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Les effets indésirables de l’aspirine, syndrome de Reye chez l’enfant en particulier, font que dans les syndromes douloureux ou fébriles courants, le praticien utilise maintenant en première intention des médicaments comme l’ibuprofène ou le paracétamol. Leurs caractéristiques pharmacocinétiques ne sont pas superposables: si tous deux sont absorbés rapidement et ont une biodisponibilité élevée, l’ibuprofène à la différence du paracétamol se caractérise par une forte liaison aux protéines plasmatiques et un volume de distribution limité

Objective: To study the pharmacokinetics of flunitrazepam (used for sedation in neonates and infants), to determine the influence of both gestational and postnatal age on the pharmacokinetic parameters, and to analyze the relationship between the hemodynamic parameters and flunitrazepam plasma concentration.Methods: Flunitrazepam was infused for 20 minutes as a single dose (0.2 mg · kg-1) and as multiple doses (0.1 mg · kg-1). Six to eight 1-mL blood samples were collected per patient. Flunitrazepam plasma concentration was measured by gas chromatography–mass spectrometry.Results: Thirty-one patients (25 neonates and six infants) were included in the study. Only three of them received multiple doses. After the single dose (n = 28), half-life was 22.6 ± 7.3 hours, clearance was 0.15 ± 0.14 L · kg · h-1, and volume of distribution was 4.6 ± 4.1 L · kg-1(mean ± SD). Plasma clearance and volume of distribution significantly increased with posnatal age (P < .05), but no pharmacokinetic parameter varied significantly with gestational age. Diastolic blood pressure significantly decreased with increasing flunitrazepam plasma concentrations (P < .05).Conclusion: Postnatal age but not gestational age influenced flunitrazepam pharmacokinetic parameters in neonates and infants. Diastolic blood pressure was inversely correlated to flunitrazepam plasma concentration.

Four premature neonates and eight infants 1–19 months old received caffeine for apnea. The usual morning oral dose was substituted by 1,3,7 13C-trimethylxanthine (13C-tri CAF) as the citrate salt. Five breath samples were collected the day before (day 1) and the day of 13C-tri CAF administration (day 2). Plasma (after each breath collection) and urine were collected on day 2.13C-CO2exhalation was determined by isotope ratio mass spectrometry. Caffeine and its metabolites were measured using high-pressure liquid chromatography. Assessment of the labeled CO2in the breath revealed no detectable 13C-tri CAF N-demethylation activity in infants before 45 wk postconceptional age. However, demethylation (as urinary metabolites) has been detected before that age. Two-, 4-, and 6-h cumulative excretion of 13C-tri CAF as 13C-CO2increased with postnatal age and correlated with caffeine plasma clearance (r = 0.840, p < 0.01). These results were consistent with those obtained for urinary metabolites. In one infant (19 months old) the cumulative excretion of 13C-CO2while crying was 65 of the value observed during quiet breathing. The measurement of caffeine demethylation using the caffeine CO2breath test is feasible in infants and is a safe and noninvasive method to determine age related changes in P4501-dependent N-demethylase activity.

Isoniazid acetylation metabolic ratio (MR) was studied in 61 children with tuberculosis after administration of isoniazid. MR was calculated as the molar acetylisoniazid to isoniazid concentration ratio. MR was used as a probe for N-acetyltransferase activity and to determine the acetylation phenotype. MR had a bimodal distribution with an antimode between 0.48 and 0.77. MR and the percentage of fast acetylators increased significantly with age. The cumulative frequency of fast acetylators increased with age, with a plateau reached around 4 years. MR value was checked during treatment in 44 children. All children but one who initially appeared as fast acetylators remained in this group after repeated testing. Among the 30 slow acetylators, 12 became fast acetylators, and 10 showed a variable phenotyping at different ages. A bimodal distribution of the isoniazid acetylation MR was shown in children, with an antimode close to that described in the literature and a maturation of isoniazid acetylation during the first 4 years.

Caffeine acetylator phenotype was studied during maturation in 54 8− to 447-d-old children hospitalized for minor disease (group A) and in five 3− to 630-d-old children with Pierre Robin syndrome (group B). In group A, the children received 2.5 mg/kg caffeine orally once between birth and 15 mo. Group B patients were chronically treated with caffeine (2.3 to 15.8 mg/kg/d) for prevention of apneas, and the acetylator phenotype was serially determined. Phenotyping was performed on a spot urine sample collected 2–6 h after drug administration. Caffeine metabolites [5-acetylamino-6-formylamino-3-methyl uracil (AFMU), 1-methylxanthine, 1-methyluric acid, 1,7-methyluric acid, and 1,7-methylxanthine) were measured using HPLC. Acetylator phenotype was determined on the basis of AFMU/1-methylxanthine (ratio 1) and AFMU/AFMU + 1-methyluric acid + 1-methylxanthine + 1,7-methylxanthine + 1,7-methyluric acid (ratio 2) molar ratios. In group A, all children were slow acetylators before 83 d of age (ratio 1 < 0.4; ratio 2 < 0.08), whereas older children included slow and fast acetylators. The acetylation molar ratios differed significantly between age groups and increased with age. The cumulative percentage of fast acetylators increased with age but the plateau was not yet reached at 15 mo. In three children, the phenotyping was repeated after 15 mo: the second determination was consistent with the first one. In group B, all children appeared as slow acetylators on the first phenotyping. Four of them appeared subsequently as fast acetylators; one remained a slow acetylator until 11 mo. These results suggest that maturation of caffeine acetylation occurs during at least the first 15 mo of life for fast acetylators but is not detectable in slow acetylators. Acetylator status cannot reliably be determined before at least 15 mo.

