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Fatima Ali, Faisal Alsayegh, Prem Sharma, Mohammad Waheedi, Tania Bayoud, Faisal Alrefai
BACKGROUND: The effects of diabetes mellitus on the differential white blood cell count are not widely studied in the Arab populations. The objective of this cross-sectional, retrospective study is to assess the influence of chronic diabetes mellitus on white blood cell counts, absolute neutrophil (ANC) and lymphocyte counts (ALC) as well as the prevalence of benign ethnic neutropenia among Arabs attending the Dasman Diabetes Institute (DDI) in Kuwait. METHODS AND FINDINGS: 1,580 out of 5,200 patients registered in the DDI database qualified for our study...
2018: PloS One
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
Md Fazlur Rahman, Radhika Raj, Rajgopal Govindarajan
Combination antiretroviral drug treatments depend on 3'-deoxy-nucleoside analogs such as AZT (3'-azido-3'-deoxythymidine) and DDI (2'3'-dideoxyinosine). Despite being effective in inhibiting HIV viral replication, these drugs produce a range of toxicities, including myopathy, pancreatitis, neuropathy and lactic acidosis, that are generally considered as sequelae to mitochondrial damage. While the cell surface localized nucleoside transporters (e.g., human equilibrative nucleoside transporter 2 (hENT2), human concentrative nucleoside transporter 1 (hCNT1)) are known to increase the carrier mediated uptake of 3'-deoxy-nucleoside analogs into cells, another ubiquitously expressed intracellular nucleoside transporter, namely, hENT3, has been implicated in the mitochondrial transport of 3'-deoxy-nucleoside analogs...
March 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Bo Wang, Yunfang Xiao, Xiaofeng Yang, Yanhao He, Ting Jing, Weirong Wang, Jiye Zhang, Rong Lin
Dihydromyricetin (DHM), a bioactive flavonoid component isolated from Ampelopsis grossedentata, is known to have anti-inflammatory effect, but the effect of DHM on acute lung injury (ALI) is largely unknown. Here, we investigated the effect of DHM on ALI and the underlying mechanism by bioinformatic analyses and animal experiments. We found that pretreatment with DHM ameliorated lung pathological changes and suppressed the inflammation response in lung tissues after LPS challenge. The potential targets of DHM were predicted by DDI-CPI and DRAR-CPI tools and analyzed using the STRING server to predict the functionally related signaling pathways, such as MAPK signaling...
March 9, 2018: Journal of Leukocyte Biology
Christine Taylor Brew, James F Blake, Anita Mistry, Fengling Liu, Diana Carreno, Deidre Madsen, YongQi Mu, Martha Mayo, Wilhelm Stahl, David Matthews, Derek Maclean, Steve Harrison
PURPOSE: Polymeric drugs, including patiromer (Veltassa®), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administered drugs during transit of the gastrointestinal tract remains. Here we elucidate the properties correlated with drug-patiromer binding using quantitative structure-property relationship (QSPR) models...
March 8, 2018: Pharmaceutical Research
Ginah Nightingale, Laura T Pizzi, Ashley Barlow, Brooke Barlow, Timothy Jacisin, Matthew McGuire, Kristine Swartz, Andrew Chapman
OBJECTIVES: Drug-drug interactions (DDIs) represent an escalating concern for older adults attributed to polypharmacy, multi-morbidity and organ dysfunction. Few studies have evaluated the prevalence of major DDIs and the variability between DDI detection software which confuses management. MATERIALS AND METHODS: Prevalence of major DDIs was examined as a secondary analysis of outpatients aged ≥65 years. Demographic and clinical information was collected from electronic health records including age, sex, race, cancer type, comorbidities, and medications...
March 3, 2018: Journal of Geriatric Oncology
Fumiyoshi Yamashita
 Drug-drug interactions mediated by drug metabolizing enzymes are serious, clinically relevant issues. Prediction and evaluation of the probability and consequences of drug-drug interactions are essential during drug development, as well as during clinical application. A physiologically based pharmacokinetic (PBPK) model, which considers the hierarchical structure of the physiological behavior of drugs, has been demonstrated to be effective for in vitro-in vivo extrapolation of the phenomena of drug-drug interaction (DDI)...
