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Effect of the proton-pump Inhibitor pantoprazole on MycoPhenolic ACid exposure in kidney and liver transplant recipienTs (IMPACT study): a randomized trial.
Sunderland, A, Russ, G, Sallustio, B, Cervelli, M, Joyce, D, Ooi, E, Jeffrey, G, Boudville, N, Chakera, A, Dogra, G, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(6):1060-1070
Abstract
BACKGROUND Mycophenolic acid (MPA) is widely utilized as an immunosuppressant in kidney and liver transplantation, with reports suggesting an independent relationship between MPA concentrations and adverse allograft outcome. Proton-pump inhibitors (PPIs) may have variable effects on the absorption of different MPA formulations leading to differences in MPA exposure. METHODS A multicentre, randomized, prospective, double-blind placebo-controlled cross-over study was conducted to determine the effect of the PPI pantoprazole on the MPA and its metabolite MPA-glucuronide (MPA-G) area under the curve (AUC) >12 h (MPA-AUC12 h) in recipients maintained on mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). We planned a priori to examine separately recipients maintained on MMF and EC-MPS for each pharmacokinetic parameter. The trial (and protocol) was registered with the Australian New Zealand Clinical Trials Registry on 24 March 2011, with the registration number of ACTRN12611000316909 ('IMPACT' study). RESULTS Of the 45 recipients screened, 40 (19 MMF and 21 EC-MPS) were randomized. The mean (standard deviation) recipient age was 58 (11) years with a median (interquartile range) time post-transplant of 43 (20-132) months. For recipients on MMF, there was a significant reduction in the MPA-AUC12 h [geometric mean (95% confidence interval) placebo: 53.9 (44.0-65.9) mg*h/L versus pantoprazole: 43.8 (35.6-53.4) mg*h/L; P = 0.004] when pantoprazole was co-administered compared with placebo. In contrast, co-administration with pantoprazole significantly increased MPA-AUC12 h [placebo: 36.1 (26.5-49.2) mg*h/L versus pantoprazole: 45.9 (35.5-59.3) mg*h/L; P = 0.023] in those receiving EC-MPS. Pantoprazole had no effect on the pharmacokinetic profiles of MPA-G for either group. CONCLUSIONS The co-administration of pantoprazole substantially reduced the bioavailability of MPA in patients maintained on MMF and had the opposite effect in patients maintained on EC-MPS, and therefore, clinicians should be cognizant of this drug interaction when prescribing the different MPA formulations.
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Effect of Gastric Acid Suppressants on Response to a Physical Activity Intervention and Major Mobility Disability in Older Adults: Results from the Lifestyle Interventions for Elders (LIFE) Study.
Squires, PJ, Pahor, M, Manini, TM, Brown, JD
Pharmacotherapy. 2019;(8):816-826
Abstract
OBJECTIVES Proton pump inhibitors (PPIs) and histamine2 receptor antagonists (H2 RAs) are associated with pharmacologic effects that may be detrimental to mobility and response to physical activity. Mobility disability and injurious fall outcomes in PPI and H2 RA users were compared with nonusers in this secondary analysis of data from the Lifestyle Interventions for Elders (LIFE) study. METHODS Participants ages 70-89 years were randomized to a physical activity (PA) or successful aging intervention and evaluated by medication use. Confounders included baseline demographic characteristics, physical function, cognitive function, sleep quality, and acid reflux symptoms that were adjusted via propensity score weighting. Outcomes were incident and persistent major mobility disability (MMD and pMMD) and injurious falls. Weighted proportional hazard models evaluated independent and interaction effects of PPIs and H2 RAs. RESULTS No interaction was found between PPIs and H2 RAs and the PA intervention. Drug use associations were significant for H2 RAs (hazard ratio [HR] 1.74 [95% confidence interval [CI] 1.12-2.68]) and PPIs (HR 1.32 [95% CI 1.02-1.70]) compared with nonusers for pMMD. PPIs were associated with increased injurious falls compared with nonusers (HR 1.44 [95% CI 1.06-1.96]). Pooling of data from the H2 RA and PPI exposure groups showed a 26% increase in MMD (HR 1.26 [95% CI 1.07-1.48]), a 44% increase in pMMD (HR 1.44 [95% CI 1.16-1.77]), and a 48% increase in injurious falls (HR 1.48 [95% CI 1.15-1.91]) compared with nonusers. All direct comparisons between PPIs and H2 RAs were nonsignificant. CONCLUSIONS Compared with nonusers, participants using either PPIs or H2 RAs had an increased risk of MMD, pMMD, and injurious falls. It is not known if these effects are related to the individual pharmacology of each medication, reduced acid secretion, or the underlying disease state. Further study is required to determine causality.
