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Tuberculosis pharmacokinetics

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https://www.readbyqxmd.com/read/28626525/identification-of-better-pharmacokinetic-benzothiazinone-derivatives-as-new-antitubercular-agents
#1
Kai Lv, Xuefu You, Bin Wang, Zengquan Wei, Yun Chai, Bo Wang, Apeng Wang, Guocheng Huang, Mingliang Liu, Yu Lu
A series of new 8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one(BTZ) derivatives containing a C-2 nitrogen spiro-heterocycle moiety based on the structures of BTZ candidates BTZ043 and PBTZ169 were designed and synthesized as new antitubercular agents. Many of them were found to have excellent in vitro activity (MIC < 0.15 μM) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically isolated multidrug-resistant strains. Compounds 11l and 11m display acceptable safety, greater aqueous solubility, and better pharmacokinetic profiles than PBTZ169, suggesting their promising potential to be lead compounds for future antitubercular drug discovery...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28623772/development-and-validation-of-a-highly-sensitive-lc-esi-ms-ms-method-for-estimation-of-iiim-mcd-211-a-novel-nitrofuranyl-methyl-piperazine-derivative-with-potential-activity-against-tuberculosis-application-to-drug-development
#2
Asmita Magotra, Anjna Sharma, Ajai Prakash Gupta, Priya Wazir, Shweta Sharma, Parvinder Pal Singh, Manoj Kumar Tikoo, Ram A Vishwakarma, Gurdarshan Singh, Utpal Nandi
In the present study, a simple, sensitive, specific and rapid liquid chromatography (LC) tandem mass spectrometry (MS/MS) method was developed and validated according to the Food and Drug Administration (FDA) guidelines for estimation of IIIM-MCD-211 (a potent oral candidate with promising action against tuberculosis) in mice plasma using carbamazepine as internal standard (IS). Bioanalytical method consisted of one step protein precipitation for sample preparation followed by quantitation in LC-MS/MS using positive electrospray ionization technique (ESI) operating in multiple reaction monitoring (MRM) mode...
June 8, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28609019/synthesis-biological-evaluation-and-molecular-docking-studies-of-novel-3-aryl-5-alkyl-thio-1h-1-2-4-triazoles-derivatives-targeting-mycobacterium-tuberculosis
#3
Navnath D Rode, Amol D Sonawane, Laxman Nawale, Vijay M Khedkar, Ramesh A Joshi, Anjali P Likhite, Dhiman Sarkar, Rohini R Joshi
A small library of new 3-aryl-5-(alkyl-thio)-1H-1,2,4-triazoles was synthesized and screened for the anti-mycobacterial potency against M. tuberculosis H37 Ra strain and M. bovis BCG both in active and dormant stage. Among the synthesized library, 25 compounds exhibited promising anti-TB activity in the range of IC50 0.03-5.88 μg/mL for dormant stage and 20 compounds in the range of 0.03-6.96 μg/mL for active stage. Their lower toxicity (>100 μg/mL) and higher selectivity (SI = >10) against all cancer cell lines screened makes them interesting compounds with potential anti-mycobacterial effects...
June 13, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28607022/pharmacokinetics-of-pyrazinamide-optimising-dosing-regimens-for-drug-sensitive-and-resistant-tuberculosis
#4
Maxwell T Chirehwa, Helen McIlleron, Roxana Rustomjee, Thuli Mthiyane, Philip Onyebujoh, Peter Smith, Paolo Denti
Pyrazinamide is used in the treatment of tuberculosis(TB) because its sterilising effect against tubercle bacilli allows treatment shortening. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multi-drug resistant tuberculosis(MDR-TB)...
June 12, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28584143/linezolid-dose-that-maximizes-sterilizing-effect-while-minimizing-toxicity-and-resistance-emergence-for-tuberculosis
#5
Shashikant Srivastava, Gesham Magombedze, Thearith Koeuth, Carleton Sherman, Jotam G Pasipanodya, Prithvi Raj, Edward Wakeland, Devyani Deshpande, Tawanda Gumbo
Linezolid has excellent sterilizing effect in tuberculosis patients, but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics, and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months...
