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Vinicius A Sortica, Juliana D Lindenau, Maristela G Cunha, Maria DO Ohnishi, Ana Maria R Ventura, Ândrea Kc Ribeiro-Dos-Santos, Sidney Eb Santos, Luciano Sp Guimarães, Mara H Hutz
BACKGROUND: Chloroquine/primaquine is the current therapy to eliminate Plasmodium vivax infection in the Amazon region. AIMS: This study investigates CYP1A2, CYP2C8, CYP2C9, CYP3A4 and CYP3A5 genetic polymorphisms influence on cloroquine/primaquine treatment. PATIENTS & METHODS: Generalized estimating equations analyses were performed to determine the genetic influence in parasitemia and/or gametocytemia clearance over treatment time in 164 patients...
October 21, 2016: Pharmacogenomics
Maïlys De Sousa Mendes, Gabrielle Lui, Yi Zheng, Claire Pressiat, Deborah Hirt, Elodie Valade, Naïm Bouazza, Frantz Foissac, Stephane Blanche, Jean-Marc Treluyer, Saik Urien, Sihem Benaboud
BACKGROUND: Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful. METHODS: A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK)...
October 21, 2016: Clinical Pharmacokinetics
Zhaoxiang Zhou, Meng Wang, Zengjun Guo, Xiaoying Zhang
This study was aimed at investigating the effect of ethanol on oral bioavailability of kaempferol in rats, namely, at disclosing their possible interaction. Kaempferol (100 or 250 mg kg-1 bm) was administered to the rats by oral gavage with or without ethanol (600 mg kg-1 bm) co-administration. Intravenous administration (10 and 25 mg kg-1 bm) of kaempferol was used to determine the bioavailability. The concentration of kaempferol in plasma was estimated by ultra high performance liquid chromatography. During coadministration, a significant increase of the area under the plasma concentration-time curve as well as the peak concentration were observed, along with a dramatic decrease in total body clearance...
December 1, 2016: Acta Pharmaceutica
Jovana Trifunović, Vladan Borčić, Momir Mikov
Some biological properties of bile acids and their oxo derivatives have not been sufficiently investigated, although the interest for bile acids as signaling molecules is rising. The aim of this work was to evaluate physico-chemical parametar b (slope) that represents lipophilicity of the examined molecules and to investigate interactions of bile acids with carbonic anhydrase I, II, androgen receptor and CYP450s. 13 candidates were investigated using normal phase thin layer chromatography in two solvent systems...
October 14, 2016: Biomedical Chromatography: BMC
Shuai-Bing He, Man-Man Li, Bai-Xia Zhang, Xiao-Tong Ye, Ran-Feng Du, Yun Wang, Yan-Jiang Qiao
During the past decades, there have been continuous attempts in the prediction of metabolism mediated by cytochrome P450s (CYP450s) 3A4, 2D6, and 2C9. However, it has indeed remained a huge challenge to accurately predict the metabolism of xenobiotics mediated by these enzymes. To address this issue, microsomal metabolic reaction system (MMRS)-a novel concept, which integrates information about site of metabolism (SOM) and enzyme-was introduced. By incorporating the use of multiple feature selection (FS) techniques (ChiSquared (CHI), InfoGain (IG), GainRatio (GR), Relief) and hybrid classification procedures (Kstar, Bayes (BN), K-nearest neighbours (IBK), C4...
October 9, 2016: International Journal of Molecular Sciences
Allison B Chambliss, Molly Resnick, Athena K Petrides, William A Clarke, Mark A Marzinke
BACKGROUND: Current methods for the detection of single nucleotide polymorphisms (SNPs) associated with aberrant drug-metabolizing enzyme function are hindered by long turnaround times and specialized techniques and instrumentation. In this study, we describe the development and validation of a high-resolution melting (HRM) curve assay for the rapid screening of variant genotypes for targeted genetic polymorphisms in the cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A5. METHODS: Sequence-specific primers were custom-designed to flank nine SNPs within the genetic regions of aforementioned drug metabolizing enzymes...
October 12, 2016: Clinical Chemistry and Laboratory Medicine: CCLM
William M Greenberg, Leslie Citrome
Lurasidone hydrochloride, a benzisothiazol derivative, is a second-generation (atypical) antipsychotic agent that has received regulatory approval for the treatment of schizophrenia in the US, Canada, the EU, Switzerland, and Australia, and also for bipolar depression in the US and Canada. In addition to its principal antagonist activity at dopamine D2 and serotonin 5-HT2A receptors, lurasidone has distinctive 5-HT7 antagonistic activity, and displays partial agonism at 5-HT1A receptors, as well as modest antagonism at noradrenergic α2A and α2C receptors...
