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Pulmonary pharmacokinetics

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https://www.readbyqxmd.com/read/28827417/pharmacokinetics-tolerability-and-bacteriological-response-of-600-900-and-1200-mg-rifampicin-daily-in-patients-with-pulmonary-tb
#1
R E Aarnoutse, G S Kibiki, K Reither, H H Semvua, F Haraka, C M Mtabho, S G Mpagama, J van den Boogaard, I M Sumari-de Boer, C Magis-Escurra, M Wattenberg, J G M Logger, L H M Te Brake, M Hoelscher, S H Gillespie, A Colbers, P P J Phillips, G Plemper van Balen, M J Boeree
Background. In a multiple dose ranging trial we have previously evaluated higher doses of rifampicin in patients for two weeks. The objectives of the current study were to administer higher doses of rifampicin for a longer period to compare pharmacokinetics, safety/tolerability and bacteriological activity of such regimens.Methods. In a double-blinded, randomized, placebo-controlled, phase II clinical trial (ClinicalTrials.gov NCT00760149) 150 Tanzanian TB patients were randomized to receive either 600 (approximately 10 mg/kg), 900 or 1200 mg rifampicin combined with standard doses of isoniazid, pyrazinamide and ethambutol administered daily for two months...
August 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807911/systematic-review-and-meta-analyses-of-the-effect-of-chemotherapy-on-pulmonary-mycobacterium-abscessus-outcomes-and-disease-recurrence
#2
Jotam G Pasipanodya, Deborah Ogbonna, Beatriz E Ferro, Gesham Magombedze, Shashikant Srivastava, Devyani Deshpande, Tawanda Gumbo
Background. In pharmacokinetic/pharmacodynamics models of pulmonary Mycobacterium abscessus complex, the recommended macrolide-containing combination therapy has poor kill rates. However, clinical outcomes are unknown.Methods We searched the literature for studies published between 1990-2017 that reported microbial outcomes in patients treated for pulmonary M. abscessus disease. Good outcome was defined as sustained sputum culture conversion (SSCC) without relapse. Random effects models were used to pool studies and estimate proportions of patients with good outcomes...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807905/pulmonary-pharmacokinetics-of-colistin-following-administration-of-dry-powder-aerosols-in-rats
#3
Yu-Wei Lin, Qi Tony Zhou, Yang Hu, Nikolas J Onufrak, Siping Sun, Jiping Wang, Alan Forrest, Hak-Kim Chan, Jian Li
Colistin has been administered via nebulization for the treatment of respiratory tract infections. Recently, dry powder inhalation (DPI) has attracted increasing attention. The current study aimed to investigate the pharmacokinetics (PK) of colistin in epithelial lining fluid (ELF) and plasma following DPI and intravenous (IV) administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intratracheally (0.66 and 1.32 mg base/kg) or IV injection (0.66 mg base/kg). Histopathological examination of lung tissue was performed at 24 h...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28799097/predicting-pulmonary-pharmacokinetics-from-in-vitro-properties-of-dry-powder-inhalers
#4
Sharvari Bhagwat, Uta Schilling, Mong-Jen Chen, Xiangyin Wei, Renishkumar Delvadia, Mohammad Absar, Bhawana Saluja, Günther Hochhaus
PURPOSE: The ability of two semi-mechanistic simulation approaches to predict the systemic pharmacokinetics (PK) of inhaled corticosteroids (ICSs) delivered via dry powder inhalers (DPIs) was assessed for mometasone furoate, budesonide and fluticasone propionate. METHODS: Both approaches derived the total lung doses and the central to peripheral lung deposition ratios from clinically relevant cascade impactor studies, but differed in the way the pulmonary absorption rate was derived...
August 10, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28796008/methicillin-resistant-staphylococcus-aureus-in-cystic-fibrosis-how-should-it-be-managed
#5
Marianne S Muhlebach
PURPOSE OF REVIEW: Methicillin-resistant Staphylococcus aureus (MRSA) remains prevalent in people with cystic fibrosis (CF). As chronic infection with worse pulmonary outcomes develops frequently, the organism is concerning to CF providers and patients. This review describes current epidemiology, our understanding of risk factors for MRSA infection, and relevant aspects of treatment with review of new and ongoing trials. RECENT FINDINGS: Prevalence ranges from a low of 3 to 4% in some European countries to a high of approximately 26% in the United States...
