RESUMEN
This investigation retrospectively assessed inexpensive non-invasive qualitative methods to monitor the ingestion of anti-tuberculosis drugs isoniazid, rifampicin and rifapentine. Results showed that commercial test strips detected the isoniazid metabolites isonicotinic acid and isonicotinylglycine as efficiently as the isonicotinic acid method in 150 urine samples. The presence of rifamycins in urine samples (n=1085) was detected by microbiological assay techniques and the sensitivity compared to the n-butanol extraction colour test in 91 of these specimens. The proportions detected by the two methods were significantly different and the sensitivity of the n-butanol procedure was only 63.8% (95% CL 51.2-76.4%) as compared to that of the superior microbiological method. Final validation (n=691) showed that qualitative assays measure isoniazid and rifamycin ingestion with an efficiency similar to high-performance liquid chromatography. The qualitative procedures may therefore be valuable in clinical trials and in tuberculosis clinics to confirm drug ingestion.
Asunto(s)
Antituberculosos/farmacocinética , Monitoreo de Drogas/métodos , Antituberculosos/administración & dosificación , Antituberculosos/orina , Humanos , Isoniazida/farmacocinética , Isoniazida/orina , Ácidos Isonicotínicos/orina , Pruebas de Sensibilidad Microbiana , Cooperación del Paciente , Reproducibilidad de los Resultados , Estudios Retrospectivos , Rifampin/análogos & derivados , Rifampin/farmacocinética , Rifampin/farmacología , Rifampin/orina , Autoadministración , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrolloRESUMEN
OBJECTIVE: To evaluate a monthly 'pulse' of rifampicin plus pyrazinamide plus streptomycin in the continuation phase of a short-course antituberculosis regimen. DESIGN: Randomised controlled trial of two 7-month chemotherapy regimens. SETTING: Inpatient chemotherapy and outpatient follow-up in Tanzania. PATIENTS: Smear-positive pulmonary tuberculosis. INTERVENTION: All patients received streptomycin plus rifampicin plus isoniazid plus pyrazinamide daily for 6 weeks followed by isoniazid daily for 24 weeks; 50%, at random, received additional doses of rifampicin, pyrazinamide and streptomycin every 4 weeks in the continuation phase. Follow-up continued for 23 months after cessation of chemotherapy. MAIN OUTCOME MEASURES: Bacteriological failure rate at the end of chemotherapy and relapse rate after stopping. RESULTS: Of the 266 patients with fully sensitive strains before treatment there was one failure in each series during chemotherapy; after stopping, 5% of the 114 who received the supplement relapsed bacteriologically compared with 10% of the 113 who did not (95% CI for the difference -0.02% to + 11.3%). The results in the 37 patients with strains resistant to isoniazid pretreatment were not as good, but similar for the two regimens. CONCLUSION: This study was not large enough to demonstrate a significant reduction in the relapse rate from 10% to 5%. If such a reduction were confirmed in a larger study it would represent an important improvement in efficacy. further, in an outpatient setting, the additional monthly doses might improve attendance.
Asunto(s)
Antituberculosos/administración & dosificación , Isoniazida/administración & dosificación , Pirazinamida/administración & dosificación , Rifampin/administración & dosificación , Estreptomicina/administración & dosificación , Tuberculosis Pulmonar/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antituberculosos/efectos adversos , Población Negra , Peso Corporal , Esquema de Medicación , Farmacorresistencia Microbiana , Quimioterapia Combinada , Femenino , Humanos , Isoniazida/efectos adversos , Ácidos Isonicotínicos/orina , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Pirazinamida/efectos adversos , Recurrencia , Rifampin/efectos adversos , Esputo/microbiología , Estreptomicina/efectos adversos , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/orinaRESUMEN
A rapid, simple, and accurate method has been developed for the determination of isoniazid and its metabolites (isonicotinic acid, isonicotinylglycine, and acetylisoniazid) in human urine by high-performance liquid chromatography. Isoniazid and its metabolites are separated by reversed-phase ion-exchange chromatography with a mobile phase containing hydrogen peroxide as a fluorogenic reagent and butanesulfonate as a hydrophobic ion exchanger, and are detected by fluorometry (excitation at 317 nm and emission at 415 nm) using in-line derivatization at high temperature (160 degrees C). The detection limits are isonicotinic acid, 0.5 mumol/L; isonicotinylglycine, 1 mumol/L; acetylisoniazid, 1 mumol/L; and isoniazid, 1.5 mumol/L. This method can be applied for acetylator phenotyping.
