Presence Of Proton Pump Inhibitors Research Articles

Mitigating the Risk of Drug Interactions in Cancer Patients Taking Oral Anticancer Agents: The Role of a Multidisciplinary Team-Based Medication Reconciliation.

Polypharmacy in cancer patients is a recognized issue and should be an integral part of comprehensive patient assessment and management. Despite this, a systematic review of concomitant drugs or a search for potential drug-drug interactions (DDIs) is not always performed. Here, we present the results of a medication reconciliation model performed by a multidisciplinary team to identify clinically meaningful potential DDIs (defined by the presence of DDIof major severity or contraindication) in cancer patients undergoing oral antineoplastic drugs. From June to December 2022, we performed a non-interventional, prospective, cross-sectional, single-center study of adult cancer patients, initiating or undergoing treatment with oral antineoplastic drugs, referred by their oncologists for therapeutic review regarding potential DDIs. DDIs were assessed by a multidisciplinary team of hospital pharmacists and medical oncologists, through research in three different drug databases as well as in the summary of product characteristics. A report detailing all potential DDIs was created for each request and provided to the patient's medical oncologist for further examination. Overall, 142 patients' medications were reviewed. Regardless of the severity or clinical importance, 70.4% of patients had at least one potential DDI. We found 184 combinations of oral anticancer and regular therapy agents with potential DDIs, 55 of whom were considered of major severity by at least one DDI database. As expected, the number of potential DDIs increased with the number of active substances in regular therapy (p <0.001), but we did not find an increased relation between age and the total number of potential DDIs (p =0.109). Thirty-nine (27.5%) patients had at least one clinically meaningful DDI identified. After adjustment through multivariable logistic regression, only the female sex (odds ratio (OR) 3.01,p= 0.029), the number of active comorbidities (OR 0.60,p= 0.029), and the presence of proton pump inhibitors in chronic medication (OR 2.99,p= 0.033) remained as predictors of potential meaningful DDI. Although drug interactions are a concern in oncology, a systematic DDI review is rarely conducted in medical oncology consultations. The availability of a medication reconciliation service, carried out by a multidisciplinary team with dedicated time for this task, is an added value for safety enhancement in cancer patients.

Lack of association of the esophageal microbiome in adults with eosinophilic esophagitis compared with non-EoE controls.

Changes in the esophageal microbiome have been reported in children with eosinophilic esophagitis (EoE), but few data exist for adults. We aimed to determine whether the esophageal microbiome differs in adults with and without EoE. In a prospective cohort study, adults undergoing outpatient endoscopy were enrolled as incident EoE cases or non-EoE controls. Clinical, endoscopic, and histologic data were collected. An esophageal biopsy was utilized for microbiome analysis. Bacterial DNA was extracted and the V3-V4 region of the 16S rRNA gene was amplified and sequenced. Analyses were performed comparing microbiome features for cases and controls, and within cases for disease features, with correction for multiple hypothesis testing. A total of 24 incident EoE cases (mean age 40 years; 63% male; 100% white; 97 eos/hpf) and 25 controls (mean age 48, 36% male; 76% white; 1 eos/hpf) were analyzed. Principal coordinate analysis ordination failed to distinguish cases from controls. There were no microbiome differences within EoE cases based on clinical phenotype, presence of atopy, or endoscopic features. Use of proton pump inhibitors (PPIs), however, was significantly associated with 5 taxa including SR1 at the phylum level and Burkholderia at the genus level. There were no significant differences in the esophageal microbiome between newly diagnosed EoE cases and non-EoE controls in adults, or within EoE cases based on clinical features. However, given the strong rationale for the esophageal microbiome in EoE pathogenesis, future studies should explicitly consider the presence of PPIs as a confounding feature.

