Influence of antisecretory treatment with proton pump inhibitors on serum pepsinogen I levels

It has been reported in literature that serum pepsinogen levels rise during omeprazole and lansoprazole administration. However, the influence of pantoprazole and esomeprazole on serum pepsinogens levels is still to be assessed. The aim of this study was to evaluate the influence of proton pump inhibitor (PPI) therapy on pepsinogen I (PGI) levels. PGI and gastrin (G17) levels (EIA; Biohit, Helsinki, Finland) in 126 consecutive patients (M 57; F 69, mean age 53, range 15-91), with upper gastrointestinal symptoms at baseline condition and after 2 months of PPI treatment, were evaluated. Patients underwent a therapy schedule based on: omeprazole 20 mg b.i.d. (20 patients), pantoprazole 40 mg b.i.d. (27 patients), esomeprazole 40 mg b.i.d. (29 patients), lansoprazole 30 mg b.i.d. (21 patients) and rabeprazole 20 mg b.i.d. (26 patients) for 2 months. A significant increase in serum PGI (sPGI) levels was found after a 2-month treatment for all five different PPIs: omeprazole, pantoprazole, esomeprazole, lansoprazole and rabeprazole (P < 0.05). The effect of rabeprazole on sPGI was less pronounced as compared with other PPIs, whereas esomeprazole achieved superior sPGI levels, with no overall statistically significant difference among the five groups (P > 0.05). However, a comparison within a single group of PPIs showed a statistical significance when the esomeprazole group was compared with the rabeprazole group (P = 0.007). sPGI levels are significantly influenced by antisecretory therapy, rising under PPI treatment. Moreover, a statistically significant difference in sPGI levels between the rabeprazole and esomeprazole groups has been demonstrated.     

Lansoprazole versus omeprazole for duodenal ulcer healing and prevention of relapse: a randomized, multicenter, double-masked trial.

The aim of this randomized, multicenter, double-masked, parallel-group study was to compare the efficacy of lansoprazole with that of omeprazole monotherapy in duodenal ulcer healing and prevention of relapse. A total of 251 patients with duodenal ulcer were treated with either lansoprazole 30 mg/d (n = 167) or omeprazole 40 mg/d (n = 84). Patients with healed ulcers were then randomly allocated to 12 months of maintenance therapy with lansoprazole 15 mg/d (n = 74), lansoprazole 30 mg/d (n = 71), or omeprazole 20 mg/d (n = 73). Healing rates at 4 weeks (intent-to-treat analysis) were 93.9% (95% confidence interval [CI], 90.2% to 97.6%) with lansoprazole and 97.5% (95% CI, 93.7% to 100%) with omeprazole; there were no significant differences between groups. Endoscopic relapse rates after 6 months were 4.5% (95% CI, 0% to 10.6%) with lansoprazole 15 mg, 0% with lansoprazole 30 mg, and 6.3% (95% CI, 1.5% to 12.5%) with omeprazole 20 mg, compared with 3.3% (95% CI, 0% to 8.2%), 0%, and 3.5% (95% CI, 0% to 8.8%), respectively, at 12 months. Again, there were no significant differences between groups. The incidence of adverse events during acute treatment was 6.0% and 7.1% in the lansoprazole and omeprazole groups, respectively; during maintenance therapy, the incidences were 12.2% (lansoprazole 15 mg), 5.6% (lansoprazole 30 mg), and 11.0% (omeprazole 20 mg). Within treatment groups, pain was significantly ameliorated after the acute phase but not after maintenance therapy (P < 0.05); no differences were observed between groups. Gastrin values increased significantly after acute therapy (P < 0.05), persisted at these increased levels during maintenance therapy, and returned to normal after 6-month follow-up. Both lansoprazole and omeprazole were highly effective and well tolerated in the treatment of duodenal ulcer; relapse rates were similar for all doses studied. Thus no additional benefit is to be gained from using a proton-pump inhibitor at a dose > 15 mg lansoprazole to prevent relapse.     

