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Pharmacokinetic

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https://www.readbyqxmd.com/read/27926532/novel-parp1-2-inhibitor-mefuparib-hydrochloride-elicits-potent-in-vitro-and-in-vivo-anticancer-activity-characteristic-of-high-tissue-distribution
#1
Jin-Xue He, Meng Wang, Xia-Juan Huan, Chuan-Huizi Chen, Shan-Shan Song, Ying-Qing Wang, Xue-Mei Liao, Cun Tan, Qian He, Lin-Jiang Tong, Yu-Ting Wang, Xiao-Hua Li, Yi Su, Yan-Yan Shen, Yi-Ming Sun, Xin-Ying Yang, Yi Chen, Zhi-Wei Gao, Xiao-Yan Chen, Bing Xiong, Xiu-Lian Lu, Jian Ding, Chun-Hao Yang, Ze-Hong Miao
The approval of poly(ADP-ribose) polymerase (PARP) inhibitor AZD2281 in 2014 marked the successful establishment of the therapeutic strategy targeting homologous recombination repair defects of cancers in the clinic. However, AZD2281 has poor water solubility, low tissue distribution and relatively weak in vivo anticancer activity, which appears to become limiting factors for its clinical use. In this study, we found that mefuparib hydrochloride (MPH) was a potent PARP inhibitor, possessing prominent in vitro and in vivo anticancer activity...
December 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27925676/population-pharmacokinetics-and-exposure-response-relationship-of-carfilzomib-in-patients-with-multiple-myeloma
#2
Ying Ou, Sameer Doshi, Anh Nguyen, Fredrik Jonsson, Sanjay Aggarwal, Kanya Rajangam, Meletios A Dimopoulos, A Keith Stewart, Ashraf Badros, Kyriakos P Papadopoulos, David Siegel, Sundar Jagannath, Ravi Vij, Ruben Niesvizky, Richard Graham, Jenn Visich
A population pharmacokinetic (PK) model and exposure-response (E-R) analysis was developed using data collected from 5 phase 1b/2 and 2 phase 3 studies in subjects with multiple myeloma. Subjects receiving intravenous infusion on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) in each cycle at doses ranging from 15 to 20/56 mg/m(2) (20 mg/m(2) in cycle 1 and, if tolerated, escalated to 56 mg/m(2) on day 8 of cycle 1). The population PK analysis indicated that among all the covariates tested, the only statistically significant covariate was body surface area on carfilzomib clearance; however, this covariate was unlikely to be clinically significant...
December 7, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27925657/population-pharmacokinetics-of-cefazolin-in-serum-and-adipose-tissue-from-overweight-and-obese-women-undergoing-cesarean-delivery
#3
Mordechai Grupper, Joseph L Kuti, Morgan L Swank, Lindsay Maggio, Brenna L Hughes, David P Nicolau
The optimal antibiotic prophylaxis dosing regimen of cefazolin for cesarean delivery (CD) in overweight and obese women is unknown. This study was done to compare the duration that cefazolin concentrations remain above the minimum inhibitory concentration (MIC) in adipose tissue (AT). Serum and AT concentrations from 3 previous studies in CD patients were comodeled using the nonparametric adaptive grid algorithm in Pmetrics. AT concentrations for 5000 overweight and obese patients receiving 1-, 2-, and 3-g cefazolin regimens were simulated to calculate the probability that free drug concentrations remained above an MIC of 2 μg/mL at 1, 1...
December 7, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27925651/model-based-dose-selection-for-intravaginal-ring-formulations-releasing-anastrozole-and-levonorgestrel-intended-for-the-treatment-of-endometriosis-symptoms
#4
Isabel Reinecke, Marcus-Hillert Schultze-Mosgau, Rüdiger Nave, Heinz Schmitz, Bart A Ploeger
Pharmacokinetics (PK) of anastrozole (ATZ) and levonorgestrel (LNG) released from an intravaginal ring (IVR) intended to treat endometriosis symptoms were characterized, and the exposure-response relationship focusing on the development of large ovarian follicle-like structures was investigated by modeling and simulation to support dose selection for further studies. A population PK analysis and simulations were performed for ATZ and LNG based on clinical phase 1 study data from 66 healthy women. A PK/PD model was developed to predict the probability of a maximum follicle size ≥30 mm and the potential contribution of ATZ beside the known LNG effects...
