Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients.

Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R2  = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events.

The prolongation effect of ilaprazole-based standard triple therapy for Helicobacter pylori.

BACKGROUND: Helicobacter pylori (HP) infection causes many diseases, such as peptic ulcers, gastritis and gastric cancer, and MALToma. It has been gradually accepted that all HP-infected patients should be treated because HP is regarded as an infection. Therefore, the importance of selecting the optimal treatment regimen has increased. Although the 14-day standard triple therapy (STT) is recommended in the current guidelines, prolonging treatment duration is controversial in real practice because of inconsistent results from previous data and the risk of adverse effects. Additionally, the effect of STT using ilaprazole has not been reported until now. We aimed to compare the eradication rate between 7 and 10 days STT using ilaprazole. METHODS: A prospective randomized controlled trial was conducted, which was divided into 2 treatment groups: the control group was 7 days of STT, and the test group was 10 days of STT. The eradication regimen was 10 mg ilaprazole, 500 mg clarithromycin, and 1000 mg amoxicillin twice daily. We included patients who were diagnosed with positive results of H pylori examination. We compared the HP eradication rate according to treatment duration, CYP2C19 subtype and endoscopic diagnosis. RESULTS: We enrolled a total of 254 patients consisting of 127 patients in each treatment arm. The eradication rates of the control and test groups were 65.4% (82/127) and 74.8% (95/127), respectively, in the intention-to-treat analysis (P = .1). In the per-protocol analysis, 70.3% (83/118) and 82.6% (94/115) were eradicated in each group, which was statistically significant (P = .027). The CYP2C19 subtype was examined in 230 patients. The eradication rate was 79.2% (57/72), 75.4% (92/122), and 72.2% (26/36) in each group, which was not significantly different (P = .704). CONCLUSION: Ten-day STT was more effective than 7-day STT for HP eradication. The eradication rate was not affected by the CYP2C19 genotype.

The study of intestinal absorption and biodistribution in vivo of proton pump inhibitors.

The major therapeutic strategy for acid-related gastrointestinal diseases in clinic is to reduce the excretion of gastric acid by oral administration of proton-pump inhibitors (PPIs). However, it is quite a challenge to study the oral absorption behaviors of PPIs considering their extreme instability under gastrointestinal environment. As a result, little information has been reported on PPI oral absorption so far, hindering the further development of PPI-contained oral preparations. Here, we first investigated the degradation rate of three representative PPIs, including ilaprazole, ilaprazole sodium and rabeprazole sodium. Then a modified in situ intestine absorption method in rat was established: through the temperature control by the heat exchangers, the perfusate was kept at physiological temperature only when passing through the intestine while it was maintained at 4 °C outside the intestine. Therefore PPIs could maintained sufficiently high stability under proper temperature control. Our data demonstrated that both ilaprazole and ilaprazole sodium exhibited significantly higher absorption efficiency than rabeprazole sodium did through the comparison of their apparent permeability coefficients and steady-state plasma concentrations after perfusion in the duodenum, jejunum, ileum and colon, mainly attributing to their more suitable oil-water partition coefficient. The duodenum could be the best site for the oral absorption of PPIs. Ilaprazole outperformed its sodium salt form with its stable absorption behavior in tested four intestinal segments. Furthermore, after intravenous or oral administration, ilaprazole exhibited a longer residence time and a higher accumulation in the stomach than in most of other tissues/organs. However, it was also found that the accumulation was heterogeneous and mainly located in mucosa cells of the stomach. Our further study indicated that there was no significant difference on the oral absorption efficiency of ilaprazole between female and male rats but ilaprazole underwent a faster metabolism in male rats after oral absorption. Our study provided a valuable guidance for the design of oral formulation and the optimization of PPI-contained formulations.

Combined ns5a & ns5b nucleotide inhibitor therapy for patients with chronic hepatitis c with stage 5 chronic kidney disease on hemodialysis / Terapia inibidora de nucleotídeo NS5A& NS5B combinada para pacientes com hepatite C crônica com doença renal crônica em estágio 5, em hemodiálise