The antipyretic activity of ibuprofen in the Sparklets form was compared, in an equivalence study, with that of paracetamol in the same formulation. The study was conducted as a double-blind multicenter trial, with random allocation of the treatments. One hundred sixteen children of both sexes, aged 4.1 ± 2.6 years, with a fever related to an infectious disease and a mean temperature of 39° ± 0.5° C at the time of inclusion, were treated with single doses of either 10.3 ± 1.9 mg/kg of ibuprofen or 9.8 ± 1.9 mg/kg of paracetamol. The subjects’ rectal temperature was regularly monitored for 6 hours. The statistical analysis of the results confirmed that ibuprofen and paracetamol are equivalent with respect to the following criteria (1) time elapsed between dosing and the lowest temperature: 3.61 ± 1.34 hours for ibuprofen and 3.65 ± 1.47 hours for paracetamol (95% confidence interval [CI] of the difference: –0.48; +0.56); (2) extent of the temperature decrease: 1.65° C ± 0.80° C for ibuprofen and 1.50° C ± 0.61° C for paracetamol, (95% CI of the difference: –0.41; +0.11); (3) rate of temperature decrease: 0.52 ± 0.32° C/hr for ibuprofen and 0.51° C ± 0.38° C/hr for paracetamol (95% CI of the difference: –0.45; +0.55); (4) duration of temperature below 38.5° C: 3.79 ± 1.33 hours for ibuprofen and 3.84 ± 1.22 hours for paracetamol (95% CI of the difference: –0.14; +0.12). (J Pediatr 1997;131:683-7)

ABSTRACT: Caffeine acetylator phenotype was studied during maturation in 54 8- to 447-d-old children hospitalized for minor disease (group A) and in five 3- to 630-d-old children with Pierre Robin syndrome (group B). In group A, the children received 2.5 mg/kg caffeine orally once between birth and 15 mo. Group B patients were chronically treated with caffeine (2.3 to 15.8 mg/kg/d) for prevention of apneas, and the acetylator phenotype was serially determined. Phenotyping was performed on a spot urine sample collected 2–6 h after drug administration. Caffeine metabolites [5-acetylamino-6-formylamino-3-methyl uracil (AFMU), 1-methylxanthine, 1-methyluric acid, 1,7-methyluric acid, and 1,7-methylxanthine) were measured using HPLC. Acetylator phenotype was determined on the basis of AFMU/1-methylxanthine (ratio 1) and AFMU/AFMU + 1-methyluric acid + 1-methylxanthine + 1,7-methylxanthine + 1,7-methyluric acid (ratio 2) molar ratios. In group A, all children were slow acetylators before 83 d of age (ratio 1 < 0.4; ratio 2 < 0.08), whereas older children included slow and fast acetylators. The acetylation molar ratios differed significantly between age groups and increased with age. The cumulative percentage of fast acetylators increased with age but the plateau was not yet reached at 15 mo. In three children, the phenotyping was repeated after 15 mo: the second determination was consistent with the first one. In group B, all children appeared as slow acetylators on the first phenotyping. Four of them appeared subsequently as fast acetylators; one remained a slow acetylator until 11 mo. These results suggest that maturation of caffeine acetylation occurs during at least the first 15 mo of life for fast acetylators but is not detectable in slow acetylators. Acetylator status cannot reliably be determined before at least 15 mo.

ABSTRACT: Four premature neonates and eight infants 1–19 months old received caffeine for apnea. The usual morning oral dose was substituted by 1,3,7 13C-trimethylxanthine (13C-tri CAF) as the citrate salt. Five breath samples were collected the day before (day 1) and the day of 13C-tri CAF administration (day 2). Plasma (after each breath collection) and urine were collected on day 2.13C-CO2exhalation was determined by isotope ratio mass spectrometry. Caffeine and its metabolites were measured using high-pressure liquid chromatography. Assessment of the labeled CO2in the breath revealed no detectable 13C-tri CAF N-demethylation activity in infants before 45 wk postconceptional age. However, demethylation (as urinary metabolites) has been detected before that age. Two-, 4-, and 6-h cumulative excretion of 13C-tri CAF as 13C-CO2increased with postnatal age and correlated with caffeine plasma clearance (r = 0.840, p < 0.01). These results were consistent with those obtained for urinary metabolites. In one infant (19 months old) the cumulative excretion of 13C-CO2while crying was 65% of the value observed during quiet breathing. The measurement of caffeine demethylation using the caffeine CO2breath test is feasible in infants and is a safe and noninvasive method to determine age related changes in P4501-dependent N-demethylase activity.

