Development of an evaluation indicator system for the rational use of proton pump inhibitors in pediatric intensive care units: An application of Delphi method.

ABSTRACT: Proton pump inhibitors are frequently used to prevent gastrointestinal bleeding in critically ill patients. But there is little information in the instructions about the usages for children. It is important to monitor the appropriate use of proton pump inhibitors, especially in pediatrics. Therefore, we developed an evaluation indicator system for the rational use of proton pump inhibitors in pediatric intensive care units.First, a systematic review was conducted to developed the initial indicators. Then 2 rounds of Delphi surveys were conducted to collecting opinions from a panel of independent experts, and the indicator system was modified to form the final indicators according to the opinions. Finally, the analytic hierarchy procedure was used to determine the weight of each indicator.A total of 6 guidelines and 2 studies met the inclusion and exclusion criteria. Based on literature and discussion among experts, an initial indicator system including 4 first-rank indicators and 12 second-rank indicators was formed. After 2 rounds of Delphi surveys, 2 indicators were added, 5 indicators were deleted, and 1 indicator was revised, so the final indicator system contained a total of 13 indicators including 3 first-rank indicators (drug selection, drug usage and dosage, duration of drug therapy) and 10 second-rank indicators (the proportion of PPIs used in children, children under 1 year old, children who is using glucocorticoids, children with nonsteroidal anti-inflammatory drugs, children with gastroesophageal reflux disease, children with sepsis, children with ventilators in PICU; the strength of PPIs' use, the proportion of omeprazole in children using PPIs during the same period; the average days of PPIs used in children). By analyzing scores, all coefficients met the standard, indicating the indicators were scientific and credible.Through a two-round Delphi survey, 3 first-rank indicators and ten second-rank indicators were developed, which will help drug administrative departments to promote the rational use of PPIs for children in PICUs. What is more, our study can constitute a methodological reference for the development of other indicator systems.

Proton Pump Inhibitor Use After Hiatal Hernia Repair: Inhibitor of Recurrent Symptoms and Potential Revisional Surgery.

BACKGROUND: Hiatal hernia recurrence after hiatal hernia repair (HHR) is often underdiagnosed and underreported but may present with recurrent gastroesophageal reflux disease (GERD) symptoms. Because of their availability, proton pump inhibitor (PPI) use is common and may mask patients who would benefit from revisional surgery, which has been shown to improve symptoms and quality of life. METHODS: A retrospective analysis was performed to evaluate recurrence patterns of patients who underwent HHR, specifically for the indication of GERD, from 2007 to 2015 at a single Veterans Administration Medical Center. Clinicopathologic parameters were reviewed for association with hiatal hernia recurrence, including postoperative PPI use. RESULTS: Sixty-four patients were identified with a median follow-up time of 57.8 mo. Thirty-eight patients developed an anatomic recurrence, which did not demonstrate any associated factors on univariate analysis. Seventy percent of patients remained or were restarted on PPI after their initial surgery. For patients with a documented recurrence, the median time to start a PPI was 224 d, but the time to identify recurrence on imaging or endoscopy was 712.5 d. Eleven (39.3%) patients had a reintervention for anatomic recurrence, of which all had developed recurrent symptoms of GERD. CONCLUSIONS: Most patients who developed recurrent hiatal hernia were restarted on PPI without workup for their symptoms. The time of initiation of PPI was much earlier than the time of identification of a recurrent hiatal hernia. The use of PPIs in patients whom have undergone HHR may delay proper workup to identify recurrent hiatal hernia amenable to surgical repair and should be reserved until patients develop recurrent symptoms and have at least begun a diagnostic workup to rule out an anatomic cause for the recurrent symptoms.

Vonoprazan vs proton pump inhibitors in treating post-endoscopic submucosal dissection ulcers and preventing bleeding: A meta-analysis of randomized controlled trials and observational studies.

