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Mechanistic insight into the interaction of gastrointestinal mucus with oral diblock copolymers synthesized via ATRP method.
Liu J, Cao J, Cao J, Han S, Liang Y, Bai M, Sun Y
(2018) Int J Nanomedicine 13: 2839-2856
MeSH Terms: Administration, Oral, Animals, Caco-2 Cells, Drug Carriers, Humans, Hydrophobic and Hydrophilic Interactions, Indoles, Intestinal Absorption, Intestinal Mucosa, Male, Methacrylates, Methylmethacrylates, Mice, Nanoparticles, Nylons, Particle Size, Polymers, Propionates, Tissue Distribution
Show Abstract · Added April 2, 2019
Introduction - Nanoparticles are increasingly used as drug carriers for oral administration. The delivery of drug molecules is largely dependent on the interaction of nanocarriers and gastrointestinal (GI) mucus, a critical barrier that regulates drug absorption. It is therefore important to understand the effects of physical and chemical properties of nanocarriers on the interaction with GI mucus. Unfortunately, most of the nanoparticles are unable to be prepared with satisfactory structural monodispersity to comprehensively investigate the interaction. With controlled size, shape, and surface chemistry, copolymers are ideal candidates for such purpose.
Materials and methods - We synthesized a series of diblock copolymers via the atom transfer radical polymerization method and investigated the GI mucus permeability in vitro and in vivo.
Results - Our results indicated that uncharged and hydrophobic copolymers exhibited enhanced GI absorption.
Conclusion - These results provide insights into developing optimal nanocarriers for oral administration.
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Seasonal patterns of Asthma medication fills among diverse populations of the United States.
Turi KN, Gebretsadik T, Lee RL, Hartert TV, Evans AM, Stone C, Sicignano NM, Wu AC, Iribarren C, Butler MG, Mitchel E, Morrow J, Larkin EK, Wu P
(2018) J Asthma 55: 764-770
MeSH Terms: Administration, Inhalation, Administration, Oral, Adolescent, Adrenergic beta-Agonists, Adult, Anti-Asthmatic Agents, Asthma, Child, Child, Preschool, Drug Prescriptions, Drug Therapy, Combination, Female, Glucocorticoids, Humans, Male, Medication Adherence, Middle Aged, Retrospective Studies, Seasons, United States, Young Adult
Show Abstract · Added March 14, 2018
OBJECTIVE - Nonadherence to controller and overuse of reliever asthma medications are associated with exacerbations. We aimed to determine patterns of seasonal asthma medication use and to identify time period(s) during which interventions to improve medication adherence could reduce asthma morbidity.
METHODS - We conducted a retrospective cohort study of asthmatics 4-50 years of age and enrolled in three diverse health insurance plans. Seasonal patterns of medications were reported by monthly prescription fill rates per 1000 individuals with asthma from 1998 to 2013, and stratified by healthcare plan, sex, and age.
RESULTS - There was a distinct and consistent seasonal fill pattern for all asthma medications. The lowest fill rate was observed in the month of July. Fills increased in the autumn and remained high throughout the winter and spring. Compared with the month of May with high medication fills, July represented a relative decrease of fills ranging from 13% (rate ratio, RR: 0.87, 95% confidence interval, 95%CI: 0.72-1.04) for the combination of inhaled corticosteroids (ICS) + long acting beta agonists (LABA) to 45% (RR: 0.55, 95%CI: 0.49-0.61) for oral corticosteroids. Such a seasonal pattern was observed each year across the 16-year study period, among healthcare plans, sexes, and ages. LABA containing control medication (ICS+LABA and LABA) fill rates were more prevalent in older asthmatics, while leukotriene receptor antagonists were more prevalent in the younger population.
CONCLUSIONS - A seasonal pattern of asthma medication fill rates likely represents a reactive response to a loss of disease control and increased symptoms. Adherence to and consistent use of asthma medications among individuals who use medications in reaction to seasonal exacerbations might be a key component in reducing the risk of asthma exacerbations.
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21 MeSH Terms
Factors Associated With Persistent Increase in Level of Alanine Aminotransferase in Patients With Chronic Hepatitis B Receiving Oral Antiviral Therapy.