ABSTRACT BACKGROUND: Hepatitis C virus (HCV) infection is the most common hepatotropic viral infection affecting the patients on maintenance hemodialysis. Treatment of chronic HCV infection in stage 4 and 5 CKD includes a combination of elbasvir/grazoprevir and glecaprevir/pibrentasvir, which are not available in many countries. OBJECTIVE: Hence, we have conducted this study to look for the safety and efficacy of sofosbuvir combination therapy in this difficult to treat population. METHODS: We conducted a single-center, prospective, open-label study in which Stage 5 CKD patients on maintenance hemodialysis with HCV infection. Total of 18 patients was included. sofosbuvir with daclatasvir or ledipasvir was used according to genotype for 12 weeks. HCV RNA, genotype, transient elastography (TE) was considered for every patient. HCV RNA was quantified at 4th week, 12th week and 12 weeks post-treatment to look for sustained virologic response (SVR 12). RESULTS: Infection due to genotype 1 was seen in 12 (66.7%) patients followed by genotype 3 in 4 (22.3%) with each patient of genotype 2 and 5. The median value of HCV RNA was 2,35,000 IU/mL. On TE, all had liver stiffness of <9.4 KPa. All patients had HCV RNA of <15 IU/mL at 4th and 12th week of treatment and 12 weeks post-treatment. No significant change in hemoglobin, eGFR and liver stiffness was observed. CONCLUSION: Full dose sofosbuvir i.e. 400 mg, in combination with NS5A inhibitors daclatasvir or ledipasvir is found to be safe and effective in patients with end stage renal disease, who are on maintenance hemodialysis.

RESUMO CONTEXTO: A infecção pelo vírus da hepatite C (HCV) é a infecção viral hepática mais comum que afeta pacientes em hemodiálise de manutenção. O tratamento da infecção crônica por HCV no estágio 4 e 5 da doença renal crônica inclui uma combinação de elbasvir/grazoprevir e glecaprevir/pibrentasvir, que não estão disponíveis em muitos países. OBJETIVO: Portanto, realizamos este estudo para procurar a segurança e eficácia da terapia combinada de sofosbuvir nesta população de difícil tratamento. MÉTODOS: Realizamos um estudo de centro único, prospectivo e aberto, no qual pacientes com doença renal crônica em estágio 5 em hemodiálise de manutenção com infecção por HCV. Um total de 18 pacientes foi incluído. Sofosbuvir com daclatasvir ou ledipasvir foi usado de acordo com o genótipo por 12 semanas. O HCV RNA, genótipo, elastografia transitória foi considerado para cada paciente. O HCV RNA foi quantificado na 4ª semana, 12ª semana e 12 semanas após o tratamento para procurar uma resposta virológica sustentada. RESULTADOS: A infecção por genótipo 1 foi observada em 12 (66,7%) pacientes, seguido pelo genótipo 3 em 4 (22,3%), em um paciente do genótipo 2 e em outro, 5. O valor mediano do HCV RNA foi de 2.35.000 IU/mL. Na elastografia transitória, todos tinham rigidez hepática de <9.4 KPa. Todos os pacientes tinham RNA HCV <15 IU/mL na 4ª e 12ª semana de tratamento e 12 semanas após o tratamento. Não foi observada nenhuma alteração significativa na hemoglobina, eGFR e rigidez hepática. CONCLUSÃO: A dose completa sofosbuvir ou seja, 400 mg, em combinação com inibidores NS5A daclatasvir ou ledipasvir foi considerada segura e eficaz em pacientes com doença renal em estágio final, que estão em manutenção hemodiálise.

The status of proton pump inhibitor use: a prescription survey of 45 hospitals in China.

BACKGROUND: proton pump inhibitors (PPI) have been widely used in the clinic but inappropriate prescribing has also increased dramatically. OBJECTIVE: to describe the prescribing patterns and assess the appropriateness of the prescribed PPI use in 45 hospitals in China. MATERIALS AND METHODS: PPI prescriptions for non-hospitalized patients were collected from hospitals in Beijing, Chengdu, Guangzhou and Hangzhou of China over a 40-day period in 2016. These data were analyzed using the prescription number, proportion and economic indicators (defined daily dose system [DDD], defined daily cost [DDC] and drug utilization index [DUI]). The evaluation criteria of PPI use was based on Martindale: The Complete Drug Reference, New Materia Medica and drug instructions. RESULTS: in total, 357,687 prescriptions using oral PPI and 38,216 prescriptions using injectable PPI were assessed. The average age of PPI users was 53 years. The most commonly used oral PPI was rabeprazole, while the most common injectable PPI was pantoprazole. The DDD of oral rabeprazole and DDC of injectable rabeprazole were the highest. Meanwhile, only the DUI values of oral rabeprazole, lansoprazole and ilaprazole were less than 1.0. The clinical diagnosis of some users included well identified risky comorbidities such as kidney disease (2.9%). Furthermore, between 32.6% and 56.8% of the PPI prescriptions were used for inappropriate indications. CONCLUSION: this survey demonstrated that PPI use was accompanied by unapproved indications and excessive dosages. Comprehensive measures are urgently needed to improve PPI use and reduce unnecessary drug costs.

