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pharmacokinetics And tuberculosis drugs

Alper Daskapan, Lusiana R Idrus, Maarten J Postma, Bob Wilffert, Jos G W Kosterink, Ymkje Stienstra, Daniel J Touw, Aase B Andersen, Adrie Bekker, Paolo Denti, Agibothu K Hemanth Kumar, Kidola Jeremiah, Awewura Kwara, Helen McIlleron, Graeme Meintjes, Joep J van Oosterhout, Geetha Ramachandran, Neesha Rockwood, Robert J Wilkinson, Tjip S van der Werf, Jan-Willem C Alffenaar
INTRODUCTION: Contrasting findings have been published regarding the effect of human immunodeficiency virus (HIV) on tuberculosis (TB) drug pharmacokinetics (PK). OBJECTIVES: The aim of this systematic review was to investigate the effect of HIV infection on the PK of the first-line TB drugs (FLDs) rifampicin, isoniazid, pyrazinamide and ethambutol by assessing all published literature. METHODS: Searches were performed in MEDLINE (through PubMed) and EMBASE to find original studies evaluating the effect of HIV infection on the PK of FLDs...
November 8, 2018: Clinical Pharmacokinetics
Simone H J van den Elsen, Marieke G G Sturkenboom, Natasha van 't Boveneind-Vrubleuskaya, Alena Skrahina, Tjip S van der Werf, Scott K Heysell, Stellah Mpagama, Giovanni B Migliori, Charles A Peloquin, Daan J Touw, Jan-Willem C Alffenaar
Levofloxacin is an anti-tuberculosis drug with substantial interindividual pharmacokinetic variability; therapeutic drug monitoring (TDM) could therefore be helpful to improve treatment results. TDM would be more feasible with limited sampling strategies (LSSs), a method to estimate area under the concentration curve for the 24 h dosing interval (AUC0-24 ) by using a limited number of samples. This study aimed to develop a population pharmacokinetic (popPK) model of levofloxacin in tuberculosis patients, along with LSSs using a Bayesian and multiple linear regression approach...
October 29, 2018: Antimicrobial Agents and Chemotherapy
Aanchal Kashyap, Pankaj Kumar Singh, Om Silakari
Tuberculosis (TB) is a serious major health concern that has existed from millennia. According to annual WHO report 2016, it is considered as world's ninth highest killer disease by single infectious agent, ranking above HIV/AIDS. To worsen the scenario the development of multi-drug resistant tuberculosis (MDR-TB) and extremely drug resistant tuberculosis (XDR-TB) have significantly reduced the success rate of TB treatment. Several efforts are being made to handle pharmacodynamic resistance (MDR and XDR-TB) involving designing of new inhibitors, targeting mutated target or by multi-targeting agents...
October 20, 2018: Drug Metabolism Reviews
Priscila Cristina Bartolomeu Halicki, Gabriela Hädrich, Raphael Boschero, Laís Andrade Ferreira, Andrea von Groll, Pedro Eduardo Almeida da Silva, Cristiana Lima Dora, Daniela Fernandes Ramos
Tuberculosis (TB) is considered an emergency global public health, mainly due to the TB-HIV co-infection, bacillus dormancy stage, and emergence of resistant strains. In addition, the therapeutic toxicity and its pharmacokinetic interactions with other drugs may influence treatment non-compliance, low serum concentration of drugs, and, consequently, treatment failure. Strategies using nanotechnology represent a new tool for the therapy, since they are effective delivery systems due to the possibility of solubilization of hydrophobic compounds, enable the production of formulations for oral use, and, in addition, increase bioavailability of drugs...
October 16, 2018: Assay and Drug Development Technologies
Feng Gao, Hua Yang, Tianyu Lu, Zijian Chen, Long Ma, Zhi Xu, Paul Schaffer, Guangming Lu
Herein we report the design and synthesis of a series of novel benzofuran-isatin hybrids, and in vitro evaluation of their anti-mycobacterial activity against both drug-susceptible and multi-drug resistant (MDR) Mycobacterium tuberculosis (MTB) strains. In parallel, cytotoxicity of these hybrids was also tested in VERO cells. Preliminary results indicated that all hybrids with acceptable cytotoxicity in VERO cells (CC50 : 128->1024 μg/mL) exhibited considerable anti-mycobacterial activities against MTB H37 Rv and MDR-TB with MIC ranging from 0...
