Comparing the Interactions of Trichomonas vaginalis/gallinae Legumain-Like Cysteine Protease 1 (LEGU-1) and Human Legumain (LGMN) Protein Sequences with Proton Pump Inhibitor Drugs (Lansoprazole, Omeprazole, and Esomeprazole) by Bioinformatics Analyses.

BackgroundNeurological disorders are at epidemic levels in the world today. Various proteins are being targeted for the development of novel molecular therapeutics; however, no small‐molecule inhibitors have been discovered. Recent studies suggest that there are few molecules in clinical trials for various secretase (α, β, and γ), caspase, and calpain inhibitors. However, recently an emerging target was highlighted i.e. asparaginyl endopeptidase (AEP). This lysosomal cysteine protease cleaves the glycine‐rich C‐terminal to form an asparagine residue. In addition, the highly conserved and spatially close catalytic triad (Oδ1ASN42‐Nε2HIS148 ̴ 3.0Å) active site residue is Asn 42, His 148‐spacer‐Cys 189, which is responsible for proteolytic activity are also impacted by the cleavage of the C‐terminal region of AEP. Therefore, the current study focuses on screening, available small molecule databases for potential interactions with the active binding sites within the AEP binding pocket for inhibiting its proteolytic activity and restoring neuronal damage.MethodVarious online available CNS‐focused databases were screened to find small molecule inhibitors using an in‐silico structure‐based virtual screening method and molecular dynamics simulation. Further selected small molecules were assayed on overexpressed AEP stable cell line (HMC‐3) with exiting peptide and compound 11ResultThere is no small molecule inhibitor for the AEP yet, and the screened small molecule could be a potential hit for drug discovery. In addition, we have observed that AEP is involved in various proteinopathies which leads to neuroinflammation and can be reversed. Moreover, we found that our in‐silico screened molecules are more potent than the compound 11 and peptide. Further assays on a stable AEP immortal HMC‐3 cell line also line up with the in‐silico results.ConclusionThe selected small molecule presented a potential non‐covalent interaction (hydrogen bonds, ionic bonds, and pi‐pi interaction) within the catalytic binding sites with high binding energies and stable complex during simulation when compared to exiting compound 11 and peptide. The findings from the current study will help identify the critical subgroups needed for the development of our lead AEP inhibitory molecule.

PRM27 - Identifying Diagnoses for Prescribed Medication in Japan Health Insurance Claim Data: An Application of Natural Language Processing Technique on Real World Healthcare Database

The introduction of omeprazole to the Canadian prescription drug market in 1989 heralded the beginning of a revolution in the treatment of acid peptic disease. The proton pump inhibitor (PPI) drug class now accounts for substantial expenditures in all Canadian pharmaceutical formularies. Understandably, the widespread use of these drugs has spurred questions regarding the appropriateness of PPI use. In this issue of The Canadian Journal of Gastroenterology, Gregoire and colleagues (pages 673-677) present a retrospective review of PPI prescribing patterns in Quebec seniors with the use of a prescription and medical services claims database. PPI prescriptions were considered to be appropriate if the user had an upper gastrointestinal endoscopy in the previous six months, if the PPI was dispensed as part of an eradication regimen for Helicobacter pylori, or if the PPI was preceded by a prescription for an H2 receptor antagonist or prokinetic drug within the previous six months. Concurrent H2 receptor antagonist use was deemed to be inappropriate. Using these criteria, the authors concluded that only 54.7% of first time omeprazole prescriptions in Quebec were appropriate. How valid are the results of this study when viewed from the clinical arena? The answer is largely determined by the definitions used for appropriateness. Utilization studies derived from medical service databases must define appropriateness in ways that can be readily measured by the database. This approach has the potential to identify overly restrictive criteria, which may be imperfect reflections of appropriate clinical care. What is appropriate PPI use according to current standards of good clinical practice? The weight of evidence currently supports the use of PPIs in the following situations: for prophylaxis of nonsteroidal anti-inflammatory drug-induced gastropathy; as part of an antibiotic regimen for H pylori eradication; for the treatment of refractory peptic ulcer disease; for the treatment of Zollinger-Ellison syndrome and other hypersecretory states; and for the treatment of symptomatically severe reflux or endoscopically proven erosive esophagitis. More controversial is the use of PPIs as initial therapy for uninvestigated dyspepsia and gastroesophageal reflux symptoms. There is good evidence that PPIs are superior to H2 blockers in the treatment of dyspepsia at the primary care level (1-3). As well, empirical drug treatment as opposed to endoscopy appears to result in lower medical costs but equal effectiveness (4). For gastroesophageal reflux, the timehonoured ‘step-up’ therapy has been challenged. A ‘stepdown’ approach (beginning with PPIs and stepping down to H2 receptor antagonists) or ‘on demand’ therapy has been advocated by some (5). Until recently, concomitant use of H2 receptor antagonists and PPIs has been thought to be redundant and wasteful. However, recent observations have noted that control of nocturnal acid secretion may be inadequate in patients with refractory gastroesophageal reflux disease. Concomitant use of both H2 receptor antagonists at bedtime and PPIs during the waking hours may offer better control of acid secretion in this patient group (6,7). The above observations demonstrate the highly fluid nature of current medical opinion regarding appropriate use of the PPI drug class. While utilization studies such as the one by Gregoire et al are provocative, I submit that suitable criteria for appropriate PPI use remain to be defined.

