Dose Of Omeprazole Research Articles

Influences of different proton pump inhibitors on the anti‐platelet function of clopidogrel in relation to CYP2C19 genotypes

Active metabolism of clopidogrel is mainly mediated by CYP2C19. There are genetic differences in the activity of CYP2C19. Therefore, active metabolism of clopidogrel is affected by CYP2C19 genotypes. The main metabolizing enzyme of proton pump inhibitors (PPIs) is CYP2C19. Therefore, the anti-platelet function of clopidogrel is attenuated by concomitant use of PPIs. There are differences in the metabolic disposition among different PPIs. Affinity to CYP2C19 differs among different PPIs. Whether a PPI attenuates the efficacy of clopidogrel depends on CYP2C19. Individuals who are decreased metabolizers, i.e. carriers the allele of CYP2C19*2 and/or *3, are more likely to convert from 'responder' to 'non-responder' to clopidogrel when placed on a concomitant PPI. We found that rabeprazole, whose affinity to CYP2C19 has been considered lower, attenuated the efficacy of clopidogrel. * We tested whether the separate dosing of a PPI and clopidogrel decreased the risk of attenuation of clopidogrel efficacy. We unfortunately found that separate dosing did not avoid the problematic interaction between clopidogrel and a PPI in subject's with CYP2C19*2 and/or CYP2C19*3. The efficacy of clopidogrel is influenced by CYP2C19 genotypes and substrates of CYP2C19, such as proton pump inhibitors (PPIs). We assessed the influence of three different PPIs on the anti-platelet function of clopidogrel in relation to CYP2C19 genotype status. Thirty-nine healthy volunteers with different CYP2C19 genotypes took clopidogrel 75 mg with or without omeprazole 20 mg, lansoprazole 30 mg or rabeprazole 20 mg in the morning for 7 days. The influence of the three PPIs on the anti-platelet function of clopidogrel was determined. A less than 30% inhibition of platelet aggregation (IPA) during clopidogrel dosing was defined as a 'low responder'. We also examined whether evening dosing of omeprazole could prevent the interaction with clopidogrel dosed in the morning. In rapid metabolizers (RMs, *1/*1, n=15) of CYP2C19, omeprazole and rabeprazole significantly attenuated the anti-platelet function of clopidogrel. In decreased metabolizers (DMs, carriers of *2 and/or *3, n=24), there was a large variation in IPA and there was a trend but no significant decrease in IPA when placed on a concomitant PPI. Some DMs became 'low-responders' when placed on a concomitant PPI. Evening omeprazole dose in RMs did not seem to cause a significant decrease in IPA in contrast to morning dosing, but did so in DMs. The three PPIs affected the efficacy of clopidogrel to different degrees. Both omeprazole and rabeprazole significantly decreased IPA in RMs but not DMs, although there was a trend towards lower IPA in DMs. Morning and evening dosing of omeprazole were both associated with lower IPA in DMs.

Pharmacokinetics of intrarectal omeprazole in alpacas

The purpose of this study was to evaluate the pharmacokinetics of omeprazole in three different vehicles when administered rectally to six alpacas. Alpacas were given single doses of omeprazole (4 mg/kg) in a double-blinded, randomized cross-over design with a 1 week washout period. Omeprazole formulations consisted of (1) Treatment A: omeprazole paste mixed in surgical lubricant (2) Treatment B: omeprazole capsule contents in 8.4% sodium bicarbonate and (3) Treatment C: omeprazole capsule contents in surgical lubricant and 8.4% sodium bicarbonate solution. Plasma samples were drawn at 0, 5, 10, 15, 30, 45, 60, 90, 120, 180, 300 and 480 min. Omeprazole plasma concentrations were determined by high-pressure liquid chromatography-mass spectrometry. Pharmacokinetic results demonstrated median peak plasma concentrations (C(max)) of 7.35 (3.2-15.2), 7.30 (1.7-10.9) and 8.65 (1.8-19.3) ng/mL and median area under the concentration curve (AUC((0-180))) of 747 (237-1681) min x ng/mL, 552.9 (39-1063) min x ng/mL, and 972 (107-1841) min x ng/mL for treatments A, B and C, respectively. The median half-lives were similar between groups: 38, 50, and 53 min. As a result of the low measured omeprazole plasma concentrations, it is assumed that rectal absorption of omeprazole is poor in alpacas and not an effective route of administration.

