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Marguerite L Monogue, George Sakoulas, Victor Nizet, David P Nicolau
β-lactam-β-lactamase inhibitors (BLIs) have previously demonstrated antimicrobial activity against Acinetobacter baumannii (AB). Colistin retains the highest susceptibility rate against A. baumannii, and has demonstrated synergy with other antimicrobials, including β-lactam-BLIs. Therefore, we assessed the potential individual activity and synergistic combinations in vivo against carbapenem-susceptible (CS) and multidrug-resistant (MDR) A. baumannii isolates in neutropenic thigh and lung infection models...
March 13, 2018: Pharmacology
Shixiang Wang, Nan Tan, Cuicui Ma, Jie Wang, Pu Jia, Jianghong Liu, Yang Yang, Zhanxiong Xie, Kun Zhao, Xiaohui Zheng
AIMS: In clinical practice, herbal medicines have played an important role in the modulation of drug transporters through the combination of conventional prescription drugs, which necessitates the elucidation of herb-drug interactions. The present study was designed to investigate the inhibitory effects and mechanisms of benzaldehyde, vanillin, muscone, and borneol on P-glycoprotein (P-gp). METHODS: The effects of the 4 compounds on the intracellular accumulation of rhodamine-123 (Rho-123) in vinblastine-treated Caco-2 (VB-Caco-2) cells were studied by monitoring fluorescence intensity through a flow cytometry assay, and the effects of these compounds on Rho-123 transport through VB-Caco-2 monolayers and Rho-123 intestinal absorption in the rat everted gut sac were investigated by high-performance liquid chromatography...
March 2, 2018: Pharmacology
Islam M Ghazi, Marguerite L Monogue, Masakatsu Tsuji, David P Nicolau
We evaluated the in vivo efficacy of humanized exposures of cefiderocol, a novel siderophore cephalosporin, against a test panel of P. aeruginosa (PSA) previously shown to develop resistance to 2 preclinical candidate siderophores (MB-1 and SMC-3176). In the thigh infection model, the PSA bacterial density in untreated controls grew from 5.54 ± 0.23 to 8.68 ± 0.57 log10 CFU over 24 h. The humanized cefiderocol exposure resulted in >1 log10 CFU reduction in all 8 isolates, while MB-1 and SMC-3176 exhibited variable activity similar to that previously reported...
February 22, 2018: Pharmacology
Alexandru-Florian Deftu, Violeta Ristoiu, Marc Rene Suter
The functioning of microglial cells inside the central nervous system depends on their ion channels expression. Microglia are capable of synthesizing different cytokines and chemokines, including CXCL1, and responding to their action via specific receptors. In this study, we explore the effect of intrathecal injection of CXCL1 on potassium currents, expressed in CX3CR1-Green Fluorescent Protein labeled microglia in transgenic mice. The results showed that CXCL1 hyperpolarized the cells by enhancing inward rectifying potassium currents and increasing the membrane area, suggesting an activating effect on microglia...
February 15, 2018: Pharmacology
Chunsheng He, Amber Griffies, Xuan Liu, Robert Adamczyk, Shu-Pang Huang
Sample size estimates for drug-drug interaction (DDI) studies are often based on variability information from the literature or from historical studies, but small sample sizes in these sources may limit the precision of the estimates obtained. This project aimed to create an intra-subject variability library of the pharmacokinetic (PK) exposure parameters, area under the curve, and maximum plasma concentration, for probes commonly used in DDI studies. Data from 66 individual DDI studies in healthy subjects relating to 18 common probe substrates were pooled to increase the effective sample size for the identified probes by 1...
February 2, 2018: Pharmacology
Yi-Wen Zhang, Xiao-Wei Zheng, Yu-Jia Liu, Luo Fang, Zong-Fu Pan, Mei-Hua Bao, Ping Huang
Oridonin, the major terpene found in Rabdosia rubescens, is widely used as a dietary supplement or therapeutic drug. However, the effects of oridonin on major CYP450s are still unclear. As oridonin can enhance the effect of other clinical drugs, in this study, we investigated the influence of oridonin on CYP450s mRNA expression and its impact on activities in human HepaRG cell to evaluate the safety by studying its potential drug interaction. HepaRG cells were cultured with series concentrations of oridonin (1, 5, 10, and 20 μmol/L), and the major CYP450s mRNA and protein expression, as well as enzyme activities were analyzed by real-time polymerase chain reaction, Western blot analysis and UPLC-MS/MS-based metabolite assay...
