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Multidrug-resistant tuberculosis (MDR-TB) has become a critical challenge to public health, and the prevention and treatment of MDR-TB are of great significance in reducing the global burden of tuberculosis. How to improve the effectiveness and safety of chemotherapy for MDR-TB is a pressing issue that needs to be addressed in tuberculosis control efforts. This article provides a comprehensive review of the clinical application of new antituberculosis drugs in MDR-TB, aiming to provide a scientific basis for the prevention and treatment strategy of MDR-TB.
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Antituberculosos , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacosRESUMEN
DRESS related to first-line antituberculosis drugs (ATD) is a challenging diagnosis. With a long-lasting combined treatment of 4-concomitantly administrated drugs, identification of the culprit drug remains difficult and may expose patients to treatment interruption and affect their outcome. A 42-year-old female, treated with isoniazid, rifampicin, pyrazinamide and ethambutol for multifocal tuberculosis, developed, 40 days later, hyperthermia, facial edema, cervical lymphadenopathy and generalized exanthema. Biological test results revealed eosinophilia, atypical lymphocytes, and liver injury. DRESS was suspected, and ATD were withdrawn. As patch tests for the 4 ATD showed negative results, we decided to reintroduce pyrazinamide, ethambutol and rifampicin separately with a 3-day interval. Pyrazinamide and rifampicin were tolerated. However, after receiving ethambutol, she developed fever and generalized rash, with no biological abnormalities. Since ethambutol was claimed to be the culprit drug, isoniazid was added, and 10 hours later, the patient developed fever, facial edema, generalized rash, eosinophilia and liver injury. This clinical and biological pattern resolved 2 weeks later. This report suggests a hypersensitivity relapse to ethambutol after isoniazid-induced DRESS.
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AIM: Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations. METHODS: We included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions. RESULTS: We included 45 participants; mean age (± standard deviation) 38 (±10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68 h (47-77 h). The median pre-infusion ALT and miR-122 concentrations were 420 U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's ρ = .54, P = .0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P = .40 and P = .68 respectively). CONCLUSIONS: miR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI.
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Acetaminofén , Acetilcisteína , Antibióticos Antituberculosos , Enfermedad Hepática Inducida por Sustancias y Drogas , MicroARNs , MicroARNs/sangre , Acetilcisteína/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Administración Intravenosa , Acetaminofén/efectos adversos , Antibióticos Antituberculosos/efectos adversos , Alanina Transaminasa/sangre , Humanos , Masculino , Femenino , Adulto , PlacebosRESUMEN
BACKGROUND: The antituberculosis drugs (ATDs), isoniazid, rifampicin, pyrazinamide and ethambutol prompt extreme hepatic and renal damage during treatment of tuberculosis. The present study aimed to investigate protective potential of naringenin against ATDs induced hepato-renal injury. METHODS: Rats were administered with ATDs (pyrazinamide; 210, ethambutol; 170, isoniazid; 85, rifampicin; 65 mg/kg b.wt) orally for 8 weeks (3 days/week) followed by naringenin at three different doses (10, 20 and 40 mg/kg b.wt) conjointly for 8 weeks (3 days/week alternately to ATDs administration) and silymarin (50 mg/kg b.wt) as positive control. RESULTS: Exposure to ATDs caused significant increase in interleukin-6 (IL-6), triglycerides, cholesterol, bilirubin whereas depletion in insulin like growth factor-1 (IGF-1), albumin and glucose in serum. Endogenous antioxidant enzymes glutathione reductase (GR), glutathione peroxidase (GPx) and glucose-6-phosphate-dehydrogenase (G-6-PDH) were diminished in liver and kidney tissues with parallel increase in triglycerides, cholesterol, microsomal LPO and aniline hydroxylase (CYP2E1 enzyme). Ultra-structural observations of liver and kidney showed marked deviation in plasma membranes of various cellular and sub-cellular organelles after 8 weeks of exposure to ATDs. CONCLUSIONS: Conjoint treatment of naringenin counteracted ATDs induced toxic manifestations by regulating IL-6, IGF-1, CYP2E1, biochemical and ultra-structural integrity in a dose dependent manner. Naringenin has excellent potential to protect ATDs induced hepato-renal injury by altering oxidative stress, modulation of antioxidant enzymes, serum cytokines and ultra-structural changes.