Combination drug therapy for gastroesophageal reflux disease

OBJECTIVE: To evaluate the role of combination therapy with proton-pump inhibitors (PPIs) and histamine(2) receptor antagonists in gastroesophageal reflux disease (GERD). DATA SOURCES: Clinical literature identified through MEDLINE (January 1966-August 2001). Key search terms included gastroesophageal reflux, benzimidazoles; omeprazole; lansoprazole; pantoprazole; rabeprazole; receptor antagonists, histamine(2); therapy, combination drug; therapy, combined modality; and combinations, drug. DATA SYNTHESIS: Approximately 80-90% of patients show healing of reflux esophagitis after 8 weeks of once-daily PPI therapy. Patients taking PPI therapy twice daily still have nocturnal acid breakthrough (periods of gastric pH <4 lasting for > or =60 min during the night) as much as 70% of the time. The clinical application of this finding has not been shown. One trial has shown that omeprazole in the morning plus ranitidine at bedtime is not as effective as omeprazole twice daily given before the morning and evening meals at controlling nocturnal acid breakthrough. Further, 1 small trial in healthy subjects without GERD showed that the addition of a 1-time dose of ranitidine at bedtime to a twice-daily regimen of omeprazole may decrease the occurrence of nocturnal acid breakthrough. However, the clinical significance of this finding is not clear. CONCLUSIONS: No studies in patients with GERD demonstrate that the addition of histamine(2) receptor antagonists to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far--nocturnal acid breakthrough--has not been proven to correlate with improvement of GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in patients refractory to standard doses of PPIs.     

Is ranitidine therapy sufficient for healing peptic ulcers associated with non‐steroidal anti‐inflammatory drug use?

Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) increases the risk of serious gastroduodenal events. To minimise these risks, patients often require concomitant acid-suppressive therapy. We conducted a literature review of clinical trials examining use of ranitidine 150 mg twice daily to heal gastroduodenal ulcers (GU) in NSAID recipients. Seven studies were identified. After 8 weeks' treatment with ranitidine, GU healing rates ranged from 50% to 74% and rates of duodenal ulcer (DU) healing ranged from 81% to 84%. Ranitidine was more effective when NSAIDs were discontinued (healing rates reaching 95% and 100%, respectively). The ulcer healing rate with sucralfate was similar to that of ranitidine. However, proton pump inhibitor (PPI) therapy was associated with significantly greater rates of both GU and DU healing than ranitidine; 8-week GU rates were 92% and 88% with esomeprazole 40 mg and 20 mg, respectively (vs. 74% with ranitidine, p < 0.01). For omeprazole, 8-week healing rates were 87% with omeprazole 40 mg and 84% with omeprazole 20 mg (vs. 64% for ranitidine, p < 0.001), and for lansoprazole the corresponding values were 73-74% and 66-69% for the 30 mg and 15 mg doses, respectively (vs. 50-53% for ranitidine, p < 0.05). In the PPI study reporting DU healing the values were 92% for omeprazole 20 mg (vs. 81% for ranitidine, p < 0.05) and 88% for omeprazole 40 mg (p = 0.17 vs. ranitidine). NSAID-associated GU are more likely to heal when patients receive concomitant treatment with a PPI rather than ranitidine.     

The proton-pump inhibitors: similarities and differences

OBJECTIVE: This paper examines the clinical pharmacology of the proton-pump inhibitors (PPIs) and briefly reviews some comparative studies of these agents. BACKGROUND: PPIs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. Although these drugs-omeprazole, lansoprazole, pantoprazole, and rabeprazole-share a common structure (all are substituted benzimidazoles) and mode of action (inhibition of H+,K+-adenosine triphosphatase [ATPase]), each differs somewhat in its clinical pharmacology. RESULTS: In comparative clinical trials found in MEDLINE, PPIs administered once daily produced endoscopic evidence of healing in >90% of patients with duodenal ulcer after 4 weeks of treatment, in >90% of those with gastric ulcer after 6 weeks of treatment, and in >90% of those with ulcerative or erosive GERD after 8 weeks of treatment. Maintenance therapy with daily doses of a PPI has been shown to be an effective means of preventing GERD relapse. PPIs also inhibit the growth of Helicobacter pylori, now recognized as an important factor in peptic ulcer disease, and, when administered in combination with antibiotics, provide the best treatment for eradication of the bacterium. Rabeprazole has a more rapid onset of H+,K+-ATPase inhibition than the other PPIs and, compared with omeprazole, a greater effect on intragastric pH after the first dose. Omeprazole and lansoprazole have a greater potential for drug-drug interactions than do pantoprazole and rabeprazole. CONCLUSION: Although the individual PPIs have similar efficacy in many cases, differences between them should be considered when choosing a treatment regimen.     

