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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 -
Therapeutic Advances in Gastroenterology 2020Whether adjunctive -acetylcysteine (NAC) may improve the efficacy of triple therapy in the first-line treatment of infection remains unknown. Our aim was to compare the...
BACKGROUND
Whether adjunctive -acetylcysteine (NAC) may improve the efficacy of triple therapy in the first-line treatment of infection remains unknown. Our aim was to compare the efficacy of 14-day triple therapy with or without NAC for the first-line treatment of .
MATERIAL AND METHODS
Between 1 January 2014 and 30 June 2018, 680 patients with infection naïve to treatment were enrolled in this multicenter, open-label, randomized trial. Patients were randomly assigned to receive triple therapy with NAC [NAC-T14, dexlansoprazole 60 mg four times daily (q.d.); amoxicillin 1 g twice daily (b.i.d.), clarithromycin 500 mg b.i.d., NAC 600 mg b.i.d.] for 14 days, or triple therapy alone (T14, dexlansoprazole 60 mg q.d.; amoxicillin 1 g b.i.d., clarithromycin 500 mg b.i.d.) for 14 days. Our primary outcome was the eradication rates by intention to treat (ITT). Antibiotic resistance and gene polymorphism were determined.
RESULTS
The ITT analysis demonstrated eradication rates in NAC-T14 and T14 were 81.7% [276/338, 95% confidence interval (CI): 77.5-85.8%] and 84.3% (285/338, 95% CI 80.4-88.2%), respectively. In 646 participants who adhered to their assigned therapy, the eradication rates were 85.7% and 88.0% with NAC-T14 and T14 therapies, respectively. There were no differences in compliance or adverse effects. The eradication rates in subjects with clarithromycin-resistant, amoxicillin-resistant, or either clarithromycin/amoxicillin resistant strains were 45.2%, 57.9%, and 52.2%, respectively, for NAC-T14, and were 66.7%, 76.9%, and 70.0%, respectively, for T14. The efficacy of NAC-T14 and T14 was not affected by polymorphism.
CONCLUSION
Add-on NAC to triple therapy was not superior to triple therapy alone for first-line eradication [ClinicalTrials.gov identifier: NCT02249546].
PubMed: 32821287
DOI: 10.1177/1756284820927306 -
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 -
ACS Medicinal Chemistry Letters Feb 2020"An important objective of modern pharmaceutical research is the discovery of new medical uses for known molecules" (UKSC 2018), a component of secondary...
"An important objective of modern pharmaceutical research is the discovery of new medical uses for known molecules" (UKSC 2018), a component of secondary pharmaceuticals. This Viewpoint's focus is the defense of the vulnerable strategy of secondary pharmaceutical patents (SPPs). Typical claims thereof are new medical uses, dosage, selection, and enatiomer patents. The attacks on secondary pharmaceuticals, including chiral switches, use negative-connotation terms, such as "evergreening", "product hopping", and "pejorative". Most enantiomer patents, including the controversial Nexium patents, were challenged in courts worldwide yet validated. This Viewpoint considers the "teaching away" defense of nonobviousness of Nexium enantiomer patents due to "unexpected results", applying stereochemistry principles. Physical organic chemistry arguments and the prediction of lower energy barriers of epimerization/racemization of benzylic anions of esomeprazole and dexlansoprazole (compared with their uncharged enantiomers) are a basis of the "teaching away". This prediction is verified by DFT computations. "Obvious to try" of many SPPs should not prevail over "unexpected results". A generalized concern about "evergreening" drugs should not be a justification for comprehensive attacks on SPPs. Following UKSC Lyrica decision (2018), plausibility, a condition of patent validity, may enter the arena of enantiomer patents, claiming second medical uses. Secondary pharmaceutical dosage, selection, improvement, and enantiomer patents are not necessarily obvious.
PubMed: 32280427
DOI: 10.1021/acsmedchemlett.9b00497 -
Journal of Gastroenterology and... Oct 2020Concomitant therapy is a recommended first-line treatment for Helicobacter pylori infection in most national or international consensuses. Reverse hybrid therapy is a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIM
Concomitant therapy is a recommended first-line treatment for Helicobacter pylori infection in most national or international consensuses. Reverse hybrid therapy is a modified 14-day concomitant therapy without clarithromycin and metronidazole in the final 7 days. This study aims to test whether 14-day reverse hybrid therapy is non-inferior to 14-day concomitant therapy in the first-line treatment of H. pylori infection.
METHODS
Helicobacter pylori-infected adult patients were randomly assigned to receive either reverse hybrid therapy (dexlansoprazole 60 mg o.d. plus amoxicillin 1 g b.d. for 14 days, and clarithromycin 500 mg plus metronidazole 500 mg b.d. for initial 7 days) or concomitant therapy (dexlansoprazole 60 mg once o.d. plus amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg b.d. for 14 days). H. pylori status was assessed 6 weeks after the end of treatment.
