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Basic & Clinical Pharmacology & Toxicology

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https://www.readbyqxmd.com/read/29155491/variation-in-the-response-of-clozapine-biotransformation-pathways-in-human-hepatic-microsomes-to-cyp1a2-and-cyp3a4-selective-inhibitors
#1
Michael Murray, Wei V Zhang, Robert J Edwards
The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to conventional antipsychotic drugs. Cytochromes P450 (CYPs) 1A2 and 3A4 oxidise CLZ to norCLZ and CLZ N-oxide in human liver. Concurrent treatment with inducers and inhibitors of CYP1A2 modulates CLZ elimination that disrupts therapy. Drug-drug interactions involving CYP3A4 are also significant but less predictable. To further characterise the factors underlying these interactions, we used samples from a cohort of human livers to assess variation in CLZ oxidation pathways in relation to intrinsic CYP3A4 and CYP1A2 activities and the effects of the corresponding selective inhibitors ketoconazole (0...
November 20, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29151273/post-treatment-with-methylene-blue-is-effective-against-delayed-encephalopathy-after-acute-carbon-monoxide-poisoning
#2
Ningjun Zhao, Pengchong Liang, Xiaoying Zhuo, Chenglei Su, Xuemei Zong, Bingnan Guo, Han Dong, Xianliang Yan, Shuqun Hu, Quanguang Zhang, Xu Tie
Delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP) is the most severe and clinically intractable complication that occurs following acute carbon monoxide poisoning. Unfortunately, the mechanism of DEACMP is still vague. Growing evidence indicates that delayed cerebral damage following CO poisoning is related to oxidative stress, abnormal neuro-inflammation, apoptosis and immune-mediated injury. Our recent report indicated that methylene blue (MB) may be a promising therapeutic agent in the prevention of neuronal cell death and cognitive deficits following transient global cerebral ischaemia (GCI)...
November 19, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29143454/high-prevalence-of-drug-drug-interactions-in-primary-health-care-is-caused-by-prescriptions-from-other-health-care-units
#3
Marine L Andersson, Ylva Böttiger, Henrik Kockum, Birgit Eiermann
Drug-drug interactions are increasingly common, as patients are getting older and the number of drugs per patient is increasing. In this study, we investigated to which extent potential drug-drug interactions originated from single or multiple prescribers. All patients attending any of 20 primary health care centres were included in a retrospective observational cohort study. Data on all prescriptions to these patients, irrespectively of the prescriber, were collected for two 4-month periods. Potential drug interactions were identified using the drug-drug interaction database SFINX...
November 15, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29136336/effect-of-polymorphisms-on-the-pharmacokinetics-pharmacodynamics-and-safety-of-sertraline-in-healthy-volunteers
#4
Miriam Saiz-Rodríguez, Carmen Belmonte, Manuel Román, Dolores Ochoa, Dora Koller, María Talegón, María C Ovejero-Benito, Rosario López-Rodríguez, Teresa Cabaleiro, Francisco Abad-Santos
Sertraline is a selective serotonin reuptake inhibitor (SSRI) widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P-glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of the present study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty-six healthy volunteers (24 men and 22 women) receiving a 100-mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP binding cassette subfamily B member 1 (ABCB1), Solute carrier family 6 member 4 (SLC6A4), 5-Hydroxytryptamine receptor 2A (HTR2A) and 5-Hydroxytryptamine receptor 2C (HTR2C) genes...
November 14, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29136335/sii-ang-ii-potentiates-insulin-receptor-signalling-and-glycogen-synthesis-in-hepatocytes
#5
Samra Joke Sanni, Christina Lyngsø, Steen Gammeltoft, Jakob Lerche Hansen
The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]-angiotensin II (SII Ang II) analogue that only activates a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance...