BACKGROUND: Vonoprazan is a potassium-competitive acid blocker (P-CAB) that is frequently used in Japan for Helicobacter pylori (H. pylori) eradication, treatment of gastroesophageal reflux disease, and treatment of post endoscopic submucosal dissection (ESD) complications. We sought to determine if vonoprazan was superior to proton pump inhibitors (PPIs) for treating ESD-induced ulcers (as assessed by ulcer healing and shrinkage ratios) and preventing delayed bleeding over various treatment durations (2, 4, and 8 weeks). METHODS: We collected randomized controlled trials (RCTs) and observational studies that discussed the effectiveness of vonoprazan and PPIs on ESD-induced ulcers and bleeding from PubMed, Cochrane Library, ClinicalTrials.gov, and Google Scholar. Studies were selected according to pre-established eligibility criteria and data were extracted separately by 2 researchers with double-check. We used the Cochrane risk of bias tool to assess RCTs and the Newcastle-Ottawa Quality Assessment Scale to assess observational studies. Meta-analyses, based on the random-effects model, were conducted to compare differences in ulcer shrinkage ratios (%) and odds ratios (ORs) for ulcer healing and delayed bleeding. Publication bias was evaluated using funnel plots and Egger regression test. Heterogeneity was assessed using I statistics. A sensitivity analysis was conducted to check the robustness of results. The evidential quality of the findings was assessed using the GRADE profiler. RESULTS: Thirteen studies were included in this meta-analysis. The OR effect sizes of vonoprazan relative to PPIs for ulcer healing were 1.33 (P = .13) with a 95% CI (0.33-3.21) at 4 weeks and 1.48 (P = .09) with a 95% CI (0.81-5.20) at 8 weeks. The overall effect size for the shrinkage ratio was 12.24% (P = .16) with a 95% CI (-4.96-29.44) at 2 weeks. The effect size of its subgroup of H. pylori-positive patients was 19.51% (P < .001) with a 95% CI (11.91-27.12). The overall OR for the occurrence of delayed bleeding was 0.66 (P = .26) with a 95% CI (0.32-1.35). After excluding combination drug studies, the overall ORs between vonoprazan and PPIs on ulcer healing and delayed bleeding were 1.44 and 0.76, respectively. CONCLUSION: During the first 2 weeks of treatment, vonoprazan was more effective than PPIs for treating H. pylori-positive patients with ESD-induced gastric ulcers.

Using a Systems Engineering Framework to Evaluate Proton Pump Inhibitor Prescribing in Critically Ill Patients.

Proton pump inhibitors (PPIs) are a risk factor for hospital-acquired Clostridium difficile infection (CDI). Much PPI use is inappropriate, and interventions to reduce PPI use, such as for stress ulcer prophylaxis in all critically ill patients, are essential to reduce CDI rates. This mixed-methods study in a combined medical-surgical intensive care unit at a tertiary academic medical center used a human factors engineering approach to understand barriers and facilitators to optimizing PPI prescribing in these patients. We performed chart review of patients for whom PPIs were prescribed to evaluate prescribing practices. Semistructured provider interviews were conducted to determine barriers and facilitators to reducing unnecessary PPI use. Emergent themes from provider interviews were classified according to the Systems Engineering Initiative for Patient Safety model. In our intensive care unit, 25% of PPI days were not clinically indicated. Barriers to optimizing PPI prescribing included inadequate provider education, lack of institutional guidelines for stress ulcer prophylaxis, and strong institutional culture favoring PPI use. Potential facilitators included increased pharmacy oversight, provider education, and embedded decision support in the electronic medical record. Interventions addressing barriers noted by front line providers are needed to reduce unnecessary PPI use, and future studies should assess the impact of such interventions on CDI rates.

Qualimetric analysis of proton pump inhibitors in Ukraine.

OBJECTIVE: Introduction: On the pharmaceutical market of Ukraine, there are six international non-proprietary names of proton pump inhibitors (PPIs) - Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Esomeprazole, Dexlansoprazole, which differ in a number of pharmacokinetic and pharmacodynamic parameters, safety profile, range of dosage forms and their cost. The aim: To investigate the competitiveness of proton pump inhibitors registered in Ukraine by comparing the parameters of their quality properties using the method of qualimetric analysis. PATIENTS AND METHODS: Materials and methods: Qualimetric analysis is based on the deductive-axiomatic approach, which allows quantifying the qualitative properties of drugs and determining the degree of competitiveness of each of them in the pharmaceutical market of Ukraine. The qualitative properties of PPIs in terms of consumer are efficacy, safety, convenience of use and cost. The subject of the study was 133 trademarks of PPIs registered in Ukraine. RESULTS: Results: The highest qualimetric values were obtained by omeprazole (Kk = 0.73) and its S-isomer esomeprazole (Kk = 0.66). Pantoprazole was inferior to them to a certain extent (Kk = 0.64). Lansoprazole (Kk = 0.53), rabeprazole (Kk = 0.50) and dexlansoprazole (Kk = 0.44) had the lowest values of the quality indices. CONCLUSION: Conclusions: According to the results of the study of the PPIs' competitiveness for parameters characterizing efficacy, safety, convenience of use and cost, assessed by qualimetric analysis, it has been established that the most completely and qualitatively satisfying consumer's needs are omeprazole and its S-isomer, esomeprazole.

