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https://www.readbyqxmd.com/read/28437278/pharmacodynamic-and-kinetic-behavior-of-low-intermediate-and-high-dose-landiolol-during-long-term-infusion-in-caucasians
#1
Günther Krumpl, Ivan Ulč, Michaela Trebs, Pavla Kadlecová, Juri Hodisch, Gabriele Maurer, Bernhard Husch
PK, PD, safety, and tolerability of long-term administration of landiolol, a fast-acting cardioselective β-blocker, were investigated for the first time in Caucasian subjects in a prospective clinical trial.Blood concentrations of landiolol and its metabolites, HR, BP and ECG parameters were studied in twelve healthy volunteers receiving continuous infusions of a new 12 mg/mL formulation of landiolol using a dose-escalation regimen (10 µg/kg BW/min for 2 hr, 20 µg/kg BW/min for 2 hr, 40 µg/kg BW/min for 20 hr, 6 hr follow-up)...
April 18, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28416614/modeling-combined-immunosuppressive-and-anti-inflammatory-effects-of-dexamethasone-and-naproxen-in-rats-predicts-the-steroid-sparing-potential-of-naproxen
#2
Xiaonan Li, Debra C DuBois, Dawei Song, Richard R Almon, William J Jusko, Xijing Chen
Dexamethasone (DEX), a widely prescribed corticosteroid (CS), has long been the cornerstone for the treatment of inflammation and immunological dysfunctions in Rheumatoid Arthritis (RA). The CS are frequently used in combination with other anti-rheumatic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) to mitigate disease symptoms and minimize unwanted effects. The steroid dose-sparing potential of the NSAID naproxen (NPX) was explored with in vitro and in vivo studies...
April 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28416552/in-vivo-pharmacodynamic-target-assessment-of-eravacycline-against-escherichia-coli-in-a-murine-thigh-infection-model
#3
Miao Zhao, Alexander J Lepak, Karen Marchillo, Jamie VanHecker, David R Andes
Eravacycline is a novel fluorocycline antibiotic with potent activity against a broad range of pathogens, including strains with tetracycline and other drug-resistance phenotypes. The goal of the studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy in the murine thigh infection model. Six E. coli were utilized for the studies. MICs were determined using CLSI methods and ranged from 0.125 to 0.25 mg/L. A neutropenic murine thigh infection model was utilized for all treatment studies...
April 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28414146/tissue-distribution-of-a-therapeutic-monoclonal-antibody-determined-by-large-pore-microdialysis
#4
Satyawan B Jadhav, Vipada Khaowroongrueng, Matthias Fueth, Michael B Otteneder, Wolfgang Richter, Hartmut Derendorf
Therapeutic monoclonal antibodies (mAbs) exhibit limited distribution to the target tissues. Determination of target tissue interstitial concentration of mAbs is an important aspect in the assessment of their pharmacokinetic/pharmacodynamics (PK/PD) relationship especially for mAbs targeting membrane bound receptors. The pharmacokinetics of R7072, a full length mAb (IgG) targeting human insulin like growth factor-1 receptor (IGF-1R) was evaluated following a single intravenous (IV) dose at 1, 6.25 and 25 mg/kg in healthy female SCID-beige mice...
April 13, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28409203/the-role-of-infection-models-and-pk-pd-modelling-for-optimising-care-of-critically-ill-patients-with-severe-infections
#5
REVIEW
T Tängdén, V Ramos Martín, T W Felton, E I Nielsen, S Marchand, R J Brüggemann, J B Bulitta, M Bassetti, U Theuretzbacher, B T Tsuji, D W Wareham, L E Friberg, J J De Waele, V H Tam, Jason A Roberts
Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens...
