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https://www.readbyqxmd.com/read/29020922/a-multiple-genome-analysis-of-mycobacterium-tuberculosis-reveals-specific-novel-genes-and-mutations-associated-with-pyrazinamide-resistance
#1
Patricia Sheen, David Requena, Eduardo Gushiken, Robert H Gilman, Ricardo Antiparra, Bryan Lucero, Pilar Lizárraga, Basilio Cieza, Elisa Roncal, Louis Grandjean, Arnab Pain, Ruth McNerney, Taane G Clark, David Moore, Mirko Zimic
BACKGROUND: Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear. RESULTS: We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping...
October 11, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29020173/time-to-sputum-culture-conversion-and-treatment-outcomes-among-patients-with-isoniazid-resistant-tuberculosis-in-atlanta-georgia
#2
Marcos C Schechter, Destani Bizune, Michelle Kagei, Mamuka Machaidze, David P Holland, Alawode Oladele, Yun F Wang, Paulina A Rebolledo, Susan M Ray, Russell R Kempker
Background: Although isoniazid-resistant tuberculosis is more common than multidrug-resistant tuberculosis, it has been much less studied. We examined the impact of isoniazid resistance and treatment regimen, including use of a fluoroquinolone, on clinical outcomes. Methods: A retrospective cohort study among patients with sputum culture-positive tuberculosis was performed. Early fluoroquinolone (FQ) use was defined as receiving ≥5 doses during the first month of treatment...
August 3, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29018250/molecular-analysis-of-pyrazinamide-resistance-in-mycobacterium-tuberculosis-in-vietnam-highlights-the-high-rate-of-pyrazinamide-resistance-associated-mutations-in-clinical-isolates
#3
Nguyen Quang Huy, Contamin Lucie, Tran Thi Thanh Hoa, Nguyen Van Hung, Nguyen Thi Ngoc Lan, Nguyen Thai Son, Nguyen Viet Nhung, Dang Duc Anh, Bañuls Anne-Laure, Nguyen Thi Van Anh
Pyrazinamide (PZA) is a key antibiotic in current anti-tuberculosis regimens. Although the WHO has stressed the urgent need to obtain data on PZA resistance, in high tuberculosis burden countries, little is known about the level of PZA resistance, the genetic basis of such resistance or its link with Mycobacterium tuberculosis families. In this context, this study assessed PZA resistance through the molecular analysis of 260 Vietnamese M. tuberculosis isolates. First-line drug susceptibility testing, pncA gene sequencing, spoligotyping and mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) typing were performed...
October 11, 2017: Emerging Microbes & Infections
https://www.readbyqxmd.com/read/28991455/pyrazinoic-acid-inhibits-mycobacterial-coenzyme-a-biosynthesis-by-binding-to-aspartate-decarboxylase-pand
#4
Pooja Gopal, Wilson Nartey, Priya Ragunathan, Jansy Passiflora Sarathy, Firat Kaya, Michelle Yee, Claudia Setzer, Malathy Sony Subramanian Manimekalai, Veronique Dartois, Gerhard Grüber, Thomas Dick
Previously, we showed that a major in vitro and in vivo mechanism of resistance to pyrazinoic acid (POA), the bioactive component of the critical tuberculosis (TB) prodrug pyrazinamide (PZA), involves missense mutations in the aspartate decarboxylase PanD, an enzyme required for coenzyme A biosynthesis. What is the mechanism of action of POA? Upon demonstrating that treatment of M. bovis BCG with POA resulted in a depletion of intracellular coenzyme A and confirming that this POA-mediated depletion is prevented by either missense mutations in PanD or exogenous supplementation of pantothenate, we hypothesized that POA binds to PanD and that this binding blocks the biosynthetic pathway...