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The Effect of Food or Omeprazole on the Pharmacokinetics of Osimertinib in Patients With Non-Small-Cell Lung Cancer and in Healthy Volunteers.
Vishwanathan, K, Dickinson, PA, Bui, K, Cassier, PA, Greystoke, A, Lisbon, E, Moreno, V, So, K, Thomas, K, Weilert, D, et al
Journal of clinical pharmacology. 2018;(4):474-484
Abstract
Two phase 1, open-label studies assessed the impact of food or gastric pH modification (omeprazole) on the exposure and safety/tolerability of osimertinib and its metabolites. The food effect study was an open-label, 2-period crossover study in patients with advanced non-small-cell lung cancer, randomized into 2 treatment sequences: single-dose osimertinib 80 mg in a fed then fasted state or fasted then fed. The gastric pH study was an open-label, 2-period fixed sequence study assessing the effect of omeprazole on osimertinib exposure in healthy male volunteers. In period 1, volunteers received omeprazole 40 mg (days 1-4), then omeprazole 40 mg plus osimertinib 80 mg (day 5). In period 2, volunteers received osimertinib 80 mg alone (single dose). Blood samples were collected at prespecified time points for pharmacokinetic analyses. Safety/tolerability was also assessed. In the food effect study 38 patients were randomized to fed/fasted (n = 18) or fasted/fed (n = 20) sequences with all patients completing treatment. Coadministration with food did not affect osimertinib exposure (geometric least-squares mean ratios [90% confidence intervals]: 106.05% [94.82%, 118.60%] [area under the plasma concentration time curve from zero to 72 hours] and 92.75% [81.40%, 105.68%] [maximum plasma concentration]). In the gastric pH study (n = 68 received treatment, n = 47 completed the study), coadministration with omeprazole did not affect osimertinib exposure (geometric least-squares mean ratios 106.66% [100.26%, 113.46%] [area under the concentration-time curve], 101.65% [94.65%, 109.16%] [peak concentration]). Osimertinib was well tolerated in both studies. Osimertinib may be administered without regard to food. Dose restriction is not required in patients whose gastric pH may be altered by concomitant agents or medical conditions. ClinicalTrials.gov: NCT02224053, NCT02163733.
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Exposure to Gastric Acid Inhibitors Increases the Risk of Infection in Preterm Very Low Birth Weight Infants but Concomitant Administration of Lactoferrin Counteracts This Effect.
Manzoni, P, García Sánchez, R, Meyer, M, Stolfi, I, Pugni, L, Messner, H, Cattani, S, Betta, PM, Memo, L, Decembrino, L, et al
The Journal of pediatrics. 2018;:62-67.e1
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Abstract
OBJECTIVE To investigate whether exposure to inhibitors of gastric acidity, such as H2 blockers or proton pump inhibitors, can independently increase the risk of infections in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit. STUDY DESIGN This is a secondary analysis of prospectively collected data from a multicenter, randomized controlled trial of bovine lactoferrin (BLF) supplementation (with or without the probiotic Lactobacillus rhamnosus GG) vs placebo in prevention of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants. Inhibitors of gastric acidity were used at the recommended dosages/schedules based on the clinical judgment of attending physicians. The distribution of days of inhibitors of gastric acidity exposure between infants with and without LOS/NEC was assessed. The mutually adjusted effects of birth weight, gestational age, duration of inhibitors of gastric acidity treatment, and exposure to BLF were controlled through multivariable logistic regression. Interaction between inhibitors of gastric acidity and BLF was tested; the effects of any day of inhibitors of gastric acidity exposure were then computed for BLF-treated vs -untreated infants. RESULTS Two hundred thirty-five of 743 infants underwent treatment with inhibitors of gastric acidity, and 86 LOS episodes occurred. After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS (OR, 1.03; 95% CI, 1.008-1.067; P = .01); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS. Risk was significant for Gram-negative (P < .001) and fungal (P = .001) pathogens, but not for Gram-positive pathogens (P = .97). On the test for interaction, 1 additional day of exposure to inhibitors of gastric acidity conferred an additional 7.7% risk for LOS (P = .003) in BLF-untreated infants, compared with 1.2% (P = .58) in BLF-treated infants. CONCLUSION Exposure to inhibitors of gastric acidity is significantly associated with the occurrence of LOS in preterm VLBW infants. Concomitant administration of BLF counteracts this selective disadvantage. TRIAL REGISTRATION isrctn.org: ISRCTN53107700.
