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Tuberculosis pharmacokinetics

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https://www.readbyqxmd.com/read/28205025/the-multistate-tuberculosis-pharmacometric-model-a-semi-mechanistic-pharmacokinetic-pharmacodynamic-model-for-studying-drug-effects-in-an-acute-tuberculosis-mouse-model
#1
Chunli Chen, Fatima Ortega, Joaquin Rullas, Laura Alameda, Iñigo Angulo-Barturen, Santiago Ferrer, Ulrika Sh Simonsson
The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day)...
February 15, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28193650/interaction-of-rifampicin-and-darunavir-ritonavir-or-darunavir-cobicistat-in-vitro
#2
Owain Roberts, Saye Khoo, Andrew Owen, Marco Siccardi
Treatment of HIV patients co-infected with tuberculosis (TB) is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and anti-TB drugs. The aim of this study was to quantify the effects of cobicistat (COBI), or ritonavir (RTV), in modulating DDIs between darunavir (DRV) and rifampicin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone, or in combination with either COBI or RTV for three days, followed by co-incubation with DRV for one hour...
February 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28174307/a-bioengineered-three-dimensional-cell-culture-platform-integrated-with-microfluidics-to-address-antimicrobial-resistance-in-tuberculosis
#3
Magdalena K Bielecka, Liku B Tezera, Robert Zmijan, Francis Drobniewski, Xunli Zhang, Suwan Jayasinghe, Paul Elkington
: Antimicrobial resistance presents one of the most significant threats to human health, with the emergence of totally drug-resistant organisms. We have combined bioengineering, genetically modified bacteria, longitudinal readouts, and fluidics to develop a transformative platform to address the drug development bottleneck, utilizing Mycobacterium tuberculosis as the model organism. We generated microspheres incorporating virulent reporter bacilli, primary human cells, and an extracellular matrix by using bioelectrospray methodology...
February 7, 2017: MBio
https://www.readbyqxmd.com/read/28163165/the-risk-of-global-epidemic-replacement-with-drug-resistant-mycobacterium-tuberculosis-strains
#4
REVIEW
Emma S McBryde, Michael T Meehan, Tan N Doan, Romain Ragonnet, Ben J Marais, Vanina Guernier, James M Trauer
OBJECTIVES: Multidrug-resistant tuberculosis (MDR-TB) is a threat to tuberculosis (TB) control. To guide TB control, it is essential to understand the extent to which and the circumstances in which MDR-TB will replace drug-susceptible TB (DS-TB) as the dominant phenotype. The issue was examined by assessing evidence from genomics, pharmacokinetics, and epidemiology studies. This evidence was then synthesized into a mathematical model. METHODS: This model considers two TB strains, one with and one without an MDR phenotype...
February 2, 2017: International Journal of Infectious Diseases: IJID
https://www.readbyqxmd.com/read/28162875/diagnosis-of-spinal-lesions-using-heuristic-and-pharmacokinetic-parameters-measured-by-dynamic-contrast-enhanced-mri
#5
Ning Lang, Huishu Yuan, Hon J Yu, Min-Ying Su
RATIONALE AND OBJECTIVES: This study aimed to evaluate the diagnostic performance of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in differentiation of four spinal lesions by using heuristic and pharmacokinetic parameters analyzed from DCE signal intensity time course. MATERIALS AND METHODS: DCE-MRI of 62 subjects with confirmed myeloma (n = 9), metastatic cancer (n = 22), lymphoma (n = 7), and inflammatory tuberculosis (TB) (n = 24) in the spine were analyzed retrospectively...
February 2, 2017: Academic Radiology
https://www.readbyqxmd.com/read/28141813/determination-of-plasma-concentrations-of-levofloxacin-by-high-performance-liquid-chromatography-for-use-at-a-multidrug-resistant-tuberculosis-hospital-in-tanzania
#6
Andrew Ebers, Suzanne Stroup, Stellah Mpagama, Riziki Kisonga, Isaack Lekule, Jie Liu, Scott Heysell
Therapeutic drug monitoring may improve multidrug-resistant tuberculosis (MDR-TB) treatment outcomes. Levofloxacin demonstrates significant individual pharmacokinetic variability. Thus, we sought to develop and validate a high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection for levofloxacin in patients on MDR-TB treatment. The HPLC-UV method is based on a solid phase extraction (SPE) and a direct injection into the HPLC system. The limit of quantification was 0.25 μg/mL, and the assay was linear over the concentration range of 0...
