Adrenal function in thalassemia major following long-term treatment with multiple transfusions and chelation therapy. Evidence for dissociation of cortisol and adrenal androgen secretion

Eight patients with beta-thalassemia who were given long-term treatment with combined multiple transfusions and chelation therapy underwent adrenal testing. The six male and two female patients ranged in age from 7 to 19 years. Six of eight patients had delayed bone ages and height greater than 2.5 SDs below the mean. Of the six patients more than 13 years of age, two had clinical evidence of isolated adrenarche and only one had evidence of true puberty. Cortisol levels were similar in patients and controls at zero time (10.6 +/- 1.8 micrograms/dL [292 +/- 50 nmol/L] vs 10.8 +/- 1.4 micrograms/dL [298 +/- 39 nmol/L]) and at 60 minutes (26.6 +/- 2.5 micrograms/dL [734 +/- 69 nmol/L] vs 24.9 +/- 1.9 micrograms/dL [687 +/- 52 nmol/L]) after insulin hypoglycemia (all values are the mean +/- SE). During an eight-hour infusion of ACTH, cortisol responses in the patients with thalassemia were not significantly different from those of controls. Baseline levels of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were significantly lower in the subjects with thalassemia compared with controls of similar bone age and pubertal status. The prolonged ACTH infusion caused a significant increase in the DHEA level (79.2 +/- 14.7 ng/dL [2.74 +/- 0.51 nmol/L] vs 538.6 +/- 38.1 ng/dL [18.67 +/- 4.79 nmol/L]) and the DHEA-S level (37.5 +/- 10.8 micrograms/dL [1.02 +/- 0.29 mumol/L] vs 70.5 +/- 18.3 micrograms/dL [1.19 +/- 0.50 mumol/L]) in the patients. The patients' peak stimulated levels of DHEA-S were significantly lower than those of the controls, whereas peak levels of DHEA were similar in the patients and the controls. These results indicate that combined multiple transfusions and chelation therapy preserve the integrity of the ACTH-cortisol axis in patients with thalassemia. The reduced levels of adrenal androgens, short stature, and delayed puberty noted in our patients suggest, however, that alternative approaches to the therapy of thalassemia are needed.     

Slow-release terbutaline and theophylline for the long-term therapy of children with asthma: a Latin square and factorial study of drug effects and interactions

To evaluate the long-term effects of slow-release formulations of theophylline and terbutaline on pulmonary function, clinical symptoms, and side effects, 24 children with stable and moderately severe perennial asthma participated in a prospective double-blind cross-over study. The patients and the treatments were randomized according to the Latin square design to eliminate all possible period/climate biases throughout the protracted study period. The treatments consisted of terbutaline, 5 mg, theophylline, 200 mg, the combination, and placebo, given twice daily orally and crossing over every 28 days. The two drugs, administered alone or in combination, improved lung function and symptoms when compared with placebo. The interaction of theophylline and terbutaline was quantitatively shown by 2 x 2 factorial statistical design to be essentially additive rather than synergistic in the control of asthma. No increase in side effects was noted when the combined therapy was used. These findings suggest therapeutic advantages to combining submaximal oral doses of sustained-release theophylline and terbutaline for the long-term treatment of children with asthma.     

Pharmacokinetics of enprofylline administered intravenously and as a sustained-release tablet at steady state in children with asthma

The pharmacokinetics of enprofylline (3-propylxanthine) were studied in 10 children with asthma (mean age 7.9 years), after enprofylline 1 mg/kg given intravenously and after enprofylline 7.5 +/- 1.3 mg/kg given as a sustained-release tablet after 8 days of oral dosing twice daily. The mean +/- SD enprofylline serum elimination half-life was 1.06 +/- 0.20 hours, considerably shorter than the half-life reported in adults. The mean steady-state volume of distribution was 0.55 +/- 0.05 L/kg. The mean clearance rate was 0.44 +/- 0.06 L/hr/kg. The mean enprofylline serum concentration at steady state was 1.7 +/- 0.5 mg/L. The mean peak to trough ratio was 3.02 +/- 1.31. On the first and ninth study days, 87% +/- 8% and 90% +/- 16%, respectively, of the dose of enprofylline was recovered as unchanged drug in the urine. Enprofylline has a short half-life in children, but the sustained-release formulation provides stable serum concentrations and satisfactory relief of asthma throughout the 12-hour dosing interval.     

