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The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two-Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers.
Shibata, M, Toyoshima, J, Kaneko, Y, Oda, K, Kiyota, T, Kambayashi, A, Nishimura, T
Clinical pharmacology in drug development. 2021;(3):283-290
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Abstract
The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open-label, randomized, 2-way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150-mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect). Bioequivalence was compared with the developmental 150-mg tablet. Samples for pharmacokinetic analysis were collected before dose and ≤72 hours after dose. Safety assessments included adverse events, vital signs, and laboratory variables. In total, 40 and 18 subjects were randomized to the bioequivalence and food effect studies, respectively. The 2 peficitinib formulations were bioequivalent (90% confidence intervals of the geometric mean ratios for Cmax and AUCt of peficitinib were within predefined limits of 0.8 to 1.25). The AUClast and the Cmax of the marketed tablet were 36.8% and 56.4% higher, respectively, under fed versus fasted conditions. Peficitinib was well tolerated. The marketed 150-mg tablet formulation of peficitinib was bioequivalent to the developmental 150-mg formulation, with no discernible safety differences. Bioavailability increased under fed conditions with the marketed tablet formulation.
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The Effect of Food on the Single-Dose Bioavailability and Tolerability of the Highest Marketed Strength of Duloxetine.
Rizea-Savu, S, Duna, SN, Ghita, A, Iordachescu, A, Chirila, M
Clinical pharmacology in drug development. 2020;(7):797-804
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Abstract
Duloxetine is a combined serotonin and norepinephrine reuptake inhibitor indicated in adults for the treatment of major depressive disorder, diabetic peripheral neuropathic pain, and generalized anxiety disorder. The aim of these studies was to evaluate the effect of food on the pharmacokinetics and safety of duloxetine 60-mg gastroresistant hard capsules following single-dose administration. The data were obtained from 2 phase 1 bioequivalence studies, 1 in a fasting state and the other under fed conditions. Both studies have shown that, when administered as a single dose in the same prandial state, the test and reference duloxetine treatments were bioequivalent and exhibited similar safety profiles. The mean fed and fasting pharmacokinetic parameters and drug-related adverse events from the 2 studies were compared in order to assess the effect of food on the duloxetine bioavailability and respectively, tolerability. Administration of duloxetine in fed conditions increased peak plasma concentration by up to 30% and delayed mean time to peak concentration by an average of 1.15 hours while having an insignificant effect on extent of absorption (area under the plasma concentration-time curve in fed state within ±6% as compared with fasting conditions). Even though peak plasma levels were substantially higher in the fed state, there was no negative impact on the drug's safety profile. Actually, administration with food resulted in a lower average number of adverse events per single dose exposure. The negligible variation in overall systemic exposure suggests that efficacy remains unchanged irrespective of administration conditions; however, a better tolerability of the 60-mg dose is expected when the drug is taken with food.
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Reintroduction failure after negative food challenges in adults is common and mainly due to atypical symptoms.
Versluis, A, Knulst, AC, van Erp, FC, Blankestijn, MA, Meijer, Y, Le, TM, van Os-Medendorp, H
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2020;(4):479-486
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Abstract
BACKGROUND Reintroduction of a food after negative food challenge (FC) faces many obstacles. There are no studies available about this subject in adults. OBJECTIVE To investigate the frequency, reasons and risk factors of reintroduction failure in adults. METHODS In this prospective study, adult patients received standardized follow-up care after negative FCs including a reintroduction scheme and supportive telephone consultations. Data were collected by telephone interview (2 weeks after FC) and questionnaires (at baseline and 6 months after FC(s)): food habits questionnaire, State-Trait Anxiety Inventory, Food Allergy Quality of Life Questionnaire-Adult Form and Food Allergy Independent Measure. Frequency and reasons of reintroduction failure were analysed using descriptive statistics and risk factors with univariate analyses. RESULTS Eighty patients were included with, in total, 113 negative FCs. Reintroduction failed on short-term (2 weeks after FC) in 20% (95% CI: 13%-28%). Common reasons were symptoms upon ingestion during the reintroduction scheme (50%) and no need to eat the food (23%). On the long-term (5-12 months after FC(s)), reintroduction failure increased to 40% (95% CI: 28%-53%). Common reasons were atypical symptoms after eating the food (59%) and fear for an allergic reaction (24%). Five risk factors for long-term reintroduction failure were found: if culprit food was not one of the 13 EU regulated allergens, reintroduction failure at short-term, atypical symptoms during FC, a lower quality of life and a higher state anxiety. CONCLUSIONS AND CLINICAL RELEVANCE Reintroduction failure after negative FCs in adults is common, increases over time, and is primarily due to atypical symptoms. This stresses the need for more patient-tailored care before and after negative food challenges.
