Pharmacokinetics and Pharmacodynamics of Lansoprazole/Sodium Bicarbonate Immediate-release Capsules in Healthy Chinese Subjects: An Open, Randomized, Controlled, Crossover, Single-, and Multiple-dose Trial.

Proton pump inhibitors (PPIs) differ in onset of action and bioavailability. This trial was conducted to investigate the pharmacokinetics and pharmacodynamics of an immediate-release capsule formulation containing lansoprazole 30 mg and sodium bicarbonate 1100 mg (T preparation) in healthy Chinese subjects. This was an open, single-center, randomized, single and multiple oral doses, and two-period crossover study in 30 healthy subjects. After single- and multiple-dose oral administration, blood samples were obtained and lansoprazole concentration in serum was measured for pharmacokinetic analysis. Meanwhile, the intragastric pH was monitored continuously to evaluate the pharmacodynamics of the investigational drugs. The Tmax of the T preparation was 0.5 hours, while the Tmax of the R preparation was 1.5 hours after multiple doses, which indicated that the absorption speed of the T preparation was significantly faster than that of the R preparation. The same characteristics also existed after single-dose administration. The area under the curve (AUC)ss of the T preparation was bio-equivalent to that of the R preparation under steady state. The time percentage of intragastric pH > 4.0 for the T preparation was higher than that of the R preparation after 1 hour for both single- and multiple-dose. It suggested compared with R preparation, the time percentage of intragastric pH > 4.0 met the criteria for superiority after 1 hour administration for the T preparation. In addition, no serious adverse events occurred in this study. Across this study, the T preparation was better than the R preparation at improving drug absorption and increasing intragastric pH, and had a favorable safety profile.

Controlled release floating drug delivery system for proton pump inhibitors lansoprazole: In-vitro, In-vivo floating and pharmacokinetic evaluation.

Lansoprazole (LPZ) show poor bioavailability because of first pass effect and absorption factors. The floating delivery systems could reduce fluctuations in plasma drug concentration through maintaining desirable plasma drug concentration. The objective of present study was to enhance bioavailability despite first pass effect through continuous availability of drug from floating system. Gum tragacanth (GT) and itaconic acid (IA) based floating hydrogels (FH) were synthesized. Parameters optimized were; microwave radiation exposure time, pH, GT:IA ratio and concentration of the glutaraldehyde. Optimized FH were evaluated for entrapment efficiency (% EE), in-vitro release, FTIR, SEM, and in- vitro and in-vivo floating study. Finally, pharmacokinetic was evaluated in ulcer-induced SD rats. Grafting percentage, swelling ratio and %EE of LPZ was 115%, Ì´250% and 90%, respectively. Microwave radiation exposure time, pH of reaction medium, GT:IA ratios and cross linker concentration were 2 min, pH 5, ratios 2:1 and 0.02%, respectively. The optimized FH showed acceptable floating behavior. The X-ray images revealed that hydrogels remained floated over gastric contents up to 24 hours. The in-vitro release and pharmacokinetics revealed availability of LPZ upto to 24h in-vitro and in ulcer-induced SD rats, respectively. The present hydrogels based floating system of lansoprazole is capable to extend the gastric residence time upto 24 hours.

In vitro evaluation of enteral tube administration of lansoprazole orally disintegrating tablets.

Lansoprazole orally disintegrating tablets (ODTs) can be administered orally or through a nasogastric (NG) tube for patients who are unable to swallow. In addition, off-label administration through gastrostomy (G) or jejunal (J) tubes has been reported. The purpose of this study was to develop in vitro methods to assess the risk of clogging during administration of two lansoprazole ODTs through enteral feeding tubes. Feeding tubes of various compositions and geometries were selected for testing. Disintegration, sedimentation, percent recovery, acid phase dissolution testing, and particle size distribution measurements were performed. The results indicated that G tubes had the greatest risk of clogging compared to NG and J tubes. In addition, larger particles and an increased amount of insoluble excipients observed in Product B resulted in more irreversible enteral tube clogging than compared to Product A. The geometry and design of the tube also had an impact on the amount of lansoprazole recovered after enteral tube administration. Lansoprazole ODTs demonstrated acid resistance stability regardless of the water used for suspension. The in vitro methods discussed in this work could be used to evaluate in vitro equivalence and to assess the risk of delivering a drug product through an enteral feeding tube.

