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pharmacokinetics And tuberculosis drugs

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https://www.readbyqxmd.com/read/29335214/in%C3%A2-vivo-potent-bm635-analogue-with-improved-drug-like-properties
#1
Giovanna Poce, Martina Cocozza, Salvatore Alfonso, Sara Consalvi, Giulia Venditti, Raquel Fernandez-Menendez, Robert H Bates, David Barros Aguirre, Lluis Ballell, Alessandro De Logu, Giulio Vistoli, Mariangela Biava
BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations around the central pyrrole core of BM635 and we describe the design, synthesis, biological evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues that show improved physicochemical properties. This hit-to-lead campaign led to the identification of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)morpholine (17), that shows excellent activity (MIC = 0...
December 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29317823/european-perspective-on-the-management-of-rheumatoid-arthritis-clinical-utility-of-tofacitinib
#2
REVIEW
Paweł Kawalec, Katarzyna Śladowska, Iwona Malinowska-Lipień, Tomasz Brzostek, Maria Kózka
Xeljanz® (tofacitinib) is an oral small-molecule inhibitor that reversibly inhibits Janus-activated kinase (JAK)-dependent cytokine signaling, thus reducing inflammation. As a result of these mechanisms, effects on the immune system such as a moderate decrease in the total lymphocyte count, a dose-dependent decrease in natural killer (NK) cell count, and an increase in B-cell count have been observed. Therefore, tofacitinib provides an innovative approach to modulating the immune and inflammatory responses in patients with rheumatoid arthritis (RA), which is especially important in individuals who do not respond to tumor necrosis factor inhibitors or show a loss of response over time...
2018: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/29311078/in-vitro-drug-susceptibility-of-mycobacterium-tuberculosis-for-amikacin-kanamycin-and-capreomycin
#3
J A Dijkstra, T van der Laan, O W Akkerman, M S Bolhuis, W C M de Lange, J G W Kosterink, T S van der Werf, J W C Alffenaar, D van Soolingen
Amikacin, kanamycin and capreomycin are listed among the most important 2nd line drugs for multidrug resistant tuberculosis. Although amikacin and kanamycin are administered in the same dose and show the same pharmacokinetics, they have different WHO breakpoints suggesting that the two drugs have a different minimal inhibitory concentrations (MIC). The aim of this paper was to investigate possible differences in MIC between the aminoglycosides and capreomycin.Using the direct concentration method, a concentration range of amikacin, kanamycin and capreomycin (0...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29311070/novel-pyrimidines-as-antitubercular-agents
#4
Daigo Inoyama, Steven D Paget, Riccardo Russo, Srinivasan Kandasamy, Pradeep Kumar, Eric Singleton, James Occi, Margareta Tuckman, Matthew D Zimmerman, Hsin Pin Ho, Alexander L Perryman, Véronique Dartois, Nancy Connell, Joel S Freundlich
Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that lack cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, physiochemical, and Absorption-Distribution-Metabolism-Excretion properties. Select pyrimidines were then evaluated for their mouse pharmacokinetic profiles...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29247506/suboptimal-anti-tuberculosis-drug-concentrations-and-outcomes-in-small-and-hiv-coinfected-children-in-india-recommendations-for-dose-modifications
#5
Benjamin Guiastrennec, Geetha Ramachandran, Mats O Karlsson, A K Hemanth Kumar, Perumal Kannabiran Bhavani, N Poorana Gangadevi, Soumya Swaminathan, Amita Gupta, Kelly E Dooley, Radojka M Savic
This work aimed to evaluate the once-daily anti-tuberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome...
December 16, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29244108/optimal-doses-of-rifampicin-in-the-standard-drug-regimen-to-shorten-tuberculosis-treatment-duration-and-reduce-relapse-by-eradicating-persistent-bacteria
#6
Yingjun Liu, Henry Pertinez, Fatima Ortega-Muro, Laura Alameda-Martin, Thomas Harrison, Geraint Davies, Anthony Coates, Yanmin Hu
Objectives: Although high-dose rifampicin holds promise for improving tuberculosis disease control by eradication of persistent bacteria, the optimal dose of rifampicin that kills persistent bacteria and shortens the treatment duration is unknown. Methods: The Cornell mouse model was used to test the efficacy of rifampicin at elevated doses combined with isoniazid and pyrazinamide to kill actively growing and persistent bacilli and to measure relapse rate. Persistent bacteria were evaluated using Mycobacterium tuberculosis culture supernatant containing resuscitation-promoting factors...
