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Basic & Clinical Pharmacology & Toxicology

Esmaeil Farzaneh, Hassan Ghobadi, Mahdieh Akbarifard, Samaneh Nakhaee, Alireza Amirabadizadeh, Ghodrat Akhavanakbari, Daniel E Keyler, Omid Mehrpour
Aluminium phosphide (AlP) is a toxic agent associated with a high mortality rate following acute exposure from various routes. The aim of this study was to determine the clinical and laboratory findings useful for predicting the medical outcomes of AlP-poisoned patients using established scoring systems. This is a prospective study of AlP-poisoned patients from 2010-2015 in Ardabil, Iran. All patients that presented with a confirmed diagnosis of Acute AlP poisoning in the study interval were included in the study...
March 12, 2018: Basic & Clinical Pharmacology & Toxicology
Jonas W Wastesson, Jaana E Martikainen, Helga Zoëga, Morten Schmidt, Øystein Karlstad, Anton Pottegård
Paracetamol (acetaminophen) is one of the most commonly used analgesics in Europe; however, both the safety and efficacy of paracetamol have recently been questioned. Little is known about cross-national differences in the sales of paracetamol. Using national wholesale statistics and nationwide prescription drug registers, we investigated trends in total and prescribed use of paracetamol in the Nordic countries. The total sales of paracetamol (Anatomical Therapeutic Chemical (ATC) classification system code: N02BE01) measured as defined daily doses (DDD) per 1000 inhabitants/day, and the sales by prescription (users per 1000 inhabitants per year), increased in the Nordic countries from 2000 to 2015...
March 12, 2018: Basic & Clinical Pharmacology & Toxicology
Jukka Hakkola, Camilla Bernasconi, Sandra Coecke, Lysiane Richert, Tommy B Andersson, Olavi Pelkonen
Pregnane X receptor (PXR), constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AHR) and peroxisome proliferator-activated receptor α (PPARα) are ligand-activated transcription factors that regulate expression of many xenobiotic metabolizing enzymes including several cytochrome P450 (CYP) enzymes. Many xenobiotics induce CYP enzymes through these intracellular receptors and consequently affect toxicokinetics and possible metabolic activation of the receptor ligands and other xenobiotics utilizing similar metabolic pathways...
March 12, 2018: Basic & Clinical Pharmacology & Toxicology
Sharon Buring Stuard, Tuula Heinonen
Structure activity relationship (SAR)-based read-across is an effective approach for addressing data gaps in human health risk assessment for 'data-poor' chemicals. In read-across, available data on chemical structural analogues are used to predict the toxicity potential of the data-poor chemical. This approach has long been recognized by regulatory agencies and used by industry to evaluate the hazards of chemicals for which there are limited direct data. Construction of a scientifically robust SAR-based read-across hazard assessment is a complex and iterative process involving multiple considerations in each step...
March 10, 2018: Basic & Clinical Pharmacology & Toxicology
Sauzanne Khalilieh, Peter Hodsman, Christine Xu, Anjela Tzontcheva, Shirley Glasgow, Diana Montgomery
Tildrakizumab, a high-affinity humanized IgG1k antibody that selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function, is under investigation for treatment of moderate-to-severe chronic plaque psoriasis. The objective of this analysis was to assess the pharmacokinetics (PK), bioavailability and safety/tolerability of single ascending doses of tildrakizumab following intravenous (IV) and subcutaneous (SC) dosing in healthy subjects. P05661 was a phase 1, single dose, randomized, placebo-controlled study of tildrakizumab IV doses of 0...
March 6, 2018: Basic & Clinical Pharmacology & Toxicology
Maria Wielsøe, Hans Eiberg, Mandana Ghisari, Peder Kern, Ole Lind, Eva Cecilie Bonefeld-Jørgensen
The present study investigated the effects of single nucleotide polymorphisms (SNPs) in xenobiotic and steroid hormone-metabolizing genes in relation to breast cancer risk and explored possible effect modifications on persistent organic pollutants (POPs) and breast cancer associations. The study also assessed effects of Greenlandic BRCA1 founder mutations. Greenlandic Inuit women (77 cases and 84 controls) were included. We determined two founder mutations in BRCA1: Cys39Gly (rs80357164) and 4684delCC, and five SNPs in xenobiotic and oestrogen-metabolizing genes: CYP17A1 -34T>C (rs743572), CYP19A1 *19C>T (rs10046), CYP1A1 Ile462Val (rs1048943), CYP1B Leu432Val (rs1056836) and COMT Val158Met (rs4680)...
March 6, 2018: Basic & Clinical Pharmacology & Toxicology
Partosch Falko, Mielke Hans, Stahlmann Ralf, Gundert-Remy Ursula
Mycobacterial diseases remain a significant cause of morbidity and mortality worldwide. Rifampicin and ethambutol are among the drugs recommended by WHO as first line treatment. In this work, we addressed the question whether doses of the two anti-tuberculosis agents ethambutol and rifampicin transferred to a nursed infant could be of health concerns when the mother is under treatment. We used the approach of pharmacokinetic modelling using a structural model with two interconnected organisms, the first one being the organism of the nursing mother, the second one being the organism of the nursed child...
