Many of the drugs currently used in medical practice are racemates. The enantiomers of a racemic drug differ in pharmacodynamics and/or pharmacokinetics, thus in some cases it is preferable to develop pure enantiomers...Many of the drugs currently used in medical practice are racemates. The enantiomers of a racemic drug differ in pharmacodynamics and/or pharmacokinetics, thus in some cases it is preferable to develop pure enantiomers by racemic switch. In a recent study by Pai et al, dexrabeprazole [R(+)-rabeprazole] (10 mg) was found to be more effective than rabeprazole (20 mg) in the treatment of gastroesophageal reflux disease. We read with great interest in this study and discussed whether such racemic switch would be applicable to other proton-pump inhibitors (PPIs). A literature review indicates that stereoselective pharmacokinetics, rather than stereoselective pharmacological activity, is the main cause of differences in clinical efficacy between pure enantiomer and racemic PPI. Racemic switches of PPI provide the therapeutic advantages such as reducing metabolic load on the body, simplifying pharmacokinetics, providing benefit to the non-responders to standard dose of racemate, more homogenous response to treatment and better efficacy with equal safety. Further studies in quantitative structure-activity relationships (QSARs) are needed to address the fact that the preferred enantiomer of PPI is not always in the same absolute configuration, i.e., S-form is for omeprazole, pantoprazole and tenatoprazole whereas R-form is for lansoprazole and rabeprazole.展开更多
Peptic ulcer disease continues to be issue especially due to its high prevalence in the developing world.Helicobacter pylori(H.pylori)infection associated duodenal ulcers should undergo eradication therapy.There are m...Peptic ulcer disease continues to be issue especially due to its high prevalence in the developing world.Helicobacter pylori(H.pylori)infection associated duodenal ulcers should undergo eradication therapy.There are many regimens offered for H.pylori eradication which include triple,quadruple,or sequential therapy regimens.The central aim of this systematic review is to evaluate the evidence for H.pylori therapy from a meta-analytical outlook.The consequence of the dose,type of proton-pump inhibitor,and the length of the treatment will be debated.The most important risk factor for eradication failure is resistance to clarithromycin and metronidazole.展开更多
Since the early reports nearly a decade ago, proton-pump inhibitor-induced hypomagnesemia （PPIH） has become a well-recognized phenomenon. While many observational studies in the inpatient and outpatient populations ...Since the early reports nearly a decade ago, proton-pump inhibitor-induced hypomagnesemia （PPIH） has become a well-recognized phenomenon. While many observational studies in the inpatient and outpatient populations have confirmed the association of PPI exposure and serum magnesium concentrations, there are no prospective,controlled studies to support causation. Molecular mechanisms of magnesium transporters, including the pH-dependent regulation of transient receptor potential melastatin-6 transporters in the colonic enterocyte, have been proposed to explain the effect of PPIs on magnesium reabsorption, but may be a small part of a more complicated interplay of molecular biology, pharmacology, and genetic predisposition. This review explores the current state of research in the feld of PPIH and the proposed mechanisms of this effect.展开更多
Objective： To determine whether patients maintain symptom control after discontinuation of PPI （proton-pump inhibitor） therapy through intervention of a pharmacist-led medication utilization program and determine a...Objective： To determine whether patients maintain symptom control after discontinuation of PPI （proton-pump inhibitor） therapy through intervention of a pharmacist-led medication utilization program and determine annual clinic cost-savings per prescription. Design： The study was conducted as a prospective, medication use evaluation. Using an electronic medical record system at a clinic, reports generated all patients receiving PP1 therapy from January 2013-June 2015. Patients were encouraged to participate in a PPI discontinuation trial through a pharmacist-led educational session. Participants were followed-up three months post enrollment to assess their quality of life through a survey assessing severity and frequency of symptoms. Participants unable to maintain symptom control after the intervention were referred back to their primary care physician for further evaluation. Results： Of