December 12, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29229639/whole-cell-screen-of-fragment-library-identifies-gut-microbiota-metabolite-indole-propionic-acid-as-antitubercular
#7
Dereje A Negatu, Joe J J Liu, Matthew Zimmerman, Firat Kaya, Véronique Dartois, Courtney C Aldrich, Martin Gengenbacher, Thomas Dick
Several key tuberculosis drugs including pyrazinamide, with a molecular weight of 123.1 g/mol, are smaller than the usual drug like molecules. Current drug discovery efforts focus on the screening of larger compounds with molecular weights centered around 400-500 g/mol. Fragment (molecular weight < 300 g/mol) libraries have not been systematically explored for antitubercular activity. Here we screened a collection of 1000 fragments, present in the Maybridge Ro3 library, for whole cell activity against Mycobacterium tuberculosis Twenty-nine primary hits showed dose-dependent growth inhibition equal or better than pyrazinamide...
December 11, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29227461/population-pharmacokinetics-of-lopinavir-in-severely-malnourished-hiv-infected-children-and-the-effect-on-treatment-outcomes
#8
Moherndran Archary, Helen Mcllleron, Raziya Bobat, Phillip La Russa, Thobekile Sibaya, Lubbe Wiesner, Stefanie Hennig
BACKGROUND: In developing countries, malnutrition remains a common clinical syndrome at antiretroviral treatment (ART) initiation. Physiological changes due to malnutrition and during nutritional recovery could affect the pharmacokinetics of antiretroviral drugs. METHODS: HIV-infected children admitted with severe acute malnutrition were randomised to early or delayed initiation of lopinavir/ritonavir, abacavir and lamivudine using WHO weight-band dosage charts...
December 8, 2017: Pediatric Infectious Disease Journal
https://www.readbyqxmd.com/read/29226732/pharmacokinetics-and-pharmacogenetics-of-anti-tubercular-drugs-a-tool-for-treatment-optimization
#9
Ilaria Motta, Andrea Calcagno, Stefano Bonora
WHO global strategy is to end tuberculosis epidemic by 2035. Pharmacokinetic and pharmacogenetic studies are increasingly performed and might confirm their potential role in optimizing treatment outcome in specific settings and populations. Insufficient drug exposure seems to be a relevant factor in tuberculosis outcome and for the risk of phenotypic resistance. Areas covered: This review discusses available pharmacokinetic and pharmacogenetic data of first and second-line antitubercular agents in relation to efficacy and toxicity...
January 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29218501/evaluating-safety-reporting-in-paediatric-antibiotic-trials-2000-2016-a-systematic-review-and-meta-analysis
#10
REVIEW
Paola Pansa, Yingfen Hsia, Julia Bielicki, Irja Lutsar, A Sarah Walker, Mike Sharland, Laura Folgori
BACKGROUND: There are very few options to treat multidrug-resistant bacterial infections in children. A major barrier is the duration and complexity of regulatory trials of new antibiotics. Extrapolation of safety data from adult trials could facilitate drug development for children. OBJECTIVE: We performed a systematic review on the safety of antibiotic clinical trials (CTs) in children (0-18 years) to evaluate the overall quality of safety trials conducted in children and to determine if age-specific adverse events (AEs) could be identified for specific antibiotic classes...
December 7, 2017: Drugs
https://www.readbyqxmd.com/read/29216273/isoniazid-concentrations-in-hair-and-plasma-area-under-the-curve-exposure-among-children-with-tuberculosis
#11
Vidya Mave, Aarti Kinikar, Anju Kagal, Smita Nimkar, Hari Koli, Sultanat Khwaja, Renu Bharadwaj, Roy Gerona, Anita Wen, Geetha Ramachandran, Hemanth Kumar, Peter Bacchetti, Kelly E Dooley, Nikhil Gupte, Amita Gupta, Monica Gandhi
We measured hair and plasma concentrations of isoniazid among sixteen children with tuberculosis who underwent personal or video-assisted directly observed therapy and thus had 100% adherence. This study therefore defined typical isoniazid exposure parameters after two months of treatment among fully-adherent patients in both hair and plasma (plasma area under the concentration-time curve, AUC, estimated using pharmacokinetic data collected 0, 2, 4, and 6 hours after drug administration). We found that INH levels in hair among highly-adherent individuals did not correlate well with plasma AUC or trough concentrations, suggesting that each measure may provide incremental and complementary information regarding drug exposure in the context of TB treatment...
