REVIEW ARTICLE
Proton pump inhibitors:an update of their clinical use and pharmacokinetics
Shaojun Shi&Ulrich Klotz
Received:21January2008/Accepted:1July2008/Published online:5August2008
#Springer-Verlag2008
Abstract
Background Proton pump inhibitors(PPIs)represent drugs of first choice for treating peptic ulcer,Helicobacter pylori infection,gastrooesophageal reflux disease,nonsteroidal anti-inflammatory drug(NSAID)-induced gastrointestinal lesions(complications),and Zollinger-Ellison syndrome. Results The available agents(omeprazole/esomeprazole,lan-soprazole,pantoprazole,and rabeprazole)differ somewhat in their pharmacokinetic properties(e.g.,time-/dose-dependent bioavailability,metabolic pattern,interaction potential,genet-ic variability).For all PPIs,there is a clear relationship between drug exposure(area under the plasma concentration/ time curve)and the pharmacodynamic response(inhibition of acid secretion).Furthermore,clinical outcome(e.g.,healing and eradication rates)depends on maintaining intragastric pH values above certain threshold levels.Thus,any changes in drug disposition will subsequently be translated directly into clinical efficiency so that extensive metabolizers of CYP2C19 will demonstrate a higher rate of therapeutic nonresponse. Conclusions This update of pharmacokinetic,pharmacody-namic,and clinical data will provide the necessary guide by which to select between the various PPIs that differ—based on pharmacodynamic assessments—in their relative poten-cies(e.g.,higher doses are needed for pantoprazole and lansoprazole compared with rabeprazole).Despite their well-documented clinical efficacy and safety,there is still a certain number of patients who are refractory to treatment with PPIs(nonresponder),which will leave sufficient space for future drug development and clinical research. Keywords Proton pump inhibitors.Pharmacokinetics. Pharmacodynamics.Peptic ulcer.Reflux disease. Helicobacter pylori infection
Introduction
Proton pump inhibitors(PPIs)are the mainstays in treating acid-related diseases.Since the introduction of omeprazole in1989,other PPIs became available,e.g.,lansoprazole (1995),pantoprazole(1997),rabeprazole(1999),and the S-enantiomer of omeprazole(2001).
PPIs inhibit selectively and irreversibly the gastric H+/K+ATPase(the proton pump)that accomplishes the final step in acid secretion.All PPIs inhibit both basal and stimulated secretion of gastric acid,independent of the nature of parietal cell stimulation[1].PPIs undergo extensive hepatic metabolism by the cytochrome P450 (CYP)system,and CYP2C19polymorphisms have been shown to substantially influence the pharmacoki-netics,pharmacodynamics,and clinical outcome of PPIs [2,3].In addition,pharmacokinetic and pharmacody-namic differences between PPIs are reflected in their influence on both speed and degree of gastric acid suppression,which subsequently may affect their clinical efficacy[4].
Eur J Clin Pharmacol(2008)64:935–951
DOI10.1007/s00228-008-0538-y
S.Shi
:U.Klotz(*)
Dr.Margarete Fischer-Bosch-Institut für
Klinische Pharmakologie,
Auerbachstra?e112,
70376Stuttgart,Germany
e-mail:ulrich.klotz@ikp-stuttgart.de
S.Shi
:U.Klotz
University of Tuebingen,
Tuebingen,Germany
Present address:
S.Shi
Department of Pharmacy of Union Hospital,Tongji Medical College,Huazhong University of Science and Technology, Wuhan,People’s Republic of China
PPIs are drugs of first choice for peptic ulcers(PU)and their complications(e.g.,bleeding),gastrooesophageal reflux disease(GERD),nonsteroidal anti-inflammatory drug(NSAID)-induced gastrointestinal(GI)lesions,Zol-linger-Ellison syndrome,dyspepsia,and eradication of Helicobacter pylori(H.pylori)with two antibiotics[5,6]. PPIs have demonstrated an excellent safety profile after approximately two decades of clinical use[7].There are some unspecific adverse events(AEs)such as headache, nausea,and diarrhea,but the main concern is emerging from the long-term suppression of acid secretion[8].
During the last few years,much new data have been published on the pharmacological characteristics and therapeutic efficacy of PPIs.Therefore,it appears appro-priate to provide an update on the pharmacokinetics, pharmacodynamic action,and clinical use of PPIs. Pharmacokinetic properties
PPIs are substituted benzimidazole derivatives and mem-brane-permeable,weak bases that accumulate in acid spaces of the active parietal cell as prodrugs.Here,they undergo acid-catalyzed conversion to the active sulfenic acid and sulfonamide derivatives.These bind covalently via disul-fide bridges to cysteine residues on the alpha subunit of the H+/K+ATPase,thus inhibiting acid secretion up to36h[1]. Whereas racemic PPI prodrugs possess a chiral center,the identical biological active principle(which is optically inactive)is formed from both enantiomers.The main pharmacokinetic parameters of all PPIs are compared in Table1[6,9].Omeprazole and esomeprazole
Omeprazole is administered as a racemic mixture of its two enantiomers,S-omeprazole(esomeprazole)and R-omepra-zole.Both prodrugs are acid labile and usually administered as encapsulated enteric-coated granules.After oral admin-istration,they are rapidly absorbed[9].They should be swallowed at least1h before eating.The bioavailability(F) of esomeprazole was significantly reduced when taken within15min before eating a high-fat meal compared with fasting conditions[10].When increasing the dose and after repeated administration of omeprazole or esomeprazole,the maximal plasma concentration(C max)and area under the concentration-time curve(AUC)increased in a nonlinear fashion[11],which is due to decreased first-pass elimina-tion and decreased systemic clearance(CL).Furthermore, due to a lower metabolic rate of esomeprazole compared with R-or racemic omeprazole,esomeprazole resulted in higher AUC values[11].Similarly,in patients with GERD, the C max and AUC values of esomeprazole increased on day7versus day1by80%and50%,respectively[12].
Omeprazole and esomeprazole are extensively metabo-lized by CYP2C19and CYP3A4.Omeprazole is converted mainly to hydroxyl and5-O-desmethyl metabolites by CYP2C19and to the sulfone by CYP3A4[6].In vitro studies suggest that esomeprazole is predominantly metab-olized by CYP3A4and consequently is less dependent on CYP2C19,which recently could be substantiated by a clinical study[13].Approximately80%of each dose is excreted as metabolites in the urine[6].
CYP2C19polymorphisms can significantly influence the metabolism of omeprazole and esomeprazole[3,14].
Table1Pharmacokinetic properties of proton pump inhibitors(according to Klotz[6])
Parameter Omeprazole Esomeprazole Lansoprazole Pantoprazole Rabeprazole t max[h]1–61–3.5 1.2–2.12–43–5
F[%]25–40(↑upon multiple
dosing)50(acute dosing)70–80
(chronic dosing)
80–907752
Linear pharmacokinetics No No Yes Yes Yes
fu[%]0.050.050.030.020.04
V[l/kg]0.13–0.350.22–0.260.40.15–
t1/2[h]0.5–1.20.8–1.30.9–2.10.8–2.00.6–1.4
CL[ml/min]400–620330(acute)160–250(chronic)400–65090–225–
CL/F[ml/min]320310125600
f e[%]Negligible Negligible Negligible Negligible Negligible Effect of age CL↓,t1/2(↑),F↑CL?,t1/2?CL↓,t1/2↑CL?,t1/2?CL↓,t1/2(↑) Renal insufficiency CL?,t1/2(?),F?–CL↓?,t1/2↑(?)CL?,t1/2?CL(↑),t1/2?Hepatic dysfunction CL↓,t1/2↑,F↑CL↓,t1/2↑CL↓,t1/2↑CL↓,t1/2↑,F?CL↓,t1/2↑
t max time to maximal plasma concentration,F oral bioavailability,fu fraction of drug unbound in plasma,V apparent volume of distribution,t1/2 elimination half life,CL systemic clearance,CL/F apparent oral clearance,f e fraction excreted in unchanged form into urine
↑increase,↓decrease,?no significant change,arrows in parentheses effects are equivocal
According to metabolic rate(phenotype),individuals can be classified as homozygous extensive metabolizers(homEM), heterozygous extensive metabolizers(hetEM)and poor metabolizers(PM).The frequencies of these three sub-groups show a wide interethnic variation.The prevalence of PM ranges from1.2%to3.8%in Caucasian Europeans and up to23%in Asian Oceanian populations[15,16].PMs exhibit a3-to10-fold and hetEMs a2-to3-fold higher AUC(drug exposure)compared with homEMs[3,14].In a recent study,mean AUC ratios of omeprazole were 1:2.7:9.0after a single oral dose of40mg and1:1.7:4.3 after a single i.v.dose of20mg in six homEMs,eight hetEMs,and six PMs,respectively.Therefore,in PMs,F was higher than that in homEMs and hetEMs(87%vs.62% and41%;P<0.001)[17].Similarly,in homEMs,hetEMs, and PMs,the relative AUC ratios were1:2.8:7.5and t1/2 ratios1:1:1.7for omeprazole,indicating that disposition of omeprazole is greatly dependent on the CYP2C19genotype [18].Similar ratios were reported after repeated doses of omeprazole[19].Interestingly,the elderly EMs showed a wide variance in their CYP2C19activity and were phenotypically closer to the PMs than the young EMs compared with the young PMs.Thus,in the elderly,the CYP2C19genotype may not be as useful as phenotyping [20].The most frequently and extensively described variant alleles for PMs are CYP2C19*2and CYP2C19*3,which encode for nonfunctional proteins.Recently,the CYP2C19*17allele has been identified,which is associated with a very rapid metabolism phenotype and has a frequency of18%both in Swedes and Ethiopians but only 4%in Chines populations[21].Such subjects need higher doses of omeprazole for acid suppression[22,23].
The pharmacokinetics of omeprazole was compared in 18healthy adults and in12children with GERD(mean age 6.1years).Oral clearance(CL/F)and apparent volume of distribution(V)in healthy adults(0.62L/h per kg and0.76 L/kg,respectively)were not significantly different from those in children with GERD(0.51L/h per kg and 0.66L/kg,respectively).Therefore,dosing on a milligram/ kilogram basis was recommended,with no further adjust-ments for treating GERD in children[24].In27children with GERD aged1–11years,the pharmacokinetic properties of esomeprazole were both dose(between5–20mg)and age dependent.The younger children(1–5years)showed a more rapid metabolism compared with older children(6–11years) [25].In28adolescent patients with GERD aged12–17 years,the mean AUC and C max values of esomeprazole were 3.5-fold higher with the40mg dose compared with the20 mg dose with single-and repeated-dose administration, confirming nonlinear pharmacokinetics[26].
All PPIs cause increases in intragastric pH,which can affect absorption of concomitantly given drugs,such as ketoconazole,vitamin B12,and digoxin[27].In addition,omeprazole carries the potential for inhibiting the hepatic elimination of a wide range of drugs,including carbamaze-pine,diazepam,mephenytoin,methotrexate,nifedipine, phenytoin,warfarin,mefloquine,pyrimethamine,and sulfa-doxine[6,27,28].Likewise,inhibitors of CYP2C19or CYP3A4,e.g.,fluconazole[29]and fluvoxamine[30],can affect the metabolism of omeprazole.Furthermore,omepra-zole is a substrate and inhibitor of P-glycoprotein.So drug interactions could be also partly due to an inhibition of P-glycoprotein-mediated drug transport[31,32].On the contrary,St.John’s wort can induce both pathways in the metabolism of omeprazole and decreased its AUC(38–44%) and C max(38–50%)[33].As with smoking,omeprazole can dose dependently induce CYP1A2[6].In general,it can be expected that the interaction potential of esomeprazole is similar to that of racemic omeprazole[27,34].
Triple therapy with omeprazole/clarithromycin/amoxicillin is widely used to eradicate H.pylori.The observed pharmacodynamic synergism of these drugs is at least partly due to pharmacokinetic interactions.The AUC of omepra-zole increased almost twofold after concomitant administra-tion of clarithromycin[35].Naproxen and rofecoxib did not interact with esomeprazole and visa versa.Apparently, esomeprazole can be used in combination with NSAIDs without the risk of pharmacokinetic interactions[36].
Lansoprazole
Lansoprazole is rapidly absorbed and displays a linear increase in plasma concentrations over a dose range of15–60mg[37].Pharmacokinetics of repeated doses is similar to that of a single https://www.doczj.com/doc/7813111991.html,nsoprazole is extensively and rapidly(t1/2:1–2h)metabolized into sulfone and5-hydroxylated metabolites by CYP3A4and CYP2C19.A sulfide metabolite is also present in smaller amounts[6, 37].As CYP2C19is involved in the metabolism of lansoprazole,it is not surprising that PMs have a4.4-fold higher AUC than homEMs[3].The pharmacokinetics of lansoprazole(15mg/day)in children with GERD aged13–24months was comparable to those in older children and adults[38].
Fluvoxamine treatment increased AUC of lansoprazole 3.8-fold(P<0.01)in homEMs and2.5-fold(P<0.05)in hetEMs,whereas in PMs,no difference was found in any pharmacokinetic parameter[39].A double-blind,random-ized controlled trial(RCT)showed that clarithromycin treatment significantly increased C max of lansoprazole 1.47-, 1.71-,and 1.52-fold and AUC 1.55-, 1.74-,and 1.80-fold in homEMs,hetEMs,and PMs,respectively. These very similar effects indicate that the drug interactions resulted from inhibition of CYP3A4[40].Surprisingly, grapefruit juice had no significant effect on the pharmaco-kinetics of lansoprazole[41].
Lansoprazole did not demonstrate relevant interactions with theophylline,phenytoin,prednisone,warfarin,diaze-pam,oral contraceptives,ivabradine,or methotrexate[37, 42,43].In renal transplant recipients receiving tacrolimus and lansoprazole(30mg)or rabeprazole(20mg),elevated blood concentrations of tacrolimus were observed only in the very rare subgroup of subjects who are PM of CYP2C19and bearing also the CYP3A5*3/*3genotype [44].Absorption of atazanavir was significantly reduced when coadministered with lansoprazole,as evidenced by a 94%decline in AUC and by a96%decrease in C max[45].
Pantoprazole
Pantoprazole is rapidly absorbed after oral administration of enteric-coated tablets,which avoid degradation of the PPI by gastric acid[6].It hardly undergoes first-pass metabo-lism and has a bioavailability of approximately77%, independent of dose and food intake.Pantoprazole shows linear pharmacokinetics after both i.v.and oral administra-tion.It is completely metabolized by CYP2C19and CYP3A4.In a major pathway,pantoprazole undergoes O-demethylation followed by sulfate conjugation and sulfone/ sulfide formation[46].Pantoprazole has apparently no clinically relevant drug interactions,other than the class effect associated with elevated intragastric pH.No drug interactions have been demonstrated between pantoprazole and a wide range of drugs,such as theophylline,diazepam, carbamazepine,digoxin,and warfarin[46,47].Unlike omeprazole,administration of clarithromycin did not increase pantoprazole levels[35].
Rabeprazole
In healthy subjects,mean F has been calculated to52% [48].C max and AUC values were linearly related to the dose,whereas t max and t1/2were dose independent. Rabeprazole’s metabolism is unique because of its reduc-tion to rabeprazole thioether via a nonenzymatic pathway with renal elimination of the metabolites.Both CYP2C19 and CYP3A4contribute only a small fraction to the overall metabolism[49].Thus,rabeprazole will be less susceptible to the influence of genetic polymorphisms of either CYP2C19or CYP3A4[50].In healthy Chinese subjects, the pharmacokinetics of rabeprazole was dependent to a certain degree on the CYP2C19genotype.AUC values for rabeprazole differed among the three genotype groups (homEM,hetEM,PM),with relative ratios of1.0:1.3:1.8 after a single dose and of1.0:1.1:1.7after repeated doses, respectively.These changes were much smaller than those observed for other PPIs[51].The modest differences in AUC of rabeprazole were also consistent with other studies [18,52].However,in12Chinese subjects receiving rabeprazole20mg b.i.d.,the mean AUC values of rabeprazole and rabeprazole thioether were higher(P< 0.001)in PMs than in EMs on day1.Similar results were observed on day4,which might be due to the high rabeprazole dose(40mg/day)used in this study[53].
Pharmacokinetic properties of rabeprazole in children 12–16years old were similar to adults,and during multiple dosing,only headache and nausea were sometimes reported [54].
As the CYP450-mediated pathways are secondary in rabeprazole metabolism,it has a low potential for drug interactions involving CYPs.Interaction studies with rabeprazole revealed no significant metabolic effect on theophylline,phenytoin,warfarin,or diazepam[27,49]. Clarithromycin or verapamil did not alter the pharmacoki-netics of rabeprazole,irrespective of the CYP2C19geno-types[55].Interestingly,fluvoxamine,an inhibitor of CYP1A2and CYP2C19,increased AUC of rabeprazole and rabeprazole thioether2.8-and5.1-fold in homEMs and 1.7-and 2.6-fold in hetEMs,respectively,whereas no difference was seen in PMs of CYP2C19[56].
According to in vitro experiments all PPIs showed some inhibition of CYP2C9,2C19,and3A4;the inhibitory potency of rabeprazole was relatively lower than that of the other PPIs[57].
Pharmacodynamic profile
The primary effect of PPIs is suppression of gastric acid secretion,which will determine healing rates in GERD and PU[58].Intragastric pH monitoring allows direct assess-ment of acid suppression,and it is a very useful measure with which to compare antisecretory therapies[59]. Typically,the antisecretory effects of PPIs have been reported as mean or median24-h intragastric pH or suppression of24-h intragastric acidity expressed as time above a predefined pH threshold.Intragastric pH value above3(PU)and4(GERD)have been defined as therapeutic targets[60].PPIs are regarded to be similarly effective,but their potency differs.Such differences may translate into a slight advantage for a particular PPI in a special clinical situation[61].
