in the control subjects. The mean 3-hour plasma lansoprazole levels elevated in proportion to the doses of clarithromycin: 385 +/- 338 ng/mL for the control subjects, 696 +/- 797 ng/mL for the H pylori-positive patients given 400 mg/day clarithromycin, and 947 +/- 806 ng/mL for the H pylori-positive patients given 800 mg/day clarithromycin (P <.05 versus the control subjects). No significant differences were observed among the groups in the mean plasma ratios of 5-hydroxylansoprazole or lansoprazole sulfone to lansoprazole. CONCLUSIONS: The 7-day H pylori eradication therapy with clarithromycin, amoxicillin, and lansoprazole may elicit substantial inhibition of in vivo CYP3A activity. Although resultant elevations in plasma lansoprazole concentrations may be beneficial for H pylori eradication, caution must be exercised for possible drug interaction with a concomitantly administered CYP3A substrate (s) in patients undergoing H pylori eradication therapy with clarithromycin, amoxicillin, and lansoprazole.     

CYP2C10基因多态性对奥美拉唑治疗十二指肠溃疡的影响

目的 探讨奥美拉唑治疗十二指肠溃疡合并幽门螺旋菌感染的疗效及其与CYP2C19基因多态性的关系.方法 应用奥美拉唑+阿莫西林+克拉霉素三联用药1周后单用奥美拉唑抑酸3周的方案治疗65例经胃镜证实的十二指肠溃疡合并幽门螺旋菌( Hpylori)感染患者.记录治疗前和用药后症状的变化,并于治疗结束时复查胃镜.患者CYP2C19的基因型检测采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)分析方法.结果 65例十二指肠溃疡患者中,24例为纯合子强代谢者,31例为杂合子强代谢者,10例为弱代谢者.纯合子强代谢组、杂合子强代谢组和弱代谢组有效率分别为75.0％、90.3％和100％,纯合子强代谢组的治愈率显著低于弱代谢组(P＜0.05).弱代谢型组患者的Hpylori清除率显著高于纯合子强代谢型和杂合子强代谢型(P＜0.05).结论 CYP2C19基因多态性与奥美拉唑治疗十二指肠溃疡合并幽门螺旋菌感染的疗效密切相关.CYP2C19基因分型检测是临床治疗酸相关性疾病中的一个重要的工具.     

Comparison of five-day Helicobacter pylori eradication regimens: rabeprazole-based and omeprazole-based regimens with and without omeprazole pretreatment

Background: The onset of antisecretory activity of rabeprazole is faster than that of omeprazole.Objective: This study was performed to compare the efficacy of short-term rabeprazole-based triple therapy with that of omeprazole-based triple therapy and to determine the influence of omeprazole pretreatment in omeprazole-based short-term triple therapy.Methods: This was a 2-center, open-label, prospective, randomized study. Patients who tested positive for Helicobacter (formerly Campylobacter) pylori were randomized to one of three 5-day regimens: (1) rabeprazole 20 mg BID, amoxicillin 500 mg TID, and clarithromycin 400 mg BID (RAC group); (2) omeprazole 20 mg BID, amoxicillin 500 mg TID, and clarithromycin 400 mg BID without omeprazole pretreatment (OAC1 group); and (3) omeprazole 20 mg BID, amoxicillin 500 mg TID, and clarithromycin 400 mg BID with 5 days of omeprazole pretreatment 20 mg BID (OAC2 group). Eradication was assessed by ¹³C-urea breath test and rapid urease test ∼1 month after completion of treatment. All patients who entered this study were included in the intent-to-treat (ITT) analysis, patients who completed the study were included in the per-protocol (PP) analysis, and patients who did not undergo the ¹³C-urea breath test and rapid urease test were included in the all-patients-treated (APT) analysis.Results: A total of 120 patients (86 men, 34 women; mean [SD] age, 55.8 [14.3] years; range, 19-86 years) were assigned to the RAC, OAC1, or OAC2 group (40 patients in each group). ITT, PP, and APT eradication rates in the RAC group were 90%, 92%, and 90%, respectively; in the OAC1 group, 75%, 83%, and 75%; and in the OAC2 group, 85%, 90%, and 87%. These eradication rates were not significantly different between groups.Conclusions: Eradication rates did not differ significantly between the three 5-day proton pump inhibitor-based triple therapies in this study population. However, 5-day rabeprazole-based triple therapy tends to be more effective than 5-day omeprazole-based triple therapy in the eradication of H pylori, and treatment with omeprazole before eradication therapy may improve the eradication rates of 5-day omeprazole-based therapy.     

