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Pharmacodynamics

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https://www.readbyqxmd.com/read/28427104/pharmacokinetics-and-pharmacodynamics-of-tofogliflozin-a-selective-sglt2-inhibitor-in-healthy-male-subjects
#1
Nahoko Kasahara-Ito, Hiroyuki Fukase, Yoichiro Ogama, Tomohisa Saito, Yasuhiro Ohba, Sumire Shimada, Yasuki Takano, Tomoko Ichihara, Kimio Terao, Noboru Nakamichi, Yuji Kumagai, Sachiya Ikeda
Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects. Three studies were conducted: single-ascending dose study (10-640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5-80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20-40 mg) in 30 Japanese subjects. Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t1/2 of 5-6 h...
April 20, 2017: Drug Research
https://www.readbyqxmd.com/read/28426740/uncovering-the-molecular-and-physiological-processes-of-anticancer-leads-binding-human-serum-albumin-a-physical-insight-into-drug-efficacy
#2
Chuanbo Liu, Zuojia Liu, Jin Wang
Human serum albumin (HSA) has its ability to bind drug molecules and influence their efficacies. Although anticancer leads NSC48693 and NSC290956 functioned at the same mechanism, the drug efficacies were obviously distinct. To gain insight into the distinct drug efficacy, the molecular and physiological processes of anticancer leads binding HSA have been investigated via a combined experimental and theoretical approach. The binding site, as characterized by fluorescence quenching and molecular modeling, is found to be located at site II in subdomain III A for NSC48693 with tight binding and at site FA1 in subdomain I B for NSC290956 with negatively cooperative binding, respectively...
2017: PloS One
https://www.readbyqxmd.com/read/28426458/anti-tnf%C3%AE-treatment-after-surgical-resection-for-crohn-s-disease-is-effective-despite-previous-pharmacodynamic-failure
#3
Amit Assa, Jiri Bronsky, Kaija-Leena Kolho, Kristyna Zarubova, Tim de Meij, Oren Ledder, Margaret Sladek, Stephanie van Biervliet, Caterina Strisciuglio, Raanan Shamir
BACKGROUND: The outcome of patients with Crohn's disease who failed anti-tumor necrosis factor alpha (anti-TNFα) therapy despite adequate serum drug levels (pharmacodynamic failure) is unclear. We aimed to assess such pediatric patients who underwent intestinal resection and were re-treated with the same anti-TNFα agent postoperatively. METHODS: Pediatric patients with Crohn's disease who underwent intestinal resection and were treated with anti-TNFα agents postoperatively were assessed retrospectively...
May 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28426226/brain-uptake-of-bioactive-flavones-in-scutellariae-radix-and-its-relationship-to-anxiolytic-effect-in-mice
#4
Sophia Yui Kau Fong, Chenrui Li, Yiu Cheong Ho, Rui Li, Qian Wang, Yin Cheong Wong, Hong Xue, Zhong Zuo
Scutellariae Radix (SR) and its bioactive flavones elicit a variety of effects in the brain. However, the brain uptake of individual SR flavones and its relationship to the elicited effects after SR administration remain unknown. Moreover, previous studies seldom measured pharmacokinetic and pharmacodynamic outcomes simultaneously. In the current study, the brain uptake of six major SR flavones and the anxiolytic behavior following oral administration of a SR extract at two clinically relevant doses (600 and 1200 mg/kg twice daily) were simultaneously investigated in mice (n=18 per group)...
April 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28424964/pharmacodynamic-effects-in-the-cerebrospinal-fluid-of-rats-after-intravenous-administration-of-different-asparaginase-formulations
#5
Andrea Ballerini, Federico Moro, Ilaria Fuso Nerini, Claudio Marcello Marzo, Angelo Di Clemente, Mariella Ferrari, Maurizio D'Incalci, Andrea Biondi, Antonella Colombini, Valentino Conter, Luca Porcu, Luigi Cervo, Carmelo Rizzari, Massimo Zucchetti
PURPOSE: Asparaginase (ASNase) is used to treat various hematological malignancies for its capacity to deplete asparagine (ASN) in serum and cerebrospinal fluid (CSF). Since the biological mechanisms underlying CSF asparagine depletion in humans are not yet fully elucidated, this study compared, for the first time, the pharmacological properties of three clinically used ASNase formulations in a rodent model. METHODS: Male Wistar rats were treated with E.coli-ASNase, PEG-ASNase, or ERW-ASNase at different doses...
