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Pharmacology Research & Perspectives

Mark Johnson, Roxanne C Jewell, Amanda Peppercorn, Elizabeth Gould, Jianfeng Xu, Yu Lou, Matthew Davies, Sandra Baldwin, Allan R Tenorio, Matthew Burke, Jerry Jeffrey, Brian A Johns
This work aimed to assess the safety, tolerability, pharmacokinetics (PK), and relative bioavailability of GSK2838232, an investigational HIV maturation inhibitor. GSK2838232 was administered over four dose-escalation studies in healthy subjects which assessed single oral doses (5-250 mg) and repeat doses (up to 200 mg once or twice daily) ±100 mg ritonavir (RTV) once daily. GSK2838232 administration (up to 250 mg) to 124 subjects across four studies resulted in few mild adverse events (AEs) with similar frequencies to placebo...
July 2018: Pharmacology Research & Perspectives
Jai Shankar K Yadlapalli, Shoban Babu Bommagani, Ryan D Mahelona, Anqi Wan, Brenda M Gannon, Narsimha R Penthala, Maxim Dobretsov, Peter A Crooks, William E Fantegrossi
Morphine-6-O-sulfate (M6S) is as a mixed-action mu/delta (μ/δ) opioid receptor agonist with high potency and analgesic efficacy. These studies used assays of drug discrimination and schedule-controlled responding to assess abuse-liability, tolerance, and physical dependence as compared to morphine in rats. Attempts to train 0.3 mg/kg (IP) M6S from saline failed, but all rats rapidly acquired the discrimination when the training dose was changed to 3.0 mg/kg morphine, and substitution tests showed that morphine and fentanyl both fully substituted for the training dose, M6S and M3A6S (3-O-acetyl ester of M6S) only partially substituted, and salvinorin A did not elicit morphine-like effects...
July 2018: Pharmacology Research & Perspectives
Florian Weinberger, Philipp Nicol, Jutta Starbatty, Mandy Stubbendorff, Peter M Becher, Sonja Schrepfer, Thomas Eschenhagen
The transcription factor Islet-1 marks a progenitor cell population of the second heart field during cardiogenesis. In the adult heart Islet-1 expression is limited to the sinoatrial node, the ventricular outflow tract, and parasympathetic ganglia. The regenerative effect in the injured mouse ventricle of thymosin beta-4 (TB4), a 43-aminoacid peptide, was associated with increased Islet-1 immunostaining, suggesting the induction of an Islet-1-positive progenitor state by TB4. Here we aimed to reassess this effect in a genetic model...
June 2018: Pharmacology Research & Perspectives
Yumi Imai, Brian D Fink, Joseph A Promes, Chaitanya A Kulkarni, Robert J Kerns, William I Sivitz
We recently reported that mitoquinone (mitoQ, 500 μmol/L) added to drinking water of C57BL/6J mice attenuated weight gain and reduced oxidative stress when administered to high-fat (HF) fed mice. Here, we examined the effects of mitoQ administered to HF fed mice on pancreatic islet morphology, dynamics of insulin secretion, and islet mitochondrial metabolism. C57BL/6J mice were fed HF for 130 days while we administered vehicle (cyclodextrin [CD]) or mitoQ added to the drinking water at up to 500 μmol/L...
June 2018: Pharmacology Research & Perspectives
Giovanni Licari, Robert W Milne, Andrew A Somogyi, Benedetta C Sallustio
Perhexiline, a chiral drug, is a potent antiischemic agent whose clinical utility is limited by hepatic and neural toxicities. It inhibits mitochondrial carnitine palmitoyltransferase-1, however, excessive inhibition predisposes toward tissue steatosis. This pilot study investigated the distribution of the two enantiomers and their toxicological potential. Dark Agouti rats (n = 4 per group) were administered vehicle or 200 mg/kg daily of racemic, (+)- or (-)-perhexiline maleate orally for 8 weeks. Plasma biochemical liver function tests and Von Frey assessments of peripheral neural function were performed...
June 2018: Pharmacology Research & Perspectives
Stefan Roepcke, Nele Plock, Josh Yuan, Eric R Fedyk, Gezim Lahu, Lin Zhao, Glennda Smithson
We are studying the fully human, IgG1λ cytolytic monoclonal antibody TAK-079, which binds CD38. CD38 is expressed on plasma and natural killer (NK) cells constitutively and upregulated on subsets of B and T lymphocytes upon activation. TAK-079 cross-reacts with CD38 expressed by cynomolgus monkeys and depletes subsets of NK, B, and T cells. Therefore, safety and function of TAK-079 was evaluated in this species, prior to clinical development, using bioanalytical, and flow cytometry assays. We pooled the data from eight studies in healthy monkeys (dose range 0...
