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Tuberculosis pharmacokinetics

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https://www.readbyqxmd.com/read/29680666/synthesis-and-biological-evaluation-of-aryl-oxadiazoles-as-inhibitors-of-mycobacterium-tuberculosis
#1
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...
April 13, 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
#2
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
#3
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
#4
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
#5
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-hiv-and-tuberculosis-burden-countries-a-systematic-review
#6
REVIEW
Daniel Atwine, Maryline Bonnet, Anne-Marie Taburet
AIMS: Efavirenz (EFV) and Rifampicin-Isoniazid (RH) are cornerstone drugs in HIV-tuberculosis (TB) co-infection 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 co-administration in co-infected 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
#7
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...
April 5, 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
#8
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
#9
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
https://www.readbyqxmd.com/read/29579424/a-selective-and-sensitive-high-performance-liquid-chromatography-assay-for-the-determination-of-cycloserine-in-human-plasma
#10
A K Hemanth Kumar, Arun Kumar Polisetty, V Sudha, A Vijayakumar, Geetha Ramachandran
BACKGROUND: Cycloserine (CYC) is a second line antitubercular drug that is used for the treatment of multidrug resistant tuberculosis (MDR-TB) along with other antitubercular agents and is often used in developing countries. Monitoring CYC levels in plasma could be useful in the clinical management of patients with MDR-TB. A high performance liquid chromatography method for the determination of CYC in human plasma was developed. METHODS: The method involved extraction of the sample using solid phase extraction cartridges and analysis of the extracted sample using a reverse phase T3 column (150mm) and detection at 240nm with Photo Diode Array (PDA) detector...
April 2018: Indian Journal of Tuberculosis
https://www.readbyqxmd.com/read/29561515/effect-of-co-administration-of-lidocaine-on-the-pain-and-pharmacokinetics-of-intramuscular-amikacin-in-children-with-multidrug-resistant-tuberculosis-a-randomized-crossover-trial
#11
Anthony J Garcia-Prats, Penelope C Rose, Heather R Draper, James A Seddon, Jennifer Norman, Helen M McIlleron, Anneke C Hesseling, H Simon Schaaf
BACKGROUND: Currently recommended treatment for multidrug-resistant (MDR) tuberculosis (TB) includes 4-8 months of an injectable medication, which is poorly tolerated. We evaluated the impact of co-administering lidocaine on pain and pharmacokinetics of intramuscular injections of amikacin in children with MDR-TB. METHODS: Children 8-18 years of age, receiving amikacin for MDR-TB treatment in Cape Town, South Africa, were eligible for this randomized crossover trial...
March 14, 2018: Pediatric Infectious Disease Journal
https://www.readbyqxmd.com/read/29541956/towards-bridging-translational-gap-in-cardiotoxicity-prediction-an-application-of-progressive-cardiac-risk-assessment-strategy-in-tdp-risk-assessment-of-moxifloxacin
#12
Nikunjkumar Patel, Oliver Hatley, Alexander Berg, Klaus Romero, Barbara Wisniowska, Debra Hanna, David Hermann, Sebastian Polak
Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis...
March 14, 2018: AAPS Journal
https://www.readbyqxmd.com/read/29529504/synthesis-and-antimycobacterial-activity-of-1-%C3%AE-d-ribofuranosyl-4-coumarinyloxymethyl-coumarinyl-1-2-3-triazole
#13
Smriti Srivastava, Devla Bimal, Kapil Bohra, Balram Singh, Prija Ponnan, Ruchi Jain, Mandira Varma-Basil, Jyotirmoy Maity, M Thirumal, Ashok K Prasad
A series of β-d-ribofuranosyl coumarinyl-1,2,3-triazoles have been synthesized by Cu-catalyzed cycloaddition reaction between azidosugar and 7-O-/7-alkynylated coumarins in 62-70% overall yields. The in vitro antimycobacterial activity evaluation of the synthesized triazolo-conjugates against Mycobacterium tuberculosis revealed that compounds were bactericidal in nature and some of them were found to be more active than one of the first line antimycobacterial drug ethambutol against sensitive reference strain H37Rv, and 7 to 420 times more active than all four first line antimycobacterial drugs (isoniazid, rifampicin, ethambutol and streptomycin) against multidrug resistant clinical isolate 591...
February 27, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29523331/the-utility-of-pharmacokinetic-studies-for-the-evaluation-of-exposure-response-relationships-for-standard-dose-anti-tuberculosis-drugs
#14
REVIEW
Christine Sekaggya-Wiltshire, Mohammed Lamorde, Agnes N Kiragga, Kelly E Dooley, Moses R Kamya, Andrew Kambugu, Jan Fehr, Yukari C Manabe, Barbara Castelnuovo
Tuberculosis (TB) is a major public health problem. Many countries still fall below the minimum World Health Organization (WHO) TB treatment target success rate. There is conflicting evidence about whether concentrations of anti-tuberculosis drugs given at standard doses have an effect on treatment outcomes. The current data correlating anti-TB drug concentrations and treatment outcome is limited. This article summarized the existing literature and their utility in evaluating the association between each anti-TB drug's concentrations using current target concentrations and treatment outcomes in patients with pulmonary tuberculosis receiving standard WHO-recommended dosing...