The Arkansas State Employee Benefits Division (EBD) is a self-insured program comprising public school and other state employees, their spouses, and dependents. Previous research published in JMCP (2006) showed drug cost savings of $2.20 per member per month (PMPM; 37.6%) or annualized savings of $3.4 million associated with a benefit design change and coverage of the proton pump inhibitor (PPI) omeprazole over-the-counter (OTC) beginning in March 2004. On May 1, 2005, brand esomeprazole was excluded from coverage, with current users grandfathered for 4 months until September 2005. Reference pricing for PPIs, including esomeprazole but excluding generic omeprazole, was implemented on September 1, 2005, and the beneficiary cost share for all PPIs except generic omeprazole was determined from comparison of the PPI actual price to the $0.90 omeprazole OTC reference price per unit. To examine PPI utilization and drug costs before and after (a) excluding esomeprazole from coverage (with grandfathering current users) and (b) implementing a therapeutic maximum allowable cost (TMAC), or reference-pricing benefit design, for the PPI class in a large state employee health plan with fairly stable enrollment of approximately 127,500 members in 2005 through 2008 and approximately 128,000 members in 2009 Q1. The pharmacy claims database for the EBD was used to examine utilization and cost data for PPIs in a longitudinal analysis for the 61-month period from March 1, 2004, through March 31, 2009. Pharmacy claims data were compared for the period 14 months prior to esomeprazole exclusion (preperiod), 4 months during the esomeprazole exclusion (postperiod 1), and the ensuing 43 months of PPI reference pricing (postperiod 2). PPI cost and utilization data for the intervention group of approximately 127,500 beneficiaries were compared with a group of 122 self-insured employers with a total of nearly 1 million beneficiaries whose pharmacy benefits did not include reference pricing for PPIs. Despite 79% of existing esomeprazole users being grandfathered during the 4-month esomeprazole-exclusion period (postperiod 1), the share of omeprazole OTC claims increased from 35.2% to 42.5% (+ 7.3 percentage points) of all PPI claims, and esomeprazole claims decreased from 16.7% to 12.0% (-4.7 percentage points), with little change in the use of other PPIs. The average allowed charge (price) per day of PPI drug therapy decreased in postperiod 1 by 8.9% from $2.81 to $2.56, while utilization increased by 2.2% from 1.83 days PMPM to 1.87 days PMPM; the net plan cost PMPM decreased by $0.40 PMPM from $3.78 to $3.38 (-10.6%), representing a reduction in spending of $35,664 per month while the average member copayment per claim was essentially unchanged. In the 43 months of reference pricing in postperiod 2, PPI utilization was essentially unchanged at 1.82 days PMPM compared with the preperiod (1.83 days PMPM) and 2.7% lower than the esomeprazole-exclusion period (1.87 days PMPM); however, price (charge per day) decreased by 38.4% during refer- RESEARCH ence pricing to $1.73 from $2.81 in the preperiod and by 32.4% compared with $2.56 in the esomeprazole-exclusion period, despite an increase in the average pharmacy dispensing fee to $5.21 per PPI claim. Net plan cost decreased by $1.87 PMPM (49.5%) to $1.91 PMPM during reference pricing compared with the preperiod ($3.78 PMPM) and by $1.47 PMPM (43.5%) compared with the esomeprazole-exclusion period 1 ($3.38 PMPM). Beneficiary costs (copayment per claim) for PPIs decreased to $1.24 PMPM ($23.27 per claim) compared with the preperiod ($1.37 PMPM, $24.95 per claim) and compared with the esomeprazole-exclusion period ($1.40 PMPM, $25.06 per claim). The reductions in net plan costs represented lower plan spending for the 43 months of reference pricing (postperiod 2) of approximately $9.4 million or an average of approximately $219,500 per month compared with the preperiod or $7.9 million (approximately $183,900 per month) compared with the esomeprazole-exclusion period. Compared with a group of self-insured health plans without pharmacy benefit reference pricing of PPIs, the cost savings over the 43-month period from September 1, 2005, through March 31, 2009, were approximately $7.2 million or $1.31 PMPM. For this state employee health plan, the policy change that excluded esomeprazole from coverage but grandfathered current users was associated with a relatively small reduction in PMPM spending on PPIs compared with the subsequent policy change that applied reference pricing to the PPI class based on the price (drug cost plus dispensing fee) for omeprazole OTC. Over 43 months of reference pricing, net plan costs fell dramatically by 49.5% PMPM compared with the preperiod or decreased by 43.5% compared with the esomeprazole-exclusion period. While utilization was essentially unchanged compared with the 18 months before reference pricing, the average pharmacy dispensing fee per PPI claim increased, and beneficiary costs PMPM decreased.

