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1.
J Pharm Biomed Anal ; 248: 116297, 2024 Sep 15.
Article in English | MEDLINE | ID: mdl-38906071

ABSTRACT

The underlying cause of tuberculosis (TB) treatment failure is still largely unknown. A 1H NMR approach was applied to identify and quantify a subset of TB drugs and drug metabolites: ethambutol (EMB), acetyl isoniazid (AcINH), isonicotinic acid, pyrazinamide (PZA), pyrazinoic acid and 5-hydroxy-pyrazinoic acid, from the urine of TB patients. Samples were collected before, during (weeks one, two and four) and after standardised TB treatment. The median concentrations of the EMB and PZA metabolites were comparable between the samples from patients with eventually cured and failed treatment outcomes. The INH metabolites showed comparatively elevated concentrations in the treatment failure patients during and after treatment. Variation in INH metabolite concentrations couldn't be associated with the varying acetylator genotypes, and it is therefore suggested that treatment failure is influenced more so by other conditions, such as environmental factors, or individual variation in other INH metabolic pathways.


Subject(s)
Antitubercular Agents , Treatment Failure , Tuberculosis , Humans , Antitubercular Agents/urine , Antitubercular Agents/therapeutic use , Antitubercular Agents/analysis , Tuberculosis/drug therapy , Tuberculosis/urine , Male , Adult , Female , Proton Magnetic Resonance Spectroscopy/methods , Middle Aged , Pyrazinamide/urine , Ethambutol/urine , Magnetic Resonance Spectroscopy/methods , Isoniazid/urine , Aged
2.
J Antimicrob Chemother ; 79(6): 1270-1278, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38661209

ABSTRACT

OBJECTIVES: Twelve weekly doses of rifapentine and isoniazid (3HP regimen) are recommended for TB preventive therapy in children with TB infection. However, they present with variability in the pharmacokinetic profiles. The current study aimed to develop a pharmacokinetic model of rifapentine and isoniazid in 12 children with TB infection using NONMEM. METHODS: Ninety plasma and 41 urine samples were collected at Week 4 of treatment. Drug concentrations were measured using a validated HPLC-UV method. MassARRAY® SNP genotyping was used to investigate genetic factors, including P-glycoprotein (ABCB1), solute carrier organic anion transporter B1 (SLCO1B1), arylacetamide deacetylase (AADAC) and N-acetyl transferase (NAT2). Clinically relevant covariates were also analysed. RESULTS: A two-compartment model for isoniazid and a one-compartment model for rifapentine with transit compartment absorption and first-order elimination were the best models for describing plasma and urine data. The estimated (relative standard error, RSE) of isoniazid non-renal clearance was 3.52 L·h-1 (23.1%), 2.91 L·h-1 (19.6%), and 2.58 L·h-1 (20.0%) in NAT2 rapid, intermediate and slow acetylators. A significant proportion of the unchanged isoniazid was cleared renally (2.7 L·h-1; 8.0%), while the unchanged rifapentine was cleared primarily through non-renal routes (0.681 L·h-1; 3.6%). Participants with the ABCB1 mutant allele had lower bioavailability of rifapentine, while food prolonged the mean transit time of isoniazid. CONCLUSIONS: ABCB1 mutant allele carriers may require higher rifapentine doses; however, this must be confirmed in larger trials. Food did not affect overall exposure to isoniazid and only delayed absorption time.


Subject(s)
Antitubercular Agents , Arylamine N-Acetyltransferase , Isoniazid , Rifampin , Tuberculosis , Humans , Rifampin/pharmacokinetics , Rifampin/analogs & derivatives , Rifampin/administration & dosage , Rifampin/therapeutic use , Isoniazid/pharmacokinetics , Isoniazid/urine , Isoniazid/administration & dosage , Isoniazid/therapeutic use , Male , Female , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/administration & dosage , Antitubercular Agents/therapeutic use , Child , Child, Preschool , Arylamine N-Acetyltransferase/genetics , Tuberculosis/drug therapy , Liver-Specific Organic Anion Transporter 1/genetics , Genotype , Polymorphism, Single Nucleotide , ATP Binding Cassette Transporter, Subfamily B/genetics , Adolescent , Infant
3.
Pediatr Infect Dis J ; 40(1): e43-e45, 2021 01.
Article in English | MEDLINE | ID: mdl-33055504

ABSTRACT

We assessed adherence in an infant tuberculosis prevention trial in Kenya with a urine isoniazid metabolite-detecting dipstick. Ninety-seven infants had 155 assays performed; 77 (49.7%) were found to be positive despite caregiver-reported adherence. Positive assays were associated with maternal secondary education, HIV suppression and no reported missed doses in past 3 days, suggesting caregiver education and self-medication use influenced infant adherence.