Efficacy, safety and pharmacokinetics of ilaprazole infusion in healthy subjects and patients with esomeprazole as positive control.

AIMS: The objectives were to investigate the pharmacokinetics, pharmacodynamics and safety of ilaprazole infusion in healthy subjects and patients with esomeprazole as positive control, and then recommend the dosage regimen for Phase 2b/3 studies. METHODS: Three clinical studies were performed. First, 16 healthy subjects received infusion of ilaprazole 30 mg or esomeprazole 80 mg. Second, 12 healthy subjects received ilaprazole 20 mg followed by 10 mg once daily for 2 days. Finally, 20 patients with duodenal ulcers received ilaprazole 20 mg followed by 10 mg for 2 days or esomeprazole 40 mg twice daily for 3 days. Serial blood samples were collected and intragastric pH was recorded. RESULTS: The mean percentages time of intragastric pH >6 was 63.6 and 51.7% for healthy subjects after receiving ilaprazole 30 mg and esomeprazole 80 mg. Linear pharmacokinetics was observed when the dose was increased to 30 mg but the effect was saturated. Ilaprazole 20 mg followed by 10 mg for 2 days provided higher plasma exposure in healthy subjects than patients, but the effect was comparable. After multiple administrations, ilaprazole provided similar effect to esomeprazole. Ilaprazole infusion was safe and well tolerated without serious adverse events. CONCLUSIONS: Ilaprazole provided comparable effect of pH control to esomeprazole, with lower dose and fewer times of administration. There was no significant difference of ilaprazole between healthy subjects and patients regarding intragastric acid inhibition. A loading dose of ilaprazole 20 mg followed by 10 mg once daily for 2 days was recommended for Phase 2b/3 studies.

Comparison of efficacy and safety of ilaprazole and esomeprazole both in initial treatment regimen and retreatment regimen of Helicobacter pylori infection in chronic gastritis.

The aim of this study was to compare the efficacy and safety of ilaprazole and esomeprazole both in initial treatment regimen and retreatment regimen of H. pylori infection in chronic gastritis and to explore risk factors for eradication failure. A total of 330 patients with chronic gastritis who were confirmed of H. pylori infection were enrolled in this study. 290 of them were initially treated patients and the 40 remained were patients with retreatment. Eradication assessment was performed at least four weeks after the completion of eradication therapy. Results showed that the eradication rates of the ilaprazole group and esomeprazole group were 91.4 % and 88.4 % for per-protocol (PP) analysis (p=0.41) and 89.0 % and 86.2 % for intention-to-treat (ITT) analysis (p=0.48) in initially treated patients. Meanwhile, they were 75.0 % and 72.2 % for PP analysis (p=0.85) and 75.0 % and 70.0 % for ITT analysis (p=0.72) in patients with retreatment. The differences were not statistically significant. There was also no significant difference in safety between the two drugs. A multiple logistic regression analysis showed that demographic factors such as age, gender, alcohol, smoking, coronary heart disease (CHD), hypertension (HTN) and diabetes mellitus (DM) did not affect eradication rates. However, patients with higher DOB values and patients with atrophic gastritis had significantly lower eradication rates than patients with lower DOB values and with non-atrophic gastritis whether the proton pump inhibitor (PPI) in eradication regimens was ilaprazole or esomeprazole. In conclusion, our findings suggest that the efficacy and safety of ilaprazole and esomeprazole were not significantly different both in initial treatment regimen and retreatment regimen of H. pylori infection in chronic gastritis and DOB values and type of chronic gastritis were to be independent risk factors for eradication failure. In addition, we discovered that a new quadruple regimen containing furazolidone and minocycline which achieved good efficacy and safety can be a promising option for retreatment of H. pylori infection.

Efficacy of three proton-pump inhibitor therapeutic strategies on laryngopharyngeal reflux disease; a prospective randomized double-blind study.