Omeprazole preferentially inhibits the metabolism of (+)‐(S)‐citalopram in healthy volunteers

Citalopram (CITA) pharmacokinetics are enantioselective in healthy volunteers and the metabolism of (+)-(S)-CITA to (+)-(S)-DCITA is dependent on CYP2C19. Omeprazole is a potent CYP2C19 inhibitor. This study indicates that omeprazole induces a loss of enantioselectivity in the CITA pharmacokinetics because of the selective inhibition of (+)-(S)-CITA metabolism. The study assessed the influence of omeprazole on the kinetic disposition of the (+)-(S)-citalopram (CITA) and (-)-(R)-CITA enantiomers in healthy volunteers. In a cross-over study, healthy volunteers (n = 9) phenotyped as extensive metabolizers of CYP2C19 and CYP2D6 and with an oral midazolam clearance ranging from 10.9 to 149.3 ml min(-1) kg(-1) received a single dose of racemic CITA (20 mg orally) in combination or not with omeprazole (20 mg day(-1) for 18 days). Serial blood samples were collected up to 240 h after CITA administration. CITA and demethylcitalopram (DCITA) enantiomers were analyzed by LC-MS/MS using a Chiralcel OD-R column. The kinetic disposition of CITA was enantioselective in the absence of treatment with omeprazole, with the observation of a greater proportion of plasma (-)-(R)-CITA [AUC S:R ratio of 0.53 (95% CI 0.41, 0.66) for CITA and 1.08 (95% CI 0.80, 1.76) for DCITA] than (+)-(S)-CITA. Racemic CITA administration to healthy volunteers in combination with omeprazole showed a loss of enantioselectivity in CITA pharmacokinetics with an increase of approximately 120% in plasma (+)-(S)-CITA concentrations [AUC S:R ratio of 0.95 (95% CI 0.72, 1.10) for CITA and 0.95 (95% CI 0.44, 1.72) for DCITA]. The administration of multiple doses of omeprazole preferentially inhibited (+)-(S)-CITA metabolism in healthy volunteers. Although omeprazole increased plasma concentrations of (+)-(S)-CITA by approximately 120%, it is difficult to evaluate the clinical outcome because the range of plasma CITA concentrations related to maximum efficacy and minimum risk of adverse effects has not been established.

Abstract A141: Chemopreventive properties of omeprazole against azoxymethane-induced colonic aberrant crypt foci formation in fats

Abstract Omeprazole is a proton-pump inhibitor which is widely used to treat ulcers and gastroesophageal reflux diseases (GERD). Previous studies show that omeprazole exhibits possible anti-tumorigenic properties in preclinical models of colon cancer. However, no systematic studies were carried to establish the potential anti-carcinogenic potential of omeprazole using established animal models of colon cancer. In the present study, omeprazole was evaluated for its colon cancer chemopreventive properties using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) as a efficacy endpoint in F344 rats. In addition, we analyzed the growth inhibitory effects and induction of apoptosis in human colon cancer HCA-7 cells. We also studied its possible anti-inflammatory properties in Raw 264.7 macrophage cell line. Prior to efficacy studies we evaluated the maximum tolerated dose (MTD) of omeprazole. For MTD assay, seven week-old rats were fed either control AIN-76 diet, diets containing 5 different dose levels of omeprazole (100, 200, 400, 600 and 800 ppm) for six weeks. Based on body weight gain and toxicity symptoms, the MTD of Omeprazole is found to be ∼600 ppm. To evaluate the inhibitory properties of omeprazole on colonic ACF, seven-week-old male F344 rats were fed experimental diets containing 0, 200, and 400 ppm of omeprazole. One week later, rats received s.c. injections of azoxymethane (AOM) (15 mg/kg body wt., once weekly for two weeks) or equal volume of normal saline (vehicle). Rats were continued on experimental diets for seven weeks before being sacrificed. Colons were evaluated histopathologically for ACF and immunohistochemistry for PCNA marker to assess the crypt cell proliferation. Administration of omeprazole at 400 ppm significantly suppressed total colonic ACF formation (∼30%, p<0.001) when compared to the control diet group. Rats fed with 200 ppm and 400 ppm of Omeprazole showed significantly lower numbers (∼30–50%, p<0.05–0.001) of multi-crypt foci (≥4 or more). Overall, omeprazole produced significant dose-response effect in preventing colonic ACF formation. In in vitro assays, Omeprazole inhibited phorbol-12-myristate 13-acetate -induced iNOS expression in macrophages in a dose dependent manner. Furthermore, omeprazole induced apoptosis by suppressing survivin in HCA-7 colon cancer cells. The results from this study provides evidence for the first time that omeprazole, a proton-pump inhibitor may be used as a chemopreventive agent against colon carcinogenesis. (Supported by NOI-N01-CN-53300). Citation Information: Cancer Prev Res 2010;3(1 Suppl):A141.