Gastric mucosal changes, and sex differences therein, after Helicobacter pylori eradication: A long-term prospective follow-up study.

BACKGROUND AND AIM: Improvement of atrophic gastritis and intestinal metaplasia (IM) is considered to reduce the gastric cancer risk, but whether it can be achieved by H. pylori eradication (HPE) remains controversial. To evaluate the effect of HPE, we observed the gastric mucosa for up to17 years after HPE and sex differences in gastric mucosa. METHODS: In total, 172 patients (94 males, 78 females) with HPE were enrolled. Annual histological evaluations were performed for up to 17 years. The grades of mononuclear cells, neutrophils, atrophy, IM in the antrum and corpus were evaluated using the updated Sydney system. RESULTS: Relative to the pre-HPE period, atrophy had improved significantly 1 year after HPE in the antrum (1.50 ± 0.75 vs. 1.21 ± 1.25, P < 0.01) and corpus (0.59 ± 0.75 vs. 0.18 ± 0.52, P < 0.05). IM showed no significant change during 17 years after HPE at either biopsy site. Atrophy scores did not differ significantly between males and females. IM scores were significantly higher in males than in females before eradication (antrum, 0.67 ± 0.94 vs. 0.44 ± 0.77, P = 0.003, corpus, 0.20 ± 0.62 vs. 0.047 ± 0.21, P = 0.0027) and at most observation timepoints. CONCLUSIONS: During 17 years after HPE, atrophy, but not IM, improved significantly at the greater curvatures of the antrum and corpus. IM was significantly more severe in males than in females. Careful follow-up after HPE based on sex differences in gastric mucosal characteristics is important.

Use of proton pump inhibitors to treat persistent throat symptoms: multicentre, double blind, randomised, placebo controlled trial.

OBJECTIVE: To assess the use of proton pump inhibitors (PPIs) to treat persistent throat symptoms. DESIGN: Pragmatic, double blind, placebo controlled, randomised trial. SETTING: Eight ear, nose, and throat outpatient clinics, United Kingdom. PARTICIPANTS: 346 patients aged 18 years or older with persistent throat symptoms who were randomised according to recruiting centre and baseline severity of symptoms (mild or severe): 172 to lansoprazole and 174 to placebo. INTERVENTION: Random blinded allocation (1:1) to either 30 mg lansoprazole twice daily or matched placebo twice daily for 16 weeks. MAIN OUTCOME MEASURES: Primary outcome was symptomatic response at 16 weeks measured using the total reflux symptom index (RSI) score. Secondary outcomes included symptom response at 12 months, quality of life, and throat appearances. RESULTS: Of 1427 patients initially screened for eligibility, 346 were recruited. The mean age of the study sample was 52.2 (SD 13.7) years, 196 (57%) were women, and 162 (47%) had severe symptoms at presentation; these characteristics were balanced across treatment arms. The primary analysis was performed on 220 patients who completed the primary outcome measure within a window of 14-20 weeks. Mean RSI scores were similar between treatment arms at baseline: lansoprazole 22.0 (95% confidence interval 20.4 to 23.6) and placebo 21.7 (20.5 to 23.0). Improvements (reduction in RSI score) were observed in both groups-score at 16 weeks: lansoprazole 17.4 (15.5 to19.4) and placebo 15.6 (13.8 to 17.3). No statistically significant difference was found between the treatment arms: estimated difference 1.9 points (95% confidence interval -0.3 to 4.2 points; P=0.096) adjusted for site and baseline symptom severity. Lansoprazole showed no benefits over placebo for any secondary outcome measure, including RSI scores at 12 months: lansoprazole 16.0 (13.6 to 18.4) and placebo 13.6 (11.7 to 15.5): estimated difference 2.4 points (-0.6 to 5.4 points). CONCLUSIONS: No evidence was found of benefit from PPI treatment in patients with persistent throat symptoms. RSI scores were similar between the lansoprazole and placebo groups after 16 weeks of treatment and at the 12 month follow-up. TRIAL REGISTRATION: ISRCTN Registry ISRCTN38578686 and EudraCT 2013-004249-17.