April 13, 2017: Intensive Care Medicine
https://www.readbyqxmd.com/read/28407419/antibiotic-treatment-of-biofilm-infections
#6
REVIEW
Oana Ciofu, Estrella Rojo-Molinero, María D Macià, Antonio Oliver
Bacterial biofilms are associated with a wide range of infections, from those related to exogenous devices, such as catheters or prosthetic joints, to chronic tissue infections such as those occurring in the lungs of cystic fibrosis patients. Biofilms are recalcitrant to antibiotic treatment due to multiple tolerance mechanisms (phenotypic resistance). This causes persistence of biofilm infections in spite of antibiotic exposure which predisposes to antibiotic resistance development (genetic resistance). Understanding the interplay between phenotypic and genetic resistance mechanisms acting on biofilms, as well as appreciating the diversity of environmental conditions of biofilm infections which influence the effect of antibiotics are required in order to optimize the antibiotic treatment of biofilm infections...
April 2017: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
https://www.readbyqxmd.com/read/28401480/target-mediated-drug-disposition-pharmacokinetic-pharmacodynamic-model-of-bosentan-and-endothelin-1
#7
Anke-Katrin Volz, Andreas Krause, Walter Emil Haefeli, Jasper Dingemanse, Thorsten Lehr
BACKGROUND AND OBJECTIVES: Bosentan is a competitive antagonist on endothelin receptor A and B (ETA and ETB), displacing the endogenous binding partner endothelin-1 (ET-1) from its binding sites. After administration of escalating single doses of 10-750 mg as an intravenous (i.v.) infusion, bosentan showed dose-dependent pharmacokinetics (PK). The aim of this analysis was to develop a PK model of bosentan after i.v. administration including competitive antagonism with ET-1 and to analyze its influence on blood pressure and heart rate with a combined pharmacokinetic/pharmacodynamic (PK/PD) model...
April 11, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28396549/in-vivo-pharmacokinetics-and-pharmacodynamics-of-zti-01-fosfomycin-for-injection-in-the-neutropenic-murine-thigh-infection-model-against-e-coli-k-pneumoniae-and-p-aeruginosa
#8
Alexander J Lepak, Miao Zhao, Brian VanScoy, Daniel S Taylor, Evelyn Ellis-Grosse, Paul G Ambrose, David R Andes
Fosfomycin is a broad-spectrum agent with activity against gram-positive and gram-negative bacteria, including drug-resistant strains, such as extended spectrum beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 E. coli (EC), 3 K. pneumoniae (KPN), and 2 P. aeruginosa (PSA) strains, including a subset with ESBL and CR phenotype...
April 10, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28382498/assessing-the-relative-potency-of-s-and-r-warfarin-with-a-new-pk-pd-model-in-relation-to-vkorc1-genotypes
#9
Myriam Ferrari, Vittorio Pengo, Massimiliano Barolo, Fabrizio Bezzo, Roberto Padrini
PURPOSE: The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin. METHODS: Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60 h after the first dose and at steady state 12-14 h after dosing...
April 5, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28378945/translational-pharmacometric-evaluation-of-typical-antibiotic-broad-spectrum-combination-therapies-against-staphylococcus-aureus-exploiting-in-vitro-information
#10
Sebastian G Wicha, Wilhelm Huisinga, Charlotte Kloft
Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid or vancomycin combined with meropenem against Staphylococcus aureus as the most frequent causative pathogen of severe infections. A semi-mechanistic PK-PD model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of linezolid, vancomycin and meropenem alone and in dual combinations...
April 5, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28378544/effects-of-cyp2c19-genetic-polymorphisms-on-pk-pd-responses-of-omeprazole-in-korean-healthy-volunteers
#11
Sunny Park, Yang Jin Hyun, Yu Ran Kim, Ju Hyun Lee, Sunae Ryu, Jeong Mi Kim, Woo Yong Oh, Han Sung Na, Jong Gu Lee, Doo Won Seo, In Yeong Hwang, Zewon Park, In Jin Jang, Jaeseong Oh, Seung Eun Choi
The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS)...