August 8, 2017: Current Opinion in Pulmonary Medicine
https://www.readbyqxmd.com/read/28791664/pharmacokinetics-of-sildenafil-in-children-with-pulmonary-arterial-hypertension
#6
Hugo Juárez Olguín, Hector Osnaya Martínez, Carmen Flores Pérez, Blanca Ramírez Mendiola, Liliana Rivera Espinosa, Juan Luis Chávez Pacheco, Janett Flores Pérez, Ignacio Mora Magaña
BACKGROUND: Recently, sildenafil was introduced to treat pulmonary arterial hypertension (PAH); however, there are currently few studies on the pharmacokinetics of sildenalfil in children. Therefore, we aimed to carry out a pharmacokinetic study of sildenafil in children with PAH using a single dose. METHODS: Twelve children diagnosed with PAH, consisting of with ten males and two females, were recruited for the study after obtaining written consent from their parents or guardians...
August 8, 2017: World Journal of Pediatrics: WJP
https://www.readbyqxmd.com/read/28789609/dose-and-time-dependency-of-the-toxicity-and-pharmacokinetic-profiles-of-bedaquiline-and-its-n-desmethyl-metabolite-in-dogs
#7
Ilham Smyej, Sandra De Jonghe, Adriana Looszova, Geert Mannens, Tom Verhaeghe, Sandy Thijssen, Sofie Starckx, Ann Lampo, Marie-Claude Rouan
Bedaquiline (BDQ) is an antibiotic to treat pulmonary multidrug-resistant tuberculosis (MDR-TB). Studies up to 39 weeks were conducted orally in dogs to assess the toxicity and pharmacokinetics of BDQ and its N-desmethyl metabolite (D-BDQ). Phospholipidosis (PLD) seen in the monocytic phagocytic system was considered an adaptive change. Skeletal muscle, heart, stomach, liver, and pancreas toxicities with D-BDQ as the main contributor were associated with a less-than-dose-proportional increase in plasma exposure and an overproportional tissue uptake of BDQ and D-BDQ at high-dose levels...
January 1, 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28777819/infection-stage-adjusted-dose-of-beta-lactams-for-parsimonious-and-efficient-antibiotic-treatments-a-pasteurella-multocida-experimental-pneumonia-in-mice
#8
Maleck V Vasseur, Marlene Z Lacroix, Pierre-Louis Toutain, Alain Bousquet-Melou, Aude A Ferran
In this study, the impact of infection stage on clinically and microbiologically efficacious doses and on antibiotic consumption was assessed during a naturally evolving infectious disease, using an original mouse model of pulmonary infection produced by air-borne contamination. When Pasteurella multocida was administered as pathogenic agent to immunocompetent mice, 60% of the animals exhibited clinical symptoms of pneumonia 2 to 4 days after bacterial contamination of the lungs. Two beta-lactam antibiotics were evaluated: amoxicillin and cefquinome, a fourth generation cephalosporin developed for food animals...
2017: PloS One
https://www.readbyqxmd.com/read/28771049/direct-oral-anticoagulants-in-the-treatment-of-pulmonary-embolism
#9
Joanna B Eldredge, Alex C Spyropoulos
OBJECTIVE: The objective of this review is to examine the management strategies for pulmonary embolism (PE) with an emphasis of the role of direct oral anticoagulants (DOACs). METHODS: PubMed was searched to identify relevant journal articles published through April 2017. Additional references were obtained from articles discovered during the database search. RESULTS: Initial heparinization followed by long-term anticoagulation with vitamin K antagonists (VKAs) has been considered the mainstay for the treatment of PE...
August 3, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28769012/in-vitro-p-glycoprotein-mediated-transport-of-tadalafil-a-comparison-with-sildenafil
#10
Hiroki Higashi, Nao Watanabe, Rika Tamura, Masato Taguchi
Tadalafil and sildenafil are selective inhibitors of phosphodiesterase type 5, showing marked pharmacokinetic variability in patients with pulmonary arterial hypertension. It has been reported that sildenafil is a substrate for P-glycoprotein (P-gp), but whether tadalafil is a substrate for P-gp remains to be determined. The objective of the present study was to elucidate whether tadalafil is a substrate for P-gp. Transcellular transport of sildenafil and tadalafil (5 µM each) was examined using renal epithelial LLC-PK1 and P-gp-expressing LLC-GA5-COL150 cell monolayers...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28768120/investigation-of-lung-pharmacokinetic-of-the-novel-pde4-inhibitor-chf6001-in-preclinical-models-evaluation-of-the-preciseinhale-technology
#11
Alessandro Fioni, Ewa Selg, Valentina Cenacchi, Fernando Acevedo, Giandomenico Brogin, Per Gerde, Paola Puccini
BACKGROUND: Preclinical evaluation of new chemical entities (NCEs) designed to be administered by inhalation route requires lung administration to rodents, especially in the discovery phase. Different administration methods have been used until now, but more efforts are required to obtain controlled and reproducible lung deposition when only small amounts of neat powder material are available. METHODS: The PreciseInhale platform used in the present study enables well-controlled powder aerosol exposures with only small amounts of micronized neat material, providing data on inhalation pharmacokinetic (PK) of NCEs at a very early stage...