June 5, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28561946/new-paradigm-for-translational-modeling-to-predict-long-term-tuberculosis-treatment-response
#6
I H Bartelink, N Zhang, R J Keizer, N Strydom, P J Converse, K E Dooley, E L Nuermberger, R M Savic
Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse-to-human translational pharmacokinetics (PKs) - pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species-specific protein binding, drug-drug interactions, and patient-specific pathology...
May 31, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28559269/pharmacokinetic-evidence-to-support-increased-doses-of-rifampin-for-tuberculosis-results-from-the-hirif-trial
#7
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
Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to 10, 15, and 20 mg/kg/day of rifampin. 168 had noncompartmental pharmacokinetic analyses: 67% were sampled twice; 33% six times. Doses were well-tolerated. Median (interquartile range) AUC0-6 was 24.9 (17.6-32.1), 43.1 (30.3-57.5), and 55.5 (35.7-73.2) h*mcg/mL; median Cmax in the experimental arms reached the target of 8 mcg/mL...
May 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28552479/biopharmaceutic-parameters-pharmacokinetics-transport-and-cyp-mediated-drug-interactions-of-iiim-017-a-novel-nitroimidazooxazole-analogue-with-anti-tuberculosis-activity
#8
Gurleen Kour, Parvinder Pal Singh, Asha Bhagat, Zabeer Ahmed
Nitroimidazoles are emerging as a new class of therapeutic agents with potent anti-tubercular activity. CSIR-IIIM has synthesized a novel nitrohydroimidazooxazole (NHIO) analogue, IIIM-017 with a MIC of 0.37μg/ml (against H37Rv). Here, we aim at further exploration of physicochemical properties and preclinical absorption, metabolism, disposition and pharmacokinetics of IIIM-017. In this study, in silico physicochemical parameters, lipophilicity, permeability, transport, hepatotoxicity, CYP mediated drug interactions and pharmacokinetics of IIIM-017 were investigated...
May 26, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28546104/development-of-a-paediatric-physiologically-based-pharmacokinetic-model-to-assess-the-impact-of-drug-drug-interactions-in-tuberculosis-co-infected-malaria-subjects-a-case-study-with-artemether-lumefantrine-and-the-cyp3a4-inducer-rifampicin
#9
Olusola Olafuyi, Michael Coleman, Raj K S Badhan
The fixed dosed combination of artemether and lumefantrine (AL) is widely used for the treatment of malaria in adults and children in sub-Sahara Africa, with lumefantrine day 7 concentrations being widely used as a marker for clinical efficacy. Both are substrates for CYP3A4 and susceptible to drug-drug interactions (DDIs); indeed, knowledge of the impact of these factors is currently sparse in paediatric population groups. Confounding malaria treatment is the co-infection of patients with tuberculosis. The concomitant treatment of AL with tuberculosis chemotherapy, which includes the CYP3A4 inducer rifampicin, increases the risk of parasite recrudescence and malaria treatment failure...
May 22, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28528008/-role-of-therapeutic-drug-monitoring-in-pulmonary-infections
#10
REVIEW
C Padoin
Pulmonary infections are common and caused by a wide range of viruses, bacteria, parasites and fungi. They consist of lower respiratory tract infections with community and hospital acquired acute pneumonia, bronchitis, lung abscess, fungal infections and tuberculosis. The management of these infections should be based on guidelines that take into account the microorganisms most frequently involved as a basis for empirical treatment, with identification of causative microorganisms allowing targeted treatments...
May 17, 2017: Revue des Maladies Respiratoires
https://www.readbyqxmd.com/read/28523106/discovery-of-fluorine-containing-benzoxazinyl-oxazolidinones-for-the-treatment-of-multidrug-resistant-tuberculosis
#11
Hongyi Zhao, Yu Lu, Li Sheng, Zishuo Yuan, Bin Wang, Weiping Wang, Yan Li, Chen Ma, Xiaoliang Wang, Dongfeng Zhang, Haihong Huang
A novel series of fluorine-containing benzoxazinyl-oxazolidinones were designed and synthesized as antidrug-resistant tuberculosis agents possessing good activity and improved pharmacokinetic profiles. Compound 21 exhibited not only outstanding in vitro activity with a MIC value of 0.25-0.50 μg/mL against drug-susceptible H37Rv strain and two clinically isolated drug-resistant Mycobacterium tuberculosis strains, but also acceptable in vitro ADME/T properties. Moreover, this compound displayed excellent mouse pharmacokinetic profiles with an oral bioavailability of 102% and a longer elimination half-life of 4...