Dose-response relationships of intravenously administered terbutaline in children with asthma

The bronchodilator effect of three successive stable plasma terbutaline levels was studied in 10 children with asthma. Each terbutaline plateau was achieved by giving a rapid intravenous infusion of terbutaline, 0.9 microgram/kg, followed by a continuous infusion for 2 hours. Mean plasma terbutaline concentrations (18, 36, and 53 nmol/L at the three plateaus) were found to correlate linearly with the maintenance dose of terbutaline (2.4, 4.5, and 6.3 micrograms/kg/hr, respectively). Mean forced expiratory volume in 1 second increased from 65% to 96%, and mean forced mid-expiratory flow from 32% to 71% of the predicted normal value during the study (p less than 0.01); maximum bronchodilation was obtained at mean terbutaline levels of about 30 nmol/L (range 20 to 60). Effective plasma terbutaline levels were associated with side effects such as headache and tremor in all patients. In addition, heart rate increased from 84 to 116 beats/min, systolic blood pressure rose from 115 to 129 mm Hg, and diastolic blood pressure dropped from 72 to 61 mm Hg during the study. We conclude that a loading dose of 2 micrograms terbutaline per kilogram of body weight over 5 minutes, followed by a continuous infusion of 4.5 micrograms terbutaline per kilogram per hour, is suitable for treatment of severe bronchoconstriction in children. Because of interindividual variations in drug metabolism and clinical effect, dose adjustment should be evaluated at regular intervals.     

Residential deleading: effects on the blood lead levels of lead-poisoned children

Acute elevations of venous blood lead levels (PbB) are periodically reported in children with chronic lead poisoning, during deleading of their houses. To evaluate this phenomenon 114 preschool children who entered the Massachusetts Childhood Lead Poisoning Prevention Program case management system during 1984 and 1985 were retrospectively studied. PbB increased from a mean (+/- SE) of 1.76 +/- 0.03 mumol/L (36.4 +/- 0.6 micrograms/dL) prior to deleading to 2.03 +/- 0.07 mumol/L (42.1 +/- 1.5 micrograms/dL) during deleading (P less than .001). Among 41 subjects for whom deleading was done by dry scraping and sanding, the mean mid-deleading PbB was higher than the pre-deleading PbB by 0.44 +/- 0.12 mumol/L (9.1 +/- 2.4 micrograms/dL). However, when deleading was done by covering or replacement of painted surfaces in the residences of 12 subjects, mid-deleading PbB decreased 0.11 +/- 0.12 mumol/L (2.25 +/- 2.4 micrograms/dL) (P less than .005). In a subset of 59 subjects who had no chelation therapy and were available for follow-up 250 +/- 14 days after completion of deleading, PbB had decreased from 1.72 +/- 0.04 mumol/L (35.7 +/- 0.9 micrograms/dL) to 1.24 +/- 0.04 mumol/L (25.5 +/- 0.9 micrograms/dL) (P less than .001). The long-term effect of deleading is a significant reduction in PbB. However, deleading resulted in a significant, albeit transient, increase in PbB.     