October 9, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28990279/achieving-high-1h-nuclear-hyperpolarization-levels-with-long-lifetimes-in-a-range-of-tuberculosis-drug-scaffolds
#5
Simon Duckett, Philip Norcott, Peter J Rayner, Gary G R Green
Despite the successful use of isoniazid, rifampicin, pyrazinamide and ethambutol in the treatment of tuberculosis (TB) it is a disease of growing global concern. We illustrate here a series of methods that will dramatically improve the magnetic resonance imaging (MRI) detectability of nineteen TB relevant agents and note that the future probing of their uptake and distribution in vivo would be expected to significantly enhance their efficacy in disease treatment. This improvement in detectability is achieved by use of the parahydrogen based SABRE protocol in conjunction with the ²H-labelling of key sites within their molecular structures, and the ²H-labelling of the magnetization transfer catalyst...
October 9, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28981007/first-line-antituberculosis-drug-pyrazinamide-its%C3%A2-pharmaceutically-relevant-cocrystals-and-a-salt
#6
Kashyap Kumar Sarmah, Trishna Rajbongshi, Sourav Bhowmick, Ranjit Thakuria
A few pyrazinamide (Pyz) cocrystals involving hydroxybenzoic/cinnamic acid derivatives [2,4-dihydroxybenzoic acid (24DHBA); 2,6-dihydroxybenzoic acid (26DHBA); 3,5-dihydroxybenzoic acid (35DHBA) and nutraceutical molecule ferulic acid (FRA)] and the first example of a molecular salt with p-toluenesulfonic acid (pTSA) have been prepared and characterized using various solid-state techniques. A high-temperature cocrystal polymorph of Pyz·FRA has been characterized from the endothermic peaks observed using differential scanning calorimetry...
October 1, 2017: Acta Crystallographica Section B, Structural Science, Crystal Engineering and Materials
https://www.readbyqxmd.com/read/28980723/role-of-pnca-gene-mutations-w68r-and-w68g-in-pyrazinamide-resistance
#7
Mansi Aggarwal, Aditi Singh, Sonam Grover, Bharati Pandey, Anchala Kumari, Abhinav Grover
Mycobacterium tuberculosis (Mtb) resistance towards anti-tuberculosis drugs is a widespread problem. Pyrazinamide (PZA) is a first line antitubercular drug that kills semi-dormant bacilli when converted into its activated form i.e. pyrazinoic acid (POA) by Pyrazinamidase (PZase) enzyme coded by pncA gene. In this study, we conducted several analyses on native and mutant structures (W68R, W68G) of PZase before and after docking with the PZA drug to explore the molecular mechanism behind PZA resistance caused due to pncA mutations...
October 5, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28959695/fatal-pulmonary-embolism-in-the-setting-of-immune-reconstitution-inflammatory-syndrome-attributed-to-ovarian-tuberculosis
#8
Israel Ugalde, Daniela Pirela, Saberio Lo Presti, Molly Bilderback, Andrés Pirela, Joseph Chan
In developed countries, tuberculosis remains a health care challenge due to human immunodeficiency virus (HIV) and immigration from endemic regions. The Centers for Disease Control and Prevention reported 9557 new cases in 2015, with extrapulmonary involvement in 20.2% of the cases. We present a 33-year-old woman from Cape Town, South Africa, who developed abdominal pain and fever while working on a cruise ship. She sought medical where she underwent computed tomography of her chest, abdomen, and pelvis with findings suggestive of pulmonary tuberculosis and an 8...
July 2017: Journal of Investigative Medicine High Impact Case Reports
https://www.readbyqxmd.com/read/28928454/a-comprehensive-characterization-of-pnca-polymorphisms-that-confer-resistance-to-pyrazinamide
#9
Adam N Yadon, Kashmeel Maharaj, John H Adamson, Yi-Pin Lai, James C Sacchettini, Thomas R Ioerger, Eric J Rubin, Alexander S Pym
Tuberculosis chemotherapy is dependent on the use of the antibiotic pyrazinamide, which is being threatened by emerging drug resistance. Resistance is mediated through mutations in the bacterial gene pncA. Methods for testing pyrazinamide susceptibility are difficult and rarely performed, and this means that the full spectrum of pncA alleles that confer clinical resistance to pyrazinamide is unknown. Here, we performed in vitro saturating mutagenesis of pncA to generate a comprehensive library of PncA polymorphisms resultant from a single-nucleotide polymorphism...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28922644/temperature-dependent-polymorphism-of-pyrazinamide-an-in-situ-raman-and-dft-study
#10
Poornima Sharma, Rajib Nandi, Debraj Gangopadhyay, Anurag Singh, Ranjan K Singh
The α and γ polymorphs of drug pyrazinamide have been detected with the help of temperature dependent Raman spectroscopic technique. Pyrazinamide is a very useful drug used for the treatment of tuberculosis (TB) and plays a significant role in destroying the dormant tubercle bacilli which are not destroyed by other common TB drugs. Temperature dependent Raman spectra suggest polymorphic phase change from α→γ form of pyrazinamide between 145 and 146°C. In situ Raman spectra of pyrazinamide between 145 and 146°C show the conversion of α→γ form by the shift in CO stretching vibration accompanied by several other changes...
