The Assessment of the Association of Proton Pump Inhibitor Usage with Chronic Kidney Disease Progression through a Process Mining Approach.

Previous studies have suggested an association between Proton Pump Inhibitors (PPIs) and the progression of chronic kidney disease (CKD). This study aims to assess the association between PPI use and CKD progression by analysing estimated glomerular filtration rate (eGFR) trajectories using a process mining approach. We conducted a retrospective cohort study from 1 January 2006 to 31 December 2011, utilising data from the Stockholm Creatinine Measurements (SCREAM). New users of PPIs and H2 blockers (H2Bs) with CKD (eGFR < 60) were identified using a new-user and active-comparator design. Process mining discovery is a technique that discovers patterns and sequences in events over time, making it suitable for studying longitudinal eGFR trajectories. We used this technique to construct eGFR trajectory models for both PPI and H2B users. Our analysis indicated that PPI users exhibited more complex and rapidly declining eGFR trajectories compared to H2B users, with a 75% increased risk (adjusted hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.49 to 2.06) of transitioning from moderate eGFR stage (G3) to more severe stages (G4 or G5). These findings suggest that PPI use is associated with an increased risk of CKD progression, demonstrating the utility of process mining for longitudinal analysis in epidemiology, leading to an improved understanding of disease progression.

Prophylactic Acid-suppression Medication to Prevent Anastomotic Strictures After Oesophageal Atresia Surgery: A Systematic Review and Meta-analysis.

BACKGROUND: Anastomotic stricture is a common postoperative complication of oesophageal atresia ± tracheoesophageal fistula (OA/TOF) repair. Acid gastro-oesophageal reflux disease (GORD) is considered to be a factor in stricture formation and acid suppression medication is recommended post-operatively in consensus guidance. We aimed to investigate whether patients who were treated prophylactically with acid suppression medication had a reduced incidence of strictures compared to those who did not receive it. METHODS: A systematic review of studies was performed, searching multiple databases without language or date restrictions. Multiple reviewers independently assessed study eligibility and literature quality. The primary outcome was anastomotic stricture formation, with secondary outcomes of GORD, anastomotic leak, and oesophagitis. Meta-analysis was performed using a random effects model, and the results were expressed as an odds ratio (OR) with 95% confidence intervals (CI). RESULTS: No randomised studies on the topic were identified. Twelve observational studies were included in the analysis with ten reporting the primary outcome. The quality assessment showed a high risk of bias in several papers, predominantly due to non-objective methods of assessment of oesophageal stricture and the non-prospective, non-randomised nature of the studies. Overall, 1395 patients were evaluated, of which 753 received acid suppression medication. Meta-analysis revealed a trend towards increased odds of anastomotic strictures in infants receiving prophylactic medication, but this was not statistically significant (OR 1.33; 95% CI 0.92, 1.92). No significant differences were found in secondary outcomes. CONCLUSIONS: This meta-analysis found no evidence of a statistically significant link between the prophylactic prescribing of acid suppression medication and the risk of developing anastomotic stricture after OA repair. The literature in this area is limited to observational studies and a randomised controlled trial is recommended to explore this question. LEVEL OF EVIDENCE: Level III.

A survey on the incidence of common musculoskeletal side effects among the patients taking long-term anti-ulcerant therapies in Bangladesh.