Clinical and bronchodilating efficacy of controlled-release theophylline as a function of its serum concentrations in preschool children

To evaluate the dose-effect relationship of a controlled-release theophylline in preschool children, 20 patients with asthma (mean age 4.8 years, range 2 1/2 to 7 years) were given three different dose levels (13.4 +/- 1.4, 18.4 +/- 1.6, and 23.5 +/- 2.0 mg/kg/day, mean +/- SD) at 12-hour intervals for 2 weeks. Subjective variables, peak expiratory flow rate, and co-medications were recorded daily; clinical condition, serum theophylline levels, and lung function measured with a multiple forced oscillation technique were assessed at the end of each period. The morning predose (through) and 4-hour postdose (peak) serum theophylline concentrations increased in an approximately linear fashion with increasing dose. In the majority of patients, dose levels of 20 to 25 mg/kg/day maintained serum concentrations within a clinically effective range, with an acceptable level of fluctuation. However, wide interindividual variations in serum theophylline concentrations were observed, indicating that for optimal treatment individualization of dosage is preferable. Efficacy was related to serum concentration and, less closely, to the dose administered. Symptom scores for night cough, wheeze, and activity showed small improvements between 5 and 10 mg X 1(-1) and marked improvements above 10 mg X 1(-1), whereas lung function values improved in a linear fashion across the serum concentration range. The serum theophylline concentration-response curves varied in an approximately parallel manner between individuals.     

Serum insulin-like growth factor-I (IGF-I) levels during long-term IGF-I treatment of children and adults with primary GH resistance (Laron syndrome).

Serum IGF-I levels were measured in 14 patients (9 children and 5 adults) with Laron syndrome (LS) during long-term treatment by IGF-I. Recombinant IGF-I (FK-780, Fujisawa Pharmaceutical Co. Ltd., Japan) was administered once daily subcutaneously before breakfast for 3-5 years to the children and for 9 months to the adults. The initial daily dose was 150 micrograms/kg for children and 120 micrograms/kg for adults. Before initiation of treatment the mean overnight fasting levels of serum IGF-I in the children was 3.2 +/- 0.8 nmol/l (mean +/- SEM), rising to 10 +/- 1.7 nmol/l during long-term treatment even on a dose of 120 micrograms/kg/day. The serum IGF-I levels 4 hours after injection rose from 31.2 +/- 3.5 to 48 +/- 2 nmol/l. In the adult patients, the initial basal IGF-I was 4.1 +/- 0.7 nmol/l, rising to 16.1 +/- 3.84 nmol/l after 8-9 months treatment. Serum IGF-I levels at 4 hours after injection rose in the adult patients from 24.1 +/- 5.8 up to 66.8 +/- 15.4 nmol/l. A progressively increasing half-life during long term exogenous administration of IGF-I to patients with Laron syndrome was demonstrated by following serum IGF-I dynamics after injection. Based on the fact that no antibodies to IGF-I were detected and on findings in previous studies, it is speculated that the increasing serum IGF-I levels during long-term IGF-I treatment are caused by an increase in serum IGFBP-3 induced by chronic IGF-I administration. It is concluded that treatment with IGF-I necessitates regular monitoring of serum IGF-I levels; in patients in whom the age adjusted maximal levels are exceeded, a reduction of the daily IGF-I dose is indicated to avoid undesirable effects.     

Routine L-ascorbic acid supplementation does not alter iron, copper, and zinc balance in low-birth-weight infants fed a cows'-milk formula

The effect of ascorbic acid (AA) [284 mumol (50 mg) twice daily] on the net intestinal absorption and maximum apparent retention of Fe, Cu, and Zn was investigated by metabolic balance studies in a randomised crossover study of six low-birth-weight (LBW) neonates fed a cows'-milk-based formula containing (mumol/L) Fe, 126; Cu, 11; Zn, 87; and AA, 400. Absorption +/- SD (Fe, -5.0 +/- 7.5; Cu, 0 +/- 0.4; Zn, -0.8 +/- 3.4) (mumol kg-1 day-1) was not altered by AA (Fe, -4.1 +/- 4.6; Cu, 0.3 +/- 0.6; Zn, -1.1 +/- 2.7) neither was retention (without AA: Fe, -6.0 +/- 8.4; Cu, -0.1 +/- 0.3; Zn, -2.4 +/- 4.2; with AA: Fe, -4.9 +/- 4.7; Cu, 0.1 +/- 0.6; and Zn, -2.7 +/- 3.1). Supplements of AA administered as in the circumstances of routine care of LBW neonates do not enhance the absorption and retention of Fe, nor do they impair these aspects of the metabolism of Cu and Zn.     