April 19, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28423431/-treatment-and-secondary-prevention-of-venous-thromboembolism-change-in-oral-anticoagulation
#6
Thomas-Maria Helms, Dietrich Gulba, Ingo Ahrens, Andreas Schäfer, Johannes Hankowitz, Peter Kuhlencordt, Hans-Peter Lipp, Sigrid Nikol, Hanno Riess, Tom Stargardt, Peter Bramlage
With the recent approval of the fourth direct non vitamin K dependent oral anticoagulant (NOAC) edoxaban the range of available NOACs for the treatment of venous thromboembolism (VTE) has expanded. Shortly thereafter, two updated guidelines for the prevention and treatment of VTE have been published. In these NOACs are listed as equal anticoagulants to low-molecular weight heparin (LMWH), or fondaparinux (FDX), and VKA for the initial or maintenance treatment of VTE. All NOACs are approved for the maintenance therapy after VTE and two NOACs (rivaroxaban and apixaban) for the initial treatment in addition in an increased dose...
April 19, 2017: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/28422745/targeting-of-the-breast-cancer-microenvironment-with-a-potent-and-linkable-oxindole-based-antiangiogenic-small-molecule
#7
Orestis Argyros, Theodoros Karampelas, Aimilia Varela, Xenophon Asvos, Athanasios Papakyriakou, Adamantia Agalou, Dimitris Beis, Constantinos H Davos, Demosthenes Fokas, Constantin Tamvakopoulos
The clinical efficacy of antiangiogenic small molecules (e.g., sunitinib) in breast carcinoma has largely failed with substantial off-target toxicity. We rationally designed and evaluated preclinically a novel sunitinib analogue, SAP, with favourable pharmacological properties and the ability to be readily conjugated to a targeting peptide or antibody for active tumour targeting.SAP was evaluated in silico and in vitro in order to verify target engagement (e.g., VEGFR2). Pharmacokinetic and biodistribution parameters were determined in mice using LC-MS/MS...
March 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422300/platelet-reactivity-in-response-to-loading-dose-of-atorvastatin-or-rosuvastatin-in-patients-with-stable-coronary-disease-before-percutaneous-coronary-intervention-the-statiplat-randomized-study
#8
Cosmo Godino, Anna Giulia Pavon, Antonio Mangieri, Anna Salerno, Michela Cera, Alberto Monello, Alaide Chieffo, Valeria Magni, Alberto Cappelletti, Alberto Margonato, Antonio Colombo
BACKGROUND: The acute effects of statin loading dose (LD) on platelet reactivity in patients with chronic stable angina (CSA) are not completely clear. HYPOTHESIS: We hypothesized that LDs of atorvastatin and rosuvastatin have different pharmacodynamic acute effects on platelet aggregability in CSA patients with baseline normal platelet reactivity while on dual antiplatelet therapy (DAPT). METHODS: From September 2011 to February 2014, all consecutive CSA patients on chronic DAPT (aspirin and clopidogrel) were evaluated before elective percutaneous coronary intervention (PCI)...
April 19, 2017: Clinical Cardiology
https://www.readbyqxmd.com/read/28421966/regulatory-forum-review-utility-of-in-vitro-secondary-pharmacology-data-to-assess-risk-of-drug-induced-valvular-heart-disease-in-humans-regulatory-considerations
#9
Thomas Papoian, Gowraganahalli Jagadeesh, Muriel Saulnier, Natalie Simpson, Arippa Ravindran, Baichun Yang, Adebayo A Laniyonu, Imran Khan, Ana Szarfman
Drug-induced valvular heart disease (VHD) is a serious side effect linked to long-term treatment with 5-hydroxytryptamine (serotonin) receptor 2B (5-HT2B) agonists. Safety assessment for off-target pharmacodynamic activity is a common approach used to screen drugs for this undesired property. Such studies include in vitro assays to determine whether the drug is a 5-HT2B agonist, a necessary pharmacological property for development of VHD. Measures of in vitro binding affinity (IC50, Ki) or cellular functional activity (EC50) are often compared to maximum therapeutic free plasma drug levels ( fCmax) from which safety margins (SMs) can be derived...
