父亲节快乐英文
Improved Efficacy of Proton Pump Inhibitor–Amoxicillin–Clarithromycin Triple Therapy for Helicobacter pylori Eradication in Low Clarithromycin Resistance Areas or for Tailored Therapy
Sanchai Prartpetmanee,*Varocha Mahachai†,‡and Ratha-korn Vilaichone*,‡
*GI Unit,Department of Medicine,Thammasat University Hospital,Pathumthani,12120,Thailand,†GI and Liver Center,Bangkok Medical Center, Bangkok,10310,Thailand,‡National Gastric Cancer and Helicobacter pylori Rearch Center,Bangkok,10310,Thailand
Keywords
amoxicillin,Helicobacter pylori,Improved triple therapy,clarithromycin,nonulcer dyspepsia,proton pump inhibitors,Thailand.
Reprint requests to:Dr.Ratha-korn Vilaichone,GI Unit,Department of Medicine,Thammasat University Hospital,Pathumthani12120and National Gastric Cancer and Helicobacter pylori Rearch Center,Bangkok,10310,Thailand.
E-mail: Objective:Standard triple therapy for Helicobacter pylori eradication is no longer effective as an empiric choice in most areas.Even in low clarithromy-cin resistance areas,res
ults 95%are infrequently achieved.This study was designed to arch for a version of standard triple therapy for u low preva-lence areas or as tailored therapy that is highly effective irrespective of CYP2C19genotype.
Design:Two prospective pilot single center studies were performed in Thai-land.H.pylori-infected subjects were randomized to7-or14-day regimens using a high-do proton pump inhibitor(PPI)triple therapy consisting of lansoprazole(60mg)twice daily,amoxicillin1g twice daily,and long-acting clarithromycin MR1g once daily.H.pylori was defined as positive H.pylori culture;or two positive tests(rapid urea test and histology);CYP2C19 genotyping was performed.H.pylori eradication was evaluated by13C-UBT4 or more weeks after treatment.
Results:Hundred and ten subjects were enrolled(55each to the7-and 14-day regimens).Antibiotic susceptibility testing(25strains)showed40% metronidazole resistance but no clarithromycin resistance.CYP2C19geno-typing(64subjects)revealed56.3%rapid metabolizer,29.7%intermediate metabolizer,and14%poor metabolizer.The eradication rate with the 14-day regimen was100%(95%CI=93.5–100%)and92.7%(95% CI=82–97%)with the7-day regimen.The difference was related to improved eradication at14days in rapid 100vs88.2%). Conclusion:Triple therapy using a14-day high-do PPI and long-acting clarithromycin provided an excellent cure rate(100%)re
gardless of the CYP2C19genotype.
Helicobacter pylori(H.pylori)is gram-negative bacteria etiologically associated with chronic gastritis,peptic ulcer dia,and gastric malignancy[1–3].H.pylori has proven difficult to cure,and standard triple therapy is no longer recommended as an empiric choice in most countries[4,5].However,triple therapy is still recom-mended in areas where clarithromycin resistance is low or when therapy is chon bad on pretreatment susceptibility as tailored therapy).Triple therapy is adverly affected by many factors besides antibiotic resistance including smoking,the dos utilized,and duration of nding the duration of proton pump inhibitor(PPI)-clarithromy-cin-containing triple therapies from7to10–14days improves the eradication success by about5%[6]).The do of the PPI has also proven important[7,8],and effectiveness can be influenced by the choice of PPI[9] and the effects of genetic polymorphism of CYP2C19on the PPI metabolism[10,11].Tho with poor PPI metabolism receive longer durations of anticretory action reflected by the time the gastric pH remains at six or above which directly affects the effectiveness of the regimen[7].Here,we report studies arching for an optimized combination of drugs and durations for triple therapy to be highly effective in areas with a low prevalence of clarithromycin resistance irrespective the CYP2C19genotype.We performed two pilot studies to asss H.pylori eradication with high-do PPI and
Helicobacter ISSN1523-5378
doi:
10.1111/hel.12041
long-acting clarithromycin administered for7or 14days.We also examined the effects of CYP2C19 genotype and antibiotic resistance.
