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Tuberculosis pharmacokinetics

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https://www.readbyqxmd.com/read/29877726/drug-penetration-gradients-associated-with-acquired-drug-resistance-in-tuberculosis-patients
#1
Keertan Dheda, Laura Lenders, Gesham Magombedze, Shashikant Srivastava, Prithvi Raj, Erland Arning, Paula Ashcraft, Teodoro Bottiglieri, Helen Wainwright, Timothy Pennel, Anthony Linegar, Loven Moodley, Anil Pooran, Jotam G Pasipanodya, Frederick A Sirgel, Paul D van Helden, Edward Wakeland, Robin M Warren, Tawanda Gumbo
RATIONALE: Acquired resistance is an important driver of multidrug-resistant tuberculosis, even with good treatment adherence. However, exactly what initiates the resistance, and how it arises remains poorly understood. OBJECTIVES: To identify the relationship between drug concentrations and drug susceptibility readouts (MICs) in the tuberculosis cavity. METHODS: We recruited patients with medically incurable tuberculosis who were undergoing therapeutic lung resection whilst on treatment with the cocktail of second line anti-tuberculosis drugs...
June 7, 2018: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29766819/synthesis-in-silico-molecular-docking-and-pharmacokinetic-studies-in-vitro-antimycobacterial-and-antimicrobial-studies-of-new-imidozolones-clubbed-with-thiazolidinedione
#2
Imran H Khan, Navin B Patel, Vatsal M Patel
BACKGROUND: A series of (E)-5-(4-((Z)-4-substitutedbenzylidene/2-thienylmethylene-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl) benzylidene)thiazolidine-2,4-dione were synthesized and evaluated for antimycobacterial and antimicrobial activity. All these ligands were docked against protein (InhA) Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, (PDB ID: 4COD). OBJECTIVE: In this report we have designed and synthesized azole scaffolds with good antitubercular activities as there is a real need to develop new candidates with less toxicity and more efficient toward pathogen...
May 15, 2018: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/29765372/is-iqg-607-a-potential-metallodrug-or-metallopro-drug-with-a-defined-molecular-target-in-mycobacterium-tuberculosis
#3
REVIEW
Bruno L Abbadi, Valnês da Silva Rodrigues-Junior, Adilio da Silva Dadda, Kenia Pissinate, Anne D Villela, Maria M Campos, Luiz G de França Lopes, Cristiano V Bizarro, Pablo Machado, Eduardo H S Sousa, Luiz A Basso
The emergence of strains of Mycobacterium tuberculosis resistant to isoniazid (INH) has underscored the need for the development of new anti-tuberculosis agents. INH is activated by the mycobacterial katG -encoded catalase-peroxidase, forming an acylpyridine fragment that is covalently attached to the C4 of NADH. This isonicotinyl-NAD adduct inhibits the activity of 2- trans -enoyl-ACP(CoA) reductase (InhA), which plays a role in mycolic acid biosynthesis. A metal-based INH analog, Na3 [FeII (CN)5 (INH)]·4H2 O, IQG-607, was designed to have an electronic redistribution on INH moiety that would lead to an intramolecular electron transfer to bypass KatG activation...
2018: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29751121/evaluation-of-dried-blood-spot-sampling-for-pharmacokinetic-research-and-therapeutic-drug-monitoring-of-anti-tuberculosis-drugs-in-children
#4
Lisa C Martial, Jordy Kerkhoff, Nilza Martinez, Mabel Rodríguez, Rosarito Coronel, Gladys Molinas, Myriam Roman, Roscio Gomez, Sarita Aguirre, Erwin Jongedijk, Justine Huisman, Daan J Touw, Domingo Pérez, Gilberto Chaparro, Felipe Gonzalez, Rob E Aarnoutse, Jan-Willem Alffenaar, Cecile Magis-Escurra
BACKGROUND: Dried blood spot (DBS) sampling for pharmacokinetic (PK) studies and therapeutic drug monitoring have unique advantages over venous sampling. This study aimed to evaluate a DBS method for first-line anti-tuberculosis drugs in children, and DBS sampling to assess PK parameters. METHODS: Paraguayan children were treated according to the revised paediatric dosing scheme of the World Health Organization. A PK curve was performed both with DBS sampling and conventional venous sampling for rifampicin, pyrazinamide and ethambutol...