October 8, 2016: Clinical Pharmacokinetics
Shiv Bahadur, Pulok K Mukherjee, S K Milan Ahmmed, Amit Kar, Ranjit K Harwansh, Subrata Pandit
OBJECTIVE: Tinospora cordifolia is used for treatment of several diseases in Indian system of medicine. In the present study, the inhibition potential of T. cordifolia extracts and its constituent tinosporaside to cause herb-drug interactions through rat and human liver cytochrome enzymes was evaluated. MATERIALS AND METHODS: Bioactive compound was quantified through reverse phase high-performance liquid chromatography, to standardize the plant extracts and interaction potential of standardized extract...
September 2016: Indian Journal of Pharmacology
Kristina M Brooks, Jomy M George, Parag Kumar
Use of complementary and alternative medicines (CAMs) and over-the-counter (OTC) medications are very common among HIV-infected patients. These products can cause clinically significant drug-drug interactions (DDIs) with antiretroviral (ARV) medications, thereby increasing risk for negative outcomes such as toxicity or loss of virologic control. Areas Covered: This article provides an updated review of the different mechanisms by which CAM and OTC products are implicated in DDIs with ARV medications. Expert Commentary: Much of the literature published to date involves studies of CAMs interacting with older ARV agents via the cytochrome P450 (CYP450) system...
October 7, 2016: Expert Review of Clinical Pharmacology
Prem Rajak, Moumita Dutta, Salma Khatun, Moutushi Mandi, Sumedha Roy
This study reveals protective role of l-ascorbic acid (25, 50 and 100μg/mL) against toxic impacts of acute sub-lethal exposure of Acephate (5μg/mL) in a non-target organism Drosophila melanogaster. Organismal effect was evident from increased impairment in climbing activities (9 folds) of treated individuals who also manifested altered ocular architecture. These anomalies were reduced with l-ascorbic acid (l-AA) supplementation. Acephate induced apoptotic lesions in eye imaginal discs and gut confirmed tissue damage that also reduced with l-AA co-treatment...
September 28, 2016: Journal of Hazardous Materials
Xianbao Shi, Brianna Mackie, Gang Zhang, Shuman Yang, Yonggui Song, Dan Su, Yali Liu, Lina Shan
Morusin, the important active component of a traditional Chinese medicine, Morus alba L., has been shown to exhibit many vital pharmacological activities. In this study, six recombinant CYP450 supersomes and liver microsomes were used to perform metabolic studies. Chemical inhibition studies and screening assays with recombinant human cytochrome P450s were also used to characterize the CYP450 isoforms involved in morusin metabolism. The morusin metabolites identified varied greatly among different species. Eight metabolites of morusin were detected in the liver microsomes from pigs (PLMs), rats (RLMs), and monkeys (MLMs) by LC-MS/MS and six metabolites were detected in the liver microsomes from humans (HLMs), rabbits (RAMs), and dogs (DLMs)...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
Anna Leonidova, Mireille Vargas, Jörg Huwyler, Jennifer Keiser
One of the major neglected tropical diseases, schistosomiasis, is currently treated and controlled with a single drug, praziquantel. The quest for an alternative drug is fueled by its lack of activity against juvenile Schistosoma and the fear of emerging resistance. The synthetic ozonide OZ418 has shown high activity against Schistosoma mansoni, S. haematobium and S. japonicum in vivo, but its drug disposition remains unknown. To bridge this gap, our study determined the basic pharmacokinetic (PK) parameters of a single oral dose (400 mg/kg) of OZ418 in uninfected mice...
October 3, 2016: Antimicrobial Agents and Chemotherapy
Susanne U Miedlich, Nima Karamooz, Stephen R Hammes
OBJECTIVE: Aromatase, or CYP19A1, is a type II cytochrome CYP450 enzyme that catalyzes the conversion of C19 androgens to C18 estrogens. Its crucial role in both female and male physiology has been deduced from human and animal studies using aromatase inhibitors, genetically altered mice, and patients with aromatase deficiency. The latter is an extremely rare disorder. Its diagnosis is particularly difficult in males, who go through puberty normally and therefore usually present as adults with elevated testosterone, bone abnormalities (e...
September 29, 2016: Bone
Fuguo Shi, Xiaobing Li, Hong Pan, Li Ding
Rifampicin (RIF) is used in regimens for infections caused by Mycobacteria accompanied by serious adverse reactions. Rifampicin-quinone (RIF-Q) is a major autoxidation product of RIF. It is not clear whether RIF-Q plays a role in RIF induced adverse reactions. Investigation of the systemic exposure of RIF-Q is helpful to better understand the role of RIF-Q in RIF induced adverse reactions. In this study, a simple and reproducible high performance liquid chromatography-mass spectrometry (LC-MS) method involving a procedure to prevent the RIF from oxidation for simultaneous quantification of RIF and RIF-Q in rat plasma has been developed and validated, and applied to elucidate the systemic exposure of RIF-Q in rats...