Onset and degree of acid suppression
All PPI prodrugs undergo accumulation and acid activation in the parietal cell,which relies on their pK a values.Based on in vitro experiments and pK a considerations,it can be estimated that rabeprazole will show the highest accumu-lation and faster conversion to the active form of the PPIs [1].This might affect the speed of acid suppression by PPIs.Apparently an earlier sustained inhibition of acid
secretion was seen with rabeprazole than with other PPIs [62].Comparing the antisecretory effects on the first day of dosing,rabeprazole achieved better acid control because the intragastric pH(3.4)and the time of pH>4during the 24-h postdose were significantly(P≤0.04)greater with rabeprazole than with lansoprazole,pantoprazole,or two formulations of omeprazole[63].In contrast,in72healthy volunteers,mean24-h pH and percentage of time for pH>4 were not significantly different between lansoprazole30mg and https://www.doczj.com/doc/7813111991.html,nsoprazole resulted in greater acid suppression during hours0–5on days1and5, whereas rabeprazole had greater suppression during hours 11–24on day5[64].
In patients with heartburn,the intragastric pH profiles of all five PPIs were compared after giving once daily esomeprazole40mg,lansoprazole30mg,omeprazole20 mg,pantoprazole40mg,and rabeprazole20mg[65,66]. The results of day5suggest that intragastric pH control with esomeprazole40mg/day was superior to other PPIs [65].Similarly,with the same dosing schedule,esomepra-zole maintained intragastric pH>4for a longer time compared with all other PPIs on days1and5[66].
In seven healthy homEMs,the median intragastric pH and percent time pH>4for24h increased dose dependently with omeprazole10,20,and40mg daily for7days,and10 and20mg b.i.d.were comparable with once-daily20and 40mg.Concerning percent time pH>4at nighttime, omeprazole20mg b.i.d.was superior(P<0.05)to40mg daily[67].
Three RCTs indicated that a single dose of esomeprazole (40mg i.v.)was superior to omeprazole(40mg i.v.)in reducing stimulated acid secretion.However,control of intragastric pH was similar for esomeprazole and omeprazole at a high dose of80mg(over30min)+8mg/h(for23.5h) [68].Esomeprazole40mg i.v.resulted in11.8h with an intragastric pH>4compared with5.6h(P<0.0001)and 7.2h(P<0.001)for pantoprazole40mg i.v.as infusion or bolus injection,respectively,suggesting that esomeprazole was more potent than pantoprazole[69].Likewise,oral administration of esomeprazole40mg b.i.d.provided better and more consistent intragastric acid control than pantopra-zole40mg b.i.d.[70].In patients with GERD,esomeprazole (40mg daily or b.i.d.)was compared with lansoprazole(30 mg daily or b.i.d.).Mean time pH>4and mean24-h pH were highest for esomeprazole40mg b.i.d.,followed by lansoprazole30mg b.i.d.,esomeprazole40mg once daily, and lansoprazole30mg once daily[71].Based on three pooled open studies in80subjects,single doses of rabeprazole(20mg)and esomeprazole(40mg)were equivalent in their effects on24-h intragastric pH.After5 days’dosing,rabeprazole(20mg)maintained pH>4longer than20mg esomeprazole(62%vs56%;P=0.046),whereas the lower dose(10mg)of rabeprazole was slightly less effective(48%;P=0.035)[72].These results were consistent with two other RCTs[73,74].
On a milligram basis,acid inhibition by rabeprazole was significantly superior to omeprazole.After the initial dose, rabeprazole(20mg)inhibited acid secretion by72%after 11h and by64%after23h compared with omeprazole 20mg(49%and38%,P<0.03).This advantage was maintained for8days of treatment[75].In addition,single and multiple doses of rabeprazole20mg produced greater acid suppression than oral or i.v.pantoprazole40mg[76,
77].Furthermore,a reduced dose of rabeprazole(10mg b.i.
d.)was comparable with the higher dosages of rabeprazole (20mg b.i.d.),to lansoprazole(30mg b.i.d.),and to omeprazole(20mg b.i.d.)for acid-suppressive efficacy [78,79].
Overall,pharmacodynamic and clinical data indicated that on a milligram basis,rabeprazole can provide the greatest degree of acid suppression among the available PPIs.It also may provide a faster onset toward a maximal antisecretory effect than other drugs of this class.This can be of therapeutic relevance,as clinical outcome depends on extent and duration of secretory inhibition.
Impact of CYP2C19polymorphism on acid suppression PPI-induced inhibition of acid secretion is closely related to AUC values[3,14].As EMs of CYP2C19have smaller AUC values than PMs,the genotype-dependent difference in pharmacokinetics will translate directly into a less pronounced acid suppression in EMs(about70%of Caucasian patients)compared with PMs(see Table2),so that EMs(and carriers of the CYP2C19*17allele)will demonstrate a higher rate of therapeutic nonresponse.This topic has been extensively investigated[80,81].
In eight healthy EMs,rabeprazole(10mg/day)showed a faster onset of rising intragastric pH and a stronger inhibition of gastric acid secretion than did lansoprazole (30mg/day)or omeprazole(20mg/day)[82].In nine healthy,H.pylori-negative homEMs treated with rabepra-zole,omeprazole and lansoprazole once daily at reduced Table2Influence of CYP2C19genotype on intragastric pH(accord-ing to Klotz[3])
Median pH over24h
PPI PM hetEM homEM
Omeprazole(20mg for7/8days) 5.7–6.6 4.4–5.5 3.1–4.1 Lansoprazole(30mg for8days) 5.4–6.2 3.5–5.0 3.1–4.5 Rabeprazole(20mg for8days) 5.8–6.0 4.6–5.0 3.8–4.8
PPI proton pump inhibitor,PM poor metabolizers,hetEM heterozygous extensive metabolizers,homEM homozygous extensive metabolizers
and standard doses for7days,the median values of the 24-h percent of time at pH>4was dose dependent but did not exceed65%under any of the regimens tested.Thus,to achieve effective acid suppression for the initial therapy of GERD,higher doses were needed in homEMs[83].
The efficacy of omeprazole(10or20mg for7days)has been shown to be significantly stronger in PMs and hetEMs than in homEMs[84].Likewise,in31Korean patients with GERD receiving omeprazole20mg daily for28days, 24-h intragastric pH in PMs(5.3)was higher(P<0.005) than that in homEMs(2.8)and hetEMs(3.6)[85].In healthy volunteers(six homEMs,nine hetEMs,five PMs) treated with lansoprazole30mg b.i.d.,the median of 24-h intragastric pH in PMs(6.1)was higher(P<0.05)than those in homEMs(4.5)and hetEMs(5.0).In contrast,when lansoprazole30mg b.i.d.was given with famotidine20mg b.i.d.,the median intragastric pH was5.4,5.7,and6.1, respectively.Thus,acid inhibition by lansoprazole was significantly influenced by the CYP2C19genotype,but apparently this genetic influence could be offset by the concomitant use of the H2-receptor antagonist famotidine [86].
The impact of the CYP2C19genotype on the efficacy of rabeprazole was less consistent.In H.pylori-negative GERD subjects given rabeprazole10mg/day for8weeks, the intragastric pH elevation was independent of CYP2C19 genotypes[87],which was consistent with another study [52].In contrast,two studies with rabeprazole20or40mg daily for8days demonstrated that acid inhibition by rabeprazole was dependent on the CYP2C19genotype [88,89].
In Korean patients,pantoprazole40mg daily exhibited a variable acid inhibition that was significantly dependent on the CYP2C19genotype[90].
As there is a significantly positive relationship between the extent and duration of elevated intragastric pH and the clinical efficacy of PPIs,it can be anticipated that the CYP2C19 genotype will have a significant impact on the therapeutic outcome of three PPIs(e.g.,omeprazole,lansoprazole,pantoprazole)that are predominantly metabolized by this polymorphic enzyme.
Therapeutic use
Peptic ulcer
For the management of PU(healing induction and remission maintenance),both suppression of gastric acid secretion and eradication of H.pylori are important mainstays.In general,there is little overall difference in PU healing rates among PPIs,and reported small differ-ences can be explained best by the variable dosage regimens applied[91–93].H.pylori eradication is accom-plished efficiently(80–90%eradication rates)by standard triple therapy with a PPI,amoxicillin,and clarithromycin or metronidazole[94–96](Table3),and there was no significant difference among the PPIs[97–101].
A consensus on the optimal duration(7,10,or14days) of first-line triple therapy is still missing.However,many controlled studies and meta-analyses[102–108]indicated that extending this strategy beyond7days is very unlikely to be clinically useful,especially if taking antibiotic-induced AEs into account[101].There are even some data suggesting that a rabeprazole-based triple therapy for4 days will result in eradication rates around90%[109,110]. More recently,sequential treatment consisting of5days of therapy with a PPI and amoxicillin followed by5days of PPI+clarithromycin and tinidazole has attracted some favorable attention[111–114].
As already outlined,the genotype of CYP2C19affects the pharmacokinetics and pharmacodynamics of most PPIs. In a recent meta-analysis of dual and triple therapies a, marked difference in the H.pylori eradication rates between PMs/hetEMs vs.homEMs was calculated,especially for omeprazole[115].Therefore,CYP2C19polymorphism is a major predictor of treatment failure for H.pylori eradication [116,117].
Table3Recommendation of Helicobacter pylori eradication formulated in the Maastricht Consensus Report(adapted from Malfertheiner et al.
[94])
Choice Statements
First-choice treatment?PPI-amoxicillin-clarithromycin or metronidazole treatment remains the recommended first-choice treatment
in populations with less than15–20%clarithromycin resistance prevalence.
?In populations with less than40%metronidazole resistance prevalence PPI-clarithromycin-metronidazole is
preferable.
?Quadruple therapies are alternative first-choice treatments.
Second-choice treatment?Bismuth-based quadruple therapies remain the best second-choice treatment.
?If not available,a PPI,amoxicillin,or tetracycline and metronidazole are recommended.
Third-choice treatment(rescue
treatment)
?Rescue treatment should be based on antimicrobial susceptibility testing.
Reflux disease
The objective of treating GERD[118]is to relieve troublesome symptoms(e.g.,heartburn,regurgitation),to restore quality of life,to heal oesophagitis(if present),and to reduce the risk of complications.Thereby,acid suppression is the mainstay of therapy,and PPIs represent the best choice because they are more potent than H2-receptor antagonists[119–122].Depend-ing on the administered dose of the PPI and treatment duration,e.g.,4or8weeks,healing in around50–60%and 80–90%of patients,respectively,has been observed[123–126].Thereby,symptom relief was apparently somewhat faster with rabeprazole than with omeprazole[127,128].
Healing of GERD can be restored either by maintenance (remission rates about85%)or,alternatively,by on-demand treatment[129–132].Several studies have demonstrated the efficacy of pantoprazole(20mg),esomeprazole(20mg),or rabeprazole(10mg)as on-demand therapy for long-term management of patients with mild GERD[133,134].
The impact of CYP2C19polymorphism on the clinical outcome was also evaluated in patients with GERD.The presence of a variant allele was associated with a significantly lower risk of gastric-acid breakthroughs during PPI therapy [135].Likewise,in two independent trials,8-week healing rates of lansoprazole(30mg)were significantly higher in PMs(85%and100%)and hetEMs(68%and95%) compared with homEMs(46%and77%)[136,137]. Furthermore,during maintenance therapy(15mg lansopra-zole)remission rates(after6months)were61.5%,78%,and 100%in homEMs,hetEMs,and PMs,respectively[138].In contrast,in three studies with esomeprazole,rabeprazole, and omeprazole,healing rates were not significantly affected by the CYP2C19genotype[13,139,140].
In patients with nonerosive reflux disease(NERD)[118], the response to standard doses of PPIs seems to be—for yet unknown reasons—lower than in patients with GERD[141, 142].Symptoms have been improved by rabeprazole(10 mg),esomeprazole(20mg),and lansoprazole(15mg),and on-demand treatment with PPIs appears to be also effective in the long-term management of NERD[129,133,143–146].
NSAID-induced gastrointestinal lesions
NSAIDs can cause GI lesions and result in dyspeptic symptoms and ulcerations and lead to increased risk of serious GI complications.Factors associated with an increased risk include intake of low-dose aspirin(ASS), history of ulcer or upper GI bleeding,age>70years,and concomitant use of NSAIDs[147,148].Therefore,patients at risk should be considered for alternatives to NSAID therapy,modifications of risk factors,as well as preventive strategies such as cotherapy with gastroprotective agents (PPIs or misoprostol)or cyclo-oxygenase-2(COX-2)-selective inhibitors(coxibs)[149].Importantly,prevention strategies must take into account both GI and cardiovascu-lar(CV)risk factors,as coxibs and probably most traditional NSAIDs increase the incidence of serious CV events[150,151].
Cotherapy with any PPI is an established option for prevention and healing of NSAID-associated GI lesions.All PPIs can provide effective acid suppression and decrease the morbidity and mortality associated with GI lesions[152,153]. One meta-analysis of118trials(76,322patients)assessed the relative effectiveness and cost-effectiveness of five strategies for the prevention of NSAID-induced GI toxicity. PPIs significantly reduced the risk of symptomatic ulcers [relative risk(RR)0.09;95%CI0.02–0.47]compared with placebo,and NSAIDs plus PPIs was the most cost-effective strategy for avoiding endoscopic ulcers in patients requiring long-term NSAIDs therapy[154].PPIs will prevent back diffusion of hydrogen ions(the major aggressive factor)into the mucosa.In addition,as shown for rabeprazole,the mucosa might be restored by an increase in gastric production of protective mucus and mucin[155,156].
Recent concern regarding potential CV risks of coxibs will favor PPI cotherapy with NSAIDs.The minor gastric-sparing effect of coxibs is offset by concomitant use of low-dose ASS,whereas use of some NSAID plus PPI regimens may negate ASS’s antiplatelet benefits.In addition, NSAIDs plus PPIs is at least as effective as the coxib strategy and may be more cost effective[157].According to a meta-analysis of four studies,NSAIDs plus PPIs afforded greater risk reduction for dyspepsia than did coxibs,and NSAIDs plus PPIs vs.NSAIDs alone revealed a66%RR reduction for PPI cotherapy with an absolute risk reduction of9%[158].Consequently,PPI should be considered for the treatment and prevention of NSAIDs-induced dyspepsia.
It has been found that H.pylori infection and NSAID use represent independent and synergistic risk factors for PU[159,160].In a meta-analysis of21studies,uncompli-cated PU was more common in H.pylori-positive than H. pylori-negative NSAID users[odds ratio(OR)1.81].In six age-matched controlled studies,H.pylori infection and NSAIDs use significantly increased the risk of PU(OR 4.03and3.10,respectively).The risk was17.5-fold higher when both factors were present[160].Evidence suggested that H.pylori eradication may prevent NSAID-induced ulcers in NSAID-naive patients,and in patients receiving long-term NSAIDs,PPIs were very effective in preventing ulcer recurrence[161,162].
Peptic ulcer bleeding
Peptic ulcer bleeding(PUB)represents an important emergency situation that is associated with considerable
morbidity,mortality,and healthcare system costs[163]. Several risk factors are involved,and elimination or modification of such etiopathogenetic factors will reduce the frequency of ulcer recurrences and PUB.Based on clinical and epidemiological data,it is evident that H.pylori infection and NSAID intake(including low-dose ASS and coxibs)are the two most important and independent risk factors[164,165].In addition,the elderly represent a population of elevated risks[164].In three recent analyses, RR factors have been estimated(see Table4).All NSAIDs and antiplatelet/anticoagulant agents have a similar poten-tial to induce PUB,and if such drugs have to be taken, preventive strategies,including H.pylori eradication, should be applied[165–168].
Several options for treating PUB and preventing rebleed-ings are available.Epinephrine injection is the most common endoscopic therapy for PUB[169],but following this successful management,rebleeding will occur in about 20%of patients[170].Meta-analyses indicate that endo-scopic hemostasis has reduced rebleeding and surgical interventions by>60%and mortality by45%[171]. Because profound acid suppression(intragastric pH>6.0) optimizes stability of blood clots overlaying the ulcer and reduces the risk of rebleeding,endoscopic hemostasis is often combined with drug-induced(H2-receptor antago-nists,PPIs)reduction of gastric acidity[172,173].
Several reviews and meta-analyses of RCTs have been published concerning whether high-dose PPIs(intravenous-ly as bolus/infusion and/or orally)affect PUB(see Table5). Assessed outcomes were most frequently30-days mortality, rebleeding,need for surgery,or endoscopic retreatment. PPIs significantly reduced the risks of rebleeding and the need for surgery.However,mortality was not affected by PPI treatment.Surprisingly,this hard outcome measure was reduced in Asian trials[174–176].Because most PPIs are primarily metabolized by the polymorphic CYP2C19,and because PMs are much most frequent(about20%)in Asians than in Caucasians(about3%),it could be speculated that in the Asian population,drug exposure by the high standard doses of PPI is more pronounced and thus more effective.
Recently it was shown by a randomized prospective study in129bleeding peptic ulcer patients that oral treatment with rabeprazole(20mg b.i.d.)was equally effective as endoscopic hemoclipping with subsequent i.v. administration of H2-receptor antagonists in terms of hemostasis(93%)and rebleeding(7%)rates[177].
Besides PPIs,(RR:0.33)H2-receptor antagonists(RR: 0.65)and nitrates(RR:0.52)can also reduce the risks for PUB associated with NSAID intake,low-dose ASS,and clopidogrel[178].There is some evidence that i.v.PPI therapy is more effective than oral treatment.However,the higher costs involved with i.v.administration do not justify this preference[179].
In conclusion,the addition of PPIs for endoscopic treatment of PUB is justified only for patients who have a high-risk lesion at endoscopy,as so far,there are no convincing data concerning the reduction of mortality.In addition,testing for and cure of H.pylori infection should be considered,as this represents an independent risk factor.