November 14, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29117643/advanced-electrocardiogram-ecg-analysis-in-the-amitriptyline-poisoned-pig-treated-with-activated-charcoal-hemoperfusion-cac-hp
#6
Tejs Jansen, Lotte C G Hoegberg, Thomas Eriksen, Christian Haarmark, Kim Dalhoff, Bo Belhage
Coated Activated Charcoal Hemoperfusion (CAC-HP) does not reduce the plasma concentration in amitriptyline (AT)-poisoned pigs. The aim of this non-blinded, randomised, controlled animal trial was to determine if CAC-HP reduces the pathological ECG changes caused by AT poisoning. Fourteen female Danish Land Race pigs (mean weight 27.7 kg, range 20-35 kg (CAC-HP) and 24.4 kg, range 18-30 kg (control group, CG), n=7 in each group were included. After randomisation, the pigs were anaesthetised and intravenously poisoned with AT...
November 8, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29117642/policy-change-and-the-national-essential-medicines-list-development-process-in-brazil-between-2000-and-2014-has-the-essential-medicine-concept-been-abandoned
#7
Claudia Garcia Serpa Osorio-de-Castro, Thiago Botelho Azeredo, Vera Lúcia Edais Pepe, Luciane Cruz Lopes, Sueli Yamauti, Brian Godman, Lars L Gustafsson
Brazil has had a National Essential Medicines List (EML) since 1964. From 2000 to 2010, five consecutive evidence-based editions were produced, building on the essential medicines concept. In 2012, the government changed course to establish a new paradigm, introducing adoption of new medicines as the main aim within the recommendation process. The objective of the paper is to report efforts to develop Brazil's national EML, policy changes from 2000 to 2014, discussing results, challenges and perspectives. Brazilian EML history and development process were collected from legislation, minutes, reports and legal ordinances, from 2000 to 2014...
November 8, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29117640/functional-characterization-of-22-cyp3a4-protein-variants-to-metabolize-ibrutinib-in-vitro
#8
Ren-Ai Xu, Jian Wen, Pengfei Tang, Chenchen Wang, Saili Xie, Bo-Wen Zhang, Quan Zhou, Jian-Ping Cai, Guo-Xin Hu
Cytochrome P450 3A4 (CYP3A4) is quantitatively the most important P450 enzyme in adults. It is suggested that CYP3A4 genetic polymorphisms may influence the rate of the metabolism and elimination of CYP3A4 substrates in humans. Ibrutinib is an anti-cancer drug and primarily metabolized by CYP3A4. The aim of this study was to systematically investigate the effects of 22 CYP3A4 protein variants on the metabolism of ibrutinib in vitro. When compared with wild-type CYP3A4.1, two variants (CYP3A4.17 and CYP3A4.24) had no detectable enzyme activity; five variants (CYP3A4...
November 8, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29117635/evaluation-of-the-influence-of-three-newly-developed-bispyridinium-anti-nicotinic-compounds-mb408-mb442-mb444-on-the-efficacy-of-antidotal-treatment-of-nerve-agent-poisoning-in-mice
#9
Jiri Kassa, Christopher M Timperley, Mike Bird, Rebecca L Williams, A Christopher Green, John E H Tattersall
The influence of three newly-developed bispyridinium antinicotinic compounds (the non-oximes MB408, MB442 and MB444) on the therapeutic efficacy of a standard antidotal treatment (atropine in combination with an oxime) of acute poisoning by the organophosphorus nerve agents tabun and soman was studied in mice. The therapeutic efficacy of atropine in combination with an oxime with or without one of the bispyridinium non-oximes was evaluated by determination of the LD50 values of the nerve agents and measurement of the survival time after supralethal poisoning...
November 8, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29076627/forensic-toxicology-perspectives-of-methadone-associated-deaths-in-tehran-iran-a-seven-year-overview
#10
Maryam Akhgari, Noushin Amini-Shirazi, Fariba Sardari Iravani
Methadone has a long history of pain relief and successful substitute for maintenance treatment in heroin and narcotic addiction. The aim of the study was to assess the trends of methadone-associated deaths in Tehran, Iran, in 2009-2015, from a forensic toxicology point of view. All methadone-associated deaths during this 7-year study period were evaluated according to demographic parameters and forensic toxicology analysis results. Results showed that 1274 cases of methadone-associated deaths were investigated during the study period...