Jacobson IM, Washington MK, Buti M, Thompson A, Afdhal N, Flisiak R, Akarca US, Tchernev KG, Flaherty JF, Aguilar Schall R, Myers RP, Subramanian GM, McHutchison JG, Younossi Z, Marcellin P, Patel K
(2017) Clin Gastroenterol Hepatol 15: 1087-1094.e2
MeSH Terms: Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Alanine Transaminase, Antiviral Agents, Biopsy, Clinical Trials, Phase III as Topic, Fatty Liver, Female, Hepatitis B e Antigens, Hepatitis B, Chronic, Histocytochemistry, Humans, Liver, Male, Middle Aged, Tenofovir, Young Adult
Show Abstract · Added March 14, 2018
BACKGROUND & AIMS - Despite complete suppression of viral DNA with antiviral agents, in some patients with chronic hepatitis B (CHB), serum levels of alanine aminotransferase (ALT) do not normalize. We investigated factors associated with persistent increases in ALT level in patients with CHB given long-term tenofovir disoproxil fumarate.
METHODS - We analyzed data from 471 hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with CHB participating in 2 phase 3 trials. We identified patients with an increased level of ALT (above the upper limit of normal range) after 5 years (240 weeks) of tenofovir disoproxil fumarate therapy. We analyzed findings from liver biopsy specimens collected from 467 patients (99%) at baseline and 339 patients (72%) at year 5 of treatment; biopsy specimens were evaluated by an independent pathologist. We performed stepwise, forward, multivariate regression analyses of specified baseline characteristics and on-treatment response parameters to identify factors associated with persistent increases in ALT level.
RESULTS - Of the 471 patients, 87 (18%) still had an increased ALT level at year 5 of treatment. Factors associated significantly with a persistent increase in ALT level were a steatosis score of 5% or greater (grade 1 or more) at baseline (odds ratio [OR], 2.236; 95% confidence interval [CI], 1.031-4.852; P = .042) and at year 5 (OR, 3.392; 95% CI, 1.560 ≥ 7.375; P = .002), HBeAg seropositivity at baseline (OR, 3.297; 95% CI, 1.653-6.576; P < .001), and age 40 years or older (OR, 2.099; 95% CI, 1.014-4.342; P = .046). Of the 42 HBeAg-positive patients with steatosis at baseline, 21 (50%) had an increased ALT level at year 5 of treatment. Patients with persistent increases in ALT level were more likely to have an increase in steatosis at year 5 than those with a normal ALT level.
CONCLUSIONS - HBeAg seropositivity and hepatic steatosis contribute to persistent increases in ALT level in patients with CHB receiving suppressive antiviral treatment. ClinicalTrials.gov registration numbers: NCT00117676 and NCT00116805.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione Core.
Nance KD, Days EL, Weaver CD, Coldren A, Farmer TD, Cho HP, Niswender CM, Blobaum AL, Niswender KD, Lindsley CW
(2017) J Med Chem 60: 1611-1616
MeSH Terms: Administration, Oral, Animals, Blood Glucose, Cells, Cultured, Central Nervous System, Glucagon-Like Peptide-1 Receptor, Halogenation, Humans, Insulin, Islets of Langerhans, Male, Pyrimidines, Rats, Sprague-Dawley
Show Abstract · Added April 6, 2017
A duplexed, functional multiaddition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant glucagon-like peptide-1 receptor (GLP-1R) noncompetitive antagonist. Antagonist 5d not only blocked exendin-4-stimulated insulin release in islets but also lowered insulin levels while increasing blood glucose in vivo.
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13 MeSH Terms
Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine.
Smith CT, Dang LC, Cowan RL, Kessler RM, Zald DH
(2016) Neuropharmacology 108: 394-402
MeSH Terms: Administration, Oral, Adolescent, Adult, Central Nervous System Stimulants, Corpus Striatum, Dextroamphetamine, Dopamine, Humans, Male, Positron-Emission Tomography, Prefrontal Cortex, Receptors, Dopamine D2, Signal Transduction, Young Adult
Show Abstract · Added February 9, 2017
Subjective responses to psychostimulants vary, the basis of which is poorly understood, especially in relation to possible cortical contributions. Here, we tested for relationships between participants' positive subjective responses to oral d-amphetamine (dAMPH) versus placebo and variability in striatal and extrastriatal dopamine (DA) receptor availability and release, measured via positron emission tomography (PET) with the radiotracer (18)F-fallypride. Analyses focused on 35 healthy adult participants showing positive subjective effects to dAMPH measured via the Drug Effects Questionnaire (DEQ) Feel, Like, High, and Want More subscales (Responders), and were repeated after inclusion of 11 subjects who lacked subjective responses. Associations between peak DEQ subscale ratings and both baseline (18)F-fallypride binding potential (BPnd; an index of D2/D3 receptor availability) and the percentage change in BPnd post dAMPH (%ΔBPnd; a measure of DA release) were assessed. Baseline BPnd in ventromedial prefrontal cortex (vmPFC) predicted the peak level of High reported following dAMPH. Furthermore, %ΔBPnd in vmPFC positively correlated with DEQ Want More ratings. DEQ Want More was also positively correlated with %ΔBPnd in right ventral striatum and left insula. This work indicates that characteristics of DA functioning in vmPFC, a cortical area implicated in subjective valuation, are associated with both subjective high and incentive (wanting) responses. The observation that insula %ΔBPnd was associated with drug wanting converges with evidence suggesting its role in drug craving. These findings highlight the importance of variability in DA signaling in specific paralimbic cortical regions in dAMPH's subjective response, which may confer risk for abusing psychostimulants.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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The antiphospholipid syndrome: still an enigma.