Background: Proton pump inhibitors (PPIs) and H2 blockers are commonly prescribed medications to treat ulcers in the stomach and the upper part of the small intestine and prescribed for some other common gastrointestinal complications such as gastroesophageal reflux disease, esophagitis, irritable bowel syndrome, and dyspepsia. Previous studies claimed that, apart from other side effects, these anti-ulcerant therapies significantly altered bone mineral density by interfering with intestinal reabsorption of minerals and vitamin B12, and the most widely prescribed PPIs were significantly associated with increased risks of hip and spine fractures. However, the potential skeletal side effects of these antiulcerants are unknown in Bangladesh. Methods: To examine safety concerns of anti-ulcer therapies and their impact on musculoskeletal health among patients in Bangladesh, the present work surveyed 200 patients in five different hospitals from December 2019 to February 2020. Results: The current study revealed that most respondents (95 %) received PPIs for gastrointestinal indications while the rest were taking H2 receptor antagonists for their gastric ailments. Most patients taking PPIs alone (> 3 years; 95 % of respondents) claimed some unusual musculoskeletal side effects, such as weakness, flank pain, spasm of hands and feet, muscle aches, numbness, and tremor. About 61 % of patients taking PPIs experienced low back pain whereas the respondents with neck pain and knee joint pain were 10 % and 7 %, respectively. However, few osteopenia and osteoporotic incidences have been also recorded. Although further studies are required to confirm the impact of these antiulcerants on the bone, these patient responses suggest that these musculoskeletal side effects might have some links with altered bone metabolism. Conclusions: It is possible that anti-ulcerant therapies may worsen the bone metabolism of patients suffering from osteoporosis or other bone disorders, and awareness and precautions should be raised among the patients and clinicians for the careful administration of PPIs to patients suffering from bone disorders.

Is acid suppression associated with the increased length of stay in diabetic ketoacidosis patients? A nationwide analysis.

BACKGROUND: Diabetic ketoacidosis (DKA) patients present with low serum bicarbonate ( HCO3-${\rm{HCO}}_{3}^{-} $ ), and an increase in its level to ≥15 mEq/L is considered one of the criteria for DKA resolution. Both proton pump inhibitors and histamine-2 receptor antagonists inhibit downstream functioning of H+ /K+ ATPase in the gastric parietal cells, which results in the decreased secretion of HCO3-${\rm{HCO}}_{3}^{-} $ into the bloodstream. OBJECTIVES: We aimed to introduce the hypothesis that DKA patients on acid-suppressive medications may have a delayed rise in serum HCO3-${\rm{HCO}}_{3}^{-} $ to >15 mEq/L that may cause increased hospital length of stay (LOS) and sought to compare the outcomes of such patients. For the sake of simplicity, conditions requiring acid suppression are grouped under the term peptic ulcer disease (PUD) in this study. METHODS: This is a retrospective study using Nationwide Inpatient Sample employing International Classification of Diseases (ICD-10) codes for adult patients with a primary diagnosis of DKA. Analyses were performed using STATA, proportions were compared using Fisher exact test, and continuous variables using Student's t-test. Confounding variables were adjusted using propensity matching, multivariate logistic, and linear regression analyses. RESULTS: DKA patients with PUD had higher adjusted LOS, intensive care unit admission, and total hospital costs. Mortality and morbidity indicators were similar in both groups. The variables found to be independent predictors of increased LOS were malnutrition, Clostridium difficile infection, pneumonia, Glasgow Coma Scale score of 3-8, and higher Charlson comorbidity score. CONCLUSION: We found that Clostridium difficile and pneumonia predicted longer LOS in DKA patients with concomitant PUD, hinting at the possible role of acid suppression in prolonging the LOS in such patients. However, further studies are needed to examine the effect of lesser HCO3-${\rm{HCO}}_{3}^{-} $ generation on LOS.

Risk and protective factors of acute kidney injury in decompensated cirrhotic patients with ascites on tolvaptan.