March 5, 2018: Basic & Clinical Pharmacology & Toxicology
Niclas Björn, Ingrid Jakobsen Falk, Ignace Vergote, Henrik Gréen
The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199G>A (rs2229109), 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642) in ABCB1, and 1196A>G (rs10509681) in CYP2C8 and their association with treatment-induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the Phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n=260) or Taxol® (Arm B, n=265), were included and genotyped using pyrosequencing...
March 5, 2018: Basic & Clinical Pharmacology & Toxicology
Bushra Parveen, Manjari Tripathi, Divya Vohora
Long-term anti-epileptic drug (AED) therapy compromises bone health. Though vitamin-D deficiency is proposed to be involved, it alone is not held responsible. This accounts for investigating other mechanisms in bone accrual. Recent studies have shown modulation of inhibitors of wnt pathway, sclerostin and dickkopf-1 (DKK-1), in glucocorticoids-induced osteoporosis. We investigated whether AED monotherapy modulates wnt inhibitors in Indian women with epilepsy. Women of age > 20-40 years with the diagnosis of epilepsy and receiving AEDs (carbamazepine, valproate and levetiracetam) for at least a year were enrolled...
March 5, 2018: Basic & Clinical Pharmacology & Toxicology
Anton Pottegård, Anne Broe, Tore B Stage, Kim Brøsen, Jesper Hallas, Per Damkier
The antibiotic dicloxacillin has been shown to induce drug-metabolizing CYP enzymes to a clinically relevant extent. In the present study, we investigated whether use of dicloxacillin confers an increased risk of unwanted pregnancy among oral contraceptive users. The study population comprised Danish women falling pregnant (1997-2015) during oral contraceptive use, defined as having filled a prescription for an oral contraceptive within 120 days both before and after the estimated date of conception. Data were analysed using a case-cross-over approach...
March 5, 2018: Basic & Clinical Pharmacology & Toxicology
David E Moody, Yueqiao Fu, Wenfang B Fang
The purpose of this study was to test the hypothesis that skeletal muscle relaxants could inhibit the in vitro metabolism of common co-medications opioids buprenorphine, methadone and oxycodone. The compounds (solubility-limited concentration (μM) studied) were: baclofen (1000), carisoprodol (200), its metabolite meprobamate (1000), chlorzoxazone (200), cyclobenzaprine (1000), metaxalone (50), methocarbamol (1000), orphenadrine (1000) and tizanidine (1000). Compounds were first incubated with human liver microsomes (HLM) ± pre-incubation, screened with pathway-specific cDNA-expressed cytochrome P450s (rCYP), and then IC50 values determined using either 8-concentration tests for those where the rCYP screen suggested an IC50 was achievable, or a 3-concentration test with downward extrapolation if screen suggested 50% inhibition was not achievable...
March 5, 2018: Basic & Clinical Pharmacology & Toxicology
Maarit Jaana Korhonen, Pekka Tiittanen, Helena Kastarinen, Arja Helin-Salmivaara, Milka Hauta-Aho, Maria Rikala, Risto Huupponen
Clinical significance of potential interaction between warfarin and statins is unclear. Our objective was to determine whether use of statins as a class or use of simvastatin modulates the rate of bleeding requiring hospitalisation among new warfarin users. Using Finnish healthcare databases, we identified a cohort of 101,588 warfarin initiators between 1 January 2009 and 30 June 2012. By the end of 2012, these patients accumulated 92,695 person-years of exposure to warfarin-only and 60,253 years of exposure to warfarin-with-statin...
March 5, 2018: Basic & Clinical Pharmacology & Toxicology
Isabelle M Larsen, Asbjørn M Drewes, Anne E Olesen
Pain involves responses in which both peripheral and central mechanisms contribute to the generation of pain. Pre-clinical laboratory data have supported that a topical formulation of combined diclofenac and methadone (Diclometh) may alleviate local pain, and potentially the side effect profile should be low. We hypothesized that anti-allodynic and anti-hyperalgesic effects of Diclometh could be demonstrated in a human experimental pain model, and that Diclometh would be safe to administer. Thus, the aims were: 1) To compare two doses of Diclometh versus placebo; 2) To assess the safety profile of Diclometh...
March 2, 2018: Basic & Clinical Pharmacology & Toxicology
Yu Chen, Lin Chen, Hong Zhang, Shibo Huang, Yuqing Xiong, Chunhua Xia
Sulfonylureas (SUs) such as glibenclamide, gliclazide, glimepiride, glipizide and gliquidone are one of the first oral medicines available for the treatment of type 2 diabetes, and are widely used for the treatment of hyperglycaemia. The hepatic transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), play an important role in the disposition of a variety of drugs by mediating their uptake from blood into hepatocytes. Drug-drug interactions mediated by OATP1B1/1B3 may result in the hepatic transporting change for drug substrates...