Acute kidney injury following the use of different proton pump inhibitor regimens: A real-world analysis of post-marketing surveillance data.

BACKGROUND AND AIM: Recent evidence has concerned acute kidney injury (AKI) after the proton pump inhibitor (PPI) application. There are few real-world studies to compare the occurrences, clinical features, and prognosis of AKI related to various PPI regimens. We aimed to evaluate and compare the links between different PPIs and AKI in a large population by investigating the Food and Drug Administration Adverse Event Reporting System (FAERS) until recently. METHODS: Disproportionality analysis and Bayesian analysis were used in data mining to screen the suspected AKI after different PPIs based on the FAERS from January 2004 to December 2019. The times to onset, fatality, and hospitalization rates of PPI-associated AKI were also investigated. RESULTS: We identified 19 522 PPI-associated AKIs, which appeared to influence more middle-aged patients than elderly ones (53.04% vs 33.94%). Women were more affected than men (55.42% vs 44.58%). Lansoprazole appeared a stronger AKI association than other PPIs, based on the highest reporting odds ratio (reporting odds ratio = 20.8, 95% confidence interval = 20.16, 21.46), proportional reporting ratio (proportional reporting ratio = 15.55, χ2  = 73 899.68), and empirical Bayes geometric mean (empirical Bayes geometric mean = 15.15, 95% confidence interval = 14.76). The median time to AKI onset was 446 (interquartile range [IQR] 16-2176) days after PPI administration. PPIs showed a significant difference in average time to AKI onset (P < 0.001), with the shortest of 9 (IQR 3-25) days for rabeprazole and the longest of 1221 (IQR 96.5-2620) days for esomeprazole. PPI-associated AKI generally led to a 5.69% fatality rate and an 8.94% hospitalization rate. The highest death rate occurred in rabeprazole (15.35%). CONCLUSIONS: Based on the FAERS database, we profiled AKI related to various PPIs with more details in occurrences, clinical characteristics, and prognosis. Concern should be paid for PPIs when applied to patients with a tendency for AKI.

Autophagy blockade mechanistically links proton pump inhibitors to worsened diabetic nephropathy and aborts the renoprotection of metformin/enalapril.

AIM: Proton pump inhibitors (PPIs) are widely used drugs recently linked to chronic kidney disease. However, the invloved mechanisms remained elusive. Since defective autophagy is identified as a new culprit in the pathogenesis of diabetic nephropathy (DN), we aimed to trace the link of autophagy blockade by PPIs to the progression of DN with and without the standard therapy of metformin and enalapril. MAIN METHODS: Male CD1 albino mice (20-25 g) were randomly assigned to normal control or diabetic mice. Diabetes was induced by intraperitoneal streptozotocin (35 mg/kg) injection combined with high fat diet. DN mice were randomized to receive vehicle, lansoprazole (5 mg/kg), metformin (200 mg/kg), lansoprazole + metformin, metformin + enalapril (0.5 mg/kg) or the three drugs together, orally daily for four weeks. At the study end, albuminuria, fasting plasma glucose, HbA1c, renal functions and malondialdehyde were assessed. Renal tissues were examined microscopically, and autophagic changes were evaluated by immunohistochemical detection of LC3-II and p62. KEY FINDINGS: Consistent with autophagic blockade, lansoprazole increased both LC3II and p62 in the glomerular and tubular cells. This was associated with impaired creatinine clearance and renal functions, enhanced albuminuria, oxidative stress and augmented DN histopathological changes. Opposite effects on autophagy markers were observed by single or combined treatment of metformin with enalapril; which also ameliorated glycemic control and signs of DN. This improvement was mitigated by combination with lansoprazole. SIGNIFICANCE: Autophagy blockade by lansoprazole augmented diabetic nephropathy and opposed the reno-protective effects of metformin and enalapril. The use of PPIs in diabetes should be considered with great caution.