December 7, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27925610/ex-vivo-cutaneous-bioavailability-of-topical-mometasone-furoate-in-an-o-w-preparation
#5
Johannes Wohlrab, Reinhard H H Neubert, Elfi Sommer, Julia Michael
Mometasone furoate (MMF) is a modern glucocorticoid of the 4th generation, which has been proven not only for inhalation but also for cutaneous treatment. Due to its lipophilic character, it is mainly used in ointments and creams with an outer lipophilic phase (W/O type). However, this study investigated the cutaneous cytotoxicology of MMF and tried to characterize its pharmacokinetic effects on the skin using an O/W preparation. An HPLC method has been developed and validated for the detection of MMF in cutaneous tissue, and concentration-time curves of MMF were created after cutaneous application on unaffected as well as lesional skin...
December 8, 2016: Skin Pharmacology and Physiology
https://www.readbyqxmd.com/read/27925271/validation-of-an-lc-ms-ms-method-for-simultaneous-detection-of-four-hdac-inhibitors-belinostat-panobinostat-rocilinostat-and-vorinostat-in-mice-plasma-and-its-application-to-a-mice-pharmacokinetic-study
#6
Kalpesh Kumar Giri, Suresh P S, Syed Mohd Saim, Mohd Zainuddin, Ravi Kanth Bhamidipati, Purushottam Dewang, Mahanandeesha S Hallur, Sridharan Rajagopal, Sriram Rajagopal, Ramesh Mullangi
A sensitive and rapid LC-MS/MS method was developed and validated for the simultaneous quantitation of four HDAC inhibitors namely belinostat (BST), panobinostat (PST), rocilinostat (RST) and vorinostat (VST) in mice plasma as per regulatory guidelines. The analytes and internal standard were extracted from 50 μL mice plasma by protein precipitation, followed by chromatographic separation using an Atlantis C18 column with an isocratic mobile phase comprising 0.1% formic acid: acetonitrile (25:75,, v/v) at a flow rate of 0...
December 7, 2016: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/27925256/pharmacokinetic-drug-drug-interactions-of-tyrosine-kinase-inhibitors-a-focus-on-cytochrome-p450-transporters-and-acid-suppression-therapy
#7
REVIEW
Caroline Gay, Delphine Toulet, Pascal Le Corre
The extensive use of tyrosine kinase inhibitors (TKI's) in hematology and oncology has shown that these drugs have a significant potential for drug-drug interactions. Since these drugs have a rather low therapeutic window, some drug interactions are of particular clinical relevance either on drug toxicity or on patient's response. Significant interactions occur with concomitant use of acid-suppressive therapy leading to a decreased oral bioavailability. However, such interactions are drug dependent according to their solubility pattern and to the duration of action of acid-suppressive therapy, which is coprescribed...
December 7, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27925239/physiologically-based-pharmacokinetic-modeling-revealed-minimal-codeine-intestinal-metabolism-in-first-pass-removal-in-rats
#8
Keumhan Noh, Shu Chen, Qi J Yang, K Sandy Pang
The physiologically-based model with segregated flow to the intestine (SFM-PBPK; partial, lower flow to enterocyte region vs. greater flow to serosal region) was found to describe first-pass glucuronidation of morphine (M) to morphine-3β-glucuronide (MG) in rats after intraduodenal (ID) and intravenous (IV) administration better than the traditional model (TM), for which a single intestinal flow perfused the whole of the intestinal tissue. The SFM described a greater extent of intestinal M glucuronidation for ID vs...
December 7, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27925234/puerarin-offsets-the-anticoagulation-effect-of-warfarin-in-rats-by-inducing-rcyps-upregulating-vitamin-k-epoxide-reductase-and-inhibiting-thrombomodulin
#9
Beikang Ge, Zhen Zhang, Teddy Taining Lam, Zhong Zuo
PURPOSE: The current study was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between warfarin and puerarin which is the most abundant component in Pueraria lobata (Gegen). In vivo and ex vivo rat models were used to reveal the underlying mechanisms of such interactions. METHODS: Apart from one control group, five groups of Sprague-Dawley rats were treated with warfarin, oral puerarin, oral puerarin with warfarin, intravenous puerarin, intravenous puerarin with warfarin...
December 7, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27925222/sulfadimethoxine-in-giant-freshwater-prawns-macrobrachium-rosenbergii-an-attempt-to-estimate-the-withdrawal-time-by-a-population-pharmacokinetic-approach
#10
A Poapolathep, M Giorgi, P L Toutain, S Poapolathep, K Imsilp, C Sakulthaew, N Wannapat, N Klangkaew
The fates of sulfadimethoxine (SDM) for different routes of administration were investigated in muscle tissue of giant freshwater prawns, Macrobrachium rosenbergii, following either intramuscular (i.m.) or gavage administration at a dosage of 50 mg/kg body weight (b.w.). The depletion patterns of SDM were also examined after medicated feed treatment at the feeding concentration of 10 g/kg of feed twice a day at a rate of 1% of total b.w. for five consecutive days. The concentration of SDM in prawn muscle tissue was measured using a high-performance liquid chromatography (HPLC) equipped with ultraviolet detector...