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Antituberculosos , Interleucina-6 , Ratas , Animales , Antituberculosos/toxicidad , Interleucina-6/metabolismo , Isoniazida/toxicidad , Isoniazida/metabolismo , Pirazinamida/metabolismo , Pirazinamida/farmacología , Etambutol/toxicidad , Etambutol/metabolismo , Rifampin/toxicidad , Rifampin/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP2E1/farmacología , Ratas Wistar , Hígado/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Estrés OxidativoRESUMEN
BACKGROUND: Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization-recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial. METHODS: Children weighing 4.0-7.9, 8.0-11.9, 12.0-15.9, or 16.0-24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0-36.9 kg received doses recommended for adultsâ <37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. RESULTS: In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4-6.6) years; 40 (52%) were male and 20 (26%) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1-45.1), 16.7 (9.2-25.9), 317 (263-399), and 9.5 (7.5-11.5) mgâ h/L, respectively, and lower in children than in adults for rifampicin in the 4.0-7.9-, 8-11.9-, andâ ≥25-kg weight bands, isoniazid in the 4.0-7.9-kg andâ ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults. CONCLUSIONS: Recommended weight band-based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization-recommended doses requires further evaluation.
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Pirazinamida , Tuberculosis , Adulto , Antituberculosos/uso terapéutico , Niño , Preescolar , Etambutol/uso terapéutico , Femenino , Humanos , Isoniazida/farmacocinética , Isoniazida/uso terapéutico , Masculino , Pirazinamida/farmacocinética , Rifampin/uso terapéutico , Tuberculosis/tratamiento farmacológico , Organización Mundial de la SaludRESUMEN
Anti-tuberculosis (TB) drug-induced hepatotoxicity (ATDH) was related to metabolic and microbial dysregulation, but only limited data was available about the metabolomes and microbiomes in ATDH. We aimed at detecting the metabolic and microbial signatures of ATDH. Urine samples were obtained from ATDH (n = 33) and non-ATDH control (n = 41) and analyzed by untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Metabolites were analyzed by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and pathway analysis. Eight ATDH and eight non-ATDH control were evaluated by sequencing of 16S rRNA genes, and the Clusters of Orthologous Groups of proteins (COG) database were used for function prediction. Linear discriminant analysis (LDA) effect size (LEfSe) was applied to detect the differential microbiotas between the two groups. The differential microbiotas were further validated by correlation analysis with differential metabolites. OPLS-DA analysis suggested 11 metabolites that differed ATDH from non-ATDH control. Pathway analysis demonstrated that metabolism of arginine and proline, metabolism of d-arginine and d-ornithine, glutathione glycine metabolism, galactose metabolism, niacin and nicotinamide metabolism, and glycine, serine and threonine metabolism were related to ATDH. LEfSe suggested significant differences in microbiotas between the two groups. The o_ Bacteroidales, f_Prevotellaceae, and g_Prevotella were significantly increased in ATDH. In contrast, the f_Chitinophagaceae, c_Gammaproteobacteria, and p_Proteobacteria were significantly increased in non-ATDH group. The biological functions of the sequenced microbiota in this study were related to amino acid transport and metabolism and defense mechanisms. Finally, we detected strong association between urine metabolites and specific urine bacteria (|r| > 0.8). d-glucoheptose showed a strong relationship to Symbiobacterium. Creatine (r = -0.901; P < 0.001) and diglycerol were strongly associated with Alishewanella. Metabolomics and microbiomes indicate ATDH characterized by metabolic and microbial profiles may differ from non-ATDH control.