OBJECTIVES: Proton-pump inhibitor (PPI) prescribing practices in laryngopharyngeal reflux disease (LPR) differ among physicians. We assessed the improvement in reflux symptom index (RSI) and reflux finding score (RFS) after treating LPR with three different regimens. DESIGN: A prospective, double-blind, randomized clinical trial. SETTING: Chungnam national university hospital in Korea. PARTICIPANTS: From July 2015 to July 2017, 100 patients with LPR included in the study. The patients were prescribed one of the following regimens for 3 months: group A, ilaprazole 10 mg, once a day (QD), n = 29; group B, ilaprazole 10 mg, twice a day (BID), n = 27; and group C, ilaprazole 10 mg BID plus mosapride citrate 5 mg three times a day (TID), n = 44. MAIN OUTCOME MEASURES: The total RSI and RFS scores and each subitems in RSI and FRS of the patients were evaluated. RESULTS: Total RFS and RSI scores improved significantly at the 3-month follow-up in all groups, and the improvements were of similar magnitudes. Regarding the RFS, the degrees of improvement in vocal cord oedema (P = 0.002) and diffuse laryngeal oedema (P = 0.003) scores differed significantly among the three groups. Moreover, overweight or obese patients in group C showed the greatest improvement in RFS. However, age had no effect on treatment efficacy. CONCLUSION: Three PPI therapeutic strategies showed similar efficacies against LPR according to total RFS and RSI scores. The addition of a prokinetic resulted in improvements in specific endoscopic findings, such as vocal cord oedema and diffuse laryngeal oedema. Furthermore, the addition of a prokinetic to PPI therapy was particularly beneficial for overweight or obese patients.

Ilaprazole Compared With Rabeprazole in the Treatment of Duodenal Ulcer: A Randomized, Double-blind, Active-controlled, Multicenter Study.

GOALS: The main goal of this study was to explore the dose-effect relationship of ilaprazole. BACKGROUND: Ilaprazole is a kind of benzimidazole proton-pump inhibitor, which was confirmed efficacious and safe in treatment of duodenal ulcer (DU). However, the dose-effect relationship of ilaprazole was not clear. STUDY: This was a double-blind, parallel, randomized study. Patients aged above 18 years with at least one endoscopically confirmed active nonmalignant DU were treated with rabeprazole 10 mg or ilaprazole 10 mg/5 mg for 4 weeks. Healing of ulcer was determined by its resolution from active to scarring stage. Symptoms relief was evaluated using a graded score. Safety and tolerability were evaluated on basis of clinical assessments. RESULTS: A total of 390 patients completed the study finally. Ulcers were successfully healed in 75.38%, 77.86%, and 83.72% of patients after 4-week treatment with rabeprazole 10 mg, ilaprazole 5 mg, and ilaprazole 10 mg, respectively. The 4-week healing rate difference between rabeprazole 10 mg and ilaprazole 5 mg was 2.48% (95% confidence interval: -7.79% to 12.74%) leading to accept the noninferiority hypothesis. Logistic regression model suggested that ilaprazole 10 mg was superior to ilaprazole 5 mg at week 2 (odds ratio, 1.92; 95% confidence interval: 1.02, 3.59; P=0.04). Most patients (80%) became asymptomatic after treatment. At the dosages administered, the 3 drug groups exhibited similar efficacy and a similar safety profile. CONCLUSIONS: Ilaprazole 5 mg is not inferior to rabeprazole 10 mg in treating DU, and a dose-effect relationship have been revealed between 5 mg and 10 mg of ilaprazole.

A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents.

BACKGROUND AND AIMS: Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers. Subsequently, we developed a population-based pharmacokinetic (PopPK) model to characterize pantoprazole disposition and evaluated appropriate pantoprazole dosing strategies for obese pediatric patients, using simulation. METHODS: Pharmacokinetic data from the only prospective study of PPIs in obese children (aged 6-17 years; n = 40) included 273 pantoprazole and 256 pantoprazole-sulfone plasma concentrations, after single oral-dose administration, and were used for pantoprazole model development and covariate analysis (NONMEM®). Model evaluation was performed via bootstrapping and predictive checks, and the final model was applied to simulate systemic pantoprazole exposures for common dosing scenarios. RESULTS: A two-compartment PopPK model, which included CYP2C19 genotype and total body weight, provided the best fit. Resultant, typical, weight-normalized pantoprazole parameter estimates were different than previously reported for children or adults, with significantly reduced pantoprazole CL/F for obese children. Of the dosing scenarios evaluated, the weight-tiered approach, approved by the US Food and Drug Administration, achieved pantoprazole exposures [area under the curve (AUC0-∞)] within ranges previously reported as therapeutic, without over- or under-prediction for obese children. CONCLUSIONS: Our data argue against empiric dose escalation of PPIs for obese children and support current FDA-approved pediatric weight-tiered dosing for pantoprazole; however, 3- to 5-fold inter-individual variability in pantoprazole AUC0-∞ remained using this dosing approach.

Vasostatin-1: A novel circulating biomarker for ileal and pancreatic neuroendocrine neoplasms.