January 26, 2018: Pharmacology
Shiro Nakamura, Toshio Watanabe, Tetsuya Tanigawa, Sunao Shimada, Yuji Nadatani, Takako Miyazaki, Masaki Iimuro, Yasuhiro Fujiwara
Activation of the NOD-Like Receptor Family, Pyrin Domain-Containing 3 (NLRP3) inflammasome, which consists of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1, triggers pro-caspase-1 cleavage promoting the processing of pro-interleukin (IL)-1β into mature IL-1β, which is critical for the development of non-steroidal anti-inflammatory drug (NSAID)-induced enteropathy. We investigated the effects of isoliquiritigenin, a flavonoid derived from the roots of Glycyrrhiza species, on NSAID-induced small intestinal damage and the inflammasome activation...
January 26, 2018: Pharmacology
Dong Wang, Jiang Song, Huasong Ma
BACKGROUND: 25-hydroxyvitamin D3 (25[OH]VD3) has recently been found to be an active hormone. Its biological actions are also demonstrated in various cell types. However, the precise influences of vitamin D3 (VD3) and its metabolites (25[OH]VD3, 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2VD3]) on the osteoblast differentiation remain largely unknown. In this work, we investigated the effects of VD3 and its metabolites in different concentrations on the early and later osteoblast differentiation and biomineralization...
January 26, 2018: Pharmacology
Katsuhito Nagai, Shuhei Fukuno, Keisuke Otani, Yoshiki Nagamine, Sachiko Omotani, Yasutoshi Hatsuda, Michiaki Myotoku, Hiroki Konishi
Doxorubicin (DOX) is a highly potent anti-neoplastic agent widely used in clinical practice, but its dosage and duration of administration are strictly limited due to dose-related organ damage. In the present study, we examined whether theanine, an amino acid derivative found in green tea leaves, can protect against DOX-induced acute nephrotoxicity in rats. Decreases in the creatinine clearance by DOX administration were attenuated by concurrent treatment with theanine, which was consistent with the change in histological renal images assessed by microscopic examination...
January 25, 2018: Pharmacology
Yugo Hamada, Kenji Ikemura, Takuya Iwamoto, Masahiro Okuda
Lansoprazole, a proton pump inhibitor, potently inhibits human organic anion transporter, hOAT3 (SLC22A8). Lansoprazole has an asymmetric atom in its structure and is clinically administered as a racemic mixture of (R)-and (S)-enantiomers. However, little is known about the stereoselective inhibitory potencies of lansoprazole against hOAT3 and its homolog, hOAT1. In the present study, the stereoselective inhibitory effect of lansoprazole was evaluated using hOAT1-and hOAT3-expressing cultured cells. hOAT1 and hOAT3 transported [14C]p-aminohippurate and [3H]estrone-3-sulfate (ES) with Michaelis-Menten constants of 29...
January 19, 2018: Pharmacology
Harumi Okuyama, Tomohito Hamazaki, Rokuro Hama, Yoichi Ogushi, Tetsuyuki Kobayashi, Naoki Ohara, Hajime Uchino
BACKGROUND: The Consensus Statement from the European Atherosclerosis Society (EAS) Consensus Panel 2017 concludes on the basis of 3 different types of clinical studies that low-density lipoprotein (LDL) causes atherosclerotic cardiovascular disease (ASCVD). In Mendelian randomization studies, rare genetic mutations affecting LDL receptor function were found to cause higher or lower LDL-C levels, which are associated with correspondingly altered ASCVD risk. In prospective cohort studies and randomized controlled trials (RCTs) of statins, a remarkably consistent log-linear association was demonstrated between the absolute magnitude of LDL-C exposure and ASCVD risk...
January 19, 2018: Pharmacology
Yoko Obayashi, Kenta Kajiwara, Eiji Nakamura
BACKGROUND: Although there are many clinical studies in which the beneficial effect of glutamine formulation on mucositis induced by chemo/radiotherapy was evaluated, the results are sometimes conflicting with the report of clinical deterioration. Then, we hypothesized that chemotherapy may increase the incidence of hyperammonemia without comparable change of major parameters of hepatic/renal disorder. METHODS: To verify our hypothesis, we examined the increase in blood ammonia level with 1-h intravenous infusion of alanyl-glutamine on day 1-4 after cisplatin (CDDP) administration in rats and assessed the correlation with hepatic/renal parameters...
January 4, 2018: Pharmacology
Zoltán Patai, András Guttman, Endre G Mikus
BACKGROUND: Drotaverine, a type 4 cyclic nucleotide phosphodiesterase (PDE4) inhibitor, blocks the degradation of 3',5'-cyclic adenosine monophosphate. However, published receptor binding data showed that drotaverin also binds to the L-type voltage-operated calcium channel (L-VOCC). Based on these molecular mechanisms of action, a direct and indirect (by blocking the constrictor response) relaxant effect on airway smooth muscle can be predicted, which has not yet been assessed. SUMMARY: Accordingly, drotaverine and reference agents were tested both on the histamine-, methacholine-, or KCl-induced contraction response and on precontracted guinea pig tracheal preparations...