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Antituberculosos/farmacología , Biomarcadores/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Adulto , Femenino , Cromatografía de Gases y Espectrometría de Masas , Glicina/metabolismo , Humanos , Masculino , Metabolómica , Microbiota , Persona de Mediana Edad , ARN Ribosómico 16S , Serina/metabolismo , Treonina/metabolismoRESUMEN
AIM: Exploring the need for optimization of drug exposure to improve tuberculosis (TB) treatment outcome is of great importance. We aimed to describe drug exposure at steady state as well as the population pharmacokinetics (PK) of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) in Chinese TB patients. METHODS: A prospective multicentre PK study of RIF, INH and PZA was conducted in China between January 2015 and December 2017. Six blood samples were collected from each subject for drug concentration measurement. Nonlinear mixed effect analyses were used to develop population PK models. RESULTS: In total, 217 patients were included. Positive correlations between body weight, clearance and volume of distribution were identified for RIF and PZA, whereas body weight only influenced clearance for INH. In addition, males had higher RIF clearance and thus lower RIF exposure than women. Acetylator status was significantly associated with INH clearance as INH exposure in intermediate and fast acetylators was significantly lower than in slow acetylators, especially in low-weight bands. Simulations also showed significantly lower drug exposures in low-weight bands for all three drugs. Patients weighing <38 kg were respectively exposed to 30.4%, 45.9% and 18.0% lower area under the concentration-time curve of RIF, INH and PZA than those weighing ≥70 kg. Higher doses by addition of one fixed-dose combination tablet or 150 mg INH were simulated and found to be effective in improving INH drug exposures, especially in low-weight bands. CONCLUSION: PK variability of first-line anti-TB drugs is common in Chinese TB patients. The developed population PK models can be used to optimize drug exposures in Chinese patients. Moreover, standard dosing needs to be adjusted to increase target attainment.
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Antituberculosos , Preparaciones Farmacéuticas , Antituberculosos/uso terapéutico , China/epidemiología , Estudios de Cohortes , Femenino , Humanos , Isoniazida , Masculino , Estudios ProspectivosRESUMEN
In vitro cytotoxicity of polymer-carriers, which in the side chains contain the cholinum ionic liquid units with chloride (Cl) or pharmaceutical anions dedicated for antituberculosis therapy, i.e., p-aminosalicylate (PAS) and clavulanate (CLV), was investigated. The carriers and drug conjugates were examined, in the concentration range of 3.125-100 µg/mL, against human bronchial epithelial cells (BEAS-2B) and adenocarcinomic human alveolar basal epithelial cells (A549) as an experimental model cancer cell line possibly coexisting in tuberculosis. The cytotoxicity was evaluated by MTT test and confluency index, as well as by the cytometric analyses, including Annexin-V FITC apoptosis assay. The polymer systems showed supporting activity towards the normal cells and no tumor progress, especially at the highest concentration (100 µg/mL). The analysis of cell death did not show meaningful changes in the case of the BEAS-2B, whereas in the A549 cell line, the cytostatic activity was observed, especially for the drug-free carriers, causing death in up to 80% of cells. This can be regulated by the polymer structure, including the content of cationic units, side-chain length and density, as well as the type and content of pharmaceutical anions. The results of MTT tests, confluency, as well as cytometric analyses, distinguished the polymer systems with Cl/PAS/CLV containing 26% of grafting degree and 43% of ionic units or 46% of grafting degree and 18% of ionic units as the optimal systems.
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Citotoxinas/farmacología , Portadores de Fármacos/farmacología , Líquidos Iónicos/farmacología , Polímeros/farmacología , Células A549 , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Citostáticos/farmacocinética , Células Epiteliales/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Mucosa Respiratoria/efectos de los fármacosRESUMEN
Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of 100 Vietnamese children with TBM were treated with an 8-month antituberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs and to simulate different dosing strategies. The pharmacokinetic properties of rifampin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while those of isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. Cerebrospinal fluid (CSF) penetration of rifampin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampin, were sufficient to achieve target exposures. The ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampin dosing at 50 mg/kg of body weight/day would be required to achieve the target exposure. Moreover, low rifampin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.