Methods
Patients who underwent gastroscopic examination at Thammasat University Hospital,Thailand,for dyspeptic symptoms were recruited for the studies between December2010and December2011.Entry criteria included age over18years of age and tho who had never received H.pylori eradication or received PPI,H2 receptor antagonists,bismuth,and antibiotics in the prior1month.We also excluded tho who were receiv-ing anticoagulants,nonsteroid anti-inflammatory drugs, who had previously undergone gastric surgery and tho patients with significan
t systemic dias,patients who abud drug or alcohol,and women who were breast-feeding or had child-bearing potential without using effective contraception.Signed informed connt was obtained to participate in this study.The diagnosis of nonulcer dyspepsia was made according to symptomatic asssment and endoscopicfindings.Dyspeptic patients with normal endoscopy and tho with gastritis without erosions or ulcer were considered of having nonulcer dyspepsia(NUD)was enrolled in this study.During endoscopy,four biopsy samples from gastric antrum were obtained for rapid urea test,culture and E-test, GenoType(â)HelicoDR(Hain Lifescience factory, Nehren,Germany),histological examination,and CYP2C19genotype.The CYP2C19genotype divided into three groups:rapid metabolizer(RM),intermediate metabolizer(IM),or poor metabolizer(PM)and was performed as described previously[10].The prence of H.pylori was defined as follows:1,positive H.pylori cul-ture;or2,positive tests(rapid urea test and histology). Therapeutic Regimens
Eligible subjects were randomized using a computer-generated randomization list to one of two pilot studies. Randomization was performed at the time of lection of either a7-day or a14-day therapy consisting of lan-soprazole(60mg),amoxicillin(1g)both given twice a day,and long-acting clarithromycin MR(1000mg) once a day.PPI therapy was limited to the7or14days of triple therapy.
Post-Therapy Follow-Up
Subjected returned for asssment of eradication respon by13C-urea breath test(UBT)at least4weeks after completion of therapy.The urea breath test was performed as described previously[4].Successful eradi-cation was defined as a negative UBT result.Pill count was conducted,and drug consumption over90%is defined as good compliance.Side effects were assd by personal interview using open-ended questions and a questionnaire administered by one of the investiga-tors.New symptoms and exacerbation of pre-existing symptoms during the therapy period are considered to be therapy-related side effects.
Questionnaire
The questionnaire included personal history of smok-ing.Smokers were defined as tho who consumed more than one pack of cigarettes a week.The medical histories and underlying hypertension, diabetes,hyperlipidemia,coronary artery dia,bone and joint dia)were recorded.The adver events evaluated included diarrhea,abdominal pain,constipa-tion,dizziness,bitter taste,headache,anorexia,naua, vomiting,and skin rashes.Tho who considered that their symptoms disturbed daily life were defined as having major adver effects.Th
o who experienced the symptoms but did not consider them a distur-bance to daily life were defined as minor adver effects.
Statistical Analysis
Subjects were randomized into two parallel groups to prevent lection bias.We expected the eradication rate of high-do PPI triple therapy as an empiric therapy to be 90%.Treatment success was prespecified as a cure rate 95%(ade A)as described in previous stud-ies[12]and failure as a cure rate of<90%per protocol. The demographic information and frequencies of adver effects were compared using chi-squared test, Fisher’s exact test,and Student’s t-test.The p-values <.05were considered to be statistically significant.The study was conducted according to the good clinical prac-tice guideline,as well as the Declaration of Helsinki, and was approved by our local ethics committee.All subjects signed informed connt to participate in this study.
Results
英语六级考试时间A total of110subjects were randomized(55received the7-day regimen and55received the14-day regimen) including39male and71female subjects with the mean age of51.7years.The baline demographic data between the two groups were similar consistent with the randomization process
(Table1).
Prartpetmanee et al.Triple Therapy for H.pylori Eradication
Eradication of H.pylori Infection and Adver Events
All subjects completed the study with no dropouts.The results intention to treat and per protocol were identical for both studies.The eradication rate with a14-day high-do PPI regimen was55/55(100%;95% CI=93.5–100%)and51/55(92.7%;95%CI=82–97%)for the7-day regimen.
Becau offloods and power loss in Bangkok
and central area of Thailand in2011,most strains were lost.Antibiotic susceptibility testing could be performed for25strains(10from E-tests(five from each regimens),15from GenoType(â)HelicoDR(five from7-day regimens and10from14-day regimens)) which demonstrated40%of metronidazole resistant with no clarithromycin resistant strains in either group.
CYP2C19genotype was performed in64cas(26 from7-day regimens and38from14-day regimens). The prevalence of CYP2C19genotype was similar between rapid and intermediate metabolizers,but poor metabolizers were more common in tho receiving 14-day 1/26vs8/38for7-and14-
day therapy,respectively),but the difference was not significant(p=.07).Although there are small numbers, the data suggest that the major benefit of the longer duration was in tho in the subgroup of rapid metabo-lizers(Table2).
