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pharmacokinetics And tuberculosis drugs

D Jaganath, G Lamichhane, M Shah
Carbapenems, a more recent β-lactam class, represent a unique anti-tuberculosis option, as emerging evidence demonstrates that they target the Mycobacterium tuberculosis cell wall and β-lactamase. This provides a potentially new agent against M. tuberculosis, in particular for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), where options are limited. In this review, we examine the current evidence on the activity of carbapenems against M. tuberculosis. The predominance of work is in vitro, and suggests that carbapenems kill M...
November 2016: International Journal of Tuberculosis and Lung Disease
Bharathkumar Inturi, Gurubasavaraj V Pujar, Madhusudhan N Purohit
Mycobacterium tuberculosis enoyl-ACP reductase (InhA) has been validated as a promising target for antitubercular agents. Isoniazid (INH), the most prescribed drug to treat tuberculosis (TB), inhibits a NADH-dependent InhA that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. It is a pro-drug that needs activation to form the inhibitory INH-NAD adduct by KatG coding for catalase-peroxidase. The INH resistance of M. tuberculosis is caused by mutations in KatG, which may lead to multidrug-resistant TB (MDR-TB)...
October 24, 2016: Archiv der Pharmazie
Bini Mathew, Judith Varady Hobrath, Larry Ross, Michele C Connelly, Hava Lofton, Malini Rajagopalan, R Kiplin Guy, Robert C Reynolds
A variety of commercial analogs and a newer series of Sulindac derivatives were screened for inhibition of M. tuberculosis (Mtb) in vitro and specifically as inhibitors of the essential mycobacterial tubulin homolog, FtsZ. Due to the ease of preparing diverse analogs and a favorable in vivo pharmacokinetic and toxicity profile of a representative analog, the Sulindac scaffold may be useful for further development against Mtb with respect to in vitro bacterial growth inhibition and selective activity for Mtb FtsZ versus mammalian tubulin...
2016: PloS One
Sunhee Kang, Young Mi Kim, Ryang Yeo Kim, Min Jung Seo, Zaesung No, Kiyean Nam, Sanghee Kim, Jaeseung Kim
The anti-tubercular activity of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo [1,2-a]pyridine-3-carboxamide (Q203) is modified by varying its side chain. In this study, we synthesized Q203 analogues with different side chains and studied their effects on anti-tubercular activity. Many analogues showed good potency against M. tuberculosis replicating in liquid broth culture medium (extracellular activity) regardless of chain length and conformational changes. However, a polar character in the side chain region was unfavorable for anti-tubercular activity...
September 28, 2016: European Journal of Medicinal Chemistry
Tawanda Gumbo, Mamodikoe K Makhene, James A Seddon
There has been a recent expansion of preclinical models to predict the efficacy of regimens to treat adults with tuberculosis. Despite increasing global interest in childhood tuberculosis, these same tools have not been employed to develop pediatric regimens. Children differ from adults in bacillary burden, spectrum of disease, the metabolism and distribution of antituberculosis drugs, and the toxicity experienced. The studies documented in this series describe a proof-of-concept approach to pediatric regimen development...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Shashikant Srivastava, Devyani Deshpande, Jotam Pasipanodya, Eric Nuermberger, Soumya Swaminathan, Tawanda Gumbo
BACKGROUND:  When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration-time curves (AUC0-24) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (MICs). Thus, each child will achieve different AUC0-24/MIC ratios when treated with the same dose. METHODS:  We used 10 000-subject Monte Carlo experiments to identify the oral doses of linezolid, moxifloxacin, and faropenem that would achieve optimal target exposures associated with optimal efficacy in children with disseminated tuberculosis...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Devyani Deshpande, Shashikant Srivastava, Eric Nuermberger, Jotam G Pasipanodya, Soumya Swaminathan, Tawanda Gumbo
BACKGROUND:  The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination. METHODS:  We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Shashikant Srivastava, Devyani Deshpande, Jotam G Pasipanodya, Tania Thomas, Soumya Swaminathan, Eric Nuermberger, Tawanda Gumbo
Children with tuberculosis are treated with drug regimens copied from adults despite significant differences in antibiotic pharmacokinetics, pathology, and the microbial burden between childhood and adult tuberculosis. We sought to develop a new and effective oral treatment regimen specific to children of different ages. We investigated and validated the concept that target drug concentrations associated with therapy failure and death in children are different from those of adults. On that basis, we proposed a 4-step program to rapidly develop treatment regimens for children...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Soumya Swaminathan, Jotam G Pasipanodya, Geetha Ramachandran, A K Hemanth Kumar, Shashikant Srivastava, Devyani Deshpande, Eric Nuermberger, Tawanda Gumbo
BACKGROUND:  The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown. METHODS:  Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Jennifer Herrmann, Tadeja Lukežič, Angela Kling, Sascha Baumann, Stephan Hüttel, Hrvoje Petković, Rolf Müller
Natural products continue to be a predominant source for new anti-infective agents. Research at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Helmholtz Centre for Infection Research (HZI) is dedicated to the development of new lead structures against infectious diseases and, in particular, new antibiotics against hard-to-treat and multidrug-resistant bacterial pathogens. In this chapter, we introduce some of the concepts currently being employed in the field of antibiotic discovery...