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Antituberculosos , Tuberculosis Meníngea , Adulto , Antituberculosos/uso terapéutico , Pueblo Asiatico , Niño , Etambutol , Humanos , Isoniazida , Pirazinamida , Tuberculosis Meníngea/tratamiento farmacológicoRESUMEN
INTRODUCTION: Lichenoid cutaneous reactions to antituberculosis drugs are rare. Herein we report a new case. PATIENTS AND METHODS: A 41-year-old patient was seen for a profuse and pruriginous rash occurring 2 weeks after administration of rifampicin and isoniazid for pulmonary tuberculosis. Dermatological examination revealed polymorphic erythemato-squamous plaques with lichenoid, psoriatic and eczematous features, associated with cheilitis, erosions on the cheeks and diffuse onychodystrophy. The skin biopsy confirmed a lichenoid reaction. The pharmacovigilance investigation incriminated isoniazid and rifampicin. The patient was treated with topical corticosteroids and UVB phototherapy. The outcome involved complete regression of the eruption but with secondary anonychia. DISCUSSION: Antituberculosis drugs including isoniazid and rifampicin are known to induce lichenoid reactions. It is difficult to distinguish the results from lichen planus. The clinical polymorphism of the rash as well as the patient's drug intake militate in favour of a diagnosis of lichenoid reaction. Widespread ungual involvement, which is extremely rare, warranted early management in order to avert irreversible anonychia.
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Antituberculosos/efectos adversos , Erupciones por Medicamentos/etiología , Isoniazida/efectos adversos , Erupciones Liquenoides/inducido químicamente , Enfermedades de la Uña/inducido químicamente , Rifampin/efectos adversos , Adulto , Erupciones por Medicamentos/complicaciones , Humanos , Isoniazida/uso terapéutico , Erupciones Liquenoides/complicaciones , Masculino , Enfermedades de la Uña/complicaciones , Rifampin/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológicoRESUMEN
Tuberculosis is a chronic infectious disease, usually localized in the respiratory system and representing one of the most important global social and biomedical health problems associated with the spread of therapy-resistant forms (multidrug-resistant and extensively drug-resistant tuberculosis). One of the most promising targets for the development of antimycobacterial drugs is the enzyme DprE1, which is involved in the synthesis of the cell wall of mycobacteria. In the series of DprE1 inhibitor drugs, the most advanced drug is PBTZ169 (INN maÑozinone). Clinical trials (CT) of the efficacy and safety of macozinone are conducted by the pharmaceutical company LLC NEARMEDIC PLUS in the Russian Federation, and in other countries (Sponsors: Innovative Medicines for Tuberculosis Foundation, cole polytechnique fdrale de Lausanne and Bill and Melinda Gates Foundation). The publication describes results of completed I, IIa and Ib phases CT, conducted in the Russian Federation. AIM: The goal of phase I CT was to assess the safety, tolerability and pharmacokinetics (PK) of PBTZ169, 40 mg capsule, after single and multiple administration under fasting conditions in increasing doses in healthy volunteers. The goal of phase IIa CT was to study the efficacy (in terms of early bactericidal activity EBA), safety and PK of the drug PBTZ169, 80 mg capsules, in various doses, when used as monotherapy in patients with newly diagnosed respiratory tuberculosis with bacterial excretion and retained sensitivity to isoniazid and rifampicin. The purpose of phase Ib CT was to evaluate the safety, tolerability, PK of PBTZ169, 80 mg capsule, after single, double and multiple administration under fasting conditions in increasing doses, as well as the effect of food on its bioavailability in healthy volunteers. MATERIALS AND METHODS: The data of 100 healthy volunteers and 15 patients with newly diagnosed pulmonary tuberculosis, who received the study medication PBTZ169, capsules 40 mg and 80 mg, in the dose range 40 mg 1280 mg of PBTZ169, obtained during phase I, IIa and Ib CTs were analyzed. During I phases CTs, safety, tolerability, and PK of the drug after a single and multiple administration under fasting condition and after meals at rising doses were evaluated. The safety assessment included evaluation of AE/SAE, vital signs, ECG results, and laboratory tests results in the safety population. In the course of phase IIa CT, in addition to safety, tolerance, and PK evaluation, the efficacy of the drug (in terms of EBA) using sputum culture on agar with