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2.
Trials ; 20(1): 57, 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651149

RESUMO

BACKGROUND: Treatment success rates of multidrug-resistant tuberculosis (MDR-TB) remain unsatisfactory, and long-term use of second-line anti-TB drugs is accompanied by the frequent occurrence of adverse events, low treatment compliance, and high costs. The development of new efficient regimens with shorter treatment durations for MDR-TB will solve these issues and improve treatment outcomes. METHODS: This study is a phase II/III, multicenter, randomized, open-label clinical trial of non-inferiority design comparing a new regimen to the World Health Organization-endorsed conventional regimen for fluoroquinolone-sensitive MDR-TB. The control arm uses a conventional treatment regimen with second-line drugs including injectables for 20-24 months. The investigational arm uses a new shorter regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for 9 or 12 months depending on time to sputum culture conversion. The primary outcome is the treatment success rate at 24 months after treatment initiation. Secondary outcomes include time to sputum culture conversion on liquid and solid media, proportions of sputum culture conversion on liquid media after 2 and 6 months of treatment, treatment success rate according to pyrazinamide resistance, and occurrence of adverse events grade 3 and above as evaluated by the Common Terminology Criteria for Adverse Events. Based on an α = 0.025 level of significance (one-sided test), a power of 80%, and a < 10% difference in treatment success rate between the control and investigational arms (80% vs. 70%) when the anticipated actual success rate in the treatment group is assumed to be 90%, the number of participants needed per arm to show non-inferiority of the investigational regimen was calculated as 48. Additionally, assuming the proportion of fluoroquinolone-susceptible MDR-TB among participants as 50%, and 5% loss to follow-up, the number of participants is calculated as N/( 0.50 × 0.95), resulting in 102 persons per group (204 in total). DISCUSSION: This trial will reveal the effectiveness and safety of a new shorter regimen comprising four oral drugs, including delamanid, linezolid, levofloxacin, and pyrazinamide, for the treatment of fluoroquinolone-sensitive MDR-TB. Results from this trial will provide evidence for adopting a shorter and more convenient treatment regimen for MDR-TB. TRIAL REGISTRATION: ClincalTrials.gov, NCT02619994 . Registered on 2 December 2015.


Assuntos
Antituberculosos/administração & dosagem , Farmacorresistência Bacteriana Múltipla , Levofloxacino/administração & dosagem , Linezolida/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Nitroimidazóis/administração & dosagem , Oxazóis/administração & dosagem , Pirazinamida/administração & dosagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Esquema de Medicação , Quimioterapia Combinada , Estudos de Equivalência como Asunto , Feminino , Humanos , Levofloxacino/efeitos adversos , Linezolida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Mycobacterium tuberculosis/patogenicidade , Nitroimidazóis/efeitos adversos , Oxazóis/efeitos adversos , Pirazinamida/efeitos adversos , República da Coreia , Fatores de Tempo , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/microbiologia , Adulto Jovem
3.
Clin Infect Dis ; 67(suppl_3): S359-S364, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30496465

RESUMO

Background: One approach that could increase the efficacy and reduce the duration of antituberculosis therapy is pharmacokinetics/pharmacodynamics-based optimization of doses. However, this could increase toxicity. Methods: We mimicked the concentration-time profiles achieved by human equivalent doses of moxifloxacin 800 mg/day, rifampin 1800 mg/day, and pyrazinamide 4000 mg/day (high-dose regimen) vs isoniazid 300 mg/day, rifampin 600 mg/day, and pyrazinamide 2000 mg/day (standard therapy) in bactericidal and sterilizing effect studies in the hollow fiber system model of tuberculosis (HFS-TB). In an intracellular Mycobacterium tuberculosis (Mtb) HFS-TB experiment, we added a 3-dimensional human organotypic liver to determine potential hepatotoxicity of the high-dose regimen, based on lactate dehydrogenase (LDH). Treatment lasted 28 days and Mtb bacterial burden was based on colony counts. We calculated the time to extinction (TTE) of the Mtb population in the HFS-TB and used morphism-based transformation and Latin hypercube sampling to identify the minimum therapy duration in patients. Results: The kill rate of standard therapy in the bactericidal effect and sterilizing effect experiments were 0.97 (95% confidence interval [CI], .91-.99) log10 colony-forming units (CFU)/mL/day, and 0.56 (95% CI, .49-.59) log10 CFU/mL/day, respectively. The high-dose regimen's bactericidal and sterilizing effect kill rates were 0.99 (95% CI, .96-.99) log10 CFU/mL/day and 0.72 (95% CI, .56-.79) log10 CFU/mL/day, respectively. The upper confidence bound for TTE in patients was 4.5-5 months for standard therapy vs 3.7 months on the high-dose regimen. There were no differences in LDH concentrations between the 2 regimens at any time point (P > .05). Conclusions: The high-dose regimen may moderately shorten therapy without increased hepatotoxicity compared to standard therapy.