one hundred participants, 25% （n = 25） were able to discontinue the use of PPI by lifestyle modifications, 43% （n = 43） refused to discontinue PP1 therapy and lifestyle changes due to the severity of their symptoms, 17% （n = 17） switched to over-the-counter H2 receptor antagonist daily to control their symptoms, 9% （n = 9） used PPIs only as needed, and 6% （n = 6） of participants were dropped from the study after three failed communication attempts. The clinic saved approximately $11 thousand annually for every one prescription of PPI＇s. Conclusions： Discontinuation of PPI or step-down therapy was possible for patients with mild-moderate GERD （Gastroesophageal Reflux Disease） symptoms when mediated by pharmacist counseling and follow-up. Also, the annual PPI expenditure at this clinic will decrease due to participant＇s discontinuation of therapy.展开更多
Proton-pump inhibitors （PPIs） are among the most widely used drugs worldwide. PPI use has recently been linked to adverse changes in semen quality in healthy men; however, the effects of PPI use on semen parameters ...Proton-pump inhibitors （PPIs） are among the most widely used drugs worldwide. PPI use has recently been linked to adverse changes in semen quality in healthy men; however, the effects of PPI use on semen parameters remain largely unknown specifically in cases with male factor infertility. We examined whether PPI use was associated with detrimental effects on semen parameters in a large population of subfertile men. We retrospectively reviewed data from 12 257 subfertile men who had visited our fertility clinic from 2003 to 2013. Patients who reported using any PPIs for 〉3 months before semen sample collection were included; 7698 subfertile men taking no medication served as controls. Data were gathered on patient age, medication use, and conventional semen parameters; patients taking any known spermatotoxic medication were excluded. Linear mixed-effect regression models were used to test the effect of PPI use on semen parameters adjusting for age. A total of 248 patients （258 samples） used PPIs for at least 3 months before semen collection. In regression models, PPI use （either as the only medication or when used in combination with other nonspermatotoxic medications） was not associated with statistically significant changes in semen parameters. To our knowledge, this is the largest study to compare PPI use with semen parameters in subfertile men. Using PPIs was not associated with detrimental effects on semen quality in this retrospective study.展开更多
AIM:To investigate the preventive effects of low-dose proton-pump inhibitors(PPIs) for upper gastrointestinal bleeding(UGIB) in end-stage renal disease.METHODS:This was a retrospective cohort study that reviewed 544 p...AIM:To investigate the preventive effects of low-dose proton-pump inhibitors(PPIs) for upper gastrointestinal bleeding(UGIB) in end-stage renal disease.METHODS:This was a retrospective cohort study that reviewed 544 patients with end-stage renal disease who started dialysis at our center between 2005 and 2013.We examined the incidence of UGIB in 175 patients treated with low-dose PPIs and 369 patients not treated with PPIs(control group).RESULTS:During the study period, 41 patients developed UGIB, a rate of 14.4/1000 person-years.The mean time between the start of dialysis and UGIB events was 26.3 ± 29.6 mo.Bleeding occurred in only two patients in the PPI group(2.5/1000 person-years) and in 39 patients in the control group(19.2/1000 person-years).Kaplan-Meier analysis of cumulative non-bleeding survival showed that the probability of UGIB was significantly lower in the PPI group than in the control group(log-rank test, P < 0.001).Univariate analysis showed that coronary artery disease, PPI use, anti-coagulation, and anti-platelet therapy were associated with UGIB.After adjustments for the potential factors influencing risk of UGIB, PPI use was shown to be significantly beneficial in reducing UGIB compared to the control group(HR = 13.7, 95%CI:1.8-101.6; P = 0.011).CONCLUSION:The use of low-dose PPIs in patients with end-stage renal disease is associated with a low frequency of UGIB.展开更多