October 27, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29076612/new-insights-into-sn-38-glucuronidation-evidence-for-the-important-role-of-udp-glucuronosyltranseferase-1a9
#11
Ling Xiao, Liangliang Zhu, Wenjuan Li, Conghu Li, Yunfeng Cao, Guangbo Ge, Xiaoyu Sun
Glucuronidation of SN-38 serves as an important metabolism pathway in determining the toxic effects of irinotecan. The role of UDP-glucoronosyltransferases (UGT) 1A9 in SN-38 glucuronidation pathway is very confusing. This study re-investigates the pathway through testing effects of bovine serum albumin (BSA) and the selective inhibitor on SN-38 glucuronidation in pooled human liver microsomes (HLM) and recombinant UGT1A1/1A9. For UGT1A1, SN-38 glucuronidation was little affected by BSA. Whether in the presence of BSA or not, the reactions both obey Michaelis-Menten kinetics with closed Vmax/Km values...
October 27, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29068170/antidote-availability-in-saudi-arabia-hospitals-in-the-riyadh-province
#12
Abdullah AlTamimi, Nidal K Malhis, Najla M Khojah, Saleh A Manea, Abdulrahman AlTamimi, Sami Ayed AlShammary
Inadequate antidote stocking is a global problem in hospitals. Insufficient supplies and delays in the administration of antidotes could lead to death and additional potentially negative clinical consequences. Our objective was to determine the availability of antidotes in hospitals listed on the Saudi Ministry of Health website in the Riyadh Province and to evaluate the leading poison in Saudi Arabia. A cross-sectional study was conducted using questionnaires. The questionnaires were distributed to pharmacist directors and emergency room-treating physicians in 17 public hospitals throughout the Riyadh Province...
October 25, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29067789/the-new-acetylcholinesterase-inhibitors-pc-37-and-pc-48-7-meota-donepezil-like-compounds-characterization-of-their-metabolites-in-human-liver-microsomes-pharmacokinetics-and-in-vivo-formation-of-the-major-metabolites-in-rats
#13
Jana Zdarova Karasova, Martin Mzik, Milos Hroch, Jan Korabecny, Eugenie Nepovimova, Viktor Vorisek, Vladimir Palicka, Kamil Kuca
The objective of this study was to elucidate the pharmacokinetics and metabolite formation of newly developed non-selective AChE/BChE 7-MEOTA-donepezil-like inhibitors for potential therapeutic use in Alzheimer disease patients. The chemical structures of metabolites were defined during incubation with human liver microsomes, and subsequently the metabolization was verified in in vivo study. In vitro metabolic profiling revealed the formation of nine major metabolites in the case of PC-37 and eight metabolites of PC-48...
October 25, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29067765/identification-of-the-molecular-determinants-of-the-antibacterial-activity-of-lmuttx-a-lys49-phospholipase-a2-homologue-isolated-from-lachesis-muta-muta-snake-venom-linnaeus-1766
#14
Rafaela Diniz-Sousa, Cleópatra A S Caldeira, Anderson M Kayano, Mauro V Paloschi, Daniel C Pimenta, Rodrigo Simões-Silva, Amália S Ferreira, Fernando B Zanchi, Najla B Matos, Fernando P Grabner, Leonardo A Calderon, Juliana P Zuliani, Andreimar M Soares
Snake venom phospholipases A2 (PLA2 s) are responsible for numerous pathophysiological effects in snakebites; however, their biochemical properties favour antimicrobial actions against different pathogens, thus constituting a true source of potential microbicidal agents. This study describes the isolation of a Lys49 PLA2 homologue from Lachesis muta muta venom using two chromatographic steps: Size Exclusion and Reverse Phase. The protein showed a molecular mass of 13,889 Da and was devoid of phospholipase activity on an artificial substrate...
