RESUMO
The pharmacokinetics and safety of amphotericin B infusion were studied in 13 infants and children (age range 3 weeks to 18 years; median age 11 years) treated with the drug for proved (n = 11) or suspected (n = 2) fungal infections. The dose during the first day was 0.5 mg/kg, followed by a daily dose of 1 mg/kg for the rest of the treatment period in most patients. The drug was infused over 4 to 6 hours. During the first day, serum concentrations were above the target therapeutic level of 0.3 microgram/ml in all patients at 2 and 6 hours from the start of the infusion, in 12 of 13 patients at 12 hours, but in only 6 of 13 patients at 24 hours. On the third day, all concentrations were greater than 0.3 microgram/ml throughout the 24-hour period, and in 12 of 13 patients were greater than 0.5 microgram/ml. The same kinetic profile prevailed on days 7 to 10 of therapy, with a tendency for increasing concentrations. Elimination half-life was 9.93 +/- 1.5 hours (mean +/- SEM), clearance rate 26 +/- 5 ml/kg.hr, and distribution volume 378 +/- 25 ml/kg. The half-life inversely correlated with patient's age. Pharmacokinetic values calculated during the first day were not different from those calculated on day 3. Significant decreases in hemoglobin, platelets, and serum potassium concentration were recorded along with significant increases in serum creatinine, urea, and aspartate transaminase values. Because of the large pharmacokinetic variability and the high rate of serious adverse effects, individualized dosing of amphotericin B based on therapeutic drug monitoring should be considered.
Assuntos
Anfotericina B/efeitos adversos , Micoses/tratamento farmacológico , Adolescente , Anfotericina B/sangue , Anfotericina B/farmacocinética , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Humanos , Lactente , Infusões IntravenosasRESUMO
A study was conducted to examine renal function in 10 healthy control subjects and eight patients with cystic fibrosis in stable condition. Sequential bolus injections of 99mTc-DTPA and 125I-OIH were administered to assess glomerular filtration rate and effective renal plasma flow, respectively. Blood was subsequently collected for 3 hours, and urine for 24 hours. Renal clearances of both radioisotope markers were virtually identical in patients and controls. Inasmuch as neither glomerular filtration rate nor effective renal plasma flow was enhanced in patients with cystic fibrosis, increased clearance of drugs in these patients is unlikely to be the result of enhanced glomerular filtration or tubular secretion.
Assuntos
Fibrose Cística/fisiopatologia , Rim/fisiopatologia , Adolescente , Adulto , Fibrose Cística/diagnóstico por imagem , Taxa de Filtração Glomerular , Humanos , Radioisótopos do Iodo , Ácido Iodoipúrico/sangue , Rim/diagnóstico por imagem , Túbulos Renais/fisiopatologia , Matemática , Taxa de Depuração Metabólica , Ácido Pentético/sangue , Cintilografia , Fluxo Sanguíneo Regional , Tecnécio/sangue , Pentetato de Tecnécio Tc 99mRESUMO
We investigated 49 children (33 boys), mean (+/- SD) age 2.6 +/- 1.8 years (range 8 months to 8 years), who had Kawasaki disease treated with acetylsalicylic acid (ASA) 30 to 180 mg/kg. There was good correlation between salicylate doses and serum concentrations (r = 0.69, P less than 0.01); however, large variability existed. With doses less than 80 mg/kg/day there was not a single therapeutic salicylate serum concentration (greater than 20 mg/dl). In children receiving 100 to 110 mg/kg/day 55% of the serum concentrations were subtherapeutic. The same pattern persisted with doses greater than 120 mg/kg/day; however, 28% of levels were in the toxic range (greater than 30 mg/dl). There was no evidence of salicylate poisoning in the group; three children receiving greater than 100 mg/kg/day had aspirin-induced gastritis. An additional four children, studied prospectively, received ASA 80 to 180 mg/kg/day. The fraction absorbed was 14% to 60%, which may be compared to a normal 85% to 90% absorption. Salicylate renal clearance in these children (7.3 to 21 ml/kg/hr) was lower than in hyperthermic children. Their steady-state serum salicylate concentrations were subtherapeutic (7 to 11.5 mg/dl). The high ASA dose needed to overcome the impaired absorption should be accompanied by frequent monitoring of levels because of the unpredictable changes in absorption.