The effect of testosterone therapy on spontaneous growth hormone secretion in boys with constitutional delay

Testosterone treatment is known to improve growth hormone (GH) secretion in boys with constitutional delay (CD). To determine whether spontaneous GH secretion is normal after treatment, we assessed GH secretion before and after a four- to five-month course of testosterone enanthate in eight adolescents with CD. Before testosterone therapy, the mean (+/- 1 SD) 24-hour integrated concentration of GH (IC-GH) by constant blood withdrawal technique was 1.7 +/- 1.0 micrograms/L (normal range for age, 3.2 to 11.5 micrograms/L), and the IC-testosterone was 1.8 +/- 2.7 nmol/L. Two patients restudied during treatment had normal IC-GH values. After testosterone treatment, the mean IC-GH of the entire group was 3.3 +/- 2.6 micrograms/L, and the IC-testosterone was 6.5 +/- 5.3 nmol/L. Five of eight patients had IC-GH values that were again subnormal. A subnormal IC-GH associated with CD may persist after testosterone therapy is discontinued. Deficiency of spontaneous GH secretion may contribute to short stature and slower growth rates in this patient group. Whether GH therapy in these patients would have a beneficial effect on final height is unknown.     

Serum beta-carotene, retinol, and alpha-tocopherol levels during mineral oil therapy for constipation

Twenty-five children with chronic constipation underwent serial monitoring of serum beta-carotene, retinol (vitamin A1), and alpha-tocopherol (vitamin E) levels during mineral oil therapy. Mineral oil was administered between meals. Patients were monitored for up to four months of therapy. Mean serum beta-carotene levels fell from 1.0 +/- 0.5 mumol/L (55.7 +/- 26.0 micrograms/dL) to 0.7 +/- 0.4 mumol/L (35.9 +/- 22.1 micrograms/dL) after the first month of mineral oil therapy and remained depressed throughout the remainder of the study. Serum alpha-tocopherol levels remained unchanged throughout the observation period. There was a modest increase in serum retinol levels during the study, especially after three months (from 1.48 +/- 0.84 mumol/L [42.3 +/- 24.1 micrograms/dL] to 2.22 +/- 0.77 mumol/L [63.5 +/- 22.1 micrograms/dL]). We conclude that while a short course of mineral oil can induce a reduction in the serum level of beta-carotene, the treatment has no adverse effect on serum levels of retinol and alpha-tocopherol.     

Bloodspot cortisol in mild asthma: the effect of inhaled corticosteroids

Bloodspot cortisol, where finger pricked blood is applied to blotting paper, is suitable for repeated measurements in the home environment. The use of bloodspot cortisol measurements in children with asthma and the effect of inhaled corticosteroids on daytime cortisol concentrations were assessed. Twenty children with mild asthma were randomised to receive double blind either placebo or beclomethasone dipropionate 200 micrograms twice daily. Blood was taken by finger prick at home on waking, and treatment administered. Blood was then taken one hour after treatment, at lunchtime, and in the evening. The area under the curve (AUC) for the four time points was calculated as a composite index of daytime cortisol. Mean (SEM) bloodspot cortisols fell progressively over the day from 199.2 (15.6) nmol/l to 58.4 (8.9) nmol/l. Cortisol in the group treated with beclomethasone dipropionate was lower at all time points, but was significant only after treatment (mean (SEM) 120.9 (14.3) v 177.5 (21.0) nmol/l) and at lunchtime (mean (SEM) 82.7 (12.4) v 128.9 (12.6) nmol/l). AUC for the beclomethasone dipropionate treated group was also significantly decreased (mean (SEM) 317 (31.4) v 446 (29.7)). Beclomethasone dipropionate at a dose of 400 micrograms/day significantly suppresses the daytime cortisol profile.     