2017: PloS One
https://www.readbyqxmd.com/read/29174840/physicochemical-pharmacokinetic-efficacy-and-toxicity-profiling-of-a-potential-nitrofuranyl-methyl-piperazine-derivative-iiim-mcd-211-for-oral-tuberculosis-therapy-via-in-silico-in-vitro-in-vivo-approach
#12
Asmita Magotra, Anjna Sharma, Samsher Singh, Probir Kumar Ojha, Sunil Kumar, Naveen Bokolia, Priya Wazir, Shweta Sharma, Inshad Ali Khan, Parvinder Pal Singh, Ram A Vishwakarma, Gurdarshan Singh, Utpal Nandi
Recent tuberculosis (TB) drug discovery programme involve continuous pursuit for new chemical entity (NCE) which can be not only effective against both susceptible and resistant strains of Mycobacterium tuberculosis (Mtb) but also safe and faster acting with the target, thereby shortening the prolonged TB treatments. We have identified a potential nitrofuranyl methyl piperazine derivative, IIIM-MCD-211 as new antitubercular agent with minimum inhibitory concentration (MIC) value of 0.0072 μM against H37Rv strain...
November 21, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29145924/pharmacokinetic-interaction-between-bedaquiline-and-clofazimine-in-patients-with-drug-resistant-tuberculosis
#13
G Maartens, M J E Brill, M Pandie, E M Svensson
<h2>BACKGROUND:</h2>Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis (DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ.<h2>METHODS:</h2>We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB...
November 16, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/29133558/pharmacokinetics-and-drug-drug-interactions-of-lopinavir-ritonavir-administered-with-first-and-second-line-antituberculosis-drugs-in-hiv-infected-children-treated-for-multidrug-resistant-tuberculosis
#14
Louvina E van der Laan, Anthony J Garcia-Prats, H Simon Schaaf, Tjokosela Tikiso, Lubbe Wiesner, Mine de Kock, Jana Winckler, Jennifer Norman, Helen McIlleron, Paolo Denti, Anneke C Hesseling
Background Lopinavir/ritonavir forms the backbone of current first-line antiretroviral regimens in young HIV-infected children. As multidrug-resistant (MDR) tuberculosis (TB) frequently occurs in young children in high-burden TB settings, it is important to identify potential interactions between MDR-TB treatment and lopinavir/ritonavir. We describe the pharmacokinetics of and potential drug-drug interactions between lopinavir/ritonavir and routine drugs used for MDR-TB treatment in HIV-infected children.Methods A combined population pharmacokinetic model was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir in 32 HIV-infected children (16 on MDR-TB treatment with combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a fluoroquinolone, and amikacin: and 16 without TB), who were established on a lopinavir/ritonavir-containing antiretroviral regimen...
November 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29130574/drug-interactions-between-rifamycin-antibiotics-and-hormonal-contraception-a-systematic-review
#15
Katharine B Simmons, Lisa B Haddad, Kavita Nanda, Kathryn M Curtis
BACKGROUND: Rifamycin antibiotics are commonly used for treatment of tuberculosis, but may reduce effectiveness of hormonal contraception (HC). OBJECTIVES: To determine whether interactions between rifamycins and HC result in decreased effectiveness or increased toxicity of either therapy. SEARCH STRATEGY: We searched MEDLINE, Embase, Cochrane and clinicaltrials. gov through May, 2017. SELECTION CRITERIA: We included trials, cohort, and case-control studies addressing pregnancy rates, pharmacodynamics, or pharmacokinetic (PK) outcomes when HC and rifamycins were administered together versus apart...