Zollinger-Ellison syndrome
The Zollinger-Ellison syndrome(ZES;gastrinoma)is characterized by hypersecretion of acid and intestinal ulcerations.Acid output and serum gastrin levels are elevated several fold in these patients.A proportion of subjects(up to40%)may be cured by resection of the gastrinoma.In addition,gastric-acid hypersecretion and the syndrome can be effectively controlled by PPIs[180].In general,high doses of PPIs(initially often administered intravenously by a short infusion)have been applied and
Table4Relative risk(RR)factors for peptic ulcer bleeding
Factor RR factor(95%CI)Analyzed cases Reference
tNSAIDs a 3.7(3.1–4.3)1,561García Rodríguez&Barreales Tolosa[168] Coxibs a 2.6(1.9–3.6)
NSAIDs 5.3(4.5–6.2)2,777Lanas et al.[166]
Rofecoxib 2.1(1.1–4.0)
Clopidogrel/ticlopidine 2.8(1.9–4.2)
ASS(100mg/day) 2.7(2.0–3.6)
Anticoagulants 2.8(2.1–3.7)
Preexisting peptic ulcer 4.3(P=0.043)822Fisher et al.[167]
Smoking 3.1(P=0.023)
Use of antiplatelet agents 6.5(P=0.046)
tNSAIDs/Coxibs 4.9(P=0.060)
CI confidence interval,tNSAIDS traditional nonsteroidal anti-inflammatory drugs
a Dose-dependent effects
control of acid secretion(measurement of acid output;24-h intragastric pH monitoring)was the primary efficacy endpoint.Doses were generally adjusted(titrated)accord-ing to the individual response in lowering basal acid output. In a short-term(7–10days)open study with11male patients with ZES,omeprazole(20–100mg/day,mean dose 63mg),lansoprazole(30–120mg/day,mean dose75mg), and pantoprazole(40–200mg/day,mean dose116mg) demonstrated a comparable antisecretory effect[181].
In46ZES patients during long-term(up to10years) treatment,the median effective lansoprazole dose to control acid secretion was approximately80mg/day(range75–360 mg/day)[182].Likewise,49patients with ZES and eight hypersecretors were treated with a daily median dose of 75mg lansoprazole(7.5–450mg/day)for up to13years. Forty-seven patients(70%)remained symptom and lesion free,and90%of patients had good to excellent clinical outcomes without surgery[183].
In26patients with ZES and in nine with idiopathic hypersecretion,control of acid secretion was achieved by individual treatment with pantoprazole at6months,with doses of40mg b.i.d.(24),80mg b.i.d.(7),and120mg b.i.d.
(2);it failed in two subjects[184].This study was extended to an observation for3years(24).With maintenance doses between40and120mg b.i.d.,acid output was controlled in all patients[185].In20patients with ZES or idiopathic hypersecretion,acid output was also controlled by rabepra-zole(60mg for most patients)for2years.Gastric biopsies showed no enterochromaffin-like(ECL)cell dysplasia or neoplasia[186].
Form these limited clinical data,it can be concluded that high,individualized doses of PPIs offer a(long-term) treatment option for patients with ZES.
Clinical safety and adverse effects
PPIs have demonstrated an excellent safety profile after approximately20years of clinical use in millions of patients with acid-related diseases,including pregnant women and children[187,188].PPIs are generally well tolerated,and the incidence of AEs is relatively low.The most frequent AEs,with incidences of1–3%reported in the clinical trials,were headache,nausea,diarrhea,skin rashes, and constipation[189].
Serious AEs are infrequent,although rare cases of toxic hepatitis and visual disturbance have been reported[189, 190].An increased risk of community-acquired pneumonia associated with PPI treatment has been found in a large cohort of patients[191].Interestingly,in a population-based case-control study,the initiation of treatment with PPIs showed a particularly strong association with community-acquired pneumonia(OR5.0;95%CI2.1–11.7),whereas the risk decreased with treatment(OR1.3;95%CI,1.2–1.4)[192].Some reports indicated that acute interstitial nephritis(AIN)was associated with PPIs[193,194]. However,a recent systematic review of64cases demon-strated that PPI-related AIN was rare,idiosyncratic,and difficult to predict;there was a low prevalence association [195].In addition,whether PPIs are a risk factor for
Table5Proton pump inhibitor(PPI)therapy for peptic ulcer bleeding:summary of recent reviews and meta-analyses
Assessed outcome (after30days)Odds ratio(95%CI)for effects of
high-dose PPI a compared with placebo
Number of trials
(number of patient)b
References
Mortality(all trials) 1.01(0.74–1.40)24(4,373)Leontiadis et al.[174–176] Mortality(7Asian trials)0.35(0.16–0.74)
Rebleeding0.49(0.37–0.65)
Endoscopic retreatment0.32(0.20–0.51)
Mortality 1.12(0.72–1.73)4(1,512)Dorward et al.[208] Rebleeding0.81(0.61–1.09)
Need for surgery0.96(0.68–1.35)
Mortality(all causes) 1.02(0.76–1.37)26(4,670)Khuroo et al.[209]
Ulcer deaths0.58(0.35–0.96)
Nonulcer deaths 1.60(1.06–2.41)
Mortality?2.7%18(1,855)Bardou et al.[210] Rebleeding?14.6%
Need for surgery?5.4%
Mortality 1.11(0.79–1.57)21(2,915)Leontiadis et.[211,212] Rebleeding0.46(0.33–0.64)
Need for surgery0.59(0.46–0.76)
Mortality and need for surgery Both rates were not different3(1,045)Andriulli et al.[213] Rebleeding0.50(0.26–0.96)
a Intravenous bolus(40–80mg)and infusion(at least6–8mg/h)
b It must be emphasized that the same trials(patients)have frequently been analyzed
Clostridium difficile-associated disease is controversial [196,197].Because long-term antisecretory therapy can affect absorption of calcium,PPIs may increase indirectly the risk of hip fracture,particularly for patients taking more than one dose per day[198,199].One nested case–control study showed that the OR for hip fractures increased over time with PPI use:1.22,1.41,1.54,and1.59for1,2,3,and 4years,respectively[199].
Of major interest is PPI-induced hypoacidity and hyper-gastrinemia.Long-term hypergastrinemia can cause ECL cell hyperplasia,which may predispose to carcinoids and might be important in gastric carcinogenesis[200].In addition,PPI therapy affects the pattern and severity of H. pylori gastritis and accelerates the process of corpus gland loss,which is considered a risk factor for the development of gastric cancer[201].To date,long-term PPI therapy was not associated with an increased risk of gastric or colorectal cancer[201–203],but apparently it was associated with an up to fourfold increase in the risk of fundic gland polyps [204].Frequency and size of adenomatous polyps in the colon cases(116)that used PPIs were not different from matched controls(194)in a series of2,868consecutive patients undergoing colonoscopies[205].
Conclusions
Since the introduction of PPIs,considerable progress has been achieved in the management of gastric-acid-related disorders(e.g.,PU,GERD,ZES)and NSAID-induced GI lesions.The success of PPIs is due both to their well-documented clinical efficacy and safety.As the active principles of available PPI-prodrugs have the identical mode of action,resulting in elevating intragastric pH,the various PPIs can be used in an interchangeable fashion.
Whereas the pharmacodynamic profile of PPIs is the same, some pharmacokinetic differences exist among these valuable agents that can slightly modify their clinical action because there are close relationships between pharmacokinetics, pharmacodynamics,and therapeutic outcome.Systemic drug exposure(AUC)will determine how fast and how long the intragastric target pH can be maintained above the threshold (target)level of>3(PU)or>4(GERD),which subsequently affects the healing rates of acid-related disorders,including H. pylori infections and NSAID-induced GI lesions.
Similar to other drugs,PPIs demonstrate a large interindividual variability in drug disposition(e.g.,bio-availability,AUC,metabolic pathways,hepatic elimination rates),which is caused by genetic and nongenetic factors.In addition,the interaction potential of PPIs in terms of drug metabolism shows some compound-specific differences.
In relation to genetic factors,the influence of poly-morphisms of CYP2C19on the clinical outcome of PPIs has been extensively investigated.As this enzyme is mainly responsible for the metabolism(hepatic elimination rate)of omeprazole,lansoprazole,and pantoprazole,their AUCs and pharmacodynamic responses are much more dependent on the genotype/phenotype of CYP2C19compared with esomeprazole(metabolic contribution by CYP3A4)or rabeprazole(eliminated mainly by a nonenzymatic path-way).It has been well documented by several clinical studies that standard doses of omeprazole and lansoprazole are too low for many EMs(especially carriers of the CYP2C19*17mutation),resulting in a larger proportion of nonresponders in this subgroup representing about70%of Caucasian populations.Thus,genotype-adjusted dosing could improve the clinical outcome of these PPIs.Likewise, a PPI should be preferred that is less dependent on CYP2C19to overcome this genetically controlled variabil-ity[206].
As all PPIs dose(AUC)-dependently elevate intragastric pH,solubility and absorption of other drugs given concom-itantly might be affected to some extent,as has been exemplified for ketoconazole,vitamin B12,digoxin,atazana-vir,or calcium.In contrast to this“class effect,”drug interactions on the level of hepatic metabolism are more compound specific.With omeprazole,induction of the CYP1A subfamily has been reported,and inhibition of hepatic elimination(mainly via CYP2C19and CYP3A4)of several drugs must be considered(the latter is seen to some extent with esomeprazole also).The other three PPIs are apparently devoid of this metabolic interaction potential.As the liver represents the major site of elimination for all PPIs, patients with moderate or severe hepatic dysfunction have a reduced CL,and dosage might be reduced for pharmacoki-netic reasons by factor2in such subjects.
Due to structural differences affecting the biophysical and biochemical properties of the PPIs,different dosages of the various agents are needed for the same pharmacody-namic response, e.g.,for control of acid secretion in patients with ZES,relative potency dose ratios can be calculated for omeprazole,lansoprazole,and pantoprazole (1:0.81:0.54).
In many cases,PPIs have to be taken long term.Under such conditions,hypergastrinemia and ECL cell hyperplasia can develop.However,so far,this has not been associated with a significantly increased risk of gastric cancer.As experience for almost20years is now available,this potential safety concern regarding all effective antisecretory strategies and conditions should not limit the use of PPIs.
For various reasons(e.g.,nonadherence,CYP2C19*1or *17EM-genotype,resistance),some patients will be refractory to PPI treatment[207].Such nonresponders might profit from an increased dose,a b.i.d.regimen,the addition of an H2-receptor antagonist,or switching to a PPI with higher potency and less impact of genetic poly-
morphisms.In addition,developing novel PPIs or other antisecretory agents might be an option for the future.In conclusion,based on long-term experience and extensive clinical data,PPIs still represent drugs of first choice for managing PU-including H.pylori infection,GERD,ZES, and NSAID-induced GI lesions.They provide a safe and cost-effective treatment.
Acknowledgements The secretarial help of Mrs.U.Hengemühle is appreciated.This work was supported by the Robert Bosch Founda-tion,Stuttgart,Germany,and an educational grant from Eisai Europe Ltd.,London.
Conflict of Interest The authors declare that they have no conflicts of interest.
References
1.Sachs G,Shin JM,Howden CW(2006)Review article:the
clinical pharmacology of proton pump inhibitors.Aliment Pharmacol Ther23(Suppl2):2–8
2.Furuta T,Shirai N,Sugimoto M,Ohashi K,Ishizaki T(2004)
Pharmacogenomics of proton pump inhibitors.Pharmacogenom-ics5:181–202
3.Klotz U(2006)Clinical impact of CYP2C19polymorphism on
the action of proton pump inhibitors:a review of a special problem.Int J Clin Pharmacol Ther44:297–302
4.Robinson M(2005)Proton pump inhibitors:update on their role in
acid-related gastrointestinal diseases.Int J Clin Pract59:709–715 https://www.doczj.com/doc/7813111991.html,ssen AT(2007)Acid-related disorders and use of antisecretory
medication.Dan Med Bull54:18–30
6.Klotz U(2000)Pharmacokinetic considerations in the eradica-
tion of Helicobacter pylori.Clin Pharmacokinet38:243–270 7.Esplugues JV,Martí-Cabrera M,Ponce J(2006)Safety of proton
pump inhibitors.Med Clin(Barc)127:790–795
8.Maffei M,Desmeules J,Cereda JM,Hadengue A(2007)Side
effects of proton pump inhibitors(PPIs).Rev Med Suisse 123:1934–1936,1938
9.Horn JR,Howden CW(2005)Review article:similarities and
differences among delayed-release proton-pump inhibitor for-mulations.Aliment Pharmacol Ther22(Suppl3):20–24
10.Sostek MB,Chen Y,Andersson T(2007)Effect of timing of
dosing in relation to food intake on the pharmacokinetics of esomeprazole.Br J Clin Pharmacol64:386–390
11.Hassan-Alin M,Andersson T,Niazi M,R?hss K(2005)A
pharmacokinetic study comparing single and repeated oral doses of20mg and40mg omeprazole and its two optical isomers,S-omeprazole(esomeprazole)and R-omeprazole,in healthy sub-jects.Eur J Clin Pharmacol60:779–784
12.Simon B,Müller P,Pascu O,Gatz G,Sander P,Huber R,
Mascher H(2003)Intra-oesophageal pH profiles and pharmaco-kinetics of pantoprazole and esomeprazole:a crossover study in patients with gastro-oesophageal reflux disease.Eur J Gastro-enterol Hepatol15:791–799
13.Schwab M,Klotz U,Hofmann U,Schaeffeler E,Leodolter A,
Malfertheiner P,Treiber G(2005)Esomeprazole-induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19:evidence from clinical and pharmacokinetic data.
Clin Pharmacol Ther78:627–634
14.Klotz U,Schwab M,Treiber G(2004)CYP2C19polymorphism
and proton pump inhibitors.Basic Clin Pharmacol Toxicol95:2–815.Xie HG,Stein CM,Kim RB,Wilkinson GR,Flockhart DA,
Wood AJ(1999)Allelic,genotypic and phenotypic distributions of S-mephenytoin4′-hydroxylase(CYP2C19)in healthy Cauca-sian populations of European descent throughout the world.
Pharmacogenetics9:539–549
16.Desta Z,Zhao X,Shin JG,Flockhart DA(2002)Clinical
significance of the cytochrome P4502C19genetic polymor-phism.Clin Pharmacokinet41:913–958
17.Uno T,Niioka T,Hayakari M,Yasui-Furukori N,Sugawara K,
Tateishi T(2007)Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19genotypes following single intravenous and oral administrations.Eur J Clin Pharmacol 63:143–149
18.Qiao HL,Hu YR,Tian X,Jia LJ,Gao N,Zhang LR,Guo YZ
(2006)Pharmacokinetics of three proton pump inhibitors in Chinese subjects in relation to the CYP2C19genotype.Eur J Clin Pharmacol62:107–112
19.Hu XP,Xu JM,Hu YM,Mei Q,Xu XH(2007)Effects of
CYP2C19genetic polymorphism on the pharmacokinetics and pharmacodynamics of omeprazole in Chinese people.J Clin Pharm Ther32:517–524
20.Ishizawa Y,Yasui-Furukori N,Takahata T,Sasaki M,Tateishi T
(2005)The effect of aging on the relationship between the cytochrome P4502C19genotype and omeprazole pharmacoki-netics.Clin Pharmacokinet44:1179–1189
21.Sim SC,Risinger C,Dahl ML,Aklillu E,Christensen M,
Bertilsson L,Ingelman-Sundberg M(2006)A common novel CYP2C19gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants.Clin Pharmacol Ther79:103–113
22.Baldwin RM,Ohlsson S,Pedersen RS,Mwinyi J,Ingelman-
Sundberg M,Eliasson E,Bertilsson L(2008)Increased omeprazole metabolism in carriers of the CYP2C19*17allele;
a pharmacokinetic study in healthy volunteers.Br J Clin
Pharmacol65:767–774
23.Hunfeld NG,Mathot RA,Touw DJ,van Schaik RH,Mulder PG,
Franck PF,Kuipers EJ,Geuss WP(2008)Effect of CYP219*2 and*17mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians.Br J Clin Pharmacol65:752–760 24.Marier JF,Dubuc MC,Drouin E,Alvarez F,Ducharme MP,
Brazier JL(2004)Pharmacokinetics of omeprazole in healthy adults and in children with gastroesophageal reflux disease.Ther Drug Monit26:3–8
25.Zhao J,Li J,Hamer-Maansson JE,Andersson T,Fulmer R,
Illueca M,Lundborg P(2006)Pharmacokinetic properties of esomeprazole in children aged1to11years with symptoms of gastroesophageal reflux disease:a randomized,open-label study.
Clin Ther28:1868–1876
26.Li J,Zhao J,Hamer-Maansson JE,Andersson T,Fulmer R,
Illueca M,Lundborg P(2006)Pharmacokinetic properties of esomeprazole in adolescent patients aged12to17years with symptoms of gastroesophageal reflux disease:A randomized, open-label study.Clin Ther28:419–427
27.Blume H,Donath F,Warnke A,Schug BS(2006)Pharmacoki-
netic drug interaction profiles of proton pump inhibitors.Drug Saf29:769–784
28.Arayne MS,Sultana N,Qureshi MS,Naseem S(2006)
Interaction studies of omeprazole with mefloquine,pyrimeth-amine and sulfadoxine.Pak J Pharm Sci19:314–321
29.Kang BC,Yang CQ,Cho HK,Suh OK,Shin WG(2002)
Influence of fluconazole on the pharmacokinetics of omeprazole in healthy volunteers.Biopharm Drug Dispos23:77–81
30.Yasui-Furukori N,Takahata T,Nakagami T,Yoshiya G,Inoue Y,
Kaneko S,Tateishi T(2004)Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes.Br J Clin Pharmacol57:487–494
31.Pauli-Magnus C,Rekersbrink S,Klotz U,Fromm MF(2001)
Interaction of omeprazole,lansoprazole and pantoprazole with P-glycoprotein.Naunyn Schmiedebergs Arch Pharmacol364:551–557
32.Takahata T,Yasui-Furukori N,Yoshiya G,Uno T,Sugawara K,
Tateishi T(2004)Fexofenadine does not affect omeprazole pharmacokinetics:both are putative P-glycoprotein substrates.
Basic Clin Pharmacol Toxicol94:252–256
33.Wang LS,Zhou G,Zhu B,Wu J,Wang JG,Abd El-Aty AM,Li
T,Liu J,Yang TL,Wang D,Zhong XY,Zhou HH(2004)St John’s wort induces both cytochrome P4503A4-catalyzed sulfoxidation and2C19-dependent hydroxylation of omeprazole.
Clin Pharmacol Ther75:191–197
34.Klotz U(2002)The interaction potential of proton pump
inhibitors.Verdauungskrankheiten20:26–31
35.Calabresi L,Pazzucconi F,Ferrara S,Di Paolo A,Tacca MD,
Sirtori C(2004)Pharmacokinetic interactions between omepra-zole/pantoprazole and clarithromycin in healthy volunteers.