Subject(s)
Isoniazid/urine , Medication Adherence , Tuberculosis , Antitubercular Agents/therapeutic use , Biomarkers/urine , Cohort Studies , Female , HIV Infections , Humans , Infant , Isoniazid/therapeutic use , Kenya , Male , Randomized Controlled Trials as Topic , Tuberculosis/drug therapy , Tuberculosis/prevention & control
4.
AIDS ; 34(1): 63-71, 2020 01 01.
Article in English | MEDLINE | ID: mdl-31567163

ABSTRACT

OBJECTIVES: Tuberculosis preventive therapy for people living with HIV is effective, widely recommended, and increasingly prescribed, but completion rates are less than ideal, and adherence is not typically monitored. We sought to quantify adherence to isoniazid preventive therapy using a urine metabolite assay. DESIGN: Two cross-sectional surveys. SETTING: Rio de Janeiro, Brazil, 2008-2009; and Northwest Province, South Africa, 2018-2019. PARTICIPANTS: Two hundred and three Brazilian and 93 South African patients attending HIV clinics with active prescriptions for isoniazid preventive therapy MAIN OUTCOME MEASURES:: Self-reported isoniazid adherence, paired with semiquantitative measurement of urine isoniazid metabolites. RESULTS: By self-report, 90% of patients [95% confidence interval (CI) 86-93%] reported having taken a dose of isoniazid on the day of enrollment or the preceding day, and 91% (95% CI 87-94%) reported missing an average of one dose or fewer per week. By urine testing, only 65% (95% CI 59-70%) of all patients, and 69% (95% CI 63-74%) of those who reported having taken isoniazid on the current or preceding day, had detectable urine metabolites (expected in 95% of patients at 24 h). Longer time since starting preventive therapy was independently associated with a negative urine test for isoniazid metabolites (adjusted prevalence ratio 1.11 per month of isoniazid, 95% CI 1.05-1.18). CONCLUSION: Adherence to isoniazid preventive therapy among patients with HIV in Brazil and South Africa is inadequate, is overestimated by self-report, and declines with time on treatment. Shorter regimens for TB preventive therapy may improve adherence and completion, but adherence support for all patients may be necessary.


Subject(s)
Antitubercular Agents/therapeutic use , HIV Infections/complications , Isoniazid/therapeutic use , Medication Adherence/statistics & numerical data , Tuberculosis/prevention & control , Adult , Anti-HIV Agents/therapeutic use , Brazil/epidemiology , Cross-Sectional Studies , Female , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , Isoniazid/urine , Male , Middle Aged , Prevalence , South Africa/epidemiology , Tuberculosis/epidemiology , Tuberculosis/urine
5.
Talanta ; 205: 120138, 2019 Dec 01.
Article in English | MEDLINE | ID: mdl-31450409

ABSTRACT

Herein, we report a novel composite fabricated via embedding rod-like Co based metal-organic framework (Co-MOF-74) crystals into MC matrix for the first time. The introduction of MC astricts the size of Co-MOF-74 crystals, enlarges the pore size and improves the electrical conductivity, which lead to the good electrochemical properties of the composite. The fabricated sensor based on Co-MOF-74@MC exhibits superior electrocatalytic activity toward the reduction of pyrazinamide (PZA) and the oxidation of isonicotinyl hydrazide (INZ). Under optimized conditions, the sensor shows two linear ranges from 0.3 to 46.5 µM and 46.5-166.5 µM with a high sensitivity of 7.2 µA µM-1 cm-2 and a detection limit of 0.21 µM for the determination of PZA. The electroanalytical sensing of INZ also gives two linear ranges of 0.15-1.55 µM and 1.55-592.55 µM with a detection limit of 0.094 µM. The mechanism involved was also discussed, briefly. The sensor is assessed toward the detection of PZA and INZ in human serum and urine samples. Recovery values varied from 97.08 to 103.20% for PZA sensing and 96.67-102.90% for INZ sensing, revealing the promising practicality of sensor for PZA and INZ detection.


