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Pharmacology Research & Perspectives

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https://www.readbyqxmd.com/read/28603639/folding-correction-of-abc-transporter-abcb1-by-pharmacological-chaperones-a-mechanistic-concept
#1
Matthias Spork, Muhammad Imran Sohail, Diethart Schmid, Gerhard F Ecker, Michael Freissmuth, Peter Chiba, Thomas Stockner
Point mutations of ATP-binding cassette (ABC) proteins are a common cause of human diseases. Available crystal structures indicate a similarity in the architecture of several members of this protein family. Their molecular architecture makes these proteins vulnerable to mutation, when critical structural elements are affected. The latter preferentially involve the two transmembrane domain (TMD)/nucleotide-binding domain (NBD) interfaces (transmission interfaces), formation of which requires engagement of coupling helices of intracellular loops with NBDs...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603638/clinician-agreement-and-influence-of-medication-related-characteristics-on-assessment-of-polypharmacy
#2
Gao-Jing Ong, Amy Page, Gillian Caughey, Sally Johns, Emily Reeve, Sepehr Shakib
It is not known how clinicians assess polypharmacy or the medication-related characteristics that influence their assessment. The aim of this study was to examine the level of agreement between clinicians when assessing polypharmacy and to identify medication-related characteristics that influence their assessment. Twenty cases of patients with varying levels of comorbidity and polypharmacy were used to examine clinician assessment of polypharmacy. Medicine-related factors within the cases included Beers and STOPP Criteria medicines, falls-risk medicines, drug burden index (DBI) medicines, medicines causing postural hypotension, and pharmacokinetic drug-drug interactions...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603637/t-type-voltage-gated-ca-2-channels-do-not-contribute-to-the-negative-feedback-regulation-of-myogenic-tone-in-murine-superior-epigastric-arteries
#3
Brendan Mullan, Jessica Pettis, William F Jackson
T-type voltage-gated Ca(2+) channels (CaV3.2 VGCC) have been hypothesized to control spontaneous transient outward currents (STOCs) through large-conductance Ca(2+)-activated K(+) channels (BKCa), and contribute to the negative-feedback regulation of myogenic tone. We tested this hypothesis in superior epigastric arteries (SEAs) isolated from male C57BL/6 mice. SEAs were isolated and enzymatically dissociated to obtain single smooth muscle cells (SMCs) for whole-cell recording of paxilline-sensitive (PAX, 1 μmol/L) STOCs at -30 mV, or cannulated and studied by pressure myography (80 cm H2O, 37°C)...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603636/make-up-a-missed-lesson-new-policy-to-ensure-the-interchangeability-of-generic-drugs-in-china
#4
Baobin Huang, Sarah L Barber, Mingzhe Xu, Shuanghong Cheng
Generic drugs should be interchangeable with originators in terms of quality and efficacy. With relative lower prices, generic drugs are playing an important role in controlling health expenditures and ensuring access. However, the widespread understanding of "cheap price equals low quality" has a negative impact on the acceptance of generic drugs. In China, medical doctors doubt the efficacy and quality of generic drugs manufactured domestically. To address these concerns, the Chinese State Council released a policy in 2016 to ensure the interchangeability by re-evaluating the quality and efficacy of generic drugs...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603635/clinical-trial-allocation-in-multinational-pharmaceutical-companies-a-qualitative-study-on-influential-factors
#5
Tilde Dombernowsky, Merete Haedersdal, Ulrik Lassen, Simon F Thomsen
Clinical trial allocation in multinational pharmaceutical companies includes country selection and site selection. With emphasis on site selection, the overall aim of this study was to examine which factors pharmaceutical companies value most when allocating clinical trials. The specific aims were (1) to identify key decision makers during country and site selection, respectively, (2) to evaluate by which parameters subsidiaries are primarily assessed by headquarters with regard to conducting clinical trials, and (3) to evaluate which site-related qualities companies value most when selecting trial sites...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603634/analgesic-and-anti-inflammatory-properties-of-novel-selective-and-potent-ep4-receptor-antagonists