奥美拉唑和雷尼替丁对十二指肠溃疡病愈合率和复发率 影响的对比研究

目的 对比奥美担唑和雷尼替丁治疗十二批肠溃疡病近期愈合率和复发率,探索质子泵抑制剂（PPI）与H2受体拮抗剂对防止溃疡病复发的远程疗效。方法 118例经内镜检查证实的性十二指肠溃疡患者,随机分成奥美拉唑组和雷尼替丁组,进行疗效对比。结果 奥美拉唑组和雷尼替丁组4周溃疡愈合率分别为88.3%(68/77)和68.3％（28／41）,雷尼替丁组6周溃疡愈合率为90.2%(37/41)。对溃疡愈合的37例进行长程治疗6－12个月,观察用药时间内的溃疡累计复发率。奥美拉唑组1年内累计复发率为5.2?/19),雷尼替丁组为16.6％（3／16）.结论 奥美拉唑组短程治疗时溃疡愈合率高于雷尼替丁组,而长程治疗时1年累计复发率明显低于雷尼替丁组,由于奥美拉唑对酸抑制程度大而且时间长,因此,临床上可迅速缓解症状,加快溃疡的愈合。     

质子泵抑制剂导致的急性泛发性发疹性脓疱病:基于真实世界的药物警戒研究

  目的  探讨不同质子泵抑制剂(proton pump inhibitors, PPIs)与急性泛发性发疹性脓疱病(acute generalized exanthematous pustulosis, AGEP)的关联性及特点。  方法  检索2004年1月至2020年6月美国食品药品监督管理局不良事件报告系统(Food and Drug Administration's adverse events reporting system, FAERS)数据库中PPIs/AGEP相关报告,采用比例失衡测量法及贝叶斯法对不同PPIs导致的AGEP进行关联性分析,并比较其发病时间及预后。  结果  共检索到此期间PPIs导致的AGEP病例报告162例。应用的PPIs药物主要为奥美拉唑(33.95%,55/162),其次为埃索美拉唑(29.63%,48/162)、泮托拉唑(26.54%,43/162)。以泮托拉唑与AGEP的关联性最强,其次为奥美拉唑和兰索拉唑,埃索美拉唑与AGEP的关联性较弱。PPIs导致AGEP发病时间的中位数为6(2,12)d,60.00%~83.33%的患者于用药后10 d内发病(除雷贝拉唑外)。3例(1.86%)AGEP患者死亡,128例(79.50%)需住院治疗。以埃索美拉唑导致的AGEP患者住院比率最高(91.49%,43/47),其次为泮托拉唑(88.37%,38/43)、兰索拉唑(85.71%,12/44),奥美拉唑(61.82%,34/55)最低。  结论  基于对FAERS数据库的药物警戒研究,揭示不同PPIs导致AGEP的风险及特点,可为临床合理用药提供依据。     

Efficacy of esomeprazole in patients with acid-peptic disorders.

Esomeprazole (Nexium) is a new proton pump inhibitor that provides more effective acid control compared with other proton pump inhibitors. In patients with gastroesophageal reflux disease, standard doses of esomeprazole maintain intragastric pH above 4 for significantly longer periods compared with standard doses of other proton pump inhibitors after 5 days of treatment. Esomeprazole is approved for the treatment of symptomatic gastroesophageal reflux disease, the healing of erosive esophagitis, and maintenance of healing. In clinical trials, esomeprazole 40 mg once daily for up to 8 weeks provided higher rates of healing of erosive esophagitis and a greater proportion of patients with sustained resolution of heartburn, than either omeprazole 20 mg or lansoprazole 30 mg once daily. For the maintenance of healing, esomeprazole 20 mg once daily provided significantly higher rates of maintained healing of erosive esophagitis after 6 months of treatment compared with lansoprazole 15 mg once daily. Esomeprazole is also approved for use as part of a triple-drug therapy regimen in combination with amoxicillin and clarithromycin for the eradication of Helicobacter pylori in patients with duodenal ulcer disease. The side effect profile of esomeprazole is similar to that of omeprazole. Many patients with acid-related disorders may benefit from the more rapid symptom relief, higher rates of healing of erosive esophagitis, and improved maintenance of healing that can be achieved with esomeprazole.     