BACKGROUND: Chromogranin A (CgA) is a plasma biomarker widely used in the follow-up of patients with neuroendocrine neoplasms (NENs). However, its accuracy as a tumor biomarker is relatively low because plasma CgA can increase also in patients with other diseases or in subjects treated with proton-pump inhibitors (PPIs), a class of widely-used drugs. METHODS: In the attempt to identify a more reliable biomarker for NENs, we investigated, by ELISA, the circulating levels of full-length CgA (CgA1-439) and of various CgA-derived fragments in 17 patients with ileal or pancreatic NENs, 10 healthy controls, and 21 healthy volunteers before and after treatment with PPIs. RESULTS: Patients with ileal or pancreatic NENs showed increased plasma levels of total-CgA and CgA1-76 fragment (vasostatin-1, VS-1) compared to controls [median (25th-75th-percentiles); total-CgA: 1.85 nM (1.01-4.28) vs 0.75 nM (0.52-0.89), p = 0.004; VS-1: 2.76 nM (1.09-7.10) vs 0.29 nM (0.26-0.32), p<0.001, respectively], but not of CgA1-439 or CgA1-373 fragment. VS-1 positively correlated with total-CgA (r = 0.65, p<0.001). The Receiver Operating Characteristic area under the curve was 0.9935 for VS-1 and 0.8824 for total-CgA (p = 0.067). Treatment of patients with somatostatin analogues decreased both total-CgA and VS-1. In contrast, administration of PPIs increased the plasma levels of total-CgA, but not of VS-1. CONCLUSION: These findings suggest that plasma VS-1 is a novel biomarker for ileal and pancreatic NENs. Considering that VS-1 is a well-defined fragment not induced by proton-pump inhibitors, this polypeptide might represent a biomarker for NENs diagnosis and follow-up more accurate and easier to standardize than CgA.

Pharmacokinetic drug interaction and safety after coadministration of clarithromycin, amoxicillin, and ilaprazole: a randomised, open-label, one-way crossover, two parallel sequences study.

PURPOSE: Ilaprazole, the latest proton pump inhibitor, can be used with clarithromycin and amoxicillin as a triple therapy regimen for eradicating Helicobacter pylori. The aim of this study was to evaluate pharmacokinetic drug interactions and safety profiles after coadministration of clarithromycin, amoxicillin, and ilaprazole. METHODS: A randomised, open-label, one-way crossover, two parallel sequences study was conducted in 32 healthy subjects. In part 1, the subjects received a single dose of ilaprazole 10 mg in period 1 and clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 6 days in period 2. In part 2, the subjects received clarithromycin 500 mg and amoxicillin 1000 mg once in period 1 and ilaprazole 10 mg twice daily for 6 days in period 2. In both sequences, the three drugs were coadministrated once on day 5 in period 2. Pharmacokinetic evaluations of ilaprazole (part 1), and clarithromycin and amoxicillin (part 2) were conducted. RESULTS: Twenty-eight subjects completed the study. For ilaprazole, the peak concentration (Cmax) slightly decreased from 479 (ilaprazole alone) to 446 ng/mL (triple therapy) [Geometric least square mean ratio (90% confidence interval), 0.93 (0.70-1.22)]. The area under the concentration-time curve from 0 h to the last measurable concentration (AUClast) slightly increased from 3301 to 3538 µg·h/mL [1.07 (0.85-1.35)]. For clarithromycin, the Cmax slightly decreased from 1.87 to 1.72 µg/mL [0.90 (0.70-1.15)], and AUClast slightly increased from 14.6 to 16.5 µg·h/mL [1.09 (0.87-1.37)]. For amoxicillin, the Cmax slightly decreased from 9.37 to 8.14 µg/mL [0.86 (0.74-1.01)], and AUClast slightly decreased from 27.9 to 26.7 µg·h/mL [0.98 (0.83-1.16)]. These changes in the PK parameters of each drug were not statistically significant. CONCLUSIONS: The coadministration of ilaprazole, clarithromycin, and amoxicillin was tolerable and did not cause a significant PK drug interaction. Thus, a triple therapy regimen comprising ilaprazole, clarithromycin, and amoxicillin may be an option for the eradication of H. pylori. Clinicaltrials.gov number: NCT02998437.

Empirical treatment of outpatients with gastroesophageal reflux disease with proton pump inhibitors: A survey of Chinese patients (the ENLIGHT Study).