Assuntos
Antituberculosos/administração & dosagem , Moxifloxacina/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/administração & dosagem , Rifampina/administração & dosagem , Tuberculose/tratamento farmacológico , Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Relação Dose-Resposta a Droga , Humanos , Fígado/efeitos dos fármacos , Modelos Biológicos , Pirazinamida/efeitos adversos , Rifampina/efeitos adversos , Fatores de Tempo , Tuberculose/microbiologia
4.
Rev Neurol ; 66(8): 286-288, 2018 Apr 16.
Artigo em Espanhol | MEDLINE | ID: mdl-29645073
5.
Biochem Biophys Res Commun ; 497(2): 485-491, 2018 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-29454961

RESUMO

Tuberculosis (TB) has become a global public health and social threat. As clinical first-line drugs, rifampicin and isoniazid used in combination with pyrazinamide and ethambutol (the HRZE regimen) usually induce hepatotoxicity. However, the mechanisms underlying this phenomenon remain unclear, and studying the metabolic impact of co-treating TB patients with the HRZE regimen can provide new hepatotoxicity evidence. In this study, urine metabolites from TB patients were profiled using a high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) platform. The tricarboxylic acid circulation, arginine and proline metabolism and purine metabolic pathways were found to be affected by anti-TB drugs. The levels of pyroglutamate, isocitrate, citrate, and xanthine were significantly decreased after the administration of HRZE. The above mentioned pathways were also different between drug-induced liver injury (DILI) and non-DILI patients. Urate and cis-4-octenedioic acid levels in the DILI group were significantly increased compared to those in the non-DILI group, while the cis-aconitate and hypoxanthine levels were significantly decreased. These results highlight that superoxide generation can aggravate the hepatotoxic effects of the HRZE regimen. In addition, our metabolomic approach had the ability to predict hepatotoxicity for clinical applications.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/urina , Fígado/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica/métodos , Tuberculose/tratamento farmacológico , Adulto , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cromatografia Líquida de Alta Pressão/métodos , Etambutol/efeitos adversos , Feminino , Humanos , Isoniazida/efeitos adversos , Fígado/metabolismo , Fígado/patologia , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Purinas/metabolismo , Pirazinamida/efeitos adversos , Rifampina/efeitos adversos , Adulto Jovem
6.
Rev Mal Respir ; 35(1): 69-73, 2018 Jan.
Artigo em Francês | MEDLINE | ID: mdl-29429561

RESUMO

INTRODUCTION: The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe drug-induced reaction. CASE REPORT: We report the case of a 35-year-old man treated by RHEZ for a first episode of a smear positive pulmonary tuberculosis and who developed a DRESS syndrome due to pyrazinamide after twenty days of treatment, associated with a viral reactivation to Human Herpes Virus 6 (HHV6). He had a skin eruption, liver involvement and hypereosinophilia. He fully recovered after drug withdrawal, associated with local and general corticosteroids. He died two weeks after discharge. CONCLUSIONS: Discovery of DRESS syndrome during tuberculosis treatment is an uncommon complication and requires a searching for the responsible drug. That should be difficult because tuberculosis drugs are often given as fixed-dose combination. Physicians have to bear in mind the potential role of pyrazinamide.


Assuntos
Antituberculosos/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Pirazinamida/efeitos adversos , Tuberculose Pulmonar/tratamento farmacológico , Corticosteroides/uso terapêutico , Adulto , Coinfecção/tratamento farmacológico , Herpesvirus Humano 6/isolamento & purificação , Humanos , Masculino , Infecções por Roseolovirus/complicações , Infecções por Roseolovirus/tratamento farmacológico , Tuberculose Pulmonar/complicações
7.
Clin Pharmacol Ther ; 104(4): 733-741, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29247506

RESUMO

This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (Punfavorable ). Model-based simulation of optimized (Punfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines.