Pharmacol Res49:493–499
36.Hassan-Alin M,Naesdal J,Nilsson-Pieschl C,L?ngstr?m G,
Andersson T(2005)Lack of pharmacokinetic interaction between esomeprazole and the nonsteroidal anti-inflammatory drugs naproxen and rofecoxib in healthy subjects.Clin Drug Investig25:731–740
37.Gremse DA(2001)Lansoprazole:pharmacokinetics,pharmaco-
dynamics and clinical uses.Expert Opin Pharmacother2:1663–1670
38.Heyman MB,Zhang W,Huang B,Chiu YL,Amer F,Winter HS
(2007)Pharmacokinetics and pharmacodynamics of lansoprazole in children13to24months old with gastroesophageal reflux disease.J Pediatr Gastroenterol Nutr44:35–40
39.Yasui-Furukori N,Saito M,Uno T,Takahata T,Sugawara K,
Tateishi T(2004)Effects of fluvoxamine on lansoprazole pharmacokinetics in relation to CYP2C19genotypes.J Clin Pharmacol44:1223–1229
40.Saito M,Yasui-Furukori N,Uno T,Takahata T,Sugawara K,
Munakata A,Tateishi T(2005)Effects of clarithromycin on lansoprazole pharmacokinetics between CYP2C19genotypes.Br J Clin Pharmacol59:302–309
41.Uno T,Yasui-Furukori N,Takahata T,Sugawara K,Tateishi T
(2005)Lack of significant effect of grapefruit juice on the pharmacokinetics of lansoprazole and its metabolites in subjects with different CYP2C19genotypes.J Clin Pharmacol 45:690–694
42.Portolés A,Calvo A,Terleira A,Laredo L,Resplandy G,
Gorostiaga C,Moreno A(2006)Lack of pharmacokinetic interaction between omeprazole or lansoprazole and ivabradine in healthy volunteers:an open-label,randomized,crossover,pharma-cokinetic interaction clinical trial.J Clin Pharmacol46:1195–1203 43.Vakily M,Amer F,Kukulka MJ,Andhivarothai N(2005)
Coadministration of lansoprazole and naproxen does not affect the pharmacokinetic profile of methotrexate in adult patients with rheumatoid arthritis.J Clin Pharmacol45:1179–1186 44.Miura M,Inoue K,Kagaya H,Satoh S,Tada H,Sagae Y,
Habuchi T,Suzuki T(2007)Influence of rabeprazole and lansoprazole on the pharmacokinetics of tacrolimus in relation to CYP2C19,CYP3A5and MDR1polymorphisms in renal transplant recipients.Biopharm Drug Dispos28:167–175
45.Tomilo DL,Smith PF,Ogundele AB,Difrancesco R,Berenson
CS,Eberhardt E,Bednarczyk E,Morse GD(2006)Inhibition of atazanavir oral absorption by lansoprazole gastric acid suppres-sion in healthy volunteers.Pharmacotherapy26:341–346
46.Cheer SM,Prakash A,Faulds D,Lamb HM(2003)Pantopra-
zole:an update of its pharmacological properties and therapeu-tic use in the management of acid-related disorders.Drugs 63:101–13347.Pan WJ,Goldwater DR,Zhang Y,Pilmer BL,Hunt RH(2000)
Lack of a pharmacokinetic interaction between lansoprazole or pantoprazole and theophylline.Aliment Pharmacol Ther14:345–352
48.Setoyama T,Laurent A,Humphries T,Hasegawa J(2005)
Pharmacokinetics of rabeprazole following single intravenous and oral administration to healthy subjects.Int J Clin Pharmacol Ther43:37–42
49.Horn J(2004)Review article:relationship between the metab-
olism and efficacy of proton pump inhibitors–focus on rabepra-zole.Aliment Pharmacol Ther20(Suppl6):11–19
50.Lim PW,Goh KL,Wong BC(2005)CYP2C19genotype and the
PPIs–focus on rabeprazole.J Gastroenterol Hepatol20(Suppl): S22–S28
51.Hu YM,Xu JM,Mei Q,Xu XH,Xu SY(2005)Pharmacody-
namic effects and kinetic disposition of rabeprazole in relation to CYP2C19genotype in healthy Chinese subjects.Acta Pharmacol Sin26:384–388
52.Hu YM,Mei Q,Xu XH,Hu XP,Hu NZ,Xu JM(2006)
Pharmacodynamic and kinetic effect of rabeprazole on serum gastrin level in relation to CYP2C19polymorphism in Chinese Hans.World J Gastroenterol12:4750–4753
53.Lin CJ,Yang JC,Uang YS,Chern HD,Wang TH(2003)Time-
dependent amplified pharmacokinetic and pharmacodynamic responses of rabeprazole in cytochrome P4502C19poor metabolizers.Pharmacotherapy23:711–719
54.James L,Walson P,Lomax K,Kao R,Varughese S,Reyes J,
Study119Pediatric Trial Investigators(2007)Pharmacokinetics and tolerability of rabeprazole sodium in subjects aged12to16 years with gastroesophageal reflux disease:an open-label,single-and multiple-dose study.Clin Ther29:2082–2092
55.Shimizu M,Uno T,Yasui-Furukori N,Sugawara K,Tateishi T
(2006)Effects of clarithromycin and verapamil on rabeprazole pharmacokinetics between CYP2C19genotypes.Eur J Clin Pharmacol62:597–603
56.Uno T,Shimizu M,Yasui-Furukori N,Sugawara K,Tateishi T
(2006)Different effects of fluvoxamine on rabeprazole pharma-cokinetics in relation to CYP2C19genotype status.Br J Clin Pharmacol61:309–314
57.Li XQ,Andersson TB,Ahlstr?m M,Weidolf L(2004)
Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole,esomeprazole,lansoprazole,pantoprazole, and rabeprazole on human cytochrome P450activities.Drug Metab Dispos32:821–827
58.Katz PO,Ginsberg GG,Hoyle PE,Sostek MB,Monyak JT,
Silberg DG(2007)Relationship between intragastric acid control and healing status in the treatment of moderate to severe erosive oesophagitis.Aliment Pharmacol Ther25:617–628
59.Katz PO(2006)Review article:intragastric and oesophageal pH
monitoring in patients with gastro-oesophageal reflux disease.
Aliment Pharmacol Ther23(Suppl1):3–11
60.Klotz U(2001)The changing target in the treatment of peptic
ulcer:from pH to Hp.In:Gupta YK(ed)Pharmacology and therapeutics in the New Millenium.Narosa Publ House,New Delhi,India,pp587–598
61.Hellstr?m PM,Vitols S(2004)The choice of proton pump
inhibitor:does it matter?Basic Clin Pharmacol Toxicol94:106–111
62.Robinson M(2004)Review article:pH,healing and symptom
relief with rabeprazole treatment in acid-related disorders.
Aliment Pharmacol Ther20(Suppl6):30–37
63.Pantoflickova D,Dorta G,Ravic M,Jornod P,Blum AL(2003)
Acid inhibition on the first day of dosing:comparison of four proton pump inhibitors.Aliment Pharmacol Ther17:1507–1514 64.Tolman KG,T?ubel J,Warrington S,Chiu YL,Pilmer BL,Pan
WJ(2006)Comparison of the effects of single and repeated oral
doses of lansoprazole and rabeprazole on ambulatory24-hour intragastric pH in healthy volunteers.Clin Drug Investig 26:21–28
65.Miner P,Katz PO,Chen Y,Sostek M(2003)Gastric acid control
with esomeprazole,lansoprazole,omeprazole,pantoprazole,and rabeprazole:a five-way crossover study.Am J Gastroenterol 98:2616–2620
66.R?hss K,Lind T,Wilder-Smith C(2004)Esomeprazole40mg
provides more effective intragastric acid control than lansopra-zole30mg,omeprazole20mg,pantoprazole40mg and rabeprazole20mg in patients with gastro-oesophageal reflux symptoms.Eur J Clin Pharmacol60:531–539
67.Shimatani T,Kuroiwa T,Moriwaki M,Xu J,Tazuma S,Inoue M
(2007)Acid-suppressive effects of various regimens of omepra-zole in Helicobacter pylori-negative CYP2C19homozygous extensive metabolizers:which regimen has the strongest effect?
Dig Dis Sci52:2826–2832
68.R?hss K,Wilder-Smith C,Kilhamn J,Fjellman M,Lind T
(2007)Suppression of gastric acid with intravenous esomepra-zole and omeprazole:results of3studies in healthy subjects.Int J Clin Pharmacol Ther45:345–354
69.Hartmann D,Eickhoff A,Damian U,Riemann JF,Schilling D
(2007)Effect of intravenous application of esomeprazole40mg versus pantoprazole40mg on24-hour intragastric pH in healthy adults.Eur J Gastroenterol Hepatol19:133–137
70.Miehlke S,Madisch A,Kirsch C,Lindner F,Kuhlisch E,Laass
M,Knoth H,Morgner A,Labenz J(2005)Intragastric acidity during treatment with esomeprazole40mg twice daily or pantoprazole40mg twice daily–a randomized,two-way cross-over study.Aliment Pharmacol Ther21:963–967
71.Johnson DA,Stacy T,Ryan M,Wootton T,Willis J,Hornbuckle
K,Brooks W,Doviak M(2005)A comparison of esomeprazole and lansoprazole for control of intragastric pH in patients with symptoms of gastro-oesophageal reflux disease.Aliment Phar-macol Ther22:129–134
72.Norris V,Baisley K,Dunn K,Warrington S,Morocutti A(2007)
Combined analysis of three crossover clinical pharmacology studies of effects of rabeprazole and esomeprazole on24-
h intragastric pH in healthy volunteers.Aliment Pharmacol Ther
25:501–510
73.Warrington S,Baisley K,Dunn K,Boyce M,Morocutti A(2006)
Effects of single doses of rabeprazole20mg and esomeprazole 40mg on24-h intragastric pH in healthy subjects.Eur J Clin Pharmacol62:685–691
74.Li ZS,Zhan XB,Xu GM,Cheng NN,Liao Z(2007)Effect of
esomeprazole and rabeprazole on intragastric pH in healthy Chinese:an open,randomized crossover trial.J Gastroenterol Hepatol22:815–820
75.Ohning GV,Walsh JH,Pisegna JR,Murthy A,Barth J,Kovacs
TO(2003)Rabeprazole is superior to omeprazole for the inhibition of peptone meal-stimulated gastric acid secretion in Helicobacter pylori-negative subjects.Aliment Pharmacol Ther 17:1109–1114
76.Armstrong D,James C,Camacho F,Chen Y,Horbay GL,
Teixeira B,Husein-Bhabha FA(2007)Oral rabeprazole vs.
intravenous pantoprazole:a comparison of the effect on intragastric pH in healthy subjects.Aliment Pharmacol Ther 25:185–196
77.Warrington S,Baisley K,Lee D,Lomax K,Delemos B,Boyce M,
Morocutti A(2007)Pharmacodynamic effects of single doses of rabeprazole20mg and pantoprazole40mg in patients with GERD and nocturnal heartburn.Aliment Pharmacol Ther25:511–517 78.Shimatani T,Inoue M,Kuroiwa T,Xu J,Tazuma S,Horikawa Y,
Nakamura M(2005)Acid-suppressive efficacy of a reduced dosage of rabeprazole:comparison of10mg twice daily rabeprazole with20mg twice daily rabeprazole,30mg twice
daily lansoprazole,and20mg twice daily omeprazole by24-hr intragastric pH-metry.Dig Dis Sci50:1202–1206
79.Shimatani T,Moriwaki M,Xu J,Tazuma S,Inoue M(2006)
Acid-suppressive effects of rabeprazole:comparing10mg and 20mg twice daily in Japanese Helicobacter pylori-negative and -positive CYP2C19extensive metabolisers.Dig Liver Dis 38:802–808
80.Kirsch C,Morgner A,Miehlke S(2006)Relevance of
cytochrome P450polymorphisms in the treatment of Helico-bacter pylori infection and gastroesophageal reflux disease.
Current Pharmacogenomics4:47–56
81.Furuta T,Shirai N,Sugimoto M,Nakamura A,Hishida A,
Ishizaki T(2005)Influence of CYP2C19pharmacogenetic polymorphism on proton pump inhibitor-based therapies.Drug Metab Pharmacokinet20:153–167
82.Saitoh T,Fukushima Y,Otsuka H,Hirakawa J,Mori H,Asano T,
Ishikawa T,Katsube T,Ogawa K,Ohkawa S(2002)Effects of rabeprazole,lansoprazole and omeprazole on intragastric pH in CYP2C19extensive metabolizers.Aliment Pharmacol Ther 16:1811–1817
83.Shimatani T,Inoue M,Kuroiwa T,Xu J,Mieno H,Nakamura M,
Tazuma S(2006)Acid-suppressive effects of rabeprazole,omepra-zole,and lansoprazole at reduced and standard doses:a crossover comparative study in homozygous extensive metabolizers of cytochrome P4502C19.Clin Pharmacol Ther79:144–152
84.Shimatani T,Inoue M,Kuroiwa T,Horikawa Y,Mieno H,
Nakamura M(2003)Effect of omeprazole10mg on intragastric pH in three different CYP2C19genotypes,compared with omeprazole20mg and lafutidine20mg,a new H2-receptor antagonist.Aliment Pharmacol Ther18:1149–1157
85.Sohn YH,Lee WS,Park CH,Joo YE,Kim HS,Choi SK,Rew
JS,Kim SJ(2006)Influence of CYP2C19polymorphism and Helicobacter pylori status on the antisecretory effect of omepra-zole in gastroesophageal reflux disease.Korean J Gastroenterol 48:162–171
86.Furuta T,Shirai N,Sugimoto M,Nakamura A,Okudaira K,
Kajimura M,Hishida A(2005)Effect of concomitant dosing of famotidine with lansoprazole on gastric acid secretion in relation to CYP2C19genotype status.Aliment Pharmacol Ther22:67–74 87.Yamano HO,Matsushita HO,Yanagiwara S(2008)Plasma
concentration of rabeprazole after8-week administration in gastro-esophageal reflux disease patients and intragastric pH elevation.J Gastroenterol Hepatol23:534–540doi:10.1111/j.1440-1746.2007.05104.x
88.Sugimoto M,Furuta T,Shirai N,Nakamura A,Kajimura M,
Hishida A,Ohashi K,Ishizaki T(2005)Comparison of an increased dosage regimen of rabeprazole versus a concomitant dosage regimen of famotidine with rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P4502C19 genotypes.Clin Pharmacol Ther77:302–311
89.Sugimoto M,Furuta T,Shirai N,Kajimura M,Hishida A,
Sakurai M,Ohashi K,Ishizaki T(2004)Different dosage regimens of rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P4502C19genotype status.Clin Pharmacol Ther76:290–301
90.Oh JH,Choi MG,Dong MS,Park JM,Paik CN,Cho YK,Jeong
JJ,Lee IS,Kim SW,Han SW,Choi KY,Chung IS(2007)Low-dose intravenous pantoprazole for optimal inhibition of gastric acid in Korean patients.J Gastroenterol Hepatol22:1429–1434 91.Louw JA(2006)Peptic ulcer disease.Curr Opin Gastroenterol
22:607–611
92.Yuan Y,Padol IT,Hunt RH(2006)Peptic ulcer disease today.
Nat Clin Pract Gastroenterol Hepatol3:80–89
93.Ji S,Kim HS,Kim JW,Jee MK,Park KW,Uh Y,Lee DK,
Song JS,Baik SK,Kwon SO(2006)Comparison of the efficacy of rabeprazole10mg and omeprazole20mg for the
healing rapidity of peptic ulcer diseases.J Gastroenterol Hepatol21:1381–1387
94.Malfertheiner P,Megraud F,O’Morain C,Bazzoli F,El-Omar E,
Graham D,Hunt R,Rokkas T,Vakil N,Kuipers EJ(2007) Current concepts in the management of Helicobacter pylori infection:the Maastricht III Consensus Report.Gut56:772–781 95.Fujioka T,Yoshiiwa A,Okimoto T,Kodama M,Murakami K
(2007)Guidelines for the management of Helicobacter pylori infection in Japan:current status and future prospects.J Gastro-enterol42(Suppl17):3–6
96.Chey WD,Wong BC,Practice Parameters Committee of the
American College of Gastroenterology(2007)American College of Gastroenterology guideline on the management of Helico-bacter pylori infection.Am J Gastroenterol102:1808–1825 97.Kumar R,Tandon VR,Bano G,Kapoor B,Sharma S,Gupta Y
(2007)Comparative study of proton pump inhibitors for triple therapy in H.pylori eradication.Indian J Gastroenterol26:100–101 98.Wang X,Fang JY,Lu R,Sun DF(2006)A meta-analysis:
comparison of esomeprazole and other proton pump inhibitors in eradicating Helicobacter pylori.Digestion73:178–186
99.Gisbert JP,Pajares JM(2004)Esomeprazole-based therapy in
Helicobacter pylori eradication:a meta-analysis.Dig Liver Dis 36:253–259
100.Gisbert JP,Khorrami S,Calvet X,Pajares JM(2004)Pantoprazole based therapies in Helicobacter pylori eradication:a systematic review and meta-analysis.Eur J Gastroenterol Hepatol16:89–99 101.Treiber G,Malfertheiner P,Klotz U(2007)Treatment and dosing of Helicobacter pylori infection:when pharmacology meets clinic.Expert Opin Pharmacother8:329–350
102.Ford A,Moayyedi P(2003)How can the current strategies for Helicobacter pylori eradication therapy be improved?Can J Gastroenterol17(Suppl B):36B–40B
103.Mégraud F(2005)Update on therapeutic options for Helico-bacter pylori-related diseases.Curr Infect Dis Rep7:115–120 104.Vakil N,Lanza F,Schwartz H,Barth J(2004)Seven-day therapy for Helicobacter pylori in the United States.Aliment Pharmacol Ther20:99–107
105.Zagari RM,Bianchi-Porro G,Fiocca R,Gasbarrini G,Roda E, Bazzoli F(2007)Comparison of1and2weeks of omeprazole, amoxicillin and clarithromycin treatment for Helicobacter pylori eradication:the HYPER Study.Gut56:475–479
106.Calvet X,Ducons J,Bujanda L,Bory F,Montserrat A,Gisbert JP,Hp Study Group of the Asociación Espa?ola de Gastro-enterología(2005)Seven versus ten days of rabeprazole triple therapy for Helicobacter pylori eradication:a multicenter randomized trial.Am J Gastroenterol100:1696–1701
107.Gisbert JP,Pajares JM(2005)Systematic review and meta-analysis: is1-week proton pump inhibitor-based triple therapy sufficient to heal peptic ulcer?Aliment Pharmacol Ther21:795–804
108.Fuccio L,Minardi ME,Zagari RM,Grilli D,Magrini N,Bazzoli F(2007)Meta-analysis:duration of first-line proton-pump inhibitor based triple therapy for Helicobacter pylori eradication.
