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Clinical and Translational Science

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https://www.readbyqxmd.com/read/27925405/animal-to-human-dose-translation-of-obiltoxaximab-for-treatment-of-inhalational-anthrax-under-the-us-fda-animal-rule
#1
C F Nagy, J Mondick, N Serbina, L S Casey, S E Carpenter, J French, R Guttendorf
Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax under the US Food and Drug Administration's (FDA) Animal Rule. The human dose was selected and justified by comparing observed obiltoxaximab exposures in healthy and infected New Zealand White rabbits and cynomolgus macaques to observed exposures in healthy humans, to simulated exposures in healthy and infected humans, and to serum PA levels in infected animals. In humans, at 16 mg/kg intravenous, obiltoxaximab AUC was >2 times that in animals, while maximum serum concentrations were comparable to those in animals and were maintained in excess of the concentration required for PA neutralization in infected animals for 2-3 weeks...
December 7, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27860267/a-phase-i-randomized-study-of-a-specifically-engineered-ph-sensitive-pcsk9-inhibitor-rn317-pf-05335810-in-hypercholesterolemic-subjects-on-statin-therapy
#2
M Levisetti, T Joh, H Wan, H Liang, P Forgues, B Gumbiner, P D Garzone
This phase I study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of RN317 (PF-05335810), a specifically engineered, pH-sensitive, humanized proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody, in hypercholesterolemic subjects (low-density lipoprotein cholesterol (LDL-C) ≥ 80 mg/dl) 18-70 years old receiving statin therapy. Subjects were randomized to: single-dose placebo, RN317 (subcutaneous (s.c.) 0.3, 1, 3, 6, or intravenous (i.v.) 1, 3, 6 mg/kg), or bococizumab (s...
November 17, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27863029/endoluminal-vacuum-therapy-for-ivor-lewis-anastomotic-leaks-a-pilot-study-in-a-swine-model
#3
R B Scott, L A Ritter, A L Shada, S H Feldman, D E Kleiner
Anastomotic leaks are a serious complication associated with Ivor Lewis esophagectomies. Endoluminal negative pressure vacuum devices create a possible treatment alternative to conventional surgical intervention. Ten pigs had an intrathoracic esophageal anastomosis with a 1-cm defect. The experimental group had the device placed intraoperatively across the defect, whereas the control group did not. Once treatment was completed, a contrast fluoroscopic study and necropsy was performed. All control pigs had contrast extravasation on fluoroscopy and contamination on necropsy...
November 11, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27806191/phase-1-studies-of-acebilustat-biomarker-response-and-safety-in-patients-with-cystic-fibrosis
#4
J S Elborn, A Horsley, G MacGregor, D Bilton, R Grosswald, S Ahuja, E B Springman
There is a significant unmet need for safe and effective anti-inflammatory treatment for cystic fibrosis. The aim of this study was to evaluate the safety of acebilustat, a leukotriene A4 hydrolase inhibitor, and its effect on inflammation biomarkers in patients with cystic fibrosis. Seventeen patients with mild to moderate cystic fibrosis were enrolled and randomized into groups receiving placebo or doses of 50 mg or 100 mg acebilustat administered orally, once daily for 15 days. Sputum neutrophil counts were reduced by 65% over baseline values in patients treated with 100 mg acebilustat...
November 2, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27792868/phase-i-studies-of-acebilustat-pharmacokinetics-pharmacodynamics-food-effect-and-cyp3a-induction
#5
J S Elborn, L Bhatt, R Grosswald, S Ahuja, E B Springman
Acebilustat is a new once-daily oral antiinflammatory drug in development for treatment of cystic fibrosis (CF) and other diseases. It is an inhibitor of leukotriene A4 hydrolase; therefore, production of leukotriene B4 (LTB4) in biological fluids provides a direct measure of the pharmacodynamic (PD) response to acebilustat treatment. Here we compare the pharmacokinetics (PK) and PD between CF patients and healthy volunteers, and investigate the food effect and CYP3A4 induction in healthy volunteers. No significant differences between study populations were observed for peak plasma level (Cmax ) or exposure (AUC)...
October 28, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27785887/exploration-of-biomarkers-for-amoxicillin-clavulanate-induced-liver-injury-multi-omics-approaches
#6
J Lee, S C Ji, B Kim, S Yi, K H Shin, J Y Cho, K S Lim, S H Lee, S H Yoon, J Y Chung, K S Yu, H S Park, S H Kim, I J Jang
To explore potential biomarkers for amoxicillin/clavulanate-induced liver injury (AC-DILI), we conducted a clinical trial in 32 healthy subjects based on multi-omics approaches. Every subject was administered amoxicillin/clavulanate for 14 days. The liver-specific microRNA-122 (miR-122) level increased prior to and correlated well with the observed alanine aminotransferase (ALT) level increase. This result indicates its potential as a sensitive early marker for AC-DILI. We also identified urinary metabolites, such as azelaic acid and 7-methylxanthine, with levels that significantly differed among the groups classified by ALT elevation level on day 8 after drug administration (P < 0...