January 2018: Tuberculosis
https://www.readbyqxmd.com/read/29522317/2-mercapto-quinazolinones-as-inhibitors-of-ndh-2-and-mycobacterium-tuberculosis-structure-activity-relationships-mechanism-of-action-and-adme-characterization
#15
Dinakaran Murugesan, Peter C Ray, Tracy Bayliss, Gareth A Prosser, Justin R Harrison, Kirsteen Green, Candice Soares de Melo, Tzu-Shean Feng, Leslie J Street, Kelly Chibale, Digby F Warner, Valerie Mizrahi, Ola Epemolu, Paul Scullion, Lucy Ellis, Jennifer Riley, Yoko Shishikura, Liam Ferguson, Maria Osuna-Cabello, Kevin D Read, Simon R Green, Dirk A Lamprecht, Peter M Finin, Adrie J C Steyn, Thomas R Ioerger, Jim Sacchettini, Kyu Y Rhee, Kriti Arora, Clifton E Barry Iii, Paul G Wyatt, Helena Ingrid M Boshoff
Mycobacterium tuberculosis (MTb) possesses two non-proton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism.. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SAR) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies...
March 9, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29514812/pharmacokinetic-study-of-isoniazid-and-pyrazinamide-in-children-impact-of-age-and-nutritional-status
#16
Rajeshwar Dayal, Yatish Singh, Dipti Agarwal, Manoj Kumar, Soumya Swaminathan, Geetha Ramachandran, Santosh Kumar, Shamrendra Narayan, Ankur Goyal, A K Hemant Kumar
OBJECTIVES: To evaluate pharmacokinetics of first-line antitubercular drugs, isoniazid (INH) and pyrazinamide (PZA), with revised WHO dosages and to assess its adequacy in relation to age and nutritional status. DESIGN: Observational study. SETTING: This study was conducted at Sarojini Naidu Medical College, Agra, and National Institute for Research in Tuberculosis, Chennai. PATIENTS: 40 subjects diagnosed with tuberculosis were registered in the study and started on daily first-line antitubercular regimen based on the revised WHO guidelines...
March 7, 2018: Archives of Disease in Childhood
https://www.readbyqxmd.com/read/29507756/integration-of-genome-scale-metabolic-networks-into-whole-body-pbpk-models-shows-phenotype-specific-cases-of-drug-induced-metabolic-perturbation
#17
Henrik Cordes, Christoph Thiel, Vanessa Baier, Lars M Blank, Lars Kuepfer
Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism...
2018: NPJ Systems Biology and Applications
https://www.readbyqxmd.com/read/29505119/exposure-of-nursed-infants-to-maternal-treatment-with-ethambutol-and-rifampicin
#18
Partosch Falko, Mielke Hans, Stahlmann Ralf, Gundert-Remy Ursula
Mycobacterial diseases remain a significant cause of morbidity and mortality worldwide. Rifampicin and ethambutol are among the drugs recommended by WHO as first line treatment. In this work, we addressed the question whether doses of the two anti-tuberculosis agents ethambutol and rifampicin transferred to a nursed infant could be of health concerns when the mother is under treatment. We used the approach of pharmacokinetic modelling using a structural model with two interconnected organisms, the first one being the organism of the nursing mother, the second one being the organism of the nursed child...
March 5, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29463541/verapamil-targets-membrane-energetics-in-mycobacterium-tuberculosis
#19
Chao Chen, Susana Gardete, Robert Sander Jansen, Annanya Shetty, Thomas Dick, Kyu Y Rhee, Véronique Dartois
Mycobacterium tuberculosis (Mtb) kills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium channel blocker, potentiates the effect of several anti-tuberculosis (TB) drugs in vitro and in vivo. This potentiation is widely attributed to inhibition of Mtb's efflux pumps, resulting in intrabacterial drug accumulation. Here, we confirm and quantify verapamil's synergy with several anti-TB drugs, including bedaquiline and clofazimine, but find that this effect is not due to increased intrabacterial drug accumulation...
February 20, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29463539/pharmacokinetics-of-second-line-anti-tuberculosis-drugs-in-children-with-multidrug-resistant-tuberculosis-in-india
#20
Agibothu Kupparam Hemanth Kumar, Alok Kumar, Thiruvengadam Kannan, Rakesh Bhatia, Dipti Agarwal, Santosh Kumar, Rajeshwar Dayal, Sheo Pratap Singh, Geetha Ramachandran
We studied the pharmacokinetics of levofloxacin (LFX), pyrazinamide (PZA), ethionamide (ETH) and cycloserine (CS) in children with multidrug-resistant tuberculosis (MDR TB) being treated according to the Revised National TB Control Programme (RNTCP) guidelines in India. This observational, pharmacokinetic study was conducted in 25 children with MDR TB at the Sarojini Naidu Medical College, Agra, India who were being treated with a 24-month daily regimen. Serial blood samples were collected after directly observed administration of drugs...
February 20, 2018: Antimicrobial Agents and Chemotherapy
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