Abstract CT168: Clinical pharmacology of AZD4635 (A2ARi): Integration of PK data from cancer patients (CP) and healthy volunteer (HV) clinical trials to provide dosing recommendations

Abstract AZD4635 is an orally administered, selective adenosine 2A receptor (A2AR) antagonist, being evaluated in patients with advanced solid tumors. In the phase 1 trial, safety and pharmacokinetics (PK) of AZD4635 nanosuspension (NS) was assessed as monotherapy or in combination with durvalumab. In the HV study, a single dose of AZD4635 was evaluated to assess relative bioavailability, effect of high fat meal and effect of proton pump inhibitor (PPI) on new capsule formulation (CF). Here we present PK results from both trials to provide dosing and formulation recommendation for ongoing clinical trials. Methods: Phase 1 Study in CP: An open-label, multicenter study in advanced solid malignancies (121 patients PK evaluable), AZD4635 was administered as a NS at various dose levels (125 mg BID, 75mg QD, 100 mg QD) as monotherapy or in combination (75 or 100 mg QD) with durvalumab (NCT02740985). The PK parameters of AZD4635 and its metabolites have been characterized in patients after single and multiple doses. Phase 1 Study in HV: An open-label, single-dose (50 mg), 2-part crossover clinical pharmacology study was conducted in 20 HV (non-smoking, male) (NCT03710434). Part A was a 2-period randomized crossover study of AZD4635 as NS or CF. Part B was a fixed-sequence crossover study to evaluate effect of high fat meal and co-administration of PPI (lansoprazole) on AZD4635 CF. PK and safety assessments were obtained for up to 120 h post-dose in each treatment period, and the treatments were separated with at least a 9-day washout period. Results: AZD4635 NS rapidly appeared in plasma after single or multiple oral administration with tmax of 1 h and Cmax were 594.13, 580.21, and 770.66 ng/mL and AUC were 4780.3, 4364.8, and 5972.89 ng•hr/mL at 75, 100 and 125 mg, respectively with a mean t1/2 of 13.1 - 18.1 h following a single-dose administration. There was minimal accumulation at steady state with high inter-individual variability (43 - 114%). Metabolites PK will be presented. In HV, administration of CF resulted in absorption rates similar to NS with tmax of 1.5 h and had 27% and 10% higher Cmax and AUC, respectively compared to NS. Administering AZD4635 CF after a high fat meal resulted in 56% and 12% decrease in Cmax and AUC, respectively compared to the fasted state. In the presence of PPI (lansoprazole), peak and overall exposures (Cmax, AUC and tmax) were similar to those for CF administered alone. Conclusion: Based on totality of exposure and safety data from ongoing Phase I study in CP at various doses of AZD4635 NS, and data from HV study for both NS and CF, a dose of 75 mg CF is proposed RP2D for further clinical studies. As food can mitigate gastrointestinal toxicities, and there was a lack of significant effect on AUC, the current fasting restrictions have been relaxed to allow patients to receive AZD4635 with or without food. No impact of PPI allows for better compliance as the target patient population may also be receiving gastric modifiers. Citation Format: Ganesh Moorthy, Gayle Pageau Pouliot, Lorraine Graham, Chris Wilks, Tinnu Sarvotham, Patrick Mitchell, Lindsey Jung, Yan Li, Wenlin Shao, Ganesh Mugundu. Clinical pharmacology of AZD4635 (A2ARi): Integration of PK data from cancer patients (CP) and healthy volunteer (HV) clinical trials to provide dosing recommendations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT168.

Proton pump inhibitors may hinder hypophosphatemic effect of lanthanum carbonate, but not of ferric citrate hydrate or sucroferric oxyhydroxide, in hemodialysis patients

