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1.
A Phase 1 Pharmacokinetic Study of Cysteamine Bitartrate Delayed-Release Capsules Following Oral Administration with Orange Juice, Water, or Omeprazole in Cystinosis.
Armas, D, Holt, RJ, Confer, NF, Checani, GC, Obaidi, M, Xie, Y, Brannagan, M
Advances in therapy. 2018;(2):199-209
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Abstract
INTRODUCTION Cystinosis is a rare, metabolic, autosomal recessive, genetic lysosomal storage disorder characterized by an accumulation of cystine in various organs and tissues. Cysteamine bitartrate (CB) is a cystine-depleting aminothiol agent approved in the United States and Europe in immediate-release and delayed-release (DR) formulations for the treatment of nephropathic cystinosis in children and adults. It is recommended that CBDR be administered with fruit juice (except grapefruit juice) for maximum absorption. Omeprazole is a proton pump inhibitor that inhibits gastric acid secretion and, theoretically, may cause the premature release of cysteamine by increasing intragastric pH, thereby affecting the PK of CBDR. METHODS This open-label, three-period, randomized study in healthy adult subjects was designed primarily to compare the pharmacokinetics of CBDR capsules after a single oral dose administered with orange juice, water, or multiple oral doses of omeprazole with water at steady state. A total of 32 subjects were randomly assigned to receive study agents in one of two treatment sequences. RESULTS All subjects completed the study and baseline characteristics of the overall population and the two treatment sequence populations were similar. Peak mean plasma cysteamine concentrations following co-administration of CBDR capsules with orange juice (1892 ng/mL) were higher compared with co-administration with water (1663 ng/mL) or omeprazole 20 mg and water (1712 ng/mL). Mean time to peak plasma concentration was shorter with omeprazole co-administration (2.5 h) compared with orange juice (3.5 h) or water (3.0 h). Statistical comparisons between treatment groups indicated that exposure as assessed by AUC0-t, AUC0-∞, and Cmax were all within the 80-125% bioequivalence ranges for all comparisons. All treatments were generally well tolerated. CONCLUSION Overall, the pharmacokinetics of cysteamine bitartrate DR capsules are not significantly impacted by co-administration with orange juice, water only, or omeprazole (with water). FUNDING Horizon Pharma, Inc.
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The Proton Pump Inhibitor Nonresponder: a Behavioral Approach to Improvement and Wellness.
Riehl, ME, Chen, JW
Current gastroenterology reports. 2018;(7):34
Abstract
PURPOSE OF REVIEW Gastroesophageal reflux disease (GERD) is a difficult to treat medical condition, where nearly 40% of patients are refractory to standard medical intervention, which typically begins with a proton pump inhibitor (PPI). These PPI nonresponders represent a population of patients, where treatment planning must be individualized; multidisciplinary and psychiatric comorbidities should be considered. This review highlights treatment options that include neuromodulators, lifestyle, and psychological interventions for the PPI nonresponder. RECENT FINDINGS Mental health specialists in the field of psychogastroenterology can aid in the management of esophageal hypersensitivity, which can drive the symptom experience of a PPI nonresponder. Considerations for comorbid anxiety and depression in this population require careful assessment and treatment. Physicians are encouraged to create realistic expectations for symptom management and offer multidisciplinary options for treatment early in care. Patients will frequently benefit from working with a GI psychologist and find value in behavioral interventions.
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Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and Vitamin B-12 Deficiency: Clinical Implications.
Miller, JW
Advances in nutrition (Bethesda, Md.). 2018;(4):511S-518S
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Abstract
There is clear evidence that proton-pump inhibitors (PPIs), H2-receptor antagonists (H2RAs), and metformin can reduce serum vitamin B-12 concentrations by inhibiting the absorption of the vitamin. However, it is unclear if the effects of these drugs on serum vitamin B-12 are associated with increased risk of biochemical or functional deficiency (as is indicated by elevated blood concentrations of homocysteine and methylmalonic acid) or clinical deficiency (including megaloblastic anemia and neurologic disorders such as peripheral neuropathy and cognitive dysfunction). This review provides an overview of vitamin B-12 absorption and biochemistry and the mechanisms by which PPIs, H2RAs, and metformin affect these functions. It also summarizes the literature relating the use of these drugs to the risk of vitamin B-12 deficiency. Also discussed is that strategies for assessing vitamin B-12 status and diagnosing vitamin B-12 deficiency have evolved in recent years beyond solely measuring serum total vitamin B-12. Multiple analyte testing, a strategy in which ≥2 of 4 biomarkers of vitamin B-12 status-serum total vitamin B-12, holotranscobalamin, homocysteine, and methylmalonic acid-are measured, increases sensitivity and specificity for diagnosing vitamin B-12 deficiency. It is concluded that randomized controlled trials are now needed that use the strategy of multiple analyte testing to determine if PPIs, H2RAs, and metformin do indeed increase the risk of vitamin B-12 deficiency. Until these studies are conducted, a reasonable recommendation for physicians and their patients who are taking these drugs is to monitor vitamin B-12 status and to provide vitamin B-12 supplements if altered blood biomarkers or clinical signs consistent with low or deficient vitamin B-12 status develop.