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Change of signs, symptoms and voice quality evaluations throughout a 3- to 6-month empirical treatment for laryngopharyngeal reflux disease.
Lechien, JR, Finck, C, Khalife, M, Huet, K, Delvaux, V, Picalugga, M, Harmegnies, B, Saussez, S
Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery. 2018;(5):1273-1282
Abstract
OBJECTIVE To assess the usefulness of voice quality measurements as a treatment outcome in patients with laryngopharyngeal reflux (LPR)-related symptoms. DESIGN Prospective uncontrolled multi-centre study. MATERIAL AND METHODS A total of 80 clinically diagnosed LPR patients with a reflux finding score (RFS)>7 and a reflux symptom index (RSI)>13 were treated with pantoprazole and diet recommendations during 3 or 6 months, according to their evolution. RSI; RFS; blinded Grade, Roughness, Breathiness, Asthenia, Strain and Instability (GRBASI) and aerodynamic and acoustic measurements were evaluated at baseline, 3 months (n = 80), and 6 months (n = 41) post-treatment. We conducted a correlation analysis between the adherence to the diet, and the evolution of both signs and symptoms and between videolaryngostroboscopic signs and acoustic measurements. RESULTS Reflux symptom index, RFS, perceptual voice quality evaluations (dysphonia, roughness, strain and instability), and aerodynamic and acoustic measurements (ie, percent jitter and percent shimmer) were significantly improved at 3 months post-treatment but not at 6 months. Percent jitter was the most useful outcome for evaluating the clinical evolution of patients throughout the treatment course. A significant relationship between globus sensation and posterior commissure hypertrophy was documented; both seemed to significantly improve from 3 to 6 months. The correlation analysis revealed correlations between adherence to diet recommendations and the improvement of symptoms and between posterior commissure granulation severity and acoustic measurement impairments. CONCLUSION Voice quality improved in a manner similar to both signs and symptoms throughout a 6-month empirical treatment with better improvement the 3 first months. Voice quality assessments can be used as indicators of treatment effectiveness in patients with LPR-related symptoms.
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Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study.
El-Kersh, K, Jalil, B, McClave, SA, Cavallazzi, R, Guardiola, J, Guilkey, K, Persaud, AK, Furmanek, SP, Guinn, BE, Wiemken, TL, et al
Journal of critical care. 2018;:108-113
Abstract
PURPOSE We investigated whether early enteral nutrition alone may be sufficient prophylaxis against stress-related gastrointestinal (GI) bleeding in mechanically ventilated patients. MATERIALS AND METHODS Prospective, double blind, randomized, placebo-controlled, exploratory study that included mechanically ventilated patients in medical ICUs of two academic hospitals. Intravenous pantoprazole and early enteral nutrition were compared to placebo and early enteral nutrition as stress-ulcer prophylaxis. The incidences of clinically significant and overt GI bleeding were compared in the two groups. RESULTS 124 patients were enrolled in the study. After exclusion of 22 patients, 102 patients were included in analysis: 55 patients in the treatment group and 47 patients in the placebo group. Two patients (one from each group) showed signs of overt GI bleeding (overall incidence 1.96%), and both patients experienced a drop of >3 points in hematocrit in a 24-hour period indicating a clinically significant GI bleed. There was no statistical significant difference in the incidence of overt or significant GI bleeding between groups (p=0.99). CONCLUSION We found no benefit when pantoprazole is added to early enteral nutrition in mechanically ventilated critically ill patients. The routine prescription of acid-suppressive therapy in critically ill patients who tolerate early enteral nutrition warrants further evaluation.
