ABSTRACT
SETTING: Isoniazid (INH) is related to the development of hepatotoxicity in some patients. OBJECTIVE: To investigate the role of N-acetyl transferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) in the hepatotoxicity of patients treated with INH in an Amazonian Brazilian population. DESIGN: Patients undergoing anti-tuberculosis treatment were investigated. Hepatotoxicity was defined as an increase of more than three times the upper limit of normal in serum alanine aminotransferase levels after treatment. NAT2 genotypes were identified by sequencing, whereas CYP2E1 alleles were detected using polymerase chain reaction based methods. RESULTS: Of the 270 individuals included in the study, 18 (6.7%) developed drug-related hepatotoxicity. A high association was found between slow acetylators and hepatotoxicity, particularly with regard to allele *5. The adjusted risk of developing hepatotoxicity was significant in individuals carrying two slow acetylation alleles (P = 0.036, OR 3.05, 95%CI 1.07-8.64). In all of the CYP2E1 markers examined, wild homozygous genotypes were more prevalent in subjects with hepatotoxicity than in controls; however, the difference was not statistically significant. Joint evaluation of the genes revealed a high risk of developing hepatotoxicity in slow acetylators with CYP2E1 wild alleles (adjusted OR 4.26; 95%CI 1.47-12.37, P = 0.008). CONCLUSIONS: Large-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects.
Subject(s)
Antitubercular Agents/adverse effects , Arylamine N-Acetyltransferase/genetics , Chemical and Drug Induced Liver Injury/genetics , Cytochrome P-450 CYP2E1/genetics , Isoniazid/adverse effects , Polymorphism, Single Nucleotide , Acetylation , Adult , Alanine Transaminase/blood , Antitubercular Agents/metabolism , Arylamine N-Acetyltransferase/metabolism , Biomarkers/blood , Brazil/epidemiology , Chemical and Drug Induced Liver Injury/blood , Chemical and Drug Induced Liver Injury/enzymology , Chemical and Drug Induced Liver Injury/epidemiology , Chi-Square Distribution , Cytochrome P-450 CYP2E1/metabolism , Female , Gene Frequency , Genetic Predisposition to Disease , Heterozygote , Homozygote , Humans , Isoniazid/metabolism , Logistic Models , Male , Middle Aged , Odds Ratio , Phenotype , Polymerase Chain Reaction , Prevalence , Risk Assessment , Risk Factors , Up-Regulation , Young AdultABSTRACT
STUDY DESIGN: The analysis of oxygen uptake (VO(2)) and energy consumption in quadriplegics after 6 months of treadmill gait with neuromuscular electrical stimulation (NMES). OBJECTIVES: To compare metabolic responses in quadriplegics after 6 months of treadmill training, with NMES (30-50% body weight relief), with quadriplegics who did not perform gait. SETTING: Ambulatory of University Hospital, Brazil. METHODS: Quadriplegics were separated into gait and control groups (CGs). On inclusion, all subjects performed VO(2) test. In the gait group (GG) (n=11), the protocol consisted of 8 min of rest, 10 min of treadmill walking using NMES and 10 min of recovery. In the CG (n=10), testing consisted of 8 min rest, 15 min of quadriceps endurance exercise in sitting position with NMES and 10 min recovery. VO(2), carbon dioxide production (VCO(2)) and energy consumption were measured. The GG performed 6 months of treadmill training, using NMES, for 20 min, twice a week. The CG did not practice any activity with NMES, performing conventional physiotherapy only; the CG was stimulated only during the cardiorespiratory test. RESULTS: All parameters increased significantly for the GG: 36% for VO(2) (l/min), 43% for VCO(2) (l/min) and 32.5% for energy consumption (J/kg/s). For the CG, during knee extension exercise, VO(2) increased without changes in the energy consumption (P<0.05); smaller values were obtained for all parameters when compared to those obtained during gait. CONCLUSIONS: Quadriplegic gait was efficient towards increasing VO(2) and energy consumption, which can decrease the risk of cardiovascular diseases.