Subject(s)
Blood Chemical Analysis/methods , Carbon/chemistry , Cobalt/chemistry , Glass/chemistry , Isoniazid/analysis , Metal-Organic Frameworks/chemistry , Pyrazinamide/analysis , Urinalysis/methods , Blood Chemical Analysis/instrumentation , Catalysis , Electrochemistry , Electrodes , Humans , Isoniazid/blood , Isoniazid/chemistry , Isoniazid/urine , Limit of Detection , Oxidation-Reduction , Porosity , Pyrazinamide/blood , Pyrazinamide/chemistry , Pyrazinamide/urine , Urinalysis/instrumentation
6.
Klin Lab Diagn ; 61(1): 21-4, 2016 Jan.
Article in Russian | MEDLINE | ID: mdl-27183725

ABSTRACT

The sampling of study included 185 examined workers. Out of them 90 work at "Opitnii zavod Neftekhim" (67 females and 23 males) and 95--at "Kaustik" (64 females and 31 males) from various workshops of the given enterprises. To determine biochemical indicators samples of blood, saliva and urine were collected. The study was carried out in concordance with ethic principles of the Helsinki world medical association declaration, 2008 ed. with receiving written consent of patient to participate in study.


Subject(s)
Chemical Industry , Hydrocarbons, Aromatic/adverse effects , Occupational Diseases/diagnosis , Occupational Exposure/adverse effects , Adult , Antipyrine/administration & dosage , Antipyrine/blood , Biomarkers/blood , Biomarkers/urine , Catalase/blood , Erythrocytes/chemistry , Erythrocytes/metabolism , Female , Glutathione/blood , Glyceraldehyde-3-Phosphate Dehydrogenases/blood , Hexokinase/blood , Humans , Isoniazid/administration & dosage , Isoniazid/urine , Male , Middle Aged , Occupational Diseases/blood , Occupational Diseases/urine , Peroxidase/blood , Pyruvate Kinase/blood , Saliva/chemistry , Sodium-Potassium-Exchanging ATPase/blood , Sulfhydryl Compounds/blood , Superoxide Dismutase/blood
7.
Antimicrob Agents Chemother ; 60(4): 2257-64, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26833163

ABSTRACT

Population level variation of drug metabolism phenotype (DMP) has great implications in treatment outcome, drug-related side effects, and resistance development. In this study, we used a gas chromatography-time of flight-mass spectrometry (GC-TOF-MS)-based untargeted urine metabolomics approach to understand the DMP of a tuberculosis (TB) patient cohort (n= 20) from Tripura, a state in the northeastern part of India. Urine samples collected at different postdose time points (2 h, 6 h, 12 h, 24 h, 36 h, and 48 h) from these newly diagnosed TB patients receiving first-line anti-TB drugs were analyzed, and we have successfully detected three of the four first-line drugs,viz, isoniazid (INH), ethambutol (ETB), and pyrazinamide (PZA). The majority of their known metabolites, acetyl-isoniazid (AcINH), isonicotinic acid (INA), isonicotinuric acid (INTA), 2,2'-(ethylenediimino)-dibutyric acid (EDBA), 5-hydroxypyrazinamide (5OH-PZA), pyrazinoic acid (POA), and 5-hydroxypyrazinoic acid (5OH-POA), were also detected. Analyzing the variation in abundances of drugs and their known metabolites and calculating the metabolic ratios in these samples, we offer comprehensive DMP information on this small patient cohort that represents Tripura, India. The majority (75%) of these patients are found to be slow acetylators of INH. The average metabolic ratios of POA/PZA and 5OH-POA/POA are 3.16 ± 3.03 and 6.09 ± 6.15, respectively. Employing correlation analysis of the metabolomics metadata and a manual prediction of drug catabolism, we have proposed 2-aminobutyric acid (AABA) as a novel metabolite of ETB. These observations indicate the usefulness of GC-MS-based metabolomics to characterize the DMP at a population level and also to identify novel drug metabolites.