May 8, 2018: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/29723418/multiple-doses-of-rifabutin-reduce-exposure-of-doravirine-in-healthy-subjects
#5
Sauzanne G Khalilieh, Ka Lai Yee, Rosa I Sanchez, Rachel Liu, Li Fan, Maureen Martell, Heather Jordan, Marian Iwamoto
Doravirine is a nonnucleoside reverse transcriptase inhibitor in clinical development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretroviral therapies. The cytochrome P450 (CYP)3A-dependent metabolism of doravirine makes it susceptible to interactions with modulators of this pathway, including the antituberculosis treatment rifampin. Rifabutin, an alternative antibiotic used to treat tuberculosis, may have a lower-magnitude effect on CYP3A. The aim of this trial was to determine the effect of steady-state rifabutin on doravirine single-dose pharmacokinetics and tolerability...
May 3, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29718967/mycobactericidal-activity-of-bedaquiline-plus-rifabutin-or-rifampin-in-ex-vivo-whole-blood-cultures-of-healthy-volunteers-a-randomized-controlled-trial
#6
Robert S Wallis, Caryn E Good, Mary A O'Riordan, Jeffrey L Blumer, Michael R Jacobs, J McLeod Griffiss, Amanda Healan, Robert A Salata
BACKGROUND: Bedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture...
2018: PloS One
https://www.readbyqxmd.com/read/29718390/greater-early-bactericidal-activity-at-higher-rifampicin-doses-revealed-by-modeling-and-clinical-trial-simulations
#7
Robin J Svensson, Elin M Svensson, Rob E Aarnoutse, Andreas H Diacon, Rodney Dawson, Stephen H Gillespie, Mischka Moodley, Martin J Boeree, Ulrika S H Simonsson
Background: The current rifampicin dose (10 mg/kg) is sub-optimal for treating tuberculosis. The PanACEA HIGHRIF1 trial evaluated pharmacokinetics and early bactericidal activity with rifampicin doses up to 40 mg/kg. Conventional statistics revealed no significant exposure-response relationship. Our objective was to explore exposure-response for high dose rifampicin using pharmacokinetic-pharmacodynamic modeling and to predict early bactericidal activity of 50 mg/kg rifampicin. Methods: Data included time-to-positivity of sputum in liquid culture from 83 tuberculosis patients treated with 10 (n=8), 20, 25, 30, 35 or 40 (n=15/group) mg/kg rifampicin for 7 days (clinicaltrials...
April 28, 2018: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29709589/effect-of-the-alkyl-group-in-the-piperazine-n-substitution-on-the-therapeutic-action-of-rifamycins-a-drug-membrane-interaction-study
#8
Emílio V Lage, Joana Magalhães, Marina Pinheiro, Salette Reis
In this work, we studied the effects of the N-alkyl group (methyl, cyclopentyl) in the piperazine ring of, respectively, rifampicin (RIF) and rifapentine (RPT) to correlate this substitution with their differential pharmacokinetic properties and overall clinical performance. Since this group is their only structural change, and given that they share the same pharmacological target, differences in their therapeutic behavior may respond to this asset, particularly in their interaction with lipid membranes across the organism...
April 27, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29697766/intermediate-susceptibility-dose-dependent-breakpoints-for-high-dose-rifampicin-isoniazid-and-pyrazinamide-treatment-in-multidrug-resistant-tuberculosis-programmes
#9
Marlanka A Zuur, Jotam G Pasipanodya, Dick van Soolingen, Tjip S van der Werf, Tawanda Gumbo, Jan-Willem C Alffenaar
Background: In infectious diseases, for some drugs, bacterial susceptibility is categorized as susceptible, intermediate-susceptible dose-dependent (ISDD), and resistant. The strategy is to use higher doses of first-line agents in the ISDD category, thereby preserving the use of these drugs. This system has not been applied to anti-tuberculosis drugs. Pharmacokinetics/pharmacodynamics (PK/PD) target exposures, in tandem with Monte Carlo experiments (MCE), recently identified susceptibility breakpoints of 0...
April 24, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29686171/influence-of-diabetes-mellitus-on-the-development-of-multi-drug-resistant-tuberculosis-in-yogyakarta
#10
Antonia Morita Iswari Saktiawati, Yanri Wijayanti Subronto
BACKGROUND: the correlation between diabetes mellitus (DM) and Multi-Drug-Resistant Tuberculosis (MDR-TB) has never been studied among patients with tuberculosis (TB) in Indonesia, while DM has been identified to alter immune response and pharmacokinetics of TB medications that may lead to a failure of TB treatment and develop MDR-TB. Our study aimed to analyze the influence of diabetes mellitus on the development of MDR-TB. METHODS: a retrospective cohort study was carried out on 356 TB patients at the Provincial Lung Clinics and Sardjito Hospital, Yogyakarta, Indonesia between 2010 and 2014...