Acute upper gastrointestinal bleed in the puerperium following weight reduction surgery.

Bariatric surgery is often a definitive treatment for obesity and is increasingly being performed on women of childbearing age. While bariatric surgery may reduce the risk of obesity in pregnancy, there are new complications which can develop following these procedures. Our case describes a 31-year-old women who presented in the puerperium with a life-threatening upper gastrointestinal bleed secondary to marginal ulceration following a Roux-en-Y procedure. This case report discusses a rare case of acute upper gastrointestinal bleed in the postnatal period and highlights the risk factors and complications which may present in the obstetrical patient following bariatric surgery. With the increasing use of weight loss surgery in obese women and the associated improvement in fertility following, we must remain aware of the risks and these women should be identified at booking so that their antenatal and postnatal care can be tailored accordingly.

Randomised clinical trial: tegoprazan, a novel potassium-competitive acid blocker, or lansoprazole in the treatment of gastric ulcer.

BACKGROUND: Tegoprazan is a novel potassium-competitive acid blocker for the treatment of acid-related disorders. AIMS: To assess whether tegoprazan is non-inferior to lansoprazole in terms of efficacy and safety in patients with gastric ulcers. METHODS: In this phase 3, double-blind, active control, multicentre study, 306 gastric ulcer patients were randomised to one of three treatment groups: tegoprazan 50 mg, tegoprazan 100 mg and lansoprazole 30 mg once daily for 4 or 8 weeks. The primary endpoint was the cumulative proportion of patients with healed ulcers confirmed by endoscopy up to 8 weeks from treatment initiation. Symptoms and safety were assessed. RESULTS: In the full analysis set, the cumulative healing rates at week 8 were 94.8% (91/96) for the tegoprazan 50 mg, 95.0% (94/99) for the tegoprazan 100 mg and 95.7% (89/93) for the lansoprazole 30 mg groups. At week 4, the respective healing rates were 90.6% (87/96), 91.9% (91/99), and 89.2% (83/93). In per protocol analysis, 4-week healing rates were 95.4% (84/88), 94.6% (88/93) and 92.9% (79/85) for tegoprazan 50 mg, tegoprazan 100 mg and lansoprazole 30 mg, respectively. Both doses of tegoprazan were non-inferior to lansoprazole in ulcer healing at 4 and 8 weeks. The incidence of drug-related treatment-emergent adverse events did not differ among groups. The increase in serum gastrin concentration was not higher in tegoprazan-treated patients than in lansoprazole-treated patients. CONCLUSIONS: Tegoprazan 50 or 100 mg were not inferior to lansoprazole 30 mg once daily in the treatment of gastric ulcers.

Efficient incorporation and protection of lansoprazole in cyclodextrin metal-organic frameworks.

Lansoprazole (LPZ) is an acid pump inhibitor, which readily degrades upon acidic or basic conditions and under heating. We investigated here LPZ stability upon incorporation in particles made of cyclodextrin metal-organic frameworks (CD-MOFs). LPZ loaded CD-MOFs were successfully synthesized, reaching high LPZ payloads of 23.2 ± 2.1 wt%, which correspond to a molar ratio of 1:1 between LPZ and γ-CD. The homogeneity of LPZ loaded CD-MOFs in terms of component distribution was confirmed by elemental mapping by STEM-EDX. Both CTAB, the surfactant used in the CD-MOFs synthesis, and LPZ compete for their inclusion in the CD cavities. CTAB allowed obtaining regular cubic particles of around 5 µm with 15 wt% residual CTAB amounts. When LPZ was incorporated, the residual CTAB amount was less than 0.1 wt%, suggesting a higher affinity of LPZ for the CDs than CTAB. These findings were confirmed by molecular simulations. Vibrational circular dichroism studies confirmed the LPZ incorporation inside the CDs. Solid-state NMR showed that LPZ was located in the CDs and that it remained intact even after three years storage. Remarkably, the CD-MOFs matrix protected the drug upon thermal decomposition. This study highlights the interest of CD-MOFs for the incorporation and protection of LPZ.