Because end-stage renal disease patients undergoing hemodialysis frequently take acid suppressants for the treatment or prevention of gastrointestinal diseases, it is important to clarify the drug-interactions between acid suppressants and phosphate binders on the control of serum phosphate levels. In the present study, we examined whether the phosphate-lowering effects of three phosphate binders, lanthanum carbonate (LC), ferric citrate hydrate (FCH), and sucroferric oxyhydroxide (SFOH), were affected by proton pump inhibitors (PPIs) in maintenance hemodialysis patients. Laboratory data for 71 patients who had been newly prescribed one of the three phosphate binders were examined. LC at a dosage of 500 ± 217 mg/day significantly decreased serum phosphate levels by −18% in the absence of a PPI (n = 9), while a dosage of 700 ± 230 mg/day only decreased it by −3% in the presence of a PPI (n = 10). Thus, the efficacy of LC in reducing serum phosphate levels was significantly hindered by the presence of PPIs. FCH significantly decreased serum phosphate levels by −18% in the absence of a PPI (n = 7, FCH: 571 ± 189 mg/day) and by −17% in the presence of a PPI (n = 20, FCH: 638 ± 151 mg/day). The decrease in serum phosphate levels by SFOH (393 ± 197 mg/day) was −7% in the absence of a PPI (n = 7), and SFOH at a dosage of 556 ± 316 mg/day significantly decreased serum phosphate levels by −13% in the presence of a PPI (n = 18). These results suggest that the phosphate-lowering effect of LC, but not of FCH or SFOH, is diminished in the presence of PPIs in hemodialysis patients.

Synthesis, Biological and Molecular Docking Study of Benzimidazole‐Clubbed Tetrahydrothieno [3, 2‐c] Pyridine as Platelet Inhibitors

AbstractTwo novel series of tetrahydrothienopyridine clubbed benzimidazole hybrids were synthesized, characterized by spectral studies 1H NMR, IR and mass analysis. Synthesized analogs were screened for in vitro antiplatelet activity. In addition, active analogs were further subjected in presence of proton pump inhibitors against standard prasugrel and aspirin to check minimization in antiplatelet activity. Active analogs 1‐(2‐(1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)‐6,7‐dihydrothieno[3,2‐c]pyridin‐5(4H)‐yl)ethan‐1‐one (11) and (2‐(1‐(2‐fluorobenzyl)‐1H‐benzo[d]imidazol‐2‐yl)‐6,7‐dihydrothieno[3,2‐c]pyridin‐5(4H)‐yl)(3,4,5‐trichlorophenyl)methanone (25) were significantly found more active than the standards in the presence of proton pump inhibitors. The structure and antiplatelet activity relationship was supported by molecular docking studies of active analogs to know how effectively, activity influenced by the merger of proton pump inhibitor precursor benzimidazole. The above studies successfully revealed that the synthesized analogs may found more active with further amendments via pharmacological point of view.

Proton pump inhibitors versus Cryptococcus species: effects on in vitro susceptibility and melanin production.

Aim: This study aimed to evaluate the effects of proton pump inhibitors (PPIs) on growth and melanin production by Cryptococcus spp. Materials & methods: Minimum inhibitory concentrations (MICs) of omeprazole, esomeprazole, rabeprazole, pantoprazole and lansoprazole against Cryptococcus spp. were determined and the effect of PPIs on melanin production was evaluated, in the presence or absence of copper sulfate or glutathione. Results: PPIs showed MICs ranging from 125-1000μg/ml and decreased melanization by Cryptococcus cells. Addition of copper sulfate or gluthatione restored melanogenesis of cells grown in the presence of PPIs. The presence of PPIs and glyphosate decreased copper sulfate toxicity (1mM). Conclusion: PPIs inhibited melanogenesis of Cryptococcus spp., possibly by chelating copper or inhibiting copper ATPase transport.

Utility of Physiologically Based Pharmacokinetic Absorption Modeling to Predict the Impact of Salt-to-Base Conversion on Prasugrel HCl Product Bioequivalence in the Presence of Proton Pump Inhibitors