March 2, 2018: Basic & Clinical Pharmacology & Toxicology
Alejandro Vicente-Carrillo
In vitro drug-induced toxicity assessment demands the usability and validation of suitable cell models, obtained non-invasively and pain-free. Sperm suspensions, painlessly and easily obtained from breeding boars, have been proven as suitable biosensors for pre-clinical toxicology screening and ranking of lead compounds in the drug development processes on a kinematics-based assay. Having a limited number of mitochondria and depending on these mitochondria and on cytoplasmic glycolysis for the energy needed for motility and for plasma membrane functionality, spermatozoa become a suitable model for capturing multiple modes of action of drugs and other chemicals acting via measurements of sperm motility...
March 2, 2018: Basic & Clinical Pharmacology & Toxicology
Giulia Milano, Stefania Chiappini, Francesca Mattioli, Antonietta Martelli, Fabrizio Schifano
A recent years' increase in misusing levels of image- and performance- enhancing drugs (IPEDs) has been observed. Out of these drugs, beta-2 agonists have recently emerged for their potential of misuse, especially for slimming and bodybuilding purposes. To this perspective, clenbuterol ('the size zero pill') has been reported as being both popular and widely available from the illegal market. All clenbuterol and salbutamol misuse/abuse/dependence/withdrawal/overdose/off-label spontaneous reports (2006-2016) from the European Medicines Agency (EMA) EudraVigilance (EV) database were collected and analysed by age range, gender, concomitant therapies and source of information...
March 2, 2018: Basic & Clinical Pharmacology & Toxicology
Grasiele de Sousa Vieira Tavares, Débora Vasconcelos Costa Mendonça, Daniela Pagliara Lage, Juliana da Trindade Granato, Flaviano Melo Ottoni, Fernanda Ludolf, Miguel Angel Chávez-Fumagalli, Mariana Costa Duarte, Carlos Alberto Pereira Tavares, Ricardo José Alves, Elaine Soares Coimbra, Eduardo Antonio Ferraz Coelho
In the present study, a quinoline derivate, clioquinol (5-chloro-7-iodoquinolin-8-ol), was evaluated against Leishmania amazonensis and L. infantum promastigotes and amastigotes. The cytotoxicity in murine macrophages and human red blood cells, as well as the efficacy in treating infected macrophages and the inhibition of infection using pre-treated parasites were also evaluated. Results showed that clioquinol inhibited L. amazonensis and L. infantum promastigotes with effective concentration 50% (EC50 ) values of 2...
February 26, 2018: Basic & Clinical Pharmacology & Toxicology
Ann Lykkegaard Soerensen, Marianne Lisby, Lars Peter Nielsen, Birgitte Klindt Poulsen, Jan Mainz
The aim of this controlled, before-and-after study in the Department of Psychiatry in a university hospital in Denmark, was to examine the potential effects and characteristics of nurses reviewing psychiatric patients' medication records to identify potentially inappropriate prescriptions (PIPs). The control group and the intervention group each consisted of two bed units chosen based on patients' diagnoses and age categories. There were 396 patients (age≥18 years) included in the study. Senior clinical pharmacology physicians performed medication reviews for all patients in the study; these medication reviews were considered gold standard...
February 24, 2018: Basic & Clinical Pharmacology & Toxicology
Antti J Tikkakoski, Pauliina Kangas, Lauri Suojanen, Anna M Tahvanainen, Arttu Eräranta, Mika A P Kähönen, Kalle Sipilä, Jukka T Mustonen, Ilkka H Pörsti
The change in augmentation index following salbutamol inhalation has been applied to evaluate endothelial function. We examined the contribution of salbutamol-induced increase in heart rate to the observed decrease in augmentation index. Haemodynamics were recorded using whole body impedance cardiography and continuous pulse-wave analysis from tonometric radial blood pressure. All subjects (n=335, mean age 46, body mass index 26, 48% men) were without medications with cardiovascular influences. The effects of salbutamol inhalation (0...
February 24, 2018: Basic & Clinical Pharmacology & Toxicology
Outi Huttala, Maaria Palmroth, Pauliina Hemminki, Tarja Toimela, Tuula Heinonen, Timo Ylikomi, Jertta-Riina Sarkanen
Many adipose tissue-related diseases, such as obesity and type 2 diabetes, are worldwide epidemics. For studying these diseases, relevant human cell models are needed. In this study, we developed a vascularized adipose tissue model where human adipose stromal cells (hASC) and human umbilical cord vein endothelial cells (HUVEC) were co-cultured with natural adipogenic and defined serum-free angiogenic media for 14 days. Several different protocols were compared to each other. The protocols varied in cell numbers and plating sequences...
February 14, 2018: Basic & Clinical Pharmacology & Toxicology
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