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Drug Metabolism and Personalized Therapy

Isabel López, Estela Sangüesa, Yves Vancraenendonck, Estefanía Zuriaga, María Pilar Ribate, Cristina Belén García
Vitamin K antagonists are highly effective antithrombotic drugs. However, appropriate dosing is difficult to establish owing to its narrow therapeutic window as well as widespread inter- and intra-individual variability in dosage. Compared with dosing solely based on clinical information, pharmacogenetics can help improve the therapy with coumarins by decreasing the time to reach a stable dose and reducing the risk of bleeding. Most of the studies about genotyping of patients using vitamin K antagonists have focused on predicting the stable dose...
October 14, 2016: Drug Metabolism and Personalized Therapy
Nicholas M Njuguna, Ken-Ichi Umehara, Felix Huth, Hilmar Schiller, Kelly Chibale, Gian Camenisch
BACKGROUND: The fraction of an absorbed drug metabolized by the different hepatic cytochrome P450 (CYP) enzymes, relative to total hepatic CYP metabolism (fmCYP), can be estimated by measuring the inhibitory effects of presumably selective CYP inhibitors on the intrinsic metabolic clearance of a drug using human liver microsomes. However, the chemical inhibition data are often affected by cross-reactivities of the chemical inhibitors used in this assay. METHODS: To overcome this drawback, the cross-reactivities exhibited by six chemical inhibitors (furafylline, montelukast, sulfaphenazole, ticlopidine, quinidine and ketoconazole) were quantified using specific CYP enzyme marker reactions...
October 8, 2016: Drug Metabolism and Personalized Therapy
Dmitriy Alexeyevich Sychev, Aleksandr Vladimirovich Rozhkov, Ruslan Evgenyevich Kazakov, Anna Viktorovna Ananichuk
BACKGROUND: Oral anticoagulants are commonly used to treat patients with thromboembolic pathology. Genetic variations could influence personal response to anticoagulant drugs. Acenocoumarol (AC) is a vitamin K antagonist used in anticoagulant therapy and as a prophylaxis measure in Europe. In this study, we assessed the effect of CYP4F2 rs2108622, ABCB1, and GGCX polymorphisms on the safety profile and regime dosing of AC in patients with nonvalvular atrial fibrillation. METHODS: Fifty patients aged 40-70 years were included...
September 1, 2016: Drug Metabolism and Personalized Therapy
Ana M Peiró, Beatriz Planelles, Gabriella Juhasz, György Bagdy, Frédéric Libert, Alain Eschalier, Jérôme Busserolles, Beata Sperlagh, Adrián Llerena
The experience of chronic pain is one of the commonest reasons for seeking medical attention, being a major issue in clinical practice. While pain is a universal experience, only a small proportion of people who felt pain develop pain syndromes. In addition, painkillers are associated with wide inter-individual variability in the analgesic response. This may be partly explained by the presence of single nucleotide polymorphisms in genes encoding molecular entities involved in pharmacodynamics and pharmacokinetics...
September 1, 2016: Drug Metabolism and Personalized Therapy
Nagaraj M Kulkarni, Sandeep Malampati, Mahamad Yunnus A Mahat, S Chandrasekaran, J Raghul, Ansar Ali Khan, Uma Maheswari Krishnan, Shridhar Narayanan
BACKGROUND: Severe forms of non-alcoholic fatty liver disease (NAFLD) adversely affect the liver physiology and hence the pharmacokinetics of drugs. Here, we investigated the effect of NAFLD on the pharmacokinetics of rosiglitazone, an insulin sensitizer used in the treatment of type 2 diabetes. METHODS: Male C57BL/6 mice were divided into two groups. The first group (n=14) was fed with normal chow feed and the second group (n=14) was fed with 60% high-fat diet (HFD) and 40% high fructose liquid (HFL) for 60 days to induce NAFLD...
September 1, 2016: Drug Metabolism and Personalized Therapy
Felicia Stefania Falvella, Susan Marelli, Stefania Cheli, Stefano Montanelli, Federico Viecca, Lucia Salvi, Alfio Ferrara, Emilio Clementi, Giuliana Trifirò, Alessandro Pini
BACKGROUND: Losartan is under evaluation for managing Marfan patients with aortic root dilatation. Cytochrome P450 (CYP) enzymes convert losartan to E3174 active metabolite. The aim of this study is to describe the distribution of CYP2C9*2, CYP2C9*3, CYP3A4*22 and CYP3A5*3 defective alleles, according to losartan tolerance in paediatric Marfan patients. METHODS: We genotyped 53 paediatric Marfan patients treated with losartan. The rate of aortic root dilatation was evaluated using the delta z-score variation...