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Toxicity of long-term use of proton pump inhibitors in children.
De Bruyne, P, Ito, S
Archives of disease in childhood. 2018;(1):78-82
Abstract
Proton pump inhibitor (PPI) use is becoming increasingly common. Although the toxicity profiles of PPIs are not well understood particularly in children, PPIs have been associated with increased risks of gastrointestinal and respiratory tract infection, vitamin B12 deficiency, hypomagnesaemia, bone fractures, and rebound hyperacidity after discontinuation. Prescribers should take into account that PPI uses pose toxicity risks, which remain to be fully characterised in infants and children.
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Pharmacologic Treatment of Eosinophilic Esophagitis: An Update.
Schoepfer, AM, Straumann, A, Safroneeva, E
Gastrointestinal endoscopy clinics of North America. 2018;(1):77-88
Abstract
Eosinophilic esophagitis (EoE) is defined as a chronic, immune-medicated or antigen-mediated, esophageal disease, characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Food allergens are identified in most patients. Treatment strategies include elimination diets, drugs, and esophageal dilation. This article focuses on pharmacologic treatment. Currently, there is no pharmacologic treatment that has been approved by regulatory authorities. Established pharmacologic options to treat EoE include proton pump inhibitors and swallowed topical steroids. Several biologic therapies are currently under evaluation and some of them have shown promising results in improving biologic endpoints and patient-reported outcomes.
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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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Comparison of the Effects of Vonoprazan and Lansoprazole for Treating Endoscopic Submucosal Dissection-Induced Artificial Ulcers.
Hirai, A, Takeuchi, T, Takahashi, Y, Kawaguchi, S, Ota, K, Harada, S, Kojima, Y, Tominaga, K, Tokioka, S, Higuchi, K
Digestive diseases and sciences. 2018;(4):974-981
Abstract
BACKGROUND Vonoprazan exhibits a more potent, rapid, and longer-lasting inhibitory effect on gastric acid secretion than proton pump inhibitors; however, whether it is more effective than PPI for treating endoscopic submucosal dissection (ESD)-induced artificial ulcers remains controversial. AIM: This study aimed to assess and compare the effects of vonoprazan and lansoprazole for treating ESD-induced artificial ulcers. METHODS This prospective, randomized controlled trial enrolled 149 patients who underwent ESD for the treatment of early gastric neoplasms from April 2015 to May 2017. They were randomly treated with either 20 mg/day vonoprazan (V group) or 30 mg/day lansoprazole (L group) orally. The primary end points were the area and shrinkage ratio of the ulcers at 4 and 8 weeks post-ESD. RESULTS Data from 127 patients were analyzed, which showed that the 4- and 8-week healing ratios were not significantly different between the V and L groups (4 weeks, 16.3 vs. 25.8%; 8 weeks, 86.9 vs. 90.9%, respectively). Similarly, the shrinkage ratio, categorized as less than 90%, 90% or more but less than 100%, or 100% at 4 weeks and as less than 100% or 100% at 8 weeks were not statistically different between the V and L groups (4 weeks: 12, 41, 8 vs. 13, 41, 12, p = 0.7246; 8 weeks: 9, 52 vs. 9, 57, p = 0.8568). Delayed bleeding was also not significantly different between both the groups (5.4 vs. 5.3%; p = 0.9844). CONCLUSIONS Vonoprazan is as effective as lansoprazole in treating ESD-induced ulcers.
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Prevalence and outcomes of proton pump inhibitor associated hypomagnesemia in chronic kidney disease.
