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pharmacokinetics And tuberculosis drugs

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https://www.readbyqxmd.com/read/28092695/absorption-distribution-and-excretion-of-the-anti-tuberculosis-drug-delamanid-in-rats-extensive-tissue-distribution-suggests-potential-therapeutic-value-for-extrapulmonary-tuberculosis
#1
Masakazu Shibata, Yoshihiko Shimokawa, Katsunori Sasahara, Noriaki Yoda, Hiroyuki Sasabe, Mitsunari Suzuki, Ken Umehara
Delamanid (OPC-67683, Deltyba(TM) , nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution, and excretion of delamanid-derived radioactivity were investigated after a single oral administration of (14) C-delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 hours postdose, and thereafter decreased slowly. Radioactivity levels were 3- to 5-fold higher in lung tissue at time to maximum concentration compared with plasma...
January 16, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28069654/reduced-chance-of-hearing-loss-associated-with-therapeutic-drug-monitoring-of-aminoglycosides-in-the-treatment-of-multidrug-resistant-tuberculosis
#2
R van Altena, J A Dijkstra, M E van der Meer, J F Borjas Howard, J G W Kosterink, D van Soolingen, T S van der Werf, J W C Alffenaar
Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our Tuberculosis Center, we have employed therapeutic drug monitoring (TDM) targeting pre-set pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto-)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of TB patients treated with amikacin or kanamycin in the period 2000 - 2012.Patients with culture-confirmed multi- or extensively drug resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study...
January 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28052847/subcellular-partitioning-and-intra-macrophage-selectivity-of-antimicrobial-compounds-against-mycobacterium-tuberculosis
#3
Michael D Schump, Douglas M Fox, Carolyn R Bertozzi, Lee W Riley
The efficacy of antimicrobial drugs against Mycobacterium tuberculosis (Mtb), an intracellular bacterial pathogen, is generally first established by testing compounds against bacteria in axenic culture. However, inside of infected macrophages bacteria encounter an environment which differs substantially from broth culture and are subject to important host-dependent pharmacokinetic phenomena which modulate drug activity. Here we describe how pH dependent partitioning drives asymmetric antimicrobial drug distribution in Mtb infected macrophages...
January 4, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28043603/individualized-treatment-of-multidrug-resistant-tuberculosis-using-therapeutic-drug-monitoring
#4
Mathieu S Bolhuis, Onno W Akkerman, Marieke G G Sturkenboom, Wiel C M de Lange, Tjip S van der Werf, Jan-Willem C Alffenaar
OBJECTIVE/BACKGROUND: Globally, approximately 50% of patients with multidrug-resistant tuberculosis (MDR-TB) experience treatment failure. MDR-TB treatment is hindered by adverse events, toxicity of the second-line anti-TB drugs, logistics and costs, especially in low-income countries, and problems with medication adherence. Pharmacokinetic variability is also attributed as one of the reasons contributing to treatment failure. In our reference Tuberculosis Center Beatrixoord (University Medical Center Groningen, Groningen, The Netherlands), we strive to individualize treatment of all MDR-TB patients based on drug-susceptibility testing using minimal inhibitory concentrations and pharmacokinetic parameters...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28043500/design-and-development-of-novel-inhibitors-for-the-treatment-of-latent-tuberculosis
#5
Rudraraju Srilakshmi Reshma, Perumal Yogeeswari, Dharmarajan Sriram
OBJECTIVE/BACKGROUND: "The captain of all these men of death", is the apt sobriquet for the age-old disease tuberculosis (TB). Despite the availability of many drugs, cases of increasing resistance in the forms of multi-drug and extensively drug-resistant TB and persistence [characteristic of Mycobacterium tuberculosis (MTB)] make the eradication of TB a nightmare. Approval of bedaquiline by the Food and Drug Administration focused attention on quinoline scaffolds for development of new anti-TB agents...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28038962/confirming-model-predicted-pharmacokinetic-interactions-between-bedaquiline-and-lopinavir-ritonavir-or-nevirapine-in-patients-with-hiv-and-drug-resistant-tuberculosis
#6
Margreke J E Brill, Elin M Svensson, Mishal Pandie, Gary Maartens, Mats O Karlsson
Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug-drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14)...