April 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28421257/histone-deacetylase-inhibitors-reverse-age-related-increases-in-side-effects-of-haloperidol-in-mice
#10
Janitza L Montalvo-Ortiz, Daniel W Fisher, Guadalupe Rodríguez, Deyu Fang, John G Csernansky, Hongxin Dong
BACKGROUND: Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility. METHODS: In this study, we treated young (2-3 months old) and aged (22-24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects...
April 18, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28420720/a-phase-i-study-of-abc294640-a-first-in-class-sphingosine-kinase-2-inhibitor-in-patients-with-advanced-solid-tumors
#11
Carolyn D Britten, Melanie B Thomas, Elizabeth Garrett-Mayer, Steven H Chin, Keisuke Shirai, Besim Ogretmen, Tricia A Bentz, Alan Brisendine, Kate Anderton, Susan L Cusack, Lynn W Maines, Yan Zhuang, Charles D Smith
Purpose:  Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and pro-inflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of ABC294640, a first-in-class orally-available inhibitor of SK2.  <p>Experimental Design:  Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid and 750 mg bid, continuously in cycles of 28 days...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28420580/comparative-pharmacodynamic-analysis-of-imidazoline-compounds-using-rat-model-of-ocular-mydriasis-with-a-test-of-quantitative-structure-activity-relationships
#12
Joanna Raczak-Gutknecht, Antoni Nasal, Teresa Frąckowiak, Anita Kornicka, Franciszek Sączewski, Renata Wawrzyniak, Łukasz Kubik, Roman Kaliszan
Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain...
April 6, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28419964/effects-of-paeonia-emodi-on-hepatic-cytochrome-p450-cyp3a2-and-cyp2c11-expression-and-pharmacokinetics-of-carbamazepine-in-rats
#13
Mohammad Raish, Ajaz Ahmad, Khalid M Alkharfy, Basit L Jan, Kazi Mohsin, Abdul Ahad, Fahad I Al-Jenoobi, Abdullah M Al-Mohizea
Herbal medicines, dietary supplements, and other foods may pharmacokinetically and/or pharmacodynamically interact with carbamazepine (CBZ), which could lead to potential clinical consequences. Paeonia emodi (PE) is one of the herbs used as complementary therapy in the treatment of epileptic patients in some cultures, and may also be co-administered with CBZ. This study evaluates the effects of PE on the pharmacokinetics of CBZ and determines a possible mechanism of interaction. Rats were administered vehicle saline or PE (200mg/kg, p...
April 15, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28419483/pharmacokinetic-study-of-intravenous-acetaminophen-administered-to-critically-ill-multiple-trauma-patients-at-the-usual-dosage-and-a-new-proposal-for-administration
#14
Oscar Fuster-Lluch, Pedro Zapater-Hernández, Manuel Gerónimo-Pardo
The pharmacokinetic profile of intravenous acetaminophen administered to critically ill multiple-trauma patients was studied after 4 consecutive doses of 1 g every 6 hours. Eleven blood samples were taken (predose and 15, 30, 45, 60, 90, 120, 180, 240, 300, and 360 minutes postdose), and urine was collected (during 6-hour intervals between doses) to determine serum and urine acetaminophen concentrations. These were used to calculate the following pharmacokinetic parameters: maximum and minimum concentrations, terminal half-life, area under serum concentration-time curve from 0 to 6 hours, mean residence time, volume of distribution, and serum and renal clearance of acetaminophen...
April 17, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28419480/characterization-of-neutropenia-in-advanced-cancer-patients-following-palbociclib-treatment-using-a-population-pharmacokinetic-pharmacodynamic-modeling-and-simulation-approach
#15
Wan Sun, Peter J O'Dwyer, Richard S Finn, Ana Ruiz-Garcia, Geoffrey I Shapiro, Gary K Schwartz, Angela DeMichele, Diane Wang
Neutropenia is the most commonly reported hematologic toxicity following treatment with palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for metastatic breast cancer. Using data from 185 advanced cancer patients receiving palbociclib in 3 clinical trials, a pharmacokinetic-pharmacodynamic model was developed to describe the time course of absolute neutrophil count (ANC) and quantify the exposure-response relationship for neutropenia. These analyses help in understanding neutropenia associated with palbociclib and its comparison with chemotherapy-induced neutropenia...