August 2, 2017: Journal of Aerosol Medicine and Pulmonary Drug Delivery
https://www.readbyqxmd.com/read/28766281/nebulized-antibiotics-in-mechanically-ventilated-patients-a-challenge-for-translational-research-from-technology-to-clinical-care
#12
REVIEW
Stephan Ehrmann, Jean Chastre, Patrice Diot, Qin Lu
Nebulized antibiotic therapy directly targets airways and lung parenchyma resulting in high local concentrations and potentially lower systemic toxicities. Experimental and clinical studies have provided evidence for elevated lung concentrations and rapid bacterial killing following the administration of nebulized antibiotics during mechanical ventilation. Delivery of high concentrations of antibiotics to infected lung regions is the key to achieving efficient nebulized antibiotic therapy. However, current non-standardized clinical practice, the difficulties with implementing optimal nebulization techniques and the lack of robust clinical data have limited its widespread adoption...
December 2017: Annals of Intensive Care
https://www.readbyqxmd.com/read/28762839/new-treatment-options-for-lower-respiratory-tract-infections
#13
Bela Kocsis, Dora Szabo
Community-acquired pneumonia (CAP) and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are among the most frequent lower respiratory tract infections (LRTIs). They represent an increased morbidity and mortality rate in adults. Areas covered: This review describes recent advances regarding solithromycin, zabofloxacin and delafoxacin antibacterial agents that have been recently developed for treatment of CAP and in AECOPD. All of them have been introduced into phase III clinical trials. We will be summarising chemical structures, pharmacokinetics, antibacterial efficacy and toxicity of these agents...
September 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28759464/pharmacokinetics-and-bioavailability-of-inhaled-esketamine-in-healthy-volunteers
#14
Kelly Jonkman, Andreas Duma, Erik Olofsen, Thomas Henthorn, Monique van Velzen, René Mooren, Liesbeth Siebers, Jojanneke van den Beukel, Leon Aarts, Marieke Niesters, Albert Dahan
BACKGROUND: Esketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability. METHODS: Three increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained...
July 31, 2017: Anesthesiology
https://www.readbyqxmd.com/read/28753067/a-randomized-placebo-controlled-phase-2-trial-of-cnto-6785-in-chronic-obstructive-pulmonary-disease
#15
Andreas Eich, Veronika Urban, Marek Jutel, Jiri Vlcek, Jae Jeong Shim, Vasiliy I Trofimov, Chong-Kin Liam, Ping-Hung Kuo, Yanyan Hou, Jun Xiao, Patrick Branigan, Christopher D O'Brien
Interleukin (IL)-17A may be an underlying factor in the pathophysiology of chronic obstructive pulmonary disease (COPD). Anti-IL-17 monoclonal antibodies have been used successfully in treating several immune-mediated inflammatory diseases. This phase 2, randomized, placebo-controlled, double-blind, parallel-group, proof-of-concept study is the first clinical study evaluating the efficacy and safety of the anti-IL-17A monoclonal antibody CNTO 6785 in patients with symptomatic moderate-to-severe COPD. Patients were treated with CNTO 6785 (n = 93) or placebo (n = 94) intravenously at Weeks 0, 2, and 4 (induction), then Weeks 8 and 12, and followed till Week 24...
July 28, 2017: COPD
https://www.readbyqxmd.com/read/28752471/calcium-phosphate-particles-as-pulmonary-delivery-system-for-interferon-%C3%AE-in-mice
#16
Tülin Morçöl, Jessica M Weidner, Anand Mehta, Stephen J D Bell, Timothy Block
Systemically administered interferons are rapidly cleared from the circulation thus requiring frequent dosing to maintain the therapeutic levels of circulating interferon. This is particularly problematic for their use in the treatment of chronic diseases. The purpose of this study was to evaluate the potential of proprietary calcium phosphate (CaP) particles to deliver biologically active interferon alpha (IFNα) via the lungs into systemic circulation. Recombinant human IFNα-2a was formulated with proprietary CaP particles...
