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Clinical pharmacokinetics

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https://www.readbyqxmd.com/read/28110155/first-in-man-study-with-a-novel-pegylated-recombinant-human-insulin-like-growth-factor-i
#1
H Kletzl, A Guenther, A Höflich, C Höflich, J Frystyk, R F Staack, E Schick, C Wandel, N Bleich, F Metzger
OBJECTIVE: This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I. DESIGN: The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels...
January 10, 2017: Growth Hormone & IGF Research
https://www.readbyqxmd.com/read/28109702/population-pharmacokinetics-and-dose-optimisation-of-ritonavir-boosted-atazanavir-in-thai-hiv-infected-patients
#2
Baralee Punyawudho, Narukjaporn Thammajaruk, Kiat Ruxrungtham, Anchalee Avihingsanon
There is evidence that Thai patients receiving standard doses of ritonavir (RTV)-boosted atazanavir (ATV/r) have high exposure to atazanavir (ATV) leading to a higher risk of toxicity. A lower dose of ATV/r may provide adequate exposure in this population. However, pharmacokinetic data on ATV/r in Thai patients required for dose adjustment are limited. This study aimed to develop a population pharmacokinetic model of ATV/r and to determine the influence of patient characteristics on ATV pharmacokinetics. Monte Carlo simulations were performed to estimate the proportion of patients achieving target ATV trough concentration (Ctrough) with the standard ATV/r dose of 300/100 mg and a low dose of 200/100 mg once daily (OD)...
January 18, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28109060/morphine-pharmacodynamics-in-mechanically-ventilated-preterm-neonates-undergoing-endotracheal-suctioning
#3
P A Välitalo, Ehj Krekels, M van Dijk, Shp Simons, D Tibboel, Caj Knibbe
To date, morphine pharmacokinetics (PKs) are well quantified in neonates, but results about its efficacy are ambiguous. This work presents an analysis of a previously published study on pain measurements in mechanically ventilated preterm neonates who received either morphine or placebo to improve comfort during invasive ventilation. The research question was whether morphine reduces the pain associated with endotracheal or nasal suctioning before, during, and after suctioning. Because these neonates cannot verbalize their pain levels, pain was assessed on the basis of several validated pain measurement instruments (i...
January 21, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28108738/spect-and-pet-radiopharmaceuticals-for-molecular-imaging-of-apoptosis-from-bench-to-clinic
#4
Xiaobo Wang, Han Feng, Shichao Zhao, Junling Xu, Xinyu Wu, Jing Cui, Ying Zhang, Yuhua Qin, Zhiguo Liu, Tang Gao, Yongju Gao, Wenbin Zeng
Owing to the central role of apoptosis in many human diseases and the wide-spread application of apoptosis-based therapeutics, molecular imaging of apoptosis in clinical practice is of great interest for clinicians, and holds great promises. Based on the well-defined biochemical changes for apoptosis, a rich assortment of probes and approaches have been developed for molecular imaging of apoptosis with various imaging modalities. Among these imaging techniques, nuclear imaging (including single photon emission computed tomography and positron emission tomography) remains the premier clinical method owing to their high specificity and sensitivity...
January 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28108402/using-pharmacokinetic-modelling-to-improve-prescribing-practices-of-intravenous-aminophylline-in-childhood-asthma-exacerbations
#5
Lewis Cooney, Antonia McBride, Andrew Lilley, Ian Sinha, Trevor N Johnson, Daniel B Hawcutt
OBJECTIVE: To evaluate physiologically based pharmacokinetic modelling (PBPK) software in paediatric asthma patients using intravenous aminophylline. METHODS: Prospective clinical audit of children receiving iv aminophylline (July 2014 to June 2016), and in-silico modelling using Simcyp software. RESULTS: Thirty-eight admissions (25 children) were included. Children with aminophylline levels ≥10 mg/l had equivalent clinical outcomes compared to those <10 mg/L, and adverse effects occurred in 57%...
January 17, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28108364/from-natalizumab-to-fingolimod-in-eight-weeks-immunological-clinical-and-radiological-data-in-quest-of-the-optimal-switch
#6
Andrea Harrer, Georg Pilz, Katrin Oppermann, Marlene Sageder, Shahrzad Afazel, Elisabeth Haschke-Becher, Theo Rispens, Annick de Vries, Mark McCoy, Vlado Stevanovic, Wolfgang Hitzl, Eugen Trinka, Jörg Kraus, Johann Sellner, Peter Wipfler
Natalizumab (NZB) discontinuation during a treatment change is associated with recurrence of disease activity in a significant proportion of multiple sclerosis (MS) patients. The immunological basis why disease reactivation occurs in selected patients is unresolved. In search of a prognostic biomarker for a safe and effective transition from NZB to fingolimod, we monitored five parameters related to pharmacokinetic and pharmacodynamic effects of the two drugs in 12 MS patients until six months on fingolimod...