Bloodspot cortisol in mild asthma: the effect of inhaled corticosteroids.

Bloodspot cortisol, where finger pricked blood is applied to blotting paper, is suitable for repeated measurements in the home environment. The use of bloodspot cortisol measurements in children with asthma and the effect of inhaled corticosteroids on daytime cortisol concentrations were assessed. Twenty children with mild asthma were randomised to receive double blind either placebo or beclomethasone dipropionate 200 micrograms twice daily. Blood was taken by finger prick at home on waking, and treatment administered. Blood was then taken one hour after treatment, at lunchtime, and in the evening. The area under the curve (AUC) for the four time points was calculated as a composite index of daytime cortisol. Mean (SEM) bloodspot cortisols fell progressively over the day from 199.2 (15.6) nmol/l to 58.4 (8.9) nmol/l. Cortisol in the group treated with beclomethasone dipropionate was lower at all time points, but was significant only after treatment (mean (SEM) 120.9 (14.3) v 177.5 (21.0) nmol/l) and at lunchtime (mean (SEM) 82.7 (12.4) v 128.9 (12.6) nmol/l). AUC for the beclomethasone dipropionate treated group was also significantly decreased (mean (SEM) 317 (31.4) v 446 (29.7)). Beclomethasone dipropionate at a dose of 400 micrograms/day significantly suppresses the daytime cortisol profile.     

Sleep quality in children with asthma treated with theophylline or cromolyn sodium

The effect of theophylline and cromolyn sodium on sleep was studied in 10 children with asthma who were 10 to 17 years of age (mean 13.5 +/- 2.4 years). Theophylline or cromolyn sodium was taken for 14 days in a double-blind, crossover, placebo-controlled trial. Theophylline blood levels before sleep were 10.2 +/- 4 micrograms/ml during the theophylline period. There was no difference in pulmonary function between the two periods. Theophylline did not disrupt sleep as measured by sleep latency, total sleep time, sleep efficiency, movement time, microarousals, and arousals. Apneic episodes (greater than or equal to 10 seconds) were of central origin and less frequent during the theophylline period (p less than 0.05). Arterial oxygen desaturation (greater than 5% decrease from baseline saturation when awake) was less frequent during the theophylline treatment (p less than 0.05). We conclude that theophylline treatment of the children's asthma did not disrupt sleep and appeared to have a protective effect in regard to apnea, hypopnea, and arterial oxygen saturation.     

Intravenous metronidazole in the newborn

Twenty four neonates at high risk of anaerobic sepsis were treated with intravenous metronidazole, 7.5 mg/kg, 8 hourly, for a mean period of 5 days. The highest observed concentration after the first dose (mean +/- SD) 9.6 +/- 4.0 mg/l (56.1 +/- 23.4 mumol/l) was significantly lower (P less than 0.001) than the highest observed concentration after the final dose (mean +/- SD) 19.3 +/- 8.6 mg/l (112.7 +/- 50.2 mumol/l). The overall metronidazole half life was (mean +/- SD) 23.4 +/- 13.1 hours. The half life after the first dose (mean +/- SD) 21.9 +/- 10.1 hours was not appreciably different from the half life after the final dose (mean +/- SD) 21.6 +/- 12.4 hours. The concentrations of the major metabolite of metronidazole (20396RP) also rose appreciably during treatment. No side effects of metronidazole were noted and its extended half life in neonates suggests that less frequent dosage would be appropriate.     