October 26, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27696690/new-york-university-school-of-medicine-drug-development-educational-program-2-year-benchmark
#7
J Plaksin, R M Cymerman, R Caso Caso, C Galeano, R Ramasamy, G Gold-von Simson
Drug development (DD) is a multidisciplinary process that spans the translational continuum, yet remains an understudied entity in medical schools and biomedical science institutes. In response to a growing interest and unmet need, we implemented a DD course series that details identification of viable molecular targets, clinical trial design, intellectual property, and marketing. Enrollment is open to faculty, postdoctoral trainees, and MD, PhD, and MS students. After 2 years, 37 students and 23 students completed the fall and spring courses, respectively...
October 1, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27860319/the-role-of-next-generation-sequencing-in-enabling-personalized-oncology-therapy
#8
C A Cummings, E Peters, L Lacroix, F Andre, M R Lackner
No abstract text is available yet for this article.
December 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27766744/pttg1-levels-are-predictive-of-saracatinib-sensitivity-in-ovarian-cancer-cell-lines
#9
I Nakachi, B A Helfrich, M A Spillman, E A Mickler, C J Olson, J L Rice, C D Coldren, L E Heasley, M W Geraci, R S Stearman
Src kinase is recognized as a key target for molecular cancer therapy. However, methods to efficiently select patients responsive to Src inhibitors are lacking. We explored the sensitivity of ovarian cancer cell lines to the Src kinase inhibitor saracatinib to identify predictive markers of drug sensitivity using gene microarrays. Pituitary tumor transforming gene 1 (PTTG1) was selected as a potential biomarker as mRNA levels were correlated with saracatinib resistance, as well as higher PTTG1 protein expression...
December 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27754602/population-pharmacokinetics-of-methylphenidate-in-healthy-adults-emphasizing-novel-and-known-effects-of-several-carboxylesterase-1-ces1-variants
#10
Y K Lyauk, C Stage, T K Bergmann, L Ferrero-Milliani, D Bjerre, R Thomsen, K P Dalhoff, H B Rasmussen, G Jürgens
The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d-MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two-compartment disposition model with absorption transit compartments...
December 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27743502/modeling-and-experimental-studies-of-obeticholic-acid-exposure-and-the-impact-of-cirrhosis-stage
#11
J E Edwards, C LaCerte, T Peyret, N H Gosselin, J F Marier, A F Hofmann, D Shapiro
Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment...
December 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27743499/quantifying-beta-galactosylceramide-kinetics-in-cerebrospinal-fluid-of-healthy-subjects-using-deuterium-labeling
#12
Kms Kanhai, S C Goulooze, J Stevens, J L Hay, G Dent, A Verma, T Hankemeier, T de Boer, H Meijering, J C Chavez, A F Cohen, G J Groeneveld
Therapeutics promoting myelin synthesis may enhance recovery in demyelinating diseases, such as multiple sclerosis. However, no suitable method exists to quantify myelination. The turnover of galactosylceramide (myelin component) is indicative of myelination in mice, but its turnover has not been determined in humans. Here, six healthy subjects consumed 120 mL 70% D2 O daily for 70 days to label galactosylceramide. We then used mass spectrometry and compartmental modeling to quantify the turnover rate of galactosylceramide in cerebrospinal fluid...
December 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27736015/estimation-of-maximum-recommended-therapeutic-dose-using-predicted-promiscuity-and-potency
#13
T Liu, T Oprea, O Ursu, C Hasselgren, R B Altman
We report a simple model that predicts the maximum recommended therapeutic dose (MRTD) of small molecule drugs based on an assessment of likely protein-drug interactions. Previously, we reported methods for computational estimation of drug promiscuity and potency. We used these concepts to build a linear model derived from 238 small molecular drugs to predict MRTD. We applied this model successfully to predict MRTDs for 16 nonsteroidal antiinflammatory drugs (NSAIDs) and 14 antiretroviral drugs. Of note, based on the estimated promiscuity of low-dose drugs (and active chemicals), we identified 83 proteins as "high-risk off-targets" (HROTs) that are often associated with low doses; the evaluation of interactions with HROTs may be useful during early phases of drug discovery...
December 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27700008/translational-pharmacokinetic-pharmacodynamic-analysis-of-myo-029-antibody-for-muscular-dystrophy
#14
P Singh, H Rong, T Gordi, J Bosley, I Bhattacharya
Suppression of the myostatin (GDF-8) pathway has emerged as an important therapeutic paradigm for muscle-wasting disorders. In this study, we conducted a translational pharmacokinetic/pharmacodynamic (PK/PD) analysis of MYO-029, an anti-myostatin monoclonal antibody, using PK data in mice, rats, monkeys, humans, mouse tissue distribution data with (125) I-labeled MYO-029, muscle weight increase in SCID mice, and muscle circumference changes in monkeys. This analysis revealed significant in vivo potency shift between mice and monkeys (72 nM vs...
