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Chemosphere Dec 2020Urgent need for treatments limit studies of therapeutic drugs before approval by regulatory agencies. Analyses of drugs after approval can therefore improve our...
Urgent need for treatments limit studies of therapeutic drugs before approval by regulatory agencies. Analyses of drugs after approval can therefore improve our understanding of their mechanism of action and enable better therapies. We screened a library of 1443 Food and Drug Administration (FDA)-approved drugs using a simple assay in the nematode C. elegans and found three compounds that caused morphological changes. While the anticoagulant ticlopidine and the antifungal sertaconazole caused both accumulations that resulted in distinct distortions of pharyngeal anatomy and lethality upon acute exposure, the proton-pump inhibitor dexlansoprazole caused molting defects and required exposure during larval development. Such easily detectable defects in a powerful genetic model system advocate the continued exploration of current medicines using a variety of model organisms to better understand drugs already prescribed to millions of patients.
Topics: Animals; Bioaccumulation; Caenorhabditis elegans; Dexlansoprazole; Drug Approval; Epigenesis, Genetic; Humans; Imidazoles; Larva; Molting; Mutation; Thiophenes; Ticlopidine; United States; United States Food and Drug Administration
PubMed: 32731027
DOI: 10.1016/j.chemosphere.2020.127756 -
Journal of Veterinary Internal Medicine Sep 2020Proton pump inhibitors (PPIs) are among the most commonly prescribed medications for esophagitis and upper gastrointestinal erosion and ulceration in cats. Newer PPIs...
BACKGROUND
Proton pump inhibitors (PPIs) are among the most commonly prescribed medications for esophagitis and upper gastrointestinal erosion and ulceration in cats. Newer PPIs such as lansoprazole and esomeprazole are believed to be effective in cats, but the effect of many of these PPIs on gastric pH in cats has not been explored.
HYPOTHESIS/OBJECTIVES
To evaluate the efficacy of PO esomeprazole, dexlansoprazole, and lansoprazole on intragastric pH in healthy cats. We hypothesized that esomeprazole and lansoprazole would provide superior acid suppression compared to dexlansoprazole and reach pH goals extrapolated from people for the treatment of esophagitis and duodenal ulceration.
ANIMALS
Twelve healthy research cats.
METHODS
Randomized, 3-way crossover study. Cats were given esomeprazole and lansoprazole at a dosage of 1 mg/kg PO q12h or dexlansoprazole at 6 mg/kg PO q12h. Intragastric pH was recorded at baseline and for 4 days of treatment. Mean pH and the mean percentage time (MPT) intragastric pH was ≥3 or ≥4 were compared among and within treatment groups.
RESULTS
Cats treated with lansoprazole had a lower MPT ± SD of intragastric pH ≥3 (8.8 ± 6.8%) and mean ± SD pH (1.6 ± 0.5) than did cats treated with dexlansoprazole (41.2 ± 34.6% and 3.11 ± 1.6, respectively) or esomeprazole (54 ± 33.8% and 4.1 ± 3.9, respectively;P ≤ .04). Esomeprazole was the only treatment that achieved the goals defined for people for the treatment of duodenal ulceration by Day 4 of treatment (MPT ± SD of intragastric pH ≥4 of 77.1 ± 29.2%).
CONCLUSIONS AND CLINICAL IMPORTANCE
Orally administered esomeprazole might be a superior acid suppressant in cats compared to PO lansoprazole or dexlansoprazole.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Anti-Ulcer Agents; Cats; Cross-Over Studies; Esomeprazole; Female; Hydrogen-Ion Concentration; Pilot Projects; Veterinary Drugs
PubMed: 32885499
DOI: 10.1111/jvim.15887 -
Clinical and Translational... Oct 2015The need for new acid suppressing agents with improved pharmacology and superior antisecretory effects to address unmet clinical needs in acid-related disorders has been...