Background：Prior studies have reported controversial conclusions regarding the risk of adverse cardiovascular events in patients using proton-pump inhibitors （PPIs） combined with clopidogrel therapy,causing much un...Background：Prior studies have reported controversial conclusions regarding the risk of adverse cardiovascular events in patients using proton-pump inhibitors （PPIs） combined with clopidogrel therapy,causing much uncertainty in clinical practice.We sought to evaluate the safety of PPIs use among high-risk cardiovascular patients who underwent percutaneous coronary intervention （PCI） in a long-term follow-up study.Methods：A total of 7868 consecutive patients who had undergone PCI and received dual antiplatelet therapy （DAPT） at a single center from January 2013 to December 2013 were enrolled.Adenosine diphosphate （ADP）-induced platelet aggregation inhibition was measured by modified thromboelastography （mTEG） in 5042 patients.Propensity score matching （PSM） was applied to control differing baseline factors.Cox proportional hazards regression was used to evaluate the 2-year major adverse cardiovascular and cerebrovascular events （MACCEs）,as well as individual events,including all-cause death,myocardial infarction,unplanned target vessel revascularization,stent thrombosis,and stroke.Results：Among the whole cohort,27.2% were prescribed PPIs.The ADP-induced platelet aggregation inhibition by mTEG was significantly lower in PPI users than that in non-PPI users （42.0 ± 30.9% vs.46.4 ± 31.4%,t =4.435,P 〈 0.001）.Concomitant PPI use was not associated with increased MACCE through 2-year follow-up （12.7% vs.12.5%,x2 =0.086,P =0.769）.Other endpoints showed no significant differences after multivariate adjustment,regardless of PSM.Conclusion：In this large cohort of real-world patients,the combination of PPIs with DAPT was not associated with increased risk of MACCE in patients who underwent PCI at up to 2 years of follow-up.展开更多
The development of new proton-pump inhibitors (PPIs) with less adverse effects by lowering the pKa values of nitrogen atoms in pyrimidine rings has been previously suggested by our group. In this work, we proposed tha...The development of new proton-pump inhibitors (PPIs) with less adverse effects by lowering the pKa values of nitrogen atoms in pyrimidine rings has been previously suggested by our group. In this work, we proposed that new PPIs should have the following features:(1) number of ring II = number of ring I+ 1;(2) preferably five, six, or seven-membered heteroatomic ring for stability;and (3) 1<pKa1<4. Six molecular scaffolds based on the aforementioned criteria were constructed, and R groups were extracted from compounds in extensive data sources. A virtual molecule dataset was established, and the pKa values of specific atoms on the molecules in the dataset were calculated to select the molecules with required pKa values. Drug-likeness screening was further conducted to obtain the candidates that significantly reduced the adverse effects of long-term PPI use. This study provided insights and tools for designing targeted molecules in silico that are suitable for practical applications.展开更多
Background:Gastroesophageal reflux disease(GERD)is a common disorder.Overall,≤35%of GERD patients fail the standard dose of proton-pump-inhibitor(PPI)treatment.Due to the high prevalence and low satisfaction rate wit...Background:Gastroesophageal reflux disease(GERD)is a common disorder.Overall,≤35%of GERD patients fail the standard dose of proton-pump-inhibitor(PPI)treatment.Due to the high prevalence and low satisfaction rate with treatment failure,there is an unmet need for new treatment.Our aim was to evaluate whether the use of the transcutaneous electrical stimulation system(TESS)can reduce esophageal-acid exposure in GERD patients unresponsive to standard-dose PPI.Methods:We enrolled 10 patients suffering from heartburn and regurgitation with an abnormal esophageal-acid exposure(off PPIs)who failed standard-dose PPI.After the placement of a wireless esophageal pH capsule,all patients were treated with TESS.The primary end point was the reduction in the baseline(pretreatment)24-hour percent total time pH<4 and/or DeMeester score by 50%.Results:Seven GERD patients(five females and two males,aged 49.3610.1 years)completed the study.At baseline,the mean percent total time pH<4 was 12.064.9.Following TESS,the mean percent total time pH<4 dropped to 5.563.4,4.562.6,3.762.9,and 4.462.5 on Days 1,2,3,and 4,respectively.At baseline,the mean DeMeester score was 39.0618.5.After TESS,the mean DeMeester score dropped to 15.869.2,13.266.8,11.269.4,and 12.066.8 on Days 1,2,3,and 4,respectively.Conclusion:TESS is a safe and potentially effective modality in reducing esophageal-acid exposure in GERD patients unresponsive to standard-dose PPI.A larger and prospective controlled study is needed to verify these preliminary results.展开更多
基金Supported by Zhejiang Provincial Bureau of Education, No. 20070227Zhejiang Medical Association, No.2007ZYC18Association of Zhejiang Hospital Administration, No. 2007AZHA-KEB312
