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Tuberculosis pharmacokinetics

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https://www.readbyqxmd.com/read/29050764/pharmacokinetic-studies-of-a-three-component-complex-that-repurposes-the-front-line-antibiotic-isoniazid-against-mycobacterium-tuberculosis
#1
Thomas J Manning, Kyle Wilkerson, Taylor Holder, Andrew Carson Bartley, Chelsea Jackson, Sydney Plummer, Dennis Phillips, Logan Krajewski, Greg Wylie
The frontline tuberculosis (Tb) antibiotic isoniazid has been repurposed using a three component complex aimed at increasing the delivery efficiency and adding new avenues to its mechanism of action. This study focuses on pharmacokinetic studies of the isoniazid-sucrose-copper (II)-PEG-3350 complex. The assays include the Plasma Protein Binding Assay (85.8%), Caco-2 Permeability Assay (B→APapp, 0.13 × 10(-6) cm/s), Cytochrome P450 Inhibition Assay (i.e. CYP2B6, IC50 = 7.26 μM), In vitro microsomal Stability Assay (t1/2 NADPH-Dependent > 240 min), and HepG2 Cytotoxicity (no toxicity)...
December 2017: Tuberculosis
https://www.readbyqxmd.com/read/29038231/evaluation-of-clinical-drug-interaction-potential-of-clofazimine-using-static-and-dynamic-modeling-approaches
#2
Ramachandra Sangana, Helen Gu, Dung Yu Chun, Heidi J Einolf
The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (CYP) inhibitor in vitro, a CYP-mediated drug interaction may be likely when clofazimine is co-administered with substrates of these enzymes. The CYP-mediated drug interaction potential of clofazimine was evaluated using both static (estimation of "R1" and area under the plasma concentration-time curve ratio [AUCR] values) and dynamic (physiologically based pharmacokinetic [PBPK]) modeling approaches...
October 16, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29037995/preclinical-pharmacokinetic-profiling-of-iqg-607-a-potential-oral-metallodrug-to-treat-tuberculosis
#3
Adilio da S Dadda, Valnês S Rodrigues-Junior, Fernando Carreño, Guilherme O Petersen, Antônio F M Pinto, Pedro F Dalberto, Nathalia D M Sperotto, Kenia Pissinate, Cristiano V Bizarro, Pablo Machado, Maria M Campos, Teresa Dalla Costa, Diógenes S Santos, Luiz A Basso
IQG-607 is an analog of isoniazid with anti-tuberculosis activity. This work describes the development and validation of an HPLC method to quantify pentacyano(isoniazid)ferrate(II) compound (IQG-607) and the pharmacokinetic studies of this compound in mice. The method showed linearity in the 0.5-50μg/mL concentration range (r=0.9992). Intra- and inter-day precision was <5%, and the recovery ranged from 92.07 to 107.68%. IQG-607 was stable in plasma for at least 30days at -80°C and, after plasma processing, for 4h in the auto-sampler maintained on ice (recovery >85%)...
October 13, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29023399/novel-anti-tuberculosis-nanodelivery-formulation-of-ethambutol-with-graphene-oxide
#4
Bullo Saifullah, Alina Chrzastek, Arundhati Maitra, Bullo Naeemullah, Sharida Fakurazi, Sanjib Bhakta, Mohd Zobir Hussein
Tuberculosis (TB) is a bacterial disease responsible for millions of infections and preventable deaths each year. Its treatment is complicated by patients' noncompliance due to dosing frequency, lengthy treatment, and adverse side effects associated with current chemotherapy. However, no modifications to the half-a-century old standard chemotherapy have been made based on a nanoformulation strategy to improve pharmacokinetic efficacy. In this study, we have designed a new nanodelivery formulation, using graphene oxide as the nanocarrier, loaded with the anti-TB antibiotic, ethambutol...
October 12, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29017426/investigations-on-the-influence-of-zidovudine-in-the-pharmacokinetics-of-isoniazid-and-its-hepatotoxic-metabolites-in-rats
#5
Raghu Ramanathan, Karthikeyan Sivanesan
The HIV-infected patients are co-infected with many bacterial infections in which tuberculosis is most common found worldwide. These patients are often administered with combined therapy of anti-retroviral and anti-tubercular drugs which leads to several complications including hepatotoxicity or adverse drug interactions. The drug-drug interactions between the anti-retroviral and anti-tubercular drugs are not clearly defined and hence, this study was conducted to evaluate the pharmacokinetic drug-drug interactions of Zidovudine (AZT) with Isoniazid (INH) and its hepatotoxic metabolites...