May 2017: Journal of Korean Medical Science
https://www.readbyqxmd.com/read/28374319/application-of-a-pk-pd-modeling-and-simulation-based-strategy-for-clinical-translation-of-antibody-drug-conjugates-a-case-study-with-trastuzumab-emtansine-t-dm1
#12
Aman P Singh, Dhaval K Shah
Successful clinical translation of antibody-drug conjugates (ADCs) can be challenging due to complex pharmacokinetics and differences between preclinical and clinical tumors. To facilitate this translation, we have developed a general pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation (M&S)-based strategy for ADCs. Here we present the validation of this strategy using T-DM1 as a case study. A previously developed preclinical tumor disposition model for T-DM1 (Singh and Shah, AAPSJ. 2015; 18(4):861-875) was used to develop a PK-PD model that can characterize in vivo efficacy of T-DM1 in preclinical tumor models...
April 3, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28371693/pharmacokinetic-pharmacodynamic-modeling-of-benazepril-and-benazeprilat-after-administration-of-intravenous-and-oral-doses-of-benazepril-in-healthy-horses
#13
Juan Manuel Serrano-Rodríguez, Manuel Gómez-Díez, María Esgueva, Cristina Castejón-Riber, Antonio Mena-Bravo, Feliciano Priego-Capote, Nahúm Ayala, Juan Manuel Serrano Caballero, Ana Muñoz
Pharmacokinetic and pharmacodynamic (PK/PD) properties of the angiotensin-converting enzyme inhibitor (ACEI) benazeprilat have not been evaluated in horses. This study was designed to establish PK profiles for benazepril and benazeprilat after intravenous (IV) and oral (PO) administration of benazepril using a PK/PD model. This study also aims to determine the effects of benazeprilat on serum angiotensin converting enzyme (ACE), selecting the most appropriate dose that suppresses ACE activity. Six healthy horses in a crossover design received IV benazepril at 0...
March 28, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28363695/in-vitro-anaerobic-pharmacokinetic-pharmacodynamic-model-to-simulate-the-bactericidal-activity-of-levornidazole-against-bacteroides-fragilis
#14
Jiali Hu, Jing Zhang, Yuancheng Chen, Wang Liang, Shi Wu
PURPOSE: This study was designed to correlate the pharmacokinetic/pharmacodynamic (PK/PD) parameters with PD indices of levornidazole against Bacteroides fragilis and to calculate the PK/PD target value for levornidazole to attain its expected maximal bactericidal effect using an in vitro anaerobic dynamic PK/PD model. METHODS: An anaerobic dynamic PK/PD model was developed in vitro. The scheme for PK modeling was designed according to the PK parameters of levornidazole in the human body...
March 28, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28356552/pharmacokinetic-pharmacodynamic-modelling-of-intracellular-mycobacterium-tuberculosis-growth-and-kill-rates-is-predictive-of-clinical-treatment-duration
#15
Ghaith Aljayyoussi, Victoria A Jenkins, Raman Sharma, Alison Ardrey, Samantha Donnellan, Stephen A Ward, Giancarlo A Biagini
Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages...
March 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28353185/pk-pd-compass-bringing-infectious-diseases-pharmacometrics-to-the-patient-s-bedside
#16
Catharine C Bulik, Justin C Bader, Li Zhang, Scott A Van Wart, Christopher M Rubino, Sujata M Bhavnani, Kim L Sweeney, Paul G Ambrose
Antimicrobial stewardship programs face many challenges, one of which is a lack of guidance regarding antimicrobial dose, interval, and duration. There is no tool that considers patient demographic, pathogen susceptibility, and pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy in order to evaluate appropriate antimicrobial dosing regimens. The PK-PD Compass, an educational mobile application, was developed to address this unmet need. The application consists of a Monte Carlo simulation algorithm which integrates pharmacokinetic (PK) and PK-PD data, patient-specific characteristics, and pathogen susceptibility data...