文摘Many of the drugs currently used in medical practice are racemates. The enantiomers of a racemic drug differ in pharmacodynamics and/or pharmacokinetics, thus in some cases it is preferable to develop pure enantiomers by racemic switch. In a recent study by Pai et al, dexrabeprazole [R(+)-rabeprazole] (10 mg) was found to be more effective than rabeprazole (20 mg) in the treatment of gastroesophageal reflux disease. We read with great interest in this study and discussed whether such racemic switch would be applicable to other proton-pump inhibitors (PPIs). A literature review indicates that stereoselective pharmacokinetics, rather than stereoselective pharmacological activity, is the main cause of differences in clinical efficacy between pure enantiomer and racemic PPI. Racemic switches of PPI provide the therapeutic advantages such as reducing metabolic load on the body, simplifying pharmacokinetics, providing benefit to the non-responders to standard dose of racemate, more homogenous response to treatment and better efficacy with equal safety. Further studies in quantitative structure-activity relationships (QSARs) are needed to address the fact that the preferred enantiomer of PPI is not always in the same absolute configuration, i.e., S-form is for omeprazole, pantoprazole and tenatoprazole whereas R-form is for lansoprazole and rabeprazole.
文摘Peptic ulcer disease continues to be issue especially due to its high prevalence in the developing world.Helicobacter pylori(H.pylori)infection associated duodenal ulcers should undergo eradication therapy.There are many regimens offered for H.pylori eradication which include triple,quadruple,or sequential therapy regimens.The central aim of this systematic review is to evaluate the evidence for H.pylori therapy from a meta-analytical outlook.The consequence of the dose,type of proton-pump inhibitor,and the length of the treatment will be debated.The most important risk factor for eradication failure is resistance to clarithromycin and metronidazole.
文摘Since the early reports nearly a decade ago, proton-pump inhibitor-induced hypomagnesemia （PPIH） has become a well-recognized phenomenon. While many observational studies in the inpatient and outpatient populations have confirmed the association of PPI exposure and serum magnesium concentrations, there are no prospective,controlled studies to support causation. Molecular mechanisms of magnesium transporters, including the pH-dependent regulation of transient receptor potential melastatin-6 transporters in the colonic enterocyte, have been proposed to explain the effect of PPIs on magnesium reabsorption, but may be a small part of a more complicated interplay of molecular biology, pharmacology, and genetic predisposition. This review explores the current state of research in the feld of PPIH and the proposed mechanisms of this effect.
文摘Objective： To determine whether patients maintain symptom control after discontinuation of PPI （proton-pump inhibitor） therapy through intervention of a pharmacist-led medication utilization program and determine annual clinic cost-savings per prescription. Design： The study was conducted as a prospective, medication use evaluation. Using an electronic medical record system at a clinic, reports generated all patients receiving PP1 therapy from January 2013-June 2015. Patients were encouraged to participate in a PPI discontinuation trial through a pharmacist-led educational session. Participants were followed-up three months post enrollment to assess their quality of life through a survey assessing severity and frequency of symptoms. Participants unable to maintain symptom control after the intervention were referred back to their primary care physician for further evaluation. Results： Of one hundred participants, 25% （n = 25） were able to discontinue the use of PPI by lifestyle modifications, 43% （n = 43） refused to discontinue PP1 therapy and lifestyle changes due to the severity of their symptoms, 17% （n = 17） switched to over-the-counter H2 receptor antagonist daily to control their symptoms, 9% （n = 9） used PPIs only as needed, and 6% （n = 6） of participants were dropped from the study after three failed communication attempts. The clinic saved approximately $11 thousand annually for every one prescription of PPI＇s. Conclusions： Discontinuation of PPI or step-down therapy was possible for patients with mild-moderate GERD （Gastroesophageal Reflux Disease） symptoms when mediated by pharmacist counseling and follow-up. Also, the annual PPI expenditure at this clinic will decrease due to participant＇s discontinuation of therapy.