Comparison of the efficiency of two different proton pump inhibitor formula in treatment of patients with atypical gastroesophageal reflux disease: a prospective randomized study.

BACKGROUND AND AIM: The prospective, open-label, randomized study aims to compare the efficacy of lansoprazole, a fast orally disintegrating proton pump inhibitor (PPI), and dexlansoprazole, a dual delayed release PPI, in patients with atypical symptoms of gastroesophageal reflux disease (GERD). METHODS: Patients with atypical GERD symptoms with a total reflux symptom index score > 10 were eligible for enrollment. From February 2018 to December 2019, 232 subjects were randomly assigned (1:1 ratio) to receive oral lansoprazole, Takepron OD 30 mg, once daily before breakfast or oral dexlansoprazole, Dexilant 60 mg, once daily before breakfast for 8 weeks. The primary end-point is to compare the symptoms response rate after an 8-week PPI therapy between the two groups. RESULTS: There were 232 study subjects enrolling in this study. After the 8-week PPI therapy, dexlansoprazole-treated group had a significantly higher response rate than lansoprazole-treated group in cough (76.5% vs 38.0%) and globus (69.7% vs 30.8%) (P all < 0.05 by intention-to-treat). Multivariate logistic regression analysis showed that the use of dexlansoprazole, presence of dyslipidemia, and typical GERD symptoms (acid reflux and heartburn) were predictors for symptom response for cough; the use of dexlansoprazole and presence of erosive esophagitis were predictors for symptom response for globus (P all < 0.05). No predictor for therapy response to hoarseness was noted. CONCLUSIONS: There is a higher response rate for cough and globus symptoms in patients with atypical GERD after the 8-week PPI therapy with dexlansoprazole rather than lansoprazole.

Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility.

A decrease in the drug release rate over time typically affects the performance of hydrophilic matrices for oral prolonged release. To address such an issue, a Non-Uniform Drug Distribution Matrix (NUDDMat) based on hypromellose was proposed and demonstrated to yield zero-order release. The system consisted of 5 overlaid layers, applied by powder layering, having drug concentration decreasing from the inside towards the outside of the matrix according to a descending staircase function. In the present study, manufacturing and performance of the described delivery platform were evaluated using drug tracers having different water solubility. Lansoprazole, acetaminophen and losartan potassium were selected as slightly (SST), moderately (MST) and highly (HST) soluble tracers. By halving the thickness of the external layer, which contained no drug, linear release of HST and MST was obtained. The release behavior of the NUDDMat system loaded with a drug having pH-independent solubility was shown to be consistent in pH 1.2, 4.5 and 6.8 media. Based on these results, feasibility of the NUDDMat platform by powder layering was demonstrated using drugs having different physico-technological characteristics. Moreover, its ability to generate zero-order release was proved in the case of drugs with water solubility in a relatively wide range.

Helicobacter pylori Eradication Regressed Gastric Hyperplastic Polyp: A Randomized Controlled Trial.

BACKGROUND: Helicobacter pylori infection and hyperplastic polyp are known to have strong connections, but there are not enough randomized controlled trial data. AIMS: To evaluate the effect of H. pylori eradication on gastric hyperplastic polyp. METHOD: This is an open-labeled, single-center, randomized controlled trial. Patients with hyperplastic polyp and current infection of H. pylori were randomly assigned to eradication or non-eradication groups. All participants underwent follow-up endoscopy to investigate the regression of gastric polyps. Gastric polyp regression was defined as the disappearance of polyps or a reduction of more than 50% in size. RESULTS: Thirty-two patients were randomized to eradication (n = 17) and non-eradication groups (n = 15). Final included patients were 14 in eradication group and 13 in non-eradication group. All patients showed polyp regression in eradication group, whereas no regression was observed in non-eradication group (P < 0.001). Disappearance of polyp (n = 7) and decrease in size (n = 7) were observed in eradication group. In non-eradication group, no change (n = 5), increase of size (n = 5), and increase of number (n = 3) were observed. Mean regression time was 6.8 months, and disappearance time was 9.8 months. In non-eradication group, hyperglycemia was noted in 50% of progression group but not noted in no change group (P = 0.057). CONCLUSIONS: H. pylori eradication induced regression of hyperplastic polyp, and persistent H. pylori infection was related to progression of gastric polyp. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03065868.

