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Pulmonary pharmacokinetics

Y Liu, L Huang, H Ye, X Lv
Interferon regulatory factor-7 (IRF-7) is involved in pulmonary infection and pneumonia. Here, a synthetic strategy that combined quantitative structure-activity relationship (QSAR)-based virtual screening and in vitro binding assay was described to identify new and potent mediator ligands of IRF-7 from natural products. In the procedure, a QSAR scoring function was developed and validated using Gaussian process (GP) regression and a structure-based set of protein-ligand affinity data. By integrating hotspot pocket prediction, pharmacokinetics profile analysis and molecular docking calculations, the scoring function was successfully applied to virtual screening against a large library of structurally diverse, drug-like natural products...
October 20, 2016: SAR and QSAR in Environmental Research
Mayank Sardana, Matthew Moll, Harrison W Farber
Management of pulmonary arterial hypertension (PAH) remains challenging even in the contemporary era. Intravenous prostacyclin therapy, while associated with decreased mortality, has practical limitations and requires significant lifestyle modifications. The recently approved long-acting oral IP prostacyclin receptor agonist for treatment of PAH, selexipag, is a non-prostanoid agent that vasodilates, impacts remodeling (anti-proliferative), reduces endothelial cell dysfunction, inhibits platelet aggregation (anti-thrombotic), and increases right heart inotropy...
October 19, 2016: Expert Opinion on Drug Metabolism & Toxicology
Christina Binder, Caroline Zotter-Tufaro, Diana Bonderman
The development of pulmonary hypertension (PH) has multifactorial underlying pathophysiological causes and can be classified into five groups. While three different classes of therapeutic drugs are licensed for the treatment of pulmonary arterial hypertension (PAH, WHO group 1), specific medical therapies are lacking for other forms of PH, such as PH due to left heart disease. In 2013 riociguat, a first-in class soluble guanylate cyclase stimulator, has also become available for the treatment of PAH. Riociguat was further introduced as the first approved pharmacotherapy for the treatment of patients with chronic thromboembolic PH (WHO group 4, CTEPH)...
October 18, 2016: Expert Opinion on Drug Safety
Thomas Ebenhan, Isabel Schoeman, Daniel D Rossouw, Anne Grobler, Biljana Marjanovic-Painter, Judith Wagener, Hendrik G Kruger, Mike M Sathekge, Jan Rijn Zeevaart
PURPOSE: Radiopharmaceuticals containing the motive tripeptide arginyl-glycyl-asparatic acid (RGD) are known to target ανβ3 integrins during tumor angiogenesis. A more generic kit radiolabeling procedure accommodating Ga-68 from different generators was developed for NOTA-RGD and evaluated for its versatile use and safety in subsequent in vivo applications. The [(68)Ga]NOTA-RGD kit was further verified for its expected biodistribution and pharmacokinetics in nonhuman primates and its clinical sensitivity to detect solitary pulmonary nodules (SPN) in cancer patients...
October 14, 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Abrar K Thabit, Jared L Crandon, David P Nicolau
Increasing antimicrobial resistance in community-acquired pneumonia (CAP) pathogens has contributed to infection-related morbidity and mortality. Delafloxacin is a novel fluoroquinolone with broad-spectrum activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to define the pharmacodynamic profile of delafloxacin against CAP pathogens using a neutropenic murine lung infection model. Five S. pneumoniae, 2 methicillin-susceptible S...
September 29, 2016: International Journal of Antimicrobial Agents
Per Bäckman, Ulrika Tehler, Bo Olsson
BACKGROUND: Exposure following oral inhalation depends on the deposition pattern of the inhaled aerosol, the extent and rate of oral and pulmonary absorption, as well as systemic distribution and clearance. For lipophilic inhaled compounds with low water solubility and high permeability, the extent and rate of pulmonary absorption can be assumed dependent on deposition pattern as well as dissolution rate. MATERIALS AND METHODS: A mechanistic model of airway deposition, mucociliary clearance, dissolution, absorption, and dissipation was applied to simulate systemic exposure of the novel selective glucocorticoid receptor modulator, AZD5423, when dosed to healthy volunteers using two different nebulizers and two different dry powder inhalers in combination with two different primary particle size distributions...
October 14, 2016: Journal of Aerosol Medicine and Pulmonary Drug Delivery
Raktim Kumar Ghosh, Kinjal Banerjee, Ramyashree Tummala, Somedeb Ball, Keyvan Ravakhah, Anjan Gupta
Heart failure continues to be a widely prevalent disease across the world, affecting millions of Americans annually. Acute heart failure (AHF) has a substantial effect on rising health care costs and one of the major causes of morbidity and mortality. The search for new drugs for symptom relief and to improve long term outcomes in heart failure has led to development of serelaxin, a recombinant human relaxin-2 hormone. Relaxin was discovered in pregnancy but eventually found to have a number of other physiological actions, not only in pregnancy, but also in non-pregnant women and men...