Ann Intern Med147:553–562
109.Giannini EG,Bilardi C,Dulbecco P,Mamone M,Santi ML, Testa R,Mansi C,Savarino V(2006)Can Helicobacter pylori eradication regimens be shortened in clinical practice?An open-label,randomized,pilot study of4and7-day triple therapy with rabeprazole,high-dose levofloxacin,and tinidazole.J Clin Gastroenterol40:515–520
110.Lüth S,Teyssen S,K?lbel CB,Singer MV(2001)4-day triple therapy with rabeprazole,amoxicillin and clarithromycin in the eradication of Helicobacter pylori in patients with peptic ulcer disease-A pilot study.Z Gastroenterol39:279–281,284–285 111.Wong VW,Chan FK(2007)10day sequential therapy was more effective than10day triple drug therapy for eradicating Helicobacter pylori infection.Evid Based Med12:146112.Moayyedi P(2007)Sequential regimens for Helicobacter pylori https://www.doczj.com/doc/7813111991.html,ncet370:1010–1012
113.Vaira D,Zullo A,Vakil N,Gatta L,Ricci C,Perna F,Hassan C, Bernabucci V,Tampieri A,Morini S(2007)Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication:a randomized trial.Ann Intern Med146:556–563 114.Zullo A,De Francesco V,Hassan C,Morini S,Vaira D(2007) The sequential therapy regimen for Helicobacter pylori eradica-tion:a pooled-data analysis.Gut56:1353–1357
115.Padol S,Yuan Y,Thabane M,Padol IT,Hunt RH(2006)The effect of CYP2C19polymorphisms on H.pylori eradication rate in dual and triple first-line PPI therapies:a meta-analysis.Am J Gastroenterol101:1467–1475
116.Furuta T,Sugimoto M,Shirai N,Ishizaki T(2007)CYP2C19 pharmacogenomics associated with therapy of Helicobacter pylori infection and gastro-esophageal reflux diseases with a proton pump inhibitor.Pharmacogenomics8:1199–1210
117.Schwab M,Schaeffeler E,Klotz U,Treiber G(2004)CYP2C19 polymorphism is a major predictor of treatment failure in white patients by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylori.Clin Pharmacol Ther76:201–209
118.Vakil N,van Zanten SV,Kahrilas P,Dent J,Jones R,Global Consensus Group(2006)The Montreal definition and classifi-cation of gastroesophageal reflux disease:a global evidence-based consensus.Am J Gastroenterol101:1900–1920
119.Moayyedi P,Talley NJ(2006)Gastro-oesophageal reflux https://www.doczj.com/doc/7813111991.html,ncet367:2086–2100
120.Pettit M(2005)Treatment of gastroesophageal reflux disease.
Pharm World Sci27:432–435
121.Ferguson DD,DeVault KR(2007)Medical management of gastroesophageal reflux disease.Expert Opin Pharmacother 8:39–47
122.van Pinxteren B,Numans ME,Bonis PA,Lau J(2006)Short-term treatment with proton pump inhibitors,H2-receptor antag-onists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease.Cochrane Database Syst Rev3:CD002095
123.Gralnek IM,Dulai GS,Fennerty MB,Spiegel BM(2006) Esomeprazole versus other proton pump inhibitors in erosive esophagitis:a meta-analysis of randomized clinical trials.Clin Gastroenterol Hepatol4:1452–1458
124.Schmitt C,Lightdale CJ,Hwang C,Hamelin B(2006)A multicenter,randomized,double-blind,8-week comparative trial of standard doses of esomeprazole(40mg)and omeprazole(20mg) for the treatment of erosive esophagitis.Dig Dis Sci51:844–850 125.Glatzel D,Abdel-Qader M,Gatz G,Pfaffenberger B(2007) Pantoprazole40mg is as effective as esomeprazole40mg to relieve symptoms of gastroesophageal reflux disease after4 weeks of treatment and superior regarding the prevention of symptomatic relapse.Digestion75(Suppl1):69–78
126.Miwa H,Sasaki M,Furuta T,Koike T,Habu Y,Ito M,Fujiwara Y,Wada T,Nagahara A,Hongo M,Chiba T,Kinoshita Y,ACID-RELATED SYMPTOM(ARS)RESEARCH GROUP(2007) Efficacy of rabeprazole on heartburn symptom resolution in patients with non-erosive and erosive gastro-oesophageal reflux disease:a multicenter study from Japan.Aliment Pharmacol Ther 26:69–77
127.Pace F,Annese V,Prada A,Zambelli A,Casalini S,Nardini P, Bianchi Porro G,Italian Rabeprazole Study Group(2005) Rabeprazole is equivalent to omeprazole in the treatment of erosive gastro-oesophageal reflux disease.A randomised,dou-ble-blind,comparative study of rabeprazole and omeprazole20 mg in acute treatment of reflux oesophagitis,followed by a maintenance open-label,low-dose therapy with rabeprazole.Dig Liver Dis37:741–750
128.Holtmann G,Bytzer P,Metz M,Loeffler V,Blum AL(2002)A randomized,double-blind,comparative study of standard-dose rabeprazole and high-dose omeprazole in gastro-oesophageal reflux disease.Aliment Pharmacol Ther16:479–485
129.Caos A,Breiter J,Perdomo C,Barth J(2005)Long-term prevention of erosive or ulcerative gastro-oesophageal reflux disease relapse with rabeprazole10or20mg vs.placebo:results of a5-year study in the United States.Aliment Pharmacol Ther 22:193–202
130.Goh KL,Benamouzig R,Sander P,Schwan T,EMANCIPATE (2007)Efficacy of pantoprazole20mg daily compared with esomeprazole20mg daily in the maintenance of healed gastroesophageal reflux disease:a randomized,double-blind comparative trial-the EMANCIPATE study.Eur J Gastroenterol Hepatol19:205–211
131.Devault KR,Johanson JF,Johnson DA,Liu S,Sostek MB(2006) Maintenance of healed erosive esophagitis:a randomized six-month comparison of esomeprazole twenty milligrams with lansoprazole fifteen milligrams.Clin Gastroenterol Hepatol4:852–859
132.Pilotto A,Franceschi M,Leandro G,Scarcelli C,D’Ambrosio LP,Paris F,Annese V,Seripa D,Andriulli A,Di Mario F(2007) Comparison of four proton pump inhibitors for the short-term treatment of esophagitis in elderly patients.World J Gastro-enterol13:4467–4472
133.Scholten T,Teutsch I,Bohuschke M,Gatz G(2007)Pantoprazole on-demand effectively treats symptoms in patients with gastro-oesophageal reflux disease.Clin Drug Investig27:287–296 134.Bour B,Staub JL,Chousterman M,Labayle D,Nalet B,Nouel O,Pariente A,Tocque E,Bonnot-Marlier S(2005)Long-term treatment of gastro-oesophageal reflux disease patients with frequent symptomatic relapses using rabeprazole:on-demand treatment compared with continuous treatment.Aliment Pharma-col Ther21:805–812
135.Egan LJ,Myhre GM,Mays DC,Dierkhising RA,Kammer PP, Murray JA(2003)CYP2C19pharmacogenetics in the clinical use of proton-pump inhibitors for gastro-oesophageal reflux disease:variant alleles predict gastric acid suppression,but not oesophageal acid exposure or reflux symptoms.Aliment Phar-macol Ther17:1521–1528
136.Furuta T,Shirai N,Watanabe F,Honda S,Takeuchi K,Iida T, Sato Y,Kajimura M,Futami H,Takayanagi S,Yamada M, Ohashi K,Ishizaki T,Hanai H(2002)Effect of cytochrome P4502C19genotypic differences on cure rates for gastroesoph-ageal reflux disease by lansoprazole.Clin Pharmacol Ther 72:453–460
137.Kawamura M,Ohara S,Koike T,Iijima K,Suzuki J,Kayaba S, Noguchi K,Hamada S,Noguchi M,Shimosegawa T,Study Group of GERD(2003)The effects of lansoprazole on erosive reflux oesophagitis are influenced by CYP2C19polymorphism.
Aliment Pharmacol Ther17:965–973
138.Kawamura M,Ohara S,Koike T,Iijima K,Suzuki H,Kayaba S, Noguchi K,Abe S,Noguchi M,Shimosegawa T(2007) Cytochrome P4502C19polymorphism influences the preventive effect of lansoprazole on the recurrence of erosive reflux esophagitis.J Gastroenterol Hepatol22:222–226
139.Ohkusa T,Maekawa T,Arakawa T,Nakajima M,Fujimoto K, Hoshino E,Mitachi Y,Hamada S,Mine T,Kawahara Y,Nagai T, Aoyama N,Yoshida N,Tadokoro K,Chida N,Konda Y,Seno H, Shimatani T,Inoue M,Sato N(2005)Effect of CYP2C19 polymorphism on the safety and efficacy of omeprazole in Japanese patients with recurrent reflux oesophagitis.Aliment Pharmacol Ther21:1331–1339
140.Ariizumi K,Ohara S,Koike T,Inomata Y,Iijima K,Sekine H, Noguchi M,Sugiyama K,Eda Y,Kayaba S,Kawamura M, Shimosegawa T(2006)Therapeutic effects of10mg/day rabeprazole administration on reflux esophagitis was not influ-
enced by the CYP2C19polymorphism.J Gastroenterol Hepatol 21:1428–1434
141.Iwakiri K,Kawami N,Tanaka Y,Sano H,Kotoyori M, Sakamoto C(2007)Management of gastroesophageal reflux disease(GERD)with refractory to standard dose of proton pump inhibitor.Nippon Rinsho65:913–920
142.Savarino V,Savarino E,Parodi A,Dulbecco P(2007)Functional heartburn and non-erosive reflux disease.Dig Dis25:172–174 143.Fock KM,Teo EK,Ang TL,Chua TS,Ng TM,Tan YL(2005) Rabeprazole vs esomeprazole in non-erosive gastro-esophageal reflux disease:a randomized,double-blind study in urban Asia.
World J Gastroenterol11:3091–3098
144.Pace F,Tonini M,Pallotta S,Molteni P,Porro GB(2007) Systematic review:maintenance treatment of gastro-oesophageal reflux disease with proton pump inhibitors taken‘on-demand’.
Aliment Pharmacol Ther26:195–204
145.Metz DC,Inadomi JM,Howden CW,van Zanten SJ,Bytzer P (2007)On-demand therapy for gastroesophageal reflux disease.
Am J Gastroenterol102:642–653
146.Bytzer P,Blum A,De Herdt D,Dubois D,The Trial Investigators(2004)Six-month trial of on-demand rabeprazole 10mg maintains symptom relief in patients with non-erosive reflux disease.Aliment Pharmacol Ther20:181–188
147.Arroyo M,Lanas A(2006)NSAIDs-induced gastrointestinal damage.Review.Minerva Gastroenterol Dietol52:249–259 https://www.doczj.com/doc/7813111991.html,nas A,Scheiman J(2007)Low-dose aspirin and upper gastrointestinal damage:epidemiology,prevention and treatment.
Curr Med Res Opin23:163–173
https://www.doczj.com/doc/7813111991.html,nas A(2006)Prevention and treatment of NSAID-induced gastroduodenal injury.Curr Treat Options Gastroenterol9:147–156 150.Scheiman JM,Fendrick AM(2007)Summing the risk of NSAID https://www.doczj.com/doc/7813111991.html,ncet369:1580–1581
151.Shi S,Klotz U(2008)Clinical use and pharmacological properties of selective COX-2inhibitors.Eur J Clin Pharmacol64:233–252 152.Morgner A,Miehlke S,Labenz J(2007)Esomeprazole: prevention and treatment of NSAID-induced symptoms and ulcers.Expert Opin Pharmacother8:975–988
153.Naesdal J,Brown K(2006)NSAID-associated adverse effects and acid control aids to prevent them:a review of current treatment options.Drug Saf29:119–132
154.Brown TJ,Hooper L,Elliott RA,Payne K,Webb R,Roberts C, Rostom A,Symmons D(2006)A comparison of the cost-effectiveness of five strategies for the prevention of non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity:a sys-tematic review with economic modelling.Health Technol Assess 10:iii–iv,xi–xiii,1–183
155.Skoczylas T,Sarosiek I,Sostarich S,McElhinney C,Durham S, Sarosiek J(2003)Significant enhancement of gastric mucin content after rabeprazole administration:its potential clinical significance in acid-related disorders.Dig Dis Sci48:322–328 156.Jaworski T,Sarosiek I,Sostarich S,Roeser K,Connor M,Brotze S,Wallner G,Sarosiek J(2005)Restorative impact of rabepra-zole on gastric mucus and mucin production impairment during naproxen administration:its potential clinical significance.Dig Dis Sci50:357–365
157.Chen JT,Pucino F,Resman-Targoff BH(2006)Celecoxib versus
a non-selective NSAID plus proton-pump inhibitor:what are the
considerations?J Pain Palliat Care Pharmacother20:11–32 158.Spiegel BM,Farid M,Dulai GS,Gralnek IM,Kanwal F(2006) Comparing rates of dyspepsia with Coxibs vs NSAID+PPI:a meta-analysis.Am J Med119:448.e27–448.e36
159.Zapata-Colindres JC,Zepeda-Gómez S,Monta?o-Loza A, Vázquez-Ballesteros E,de Jesús Villalobos J,Valdovinos-Andraca F(2006)The association of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs in peptic ulcer disease.Can J Gastroenterol20:277–280
160.Papatheodoridis GV,Sougioultzis S,Archimandritis AJ(2006) Effects of Helicobacter pylori and nonsteroidal anti-inflammato-ry drugs on peptic ulcer disease:a systematic review.Clin Gastroenterol Hepatol4:130–142
161.Shimada T,Yamagata M,Hiraishi H(2007)Role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users.Nippon Rinsho65:1824–1829
162.de Leest HT,Steen KS,Lems WF,Bijlsma JW,van de Laar MA, Huisman AM,V onkeman HE,Houben HH,Kadir SW,Kostense PJ,van Tulder MW,Kuipers EJ,Boers M,Dijkmans BA(2007) Eradication of Helicobacter pylori does not reduce the incidence of gastroduodenal ulcers in patients on long-term NSAID treatment:double-blind,randomized,placebo-controlled trial.
Helicobacter12:477–485
163.Zullo A,Hassan C,Campo SM,Morini S(2007)Bleeding peptic ulcer in the elderly:risk factors and prevention strategies.Drugs Aging24:815–828
164.Holtmann G,Howden CW(2004)Review article:management of peptic ulcer bleeding-the roles of proton pump inhibitors and Helicobacter pylori eradication.Aliment Pharmacol Ther19 (Suppl1):66–70
165.Mahachai V,Thomson AB,Vilaichone RK(2004)Effect of Helicobacter pylori infection and NSAIDs on the risk of peptic ulcer bleeding.J Med Assoc Thai87(Suppl2):S295–S299 https://www.doczj.com/doc/7813111991.html,nas A,García-Rodríguez LA,Arroyo MT,Gomollón F,Feu F, González-Pérez A,Zapata E,Bástida G,Rodrigo L,Santolaria S, Güell M,de Argila CM,Quintero E,Borda F,PiquéJM,Asociación Espa?ola de Gastroenterología(2006)Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2inhib-itors,traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations.Gut55:1731–1738
167.Fisher L,Fisher A,Pavli P,Davis M(2007)Perioperative acute upper gastrointestinal haemorrhage in older patients with hip fracture:incidence,risk factors and prevention.Aliment Phar-macol Ther25:297–308
168.García Rodríguez LA,Barreales Tolosa L(2007)Risk of upper gastrointestinal complications among users of traditional NSAIDs and COXIBs in the general population.Gastroenterol-ogy132:498–506
169.Lin HJ,Lo WC,Cheng YC,Perng CL(2006)Role of intravenous omeprazole in patients with high-risk peptic ulcer bleeding after successful endoscopic epinephrine injection:a prospective random-ized comparative trial.Am J Gastroenterol101:500–505
170.Zargar SA,Javid G,Khan BA,Yattoo GN,Shah AH,Gulzar GM,Sodhi JS,Mujeeb SA,Khan MA,Shah NA,Shafi HM (2006)Pantoprazole infusion as adjuvant therapy to endoscopic treatment in patients with peptic ulcer bleeding:prospective randomized controlled trial.J Gastroenterol Hepatol21:716–721 171.McCarthy DM(2004)Management of bleeding peptic ulcer: current status of intravenous proton pump inhibitors.Best Pract Res Clin Gastroenterol18(Suppl):7–12
172.Armstrong D(2005)Intravenous proton pump inhibitor therapy:a rationale for use.Rev Gastroenterol Disord5(Suppl2):S18–S30 173.Julapalli VR,Graham DY(2005)Appropriate use of intravenous proton pump inhibitors in the management of bleeding peptic ulcer.Dig Dis Sci50:1185–1193
174.Leontiadis GI,Sharma VK,Howden CW(2005)Systematic review and meta-analysis:enhanced efficacy of proton-pump inhibitor therapy for peptic ulcer bleeding in Asia-a post hoc analysis from the Cochrane collaboration.Aliment Pharmacol Ther21:1055–1061
175.Leontiadis GI,Sharma VK,Howden CW(2006)Proton pump inhibitor treatment for acute peptic ulcer bleeding.Cochrane Database Syst Rev(1):CD002094doi:10.1002/14651858 176.Leontiadis GI,Sharma VK,Howden CW(2007)Proton pump inhibitor therapy for peptic ulcer bleeding:Cochrane collabora-
tion meta-analysis of randomized controlled trials.Mayo Clin Proc82:286–296
177.Kim JI,Cheung DY,Cho SH,Park SH,Han JY,Kim JK,Han SW, Choi KY,Chung IS(2007)Oral proton pump inhibitors are as effective as endoscopic treatment for bleeding peptic ulcer:a prospective,randomized,controlled trial.Dig Dis Sci52:3371–3376 https://www.doczj.com/doc/7813111991.html,nas A,García-Rodríguez LA,Arroyo MT,Bujanda L, Gomollón F,FornéM,Aleman S,Nicolas D,Feu F,González-Pérez A,Borda A,Castro M,Poveda MJ,Arenas J,Investigators of the Asociación Espa?ola de Gastroenterología(AEG)(2007) Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents,and anticoagulants.Am J Gastroenterol 102:507–515
179.Spiegel BM,Dulai GS,Lim BS,Mann N,Kanwal F,Gralnek IM (2006)The cost-effectiveness and budget impact of intravenous versus oral proton pump inhibitors in peptic ulcer hemorrhage.