Safe use of proton pump inhibitors in patients with cirrhosis.

AIMS: Proton pump inhibitors (PPIs) belong to the most frequently used drugs, also in patients with cirrhosis. PPIs are extensively metabolized by the liver, but practice guidance on prescribing in cirrhosis is lacking. We aim to develop practical guidance on the safe use of PPIs in patients with cirrhosis. METHODS: A systematic literature search identified studies on the safety (i.e. adverse events) and pharmacokinetics of PPIs in cirrhotic patients. This evidence and data from the product information was reviewed by an expert panel who classified drugs as safe; no additional risks known; additional risks known; unsafe; or unknown. Guidance was aimed at the oral use of PPIs and categorized by the severity of cirrhosis, using the Child-Turcotte-Pugh (CTP) classification. RESULTS: A total of 69 studies were included. Esomeprazole, omeprazole and rabeprazole were classified as having 'no additional risks known'. A reduction in maximum dose of omeprazole and rabeprazole is recommended for CTP A and B patients. For patients with CTP C cirrhosis, the only PPI advised is esomeprazole at a maximum dosage of 20 mg per day. Pantoprazole and lansoprazole were classified as unsafe because of 4- to 8-fold increased exposure. The use of PPIs in cirrhotic patients has been associated with the development of infections and hepatic encephalopathy and should be carefully considered. CONCLUSIONS: We suggest using esomeprazole, omeprazole or rabeprazole in patients with CTP A or B cirrhosis and only esomeprazole in patients with CTP C. Pharmacokinetic changes are also important to consider when prescribing PPIs to vulnerable, cirrhotic patients.

In vitro comparative quality evaluation of different brands of esomeprazole tablets available in selected community pharmacies in Dhaka, Bangladesh.

OBJECTIVE: Esomeprazole is the S-isomer of omeprazole, used to treat gastro esophageal reflux disease. It is one of the widely manufactured and marketed drugs by many pharmaceutical companies in Bangladesh. The aim of the study is to compare the different physical parameters including hardness, friability, diameter, thickness, disintegration time, dissolution test and assay for quality evaluation and characterization of tablets of five different brands of Bangladeshi pharmaceutical company. The specified compendial method was followed for their evaluation test. RESULTS: Esomeprazole Mg tablets are enteric coated tablet, there was no disintegration for any brand occurred in 0.1 N HCl after 2 h and all tablets were disintegrated within 19.93 ± 0.04 to 29.05 ± 0.14 min in phosphate buffer (pH 6.8). Weight variation and Hardness were between 1.01 ± 0.29 to 2.01 ± 0.14% and 5.32 ± 0.06 to 7.12 ± 0.12 kgf respectively. Medicine released after 2 h in 0.1 N HCl were varied from 2.55 ± 0.24 to 4.47 ± 0.31% which was less than 10% and in phosphate buffer (pH 6.8) the percentage of medicine release were between 100.9 and 105.9% after 60 min. In case of assay the results of all brands were between 95.28 ± 0.08 and 99.40 ± 0.11%. The obtained results of all parameters were complied with pharmacopoeial limit. So from this study we can conclude that products of esomeprazole available in Bangladeshi pharmaceutical market meet the quality parameter to satisfy therapeutic efficacy.

Development of a stability- indicating HPLC method for simultaneous determination of ten related substances in vonoprazan fumarate drug substance.