December 14, 2016: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/27994440/use-of-bedaquiline-and-delamanid-in-diabetes-patients-clinical-and-pharmacological-considerations
#7
REVIEW
Minhui Hu, Chunlan Zheng, Feng Gao
Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo(®) (bedaquiline) and Deltyba(®) (delamanid), novel drugs for multidrug-resistant tuberculosis (MDR-TB), are recommended for diabetes patients when another effective treatment regimen cannot be provided. Currently, there are no clinical data related to the use of these agents in diabetes patients...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27865404/formulation-studies-of-inha-inhibitors-and-combination-therapy-to-improve-efficacy-against-mycobacterium-tuberculosis
#8
Susan E Knudson, Jason E Cummings, Gopal R Bommineni, Pan Pan, Peter J Tonge, Richard A Slayden
Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient efficacy in the acute murine Mtb infection model. A next generation series of compounds were designed with improved specificity, potency against InhA, and reduced cytotoxicity in vitro, but these compounds also had limited solubility. Accordingly, solubility and pharmacokinetics studies were performed to develop formulations for this class and other experimental drug candidates with high logP values often encountered in drug discovery...
December 2016: Tuberculosis
https://www.readbyqxmd.com/read/27863179/population-pharmacokinetics-of-bedaquiline-and-metabolite-m2-in-patients-with-drug-resistant-tuberculosis-the-effect-of-time-varying-weight-and-albumin
#9
E M Svensson, A-G Dosne, M O Karlsson
Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time...
December 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27855070/pharmacokinetics-of-the-first-line-antituberculosis-drugs-in-ghanaian-children-with-tuberculosis-with-and-without-hiv-coinfection
#10
Sampson Antwi, Hongmei Yang, Anthony Enimil, Anima M Sarfo, Fizza S Gillani, Daniel Ansong, Albert Dompreh, Antoinette Orstin, Theresa Opoku, Dennis Bosumtwe, Lubbe Wiesner, Jennifer Norman, Charles A Peloquin, Awewura Kwara
Although human immunodefiency virus (HIV) coinfection is the most important risk factor for poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with tuberculosis (TB) with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide and ethambutol for at least 4 weeks had blood samples collected at pre-dose, 1, 2, 4, and 8-hours post-dose...
November 14, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27842973/pharmacokinetics-of-ethionamide-delivered-in-spray-dried-microparticles-to-the-lungs-of-guinea-pigs
#11
Lucila Garcia-Contreras, Danielle J Padilla-Carlin, Jean Sung, Jarod VerBerkmoes, Pavan Muttil, Katharina Elbert, Charles Peloquin, David Edwards, Anthony Hickey
The use of ethionamide (ETH) in treating multidrug-resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray-dried particles might minimize systemic exposure and side effects. To explore this hypothesis, spray-dried ETH particles were optimized for performance in a dry powder aerosol generator and exposure chamber. ETH particles were administered by the intravenous (IV), oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage, and lung tissues was measured and subjected to noncompartmental pharmacokinetic analysis...
January 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27832142/predictors-of-prolonged-tb-treatment-in-a-dutch-outpatient-setting
#12
Natasha Van't Boveneind-Vrubleuskaya, Alper Daskapan, Jos G W Kosterink, Tjip S van der Werf, Susan van den Hof, Jan-Willem C Alffenaar
INTRODUCTION: Standard treatment duration for drug-susceptible tuberculosis (TB) treatment is 6 months. Treatment duration is often extended-and for various different reasons. The aim of this study was to determine the prevalence and to assess risk factors associated with extended TB treatment. METHODS: A cross-sectional study was conducted. Data including demographic, clinical, radiological and microbiological information from the Netherlands TB Register (NTR) of 90 patients with smear and culture positive pulmonary TB of the region Haaglanden, The Netherlands, was eligible for analysis...
2016: PloS One
https://www.readbyqxmd.com/read/27813241/population-pharmacokinetics-of-rifampicin-in-adult-patients-with-osteoarticular-infections-interaction-with-fusidic-acid
#13
A Marsot, A Ménard, J Dupouey, C Muziotti, R Guilhaumou, O Blin
AIMS: Rifampicin represents the key antibiotic for management of osteoarticular infections. An important pharmacokinetic variability has already been described, incriminating notably absorption and metabolism. All previous pharmacokinetic studies were only focused on patient treated for tuberculosis. The objective of this study was to describe a population pharmacokinetic model of rifampicin in patients with staphylococcal osteoarticular infections, data which have not been investigated to date...