October 15, 2016: Current Topics in Microbiology and Immunology
Yumi Park, Angela Pacitto, Tracy Bayliss, Laura A T Cleghorn, Zhe Wang, Travis Hartman, Kriti Arora, Thomas R Ioerger, Jim Sacchettini, Menico Rizzi, Stefano Donini, Tom L Blundell, David B Ascher, Kyu Y Rhee, Ardala Breda, Nian Zhou, Veronique Dartois, Surendranadha Reddy Jonnala, Laura E Via, Valerie Mizrahi, Ola Epemolu, Laste Stojanovski, Frederick Ryan Carne Simeons, Maria Osuna-Cabello, Lucy Ellis, Claire J MacKenzie, Alasdair R C Smith, Susan Helen Davis, Dinakaran Murugesan, Kirsteen I Buchanan, Penelope A Turner, Margaret Huggett, Fabio Zuccotto, Maria Jose Rebollo-Lopez, Maria Jose Lafuente-Monasterio, Olalla Sanz, Gracia Santos Diaz, Joël Lelièvre, Lluis Ballell, Carolyn Selenski, Matthew Axtman, Sonja Ghidelli-Disse, Hannah Pflaumer, Markus Boesche, Gerard Drewes, Gail Freiberg, Matthew D Kurnick, Myron Srikumaran, Dale J Kempf, Simon R Green, Peter Christopher Ray, Kevin D Read, Paul G Wyatt, Clifton E Barry Rd, Helena I M Boshoff
A potent, non-cytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This non-cytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH)...
October 5, 2016: ACS Infectious Diseases
Morris Muliaditan, Geraint R Davies, Ulrika S H Simonsson, Stephen H Gillespie, Oscar Della Pasqua
Despite promising advances in the field and highly effective first-line treatment, an estimated 9.6 million people are still infected with tuberculosis (TB). Innovative methods are required to effectively transition the growing number of compounds into novel combination regimens. However, progression of compounds into patients occurs despite the lack of clear understanding of the pharmacokinetic-pharmacodynamic (PK/PD) relations. The PreDiCT-TB consortium was established in response to the existing gaps in TB drug development...
September 28, 2016: Drug Discovery Today
Eric F Egelund, Ramiro Isaza, Abdullah Alsultan, Charles A Peloquin
This report describes the pharmacokinetic profiles of chronically administered oral isoniazid and rifampin in one adult male and one adult female Asian elephant ( Elephas maximus ) that were asymptomatically infected with Mycobacterium tuberculosis . Rifampin's half-life was reduced when compared to previous single-dose pharmacokinetic profiles of healthy uninfected Asian elephants. Both elephants experienced delayed absorption of isoniazid and rifampin as compared to previous pharmacokinetic studies in this species...
September 2016: Journal of Zoo and Wildlife Medicine: Official Publication of the American Association of Zoo Veterinarians
Eric F Egelund, Charles A Peloquin
INTRODUCTION: The goal of this article is to review the use of rifapentine in the treatment of latent tuberculosis infection (LTBI). Controlling LTBI is an important part of the global strategy to end the spread of tuberculosis. Rifapentine's potent sterilizing effect against Mycobacterium tuberculosis combined with its long half-life make it an attractive LTBI treatment option. AREAS COVERED: A systematic literature search of Pubmed using the terms 'rifapentine' and 'tuberculosis' was performed...