Clin Gastroenterol Hepatol4:988–997
180.Jensen RT(2006)Consequences of long-term proton pump blockade:insights from studies of patients with gastrinomas.
Basic Clin Pharmacol Toxicol98:4–19
181.Ramdani A,Mignon M,Samoyeau R(2002)Effect of pantoprazole versus other proton pump inhibitors on24-h intra-gastric pH and basal acid output in Zollinger-Ellison syndrome.
Gastroenterol Clin Biol26:355–359
182.Hirschowitz BI,Simmons J,Mohnen J(2001)Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors:a prospective10-year study.Aliment Pharmacol Ther15:1795–1806
183.Hirschowitz BI,Simmons J,Mohnen J(2005)Clinical outcome using lansoprazole in acid hypersecretors with and without Zollinger-Ellison syndrome:a13-year prospective study.Clin Gastroenterol Hepatol3:39–48
184.Metz DC,Soffer E,Forsmark CE,Cryer B,Chey W,Bochenek W,Pisegna JR(2003)Maintenance oral pantoprazole therapy is effective for patients with Zollinger-Ellison syndrome and idiopathic hypersecretion.Am J Gastroenterol98:301–307 185.Metz DC,Comer GM,Soffer E,Forsmark CE,Cryer B,Chey W, Pisegna JR(2006)Three-year oral pantoprazole administration is effective for patients with Zollinger-Ellison syndrome and other hypersecretory conditions.Aliment Pharmacol Ther23:437–444 186.Morocutti A,Merrouche M,Bjaaland T,Humphries T,Mignon M(2006)An open-label study of rabeprazole in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hyperse-cretion.Aliment Pharmacol Ther24:1439–1444
187.Diav-Citrin O,Arnon J,Shechtman S,Schaefer C,van Tonningen MR,Clementi M,De Santis M,Robert-Gnansia E, Valti E,Malm H,Ornoy A(2005)The safety of proton pump inhibitors in pregnancy:a multicentre prospective controlled study.Aliment Pharmacol Ther21:269–275
188.Tolia V,Boyer K(2008)Long-term proton pump inhibitor use in children:a retrospective review of safety.Dig Dis Sci53:385–393 189.Martín de Argila C(2005)Safety of potent gastric acid inhibition.Drugs65(Suppl1):97–104
190.Sánchez Garrido A(2007)Omeprazole-induced acute cholestatic hepatitis.Gastroenterol Hepatol30:54
https://www.doczj.com/doc/7813111991.html,heij RJ,Sturkenboom MC,Hassing RJ,Dieleman J,Stricker BH,Jansen JB(2004)Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs.JAMA292:1955–1960
192.Gulmez SE,Holm A,Frederiksen H,Jensen TG,Pedersen C, Hallas J(2007)Use of proton pump inhibitors and the risk of community-acquired pneumonia:a population-based case-con-trol study.Arch Intern Med167:950–955
193.Brewster UC,Perazella MA(2007)Proton pump inhibitors and the kidney:critical review.Clin Nephrol68:65–72
194.H?rmark L,van der Wiel HE,de Groot MC,van Grootheest AC (2007)Proton pump inhibitor-induced acute interstitial nephritis.
Br J Clin Pharmacol64:819–823
195.Sierra F,Suarez M,Rey M,Vela MF(2007)Systematic review: Proton pump inhibitor-associated acute interstitial nephritis.
Aliment Pharmacol Ther26:545–553
196.Akhtar AJ,Shaheen M(2007)Increasing incidence of clostrid-ium difficile-associated diarrhea in African-American and His-panic patients:association with the use of proton pump inhibitor therapy.J Natl Med Assoc99:500–504
197.Lowe DO,Mamdani MM,Kopp A,Low DE,Juurlink DN (2006)Proton pump inhibitors and hospitalization for Clostrid-ium difficile-associated disease:a population-based study.Clin Infect Dis43:1272–1276
198.Vestergaard P,Rejnmark L,Mosekilde L(2006)Proton pump inhibitors,histamine H2receptor antagonists,and other antacid medications and the risk of fracture.Calcif Tissue Int79:76–83 199.Yang YX,Lewis JD,Epstein S,Metz DC(2006)Long-term proton pump inhibitor therapy and risk of hip fracture.JAMA 296:2947–2953
200.Waldum HL,Qvigstad G(2007)Proton pump inhibitors and gastric neoplasia.Gut56:1019–1020
201.Kuipers EJ(2006)Proton pump inhibitors and gastric neoplasia.
Gut55:1217–1221
202.Yang YX,Hennessy S,Propert K,Hwang WT,Sedarat A,Lewis JD(2007)Chronic proton pump inhibitor therapy and the risk of colorectal cancer.Gastroenterology133:748–754
203.Robertson DJ,Larsson H,Friis S,Pedersen L,Baron JA, S?rensen HT(2007)Proton pump inhibitor use and risk of colorectal cancer:a population-based,case-control study.Gas-troenterology133:755–760
204.Jalving M,Koornstra JJ,Wesseling J,Boezen HM,DE Jong S, Kleibeuker JH(2006)Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy.Aliment Pharmacol Ther24:1341–1348205.Singh M,Dhindsa G,Friedland S,Triadafilopoulos G(2007) Long-term use of proton pump inhibitors does not affect the frequency,growth,or histologic characteristics of colon adeno-mas.Aliment Pharmacol Ther26:1051–1061
206.Fock KM,Ang TL,Bee LC,Lee EJ(2008)Proton pump inhibitors:do differences in pharmacokinetics translate into differences in clinical outcomes?Clin Pharmacokinet47:1–6 207.Fass R(2007)Proton-pump inhibitor therapy in patients with gastro-oesophageal reflux disease:putative mechanisms of failure.Drugs67:1521–1530
208.Dorward S,Sreedharan A,Leontiadis GI,Howden CW,Moayyedi P,Forman D(2006)Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding.
Cochrane Database Syst Rev(4):CD005415doi:10.1002/ 14651858
209.Khuroo MS,Khuroo MS,Farahat KL,Kagevi IE(2005) Treatment with proton pump inhibitors in acute non-variceal upper gastrointestinal bleeding:a meta-analysis.J Gastroenterol Hepatol20:11–25
210.Bardou M,Toubouti Y,Benhaberou-Brun D,Rahme E,Barkun AN(2005)Meta-analysis:proton-pump inhibition in high-risk patients with acute peptic ulcer bleeding.Aliment Pharmacol Ther21:677–686
211.Leontiadis GI,McIntyre L,Sharma VK,Howden CW(2004) Proton pump inhibitor treatment for acute peptic ulcer bleeding.
Cochrane Database Syst Rev(3):CD002094doi:10.1002/ 14651858
212.Leontiadis GI,Sharma VK,Howden CW(2005)Systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding.BMJ330:568
213.Andriulli A,Annese V,Caruso N,Pilotto A,Accadia L,Niro AG,Quitadamo M,Merla A,Fiorella S,Leandro G(2005) Proton-pump inhibitors and outcome of endoscopic hemostasis in bleeding peptic ulcers:a series of meta-analyses.Am J Gastroenterol100:207–219
历史街区保护与更新——以成都宽窄巷子为例 作者： 学号： 年级： 调查与分析 调研思路 调研报告的分析方法采用调查访谈与理论分析紧密结合的方法。调研过程有文献收集，确定调研方向，实地勘探、获取现状资料 、整理归纳资料 、分析结果。 调查主要采用下列方式、方法：现场勘踏、拍照、观测记录、数据统计分析、定量分析的问卷调查以及定性分析的访谈等，分析评价建立在坚实的数据资料基础上。问卷调查中总样本量为100份，有效问卷82份，有效率为82%；访谈中共10名被访者.在表达形式上，每一部分分析都由调查访谈的内容和理论知识两部分结合存在，充分体现了社会调研应联系实际，并最终分析解决问题。调查主要解决的问题是宽窄巷子是如何围绕休闲这一主题展开保护与改造，研究其规模、特色、空间处理以及如何与周边历史环境结合，侧重点是接到的尺度比例，如何处理使其更适宜现代人生活，在保护历史遗迹的同时，发展现代空间，不使之冲突。 【摘要】 当代历史建筑与街区保护对历史街区整体和区域的保护理念的强调，不仅强调对历史、艺术价值较高的文物性历史建筑进行原真性保护，而且主张对大量存在的一般性的历史建筑、街区以及存在期间的文化内容、生活方式进行整体的规划保护，同时也要求保持地区活力，瞒住现代生活的要求；重视对历史见证遗产的再利用，对于大量存在的一般性历史建筑既反对大拆大改，也不再主张不做任何变动的保护方式，而是主张保护和发展相结合，保护应到满足现代生活所需的内容。较好的协调保护与历史遗产与现代生活、传统保持与经济利益之间的矛盾。 【关键词】 街道尺度； 比例； 公共空间； 改造 前言 李白有诗云：“九天开出一成都，万户千门入画图”；在诗圣杜甫眼里，“晓看红湿处，花重锦官城”，诗人陆游又以“当年走马锦城西，曾为梅花醉似泥。二十里路香不断，青羊宫到浣花溪”的诗句，真切道出当年成都的优美环境与休闲生活。近年来，成都又先后荣获 调研流程图 深入研究阶段 验证阶段 结题阶段
历史文化街区保护管理办法 历史文化街区保护管理办法历史文化名镇名村保护管理办法历史文化名城名镇名村保护规划编制办法 (征求意见稿) 2010年11月2日 历史文化街区保护管理办法 历史文化街区保护管理办法 目录 第一章总则 第二章历史文化街区的设立和撤销 第三章保护规划的编制、审批、公布、修改与备案第四章保护规划实施第五章监督管理 第六章附则 - 1 - 历史文化街区保护管理办法 第一章总则 第一条 (制定目的)为了加强历史文化街区的保护与管理，继承和弘扬中华民族优秀历史文化遗产，依据《中华人民共和国城乡规划法》、《中华人民共和国文物保护法》、《历史文化名城名镇名村保护条例》，制定本办法。 第二条 (历史文化街区的定义)本办法所称历史文化街区，是指经省、自治区、直辖市人民政府核定公布的保存文物特别丰富、历史建筑集中成片、能够较完整和真实地体现传统格局和历史风貌，并具有一定规模的区域。
第三条 (适用范围)历史文化街区的设立、规划制定与实施、监督和管理，适用本办法。 第四条 (管理主体层级)国务院建设行政主管部门会同国务院文物主管部门负责历史文化街区的管理工作。 地方各级人民政府负责本行政区域的历史文化街区的管理工作。 第五条 (保护原则)历史文化街区的保护应当遵循保护遗产，继承文化，科学规划，严格保护的原则，突出历史风貌的整体保护，保护历史遗存的真实性，维护风貌的完整性，维持功能的延续性，采取政府主导、居民参与的方式改善基础设施和居住环境，正确处理更新改造和保护的关系。 第六条 (保护资金)历史文化街区所在地的县级以上地方人民政府，根据本地实际情况安排保护资金，列入本级财政预算。 国家鼓励企业、事业单位、社会团体和个人参与历史文化街区的保护。 第七条 (支持奖励)县级以上地方人民政府及其有关部门对在历史文化街区保护工作中做出突出贡献的单位和个人，按照国家有关规定给予表彰和奖励。 第八条 (资质管理)承担历史文化街区保护规划的编制单位，应当符合相应的规划资质管理规定。 第二章历史文化街区的设立和撤销 第九条 (设立标准)历史文化街区必须具备下列条件: (一)有比较完整的历史格局和风貌; - 2 - 历史文化街区保护管理办法 (二)有比较丰富的历史建筑和历史环境要素; 2(三)占地面积不小于2.5hm;
深圳市城市更新办法实施细则解读 1 2020年4月19日
《深圳市城市更新办法实施细则》解读 一、出台背景 ● 8月,广东省“三旧”改造政策出台,实现“三旧”改造用地出让、完善历史用地手续等六大突破。 ● 12月1日,《深圳市城市更新办法》正式施行,成为国内首部系统规范城市更新工作的政府规章,形成我市城市更新政策体系的核心。 ●明确了“政府引导、市场运作、规划统筹、节约集约、保障权益、公众参与”的原则,并确立了综合整治、功能改变和拆除重建三种更新模式。 ● 至今,市政府、市规划国土委相继出台一系列配套文件,形成了较为系统的城市更新政策体系,确立了“大力推进城中村和旧工业区改造、积极推进旧商业区改造、稳步推进旧住宅区改造”的策略,规范了相关运作流程。 ●《关于深入推进城市更新工作的意见》 ●《深圳市城市更新提速专项行动计划》 ●《深圳市城市更新单元规划制定计划申报指引》 2 2020年4月19日
●《城市更新单元规划审批操作规则》 ●《市规划国土委城市更新项目用地审查操作规程》 ●《深圳市城市更新项目保障性住房配建比例暂行规定》 ●《拆除重建类城市更新项目房地产证注销操作规则》 ●《深圳市宝安区、龙岗区、光明新区及坪山新区拆除重建类城市更新单元旧屋村范围认定办法》 ●…… ●当前,城市更新工作依然是市委、市政府高度重视的一项战略性工作。许勤市长在今年的政府工作报告中指出,“要以城市更新释放发展空间,推动城市发展由依赖增量土地向存量土地二次开发转变”,对城市更新工作寄予重望。●今年1月21日,市政府以 1号文的形式正式发布了《深圳市城市更新办法实施细则》。 二、主要原则及创新 ●原则一:与国务院《国有土地上房屋征收与补偿条例》、广东省“三旧”改造政策、市政府《深圳市城市更新办法》及《关于深入推进城市更新工作的意见》等相关文件保持衔接。 3 2020年4月19日
党员创建文明城市心得体会 心得体会就是一种读书、实践后所写的感受文字。以下是XXXX为您整理的，供您参考。 创建文明建设和物质文明建设相辅相成，相互促进，然而在现实当中，有许多人往往忽视精神文明建设对物质文明建设的推动作用。因而，正确认识精神文明建设的经济意义对构建和谐社会，具有重要的现实意义。 社会主义思想道德建设是社会主义精神文明建设的灵魂和核心，决定着精神文明的性质和方向。同时，思想道德建设对于经济发展有着重要推动作用。 思想道德是实现资源合理配置的重要保证。社会主义市场经济一个最基本的目标就是实现资源的合理配置，从而实现最佳的经济效益。资源包括人力资源和物质资源。合理配置就是这两方面能得到合理、最优的发展，实现人尽其才，物尽其用。而资源的合理配置往往又直接取决于人的思想道德素质。当前一些领域道德失范，拜金主义、享乐主义滋长，使假冒伪劣、欺诈活动、偷税漏税等成为社会公害，直接扰乱了社会主义市场经济秩序，也破坏了物质资源合理配置的进程和效益。这就需要加强适应市场经济的思想道德建设，用来约束和调节人们的市场经济行为。 思想道德是经济运行中的无形资产。如果把经济运行中