Chaturvedi S, McCrae KR
(2015) Hematology Am Soc Hematol Educ Program 2015: 53-60
MeSH Terms: Administration, Oral, Antibodies, Antiphospholipid, Anticoagulants, Antiphospholipid Syndrome, Female, Heparin, Low-Molecular-Weight, Humans, Hydroxychloroquine, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Immune System, Inflammation, Lupus Coagulation Inhibitor, Pregnancy, Pregnancy Complications, Cardiovascular, Protein Binding, Protein Structure, Tertiary, Risk, Thrombosis, Treatment Outcome, beta 2-Glycoprotein I
Show Abstract · Added December 16, 2015
Antiphospholipid syndrome (APS) is defined by clinical manifestations that include thrombosis and/or fetal loss or pregnancy morbidity in patients with antiphospholipid antibodies (aPL). Antiphospholipid antibodies are among the most common causes of acquired thrombophilia, but unlike most of the genetic thrombophilias are associated with both venous and arterial thrombosis. Despite an abundance of clinical and basic research on aPL, a unified mechanism that explains their prothrombotic activity has not been defined; this may reflect the heterogeneity of aPL and/or the fact that they may influence multiple pro- and/or antithrombotic pathways. Antiphospholipid antibodies are directed primarily toward phospholipid binding proteins rather than phospholipid per se, with the most common antigenic target being β2-glycoprotein 1 (β2GPI) although antibodies against other targets such as prothrombin are well described. Laboratory diagnosis of aPL depends upon the detection of a lupus anticoagulant (LA), which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin and anti-β2-glycoprotein 1 antibodies. Indefinite anticoagulation remains the mainstay of therapy for thrombotic APS, although new strategies that may improve outcomes are emerging. Preliminary reports suggest caution in the use of direct oral anticoagulants in patients with APS-associated thrombosis. Based on somewhat limited evidence, aspirin and low molecular weight heparin are recommended for obstetrical APS. There remains a pressing need for better understanding of the pathogenesis of APS in humans, for identification of clinical and laboratory parameters that define patients at greatest risk for APS-related events, and for targeted treatment of this common yet enigmatic disorder.
© 2015 by The American Society of Hematology. All rights reserved.
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Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress.
Yeung CK, Billings FT, Claessens AJ, Roshanravan B, Linke L, Sundell MB, Ahmad S, Shao B, Shen DD, Ikizler TA, Himmelfarb J
(2015) BMC Nephrol 16: 183
MeSH Terms: Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Dietary Supplements, Dose-Response Relationship, Drug, Drug Tolerance, Female, Humans, Kidney Failure, Chronic, Male, Maximum Allowable Concentration, Middle Aged, Oxidative Stress, Renal Dialysis, Ubiquinone, United States, Young Adult
Show Abstract · Added November 5, 2015
BACKGROUND - Coenzyme Q10 (CoQ10) supplementation improves mitochondrial coupling of respiration to oxidative phosphorylation, decreases superoxide production in endothelial cells, and may improve functional cardiac capacity in patients with congestive heart failure. There are no studies evaluating the safety, tolerability and efficacy of varying doses of CoQ10 in chronic hemodialysis patients, a population subject to increased oxidative stress.
METHODS - We performed a dose escalation study to test the hypothesis that CoQ10 therapy is safe, well-tolerated, and improves biomarkers of oxidative stress in patients receiving hemodialysis therapy. Plasma concentrations of F2-isoprostanes and isofurans were measured to assess systemic oxidative stress and plasma CoQ10 concentrations were measured to determine dose, concentration and response relationships.