Prasugrel HCl may convert to prasugrel base during manufacturing or storage. It was reported that formulations with different ratios of salt to base were bioequivalent in healthy subjects, but formulations with a higher extent of conversion were not bioequivalent in subjects taking proton pump inhibitor (PPI) whose stomach pH is elevated. The objective of this study was to assess the magnitude of impact of salt-to-base conversion on prasugrel HCl products BE evaluation in healthy subjects on PPI. A physiologically based pharmacokinetic (PBPK) absorption model was constructed to predict pharmacokinetic (PK) profiles of active metabolite after oral administration of prasugrel HCl products containing various fractions of base based on the prasugrel salt and base intrinsic solubility. The intrinsic solubility was obtained by deconvoluting the model against the observed active metabolite PK profiles with various fractions of base in healthy subjects with or without PPI. The developed PBPK absorption model accurately predicted the average active metabolite PK profiles in healthy subjects without PPI for the product containing 100% salt. A model based on assumptions of the fraction of a dose absorbed remaining unchanged for formulations containing different fractions of base over predicted the reduction of bioavailability upon conversion to the base. Therefore, this represented the conservative estimate with respect to the impact of free base in a product on BE evaluation. Virtual BE trial simulation predicted that less than 20% free base in prasugrel HCl product ensures in vivo BE of the generic product including in subjects that maybe taking PPI.

Influences of proton pump inhibitor on Helicobacter pylori adherence to the gastrointestinal cell lines.

Helicobacter pylori is a carcinogenic bacterium that could induce P-glycoprotein expression in the human gastrointestinal tract. Bacterial adherence to the gastrointestinal cell lines could be influenced by the level of P-glycoprotein. This study aimed to determine the influence of proton pump inhibitors that exhibit an inhibitory effect on P-glycoprotein in gastrointestinal carcinoma cell lines, namely Caco-2 and LS174T, in relation to H. pylori adherence. Caco-2 and LS174T cells lines treated with omeprazole and esomeprazole were used in this study to assess the bacterial attachment of H. pylori within certain incubation periods. The presence of proton pump inhibitors increased the H. pylori adherence in a time-dependent manner in both Caco-2 and LS174T cell lines. The double inhibition of P-glycoprotein using proton pump inhibitor and P-glycoprotein inhibitor caused low P-glycoprotein expression in the cell lines, resulting in higher H. pylori adherence compared to the control cell lines. Proton pump inhibitors may alter P-glycoprotein expression in the gastrointestinal tract, and subsequently H. pylori adherence on the cell lines, and may contribute to resistance to drug therapy.

Interaction of Manganese(II) with Proton Pump Inhibitor at Different pH: A Cyclic Voltammetric Study

The electrochemistry of Mn2+ at different pH (3.5-4.5) in acetate buffer solution has been investigated, using cyclic voltammetric method at glassy carbon electrode (GCE). Cyclic voltammograms (CVs) of Mn2+ show two cathodic and an anodic peaks over the entire investigated pH. The CVs of Mn2+ has also been performed in presence of proton pump inhibitors (PPIs) such as omeprazole, pantoprazole, esomeprazole and rabeprazole to elucidate the interaction of Mn2+ with the PPIs in acetate buffer solution. At the studied pH, a reasonably strong interaction was observed between Mn2+ and PPIs at different molar ratio of Mn2+ ion and PPIs. However, maximum interaction has been found at 1:2 molar ratio of Mn2+ and PPIs. This indicates the most suitable condition for the interaction between Mn2+ and PPIs. These results could allow insight into the interactions of metal ions with the PPIs.&#x0D; Dhaka Univ. J. Sci. 64(2): 115-120, 2016 (July)

The use of proton pump inhibitors is positively associated with osteoporosis in postmenopausal women in Germany