The need for new acid suppressing agents with improved pharmacology and superior antisecretory effects to address unmet clinical needs in acid-related disorders has been evident for over a decade. Recent new antisecretory drugs (IR-omeprazole and MR-dexlansoprazole) only provide a small incremental advance in control of acid secretion over the delayed-release proton pump inhibitors. Vonoprazan (a new potassium-competitive acid blocker) displays more potent and extended 24 h acid suppression and preliminary Japanese trials translate this into meaningful clinical benefits in gastro-esophageal reflux disease and Helicobacter pylori eradication. We review the vonoprazan information to date and the indications, benefits, and concerns of more effective therapeutic control of acid secretion.
PubMed: 26513137
DOI: 10.1038/ctg.2015.39 -
Neurogastroenterology and Motility Jan 2023The comparative efficacy and safety of medical therapies for gastro-esophageal reflux symptoms in endoscopy-negative reflux disease is unclear. We conducted a network... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The comparative efficacy and safety of medical therapies for gastro-esophageal reflux symptoms in endoscopy-negative reflux disease is unclear. We conducted a network meta-analysis to evaluate efficacy and safety of proton pump inhibitors (PPIs), histamine-2-receptor antagonists, potassium-competitive acid blockers (PCABs), and alginates in patients with endoscopy-negative reflux disease.
METHODS
We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials from inception to February 1, 2022. We included randomized controlled trials (RCTs) comparing efficacy of all drugs versus each other, or versus a placebo, in adults with endoscopy-negative reflux disease. Results were reported as pooled relative risks with 95% confidence intervals to summarize effect of each comparison tested, with treatments ranked according to P-score.
KEY RESULTS
We identified 23 RCTs containing 10,735 subjects with endoscopy-negative reflux disease. Based on failure to achieve complete relief of symptoms between ≥2 and <4 weeks, omeprazole 20 mg o.d. (P-score 0.94) ranked first, with esomeprazole 20 mg o.d. or 40 mg o.d. ranked second and third. In achieving adequate relief, only rabeprazole 10 mg o.d. was significantly more efficacious than placebo. For failure to achieve complete relief at ≥4 weeks, dexlansoprazole 30 mg o.d. (P-score 0.95) ranked first, with 30 ml alginate q.i.d. combined with omeprazole 20 mg o.d., and 30 ml alginate t.i.d. second and third. In terms of failure to achieve adequate relief at ≥4 weeks, dexlansoprazole 60 mg o.d. ranked first (P-score 0.90), with dexlansoprazole 30 mg o.d. and rabeprazole 20 mg o.d. second and third. All drugs were safe and well-tolerated.
CONCLUSIONS & INFERENCES
Our results confirm superiority of PPIs compared with most other drugs in treating endoscopy-negative reflux disease. Future RCTs should aim to better classify patients with endoscopy-negative reflux disease, and to establish the role of alginates and PCABs in achieving symptom relief in both the short- and long-term.
Topics: Adult; Humans; Gastrointestinal Agents; Rabeprazole; Dexlansoprazole; Heartburn; Network Meta-Analysis; Gastroesophageal Reflux; Proton Pump Inhibitors; Omeprazole; Endoscopy, Gastrointestinal; Alginates; Treatment Outcome
PubMed: 36153790
DOI: 10.1111/nmo.14469 -
Therapeutic Advances in Gastroenterology Nov 2016Dual delayed-release dexlansoprazole is approved for use in adults as a 30 mg orally disintegrating tablet (ODT) or as 30 mg and 60 mg capsules. The pharmacokinetics,...
BACKGROUND
Dual delayed-release dexlansoprazole is approved for use in adults as a 30 mg orally disintegrating tablet (ODT) or as 30 mg and 60 mg capsules. The pharmacokinetics, pharmacodynamics, and safety profile of two dexlansoprazole 30 mg ODTs were compared with one dexlansoprazole 60 mg capsule in this randomized, phase I, open-label, single-center, multiple-dose, two-period crossover study.
METHODS
Participants were randomized in one of two treatment sequences, each comprised two 5-day treatment periods during which two dexlansoprazole 30 mg ODTs or one 60 mg capsule was administered once daily. Pharmacokinetic parameters and the mean intragastric pH profile for the 24-hour period after dosing on days 1 and 5 were described. Adverse events were monitored during study duration and followed up with a phone call 5-10 days after the last dose of study drug.