January 1, 2017: Journal of Pharmacy Practice
https://www.readbyqxmd.com/read/29017219/-consensus-based-guidelines-for-diagnosis-prevention-and-treatment-of-tuberculosis-in-children-and-adolescents-a-guideline-on-behalf-of-the-german-society-for-pediatric-infectious-diseases-dgpi
#6
C Feiterna-Sperling, F Brinkmann, C Adamczick, F Ahrens, M Barker, C Berger, L D Berthold, M Bogyi, U von Both, T Frischer, W Haas, P Hartmann, D Hillemann, F W Hirsch, K Kranzer, F Kunitz, E Maritz, A Pizzulli, N Ritz, R Schlags, T Spindler, S Thee, K Weizsäcker
Recently, epidemiological data shows an increase of childhood tuberculosis in Germany. In addition to this, drug resistant tuberculosis becomes more frequent. Therefore, diagnosis, prevention and therapy in childhood and adolescence remain a challenge. Adult guidelines do not work for children, as there are age specific differences in manifestation, risk of progression and diagnostic as well as therapeutic pathways.The German Society for Pediatric Infectious Diseases (DGPI) has initiated a consensus-based (S2k) process and completed a paediatric guideline in order to improve and standardize care for children and adolescents with tuberculosis exposure, infection or disease...
October 2017: Pneumologie
https://www.readbyqxmd.com/read/28994740/antibacterial-and-antitubercular-activities-of-cinnamylideneacetophenones
#7
Carlos R Polaquini, Guilherme S Torrezan, Vanessa R Santos, Ana C Nazaré, Débora L Campos, Laíza A Almeida, Isabel C Silva, Henrique Ferreira, Fernando R Pavan, Cristiane Duque, Luis O Regasini
Cinnamaldehyde is a natural product with broad spectrum of antibacterial activity. In this work, it was used as a template for design and synthesis of a series of 17 cinnamylideneacetophenones. Phenolic compounds 3 and 4 exhibited MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) values of 77.9 to 312 µM against Staphylococcus aureus, Streptococcus mutans, and Streptococcus sanguinis. Compounds 2, 7, 10, and 18 presented potent effects against Mycobacterium tuberculosis (57...
October 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28993169/anti-tuberculosis-drug-combination-for-controlled-oral-delivery-using-3d-printed-compartmental-dosage-forms-from-drug-product-design-to-in-vivo-testing
#8
Natalja Genina, Johan Peter Boetker, Stefano Colombo, Necati Harmankaya, Jukka Rantanen, Adam Bohr
The design and production of an oral dual-compartmental dosage unit (dcDU) was examined in vitro and in vivo with the purpose of physically isolating and modulating the release profile of an anti-tuberculosis drug combination. Rifampicin (RIF) and isoniazid (ISO) are first line combination drugs for treatment of tuberculosis (TB) that negatively interact with each other upon simultaneous release in acidic environment. The dcDUs were designed in silico by computer aided design (CAD) and fabricated in two steps; first three-dimensional (3D) printing of the outer structure, followed by hot-melt extrusion (HME) of the drug-containing filaments...
October 6, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28957755/multiple-receptor-conformers-based-molecular-docking-study-of-fluorine-enhanced-ethionamide-with-mycobacterium-enoyl-acp-reductase-inha
#9
Akib Mahmud Khan, Jakaria Shawon, Mohammad A Halim
A major limitation in current molecular docking method is that of failure to account for receptor flexibility. Herein we report multiple receptor conformers based molecular docking as a practical alternative to account for the receptor flexibility. Multiple (forty) conformers of Mycobacterium Enoyl ACP Reductase (InhA) are generated from Molecular Dynamics simulation and twenty crystallographic structures of InhA bound to different inhibitors are obtained from the Protein Data Bank. Fluorine directed modifications are performed to currently available anti-tuberculosis drug ethionamide...
September 14, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28953378/discovery-of-a-potent-and-specific-m-tuberculosis-leucyl-trna-synthetase-inhibitor-s-3-aminomethyl-4-chloro-7-2-hydroxyethoxy-benzo-c-1-2-oxaborol-1-3h-ol-gsk656
#10
Xianfeng Li, Vincent Hernandez, Fernando L Rock, Wai Choi, Yvonne S L Mak, Manisha Mohan, Weimin Mao, Yasheen Zhou, Eric E Easom, Jacob J Plattner, Wuxin Zou, Esther Pérez-Herrán, Ilaria Giordano, Alfonso Mendoza-Losana, Carlos Alemparte, Joaquín Rullas, Iñigo Angulo-Barturen, Sabrinia Crouch, Fátima Ortega, David Barros, M R K Alley
There is an urgent need to develop new and safer antitubercular agents that possess a novel mode of action. We synthesized and evaluated a novel series of 3-aminomethyl 4-halogen benzoxaboroles as Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS) inhibitors. A number of Mtb LeuRS inhibitors were identified that demonstrated good antitubercular activity with high selectivity over human mitochondrial and cytoplasmic LeuRS. Further evaluation of these Mtb LeuRS inhibitors by in vivo pharmacokinetics (PK) and murine tuberculosis (TB) efficacy models led to the discovery of GSK3036656 (abbreviated as GSK656)...