BACKGROUND AND AIM: Acute kidney injury (AKI) is a life-threatening complication of liver cirrhosis. Here, we evaluated the risk factors and characteristics of AKI in cirrhosis. PATIENTS/METHODS: This was a single-center retrospective study. A total of 199 Japanese patients with decompensated liver cirrhosis (104 men, median age 61 years) were enrolled and received tolvaptan orally. Survival rates and new onset of AKI were monitored, and risk factors were evaluated. RESULTS: Forty-six patients (23.1%) suffered an AKI complication and exhibited significantly poorer survival (P < 0.01). The rates of hepatic encephalopathy (P < 0.01) and chronic kidney disease (CKD; P = 0.02) were significantly increased in patients with AKI. The rate of proton pump inhibitor (PPI)/H2 blocker treatment (P = 0.04) was significantly lower, whereas that of ascites drainage was significantly higher in the AKI cases (P < 0.01). The AKI risk was significantly increased in patients with hepatic encephalopathy (HR 4.18, 95% CI 1.618-10.771). In contrast, the incidence of AKI was significantly lower in patients with a higher serum albumin level (HR 0.36, 95% CI 0.142-0.914, P = 0.03). Treatment with PPI/H2 blockers (HR 0.30, 95% CI 0.126-0.711, P < 0.01) or kanamycin/rifaximin (HR 0.26, 95% CI 0.075-0.929, P = 0.04) was significantly associated with a reduced risk of AKI development. CONCLUSIONS: AKI incidence was increased in patients with decreased liver function and was associated with poor survival. PPI/H2 blocker or kanamycin/rifaximin treatment may reduce the risk of AKI.

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis.

Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. In vivo drug dissolution depends on the GI tract's physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. et al. Mol. Pharm.2018 and Bermejo, et al. M. Mol. Pharm.2018). The dissolution of an ionizable drug may benefit from manipulating in vivo variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. A successful example is the use of such agents for dissolution enhancement of BCS class IIb (high-permeability, low-solubility, and weak base) drugs under high gastric pH due to the disease conditions or by co-administration of acid-reducing agents (i.e., proton pump inhibitors, H2-antagonists, and antacids). This study provides a rational approach for selecting pH modifiers to improve monobasic and dibasic drug compounds' dissolution rate and extent under high-gastric pH dissolution conditions, since the oral absorption of BCS class II drugs can be limited by either the solubility or the dissolution rate depending on the initial dose number. Betaine chloride, fumaric acid, and tartaric acid are examples of promising pH modifiers that can be included in oral dosage forms to enhance the rate and extent of monobasic and dibasic drug formulations. However, selection of a suitable pH modifier is dependent on the drug properties (e.g., solubility and pKa) and its interplay with the pH modifier pKa or pKas. As an example of this complex interaction, for basic drugs with high pKa and intrinsic solubility values and large doses, a polyprotic pH modifier can be expected to outperform a monoacid pH modifier. We have developed a hierarchical mass transport model to predict drug dissolution of formulations under varying pH conditions including high gastric pH. This model considers the effect of physical and chemical properties of the drug and pH modifiers such as pKa, solubility, and particle size distribution. This model also considers the impact of physiological conditions such as stomach emptying rate, stomach acid and buffer secretion, residence time in the GI tract, and aqueous luminal volume on drug dissolution. The predictions from this model are directly applicable to in vitro multi-compartment dissolution vessels and are validated by in vitro experiments in the gastrointestinal simulator. This model's predictions can serve as a potential data source to predict plasma concentrations for formulations containing pH modifiers administered under the high-gastric pH conditions. This analysis provides an improved formulation design procedure using pH modifiers by minimizing the experimental iterations under both in vitro and in vivo conditions.

Factors affecting high-grade hepatotoxicity of tyrosine kinase inhibitors in cancer patients: a multi-center observational study.