June 2018: Pharmacology Research & Perspectives
Satoshi Kamata, Naoya Fujino, Mitsuhiro Yamada, Ken Grime, Satoshi Suzuki, Chiharu Ota, Yukiko Tando, Yoshinori Okada, Akira Sakurada, Masafumi Noda, Yasushi Matsuda, Hisatoshi Sugiura, Masakazu Ichinose
Inhaled drugs are critical for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). To develop better therapeutics for pulmonary disease it is of potential importance to understand molecular mechanisms of local biotransformation in the lung. Alveolar epithelial type II (ATII) cells have a key role in homeostasis in the lung, but little is known about expression patterns of genes encoding cytochrome P450 (CYP) enzymes in ATII cells. In addition, alteration of CYP gene expression has not been fully defined in COPD...
June 2018: Pharmacology Research & Perspectives
Peter Ihle, Franz-Werner Dippel, Ingrid Schubert
Aim of the study was to assess the incidence of statin-associated myopathy (SAM) under real-life conditions in Germany. DATABASE: Administrative data (master data, diagnoses, prescriptions) for all individuals in Germany insured with the Statutory Health Insurance. Basic population: individuals 18 years and older who have been insured continually from 2009 to 2011 (52.9 million; 29.9 million men, 23.9 million women). Data access is provided by the German Institute of Medical Documentation and Information, DIMDI) according to the Data Transparency Regulation of 2012...
June 2018: Pharmacology Research & Perspectives
Bamidele S Ajilore, Adetayo A Alli, Tolulope O Oluwadairo
The present study investigated possible benefits of magnesium ion (as MgCl2 ) in organophosphorus poisoning targeting its ability to interact with substrates and membrane enzymes. Blood samples collected from volunteered healthy adult by venepuncture into anticoagulant test tubes containing EDTA were separated into plasma and red blood cell and divided into three groups namely: normal, pesticide only (0.25-2.0 mmol/L chlorpyrifos) and pesticide (0.25-2.0 mmol/L chlorpyrifos) + 0.1 mol/L MgCl2 . Acetylcholinesterase, Na+ /K+ ATPase and Ca2+ ATPase activities were evaluated...
June 2018: Pharmacology Research & Perspectives
Sharath S Hegde, M Teresa Pulido-Rios, Mark A Luttmann, James J Foley, Gerald E Hunsberger, Tod Steinfeld, TaeWeon Lee, Yuhua Ji, Mathai M Mammen, Jeffrey R Jasper
Revefenacin (TD-4208) is a novel, long-acting, and lung-selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pKI  = 8.2-9.8) and behaved as a competitive antagonist (pKI, apparent = 9...
June 2018: Pharmacology Research & Perspectives
Laurence Del Frari, Christine Léauté-Labrèze, Laurent Guibaud, Sébastien Barbarot, Jean-Philippe Lacour, Christine Chaumont, Alain Delarue, Jean-Jacques Voisard, Valérie Brunner
Propranolol has become the first choice therapy for complicated Infantile Hemangiomas (IH). The pharmacokinetics of propranolol were evaluated after repeated oral administration of a new pediatric solution of propranolol at 3 mg kg-1  day-1 given twice daily (BID) in infants (77-243 days) with IH. A population model was built to describe the pharmacokinetics of propranolol in infants and to simulate different dosing regimens. One hundred and sixty-seven plasma concentrations from 22 infants were used in the population analysis...
June 2018: Pharmacology Research & Perspectives
Thomas N Kakuda, Matthew W McClure, Christopher Westland, Jennifer Vuong, Marie-Claude Homery, Gwendoline Poizat, Laure Viguerie, Caroline Denot, Alain Patat, Qingling Zhang, James Hui, David Apelian, David B Smith, Sushmita M Chanda, John Fry
This Phase I, open-label, two-group, fixed-sequence study evaluated the pharmacokinetics and safety of AL-335, odalasvir, and simeprevir in healthy subjects. Group 1 (n   =   16) received AL-335 800 mg once daily (QD) (days 1-3, 11-13, and 21-23), simeprevir 150 mg QD (days 4-23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15-23). Group 2 (n   =   16) received the same AL-335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5-23) and simeprevir 150 mg QD (days 14-23)...
June 2018: Pharmacology Research & Perspectives
Christina Gade, Hanne R Christensen, Kim P Dalhoff, Jens Christian Holm, Helle Holst
Obesity can affect the pharmacokinetics of most drugs, which may result in under- or overdosing if traditional pediatric dosing strategies are used. To investigate currently applied dosage strategies in children with overweight or obesity (overweight/obesity), in a clinical treatment facility. In particular, whether dosing guidelines were available and metrics of body size applied. A retrospective cohort study of 200 patients admitted to the Danish Children's Obesity Clinic. Data were collected from 2007 to 2015...