文摘Proton-pump inhibitors （PPIs） are among the most widely used drugs worldwide. PPI use has recently been linked to adverse changes in semen quality in healthy men; however, the effects of PPI use on semen parameters remain largely unknown specifically in cases with male factor infertility. We examined whether PPI use was associated with detrimental effects on semen parameters in a large population of subfertile men. We retrospectively reviewed data from 12 257 subfertile men who had visited our fertility clinic from 2003 to 2013. Patients who reported using any PPIs for 〉3 months before semen sample collection were included; 7698 subfertile men taking no medication served as controls. Data were gathered on patient age, medication use, and conventional semen parameters; patients taking any known spermatotoxic medication were excluded. Linear mixed-effect regression models were used to test the effect of PPI use on semen parameters adjusting for age. A total of 248 patients （258 samples） used PPIs for at least 3 months before semen collection. In regression models, PPI use （either as the only medication or when used in combination with other nonspermatotoxic medications） was not associated with statistically significant changes in semen parameters. To our knowledge, this is the largest study to compare PPI use with semen parameters in subfertile men. Using PPIs was not associated with detrimental effects on semen quality in this retrospective study.
基金Supported by Grant from Hallym University Medical Center Research Fund
文摘AIM:To investigate the preventive effects of low-dose proton-pump inhibitors(PPIs) for upper gastrointestinal bleeding(UGIB) in end-stage renal disease.METHODS:This was a retrospective cohort study that reviewed 544 patients with end-stage renal disease who started dialysis at our center between 2005 and 2013.We examined the incidence of UGIB in 175 patients treated with low-dose PPIs and 369 patients not treated with PPIs(control group).RESULTS:During the study period, 41 patients developed UGIB, a rate of 14.4/1000 person-years.The mean time between the start of dialysis and UGIB events was 26.3 ± 29.6 mo.Bleeding occurred in only two patients in the PPI group(2.5/1000 person-years) and in 39 patients in the control group(19.2/1000 person-years).Kaplan-Meier analysis of cumulative non-bleeding survival showed that the probability of UGIB was significantly lower in the PPI group than in the control group(log-rank test, P < 0.001).Univariate analysis showed that coronary artery disease, PPI use, anti-coagulation, and anti-platelet therapy were associated with UGIB.After adjustments for the potential factors influencing risk of UGIB, PPI use was shown to be significantly beneficial in reducing UGIB compared to the control group(HR = 13.7, 95%CI:1.8-101.6; P = 0.011).CONCLUSION:The use of low-dose PPIs in patients with end-stage renal disease is associated with a low frequency of UGIB.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 81470486）, and the National Key Research and Development Program of China during the 13^th 5-Year Plan Period （No. 2016YFC1301301）.