Assuntos
Antituberculosos/administração & dosagem , Coinfecção , Cálculos da Dosagem de Medicamento , Infecções por HIV/epidemiologia , Isoniazida/administração & dosagem , Modelos Biológicos , Pirazinamida/administração & dosagem , Rifampina/administração & dosagem , Tuberculose/tratamento farmacológico , Adolescente , Fatores Etários , Antituberculosos/efeitos adversos , Antituberculosos/farmacocinética , Peso Corporal , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/diagnóstico , Humanos , Índia/epidemiologia , Lactente , Isoniazida/efeitos adversos , Isoniazida/farmacocinética , Masculino , Pirazinamida/efeitos adversos , Pirazinamida/farmacocinética , Rifampina/efeitos adversos , Rifampina/farmacocinética , Fatores de Tempo , Resultado do Tratamento , Tuberculose/sangue , Tuberculose/diagnóstico , Tuberculose/epidemiologia
8.
Int J Immunopathol Pharmacol ; 30(4): 434-438, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28934901

RESUMO

Anti-tuberculosis drug-induced liver injury (ATLI) is common during the treatment of tuberculosis (TB). As an important enzyme in the metabolism of many drugs, UGT2B7 (uridine diphosphate glucuronyl transferase 2B7) was associated with drug-induced liver disorder. This study investigated the association between the polymorphisms of UGT2B7 and ATLI in Chinese Han. Totally, 280 newly diagnosed TB patients had been followed up for 3 months after the prescription of anti-TB therapy. Tag-single-nucleotide polymorphism (tag-SNPs) (rs10028494 and rs7668282) were genotyped with the MassARRAY platform. The associations between tag-SNPs and ATLI risk were analyzed by logistic regression analysis adjusting for confounding factors. In this prospective study, 33 patients were lost to follow-up, and 24 patients were diagnosed with ATLI and considered as the case group. The remaining 223 subjects without ATLI were considered as the control group. No significant association was observed in allele and genotype frequencies of UGT2B7 between the two groups. This study is the first attempt to investigate the association of genetic polymorphisms of UGT2B7 with ATLI in Chinese Han. There is no significant association between UGT2B7 polymorphisms and ATLI in Chinese Han.


Assuntos
Antituberculosos/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Glucuronosiltransferase/genética , Tuberculose Pulmonar/genética , Adulto , Antituberculosos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Quimioterapia Combinada , Etambutol/efeitos adversos , Etambutol/uso terapêutico , Feminino , Predisposição Genética para Doença , Humanos , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Pirazinamida/efeitos adversos , Pirazinamida/uso terapêutico , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Risco , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/enzimologia , Adulto Jovem
9.
Ann Intern Med ; 167(4): 248-255, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28761946

RESUMO

Background: Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI. Purpose: To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children. Data Sources: PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied. Study Selection: Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB). Data Extraction: 2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol. Data Synthesis: The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy. Limitation: Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies. Conclusion: Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin. Primary Funding Source: U.K. National Institute for Health Research. (PROSPERO: CRD42016037871).


Assuntos
Antituberculosos/uso terapêutico , Isoniazida/uso terapêutico , Tuberculose Latente/tratamento farmacológico , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Adulto , Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Criança , Combinação de Medicamentos , Humanos , Isoniazida/efeitos adversos , Meta-Análise em Rede , Pirazinamida/efeitos adversos , Rifampina/efeitos adversos
10.
BMJ Case Rep ; 20172017 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-28784884

RESUMO

A 40-year-old woman with HIV (CD4 270, viral load undetectable) from Zambia presented with fevers, urinary tract infection symptoms, sterile pyuria and haematuria. She was found to have genitourinary tuberculosis (TB) via mycobacterial culture of urine and ascites, and treated with rifabutin, isoniazid, pyrazinamide and ethambutol. She later had multiple episodes of asymptomatic transaminitis, triggering changes to both TB and HIV regimens. The patient then presented with diffuse rash, fevers, transaminitis and eosinophilia concerning for drug reaction with eosinophilia and systemic symptoms (DRESS). After initial improvement on discontinuation of likely responsible medications and completion of corticosteroid therapy, the patient returned with acute liver failure. This new episode was felt to be severe organ dysfunction due to DRESS, and she was treated with a prolonged corticosteroid taper and changes to her TB regimen. She has since completed therapy for TB, has improving CD4 counts and is without evidence of liver dysfunction.