基于可视化基因芯片技术指导幽门螺杆菌个体化治疗的临床研究

目的利用可视化基因芯片检测技术检测结果指导幽门螺杆菌"个体化"治疗,评价其优越性。方法 244例初诊幽门螺旋杆菌感染患者的胃黏膜组织,检测组织标本中幽门螺旋杆菌gyrA基因上喹诺酮耐药相关的Asn87(N87K)、Asp91(D91G/Y/N)突变位点和23s rRNA基因上克拉霉素耐药相关的A2142G、A2143G突变位点,以及人CYP2C19上与PPI代谢相关的等位基因2C19*2、2C19*3突变位点。根据检测结果喹诺酮和克拉霉素的敏感性分为敏感及耐药;PPI药物代谢活性分为强代谢型(EM)、中代谢型(IM)和弱代谢型(PM);结合检测结果给予幽门螺杆菌"个体化"四联根除治疗,并统计根除率。结果 244例中检出63例对抗生素耐药,耐药率25.80%(63/244),其中左氧氟沙星和克拉霉素耐药率耐药率2.86%(7/244)和20.49%(50/244),两者双重耐药率2.45%(6/244)。244例中检出CYP2C19代谢类型有242例(99.18%),其中EM、IM、PM、分别占40.08%(97/242)、58.26%(141/242)和1.65%(4/242)。242例检测结果阳性患者根据检测结果给予幽门螺杆菌个体化的"四联"治疗,240例完成治疗,初次根除率达到91.67%。EM、IM、PM的根除率分别为89.58%、92.86%和100%,差异无统计学意义(P>0.05)。结论可视化基因芯片技术能够同时提供准确的CYP2C19代谢类型和克拉霉素、左氧氟沙星耐药情况,指导临床用药,具有较好的临床应用价值。     

序贯疗法与三联疗法根除儿童幽门螺杆菌感染的临床研究

目的比较分析由奥美拉唑、克拉霉素、阿莫西林和甲硝唑组成的10 d序贯疗法与标准三联疗法根除儿童幽门螺杆菌（Hp）感染的临床疗效。方法将109例诊断为Hp感染的患儿按随机数字表法分为3组：10 d序贯疗法组（37例）、10 d三联疗法组（36例）和14 d三联疗法组（36例）。10 d序贯疗法组：前5 d给予奥美拉唑0.6-0.8 mg·kg^-1·次-1＋阿莫西林50 mg·kg^-1·d-1,口服,每日早晚各1次;后5 d改用奥美拉唑0.6-0.8 mg·kg^-1·次-1＋克拉霉素15-30 mg·kg^-1·d-1＋甲硝唑片25-30 mg·kg^-1·d-1,口服,每日早晚各1次。10 d和14 d三联疗法2组：奥美拉唑0.6-0.8 mg·kg^-1·次-1＋克拉霉素15-30 mg·kg^-1·d-1＋阿莫西林50 mg·kg^-1·d-1或甲硝唑片25-30 mg·kg^-1·d-1,口服,每日早晚各1次,疗程分别为10 d和14 d。所有患儿在停药后至少4周复查13C尿素呼气试验（13C-UBT）,观察Hp根除率、疗效及不良反应（食欲不振、恶心、呕吐、腹泻、便秘、头痛、皮疹等症状）的发生情况。结果 109例患儿中失访7例（6.4%,10 d序贯疗法组1例,10 d三联疗法组2例,14 d三联疗法组4例）。10 d序贯疗法组Hp根除率按意向治疗分析（ITT）及试验方案分析（PP）均明显高于10 d三联疗法组（χ^2=5.408,5.137,均P〈0.05）,与14 d三联疗法组比较差异均无统计学意义（χ^2=2.510,0.868,均P〉0.05）。3组患儿治疗后总有效率比较差异均无统计学意义（χ^2=0.320,P〉0.05）。3组患儿均未出现严重的不良反应。结论 10 d序贯疗法是一种安全、有效的儿童Hp根除方案。