Chapter 9 - Neuroendocrine tumors

This study involved the development, validation and application of a three-phase hollow-fiber liquid-phase microextraction (HF-LPME) and liquid chromatography with diode array detection (LC-DAD) method for the simultaneous determination of the proton pump inhibitor (PPI) drugs omeprazole, pantoprazole and lansoprazole in human plasma. The evaluation of the HF-LPME parameters was crucial for the determination of the drugs and the conditions selected were: 1-octanol as solvent; phosphate buffer at pH 5 as donor phase; borate buffer at pH 10 as acceptor phase; extraction time of 15 min; stirring at 750 rpm and NaCl was added at 5% (w/v). Validation of the method according to US-FDA recommendations showed a good linear range (0.2-2.0 μg/mL) for all analytes, with a determination coefficient >0.9910. Precision was evaluated using intra- and inter-day assays, which showed relative standard deviations (RSD), <15% for all concentrations, with a limit of quantification (LOQ) of 0.2 μg/mL. Accuracy was also assessed at these concentration levels and was in the range from 80 to 130%. Finally, the sensitive, selective and reproducible HF-LPME/LC-DAD developed method was successfully applied to human plasma samples from patients undergoing therapy with the PPI drugs.

Dyspepsia is a health problem often encountered by doctors in daily practice. Many people complain of symptoms of dyspepsia but do not seek help for treatment. Proton pump inhibitors are the drugs for the treatment of dyspepsia, such as omeprazol, lansoprazol, esomeprazol, rabeprazol, and pantoprazol. Some studies have explained that proton pump inhibitor drugs can interfere with kidney function due to acute interstitial nephritis due to the consumption of proton pump inhibitors, and this condition can end with chronic kidney disease that occurs due to undiagnosed acute interstitial nephritis. This study aimed to see how urea and creatinine levels in dyspepsia patients at Universitas Kristen Indonesia Hospital were taking proton pump inhibitors. This research is a descriptive research content analysis, hospital-based. Based on medical records at Universitas Kristen Indonesia Hospital in 2018, 80.3% high ureum levels and 19.7% normal ureum levels were found. In creatinine levels, it was found that men had more normal creatinine levels of 57.7% and high ureum levels of 42.3%, and women found more normal creatinine levels of 62.5% and high creatinine levels of 37.5%. Keywords: Dyspepsia, Proton Pump Inhibitor, Creatinine, Ureum