Original research Treatment with double dose of omeprazole increases -endorphin plasma level in patients with coronary artery disease

IntroductionThe proton pump inhibitor empirical trial, besides the analysis of symptoms, is the main method in the diagnosis of gastro-oesophageal reflux disease-related chest pain. β-Endorphin acts as an endogenous analgesia system. The aim of the study was verify whether β-endorphin plasma level is affected by omeprazole administration and influences the severity of anginal symptoms and outcome of the “omeprazole test” in patients with coronary artery disease (CAD) and chest pain of suspected non-cardiac origin.Material and methodsOmeprazole was administered to 48 patients with CAD in a randomized, placebo-controlled, crossover study design. At the beginning of the study, and again after the 14-day omeprazole and placebo treatment, the β-endorphin plasma concentration was determined.ResultsThe level of plasma β-endorphin after the administration of omeprazole was significantly greater than at the start of the study and following the placebo. Responders to omeprazole had an average lower β-endorphin plasma concentration than subjects who failed to respond to this therapy. Subjects with symptoms in class III (according to the Canadian Cardiovascular Society classification) after omeprazole administration had a greater β-endorphin plasma level than subjects in class II for anginal symptom severity.ConclusionsFourteen-day therapy with a double omeprazole dose significantly increases the β-endorphin plasma concentration in patients with CAD. Circulating β-endorphin does not seem to be involved in the mechanism for the “omeprazole test” outcome, although an individually different effect on pain threshold cannot be excluded.

Management of gastroesophageal reflux disease and erosive esophagitis in pediatric patients: Focus on delayed-release esomeprazole

ObjectiveTo review the literature on the treatment of gastroesophageal reflux disease (GERD) with emphasis on proton pump inhibitors (PPIs), particularly on delayed-release esomeprazole, and to identify properties and adverse effects of PPIs observed in the treatment of GERD in children and adolescents.SourcesElectronic search of PubMed/Medline and Cochrane Collaboration databases, and of abstracts on DDW, NASPGHAN, and ESPGHAN. We focused on controlled and randomized studies published since 2000 and identified reviews that presented a consensual position, and directives published within the last 10 years.Main resultsPPIs are considered better antisecretory agents than H2-receptor antagonists. Although all PPIs are similar, they are not identical in their pharmacologic properties. For example, the acid-suppressive effect of esomeprazole, the S-isomer of omeprazole, persists for more than 16 hours after administration of the morning dose. Therefore, it can control acidity after night meals better than a single dose of omeprazole. Moreover, the onset of the suppressive effect of esomeprazole is faster. It achieves acid inhibition faster than other PPIs.ConclusionCurrently, the mainstream treatment for GERD in children is a PPI. Although PPIs are safe drugs, effective in healing erosive esophagitis, and in relieving symptoms, studies with esomeprazole have shown that this drug has as powerful an ability to inhibit acid secretion as omeprazole. It also seems that some pharmacologic properties of esomeprazole are actually better for the treatment of GERD.

The effect of omeprazole on oesophageal pH in dogs during anaesthesia

Intra-operative, gastro-oesophageal reflux may be associated with post-anaesthestic complications such as oesophagitis and oesophageal stricture in dogs. The aim of this study was to investigate the effect of preoperative administration of omeprazole, a proton pump inhibitor, on oesophageal pH in anaesthetised dogs. Forty-seven dogs undergoing elective pelvic limb orthopaedic surgery were enrolled into the study. These were randomly allocated to treatment group (n=22) or control group (n=25). The treatment group received one dose of omeprazole (1 mg/kg po) at least 4 h before anaesthesia. All dogs were anaesthetised by the same standardised protocol. A pH probe was inserted into the distal oesophagus after induction of anaesthesia and oesophageal pH was continuously monitored. In the treatment group, four animals (18 per cent) showed a sudden decrease in oesophageal pH (<4). In the control group the same phenomenon was detected in 13 animals (52 per cent). Gastro-oesophageal reflux occurred more frequently in the control group compared with the omeprazole group (odds ratio 4.7, 95 per cent C.I. 1.1 to 24.7, P=0.032). This study suggests that the preoperative administration of omeprazole is effective in reducing the incidence of gastro-oesophageal reflux during anaesthesia in dogs.