的资产仅仅理解为有形资产，那只是认识或掌握了资产的一半或是一小半。经济的发展、高效益的实现，往往取决于作为无形资产的人的思想道德觉悟。我们作为城市管理员，要规范自己的行为，坚持以人为本，努力做好协调、完善和激励工作，把人和人的素质放到平等、敬业、诚信，这个集体才会顺利发展。 作为精神文明建设的重要内容，文化建设既是建设物质文明的重要基础，又是提高人们思想觉悟和道德水平的重要条件。它对经济发展的推动作用，更是显而易见的。文化建设可激发人们为经济发展建功立业的积极性和主动性。文化建设一方面同经济共融，一方面又有着相对的独立性。其经济意义主要表现在文化产品中，具有鲜明的形象性、情绪的感召性、影响的普及性。健康的、优秀的文化产品，可以转化为人们从事经济建设的精神力量;消极颓废的文化产品可以把人们引向歧途，成为经济发展和现代化建设的阻碍因素。加强文化建设，发挥文化启迪人们智慧、陶冶人们的情操、美化人们的心灵、振兴民族精神的作用，必将激发人们投身改革开放的巨大热情，更加积极地为经济建设服务。 我是这个城市的党员，坚持岗位，努力工作，为xx市的大建设发展做出自己的贡献。 XX
浅谈历史文化街区的保护和改造 摘要：分析历史文化街区保护的意义及开发运作等问题。并结合孔城老街的实例，提出保护设想，希望找到既有利于文化保护和延续，又具有可操作性的改造方式。 关键词：历史街区、保护、开发 1引言 一座城市的特色，除了要有时代气息外，还要有历史文化传统。历史文化是城市文化遗产的重要组成部分，也是一个地区、一座城市悠久历史和灿烂文明的最好见证。同时，作为城市文化遗产保存最完整、最丰富的地区，历史文化街区被世代生活于此的人们倾注着很多复杂的情感。 2002年重新修订的《中华人民共和国文物保护法》明确规定历史文化街区所在地的县级以上地方人民政府应当组织编制专门的历史文化街区保护规划，并纳入城市总体规划。历史文化街区保护首次被以法律的形式确定下来。 2.历史文化街区保护的意义 2.2概念 历史文化街区是指经省、自治区、直辖市人民政府核定公布的保存文物特别丰富、历史建筑集中成片、能够较完整和真实地体现传统格局和历史风貌，并有一定规模的区域。《文物保护法》中对历史文化街区的界定是：法定保护的区域，学术上叫“历史地段”。 2.3意义 历史文化街区也是城市发展的重要资源，保护历史文化街区，对于建设特色城市有现实意义。文化被誉为"经济发展的原动力",这一点已经在很多城市的发展进程中得以证实。作为城市发展独特见证的历史文化街区，更是具有多方面的资源效应，在城市形象宣传、历史文化教育、乡土情结的维系、文化身份的认同、生态环境建设、和谐人居环境的构建等多方面具有综合的价值。 历史文化街区不仅仅是要保护构成历史风貌的文物古迹、历史建筑，还要保存构成整体风貌的所有要素，如道路、街巷、院墙、小桥、溪流、驳岸乃至古树等。历史文化街区是一个成片的地区，有大量居民在其间生活，是活态的文化遗产，有其特有的社区文化，不能只保护那些历史建筑的躯壳，还应该保存它承载的文化，保护非物质形态的内容，保存文化多样性。这就要维护社区传统，改善生活环境，促进地区经济活力。 3.历史文化街区的保护—以孔城老街为例 3.1历史沿革 孔城镇位于安徽省桐城市的东部，距今已有两千多年的历史。春秋中期（公元前770-481年），即为桐国南部门户，扼大别山东南区域通往长江水运通道之要冲，是古代重要的军事要塞，距今2500多年。三国（公元220-280年）时期，吴将吕蒙曾屯兵于此，建筑堡垒。距今1700多年。南宋时，孔城是民间抗金要塞，著名的抗金战场。元代为大别山东侧，江淮分水岭至长江大别山边缘地区的九大商镇之一。到明代有居民600余家，清代中、后期本镇发展为旧桐城县内“枞、汤、孔、练”四大名镇之首，达到古镇发展的高峰。现存约2公里长的石板古街和古建筑群就是晚清和民初遗留下来的历史文化遗产。 3.2老街概况 孔城老街是以南北向中大街为主轴，大街呈“S”形，地势南低北高，有主街一条，横街两条，另有七巷十三弄。连同两侧各甲之间（一甲到九甲）的巷道，形成鱼刺状的外部空间结构。总建筑面积约17万平方米。 街巷弄均为麻石所铺，店铺房舍皆青砖灰瓦，颇具江南水乡特色。著名的《桐乡书院四议》，戴钧衡即作于此，它为全国书院所奉崇，并载入《皇朝政典类纂》。镇东大沙河，平沙浩瀚，极目无垠，夕阳照射，宛如白雪，故有“孔城暮雪”之称。镇西南界荻埠河，碧波粼粼，
上海市城市更新规划实施办法 （试行） （讨论稿） 目录 第一条 （目的） (1) 第二条 （定义和适用范围） (1) 第三条 （工作制度） (1) 第四条 （管理职责） (1) 第五条 （组织实施机构） (2) 第六条 （区域评估） (2) 第七条 （实施方案） (2) 第八条 （规划政策） (3) 第九条 （土地政策） (4) 第十条 （实施管理） (5) 第十一条 （公众参与） (5) 第十二条 （附则） (5) 附：上海市城市更新规划技术要求（试行）
第一条（目的） 为深化落实城市总体规划的要求，有效调动政府、市场、社会等多方资源，优化城市功能、完善公共设施，提升城市品质、改善城市环境、完善基础设施，激发城市发展活力，提高土地利用效率，有序推进城市更新，促进经济、社会、生态、文化协调发展，根据有关法律、法规，结合本市实际，制定本办法。 第二条（定义和适用范围） 本办法所称城市更新，是指为优化城市功能、完善公共设施，提升城市品质、改善城市环境、完善基础设施等而进行的各类建设活动。 本办法适用于在本市中心城、新城、新市镇已基本建成区域中认定的城市更新地区，已纳入土地征收范围的旧城改造、工业转型、城中村改造地区，应当按其它相关规定执行。 第三条（工作制度） 城市更新实行区域评估和实施方案相结合的工作制度，按照政府引导、市场运作、多方参与、利益共享的原则，依法合规地推进实施。 第四条（管理职责） 市规划土地管理部门负责统筹协调全市城市更新工作，依法制定规划和土地政策以及相关技术规范，指导、管理、监督区、县开展城市更新工作。 市政府其他相关职能部门应当在职责范围内，依法制定有关城市更新的配套政策和标准，依法履行相应的指导、管理和监督职责。
创建文明城市的心得体会八篇 创建文明城市的心得体会八篇 【篇一】 文明是冬日里的太阳，温暖了人们的心田。文明是黑夜里的一盏明灯。照亮了人们的前程。 一天晚上，我和爸爸、妈妈准备去三水广场购物，来到红绿灯路口，我们站在路边等待指示。这时，我发现绿灯还没有亮，有一些 人就匆匆横过马路，我们和其他人一直好比说“三大群体”的塑造——把传统农民塑造成现代市民，把企业员工塑造成现代产业工人， 把未成年人塑造成现代化事业的接班人。为的是使人的思想观念、 道德规范和行为方式与时代的要求和谐共进。 政府还给人们作宣传、教育，尤其加强对青少年的教育，让人们养成健康文明的生活方式和行为习惯。而东莞也依据国家发布的 《创建全国文明城市对市民行为的10点基本要求》，通过讨论，制 订了“东莞市文明公约”和“东莞市民文明行为规范”。 凡事贵在实践。政府不但对市民进行宣传教育，开展关于城市形象、城市暖流、社会公德、环境并且也举办了相应的教育实践活动，如，“文明三有序”良好习惯养成活动。为了提高市民文化而且根据“酒泉市民文明行为规范”去做，为的是争取做一名合格的文明市民，为酒泉创建文明城市加分。 我们应对体现出文明城市的精神。 我们也要提高自身的不停的填充模范感染……每个人的精神境界都得以升华。 在工作上我们各司其职、各尽所能；在社会中体现积极、心态上进、追求完美；在精神上彼此监督、互相学习；在人与人之间，我 们更是相处融洽、互帮互助、诚信礼貌。整个社会呈现了一个全新 的面貌——一派和谐相处、积极上进的景象。
在一开始，人类还是野蛮人，但经过时间的磨练、时代的推动，人类世界已进步为一个人性化和个性化的社会。一个原本充满暴力 的世界，现在则演变成一个温馨和谐的大家庭，可见文明的意识是 多么重要。所以世界才需要文明，我们才需要追求文明。 而一个文明城市的创建绝不是单靠政府完成的，“文明城市”也绝 不是表面上的称呼，所以我们每一个人都得行动起来，带着同一个 追求，共同努力奋斗。 【篇二】 文明城市是一个地区物质文明、精神文明、政治文明和生态文明的和谐统一，是城市形象和发展水平的重要体现，也是居民整体素质、文明水平的体现。县委、县政府着眼全局，顺应时代潮流和经 济社会发展规律作出了开展省级文明城市创建活动重大决策。我们 务必站在战略高度，充分认识创建的重大意义，增强做好创建工作 的责任感和使命感。笔者认为，我们必须凝聚共识创文明，真抓实 干治环境，全力做好以下四个方面的工作。 一、深入宣传教育，营造文明创建氛围。 市民是城市的主人，是文明创建的实践者和受益者，只有调动全民积极性，才能为创建文明城市提供持久动力;只有从根本上提高广 大市民的素质，文明城市创建才能取得成效。因此，我们必须把宣 传教育作为主线，贯穿文明创建工作的始终。一是加强社会宣传。 通过广播、电视、报纸、网络，散发宣传资料等形式，全方位，多 层面宣传新《环境保护法》和创建文明城市的重要性和必要性，营 造良好的社会氛围。二是强化社会监督。公开环境质量、环境管理、环境行为等信息，维护公众的环境知情权，参与权和监督权。动员 市民靠自己辛勤努力，共同创建美好家园。三是文明创建进村入户。深入开展文明创建进机关、进学校、进企业、进乡村、进社区等活动，提升全民的法治意识和环境意识，增强全民争当文明市民的自 觉性和主动性。 二、狠抓环境整治，大力改善城市形象。
历史文化街区保护管理办法 历史文化名镇名村保护管理办法 历史文化名城名镇名村保护规划编制办法 （征求意见稿） 2010年11月2日
历史文化街区保护管理办法 目录 第一章总则 第二章历史文化街区的设立和撤销 第三章保护规划的编制、审批、公布、修改与备案 第四章保护规划实施 第五章监督管理 第六章附则 第一章总则 第二章保护规划的审批、公布、修改与备案 第三章保护措施管理 第四章监督管理 第五章附则 第一章总则 第二章编制要求 第三章调查和评估 第四章历史文化名城保护规划编制 第五章历史文化街区保护规划编制 第六章历史文化名镇名村保护规划编制 第七章成果要求 第八章附则 附件一保护规划制图统一标准和要求
第一章总则 第一条（制定目的）为了加强历史文化街区的保护与管理，继承和弘扬中华民族优秀历史文化遗产，依据《中华人民共和国城乡规划法》、《中华人民共和国文物保护法》、《历史文化名城名镇名村保护条例》，制定本办法。 第二条（历史文化街区的定义）本办法所称历史文化街区，是指经省、自治区、直辖市人民政府核定公布的保存文物特别丰富、历史建筑集中成片、能够较完整和真实地体现传统格局和历史风貌，并具有一定规模的区域。 第三条（适用范围）历史文化街区的设立、规划制定与实施、监督和管理，适用本办法。 第四条（管理主体层级）国务院建设行政主管部门会同国务院文物主管部门负责历史文化街区的管理工作。 地方各级人民政府负责本行政区域的历史文化街区的管理工作。 第五条（保护原则）历史文化街区的保护应当遵循保护遗产，继承文化，科学规划，严格保护的原则，突出历史风貌的整体保护，保护历史遗存的真实性，维护风貌的完整性，维持功能的延续性，采取政府主导、居民参与的方式改善基础设施和居住环境，正确处理更新改造和保护的关系。 第六条（保护资金）历史文化街区所在地的县级以上地方人民政府，根据本地实际情况安排保护资金，列入本级财政预算。 国家鼓励企业、事业单位、社会团体和个人参与历史文化街区的保护。 第七条（支持奖励）县级以上地方人民政府及其有关部门对在历史文化街区保护工作中做出突出贡献的单位和个人，按照国家有关规定给予表彰和奖励。 第八条（资质管理）承担历史文化街区保护规划的编制单位，应当符合相应的规划资质管理规定。 第二章历史文化街区的设立和撤销 第九条（设立标准）历史文化街区必须具备下列条件： （一）有比较完整的历史格局和风貌；
城市更新改造项目合作协议书 协议编号： 甲方：股份合作公司 地址： 邮政编码：电话： 法定代表人： □身份证/□护照/□其它证件号码： 乙方： 地址： 邮政编码：电话： 法定代表人： □身份证/□护照/□其它证件号码： 根据《中华人民共和国土地管理法》、《中华人民共和国城市房地产管理法》、《中华人民共和国合同法》、《深圳市城市更新办法》及相关法律法规、政 策规定，为改变拟更新改造区域[1]----片区老工业厂房/旧住宅区城市基础设施、公共服务设施配套差/产业收益低/环境落后/存在安全隐患/土地用途和利用效率与规划功能不符等状况，甲乙双方经多次协商，本着“改造增值，优于现状收益，互惠互利共赢”的原则，就------片区的城市更新项目的合作事宜订立合同，内容如下，双方共同遵守履行。 第一条项目更新范围及现状 本城市更新改造项目获得相关部门批准纳入城市更新单元规划制定计划后， 项目区域现状见附件一。（本城市更新改造项目的城市更新单元规划制定计 划的申报材料：地块现状一览表、更新单元范围图、现状权属图、建筑物信 息图。） 本城市更新改造项目的专项规划情况见附件二（城市更新单元规划通过审批，可附本城市更新项目的专项规划） 甲方在项目区域内的房地产占地（包括构筑附属物）平方米，建筑面 积平方米（其中住宅面积平方米，厂房面积平方米），详细情 况见附件三。 第二条项目改造期限： 2.1本协议签订后，应在个月内（建议12个月内）制定房地产收购搬迁补 偿安置方案，并通过甲方的股东代表大会表决同意； 2.2本协议签订后，应在个月内（建议24个月内）完成%以上(建议90%以上)的房地产收购搬迁补偿安置协议的签订工作；分期建设的，应在个月
创建文明城市心得体会150字 一说起“创建文明城市”，也许大家会认为这是家常便饭了，因为自佛山创建文明城市以来，家家户户都很熟悉了。但这样熟悉到 恐怕连幼儿园小朋友也知道的事情，不知道能有几个人真正地做到呢? 我一直沉思—直到我看见了这些事情。 在马路上，人们已不再闯红灯。即使在披上了朦胧轻纱，宁静得能让声音滴在人们心上，车子也隐形在道路上的深夜，人们也依旧 这样做。 在公车里，人们已自觉让座。孕妇、老人、残疾人享受了人们对他们的尊重。大家从不怠慢，甚至在地铁里也看到那些人让座的身影。 而且，许多社区都出现了“文明打扫团”，也要许多志愿者为文明站岗。 我想佛山当初创建文明城市是对的，“创建文明城市”—这样熟悉到恐怕连幼儿园小朋友也知道的事情，果然很多人做到。 建筑是城市的骨干，绿化是城市的服装，环境是城市的外貌，市民是城市的灵魂，而文明是城市的精神。文明城市不仅是要看她的 楼多高，街多宽，树多绿，花多丽，景多美，更要看市民的素质， 一点一点的文明事。 于是，我也加快了我文明的步伐。 文明一词，对于我们来说并不陌生。中华民族是一个有着悠久历史和文化传统的文明古国，中华文明对世界的发展做出过巨大贡献。当今时代，历史的传承、世界的瞩望、人民的重托，决定了我们发 展的目标和目的只能是文明。
近段时日，宁波为争创“全国首批文明城市”而方方面面努力着。所以我们每个人都要争做“文明市民”。那么从何做起呢?现在乱贴 牛皮癣、乱倒垃圾的现象很严重，这样都会污染环境，影响市容。 有的工厂为了自己的利益，排放废水、废气等有害物质。这样，势 必对环境造成了污染，对人类造成了伤害。 现在闯红灯的现象也很严重。在马路上随处可见有人看见前面是红灯，依然我行我素往前走。这样很容易引发交通事故，也为我们 的文明城市增添了一道不光彩的风景线。 我们只有一个地球，地球上的资源是有限的。尽管现在的环境污染很严重，但是生活在地球上的我们都不能灰心，只要齐心协力， 我们所生存的环境就会变得美好起来。我们始终要相信： “沉舟侧畔千帆过，病树前头万木春。” 文明是冬日里的太阳，温暖了人们的心田。文明是黑夜里的一盏明灯。照亮了人们的前程。 一天晚上，我和爸爸、妈妈准备去**广场购物，来到红绿灯路口，我们站在路边等待指示。这时，我发现绿灯还没有亮，有一些人就 匆匆横过马路，我们和其他人一直等到绿灯亮了才走过马路。我觉 得那些闯红灯的人是不对的，没有遵守交通规则，也影响了**这个 城市的市容市貌。创建文明城市，应该从每个人做起。 作为**的一份子，我们也要为“创建文明城市”献出自己的一份力，我们要做到用礼貌用语，尊老爱幼，爱护公物，不要在公共场 所大声喧哗，不要随地吐痰，保证城市的卫生………让文明气息洋 溢城市的每个角落。 花儿用美丽装扮世界，我们用行动创建文明城市。 文明行为是社会发展的标志，它使我们告别过去、告别愚昧、告别落后。可迄今为止，文明行为的逆流——陋习，仍随着某些人的 不良习惯而扩散、蔓延。 人本来伴随着文明，才使自己脱离了动物性。现代文明更让人类的生活方式、讲文明观念、卫生习惯、饮食爱好、公共道德，变得
历史文化街区国内外研究现状 我国对历史文化街区的研究始于1986年，但直到2012年，有关历史文化街区的研究文献数量才开始激增。尤其随着历史文化街区保护实践的不断深人，学术界对历史文化街区的研究不断跟进，形成了不少有价值的研究成果。归纳起来，学者们对历史文化街区的研究主要集中在以下几个方面。 1．历史文化街区的概念研究。 目前，学术界对“历史文化街区”相关概念的表述有多种称谓，如“历史地区”、“历史地段”和“历史城区”等。“历史文化街区”作为2002年以后我国历史文化名城保护体系中“中观层面”的核心概念，其前身为1986年提出的“历史文化保护区”。2002年10月修订的《中华人民共和国文物保护法》规定，所谓“历史(文化)街区”是指保存文物特别丰富并具有重大历史价值或者革命意义的城镇、街道、村庄。国家建设部和国家文物局起草的《历史文化名城保护条例(送审稿)》中，将“历史文化街区”定义为城市中保留遗存较为丰富，能够比较完整真实地反映一定历史时期传统风貌或民族地方特色，存有较多文物古迹、近现代史迹和历史建筑，并具有一定规模的地区。其中，前者指代了城镇和乡村环境中的特定区域，而后者则特指城镇环境中的某一特定区域，且前者的规模大于后者。2012年，《历史文化名城保护规划规范》(GB50357—2012)的发布，使“历史城区”、“历史地段”、“历史文化街区”等成为我国名城保护体系“中观层面的规范用语。其中，“历史地区”的范畴最广、包含内容最多，其他概念都内含于“历史地区”之中；“历史文化街区”又内含于“历史地段”之中，两者的主要区别在于前者为“经省、自治区、直辖市人民政府核定公布应予重点保护的历史地段。 2．历史文化街区保护与更新研究。 (1)历史文化街区的保护现状与存在问题。 近年来，随着城市化进程的加快，历史文化街区保护问题受到越来越多的学者的关注，尤其对历史文化街区开发中暴露出的诸多问题，学者们给予了更多
武汉市历史文化风貌街区保护规划和修建性 详细规划编制技术规定(试行) 时间:2014年03月05日来源:本站原创作者:武汉魅力村镇点击:522次 1.1依据为了保护历史文化资源，规范历史文化风貌街区保护规划的编制和管理，根据《中华人民 共和国城乡规划法》、《中华人民共和国文物保护法》、《城市紫线管理办法》、《历史文化名城保护规划规范(GB50357-2005) 1.1 依据 为了保护历史文化资源，规范历史文化风貌街区保护规划的编制和管理，根据《中华人民共和国城乡规划法》、《中华人民共和国文物保护法》、《城市紫线管理办法》、《历史文化名城保护规划规范(GB 50357-2005)》、《武汉市旧城风貌区和优秀历史建筑保护管理办法》(2003年)、《武汉市历史文化名城和优秀历史建筑保护条例》(2013)，结合武汉市历史文化资源保 护和规划管理的实际需要，制定本技术规定。 编制历史文化风貌街区保护规划及修建性详细规划，应依据《武汉市历史文化名城保护专 项规划》、《武汉主城历史文化与风貌街区体系规划》、《武汉市都市发展区紫线专项规划》、《武汉市主城区紫线专项规划》、《武汉市主城区控制性详细规划导则》等上位规划及本技术规定进行编制。 1.2 作用 本技术规定是结合武汉市历史保护的特点，对《历史文化名城保护规划规范 (GB 50357-2005)》中历史文化街区保护规划编制内容的深化。编制完成的保护规划和修建 性详细规划将作为武汉历史文化风貌街区建设和管理的依据。 1.3 适用范围 本技术规定适用于武汉市主城区历史文化风貌街区(包括历史文化街区、历史地段及传统 特色街区)保护规划和修建性详细规划的编制。其他历史文化资源集中的区域可参照本技术 规定执行。 1.4 规划编制组织、审批、修改程序 市规划主管部门应当会同市房屋、文物主管部门组织编制历史文化风貌街区保护规划，并征求所在地区人民政府和相关管理部门的意见，依法报市人民政府批准后向社会公布。 市规划主管部门应当根据历史文化风貌街区保护规划组织编制历史文化风貌街区修建性 详细规划。
历史文化街区与历史建筑的保护——以开封市双龙巷历史文化街区的保护规划为例 历史文化街区是历史文化名城的重要组成部分,也是名城历史文化和风貌的体现,而其中的历史建筑是构成历史文化街区的主体,历史建筑的数量也是确定历史文化街区最重要的依据. 对于历史建筑的保护研究目前还处于起步阶段,本文以开封市双龙巷历史文化街区的保护规划为例,对历史建筑的保护与利用提出建议. 对历史建筑的保护措施以修缮和改善为主,即不改变其外部历史风貌,对其内部结构,空间布局,内部设施,使用功能做适当的变动,以达到永续利用的目的,鼓励有利于保护的各种使用功能,引用市场机制解决历史建筑的保护、维修、臵换等,探索出适用于历史建筑的保护新路. 项目概况 开封市双龙巷历史文化街区位于开封市老城区东偏北的区域,是老城区内划定的两片历史文化街区之一,相邻周边用地多为未经改造的低层民居,建筑风格及色彩,空间尺度上较为协调,保持着良好的古城风韵.双龙巷传统民居保护区以北方古城传统四合院住宅形式为主,是清末民初民用建筑的典范,较好地保留了当时的居住格局,在开封历史文化名城保护中具有相当重要地位.