The proton pump inhibitor, lansoprazole, prevents the development of non-traumatic osteonecrosis of the femoral head: an experimental and prospective clinical trial.

BACKGROUND: An effective prevention strategy for osteonecrosis of the femoral head (ONFH) has yet to be established. We previously reported that the innate immune system via the toll-like receptor (TLR) response induced by corticosteroids leads to the development of ONFH and that repression of IRF7 activity by an inhibitor could interfere with the development of ONFH while maintaining the therapeutic effect of the corticosteroids. OBJECTIVE: In the present study, we hypothesize that lansoprazole has the potential to suppress IRF7 activity and prevent corticosteroid-induced ONFH in rats. Furthermore, we conducted a preliminary clinical trial to prevent corticosteroid-induced ONFH in autoimmune disease patients. METHODS: Male Wistar rats were randomly divided into four groups. On Day 1, each rat was injected with TLR4 ligand (LPS) or TLR7 ligand (imiquimod), followed by methylprednisolone with or without lansoprazole on Day 2. They were killed at 1 or 14 days after the last injection.We prospectively recruited 30 patients requiring primary high-dose corticosteroid treatment for immune diseases. All patients were administered lansoprazole, starting the night before corticosteroid treatment began. MRI was performed before corticosteroid treatment, and at 4, 12 and 24 weeks afterward. RESULTS: In rats, co-treatment of lansoprazole with corticosteroids significantly repressed both IRF7 activity and the development of ONFH. Moreover, in the human patients, the incidence of ONFH was significantly decreased from 53.4 to 13.3%. CONCLUSIONS: Although the present study is preliminary, the results show that co-treatment of lansoprazole with corticosteroids prevents ONFH development. Lansoprazole may be both safe and effective in preventing osteonecrosis of the femoral head in patients needing corticosteroid treatment.

Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis.

OBJECTIVE: To establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO). DESIGN: In this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI -3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI -1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI -4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI -5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI -8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI -9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively. CONCLUSION: Our findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms. TRIAL REGISTRATION NUMBER: NCT02388724.

Long-term changes of gut microbiota, antibiotic resistance, and metabolic parameters after Helicobacter pylori eradication: a multicentre, open-label, randomised trial.