Clopidogrel Inhibits CYP2C19‐Dependent Hydroxylation of Omeprazole Related to CYP2C19 Genetic Polymorphisms

This study explores the impact of clopidogrel on the pharmacokinetics of omeprazole related to CYP2C19 genetic polymorphisms. Twelve healthy volunteers (6 CYP2C19*1/*1, 5 CYP2C19*2/*2, and 1 CYP2C19*2/*3) are enrolled in a 2-phase randomized crossover trial. In each phase, the volunteers are administered a single oral dose of omeprazole 40 mg after pretreatment of either placebo or clopidogrel (300 mg on the first day and then 75 mg once daily for 3 consecutive days). Plasma concentrations of omeprazole and its metabolites are quantified by high-performance liquid chromatography with UV detection. After clopidogrel treatment, the AUC(0-infinity) of omeprazole increases by 30.02% +/- 18.03% (P = .004) and that of 5-hydroxyomeprazole decreases by 24.30% +/- 11.66% (P = .032) in CYP2C19*1/*1. The AUC(0-infinity) ratios of omeprazole to 5-hydroxyomeprazole increase by 74.98% +/- 35.48% (P = .001) and those of omeprazole to omeprazole sulfone do not change significantly (P = .832) in CYP2C19*1/*1. No significant alteration is observed in CYP2C19*2/*2 or *3. Clopidogrel inhibits CYP2C19-dependent hydroxylation of omeprazole in CYP2C19*1/*1 and has no impact on CYP3A4-catalyzed sulfoxidation of omeprazole.

226 Scheduled 2nd Endoscopy or High Dose Omeprazole Infusion in Preventing Peptic Ulcer Rebleeding - A Prospective Randomized Trial

and quantified CagA translocation by Western blot using anti-phosphotyrosine and antiCagA antibodies. Significantly higher levels of CagA were translocated by the 7.13 0310mutant compared to wild-type H. pylori strain 7.13. By utilizing proteomics technology to contrast two closely related H. pylori strains that induce distinct phenotypes, we have shown that HP0310 may function to alter levels of peptidoglycan, thereby affecting the composition of substrates translocated by the cag secretion system. These studies also provide an important foundation for investigating the role of bacterial virulence factors in H. pylori-induced pathologic sequelae, as such results would ultimately allow for generation of a profile of H. pylori proteins to use for screening persons infected with strains most likely to induce severe disease.

Control of 24-hour Intragastric Acidity With Morning Dosing of Immediate-release and Delayed-release Proton Pump Inhibitors in Patients With GERD

To compare the effects of immediate-release omeprazole and 2 different delayed-release proton pump inhibitors on 24-hour intragastric acidity in gastroesophageal reflux disease patients. Because of its unique pharmacokinetic properties, immediate-release omeprazole does not need to be dosed before a meal to control intragastric acidity. Previous studies showed effectiveness of immediate-release omeprazole in controlling nocturnal intragastric acidity with bedtime dosing. This is the first study to compare the effects of prebreakfast dosing of immediate-release omeprazole and delayed-release lansoprazole and pantoprazole on 24-hour intragastric acidity. To compare the effects of prebreakfast dosing of immediate-release omeprazole 40 mg capsules, lansoprazole 30 mg capsules, and pantoprazole 40 mg tablets on 24-hour intragastric acidity. Fifty-five patients with gastroesophageal reflux disease received 7 consecutive once-daily morning doses of each drug in this open-label, randomized, 3-period crossover study. On day 7, intragastric pH was recorded for 24 hours. After 7 days, the percentage of time with intragastric pH >4 over 24 hours was 59.7% (14.3 hours) with immediate-release omeprazole, 48.8% (11.7 hours) with lansoprazole (P=0.005), and 41.8% (10.0 hours) with pantoprazole (P<0.001). Median intragastric pH was significantly higher with immediate-release omeprazole than with lansoprazole (P=0.003) or pantoprazole (P<0.001). All drugs were well tolerated. When dosed in the morning, immediate-release omeprazole provided significantly better control of 24-hour intragastric acidity than lansoprazole and pantoprazole.