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Effects of Food and Gender on Pharmacokinetics of Rosuvastatin in a Chinese Population Based on 4 Bioequivalence Studies.
Chen, J, Lou, H, Jiang, B, Shao, R, Yang, D, Hu, Y, Xu, Y, Ruan, Z
Clinical pharmacology in drug development. 2020;(2):235-245
Abstract
The effects of food and gender on the pharmacokinetics of rosuvastatin in healthy Chinese subjects were investigated from 4 bioequivalence studies. These studies were designed as randomized, open-label, and 2-period crossover in both fasting and fed states. A total of 204 subjects were enrolled, 134 men and 70 women. These subjects received a single oral 10-mg dose of rosuvastatin with a 7-day washout between 2 periods. The plasma concentrations were determined using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters were calculated by noncompartmental methods. Compared with the fasting condition, administration after a high-fat and high-calorie meal resulted in an approximately 40% reduction of rosuvastatin exposure and a near 50% decrease in absorption rate. Moreover, the apparent clearance was significantly greater in the fed state than that in the fasting state. It was noted that the adverse events incidence is increased by approximately 30% in the fasting state; however, no serious adverse events were observed. Additionally, small differences in pharmacokinetic characteristics were found between male and female subjects. Food effect might be considered for optimal effectiveness and safety of rosuvastatin therapy.
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Impact of food challenge on local oesophageal immunophenotype in eosinophilic oesophagitis.
Philpott, H, Lee, SZ, Arrington, A, McGee, SJ, Dellon, ES
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2020;(4):463-470
Abstract
BACKGROUND Eosinophilic oesophagitis (EoE) is caused by the ingestion of food antigens. Dietary avoidance can result in clinical and histological remission, while food reintroduction can cause recurrence. It is uncertain if food antigen processing and immune activation occurs locally, in the oesophagus. Therefore, we performed a comparative study of the density of cell surface proteins (known to be involved with antigen presentation) on oesophageal tissue prior to, and following food antigen induced disease recurrence. A secondary aim was to consider novel biomarkers. METHOD Adult patients with a diagnosis of EoE, who had achieved histological remission with an elimination diet (<15 eosinophils per high power field at oesophageal biopsy), and who underwent food challenge with proven recurrence were included. Immunohistochemistry/immunofluorescence for CD1a, CD3, CD28, CD40, CD69, CD80, CD138, CXCR3 and HLA-DR was performed. Staining intensity of each biomarker (pixels/mm2 ) was quantified by semi-automated analysis (Studio-FL software). RESULTS Fourteen cases of EoE (pre and post food challenge), 6 GORD and 5 healthy controls were included. HLA-DR, CD3, CD28, CD40 and CD 138 significantly increased with food reintroduction (P = <0.05). CD1a, CD 69, CD 80 and CXCR3 did not measurably change. CONCLUSION The presence of cell surface proteins typically associated with antigen presentation (following food antigen induced recurrence) suggests immune activation occurs in the oesophagus, and the relative lack of langerhans cells (CD1a) may indicate this cell type is unimportant. The cell surface protein CD 138 increases with disease recurrence, is not elevated in GORD or healthy controls, and has promise as a biomarker.