This study aimed to evaluate the role of the clinical pharmacist in the rational use of proton pump inhibitors (PPIs) in a general surgery department. All enrolled patients had attended the general surgery department of a tertiary hospital. This single-center prospective study compared differences in the overall rate of rational PPI use, proportion of unindicated PPI use, utilization rate, average defined daily dose (DDD), drug costs, PPI costs, and cost-effectiveness of clinical pharmacist intervention between the intervention (538 cases) and control (536 cases) groups. In the intervention group, Pareto and fishbone diagram analyses were combined with the Plan-Do-Check-Act cycle; Statistical Package for the Social Sciences was used for analyzing all data. The overall rate of rational PPI use was significantly higher in the intervention group than in the control group (p < 0.01). The proportion of unindicated PPI use, utilization rate, average DDD, drug costs, and PPI costs were significantly lower in the intervention group than in the control group (p < 0.05). Cost-effectiveness analysis for the overall rate of rational PPI use indicated a positive impact of intervention, with economic benefits in the intervention group. Clinical pharmacist intervention for rational use of PPIs in general surgery departments could significantly increase the overall rate of rational PPI use; it could also reduce the proportion of unindicated PPI use, utilization rates, average DDDs, drug costs, and PPIs costs. Pharmacist intervention also offers economic benefits by improving the overall rate of rational PPI use.

The rise and rise of proton pump inhibitor drugs: Patients' perspectives

This work evaluated the effects of proton pump inhibitors (PPIs) on cardiovascular events (CVEs) and inflammatory factors in patients with upper gastrointestinal bleeding (UGIB) undergoing dual antiplatelet therapy (DAPT) after percutaneous coronary intervention. Clinical data from these patients were analysis, intending to provide relevant theoretical evidence for clinical practice. Data of 166 patients who underwent percutaneous coronary intervention and developed UGIB while on DAPT at The First People' Hospital of Linping District from April 2021 to April 2023 were retrospectively analyzed. The patients were rolled into two groups: those who received PPI treatment and those who did not, namely, PPI and non-PPI group, respectively. Furthermore, occurrence of CVEs and the levels of inflammatory factors of patients in all groups were statistically analyzed. In patients with UGIB, melena is a common presentation. The incidence of CVE in the PPI group showed no statistically significant difference compared to the control group, and there was no significant variance observed in the distribution of CVE incidence among different PPIs. However, levels of C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α) were significantly lower in the PPI group compared to the non-PPI group (P < 0.05). Melena was the most frequent clinical manifestation in UGIB patients. The use of PPIs did not increase the risk of CVEs, and different PPI drugs did not affect the occurrence of CVEs. Furthermore, PPIs lowered CRP and TNF-α levels in serum of these patients.

Amaç: Hastanede yatmakta olanhastalarda proton pompa inhibitörleri (PPİ) ve histamine-2 reseptörantagonistlerinin (H2RA) kullanılma sıklığı ve tercihine ilişkin verileryoktur.İç Hastalıkları servislerinde sık olarak kullanılan PPİ ve H2RAkullanım sıklıklarını belirlemektir. Yöntem: Retrospektifolarak, 1 Ocak ve 31 Aralık 2010 tarihleri arasında bir üçüncü basamaküniversite hastanesinin İç Hastalıkları servislerinde ve yoğun bakımünitelerinde (YBÜ) yatırılan hastaların tıbbi kayıtları incelendi; herhangi birPPİ veya H2RA kullanımı olan olguların dörtte biri rastgele olacak şekildeseçildi. Bulgular: 2010yılında, İç Hastalıkları servislerinde yatırılan toplam 4730 hastanın yarısıbir H2RA veya PPİ kullanmıştı. Bunların içinden 556 (%25.5) olgu incelendi.Olguların büyük çoğunluğu (%76) PPİ kullanmaktaydı. Servislerde, PPİ olguların%90.3’ünde kullanılırken, YBÜ’de olguların %74.8’i H2RA kullanmaktaydı(p&amp;amp;lt;0.001). YBÜ’den servislere transfer edilen olguların %61’inde (58/95),herhangi özel bir neden olmadan, H2RA kesilerek PPİ kullanımına geçildiğigörüldü. Hastaneye yatmadan önce olguların %8’i PPİ ve %5’i bir H2RAkullanırken, taburculuk sırasında %79 PPİ ve %21 H2RA olacak şekilde kullanımanlamlı şekilde artmıştı (p&amp;amp;lt;0.001). Sonuç: Hastanede yatmaktaolan hastalarda ve taburcu edilirken verilen reçetelerde yüksek oranda asitbaskılayıcı tedavi kullanılmaktadır. Bu ilaçların akılcı şekilde kullanılmadurumlarını değerlendirmek için ileri araştırmalara ihtiyaç vardır.