#6
Srinivasan Chandrasekhar, Xiao-Peng Yu, Anita K Harvey, Jennifer L Oskins, Chaohua Lin, Xushan Wang, Maria-Jesus Blanco, Matthew J Fisher, Steven L Kuklish, Matthew A Schiffler, Tatiana Vetman, Alan M Warshawsky, Jeremy S York, Alison M Bendele, Mark G Chambers
Prostaglandin (PG) E2 is the key driver of inflammation associated with arthritic conditions. Inhibitors of PGE 2 production (NSAIDs and Coxibs) are used to treat these conditions, but carry significant side effect risks due to the inhibition of all prostanoids that play important physiological function. The activities of PGE 2 are transduced through various receptor sub-types. Prostaglandin E2 type 4 receptor (EP4) is associated with the development of inflammation and autoimmunity. We therefore are interested in identifying novel EP4 antagonists to treat the signs and symptoms of arthritis without the potential side effects of PGE 2 modulators such as NSAIDs and Coxibs...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603633/in-vitro-metabolism-of-exemestane-by-hepatic-cytochrome-p450s-impact-of-nonsynonymous-polymorphisms-on-formation-of-the-active-metabolite-17%C3%AE-dihydroexemestane
#7
Amity Peterson, Zuping Xia, Gang Chen, Philip Lazarus
Exemestane (EXE) is an endocrine therapy commonly used by postmenopausal women with hormone-responsive breast cancer due to its potency in inhibiting aromatase-catalyzed estrogen synthesis. Preliminary in vitro studies sought to identify phase I EXE metabolites and hepatic cytochrome P450s (CYP450s) that participate in EXE biotransformation. Phase I metabolites were identified by incubating EXE with HEK293-overexpressed CYP450s. CYP450s 1A2, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5 produce 17β-dihydroexemestane (17β-DHE), an active major metabolite, as well as two inactive metabolites...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603632/exemestane-potency-is-unchanged-by-common-nonsynonymous-polymorphisms-in-cyp19a1-results-of-a-novel-anti-aromatase-activity-assay-examining-exemestane-and-its-derivatives
#8
Amity Peterson, Zuping Xia, Gang Chen, Philip Lazarus
Exemestane (EXE) treats estrogen receptor positive (ER+) breast cancer in postmenopausal women by inhibiting the estrogen-synthesizing cytochrome P450 CYP19A1. Variability in the severity and incidence of side effects as well as overall drug efficacy may be partially explained by genetic factors, including nonsynonymous variation in CYP19A1, also known as aromatase. The present study identified phase I EXE metabolites in human liver microsomes (HLM) and investigated mechanisms that may alter the extent of systemic estrogen deprivation in EXE-treated women with breast cancer, including whether functional polymorphisms in aromatase cause differential inhibition by EXE and whether EXE metabolites possess anti-aromatase activity...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603631/hepatic-expression-profiles-in-retroviral-infection-relevance-to-drug-hypersensitivity-risk
#9
Yat Yee Wong, Brian Johnson, Thomas C Friedrich, Lauren A Trepanier
HIV-infected patients show a markedly increased risk of delayed hypersensitivity (HS) reactions to potentiated sulfonamide antibiotics (trimethoprim/sulfamethoxazole or TMP/SMX). Some studies have suggested altered SMX biotransformation in HIV infection, but hepatic biotransformation pathways have not been evaluated directly. Systemic lupus erythematosus (SLE) is another chronic inflammatory disease with a higher incidence of sulfonamide HS, but it is unclear whether retroviral infection and SLE share risk factors for drug HS...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603630/a-three-parameter-two-state-model-of-receptor-function-that-incorporates-affinity-efficacy-and-signal-amplification
#10
Peter Buchwald
A generalized model of receptor function is proposed that relies on the essential assumptions of the minimal two-state receptor theory (i.e., ligand binding followed by receptor activation), but uses a different parametrization and allows nonlinear response (transduction) for possible signal amplification. For the most general case, three parameters are used: Kd, the classic equilibrium dissociation constant to characterize binding affinity; ε, an intrinsic efficacy to characterize the ability of the bound ligand to activate the receptor (ranging from 0 for an antagonist to 1 for a full agonist); and γ, a gain (amplification) parameter to characterize the nonlinearity of postactivation signal transduction (ranging from 1 for no amplification to infinity)...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603629/anticholinergic-drug-exposure-is-associated-with-delirium-and-postdischarge-institutionalization-in-acutely-ill-hospitalized-older-patients
