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Clinical and Translational Science

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...
October 15, 2016: Clinical and Translational Science
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...
October 15, 2016: Clinical and Translational Science
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...
October 13, 2016: Clinical and Translational Science
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...
October 4, 2016: Clinical and Translational Science
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
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
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
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
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
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
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
J Luo, H Imai, T Ohyama, S Hashimoto, T Hasunuma, Y Inoue, T Kotegawa, K Ohashi, N Uemura
Pharmacokinetic exposures to fexofenadine (FEX) are reduced by apple juice (AJ); however, the relationship between the AJ volume and the degree of AJ-FEX interaction has not been understood. In this crossover study, 10 healthy subjects received single doses of FEX 60 mg with different volumes (150, 300, and 600 mL) of AJ or water (control). To identify an AJ volume lacking clinically meaningful interaction, we tested a hypothesis that the 90% confidence interval (CI) for geometric mean ratio (GMR) of FEX AUCAJ /AUCwater is contained within a biocomparability bound of 0...
August 2016: Clinical and Translational Science
Y Xu, Y F Li, D Zhang, M Dockendorf, E Tetteh, M L Rizk, J A Grobler, M-T Lai, J Gobburu, W Ankrom
We applied model-based meta-analysis of viral suppression as a function of drug exposure and in vitro potency for short-term monotherapy in human immunodeficiency virus type 1 (HIV-1)-infected treatment-naïve patients to set pharmacokinetic targets for development of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (InSTIs). We developed class-specific models relating viral load kinetics from monotherapy studies to potency normalized steady-state trough plasma concentrations...
August 2016: Clinical and Translational Science
S Karovic, E F Shiuan, S Q Zhang, H Cao, M L Maitland
Novel characterization of patterns of adverse events (AEs) of kinase inhibitors (KIs) could reveal new insights on human molecular physiology and methods to improve the therapeutic index of KIs. Incidence and severity of AEs for each of 157 patients enrolled in sorafenib clinical trials were determined for three clinically relevant treatment intervals: weeks 0-3, weeks 3-7, and after 7 weeks. The most common within patient co-occurrences were mucositis with dermatologic events: hand-foot syndrome (HFS; odds ratio [OR] = 4...
July 21, 2016: Clinical and Translational Science
A Ahmad, S Sheikh, T Shah, M S Reddy, Bsv Prasad, K K Verma, B B Chandrakant, M Paithankar, P Kale, R V Solanki, R Patel, H Barkate, I Ahmad
The protein kinase C (PKC) signaling system plays a role in mood disorders and PKC inhibitors such as endoxifen may be an innovative medicine for bipolar disorder (BP) patients. In this study we show for the first time the antimanic properties of endoxifen in patients with bipolar I disorder (BPD I) with current manic or mixed episode. In a double-blind, active-controlled study, 84 subjects with BPD I were randomly assigned to receive endoxifen (4 mg/day or 8 mg/day) or divalproex in a 2:1 ratio. Patients orally administered 4 mg/day or 8 mg/day endoxifen showed significant improvement in mania assessed by the Young Mania Rating Scale as early as 4 days...
June 27, 2016: Clinical and Translational Science
D R Krieger, D S Kalman, S Feldman, L Arnillas, D Goldberg, O Gisbert, S Nader
This double-blind crossover clinical trial randomized 12 adult males to receive 200 mg of caffeine from a green coffee extract, a guayusa leaf extract, and a synthetic control to compare their safety, absorption, and effect on neurotransmitters. The results showed no statistically significant changes in blood pressure or heart rate from baseline to 120 min postdose of each natural source compared with changes from baseline in the control (0.094 < = P < = 0.910). The ratios of Cmax , AUC0-4 , and AUC0-∞ of each natural source to the control were bioequivalent by US Food and Drug Administration standards (90% CI within 80-125%)...
June 20, 2016: Clinical and Translational Science
S Nagalla, L Thomson, Y Oppong, B Bachman, I Chervoneva, W K Kraft
It was hypothesized that the four-factor prothrombin complex concentrate (4F-PCC) Kcentra 25 unit/kg would reverse impairment of thrombin generation in healthy volunteers dosed with apixaban to steady state. In this randomized, two-period crossover, assessor-blinded trial, 12 healthy subjects received 5 mg apixaban every 12 h. Three h after the fifth dose, four-factor prothrombin complex concentrate (4F-PCC) 25 unit/kg or saline were infused. Serial blood samples were assessed for thrombin generation using PPP-reagent and PPP-reagent low, anti-Xa, PT, and PTT assays...
June 2016: Clinical and Translational Science
E Lefebvre, M Gottwald, K Lasseter, W Chang, M Willett, P F Smith, A Somasunderam, N S Utay
Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic-impaired participants for pharmacokinetic changes. Participants with mild-to-moderate hepatic impairment (HI) (Child-Pugh class A (N  =  7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained on Days 1 and 14...
June 2016: Clinical and Translational Science
R S Funk, R Singh, L Pramann, N Gigliotti, S Islam, D P Heruth, S Q Ye, M A Chan, J S Leeder, M L Becker
Variability in response to methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA) remains unpredictable and poorly understood. Based on previous studies implicating an interaction between nicotinamide phosphoribosyltransferase (NAMPT) expression and MTX therapy in inflammatory arthritis, we hypothesized that increased NAMPT expression would be associated with reduced therapeutic response to MTX in patients with JIA. A significant association was found between increased plasma concentrations of NAMPT and reduced therapeutic response in patients with JIA treated with MTX...
June 2016: Clinical and Translational Science
G Shroff
Human embryonic stem cells (hESCs) have a role in treating neurological disorders. The efficacy and safety of hESC in treating spinal cord injury (SCI) was reported in our previous study. In the present study, we have evaluated the efficacy and safety of hESC therapy in 226 patients with SCI. In the first treatment phase (T1), 0.25 mL hESCs were administered intramuscularly twice daily, 1 mL every 10 days i.v., and 1-5 mL every 7 days. Of 153 patients in the American Spinal Injury Association (ASIA) scale A at the beginning of T1, a significant number of patients (n = 80; 52...
June 2016: Clinical and Translational Science
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