October 11, 2016: Cardiovascular Therapeutics
Ronald Dahl, Alan Kaplan
BACKGROUND: In many countries worldwide, the long-acting anticholinergic drug tiotropium is available as a dry powder formulation delivered by means of the HandiHaler® inhalation device and as an aqueous solution delivered via the Respimat® Soft Mist™ Inhaler. Tiotropium HandiHaler® is a single-dose, dry powder, breath-actuated inhaler that provides delivered doses and lung deposition of tiotropium that are, over a wide range, not influenced by the severity of chronic obstructive pulmonary disease (COPD)...
October 11, 2016: BMC Pulmonary Medicine
S Giguère, A J Burton, L J Berghaus, A D Haspel
The objective of this study was to compare the pharmacokinetics of minocycline in foals vs. adult horses. Minocycline was administered to six healthy 6- to 9-week-old foals and six adult horses at a dose of 4 mg/kg intragastrically (IG) and 2 mg/kg intravenously (i.v.) in a cross-over design. Five additional oral doses were administered at 12-h intervals in foals. A microbiologic assay was used to measure minocycline concentration in plasma, urine, synovial fluid, and cerebrospinal fluid (CSF). Liquid chromatography-tandem mass spectrometry was used to measure minocycline concentrations in pulmonary epithelial lining fluid (PELF) and bronchoalveolar (BAL) cells...
September 29, 2016: Journal of Veterinary Pharmacology and Therapeutics
Raktim K Ghosh, Somedeb Ball, Avash Das, Dhrubajyoti Bandyopadhyay, Samhati Mondal, Debjit Saha, Anjan Gupta
Pulmonary arterial hypertension (PAH) is a relatively rare disease which due to its chronic nature has always been difficult to treat effectively. Selexipag is an oral prostacyclin (PGI2) agonist, which was approved by US Food and Drug Administration (US FDA) in December 2015 for the treatment of PAH. After its success in Phase 1 and Phase 2 clinical trials regarding the convenient oral twice daily dosing and low side-effect profile, selexipag raised the hope of controlling the disease progression in PAH patients...
September 27, 2016: Journal of Clinical Pharmacology
Sara I Ruiz, Nashwa El-Gendy, Larry E Bowen, Cory Berkland, Mark M Bailey
Melioidosis is an infectious disease caused by Burkholderia pseudomallei. The disease is responsible for a high proportion of human pneumonia and fatal bacteremia in the endemic areas of the world and is highly resistant to most commonly available antibiotics. Studies have shown that prophylactic antibiotic treatment, when administered 24 h following bacterial challenge, can prevent infection in a murine model. Prophylactic treatment against this disease using a pulmonary antibiotic formulation has not previously been examined, but may reduce the number of treatments required, allow for the delivery of higher doses, eliminate the need for intravenous administration, and help to minimize systemic side effects...
November 2016: Journal of Pharmaceutical Sciences
Hiroki Suzuki, Kodai Ueno, Takahiro Mizumoto, Yoshiki Seto, Hideyuki Sato, Satomi Onoue
The present study aimed to develop an inhalable self-micellizing solid dispersion of cyclosporine A (SMSD/CsA) for the direct delivery to the respiratory system with improved therapeutic efficacy and minimized systemic exposure. SMSD/CsA was obtained by wet-milling, and then jet-milled SMSD/CsA was blended with lactose carrier, producing a respirable powder of SMSD/CsA (SMSD/CsA-RP). The physicochemical, pharmacological, and pharmacokinetic properties of SMSD/CsA-RP were characterized, and the hepatotoxic and nephrotoxic potentials were investigated by biomarker analysis...
September 12, 2016: European Journal of Pharmaceutical Sciences
J T Ramos, L Francisco, Z Daoud
Invasive fungal infections (IFI) are a major cause of morbidity and mortality in immunocompromised adults and children. The purpose of this review was to update the epidemiological, clinical and therapeutic options in children, and to compare them with the adult population. Although there are important differences, the epidemiology, clinical features and risk factors for IFI have many similarities. Patient at risk include neutropenic hematology children, in whom Candida spp. y Aspergillus spp. predominate; primary immunodeficiencies, particularly chronic granulomatous disease with high susceptibility for Aspergillus spp...