BACKGROUND AND AIM: Empirical proton pump inhibitor (PPI) treatment is recommended as a diagnostic indicator for gastroesophageal reflux disease (GERD) and as a therapy for symptomatic control, with responses generally seen within 4 weeks. However, there are no real-world data assessing the effectiveness of short-term empirical treatment with PPIs in patients with GERD in China. METHODS: The ENLIGHT study was a multicenter, prospective, observational study conducted in China. The primary outcome was the overall response rate after 4 weeks' empirical treatment with PPIs. Adult patients aged between 18 and 65 years of age, with a gastroesophageal reflux disease questionnaire score of ≥ 8, prescribed empirical PPI treatment by their physicians and with no planned endoscopy were eligible to participate. Statistical analyses were primarily descriptive. RESULTS: Overall, 987 patients were eligible to participate and were included in the full analysis set (FAS); 707 patients were included in the per protocol set. In the FAS, esomeprazole was received by 57.1% of patients and was the most commonly used PPI. After 4-week treatment, 71.1% (95% confidence interval [CI], 67.9% to 74.2%) of patients were considered responders to PPI. The response rate at the end of 2-week PPI treatment reached 57.0% (95% CI, 52.5% to 61.7%). The median time to response was 13 days (95% CI, 12 to 15). Response rates at 2 and 4 weeks of the per protocol set were similar to those of the FAS. CONCLUSIONS: Short-term empirical PPI treatment can provide an effective relief of GERD symptoms in most Chinese patients in real-world practice.

A randomized, double blind, controlled, multi center study of Ilaparazole in the treatment of reflux esophagitis-Phase III clinical trial.

AIM AND BACKGROUND: Proton pump inhibitors (PPIs) are the main drugs for the treatment of reflux esophagitis. Phase II clinical trials showed that, compared with Esomeprazole, the new PPI Ilaparazole is great in terms of efficacy for reflux symptoms relief and curling for esophagitis. The aim of this study was to confirm suitable dose of Ilaparazole in the treatment of reflux esophagitis. METHODS: This study used a randomized, double-blind, parallel positive drug control, multi-center design. A total of 537patients diagnosed as reflux esophagitis by gastroscopy were randomly divided into Ilaparazole group (n = 322, Ilaparazole 10 mg QD) and esomeprazole group (n = 215, Esomeprazole 40 mg QD). The patients in the two groups were treated for 8 weeks. Heartburn and reflux symptoms prior to treatment, and 2, 4 and 8 weeks after the treatment were assessed. Gastroscopy was performed after 4 weeks of treatment. Unhealed patients within 4 weeks underwent gastroscopy again at the end of 8 weeks. RESULTS: A total of 471 cases completed the treatment. In Esomeprazole and Ilaparazole groups. After 8 weeks treatment, the healing rate in Esomeprazole group and Ilaparazole group were 82.79% (94.94%) and 83.54% (92.50%), respectively. The corresponding rate difference [Ilaparazole-esomeprazole] was 0.75% (-2.44%) and the two-sided 95% CI was -5.72 to 7.22 (-6.90 to 2.01). The symptom disappearance rates for FAS (PPS) were 75.81% (82.02%) and 76.71% (80.36%) P = 0.8223 (0.7742). Adverse reactions related to the drugs were: 10.70% and 11.80%, (P = 0.7817). CONCLUSIONS: The efficacy and safety of Ilaparazole (10 mg/day) in treating reflux esophagitis was similar to esomeprazole (40 mg/day). Ilaparazole (10 mg/day) can be used in the treatment of esophagitis. The clinical trial registration number of the study is NCT 02860624.

High-dose vs. Low-dose Proton Pump Inhibitors post-endoscopic hemostasis in patients with bleeding peptic ulcer. A meta-analysis and meta-regression analysis.

BACKGROUND/AIMS: Present meta-analysis aims to evaluate studies of low- versus high-dose proton pump Inhibitors (PPI) post-endoscopic hemostasis, including the newly published randomized controlled trials (RCTs) and to conclude whether low-dose PPI can generate the comparable results as high-dose PPI. MATERIALS AND METHODS: To identify suitable trials, the electronic databases PubMed, Medline, Cochrane Library, and the Embase were used. All RCTs concerning low- versus high-dose PPI administration post-endoscopic hemostasis published until December 2016 were identified. Primary outcomes were rebleeding rates, need for surgical intervention, and mortality. RESULTS: Studies included a total of 1.651 participants. There were significantly less cases of rebleeding in the low-dose PPI treatment arm (p=0.003). All but one study provided data concerning need for Surgical Intervention and Mortality. The respective effect sizes were [odds ratio (OR), 95% confidence intervals (CI): 1.35, 0.72-2.53] and [OR, 95% CI: 1.20, 0.70-2.05]. Both treatment arms were comparable considering the aforementioned outcomes (p=0.35 and p=0.51, respectively). Meta-regression analysis likewise unveiled comparable outcomes between studies using pantoprazole versus lansoprazole concerning all three outcomes [rebleeding (p=0.944), surgical intervention (p=0.884), and mortality (p=0.961)]. CONCLUSION: A low-dose PPI treatment is equally effective as a high-dose PPI treatment following endoscopic arresting of bleeding. However, we anticipate the completion of more high-quality RCTs that will embrace distinct ethnicities, standardized endoscopic diagnosis and management, double-blind strategies, and appraisal of results working specific standards over clear-cut follow-up periods.

Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study.

PURPOSE: We investigated whether early enteral nutrition alone may be sufficient prophylaxis against stress-related gastrointestinal (GI) bleeding in mechanically ventilated patients. MATERIALS AND METHODS: Prospective, double blind, randomized, placebo-controlled, exploratory study that included mechanically ventilated patients in medical ICUs of two academic hospitals. Intravenous pantoprazole and early enteral nutrition were compared to placebo and early enteral nutrition as stress-ulcer prophylaxis. The incidences of clinically significant and overt GI bleeding were compared in the two groups. RESULTS: 124 patients were enrolled in the study. After exclusion of 22 patients, 102 patients were included in analysis: 55 patients in the treatment group and 47 patients in the placebo group. Two patients (one from each group) showed signs of overt GI bleeding (overall incidence 1.96%), and both patients experienced a drop of >3 points in hematocrit in a 24-hour period indicating a clinically significant GI bleed. There was no statistical significant difference in the incidence of overt or significant GI bleeding between groups (p=0.99). CONCLUSION: We found no benefit when pantoprazole is added to early enteral nutrition in mechanically ventilated critically ill patients. The routine prescription of acid-suppressive therapy in critically ill patients who tolerate early enteral nutrition warrants further evaluation.

Additive Effects of Rebamipide Plus Proton Pump Inhibitors on the Expression of Tight Junction Proteins in a Rat Model of Gastro-Esophageal Reflux Disease.

BACKGROUND/AIMS: The aim of this study was to investigate the effects of rebamipide on tight junction proteins in the esophageal mucosa in a rat model of gastroesophageal reflux disease (GERD). METHODS: GERD was created in rats by tying the proximal stomach. The rats were divided into a control group, a proton pump inhibitor (PPI) group, and a PPI plus rebamipide (PPI+R) group. Pantoprazole (5 mg/kg) was administered intraperitoneally to the PPI and PPI+R groups. An additional dose of rebamipide (100 mg/kg) was administered orally to the PPI+R group. Mucosal erosions, epithelial thickness, and leukocyte infiltration into the esophageal mucosa were measured in isolated esophagi 14 days after the procedure. A Western blot analysis was conducted to measure the expression of claudin-1, -3, and -4. RESULTS: The mean surface area of mucosal erosions, epithelial thickness, and leukocyte infiltration were lower in the PPI group and the PPI+R group than in the control group. Western blot analysis revealed that the expression of claudin-3 and -4 was significantly higher in the PPI+R group than in the control group. CONCLUSIONS: Rebamipide may exert an additive effect in combination with PPI to modify the tight junction proteins of the esophageal mucosa in a rat model of GERD. This treatment might be associated with the relief of GERD symptoms.

Safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole sodium injections after single and multiple intravenous doses in healthy Chinese subjects.

PURPOSE: The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole (PPZ) sodium injections following single and multiple intravenous doses in healthy Chinese subjects. METHODS: The dosage groups were set as followed: 20 mg of single and multiple intravenous administration of S-(-)-PPZ, 40 mg of single and multiple intravenous administration of S-(-)-PPZ or pantoprazole, and 80 mg of single dosage group of S-(-)-PPZ. Subjects were sampled for pharmacokinetic analysis and were monitored for 24-h intragastric pH prior to and 48-h intragastric pH after administration for the pharmacodynamic study. The pharmacokinetic and pharmacodynamic parameters were compared between S-(-)-PPZ and PPZ. Safety was evaluated on the basis of adverse events, vital signs, laboratory tests, and physical examination. RESULTS: All adverse events were mild and of limited duration. Maximum plasma concentration and area under the concentration-time curve for S-(-)-PPZ were dose proportional over the range of 20-80 mg following a single intravenous administration. Elimination rate constant and half-life observed statistical difference from a single dose to multiple doses in 40 mg of S-(-)-PPZ groups. After administration of a single dose, the mean 24-h intragastric pH value was observed higher in 80-mg group than in 40- and 20-mg groups. Slightly increase of intragastric pH was found after a single dose of 40 mg S-(-)-PPZ than 40 mg PPZ; however, the differences were not statistically significant. CONCLUSIONS: Twice daily of 40 mg S-(-)-PPZ sodium injections is effective in achieving satisfying acid inhibition. Compared with plasma R-(+)-PPZ levels, most subjects presented more potent and prolonged suppression of gastric acid of S-(-)-PPZ, while a few subjects showed faster metabolic rate of S-(-)-PPZ in vivo.