2018: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Gabrielle Shall, Megan Menosky, Sarah Decker, Priya Nethala, Ryan Welchko, Xavier Leveque, Ming Lu, Michael Sandstrom, Ute Hochgeschwender, Julien Rossignol, Gary Dunbar
Multiple studies have demonstrated the ability of mesenchymal stem cells (MSCs) to differentiate into dopamine-producing cells, in vitro and in vivo, indicating their potential to be used in the treatment of Parkinson's disease (PD). However, there are discrepancies among studies regarding the optimal time (i.e., passage number) and method for dopaminergic induction, in vitro. In the current study, we compared the ability of early (P4) and later (P40) passaged bone marrow-derived MSCs to differentiate into dopaminergic neurons using two growth-factor-based approaches...
March 2, 2018: International Journal of Molecular Sciences
Yvette Low, Sajita Setia, Graca Lima
Psychiatric and physical conditions often coexist, and there is robust evidence that associates the frequency of depression with single and multiple physical conditions. More than half of patients with depression may have at least one chronic physical condition. Therefore, antidepressants are often used in cotherapy with other medications for the management of both psychiatric and chronic physical illnesses. The risk of drug-drug interactions (DDIs) is augmented by complex polypharmacy regimens and extended periods of treatment required, of which possible outcomes range from tolerability issues to lack of efficacy and serious adverse events...
2018: Neuropsychiatric Disease and Treatment
Kyoichiro Yazaki, Masahiro Watarai, Mitsuru Kahata, Asako Kumagai, Koji Inoue, Hiroshi Koganei, Kenji Enta, Masato Otsuka, Yasuhiro Ishii
A 67-year old male with a dual-chamber pacemaker visited for a regular check-up. An unfamiliar message emerged on the display just after placing the programmer wand. We could recognize that the pacemaker had already been in the safe back-up mode of DDI, and the programmer prompted a re-initialization request. We are so surprised because there was no indication of device malfunction the day before in daily monitoring and a 12-lead electrocardiogram revealed normally working in the DDD mode just before checking the device...
February 22, 2018: Indian Pacing and Electrophysiology Journal
Jiachang Gong, Lisa Iacono, Ramaswamy A Iyer, W Griffith Humphreys, Ming Zheng
AIMS: Previous studies demonstrated direct correlation between CYP2C19 genotype and BMS-823778 clearance in healthy volunteers. The objective of the present study was to develop a PBPK model for BMS-823778 and utilize the model to predict PK and DDI in virtual populations with multiple polymorphic genes. METHODS: The PBPK model was built and verified utilizing existing clinical data. The verified model was simulated to predict PK of BMS-823778 and significance of DDI with a strong CYP3A4 inhibitor in subjects with various CYP2C19 and UGT1A4 genotypes...
February 22, 2018: British Journal of Clinical Pharmacology
Venkatesh Pilla Reddy, Michael Walker, Pradeep Sharma, Peter Ballard, Karthick Vishwanathan
Osimertinib is a potent, highly selective, irreversible inhibitor of Epidermal Growth Factor Receptor and T790M resistance mutation receptor. In vitro metabolism data suggested osimertinib is a substrate of CYP3A4/5, a weak inducer of CYP3A and an inhibitor of BCRP. A combination of in vitro data, clinical pharmacokinetic data and drug-drug interaction (DDI) data of osimertinib in oncology patients were used to develop the physiologically based pharmacokinetic (PBPK) model and verify the DDI data of osimertinib...
February 22, 2018: CPT: Pharmacometrics & Systems Pharmacology
Mohamed Anwar Hammad, Balamurugan Tangiisuran, Abeer Mohamed Kharshid, Noorizan Abdul-Aziz, Yahaya Hassan, Nor Azizah Aziz, Tarek Mohamed Elsayed
Context: The literature of drug-drug interaction (DDI)-related uncontrolled causality, and preventability of DDI-induced UCG (HbA1c >7%) in outpatients glycemia (UCG) among outpatients with Type 2 diabetes mellitus is still limited. Aims: The aim of this study is to identify the prevalence, mechanism, severity, with Type 2 diabetes. Settings and Design: A cross-sectional study was conducted in Penang General Hospital. Methods: A computerized system for DDI checking was used to assess the severity and mechanism of DDIs...
October 2017: Journal of Pharmacy & Bioallied Sciences
Ruijuan Xu, Weihong Ge, Qing Jiang
PURPOSE: Rivaroxaban is a direct oral anticoagulant with a large inter-individual variability. The present study is to develop a physiologically based pharmacokinetic (PBPK) model to predict several scenarios in clinical practice. METHODS: A whole-body PBPK model for rivaroxaban, which is metabolized by the cytochrome P450 (CYP) 3A4/5, 2J2 pathways and excreted via kidneys, was developed to predict the pharmacokinetics at different doses in healthy subjects and patients with hepatic or renal dysfunction...