September 13, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/28921911/update-of-antitubercular-prodrugs-in-a-molecular-perspective-mechanisms-of-action-bioactivation-pathways-and-associated-resistances
#11
Vania Bernardes Genisson, Julie Laborde, Céline Deraeve
The place of prodrugs in the current antitubercular therapeutic arsenal is preponderant, since two of the four first-line antitubercular agents, isoniazid (INH) and pyrazinamide (PZA), need to be activated by Mycobacterium tuberculosis before exerting their activity. In addition, six other prodrugs can be found in the second- and third-line therapeutic regimens, namely ethionamide (ETH), prothionamide (PTH), p-aminosalicylic acid (PAS), thiacetazone (TAC), isoxyl (ISO) and the recently approved delamanid. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy...
September 16, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28911608/effect-of-goat-milk-on-hepatotoxicity-induced-by-antitubercular-drugs-in-rats
#12
Sonam Miglani, Rakesh Raman Patyar, Sazal Patyar, Mohammad Rafi Reshi
Aim of the present study was to assess the hepatoprotective activity of goat milk on antitubercular drug-induced hepatotoxicity in rats. Hepatotoxicity was induced in rats using a combination of isoniazid, rifampicin, and pyrazinamide given orally as a suspension for 30 days. Treatment groups received goat milk along with antitubercular drugs. Liver damage was assessed using biochemical and histological parameters. Administration of goat milk (20 mL/kg) along with antitubercular drugs (Group III) reversed the levels of serum alanine aminotransferase (82 ± 25...
October 2016: Journal of Food and Drug Analysis
https://www.readbyqxmd.com/read/28904184/improved-bactec-mgit-960-pyrazinamide-test-decreases-detection-of-false-mycobacterium-tuberculosis-pyrazinamide-resistance
#13
Alessandro Mustazzolu, Angelo Iacobino, Federico Giannoni, Claudio Piersimoni, Lanfranco Fattorini
Pyrazinamide (PZA) is a key drug for the treatment of tuberculosis (TB).….
September 13, 2017: Journal of Clinical Microbiology
https://www.readbyqxmd.com/read/28895161/therapeutic-drug-monitoring-of-antitubercular-agents-for-disseminated-mycobacterium-tuberculosis-during-intermittent-haemodialysis-and-continuous-venovenous-haemofiltration
#14
J H Sin, R H Elshaboury, R M Hurtado, A R Letourneau, R G Gandhi
WHAT IS KNOWN AND OBJECTIVE: There is a lack of data regarding therapeutic drug monitoring (TDM) of antitubercular agents in the setting of continuous venovenous haemofiltration (CVVH). We describe TDM results of numerous antitubercular agents in a critically ill patient during CVVH and haemodialysis. CASE SUMMARY: A 49-year-old man was initiated on treatment for disseminated Mycobacterium tuberculosis. During hospital admission, the patient developed critical illness and required renal replacement therapy...
September 11, 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/28880230/design-synthesis-antimycobacterial-evaluation-and-in-silico-studies-of-3-phenylcarbamoyl-pyrazine-2-carboxylic-acids
#15
Lucia Semelková, Petra Janošcová, Carlos Fernandes, Ghada Bouz, Ondřej Janďourek, Klára Konečná, Pavla Paterová, Lucie Navrátilová, Jiří Kuneš, Martin Doležal, Jan Zitko
Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine-2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity...