PURPOSE: Although several studies have examined tyrosine kinase inhibitor (TKI)-induced hepatotoxicity, the majority of patients in those studies displayed low-grade (grade I-II) hepatotoxicity. The purpose of this study was to investigate factors affecting high-grade (grade III-IV) hepatotoxicity of TKIs. METHODS: This multi-center, retrospective study used individual patient data from five studies that examined factors affecting hepatotoxicity by TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib). Odds ratio (OR) and adjusted OR (AOR) were estimated from univariate and multivariate analyses, respectively. RESULTS: Data from 1279 patients treated with TKIs were analyzed. The rate of patients who experienced high-grade hepatotoxicity after TKI administration was 5.5%. In multivariable analysis, H2 blockers and CYP3A4 inducers increased high-grade hepatotoxicity 2.2- (95% CI 1.255-3.944) and 3.3-fold (95% CI 1.260-8.698), respectively. Patients with liver metastasis revealed a 3.4-fold (95% CI 1.561-7.466) higher risk of high-grade hepatotoxicity. Among underlying malignancies, pancreatic cancer and other cancers including acute lymphoblastic leukemia increased the risk of high-grade hepatotoxicity by 2.6- and 24.3-fold, respectively, whereas breast cancer decreased the risk (AOR 0.3, 95% CI 0.106-0.852), compared to non-small cell lung cancer. In patients who administrated TKIs which form reactive metabolites, use of CYP3A4 inducers and liver metastasis increased incidence of high-grade hepatotoxicity by 3.0- and 2.3-fold, respectively. In patients with EGFR mutation, exon 19 deletion and use of proton pump inhibitors were risk factors for high-grade hepatotoxicity in addition to liver metastasis and use of H2 blockers. CONCLUSION: The use of H2 blockers, presence of liver metastasis, and CYP3A4 inducers were associated with high-grade hepatotoxicity of TKIs. In subgroup analyses, presence of exon 19 deletion, and/or proton pump inhibitors, was additional risk factors for high-grade hepatotoxicity in special patients and use of specific TKIs. Close liver function monitoring is recommended, especially in patients with liver metastasis or using H2 blockers or CYP3A4 inducers.

Proton Pump Inhibitors and the Kidney: Implications of Current Evidence for Clinical Practice and When and How to Deprescribe.

Proton pump inhibitors (PPIs), long thought to be safe, are associated with a number of nonkidney adverse health outcomes and several untoward kidney outcomes, including hypomagnesemia, acute kidney injury, acute interstitial nephritis, incident chronic kidney disease, kidney disease progression, kidney failure, and increased risk for all-cause mortality and mortality due to chronic kidney disease. PPIs are abundantly prescribed, rarely deprescribed, and frequently purchased over the counter. They are frequently used without medical indication, and when medically indicated, they are often used for much longer than needed. In this In Practice review, we summarize evidence linking PPI use with adverse events in general and adverse kidney outcomes in particular. We review the literature on the association of PPI use and risk for hypomagnesemia, acute kidney injury, acute interstitial nephritis, incident chronic kidney disease, kidney disease progression, end-stage kidney disease, and death. We provide an assessment of how this evidence should inform clinical practice. We review the impact of this evidence on patients' perception of risk, synthesize PPI deprescription literature, and provide our recommendations on how to approach PPI use and deprescription.

Exposure to Gastric Acid Inhibitors Increases the Risk of Infection in Preterm Very Low Birth Weight Infants but Concomitant Administration of Lactoferrin Counteracts This Effect.

OBJECTIVE: To investigate whether exposure to inhibitors of gastric acidity, such as H2 blockers or proton pump inhibitors, can independently increase the risk of infections in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit. STUDY DESIGN: This is a secondary analysis of prospectively collected data from a multicenter, randomized controlled trial of bovine lactoferrin (BLF) supplementation (with or without the probiotic Lactobacillus rhamnosus GG) vs placebo in prevention of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants. Inhibitors of gastric acidity were used at the recommended dosages/schedules based on the clinical judgment of attending physicians. The distribution of days of inhibitors of gastric acidity exposure between infants with and without LOS/NEC was assessed. The mutually adjusted effects of birth weight, gestational age, duration of inhibitors of gastric acidity treatment, and exposure to BLF were controlled through multivariable logistic regression. Interaction between inhibitors of gastric acidity and BLF was tested; the effects of any day of inhibitors of gastric acidity exposure were then computed for BLF-treated vs -untreated infants. RESULTS: Two hundred thirty-five of 743 infants underwent treatment with inhibitors of gastric acidity, and 86 LOS episodes occurred. After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS (OR, 1.03; 95% CI, 1.008-1.067; P = .01); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS. Risk was significant for Gram-negative (P < .001) and fungal (P = .001) pathogens, but not for Gram-positive pathogens (P = .97). On the test for interaction, 1 additional day of exposure to inhibitors of gastric acidity conferred an additional 7.7% risk for LOS (P = .003) in BLF-untreated infants, compared with 1.2% (P = .58) in BLF-treated infants. CONCLUSION: Exposure to inhibitors of gastric acidity is significantly associated with the occurrence of LOS in preterm VLBW infants. Concomitant administration of BLF counteracts this selective disadvantage. TRIAL REGISTRATION: isrctn.org: ISRCTN53107700.