Assuntos
Antibióticos Antituberculose/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Tuberculose Urogenital/tratamento farmacológico , Adulto , Quimioterapia Combinada , Etambutol/efeitos adversos , Feminino , Humanos , Isoniazida/efeitos adversos , Pirazinamida/efeitos adversos , Rifabutina/efeitos adversos
11.
Microbiome ; 5(1): 71, 2017 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-28683818

RESUMO

BACKGROUND: Effective treatment of Mycobacterium tuberculosis (Mtb) infection requires at least 6 months of daily therapy with multiple orally administered antibiotics. Although this drug regimen is administered annually to millions worldwide, the impact of such intensive antimicrobial treatment on the host microbiome has never been formally investigated. Here, we characterized the longitudinal outcome of conventional isoniazid-rifampin-pyrazinamide (HRZ) TB drug administration on the diversity and composition of the intestinal microbiota in Mtb-infected mice by means of 16S rRNA sequencing. We also investigated the effects of each of the individual antibiotics alone and in different combinations. RESULTS: While inducing only a transient decrease in microbial diversity, HRZ treatment triggered a marked, immediate and reproducible alteration in community structure that persisted for the entire course of therapy and for at least 3 months following its cessation. Members of order Clostridiales were among the taxa that decreased in relative frequencies during treatment and family Porphyromonadaceae significantly increased post treatment. Experiments comparing monotherapy and different combination therapies identified rifampin as the major driver of the observed alterations induced by the HRZ cocktail but also revealed unexpected effects of isoniazid and pyrazinamide in certain drug pairings. CONCLUSIONS: This report provides the first detailed analysis of the longitudinal changes in the intestinal microbiota due to anti-tuberculosis therapy. Importantly, many of the affected taxa have been previously shown in other systems to be associated with modifications in immunologic function. Together, our findings reveal that the antibiotics used in conventional TB treatment induce a distinct and long lasting dysbiosis. In addition, they establish a murine model for studying the potential impact of this dysbiosis on host resistance and physiology.


Assuntos
Antituberculosos/efeitos adversos , Disbiose/etiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/patologia , Isoniazida/efeitos adversos , Pirazinamida/efeitos adversos , Rifampina/efeitos adversos , Animais , Antituberculosos/administração & dosagem , Antituberculosos/uso terapêutico , Clostridiales/genética , Clostridiales/isolamento & purificação , Combinação de Medicamentos , Microbioma Gastrointestinal/genética , Intestinos/microbiologia , Isoniazida/administração & dosagem , Isoniazida/uso terapêutico , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Porphyromonas/genética , Porphyromonas/isolamento & purificação , Pirazinamida/administração & dosagem , Pirazinamida/uso terapêutico , RNA Ribossômico 16S , Rifampina/administração & dosagem , Rifampina/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia
12.
Indian J Tuberc ; 64(2): 144-146, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28410699

RESUMO

Rifampicin (RFP) and pyrazinamide (PZA) are the primary anti-tubercular drugs with a considerably safe profile. However, none of the drugs are without adverse reactions. They both can lead to a variety of adverse effects including life-threatening anaphylaxis. We report an interesting and possibly the first case of concurrent hypersensitivity to two primary anti-tubercular treatment (ATT) drugs. Hypersensitivity to RFP and PZA was confirmed in this patient by drug provocation and intradermal skin testing. He improved on alternative ATT regime withdrawing RFP and PZA.


Assuntos
Anafilaxia/etiologia , Antituberculosos/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Pirazinamida/efeitos adversos , Rifampina/efeitos adversos , Tuberculose Meníngea/tratamento farmacológico , Criança , Humanos , Masculino
13.
Infect Genet Evol ; 51: 198-202, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28389387