September 26, 2016: Journal of Pharmaceutical and Biomedical Analysis
Shilong Zhong, Weichao Han, Chuqi Hou, Junjin Liu, Lili Wu, Menghua Liu, Zhi Liang, Haoming Lin, Lili Zhou, Shuwen Liu, Lan Tang
Cytochrome P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) play important roles in the metabolism of exogenous and endogenous compounds. The gene transcription of CYPs and UGTs can be enhanced or reduced by transcription factors (TFs). This study aims to explore novel TFs involved in the regulatory network of human hepatic UGTs/CYPs. Correlations between the transcription levels of 683 key TFs and CYPs/UGTs in three different human liver expression profiles (n = 640) were calculated first. Supervised weighted correlation network analysis (sWGCNA) was employed to define hub genes among the selected TFs...
September 28, 2016: AAPS Journal
Fernanda de Lima Moreira, Maísa D Habenschus, Thiago Barth, Lucas M M Marques, Alan Cesar Pilon, Vanderlan da Silva Bolzani, Ricardo Vessecchi, Norberto P Lopes, Anderson R M de Oliveira
Piperlongumine (PPL), a natural plant product, has been extensively studied in cancer treatment going up on clinical trials. Since the first report related to its use on cancer research (in 2011) around 80 papers have been published in less than 10 years, but a gap still remaining. There are no metabolism studies of PPL in human organism. For the lack of a better view, here, the CYP450 in vitro oxidation of PPL was described for the first time. In addition, the enzymatic kinetic data, the predicted in vivo parameters, the produced metabolites, the phenotyping study and possible piperlongumine-drug interactions in vivo is presented...
September 29, 2016: Scientific Reports
Jonathan R Scarff
Schizophrenia occurs in approximately 0.3 to 0.7 percent of the world's population and is associated with significant morbidity and mortality. Although atypical antipsychotics reduce positive and negative symptoms, they are associated with varying degrees of metabolic adverse effects. This necessitates continued development of efficacious yet metabolically favorable treatments. This article reviews brexpiprazole, a medication recently approved to treat patients with schizophrenia. Brexpiprazole was well-tolerated, and adverse reactions were statistically insignificant...
July 2016: Innovations in Clinical Neuroscience
Šárka Doleželová, Šárka Jíchová, Zuzana Husková, Alžběta Vojtíšková, Petr Kujal, Lenka Hošková, Josef Kautzner, Janusz Sadowski, Luděk Červenka, Libor Kopkan
The fawn-hooded hypertensive (FHH) rat serves as a genetic model of spontaneous hypertension associated with glomerular hyperfiltration and proteinuria. However, the knowledge of the natural course of hypertension and kidney disease in FHH rats remains fragmentary and the underlying pathophysiological mechanisms are unclear. In this study, over the animals' lifetime, we followed the survival rate, blood pressure (telemetry), indices of kidney damage, the activity of renin-angiotensin (RAS) and nitric oxide (NO) systems, and CYP450-epoxygenase products (EETs)...
2016: Clinical and Experimental Hypertension: CHE
Sorin Tunaru, Ramesh Chennupati, Rolf M Nüsing, Stefan Offermanns
19(S)-hydroxy-eicosatetraenoic acid (19(S)-HETE) belongs to a family of arachidonic acid metabolites produced by cytochrome P450 enzymes, which play critical roles in the regulation of cardiovascular, renal and pulmonary functions. Although it has been known for a long time that 19(S)-HETE has vascular effects, its mechanism of action has remained unclear. In this study we show that 19(S)-HETE induces cAMP accumulation in the human megakaryoblastic leukemia cell line MEG-01. This effect was concentration-dependent with an EC50 of 520 nM, insensitive to pharmacological inhibition of COX-1/2 and required the expression of the G-protein Gs...
2016: PloS One
Cameron L Jordan, Terry L Noah, Marianna M Henry
This review seeks to re-introduce cystic fibrosis (CF) clinicians to the pharmacology of drug-drug interactions among medications commonly used in CF and provide a framework for understanding these interactions among medications outside the scope of this discussion. We here focus on drugs impacted by the cytochrome P-450 (CYP450) enzyme system and on interactions involving antimicrobials, psychotropic medications, and cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Particular attention is needed when prescribing rifampin, azole antifungals and the CFTR modulators, ivacaftor, and lumacaftor/ivacaftor, in combination with other medications...
October 2016: Pediatric Pulmonology
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