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28518128/an-in-vitro-caseum-binding-assay-that-predicts-drug-penetration-in-tuberculosis-lesions
#12
Jansy P Sarathy, Hsin-Pin Ho Liang, Danielle Weiner, Jacqueline Gonzales, Laura E Via, Véronique Dartois
The eradication of tuberculosis disease requires drug regimens that can penetrate the multiple layers of complex pulmonary lesions. Drug distribution in the caseous cores of cavities and lesions is especially crucial because they harbor subpopulations of drug-tolerant bacteria also commonly referred to as persisters. Existing methods for the measurement of drug penetration in tuberculosis lesions involve costly and time-consuming in vivo pharmacokinetic studies coupled to bioanalytical or imaging techniques...
May 8, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28510480/dry-powder-inhaler-formulation-of-rifampicin-an-improved-targeted-delivery-system-for-alveolar-tuberculosis
#13
Tejal Rawal, Laurent Kremer, Iman Halloum, Shital Butani
BACKGROUND: The delivery of antitubercular drugs through direct lung targeting can lead to reduction in the dose as well as side effects of the drug. In the present investigation, carrier (lactose)-based dry-powder inhaler of rifampicin was prepared to achieve direct targeting of the drug into the lungs. METHODS: The dry powder inhaler formulation was prepared by simply mixing micronized rifampicin with coarse and fine lactose preblend. Preliminary blends of the drug were prepared with various lactose grades (Inhalac(®), Respitose,(®) and Lactohale(®))...
May 16, 2017: Journal of Aerosol Medicine and Pulmonary Drug Delivery
https://www.readbyqxmd.com/read/28510418/conjugation-reaction-with-8-arm-peg-markedly-improves-the-immunogenicity-of-mycobacterium-tuberculosis-cfp10-tb10-4-fusion-protein
#14
Xiaowei Sun, Weili Yu, Quanhai Pang, Tao Hu
Mycobacterium tuberculosis (Mtb) is a serious fatal pathogen responsible for tuberculosis (TB). Effective vaccination is highly desired for immunoprotection against Mtb infection. CFP10 and TB10.4 are two important immunodominant Mtb-secreted protein antigens, which suffer from poor immunogenicity. Thus, an antigen delivery system and adjuvants are needed to improve the immunogenicity of the two proteins. A CFP10-TB10.4 fusion protein (CT) was used as the antigen in the present study. Conjugation of 4-6 CT molecules in one entity with 8-arm polyethylene glycol (PEG) acted as an antigen delivery system...
June 21, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28507117/pharmacokinetics-of-levofloxacin-in-multidrug-and-extensively-drug-resistant-tuberculosis-patients
#15
Natasha Van't Boveneind-Vrubleuskaya, Tatiana Seuruk, Kai van Hateren, Tridia van der Laan, Jos G W Kosterink, Tjip S van der Werf, Dick van Soolingen, Susan van den Hof, Alena Skrahina, Jan-Willem C Alffenaar
Pharmacodynamics are important in treatment of especially multidrug- and extensively resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to minimal inhibitory concentration (fAUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter to predict the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for fAUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of treatment regimen at a dose of 15 mg/kg once daily...
May 15, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28506804/chloroquine-enhances-the-antimycobacterial-activity-of-isoniazid-and-pyrazinamide-by-reversing-inflammation-induced-macrophage-efflux
#16
U Matt, P Selchow, M Dal Molin, S Strommer, O Sharif, K Schilcher, F Andreoni, A Stenzinger, A S Zinkernagel, M Zeitlinger, P Sander, J Nemeth
Mycobacterium tuberculosis (MTB) is notorious for persisting within host macrophages. Efflux pumps decrease intracellular drug levels, thus fostering persistence of MTB during therapy. Isoniazid (INH) and pyrazinamide (PZA) are substrates of the efflux pump breast cancer resistance protein-1 (BCRP-1), which is inhibited by chloroquine (CQ). In this study, BCRP-1 was found to be expressed on macrophages of human origin and on foamy giant cells at the site of MTB infection. In the current in vitro study, interferon-gamma (IFNγ) increased the expression of BCRP-1 in macrophages derived from the human monocytic leukaemia cell line THP-1...