RESUMO

OBJECTIVES: Antituberculosis drug-induced hepatotoxicity (ATDH) remains a common and severe challenge in tuberculosis (TB) chemotherapy. A growing number of studies have revealed that genetic polymorphisms affect an individual's susceptibility to ATDH. The aim of this study was to explore the role of cytochrome P450 family 2 subfamily B member 6 (CYP2B6) gene polymorphisms in the development of ATDH in Chinese TB patients. METHODS: CYP2B6*6 genotypes were determined in TB patients with and without ATDH. Association between polymorphisms and risk of ATDH was estimated by multiple logistic regression analysis. RESULTS: A total of 343 eligible TB patients (166 with ATDH; 177 without ATDH) were included in this study. Analysis of all subjects revealed no statistical differences in genotype distribution between the two groups. However, the CYP2B6 *6/*6 genotype was significantly associated with decreased risk of ATDH in the male subgroup (P=0.039, OR=0.097, 95% CI: 0.011-0.885). Furthermore, in male patients, the presence of the CYP2B6*6 allele was significantly higher in the non-ATDH group compared with the ATDH group (26.2% vs. 15.5%, P=0.020, OR=0.522, 95% CI: 0.301-0.903). CONCLUSIONS: This study is the first to demonstrate an association between CYP2B6 polymorphisms and the risk of ATDH in the Chinese population. We have shown that males who have the CYP2B6 *6/*6 genotype may be less susceptible to the development of ATDH. Further studies are required to confirm this genetic association result.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Citocromo P-450 CYP2B6/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Alelos , Antituberculosos/administração & dosagem , Grupo com Ancestrais do Continente Asiático , Doença Hepática Induzida por Substâncias e Drogas/etnologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/microbiologia , Citocromo P-450 CYP2B6/metabolismo , Etambutol/administração & dosagem , Etambutol/efeitos adversos , Feminino , Expressão Gênica , Frequência do Gene , Haplótipos , Humanos , Isoniazida/administração & dosagem , Isoniazida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Mycobacterium tuberculosis/fisiologia , Estudos Prospectivos , Pirazinamida/administração & dosagem , Pirazinamida/efeitos adversos , Rifampina/administração & dosagem , Rifampina/efeitos adversos , Tuberculose Pulmonar/etnologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/microbiologia
14.
Eur Respir J ; 49(3)2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28331044

RESUMO

Although clofazimine is used to treat multidrug-resistant tuberculosis (MDR-TB), there is scant information on its effectiveness and safety. The aim of this retrospective, observational study was to evaluate these factors as well as the tolerability of clofazimine in populations in Brazil, where it was administered at a daily dose of 100 mg·day-1 (body weight ≥45 kg) as part of a standardised MDR-TB treatment regimen until 2006 (thereafter pyrazinamide was used).All MDR-TB patients included in the Sistema de Informação de Tratamentos Especiais da Tuberculose (SITETB) individual electronic register were analysed. The effectiveness of clofazimine was assessed by comparing the treatment outcomes of patients undergoing clofazimine-containing regimens against those undergoing clofazimine-free regimens and its safety by describing clofazimine-attributed adverse events. A total of 1446 patients were treated with clofazimine-containing regimens and 1096 with pyrazinamide-containing regimens.Although success rates were similar in patients treated with clofazimine versus those treated with pyrazinamide (880 out of 1446, 60.9%, versus 708 out of 1096, 64.6%; p=0.054), clofazimine-treated cases exhibited higher death rates due to tuberculosis than pyrazinamide-treated ones (314 out of 1446, 21.7%, versus 120 out of 1096, 10.9%) but fewer failures (78 out of 1446, 5.4%, versus 95 out of 1096, 8.7%) and less loss to follow-up (144 out of 1446, 10.0%, versus 151 out of 1096, 13.8%). No relevant differences were detected when comparing adverse events in patients treated with clofazimine-containing regimens to those treated with clofazimine-free regimens. However, the incidence of side-effects was less than previously reported (gastro-intestinal complaints: 10.5%; hyper-pigmentation: 50.2%; neurological disturbances: 9-13%).


Assuntos
Antituberculosos/administração & dosagem , Clofazimina/administração & dosagem , Pirazinamida/administração & dosagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Adulto , Antituberculosos/efeitos adversos , Brasil/epidemiologia , Clofazimina/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
16.
Am J Ther ; 24(2): e144-e149, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-26057141