RESULTS
On day 1, peak observed plasma concentration () values were similar between two 30 mg ODTs (1047 ng/ml) and one 60 mg capsule (1164 ng/ml). Systemic exposure, measured by the area under the plasma concentration-time curve (AUC), was approximately 25% lower after ODT administration. On day 5, mean pH after daily doses of two 30 mg ODT or one 60 mg capsule was 4.33 and 4.36, respectively; both regimens maintained intragastric pH above 4.0 for 60% of the 24-hour period. Headache was the most commonly reported adverse event (observed in 19.2% of participants); no adverse events leading to study withdrawal occurred.
CONCLUSIONS
While systemic exposure (AUC) was 25% lower with ODT, peak concentrations () after administration of two dexlansoprazole 30 mg ODTs and one 60 mg capsule were similar. The 24-hour intragastric pH control after administration of two dexlansoprazole 30 mg ODTs was equivalent to one dexlansoprazole 60 mg capsule. Both ODT and capsule were well tolerated.
PubMed: 27803732
DOI: 10.1177/1756283X16666800 -
Journal of the American College of... Apr 2012The aim of this study was to assess the effects of different proton pump inhibitors (PPIs) on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel. (Comparative Study)
Comparative Study Randomized Controlled Trial
A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers.
OBJECTIVES
The aim of this study was to assess the effects of different proton pump inhibitors (PPIs) on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel.
BACKGROUND
Metabolism of clopidogrel requires cytochrome P450s (CYPs), including CYP2C19. However, PPIs may inhibit CYP2C19, potentially reducing the effectiveness of clopidogrel.
METHODS
A randomized, open-label, 2-period, crossover study of healthy subjects (n = 160, age 18 to 55 years, homozygous for CYP2C19 extensive metabolizer genotype, confined, standardized diet) was conducted. Clopidogrel 75 mg with or without a PPI (dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or, as a positive control to maximize potential interaction and demonstrate assay sensitivity, omeprazole 80 mg) was given daily for 9 days. Pharmacokinetics and pharmacodynamics were assessed on days 9 and 10. Pharmacodynamic end-points were vasodilator-stimulated phosphoprotein P2Y(12) platelet reactivity index, maximal platelet aggregation to 5 and 20 μmol/l adenosine diphosphate, and VerifyNow P2Y12 platelet response units.
RESULTS
Pharmacokinetic and pharmacodynamic responses with omeprazole demonstrated assay sensitivity. The area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole but not with dexlansoprazole or lansoprazole. Similarly, esomeprazole but not dexlansoprazole or lansoprazole significantly reduced the effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reactivity index. All PPIs decreased the peak plasma concentration of clopidogrel active metabolite (omeprazole > esomeprazole > lansoprazole > dexlansoprazole) and showed a corresponding order of potency for effects on maximal platelet aggregation and platelet response units.
CONCLUSIONS
Generation of clopidogrel active metabolite and inhibition of platelet function were reduced less by the coadministration of dexlansoprazole or lansoprazole with clopidogrel than by the coadministration of esomeprazole or omeprazole. These results suggest that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Area Under Curve; Blood Coagulation; Blood Platelets; Clopidogrel; Confidence Intervals; Cross-Over Studies; Dexlansoprazole; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Esomeprazole; Female; Humans; Lansoprazole; Male; Middle Aged; Omeprazole; Proton Pump Inhibitors; Reference Values; Ticlopidine; Young Adult
PubMed: 22464259
DOI: 10.1016/j.jacc.2011.12.024 -
Helicobacter Aug 2014Helicobacter pylori infections have become increasingly difficult to treat. (Clinical Trial)
Clinical Trial
BACKGROUND
Helicobacter pylori infections have become increasingly difficult to treat.
AIM
To examine whether amoxicillin and high-dose dexlansoprazole would reliably achieve an H. pylori eradication rate of ≥90%.
METHODS
An open-label prospective pilot study of H. pylori eradication in treatment-naïve subjects with active H. pylori infection (positive by two tests).
THERAPY
amoxicillin 1 g and dexlansoprazole 120 mg each twice a day at approximately 12-hour intervals for 14 days. Success was accessed by urea breath test. An effective therapy was defined as a per-protocol treatment success of 90% or greater; treatment success of 80% or less was prespecified as an unacceptable result.
