质子泵抑制剂和结肠息肉相关性研究

目的探讨质子泵抑制剂(PPIs)和结肠息肉形成两者间的关系。方法将本院结肠息肉的患者设为病例组(154例),肠炎及未见异常者设为对照组(98例)。调查所有入组人员饮食及生活习惯、PPIs服用等情况,并测定血胃泌素水平。各因素先进行单因素分析,有统计学意义者进一步行多因素Logistic回归。结果单因素分析提示PPIs与结肠息肉的发生及生长部位有关(P0.05),结肠息肉组中服用PPIs的患者与未服用PPIs患者的胃泌素水平有显著差异[(115±19.4)ng/Lvs(66.4±8.4)ng/L],P0.001),但病例组与对照组两者间胃泌素水平无明显差异(P=0.191,P0.05),且进一步多因素Logistic分析提示PPIs变量无统计学意义(P=0.081,P0.05)。结论本研究无法证实与结肠息肉形成是否存在必然相关性,PPIs与结肠息肉之间是否存在关联尚待进一步研究。     

The potential anti‐xanthoma and anti‐atherosclerotic effects of proton pump inhibitors

Xanthoma and atherosclerosis are similar in having infiltrations of macrophages that have transformed into foam cells. The oxidized low‐density lipoprotein (LDL) promotes adhesion of monocytes to endothelial cells by inducing expression of adhesion molecules on vascular endothelial cells. Macrophages transform into foam cells by incorporating oxidized LDL using several kinds of scavenger receptors. Very recently, it has been shown that LDL oxidation occurs within lysosomes in macrophages in atherosclerotic lesions and the increase of intra‐lysosomal PH can prevent LDL oxidation. Given that proton pump inhibitors can decrease the intra‐lysosomal acidicty through inhibition of the lysosomal membrane H+/K+ATPase, theses agents could afford protection against atherosclerosis and xanthoma formation.     

A succinct review of the general and immunological pharmacologic effects of proton pump inhibitors

Proton pump inhibitors (PPI) are a group of anti-ulcer agents. PPI have selective anti-cancer effects via apoptosis of tumour, sensitization of cancer cell to chemotherapy and radiotherapy. Also PPI have anti-malarial and anti-leishmanial activity. Rising of endosomal (P)H inhibits the presentation of antigens that enter cell through endocytosis. PPI can affect transmigration of leucocytes from vessels to inflammatory sites and also can mitigate neutrophile adherence to endothelial cell. PPI increase the intralysosomal (P)H and decrease the expression of intracellular adhesion molecules. Therefore PPI can exert immunomodulation in immunological diseases through hampering antigen processing, antigen presentation, and leucocytes transmigration.     

The role of proton pump inhibitors in the treatment of heartburn during pregnancy

PURPOSE: To review the problem of heartburn in gravid women, discuss the present treatment options, and examine the use of proton pump inhibitors (PPIs) as one of the treatment options for moderate to severe heartburn. DATA SOURCES: Extensive review of worldwide scientific literature on the use and safety of PPIs during pregnancy and heartburn during pregnancy. CONCLUSIONS: Preliminary information indicates that use of PPIs during pregnancy is safe for both the fetus and the woman and that obstetrical practitioners are using them more frequently. Randomized controlled trials are needed to examine the efficacy of PPIs to treat heartburn during pregnancy, especially as they are compared to histamine(2) receptor antagonists. IMPLICATIONS FOR PRACTICE: Heartburn during pregnancy is at risk for being undertreated, given that delivery is the cure. As PPIs are more widely used by women, questions will arise regarding their use in the first trimester as well as throughout pregnancy. This article brings nurse practitioners up to date on the safety of PPIs through the literature review and suggests various treatment options that can be discussed with the patient.     