September 1, 2016: Drug Metabolism and Personalized Therapy
Georgia Ragia, Ivan Veresies, Louiza Veresie, Kyriakos Veresies, Vangelis G Manolopoulos
BACKGROUND: The reinforcing effects of alcohol are mediated through complex interactions between multiple neurochemical systems. Genes of dopaminergic (DRD2, DRD3 and DβH), opioid (OPRM1) and glutaminergic (GRIK1) systems mediate the dependent behavior via different mechanisms; however, they all target the serotonergic and dopaminergic pathways in the ventral tegmental area. METHODS: In the present study, DRD2 A2/A1, DRD3 Ser9Gly, DβH -1021C>T, OPRM1 A118G and GRIK1 rs2832407C>A polymorphisms and their interactions were analyzed in 72 alcohol-dependent patients and 74 controls of Greek-Cypriot origin, using the PCR-RFLP method...
September 1, 2016: Drug Metabolism and Personalized Therapy
Athira Bindu Murali, Belsy Boban, Aswathy Karoor Shanmughan, Karthikeyan Marimuthu, Aravind Ramakrishnan Sreelatha, Augustine Xavier
BACKGROUND: Medication therapy management (MTM) is a pharmacist-led professional service, one of the main aims of which is to improve patient medication adherence. Ensuring adequate adherence to the prescribed therapeutic regimen is one of the major challenges in attaining the desired therapeutic goals in diabetics. The objective of this study was to implement MTM in diabetic patients and to identify its effectiveness in improving patient medication adherence. METHODS: A prospective interventional study was carried out within a 1-year period in KIMS-Al-Shifa Hospital, which is a tertiary care referral hospital in Malabar region of Kerala, including inpatients with type 2 diabetes mellitus in the general medicine department of the hospital...
September 1, 2016: Drug Metabolism and Personalized Therapy
Mark J Bartlett, Elizabeth A Shephard
The study of pharmacogenomics has, by harnessing sequence information from human genomes, the potential to lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. For this potential to be realized results need to be interpreted to the prescriber into a format which dictates an action. This mini review briefly describes the history, the regulatory environment, opinions towards, and implementation, integration and interpretation of pharmacogenomics in the United States of America and Europe...
June 1, 2016: Drug Metabolism and Personalized Therapy
Clifford Jacobs, Brendon Pearce, Nisreen Hoosain, Mongi Benjeddou
BACKGROUND: Multidrug and toxin extrusion 1 (MATE1) is an organic cation/H+ exchanger, localized in the apical membrane of proximal renal tubules, which mediates the cellular elimination of organic cations into the renal lumen. These organic cations include clinically important drugs such as metformin, oxaliplatin and cimetidine. Moreover, genetic polymorphisms of SLC47A1, the pharmacogenetically relevant gene encoding human MATE1, have been implicated in reduced transport or accumulation to cytotoxic levels of these drugs in vitro...
June 1, 2016: Drug Metabolism and Personalized Therapy
Thirumaleswara Goud, Srinivas Maddi, Devanna Nayakanti, Rajendra Prasad Thatipamula
BACKGROUND: Ritonavir is an antiretroviral drug to treat HIV AIDS and inhibits cytochrome P450 3A4. To treat diabetes mellitus in HIV, repaglinide is coadministered with ritonavir in the clinic. Multiple cytochrome P450 (CYP) isoforms are involved in the metabolism of repaglinide like CYP2C8 and CYP 3A4. In order to predict and understand drug-drug interactions of these two drugs, the pharmacokinetics and pharmacodynamics (PK/PD) of repaglinide and ritonavir were studied in normal, diabetic and hepatic impaired rats...
June 1, 2016: Drug Metabolism and Personalized Therapy
Nicolás González-Vacarezza, Isabel Alonso, Gustavo Arroyo, Jorge Martínez, Fernando De Andrés, Adrián LLerena, Francisco Estévez-Carrizo
Bevacizumab was the first molecular-targeted antiangiogenic therapy approved for the treatment of metastatic colorectal cancer. Until now, there are no predictive biomarkers available to decide the prescription of bevacizumab in patients with colorectal cancer. The purposes of this review were to provide a critical appraisal of the evidence and to identify possible predictive genetic biomarkers. A literature search was performed to identify studies that determine different levels of treatment response between patients stratified according to defined biomarkers...
June 1, 2016: Drug Metabolism and Personalized Therapy
Madhav Seervi, Shweta Lotankar, Shrikant Barbar, Sadhana Sathaye
BACKGROUND: Lupeol and betulin are triterpenoids that are majorly found in dietary substances. The aim of present study was to investigate the inhibition and induction potential of lupeol and betulin on cytochrome P450 (CYP)1A2, CYP2C11, CYP2D6 and CYP3A2 activities in rat liver microsomes. METHODS: The inhibition and induction studies were conducted using ethoxy resorufin-O-deethylase (CYP1A2), tolbutamide hydroxylase (CYP2C9), and midazolam hydroxylase (CYP3A4) activity assays...