居住在双龙巷的居民几乎人人皆知双龙巷的故事,相传宋代皇帝赵匡胤, 匡义两兄弟曾住该巷,古代皇帝称真龙天子,故得名后人在双龙巷西口两侧各筑一龙头以示纪念.后开封城几遭破坏,现在仅存在的一个龙头为清代所建,其表面虽已斑驳,却依然是附近居民的骄傲. 保护范围及价值 双龙巷历史文化街区的保护范围是域,其核心保护区范围北至水车胡同,轱辘湾街一线,南至朝阳胡同,东至塘坊口街,南聚奎街,屈家胡同一线,西护面积16l7公顷.建设控制区范围北至以开封市双龙巷历史文化街区的保护规划为例延寿寺街,南至财政厅东街,平等街一线,东至内环东路,西至北道门,右司官口,北兴街一线,面积侣.8 公顷. 双龙巷历史文化街区的价值是以双龙巷、双井巷为代表的开封古城内保存最完整、规模最大的传统居住街区. 历史建筑集中,风貌相对完整.留存较多的有传统特色和文革历史特色的民居院落,有关于赵匡胤、史可法等传说。规划要点搬迁区内所有工厂,为街区保护提供发展用地.恢复僧忠亲王祠、史可法祠等历史古迹.最大范围的保护双龙巷街区历史风貌完整的区域,积极修缮历史建筑,改善居住环境.划定有价值的历史建筑为保护建筑,重点修缮,并整治建设周边环境,改造基础设施,尤其道路改造及宅院内部给排水工程改造. 公认的三个历史街区的核定标准:历史真实性、生活真实
城市更新项目操作程序
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城市更新项目操作程序 城市更新单元规划计划 受理部门大致工作及主要审批程序所需材料最终结果 辖区街道办1、申报主体与权利人签订合作开发及相关协议； 2、按政府相关规定多个或单一权利人委托一个公司或个人做为申报主体； 3、权利人或申报主体向街道办提出申请，要求在划定范围纳入城市更新计 划；主要审核权利人的更新意愿及土地权属的真实情况； 3、提交《指引》规定的申报资料预审。 1、拆迁范围内房屋权利人或申报主体致函所辖街道办； 2、提供上述文字图纸及电子版本的相关资料。 街道办审核后致函区旧改办，阐 述街道办对更新单元的意见。 区旧改办1、区旧改办审核更新单元范 围内的建筑物的权属是否清晰；权利人的更新意愿是否符合要求；满足上述 要求，核发复函； 2、将区旧改办的复函连同相 关申报资料报区国土局更新办，核实更新范围内建筑物产权及土地权属情 况；核实该区域是否与法定图则规定相冲突；无异议则给予复函；并转呈市 规土委更新办审批； 1、初步划定拆除重建区域作为城市更新单元范围，并 将该区域内地上建筑物、构筑物逐一拍摄照片，统 计拆除建筑面积等相关数据； 2、委托设计院将初步划定的更新单元范围依据《深圳 市城市更新单元规划制定计划申报指引（试行）》之 规定绘制范围图、现状权属图、建筑物信息图及更 新单元规划制定计划申报表、更新单元规划制定计 划申请书、地块现状详细信息一览表、更新意愿表 （包括上述信息的电子光盘）。 审核并确认申报主体。 区旧改办收到辖区街道办同意更新改造的函后，申报主体将《指引》规定的资料呈报 给旧改办。 旧改办主要审核： 1、审核申报区域权利主体权属情况是否清晰； 2、该区域是否与法定图则规定相冲突； 3、该区域是否与其他宗地红线重叠； 4、单一权利主体的申报，区旧改办无需做更新意愿的公示程序； 5、多个权利主体申报纳入更新单元规划计划的，必须做更新意愿的公示 15个自然日。 辖区街道办的批复，同意该更新单元纳入更新单元规划 制定计划及上述文字资料。 区旧改办汇总公示意见呈区规 划国土局更新科。 区国土局更新科旧改办将公示的意见整理汇总并提交给区规土局更新科。 1、区规土局更新科牵头征求各职能部门意见并会签意见后，提交区规土局 上会审议、批复； 2、市规土委相关部门组织申报主体单位共同委托指定有资质设计院拟订 城市更新单元规划草案。 草案提交区国土局上会审议并公示； 市城市更新办征求相关部门意见后，45个工作日内形成 审定的规划草案，报请市规划国土委技术委员会审议。 汇总公示后的意见。 上报市规委 区旧改办区旧改办或区规土局牵头组织申报主体委托有资质的设计单位，对更新区凭区规土局同意纳入更新单元规划制定计划的批复。《城市更新单元规划制定计划
小学生创建文明城市心得体会 导读：本文小学生创建文明城市心得体会，仅供参考，如果能帮助到您，欢迎点评和分享。 文明创建事关你我他美好当阳靠大家，小学生关于创建文明城市有什么心得体会呢?下面是为大家整理的：小学生创建文明城市心得体会，欢迎大家参阅，资讯尽在心得体会栏目! 小学生创建文明城市心得体会(一) 文明是冬日里的太阳，温暖了人们的心田。文明是黑夜里的一盏明灯。照亮了人们的前程。 一天晚上，我和爸爸、妈妈准备去三水广场购物，来到红绿灯路口，我们站在路边等待指示。这时，我发现绿灯还没有亮，有一些人就匆匆横过马路，我们和其他人一直等到绿灯亮了才走过马路。我觉得那些闯红灯的人是不对的，没有遵守交通规则，也影响了三水这个城市的市容市貌。创建文明城市，应该从每个人做起。 作为三水的一份子，我们也要为“创建文明城市”献出自己的一份力，我们要做到用礼貌用语，尊老爱幼，爱护公物，不要在公共场所大声喧哗，不要随地吐痰，保证城市的卫生………让文明气息洋溢城市的每个角落。 花儿用美丽装扮世界，我们用行动创建文明城市。 小学生创建文明城市心得体会(二) 文明是一阵清风，爽朗了人们的心情;文明是一盏灯，照亮了前程的光明;文明是一场雨，滋润了干涸的心灵。
从柏拉图的“理想国”、莫尔的“乌托邦”到康帕内拉的“太阳城”、欧文的“新和谐公社”，无一不反映了人类对“和谐社会”的不懈追求，生活在这个被和谐之光笼罩下的社会，我们是幸福的。当然，作为文明城市的建设者和继承人，我们任重而道远。 要想改变城市面貌，不但要把建设搞好，还要把精神文明传播好。人民是城市的主人，既是城市文明的受益者，更是城市文明的建设者，城市文明离不开个人文明、依托于个人文明。作为城市大家庭的一员，每位公民都有责任、有义务通过自己的文明行为，为我们的城市增色添彩。把一座城市建设的更美好，不仅仅是政府的事，也是我们每一个公民的事。只有齐心协力，从点滴做起，从我做起，从今天做起，积极为创建文明城市做出贡献，才能把我们的城市建设的越来越美丽。 我曾经看过一则公益广告：有人这样问过我，播出的一条公益广告，能不能改变我们生活中的那些陋习?我说不能。公益广告对于社会中的那些不文明的现象也许不可能药到病除，但是我相信，一条公益广告就好像是一盏灯，灯光亮一些，我们身边的黑暗就会少一些。并且我相信，每个人的心灵都像是一扇窗，窗户打开，光亮就会进来。我相信，文明就在我们身边，离我们很近很近，近得触手可及。有时候，文明离我们只不过是10公分的距离，有时候，也许只是几十厘米的宽度，也有时候，可能只是一张纸的厚度……文明在我们心中，会在我们生活中不经意地流露着。有时候，多一个手势，对别人来说，就是多一份体谅;有时候，多一点耐心的等待，对别人来说就是一种关爱;还有时，多一点点分享，对别人来说，就是多份温暖。我们每
历史街区的保护与规划专题研究 摘要：本文是对历史街区的保护与规划专题的总结性思考。结合这一学期所学，对历史街区的保护与规划专题的认识，汇报案例（绍兴仓桥直街规划）的介绍和总结，对本专题同学所做的内容的总结和思考，以及对历史街区保护与规划的个人观点。 关键词：城市建设历史街区保护规划文化 随着对历史街区问题的研究不断深入，城市建设与历史街区的保护及规划的问题已不仅仅是规划师或建筑师的研究课题，更关系到市民的切身利益，保护的内容也不再是某一文物,某一街区的形态特征，在某种意义上是使城市生活文化得以更好延续。历史街区保护是一项具有社会实践性特征的复杂工作,既需要不断推进城市保护理念的提升,还需要不断加强保护规划的实施以及控制机制的完善。历史文化遗产凝结了民族的智慧，对我们现代城市的硬件和人们文化思想的软件发展有极其重要的指导作用，然而，目前看来，历史文化遗产与城市建设的矛盾还没有得到很好的解决，本文拟就城市建设与历史街区的保护及规划的问题研究。现行的历史街区保护规划中存在着一些问题，这些问题的根源主要体现在经济、文化及保护制度上，通过研究历史街区的本质特征，对历史街区的保护规划实践进行思考，以总结城市建设过程中历史街区的保护及规划的经验和教训。 城市建设与历史街区的保护及规划的问题研究主要概括为三个方向，与时代的关系，与自然的关系，与文化的关系。与时代的关系：要正确认识到时代变迁是引发历史街区保护矛盾的根源，在保护过程中强调分析，针对不同类型寻求不同策略。探寻历史街区发展源动力，寻求新的社会因素的介入。与自然的关系：人居环境的建设可以追溯到整个人类进化以及迁徙历程，人类对于生存环境的选择受制于当时的生产水平，反映了人类改造自然寻求理想人居环境的历程。与文化的关系：每一个国家、民族和地区都有自己独特的气候条件、地理条件、文化传统、生活习惯和建筑风格，城市开发需要对历史文脉和地方文脉的重视和恰当的运用。在城市开发和建筑设计中，引用国际城市规划理论成果是必要的，但是如果抛弃了自己本土文化和悠久历史所沉淀下来的建筑经验和理论，就是本末倒置了。另外，对待传统街区的复原也要持审慎的态度，传统的美不在于符号的简单堆砌，而表现在经过艺术考虑的内在结构。建筑物的营造如同写文章，应从实际需求出发，理清地区文化脉络，将文化符号、地域符号进行重组。城市是我们赖以生存的家园，保护和发展历史街区，进行合理的规划安排，结合时代，自然，文化的关系，使历史街区在保护中发挥它的重要价值。 结合本专题研究，找的案例为浙江省绍兴仓桥直街。绍兴仓桥直街全长一点五公里的绍兴仓桥直街由河道、民居、街坊三部分组成，民居多为清末民初建筑，众多富有地方特色的台门保存完好，具有浓郁的水乡风貌。2003年获“二零零三年联合国教科文组织亚太地区文化遗产保护优秀奖”。 绍兴仓桥历史街区保护与整治是国内成功的保护规划，而在规划设计上采用
将军庙历史文化街区保护规划 一、规划范围 南至泉城路，北临大明湖路，东至鞭指巷，西临太平寺街、西城根街，总用地面积16.08公顷。 图1 现状航拍图 二、规划原则
以科学发展观为指导，遵循保护遗产本体及环境的真实性、完整性、生活延续性和保护利用的可持续性的原则，保护历史文化遗产，引导商业发展，改善人居环境，促进经济社会协调发展。 三、指导思想 规划坚持保护为主、合理利用、改善环境、加强引导，有效管理的指导思想，按照“政府主导，居民参与，实体运作，小规模、渐进式更新”指导思路开展工作。 四、规划目标 1、保护街区整体空间格局和历史风貌，尤其是体现街区价值特色的传统街区风貌，包括：具有济南“城泉共生”特色的传统居住区;济南古城多元宗教信仰的文化中心;多类型建筑集中展示区;济南古城内中西文化交汇融合、商贸交流繁荣之地。 2、保护街区丰富的历史文化遗存，保持历史文化街区的传统居住功能为主，使其成为城市发展历史的见证。 3、整治街区环境，完善基础设施配套，优化人居环境，促进社区健康发展，使其成为传统居住文化突出的特色社区。 4、结合街区现状情况，综合研究符合街区特点的规划实施模式，提出规划实施建议，加强保护规划中提出的对街区保护与整治措施的可行性。 五、街区价值与特色 作为济南古城现存的保留较完整的、最具传统特色的地区，将军庙街区具有历史、艺术、科学研究方面的极高价值。街区是古城的传统居住区;街区还集中了大量宗教建筑，是中西
文化交流繁荣的区域;街区内整体风貌保存尚好，传统街巷空间基本保留完好，名泉水体、大树丰富，建筑遗产多样。将军庙街区的总体价值为： 1、将军庙街区是具有济南“城泉共生”特色的传统居住区之一; 2、将军庙街区是济南古城宗教建筑分布最为集中，同时最能体现多元宗教信仰的文化中心; 3、将军庙街区建筑类型多样，体现了中西建筑精湛的建造技艺; 4、将军庙街区是济南古城内中西文化交汇融合、商贸交流繁荣之地。 六、保护内容及保护要素 本规划从物质文化遗存要素和非物质文化遗存要素两部分确定保护内容及各项保护要素。其中物质文化遗存要素包括传统格局、传统街巷、不可移动文物、历史建筑、泉水历史文化遗存、历史环境要素等七个方面;非物质文化遗存要素包括非物质文化遗产及优秀传统文化要素和与泉水相关的优秀传统文化要素。
历史街区保护与更新常见模式及案例分析 摘要：历史街区的保护是当下很多人关心的问题，过快的城市更新速度已经严重的威胁到了它们的存在。本文对当下的一些历史街区保护模式进行了总结，并分别分析了其成功的方式，希望可以为相关部门提供一点参考。 关键词：历史街区；保护；更新 Abstract: the historical block protection is instantly many people care about, and the rapid urban renewal rate has a serious threat to their existence. In this paper, the present some historical block protection mode are summarized, and analyzes its successful respectively way, the hope can provide some reference for the related department. Key words: the historical block; Protection; update 历史是一面镜子，我国是四大文明古国之一，历史尤为悠久，很多古老的建筑既见证着我们曾经的辉煌，又具有很高的研究价值，因此必须予以积极保护。但是近年来，随着我国城市化运动的不断高涨，原有的建筑逐步被高楼大厦所取代，这其中有很多历史建筑也惨遭不幸，造成了非常大的经济损失和人文损失，有志之士已经注意到了这一点，积极呼吁相关部门的保护和支持，也取得了一定的成效，但是这项工作任重而道远，需要我们所有人都有足够的认识才是根本之道。 很多古城的历史文化气息浓厚，古建筑非常多，难能可贵的是，这些建筑都是成片存在的，我们称之为历史街区，这些历史街区的存在让我们对过去的生活有了很多的理解，价值极大，但是只是单纯的进行保护效果又不好，最好的方式就是保护与利用合为一体，使其重换青春，本文即基于这样的目的做了探讨，希望能引起相关部门的重视。 我国的历史街区归纳而言有以下四种，其一是以古城文化为依托发展文化经济的历史街区，如丽江、平遥等均通过政府资金进行了大规模的整伤修缮，成为了著名的文化旅游城市。其二是处于城市黄金地段的老商业街区和办公街区的“置换”，典型案例就是上海的外滩。其三是以艺术家自发改造为主的产业建筑历史街区，最初是在上海，一些艺术家在苏州河沿岸地区自发改造的中小型产业建筑遗产成为了艺术家的工作室，随后在北京、杭州、成都出现了有类似的项目。其四是城市居住型历史街区的商业化改造，最典型的就是上海的“新天地”，随后这一模式迅速在全国范围内推广。