Appropriate choice of proton pump inhibitor therapy in the prevention and management of NSAID-related gastrointestinal damage

Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal adverse effects, ranging from dyspepsia and peptic ulcer disease to more serious complications such as haemorrhage or perforation. NSAID-induced gastrointestinal toxicity is a significant medical problem worldwide. Misoprostol is effective in reducing NSAID-induced mucosal damage, but patient compliance is limited by poor tolerance. Histamine receptor antagonists are relatively effective against duodenal ulcers but offer no significant protection against gastric ulcers. Proton pump inhibitors (PPIs), such as pantoprazole, omeprazole and lansoprazole, have been shown to be effective in preventing the development of gastric and duodenal ulcers in high-risk patients taking NSAIDs. PPI therapy is also beneficial in healing NSAID-induced ulcers and preventing their recurrence in patients requiring ongoing NSAID therapy. PPIs have an excellent safety profile, and pantoprazole--with its low potential for drug-drug interactions--is particularly suitable for administration to elderly patients who often require concomitant treatment with other medications.     

In vitro activities of rabeprazole, a novel proton pump inhibitor, and its thioether derivative alone and in combination with other antimicrobials against recent clinical isolates of Helicobacter pylori

The MICs of rabeprazole sodium (RPZ), a newly developed benzimidazole proton pump inhibitor (PPI), against 133 clinical Helicobacter pylori strains revealed a higher degree of activity than the another two PPIs, lansoprazole and omeprazole. Time-kill curve assays of RPZ, when combined with amoxicillin, clarithromycin, or metronidazole, disclosed that synergistic effects were demonstrated in combination with each antibiotic examined. Moreover, no apparent antagonistic effect appeared among all of the strains tested.     

Proton pump inhibitor for maintenance therapy of peptic ulcer]

The strategy for peptic ulcer therapy has been changing with the clinical application of the gastric proton pump inhibitor (PPI). In Japan, Miyoshi et al and Takemoto et al reported an earlier reepithelialization of peptic ulcer with omeprazole (OME) or lansoprazole (LAN) than famotidine (FAM). Miyoshi et al also reported that there was no significant difference between OME and FAM in ulcer relapse rate during a one year follow-up period. Therefore, there were two problems. One is application of PPI for prevention of ulcer relapse, and the other is the more accurate diagnosis of ulcer healing. Application of PPI for maintenance therapy is not yet realized in Japan, but, Lauritsen et al had already reported on the efficacy and safety of OME, 20 mg, three days a week and 10 mg, daily in prevention of duodenal ulcer relapse. Reepithelialization (red scar) is already established as a starting point of maintenance therapy, and from Miyake's report, a white scar is believed a favorable (non relapsing) end point.     

Acid-suppressive effects of rabeprazole, omeprazole, and lansoprazole at reduced and standard doses: a crossover comparative study in homozygous extensive metabolizers of cytochrome P450 2C19