Asunto(s)
Fluorometría/métodos , Isoniazida/orina , Cromatografía Líquida de Alta Presión/métodos , Cromatografía por Intercambio Iónico , Humanos , Concentración de Iones de Hidrógeno , Isoniazida/análogos & derivados , Ácidos Isonicotínicos/orina , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , TemperaturaRESUMEN
1. The metabolism of 4'-chloro-2'-(alpha-hydroxybenzyl) isonicotinanilide (Inabenfide, IBF) was studied in the rat. After intraperitoneal administration of IBF to rats, eight metabolites were detected in urine by g.l.c.-mass spectrometry and a stable isotope technique. 2. The major metabolites were hydroxylated IBF, and minor metabolites were dihydrodiol IBF, methylated catechol IBF, IBF ketone, IBF N-oxide and an amine derivative. 3. Of these metabolites, IBF ketone was produced by oxidation of the carbinol between the benzene rings, which is an interesting metabolite since similar oxidation between benzene rings is not well known. 4. Metabolism involving an NIH shift of chlorine and an epoxide-diol pathway for IBF are presented.
Asunto(s)
Ácidos Isonicotínicos/farmacocinética , Reguladores del Crecimiento de las Plantas/farmacocinética , Animales , Biotransformación , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Cromatografía de Gases y Espectrometría de Masas , Ácidos Isonicotínicos/orina , Masculino , Reguladores del Crecimiento de las Plantas/orina , Ratas , Ratas EndogámicasRESUMEN
A high-performance liquid chromatography method for quantitation of urinary 4-pyridoxic acid excretion is presented. Urine samples were treated with HCl to form 4-pyridoxic acid lactone. Acid-treated urine samples were diluted and analyzed by cation-exchange chromatography involving post-column alkalinization and fluorescence detection. Absence of interfering fluorescent urinary compounds was demonstrated by analyzing urine samples without lactonization and rechromatography of aliquots of 4-pyridoxic acid lactone peaks employing reverse-phase chromatography. The method is suitable for determination of urinary 4-pyridoxic acid excretion in nutritional, metabolic, and pharmacokinetic studies.
Asunto(s)
Ácidos Isonicotínicos/orina , Ácido Piridóxico/orina , Cromatografía Líquida de Alta Presión , Humanos , Indicadores y Reactivos , Ácido Piridóxico/análogos & derivadosRESUMEN
Factors that regulate the clearance of plasma pyridoxal-P (PLP) are unknown. Four volunteers were given a diet supplying approximately 12 mumol pyridoxine (PN) per day. The pharmacokinetics of plasma PLP clearance were measured in these subjects before and after 4 weeks of intravenous PN supplementation (122 mumol/day). Urinary B6 excretion, mainly as 4-pyridoxic acid (4-PA), increased progressively after initiation of PN supplementation until a new steady state was reached on day 10 of supplementation, whereupon greater than 93% of the daily injected PN could be recovered in the urine. Hence, urinary excretion is almost the sole route for vitamin B6 elimination. Fasting plasma PLP concentration increased with supplementation and also reached a new steady state at this time. When supplementation was terminated, urinary B6 excretion decreased in 5 days to an amount only slightly higher than that before supplementation. This amount was maintained for 2 months. By comparison, plasma PLP decreased more slowly and remained considerably higher than the presupplementation level for the rest of the study. These data confirm that urinary 4-PA excretion is a better indicator of B6 intake than is plasma PLP content, whereas plasma PLP content is a better indicator of the body store of the vitamin. Plasma clearance and volume of distribution of PLP decreased significantly after supplementation, but half-life t 1/2 did not change. Plasma clearance of PLP, therefore, is dependent on the vitamin B6 status of an individual.
Asunto(s)
Ácidos Isonicotínicos/orina , Fosfato de Piridoxal/sangre , Ácido Piridóxico/orina , Piridoxina/metabolismo , Adulto , Dieta , Semivida , Humanos , Cinética , Masculino , Tasa de Depuración Metabólica , Piridoxal/orina , Fosfato de Piridoxal/metabolismo , Piridoxamina/análogos & derivados , Piridoxamina/orina , Piridoxina/administración & dosificación , Piridoxina/orinaRESUMEN
Urinary excretion of 4-pyridoxic acid (4PA) in 19 men (n = 5) and women (n = 14) was measured to evaluate the validity of determining the 4PA/creatinine ratio in random urine samples as an alternative to total 24-h 4PA excretion in assessing vitamin B6 nutritional status. The relationships among dietary vitamin B6 intake, 4PA excretion, plasma pyridoxal 5'-phosphate levels, and erythrocyte aspartate aminotransferase activity and in vitro stimulation by added plasma pyridoxal 5'-phosphate were examined. The subjects consumed all meals for 3 days in a metabolic unit, and protein intake was kept constant. Plasma pyridoxal 5'-phosphate concentration was positively correlated with vitamin B6 intake of the previous day (r = 0.61, p less than 0.01). There was a positive correlation (r = 0.59, p less than 0.01) between total 4PA and 4PA/creatinine in the 24-h urine samples. No difference (p greater than 0.05) in 4PA/creatinine between the 24-h samples and either morning or afternoon random samples taken the next day was found. These findings support the use of the 4PA/creatinine ratio in random urine samples as an alternative to 24-h urinary 4PA excretion.