Subject(s)
Aminobutyrates/urine , Antitubercular Agents/urine , Ethambutol/urine , Metabolomics , Tuberculosis, Pulmonary/urine , Adult , Aged , Aged, 80 and over , Antitubercular Agents/therapeutic use , Biotransformation , Case-Control Studies , Chromatography, Gas , Ethambutol/therapeutic use , Female , Humans , India , Isoniazid/therapeutic use , Isoniazid/urine , Male , Middle Aged , Mycobacterium tuberculosis/physiology , Pyrazinamide/therapeutic use , Pyrazinamide/urine , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/microbiology
8.
J Pharm Biomed Anal ; 117: 109-17, 2016 Jan 05.
Article in English | MEDLINE | ID: mdl-26355768

ABSTRACT

A simple and sensitive UPLC-MS/MS assay was developed and validated for rapid determination of thiosemicarbazide derivative of isoniazid (TSC-INH), a potent anti-candidal agent in rat plasma, tissues, urine and feces. All biological samples were prepared by protein precipitation method using celecoxib as an internal standard (IS). Chromatographic separation was achieved on Acquity BEH™ C18 (50×2.1 mm, 1.7 µm) column using gradient mobile phase of acetonitrile and water (containing 0.1% formic acid) at flow rate of 0.3 mL/min. The MRM transitions were monitored at m/z 305.00→135.89 for TSC-INH and m/z 380.08→316.03 for IS in ESI negative mode. All validation parameter results were within the acceptable range described in guideline for bioanalytical method validation. The pharmacokinetic study showed that the compound TSC-INH was orally active with 66% absolute bioavailability in rats. It was rapidly absorbed with peak plasma concentration of 1985.92 ng/mL achieved within 1 h after single oral dose (10 mg/kg) administration. TSC-INH exhibited rapid distribution across the body with highest levels in liver and lungs. Penetration in brain tissues suggests that TSC-INH crossed the blood brain barrier. Only 5.23% of the orally administered drug was excreted as unconverted form in urine and feces implying that TSC-INH was metabolized extensively before excretion. With the preliminary knowledge of in vivo pharmacokinetics and disposition properties, this study will be beneficial for further development of compound TSC-INH in future studies.


Subject(s)
Antifungal Agents/pharmacokinetics , Isoniazid/blood , Isoniazid/urine , Semicarbazides/blood , Semicarbazides/urine , Tandem Mass Spectrometry/standards , Animals , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/standards , Feces/chemistry , Isoniazid/pharmacokinetics , Male , Rats , Rats, Wistar , Reproducibility of Results , Semicarbazides/pharmacokinetics , Tandem Mass Spectrometry/methods , Tissue Distribution/drug effects , Tissue Distribution/physiology
9.
Colloids Surf B Biointerfaces ; 121: 444-50, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25023902

ABSTRACT

A simple and sensitive electrochemical method has been proposed for the determination of isoniazid (INZ). For the first time, rhodium (Rh) modified glassy carbon electrode (GCE) has been employed for the determination of INZ by linear sweep voltammetry technique (LSV). Compared with the unmodified electrode, the proposed Rh modified electrode provides strong electrocatalytic activity toward INZ with significant enhancement in the anodic peak current. Scanning electron microscopy (SEM) and field emission scanning electron microscopy (FESEM) results reveal the morphology of Rh particles. With the advantages of wide linearity (70-1300µM), good sensitivity (0.139µAµM(-1)cm(-2)) and low detection limit (13µM), this proposed sensor holds great potential for the determination of INZ in real samples. The practicality of the proposed electrode for the detection of INZ in human urine and blood plasma samples has been successfully demonstrated using LSV technique. Through the determination of INZ in commercially available pharmaceutical tablets, the practical applicability of the proposed method has been validated. The recovery results are found to be in good agreement with the labeled amounts of INZ in tablets, thus showing its great potential for use in clinical and pharmaceutical analysis.