Suppression of osteogenic differentiation in mesenchymal stem cells from patients with ossification of the posterior longitudinal ligament by a histamine-2-receptor antagonist.

Mesenchymal stem cells (MSCs) in ossification of the posterior longitudinal ligament (OPLL) patients have a high propensity toward osteogenesis. Histamine receptor H2 (H2R) antagonists (H2 blockers) like famotidine decrease ossification in patients, by an unclear mechanism. To confirm that MSCs express H2R and to clarify how H2 blockers suppress osteogenic differentiation, we used spinal-ligament MSCs from patients with OPLL or with cervical spondylotic myelopathy (CSM) (control). The MSCs were treated with 10, 30, or 100nM famotidine for 7 or 21 days. Flow cytometry revealed that cells from both groups expressed MSC surface markers CD44, CD90, and CD105 (> 97.5%) but not CD34 or CD45 (< 2.5%). Immunoblotting showed that the MSCs from both groups expressed H2R, but those from OPLL patients expressed it at higher levels. Real-time qPCR indicated the H2R expression was significantly suppressed by 30nM famotidine for 7 days or by 30 or 100nM for 21 days. However, histidine decarboxylase, a key enzyme in histamine production, did not change significantly after famotidine addition. Famotidine treatment at 100nM for 21 days significantly suppressed mRNA expression of the osteogenic markers osteocalcin (OCN), bone morphogenetic protein 2 (BMP2), and runt-related transcription factor 2 (RUNX2) only in OPLL-derived MSCs. Immunoblots showed that famotidine suppressed BMP2 and OCN in the OPLL group and H2R and RUNX2 in both groups. These results suggest famotidine inhibits osteogenic differentiation in OPLL-derived MSCs by acting as an H2R antagonist, but also by decreasing H2R expression, and support the clinical use of famotidine to treat OPLL.

Safety of histamine-2 receptor blockers in hospitalized VLBW infants.

BACKGROUND: Histamine-2 receptor (H2) blockers are often used in very low birth weight infants despite lack of population specific efficacy and safety data. AIMS: We sought to describe safety and temporal trends in histamine-2 receptor (H2) blocker use in hospitalized very low birth weight (VLBW) infants. STUDY DESIGN: We conducted a retrospective cohort study using a clinical database populated by an electronic health record shared by 348 neonatal intensive care units in the United States. SUBJECTS: We included all VLBW infants without major congenital anomalies. OUTCOME MEASURES: We used multivariable logistic regression with generalizing estimating equations to evaluate the association between days of H2 blocker exposure and risk of: 1) death or necrotizing enterocolitis (NEC); 2) death or sepsis; and 3) death, NEC, or sepsis. RESULTS: Of 127,707 infants, 20,288 (16%) were exposed to H2 blockers for a total of 6,422,352days. Median gestational age for infants exposed to H2 blockers was 27weeks (25th 75th percentile 26, 29). H2 blocker use decreased from 18% of infants in 1997 to 8% in 2012 (p<0.001). On multivariable analysis, infants were at increased risk of the combined outcome of death, NEC, or sepsis on days exposed to H2 blockers (odds ratio=1.14) (95% confidence interval 1.08, 1.19). CONCLUSIONS: H2 blocker use is associated with increased risk of the combined outcome of death, NEC, or sepsis in hospitalized VLBW infants.

Prenatal exposure to H2 blockers and to proton pump inhibitors and asthma development in offspring.