Proton Pump Inhibitor-Induced Leak Across Gastric Mucosa: Effect of H-2 Blockers

Previous patient-based studies by our group have shown that the proton pump inhibitor, esomeprazole, induces a transmural leak in gastric mucosa (Mullin et al., Alimentary Pharmacology and Therapeutics, 28(11-12): 1317-25, 2008). Subsequent studies by our group using rat gastric corpus mucosa showed that this leak is bidirectional, has an upper size limit of 10 kDa, and is a class effect for PPIs in general, holding true for omeprazole and lansoprazole as well as esomeprazole. Additionally, we have demonstrated that the small molecule drug, digoxin, is capable of passing through this leak, with the potential of thereby elevating digoxin blood levels above their therapeutic target. In this current study we asked whether the H-2 blocker, famotidine, would have a similar effect to PPIs. Test subjects performed an initial (baseline) sucrose permeability test just prior to beginning medication. Subjects then took a daily (morning) dose of famotidine (40 mg) or omeprazole (20 mg) for 5 days. On the evening of the 5th (last) day, subjects performed a second sucrose permeability test. Subjects taking omeprazole for 5 days (n = 10) manifested a 5-fold increase in sucrose leak. Subjects taking famotidine for 5 days (n = 10) manifested only a 15% increase in leak, which was not statistically significant (P = 0.54, Student's t test). The increased leak of subjects on omeprazole was highly significant (P<0.0005). These findings support the hypothesis that induction of transmucosal gastric leak is not simply a function of inhibition of acid secretion, but instead is a property more specific to PPIs per se. Future studies will however test whether longer duration exposure to famotidine can induce leak, or whether a famotidine-induced leak disappears in 12-24 hrs after a 40 mg oral dose. This work was supported by funding from the Sharpe/Strumia Foundation.

Variation in Paediatric Omeprazole Dosing

ABSTRACTAimTo characterise enteral omeprazole prescribing for paediatric inpatients; to compare doses prescribed for tablets and mixtures; and to compare doses prescribed to a nationally recognised paediatric dosing guideline.MethodA cross‐sectional study conducted at a paediatric hospital where pharmacists prospectively collected dose and formulation data for all paediatric inpatients prescribed enteral omeprazole over a 2–week period.Result35 children (8.6% inpatients) were prescribed enteral omeprazole. Omeprazole doses varied from 0.5 to 3.7 mg/kg/day (median 1.2), higher doses were prescribed for infants and for the mixture formulation. Less than half of the prescriptions followed the nationally recognised paediatric dosing guideline.ConclusionThere was a wide variation in omeprazole dosing in children. Studies of the stability and bioavailability of omeprazole along with clinical outcomes are needed to establish optimal dosing, especially in younger children.

PPI Dosing Patterns for Recently Bleeding Gastroduodenal Ulcer Disease

Purpose: Studies have demonstrated equivalent healing rates in patients receiving standard (20 mg) versus higher dose omeprazole taken for uncomplicated gastroduodenal ulcer disease (GD). Many experts also recommend standard dose, once daily omeprazole or equivalent for non-acute, recently bleeding GD. We sought to determine PPI dosing patterns for recently bleeding, GD within a single-center, university hospital setting. Methods: Single-center chart review of patients discharged on PPI therapy after endoscopic confirmation of recently bleeding, GD between the years 2003–2007. Inclusion criteria: adults 18–80 years old, acutely or recently bleeding GD confirmed endoscopically, PPI prescribed at hospital discharge. Exclusion criteria: prior h/o GD, h/o GERD/esophagitis, Zollinger-Ellison syndrome, GI malignancy, confirmed or suspected intestinal metaplasia of esophagus, positive/indeterminate H. pylori testing. Ascertainment of PPI type and dose was made from discharge summary or, when unavailable, endoscopy reports. Results: 383, 209 and 57 subjects with recently bleeding gastric, duodenal and dual location ulcers were identified, respectively, over the 5 year study period. Of these, 39, 31 and 10, respectively, met pre-specifed study criteria. 69%, 68% and 100%, respectively, were prescribed PPIs at discharge in excess of standard dosing (see Table). 95% of subjects prescribed PPIs with suprastandard dosing were placed on a twice-daily schedule. Among the entire study cohort, 50% were on NSAIDs, 17% had high-risk stigmata at time of endoscopy. In cases of active bleeding, patients were discharged no sooner than 24 hours from the time of endoscopy. There was no significant trend from year to year in the number of patients receiving PPIs in excess of standard dosing (χ2= 0.61). In the majority of cases no temporal endpoint of therapy was given at the time of PPI prescription. Conclusion: At a university hospital, the majority of patients with recently bleeding GD were discharged on PPI dosages in excess of that generally considered sufficient for ulcer healing. These data build upon the growing recognition of inappropriate PPI usage in a variety of practice settings. A more rational approach to PPI dosing for GD may have many beneficial consequences including significant cost savings.Table