Objectives: To analyze the association between the use of proton pump inhibitors (PPIs) and osteoporosis in German postmenopausal women.Methods: This study included 3092 women with osteoporosis and 3092 women without osteoporosis. Cases and controls were matched on the basis of age, health insurance, index year, and physician. The main outcome of the study was the risk of osteoporosis dependent on predefined risk factors. Gastrointestinal disorders potentially associated with osteoporosis were determined. The presence of PPIs including the duration of therapy was also assessed. Multivariate logistic regression models were fitted with osteoporosis as a dependent variable.Results: The mean age was 72.3 years; 5.6% of both osteoporosis patients and controls had private health insurance coverage. Gastrointestinal disorders occurred significantly more frequently in osteoporosis patients than in controls. The use of PPI drugs was also significantly more common in osteoporosis patients than in matched controls. Osteoporosis development was found to be associated with disorders of the esophagus (odds ratio (OR) 1.19, p = 0.013) and gastritis/duodenitis (OR 1.14; p = 0.045). Interestingly, the use of PPIs also led to an increase in the risk of developing osteoporosis (OR 1.62; p < 0.001). Finally, the odds of being diagnosed with osteoporosis increased with the duration of PPI therapy from 1.58 for 1 year of therapy or less to 1.72 for at least 5 years of treatment.Conclusions: The use of PPIs was a risk factor for osteoporosis and this risk increased with therapy duration in German women. Esophagus disorders and gastritis/duodenitis also increased the risk of developing this chronic condition.

Voltammetric study of the interaction of Cu(II) with proton pump inhibitor at different pH

The electrochemical redox behavior of transition metal ion, Cu(II) at different pH in acetate buffer solution has been investigated using cyclic voltammetric method at glassy carbon electrode (GCE). Cyclic voltammograms of Cu(II) show two cathodic and an anodic peaks those remain identical at various pH. The cyclic voltammetric response of the metal ion has been observed in presence of proton pump inhibitors (PPIs) such as omeprazole, pantoprazole, esomeprazole and rabeprazole at various proportions of metal ion and PPIs. The nature of cyclic voltammograms of Cu(II) has been changed dramatically in presence of the PPIs due to the strong interaction between metal ion and PPIs. Almost similar interaction was noticed for all the PPIs. However, the maximum interaction was found at 1:2 molar ratio of Cu(II) and PPIs. The result could provide deep insight into the interaction between various metal ions and the PPIs that have been taken quite regularly in human bodyBangladesh J. Sci. Ind. Res. 50(3), 219-226, 2015

Inhibiteurs de pompe à proton et méthotrexate haute dose : à propos de deux cas

Methotrexate (MTX) is a cytotoxic agent prescribed at high dose in treatment of malignancy. Association of MTX to proton pump inhibitor (PPI) is not recommended if doses are more than 20mg per weeks and only to take into account for smaller doses. Review relate some cases of delayed elimination of methotrexate in patients taking PPI, which increase risk of toxic event. However, currently there is no status quo on interaction between PPI and MTX according to available data. We report two clinical cases illustrating one more time a toxic event to MTX in presence of PPI. In absence of risk/benefit ratio set correctly, an assessment of appropriateness of PPI prescription before MTX therapy can limit an iatrogenic risk.

Evaluating the Clopidogrel-Proton Pump Inhibitor Interaction by Comparing Platelet Aggregation to ADP with Clopidogrel in the Presence of Proton Pump Inhibitors (P5.144)

Evaluating the Clopidogrel-Proton Pump Inhibitor Interaction by Comparing Platelet Aggregation to ADP with Clopidogrel in the Presence of Proton Pump Inhibitors (P5.144)

Effect of Proton Pump Inhibitors on In Vitro Activity of Tigecycline against Several Common Clinical Pathogens

In this study, we evaluated the effect of proton pump inhibitors (PPIs) on in vitro antimicrobial activity of tigecycline against several species of clinical pathogens. Clinical non-duplicate isolates of Acinetobacter baumannii, Staphylococcus aureus, Enterococcus faecalis and three species of Enterobacteriaceae (Escherichia coli, Klebsiella pneumonia and Enterobacter cloacae) were collected from a tertiary hospital and their MICs of tigecycline alone and in combination with PPIs (omeprazole, lansoprazole and pantoprazole) were determined. With one randomly selected isolate of each bacterial species, an in vitro time–kill study was performed for the confirmation of the effect of PPIs on tigecycline activity. The MIC changes after PPIs addition correlated with the PPIs concentrations in the test media. Compared with tigecycline alone, the addition of 5 mg/L PPIs could increase the MICs of tigecycline by 0 to 2-fold and the addition of 50 mg/L PPIs could increase the MICs of tigecycline by 4 to >128-fold. The time–kill study confirmed that the addition of PPIs could affect the in vitro activity of tigecycline. Even at low concentration (5 mg/L) of omeprazole and pantoprazole, antagonistic effect could be observed in E. cloacae and E. faecalis strains. We conclude that In vitro activity of tigecycline can be influenced by the presence of PPIs in a concentration-dependent manner.