September 2016: Revista Española de Quimioterapia: Publicación Oficial de la Sociedad Española de Quimioterapia
Paola Tocchetti, Elena Tudone, Jean-Francois Marier, Thomas C Marbury, Katie Zomorodi, Mark Eller
Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD) on defibrotide pharmacokinetics (PK)...
2016: Drug Design, Development and Therapy
Dejan Radovanovic, Marco Mantero, Giuseppe Francesco Sferrazza Papa, Vincenzo Valenti, Stefano Aliberti, Fabiano Di Marco, Pierachille Santus
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterized by a high disability and increasing mortality. Bronchodilators are the cornerstone of pharmacological treatment in COPD, while therapeutic optimization with an improvement in symptoms and compliance represent the actual goals. This has led to the development of devices that combine different classes of inhalatory drugs. Recently, a novel combination of the long acting antimuscarinic agent glycopyrronium bromide and the beta2-agonist formoterol fumarate has been developed in a metered dose inhaler delivery system...
October 2016: Expert Review of Respiratory Medicine
Jennifer J Furin, Jeannine Du Bois, Elana van Brakel, Phalkun Chheng, Amour Venter, Charles A Peloquin, Abdullah Alsultan, Bonnie Thiel, Sara M Debanne, W Henry Boom, Andreas H Diacon, John L Johnson
RATIONALE: AZD5847 is an oxazolidinone antibiotic, with in vitro activity against Mycobacterium tuberculosis OBJECTIVES: To evaluate the antimycobacterial activity, safety, and pharmacokinetics of AZD5847 in patients with pulmonary tuberculosis. METHODS: Groups of 15 treatment-naive, sputum smear-positive adults with pulmonary tuberculosis were randomly assigned to AZD5847 at 4 doses (500 mg once daily, 500 mg twice daily, 1200 mg once daily and 800 mg twice daily) or daily standard chemotherapy...
August 22, 2016: Antimicrobial Agents and Chemotherapy
Marguerite L Monogue, Rebecca S Pettit, Marianne Muhlebach, Jeffrey J Cies, David P Nicolau, Joseph L Kuti
Ceftolozane/tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we describe the population pharmacokinetics and safety of ceftolozane/tazobactam 3g every 8 hours (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were performed by Non-Parametric Adaptive Grid in Pmetrics for R...
August 22, 2016: Antimicrobial Agents and Chemotherapy
Dingsheng Li, Masako Morishita, James G Wagner, Mohammad Fatouraie, Margaret Wooldridge, W Ethan Eagle, James Barres, Ulrika Carlander, Claude Emond, Olivier Jolliet
BACKGROUND: Cerium oxide (CeO2) nanoparticles used as a diesel fuel additive can be emitted into the ambient air leading to human inhalation. Although biological studies have shown CeO2 nanoparticles can cause adverse health effects, the extent of the biodistribution of CeO2 nanoparticles through inhalation has not been well characterized. Furthermore, freshly emitted CeO2 nanoparticles can undergo an aging process by interaction with other ambient airborne pollutants that may influence the biodistribution after inhalation...
2016: Particle and Fibre Toxicology
Daniela Mastroiacovo, Girolamo Sala, Francesco Dentali
INTRODUCTION: Venous thromboembolism (VTE) is a common and potentially fatal disease. Fondaparinux is a synthetic agent able to act on single factors involved in the coagulation network, which could be administered at fixed doses and with a more predictable response. AREAS COVERED: This review will focus on the efficacy and safety of fondaparinux in the treatment of major VTE (deep vein thrombosis and pulmonary embolism) and in the treatment of superficial vein thrombosis (SVT)...
September 2016: Expert Opinion on Drug Safety
Marcello Di Nisio, Maria C Vedovati, Antoni Riera-Mestre, Martin H Prins, Katharina Mueller, Alexander T Cohen, Philip S Wells, Jan Beyer-Westendorf, Paolo Prandoni, Henri Bounameaux, Dagmar Kubitza, Jonas Schneider, Ron Pisters, Jan Fedacko, Ricardo Fontes-Carvalho, Anthonie W A Lensing
The pharmacokinetics of oral rivaroxaban are highly predictable and only affected to a limited extent by bodyweight; therefore, dose adjustments for bodyweight are not required. However, this raises concerns among physicians for potential under- or overdosing. This substudy of the randomised EINSTEIN DVT and EINSTEIN PE trials, which compared rivaroxaban with enoxaparin/vitamin K antagonist (VKA) therapy, aimed to determine the incidence of major bleeding in patients with a low bodyweight and recurrent venous thromboembolism (VTE) in patients with a high bodyweight during rivaroxaban or enoxaparin/VKA therapy...
September 27, 2016: Thrombosis and Haemostasis
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