Asunto(s)
Ácidos Isonicotínicos/orina , Ácido Piridóxico/orina , Piridoxina/administración & dosificación , Deficiencia de Vitamina B 6/diagnóstico , Adolescente , Adulto , Aspartato Aminotransferasas/sangre , Creatinina/orina , Eritrocitos/enzimología , Femenino , Humanos , Masculino , Fosfato de Piridoxal/sangre , Manejo de Especímenes , Factores de Tiempo , Deficiencia de Vitamina B 6/orinaRESUMEN
A method based on the fluorimetric determination of the 4-PA-lactone is described. The applied method saves time and work compared to others. The analytical procedure may be interrupted for a few days after eluting the 4-PA from the ion exchanger as well as before measuring the transmission. Accuracy, precision and sensitivity of the method are demonstrated. Interfering substances influencing the fluorescence measurement and probable errors caused by the reference value creatinine are discussed. Storage tests applied with the urine samples at--18 degrees C have shown that 4-PA-values do not change considerably within two months.
Asunto(s)
Ácidos Isonicotínicos/orina , Ácido Piridóxico/orina , Piridoxina/metabolismo , Cromatografía por Intercambio Iónico , Humanos , Ácido Piridóxico/análogos & derivados , Espectrometría de Fluorescencia/métodosAsunto(s)
Alcaloides , Niacinamida/análogos & derivados , Ácidos Nicotínicos/metabolismo , Ácidos Nicotínicos/orina , Piridonas/orina , Animales , Cromatografía Líquida de Alta Presión/métodos , Ácidos Isonicotínicos/orina , Masculino , Niacinamida/orina , Ácidos Nicotínicos/deficiencia , Ratas , Ratas EndogámicasRESUMEN
1. The possibility of using minute doses of the antituberculosis drug isoniazid (INH) or of its metabolites acetylisoniazid (AcINH) or isonicotinic acid (INA) as innocuous markers for monitoring patient compliance has been investigated. 2. The ingestion of these colourless and tasteless compounds can readily be demonstrated using a sensitive and specific colorimetric method for detecting INA and its metabolite isonicotinylglycine (INAG) in the urine that is rapid and simple to perform. 3. Studies on the kinetics of the urinary elimination of INA and INAG after the ingestion of 6 mg doses of either INH, AcINH or INA by small groups of volunteers indicated the potential suitability of INH or AcINH for monitoring daily or twice-daily self-medication and the appropriateness of INA as a marker for investigating the compliance of drugs prescribed for thrice-daily ingestion. 4. More extensive studies showed that over 99% of the urine samples collected within 18h of dosage with 6 mg INH would give positive results when tested for the presence of INA and INAG, and that doses of 2-6 mg INH could readily by incorporated into capsules or tablets and used as markers for monitoring the ingestion of the antituberculosis or antileprosy drugs dapsone, thiacetazone, ethionamide or prothionamide, or the antihypertensive oxprenolol. Such doses are less than a fiftieth of the normal therapeutic INH dose used in the treatment of tuberculosis. 5. Evidence is presented that INH, AcINH and INA possess most of the characteristics that one would hope to find in a marker for monitoring compliance including very limited inter-individual variability in the rates at which they are converted to the compounds being detected in the urine.