Concurrent use of proton pump inhibitors or H2 blockers did not adversely affect nilotinib efficacy in patients with chronic myeloid leukemia

The impact of proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (H2 blockers) on the efficacy of nilotinib was evaluated. Retrospective analyses were performed in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP; N=492) and in patients with imatinib-resistant or imatinib-intolerant Ph+ CML-CP (N=256) treated with nilotinib. In the newly diagnosed population, 87 (17.7%) and 49 (10.0%) patients received PPIs and H2 blockers, respectively. Major molecular response at 12months was achieved by 59 (49.6%) patients who received at least one PPI or H2 blocker (n=119) and 153 (41.0%) patients who did not receive any comedication (n=373; P=0.13). PPIs and H2 blockers were used by 77 (30.1%) and 17 (6.6%) patients with imatinib-resistant or imatinib-intolerant CML-CP, respectively. Major cytogenetic response by 12months was achieved by 55 (64.0%) patients who received at least one PPI or H2 blocker (n=86) versus 98 (57.6%) patients who did not receive any comedication (n=170; P=0.40); 39 (45.3%) versus 65 (38.2%), respectively, achieved complete cytogenetic response by 12months (P=0.34). Similar findings were observed in patients who received comedication for >50% of the time on nilotinib therapy. Nilotinib steady-state trough concentration was not affected by the presence of PPIs or H2 blockers. Concurrent use of PPIs or H2 blockers did not affect the pharmacokinetics and efficacy of nilotinib in patients with Ph+ CML-CP.

Clopidogrel and PPI Interaction: Clinically Relevant or Not?

Proton pump inhibitors and clopidogrel are commonly prescribed medications, both alone and in combination. In January of 2009 the US Food and Drug Administration and the European Medicines Agency issued warnings with regard to the concomitant use of clopidogrel and proton pump inhibitors. Later that year, these warnings were limited to the proton pump inhibitor omeprazole. These warnings were largely based on in-vitro studies and observational analyses suggesting decreased efficacy of clopidogrel in the presence of proton pump inhibitors. Recent literature has suggested there may not be a clinically meaningful interaction.

Using Absorption Simulation and Gastric pH Modulated Dog Model for Formulation Development To Overcome Achlorhydria Effect

Impaired absorption of weakly basic drugs in patients with reduced gastric acidity can lead to loss of efficacy of the therapeutic agent. Hence, a robust formulation which can provide adequate exposure in achlorhydric patients is imperative to achieve the desired efficacy. In this report, formulation development of a weakly basic Merck compound A is described. Compound A shows lower solubility at higher pH and thus is prone to reduced exposure under conditions of achlorhydria, as the compound's solubility increases only in environments of less than pH 2. Several formulations with or without an acidifier were developed and characterized by in vitro dissolution and in gastric pH modified dog model to assess their bioperformance in high gastric pH conditions. To predict the bioperformance of these formulations in humans, a dissolution based absorption model was developed and validated against the observed PPI-interaction data in the clinic and the gastric pH-adjusted dog data. An additional absorption model was developed to allow for incorporation of the dog PK data to provide translation of preclinical to clinical exposure. Based on the in vitro dissolution, in silico absorption modeling and preclinical in vivo data, a citric acid-based formulation (F2) was selected for a human pharmacokinetic study. This study showed that exposures from F2 were not meaningfully different in the presence of proton pump inhibitor (PPI) as compared to non-PPI, thus confirming that the F2 formulation was successful in overcoming the achlorhydria effect. These efforts also highlighted that the complementary use of in vitro/in silico/in vivo (IVISIV) tools may be a helpful strategy in the development of formulations to overcome the achlorhydria effect and achieve adequate exposure in patients with high gastric pH.