#11
Angelique Egberts, Saskia T van der Craats, Melissa D van Wijk, Shams Alkilabe, Patricia M L A van den Bemt, Francesco U S Mattace-Raso
Several studies investigated the possible association between anticholinergic drugs and diverse clinical outcomes in older persons, but the results are inconsistent. The aim of this study was to investigate whether anticholinergic drug exposure is associated with delirium on admission, length of hospital stay, postdischarge institutionalization and in-hospital mortality in acutely ill hospitalized older patients. In this observational chart review study, we included acutely ill patients aged 65 and older who were admitted to the geriatric ward of the Erasmus University Medical Center, Rotterdam, The Netherlands, between 2012 and 2015 (n = 905)...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603628/medication-errors-involving-anticoagulants-data-from-the-danish-patient-safety-database
#12
Jakob Nørgaard Henriksen, Lars Peter Nielsen, Annemarie Hellebek, Birgitte Klindt Poulsen
Reporting of adverse incidents is mandatory in Denmark. All reported adverse incidents are made anonymously, and stored in an encrypted database. It is the purpose of this descriptive study to describe the severity of adverse medication incidents caused by oral anticoagulants in hospitals. All moderate, severe and fatal reports concerning non-vitamin K antagonist oral anticoagulants were analyzed from date of marketing until July 8 2014. The data collection for warfarin was from January 1 2014 until July 8 2014...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603627/chronic-treatment-of-r-%C3%AE-lipoic-acid-reduces-blood-glucose-and-lipid-levels-in-high-fat-diet-and-low-dose-streptozotocin-induced-metabolic-syndrome-and-type-2-diabetes-in-sprague-dawley-rats
#13
Hardik Ghelani, Valentina Razmovski-Naumovski, Srinivas Nammi
(R)- α -lipoic acid (ALA), an essential cofactor in mitochondrial respiration and a potential antioxidant, possesses a wide array of metabolic benefits including anti-obesity, glucose lowering, insulin-sensitizing, and lipid-lowering effects. In this study, the curative effects of ALA (100 mg/kg) on a spectrum of conditions related to metabolic syndrome and type 2 diabetes (T2D) were investigated in a high-fat diet (HFD)-fed and low-dose streptozotocin (STZ)-induced rat model of metabolic syndrome and T2D...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28603626/physiologically-based-pharmacokinetic-modeling-of-tea-catechin-mixture-in-rats-and-humans
#14
Francis C P Law, Meicun Yao, Hui-Chang Bi, Stephen Lam
Although green tea (Camellia sinensis) (GT) contains a large number of polyphenolic compounds with anti-oxidative and anti-proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins (TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic (PBPK) model of tea catechin mixture (TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E (PE)...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28480041/risk-of-qt-prolongation-and-torsade-de-pointes-associated-with-exposure-to-hydroxyzine-re-evaluation-of-an-established-drug
#15
Anne-Françoise Schlit, Annie Delaunois, Aurore Colomar, Branderley Claudio, Luca Cariolato, Rossen Boev, Jean-Pierre Valentin, Christopher Peters, Victor S Sloan, Jürgen W G Bentz
Several noncardiac drugs have been linked to cardiac safety concerns, highlighting the importance of post-marketing surveillance and continued evaluation of the benefit-risk of long-established drugs. Here, we examine the risk of QT prolongation and/or torsade de pointes (TdP) associated with the use of hydroxyzine, a first generation sedating antihistamine. We have used a combined methodological approach to re-evaluate the cardiac safety profile of hydroxyzine, including: (1) a full review of the sponsor pharmacovigilance safety database to examine real-world data on the risk of QT prolongation and/or TdP associated with hydroxyzine use and (2) nonclinical electrophysiological studies to examine concentration-dependent effects of hydroxyzine on a range of human cardiac ion channels...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28480040/fty720-elevates-smooth-muscle-contraction-of-aorta-and-blood-pressure-in-rats-via-erk-activation