RESULTS
Helicobacter pylori-infected participants (n = 248) were randomized to receive either 14-day reverse hybrid therapy (n = 124) or 14-day concomitant therapy (n = 124). Intention-to-treat analysis demonstrated that the two therapies had comparable eradication rate (95.2% vs 93.5%; 95% confidence interval, -4.0% to 7.4%; P = 0.582). However, reverse hybrid therapy had a much lower frequency of adverse events than concomitant therapy (20.2% vs 38.7%, P = 0.001). The two therapies exhibited comparable drug adherence (93.5% vs 87.9%, P = 0.125).
CONCLUSIONS
Fourteen-day reverse hybrid therapy and 14-day concomitant therapy are equivalent in efficacy for the first-line treatment of H. pylori infection. However, reverse hybrid therapy has fewer adverse events compared with concomitant therapy.
Topics: Adult; Aged; Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Dexlansoprazole; Drug Administration Schedule; Drug Therapy, Combination; Female; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Metronidazole; Middle Aged; Treatment Outcome
PubMed: 32167605
DOI: 10.1111/jgh.15034 -
Frontiers in Microbiology 2019Omeprazole was shown to improve the anti-cancer effects of the nucleoside analogue 5-fluorouracil. Here, we combined omeprazole with the antiviral nucleoside analogues...
Omeprazole was shown to improve the anti-cancer effects of the nucleoside analogue 5-fluorouracil. Here, we combined omeprazole with the antiviral nucleoside analogues ribavirin and acyclovir. Omeprazole did not affect the antiviral effects of ribavirin in non-toxic concentrations up to 80 μg/mL but increased the acyclovir-mediated effects on herpes simplex virus 1 and 2 (HSV-1 and -2) replication in a dose-dependent manner. Omeprazole alone reduced HSV-1 and -2 titers [but not HSV-induced formation of cytopathogenic effects (CPE)] at concentrations ≥40 μg/mL. However, it exerted substantially stronger effects on acyclovir activity and also increased acyclovir activity at lower concentrations that did not directly interfere with HSV replication. Omeprazole 80 μg/mL caused a 10.8-fold (Vero cells) and 47.7-fold (HaCaT cells) decrease of the acyclovir concentrations that reduced HSV-1-induced CPE formation by 50% (IC). In HSV-2-infected cells, omeprazole 80 μg/mL reduced the acyclovir IC by 7.3- (Vero cells) and 12.9-fold (HaCaT cells). In HaCaT cells, omeprazole 80 μg/mL reduced the HSV-1 titer in the presence of acyclovir 1 μg/mL by 1.6 × 10-fold and the HSV-2 titer in the presence of acyclovir 2 μg/mL by 9.2 × 10-fold. The proton pump inhibitors pantoprazole, rabeprazole, lansoprazole, and dexlansoprazole increased the antiviral effects of acyclovir in a similar fashion as omeprazole, indicating this to be a drug class effect. In conclusion, proton pump inhibitors increase the anti-HSV activity of acyclovir and are candidates for antiviral therapies in combination with acyclovir, in particular for topical preparations for the treatment of immunocompromised individuals who are more likely to suffer from severe complications.
PubMed: 31849920
DOI: 10.3389/fmicb.2019.02790 -
Journal of Neurogastroenterology and... Jan 2020Since the use of dexlansoprazole in Asian subjects with gastroesophageal reflux disease (GERD) has not been adequately characterized, this study was conducted to...
BACKGROUND/AIMS
Since the use of dexlansoprazole in Asian subjects with gastroesophageal reflux disease (GERD) has not been adequately characterized, this study was conducted to evaluate the efficacy and safety of dexlansoprazole modified-release in Asian subjects with non-erosive reflux disease (NERD) and erosive esophagitis (EE).
METHODS
In this phase 4, open-label, non-randomized, uncontrolled, multicenter, multi-country study sponsored by Takeda, subjects aged ≥ 20 years with persistent typical GERD symptoms for at least 6 months underwent endoscopy. Based on endoscopic findings, they were assigned to either dexlansoprazole modified-release 30 mg once-daily for 4 weeks (NERD group) or dexlansoprazole modified-release 60 mg once-daily for 8 weeks (EE group). The primary endpoint was the percentage of days that subjects did not experience any 24hour heartburn or acid regurgitation.
RESULTS
Of the 445 subjects screened from Hong Kong, South Korea, and Taiwan, 208 were enrolled in the NERD group (mean age: 53.6 years, male: 34.6%) and 88 in the EE group (mean age: 51.7 years, male: 55.7%). Over the treatment period, the median percentage of days that subjects did not experience any 24-hour heartburn or acid regurgitation was 26.9% and 65.5% in the NERD and EE groups, respectively; for nighttime heartburn or acid regurgitation the proportions were 59.3% and 83.3%, respectively. The treatment was well tolerated with low incidence of treatment-related adverse events in NERD and EE groups (6.7% and 5.7%, respectively).