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Do sleeve gastrectomy and gastric bypass influence treatment with proton pump inhibitors 4 years after surgery? A nationwide cohort.
Thereaux, J, Lesuffleur, T, Czernichow, S, Basdevant, A, Msika, S, Nocca, D, Millat, B, Fagot-Campagna, A
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2017;(6):951-959
Abstract
BACKGROUND Gastroesophageal reflux disease (GERD) is a common obesity-related co-morbidity that routinely is treated by continuous proton pump inhibitor (PPI) therapy. A number of concerns have been raised regarding the risk of de novo GERD or exacerbation of preexisting GERD after sleeve gastrectomy (SG). OBJECTIVE To assess PPI use at 4 years after bariatric surgery. SETTING French National Health Insurance. METHODS Data were extracted from the French National Health Insurance database. All adult obese patients who had undergone gastric bypass (GBP) (n = 8250) or SG (n = 11,923) in 2011 in France were included. Patients were considered to be on continuous PPI therapy when PPIs were dispensed≥6 times per year. Logistic regression models were used to compute odds ratios for potential risk factors for PPI reimbursement 4 years after surgery. RESULTS Overall, continuous use of PPIs increased from baseline to 4 years after SG and GBP, from 10.9% to 26.5% (P<.001) and from 11.4% to 21.9% (P<.001), respectively. Among patients who underwent PPI therapy before surgery, those who had undergone SG were more likely to continue PPI therapy 4 years after surgery compared with those who underwent GBP (72.7% versus 59.2%; P<.001). In multivariate analyses, the major risk factors for persistent continuous PPI treatment 4 years after surgery were the following: SG (odds ratio [OR] = 1.87; 95% confidence interval [CI] 1.55-2.25), higher body mass index (OR 1.85; 95% CI 1.35-2.5), and preoperative antidepressant treatment (OR 1.89; 95% CI 1.56-2.29). CONCLUSION At a nationwide scale, continuous PPI treatment is used by 1 of 10 obese patients before bariatric surgery, but by 1 of 4 patients 4 years after surgery. SG compared with GBP, higher body mass index, and other coexisting conditions are the 3 major risk factors for medium-term continuous PPI therapy.
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Randomised clinical trial: vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the healing of erosive oesophagitis.
Ashida, K, Sakurai, Y, Hori, T, Kudou, K, Nishimura, A, Hiramatsu, N, Umegaki, E, Iwakiri, K
Alimentary pharmacology & therapeutics. 2016;(2):240-51
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BACKGROUND Vonoprazan is a novel potassium-competitive acid blocker which may provide clinical benefit in acid-related disorders. AIM: To verify the non-inferiority of vonoprazan vs. lansoprazole in patients with erosive oesophagitis (EE), and to establish its long-term safety and efficacy as maintenance therapy. METHODS In this multicentre, randomised, double-blind, parallel-group comparison study, patients with endoscopically confirmed EE (LA Classification Grades A-D) were randomly allocated to receive vonoprazan 20 mg or lansoprazole 30 mg once daily after breakfast. The primary endpoint was the proportion of patients with healed EE confirmed by endoscopy up to week 8. In addition, subjects who achieved healed EE in the comparison study were re-randomised into a long-term study to investigate the safety and efficacy of vonoprazan 10 or 20 mg as maintenance therapy for 52 weeks. RESULTS Of the 409 eligible subjects randomised, 401 completed the comparison study, and 305 entered the long-term maintenance study. The proportion of patients with healed EE up to week 8 was 99.0% for vonoprazan (203/205) and 95.5% for lansoprazole (190/199), thus verifying the non-inferiority of vonoprazan (P < 0.0001). Vonoprazan was also effective in patients with more severe EE (LA Classification Grades C/D) and CYP2C19 extensive metabolisers. In the long-term maintenance study, there were few recurrences (<10%) of EE in patients treated with vonoprazan 10 or 20 mg. Overall, vonoprazan was well-tolerated. CONCLUSIONS The non-inferiority of vonoprazan to lansoprazole in EE was verified in the comparison study, and vonoprazan was well-tolerated and effective during the long-term maintenance study.