Vonoprazan fumarate is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. In the present study, a simple, fast, and economic reversed-phase liquid chromatography (LC) method was developed for the analysis of ten related substances (raw materials, by-products and degradants) in vonoprazan fumarate. The optimized separation was performed on a Phenomenex Kinetex EVO C18 (250mm×4.6mm, 5.0µm) column. The mobile phase consisted of (A) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - methanol - acetonitrile (72:25:3, v/v/v) and (B) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - acetonitrile (30:70, v/v). Detection of the analytes was conducted at 230nm using a UV detector. The stability-indicating ability of this method was demonstrated by carrying out forced degradation studies. Vonoprazan underwent significant degradation when subjected to alkaline and oxidative stress conditions, while the drug proved to be stable to acidic, thermal and photolytic degradation. The degradants did not interfere with the detection of vonoprazan fumarate and its impurities. The performance of this method was validated in accordance to the regulatory guidelines recommended by the International Conference on Harmonisation (ICH) and this validation included specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and robustness. The method proposed in this paper could be applied for process development as well as quality assurance of vonoprazan in bulk drug, since no monograph is available in official compendia.

Helicobacter pylori therapy: a paradigm shift.

Helicobacter pylori (H. Pylori) is a leading cause of gastroduodenal disease, including gastric cancer. H. pylori eradication therapies and their efficacy are summarized. A number of current treatment regimens will reliably yield >90% or 95% cure rates with susceptible strains. None has proven to be superior. We show how to predict the efficacy of a regimen in any population provided one knows the prevalence of antibiotic resistance. As with other infectious diseases, therapy should always be susceptibility-based. Susceptibility testing should be demanded. We provide recommendations for empiric therapies when that is the only option and describe how to distinguish studies providing misinformation from those providing reliable and interpretable data. When treated as an infectious disease, high H. pylori cure rates are relatively simple to reliably achieve.

The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults.

BACKGROUND & AIMS: Helicobacter pylori infection is increasingly difficult to treat. The purpose of these consensus statements is to provide a review of the literature and specific, updated recommendations for eradication therapy in adults. METHODS: A systematic literature search identified studies on H pylori treatment. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an online platform, finalized, and voted on by an international working group of specialists chosen by the Canadian Association of Gastroenterology. RESULTS: Because of increasing failure of therapy, the consensus group strongly recommends that all H pylori eradication regimens now be given for 14 days. Recommended first-line strategies include concomitant nonbismuth quadruple therapy (proton pump inhibitor [PPI] + amoxicillin + metronidazole + clarithromycin [PAMC]) and traditional bismuth quadruple therapy (PPI + bismuth + metronidazole + tetracycline [PBMT]). PPI triple therapy (PPI + clarithromycin + either amoxicillin or metronidazole) is restricted to areas with known low clarithromycin resistance or high eradication success with these regimens. Recommended rescue therapies include PBMT and levofloxacin-containing therapy (PPI + amoxicillin + levofloxacin). Rifabutin regimens should be restricted to patients who have failed to respond to at least 3 prior options. CONCLUSIONS: Optimal treatment of H pylori infection requires careful attention to local antibiotic resistance and eradication patterns. The quadruple therapies PAMC or PBMT should play a more prominent role in eradication of H pylori infection, and all treatments should be given for 14 days.

Precision improvement for omeprazole determination through stability evaluation.

A new spectrofluorimetric method for the determination of omeprazole (OMP) based on its degradation reaction catalyzed by ultraviolet (UV) light is proposed. OMP in aqueous solution is very unstable, which renders a serious difficulty for controlling its quality. It does not show native fluorescence, but when exposed to UV radiation, it generates a highly fluorescent degradation product with adequate stability for indirect OMP quantification. Under the studied optimal experimental conditions (pH, temperature, exposure time to UV radiation), a specific rate constant of 2.851 min⁻¹--described by zero-order kinetic--was obtained for the degradation reaction. Using λ(exc) 293 nm and λ(em) 317 nm, a linear relationship was obtained (r² 0.9998) in the concentration range of 0.1 to 1.3 µg mL⁻¹, with a detection limit of 1.07 10⁻³ µg mL⁻¹ (S/N = 3). The methodology developed was successfully applied to OMP quality control in pure drugs and tablet dosage forms without previous treatment, with good tolerance to common excipient, and a high level of concordance between the nominal and experimental values. This work constitutes an important contribution to knowledge of the degradation mechanism of OMP. It has been shown to be appropriate for OMP quality control, to have an adequate sampling rate, low cost instrument, and to be a less polluting procedure.