Subject(s)
Electrochemical Techniques/methods , Isoniazid/blood , Isoniazid/urine , Rhodium/chemistry , Adult , Carbon/chemistry , Catalysis , Dielectric Spectroscopy , Electrodes , Glass/chemistry , Humans , Hydrogen-Ion Concentration , Isoniazid/chemistry , Microscopy, Electron, Scanning , Oxidation-Reduction , Reproducibility of Results , Surface Properties
10.
Int J Tuberc Lung Dis ; 18(5): 528-30, 2014 May.
Article in English | MEDLINE | ID: mdl-24903787

ABSTRACT

The Arkansas colorimetric method monitors adherence to isoniazid (INH) by the detection of INH metabolites in urine. Urine samples 4 h after INH administration in 31 human immunodeficiency virus infected children receiving daily or thrice weekly INH preventive therapy were Arkansas test-positive for 29/31 (94%), while acetylisoniazid (AcINH) was detected in 30/31 (97%) using mass spectrometry. At 24, 48 and 72 h, only 78%, 23% and 0 samples, respectively, were Arkansas-positive, while INH or AcINH was detected in respectively 94%, 69% and 33%. The Arkansas test reliably predicted INH ingestion at a clinic visit 4 h after morning doses, but did not perform well at 24 h.


Subject(s)
Antitubercular Agents/urine , Coinfection , Drug Monitoring/methods , HIV Infections/complications , Isoniazid/analogs & derivatives , Medication Adherence , Primary Prevention/methods , Tuberculosis/prevention & control , Age Factors , Antitubercular Agents/administration & dosage , Antitubercular Agents/pharmacokinetics , Biomarkers/urine , Biotransformation , Child , Chromatography, High Pressure Liquid , Colorimetry , HIV Infections/diagnosis , Humans , Isoniazid/administration & dosage , Isoniazid/pharmacokinetics , Isoniazid/urine , Predictive Value of Tests , Reproducibility of Results , South Africa , Tandem Mass Spectrometry , Tuberculosis/complications , Tuberculosis/diagnosis
11.
Luminescence ; 29(8): 1053-8, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24753178

ABSTRACT

Based on the oxidation of acridine yellow by permanganate in basic medium, a new chemiluminescence system was developed for the sensitive determination of some important drugs. The remarkable inhibiting effect of fluvoxamine, ceftriaxone and isoniazid on this reaction was applied to their detection. A possible mechanism was proposed for this system based on chemiluminescence emission wavelengths and experimental observations. Under optimum conditions, calibration graphs were obtained for 1 × 10(-9) to 1 × 10(-6) mol/L of fluvoxamine; 2 × 10(-8) to 8 × 10(-6) mol/L of ceftriaxone and 5 × 10(-8) to 4 × 10(-5) mol/L of isoniazid. This proposed method was satisfactorily used in the determination of these drugs in pharmaceutical samples and human urine and serum.


Subject(s)
Aminoacridines/chemistry , Ceftriaxone/analysis , Fluvoxamine/analysis , Isoniazid/analysis , Luminescent Measurements/methods , Potassium Permanganate/chemistry , Ceftriaxone/blood , Ceftriaxone/urine , Fluvoxamine/blood , Fluvoxamine/urine , Humans , Isoniazid/blood , Isoniazid/urine , Reproducibility of Results , Tablets/analysis
13.
PLoS One ; 7(9): e45913, 2012.
Article in English | MEDLINE | ID: mdl-23029310

ABSTRACT

BACKGROUND: Poor adherence to isoniazid (INH) preventive therapy (IPT) is an impediment to effective control of latent tuberculosis (TB) infection. TB patients who smoke are at higher risk of latent TB infection, active disease, and TB mortality, and may have lower adherence to their TB medications. The objective of our study was to validate IsoScreen and SmokeScreen (GFC Diagnostics, UK), two point-of-care tests for monitoring INH intake and determining smoking status. The tests could be used together in the same individual to help identify patients with a high-risk profile and provide a tailored treatment plan that includes medication management, adherence interventions, and smoking cessation programs. METHODOLOGY/PRINCIPAL FINDINGS: 200 adult outpatients attending the TB and/or the smoking cessation clinic were recruited at the Montreal Chest Institute. Sensitivity and specificity were measured for each test against the corresponding composite reference standard. Test reliability was measured using kappa statistic for intra-rater and inter-rater agreement. Univariate and multivariate logistic regression models were used to explore possible covariates that might be related to false-positive and false-negative test results. IsoScreen had a sensitivity of 93.2% (95% confidence interval [CI] 80.3, 98.2) and specificity of 98.7% (94.8, 99.8). IsoScreen had intra-rater agreement (kappa) of 0.75 (0.48, 0.94) and inter-rater agreement of 0.61 (0.27, 0.90). SmokeScreen had a sensitivity of 69.2% (56.4, 79.8), specificity of 81.6% (73.0, 88.0), intra-rater agreement of 0.77 (0.56, 0.94), and inter-rater agreement of 0.66 (0.42, 0.88). False-positive SmokeScreen tests were strongly associated with INH treatment. CONCLUSIONS: IsoScreen had high validity and reliability, whereas SmokeScreen had modest validity and reliability. SmokeScreen tests did not perform well in a population receiving INH due to the association between INH treatment and false-positive SmokeScreen test results. Development of the next generation SmokeScreen assay should account for this potential interference.