May 12, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28495479/limited-sampling-strategies-for-determining-the-area-under-the-plasma-concentration-time-curve-for-isoniazid-might-be-a-valuable-approach-for-optimizing-treatment-in-adult-patients-with-tuberculosis
#17
Piergiorgio Cojutti, Manuela Giangreco, Miriam Isola, Federico Pea
This study aimed to develop clinically feasible models of limited sampling strategy (LSS) for estimation of the area under the concentration-time curve (AUC24h) for isoniazid, that could be applied easily in daily clinical practice for dosage adjustment in adult patients with tuberculosis. Isoniazid plasma concentrations (n = 1665) from 185 adult tuberculous patients were used for the development and validation of LSS models to estimate AUC24h following administration of the standard 5 mg/kg dose of isoniazid...
May 8, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28461315/genetic-determinants-of-the-pharmacokinetic-variability-of-rifampicin-in-malawian-adults-with-pulmonary-tuberculosis
#18
Derek J Sloan, Andrew D McCallum, Alessandro Schipani, Deirdre Egan, Henry C Mwandumba, Steve A Ward, David Waterhouse, Gertrude Banda, Theresa J Allain, Andrew Owen, Saye H Khoo, Geraint R Davies
Variable exposure to anti-tuberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampicin. We evaluated the contribution of Single Nucleotide Polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC, CES-1) to inter-individual pharmacokinetic variability in Malawi. 174 adults with pulmonary TB underwent sampling of plasma rifampicin concentrations at 2- and 6-hours post-dose...
May 1, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28423019/design-synthesis-and-structure-activity-relationship-study-of-wollamide-b-a-new-potential-anti-tb-agent
#19
Henok Asfaw, Katja Laqua, Anna Maria Walkowska, Fraser Cunningham, Maria Santos Martinez-Martinez, Juan Carlos Cuevas-Zurita, Lluís Ballell-Pages, Peter Imming
Wollamide B is a cationic antimycobacterial cyclohexapeptide that exhibits activity against Mycobacterium bovis (M. bovis) (IC50 of 3.1 μM). Aiming to define its structural activity relationship (SAR), optimizing potency and pharmacokinetic properties, libraries of analogues were synthesized following a standard Fmoc-based solid phase peptide synthesis approach. The antimycobacterial activities of wollamide B and all the synthesized analogues were tested against Mycobacterium tuberculosis (Mtb) H37Rv. Parallely, in vitro drug metabolism and pharmacokinetic (ADME) profiling was done for the synthesized compounds to evaluate their drug likeness...
2017: PloS One
https://www.readbyqxmd.com/read/28408267/population-pharmacokinetics-of-moxifloxacin-cycloserine-p-aminosalicylic-acid-and-kanamycin-for-the-treatment-of-multi-drug-resistant-tuberculosis
#20
Min Jung Chang, Byunghak Jin, Jung-Woo Chae, Hwi-Yeol Yun, Eun Sun Kim, Yeon Joo Lee, Young-Jae Cho, Ho Il Yoon, Choon-Taek Lee, Kyoung Un Park, Junghan Song, Jae-Ho Lee, Jong Sun Park
Control of multi-drug-resistant tuberculosis (MDR-TB) requires extensive, supervised chemotherapy because second-line anti-TB drugs have a narrower therapeutic range than first-line drugs. This study aimed to develop population pharmacokinetic (PK) models for second-line drugs in patients with MDR-TB, evaluate the recommended dosage regimens and, if necessary, suggest new dosage regimens. A prospective, single-centre PK study was performed on second-line anti-TB drugs in patients with MDR-TB. Moxifloxacin, cycloserine, p-aminosalicylic acid (PAS), kanamycin and other second-line drugs were administered to the patients...
June 2017: International Journal of Antimicrobial Agents
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