CONCLUSIONS
In Asian patients with GERD, treatment with dexlansoprazole modified-release indicates a favorable efficacy and safety profile in relieving heartburn and acid regurgitation symptoms.
PubMed: 31597230
DOI: 10.5056/jnm19031 -
Infection and Drug Resistance 2019[This corrects the article DOI: 10.2147/IDR.S213998.].
Erratum: A Comparison Between Dexlansoprazole Modified Release-Based And Lansoprazole-Based Nonbismuth Quadruple (Concomitant) Therapy For First-Line Eradication: A Prospective Randomized Trial [Corrigendum].
[This corrects the article DOI: 10.2147/IDR.S213998.].
PubMed: 31576155
DOI: 10.2147/IDR.S231699 -
Infection and Drug Resistance 2019Steadily maintaining high intra-gastric PH is the major factor for successful eradication. It is important to search for a stronger PPI. Dexlansoprazole MR is a dual...
A comparison between dexlansoprazole modified release-based and lansoprazole-based nonbismuth quadruple (concomitant) therapy for first-line eradication: a prospective randomized trial.
PURPOSE
Steadily maintaining high intra-gastric PH is the major factor for successful eradication. It is important to search for a stronger PPI. Dexlansoprazole MR is a dual delayed release formulation PPI taken once daily which is capable of maintaining longer duration of high intra-gastric PH. It is very effective in treating gastroesophageal disease but reports on eradication is very rare. This study sought to compare dexlansoprazole MR-based concomitant treatment and lansoprazole-based concomitant treatment in infection and to investigate the factors that affect the eradication rates.
METHODS
Two hundred two participants with infection were included and randomly assigned to seven days of dexlansoprazole MR-based concomitant therapy (dexlansoprazole MR 60 mg once daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily and metronidazole 500 mg twice daily; DACM group) or a seven days of lansoprazole-based concomitant therapy (lansoprazole 30 mg twice daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily, and metronidazole 500 mg twice daily; LACM group). The participants were asked to perform urea breath tests eight weeks later.
RESULTS
The eradication rates in the DACM group were 86.1% [95% confidence interval (CI): 77.8%-92.2%] in the ITT analysis and 90.6% (95% CI: 82.9%-95.6%) in the PP analysis, respectively, as compared with 90.1% (95% CI: 82.6%-95.2%) and 92.6% (95% CI: 85.5%-96.9%) (=0.384 and =0.572, respectively) in the LACM group for the same analyses. The adverse event rates were 11.5% in the DACM group and 10.2% in the LACM group (=0.779).
CONCLUSION
As a first-line treatment regimen, dexlansoprazole MR-based concomitant therapy attained a successful eradication rate of 90%, which was non inferior to that of lansoprazole-based concomitant treatment.
CLINICALTRIALSGOV IDENTIFIER
NCT03829150.
PubMed: 31571945
DOI: 10.2147/IDR.S213998 -
Therapeutic Advances in Gastroenterology 2019Dexlansoprazole has been shown to be efficacious for the treatment of gastroesophageal reflux disease. However, there is a paucity of data about its efficacy for...
BACKGROUND
Dexlansoprazole has been shown to be efficacious for the treatment of gastroesophageal reflux disease. However, there is a paucity of data about its efficacy for eradication. The aim of this study was to evaluate the efficacy of dexlansoprazole for eradication as triple therapy in real-world practice.
METHODS
Adult patients with endoscopically proven related peptic ulcer diseases or gastritis were recruited for this study. The eradication status was assessed based on the results of the C-urea breath test performed 4 weeks after treatment. According to the different treatment regimens, the patients were allocated to group A: Esomeprazole 40 mg b.i.d. + amoxicillin 1 g b.i.d. + clarithromycin 500 mg b.i.d. for 7 days; group B: Esomeprazole 40 mg q.d. + amoxicillin 1 g b.i.d. + clarithromycin 500 mg b.i.d. for 7 days, or group C: Dexlansoprazole 60 mg q.d. + amoxicillin 1 g b.i.d. + clarithromycin 500 mg b.i.d. for 7 days.
RESULTS
A total of 215 patients (49% males) were enrolled in this study, with a mean age of 55 years. The eradication rates in group A, B, and C were 94.7% (71/75), 89.6% (69/77), and 93.7% (59/63) ( = 0.457), respectively. The adverse events were similar between the three groups ( = 0.068).
CONCLUSIONS
This study suggests that dexlansoprazole-based triple therapy has an acceptable eradication rate for infection.
PubMed: 31523277
DOI: 10.1177/1756284819870960