June 1, 2016: Drug Metabolism and Personalized Therapy
Ingrid Fricke-Galindo, Helgi Jung-Cook, Adrián LLerena, Marisol López-López
Mexico presents a complex population diversity integrated by Mexican indigenous (MI) (7% of Mexico's population) and Mexican mestizos (MMs). This composition highlights the importance of pharmacogenetic studies in Mexican populations. The aims of this study were to analyze the reported frequencies of the most relevant pharmacogenetic biomarkers and metabolic phenotypes in healthy volunteers from Mexican populations and to assess its interethnic variability across MI and MM populations. After a literature search in PubMed, and according to previously defined inclusion criteria, 63 pharmacogenetic studies performed in Mexican healthy volunteers up to date were selected...
June 1, 2016: Drug Metabolism and Personalized Therapy
Jacob K Akintunde, Olakunle Enock Bolarin, Daniel G Akintunde
BACKGROUND: Garlic capsule (GAR) and/or selenium- vitamin A, C, E (S-VACE) might be useful in the treatment of lung diseases. The present study evaluated the toxicity of lisinopril (LIS) in the lungs of male rats and the reversal effect of GAR and/or selenium-vitamins A, C, and E (S-VACE). METHODS: Group I served as the control, whereas animals in groups II, III, IV, and V received 28 mg of LIS/kg body weight by gavage. Group III was co-treated with GAR at a therapeutic dosage of 250 mg/kg body weight per day...
March 1, 2016: Drug Metabolism and Personalized Therapy
Olalla Maroñas, Ana Latorre, Joaquín Dopazo, Munir Pirmohamed, Cristina Rodríguez-Antona, Gérard Siest, Ángel Carracedo, Adrián LLerena
Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside...
March 2016: Drug Metabolism and Personalized Therapy
Loes Mandigers, Pauline D J Bollen, Peter J Bijlstra, Els Brands
We report a case of an adult patient using chronic low-dose verapamil who developed severe verapamil intoxication. A 57-year-old male patient was presented at the emergency room after a collapse of unknown etiology. The airway was compromised, and thus, an endotracheal tube was inserted. The patient deteriorated hemodynamically. Because of verapamil use and bradycardia, verapamil intoxication was suspected. The treatment was supported with intravenous fluids, calcium, inotropes, and a transvenous pacemaker...
March 1, 2016: Drug Metabolism and Personalized Therapy
Ana E Rodríguez-Vicente, Eva Lumbreras, Jesus M Hernández, Miguel Martín, Antonio Calles, Carlos López Otín, Salvador Martín Algarra, David Páez, Miquel Taron
Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the genetic basis for the interindividual differences in drug response. PGx approaches have been applied to many anticancer drugs in an effort to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. In this article, we discuss the advances in the field of cancer pharmacogenetics and pharmacogenomics, driven by the recent technological advances and new revolutionary massive sequencing technologies and their application to elucidate the genetic bases for interindividual drug response and the development of biomarkers able to personalize drug treatments...
March 1, 2016: Drug Metabolism and Personalized Therapy
Ossyneidee Gutiérrez-Álvarez, Ismael Lares-Asseff, Carlos Galaviz-Hernández, Elio-Aarón Reyes-Espinoza, Horacio Almanza-Reyes, Martha Sosa-Macías, Isaías Chairez Hernández, José-Manuel Salas-Pacheco, Claudia E Bailón-Soto
BACKGROUND: Folate metabolism plays an essential role in the processes of DNA synthesis and methylation. Deviations in the folate flux resulting from single-nucleotide polymorphisms in genes encoding folate-dependent enzymes may affect the susceptibility to leukemia. This case-control study aimed to assess associations among MTHFR (C677T, A1298C) and TPMT (*2, *3A) mutations as well as to evaluate the synergistic effects of combined genotypes for both genes. Therefore, these genetic variants may lead to childhood acute lymphoblastic leukemia (ALL) susceptibility, in a Mexican population study...
March 1, 2016: Drug Metabolism and Personalized Therapy
Xandra García-González, Teresa Cabaleiro, María José Herrero, Howard McLeod, Luis A López-Fernández
In the last decade, pharmacogenetic research has been performed in different fields. However, the application of pharmacogenetic findings to clinical practice has not been as fast as desirable. The current situation of clinical implementation of pharmacogenetics is discussed. This review focuses on the advances of pharmacogenomics to individualize cancer treatments, the relationship between pharmacogenetics and pharmacodynamics in the clinical course of transplant patients receiving a combination of immunosuppressive therapy, the needs and barriers facing pharmacogenetic clinical application, and the situation of pharmacogenetic testing in Spain...
March 1, 2016: Drug Metabolism and Personalized Therapy
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