Subject(s)
Antitubercular Agents/urine , Cotinine/urine , Isoniazid/urine , Latent Tuberculosis/urine , Point-of-Care Systems , Smoking/urine , Urinalysis/methods , Adolescent , Adult , Aged , Aged, 80 and over , Antitubercular Agents/therapeutic use , Female , Humans , Isoniazid/therapeutic use , Latent Tuberculosis/drug therapy , Male , Medication Adherence , Middle Aged , Multivariate Analysis , Reference Standards , Regression Analysis , Reproducibility of Results , Sensitivity and Specificity , Urinalysis/standards , Young Adult
14.
PLoS One ; 7(3): e32140, 2012.
Article in English | MEDLINE | ID: mdl-22427820

ABSTRACT

BACKGROUND: Good adherence to treatment is crucial to control tuberculosis (TB). Efficiency and feasibility of directly observed therapy (DOT) under routine program conditions have been questioned. As an alternative, Médecins sans Frontières introduced self-administered therapy (SAT) in several TB programs. We aimed to measure adherence to TB treatment among patients receiving TB chemotherapy with fixed dose combination (FDC) under SAT at the Homa Bay district hospital (Kenya). A second objective was to compare the adherence agreement between different assessment tools. METHODS: We conducted a cross-sectional survey amongst a series of new TB patients receiving 6 months of standard TB chemotherapy with FDC under SAT. Adherence was assessed at home with urine testing for Isoniazid (INH), pill count, interviewer-administered questionnaire and visual analogue scale (VAS). RESULTS: In November 2008 and in June 2009, 212 of 279 eligible patients were assessed for adherence. Overall, 95.2% [95%CI: 91.3-97.7] of the patients reported not having missed a tablet in the last 4 days. On the VAS, complete adherence was estimated at 92.5% [95%CI: 88.0-95.6]. INH urine test was positive for 97.6% [95%CI: 94.6-99.2] of the patients. Pill count could be assessed among only 70% of the interviewed patients. Among them, it was complete for 82.3% [95%CI: 75.1-88.1]. Among the 212 surveyed patients, 193 (91.0%) were successfully treated (cured or treatment completed). The data suggest a fair agreement between the questionnaire and the INH urine test (k = 0.43) and between the questionnaire and the VAS (k = 0.40). Agreement was poor between the other adherence tools. CONCLUSION: These results suggest that SAT, together with the FDC, allows achieving appropriate adherence to antituberculosis treatment in a high TB and HIV burden area. The use of a combination of a VAS and a questionnaire can be an adequate approach to monitor adherence to TB treatment in routine program conditions.


Subject(s)
Patient Compliance/statistics & numerical data , Tuberculosis/drug therapy , Cross-Sectional Studies , Humans , Isoniazid/urine , Kenya , Self Administration/statistics & numerical data , Surveys and Questionnaires
15.
Antimicrob Agents Chemother ; 56(1): 28-35, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22037847

ABSTRACT

One of the most effective and widely used antituberculosis (anti-TB) drugs is isoniazid (INH), a prodrug activated via oxidation that forms an adduct with NAD(+) to inhibit NADH-dependent targets of Mycobacterium tuberculosis, such as enoyl-acyl carrier protein reductase (InhA). The metabolic by-products and potentially toxic intermediates resulting from INH therapy have been identified through a large body of work. However, an INH-NAD adduct or structures related to this adduct have not been identified in specimens from human TB patients or animal models of TB. Analyses by mass spectrometry of urine collected from TB patients in a study conducted by the NIAID-funded Tuberculosis Research Unit identified 4-isonicotinoylnicotinamide (C(12)H(9)N(3)O(2)) as a novel metabolite of INH therapy. This compound was formed by M. tuberculosis strains in a KatG-dependent manner but could also be produced by mice treated with INH independent of an M. tuberculosis infection. Thus, the 4-isonicotinoylnicotinamide observed in human urine samples is likely derived from the degradation of oxidized INH-NAD adducts and provides direct evidence of host INH activation.