January 2018: Acta Medica Indonesiana
https://www.readbyqxmd.com/read/29686169/risk-factors-for-multidrug-resistant-tuberculosis
#11
Cleopas Martin Rumende
In 2015, 10.4 million people developed tuberculosis (TB) and 580,000 amongst them suffered from multidrug-resistant TB (MDR-TB). From those 580,000 cases of MDR-TB, only 125,000 were detected and reported. A total of 111,000 people began to receive MDR-TB treatment in 2014 while 190,000 MDR-TB patients were estimated to have died, largely due to lack of access to effective treatment. The mechanism of drug resistance can be caused by genetic factors, factors related to previous treatment and other factors such as comorbidity with diabetes mellitus...
January 2018: Acta Medica Indonesiana
https://www.readbyqxmd.com/read/29680666/synthesis-and-biological-evaluation-of-aryl-oxadiazoles-as-inhibitors-of-mycobacterium-tuberculosis
#12
Maria Angeles Martinez-Grau, Isabel C Gonzalez Valcarcel, Julie V Early, Richard Klaus Gessner, Candice Soares de Melo, Eva Maria Martin de la Nava, Aaron Korkegian, Yulia Ovechkina, Lindsay Flint, Anisa Gravelle, Jeff W Cramer, Prashant V Desai, Leslie J Street, Joshua Odingo, Thierry Masquelin, Kelly Chibale, Tanya Parish
Despite increased research efforts to find new treatments for tuberculosis in recent decades, compounds with novel mechanisms of action are still required. We previously identified a series of novel aryl-oxadiazoles with anti-tubercular activity specific for bacteria using butyrate as a carbon source. We explored the structure activity relationship of this series. Structural modifications were performed in all domains to improve potency and physico-chemical properties. A number of compounds displayed sub-micromolar activity against M...
June 1, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29673395/shorter-treatment-for-minimal-tuberculosis-tb-in-children-shine-a-study-protocol-for-a-randomised-controlled-trial
#13
Chishala Chabala, Anna Turkova, Margaret J Thomason, Eric Wobudeya, Syed Hissar, Vidya Mave, Marieke van der Zalm, Megan Palmer, Monica Kapasa, Perumal K Bhavani, Sarath Balaji, Priyanka A Raichur, Anne-Marie Demers, Graeme Hoddinott, Ellen Owen-Powell, Aarti Kinikar, Philippa Musoke, Veronica Mulenga, Rob Aarnoutse, Helen McIlleron, Anneke Hesseling, Angela M Crook, Mark Cotton, Diana M Gibb
BACKGROUND: Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible...
April 19, 2018: Trials
https://www.readbyqxmd.com/read/29665950/conducting-efficacy-trials-in-children-with-mdr-tb-what-is-the-rationale-and-how-should-they-be-done
#14
J A Seddon, E D Weld, H S Schaaf, A J Garcia-Prats, S Kim, A C Hesseling
Paediatric anti-tuberculosis treatment trials have traditionally been limited to Phase I/II studies evaluating the drug pharmacokinetics and safety in children, with assumptions about efficacy made by extrapolating data from adults. However, it is increasingly being recognised that, in some circumstances, efficacy trials are required in children. The current treatment for children with multidrug-resistant tuberculosis (MDR-TB) is long and toxic; shorter, safer regimens, using novel agents, require urgent evaluation...
May 1, 2018: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/29665949/current-status-of-pharmacokinetic-and-safety-studies-of-multidrug-resistant-tuberculosis-treatment-in-children
#15
A J Garcia-Prats, E M Svensson, E D Weld, H S Schaaf, A C Hesseling
After decades of neglect, data are finally becoming available on the appropriate, safe dosing of key second-line anti-tuberculosis drugs used for treating multidrug-resistant tuberculosis (MDR-TB) in children, including levofloxacin (LVX), moxifloxacin (MFX), linezolid (LZD) and delamanid (DLM). Much needed data on some novel and repurposed drugs are still lacking, including for bedaquiline (BDQ), pretomanid (PTM) and clofazimine (CFZ). We review the status of pharmacokinetic (PK) and safety studies of key anti-tuberculosis medications in children with MDR-TB, identify priority knowledge gaps and note ongoing work to address those gaps, in the context of planning for an efficacy trial in children with MDR-TB...