文摘Background：Prior studies have reported controversial conclusions regarding the risk of adverse cardiovascular events in patients using proton-pump inhibitors （PPIs） combined with clopidogrel therapy,causing much uncertainty in clinical practice.We sought to evaluate the safety of PPIs use among high-risk cardiovascular patients who underwent percutaneous coronary intervention （PCI） in a long-term follow-up study.Methods：A total of 7868 consecutive patients who had undergone PCI and received dual antiplatelet therapy （DAPT） at a single center from January 2013 to December 2013 were enrolled.Adenosine diphosphate （ADP）-induced platelet aggregation inhibition was measured by modified thromboelastography （mTEG） in 5042 patients.Propensity score matching （PSM） was applied to control differing baseline factors.Cox proportional hazards regression was used to evaluate the 2-year major adverse cardiovascular and cerebrovascular events （MACCEs）,as well as individual events,including all-cause death,myocardial infarction,unplanned target vessel revascularization,stent thrombosis,and stroke.Results：Among the whole cohort,27.2% were prescribed PPIs.The ADP-induced platelet aggregation inhibition by mTEG was significantly lower in PPI users than that in non-PPI users （42.0 ± 30.9% vs.46.4 ± 31.4%,t =4.435,P 〈 0.001）.Concomitant PPI use was not associated with increased MACCE through 2-year follow-up （12.7% vs.12.5%,x2 =0.086,P =0.769）.Other endpoints showed no significant differences after multivariate adjustment,regardless of PSM.Conclusion：In this large cohort of real-world patients,the combination of PPIs with DAPT was not associated with increased risk of MACCE in patients who underwent PCI at up to 2 years of follow-up.
基金National Natural Science Foundation of China (Nos.31200986 and 41530105)(to RZ)Natural Science Foundation, the Shanghai Committee of Science and Technology (No.16ZR1449800)(to RZ)+4 种基金the Fundamental Research Funds for the Central Universities (Nos.10247201546 and 2000219083)(to RZ)a departmental start-up fund (to LZ)the Peter and Tommy Fund,Inc.,Buffalo,NY (to LZ),Funds from the University at Buffalo Community of Excellence in GenomeEnvironment and Microbiome (GEM)(to LZ)UTHealth Innovation for Cancer Prevention Research Training Program Post-doctoral Fellowship (Cancer Prevention and Research Institute of Texas,grant #RP160015)(to HK).
文摘The development of new proton-pump inhibitors (PPIs) with less adverse effects by lowering the pKa values of nitrogen atoms in pyrimidine rings has been previously suggested by our group. In this work, we proposed that new PPIs should have the following features:(1) number of ring II = number of ring I+ 1;(2) preferably five, six, or seven-membered heteroatomic ring for stability;and (3) 1<pKa1<4. Six molecular scaffolds based on the aforementioned criteria were constructed, and R groups were extracted from compounds in extensive data sources. A virtual molecule dataset was established, and the pKa values of specific atoms on the molecules in the dataset were calculated to select the molecules with required pKa values. Drug-likeness screening was further conducted to obtain the candidates that significantly reduced the adverse effects of long-term PPI use. This study provided insights and tools for designing targeted molecules in silico that are suitable for practical applications.
文摘Background:Gastroesophageal reflux disease(GERD)is a common disorder.Overall,≤35%of GERD patients fail the standard dose of proton-pump-inhibitor(PPI)treatment.Due to the high prevalence and low satisfaction rate with treatment failure,there is an unmet need for new treatment.Our aim was to evaluate whether the use of the transcutaneous electrical stimulation system(TESS)can reduce esophageal-acid exposure in GERD patients unresponsive to standard-dose PPI.Methods:We enrolled 10 patients suffering from heartburn and regurgitation with an abnormal esophageal-acid exposure(off PPIs)who failed standard-dose PPI.After the placement of a wireless esophageal pH capsule,all patients were treated with TESS.The primary end point was the reduction in the baseline(pretreatment)24-hour percent total time pH<4 and/or DeMeester score by 50%.Results:Seven GERD patients(five females and two males,aged 49.3610.1 years)completed the study.At baseline,the mean percent total time pH<4 was 12.064.9.Following TESS,the mean percent total time pH<4 dropped to 5.563.4,4.562.6,3.762.9,and 4.462.5 on Days 1,2,3,and 4,respectively.At baseline,the mean DeMeester score was 39.0618.5.After TESS,the mean DeMeester score dropped to 15.869.2,13.266.8,11.269.4,and 12.066.8 on Days 1,2,3,and 4,respectively.Conclusion:TESS is a safe and potentially effective modality in reducing esophageal-acid exposure in GERD patients unresponsive to standard-dose PPI.A larger and prospective controlled study is needed to verify these preliminary results.