Recent advances in the treatment of GERD in the elderly: focus on proton pump inhibitors

The prevalence of gastroesophageal reflux disease (GERD) increases with age, and older people are more likely to develop severe disease. Studies of elderly patients with GERD indicate differences in presentation and diagnosis, compared with GERD in younger adults. Indeed, an older patient with GERD may present with atypical symptoms such as dysphagia, vomiting, weight loss, anaemia and anorexia, and less frequently with typical symptoms such as heartburn or acid regurgitation. These findings are attributed to pathophysiological changes in esophageal function that occur with age. Therefore, GERD in elderly patients is more likely to be poorly diagnosed or undiagnosed. Although few studies have concentrated specifically on elderly patients, the proton pump inhibitors (PPIs) have been shown to be more effective than histamine receptor antagonists for healing reflux esophagitis and for preventing its recurrence when they are given as maintenance therapy. In addition, the PPIs seem to be safe both in short- and in long-term therapy of elderly patients with GERD.     

Paradoxical relationship between proton pump inhibitors and COVID-19: A systematic review and meta-analysis

BACKGROUNDThe proton pump inhibitors (PPIs), used to reduce gastric acid secretion, represent one of the most widely used pharmaceutical classes in the world. Their consumption as a risk factor for the evolution of severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been investigated as well as the mortality of these patients. These risks also appear to be linked to the duration and the dosage. On the other hand, several studies have emerged with regard to the protective or therapeutic effects of these drugs. More and more evidence underlines the immunomodulatory and anti-fibrotic role of PPIs. In addition, their ability to alkalize the contents of endosomes and lysosomes serves as an obstacle to the entry of the virus into the host cells.AIMTo identify studies on the relationship between the intake of PPIs and coronavirus disease 2019 (COVID-19) in patients affected by SARS-CoV-2 infection, with the main objective of evaluating the outcomes related to severity and mortality.METHODSA literature review was performed in November 2020. The MEDLINE/PubMed, Cochrane Library, EMBASE and Google Scholar databases were searched for all relevant articles published in English on this topic. The search terms were identified by means of controlled vocabularies, such as the National Library of Medicine’s MESH (Medical Subject Headings) and keywords. The MESH terms and keywords used were as follows: “COVID-19”, “proton pump inhibitors”, ”PPIs”, “SARS-CoV-2”, “outcomes”, “severity” and “mortality”. The inclusion criteria regarding the studies considered in our analysis were: meta-analysis, case-control, hospital-based case-control, population-based case-control, retrospective studies, online survey, as well as cohort-studies, while articles not published as full reports, such as conference abstracts, case reports and editorials were excluded. We tried to summarize and pool all the data if available.RESULTSA total of 9 studies were found that described the use of PPIs, of which only 5 clearly reported the severity and mortality data in SARS-CoV-2 patients. Our pooled incidence analysis of severe events did not differ between patients with and without PPIs (odds ratio 1.65, 95% confidence interval: 0.62-4.35) (P = 0.314), or for mortality (odds ratio 1.77, 95% confidence interval: 0.62-5.03) (P = 0.286).CONCLUSIONDetailed and larger case studies are needed to accurately understand the role of PPIs in this viral infection.     

Nefopam hydrochloride compatibility and stability with selected proton pump inhibitors in bionolyte G5 injection for intravenous infusion

Background: The use of extemporaneously prepared admixtures of drugs must be supported by documentation of their chemical stability. Objective: To assess the physical compatibility and the chemical stability of nefopam hydrochloride, a centrally acting non‐opioid analgesic, when admixed with selected proton pump inhibitors (omeprazole, esomeprazole or pantoprazole), in bionolyte G5 injection for intravenous infusion. Method: Admixtures were assessed for periods of up to 72 h after storage at ambient temperature without protection from light and at +4 °C protected from light. A preparation was considered stable if the compounds of the mixture retained at least 90% of their original potency during the storage. Triplicate samples of nefopam and the selected proton pump inhibitors as well as the following mixtures (nefopam/omeprazole, nefopam/esomeprazole and nefopam/pantoprazole) were prepared in the concentrations required, in polypropylene bottles of bionolyte G5 injection. The physical compatibility was assessed by visual observation at each sampling interval. The chemical stability of the drugs was evaluated by high‐performance liquid chromatography and by measurement of pH values. Results: During refrigerated storage, nefopam as well as the selected proton pump inhibitors, when prepared separately in bionolyte G5 injection maintained chemical stability for up to 7 days. At ambient storage conditions, the protons pump inhibitors maintained chemical stability for 24 h, but thereafter their concentrations decreased significantly at day 1. Nefopam maintained chemical stability for up to 72 h at +25 °C. Nefopam/omeprazole and nefopam/esomeprazole mixtures in bionolyte were physically incompatible with the mixtures exhibiting a black colour. They underwent rapid and extensive loss, making the combination unacceptable within minutes of mixing. However, the nefopam/pantoprazole mixture was compatible over the study period, but with a reduced duration of the stability. Conclusion: Within the limits defined above, nefopam and the selected proton pump inhibitors may be prepared separately in advance in bionolyte G5 injection. The nefopam/pantoprazole mixture was stable for a short period, while the nefopam/omeprazole and the nefopam/esomeprazole mixtures were incompatible and unusable, immediately upon admixture.     