November 5, 2018: European Journal of Medicinal Chemistry
Alexander Kay, Anthony J Garcia-Prats, Anna Maria Mandalakas
PURPOSE OF REVIEW: The detrimental synergy of colliding HIV and tuberculosis (TB) epidemics is most devastating among children and adolescents living with HIV (CALWH) who shoulder a disproportionate burden of all child TB mortality. RECENT FINDINGS: CALWH benefit less from Bacille-Calmette Guerin vaccination than HIV-uninfected children and are not receiving TB preventive therapy despite global recommendations. Further, the predictive utility of most diagnostic tools is reduced in CALWH...
November 2018: Current Opinion in HIV and AIDS
Bronwyn Myers, Tara C Bouton, Elizabeth J Ragan, Laura F White, Helen McIlleron, Danie Theron, Charles D H Parry, C Robert Horsburgh, Robin M Warren, Karen R Jacobson
BACKGROUND: An estimated 10% of tuberculosis (TB) deaths are attributable to problematic alcohol use globally, however the causal pathways through which problem alcohol use has an impact on TB treatment outcome is not clear. This study aims to improve understanding of these mechanisms. Specifically, we aim to 1) assess whether poor TB treatment outcomes, measured as delayed time-to-culture conversion, are associated with problem alcohol use after controlling for non-adherence to TB pharmacotherapy; and 2) to determine whether pharmacokinetic (PK) changes in those with problem alcohol use are associated with delayed culture conversion, higher treatment failure/relapse rates or with increased toxicity...
September 29, 2018: BMC Infectious Diseases
Tan N Doan, Pengxing Cao, Theophilus I Emeto, James M McCaw, Emma S McBryde
Short-course regimens for multi-drug resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug, bedaquiline (BDQ), may have the potential to shorten MDR-TB treatment to less than six months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modelling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment...
September 24, 2018: Antimicrobial Agents and Chemotherapy
Fiona V Cresswell, Kenneth Ssebambulidde, Daniel Grint, Lindsey Te Brake, Abdul Musabire, Rachel R Atherton, Lillian Tugume, Conrad Muzoora, Robert Lukande, Mohammed Lamorde, Rob Aarnoutse, David Meya, David R Boulware, Alison M Elliott
Background : Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration.  With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration for M. tuberculosis . Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms...
2018: Wellcome Open Research
Maddie R Lemieux, Shajila Siricilla, Katsuhiko Mitachi, Shakiba Eslamimehr, Yuehong Wang, Dong Yang, Jeffrey D Pressly, Ying Kong, Frank Park, Scott G Franzblau, Michio Kurosu
Pleuromutilin is a promising pharmacophore to design new antibacterial agents for Gram-positive bacteria. However, there are limited studies on the development of pleuromutilin analogues that inhibit growth of Mycobacterium tuberculosis (Mtb). In screening of our library of pleuromutilin derivatives, UT-800 (1) was identified to kill replicating- and non-replicating Mtb with the MIC values of 0.83 and 1.20 μg/mL, respectively. UT-800 also kills intracellular Mtb faster than rifampicin at 2× MIC concentrations...
September 15, 2018: Bioorganic & Medicinal Chemistry
M Daben J Libardo, Helena Im Boshoff, Clifton E Barry
Tuberculosis now ranks as the leading cause of death in the world due to a single infectious agent. Current standard of care treatment can achieve very high cure rates for drug-sensitive disease but requires a 6-month duration of chemotherapy. Drug-resistant disease requires significantly longer treatment durations with drugs associated with a higher risk of adverse events. Thus, there is a pressing need for a drug regimen that is safer, shorter in duration and superior to current front-line chemotherapy in terms of efficacy...
October 2018: Current Opinion in Pharmacology
Paul W Smith, Fabio Zuccotto, Robert H Bates, Maria Santos Martinez-Martinez, Kevin D Read, Caroline Peet, Ola Epemolu
β-Lactams represent perhaps the most important class of antibiotics yet discovered. However, despite many years of active research, none of the currently approved drugs in this class combine oral activity with long duration of action. Recent developments suggest that new β-lactam antibiotics with such a profile would have utility in the treatment of tuberculosis. Consequently, the historical β-lactam pharmacokinetic data have been compiled and analyzed to identify possible directions and drug discovery strategies aimed toward new β-lactam antibiotics with this profile...
September 10, 2018: ACS Infectious Diseases
Omamah Alfarisi, Vidya Mave, Sanjay Gaikwad, Tushar Sahasrabudhe, Geetha Ramachandran, Hemanth Kumar, Nikhil Gupte, Vandana Kulkarni, Sona Deshmukh, Sachin Atre, Swapnil Raskar, Rahul Lokhande, Madhusudan Barthwal, Arjun Kakrani, Sandy Chon, Amita Gupta, Jonathan E Golub, Kelly E Dooley
Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-TB drugs remains poorly characterized. Newly diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (predose and 0.5, 2, and 6 h postdose) during the intensive and continuation phases of treatment...
