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Clinical pharmacokinetics

Ruo Wang, Xueyang Yin, Yaohuan Zhang, Weitao Yan
Twelve novel propylene-tethered ciprofloxacin-isatin hybrids 3a-f and 4a-f were designed, synthesized and characterized by MS, HRMS, 1 H NMR and 13 C NMR. All hybrids were evaluated for their in vitro antimicrobial activities against representative Gram-positive, Gram-negative and mycobacterial pathogens, cytotoxicity in VERO cell line as well as metabolic stability and in vivo pharmacokinetic (PK) properties. The preliminary results indicated that all mono-isatin-ciprofloxacin hybrids exhibited excellent antibacterial activities with MIC ranging from ≤0...
July 16, 2018: European Journal of Medicinal Chemistry
Barbara Błaszczyk, Barbara Miziak, Piotr Czuczwar, Ewa Wierzchowska-Cioch, Ryszard Pluta, Stanisław J Czuczwar
Considering that there are around 30% of patients with epilepsy resistant to monotherapy, the use of synergistic combinations of antiepileptic drugs is of particular importance. This review shows most beneficial as well as irrational combined treatments both from an experimental and clinical point of view. Areas covered: Preferably, experimental data derived from studies evaluating synergy, additivity or antagonism by relevant methods, in terms of anticonvulsant or neurotoxic effects and pharmacokinetic data have been considered...
July 19, 2018: Expert Review of Clinical Pharmacology
Zhipeng Zeng, Pengfei Zhao, Lixin Liu, Xiaohu Gao, Hai-Quan Mao, Yongming Chen
Nanoparticle-based chemotherapeutics have gained widespread interest in medicine due to their tunable pharmacokinetics and pharmacodynamics. Various drug delivery vehicles have been developed including polymer, liposome nanoparticles, and some of them have already made clinical impacts. Despite these ad-vances, drug payload of these formulations is limited (typically < 10%). Here, we report a general and scalable approach to prepare lipid-coated solid drug nanoparticles by combining flash nanoprecipitation and extrusion technique, which enables optimization of individual steps separately and flexibility in selec-tion of nanoparticle surface functionalities...
July 19, 2018: ACS Applied Materials & Interfaces
Stefanie Felicitas Färber, Alexander Wurzer, Florian Reichart, Roswitha Beck, Horst Kessler, Hans-Jürgen Wester, Johannes Notni
The epithelial integrin αvβ6 is expressed by many malignant carcinoma cell types, including pancreatic cancer, and thus represents a promising target for radionuclide therapy. The peptide cyclo(FRGDLAFp( N Me)K) was decorated with different chelators (DOTPI, DOTAGA, and DOTA). The Lu(III) complexes of these conjugates exhibited comparable αvβ6 integrin affinities (IC50 ranging from 0.3 to 0.8 nM) and good selectivities against other integrins (IC50 for αvβ8 >43 nM; for α5β1 >238 nM; and for αvβ3, αvβ5, and αIIbβ3 >1000 nM)...
February 28, 2018: ACS Omega
Alan R Noel, Karen E Bowker, Marie Attwood, Alasdair P MacGowan
Objectives: To use a pre-clinical infection model to assess the antibacterial effect of human simulations of dosing with ceftolozane/tazobactam (with or without amikacin) or meropenem against Enterobacteriaceae and Pseudomonas aeruginosa. Methods: An in vitro pharmacokinetic model was used to assess changes in bacterial load and profiles after exposure to mean human serum concentrations over 168 h. Changes in area under the bacterial kill curve (AUBKC; log cfu/mL·h) and growth on 4 × MIC recovery plates were the co-primary outcome measures...
July 17, 2018: Journal of Antimicrobial Chemotherapy
Hugo Geerts, Ronald Gieschke, Richard Peck
The success rate of pharmaceutical Research & Development (R&D) is much lower compared to other industries such as micro-electronics or aeronautics with the probability of a successful clinical development to approval In Central Nervous Systems (CNS) disorders hovering in the single digits (7%). Areas Covered. Inspired by adjacent engineering-based industries, we argue that quantitative modeling in CNS R&D might improve success rates. We will focus on quantitative techniques in early clinical development, such as PharmacoKinetic-PharmacoDynamic modeling, Clinical Trial Simulation, Model-based meta-analysis and the mechanism-based Physiology-based Pharmacokinetic Modeling and Quantitative Systems Pharmacology...