CFU/ml counting (main method) and quantitative PCR method (auxiliary method) was evaluated. RESULTS: During all CTs, a high safety and tolerability profile was shown, the main PK parameters of the drug and the efficacy were described. PBTZ169 demonstrated linear PK in the dosage range up to 640 mg after single and multiple administration, a statistically significant of EBA of the drug after monotherapy at the dose of 640 mg/day was demonstrate, and it was concluded that the preferred regimen of the drug PBTZ169 intake is administration after meals. Good tolerability and a favorable safety profile of the drug in the studied doses range were demonstrate during all the CTs. CONCLUSION: One of the most promising and currently studied drugs-inhibitors of DprE1, a new target for the cell wall of mycobacteria, is PBTZ169 or macozinone, which is being develop by the Russian pharmaceutical company NEARMEDIC PLUS ltd.
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Preparaciones Farmacéuticas , Tuberculosis/tratamiento farmacológico , Antituberculosos/uso terapéutico , Humanos , Piperazinas , Federación de Rusia , TiazinasRESUMEN
BACKGROUND: Antituberculosis drug-induced liver injury (ATDILI) is increasing globally and, hence, it is crucial to predict its risk in the clinical management of antituberculosis therapy. As a major antioxidant, superoxide dismutase (SOD) is mainly responsible for providing defence against oxidative stress, which is involved in ATDILI. The present study aimed to investigate the associations between polymorphisms in SOD genes, including Cu/ZnSOD (SOD1), mitochondrial manganese SOD (MnSOD or SOD2) and extracellular SOD (SOD3), as well as the susceptibility to ATDILI in a Chinese Han population. METHODS: In total, 1060 Chinese Han subjects highly suspected to have tuberculosis (TB) were prospectively enrolled from West China Hospital of Sichuan University. Overall, 746 subjects comprising 118 ATDILI and 628 ATD-tolerant TB patients were eligible and were genotyped for seven single-nucleotide polymorphisms in three SOD genes (SOD1: rs4816407 and rs1041740; SOD2: rs4880; SOD3: rs699473, rs2536512, rs2855262 and rs8192290). RESULTS: Logistic regression analysis showed that none of the seven genetic variants in the three SOD genes were significantly associated with susceptibility to ATDILI in the Chinese Han population after Bonferroni correction, except for a potential association for the SOD2 rs4880 A>G (G allele, p = 0.190, odds ratio = 1.53, 95% confidence interval = 1.05-2.23; GG genotype, p = 0.155). CONCLUSIONS: The promising application of single-nucleotide polymorphisms in the SOD1, SOD2 and SOD3 genes as genetic markers for ATDILI is challenged, and further studies are needed with larger sample sizes and different ethnicities, especially for SOD2 rs4880.
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Antituberculosos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Superóxido Dismutasa/genética , Adulto , Alelos , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , China/epidemiología , Etnicidad/genética , Femenino , Genotipo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Familia de Multigenes , Fenotipo , Sitios de Carácter CuantitativoRESUMEN
BACKGROUND: Patients suffering from drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome caused by first-line antituberculosis drugs often need to be retreated rapidly. Patch tests prior to the reintroduction of antituberculosis drugs are rarely performed. OBJECTIVES: To highlight those drugs most often involved in DRESS caused by antituberculosis drugs, illustrate the potential value of patch tests to identify these culprit(s), and provide insights into how to rapidly retreat these patients. METHODS: A detailed description of the work-up of two illustrative patients, together with a literature review of similar cases, is provided. RESULTS: All first-line antituberculosis drugs may cause DRESS syndrome, but rifampicin and isoniazid are most frequently involved. Patch tests can be performed sooner than usually advised in the context of DRESS syndrome, and potentially with lower test concentrations, but false-negative results are possible. Sequential reintroduction of patch test-negative drugs is feasible, although the dose and order of drugs to be readministered, as well as the use of concomitant systemic corticosteroids, remain a matter of debate. CONCLUSION: Patch tests in the context of DRESS syndrome caused by antituberculosis drugs, despite their shortcomings, may potentially guide rapid retreatment of these patients.