Proton-pump inhibitor (PPIs) drugs are widely used in the treatment of gastric diseases. Almost all PPI drugs have some side effects depend on the physical condition and limit of doses. In this study, the physicochemical and pharmacokinetic studies of Omeprazole, Esomeprazole, Lansoprazole and Pantoprazole have been investigated. Density functional theory (DFT) with B3LYP/3-21g basis set has been employed to optimize the geometry and to elucidate their thermochemical, molecular orbital, molecular electrostatic potential properties. Pharmacokinetic parameters are also investigated to compare their absorption, distribution, excretion, metabolism, and toxicity.

The rapidly increasing rate of antibiotic resistance is of great concern. Approximately two million deaths result annually from bacterial infections worldwide. Therefore, there is a paramount requirement to develop innovative and novel antibacterial agents with new mechanisms of action and activity against resistant bacterial strains. For this purpose, a set of benzothiazole and N-phenylpyrrolamides derivatives reported as DNA Gyrase B (GyrB) inhibitors were collected from the literature and docked inside the receptor cavity of DNA Gyrase B (PDB ID: 5L3J). The best 10 docked complexes were used to identify novel antibacterial chemical agents through a de novo design approach. Out of initial 300 chemical analogues, the best six analogues were identified using screening with a set of criteria followed by pharmacokinetic analysis. The binding interactions of the best six analogues revealed that all molecules formed a number of critical interactions with catalytic amino residues of DNA Gyrase B with high binding energy. The predicted inhibitory constant biological activity based on binding energy supported the potential of the molecules as DNA Gyrase B ligands. The RMSD, RMSF, and radius of gyration parameters obtained from the 100 ns molecular dynamics simulation study clearly demonstrated that all six analogues were efficient enough to form stable complexes with DNA Gyrase B. High negative binding energy of all ligands obtained from MM-GBSA approach undoubtedly explained the strong affinity toward the DNA Gyrase B. Therefore, the proposed de novo designed molecules can be considered as promising antibacterial chemical agents subject to experimental validation, in vitro.Communicated by Ramaswamy H. Sarma

To evaluate the financial effects in a state employee health plan of a change in the drug coverage policy to include over-the-counter (OTC) omeprazole in a tier-copayment drug benefit design that favored the OTC drug. The policy change in the Arkansas State Employee Benefit Division (EBD) involved 2 principal parts: OTC omeprazole placed in a new OTC copayment tier (5 dollars) and an increase in pharmacy reimbursement to a 13 dollars dispensing fee for each OTC omeprazole prescription. The prescription claims database was used to examine utilization and cost data for beneficiaries who received prescriptions for a proton pump inhibitor (PPI) during the 2-month period (January and February 2004) preceding the change in policy to cover OTC omeprazole compared with the 2-month period following the policy change (March and April 2004). During the first week of the new policy (March 1-7, 2004), OTC omeprazole accounted for 47% of all PPI claims. From the third week through the end of the 2-month study period, OTC omeprazole represented 60% of PPI claims. This shift to OTC omeprazole from prescription PPIs produced EBD average savings of 40.86 dollars (40.5%) per PPI claim in the first 2 months after implementation of coverage of OTC omeprazole compared with the immediate previous 2-month period. The average copayment savings for EBD beneficiaries were 4.20 dollars (16.5%) per PPI claim. The average increase in pharmacy reimbursement was 118% (6.27 dollars per claim in the postperiod versus 2.88 dollars per claim in the preperiod). Despite a 17.2% increase in utilization as measured by days of PPI therapy per member per month (1.91 PMPM) in the postperiod versus 1.63 in the preperiod, EBD savings were 2.11 dollars (38.9%) PMPM. Based upon PMPM savings of 2.56 dollars in the second month of coverage of OTC omeprazole, annual savings would be about 3,978,240 dollars for average eligible membership of 129,500 in this state employee health plan. This policy change to include coverage of OTC omeprazole in the state employee drug benefit plan produced savings to the state of as much as 50% of the total cost of PPI drugs despite an apparent small increase in utilization of PPIs and an increase in pharmacy reimbursement of more than 100%. Plan beneficiaries realized significant savings on average for PPI drugs and particularly for each OTC omeprazole prescription.

Proton Pump Inhibitors for Inducing and Maintaining Remission in Eosinophilic Esophagitis: An Updated Systematic Review and Meta-Analysis.