RESUMO

Drug-induced hepatitis (DIH) is one of the major complications among the treatment of patients with tuberculosis (TB); it might even be fatal. This study tries to address the recurrence of DIH with 2 anti-TB regimens. In the retrospective study from 2007 to 2010, 135 TB patients with DIH who were older than 16 years were entered to study. The patients with DIH were randomly treated with a regimen, including isoniazid, rifampin, and ethambutol, plus either ofloxacin or pyrazinamide. The patients were reviewed for occurrence of recurrent DIH. Cure and completed treatment were considered as acceptable treatment outcomes, whereas default of treatment, treatment failure, and death were considered to be unacceptable outcomes. Therefore, 135 subjects with DIH were reviewed, and 23 patients (17%) experienced recurrence of hepatitis (19 cases in the ofloxacin group and 4 cases in the pyrazinamide group). There is no significant difference in recurrence of hepatitis between these 2 groups (P = 0.803). An acceptable outcome was observed in 95 patients (70.4%), and an unacceptable outcome was seen in 14 cases (10.3%). There was no significant difference in outcomes between these 2 regimens (P = 0.400, odds ratio = 1.62, 95% confidence interval, 0.524-4.98). The results of our study suggest that ofloxacin-based anti-TB regimen does not decrease the risk of recurrent DIH. Therefore, adding ofloxacin in the case of DIH is not recommended.


Assuntos
Antibacterianos/efeitos adversos , Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ofloxacino/efeitos adversos , Pirazinamida/efeitos adversos , Tuberculose Pulmonar/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/uso terapêutico , Quimioterapia Combinada , Etambutol/uso terapêutico , Feminino , Hepatite/etiologia , Humanos , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Rifampina/uso terapêutico , Adulto Jovem
17.
Antimicrob Agents Chemother ; 60(12): 7347-7356, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27697757

RESUMO

Pyrazinamide (PZA) is an essential antitubercular drug, but little is still known about its hepatotoxicity potential. This study examined the effects of PZA exposure on zebrafish (Danio rerio) larvae and the mechanisms underlying its hepatotoxicity. A transgenic line of zebrafish larvae that expressed enhanced green fluorescent protein (EGFP) in the liver was incubated with 1, 2.5, and 5 mM PZA from 72 h postfertilization (hpf). Different endpoints such as mortality, morphology changes in the size and shape of the liver, histological changes, transaminase analysis and apoptosis, markers of oxidative and genetic damage, as well as the expression of certain genes were selected to evaluate PZA-induced hepatotoxicity. Our results confirm the manner of PZA dose-dependent hepatotoxicity. PZA was found to induce marked injury in zebrafish larvae, such as liver atrophy, elevations of transaminase levels, oxidative stress, and hepatocyte apoptosis. To further understand the mechanism behind PZA-induced hepatotoxicity, changes in gene expression levels in zebrafish larvae exposed to PZA for 72 h postexposure (hpe) were determined. The results of this study demonstrated that PZA decreased the expression levels of liver fatty acid binding protein (L-FABP) and its target gene, peroxisome proliferator-activated receptor α (PPAR-α), and provoked more severe oxidative stress and hepatitis via the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and transforming growth factor ß (TGF-ß). These findings suggest that L-FABP-mediated PPAR-α downregulation appears to be a hepatotoxic response resulting from zebrafish larva liver cell apoptosis, and L-FABP can be used as a biomarker for the early detection of PZA-induced liver damage in zebrafish larvae.


Assuntos
Antituberculosos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/metabolismo , Hepatite/patologia , Larva/efeitos dos fármacos , Pirazinamida/farmacologia , Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Antituberculosos/efeitos adversos , Proteínas de Fluorescência Verde/genética , Inflamação , Fígado/efeitos dos fármacos , Estresse Oxidativo , PPAR alfa/metabolismo , Pirazinamida/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Transaminases/metabolismo , Fator de Crescimento Transformador beta/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Peixe-Zebra/genética
18.
Indian J Pharmacol ; 48(5): 522-525, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27721537

RESUMO

OBJECTIVES: To compare the efficacy and safety of febuxostat and allopurinol in pyrazinamide (PZA)-induced hyperuricemia in patients taking antitubercular therapy (ATT). METHODS: This randomized controlled study was conducted at a tertiary care teaching institute of Rajasthan in all the sputum-positive tubercular patients aged between 18 and 65 years of either sex. Serum uric acid level was monitored at 0th, 2nd, 4th, 6th, and 8th week of ATT. Patients whose uric acid level was found to be increased at 2nd week were finally recruited in the study. Ninety patients who developed hyperuricemia due to ATT were divided randomly into three groups (Group A - febuxostat, Group B - allopurinol, and Group C - control) of thirty patients each. Mean serum uric acid levels were calculated at all the weeks in all the groups, and serum uric acid levels were compared by applying student's t-test and ANOVA. RESULTS: Mean serum uric acid level decreased from 10.698 mg/dl (at 2nd week) to 7.846 mg/dl (at 8th week) in Group A and from 11.34 mg/dl (at 2nd week) to 7.280 mg/dl (at 8th week) in Group B. Numbers of adverse events encountered across both the treatment groups were same with both the drugs. CONCLUSION: Allopurinol and febuxostat were equally efficacious in lowering PZA induced raised serum uric acid level in tubercular patients, and it was possible to continue ATT without withdrawing PZA.