December 7, 2016: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27925221/pharmacokinetic-pharmacodynamic-evaluation-of-grapiprant-in-a-carrageenan-induced-inflammatory-pain-model-in-the-rabbit
#11
V De Vito, M Salvadori, A Poapolathep, H Owen, R Rychshanova, M Giorgi
Grapiprant is the novel selective EP4 receptor inhibitor recently issued on the veterinary market for dogs affected by osteoarthritis. The aim of this study was twofold: to evaluate the pharmacokinetics and the pharmacodynamics of grapiprant in the induced inflammatory pain model in the rabbit after a single IV injection of 2 mg/kg; to compare the thermal antinociception effect after 2 mg/kg IV grapiprant, with that generated by 0.5 mg/kg meloxicam SC injected. Rabbits (n = 12) were randomly assigned to two crossover studies (single-dose, two-period crossover)...
December 7, 2016: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27924817/in-vitro-human-epidermal-permeation-of-nicotine-from-electronic-cigarette-refill-liquids-and-implications-for-dermal-exposure-assessment
#12
H Frederick Frasch, Ana M Barbero
Nicotine plus flavorings in a propylene glycol (PG) vehicle are the components of electronic cigarette liquids (e-liquids), which are vaporized and inhaled by the user. Dermal exposure to nicotine and e-liquids may occur among workers in mixing and filling of e-cigarettes in the manufacturing process. Inadvertent skin contact among consumers is also a concern. In vitro nicotine permeation studies using heat-separated human epidermis were performed with surrogate and two commercial e-liquids, neat and aqueous nicotine donor formulations...
December 7, 2016: Journal of Exposure Science & Environmental Epidemiology
https://www.readbyqxmd.com/read/27924732/the-effect-of-a-hexanoic-acid-linker-insertion-on-the-pharmacokinetics-and-tumor-targeting-properties-of-the-melanoma-imaging-agent-99mtc-hynic-cycmsh
#13
Vania Teixeira, Marcelo Fernández, Natalia Oddone, Xiuli Zhang, Fabio Gallazzi, Hugo Cerecetto, Juan Pablo Gambini, Williams Porcal, Pablo Cabral, Thomas P Quinn
BACKGROUND: Lactam cyclized alpha-melanocyte stimulating hormone (α-MSH) analogues exhibit high stability and affinity for the MC1-R receptors over expressed in melanoma cells. Recently, we reported a novel <sup>99m</sup>Tc-HYNIC-cycMSH<sub>4-13</sub> analogue with the HYNIC chelator directly attached to the lactam cyclized ring. OBJECTIVE: In this study we proposed the introduction of a 6-aminohexanoic acid (Ahx) linker between the HYNIC chelator and lactam cyclized peptide cycMSH4-13 to reduce steric hindrance and improve the melanoma targeting and imaging proprieties of the radiolabeled peptide...
December 6, 2016: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/27924725/anticancer-drug-targets-of-salvia-phytometabolites-chemistry-biology-and-omics
#14
Da-Cheng Hao, Guang-Bo Ge, Pei-Gen Xiao
Salvia displays diverse anticancer properties, which are attributable to their diterpene and phenolic contents. There is no comprehensive review on the anticancer diversity and molecular targets of Salvia components. We investigate the diversity and molecular targets of Salvia phytometabolites responsible for the prevention and treatment of cancer and sarcoma. Traditional therapeutic knowledge suggests that Salvia species can be used to develop anticancer drugs. Lots of concerns have been raised for tanshinone (Tan) IIA and cryptotanshinone...
December 7, 2016: Current Drug Targets
https://www.readbyqxmd.com/read/27924636/safety-and-tolerability-of-glucagon-like-peptide-1-receptor-agonists-unresolved-and-emerging-issues
#15
Denis Raccah
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a mainstay of treatment options for Type 2 diabetes. They contribute to lowering blood glucose levels, generally have a favorable tolerability profile, and can be used alone or in combination with other antidiabetic agents. Based on the duration of their effects, GLP-1 RAs can be divided into two classes: short-acting and long-acting. Differences exist between these sub-classes, and between each drug, in terms of pharmacokinetic and pharmacodynamic profiles...