Subject(s)
Antitubercular Agents/urine , Isoniazid/analogs & derivatives , Isoniazid/urine , Mycobacterium tuberculosis/drug effects , NAD/analogs & derivatives , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/urine , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Bacterial Proteins/metabolism , Biotransformation , Catalase/metabolism , Chromatography, Liquid , Drug Resistance, Bacterial , Female , Humans , Isoniazid/pharmacology , Mass Spectrometry , Mice , Mice, Inbred C57BL , Mycobacterium tuberculosis/enzymology , NAD/urine , Oxidation-Reduction , Oxidoreductases/metabolism , Tuberculosis, Pulmonary/microbiology
16.
Drug Metab Pharmacokinet ; 26(6): 569-76, 2011.
Article in English | MEDLINE | ID: mdl-21844656

ABSTRACT

Isoniazid (INH) is a first-line drug for tuberculosis control; the side effects of INH are thought to be associated with its metabolism, and this study was designed to globally characterize isoniazid metabolism. Metabolomic strategies were used to profile isoniazid metabolism in humans. Eight known and seven novel INH metabolites and hydrazones were identified in human urine. The novel products included two hydroxylated INH metabolites and five hydrazones. The two novel metabolites were determined as 2-oxo-1,2-dihydro-pyridine-4-carbohydrazide and isoniazid N-oxide. Five novel hydrazones were produced by condensation of isoniazid with keto acids that are intermediates in the metabolism of essential amino acids, namely, leucine and/or isoleucine, lysine, tyrosine, tryptophan, and phenylalanine. This study enhances our knowledge of isoniazid metabolism and disposition and may offer new avenues for investigating INH-induced toxicity.


Subject(s)
Antitubercular Agents/urine , Hydrazones/urine , Isoniazid/urine , Adult , Amino Acids, Essential/metabolism , Antitubercular Agents/adverse effects , Antitubercular Agents/chemistry , Antitubercular Agents/therapeutic use , Female , Humans , Hydroxylation , Isoniazid/adverse effects , Isoniazid/metabolism , Isoniazid/therapeutic use , Male , Metabolome , Metabolomics/methods , Middle Aged
17.
PLoS One ; 6(4): e18435, 2011 Apr 25.
Article in English | MEDLINE | ID: mdl-21541021

ABSTRACT

BACKGROUND: Participant non-adherence and loss to follow-up can compromise the validity of clinical trial results. An assessment of these issues was made in a 3-year tuberculosis prevention trial among HIV-infected adults in Botswana. METHODS AND FINDINGS: Between 11/2004-07/2006, 1995 participants were enrolled at eight public health clinics. They returned monthly to receive bottles of medication and were expected to take daily tablets of isoniazid or placebo for three years. Non-adherence was defined as refusing tablet ingestion but agreeing to quarterly physical examinations. Loss to follow-up was defined as not having returned for appointments in ≥60 days. Between 10/2008-04/2009, survey interviews were conducted with 83 participants identified as lost to follow-up and 127 identified as non-adherent. As a comparison, 252 randomly selected adherent participants were also surveyed. Multivariate logistic regression analysis was used to identify associations with selected risk factors. Men had higher odds of being non-adherent (adjusted odds ratio (AOR), 2.24; 95% confidence interval [95%CI] 1.24-4.04) and lost to follow-up (AOR 3.08; 95%CI 1.50-6.33). Non-adherent participants had higher odds of reporting difficulties taking the regimen or not knowing if they had difficulties (AOR 3.40; 95%CI 1.75-6.60) and lower odds associated with each year of age (AOR 0.95; 95%CI 0.91-0.98), but other variables such as employment, distance from clinic, alcohol use, and understanding study requirements were not significantly different than controls. Among participants who were non-adherent or lost to follow-up, 40/210 (19.0%) reported that they stopped the medication because of work commitments and 33/210 (15.7%) said they thought they had completed the study. CONCLUSIONS: Men had higher odds of non-adherence and loss to follow-up than women. Potential interventions that might improve adherence in trial participants may include:targeting health education for men, reducing barriers, clarifying study expectations, educating employers about HIV/AIDS to help reduce stigma in the workplace, and encouraging employers to support employee health. TRIAL REGISTRATION: ClinicalTrials.gov NCT00164281.