August 22, 2016: Expert Review of Clinical Pharmacology
Sean Wasserman, Graeme Meintjes, Gary Maartens
INTRODUCTION: Linezolid is an oxazolidinone with potent activity against M tuberculosis, and improves culture conversion and cure rates when added to treatment regimens for drug resistant tuberculosis. However, linezolid has a narrow therapeutic window, and the optimal dosing strategy that minimizes the substantial toxicity associated with linezolid's prolonged use in tuberculosis treatment has not been determined, limiting the potential impact of this anti-mycobacterial agent. AREAS COVERED: This paper aims to review and summarize the current knowledge on linezolid for the treatment of drug-resistant tuberculosis...
October 2016: Expert Review of Anti-infective Therapy
Jun-Jie Koh, Hanxun Zou, Devika Mukherjee, Shuimu Lin, Fanghui Lim, Javey Khiapeng Tan, Dhi-Zen Tan, Bridget L Stocker, Mattie S M Timmer, Hilary M Corkran, Rajamani Lakshminarayanan, Donald T H Tan, Derong Cao, Roger W Beuerman, Thomas Dick, Shouping Liu
Tuberculosis (TB) remains a deadly disease and infects one-third of the world's population. Given the low success rates encountered in clinical development, there is an urgent need to identify structurally novel antimicrobials for tuberculosis. The present report details the anti-mycobacterial activities, structure-activity relationships (SARs) and mechanism of action of amphiphilic xanthone derivatives. The xanthones exhibited potent MIC, rapid time-kill and no cross-resistance with the current anti-TB drugs...
November 10, 2016: European Journal of Medicinal Chemistry
A K Hemanth Kumar, T Kannan, V Chandrasekaran, V Sudha, A Vijayakumar, K Ramesh, J Lavanya, S Swaminathan, G Ramachandran
OBJECTIVE: To study the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in adult tuberculosis (TB) patients and examine factors that influence drug pharmacokinetics. METHODS: Adult TB patients (n = 101) receiving thrice-weekly anti-tuberculosis treatment in the Revised National TB Control Programme (RNTCP) were studied. The study was conducted at steady state after directly observed drug administration. RMP, INH and PZA concentrations were estimated using high-performance liquid chromatography and NAT2 genotyping by real-time polymerase chain reaction...
September 2016: International Journal of Tuberculosis and Lung Disease
Chunli Chen, Fatima Ortega, Laura Alameda, Santiago Ferrer, Ulrika S H Simonsson
The current first-line therapy for drug-susceptible tuberculosis consists of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). In this study, we determined the population pharmacokinetics (PopPK) of RIF, INH, EMB and PZA using original experimental sampling designs for single-dose intravenous (IV) and single- and multiple-dose oral administration studies in the mouse model, and used these PopPK models to develop and evaluate new, more informative sampling designs with the aim of reducing the number of animals required for each drug...
October 10, 2016: European Journal of Pharmaceutical Sciences
Gurleen Kour, Anil Kumar, Parvinder Pal Singh, Sumit Sharma, Asha Bhagat, Ram A Vishwakarma, Zabeer Ahmed
New compounds against tuberculosis are urgently needed to combat the crisis of drug resistance in tuberculosis (TB). We have identified a nitrodihydroimidazooxazole analog, IIIM-019 as a new anti-tubercular agent with a MIC of 0.23 μM against H37Rv. Physicochemical properties, in-vitro pharmacokinetics and in-vivo multiple-doses pharmacokinetics were studied for the compound. In silico physicochemical parameters and Lipinski's violations were determined for drug like properties. Lipophilicity was determined experimentally as Octanol-PBS partition coefficient (log P)...
October 2016: Pulmonary Pharmacology & Therapeutics
Natanael Dante Segretti, Cristina Kortstee Simões, Michelle Fidelis Corrêa, Veni Maria Andres Felli, Marcelo Miyata, Sang Hyun Cho, Scott Gary Franzblau, João Paulo Dos Santos Fernandes
Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present...
July 2016: Tuberculosis
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