July 18, 2018: Expert Review of Clinical Pharmacology
Sharjeel Usmani, Tim Van den Wyngaert, Najeeb Ahmed, Fahad Marafi, Abdulredha Esmail, Fareeda Al Kandari, Mishari Al Nuaimi, Gopinath Gnanasegaran
PURPOSE: The role of 18 F-fluoride (18 F-NaF) PET-CT for the detection of bone metastases in adults is well established and is considered superior to conventional bone scintigraphy. However, data pertaining use of 18 F-NaF PET-CT in pediatric oncology is relatively sparse. The aim of the present study is to retrospectively analyze and share a single-center experience of 18 F-NaF PET-CT in pediatric population and to provide preliminary information regarding imaging technique, feasibility of this modality in young patients and radiation dosimetry measurements in pediatric oncology cases...
July 17, 2018: Annals of Nuclear Medicine
Can Hu, Wen-Jun Yin, Dai-Yang Li, Jun-Jie Ding, Ling-Yun Zhou, Jiang-Lin Wang, Rong-Rong Ma, Kun Liu, Ge Zhou, Xiao-Cong Zuo
PURPOSE: Numerous studies have been conducted on the population pharmacokinetics of tacrolimus in adult renal transplant recipients. It has been reported that the cytochrome P450 (CYP) 3A5 genotype is an important cause of variability in tacrolimus pharmacokinetics. However, the predictive performance of population pharmacokinetic (PK) models of tacrolimus should be evaluated prior to their implementation in clinical practice. The aim of the study reported here was to test the predictive performance of these published PK models of tacrolimus...
July 17, 2018: European Journal of Clinical Pharmacology
Marko M Sahinovic, Michel M R F Struys, Anthony R Absalom
Propofol is an intravenous hypnotic drug that is used for induction and maintenance of sedation and general anaesthesia. It exerts its effects through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABAA receptor, and has gained widespread use due to its favourable drug effect profile. The main adverse effects are disturbances in cardiopulmonary physiology. Due to its narrow therapeutic margin, propofol should only be administered by practitioners trained and experienced in providing general anaesthesia...
July 18, 2018: Clinical Pharmacokinetics
Katherine Elizabeth Warren
Over the past decade, we have made considerable progress in establishing diffuse intrinsic pontine glioma (DIPG) as a disease entity and developing preclinical tools to interrogate potential therapeutics. However, translation to improved clinical outcomes in children with DIPG has not yet been realized. This is in part due to difficulties encountered in delivering active drugs adequately to the tumor site. However, most preclinical evaluations gloss over the fundamental concepts of central nervous system (CNS) pharmacokinetics and requirements needed to optimize drug delivery and exposure and translate this into efficacious therapy...
2018: Frontiers in Oncology
Walter Fiedler, Herbert Stoeger, Antonella Perotti, Guenther Gastl, Jens Weidmann, Bruno Dietrich, Hans Baumeister, Antje Danielczyk, Steffen Goletz, Marc Salzberg, Sara De Dosso
Purpose: TrasGEX is a second-generation monoclonal antibody of trastuzumab, glyco-optimised to enhance antibody-dependent cellular cytotoxicity while fully retaining trastuzumab's antigen-binding properties to human epidermal growth factor receptor 2 (HER2). A phase I dose-escalation study was conducted to establish the optimal TrasGEX dose and regimen for phase II studies and to define the safety, pharmacokinetics (PK) and preliminary antitumour activity of TrasGEX. Patients and methods: A total of 37 patients with advanced HER2-positive carcinomas and progressive disease received TrasGEX intravenously every 3 weeks until disease progression in doses of 12-720 mg in a three-plus-three dose escalation design, including an expansion cohort at the highest dose...
2018: ESMO Open
Natalia Cullell, Caty Carrera, Elena Muiño, Nuria Torres, Jerzy Krupinski, Israel Fernandez-Cadenas
Oral anticoagulants (OAs) are the recommended drugs to prevent cardiovascular events and recurrence in patients with atrial fibrillation (AF) and cardioembolic stroke. We conducted a literature search to review the current state of OAs pharmacogenomics, focusing on Genome Wide Association Studies (GWAs) in patients treated with vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). VKAs: Warfarin, acenocoumarol, fluindione and phenprocoumon have long been used, but their interindividual variability and narrow therapeutic/safety ratio makes their dosage difficult...
June 26, 2018: Oncotarget
Nan Li, Lingling Feng, Yujun Tan, Yan Xiang, Ruoqi Zhang, Ming Yang
The dry root of Scutellaria baicalensis , has traditionally been applied in the treatment of cerebral ischemia in Chinese clinics. Baicalin (BA) is considered the key ingredient in it for the brain protection effects. The bioavailability of BA is very low because of its poor lipid and water solubility, which limits the therapeutic effects and clinical application. The aim of the present study was to develop a novel BA-loaded liposome (BA-LP) formulation to improve the drug lipophilicity and further to enhance the drug-concentration in the brain tissues...