Effects of the CYP3A5 genotype on omeprazole sulfoxidation in CYP2C19 PMs

Omeprazole is metabolized by the two cytochrome P450 isoforms, CYP3A (sulfoxidation) and CYP2C 19 (hydroxydation). The aim of this study was to determine whether the CYP3A5 genotype is an important determinant of inter-individual variability of total CYP3A activity in vivo. Plasma levels of omeprazole and omeprazole sulfone were analyzed by high-performance liquid chromatography in blood samples drawn 4-5 h after 43 CYP2C19 poor metabolizers (PMs) had ingested a single oral 40 mg dose of omeprazole. The CYP3A5*3 allele was identified using a PCR-restriction fragment length polymorphism assay. Among the 43 CYP2C19 PMs, 24 were CYP3A5*3/*3 carriers and 19 were CYP3A5*1 carriers (CYP3A5*I/*I in one subject and CYP3A5*1/*3 in 18 subjects). No significant difference was found between the mean log10 (metabolic ratio) of the CYP3A5*3/*3 carriers (0.314 +/- 0.369) and CYP3A5*1 carriers (0.330 +/- 0.313). The CYP3A5 genotype was not an important factor underlying the inter-individual variation in the metabolic ratio of omeprazole to omeprazole sulfone in our study cohort, although genotype can be considered to be responsible for the inter-individual variation of many CYP3A substrates in vivo.

Interaction Profile of Armodafinil with Medications Metabolized by Cytochrome P450 Enzymes 1A2, 3A4 and 2C19 in Healthy Subjects

Armodafinil, a wakefulness-promoting agent, is the pure R-enantiomer of racemic modafinil. The objective of this article is to summarize the results of three clinical drug-interaction studies assessing the potential for drug interactions of armodafinil with agents metabolized by cytochrome P450 (CYP) enzymes 1A2, 3A4 and 2C19. Study 1 evaluated the potential for armodafinil to induce the activity of CYP1A2 using oral caffeine as the probe substrate. Study 2 evaluated the potential for armodafinil to induce gastrointestinal and hepatic CYP3A4 activity using intravenous and oral midazolam as the probe substrate. Study 3 evaluated the potential for armodafinil to inhibit the activity of CYP2C19 using oral omeprazole as the probe substrate. Healthy men and nonpregnant women aged 18-45 years with a body mass index of </=30 kg/m(2) each participated in one of three open-label studies. Studies 1 and 2 were sequential design studies in which caffeine (oral 200 mg) or midazolam (2 mg intravenously followed by 5 mg orally) was administered before initiation of oral armodafinil administration and again after at least 22 days of oral armodafinil administration at 250 mg/day. Study 3 was a two-way crossover study in CYP2C19 extensive metabolizers to whom omeprazole (oral 40 mg) was administered alone or with oral administration of armodafinil 400 mg 2 hours before the omeprazole dose. Pharmacokinetic samples were obtained for caffeine, midazolam and omeprazole for up to 48 hours postdose. The primary pharmacokinetic parameters included the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and the maximum observed drug plasma concentration (C(max)). Safety and tolerability were also assessed. A total of 77 healthy subjects participated in the three studies (study 1, n = 29; study 2, n = 24; study 3, n = 24). Prolonged armodafinil administration had no effect on the C(max) or the AUC of oral caffeine compared with administration of caffeine alone. However, prolonged administration of armodafinil reduced the AUC of midazolam after intravenous and oral doses by approximately 17% and 32%, respectively, and decreased the C(max) of oral midazolam by approximately 19% compared with administration of midazolam alone. Armodafinil coadministration increased the AUC of oral omeprazole by approximately 38% compared with administration of omeprazole alone. Armodafinil alone or in combination with each of the three probe substrates was well tolerated, with headache and dizziness being the most commonly reported adverse events. Armodafinil did not induce CYP1A2 but was a moderate inducer of CYP3A4 and a moderate inhibitor of CYP2C19 in healthy subjects. Armodafinil was generally well tolerated when administered with caffeine, midazolam or omeprazole. Dosage adjustments may be required for drugs that are substrates of CYP3A4 (e.g. ciclosporin, triazolam) and CYP2C19 enzymes (e.g. diazepam, phenytoin) when administered with armodafinil.

Association of gastric cancer with cytochrome P450 2C19 single-nucleotide polymorphisms in Koreans

Cytochrome P450 2C19 (CYP2C19) is a clinically important enzyme involved in the metabolism of therapeutic drugs, including (S)-mephenytoin, omeprazole, proguanil, and diazepam. Individuals are characterized as either extensive metabolizers (EM) or poor metabolizers (PM) on the basis of CYP2C19 enzyme activity. The PM phenotype occurs in 2-5% of Caucasians, but in 18-23% of Asians. To clarify the association between CYP2C19 polymorphisms and gastric cancer in Koreans, we investigated CYP2C19 genotypes (<TEX>$CYP2C19^*1,\;{^*2},\;and\;^*3$</TEX>) in 109 patients with gastric cancer and 211 controls. Normal (<TEX>$CYP2C19^*1$</TEX>) and defective alleles were detected with polymerase chain reaction/restriction enzyme analysis. CYP2C19 has three hereditary genotypes: homozygous EM, with high enzymatic activity; heterozygous EM, with moderate enzymatic activity; and PM, with no enzyme activity. We found that CYP2C19 heterozygous EM is more closely associated with gastric cancer than is homozygous EM. Because the CYP2C19 genotype varies in Koreans, a genotyping test is desirable to prevent gastropathy recurrence in patients before their doses of omeprazole are reduced during maintenance therapy.