January 4, 2018: Pharmacology
Katsuaki Dan, Keita Takanashi, Hiroko Akiyoshi, Kaori Munakata, Hideki Hasegawa, Kaoru Ogawa, Kenji Watanabe
When the Kampo medicine, Hochuekkito (Hochu), was administered to normal mice for 2 weeks, influenza virus titer was reduced. The mechanism of action of Hochu was examined using the plaque assay method. It was suggested that Hochu may either obstruct the first stage of the infection process (adsorption and entry) or may directly target viral particles. Using the plaque assay method, these 2 modes of action could not be differentiated. Virus RNA in the infected cell was verified by quantitative real-time polymerase chain reaction...
December 22, 2017: Pharmacology
Shan Jiang, De-Fang Fang, Ying Chen
OBJECTIVE: Ginsenosides, Rb1 and Rb3, are the major protopanaxadiol components of ginseng saponin. In the present study, the influences of ginsenosides Rb1 and Rb3 on N-methyl-D-aspartic acid (NMDA) receptor or DL-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated synaptic transmission after oxygen-glucose deprivation (OGD) were investigated. METHODS: NMDA receptor population spike (NMDA-PS) or AMPA receptor-mediated population spike (AMPA-PS) was recorded in the CA1 pyramidal cell layer of rat hippocampal slices by electrophysiological techniques...
2018: Pharmacology
Anne-Sofie Grell, Maryam Mostajeran, Lars Edvinsson, Saema Ansar
Stroke is one of the leading causes of mortality and morbidity worldwide, and few therapeutic treatments have shown beneficial effect clinically. One reason for this could be the lack of risk factors incorporated into the preclinical stroke research. We have previously demonstrated phenotypic receptor changes to be one of the injurious mechanisms occurring after stroke but mostly in healthy rats. The aim of this study was to investigate if hypertension has an effect on vasoconstrictive receptor responses to endothelin 1, sarafotoxin 6c and angiotensin II after stroke by inducing transient middle cerebral artery occlusion in spontaneously hypertensive rats and Wistar-Kyoto rats using the wire-myograph...
2018: Pharmacology
Tae Woo Jung, Sung Tae Kim, Jun Ho Lee, Soo In Chae, Kwang Woo Hwang, Yoon Hee Chung, Hyoung-Chun Kim, A M Abd El-Aty, Tae Jin Lee, Eon Sub Park, Ji Hoon Jeong
A phosphatidylcholine (PPC) formulation has been used to treat cellulite; however, its underlying mechanism of action remains unclear. In this study, we demonstrated that PPC induces lipolysis and apoptosis in adipocytes, and evaluated a possible tumor necrosis factor alpha (TNFα)-dependent pathway, whereby PPC exerts these effects. For in vitro study, fully differentiated 3T3-L1 cells, mouse adipocytes were treated with various concentrations of PPC and cell apoptosis and lipolysis were assayed. For in vivo experiments, mice fed on a high-fat diet for 8 weeks were injected twice to abdominal subcutaneous fat tissues of either vehicle or PPC...
2018: Pharmacology
Bo Zhang, Qin Li, Chenyang Shi, Xinyue Zhang
Adverse drug reactions occur frequently and can trigger pseudoallergy, which has become a serious threat to public health. Pseudoallergy is a typical non-immune anaphylactic reaction characterized by the independence of antigen-specific immune responses. In the clinic, pseudoallergy is often elicited by the first dose of medication, and here lies its unpredictability and occasional lethal outcome. However, the mechanisms of pseudoallergy are not well understood. This review focusses on the causes and mechanisms of pseudoallergy induced by drugs...
2018: Pharmacology
Amin Polzin, Betül Knoop, Andreas Böhm, Lisa Dannenberg, Mark Zurek, Tobias Zeus, Malte Kelm, Bodo Levkau, Bernhard H Rauch
BACKGROUND: Aspirin plays a crucial role in the prevention of cardiovascular diseases. We previously described that aspirin has effects beyond inhibition of platelet aggregation, as it inhibited thrombin-mediated release of sphingosine-1-phosphate (S1P) from human platelets. S1P is a bioactive lipid with important functions on inflammation and apoptosis. In endothelial cells (EC), S1P is a key regulator of cell migration. In this study, we aimed to analyze the effects of aspirin on platelet-induced EC migration...
2018: Pharmacology
Yuko Honda, Taketoshi Furugohri, Yoshiyuki Morishima
BACKGROUND/AIMS: Agents to reverse the anticoagulant effect of edoxaban, an oral direct factor Xa inhibitor, would be desirable in emergency situations. The aim of this study is to determine the effect of tranexamic acid, an antifibrinolytic agent, on the anticoagulant activity and bleeding by edoxaban in rats. METHODS: A supratherapeutic dose of edoxaban (3 mg/kg) was intravenously administered to rats. Three minutes after dosing, tranexamic acid (100 mg/kg) was given intravenously...
2018: Pharmacology
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