April 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28339766/higher-bioavailability-of-doxycycline-in-broiler-chickens-with-a-novel-in-feed-pharmaceutical-formulation
#17
Lilia Gutiérrez, Juan Zermeño, Yazmín Alcalá, Héctor Sumano
Bioavailability of a new, long-acting (LA) pharmaceutical preparation for administering doxycycline as in-feed medication to broiler chickens was compared to the standard in-feed administration of doxycycline. A commercial poultry house harboring Ross-308 broiler chickens, weighing 450 g, was divided into 7 sections as follows: doxy-FOLA group (n = 6,000 chickens divided into 3 replicates) medicated with 10% doxycyline, long-acting pellets at a dose of 400 g of doxycycline HCl/ton of food, resulting in a calculated dose of 48 mg/kg for 5 d; doxy-ref group (n = 6,000, divided into 3 replicates) medicated as for doxy-FOLA, but using a 20% commercial preparation of doxycycline...
February 23, 2017: Poultry Science
https://www.readbyqxmd.com/read/28327200/a-first-in-human-phase-1-study-of-a-hepcidin-monoclonal-antibody-ly2787106-in-cancer-associated-anemia
#18
Saroj Vadhan-Raj, Rafat Abonour, Jonathan W Goldman, David A Smith, Christopher A Slapak, Robert L Ilaria, Ramon V Tiu, Xuejing Wang, Sophie Callies, Joanne Cox, Jay L Tuttle, Yiu-Keung Lau, Eric J Roeland
BACKGROUND: Hepcidin plays a central role in iron homeostasis and erythropoiesis. Neutralizing hepcidin with a monoclonal antibody (mAb) may prevent ferroportin internalization, restore iron efflux from cells, and allow transferrin-mediated iron transport to the bone marrow. This multicenter, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of a fully humanized mAb (LY2787106) with high affinity for hepcidin in cancer patients with anemia...
March 21, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28323965/long-acting-ctp-modified-hgh-mod-4023-results-of-a-safety-and-dose-finding-study-in-ghd-children
#19
Nataliya Zelinska, Violeta Iotova, Julia Skorodok, Oleg Malievsky, Valentina Peterkova, Lubov Samsonova, Ron G Rosenfeld, Zvi Zadik, Michal Jaron-Mendelson, Ronit Koren, Leanne Amitzi, Dmitri Raduk, Oren Hershkovitz, Gili Hart
Context: Daily injections are required for growth hormone replacement therapy, which may cause low compliance as a result of inconvenience and distress in patients. Objective: CTP-modified human growth hormone (MOD-4023) is developed for once-a-week dosing regimen in GH-deficient (GHD) adults and children. The present trial was a safety and dose-finding study for weekly MOD-4023 in GHD children. Design: a multi-center, open-label, randomized, controlled Phase 2 study in children with GHD, evaluating the safety, tolerability, PK/PD and efficacy of 3 different weekly MOD-4023 doses, compared to daily r-hGH...
January 31, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28294376/influence-of-the-pharmacokinetic-profile-on-the-plasma-glucose-lowering-effect-of-ppar%C3%AE-agonist-pioglitazone-in-wistar-fatty-rats
#20
Akihiko Goto, Yoshihiko Tagawa, Yoshiaki Kimura, Akifumi Kogame, Yuu Moriya, Nobuyuki Amano
Although the mechanism of action for peroxisome proliferator-activated receptor gamma (PPARγ) agonists has been extensively explored, the impact of the pharmacokinetic (PK) profile on the pharmacodynamic (PD) effects of PPARγ agonists has not been elucidated in detail. We evaluated the importance of the PK profile of PPARγ agonist for its PD effect based on population PK/PD analysis. Pioglitazone hydrochloride, the PPARγ agonist, was administered orally to Wistar fatty rats once a day (qd) or once every other day (q2d) as double the amount for the qd treatment...
March 11, 2017: Biopharmaceutics & Drug Disposition
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