BACKGROUND: In first-line treatment of Helicobacter pylori, we have previously shown that the eradication frequency was 83·7% (95% CI 80·4-86·6) for triple therapy for 14 days (T14; lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily), 85·9% (82·7-88·6) for concomitant therapy for 10 days (C10; lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily), and 90·4% (87·6-92·6) for bismuth quadruple therapy for 10 days (BQ10; bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day). In this follow-up study, we assess short-term and long-term effects of these therapies on the gut microbiota, antibiotic resistance, and metabolic parameters. METHODS: This was a multicentre, open-label, randomised trial done at nine medical centres in Taiwan. Adult patients (>20 years) with documented H pylori infection were randomly assigned (1:1:1, with block sizes of six) to receive T14, C10, or BQ10. We assessed long-term outcomes (reinfection frequency, changes in the gut microbiota, antibiotic resistance, and metabolic parameters) in patients with available data, excluding all protocol violators and those with unknown post-treatment H pylori status. Faecal samples were collected before treatment and 2 weeks, 2 months, and at least 1 year after eradication therapy. Amplification of the V3 and V4 hypervariable regions of the 16S rRNA was done followed by high-throughput sequencing. Susceptibility testing for faecal Escherichia coli and Klebsiella pneumoniae was done. This trial is complete and registered with ClinicalTrials.gov, NCT01906879. FINDINGS: Between July 17, 2013, and April 20, 2016, 1620 participants were randomly assigned to the three treatment groups (540 [33%] per group). 1214 (75%) attended 1-year follow-up and are included in this analysis. Compared with baseline, alpha diversity was significantly reduced 2 weeks after T14 (p=0·0002), C10 (p<0·0001), and BQ10 (p<0·0001) treatment. Beta diversity was also significantly altered 2 weeks after T14 (p=0·0010), C10 (p=0·0001), and BQ10 (p=0·0001). Alpha diversity and beta diversity were restored at week 8 (p=0·14 and p=0·918, respectively) and 1 year (p=0·14 and p=0·918) after T14, but were not fully recovered at week 8 and after 1 year in patients treated with C10 (p=0·0001 and p=0·013 at week 8; p=0·019 and p=0·064 at 1 year) and BQ10 (p<0·0001 and p=0·0002; p=0·001 and p=0·029). A transient increase at week 2 after T14 and C10 of the resistance rates of E coli to ampicillin-sulbactam (12% [15/127] to 66% [38/58] for T14, 7% [10/135] to 64% [28/44] for C10), cefazolin (13% [16/127] to 43% [25/58] for T14, 10% [13/135] to 41% [18/44] for C10), cefmetazole (8% [10/127] to 26% [15/58] for T14, 4% [5/135] to 18% [8/44] for C10), levofloxacin (8% [10/127] to 35% [20/58] for T14, 7% [10/135] to 32% [14/44] for C10), gentamicin (13% [19/146] to 47% [27/58] for T14, 15% [22/149] to 45% [20/44] for C10), and trimethoprim-sulfamethoxazole (33% [48/146] to 86% [50/58] for T14, 28% [42/148] to 86% [38/44] for C10; p<0·05 in paired samples in the above analyses) returned to basal state at week 8 and after 1 year. Although bodyweight and body-mass index slightly increased, there were significant improvements in metabolic parameters, with a decrease in insulin resistance, triglycerides, and LDL and an increase in HDL. Overall, there was no significant change in the prevalence of metabolic syndrome at week 8 and 1 year after T14, C10, and BQ10. INTERPRETATION: Eradication of H pylori infection has minimal disruption of the microbiota, no effect on antibiotic resistance of E coli, and some positive effects on metabolic parameters. Collectively, these results lend support to the long-term safety of H pylori eradication therapy. FUNDING: National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.

Ten-Day Concomitant, 10-Day Sequential, and 7-Day Triple Therapy as First-Line Treatment for Helicobacter pylori Infection: A Nationwide Randomized Trial in Korea.

Background/Aims: This nationwide, multicenter prospective randomized controlled trial aimed to compare the efficacy and safety of 10-day concomitant therapy (CT) and 10-day sequential therapy (ST) with 7-day clarithromycin-containing triple therapy (TT) as first-line treatment for Helicobacter pylori infection in the Korean population. Methods: Patients with H. pylori infection were assigned randomly to 7d-TT (lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg twice daily for 7 days), 10d-ST (lansoprazole 30 mg and amoxicillin 1 g twice daily for the first 5 days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and metronidazole 500 mg twice daily for the remaining 5 days), or 10d-CT (lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg twice daily for 10 days). The primary endpoint was eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. Results: A total of 1,141 patients were included. The 10d-CT protocol achieved a markedly higher eradication rate than the 7d-TT protocol in both the ITT (81.2% vs 63.9%) and PP analyses (90.6% vs 71.4%). The eradication rate of the 10d-ST protocol was superior to that of the 7d-TT protocol (76.3% vs 63.9%, ITT analysis; 85.0% vs 71.4%, PP analysis). No significant differences in adherence or serious side effects were found among the three treatment arms. Conclusions: The 10d-CT and 10d-ST regimens were superior to the 7d-TT regimen as standard first-line treatment in Korea.