Minor side effects including naua and metallic taste were reported,with mostly higher proportion in 14-day regimen than7-day regimen,but the difference was not significant(Table3).No subject experienced a major adver event.Discussion
决赛英文
Currently,H.pylori eradication rate with standard clari-thromycin-containing triple therapy has declined to 80%or below worldwide becau of antibiotic resis-tance,especially from clarithromycin resistance [2–4,13,14].CYP2C19genotype has recently been found to have an impact on H.pylori eradication,peptic ulcer healing,and therapeutic efficacy of PPI[10,11]. CYP2C19genotypes can be determined by polymera chain reaction and restriction fragment length polymor-phism analysis and fall into3groups in relation to PPI metabolism;rapid metabolizer(RM),intermediate metabolizer(IM),or poor metabolizer(PM).RM geno-type individual experiences rapid clearance of PPI and generally has less effective results with triple therapy than poor metabolizers[10,15].Among phenotypic rapid and intermediate metabolizers,higher do PPI tri-ple therapy or frequent dosing of PPI may increa the efficacy of triple therapy,suggesting that increasing the do and frequency of
siuPPI administration acts in part by overcoming the adver effects of unfavorable CYP2C19 genotypes[16].This approach has been ud to as part of tailored therapy for H.pylori eradication[7].
Table1The baline demographic and clinical characteristics of sub-jects in the two pilot studies
Characteristic data 7-day high-do
triple PPI regimen
(n=55)
14-day high-do
triple PPI regimen
(n=55)
Age50.752.8 Sex
阅读
Male2316 Female3239 Underlying dias
Cardiovascular dias32 Diabetes Mellitus67 Hypertension1312 Dyslipidemia1211 Smoking43 Alcohol consumption32
PPI,proton pump inhibitor.Table2CYP2C19genotype,metronidazole resistance,and outcome of treatment.
CYP2C19genotype
7-day therapy
(n=26)
(%eradication rate)
14-day therapy
(n=38)
(%eradication
rate)
Rapid metabolizer(RM)17(88.2%)19(100%) Intermediate metabolizer(IM)8(100%)11(100%) Poor metabolizer(PM)1(100%)8(100%) Prevalence of metronidazole
got you什么意思resistance(MIC>8l g/mL)
40%40%
Table3Adver reactions of subjects in the two pilot studies Adver reactions
7-day high-do
triple PPI regimen
(n=55)
14-day high-do
triple PPI regimen
(n=55)
Naua3(5.5%)5(9.1%)
Bitter taste4(7.3%)6(10.9%) Headache2(3.6%)1(1.8%) Dizziness1(1.8%)2(3.6%) Vomiting0(0%)2(3.6%)
Fatigue1(1.8%)4(7.3%) Palpitation1(1.8%)1(1.8%)
PPI,proton pump inhibitor.
Triple Therapy for H.pylori Eradication Prartpetmanee et al.
We found that the14-day combination of high-do PPI with long-acting clarithromycin triple therapy pro-duced an excellent efficacy(100%)for H.pylori eradi-cation in our area which has a low prevalence of clarithromycin resistance.In contrast,a7-day regimen of the same drugs yielded treatment success of only 92.7%.The results suggest that the14-day regimen described may be ideal for areas with low rates of clari-thromycin resistance or for tailored therapy where only tho with susceptible strains are treated[13].
The limitations of our study include the fact that we could not asss antimicrobial susceptibility in the majority of patients.In addition,Japan study have reported that high-do PPI plus amoxicillin was effec-tive[17],but in tho studies,the PPI and amoxicillin were given four times daily,and other s
tudies have shown that twice a day and three times a day dosing was not as effective[18,19].Finally,the frequency of rapid and intermediate metabolizers of our study was not different between two studies regimens,but poor metabolizers were higher in tho receiving the14-day regimen compared with the7-day regimen.
In summary,a14-day triple therapy consisting of high-do PPI,long-acting clarithromycin,and amoxi-cillin may provide near100%eradication for clarithro-mycin susceptible H.pylori infections irrespective of the CYP2C19genotype.Larger multi-center studies will be needed to test this hypothesis. Acknowledgements and Disclosures
This study was partially supported by Rearch Fund at Faculty of Medicine,Thammasat University Hospital,Thailand,Gastro-enterology Association of Thailand(GAT)and the National Rearch University Project of Thailand Office of Higher Edu-cation Commission.We thank Takeda(Thailand)for helping to provide lansoprazole for the eradication regimens. Competing interests:the authors have no competing interest.
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