Hughes, J, Y Y Chiu, D, Kalra, PA, Green, D
PloS one. 2018;(5):e0197400
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are one of the most widely prescribed medications across the world. PPIs have been associated with significant electrolyte abnormalities including hypomagnesaemia. We explored the prevalence of PPI associated hypomagnesaemia (PPIH) in different Chronic Kidney Disease (CKD) stages, in different PPI agents, and the impact of PPIH on survival in CKD. METHODS This was a subgroup analysis of the Salford Kidney Study, a prospective, observational, longitudinal study of non-dialysis CKD patients. Patients with outpatient magnesium samples obtained between 2002 and 2013 were included in the analysis. The prevalence hypomagnesaemia based on mean values over 12 months as well as 'ever' hypomagnesaemia were investigated. RESULTS 1,230 patients were included in this analysis, mean age 64.3± 32.3 years and mean eGFR 29.2±15.8 ml/min/1.73m2. Mean serum magnesium in those on PPI was significantly lower than those not on PPI overall (0.85±0.10 mmolL-1 versus 0.79±0.12 mmolL-1 respectively, p<0.001). This finding was maintained at all CKD stages. The adjusted odds ratio (OR) for mean hypomagnesaemia in PPI use was 1.12 (95% CI 1.06-1.18) p = <0. 'Ever hypomagnesaemia' had an OR of 1.12 (95% CI 1.07-1.16) p = <0.001. The expected rise in serum magnesium with declining eGFR was not observed in those on a PPI but was seen in those not on PPI. There was no difference in serum magnesium between PPI drugs. Thiazide diuretics were also associated with hypomagnesaemia independent of PPI use. Cox regression analysis demonstrated no reduction in survival in patients with PPI associated hypomagnesaemia. CONCLUSION No specific PPI drugs show a favourable profile in regards of risk for hypomagnesaemia in CKD. Avoiding concurrent use of PPI and thiazide may be of value in patients with hypomagnesaemia.
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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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Maintenance for healed erosive esophagitis: Phase III comparison of vonoprazan with lansoprazole.
Ashida, K, Iwakiri, K, Hiramatsu, N, Sakurai, Y, Hori, T, Kudou, K, Nishimura, A, Umegaki, E
World journal of gastroenterology. 2018;(14):1550-1561
Abstract
AIM: To compare vonoprazan 10 and 20 mg vs lansoprazole 15 mg as maintenance therapy in healed erosive esophagitis (EE). METHODS A total of 607 patients aged ≥ 20 years, with endoscopically-confirmed healed EE following 8 wk of treatment with vonoprazan 20 mg once daily, were randomized 1:1:1 to receive lansoprazole 15 mg (n = 201), vonoprazan 10 mg (n = 202), or vonoprazan 20 mg (n = 204), once daily. The primary endpoint of the study was the rate of endoscopically-confirmed EE recurrence during a 24-wk maintenance period. The secondary endpoint was the EE recurrence rate at Week 12 during maintenance treatment. Additional efficacy endpoints included the incidence of heartburn and acid reflux, and the EE healing rate 4 wk after the initiation of maintenance treatment. Safety endpoints comprised adverse events (AEs), vital signs, electrocardiogram findings, clinical laboratory results, serum gastrin and pepsinogen I/II levels, and gastric mucosa histopathology results. RESULTS Rates of EE recurrence during the 24-wk maintenance period were 16.8%, 5.1%, and 2.0% with lansoprazole 15 mg, vonoprazan 10 mg, and vonoprazan 20 mg, respectively. Vonoprazan was shown to be non-inferior to lansoprazole 15 mg (P < 0.0001 for both doses). In a post-hoc analysis, EE recurrence at Week 24 was significantly reduced with vonoprazan at both the 10 mg and the 20 mg dose vs lansoprazole 15 mg (5.1% vs 16.8%, P = 0.0002, and 2.0% vs 16.8%, P < 0.0001, respectively); by contrast, the EE recurrence rate did not differ significantly between the two doses of vonoprazan (P = 0.1090). The safety profiles of vonoprazan 10 and 20 mg were similar to that of lansoprazole 15 mg in patients with healed EE. Treatment-related AEs were reported in 11.4%, 10.4%, and 10.3% of patients in the lansoprazole 15 mg, vonoprazan 10 mg, and vonoprazan 20 mg arms, respectively. CONCLUSION Our findings confirm the non-inferiority of vonoprazan 10 and 20 mg to lansoprazole 15 mg as maintenance therapy for patients with healed EE.