2017: PloS One
https://www.readbyqxmd.com/read/28137814/pharmacokinetic-modeling-and-limited-sampling-strategies-based-on-healthy-volunteers-for-monitoring-of-ertapenem-in-mdr-tb-patients
#7
S P van Rijn, M A Zuur, R van Altena, O W Akkerman, J H Proost, W C M de Lange, H A M Kerstjens, D J Touw, T S van der Werf, J G W Kosterink, J W C Alffenaar
BACKGROUND: Ertapenem is a broad spectrum carbapenem antibiotic and is being explored against Mycobacterium tuberculosis Carbapenems have anti-bacterial activity when the plasma concentration exceeds the minimal inhibitory concentration at least 40% of the time (40%T>MIC). To assess 40%T>MIC in multidrug-resistant tuberculosis (MDR-TB) patients, a limited sampling strategy was developed using a population pharmacokinetic model based on healthy volunteers. METHODS: A two-compartment population pharmacokinetic model was developed from data in forty-two healthy volunteers, using an iterative two-stage Bayesian method...
January 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28124478/defining-the-optimal-dose-of-rifapentine-for-pulmonary-tuberculosis-exposure-response-relations-from-two-phase-2-clinical-trials
#8
Radojka M Savic, Marc Weiner, William R Mac Kenzie, Melissa Engle, William C Whitworth, John L Johnson, Pheona Nsubuga, Payam Nahid, Nhung Viet Nguyen, Charles A Peloquin, Kelly E Dooley, Susan E Dorman
Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling...
January 25, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28122892/safety-efficacy-and-pharmacokinetics-of-humanized-anti-cd52-monoclonal-antibody-alemtuzumab-in-japanese-patients-with-relapsed-or-refractory-b-cell-chronic-lymphocytic-leukemia
#9
Kenichi Ishizawa, Noriko Fukuhara, Chiaki Nakaseko, Shigeru Chiba, Michinori Ogura, Akihiko Okamoto, Yoshinori Sunaga, Kensei Tobinai
OBJECTIVE: To evaluate the safety, efficacy and pharmacokinetics of alemtuzumab in Japanese patients, we conducted a phase I study in patients with relapsed or refractory B-cell chronic lymphocytic leukemia. METHODS: Six patients received alemtuzumab by intravenous infusion every other day three times a week for 12 weeks. The dose was gradually escalated on daily basis (3, 10 and then 30 mg) until the patient tolerated. The primary objective was to evaluate the safety of alemtuzumab in Japanese patients and the secondary objectives were to evaluate the overall response rate and the pharmacokinetics...
January 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28111912/in-silico-approaches-and-chemical-space-of-anti-p-type-atpase-compounds-for-discovering-new-antituberculous-drugs
#10
REVIEW
Paola Santos, Fabian López-Vallejo, Carlos-Y Soto
Tuberculosis (TB) is one of the most important public health problems around the world. The emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis strains has driven the finding of alternative anti-TB targets. In this context, P-type ATPases are interesting therapeutic targets due to their key role in ion homeostasis across the plasma membrane and the mycobacterial survival inside macrophages. In this review, in silico and experimental strategies used for the rational design of new anti-TB drugs are presented; in addition, the chemical space distribution based on the structure and molecular properties of compounds with anti-TB and anti-P-type ATPase activity is discussed...
January 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28092695/absorption-distribution-and-excretion-of-the-anti-tuberculosis-drug-delamanid-in-rats-extensive-tissue-distribution-suggests-potential-therapeutic-value-for-extrapulmonary-tuberculosis
#11
Masakazu Shibata, Yoshihiko Shimokawa, Katsunori Sasahara, Noriaki Yoda, Hiroyuki Sasabe, Mitsunari Suzuki, Ken Umehara
Delamanid (OPC-67683, Deltyba(TM) , nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution, and excretion of delamanid-derived radioactivity were investigated after a single oral administration of (14) C-delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 hours postdose, and thereafter decreased slowly. Radioactivity levels were 3- to 5-fold higher in lung tissue at time to maximum concentration compared with plasma...
January 16, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28069654/reduced-chance-of-hearing-loss-associated-with-therapeutic-drug-monitoring-of-aminoglycosides-in-the-treatment-of-multidrug-resistant-tuberculosis
#12
R van Altena, J A Dijkstra, M E van der Meer, J F Borjas Howard, J G W Kosterink, D van Soolingen, T S van der Werf, J W C Alffenaar
Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our Tuberculosis Center, we have employed therapeutic drug monitoring (TDM) targeting pre-set pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto-)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of TB patients treated with amikacin or kanamycin in the period 2000 - 2012.Patients with culture-confirmed multi- or extensively drug resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study...
January 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28052847/subcellular-partitioning-and-intra-macrophage-selectivity-of-antimicrobial-compounds-against-mycobacterium-tuberculosis
#13
Michael D Schump, Douglas M Fox, Carolyn R Bertozzi, Lee W Riley
The efficacy of antimicrobial drugs against Mycobacterium tuberculosis (Mtb), an intracellular bacterial pathogen, is generally first established by testing compounds against bacteria in axenic culture. However, inside of infected macrophages bacteria encounter an environment which differs substantially from broth culture and are subject to important host-dependent pharmacokinetic phenomena which modulate drug activity. Here we describe how pH dependent partitioning drives asymmetric antimicrobial drug distribution in Mtb infected macrophages...
