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Pharmacology Research & Perspectives

Mulugeta Russom, Merhawi Debesai, Mehari Zeregabr, Araia Berhane, Theodros Tekeste, Teklezghi Teklesenbet
WHO information note indicates that isoniazid preventive therapy (IPT) is generally safe with little risk of hepatotoxicity. However, when the policy of IPT for HIV patients was introduced in Eritrea, frequent IPT-associated hepatotoxicity and fatality have been reported to the Pharmacovigilance Centre. The aim of the study is to assess the causal association of IPT and hepatotoxicity and identify possible risk factors in patients on Highly Active Anti-retroviral Therapy (HAART). This is a case series assessment of spontaneously reported cases to the Eritrean Pharmacovigilance Centre...
July 2018: Pharmacology Research & Perspectives
Noriko Iwamoto, Kotoko Yokoyama, Megumi Takanashi, Atsushi Yonezawa, Kazuo Matsubara, Takashi Shimada
The principle of nano-surface and molecular-orientation limited (nSMOL) proteolysis has a unique characteristic Fab-selective proteolysis for antibody bioanalysis that is independent of a variety of monoclonal antibodies by the binding antibody Fc via Protein A/G in a pore with 100 nm diameter and modified trypsin immobilization on the surface of nanoparticles with 200 nm diameter. Since minimizing peptide complexity and protease contamination while maintaining antibody sequence specificity enables a rapid and broad development of optimized methods for liquid chromatography-mass spectrometry (LC-MS) bioanalysis, the application of regulatory LC-MS for monitoring antibody biopharmaceuticals is expected...
July 2018: Pharmacology Research & Perspectives
Yoshie Shimai, Toshihiro Takeda, Katsuki Okada, Shirou Manabe, Kei Teramoto, Naoki Mihara, Yasushi Matsumura
Because drug-induced interstitial pneumonia (DIP) is a serious adverse drug reaction, its quantitative risk with individual medications should be taken into due consideration when selecting a medicine. We developed an algorithm to detect DIP using medical record data accumulated in a hospital. Chest computed tomography (CT) is mainly used for the diagnosis of IP, and chest X-ray reports, KL-6, and SP-D values are used to support the diagnosis. The presence of IP in the reports was assessed by a method using natural language-processing, in which IP was estimated according to the product of the likelihood ratio of characteristic keywords in each report...
July 2018: Pharmacology Research & Perspectives
Pernilla Haage, Robert Kronstrand, Martin Josefsson, Simona Calistri, Ron H N van Schaik, Henrik Green, Fredrik C Kugelberg
Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O -desmethyltramadol, N -desmethyltramadol, and N,O -didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained...
July 2018: Pharmacology Research & Perspectives
Mahmud Hasan, Rehana K Leak, Robert E Stratford, Darius P Zlotos, Paula A Witt-Enderby
Breast cancer treatment using a single drug is associated with a high failure rate due, in part, to the heterogeneity of drug response within individuals, nonspecific target action, drug toxicity, and/or development of resistance. Use of dual-drug therapies, including drug conjugates, may help overcome some of these roadblocks by more selective targeting of the cancer cell and by acting at multiple drug targets rather than one. Drug-conjugate approaches include linking drugs to antibodies (antibody-drug conjugates), radionuclides (radioimmunoconjugates), nanoparticles (nanoparticle-drug conjugates), or to other drugs (drug-drug conjugates)...
July 2018: Pharmacology Research & Perspectives
James Auta, Eleonora Gatta, John M Davis, Subhash C Pandey, Alessandro Guidotti
Corroborating evidence indicate that the downregulation of GABAA receptor subunit expression may underlie tolerance to the anticonvulsant and anxiolytic actions of benzodiazepine (BZ) ligands that act as full allosteric modulators (FAMs) of GABA actions at a variety of GABAA receptor subtypes. We and others have shown that 10-14 days treatment with increasing doses of diazepam (a FAM) resulted in anticonvulsant tolerance and decreased the expression of the α1 GABAA receptor subunit mRNA and protein in frontal cortex...
July 2018: Pharmacology Research & Perspectives
Kirk W Evanson, Jacob A Goldsmith, Payal Ghosh, Michael D Delp
The G protein-coupled estrogen receptor (GPER) is a significant modulator of arterial contractility and blood flow. The GPER-specific activator, G-1, has been widely used to characterize GPER function in a variety of tissue types. Large conductance, calcium (Ca2+ )-activated K+ (BK) channels are sensitive to 17β-estradiol (17β-E2) and estrogenic compounds (e.g., tamoxifen, ICI 182 780) that target estrogen receptors. The purpose of this study was to investigate the effects of G-1 on BK channel activation and function in cerebral arterial myocytes...
July 2018: 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
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