RESULTS - Fifteen of the 20 subjects completed the entire dose escalation sequence. Mean CoQ10 levels increased in a linear fashion from 704 ± 286 ng/mL at baseline to 4033 ± 1637 ng/mL, and plasma isofuran concentrations decreased from 141 ± 67.5 pg/mL at baseline to 72.2 ± 37.5 pg/mL at the completion of the study (P = 0.003 vs. baseline and P < 0.001 for the effect of dose escalation on isofurans). Plasma F2-isoprostane concentrations did not change during the study.
CONCLUSIONS - CoQ10 supplementation at doses as high as 1800 mg per day was safe in all subjects and well-tolerated in most. Short-term daily CoQ10 supplementation decreased plasma isofuran concentrations in a dose dependent manner. CoQ10 supplementation may improve mitochondrial function and decrease oxidative stress in patients receiving hemodialysis.
TRIAL REGISTRATION - This clinical trial was registered on clinicaltrials.gov [NCT00908297] on May 21, 2009.
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Urinary metabolites of prostanoids and risk of recurrent colorectal adenomas in the Aspirin/Folate Polyp Prevention Study (AFPPS).
Fedirko V, Bradshaw PT, Figueiredo JC, Sandler RS, Barry EL, Ahnen DJ, Milne GL, Bresalier RS, Baron JA
(2015) Cancer Prev Res (Phila) 8: 1061-8
MeSH Terms: Adenoma, Administration, Oral, Aged, Aspirin, Chromatography, Gas, Chromatography, Liquid, Colonoscopy, Colorectal Neoplasms, Double-Blind Method, Female, Folic Acid, Humans, Male, Mass Spectrometry, Middle Aged, Neoplasm Recurrence, Local, Poisson Distribution, Prostaglandins
Show Abstract · Added March 10, 2016
Aspirin has been shown to protect against colorectal neoplasms; however, the optimal chemopreventive dose and underlying mechanisms are unclear. We aimed to study the relationship between prostanoid metabolites and aspirin's effect on adenoma occurrence. We used data from the Aspirin/Folate Polyp Prevention Study, in which 1,121 participants with a recent adenoma were randomized to placebo or two doses of aspirin (81 or 325 mg/d) to be taken until the next surveillance colonoscopy, anticipated about 3 years later. Urinary metabolites of prostanoids (PGE-M, PGI-M, and dTxB2) were measured using liquid chromatography/mass spectrometry or GC/NICI-MS in 876 participants near the end of treatment follow-up. Poisson regression with a robust error variance was used to calculate relative risks and 95% confidence intervals. PGE-M, PGI-M, and dTxB2 levels were 28%, 37%, and 60% proportionately lower, respectively, in individuals who took 325 mg of aspirin compared with individuals who took placebo (all P < 0.001). Similarly, among individuals who took 81 mg of aspirin, PGE-M, PGI-M, and dTxB2 were, respectively, 18%, 30%, and 57% proportionally lower compared with placebo (all P < 0.005). None of the metabolites or their ratios were statistically significantly associated with the risk of adenoma occurrence. The effect of aspirin in reducing adenoma risk was independent of prostanoid levels. Aspirin use is associated with lower levels of urinary prostanoid metabolites. However, our findings do not support the hypothesis that these metabolites are associated with adenoma occurrence, suggesting that COX-dependent mechanisms may not completely explain the chemopreventive effect of aspirin on colorectal neoplasms.
©2015 American Association for Cancer Research.
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18 MeSH Terms
Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma.
Johnson AS, Crandall H, Dahlman K, Kelley MC
(2015) J Am Coll Surg 220: 581-93.e1
MeSH Terms: Administration, Oral, Adult, Aged, Biomarkers, Tumor, Biopsy, DNA Mutational Analysis, DNA, Neoplasm, Dose-Response Relationship, Drug, Drug Therapy, Combination, Feasibility Studies, Female, Follow-Up Studies, Humans, Imidazoles, MAP Kinase Kinase 1, Male, Melanoma, Middle Aged, Mitogen-Activated Protein Kinases, Mutation, Oximes, Preoperative Care, Prospective Studies, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones, Skin Neoplasms, Young Adult
Show Abstract · Added February 16, 2016
BACKGROUND - We conducted a prospective trial of BRAF and mitogen-activated protein kinase kinase (MEK) targeted therapy in advanced, operable BRAF mutation-positive melanoma to determine feasibility, tumor response rates, and biomarkers of response and resistance.