Quality evaluation of extemporaneous delayed-release liquid formulations of lansoprazole.

PURPOSE: The quality attributes of extemporaneous delayed-release liquid formulations of lansoprazole for oral administration were evaluated. METHODS: A novel liquid formulation (3 mg/mL) of Prevacid FasTab in an Ora-Blend vehicle was prepared and compared with the Prevacid FasTab 30 mg and Prevacid-sodium bicarbonate 1 M formulation (3 mg/mL). The latter formulation was combined with hydrochloric acid 0.1 N, and the remaining lansoprazole content was assayed by high-performance liquid chromatography (HPLC). A batch of delayed-release liquid formulation was prepared to evaluate content uniformity. For content assay, three samples were prepared for each evaluated condition and each sample was analyzed in triplicate by HPLC. RESULTS: The lansoprazole in the sodium bicarbonate formulation was extensively degraded by quantities of hydrochloric acid 0.1 N in excess of 100 mL. Storage time and temperature had a significant effect on lansoprazole stability in the Ora-Blend formulation. The drug remained stable for seven days when the formulation was stored at 4.5-5.5 °C, but storage at 21-22 °C or the reduction of pH with citric acid accelerated lansoprazole degradation. The amount of lansoprazole released from the Ora-Blend formulation during the buffer stage of the dissolution test decreased with increases in formulation storage time, in formulation storage temperature, and in the amount of lansoprazole released and degraded during the acid stage of the test. CONCLUSION: An extemporaneous formulation consisting of lansoprazole microgranules in Ora-Blend maintained acceptable quality attributes when stored for three days at 4.5-5.5 °C.

Use and overuse of proton pump inhibitors in cirrhotic patients.

BACKGROUND: There are several indications for the use of proton pump inhibitors (PPIs) but little evidence to support their use in patients with chronic liver disease. Moreover, the pattern of clinical use is unknown. The aim of the present study was to analyze the use of PPIs in patients with chronic liver disease in an ambulatory setting. MATERIAL/METHODS: This was a retrospective study in a clinical setting. Clinical variables, severity indexes, and endoscopic findings were assessed. Management of PPIs was classified according to proven indication as: G1, proven indication and a prescription; G2, no proven indication and prescription; G3, proven indication and no prescription; and G4, no proven indication and no prescription. G1+G4 were considered proper use of PPIs. The classification was used to identify variables associated with proper use. RESULTS: The study included 243 patients (mean age: 55.82+/-12.9 years). The most common etiologies of chronic liver disease were hepatitis C virus infection and chronic alcoholic liver disease. PPIs were indicated in 46.1% patients. Multivariate analysis showed that a MELD score < or =8 points (OR: 2.6, 95% CI: 1.3-5.3), esophageal varices (OR: 0.38, 95% CI: 0.16-0.90), and previous in-hospital use of PPIs (OR: 0.78, 95% CI: 0.6-0.9) were associated with G1+G4. CONCLUSIONS: Clinical use of PPIs in chronic liver disease was inappropriate in nearly one half of all patients. A less severe disease was associated with proper use and previous in-hospital use was associated with inappropriate use. Future research into the clinical use of PPIs in cirrhotic patients is mandatory.

Quantification of tenatoprazole in rat plasma by HPLC: validation and its application to pharmacokinetic studies.

A simple, reliable HPLC method with UV detection (295 nm) in rat plasma was developed and validated for quantification of tenatoprazole, a novel proton pump inhibitor, which is in clinical trials. Following a single-step liquid-liquid extraction, the analyte and internal standard were separated using an isocratic mobile phase on a reverse phase C(18) column. The lower limit of quantitation was 20 ng/mL, with a relative standard deviation of less than 10%. A linear dynamic range of 20-6000 ng/mL was established. This HPLC method was validated with between-batch and within-batch precision of 2.9-6.3 and 1.4-5.8%, respectively. The between-batch and within-batch accuracy was 95.1-104.1 and 92.4-101.0%, respectively. This validated method is simple and repeatable enough to be used in pharmacokinetic studies.