Stability of Partial Doses of Omeprazole–Sodium Bicarbonate Oral Suspension

Omeprazole-sodium bicarbonate powder for oral suspension has recently been marketed. The manufacturer provides no information regarding the acceptability of using partial doses and recommends that the reconstituted suspension be administered immediately after preparation. To determine the stability of the powder for oral suspension over 45 days, evaluate the stability of a partial dose (<20 mg) following exposure to Simulated Gastric Fluid USP (SGF) over 2 hours, and determine the feasibility of administering the suspension through neonatal and pediatric nasogastric feeding tubes compared with lansoprazole. Three identical samples of omeprazole-sodium bicarbonate suspension 2 mg/mL were stored in the refrigerator (3-5 degrees C) and assayed by high-performance liquid chromatography immediately after preparation and at 7, 15, 30, and 45 days. Stability of a 1 mg/kg dose with an estimated volume of SGF for a simulated 12.7 kg pediatric patient was determined in triplicate over 2 hours at 37 degrees C. The ability to administer a typical dose of omeprazole suspension and lansoprazole suspension (microgranules and water compounded from lansoprazole oral disintegrating tablets) was assessed in triplicate using 3 different sizes of neonatal/pediatric nasogastric feeding tubes. At least 98% of the initial concentration of omeprazole remained throughout the 45 day study period in all suspensions. The suspension maintained at least 93% of the initial concentration following exposure to SGF for 2 hours. The lansoprazole bead mixture partially clogged the 6 French feeding tube and completely clogged the 5 French feeding tube. The omeprazole-sodium bicarbonate suspension was easily administered through all 3 sizes of neonatal/pediatric feeding tubes. Omeprazole-sodium bicarbonate suspension 2 mg/mL prepared from 20 mg packets was stable for at least 45 days when stored at 3-5 degrees C. A partial dose of 12.7 mg was stable following exposure to SGF for 2 hours at 37 degrees C. This suspension can be easily administered through 5, 6, and 8 French neonatal/pediatric feeding tubes and, when taking time and ease of preparation into account, it is cost competitive with simple omeprazole suspension.

The Effect of the Interaction between Proton Pump Inhibitors (PPI) and Tyrosine Kinase Inhibitors (Imatinib, Nilotinib and Dasatinib).

Background: Proton Pump Inhibitors (PPI) (omeprazole, lansoprazole and pantoprazole) are widely used for the treatment of the gastro-oesophageal reflux disease, as well as other acid- related disorders. All PPI act by covalent binding to the proton pump of the gastric parietal cell and inhibition of the H+, K+ -adenosine triphosphatase [ATPase]. It is known that imatinib mesylate enters the cells through an active pump called hOCT-1. We therefore investigated whether proton pump inhibitors (PPI) could affect OCT-1 function thereby modifying the sensitivity of CML cells to Imatinib and other Tyrosine Kinase Inhibitors (TKI) such as Nilotinib and Dasatinib.Methods: We pretreated K562 cell line for 2 hours with increasing dose of omeprazole (5, 50, and 100 mM), lansoprazole (5, 50, and 100 mM) and pantoprazole (9, 50, and 100 mM). Imatinib (1mM), Dasatinib (5 nM), Nilotinib (0,1 mM) were added and their cytotoxicity was evaluated after 24 hours of incubation using cell death assays (Trypan Blue). As a control the cells were pretreated with ranitidine, an histamine H(2)- receptor blocker, but not proton pump inhibitors.Results: (Table1). Imatinib induced citotoxicity was significantly reduced when cells were pre-treated with 100 μM-omeprazole, 50 and 100 μM-pantoprazole, 50 and 100 μM-lansoprazole. Dasatinib induced cytotoxicity was only slightly decreased at the different doses of PPI, while nilotinib induced cytotoxicity was significantly increased by the highest doses of PPI.Conclusion: Our data provide evidence that proton pump inhibitors might interfere with TKIs activity. The reduction of imatinib cytotoxicity could be due to PPI interaction with OCT-1 that is the active transporter of imatinib. On the contrary, the increase of nilotinib cytotoxicity could be due to PPI inhibition of the efflux pumps such as ABCB1. Similar data (except for dasatinib) have already been reported at 2007 EHA meeting (White, #907) but using very high dose of PPI (> 200 μM). We here demonstrate that this phenomenon starts at low-intermediate concentration of PPI (that are closer to those achievable in vivo after standard dose administration). These interactions may also modify the toxic profile of the TKI and should be kept in mind in clinical practice.Table IImatinib induced citotoxicity47,5%at different concentration PPI (μM):5950100omeprazole47%45%33,8%p value0,70,54<0,0005pantoprazole46,4%28%21,5%p value0,670,0005<0,0005lansoprazole45%35,9%33,8%p value0,260,005<0,0005Dasatinib induced citotoxicity29%at different concentration PPI (μM):5950100omeprazole26%27%27%p value0,010,110,11pantoprazole28,9%27%20,2%p value110,030,005lansoprazole27%24%22,3%p value0,170,0090,0017Nilotinib induced citotoxicity27%at different concentration PPI (μM):5950100omeprazole27%30,5%40,4%p value0,80,09<0,0005pantoprazole25,5%30,3%25,5%p value0,470,0010,01lansoprazole29%34,2%37,9%p value0,490,02<0,0005

