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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 -
Pharmacological Research Feb 2020Proton pump inhibitors (PPIs) are used widely for the treatment of acid-related disorders. Despite their excellent efficacy and tolerance, the pharmacodynamics and... (Review)
Review
Proton pump inhibitors (PPIs) are used widely for the treatment of acid-related disorders. Despite their excellent efficacy and tolerance, the pharmacodynamics and pharmacokinetics of PPIs are affected by each patient's CYP2C19 and gastric H,K-ATPase genotype. The aim of this review was to analyze the effect of genetic polymorphisms on the pharmacodynamic and pharmacokinetic properties of PPIs. The gastric acid-suppressive effect of PPIs is affected by both gastric H,K-ATPase and CYP2C19 polymorphisms, although gastric H,K-ATPase polymorphisms may have larger effects. Ilaprazole and rabeprazole show relatively small differences in the pharmacokinetic and pharmacodynamic properties and clinical efficacy among the different CYP2C19 genotypes. Compared with oral administration, the intravenous infusion of PPIs is less affected by CYP2C19 polymorphism. At the same dose, each enantiomer has less variation among different CYP2C19 genotypes than a racemate mixture.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Humans; Pharmacogenomic Variants; Proton Pump Inhibitors
PubMed: 31846760
DOI: 10.1016/j.phrs.2019.104606 -
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 -
Arquivos de Gastroenterologia Aug 2019Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal diseases. GERD generates significant impairment in patients' quality of life and it... (Review)
Review
BACKGROUND
Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal diseases. GERD generates significant impairment in patients' quality of life and it is associated to relevant medical resources utilization. A better understanding of GERD pathophysiology in the past five decades has favored the evolution of therapeutic strategies from non-drug interventions and antacids to more efficacious and safer alternatives.
OBJECTIVE
To summarize data about the historical evolution of GERD management in Brazil, focusing on medical therapy and addressing evidence on efficacy and safety of drug classes currently recommended.
METHODS
A narrative review was conducted by systematizing information about discoveries on GERD pathophysiology. We also addressed efficacy and safety of medications currently used to reduce symptoms and improve endoscopic healing of esophageal lesions. A structured search on Pubmed was performed to identify systematic reviews and meta-analysis investigating GERD outcomes positively impacted by proton pump inhibitors (PPIs), the first choice of pharmacotherapy for the disease.
RESULTS
The chronological development of therapeutic measures for GERD in Brazil evolved from lifestyle interventions with relative poor effect on symptoms related to esophageal acid exposure, particularly heartburn, to effective and safe pharmacological interventions such as histamine H2-receptor antagonists and PPIs. In the present days, some drug classes play a minor role in disease management, namely prokinetics and antacids, due to their reduced efficacy and relevant safety concerns (particularly with prokinetics). The main challenge for prescribers and researchers seems to be finding long-acting acid suppressants strategies able to ameliorate patients' symptoms and quality of life, thereafter, reducing medical resource consumption. The dual delayed-release PPI dexlansoprazole seems to respond for some of the limitations other PPIs have.
CONCLUSION
Recognizing the historical evolution of GERD management can help care providers to better understand therapeutic options for their patients, as well as focus on unmet needs that deserve further attention. PPIs are still the first choice therapy, with good evidence in favor of their efficacy, despite some safety concerns. However, as with any medical intervention, it is recommended to prescribe PPIs for patients with clear indication, using adequate dosing and monitoring for adverse events.
Topics: Antacids; Antiemetics; Behavior Therapy; Evidence-Based Medicine; Gastroesophageal Reflux; Histamine H2 Antagonists; Humans; Life Style; Proton Pump Inhibitors
PubMed: 31460587
DOI: 10.1590/S0004-2803.201900000-41 -
Journal of Pharmaceutical Sciences Nov 2019Proton pump inhibitors (PPIs) are widely used for treating acid-related disorders. For an "ideal PPI," achieving maximal absorption and sustaining pharmacodynamic... (Review)
Review
Proton pump inhibitors (PPIs) are widely used for treating acid-related disorders. For an "ideal PPI," achieving maximal absorption and sustaining pharmacodynamic effects through the 24-h dosing cycle are critical features. Dexlansoprazole offers a relevant case study on how an improved PPI was developed capitalizing on the rational optimization of a precursor molecule-in this case, using lansoprazole as a starting point, leveraging its chemical properties on pharmacokinetics, and exploring optimized formulations. Dexlansoprazole is the R(+)-enantiomer of lansoprazole and shows stereoselective differences in absorption and metabolism compared with the racemic mixture of lansoprazole. The formulation was further refined to use pulsate-type granules with enteric coating to withstand acidic gastric conditions, while allowing prolonged absorption in the proximal and distal small intestine. As a result, the dual delayed-release formulation of dexlansoprazole has a plasma concentration-time profile characterized by 2 distinct peaks, leading to an extended duration of therapeutic plasma drug concentrations compared with the conventional delayed-release lansoprazole formulation. The dual delayed-release formulation maintains plasma drug concentrations longer than the lansoprazole delayed-release formulation at all doses.
Topics: Capsules; Chemistry, Pharmaceutical; Delayed-Action Preparations; Dexlansoprazole; Humans; Intestine, Small; Lansoprazole; Proton Pump Inhibitors
PubMed: 31386865
DOI: 10.1016/j.xphs.2019.07.023