September 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28928173/cohort-profile-of-a-study-on-outcomes-related-to-tuberculosis-and-antiretroviral-drug-concentrations-in-uganda-design-methods-and-patient-characteristics-of-the-south-study
#11
Christine Sekaggya-Wiltshire, Barbara Castelnuovo, Amrei von Braun, Joseph Musaazi, Daniel Muller, Allan Buzibye, Ursula Gutteck, Lars Henning, Bruno Ledergerber, Natascia Corti, Mohammed Lamorde, Jan Fehr, Andrew Kambugu
PURPOSE: Tuberculosis (TB) is a leading cause of death among people living with HIV in sub-Saharan Africa. Several factors influence the efficacy of TB treatment by leading to suboptimal drug concentrations and subsequently affecting treatment outcome. The aim of this cohort is to determine the association between anti-TB drug concentrations and TB treatment outcomes. PARTICIPANTS: Patients diagnosed with new pulmonary TB at the integrated TB-HIV outpatient clinic in Kampala, Uganda, were enrolled into the study and started on first-line anti-TB treatment...
September 18, 2017: BMJ Open
https://www.readbyqxmd.com/read/28895161/therapeutic-drug-monitoring-of-antitubercular-agents-for-disseminated-mycobacterium-tuberculosis-during-intermittent-haemodialysis-and-continuous-venovenous-haemofiltration
#12
J H Sin, R H Elshaboury, R M Hurtado, A R Letourneau, R G Gandhi
WHAT IS KNOWN AND OBJECTIVE: There is a lack of data regarding therapeutic drug monitoring (TDM) of antitubercular agents in the setting of continuous venovenous haemofiltration (CVVH). We describe TDM results of numerous antitubercular agents in a critically ill patient during CVVH and haemodialysis. CASE SUMMARY: A 49-year-old man was initiated on treatment for disseminated Mycobacterium tuberculosis. During hospital admission, the patient developed critical illness and required renal replacement therapy...
September 11, 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/28862186/food-significantly-reduces-plasma-concentrations-of-first-line-anti-tuberculosis-drugs
#13
Agibothu Kupparam Hemanth Kumar, Vedachalam Chandrasekaran, Angadi Kiran Kumar, M Kawaskar, J Lavanya, Soumya Swaminathan, Geetha Ramachandran
BACKGROUND & OBJECTIVES: Concomitant feeding and anti-tuberculosis (TB) drug administration are likely to reduce nausea and enhance compliance to treatment. However, food could lower plasma drug concentrations. This study was undertaken to examine the effect of food on two-hour plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA), and pharmacokinetics of these drugs in adult TB patients. METHODS: Newly diagnosed adult TB patients were recruited from the Revised National Tuberculosis Control Programme (RNTCP) treatment centres in Chennai Corporation, Chennai, India...
April 2017: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/28861054/screening-of-tb-actives-for-activity-against-nontuberculous-mycobacteria-delivers-high-hit-rates
#14
Jian Liang Low, Mu-Lu Wu, Dinah Binte Aziz, Benoît Laleu, Thomas Dick
The prevalence of lung disease due to infections with nontuberculous mycobacteria (NTM) has been increasing and surpassed tuberculosis (TB) in some countries. Treatment outcomes are often unsatisfactory, highlighting an urgent need for new anti-NTM medications. Although NTM in general do not respond well to TB specific drugs, the similarities between NTM and Mycobacterium tuberculosis at the molecular and cell structural level suggest that compound libraries active against TB could be leveraged for NTM drug discovery...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28859520/the-downfall-of-tba-354-a-possible-explanation-for-its-neurotoxicity-via-mass-spectrometric-imaging
#15
Sphamandla Ntshangase, Adeola Shobo, Hendrik G Kruger, Arndt Asperger, Dagmar Niemeyer, Per I Arvidsson, Thavendran Govender, Sooraj Baijnath
TBA-354 was a promising antitubercular compound with activity against both replicating and static Mycobacterium tuberculosis (M.tb), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LC-MS/MS) and mass spectrometric imaging (MSI), respectively...