July 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Ginah Nightingale, Rowena Schwartz, Ekaterina Kachur, Brianne N Dixon, Christine Cote, Ashley Barlow, Brooke Barlow, Patrick Medina
Unique challenges exist when managing older adults with cancer. Associations between cancer and age-related physiologic changes have a direct impact on pharmacokinetics and pharmacodynamics of cancer therapies and can affect drug dosing, dose intensity, efficacy, safety and quality of life. The breadth and depth of these issues, however, have not been fully evaluated because the majority of clinical trials have focused on a younger and healthier population. As a consequence, little information is available to support clinicians in making evidence-based decisions regarding treatment with cancer therapies in older adults, especially those over age 75...
July 12, 2018: Journal of Geriatric Oncology
Wei Wei, Cong Luo, Jincheng Yang, Bingjun Sun, Dongyang Zhao, Yan Liu, Yingli Wang, Wenqian Yang, Qiming Kan, Jin Sun, Zhonggui He
The anticancer efficacy of chemotherapy is greatly limited by short blood circulation and poor tumor selectivity. Thus, anticancer prodrugs with prolonged systemic circulation, tumor-specific distribution and bioactivation, could significantly strengthen the chemotherapy efficacy. Herein, we design two novel tumor cell reduction/oxidation-responsive docetaxel (DTX) prodrugs, DTX-maleimide conjugates with disulfide bond (DSSM) or thioether bond (DSM) linkages, to evaluate the roles of different sensitive linkages in drug release, pharmacokinetics and therapeutic efficacy...
July 12, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Cheng-Zi Zuo, Yi Gong, Xiang-Yu Hou, Yi-Fan Zhang, Wen-Xing Peng, Rong-Hua Zhu, Da-Fang Zhong, Xiao-Yan Chen
PURPOSE: Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co-administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib's pharmacokinetic (PK) parameters. METHODS: In this single-center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22...
July 13, 2018: Clinical Therapeutics
Nicholas Z Kerin
The pharmacologic treatment of arrhythmias has seen little advance over the past few years. Physicians treating life threatening or hemodynamically destabilizing arrhythmias depend almost entirely on intravenous (IV) amiodarone. This is regrettable due to the multiple toxicities of amiodarone and its long half-life. Once administered, it is a therapeutic commitment to long-term therapy. Given the very long terminal elimination half-life, treatment with amiodarone may interfere with baseline electrophysiologic studies and ablation procedures...
July 17, 2018: Cardiology
Ada W Y Leung, Malathi Anantha, Wieslawa H Dragowska, Mohamed Wehbe, Marcel B Bally
CX-5461 is currently in Phase I/II clinical trials for advanced hematologic malignancies and triple negative or BRCA-deficient breast cancer. The compound is currently administered to patients intravenously (i.v.) at low pH (3.5) due to solubility challenges. Reliance of low pH to enhance solubility of CX-5461 can adversely impact pharmacokinetics, biodistribution and therapeutic potential. We have addressed this solubility issue through a formulation method that relies on the interactions between CX-5461 and copper...
July 14, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Michael R Savona, Kathryn Kolibaba, Paul Conkling, Edwin C Kingsley, Carlos Becerra, John C Morris, Robert M Rifkin, Eric Laille, Amy Kellerman, Stacey M Ukrainskyj, Qian Dong, Barry S Skikne
CC-486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC-486 dosing included patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n=18, CMML n=4, and AML n=9) entered a clinical phase in which they received CC-486 300 mg once-daily for 21 days of repeated 28-day cycles. Median age was 71 years (range: 53-93); 42% of patients were aged ≥75 years...
July 17, 2018: American Journal of Hematology
Mei Zhang, Grant A Moore, Paul Kl Chin, Richard Everts, Evan J Begg
BACKGROUND: Pharmacokinetic studies and therapeutic drug monitoring (TDM) of antibiotics require a simple, rapid and reliable analytical method for monitoring the concentrations in plasma, including unbound concentrations for highly protein-bound drugs. The aim of the current work was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of total and unbound concentrations of three widely used β-lactam antibiotics (cefalexin, cefazolin and flucloxacillin) and the often co-administered drug probenecid in human plasma, suitable for pharmacokinetic studies and for routine use in ordinary, busy hospital laboratories...
July 10, 2018: Therapeutic Drug Monitoring
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