January 17, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28107923/a-sensitive-and-rapid-uflc-apci-ms-ms-bioanalytical-method-for-quantification-of-endogenous-and-exogenous-vitamin-k1-isomers-in-human-plasma-development-validation-and-first-application-to-a-pharmacokinetic-study
#7
Nagaraj Kumar Nannapaneni, Sunil S Jalalpure, Rajendraprasad Muppavarapu, Sunil Kumar Sirigiri
Due to lack of suitable bioanalytical methods in previous literature, for simultaneous estimation of Vitamin K1 isomers, in compliance with the current regulatory expectation, we aimed to develop a sensitive and rapid method with UFLC-APCI-MS/MS (ultrafast liquid chromatography - tandem mass spectrometry) using human plasma. A simple and cost effective procedure was implemented with the combination of protein precipitation and liquid extraction, to isolate the targets from plasma sample, while achieving an insignificant matrix effects and high recovery (≥88...
March 1, 2017: Talanta
https://www.readbyqxmd.com/read/28107561/beta-blockers-for-hypertension
#8
REVIEW
Charles S Wiysonge, Hazel A Bradley, Jimmy Volmink, Bongani M Mayosi, Lionel H Opie
BACKGROUND: Beta-blockers refer to a mixed group of drugs with diverse pharmacodynamic and pharmacokinetic properties. They have shown long-term beneficial effects on mortality and cardiovascular disease (CVD) when used in people with heart failure or acute myocardial infarction. Beta-blockers were thought to have similar beneficial effects when used as first-line therapy for hypertension. However, the benefit of beta-blockers as first-line therapy for hypertension without compelling indications is controversial...
January 20, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28106796/preparative-scale-resolution-of-enantiomers-enables-accelerated-drug-discovery-and-development
#9
Hanna Leek, Shalini Andersson
The provision of pure enantiomers is of increasing importance not only for the pharmaceutical industry but also for agro-chemistry and biotechnology. In drug discovery and development, the enantiomers of a chiral drug depict unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of the chiral drugs determines their pharmacokinetic, pharmacodynamic and toxicological properties. We present a number of challenging case studies of up-to-kilogram separations of racemic or enriched isomer mixtures using preparative liquid chromatography and super critical fluid chromatography to generate individual enantiomers that have enabled the development of new candidate drugs within AstraZeneca...
January 18, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28106709/systemic-pharmacokinetics-and-pharmacodynamics-of-intravitreal-aflibercept-bevacizumab-and-ranibizumab
#10
Robert L Avery, Alessandro A Castellarin, Nathan C Steinle, Dilsher S Dhoot, Dante J Pieramici, Robert See, Stephen Couvillion, Maʼan A Nasir, Melvin D Rabena, Mauricio Maia, Sherri Van Everen, Kha Le, William D Hanley
PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). METHODS: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2...
January 18, 2017: Retina
https://www.readbyqxmd.com/read/28106531/preclinical-characterization-of-the-novel-hcv-ns3-protease-inhibitor-gs-9256
#11
Huiling Yang, Chris Yang, Yujin Wang, Gerry Rhodes, Margaret Robinson, Guofeng Cheng, Xiaoping Qi, Hongmei Mo, Yang Tian, Rowchanak Pakdaman, X Christopher Sheng, Choung U Kim, William E Delaney
BACKGROUND: GS-9256 is an inhibitor of hepatitis C virus (HCV) NS3 protease with a macrocyclic structure and novel phosphinic acid pharmacophore. METHODS: Key preclinical properties of GS-9256 including in vitro antiviral activity, cross-resistance, and pharmacokinetic properties were investigated in non-human species. RESULTS: In genotype (GT) 1b Huh-luc cells with a replicon encoding luciferase, GS-9256 had a mean EC50 value of 20.0 nM, with minimal cytotoxicity...
January 20, 2017: Antiviral Therapy
https://www.readbyqxmd.com/read/28105598/clinical-pharmacokinetics-and-pharmacodynamics-of-dexmedetomidine
#12
REVIEW
Maud A S Weerink, Michel M R F Struys, Laura N Hannivoort, Clemens R M Barends, Anthony R Absalom, Pieter Colin
Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2-receptors with an α2:α1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug's peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2-receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative...
January 19, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28105286/discovery-of-a-potent-selective-and-orally-available-pi3k%C3%AE-inhibitor-for-the-treatment-of-inflammatory-diseases
#13
Montse Erra, Joan Taltavull, Angelique Gréco, Francisco Javier Bernal, Juan Francisco Caturla, Jordi Gràcia, María Domínguez, Mar Sabaté, Stéphane Paris, Salomé Soria, Begoña Hernández, Clara Armengol, Judit Cabedo, Mónica Bravo, Elena Calama, Montserrat Miralpeix, Martin D Lehner
The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105283/rational-design-of-a-boron-modified-triphenylethylene-gll398-as-an-oral-selective-estrogen-receptor-downregulator
#14
Jiawang Liu, Shilong Zheng, Shanchun Guo, Changde Zhang, Qiu Zhong, Qiang Zhang, Peng Ma, Elena V Skripnikova, Melyssa R Bratton, Thomas E Wiese, Guangdi Wang
Development of orally bioavailable nonsteroidal selective estrogen receptor downregulators (SERDs) provides clinical opportunities for the long-term treatment and adjuvant therapy of breast cancer at all stages. We describe the design, synthesis, and identification of a boron-modified GW7604 derivative (GLL398, 9), a SERD candidate, in which a boronic acid functional group replaces the phenolic hydroxyl group of GW7604. Compound 9 strongly binds to ERα in a fluorescence resonance energy transfer binding assay (IC50 = 1...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28104414/dissolution-failure-of-solid-oral-drug-products-in-field-alert-reports
#15
Dajun Sun, Meng Hu, Mark Browning, Rick L Friedman, Wenlei Jiang, Liang Zhao, Hong Wen
From 2005 to 2014, 370 data entries of dissolution failures of solid oral drug products were assessed with respect to the solubility of drug substances, dosage forms (immediate release (IR) vs. modified release (MR)), and manufacturers (brand-name vs. generic). The study results show that the solubility of drug substances does not play a significant role in dissolution failures; however, MR drug products fail dissolution tests more frequently than IR drug products. When multiple variables were analyzed simultaneously, poorly water-soluble IR drug products failed the most dissolution tests, followed by poorly soluble MR drug products and very soluble MR drug products...