November 4, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27798497/recent-advances-in-the-diagnosis-and-management-of-tuberculous-meningitis
#14
Nguyen T H Mai, Guy E Thwaites
PURPOSE OF REVIEW: Tuberculous meningitis is a devastating infection that is hard to diagnose and treat. We have reviewed tuberculous meningitis original research published within the past 18 months, selecting studies which we consider have most advanced knowledge. RECENT FINDINGS: We review advances in diagnostic methods, anti-tuberculosis chemotherapy, and the common complications of tuberculous meningitis. New commercial molecular diagnostic tests, such as GeneXpert MTB/RIF, have an important role in tuberculous meningitis diagnosis, but as with all other available tests, they lack sensitivity and cannot rule out the disease...
February 2017: Current Opinion in Infectious Diseases
https://www.readbyqxmd.com/read/27798208/mechanisms-of-action-and-therapeutic-efficacies-of-the-lipophilic-antimycobacterial-agents-clofazimine-and-bedaquiline
#15
REVIEW
Moloko C Cholo, Maborwa T Mothiba, Bernard Fourie, Ronald Anderson
Drug-resistant (DR)-TB is the major challenge confronting the global TB control programme, necessitating treatment with second-line anti-TB drugs, often with limited therapeutic efficacy. This scenario has resulted in the inclusion of Group 5 antibiotics in various therapeutic regimens, two of which promise to impact significantly on the outcome of the therapy of DR-TB. These are the 're-purposed' riminophenazine, clofazimine, and the recently approved diarylquinoline, bedaquiline. Although they differ structurally, both of these lipophilic agents possess cationic amphiphilic properties that enable them to target and inactivate essential ion transporters in the outer membrane of Mycobacterium tuberculosis...
October 20, 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/27795624/rifampicin-and-anti-hypertensive-drugs-in-chronic-kidney-disease-pharmacokinetic-interactions-and-their-clinical-impact
#16
A Agrawal, S K Agarwal, T Kaleekal, Y K Gupta
Patients on dialysis have an increased incidence of tuberculosis (TB). Rifampicin, a first-line antitubercular therapy (ATT) drug, is a potent inducer of hepatic cytochrome P450 (CYP). There is potential for pharmacokinetic interaction between rifampicin and anti-hypertensives that are CYP substrates: amlodipine and metoprolol. Therefore, hypertensive patients receiving rifampicin-based ATT are at risk for worsening of hypertension. However, this hypothesis has not yet been systematically studied. In this prospective study, hypertensive CKD 5D patients with TB were followed after rifampicin initiation...
September 2016: Indian Journal of Nephrology
https://www.readbyqxmd.com/read/27792837/isoniazid-clearance-is-impaired-among-human-immunodeficiency-virus-tuberculosis-patients-with-high-levels-of-immune-activation
#17
Christopher Vinnard, Shruthi Ravimohan, Neo Tamuhla, Vijay Ivaturi, Jotam Pasipanodya, Shashikant Srivastava, Chawangwa Modongo, Nicola M Zetola, Drew Weissman, Tawanda Gumbo, Gregory P Bisson
AIMS: Immune activation, which is characteristic of both tuberculosis (TB) and human immunodeficiency virus (HIV) infection, is associated with impaired drug metabolism. We tested the hypothesis that elevated levels of systemic immune activation among adults with HIV/TB initiating antiretroviral therapy (ART) would be associated with impaired clearance of isoniazid. METHODS: We conducted a prospective observational study of isoniazid pharmacokinetics (PK) and systemic immune activation prior to and 1 month after ART initiation...
October 28, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27776583/carbapenems-against-mycobacterium-tuberculosis-a-review-of-the-evidence
#18
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
https://www.readbyqxmd.com/read/27775177/recent-advances-and-structural-features-of-enoyl-acp-reductase-inhibitors-of-mycobacterium-tuberculosis
#19
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)...
November 2016: Archiv der Pharmazie
https://www.readbyqxmd.com/read/27768711/screening-and-development-of-new-inhibitors-of-ftsz-from-m-tuberculosis
#20
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
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