BACKGROUND AND OBJECTIVES: To improve clinical outcomes of the initial therapy for gastroesophageal reflux disease, intragastric pH should be above 4.0 for more than 20 hours a day (83.3%) and nocturnal gastric acid breakthrough, defined as 60 continuous minutes of intragastric pH below 4.0 at night, should be inhibited. A "step-down" therapy sometimes fails because of insufficient acid suppression. Therefore we compared the acid-suppressive effects of proton pump inhibitors. METHODS: This was a prospective, randomized, open-label, 8-way crossover study. In 9 healthy Helicobacter pylori-negative cytochrome P450 (CYP) 2C19 homozygous extensive metabolizers, intragastric pH was measured for 24 hours on day 7 of treatment with rabeprazole, omeprazole, and lansoprazole orally administered once daily at reduced and standard doses. RESULTS: Compared with baseline data (7% [range, 5%-20%]), the median values of the 24-hour percent of time that intragastric pH was above 4.0 significantly increased but did not exceed 83.3% under any of the 7 regimens, which were as follows: 10 mg rabeprazole (51% [range, 28%-78%], P < .01), 20 mg rabeprazole (59% [range, 36%-83%], P < .01), 10 mg omeprazole (26% [range, 4%-33%], P < .05), 20 mg omeprazole (48% [range, 31%-73%], P < .01), 40 mg omeprazole (62% [range, 47%-87%], P < .01), 15 mg lansoprazole (34% [range, 5%-51%], P < .05), and 30 mg lansoprazole (56% [range, 20%-76%], P < .05). Significant differences were observed among 10, 20, and 40 mg omeprazole (10 mg versus 20 mg, P < .01; 10 mg versus 40 mg, P < .01; and 20 mg versus 40 mg, P < .05) and between 15 and 30 mg lansoprazole (P < .01), whereas no significant difference was observed between 10 and 20 mg rabeprazole. Nocturnal gastric acid breakthrough was observed under all regimens. CONCLUSIONS: Rabeprazole, omeprazole, and lansoprazole, given once daily at standard doses, cannot be expected to achieve ideal acid suppression for the initial therapy for gastroesophageal reflux disease in Helicobacter-negative CYP2C19 homozygous extensive metabolizers. Rabeprazole 10 mg may be appropriate for step-down therapy.     

Triple therapy regimens involving H2 blockaders for therapy of Helicobacter pylori infections

Comparison of ranitidine and lansoprazole in short-term low-dose triple therapy for Helicobacter pylori infection. To evaluate the efficacy and safety of two 1-week low-dose triple-therapy drug regimens involving antisecretory drugs for Helicobacter pylori infection, 99 patients with H. pylori infection were treated with either lansoprazole (LPZ) or ranitidine (RNT) used together with clarithromycin (CAM) and metrinidazole (MTZ). The drug combination and administration periods in the PPI group were LPZ 30 mg, CAM 400 mg, MTZ 500 mg (LCM group). The ranitidine group received RNT 300 mg, CAM 400 mg, MTZ 500 mg (RCM group). The cure rate of H. pylori infection was 88% in the LCM group; 95% CI 79-97 and 92% in the RCM group; 95% CI 84-99.     

Diarrhea Caused by Proton Pump Inhibitor Administration: Comparisons Among Lansoprazole,Rabeprazole, and Omeprazole

BackgroundThe number of patients who require treatment with proton pump inhibitors (PPIs) is increasing in Japan. One of their adverse effects is diarrhea.ObjectivesWe investigated the incidence of diarrhea caused by 3 different PPIs: lansoprazole, rabeprazole, and omeprazole.MethodsPatients using PPIs for >1 month were enrolled. Enrolled patients recorded daily stool frequency, stool consistency using the Bristol Stool Scale Form, and impaired quality of life caused by diarrhea for 1 month. Their attending physicians described the types and dosages, and duration of PPI administration, as well as other necessary information.ResultsA total of 255 patients participated. Mean age of the patients was 70.7 years old. During the 1-month observation period, 3.5% of the patients complained of diarrhea. There was no significant difference for the incidence of diarrhea among the 3 types of PPIs. Furthermore, no correlations between diarrhea and length and dosage of PPI administration were found.ConclusionsThe incidence of diarrhea in patients receiving long-term therapy did not differ among 3 different PPIs. ClinicalTrials.gov identifier: UMIN ID 000005300.     

The efficacy of extended-interval dosing of omeprazole in keeping gastroesophageal reflux disease patients symptom free.