Assuntos
Alopurinol/uso terapêutico , Antituberculosos/efeitos adversos , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Pirazinamida/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Humanos , Hiperuricemia/sangue , Hiperuricemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Ácido Úrico/sangue , Adulto Jovem
19.
J Assoc Physicians India ; 64(5): 90-92, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27735167

RESUMO

A 22 year-old lady with multi-drug-resistant pulmonary tuberculosis was on Kanamycin, Cycloserine, Ethionamide, Pyrazinamide and Moxifloxacin since more than two months. She presented with muscle cramps and carpopedal spasm. Investigation revealed hypokalemia and metabolic alkalosis. She also had hypomagnesemia, hypochloremia and hypocalciuria. Serum urea and creatinine levels were normal. Patient was treated with intravenous and oral potassium chloride. Kanamycin was stopped. Metabolic alkalosis and hypokalemia improved gradually over one month. Biochemical parameters were like Gitelman's syndrome but it reversed with stoppage of Kanamycin. Gitelman-like syndrome with Kanamycin toxicity has not been reported in literature previously.


Assuntos
Alcalose/induzido quimicamente , Antibacterianos/uso terapêutico , Antituberculosos/uso terapêutico , Hipopotassemia/induzido quimicamente , Canamicina/efeitos adversos , Potássio/administração & dosagem , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Antibacterianos/administração & dosagem , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Ciclosserina/administração & dosagem , Ciclosserina/efeitos adversos , Etionamida/administração & dosagem , Etionamida/efeitos adversos , Feminino , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/efeitos adversos , Humanos , Canamicina/administração & dosagem , Moxifloxacina , Cãibra Muscular/etiologia , Potássio/sangue , Pirazinamida/administração & dosagem , Pirazinamida/efeitos adversos , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/microbiologia
20.
Genet Mol Res ; 15(3)2016 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-27706680

RESUMO

Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse reaction to anti-tuberculosis (TB) treatment. Thioredoxin reductase 1 (TXNRD1), encoded by the TXNRD1 gene, is an important enzyme involved in oxidant challenge. TXNRD1 plays a key role in regulating cell growth and transformation, and protects cells against oxidative damage. We investigated the association between TXNRD1 polymorphisms and ATDH susceptibility. In this prospective study, 280 newly diagnosed TB patients were followed-up for 3 months after beginning anti-TB therapy. Tag single-nucleotide polymorphisms (tag-SNPs) of TXNRD1 were selected using Haploview 4.2 based on the HapMap database of the Chinese Han in Beijing (CHB) panel. Genotyping was performed using the MassARRAY platform. Of the 280 patients enrolled in this study, 33 were lost to follow-up, 24 had ATDH, and 223 were free from ATDH. After adjusting for sex, age, smoking status, and body mass index, there were no significant differences in the allele and genotype frequency distributions of TXNRD1 SNPs between the ATDH and non-ATDH groups (all P > 0.05). The haplotype analysis showed that haplotype TCAGCC was associated with an increased risk of ATDH susceptibility [P = 0.024, OR (95%CI) = 6.273 (1.023-38.485)]. Further stratified analyses showed that the haplotype TCAGCC was associated with ATDH susceptibility in female subjects [P = 0.036, OR (95%CI) = 5.711 (0.917-35.560)] and non-smokers [P = 0.029, OR (95%CI) = 6.008 (0.971-37.158)]. Our results suggest that TXNRD1 variants may favor ATDH susceptibility in females and non-smokers. Further studies are required to verify this association.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Polimorfismo de Nucleotídeo Único , Tiorredoxina Redutase 1/genética , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Fatores Etários , Alelos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Etambutol/efeitos adversos , Feminino , Expressão Gênica , Frequência do Gene , Haplótipos , Humanos , Isoniazida/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Estudos Prospectivos , Pirazinamida/efeitos adversos , Rifampina/efeitos adversos , Fatores de Risco , Fatores Sexuais , Tuberculose Pulmonar/microbiologia
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