July 27, 2017: AAPS PharmSciTech
https://www.readbyqxmd.com/read/28751847/anmco-position-paper-the-use-of-non-vitamin-k-dependent-new-oral-anticoagulant-s-in-pulmonary-embolism-therapy-and-prevention
#17
Iolanda Enea, Loris Roncon, Michele Massimo Gulizia, Michele Azzarito, Cecilia Becattini, Amedeo Bongarzoni, Franco Casazza, Claudio Cuccia, Carlo D'Agostino, Matteo Rugolotto, Marco Vatrano, Eugenio Vinci, Paride Fenaroli, Dario Formigli, Paolo Silvestri, Federico Nardi, Maria Cristina Vedovati, Marino Scherillo
The new oral anticoagulants (NOACs) have radically changed the approach to the treatment and prevention of thromboembolic pulmonary embolism. The authors of this position paper face, in succession, issues concerning NOACs, including (i) their mechanism of action, pharmacodynamics, and pharmacokinetics; (ii) the use in the acute phase with the 'double drug single dose' approach or with 'single drug double dose'; (iii) the use in the extended phase with demonstrated efficacy and with low incidence of bleeding events; (iv) the encouraging use of NOACs in particular subgroups of patients such as those with cancer, the ones under- or overweight, with renal insufficiency (creatinine clearance > 30 mL/min), the elderly (>75 years); (v) they propose a possible laboratory clinical pathway for follow-up; and (vi) carry out an examination on the main drug interactions, their potential bleeding risk, and the way to deal with some bleeding complications...
May 2017: European Heart Journal Supplements: Journal of the European Society of Cardiology
https://www.readbyqxmd.com/read/28750090/target-specificity-in-vivo-pharmacokinetics-and-efficacy-of-the-putative-stat3-inhibitor-ly5-in-osteosarcoma-ewing-s-sarcoma-and-rhabdomyosarcoma
#18
Peter Y Yu, Heather L Gardner, Ryan Roberts, Hakan Cam, Seethalakshmi Hariharan, Ling Ren, Amy K LeBlanc, Hui Xiao, Jiayuh Lin, Denis C Guttridge, Xiaokui Mo, Chad E Bennett, Christopher C Coss, Yonghua Ling, Mitch A Phelps, Peter Houghton, Cheryl A London
BACKGROUND: STAT3 is a transcription factor involved in cytokine and receptor kinase signal transduction that is aberrantly activated in a variety of sarcomas, promoting metastasis and chemotherapy resistance. The purpose of this work was to develop and test a novel putative STAT3 inhibitor, LY5. METHODS AND FINDINGS: An in silico fragment-based drug design strategy was used to create LY5, a small molecule inhibitor that blocks the STAT3 SH2 domain phosphotyrosine binding site, inhibiting homodimerization...
2017: PloS One
https://www.readbyqxmd.com/read/28744115/bronchodilator-efficacy-of-extrafine-glycopyrronium-bromide-the-glyco-2-study
#19
Dave Singh, Mario Scuri, Sara Collarini, Stefano Vezzoli, Fabrizia Mariotti, Annamaria Muraro, Daniela Acerbi
An extrafine formulation of the long-acting muscarinic antagonist glycopyrronium bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate - a "fixed triple". This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 μg versus placebo; Part 2: repeat-dose (7-day), four-period crossover, GB 12.5, 25 or 50 μg twice daily (BID) versus placebo, with an open-label extension in which all patients received tiotropium 18 μg once daily...
2017: International Journal of Chronic Obstructive Pulmonary Disease
https://www.readbyqxmd.com/read/28739794/population-pharmacokinetics-of-azd-5847-in-adults-with-pulmonary-tuberculosis
#20
Abdullah Alsultan, Jennifer J Furin, Jeannine Du Bois, Elana van Brakel, Phalkun Chheng, Amour Venter, Bonnie Thiel, Sara A Debanne, W Henry Boom, Andreas H Diacon, John L Johnson, Charles A Peloquin
AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis. In this study we describe the population pharmacokinetics of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug susceptible TB. Patients were randomized to four doses (500 mg once daily, 1200 mg once daily, 500 mg twice daily and 800 mg twice daily). Patients were intensively sampled on day 1 and 14. AZD-5847 pharmacokinetics were best described with a two compartment system with tlag for absorption...
July 24, 2017: Antimicrobial Agents and Chemotherapy
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