May 1, 2018: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/29661865/modeling-and-simulation-of-pretomanid-pharmacokinetics-in-pulmonary-tuberculosis-patients
#16
Michael A Lyons
Pretomanid is a nitroimidazole antibiotic in late phase clinical testing as a component of several novel antituberculosis (anti-TB) regimens. A population pharmacokinetic model for pretomanid was constructed using a Bayesian analysis of data from two phase 2 studies, PA-824-CL-007 and PA-824-CL-010, conducted with newly diagnosed adult (median age 27 years) pulmonary TB patients in Cape Town, South Africa. Combined, these studies included 63 males and 59 females administered once daily oral pretomanid doses of 50, 100, 150, 200, 600, 1000, or 1200 mg for 14 days...
April 16, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29624706/pharmacokinetics-of-efavirenz-in-patients-on-antituberculosis-treatment-in-high-human-immunodeficiency-virus-and-tuberculosis-burden-countries-a-systematic-review
#17
REVIEW
Daniel Atwine, Maryline Bonnet, Anne-Marie Taburet
AIMS: Efavirenz (EFV) and rifampicin-isoniazid (RH) are cornerstone drugs in human immunodeficiency virus (HIV)-tuberculosis (TB) coinfection treatment but with complex drug interactions, efficacy and safety challenges. We reviewed recent data on EFV and RH interaction in TB/HIV high-burden countries. METHODS: We conducted a systematic review of studies conducted in the high TB/HIV-burden countries between 1990 and 2016 on EFV pharmacokinetics during RH coadministration in coinfected patients...
April 6, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29621407/critical-review-on-the-analytical-methods-for-the-estimation-of-clofazimine-in-bulk-biological-fluids-and-pharmaceutical-formulations
#18
REVIEW
Tulshidas S Patil, Ashwini S Deshpande, Shirish Deshpande
Clofazimine (CFZ), a riminophenazine derivative and a crucial drug in the treatment of lepromatous leprosy, has been reintroduced clinically to treat multidrug-resistant tuberculosis. CFZ holds both antimycobacterial and anti-inflammatory properties. But, due to its highly hydrophobic, polar and photosensitive nature, it is challenging to extract and quantify the drug from different biological fluids and its pharmaceutical formulations. This has also hampered the pharmacokinetic evaluation of the CFZ. This article accentuates various analytical methods viz...
November 2, 2018: Critical Reviews in Analytical Chemistry
https://www.readbyqxmd.com/read/29618565/pharmacokinetics-of-rifapentine-and-rifampin-in-a-rabbit-model-of-tuberculosis-and-correlation-with-clinical-trial-data
#19
Dalin Rifat, Brendan Prideaux, Radojka M Savic, Michael E Urbanowski, Teresa L Parsons, Brian Luna, Mark A Marzinke, Alvaro A Ordonez, Vincent P DeMarco, Sanjay K Jain, Veronique Dartois, William R Bishai, Kelly E Dooley
In clinical trials of two rifamycin antibiotics (rifampin and rifapentine) for treating tuberculosis (TB), patients with cavitary lung lesions did not appear to derive benefit from rifapentine. Rifapentine was found not to outperform rifampin, despite a lower minimum inhibitory concentration against Mycobacterium tuberculosis in mouse models of TB. To understand these findings, we have developed a rabbit model of TB that reliably develops lung cavities with features similar to those of patients with pulmonary cavitary TB...
April 4, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29600438/functionalization-of-plga-nanoparticles-with-1-3-%C3%AE-glucan-enhances-the-intracellular-pharmacokinetics-of-rifampicin-in-macrophages
#20
Matshawandile Tukulula, Luis Gouveia, Paulo Paixao, Rose Hayeshi, Brendon Naicker, Admire Dube
PURPOSE: Mycobacterium tuberculosis which causes tuberculosis, is primarily resident within macrophages. 1,3-β-glucan has been proposed as a ligand to target drug loaded nanoparticles (NPs) to macrophages. In this study we characterized the intracellular pharmacokinetics of the anti-tubercular drug rifampicin delivered by 1,3-β-glucan functionalized PLGA NPs (Glu-PLGA). We hypothesized that Glu-PLGA NPs would be taken up at a faster rate than PLGA NPs, and consequently deliver higher amounts of rifampicin into the macrophages...
March 29, 2018: Pharmaceutical Research
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