November 2018: Antimicrobial Agents and Chemotherapy
Jeffrey A Tornheim, Kelly E Dooley
PURPOSE OF REVIEW: In the past few years, tuberculosis (TB) has overtaken HIV as the infectious disease with the highest global mortality. Successful management of this syndemic will require improved diagnostic tests, shorter preventive therapies, and more effective treatments, particularly in light of drug-resistant TB. RECENT FINDINGS: Results from several major studies have been published or presented recently, including the development of a more sensitive rapid, molecular assay for TB; several new symptom-based screening tools; use of a 1-month regimen for TB prevention; the results of early vs...
November 2018: Current Opinion in HIV and AIDS
Linhu Li, Kai Lv, Yupeng Yang, Jingquan Sun, Zeyu Tao, Apeng Wang, Bin Wang, Hongjian Wang, Yunhe Geng, Mingliang Liu, Huiyuan Guo, Yu Lu
A series of benzamide scaffolds were designed and synthesized by the thiazinone ring opening of PBTZ169, and N -benzyl 3,5-dinitrobenzamides were finally identified as anti-TB agents in this work. 3,5-Dinitrobenzamides D5 , 6 , 7 , and 12 exhibit excellent in vitro activity against the drug susceptive Mycobacterium tuberculosis H37Rv strain (MIC: 0.0625 μg/mL) and two clinically isolated multidrug-resistant strains (MIC < 0.016-0.125 μg/mL). Compound D6 displays acceptable safety and better pharmacokinetic profiles than PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery...
July 12, 2018: ACS Medicinal Chemistry Letters
Henok Asfaw, Thomas Wetzlar, Maria Santos Martinez-Martinez, Peter Imming
A convenient solid phase peptide synthetic (SPPS) route is reported for the preparation of antimycobacterial wollamides. The method is based on on-resin head-to-tail cyclization and is fast, efficient and amenable to automation. The in vitro antimycobacterial activities of the newly synthesized wollamides were evaluated against M. tuberculosis H37Rv (Mtb H37Rv). To assess their drug-likeness, in vitro pharmacokinetic (ADME) profiling was also performed. For wollamides with potent extracellular potency, intracellular activities and in vivo efficacy were determined...
September 15, 2018: Bioorganic & Medicinal Chemistry Letters
Padam Singh, Shashi Kant Kumar, Vineet Kumar Maurya, Basant Kumar Mehta, Hafsa Ahmad, Anil Kumar Dwivedi, Vinita Chaturvedi, Tejender S Thakur, Sudhir Sinha
A synthetic molecule S006-830, belonging to the class of thiophene-containing trisubstituted methanes, had shown good in vitro and in vivo bactericidal activity against drug-sensitive and drug-resistant Mycobacterium tuberculosis (Mtb). The molecule had also shown good druglike pharmacokinetic properties. However, S006-830 is a racemic mixture of two enantiomers, one of which could possess a better pharmacological profile than the other. We purified both the enantiomers on a chiral column and observed that S-enantiomer has a significantly higher inhibitory and cidal activity against Mtb than the R-enantiomer...
November 30, 2017: ACS Omega
Charles A Peloquin, Patrick P J Phillips, Carole D Mitnick, Kathleen Eisenach, Ramonde F Patientia, Leonid Lecca, Eduardo Gotuzzo, Neel R Gandhi, Donna Butler, Andreas H Diacon, Bruno Martel, Juan Santillan, Kathleen Robergeau Hunt, Dante Vargas, Florian von Groote-Bidlingmaier, Carlos Seas, Nancy Dianis, Antonio Moreno-Martinez, Pawandeep Kaur, C Robert Horsburgh
Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0-24 ) were 109.49, 97.86, 145.33, and 207.04 μg · h/ml. Median maximum plasma concentration ( C max ) were 11.90, 12.02, 14...
October 2018: Antimicrobial Agents and Chemotherapy
Deborah Ford, Rebecca Turner, Anna Turkova, Martina Penazzato, Victor Musiime, Mutsa Bwakura-Dangarembizi, Avy Violari, Chishala Chabala, Thanyawee Puthanakit, Tavitiya Sudjaritruk, Tim R Cressey, Marc Lallemant, Diana M Gibb
For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission...
August 15, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
R K R Rajoli, A T Podany, D M Moss, S Swindells, C Flexner, A Owen, M Siccardi
SETTING: Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues. OBJECTIVE: niazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI). DESIGN: PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution...
August 1, 2018: International Journal of Tuberculosis and Lung Disease
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