#16
Zhen Zhao, Jinxin Wang, Zhijun Huo, Zhiyong Wang, Qibing Mei
Sphingosine 1-phosphate (S1P) is an important signaling sphingolipid involved in the pathogenesis of various cardio cerebral vascular diseases such as ischemic stroke. In particular, the S1P mimetic FTY720 is protective for brain against ischemic conditions. However, whether and how FTY720 can modulate vascular tone and blood pressure remains to be determined. We showed that FTY720 (1 mg/kg) enhanced the contractile response of rat thoracic aortic rings induced by high potassium and phenylephrine, respectively...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28357130/off-label-drug-use-in-hospitalized-children-a-prospective-observational-study-at-gondar-university-referral-hospital-northwestern-ethiopia
#17
Yonas G Tefera, Begashaw M Gebresillassie, Abebe B Mekuria, Tamrat B Abebe, Daniel A Erku, Nurahmed Seid, Habiba B Beshir
Most of the medications which are currently used for the treatment of childhood diseases are either not licensed or being prescribed outside the terms of the product license (off-label prescribing). This study aimed at determining the extent of unlicensed and off-label drug uses and associated factors in children hospitalized in Gondar University Referral Hospital, Northwest Ethiopia. An institution-based prospective cross-sectional study was employed from April 15 to July 15, 2016. A total of 243 pediatric patients admitted to Gondar university referral hospital were included in the study using simple random sampling method...
April 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28357129/ultraviolet-irradiation-increases-green-fluorescence-of-dihydrorhodamine-dhr-123-false-positive-results-for-reactive-oxygen-species-generation
#18
Pascal Djiadeu, Dhia Azzouz, Meraj A Khan, Lakshmi P Kotra, Neil Sweezey, Nades Palaniyar
Dihydrorhodamine (DHR) 123 is a fluorophore commonly used for measuring reactive oxygen species (ROS), often after exposing cells to ultraviolet (UV) irradiation or oxidative burst inducers such as Phorbol 12-myristate 13-acetate (PMA). However, the negative effects of UV irradiation on oxidation of DHR123 itself to green fluorescence rhodamine (R) 123 under different experimental conditions (e.g., different buffers, media, cells, ROS detection techniques) have not been fully appreciated. We determined the effect of UV on DHR123 fluorescence, using a cell-free system, and A549 epithelial cells, NIH/3T3 fibroblast cells, Jurkat T cells, primary human T cells, HL-60 neutrophils and primary human neutrophils...
April 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28357128/impact-of-comorbidity-on-adverse-drug-reaction-profile-in-a-cohort-of-patients-treated-with-artemisinin-combination-therapies-for-uncomplicated-malaria-in-nigeria
#19
Peter U Bassi, Adeline I Osakwe, Comfort K Ogar, Cassandra Elagbaje, Biyaya B Nwankwo, Sulayman T Balogun, Godwin N Ntadom, Ambrose O Isah
Artemisinin-based combination antimalarial therapy (ACTs), is still highly effective in uncomplicated falciparum malaria, however, there remain some concerns in relation to its safety and tolerability. Comorbid disease conditions may influence susceptibility to adverse drug reactions (ADRs) as the presence of multiple disease conditions may predisposes patients to ADRs due to the use of many medicines. There is therefore need to assess the impact of comorbidities on the ADR profile of malaria patients treated with ACTs...
April 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28357127/metabolic-effects-of-a-mitochondrial-targeted-coenzyme-q-analog-in-high-fat-fed-obese-mice
#20
Brian D Fink, Deng Fu Guo, Chaitanya A Kulkarni, Kamal Rahmouni, 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, decreased food intake, increased hypothalamic orexigenic gene expression, and mitigated oxidative stress when administered from the onset of high-fat (HF) feeding. Here, we examined the effects of mitoQ on pre-existing obesity in C57BL/6J mice first made obese by 107 days of HF feeding. In contrast to our preventative study, we found that already obese mice did not tolerate mitoQ at 500 μmol/L...
April 2017: Pharmacology Research & Perspectives
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