Comparative effectiveness and acceptability of the FDA-licensed proton pump inhibitors for erosive esophagitis: A PRISMA-compliant network meta-analysis.

BACKGROUND: This study compared the effectiveness and acceptability of all Food and Drug Administration (FDA)-recommended dose proton pump inhibitors (PPIs) in erosive esophagitis (EE): Dexlansoprazole 60 mg, Esomeprazole 40 mg, Esomeprazole 20 mg, Pantoprazole 40 mg, Lansoprazole 30 mg, Rabeprazole 20 mg, Omeprazole 20 mg. METHODS: A systematic literature search was performed using PubMed, Embase, and Cochrane Library. Totally, 25 randomized controlled trials (RCTs) met study selection criteria and were incorporated in this network meta-analysis (NMA) study. RESULTS: For the NMA, eligible RCTs of adults with EE verified by endoscopic examination were randomly assigned to the licensed PPIs at least 4 weeks of continuous therapy. The primary efficacy outcome was the endoscopic healing rates at 4 and 8 weeks. Heartburn relief rates were a secondary efficacy outcome. The rates of withdrawal were analyzed as a safety outcome. In comparison to the common comparator omeprazole 20 mg, esomeprazole 40 mg provided significantly healing rates at 4 weeks [odds ratio (OR), 1.46 (95% confidence interval, 95% CI, 1.24-1.71)] and 8 weeks [1.58 (1.29-1.92)], and improved the heartburn relief rates [1.29 (1.07-1.56)]. In comparison to lansoprazole 30 mg, esomeprazole 40 mg provided significantly healing rates at 4 weeks [1.30 (1.10-1.53)] and 8 weeks [1.37 (1.13-1.67)], and improved the heartburn relief rates [1.29 (1.03-1.62)]. In terms of acceptability, only dexlansoprazole 60 mg had significantly more all-cause discontinuation than omeprazole 20 mg [1.54 (1.03-2.29)], pantoprazole 40 mg [1.68 (1.08-2.63)], and lansoprazole 30 mg [1.38 (1.02-1.88)]. CONCLUSION: The standard-dose esomeprazole 40 mg had more superiority in mucosal erosion healing and heartburn relief. Esomeprazole 40 mg, pantoprazole 40 mg, esomeprazole 20 mg, and lansoprazole 30 mg showed more benefits in effectiveness and acceptability than other interventions.

Impact of age on laryngopharyngeal reflux disease presentation: a multi-center prospective study.

The objective is to assess the differences in the severity of symptoms, signs, voice quality, and quality of life before and after treatment according to age in suspected laryngopharyngeal reflux (LPR) patients. The design used in this paper is prospective multi-center study. Eighty clinically diagnosed LPR patients with a reflux finding score (RFS) >7 and a reflux symptom index (RSI) >13 were treated with pantoprazole and diet recommendations for 3 months. Patients were subdivided into three groups according their age: group 1 (18-39 years, N = 21), group 2 (40-59 years, N = 31), and group 3 (≥60 years, N = 28). RSI, RFS, Voice Handicap Index (VHI), Short Form 36 questionnaire (SF36), aerodynamic, and acoustic measurements were evaluated at baseline and after treatment. The response to the empiric treatment was also assessed. Significant improvements in RSI, RFS, and VHI were found in all patient groups. The elderly patients showed a significantly lower RSI score than younger subjects (p = 0.035) without RFS difference among groups. At baseline, the SF36 score was better in group 3 with respect to social functioning (p = 0.049). At the 3-month follow-up, we found significant improvement of acoustic parameters only in the younger age groups (group 1 and group 2). The rate of resistant patients to the empiric treatment was higher in the younger group than in the elderly patient group (42.9 versus 28.6%). Age appears to reduce the subjective LPR symptom perception, leading to a lower rate of uncured patients. The utilization of acoustic parameters as an indicator of treatment effectiveness seems less useful for elderly subjects, probably due to an overlap between an aging voice and LPR.