Proton Pump Inhibitor and Clopidogrel Interaction: Fact or Fiction?

Current consensus recommendations state that patients prescribed clopidogrel plus aspirin should receive a proton pump inhibitor (PPI) to reduce gastrointestinal bleeding. Clopidogrel is converted to its active metabolite by cytochrome P450 (CYP) enzymes. Clopidogrel users with decreased CYP2C19 function have less inhibition of platelet aggregation and increased cardiovascular (CV) events. As PPI metabolism also involves CYP2C19, it was hypothesized that competition by PPIs might interfere with clopidogrel's action. Omeprazole, but not other PPIs, worsens surrogate markers of clopidogrel efficacy. Some (but not all) observational studies show that clopidogrel users prescribed PPIs have increased risks of CV events (hazard/odds ratios=1.25-1.5). When effect sizes are small to moderate (relative risks<1.5-2.0), however, it is only possible to conclude whether statistical associations are valid in randomized trials. A randomized trial of omeprazole vs. placebo in clopidogrel users showed no difference in CV events (hazard ratio=1.02,0.70-1.51). Thus, current evidence does not justify a conclusion that PPIs are associated with CV events among clopidogrel users, let alone a judgment of causality. Nonetheless, positive results from some observational studies and biological plausibility have led some health-care providers to accept that PPIs reduce clopidogrel's efficacy. The US Food and Drug Administration (FDA) recommends that "concomitant use of drugs that inhibit CYP2C19 (e.g., omeprazole) should be discouraged." As the presence of PPIs and clopidogrel in plasma is short lived, separation by 12-20 h should in theory prevent competitive inhibition of CYP metabolism and minimize any potential, though unproven, clinical interaction. PPI may be given before breakfast and clopidogrel at bedtime, or PPI may be taken before dinner and clopidogrel at lunchtime.

Molecular mechanisms involved in anti-inflammatory effects of proton pump inhibitors

Interleukin (IL)-8 has been reported to participate in neutrophil infiltration in Helicobacter pylori (H. pylori)-induced gastritis in humans. In this study, we investigated the anti-inflammatory actions beyond the suppression of acid secretion by proton pump inhibitors (PPI), such as omeprazole and lansoprazole, on IL-8 production by gastric epithelial cells (MKN45) and human umbilical vein endothelial cells (HUVEC) and on the transendothelial migration of polymorphonuclear neutrophils (PMN). MKN45 and HUVEC were stimulated with H. pylori water extract (HPE) and IL-1beta, respectively, and nuclear factor kappa B (NFkappaB) activation and subsequent IL-8 production was assessed in the absence or presence of PPI. We also assessed the effect of PPI on IL-8-induced PMN transendothelial migration and on the alteration of cytoplasmic calcium concentration in formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN. HPE and IL-1beta induced a significant increase in IL-8 production by MKN45 and HUVEC, respectively, along with NFkappaB activation, which was significantly inhibited by PPI. PPI also inhibited the IL-8-induced transendothelial migration of PMN and the fMLP-induced cytosolic calcium increase in PMN. PPI attenuate PMN-dependent gastric mucosal inflammation partly by interfering with NFkappaB activation in vascular endothelial cells and gastric epithelial cells, and partly by modulating the calcium concentration of PMN.

Lack of Interaction Between Atazanavir and Proton Pump Inhibitors in HIV-Infected Patients Treated With Ritonavir-Boosted Atazanavir