Monitoring theophylline therapy using citric acid-stimulated saliva in infants and children with asthma

Saliva stimulation is required for measurement of drugs in saliva. Chewing on a piece of paraffin, which is the method usually used for saliva stimulation, requires cooperation of the patient and, thus, is inapplicable in infants and young children. To assess the value of determining theophylline concentrations from noninvasively obtained saliva in this age group, we studied the theophylline plasma to saliva concentration ratio in citric acid-stimulated saliva. Theophylline concentration was measured in 137 simultaneously obtained paired specimens of plasma and saliva from 68 patients 2 1/2 months to 14 years of age treated with theophylline for asthma (dosage 20.8 +/- 5.2 mg/kg/d, mean +/- SD). Saliva secretion was stimulated by placing citric acid crystals on the tongue. A strong and highly significant correlation was observed between both determinations (r = .96; P less than .01). The plasma to saliva ratio was 1.78 +/- 0.22 (mean +/- SD), with theophylline concentrations between 3.1 and 32.1 micrograms/mL of plasma. The ratio of estimated to actual plasma theophylline concentrations was 1.02 +/- 0.12 (mean +/- SD). Interindividual coefficient of variation of plasma to saliva theophylline concentrations ratios was 12.4%; mean intraindividual coefficient of variation was 5.3%. The use of citric acid for saliva stimulation is easily applicable to infants and young children. Compared with blood drawing, stimulation of saliva secretion by citric acid is painless and noninvasive, is more readily accepted to patients, is at least as clinically relevant for theophylline determination, and allows frequent measurements of drug levels for individualization of the dosage with samples taken at home.(ABSTRACT TRUNCATED AT 250 WORDS)     

Children with moderately elevated lead levels: is chelation with DMSA helpful?

This study evaluates the effectiveness (use under routine circumstances) of DMSA (2,3 dimercaptosuccinic acid) and environmental remediation as compared with placebo and environmental remediation on children with blood lead (BPb) levels of 30-45 micrograms/dL (1.45-2.17 mumol/L). The endpoints were BPb at 1 month and 6 months after study entry. This double-blind placebo-controlled trial involved 39 children aged 2-5 years, who were randomized to one course of DMSA or placebo. The mean BPb levels of the two groups at study entry were similar, placebo group 33.0 micrograms/dL (1.59 mumol/L) and the DMSA group 34.9 micrograms/dL (1.68 mumol/L). At 1 month (the end of treatment) the mean BPb levels of the two groups were: placebo group 33.2 micrograms/dL (1.60 mumol/L) and the DMSA group 27.4 micrograms/dL (1.32 mumol/L), p = 0.16. At 6 months, the mean BPb levels were 25.1 micrograms/dL (1.21 mumol/L) for the placebo group and 28.8 micrograms/dL (1.39 mumol/L) for the DMSA-treated group, p = 0.06. Neither of these differences is statistically significant. All children with BPb, in the range studied here, should receive environmental evaluation and remediation; DMSA does not improve long-term blood lead levels.     

Effect of aminophylline on diaphragmatic contractility in the piglet

Minute ventilation, arterial blood gases, arterial pH, cardiac output, and transdiaphragmatic force generation, both during spontaneous ventilation and in response to phrenic nerve stimulation during airway occlusion at end expiration, were measured in nine anesthetized, tracheostomized piglets before and 30 min after parenteral infusion of 20 mg/kg aminophylline. Serum theophylline levels averaged 109 +/- 21 mumol/L (19.7 +/- 3.7 micrograms/mL) at 30 min postinfusion. No significant changes were noted in pH, blood gases, blood pressure, or ventilatory measures after aminophylline. Aminophylline infusion also had no effect on transdiaphragmatic force generation at any frequency of phrenic nerve stimulation studied. It is concluded that aminophylline has no effect on diaphragmatic contractility in the quietly breathing, nonfatigued piglet.     