The potential economic advantage of alternate-day therapy for GERD maintenance must be weighed against the potential cost of failure before it can be widely instituted. The studies presented have helped develop a clinical picture of the patients who may benefit from alternate-day therapy without risk of complications or potential increases in management costs. Bank et al., reporting on a group of patients, found that patients with Grade II-IV disease had a 61% success rate at two to eight years. Bank defined success as both maintenance of endoscopic healing and symptom control. Ladas et al. found a 66.7% success rate defined as clinical and endoscopic remission in Grades II-III disease. Kurucar et al. monitored symptom control and esophageal complications in his patients and found the regimen to have a 26% success rate in Grades III-IV disease. Lind et al. found that 83% of patients could remain symptom free with on-demand therapy if they were endoscopy-negative at baseline. The results of the Mantides et al. study are important because they imply that alternate-day omeprazole therapy may be more effective than alternatives for step-down treatment, such as ranitidine or cisapride. Furthermore, patients can be educated to increase their frequency of use if symptoms should arise. Not only does this give the patient a sense of self-empowerment over his or her disease state, but it avoids the cost of switching to a PPI due to failure with an H2RA or a motility agent. Alternate-day use of omeprazole should be attempted only during the maintenance phase of GERD therapy. Patients requiring >20 mg/d to achieve healing appeared to be poor candidates for alternate-day omeprazole maintenance therapy. Based on available studies, it would seem that patients with Grades 0-II GERD would benefit most from alternate-day therapy. A role for alternate-day therapy in Grades III-IV is apparent from the results presented but requires greater caution in view of the differing success rates (26-61%) in various studies. With Grades II-III esophagitis, a mean 24-hour gastric pH >6 and a gastric pH <4 less than 10% of the time during the initial healing phase with omeprazole 20 mg/d appeared to be associated with success on alternate-day therapy. Evidence that all marketed PPIs have similar success is not available and should not be extrapolated from the data presented. Evidence that downward dosage adjustments of PPIs versus extending dosage intervals are effective in the maintenance of GERD should be recognized. Lansoprazole has been approved for treating erosive esophagitis at 30 mg/d, with the maintenance dose established at 15 mg/d. Studies showing that lansoprazole 15 mg/d is more effective than alternate-day therapy with lansoprazole 30 mg exist, although similar studies with omeprazole have not been performed. The abstracts describing the use of alternate-day omeprazole accounted for all enrollees and included endoscopic grading or pH monitoring to document disease severity at baseline. Most also included these same objective measures as end points in combination with symptom control. This strengthens the data since the positive predictive value of typical symptoms is variable. However, there are also several significant limitations. Abstracts provide only limited information on methods. All studies other than Lind et al. lacked randomization. This study was also the only one that blinded patients to their treatment. Sample sizes for the majority of the trials were quite small. Statistical analyses were not performed on any of the trial results with the exception of the trial by Lind et al. In light of the lack of evidence of statistical significance as well as study design flaws, conclusions should be drawn cautiously. Larger well-designed trials looking at both the efficacy and cost-effectiveness of alternate day omeprazole are required before a definitive recommendation can be made.     

In Vitro Study of the Variable Effects of Proton Pump Inhibitors on Voriconazole

Voriconazole is a broad-spectrum antifungal agent used for the treatment of severe fungal infections. Maintaining therapeutic concentrations of 1 to 5.5 μg/ml is currently recommended to maximize the exposure-response relationship of voriconazole. However, this is challenging, given the highly variable pharmacokinetics of the drug, which includes metabolism by cytochrome P450 (CYP450) isotypes CYP2C19, CYP3A4, and CYP2C9, through which common metabolic pathways for many medications take place and which are also expressed in different isoforms with various metabolic efficacies. Proton pump inhibitors (PPIs) are also metabolized through these enzymes, making them competitive inhibitors of voriconazole metabolism, and coadministration with voriconazole has been reported to increase total voriconazole exposure. We examined the effects of five PPIs (rabeprazole, pantoprazole, lansoprazole, omeprazole, and esomeprazole) on voriconazole concentrations using four sets of human liver microsomes (HLMs) of different CYP450 phenotypes. Overall, the use of voriconazole in combination with any PPI led to a significantly higher voriconazole yield compared to that achieved with voriconazole alone in both pooled HLMs (77% versus 59%; P < 0.001) and individual HLMs (86% versus 76%; P < 0.001). The mean percent change in the voriconazole yield from that at the baseline after PPI exposure in pooled microsomes ranged from 22% with pantoprazole to 51% with esomeprazole. Future studies are warranted to confirm whether and how the deliberate coadministration of voriconazole and PPIs can be used to boost voriconazole levels in patients with difficult-to-treat fungal infections.     