A drug-drug interaction study to assess the potential effect of acid-reducing agent, lansoprazole, on quizartinib pharmacokinetics.

PURPOSE: Quizartinib, a potent, selective FMS-like tyrosine kinase 3 (FLT3) inhibitor, is currently in phase 3 development for patients with FLT3-internal tandem duplication-mutated acute myeloid leukemia (AML). Acid-reducing agents (ARAs; e.g., proton pump inhibitors) are frequently used during AML treatment. Since quizartinib demonstrates pH-dependent solubility, the effect of lansoprazole coadministration on pharmacokinetics (PK) of quizartinib tablet formulation was assessed. METHODS: An open-label, parallel-group study randomized 64 healthy adults to single-dose quizartinib 30 mg alone (reference) or lansoprazole (60 mg once daily, days 1-5) + single-dose quizartinib 30 mg (day 5) (test). Plasma concentrations of quizartinib and its active metabolite, AC886, were measured to 504 h postdose; the effect of lansoprazole on quizartinib PK was assessed by analysis of variance. RESULTS: Quizartinib geometric mean ratios (test/reference) and 90% confidence intervals for maximum observed plasma concentration (Cmax), area under the concentration-time curve to last measurable drug concentration (AUClast), and AUC to infinity were 86.11% (78.4%, 94.6%), 93.96% (79.6%, 110.9%), and 95.30% (80.2%, 113.3%), respectively. Comparisons showed a modest decrease in quizartinib absorption when co-administered with lansoprazole, with lower limits for Cmax and AUClast just below 80-125% limits. Treatment-emergent adverse events were mild or moderate; the most frequent in either treatment group were headache [quizartinib alone: (n = 3) 10%], upper respiratory tract infection [quizartinib alone: (n = 2) 6.7%; lansoprazole + quizartinib: (n = 3) 9.1%], and muscle tightness [quizartinib alone: (n = 2) 6.7%]. CONCLUSIONS: Concomitant lansoprazole had minimal effect on quizartinib PK as a formulated tablet, indicating that quizartinib can be administered with ARAs.

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.

Different Clopidogrel Response Elicited by Lansoprazole or Esomeprazole in Patients Undergoing Neurointervention with Dual Antiplatelet Therapy.

BACKGROUND: Aspirin-clopidogrel dual antiplatelet therapy and a proton-pump inhibitor are used worldwide to prevent thromboembolism and peptic ulceration in patients undergoing neurointervention. We performed VerifyNow assays (Accumetrics, San Diego, CA, USA) to retrospectively examine the relationship between the effectiveness of antiplatelet agents and different proton-pump inhibitor types. METHODS: Sixty-four patients with unruptured intracranial aneurysm scheduled for neurointervention received aspirin-clopidogrel dual antiplatelet therapy plus the proton-pump inhibitor lansoprazole (n = 34) or esomeprazole (n = 30). A low response to aspirin and clopidogrel was defined in terms of aspirin reaction units > 550 and P2Y12 reaction units ≥ 230, respectively, by VerifyNow assay. The characteristics, response to antiplatelet therapy, and clinical outcomes were compared in patients treated with lansoprazole or esomeprazole. RESULTS: The preoperative mean VerifyNow aspirin reaction units and P2Y12 reaction units were 466.0 ± 67.3 and 205.0 ± 67.6, respectively. The mean aspirin reaction unit value was 482.0 ± 64.1 in the lansoprazole group, and 461.5 ± 70.9 in the esomeprazole group (p = 0.77). The mean P2Y12 reaction unit was 220.0 ± 64.4 in the lansoprazole group, and 174.5 ± 65.0 in the esomeprazole group; there was a significant difference in the clopidogrel response of patient treated with lansoprazole or esomeprazole (p = 0.005). CONCLUSIONS: Our VerifyNow assay results suggest that when on lansoprazole fewer patients achieved the therapeutic goal and required extra therapy before neurointervention.