Sustained-release theophylline preparations in asthmatic children. A short-term comparison of two products and the relationship of serum theophylline levels and pulmonary function changes

In a four-week study, 20 children with chronic asthma were treated in a randomized, double-blind, crossover manner with two sustained-release theophylline preparations (Theo-Dur and Uniphyl) to compare their drug concentrations and clinical efficacy. In addition, the effects of serum theophylline concentration on results of pulmonary function tests (PFTs) were evaluated. Twelve-hour doses (to achieve serum concentrations between 10 and 20 mg/L) of each drug were given for two weeks. Diaries of asthma symptoms and peak flows were kept daily. After 14 days of each treatment, children returned for measurement of theophylline levels and PFTs over a 12-hour period. The two drugs were equally effective in clinically controlling asthma over the two weeks of treatment. Serum theophylline levels obtained over the 12-hour dosing periods were not significantly different. Uniphyl provided less (but not significantly) deviation between peak and trough levels. Analysis of individual patient data did not reveal a predictable relationship between serum theophylline concentrations and results of PFTs.     

Pharmacokinetic analysis of the disposition of intravenous theophylline in young children.

The disposition of a single intravenous dose of theophylline, 3.2 mg/kg, was studied using a high-pressure liquid chromatographic assay in ten asthmatic children one to four years of age. The man plasma theophylline clearance was 0.100 +/- 0.036 l/kg/hr, kel 0.49 +/- 0.30 hr-1, betat1/2 3.38 +/- 1.11 hr, alphat1/2 0.13 +/- 0.09 hr, and V1 0.25 +/- 0.13 1/kg. Plasma theophylline clearance was approximately 40% greater in these children than that reported in adults, mainly due to an increased rate of drug elimination. Large interindividual differences were observed. Analysis of data using either a two- or one-compartment model yielded almost identical dosage regimens designed to rapidly achieve and maintain a chosen plasma theophylline concentration. Calculations based upon mean values of pharmacokinetic constants predict that a maintenance dose rate for aminophylline of 30 mg/kg/day, after a loading dose of 5.6 mg/kg, would rapidly achieve and maintain a mean steady-state plasma concentration of theophylline of 10 mg/1. Potential toxicity of such a regimen has not been excluded, since therapeutic trials (with achievement of steady state) have not yet been conducted.     

Decreased fasting free fatty acids with L-carnitine in children with carnitine deficiency

At the time of acute presentation, children with carnitine deficiency may have increased free fatty acid concentrations and hypoglycemia. However, whether carnitine replacement affects the plasma concentration of these substrates remains to be determined. Therefore, to evaluate the effect of carnitine replacement on plasma substrate and hormone concentrations, five children with carnitine deficiency (two idiopathic, two secondary to long-chain acyl coenzyme A dehydrogenase deficiency, one secondary to isovaleric acidemia) were fasted overnight before and after treatment with oral carnitine (80 +/- 7 mg.kg-1.day-1). During carnitine supplementation, plasma total carnitine (19 +/- 4 versus 45 +/- 6 nmol/ml, pretreatment versus treatment, respectively) and free carnitine (11 +/- 3 versus 31 +/- 6 nmol/ml), as well as red blood cell total carnitine (0.057 +/- 0.019 versus 0.130 +/- 0.019 nmol/mg of hemoglobin) increased (p less than 0.05). Fasting plasma glucose (83 +/- 4 versus 85 +/- 3 mg/dl) and ketone body (0.54 +/- 0.18 and 0.56 +/- 0.20 mM) concentrations did not change with carnitine supplementation, but plasma free fatty acids (1.28 +/- 0.32 versus 0.77 +/- 0.07 mM) decreased (p less than 0.05). No differences in fasting insulin, growth hormone, or cortisol concentrations were observed. Urinary excretion of free carnitine (0.1 +/- 0.0 versus 2.4 +/- 0.7 mumol/mg creatinine), total carnitine (0.3 +/- 0.1 versus 3.4 +/- 0.9 mumol/mg creatinine) and acyl carnitine (0.2 +/- 0.1 versus 0.9 +/- 0.3 mumol/mg creatinine) increased (p less than 0.05) with carnitine supplementation. The decreased plasma free fatty acid concentrations with carnitine supplementation may be due to more efficient fatty acid oxidation and/or increased urinary excretion of fatty acids as acylcarnitines.