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Changes in Food Cravings and Eating Behavior after a Dietary Carbohydrate Restriction Intervention Trial.
Anguah, KO, Syed-Abdul, MM, Hu, Q, Jacome-Sosa, M, Heimowitz, C, Cox, V, Parks, EJ
Nutrients. 2019;(1)
Abstract
Compared to low-fat diets, low-carbohydrate (CHO) diets cause weight loss (WL) over a faster time frame; however, it is unknown how changes in food cravings and eating behavior contribute to this more rapid WL in the early phases of dieting. We hypothesized that reductions in food cravings and improved eating behaviors would be evident even after a relatively short (4-week) duration of CHO-restriction, and that these changes would be associated with WL. Adult participants (n = 19, 53% males, mean ± SD: BMI = 34.1 ± 0.8 kg/m2; age 40.6 ± 1.9 years) consumed a CHO-restricted diet (14% CHO, 58% fat, 28% protein) for 4 weeks. Before and after the intervention, specific and total cravings were measured with the Food Craving Inventory (FCI) and eating behaviors assessed with the Three-Factor Eating questionnaire. Food cravings were significantly reduced at week 4, while women had significantly greater reductions in sweet cravings than men. Dietary restraint was significantly increased by 102%, while disinhibiton and hunger scores were reduced (17% and 22%, respectively, p < 0.05). Changes in cravings were unrelated to changes in body weight except for the change in high-fat cravings where those who lost the most weight experienced the least reductions in fat cravings (r = -0.458, p = 0.049). Changes in dietary restraint were inversely related to several FCI subscales. A short-term, low-CHO diet was effective in reducing food cravings. These data suggest that in subjects that have successfully lost weight on a low-CHO diet, those who craved high-fat foods at the onset were able to satisfy their cravings-potentially due to the high-fat nature of this restricted diet.
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The Inflammatory Potential of Dietary Manganese in a Cohort of Elderly Men.
Kresovich, JK, Bulka, CM, Joyce, BT, Vokonas, PS, Schwartz, J, Baccarelli, AA, Hibler, EA, Hou, L
Biological trace element research. 2018;(1):49-57
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Abstract
Manganese is an essential nutrient that may play a role in the production of inflammatory biomarkers. We examined associations between estimated dietary manganese intake from food/beverages and supplements with circulating biomarkers of inflammation. We further explored whether estimated dietary manganese intake affects DNA methylation of selected genes involved in the production of these biomarkers. We analyzed 1023 repeated measures of estimated dietary manganese intakes and circulating blood inflammatory biomarkers from 633 participants in the Normative Aging Study. Using mixed-effect linear regression models adjusted for covariates, we observed positive linear trends between estimated dietary manganese intakes and three circulating interleukin proteins. Relative to the lowest quartile of estimated intake, concentrations of IL-1β were 46% greater (95% CI - 5, 126), IL-6 52% greater (95% CI - 9, 156). and IL-8 32% greater (95% CI 2, 71) in the highest quartiles of estimated intake. Estimated dietary manganese intake was additionally associated with changes in DNA methylation of inflammatory biomarker-producing genes. Higher estimated intake was associated with higher methylation of NF-κβ member activator NKAP (Q4 vs Q1: β = 3.32, 95% CI - 0.6, 7.3). When stratified by regulatory function, higher manganese intake was associated with higher gene body methylation of NF-κβ member activators NKAP (Q4 vs Q1: β = 10.10, 95% CI - 0.8, 21) and NKAPP1 (Q4 vs Q1: β = 8.14, 95% CI 1.1, 15). While needed at trace amounts for various physiologic functions, our results suggest estimated dietary intakes of manganese at levels slightly above nutritional adequacy contribute to inflammatory biomarker production.
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Glycemic index and microstructure analysis of a newly developed fiber enriched cookie.