Fetal exposure to H2 blockers (H2 Bs) or proton pump inhibitors (PPIs) has been reported to be associated with asthma in children. We evaluated the risk of asthma in offspring following prenatal H2 Bs. We enrolled 91 428 children and their mothers who resided in southern Israel during 1998-2011. The computerized medications database was linked with records from the district hospital. Of the eligible children, 11 227 developed asthma, and overall 5.5% had been exposed to H2 Bs or PPIs prenatally. The risk of developing asthma was slightly higher in the group exposed to H2 Bs or PPIs (RR, 1.09; P = .023). At greater risk were children whose mothers purchased these medications more than 3 times (RR, 1.22; P = .038) or exposed to >20 defined daily doses or prenatally exposed to lansoprazole. The statistical association was significant and depended on magnitude of exposure and specific medication, but the absolute risk was low. The association between maternal consumption of H2 Bs or PPIs and asthma and childhood remained statistically significant 2 years after delivery, raising the possibility of confounding by the indication phenomenon. In view of the findings, a causal relationship could not be ascertained, and an unidentified etiological factor could be operative.

Role of ranitidine in negative symptoms of schizophrenia--an open label study.

In this open label study, 75 patients with a diagnosis of schizophrenia were randomized to three groups of 25 each, receiving 150mg/day ranitidine, 300mg/day ranitidine and receiving only olanzapine. They were rated on PANSS at baseline, 4 and 8 weeks. There was a significant reduction in the scores of negative scale in patients receiving 300mg/day ranitidine in comparison to patients not receiving ranitidine at the end of 4 weeks but was not seen again when assessed at the end of 8 weeks. Though effective in reducing the negative symptoms, the effect was not sustained due to the tolerance to the actions of ranitidine.

Comparison and analysis of delirium induced by histamine h(2) receptor antagonists and proton pump inhibitors in cancer patients.

OBJECTIVE: H(2) blockers have been reported to be responsible for drug-induced delirium. We compared the incidence of delirium between two groups of patients who were treated with H(2) blockers (H(2) group) or proton pump inhibitors (PPI group) for anastomotic ulcer prevention following surgical treatment of esophageal cancer. METHOD: The incidence and severity of delirium were retrospectively compared in patients of the H(2) group (30 cases; age, 65.2 ± 8.1 years) and the PPI group (30 cases; 65.2 ± 6.5 years). The diagnosis of delirium was based on the Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision. Delirium severity was rated on the Delirium Rating Scale (DRS). RESULTS: The incidence of delirium was significantly lower in the PPI group than in the H(2) group (p = 0.047). In the 11 patients from the H(2) group who developed delirium, discontinuation of H(2) blockers resulted in a significant reduction in the DRS score (p = 0.009). In three patients for whom H(2) blockers were discontinued, DRS scores decreased by 50% or more three days after discontinuation compared to the prediscontinuation score. CONCLUSIONS: These results suggested that switching antiulcer drugs from H(2) blockers to PPIs reduced delirium and thus provided an appropriate coping method for drug-induced delirium from antiulcer drugs.

Delayed-release oral suspension of omeprazole for the treatment of erosive esophagitis and gastroesophageal reflux disease in pediatric patients: a review.

Omeprazole is a proton-pump inhibitor indicated for gastroesophageal reflux disease and erosive esophagitis treatment in children. The aim of this review was to evaluate the efficacy of delayed-release oral suspension of omeprazole in childhood esophagitis, in terms of symptom relief, reduction in reflux index and/or intragastric acidity, and endoscopic and/or histological healing. We systematically searched PubMed, Cochrane and EMBASE (1990 to 2009) and identified 59 potentially relevant articles, but only 12 articles were suitable to be included in our analysis. All the studies evaluated symptom relief and reported a median relief rate of 80.4% (range 35%-100%). Five studies reported a significant reduction of the esophageal reflux index within normal limits (<7%) in all children, and 4 studies a significant reduction of intra-gastric acidity. The endoscopic healing rate, reported by 9 studies, was 84% after 8-week treatment and 95% after 12-week treatment, the latter being significantly higher than the histological healing rate (49%). In conclusion, omeprazole given at a dose ranging from 0.3 to 3.5 mg/kg once daily (median 1 mg/kg once daily) for at least 12 weeks is highly effective in childhood esophagitis.