Asunto(s)
Isoniazida/análogos & derivados , Isoniazida/metabolismo , Ácidos Isonicotínicos/metabolismo , Cooperación del Paciente , Glicina/análogos & derivados , Glicina/orina , Semivida , Humanos , Absorción Intestinal , Isoniazida/administración & dosificación , Ácidos Isonicotínicos/orina , Masculino , Riboflavina/orina , Autoadministración , Factores de TiempoRESUMEN
PIP: The requirement for vitamin B6 in oral contraceptive users was studied in 8 college-age women who used combined (7) or sequential (1) oral contraceptives. The subjects and 8 controls consumed a basal diet supplemented to result in daily intake of 2.06 mg pyridoxine hydrochloride for 10 days (predepletion) and then containing only .36 mg of vitamin B6 for 32 days. After the depletion period, the diet was supplemented with pyridoxine hydrochloride to increase the intake of B6 to .96, 1.56, and 5.06 mg for 8, 9, and 7 days respectively. Complete 14-hour urine collections were analyzed for xanthurenic acid, kynurenic acids, kynurenine, and 3-hydroxykynurenine after administration of a l load-dose of 2 gm L-trytophan on days 2, 11, 18, 25, 32, 39, 43, 50 , 59, and 66 for the subjects and days 2 and 10 for the controls. Pretryptophan urine was analyzed for vitamin B6. Posttryptophan urine was analyzed for 4-pyridoxic acid. It was found that during the depletion phase the excretion of tryptophan metabolites increased significantly. Excretion dropped significantly upon supplementation with 1.56 or 5.06 mg of vitamin B6, returning values to normal. Levels of vitamin B6 and 4-pyridoxic acid in the urine decreased during depletion to be restored to normal upon supplementation with 1.56 mg/day. Since an intake of 5.0 mg vitamin B6 caused a loss of the vitamin in the urine and all levels were returned to normal with an intake of 1.56 mg, it is suggested that 1.5 mg of vitamin B6 is sufficient to meet the needs of most oral contraceptive users and that there is no significant difference in the vitamin B6 requirement of oral contraceptive users and nonusers.^ieng
Asunto(s)
Anticonceptivos Sintéticos Orales/farmacología , Anticonceptivos Orales/farmacología , Ácidos Isonicotínicos/orina , Ácido Piridóxico/orina , Piridoxina/metabolismo , Triptófano/metabolismo , Adolescente , Adulto , Femenino , Humanos , Ácido Quinurénico/orina , Quinurenina/análogos & derivados , Quinurenina/orina , Necesidades Nutricionales , Piridoxina/uso terapéutico , Piridoxina/orina , Deficiencia de Vitamina B 6/tratamiento farmacológico , Deficiencia de Vitamina B 6/metabolismo , Xanturenatos/orinaRESUMEN
A high performance liquid chromatographic method is presented for the determination of the vitamin B6 metabolite, 4-pyridoxic acid, in urine. Urine samples are treated with trichloroacetic acid to precipitate protein. An aliquot of the supernatant is chromatographed using 0.033 M phosphate buffer containing 5% (v/v) methanol (pH 2.2), a fluorometric detector and a commercial reverse phase octadecylsilica column. The high precision of the method and the absence of interfering compounds have been demonstrated. This method provides a rapid, sensitive, and quantitative technique for the measurement of urinary 4-pyridoxic acid for use in metabolic and nutritional studies.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Ácidos Isonicotínicos/orina , Ácido Piridóxico/orina , Humanos , Espectrometría de FluorescenciaRESUMEN
Vitamin B6 intake and 4-pyridoxic acid excretions of 22 children were determined. Mean intake of vitamin B6 per day was 1.10 mg +/- 0.47. Mean percentage of vitamin B6 intake excreted as 4-pyridoxic acid was 48% +/- 23. Excretion of 4-pyridoxic acid was significantly correlated to vitamin B6 intake but not to vitamin B6/protein ratios or vitamin B6/kilocalorie levels. Excretions of 4-pyridoxic acid equal to or below 0.15 mg appeared to be indicative of poor vitamin B6 intake for the children which was similar to the excretions found by others for depleted adults.
Asunto(s)
Ácidos Isonicotínicos/orina , Ácido Piridóxico/orina , Piridoxina , Niño , Preescolar , Proteínas en la Dieta , Femenino , Humanos , Masculino , Necesidades Nutricionales , Piridoxina/metabolismoRESUMEN
Urinary excretion of 4-pyridoxic acid and oxalic acid was investigated in 75 patients with urinary calculi and in 50 normal subjects on regular diet. Mean excretion of 4-pyridoxic acid was 0.85 and 0.90 mg per day, respectively, and mean excretion of oxalic acid was 27.5 and 28.0 mg per day, respectively. Statistically there was no difference between the two groups in 4-pyridoxic acid excretion or in oxalic acid excretion. There was a weak positive correlation between the urinary excretion of 4-pyridoxic acid and oxalic acid. Patients who were on ascorbic acid supplementation during the urine collection period excreted increased amounts of oxalic acid. It was concluded from this investigation that most patients with urinary calculi had 4-pyridoxic acid excretion and oxalic acid excretion within normal limits. Low 4-pyridoxic acid values were not combined with high excretion values of oxalic acid, and the nutritional state of vitamin B6 in patients with urinary calculi was assumed to be satisfactory in order to control the endogenous oxalic acid production. The significance of high excretion values of 4-pyridoxic acid and oxalic acid is discussed.
Asunto(s)
Ácidos Isonicotínicos/orina , Oxalatos/orina , Ácido Piridóxico/orina , Cálculos Urinarios/orina , Ácido Ascórbico/farmacología , Femenino , Humanos , Masculino , Piridoxina/farmacologíaRESUMEN
A method is described for monitoring the ingestion of isoniazid based on detecting its metabolites, isonicotinic acid, and isonicotinylglycine in the urine. The sensitivity of the method is high so that reliably positive results were obtained up to about 24 hours after the ingestion of 100 mg isoniazid. The method should facilitate monitoring the taking of isoniazid by tuberculosis patients and the use of isoniazid as a marker for assessing the regularity with which other drugs prescribed for self-administration are actually ingested.