Schuchardt, JP, Wonik, J, Bindrich, U, Heinemann, M, Kohrs, H, Schneider, I, Möller, K, Hahn, A
Food & function. 2016;(1):464-74
Abstract
A diet with a high glycemic index (GI) is associated with an elevated risk for obesity or type 2 diabetes. We investigated the GI of a newly-developed fiber enriched cookie and characterized the microstructure of ingredients used. In a study with 26 non-diabetic healthy volunteers it was shown that the fiber enriched cookie has a GI of 58.9 in relation to white bread as reference. Using a conversion factor of 1.4, the GI of the fiber enriched cookie in relation to a glucose-solution is 42.0 and can be classified as a low-GI food. Postprandial insulin concentration was significantly lower after consumption of fiber enriched cookies compared to white bread. Glucose release after in vitro digestion was significantly lower from fiber enriched cookies compared to other cookies tested. In addition to its high percentage of fiber, the cookies' low GI can be attributed to the limited gelatinization potential of the starch granules found in the ingredients used. Using confocal laser scanning microscopy it is shown that starch granule surface area of whole grain barley flour, spelt flour and oat flakes bears cluster-shaped protein-NSPS complexes that preferentially absorb water in conditions of water shortage and thereby prevent starch gelatinization.
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Late reactions in food-allergic children and adolescents after double-blind, placebo-controlled food challenges.
Saleh-Langenberg, J, Flokstra-de Blok, BM, AlAgla, N, Kollen, BJ, Dubois, AE
Allergy. 2016;(7):1069-73
Abstract
The time during which children are observed following a double-blind, placebo-controlled food challenge (DBPCFC) varies in clinical practice. There are little data on late reactions (LRs) following DBPCFCs. Therefore, we determined the prevalence, severity and clinical characteristics of late reactions in food-allergic children and adolescents after DBPCFC, and ascertained which factors are associated with, and may predict, LRs. Logistic regression analyses were performed to investigate which factors were associated with LRs and to develop the association and prediction models. A total of 1142 children underwent DBPCFCs (child-test combinations). Of these 1142 child-test combinations, 400 reported LRs following the DBPCFC. LRs in food-allergic children after DBPCFC are poorly predictable and are generally not severe. All LRs, including those on the placebo day, are more frequently reported in younger children. Children who do not experience severe immediate reactions may be safely discharged home 2 h after a DBPCFC.
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Elemental diet induces histologic response in adult eosinophilic esophagitis.
Peterson, KA, Byrne, KR, Vinson, LA, Ying, J, Boynton, KK, Fang, JC, Gleich, GJ, Adler, DG, Clayton, F
The American journal of gastroenterology. 2013;(5):759-66
Abstract
OBJECTIVES Elemental diets have not been studied in adults with eosinophilic esophagitis (EoE). The goal of this trial was to assess the efficacy of an elemental diet in adults with EoE. METHODS A total of 18 adults with EoE were given an elemental diet for 4 weeks, or just 2 weeks if their response was complete. Symptoms and histologic findings, based on biweekly biopsies, were monitored. Six subjects were rebiopsied 2-7 days after resuming a normal diet. RESULTS After therapy, esophageal tissue eosinophil content decreased from 54 to 10 per maximal high power field (P=0.0006). There was complete or nearly complete response (≤10 eosinophils) in 72% of subjects. Mast cell content, parabasal layer thickness, and endoscopic furrows and exudates also significantly decreased. Of the 29 qualified subjects, 11 (38%) failed to adhere to the diet. Several subjects had significant weight loss. Symptoms and endoscopic fixed strictures did not improve. After the subjects resumed a normal diet, the eosinophil content increased substantially in 3-7 days. CONCLUSIONS While symptoms did not improve and dietary compliance was problematic, there was substantial histologic improvement after 4 weeks on the elemental diet. EoE in adults is substantially triggered by foods.