December 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27546282/best-practices-for-clinical-and-translational-research-and-practice
#15
Deanna L Kroetz
Scientists in all sectors have been raising concerns in recent years about the lack of reproducibility of biomedical research results. An analysis of in house validation efforts at Bayer HealthCare found that <25% of potential targets could be reproduced in house (1). Similarly, of 53 "landmark" studies selected because they described completely new findings, only 11% could be confirmed in house by Amgen scientists (2). Such dismal numbers has raised concern among scientists in all sectors about the lack of transparency in reporting scientific results and the need to share best laboratory and clinical practices...
August 22, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27540720/matrix-metalloproteinase-1-expression-in-women-with-and-without-pelvic-organ-prolapse-a-systematic-review-and-meta-analysis
#16
Y Feng, Y Wang, B Yan, L Li, Y Deng
This meta-analysis was conducted to estimate the association between matrix metalloproteinase-1 (MMP-1) expression and pelvic organ prolapse (POP) in women. Relevant studies published before 6 December 2015 were identified by searching PubMed, Ovid, EBSCO, and EMBASE. A total number of five case-control studies, including 182 POP cases and 192 controls, were identified. The results indicated that women without POP had a lower MMP-1 level of expression compared with women with POP (odds ratio = 0.54, 95% confidence interval: 0...
August 19, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27306191/a-pilot-metabolic-profiling-study-of-patients-with-neonatal-jaundice-and-response-to-phototherapy
#17
A Cai, S Qi, Z Su, H Shen, Y Yang, W Cai, Y Dai
Phototherapy has been widely used in treating neonatal jaundice, but detailed metabonomic profiles of neonatal jaundice patients and response to phototherapy have not been characterized. Our aim was to depict the serum metabolic characteristics of neonatal jaundice patients relative to controls and changes in response to phototherapy. A (1) H nuclear magnetic resonance (NMR)-based metabonomic approach was employed to study the metabolic profiling of serum from healthy infants (n = 25) and from infants with neonatal jaundice (n = 30) pre- and postphototherapy...
August 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27304394/a-novel-method-for-studying-the-pharmacokinetics-of-14-c-umeclidinium-after-application-to-the-axilla-or-palm-of-healthy-male-subjects
#18
T Pene Dumitrescu, L L Santos, S C Hughes, A I Pereira, G C Young, E Hussey, P Charlton, S Baptiste-Brown, J S Stuart, V Vincent, S P van Marle, V D Schmith
Umeclidinium (UMEC), a long-acting muscarinic antagonist approved for chronic obstructive pulmonary disease (COPD), was investigated for primary hyperhidrosis as topical therapy. This study evaluated the pharmacokinetics, safety, and tolerability of a single dose of [(14) C]UMEC applied to either unoccluded axilla (UA), occluded axilla (OA), or occluded palm (OP) of healthy males. After 8 h the formulation was removed. [(14) C]UMEC plasma concentrations (Cp) were quantified by accelerator mass spectrometry...
August 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27304196/effect-of-vorapaxar-alone-and-in-combination-with-aspirin-on-bleeding-time-and-platelet-aggregation-in-healthy-adult-subjects
#19
W K Kraft, J H Gilmartin, D L Chappell, F Gheyas, B M Walker, S Nagalla, U P Naik, J C Horrow, R E Wrishko, S Zhang, M S Anderson
The effect of the protease-activated receptor-1 (PAR-1) antagonist vorapaxar on human bleeding time is not known. This was a randomized, two-period, open-label trial in healthy men (n = 31) and women (n = 5). In period 1, subjects received 81 mg aspirin q.d. or a vorapaxar regimen achieving steady-state plasma concentrations equivalent to chronic 2.5 mg q.d. doses, for 7 days. In period 2, each group added 7 days of the therapy alternate to that of period 1 without washout. Bleeding time and platelet aggregation using arachidonic acid, ADP, and TRAP agonists were assessed...
August 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27277845/chronic-kidney-disease-alters-vitamin-a-homeostasis-via-effects-on-hepatic-rbp4-protein-expression-and-metabolic-enzymes
#20
J Jing, N Isoherranen, C Robinson-Cohen, I Petrie, B R Kestenbaum, C K Yeung
Vitamin A, via retinoic acid (RA), is a critical micronutrient. Normally, plasma concentrations are tightly regulated. Concentrations of vitamin A metabolites (13cis-RA, atRA) and relationships between RBP4 and retinoids have never been fully evaluated in adult patients with CKD. We measured retinoid and RBP4 concentrations in plasma and urine from 55 adult patients with CKD and 21 matched healthy subjects. RBP4 and retinol levels were increased approximately twofold in patients with CKD, with a negative correlation between plasma retinol and eGFR (p = 0...
August 2016: Clinical and Translational Science
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