January 4, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28043603/individualized-treatment-of-multidrug-resistant-tuberculosis-using-therapeutic-drug-monitoring
#14
Mathieu S Bolhuis, Onno W Akkerman, Marieke G G Sturkenboom, Wiel C M de Lange, Tjip S van der Werf, Jan-Willem C Alffenaar
OBJECTIVE/BACKGROUND: Globally, approximately 50% of patients with multidrug-resistant tuberculosis (MDR-TB) experience treatment failure. MDR-TB treatment is hindered by adverse events, toxicity of the second-line anti-TB drugs, logistics and costs, especially in low-income countries, and problems with medication adherence. Pharmacokinetic variability is also attributed as one of the reasons contributing to treatment failure. In our reference Tuberculosis Center Beatrixoord (University Medical Center Groningen, Groningen, The Netherlands), we strive to individualize treatment of all MDR-TB patients based on drug-susceptibility testing using minimal inhibitory concentrations and pharmacokinetic parameters...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28043500/design-and-development-of-novel-inhibitors-for-the-treatment-of-latent-tuberculosis
#15
Rudraraju Srilakshmi Reshma, Perumal Yogeeswari, Dharmarajan Sriram
OBJECTIVE/BACKGROUND: "The captain of all these men of death", is the apt sobriquet for the age-old disease tuberculosis (TB). Despite the availability of many drugs, cases of increasing resistance in the forms of multi-drug and extensively drug-resistant TB and persistence [characteristic of Mycobacterium tuberculosis (MTB)] make the eradication of TB a nightmare. Approval of bedaquiline by the Food and Drug Administration focused attention on quinoline scaffolds for development of new anti-TB agents...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28038962/confirming-model-predicted-pharmacokinetic-interactions-between-bedaquiline-and-lopinavir-ritonavir-or-nevirapine-in-patients-with-hiv-and-drug-resistant-tuberculosis
#16
Margreke J E Brill, Elin M Svensson, Mishal Pandie, Gary Maartens, Mats O Karlsson
Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug-drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14)...
December 14, 2016: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/27994440/use-of-bedaquiline-and-delamanid-in-diabetes-patients-clinical-and-pharmacological-considerations
#17
REVIEW
Minhui Hu, Chunlan Zheng, Feng Gao
Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo(®) (bedaquiline) and Deltyba(®) (delamanid), novel drugs for multidrug-resistant tuberculosis (MDR-TB), are recommended for diabetes patients when another effective treatment regimen cannot be provided. Currently, there are no clinical data related to the use of these agents in diabetes patients...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27955992/pediatric-multidrug-resistant-tuberculosis-clinical-trials-challenges-and-opportunities
#18
REVIEW
S E McAnaw, A C Hesseling, J A Seddon, K E Dooley, A J Garcia-Prats, S Kim, H E Jenkins, H S Schaaf, T R Sterling, C R Horsburgh
On June 17, 2016, RESIST-TB, IMPAACT, Vital Strategies, and New Ventures jointly hosted the Pediatric Multidrug Resistant Tuberculosis Clinical Trials Landscape Meeting in Arlington, Virginia, USA. The meeting provided updates on current multidrug-resistant tuberculosis (MDR-TB) trials targeting pediatric populations and adult trials that have included pediatric patients. A series of presentations were given that discussed site capacity needs, community engagement, and additional interventions necessary for clinical trials to improve the treatment of pediatric MDR-TB...
December 9, 2016: International Journal of Infectious Diseases: IJID
https://www.readbyqxmd.com/read/27865404/formulation-studies-of-inha-inhibitors-and-combination-therapy-to-improve-efficacy-against-mycobacterium-tuberculosis
#19
Susan E Knudson, Jason E Cummings, Gopal R Bommineni, Pan Pan, Peter J Tonge, Richard A Slayden
Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient efficacy in the acute murine Mtb infection model. A next generation series of compounds were designed with improved specificity, potency against InhA, and reduced cytotoxicity in vitro, but these compounds also had limited solubility. Accordingly, solubility and pharmacokinetics studies were performed to develop formulations for this class and other experimental drug candidates with high logP values often encountered in drug discovery...
December 2016: Tuberculosis
https://www.readbyqxmd.com/read/27863179/population-pharmacokinetics-of-bedaquiline-and-metabolite-m2-in-patients-with-drug-resistant-tuberculosis-the-effect-of-time-varying-weight-and-albumin
#20
E M Svensson, A-G Dosne, M O Karlsson
Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time...
December 2016: CPT: Pharmacometrics & Systems Pharmacology
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