September 1, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28843937/determination-of-protein-unbound-active-rifampicin-in-serum-by-ultrafiltration-and-ultra-performance-liquid-chromatography-with-uv-detection-a-method-suitable-for-standard-and-high-doses-of-rifampicin
#16
Eleonora W J van Ewijk-Beneken Kolmer, Marga J A Teulen, Erik C A van den Hombergh, Nielka E van Erp, Lindsey H M Te Brake, Rob E Aarnoutse
Rifampicin is the most important antibiotic in use for the treatment of tuberculosis (TB). Preclinical and clinical data suggest that higher doses of rifampicin, resulting in disproportionally higher systemic exposures to the drug, are more effective. Serum concentrations of rifampicin are the intermediary link between the dose administered and eventual response and only protein-unbound (free) rifampicin is pharmacologically active. The objective of this work was to develop an ultra performance liquid chromatography assay for protein-unbound rifampicin in serum with ultrafiltration, carried out at a sample temperature of 37°C, suitable for measurement of concentrations achieved after currently used and higher doses of rifampicin...
September 15, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28839086/erratum-for-peloquin-et-al-pharmacokinetic-evidence-from-the-hirif-trial-to-support-increased-doses-of-rifampin-for-tuberculosis
#17
C A Peloquin, G E Velásquez, L Lecca, R I Calderón, J Coit, M Milstein, E Osso, J Jimenez, K Tintaya, E Sanchez Garavito, D Vargas Vasquez, C D Mitnick, G Davies
No abstract text is available yet for this article.
September 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28838610/toxicological-profile-of-iqg-607-after-single-and-repeated-oral-administration-in-minipigs-an-essential-step-towards-phase-i-clinical-trial
#18
Valnês S Rodrigues-Junior, Luciana Cintra, Pablo Machado, Adílio Dadda, Luiz Augusto Basso, Ana Carolina Cintra Nunes Mafra, Alexandre Holthausen Campos, Maria Martha Campos, Diógenes Santiago Santos
IQG-607 is an anti-tuberculosis drug candidate, with a promising safety and efficacy profile in models of tuberculosis infection both in vitro and in vivo. Here, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in minipigs. Single oral administration of IQG-607 (220 mg/kg) to female and male minipigs did not result in any morbidity or mortality. No gross lesions were observed in the minipigs at necropsy. Repeated administration of IQG 607 (65, 30, or 15 mg/kg), given orally, for 90 days, in both male and female animals did not cause any mortality and no significant body mass alteration...
August 23, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28835350/development-of-water-soluble-3-5-dinitrophenyl-tetrazole-and-oxadiazole-antitubercular-agents
#19
Jaroslav Roh, Galina Karabanovich, Hana Vlčková, Alejandro Carazo, Jan Němeček, Pavel Sychra, Lenka Valášková, Oto Pavliš, Jiřina Stolaříková, Věra Klimešová, Kateřina Vávrová, Petr Pávek, Alexandr Hrabálek
In this work, four series of tertiary amine-containing derivatives of 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents were prepared, and their in vitro antimycobacterial effects were evaluated. We found that the studied compounds showed lipophilicity-dependent antimycobacterial activity. The N-benzylpiperazine derivatives, which had the highest lipophilicity among all of the series, showed the highest in vitro antimycobacterial activities against Mycobacterium tuberculosis CNCTC My 331/88 (H37Rv), comparable to those of the first-line drugs isoniazid and rifampicin...
August 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28817561/comparing-efficacies-of-moxifloxacin-levofloxacin-and-gatifloxacin-in-tuberculosis-granulomas-using-a-multi-scale-systems-pharmacology-approach
#20
Elsje Pienaar, Jansy Sarathy, Brendan Prideaux, Jillian Dietzold, Véronique Dartois, Denise E Kirschner, Jennifer J Linderman
Granulomas are complex lung lesions that are the hallmark of tuberculosis (TB). Understanding antibiotic dynamics within lung granulomas will be vital to improving and shortening the long course of TB treatment. Three fluoroquinolones (FQs) are commonly prescribed as part of multi-drug resistant TB therapy: moxifloxacin (MXF), levofloxacin (LVX) or gatifloxacin (GFX). To date, insufficient data are available to support selection of one FQ over another, or to show that these drugs are clinically equivalent. To predict the efficacy of MXF, LVX and GFX at a single granuloma level, we integrate computational modeling with experimental datasets into a single mechanistic framework, GranSim...
August 2017: PLoS Computational Biology
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