November 12, 2017: BJOG: An International Journal of Obstetrics and Gynaecology
https://www.readbyqxmd.com/read/29120971/a-systematic-review-of-salivary-versus-blood-concentrations-of-anti-tuberculosis-drugs-and-their-potential-for-salivary-therapeutic-drug-monitoring
#16
Simone H J van den Elsen, Lisette M Oostenbrink, Scott K Heysell, Daiki Hira, Daan J Touw, Onno W Akkerman, Mathieu S Bolhuis, Jan-Willem C Alffenaar
BACKGROUND: Therapeutic drug monitoring is useful in the treatment of tuberculosis to assure adequate exposure, minimize antibiotic resistance, and reduce toxicity. Salivary therapeutic drug monitoring could reduce the risks, burden, and costs of blood-based therapeutic drug monitoring. This systematic review compared human pharmacokinetics of anti-tuberculosis drugs in saliva and blood to determine if salivary therapeutic drug monitoring could be a promising alternative. METHODS: On December 2, 2016, PubMed and the Institute for Scientific Information Web of Knowledge were searched for pharmacokinetic studies reporting human salivary and blood concentrations of anti-tuberculosis drugs...
November 8, 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29101806/tetrandrine-and-cancer-an-overview-on-the-molecular-approach
#17
REVIEW
Bhagya N, Chandrashekar K R
Tetrandrine has been known in the treatment of tuberculosis, hyperglycemia, negative ionotropic and chronotropic effects on myocardium, malaria, cancer and fever since years together. It has been known that, tetrandrine could modulate multiple signaling molecules such as kinases of cell cycle and rat sarcoma (RAS) pathway along with proteins of tumor suppressor genes, autophagy related, β-catenins, caspases, and death receptors. Moreover, tetrandrine exhibited reversal of drug resistance by modulating P-glyco protein (P-gp) expression levels in different cancers which is an added advantage of this compound compared to other chemotherapy drugs...
November 1, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29095954/pyrazinamide-clearance-is-impaired-among-hiv-tuberculosis-patients-with-high-levels-of-systemic-immune-activation
#18
Christopher Vinnard, Shruthi Ravimohan, Neo Tamuhla, Jotam Pasipanodya, Shashikant Srivastava, Chawangwa Modongo, Nicola M Zetola, Drew Weissman, Tawanda Gumbo, Gregory P Bisson
Pyrazinamide is the main driver of sterilizing effect in the standard regimen in adults and older children, and this effect is concentration-dependent. Tuberculosis patients co-infected with human immunodeficiency virus (HIV) have an increased risk for poor tuberculosis treatment outcomes and adverse drug events. We sought to determine whether measures of systemic immune activation were related to pyrazinamide pharmacokinetics among HIV/tuberculosis patients. We conducted a prospective cohort study of pyrazinamide pharmacokinetics in HIV/tuberculosis patients in Gaborone, Botswana...
2017: PloS One
https://www.readbyqxmd.com/read/29066867/clinical-and-pharmacological-hallmarks-of-rifapentine-s-use-in-diabetes-patients-with-active-and-latent-tuberculosis-do-we-know-enough
#19
REVIEW
Chunlan Zheng, Xiufen Hu, Li Zhao, Minhui Hu, Feng Gao
Rifapentine is a rifamycin derivate approved by the US Food and Drug Administration in 1998 for the treatment of active, drug-susceptible tuberculosis (TB). In 2014, rifapentine was approved for the treatment of latent TB infection in patients at high risk of progression to active disease and is currently under evaluation by the European Medicines Agency. Expanding indications of rifapentine largely affect diabetes patients, since about one-third of them harbor latent TB. Clinical consequences of rifapentine use in this population and potentially harmful interactions with hypoglycemic agents are widely underexplored and generally considered similar to the ones of rifampicin...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29063794/critical-physicochemical-and-biological-attributes-of-nanoemulsions-for-pulmonary-delivery-of-rifampicin-by-nebulization-technique-in-tuberculosis-treatment
#20
Kifayatullah Shah, Lai Wah Chan, Tin Wui Wong
The study investigated aerosolization, pulmonary inhalation, intracellular trafficking potential in macrophages and pharmacokinetics profiles of rifampicin-oleic acid first-generation nanoemulsion and its respective chitosan- and chitosan-folate conjugate-decorated second and third-generation nanoemulsions, delivered via nebulization technique. The nanoemulsions were prepared by conjugate synthesis and spontaneous emulsification techniques. They were subjected to physicochemical, drug release, aerosolization, inhalation, cell culture and pharmacokinetics analysis...
November 2017: Drug Delivery
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