The effect of double dose of omeprazole on the course of angina pectoris and treadmill stress test in patients with coronary artery disease — A randomised, double-blind, placebo controlled, crossover trial

Background Gastroesophageal reflux (GER) and coronary artery disease (CAD) frequently overlap, making the proper diagnosis of chest pain more difficult. GER symptoms may mistake anginal chest pain, and oesophageal acidification may induce myocardial ischaemia both in the rest and in the effort. Increase of oesophageal pH should prevent these conditions. Aim To estimate the effect of double omeprazole dose on the course of angina pectoris and treadmill stress test in patients with coronary artery disease (CAD), using double-blind, crossover randomised, placebo-controlled study design. Methods We studied 48 patients with angina pectoris symptoms and significant narrowing of coronary vessels in angiography. After baseline examination and treadmill stress test all subjects were randomised to treat either with omeprazole (20 mg b.i.d.) or placebo for 14 days, using a double-blind, crossover placebo controlled design. Results Seventeen (35%) subjects reported more than by half decrease in symptoms severity after omeprazole and 6 (12%) after placebo ( p = 0,01). Omeprazole significantly decreased the number of chest pain episodes and number of nitroglycerin doses taken in the second week of both study phases, as well as the percentage of subjects with significant decrease of ST interval during the stress test (64% vs. 73%, p < 0,05). However majority of other stress test parameters (i.e. test duration, DUKE index) have improved both after omeprazole and placebo administration (by 9–38%). Conclusion Double dose of omeprazole significantly decreased symptoms severity in 35% of patients with CAD, as well as frequency of some electrocardiographic signs of myocardial ischaemia during stress test.

Gastric Antisecretory Drugs Induce Leukocyte-Endothelial Cell Interactions through Gastrin Release and Activation of CCK-2 Receptors

Antisecretory drugs are effective antiulcer agents, but its chronic use generates hypergastrinemia and accelerates the development of atrophic gastritis in Helicobacter pylori-positive patients. We have recently shown that gastrin exerts a proinflammatory effect in rats through CCK-2 receptor activation that contributes to the inflammation induced by H. pylori. The present study was designed to examine whether gastrin hypersecretion in response to treatment with antisecretory drugs induces an inflammatory response that could promote mucosal atrophy. The effects of omeprazole or famotidine on leukocyte/endothelial cell interactions in vivo were analyzed in rat mesenteric venules using intravital microscopy. Administration of a single dose of omeprazole or famotidine acutely increased gastrinemia and leukocyte rolling and adhesion, but not emigration into the interstitium. Daily treatment with omeprazole for a short period (3 days) induced a similar response, but when this treatment was extended to 14 days and a steady hyper-gastrinemic state was established, increased leukocyte rolling, adhesion, and emigration was observed. Pretreatment with the CCK-2 receptor antagonist proglumide prevented these inflammatory events in all cases. Leukocytes from rats treated with omeprazole showed increased expression of CD11b/CD18 initially in granulocytes (3-day protocol) and later in monocytes and lymphocytes (14-day protocol). These changes were not observed in animals pretreated with proglumide, and they were not reproduced by incubation of leukocytes from untreated animals in vitro with gastrin. Thus, hypergastrinemia induced by chronic treatment with antisecretory drugs may promote inflammation, which could partly explain their worsening effect in corpus gastritis observed in H. pylori-infected patients.