To the Editor: Conflicting results have been recently published concerning drug interaction between atazanavir (ATV) and antacid treatments, especially proton pump inhibitors (PPIs). In the August 1, 2005 issue of this journal, Khanlou and Farthing1 summarized the results they collected in 10 HIV clinics in Los Angeles, saying that the use of ATV, even boosted with ritonavir (RTV), with PPIs should be avoided. These data require some comments. In this study, the prospective method of plasma collection is not clearly defined. Were the patients interviewed by a physician on the treatment they were really taking? Did the nurse who drew the blood samples ask the patients when they had taken their last dose of ATV and antacid treatment? The median ATV minimum concentrations (Cmins) reported are not in keeping with values observed in recent published studies and in our experience on HIV-infected patients treated with boosted ATV (Table 1).TABLE 1: Median ATV Cmin in Patients Treated With Boosted ATV (300/100 mg/d)Because of its chemical structure, ATV absorption is highly dependent on an appropriate gastric pH. The potential interaction between ATV and PPIs or histamine-2 receptor blockers (H2RBs) is expected to reduce ATV exposure. In the presence of an H2RB, however, the median ATV Cmin reported in this study was 2-fold higher than values observed in the previously reported series (performed in patients without antacid treatment). Such a high ATV Cmin was found in only 1 study on healthy volunteers.2 In presence of PPIs, the median ATV Cmin was found to be strictly comparable to those observed in the previous studies, where a significant reduction should be expected. These results could be explained by too short a time between blood sample collection and drug intake. Assessing the time between ATV intake and blood collection precisely is fundamental in such a study. Only ATV plasma concentrations measured 24 ± 4 hours (Cmin) after the last intake should be taken into account in patients who have received a stable ATV regimen for at least 1 week before blood sampling. Treatments received by the patients included in this study should be detailed. The proportion of patients receiving ATV boosted with RTV may indeed highly influence the Cmin values observed. The results collected in such patients should therefore be distinguished from those collected in patients receiving ATV without RTV. In our prospective cohort of 184 patients, median Cmins measured at 24 ± 4 hours were 499 [26-2205] ng/mL and 99 [12-1159] ng/mL among the 141 patients treated with 300 mg of ATV plus 100 mg of RTV and the 43 patients receiving 400 mg of ATV alone, respectively (P < 0.0001). The combination of ATV with another protease inhibitor or nonnucleoside reverse transcriptase inhibitor may lead to significant drug interactions and should also be noted. During PPI treatment, the time during which the intragastric pH is above 4.0 increases with the acid-suppressive dose, and pH can vary widely during the day in a given individual. Doses of PPIs may affect ATV absorption differently and have to be precisely described. The time interval between ATV and antacid drug administration may also play a role. This is a possible confusion bias if patients did not state the time of their last drug intake accurately. In our cohort, we prospectively compared ATV Cmin in HIV-infected patients receiving ATZ plus RTV, with or without a PPI, to assess this specific drug interaction in clinical practice. Among the first 92 patients enrolled, 13 stated that they were taking a PPI. Among these 13 patients, 10 were using omeprazole (20 mg/d, except for 1 patient who was taking 40 mg/d) and 3 were using rabeprazole (30 mg/d). Median ATV trough concentrations were 551 ng/mL (range: 203-1976 ng/mL) in the patients receiving PPIs and 469 ng/mL (range: 65-1944 ng/mL) in the group without PPIs. Results showed that PPI treatment did not affect ATV Cmin values in our patients.3 A recent case report with pharmacokinetic study showed no interaction between boosted ATV and lansoprazole. Another study showed no clinical or immunovirologic failures in 14 patients treated with ATV and PPIs after a 6-month follow-up.4,5 Our findings are in keeping with these results. Our conclusion is therefore completely different from that of Khanlou and Farthing1 because we observed that PPIs seem to be compatible with boosted ATZ therapy in clinical practice. It is nonetheless recommended to monitor ATV drug concentrations in case of concomitant antacid treatment. Jean-Baptiste Guiard-Schmid, MD* Jean-Marie Poirier, MD† Philippe Bonnard, MD* Jean-Luc Meynard, MD† *Service des Maladies Infectieuses et Tropicales Hôpital Tenon †Service de Pharmacologie Faculté de Médecine St. Antoine and ‡Service des Maladies Infectieuses et Tropicales Hôpital St. Antoine Université Pierre et Marie Curie (Paris VI) Paris, France