In vitro and in vivo evaluation of drug–drug interaction between dabigatran and proton pump inhibitors

To quantify the drug–drug interactions between dabigatran etexilate (DE) and proton pump inhibitors (PPI) and in particular the role of P‐gp activity modulation. In the first part of the study, efflux ratios of DE were evaluated using the caco‐2 cell line in the presence of pantoprazole, omeprazole, rabeprazole, lansoprazole and ciclosporin A (positive control). The two PPI that reduced the efflux ratio of dabigatran to the greatest and least extent, respectively, were used during the second part of the study, comprising a single‐centre, randomised, open‐label study with an incomplete Latin square design. Nine healthy volunteers received DE (150 mg) alone, DE (150 mg) with the first PPI and DE (150 mg) with the second PPI in randomised sequence. Dabigatran plasma concentration and thrombin time were measured in blood samples withdrawn at 11 time points after each treatment. Models were built using a nonlinear mixed‐effect modelling approach. Omeprazole and rabeprazole were the two PPI that reduced the efflux ratio of DE least and most, respectively. The PK model was based on an inverse Gaussian absorption process with one compartment. The relationship between dabigatran concentration and thrombin time was considered linear. Some PK profiles had dramatically low concentration values due to poor absorption. These profiles were clustered using a between subject model mixture with interoccasion variability. The concomitant administration of PPI did not significantly change dabigatran pharmacokinetics. DE is subject to high absorption variability, precluding evaluation of the effect of PPI on its pharmacokinetics.     

A review of the clinical and economic impact of using esomeprazole or lansoprazole for the treatment of erosive esophagitis

BACKGROUND: The use of proton pump inhibitors (PPIs) for the treatment of erosive esophagitis has had a major impact on the prescribing budgets of primary care organizations in the United Kingdom. Assessments of the clinical and economic effectiveness of PPIs would provide useful tools for decision-making. OBJECTIVE: The goal of this study was to review the available preclinical and clinical studies comparing esomeprazole with lansoprazole in the healing and maintenance of erosive esophagitis, and to compare the budgeting impact of the 2 strategies. Comparative tolerability was also reviewed. METHODS: MEDLINE (1966-September 2002) and EMBASE (1980-September 2002) were searched for abstracts and articles reporting comparative studies of esomeprazole and lansoprazole. The search terms used were gastroesophageal reflux disease, reflux esophagitis, and proton pump inhibitor; all comparisons of esomeprazole and lansoprazole at any dose were considered. The database search was supplemented based on the authors' familiarity with the literature. RESULTS: The comparative studies that were identified fell into 4 categories: (1) intragastric acid suppression studies; (2) randomized controlled trials in the healing of erosive esophagitis; (3) randomized controlled trials in the maintenance of erosive esophagitis; and (4) health economic analyses. Based on these studies, when healing doses (esomeprazole 40 mg once daily, lansoprazole 30 mg once daily) and low doses (20 and 15 mg once daily, respectively) were compared, esomeprazole was more efficacious than lansoprazole in suppressing acid in the intragastric compartment (both comparisons, P < 0.05). More patients with erosive esophagitis experienced healing at 4 and 8 weeks with esomeprazole 40 mg once daily than with lansoprazole 30 mg once daily (P < 0.001 at 4 and 8 weeks). At 6 months, remission was maintained in more patients receiving esomeprazole 20 mg once daily than in those receiving lansoprazole 15 mg once daily (P < 0.001). No significant differences in tolerability were noted in clinical trials that directly compared the 2 PPIs. When the cost-effectiveness of esomeprazole treatment was compared with that of lansoprazole treatment in the healing and maintenance of erosive esophagitis, the greater efficacy of esomeprazole translated into potential cost savings and better outcomes. CONCLUSION: The currently available comparative data for esomeprazole and lansoprazole indicate clinical and cost-effectiveness advantages for esomeprazole in the healing and maintenance of erosive esophagitis compared with lansoprazole.