December 7, 2016: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/27924615/a-model-for-predicting-the-interindividual-variability-of-drug-drug-interactions
#16
M Tod, L Bourguignon, N Bleyzac, S Goutelle
Pharmacokinetic drug-drug interactions are frequently characterized and quantified by an AUC ratio (Rauc). The typical value of the AUC ratio in case of cytochrome-mediated interactions may be predicted by several approaches, based on in vitro or in vivo data. Prediction of the interindividual variability of Rauc would help to anticipate more completely the consequences of a drug-drug interaction. We propose and evaluate a simple approach for predicting the standard deviation (sd) of Ln(Rauc), a metric close to the interindividual coefficient of variation of Rauc...
December 6, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27924487/antagonists-of-the-mirna-argonaute-2-protein-complex-anti-mir-agos
#17
Marco F Schmidt, Oliver Korb, Chris Abell
microRNAs (miRNAs) have been identified as high-value drug targets. A widely applied strategy in miRNA inhibition is the use of antisense agents. However, it has been shown that oligonucleotides are poorly cell permeable because of their complex chemical structure and due to their negatively charged backbone. Consequently, the general application of oligonucleotides in therapy is limited. Since miRNAs' functions are executed exclusively by the Argonaute 2 protein, we therefore describe a protocol for the design of a novel miRNA inhibitor class: antagonists of the miRNA-Argonaute 2 protein complex, so-called anti-miR-AGOs, that not only block the crucial binding site of the target miRNA but also bind to the protein's active site...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27924471/mirna-targeting-drugs-the-next-blockbusters
#18
Marco F Schmidt
Only 20 years after the discovery of small non-coding, single-stranded ribonucleic acids, so-called microRNAs (miRNAs), as post-transcriptional gene regulators, the first miRNA-targeting drug Miravirsen for the treatment of hepatitis C has been successfully tested in clinical Phase II trials. Addressing miRNAs as drug targets may enable the cure, or at least the treatment of diseases, which presently seems impossible. However, due to miRNAs' chemical structure, generation of potential drug molecules with necessary pharmacokinetic properties is still challenging and requires a re-thinking of the drug discovery process...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27924364/metabolic-characterization-of-1-5-fluoropentyl-1h-indol-3-yl-4-methyl-1-naphthalenyl-methanone-mam-2201-using-human-liver-microsomes-and-cdna-overexpressed-cytochrome-p450-enzymes
#19
Tae Yeon Kong, Ju-Hyun Kim, Won Gu Choi, Joo Young Lee, Hee Seung Kim, Jin Young Kim, Moon Kyo In, Hye Suk Lee
MAM-2201 is a synthetic cannabinoid that is increasingly found in recreational drug abusers and cases of severe intoxication. Thus, characterization of the metabolic pathways of MAM-2201 is necessary to predict individual pharmacokinetics and toxicity differences, and to avoid toxic drug-drug interactions. Collectively, 19 phase 1 metabolites of MAM-2201 were identified using liquid chromatography-Orbitrap mass spectrometry following human liver microsomal incubations in the presence of NADPH: 7 hydroxy-MAM-2201 (M1-M7), 4 dihydroxy-MAM-2201 (M8-M11), dihydrodiol-MAM-2201 (M12), N-(5-hydroxypentyl)-MAM-2201 (M13), hydroxy-M13 (M14), N-dealkyl-MAM-2201 (M15), 2 hydroxy-M15 (M16, M17), MAM-2201 N-pentanoic acid (M18), and hydroxy-M18 (M19)...
December 6, 2016: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/27924159/in-vitro-and-in-vivo-evaluation-of-89-zr-ds-8273a-as-a-theranostic-for-anti-death-receptor-5-therapy
#20
Ingrid J G Burvenich, Fook-Thean Lee, Nancy Guo, Hui K Gan, Angela Rigopoulos, Adam C Parslow, Graeme J O'Keefe, Sylvia J Gong, Henri Tochon-Danguy, Stacey E Rudd, Paul S Donnelly, Masakatsu Kotsuma, Toshiaki Ohtsuka, Giorgio Senaldi, Andrew M Scott
Background: DS-8273a, an anti-human death receptor 5 (DR5) agonistic antibody, has cytotoxic activity against human cancer cells and induces apoptosis after specific binding to DR5. DS-8273a is currently being used in clinical Phase I trials. This study evaluated the molecular imaging of DR5 expression in vivo in mouse tumor models using SPECT/CT and PET/MRI, as a tool for drug development and trial design. Methods: DS-8273a was radiolabeled with indium-111 and zirconium-89. Radiochemical purity, immunoreactivity, antigen binding affinity and serum stability were assessed in vitro...
2016: Theranostics
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