January 16, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28104251/efficacy-safety-and-pharmacokinetics-of-natalizumab-in-japanese-multiple-sclerosis-patients-a-double-blind-randomized-controlled-trial-and-open-label-pharmacokinetic-study
#16
Takahiko Saida, Jun-Ichi Kira, Shuji Kishida, Takashi Yamamura, Yukiko Sudo, Kazutaka Ogiwara, J T Tibung, Nisha Lucas, Meena Subramanyam
BACKGROUND: Natalizumab, an anti-α4 integrin monoclonal antibody, has demonstrated efficacy in phase 2 and 3 studies of predominantly Caucasian patients with relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese RRMS patients. METHODS: This multicenter, phase 2 study included an open-label PK/PD study in 12 patients (part A) and a double-blind, placebo-controlled, randomized (computer-generated sequence) study in 94 patients (part B)...
January 2017: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/28104136/acute-calcineurin-inhibitor-nephrotoxicity-secondary-to-turmeric-intake-a-case-report
#17
A Nayeri, S Wu, E Adams, C Tanner, J Meshman, I Saini, W Reid
Tacrolimus, also known as FK-506, is a potent immunosuppressant agent with a host of drug-drug and food-drug interactions. We present the first case of a probable food-drug interaction between the herb turmeric and tacrolimus leading to acute calcineurin inhibitor nephrotoxicity. A 56-year-old man with a history of orthotopic liver transplantation presented to the emergency department from the clinic with worsening edema in the setting of an elevated creatinine level of 4.2 mg/dL. Before the current presentation, the patient had been recently discharged on a previously tolerated low-dose regimen of tacrolimus with a whole-blood tacrolimus level within the desired range...
January 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28102465/risks-and-benefits-of-phase-i-liver-dysfunction-studies-should-patients-with-severe-liver-dysfunction-be-included-in-these-trials
#18
Christos Fountzilas, Selena Stuart, Brian Hernandez, Elizabeth Bowhay-Carnes, Joel Michalek, John Sarantopoulos, Anand Karnad, Sukeshi Patel, Steven Weitman, Devalingam Mahalingam
Introduction The goal of organ dysfunction Phase I trials is to characterize the safety and pharmacokinetics of novel agents in cancer patients with liver or kidney dysfunction, but the clinical benefit is not well established. Methods We reviewed 170 patients across 15 liver dysfunction studies at our institution, grouped based on the NCI-Organ Dysfunction Working Group criteria or Child-Pugh Score. Results The median survival for the entire cohort was two months and just one month amongst patients with severe liver dysfunction...
January 19, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28101764/diazepam-in-the-treatment-of-moderate-to-severe-alcohol-withdrawal
#19
Steven J Weintraub
Benzodiazepines ameliorate or prevent the symptoms and complications of moderate to severe alcohol withdrawal, which can include autonomic hyperactivity, agitation, combativeness, hallucinations, seizures, delirium, and death. The benzodiazepines most commonly used for this purpose are lorazepam, chlordiazepoxide, oxazepam, and diazepam. It is widely asserted that no member of this group is superior to the others for treatment of alcohol withdrawal. However, of these, diazepam has the shortest time to peak effect, which facilitates both rapid control of symptoms and accurate titration to avoid over-sedation...
January 18, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28101651/eslicarbazepine-acetate-its-effectiveness-as-adjunctive-therapy-in-clinical-trials-and-open-studies
#20
REVIEW
S D Shorvon, E Trinka, B J Steinhoff, M Holtkamp, V Villanueva, J Peltola, E Ben-Menachem
Eslicarbazepine acetate (ESL) is a once-daily antiepileptic drug that is approved as adjunctive therapy in adults with focal-onset seizures. Following oral administration, ESL is rapidly metabolized to its active metabolite, eslicarbazepine, which acts primarily by enhancing slow inactivation of voltage-gated sodium channels. The efficacy and safety/tolerability of ESL in the adjunctive setting were established in a comprehensive Phase III program (n = 1702 randomized patients) and this evidence has been supported by several open studies (n = 864)...
January 18, 2017: Journal of Neurology
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