October 25, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29024496/higher-levels-of-cystatin-c-in-hiv-aids-patients-with-metabolic-syndrome
#15
Gordana Dragović, Danica Srdić, Khawla Al Musalhi, Ivan Soldatović, Jovana Kušić, Djordje Jevtović, Devaki Nair
Data about Cystatin-C levels in HIV-infected patients with metabolic syndrome (MetS) are still limited. Therefore, the aim of this study was to evaluate the possible correlations of serum levels of Cystatin-C in HIV/AIDS patients treated with combined antiretroviral therapy (cART) with or without MetS. This cross-sectional study included 89 HIV/AIDS Caucasian patients receiving cART at the HIV/AIDS Centre Belgrade, Serbia, divided into two groups according to the presence of MetS. Cystatin-C and other biochemical parameters were measured using Cytokine-Array-I, Metabolic-Array-I and Metabolic-Array-II, at the Department of Clinical Biochemistry, Royal Free Hospital and University College London, United Kingdom...
October 11, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29024451/activation-of%C3%A2-group-ii-metabotropic-glutamate-receptors-increases-proliferation-but-does-not-influence-neuronal-differentiation-of-a-human-neural-stem-cell-line
#16
Anne Dindler, Morten Blaabjerg, Morad Kamand, Helle Bogetofte, Morten Meyer
The multiple functions of glutamate include regulation of neural development and stem cells. While the importance of the ionotropic glutamate receptors is well established, less is known about the role of metabotropic glutamate receptors (mGluRs). In this study, we examined the effects of pharmacological activation and inhibition of mGluR2/3 on proliferation, differentiation and viability of a human neural stem cell line. Immunofluorescence staining revealed the presence of mGluR2/3 receptors on both proliferating and differentiating stem cells, including cells differentiated into β-tubulin III-positive immature neurons and glial fibrillary acidic protein-positive astrocytes...
October 11, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29024354/cyclodextrins-based-formulations-a-non-invasive-platform-for-targeted-drug-delivery
#17
Chutimon Muankaew, Thorsteinn Loftsson
Cyclodextrins (CDs) are recognised as promising pharmaceutical excipients due to their unique ability to form water-soluble inclusion complexes with various poorly soluble compounds. The numerous investigations on CDs and their use in nanomedicine have received considerable attention in the last three decades, leading to the rapid development of new CD-containing formulations that significantly facilitate targeted drug delivery and controlled drug release, with consequent improvements in drug bioavailability...
October 10, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28990353/professor-thue-w-schwartz-is-the-bcpt-nordic-prize-winner-2017-in-basic-clinical-pharmacology-toxicology
#18
LETTER
Kim Brøsen
No abstract text is available yet for this article.
October 9, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28990335/next-generation-magnetic-nanocomposites-cytotoxic-and-genotoxic-effects-of-coated-and-uncoated-ferric-cobalt-boron-fecob-nanoparticles-in-vitro
#19
Katharina Netzer, Galateja Jordakieva, Angelika M Girard, Alexandra C Budinsky, Alexander Pilger, Lukas Richter, Nadezhda Kataeva, Joerg Schotter, Jasminka Godnic-Cvar, Peter Ertl
Metal nanoparticles (NPs) have unique physicochemical properties and a widespread application scope depending on their composition and surface characteristics. Potential biomedical applications and the growing diversity of novel nanocomposites highlight the need for toxicological hazard assessment of next-generation magnetic nanomaterials. Our study aimed to evaluate the cytotoxic and genotoxic properties of coated and uncoated ferric cobalt boron (FeCoB) NPs (5-15 nm particle size) in cultured human dermal fibroblasts (NHDFs)...
October 9, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28990360/effects-of-genetic-variants-on-carboxylesterase-1-gene-expression-and-clopidogrel-pharmacokinetics-and-antiplatelet-effects
#20
Mikko Neuvonen, E Katriina Tarkiainen, Aleksi Tornio, Päivi Hirvensalo, Tuija Tapaninen, Maria Paile-Hyvärinen, Matti K Itkonen, Mikko T Holmberg, Vesa Kärjä, Ville T Männistö, Pertti J Neuvonen, Jussi Pihlajamäki, Janne T Backman, Mikko Niemi
Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n=106) and pharmacodynamics (n=46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel...
October 8, 2017: Basic & Clinical Pharmacology & Toxicology
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