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Antituberculosos/efectos adversos , Síndrome de Hipersensibilidad a Medicamentos/etiología , Isoniazida/efectos adversos , Rifampin/efectos adversos , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Reacciones Falso Negativas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The genome of Mycobacterium tuberculosis (Mtb) encodes three ß-carbonic anhydrases (CAs, EC 4.2.1.1) that are crucial for the life cycle of the bacterium. The Mtb ß-CAs have been cloned and characterized, and the catalytic activities of the enzymes have been studied. The crystal structures of two of the enzymes have been resolved. In vitro inhibition studies have been conducted using different classes of carbonic anhydrase inhibitors (CAIs). In vivo inhibition studies of pathogenic bacteria containing ß-CAs showed that ß-CA inhibitors effectively inhibited the growth of pathogenic bacteria. The in vitro and in vivo studies clearly demonstrated that ß-CAs of not only mycobacterial species, but also other pathogenic bacteria, can be targeted for developing novel antimycobacterial agents for treating tuberculosis and other microbial infections that are resistant to existing drugs. In this review, we present the molecular and structural data on three ß-CAs of Mtb that will give us better insights into the roles of these enzymes in pathogenic bacterial species. We also present data from both in vitro inhibition studies using different classes of chemical compounds and in vivo inhibition studies focusing on M. marinum, a model organism and close relative of Mtb.
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Antituberculosos/química , Anhidrasas Carbónicas/química , Mycobacterium tuberculosis/efectos de los fármacos , Secuencia de Aminoácidos , Inhibidores de Anhidrasa Carbónica/farmacología , Dominio Catalítico , Cristalografía por Rayos X , Genoma Bacteriano , Filogenia , Estructura Terciaria de Proteína , Alineación de Secuencia , Análisis de Secuencia de ProteínaRESUMEN
Tuberculosis continues to be the most dangerous infectious disease globally and need for development of new therapies is of utmost importance. In this study we describe the rationale design for synthesis using molecular hybridization and subsequent in-vitro antimycobacterial activity of various indolo-pyridone hybrid molecules against Mycobacterium tuberculosis H37Rv. A total of 16 indolo-pyridone hybrid molecules were synthesized with 85-90% yields and characterized by various spectroscopic techniques. Four compounds were ineffective with MIC >256 µg/ml (highest concentration tested), six exhibited poor activity with MIC > 100 µg/ml, four showed moderate activity with MIC > 50 µg/ml and two had notable anti-TB activity with MIC values 32 µg/ml. Interestingly the last two compounds were observed equally effective against drug susceptible and various drug resistant strains including multidrug-resistant (MDR) strains, thereby clearly demonstrating their potential against MDR-TB. Our results showed that un-substituted aryl rings posses better antituberculosis activity than those having any kind of substitution and derivatives with small sized electron withdrawing groups in aryl ring exhibited activity while bigger groups lead to considerable loss in activity. The results of this study open up a new door for further SAR guided synthesis on one hand and on the other hand provide a promising opportunity that may lead to the discovery of a new class of antituberculosis agents.
