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pharmacokinetics And tuberculosis drugs

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...
August 18, 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...
August 22, 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, Amita Gupta, Jonathan E Golub, Kelly E Dooley
Background: 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 and pharmacodynamics of anti-TB drugs remains poorly-characterized. Methods: Newly-diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (pre-dose, 0.5, 2, 6 hours post-dose) during intensive and continuation phases of treatment...
August 20, 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...
August 4, 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 weight-banded nominal doses of 11, 14, 17 or 20 mg/kg/day levofloxacin (minimum 750 mg) in combination with other second-line agents. 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median AUC0-24 were 109.49, 97.86, 145.33 and 207.04 h*mcg/ml. Median Cmax were 11.90, 12.02, 14.86, and 19.17 mcg/ml. Higher levofloxacin doses, up to 1500 mg daily, resulted in higher exposures. ClinicalTrials...
July 16, 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
Elise D Pieterman, Lindsey H M Te Brake, Gerjo J de Knegt, Aart van der Meijden, Jan-Willem C Alffenaar, Hannelore I Bax, Rob E Aarnoutse, Jurriaan E M de Steenwinkel
The favorable treatment outcome rate for multidrug-resistant tuberculosis (MDR-TB) is only 54%, and therefore new drug regimens are urgently needed. In this study, we evaluated the activity of the combination of moxifloxacin and linezolid as a possible new MDR-TB regimen in a murine TB model and the value of the addition of the efflux pump inhibitor verapamil to this backbone. BALB/c mice were infected with drug-sensitive Mycobacterium tuberculosis and were treated with human-equivalent doses of moxifloxacin (200 mg/kg of body weight) and linezolid (100 mg/kg) with or without verapamil (12...
September 2018: Antimicrobial Agents and Chemotherapy
Prakash Khadka, Jack Dummer, Philip C Hill, Shyamal C Das
Drug delivery via the inhaled route has advantages for treating local and systemic diseases. Pulmonary drug delivery may have potential in treating tuberculosis (TB), which is mainly localised in the lung (pulmonary tuberculosis ∼75%) while also affecting other organs (extra-pulmonary tuberculosis). Currently, rifampicin, a first-line anti-tubercular drug, is given orally and the maximum daily oral dose is the lesser of 10 mg/kg or 600 mg. Since only a small fraction of this dose is available in the lung, concentrations may frequently fail to reach bactericidal levels, and therefore, contribute to the development of multi-drug resistant pulmonary TB...
September 5, 2018: International Journal of Pharmaceutics
Samuel K Kwofie, Bismark Dankwa, Emmanuel A Odame, Francis E Agamah, Lady P A Doe, Joshua Teye, Odame Agyapong, Whelton A Miller, Lydia Mosi, Michael D Wilson
Buruli ulcer (BU) is caused by Mycobacterium ulcerans and is predominant in both tropical and subtropical regions. The neglected debilitating disease is characterized by chronic necrotizing skin lesions attributed to a mycolactone, which is a macrolide toxin secreted by M. ulcerans . The preferred treatment is surgical excision of the lesions followed by a prolonged combination antibiotic therapy using existing drugs such as rifampicin and streptomycin or clarithromycin. These antibiotics appear not to be adequately potent and efficacious against persistent and late stage ulcers...
June 27, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Elin M Svensson, Jeannine du Bois, Rene Kitshoff, Veronique R de Jager, Lubbe Wiesner, Jennifer Norman, Sharon Nachman, Betsy Smith, Andreas H Diacon, Anneke C Hesseling, Anthony J Garcia-Prats
AIMS: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets. METHODS: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers...
June 27, 2018: British Journal of Clinical Pharmacology
Mwila Mulubwa, Pierre Mugabo
A chromatographic method has been developed and validated for the first time for analysis of terizidone in plasma. Terizidone was extracted from plasma by protein precipitation using a mixture of acetonitrile and methanol (1:1, v/v). The chromatographic separation was achieved with a gradient of acetonitrile and water both containing 0.1% formic acid on a Supelco Discovery® HS C18 (150 × 4.6 mm, 5 μm) reversed-phase column. Propranolol was used as the internal standard. The total run-time was 18 min...
June 26, 2018: Biomedical Chromatography: BMC
Lloyd Tanner, Paolo Denti, Lubbe Wiesner, Digby F Warner
Anti-tuberculosis (TB) drugs possess diverse abilities to penetrate the different host tissues and cell types in which infecting Mycobacterium tuberculosis bacilli are located during active disease. This is important since there is increasing evidence that the respective "lesion-penetrating" properties of the front-line TB drugs appear to correlate well with their specific activity in standard combination therapy. In turn, these observations suggest that rational efforts to discover novel treatment-shortening drugs and drug combinations should incorporate knowledge about the comparative abilities of both existing and experimental anti-TB agents to access bacilli in defined physiological states at different sites of infection, as well as avoid elimination by efflux or inactivation by host or bacterial metabolism...
September 2018: IUBMB Life
Elin M Svensson, Robin J Svensson, Lindsey H M Te Brake, Martin J Boeree, Norbert Heinrich, Sarah Konsten, Gavin Churchyard, Rodney Dawson, Andreas H Diacon, Gibson S Kibiki, Lilian T Minja, Nyanda E Ntingiya, Ian Sanne, Stephen H Gillespie, Michael Hoelscher, Patrick P J Phillips, Ulrika S H Simonsson, Rob Aarnoutse
Background: Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods: Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg...
June 18, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Yasuhiro Horita, Abdullah Alsultan, Awewura Kwara, Sampson Antwi, Antony Enimil, Antoinette Ortsin, Albert Dompreh, Hongmei Yang, Lubbe Wiesner, Charles A Peloquin
Optimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosage ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose...
September 2018: Antimicrobial Agents and Chemotherapy
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