Subject(s)
Lost to Follow-Up , Patient Compliance , Adult , Botswana , Case-Control Studies , Female , Health Surveys , Humans , Interviews as Topic , Isoniazid/therapeutic use , Isoniazid/urine , Male , Multivariate Analysis , Regression Analysis , Risk Factors , Self Report
18.
Clin Nurs Res ; 19(2): 131-43, 2010 May.
Article in English | MEDLINE | ID: mdl-20435784

ABSTRACT

The Arkansas method (AM) for isoniazid (INH) metabolite detection is a relatively inexpensive, simple, objective measure of adherence. The purpose of the study was to explore whether variations in urine sample handling and storage will produce accurate assay outcomes. Participants were a convenience sample of 28 adults and adolescents prescribed INH for latent tuberculosis infection. Participants provided one sample to test effects of the following: mixing processes; durations at room temperature, in a refrigerator, or frozen; and effects of freeze/thaw cycles on AM outcomes. No manipulations had a discernible impact on outcomes with concordant positive rates from 85% to 100%. Concordance rates of manipulated samples did not appear to differ from rates of norm samples. Results suggest that urine samples can withstand a variety of manipulations in both handling and storage without affecting the accuracy of AM assay results. These findings have important implications for providers of treatment and researchers and provide the impetus for both to examine the potential of using the AM of INH metabolite testing as a measure of medication adherence.


Subject(s)
Antitubercular Agents/urine , Drug Monitoring/methods , Isoniazid/urine , Patient Compliance/statistics & numerical data , Specimen Handling/methods , Urinalysis/methods , Adolescent , Adult , Aged , Antitubercular Agents/therapeutic use , Drug Monitoring/standards , Female , Freezing , Humans , Isoniazid/therapeutic use , Latent Tuberculosis/drug therapy , Latent Tuberculosis/urine , Male , Middle Aged , Refrigeration/methods , Specimen Handling/standards , Temperature , Urinalysis/standards
19.
Respir Med ; 104(5): 754-7, 2010 May.
Article in English | MEDLINE | ID: mdl-20202806

ABSTRACT

We evaluated the accuracy of a point-of-care test designed to measure adherence to isoniazid (INH) preventive therapy in a hospital setting in Rio de Janeiro, Brazil. Patients on treatment with daily INH and patients not receiving INH were included. Sensitivity and specificity of the test were 84%/98% at the first minute, and 95%/98% at the fifth minute, respectively. Among smokers, sensitivity and specificity was reduced (80%/89% at the fifth minute, respectively), but only 17% smoked. This test accurately detected INH metabolites 24h following directly observed INH intake, though sensitivity and specificity may be compromised by tobacco smoke exposure.


Subject(s)
Antitubercular Agents/urine , Isoniazid/urine , Medication Adherence , Tuberculosis, Pulmonary/urine , Adult , Antitubercular Agents/administration & dosage , Brazil , Female , Humans , Isoniazid/administration & dosage , Male , Sensitivity and Specificity , Tuberculosis, Pulmonary/drug therapy
20.
Bioelectrochemistry ; 77(2): 133-8, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19716352

ABSTRACT

A sensitive voltammetric method for trace measurements of isoniazid (INZ) in synthetic human urine sample is described. The method is based on its electroreduction at -0.98V vs. Ag/AgCl on screen-printed carbon electrode (SPCE) modified with poly-l-histidine (PH). A film of good adherence on SPCE and electrocatalytic properties was obtained coating the electrode by histidine monomer electropolymerization process (SPCE/EPH). The electrochemical behavior of the modified SPCE was investigated by cyclic, linear sweep (LSV), differential pulse (DPV), square-wave voltammetry (SWV), and electrochemical impedance spectroscopy (EIS). Limits of detection of 5.0x10(-7) mol L(-1), 1.7x10(-7) mol L(-1) and 2.5x10(-7) mol L(-1) were estimated from LSV, DPV and SWV determinations, respectively. The method was successfully applied to the determination of INZ in human urine samples.


Subject(s)
Antitubercular Agents/urine , Carbon/chemistry , Histidine/chemistry , Isoniazid/urine , Electrochemistry , Electrodes , Humans , Limit of Detection
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