April 18, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28419132/spectrophotometric-and-molecular-modelling-studies-on-in-vitro-interaction-of-tyrosine-kinase-inhibitor-linifanib-with-bovine-serum-albumin
#16
Tanveer A Wani, Ahmed H Bakheit, Seema Zargar, Mohammed A Hamidaddin, Ibrahim A Darwish
Linifanib (LNF) possess antitumor activity and acts by inhibiting receptor tyrosine kinase VEGF and PDGF. The interaction of BSA with the drug can provide valuable information regarding the pharmacokinetic and pharmacodynamics behavior of drug. In our study the spectrophotometric methods and molecular docking studies were executed to understand the interaction behavior of BSA and LNF. BSA has an intrinsic fluorescence and that fluorescence was quenched by LNF. This quenching process was studied at three different temperatures of 288, 300and 308 K...
2017: PloS One
https://www.readbyqxmd.com/read/28418852/structural-homologies-between-phenformin-lipitor-and-gleevec-aim-the-same-metabolic-oncotarget-in-leukemia-and-melanoma
#17
REVIEW
Gábor Somlyai, T Que Collins, Emmanuelle J Meuillet, Patel Hitendra, Dominic P D'Agostino, László G Boros
Phenformin's recently demonstrated efficacy in melanoma and Gleevec's demonstrated anti-proliferative action in chronic myeloid leukemia may lie within these drugs' significant pharmacokinetics, pharmacodynamics and structural homologies, which are reviewed herein. Gleevec's success in turning a fatal leukemia into a manageable chronic disease has been trumpeted in medical, economic, political and social circles because it is considered the first successful targeted therapy. Investments have been immense in omics analyses and while in some cases they greatly helped the management of patients, in others targeted therapies failed to achieve clinically stable recurrence-free disease course or to substantially extend survival...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418845/preclinical-development-of-g1t38-a-novel-potent-and-selective-inhibitor-of-cyclin-dependent-kinases-4-6-for-use-as-an-oral-antineoplastic-in-patients-with-cdk4-6-sensitive-tumors
#18
John E Bisi, Jessica A Sorrentino, Jamie L Jordan, David D Darr, Patrick J Roberts, Francis X Tavares, Jay C Strum
Inhibition of the p16INK4a/cyclin D/CDK4/6/RB pathway is an effective therapeutic strategy for the treatment of estrogen receptor positive (ER+) breast cancer. Although efficacious, current treatment regimens require a dosing holiday due to severe neutropenia potentially leading to an increased risk of infections, as well as tumor regrowth and emergence of drug resistance. Therefore, a next generation CDK4/6 inhibitor that can inhibit proliferation of CDK4/6-dependent tumors while minimizing neutropenia could reduce both the need for treatment holidays and the risk of inducing drug resistance...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418731/why-do-some-concentrated-insulins-maintain-their-pharmacokinetics-pharmacodynamics-profile
#19
Robert C Hood
No abstract text is available yet for this article.
April 2017: Diabetes Technology & Therapeutics
https://www.readbyqxmd.com/read/28418664/selective-ikur-inhibitors-for-the-potential-treatment-of-atrial-fibrillation-optimization-of-the-phenyl-quinazoline-series-leading-to-clinical-candidate-5-5-phenyl-4-pyridin-2-ylmethylamino-quinazolin-2-yl-pyridine-3-sulfonamide
#20
Prashantha Gunaga, John L Lloyd, Somanadham Mummadi, Abhisek Banerjee, Naveen Kumar Dhondi, James K Hennan, Veena Subray, Ramya Jayaram, Nagendra Rajugowda, Umamaheshwar Reddy, Duraimurugan Kumaraguru, Umasankar Mandal, Dasthagiri Beldona, Ashok Kumar Adisechan, Navnath Yadav, Jayakumar Warrier, James A Johnson, Harinath Sale, Siva Prasad Putlur, Ajay Saxena, Anjaneya Chimalakonda, Sandhya Mandlekar, Mary Lee Conder, Dezhi Xing, Arun Kumar Gupta, Anuradha Gupta, Richard A Rampulla, Arvind Mathur, Paul C Levesque, Ruth R Wexler, Heather J Finlay
We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels and an acceptable preclinical PK profile. On further characterization in vivo, Compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogs by employing hydrogen bond donors...
April 18, 2017: Journal of Medicinal Chemistry
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