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Antituberculosos/síntesis química , Antituberculosos/farmacología , Diseño de Fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Indoles/química , Indoles/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nitrilos/química , Nitrilos/farmacología , Piridonas/química , Piridonas/farmacología , Tuberculosis/tratamiento farmacológicoRESUMEN
The DNA ligases, enzymes that seal breaks in the backbones of DNA, are essential for all organisms, however bacterial ligases essential for DNA replication use ß-nicotinamide adenine dinucleotide as their co-factor, whereas those that are essential in eukaryotes and viruses use adenosine-5'-triphosphate. This fact leads to the conclusion that NADâº-dependent DNA ligases in bacteria could be targeted by their co-factor specific inhibitors. The development of novel alternative medical strategies, including new drugs, are a top priority focus areas for tuberculosis research due to an increase in the number of multi-drug resistant as well as totally drug resistant tubercle bacilli strains. Here, through the use of a virtual high-throughput screen and manual inspection of the top 200 records, 23 compounds were selected for in vitro studies. The selected compounds were evaluated in respect to their Mycobacterium tuberculosis NAD⺠DNA ligase inhibitory effect by a newly developed assay based on Genetic Analyzer 3500 Sequencer. The most effective agents (e.g., pinafide, mitonafide) inhibited the activity of M. tuberculosis NADâº-dependent DNA ligase A at concentrations of 50 µM. At the same time, the ATP-dependent (phage) DNA LigT4 was unaffected by the agents at concentrations up to 2 mM. The selected compounds appeared to also be active against actively growing tubercle bacilli in concentrations as low as 15 µM.
Asunto(s)
Antituberculosos/farmacología , ADN Ligasas/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Naftalimidas/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento , Isoquinolinas/farmacología , Simulación del Acoplamiento Molecular , NADRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Tuberculosis, an infectious disease caused by the bacteria Mycobacterium tuberculosis, has significant public health implications. Despite the decreasing prevalence of tuberculosis cases and the availability of well-established treatment guidelines, errors with antituberculosis medications remain a concern as clinician experience with the infection has waned and the goal of eradicating tuberculosis has remained unfulfilled. Whereas inappropriate use of other anti-infective classes has been extensively studied, the evaluation of medication errors associated with antituberculosis therapy has been limited to a small number of studies conducted more than two decades ago. This study evaluated the prevalence of inpatient medication errors with antituberculosis therapy in patients with suspected or confirmed tuberculosis disease. METHODS: All admitted patients treated with at least one antituberculosis medication between July 2010 and June 2013 were evaluated for inclusion in the retrospective study. Multidrug antituberculosis regimens were reviewed for medication errors, which were categorized as dosing errors, drug interactions, omission of therapy and inappropriate continuation of therapy in the presence of drug toxicity. Appropriate management was determined in accordance with the national guidelines for the treatment of tuberculosis, as well as guidelines on the use of antiretroviral agents for patients with both human immunodeficiency virus (HIV) infection and tuberculosis disease. The impact of infectious diseases and pulmonary consultation on the prevalence of medication errors was also examined. RESULTS AND DISCUSSION: More than half of all study patients (44/72, 61%) experienced at least one medication error associated with antituberculosis therapy. Dosing errors were the most common type of medication error identified and were predominantly related to weight-based dosing. Seven dosing errors were related to drug interactions between rifamycins and antiretroviral therapy in HIV-infected patients. Medication error rates were similar between patients receiving consultation from infectious diseases and/or pulmonary specialties and those without consultation. The large majority of antituberculosis medication errors (56/66 errors, 85%) remained uncorrected during the patient's hospital admission. WHAT IS NEW AND CONCLUSION: Medication errors associated with antituberculosis therapy remain a common occurrence in the current clinical practice setting. Greater vigilance when prescribing medications for tuberculosis disease is needed.