RESULTS
After 13 subjects were entered (12 men, one woman; average age of 54 years), the prespecified stopping rule of six treatment failures was achieved (i.e., the 95% confidence interval excluded achieving the required 90% success rate even if the proposed study of 50 completed patients were entered) and enrollment was stopped. Per-protocol and intention-to-treat treatment success were both 53.8%; (7/13); 95% CI = 25-80%. Compliance was 100%. Three patients (23%) reported side effects, all of which were mild and none interrupted therapy.
CONCLUSION
Theoretically, dual PPI plus amoxicillin should reliably eradicate H. pylori provided nearly neutral intragastric pH can be maintained. Clearly, dexlansoprazole, despite being administered at high dose and twice a day (i.e., total daily dose 240 mg), failed to achieve an intragastric milieu consistent with dual PPI plus amoxicillin therapy being an effective anti-H. pylori regimen.
Topics: Amoxicillin; Anti-Bacterial Agents; Breath Tests; Dexlansoprazole; Drug Therapy, Combination; Female; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Proton Pump Inhibitors; Treatment Outcome; Urea
PubMed: 24698653
DOI: 10.1111/hel.12126 -
Asian Pacific Journal of Cancer... Oct 2017Background: Helicobacter pylori (H. pylori) is important cause of peptic ulcer and gastric cancer. Moxifloxacin is effective antibiotic for treatment for H. pylori....
Effectiveness of 7-Day and 14-Day Moxifloxacin-Dexlansoprazole Based Triple Therapy and Probiotic Supplement for Helicobacter Pylori Eradication in Thai Patients with Non-Ulcer Dyspepsia: A Double-Blind Randomized Placebo-Controlled Study.
Background: Helicobacter pylori (H. pylori) is important cause of peptic ulcer and gastric cancer. Moxifloxacin is effective antibiotic for treatment for H. pylori. However, there were limited studies as first line therapy. Probiotics had been shown to decrease therapy-related side-effect and increase eradication rate. Aim of this study was to evaluate the efficacy of moxifloxacin-dexlansoprazole based triple therapy with probiotic for H. pylori treatment in Thailand. Methods: Patients with H. pylori infected gastritis were randomized to receive 7- or 14-day moxifloxacin-dexlansoprazole based triple therapy with probiotic or placebo. Regimen consisted of 60 mg dexlansoprazole twice daily, 400mg moxifloxacin once daily, 1g clarithromycin MR once daily. Probiotic used in this study was 282.5mg Saccharomyces boulardii (S. boulardii) in capsule prescribed twice daily. CYP2C19 genotyping, antibiotic susceptibility tests, and CagA genotyping were also done. Successful eradication was defined as a negative 13C-urea breath test at least 4 weeks after treatment. Results: Total of 108 subjects was enrolled (27 each to 7-and 14-day regimens with probiotic or placebo). Antibiotic susceptibility tests showed 29% fluoroquinolone, 19% metronidazole and 4% clarithromycin resistance. CYP2C19 genotyping demonstrated 43%, 47% and 11% were rapid, intermediate and poor metabolizers, respectively. CagA genes were positive in all patients. Eradication rates of 7-day and 14-day regimens with probiotic were 100%, and 93% respectively. There were no significant differences between eradication rate of 7-day and 14-day regimen with or without probiotics. Regarding side-effects, incidence of nausea, abdominal discomfort, bitter taste, and diarrhea were significantly lower in regimen with probiotic group compared with placebo(7.4%vs. 22.2%; p=0.028, 0.00%vs.14.8%; p=0.003, 35.2%vs.70.4%; p=0.0002, and 0.00%vs.9.3%; p=0.028, respectively). Conclusions: 7-day moxifloxacindexlansoprazole therapy plus S. boulardii provide an reliable cure rate of H. pylori in non-ulcer dyspeptic patients in Thailand, independent of CYP2C19 genotype. Probiotic adding also decreased side effects during the treatment.
PubMed: 29072432
DOI: 10.22034/APJCP.2017.18.10.2839 -
Alimentary Pharmacology & Therapeutics May 2009Proton pump inhibitors (PPIs) provide the most effective pharmacotherapy for treating acid-related disorders. However, PPIs do not completely control acid over 24 h with... (Review)
Review
Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy.