September 7, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28874368/immunodeficiency-and-intermittent-dosing-promote-acquired-rifamycin-monoresistance-in-murine-tuberculosis
#16
Sang-Won Park, Rokeya Tasneen, Paul J Converse, Eric L Nuermberger
More permissive preclinical models may be useful in evaluating anti-tuberculosis regimens for their propensity to select drug-resistant mutants. To evaluate whether acquired rifamycin monoresistance could be recapitulated in mice and, if so, to evaluate the effects of immunodeficiency, intermittent dosing and drug exposures. Athymic nude and BALB/c mice were infected. Controls received daily rifapentine alone or 2 months of rifampin, isoniazid, pyrazinamide and ethambutol, followed by 4 months of rifampin/isoniazid, either daily or twice-weekly with one of two isoniazid doses...
September 5, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28870094/design-synthesis-and-biological-activity-of-pyrazinamide-derivatives-for-anti-mycobacterium-tuberculosis
#17
Shiyang Zhou, Shanbin Yang, Gangliang Huang
A total of 11 pyrazinamide derivatives were designed and synthesised using pyrazinamide as the lead compound, which was optimised by structural modification with alkyl chains, six-membered rings, and bioisosterism, respectively. The target compounds were synthesised using pyrazinecarboxylic acid as the starting material by acylation, amidation, and alkylation, respectively. Their structures were confirmed by (1)H NMR, (13)C NMR, HRESIMS, and elemental analysis, respectively. The bioactivities of derivatives were assayed using bacteriostatic experiment and minimum inhibitory concentration experiment...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28862186/food-significantly-reduces-plasma-concentrations-of-first-line-anti-tuberculosis-drugs
#18
Agibothu Kupparam Hemanth Kumar, Vedachalam Chandrasekaran, Angadi Kiran Kumar, M Kawaskar, J Lavanya, Soumya Swaminathan, Geetha Ramachandran
BACKGROUND & OBJECTIVES: Concomitant feeding and anti-tuberculosis (TB) drug administration are likely to reduce nausea and enhance compliance to treatment. However, food could lower plasma drug concentrations. This study was undertaken to examine the effect of food on two-hour plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA), and pharmacokinetics of these drugs in adult TB patients. METHODS: Newly diagnosed adult TB patients were recruited from the Revised National Tuberculosis Control Programme (RNTCP) treatment centres in Chennai Corporation, Chennai, India...
April 2017: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/28839080/reply-to-srivastava-et-al-ph-conditions-under-which-pyrazinamide-works-in-humans
#19
Russell R Kempker, Charles A Peloquin, Henry M Blumberg, Sergo Vashakidze
No abstract text is available yet for this article.
September 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28827417/pharmacokinetics-tolerability-and-bacteriological-response-of-600-900-and-1200-mg-rifampicin-daily-in-patients-with-pulmonary-tb
#20
R E Aarnoutse, G S Kibiki, K Reither, H H Semvua, F Haraka, C M Mtabho, S G Mpagama, J van den Boogaard, I M Sumari-de Boer, C Magis-Escurra, M Wattenberg, J G M Logger, L H M Te Brake, M Hoelscher, S H Gillespie, A Colbers, P P J Phillips, G Plemper van Balen, M J Boeree
Background. In a multiple dose ranging trial we have previously evaluated higher doses of rifampicin in patients for two weeks. The objectives of the current study were to administer higher doses of rifampicin for a longer period to compare pharmacokinetics, safety/tolerability and bacteriological activity of such regimens.Methods. In a double-blinded, randomized, placebo-controlled, phase II clinical trial (ClinicalTrials.gov NCT00760149) 150 Tanzanian TB patients were randomized to receive either 600 (approximately 10 mg/kg), 900 or 1200 mg rifampicin combined with standard doses of isoniazid, pyrazinamide and ethambutol administered daily for two months...
August 21, 2017: Antimicrobial Agents and Chemotherapy
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