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Comparative clinical evaluation on herbal formulation Pepsil, Safoof-e-Katira and Omeprazole in gastro esophageal reflux disease.
Toseef, MU, Saeed, A, Mohi-Ud-Din, E, Usmanghani, K, Nazar, H, Nawaz, A, Ahmad, I, Siddiqui, FA
Pakistan journal of pharmaceutical sciences. 2015;(3):863-70
Abstract
This study was conducted to evaluate the role of Unani herbal drugs Pepsil and Safoof-e-katira on the gastro esophageal reflux disease (GERD). This was multicentre randomized case control study conducted at Matab Hakeem Muhammad Noor-ud-din, Burewala; Aziz Muhammad din Medical and Surgical Centre, Burewala and Shifa-ul-mulk Memorial Hospital, Hamdard University Karachi. The patients were selected according to inclusion and exclusion criteria. In test group-1 the male female ratio was 40%, 60%; test group-2 was 42%, 58% and in control group was 44%, 56% respectively. The observed symptoms in the study were increased appetite (TG-1-95%, TG-2-95% and CG-89%), difficulty in swallowing (TG-1-93%, TG-2-96% and TC-94%), belching/burping (TG-1-97%, TG-2-97% and CG-95%), vomiting (TG-1-90%, TG-2-96% and CG-89%), heart burn (TG-1-100%, TG-2-100% and CG-98%), palpitation (TG-1-100%, TG-2-100% and CG-97%), epigastric pain (TG-1-97%, TG-2-97% and CG-90%), abdominal cramps (TG-1-97%, TG-2-98% and CG-95%), tenesmus (TG-1-100%, TG-2-100% and CG-97%), flatulence (TG-1-100%, TG-2-75% and CG-95%), wakeup during sleep (TG-1-94%, TG-2-87% and CG-94%). The p-value of the results of the symptoms was 0.000 except flatulence where the value was 0.001. The statistical results of the study prescribed that all the drugs studied (Pepsil, Safoof-e-katira and Omeprazole) are highly significant. The herbal coded drug Pepsil showed no side effects and unani herbal drug safoof-e-katira showed minimum result of 75% in the patients while Omeprazole resulted with some side effects. In the result it can be concluded that the herbal coded drug Pepsil is a potent herbal drug for gastro esophageal reflux disease.
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Randomised clinical trial: a dose-ranging study of vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the treatment of erosive oesophagitis.
Ashida, K, Sakurai, Y, Nishimura, A, Kudou, K, Hiramatsu, N, Umegaki, E, Iwakiri, K, Chiba, T
Alimentary pharmacology & therapeutics. 2015;(6):685-95
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BACKGROUND The potassium-competitive acid blocker vonoprazan (VPZ) has potent acid-inhibitory effects and may offer clinical advantages over conventional therapy for acid-related disorders. AIM: To investigate the efficacy and safety of VPZ in patients with erosive oesophagitis (EO). METHODS In this multicentre, randomised, double-blind, parallel-group, dose-ranging study, patients ≥20 years with endoscopically confirmed EO [Los Angeles (LA) grades A-D] received VPZ 5, 10, 20 or 40 mg, or lansoprazole (LPZ) 30 mg once daily for 8 weeks. The primary endpoint was the proportion of healed EO subjects as shown by endoscopy at week 4. RESULTS A total of 732 subjects received VPZ or LPZ. The proportion of healed EO subjects at week 4 was 92.3%, 92.5%, 94.4%, 97.0% and 93.2%, respectively, with VPZ 5, 10, 20 and 40 mg and LPZ 30 mg. All VPZ doses were non-inferior to LPZ when adjusted for baseline LA grades A/B and C/D. Among those with LA grades C/D, the proportions of healed EO subjects were 87.3%, 86.4%, 100%, 96.0% and 87.0%, respectively, with VPZ 5, 10, 20 and 40 mg and LPZ 30 mg. The incidence of adverse events was similar across the groups. CONCLUSIONS Vonoprazan was effective and non-inferior to LPZ in healing EO. VPZ 20 mg or higher was highly efficacious for severe EO (LA grades C/D). VPZ was associated with no safety concern during this 8-week study, while there was a dose-dependent increase in serum gastrin. Once-daily VPZ 20 mg is the recommended clinical dose for treating EO.