BACKGROUND
Proton pump inhibitors (PPIs) provide the most effective pharmacotherapy for treating acid-related disorders. However, PPIs do not completely control acid over 24 h with once-daily dosing.
AIMS
To discuss limitations inherent in the pharmacokinetics (PK) and pharmacodynamics of conventional PPI formulations, which provide a single drug release. Also, to consider approaches to extending the duration of acid suppression focusing on dexlansoprazole MR, a PPI with a novel Dual Delayed Release (DDR) formulation.
METHOD
We reviewed the available literature regarding marketed and investigational PPIs.
RESULTS
Non-standard dosing of currently marketed PPIs has produced incremental advances in acid control. Multiple approaches are being evaluated to enhance acid suppression with PPIs. Dexlansoprazole MR is a DDR formulation of dexlansoprazole, an enantiomer of lansoprazole, with two distinct drug release periods to prolong the plasma dexlansoprazole concentration-time profile and extend duration of acid suppression. Clinical studies show that dexlansoprazole MR produces a dual-peak PK profile that maintains therapeutic plasma drug concentrations longer than lansoprazole, with a single-peak PK profile, and increases the percentage of time that intragastric pH >4.
CONCLUSIONS
Novel drug delivery platforms, including the dexlansoprazole MR DDR formulation, may improve acid suppression and offer benefits over conventional single release PPI formulations.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Anti-Ulcer Agents; Cross-Over Studies; Delayed-Action Preparations; Dexlansoprazole; Humans; Lansoprazole; Proton Pump Inhibitors; Randomized Controlled Trials as Topic
PubMed: 19298580
DOI: 10.1111/j.1365-2036.2009.03984.x -
Digestive Diseases and Sciences Nov 2017Proton pump inhibitors are commonly used to treat gastro-esophageal reflux disease (GERD) and nonerosive GERD (NERD) in adolescents and adults. Despite the efficacy of...
BACKGROUND
Proton pump inhibitors are commonly used to treat gastro-esophageal reflux disease (GERD) and nonerosive GERD (NERD) in adolescents and adults. Despite the efficacy of available medications, many patients have persisting symptoms, indicating a need for more effective agents.
AIMS
To assess the safety and efficacy of dexlansoprazole dual delayed-release capsules in adolescents for treatment of symptomatic NERD.
METHODS
A phase 2, open-label, multicenter study was conducted in adolescents aged 12-17 years. After a 21-day screening period, adolescents with endoscopically confirmed NERD received a daily dose of 30-mg dexlansoprazole for 4 weeks. The primary endpoint was treatment-emergent adverse events (TEAEs) experienced by ≥5% of patients. The secondary endpoint was the percentage of days with neither daytime nor nighttime heartburn. Heartburn symptoms and severity were recorded daily in patient electronic diaries and independently assessed by the investigator, along with patient-reported quality of life, at the beginning and end of the study.
RESULTS
Diarrhea and headache were the only TEAEs reported by ≥5% of patients. Dexlansoprazole-treated patients (N = 104) reported a median 47.3% of days with neither daytime nor nighttime heartburn. Symptoms such as epigastric pain, acid regurgitation, and heartburn improved in severity for 73-80% of patients. Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire-Adolescents-Short Form symptom and impact subscale scores (scaled 1-5) each decreased by an average of 0.7 units at week 4.
CONCLUSIONS
Use of 30-mg dexlansoprazole in adolescent NERD was generally well tolerated and had beneficial effects on improving heartburn symptoms and quality of life.
TRIAL REGISTRATION
This study has the ClinicalTrials.gov identifier NCT01642602.
Topics: Administration, Oral; Adolescent; Age of Onset; Capsules; Child; Delayed-Action Preparations; Dexlansoprazole; Europe; Female; Gastroesophageal Reflux; Heartburn; Humans; Latin America; Male; North America; Proton Pump Inhibitors; Quality of Life; Remission Induction; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Treatment Outcome
PubMed: 28916953
DOI: 10.1007/s10620-017-4743-3