Assuntos
Aspirina/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/sangue , Salicilatos/sangue , Aspirina/administração & dosagem , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Ácido SalicílicoRESUMO
Because of reports of lowered antibiotic serum concentrations in patients with cystic fibrosis (CF), a bioavailability and pharmacokinetic study of cloxacillin was conducted in 12 control and 16 patients with CF after intravenously and orally administered doses of cloxacillin 25 mg/kg. The patients had mild to moderate CF and were in stable condition. Significantly lower serum concentrations in CF were a result of a 78% increase in total body clearance (P less than 0.005) and a 38% increase in the apparent volume of distribution (P less than 0.025). The bioavailability in CF (0.50) was not significantly different than in controls (0.38), but more variability was seen in the group with CF. After the intravenously given dose the fraction of cloxacillin excreted in the urine unchanged was similar in controls (0.644) and patients with CF (0.547). Compared with that in the control subjects, the mean renal clearance in patients with CF was 30% greater (P less than 0.10) and the nonrenal clearance was 144% greater (P less than 0.07). Enhanced nonrenal clearance explains most of the demonstrated difference between serum concentrations in controls and patients with CF after identical weight-adjusted doses. The data suggest enhanced cloxacillin biotransformation in CF.
Assuntos
Cloxacilina/metabolismo , Fibrose Cística/metabolismo , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Cloxacilina/administração & dosagem , Cloxacilina/sangue , Fibrose Cística/tratamento farmacológico , Humanos , Infusões Parenterais , Rim/metabolismo , CinéticaRESUMO
The addition of amiodarone to digoxin therapy in nine children caused a sharp increase in digoxin serum concentrations (68% to 800%) in the presence of preserved serum creatinine and BUN concentrations. Digoxin half-life was prolonged. Digoxin accumulation could be attributed in part to the decrease in the renal clearance of digoxin resulting from inhibited tubular secretion of the drug and to the reduction in the distribution volume of digoxin caused by amiodarone. Creatinine clearance was not affected by amiodarone. This interaction appears to be more acute in children than in adults, presumably because of the more important role of the renal tubular secretion of digoxin in children. Whenever digoxin and amiodarone therapy are combined, the digoxin serum concentration should be monitored carefully, with appropriate reduction of the digoxin dose.
Assuntos
Amiodarona/efeitos adversos , Benzofuranos/efeitos adversos , Digoxina/efeitos adversos , Cardiopatias/tratamento farmacológico , Adolescente , Amiodarona/administração & dosagem , Amiodarona/sangue , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/tratamento farmacológico , Cardiomiopatia Dilatada/urina , Criança , Pré-Escolar , Creatinina/urina , Digoxina/administração & dosagem , Digoxina/sangue , Interações Medicamentosas , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/tratamento farmacológico , Cardiopatias Congênitas/urina , Cardiopatias/sangue , Cardiopatias/urina , Humanos , Lactente , Masculino , Estudos ProspectivosRESUMO
Many drugs require oxidative metabolism for termination of action and/or for elimination from the body. Many oxidative reactions are catalyzed by hepatic microsomal enzymes. The activities of various drug-metabolizing enzymes, namely, NADPH cytochrome c reductase, NADPH oxidase, aminopyrine-N-demethylase, and analine P-hydroxylase, and the content of cytochrome P-450, were measured in hepatic microsomes obtained from seven newborn infants and four adult patients. The results in the newborn infant show increasing activities of these enzymes (except aminopyrine-N-demethylase) related to advancing age. Good correlation between three components of the hepatic microsomal mixed function oxidase system and aniline p-hydroxylase was established, whereas only NADPH oxidation correlated with aminopyrine N-demethylation. The rate of substrate or drug oxidation and the activities of the components of the microsomal electron transport pathway were lower than comparable values in the adult. The data demonstrate a possible biochemical basis for the transient deficiency in drug metabolism seen in newborn infants.