Asunto(s)
Antituberculosos/uso terapéutico , Errores de Medicación/estadística & datos numéricos , Guías de Práctica Clínica como Asunto , Tuberculosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Fármacos Anti-VIH/uso terapéutico , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Lactante , Recién Nacido , Pacientes Internos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenAsunto(s)
Antituberculosos/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Adulto , Antituberculosos/administración & dosificación , Hipersensibilidad a las Drogas/tratamiento farmacológico , Síndrome de Hipersensibilidad a Medicamentos , Sustitución de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Eosinofilia , Etambutol/administración & dosificación , Etambutol/efectos adversos , Exantema , Femenino , Humanos , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Prednisolona/uso terapéutico , Pirazinamida/administración & dosificación , Pirazinamida/efectos adversos , Rifampin/administración & dosificación , Rifampin/efectos adversosRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Tuberculosis is still a major infectious disease in Indonesia. Patients are treated mostly using fixed-dose combination treatment in primary public health facilities. The incidence of antituberculosis drug-induced liver injury (AT-DILI) is approximately 10% among Indonesian tuberculosis patients who used standard fixed combination regimens during the intensive phase of treatment. However, information regarding genetic polymorphism associated with the increase risk of drug-induced liver injury is still limited. The aim of this study was to investigate pregnane X receptor (PXR) gene polymorphisms as one of the risk factors of AT-DILI. METHODS: In this prospective cohort study, we recruited 106 adult patients diagnosed with pulmonary tuberculosis and treated with category I FDC (fixed-dose combination). The identification of SNP -25385C>T (rs3814055) was conducted by ARMS (amplification refractory mutation system). Hepatotoxicity was defined as ALT and/or AST levels above the normal threshold on the second, fourth and sixth months of monitoring during tuberculosis treatment. RESULTS AND DISCUSSION: The logistic regression analysis showed that patients with the TT genotype of PXR gene (rs3814055) significantly had a greater risk of AT-DILI (OR 8·89; 95% CI 1·36-57·93, P < 0·05), compared with those of wild-type CC genotype. WHAT IS NEW AND CONCLUSION: The result suggests that in Indonesian patients with tuberculosis, the risk of having AT-DILI was associated with TT genotype of the PXR gene.
Asunto(s)
Antituberculosos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Esteroides/genética , Tuberculosis Pulmonar/genética , Adolescente , Adulto , Antituberculosos/uso terapéutico , Femenino , Genotipo , Humanos , Indonesia , Masculino , Persona de Mediana Edad , Receptor X de Pregnano , Estudios Prospectivos , Receptores de Esteroides/uso terapéutico , Factores de Riesgo , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto JovenRESUMEN
BACKGROUND/PURPOSE: Under the directly observed treatment, short course (DOTS) program, antituberculosis (anti-TB) medications were possibly taken at random time, regardless of whether it was prior to or after meals. This study was to evaluate the impact of food intake on pharmacokinetic profiles of first-line TB drugs in Taiwanese TB patients, as well as the relationship between drug levels and pharmacogenetics. METHODS: This open-label, randomized, cross-over study included newly diagnosed Taiwanese TB patients treated between January 2010 and February 2011 at Taipei Medical University-Wan Fang Hospital. Rifater [a fixed-dose combination formulation of isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA)] and ethambutol (EMB) were given according to national TB guidelines. Blood samples were collected prior to and 1 hour, 2 hours, 4 hours, 6 hours, and 10 hours after dosing under fasting or postprandial conditions. Pharmacokinetic parameters of the maximum serum concentration (Cmax), time to Cmax, and area under the serum concentration-time curve from the beginning to the 10(th) hour (AUC0-10) were calculated. RESULTS: Sixteen TB patients were included and received anti-TB treatment under the DOTS program after discharge. The overall effects showed that food intake reduced the mean Cmax (INH: 40.6%, RIF: 40.2%, EMB 34.4%, PZA: 24.4%) and AUC0-10 (INH: 21.3%, RIF: 26.4%, EMB: 12.2%, PZA: 12.0%). Meanwhile, food increased the time to Cmax (INH: 78.1%, RIF: 151.3%, EMB: 41.4%, PZA: 148.9%). CONCLUSION: Significantly lower serum drug concentrations were observed under postprandial conditions than fasting conditions for INH, RIF, and PZA. The impact of taking random anti-TB drugs under the DOTS program instead of taking drugs regularly prior to meals requires further study.