STUDY DESIGN - Thirteen patients with locally or regionally advanced BRAF mutation-positive melanoma received dabrafenib 150 mg po bid for 14 days, followed by dabrafenib plus trametinib 2 mg po daily for 14 days before operation. Biopsies and tumor measurements were obtained at baseline and days 14 and 28. Formalin-fixed paraffin embedded specimens were analyzed with hematoxylin and eosin, Ki-67, cleaved caspase-3, CD8, phosphorylated extracellular signal-regulated kinase (ERK), and phosphorylated MEK immunostains.
RESULTS - Therapy was tolerated well, with toxicity ≥ grade 3 in 2 of 13 (15%) patients. All 12 patients receiving >14 days of therapy had substantial reduction in tumor volume (65% at day 14 and 78% at day 28) and underwent resection. After 14 days of dabrafenib therapy, there was a marked reduction in viable melanoma cells and a CD8 T-cell--rich infiltrate. Proliferation of the residual melanoma cells was reduced and apoptosis was increased. The cells continued to express phosphorylated ERK and phosphorylated MEK consistent with incomplete mitogen-activated protein kinase pathway inhibition.
CONCLUSIONS - Preoperative targeted therapy of advanced BRAF-mutant melanoma is feasible, well tolerated, induces brisk tumor responses, and facilitates correlative science. A CD8 T-cell-rich infiltrate indicates a potential immune-mediated mechanism of action. Both proliferation and apoptosis were inhibited, but the mitogen-activated protein kinase pathway remained activated, suggesting intrinsic resistance in a subset of tumor cells. Additional investigation of the anti-tumor immune response during targeted therapy and the mechanisms of intrinsic resistance can yield novel therapeutic strategies.
Copyright © 2015. Published by Elsevier Inc.
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Apolipoprotein A-V deficiency enhances chylomicron production in lymph fistula mice.
Zhang LS, Xu M, Yang Q, Ryan RO, Howles P, Tso P
(2015) Am J Physiol Gastrointest Liver Physiol 308: G634-42
MeSH Terms: Administration, Oral, Animals, Apolipoprotein A-V, Apolipoproteins, Cholesterol, Chylomicrons, Disease Models, Animal, Duodenum, Fistula, Intestinal Absorption, Lymph, Lymphatic Diseases, Lymphatic System, Male, Mice, Inbred C57BL, Mice, Knockout, Postprandial Period, Time Factors, Triolein, Up-Regulation
Show Abstract · Added August 24, 2015
Apolipoprotein A-V (apoA-V), a liver-synthesized apolipoprotein discovered in 2001, strongly modulates fasting plasma triglycerides (TG). Little is reported on the effect of apoA-V on postprandial plasma TG, an independent predictor for atherosclerosis. Overexpressing apoA-V in mice suppresses postprandial TG, but mechanisms focus on increased lipolysis or clearance of remnant particles. Unknown is whether apoA-V suppresses the absorption of dietary lipids by the gut. This study examines how apoA-V deficiency affects the steady-state absorption and lymphatic transport of dietary lipids in chow-fed mice. Using apoA-V knockout (KO, n = 8) and wild-type (WT, n = 8) lymph fistula mice, we analyzed the uptake and lymphatic transport of lipids during a continuous infusion of an emulsion containing [(3)H]triolein and [(14)C]cholesterol. ApoA-V KO mice showed a twofold increase in (3)H (P < 0.001) and a threefold increase in (14)C (P < 0.001) transport into the lymph compared with WT. The increased lymphatic transport was accompanied by a twofold reduction (P < 0.05) in mucosal (3)H, suggesting that apoA-V KO mice more rapidly secreted [(3)H]TG out of the mucosa into the lymph. ApoA-V KO mice also produced chylomicrons more rapidly than WT (P < 0.05), as measured by the transit time of [(14)C]oleic acid from the intestinal lumen to lymph. Interestingly, apoA-V KO mice produced a steadily increasing number of chylomicron particles over time, as measured by lymphatic apoB output. The data suggest that apoA-V suppresses the production of chylomicrons, playing a previously unknown role in lipid metabolism that may contribute to the postprandial hypertriglyceridemia associated with apoA-V deficiency.
Copyright © 2015 the American Physiological Society.
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20 MeSH Terms