Sirolimus and everolimus intestinal absorption and interaction with calcineurin inhibitors: a differential effect between cyclosporine and tacrolimus

The mTOR inhibitors (ImTORs) sirolimus (SRL) and everolimus (EVR) have been increasingly used in renal transplantation as part of calcineurin inhibitor (CNI) sparing or avoidance regimens. Those drugs have low and variable oral bioavailability that is increased when combined with cyclosporine or tacrolimus (TAC). We investigated the mechanisms involved in ImTORs intestinal absorption in vitro and associated it with their drug-drug interactions with CNIs. The transport of ImTORs across Caco-2 cells was studied in the apical (A) to basolateral (B) and B to A directions, in the absence or presence of cyclosporine, TAC, and GF120918 (P-gp inhibitor). In Caco-2 cells, EVR and SRL displayed a polarized transport with 8.7- and 5.9-fold higher P(app,B→A) than P(app,A→B), respectively. P-gp inhibition by GF120918 resulted in a 70 and 41% decrease in EVR and SRL efflux, respectively. Cyclosporine and TAC led to a comparable and significant decrease in the efflux ratio of ImTORs, suggesting inhibition of a P-gp-mediated efflux transport. Cyclosporine also exhibited a specific increase of P(app,B→A), which may be attributed to the inhibition of other transporters and/or metabolizing enzymes. In conclusion, EVR and SRL are both subject to an apically directed efflux mediated by P-gp. TAC mainly inhibits this efflux mechanism, while the effect of cyclosporine appears to be more complex with mechanisms to be confirmed by further studies.     

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.     

Clinical implications of drug–drug interactions with P2Y12 receptor inhibitors

Polypharmacy in patients undergoing coronary artery stenting or in those presenting with an acute coronary syndrome is common. Nevertheless, the risk of drug–drug interactions in patients treated simultaneously with P2Y₁₂ receptor inhibitors is less well considered in routine clinical practice. Whereas the irreversible P2Y₁₂ receptor inhibitors clopidogrel and prasugrel are prodrugs requiring cytochrome P450 (CYP) enzymes for metabolic activation, such activation is not necessary for the direct‐acting reversible P2Y₁₂ receptor inhibitor ticagrelor. Several drugs frequently used in cardiology have been shown to interact with the metabolism of P2Y₁₂ receptor inhibitors in pharmacodynamic studies. Whereas several drug–drug interactions have been described for clopidogrel and ticagrelor, prasugrel seems to have a low potential for drug–drug interactions. The clinical implications of these interactions have raised concern. In general, concomitant administration of P2Y₁₂ receptor antagonists and strong inhibitors or inducers of CYP3A/CYP2C19 should be performed with caution in patients treated with clopidogrel/ticagrelor. Under most circumstances, clinicians have the option of prescribing alternative drugs with less risk of drug–drug interactions when used concomitantly with P2Y₁₂ receptor inhibitors.     

Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial

Summary. Background: Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity. Objectives: To characterize the pharmacokinetics of dabigatran in patients with non‐valvular atrial fibrillation (AF) from the Randomized Evaluation of Long‐term Anticoagulant Therapy (RE‐LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters. Patients and methods: A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non‐linear mixed‐effects modeling. Results: The pharmacokinetics of dabigatran were best described by a two‐compartment disposition model with first‐order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup ‘South Asian’ exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton‐pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15–30 mL min^?1 and patients with normal renal function receiving 150 mg twice daily. Conclusions: The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE‐LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment.     

Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta‐analysis

Summary. To investigate whether proton pump inhibitors (PPIs) negatively affect clinical outcome in patients treated with clopidogrel. Systematic review and meta‐analysis. Outcomes evaluated were combined major adverse cardiac events (MACE), myocardial infarction (MI), stent thrombosis, death and gastrointestinal bleeding. Studies included were randomized trials or post‐hoc analyzes of randomized trials and observational studies reporting adjusted effect estimates. Twenty five studies met the selection criteria and included 159 138 patients. Administration of PPIs together with clopidogrel corresponded to a 29% increased risk of combined major cardiovascular events [risk ratio (RR) = 1.29, 95% confidence intervals (CI) = 1.15–1.45] and a 31% increased risk of MI (RR = 1.31, 95%CI = 1.12–1.53). In contrast, PPI use did not negatively influence the mortality (RR = 1.04, 95%CI = 0.93–1.16), whereas the risk of developing a gastrointestinal bleed under PPI treatment decreased by 50% (RR = 0.50, 95% CI = 0.37–0.69). The presence of significant heterogeneity might indicate that the evidence is biased, confounded or inconsistent. The sensitivity analysis, however, yielded that the direction of the effect remained unchanged irrespective of the publication type, study quality, study size or risk of developing an event. Two studies indicate that PPIs have a negative effect irrespective of clopidogrel exposure. In conclusion, concomitant PPI use might be associated with an increased risk of cardiovascular events but does not influence the risk of death. Prospective randomized trials are required to investigate whether a cause‐and‐effect relationship truly exists and to explore whether different PPIs worsen clinical outcome in clopidogrel treated patients as the PPI‐clopidogrel drug–drug interaction does not seem to be a class effect.     

In vitro and in vivo evaluation of Adacolumn cytapheresis in healthy subjects

Adacolumn is a medical device for adsorptive cytapheresis. It has been developed for selective adsorption of granulocytes and monocytes from peripheral blood of patients with immune disorders, such as autoimmune diseases and chronic inflammatory diseases. A double blind sham-controlled crossover study design was used in order to evaluate in vivo biological responses of leukocytes as well as biocompatibility during and after Adacolumn cytapheresis in healthy volunteers. In addition, experiments were undertaken to further evaluate leukocyte reactions to Adacolumn carrier (G-1: cellulose diacetate) beads in vitro. Six healthy volunteers, 4 males and 2 females, with a mean age of 26.7 years were randomly assigned to one of the two treatment arms in a crossover fashion. Three subjects received a single Adacolumn treatment, followed by a single sham treatment at an interval of 7 days. The other three subjects received the two treatments in reverse order. All subjects were followed up 7 days after the last treatment. Additionally, in vitro investigations were carried out using blood from the healthy donors to examine the effect of G-1 beads on granulocyte functions. In vitro exposure of human peripheral blood to G-1 beads caused downregulation of L-selectin expression and upregulation of Mac-1 expression on granulocytes, leading to a marked reduction of adhesive capacity of granulocytes to endothelial cells. The exposure also led to decreased granulocyte chemotactic activity to IL-8. The number of granulocytes and monocytes clearly decreased during Adacolumn cytapheresis. Granulocytes showed marked phenotypic changes of L-selectin(Low) and Mac-1(Hi) after passing through Adacolumn in vivo. Expression of TNF-alpha and chemokine receptors was downregulated. In addition, TNF-alpha and IL-1beta producing capacity of peripheral blood leukocytes was decreased after Adacolumn cytapheresis and these changes lasted even one week after the cytapheresis. The level of complement fragments, C3a and C5a, increased, while bradykinin concentration did not change during Adacolumn cytapheresis. Exposure of human peripheral blood to G-1 beads, both in vitro and in vivo, caused a significant reduction of adhesive capacity and proinflammatory cytokine producing capacity of peripheral blood leukocytes. Such changes were not observed after sham apheresis. Despite complement activation, tolerability of Adacolum cytapheresis was not influenced. These findings may at least partly explain the beneficial effect of Adacolumn cytapheresis in the treatment of autoimmune diseases.