February 17, 2018: European Journal of Clinical Pharmacology
Nicole A Kratochwil, Miriam Triyatni, Martina B Mueller, Florian Klammers, Brian Leonard, Dan Turley, Josephine Schmaler, Aynur Ekiciler, Birgit Molitor, Isabelle Walter, Pierre-Alexis Gonsard, Charles A Tournillac, Alexandre Durrwell, Michaela Marschmann, Russell Jones, Mohammed Ullah, Franziska Boess, Giorgio Ottaviani, Yuyan Yin, Neil J Parrott, Stephen Fowler
Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross species metabolism, comparison of low clearance drugs as well as induction studies. Here, we present studies using a long-term liver model which show how metabolism and active transport, drug-drug interactions and enzyme induction in healthy and diseased states, e.g. hepatitis B virus (HBV) infection, may be assessed in a single test system to enable effective data integration for PBPK modeling...
February 16, 2018: Journal of Pharmacology and Experimental Therapeutics
Ken-Ichi Umehara, Felix Huth, Christina S Won, Tycho Heimbach, Handan He
Ritonavir is one of several ketoconazole alternatives used to evaluate strong CYP3A4 inhibition potential in clinical drug-drug interaction (DDI) studies. In this study, four physiologically-based pharmacokinetic (PBPK) models of ritonavir as an in vivo time-dependent inhibitor of CYP3A4 were created and verified for the oral doses of 20, 50, 100 and 200 mg using fraction absorbed (Fa) and oral clearance (CLoral) values reported in the literature, as transporter and CYP enzyme reaction phenotyping data were not available...
February 16, 2018: Biopharmaceutics & Drug Disposition
Jamie E Moscovitz, Amit S Kalgutkar, Kelly Nulick, Nathaniel Johnson, Zhiwu Lin, Theunis C Goosen, Yan Weng
The potential for drug-drug interactions (DDIs) arising from transcriptional regulation of drug disposition genes via activation of nuclear receptors (NRs) such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and/or aryl hydrocarbon receptor (AhR) remains largely unexplored, as highlighted in a recent guidance document from the European Medicines Agency. The goal of this research was to establish PXR/CAR/AhR-specific drug metabolizing enzyme (DME) and transporter gene expression signatures in sandwich-cultured cryopreserved human hepatocytes using selective activators of PXR (rifampin), CAR (CITCO) and AhR (omeprazole)...
February 12, 2018: Journal of Pharmacology and Experimental Therapeutics
Ansha Subramanian, Mangaiarkkarasi Adhimoolam, Suresh Kannan
Aim: Drug-drug interactions (DDIs) are one of the major but preventable cause of adverse drug reaction. Study of prevalence and prediction of DDIs will make the physician easier to provide better patient care and mitigate patient's harm. Hence, the study was planned to evaluate the potential DDIs among medication prescribed to hypertensive patients in our hospital. Materials and Methods: A prospective, cross-sectional study was conducted among the hypertensive patients in medicine (outpatient/inpatient) department over the period of three months in a tertiary care hospital...
January 2018: Perspectives in Clinical Research
Subo Yuan, Yuqiang Shi, Kaiwen Guo, Shao-Jun Tang
Highly Active Antiretroviral Therapy (HAART) has significantly contributed to the increase of HIV-infected survivors over 50 years of age. Unfortunately, patients are required to stay on long-term HAART, which may be causally related to the development of neurological problems such as chronic pain. Little is known about the contribution of HAART or its therapeutic agents to the pathogenesis of pain during aging. In this study, we determined the effect of nucleoside reverse transcriptase inhibitors (NRTIs) on the development of mechanical allodynia and the potential underlying mechanism in aging mice (15...
February 10, 2018: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Joana Bicker, Gilberto Alves, Ana Fortuna, Patrício Soares-da-Silva, Amílcar Falcão
Inhibition of the biosynthesis of noradrenaline is a currently explored strategy for the treatment of hypertension, congestive heart failure and pulmonary arterial hypertension. While some dopamine β-hydroxylase (DBH) inhibitors cross the blood-brain barrier (BBB) and cause central as well as peripheral effects (nepicastat), others have limited access to the brain (etamicastat, zamicastat). In this context, peripheral selectivity is clinically advantageous, in order to prevent alterations of noradrenaline levels in the CNS and the occurrence of adverse central effects...
February 8, 2018: European Journal of Pharmaceutical Sciences
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