June 2018: Pharmacology Research & Perspectives
Maciej Czerwiński, Immaculate Amunom, Victor Piryatinsky, Hussein Hallak, Yousif Sahly, Oren Bar-Ilan, Paul Bolliger, Merav Bassan
Some biologics can modulate cytokines that may lead to changes in expression of drug-metabolizing enzymes and cause drug-drug interactions (DDI). DDI potential of TV-1106-an albumin-fused growth hormone (GH)-was investigated. In this study, human blood was exposed to recombinant human growth hormone (rhGH) or TV-1106, followed by isolation of the plasma and its application to human hepatocytes. While the treatment of blood with rhGH increased multiple cytokines, treatment of blood with TV-1106 had no effect on any of the nine cytokines tested...
June 2018: Pharmacology Research & Perspectives
Gideon Koren, Galia Nordon, Kira Radinsky, Varda Shalev
Despite effective medications, rates of uncontrolled hypertension remain high. Treatment protocols are largely based on randomized trials and meta-analyses of these studies. The objective of this study was to test the utility of machine learning of big data in gaining insight into the treatment of hypertension. We applied machine learning techniques such as decision trees and neural networks, to identify determinants that contribute to the success of hypertension drug treatment on a large set of patients. We also identified concomitant drugs not considered to have antihypertensive activity, which may contribute to lowering blood pressure (BP) control...
June 2018: Pharmacology Research & Perspectives
Sumner H Burstein
Ajulemic acid (AJA, CT-3, IP-751, JBT-101, anabasum) is a first-in-class, synthetic, orally active, cannabinoid-derived drug that preferentially binds to the CB2 receptor and is nonpsychoactive. In preclinical studies, and in Phase 1 and 2 clinical trials, AJA showed a favorable safety, tolerability, and pharmacokinetic profile. It also demonstrated significant efficacy in preclinical models of inflammation and fibrosis. It suppresses tissue scarring and stimulates endogenous eicosanoids that resolve chronic inflammation and fibrosis without causing immunosuppression...
April 2018: Pharmacology Research & Perspectives
Md A Hakim, John N Buchholz, Erik J Behringer
Electrical dynamics of freshly isolated cerebral endothelium have not been determined independently of perivascular nerves and smooth muscle. We tested the hypothesis that endothelium of cerebral and skeletal muscle arteries differentially utilizes purinergic and muscarinic signaling pathways to activate endothelium-derived hyperpolarization. Changes in membrane potential ( V m ) were recorded in intact endothelial tubes freshly isolated from posterior cerebral and superior epigastric arteries of male and female C57BL/6 mice (age: 3-8 months)...
April 2018: Pharmacology Research & Perspectives
Florence Vallelian, Christian A Schaer, Jeremy W Deuel, Giada Ingoglia, Rok Humar, Paul W Buehler, Dominik J Schaer
Activation of the innate immune system by free heme has been proposed as one of the principal consequences of cell-free hemoglobin (Hb) exposure. Nonetheless, in the absence of infection, heme exposures within a hematoma, during hemolysis, or upon systemic administration of Hb (eg, as a Hb-based oxygen carrier) are typically not accompanied by uncontrolled inflammation, challenging the assumption that heme is a major proinflammatory mediator in vivo. Because of its hydrophobic nature, heme liberated from oxidized hemoglobin is rapidly transferred to alternative protein-binding sites (eg, albumin) or to hydrophobic lipid compartments minimizing protein-free heme under in vivo equilibrium conditions...
April 2018: Pharmacology Research & Perspectives
Brandon T Gufford, Jason D Robarge, Michael T Eadon, Hongyu Gao, Hai Lin, Yunlong Liu, Zeruesenay Desta, Todd C Skaar
Rifampin is a pleiotropic inducer of multiple drug metabolizing enzymes and transporters. This work utilized a global approach to evaluate rifampin effects on conjugating enzyme gene expression with relevance to human xeno- and endo-biotic metabolism. Primary human hepatocytes from 7 subjects were treated with rifampin (10 μmol/L, 24 hours). Standard methods for RNA-seq library construction, EZBead preparation, and NextGen sequencing were used to measure UDP-glucuronosyl transferase UGT, sulfonyltransferase SULT, N acetyltransferase NAT, and glutathione-S-transferase GST mRNA expression compared to vehicle control (0...
April 2018: Pharmacology Research & Perspectives
Stephen Caltabiano, Kelly M Mahar, Karyn Lister, David Tenero, Ramiya Ravindranath, Borut Cizman, Alexander R Cobitz
This study was conducted to evaluate the likelihood of daprodustat to act as a perpetrator in drug-drug interactions (DDI) with the CYP2C8 enzyme and OATP1B1 transporter using the probe substrates pioglitazone and rosuvastatin as potential victims, respectively. Additionally, this study assessed the effect of a weak CYP2C8 inhibitor, trimethoprim, as a perpetrator of a DDI with daprodustat. This was a two-part study: Part A assessed the effect of coadministration of daprodustat on the pharmacokinetics of pioglitazone and rosuvastatin in 20 subjects; Part B assessed the coadministration of trimethoprim on the pharmacokinetics of daprodustat in 20 subjects...
April 2018: Pharmacology Research & Perspectives
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