This retrospective analysis was designed to evaluate the inactivation index (I3) method used to adjust the isoniazid dose during long-term administration in a pediatric population. Before starting on antituberculosis therapy, sixty-one children received one 10 mg · kg-1isoniazid test-dose (D). The isoniazid and acetyl isoniazid concentrations were measured by high-performance liquid chromatography on a plasma sample collected 3 hours (C3h) after administration. The patients were separated into slow and fast acetylator groups according to the metabolic ratio. The dose adjustment method using the I3is based on the assumption that there is a linear correlation between C3hand D[C3h= (I3× D) - 0.6] in which the slope is I3and the Y intercept is equal to -0.6 mg · l-1. I3was determined from a single plasma concentration determination and used to calculate the dose recommended to obtain a desired C3hequal to 1.5µg · ml-1: recommended dose (mg · kg-1) =(1.5 + 0.6)/I3· I3was significantly higher in the slow acetylator group (0.55 ± 0.16) than in the fast one (0.26 ± 0.13), which leads us to recommend a significantly lower dose in the slow acetylator group (4.2 ± 1.5 mg · kg-1) than in the fast one (10.3 ± 4.6 mg · kg-1). The data obtained in a subgroup of 21 patients who had at least three consecutive determinations of C3hafter different dosages allowed us to verify that there was a linear correlation between C3hand the dose. The mean slope of the correlation lines in that subgroup was 0.61 ± 0.25 and the 95% confidence interval of the estimated Y-intercept include the theoretical value of -0.60, which shows that our data are consistent with those previously reported in adults. The percentage of patients with a C3hplasma concentration within the expected range (1.5 ± 0.5 µg · ml-1) was significantly higher (69%) in those whose dose was derived from the calculation than in the others (25%). Within each acetylator group, the range of the recommended dose varied widely, and these results emphasize the usefulness of individual dose adjustment based on the inactivation index method.

We studied the possible interaction between aspirin and nitroglycerin (NTG) in seven healthy volunteers. Effects of NTG (0.8 mg sublingual spray) were assessed by the decrease in diastolic arterial pressure, increase in heart rate, and decrease in M-mode echocardiographic end-diastolic and end-systolic diameters of the left ventricle. Measurements were performed before and during 30 min after NTG. Plasma levels of NTG were monitored during the experimental procedure. Each of the following trials was repeated three times, in random order, in each volunteer: NTG without aspirin pretreatment, NTG 1 h after 1 g of oral aspirin, and NTG after 8 days of aspirin. 500 mg every 48 h. Aspirin at the 1-g dose level significantly increased the effects of NTG on diastolic blood pressure (p < 0.05) and left ventricular end-diastolic (p < 0.001) and end-systolic (p < 0.001) diameters. Aspirin (1 g) significantly increased (p < 0.01) mean NTG plasma levels from 0.24 ± 0.13 ng .ml−1(control) to 0.37 ± 0.26 ng .ml−1. We conclude that pretreatment with 1 g of aspirin increases NTG plasma levels and therefore significantly enhances the pharmacodynamic effects of NTG.

Objective: The spectrum of cytochrome P450 inhibition of stiripentol, a new anticonvulsant, was characterized in vitro and in vivo.Methods: Stiripentol was incubated in vitro with (R)-warfarin, coumarin, (S)-warfarin, (S)-mephenytoin, bufuralol, p-nitrophenol, and carbamazepine as probes for CYPs 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, respectively. Caffeine demethylation and the 6β-hydroxycortisol/cortisol ratio were monitored in vivo before and after 14 days of treatment with stiripentol as measures of CYP1A2 and CYP3A4 activity, and dextromethorphan O- and N-demethylation were used to measure CYP2D6 and CYP3A4 activity, respectively. In vivo inhibition constants for CYP3A4 were calculated with use of data that previously documented the interaction between stiripentol and carbamazepine.Results: In vitro, stiripentol inhibited CYPs 1A2, 2C9, 2C19, 2D6, and 3A4, with inhibition constant values at or slightly higher than therapeutic (total) concentrations of stiripentol, but it did not inhibit CYPs 2A6 and 2E1 even at tenfold therapeutic concentrations. In vivo inhibition of caffeine demethylation and dextromethorphan N-demethylation were consistent with inhibition of CYP1A2 and CYP3A4, respectively. The 6β-hydroxycortisol/cortisol ratio did not provide a reliable index of CYP3A4 inhibition. Inhibition of CYP2D6-mediated O-demethylation was not observed in vivo. With use of carbamazepine, in vivo inhibition constants for CYP3A4 ranged between 12 and 35 μmol/L, whereas the corresponding in vitro value was 80 μmol/L.Conclusions: Stiripentol appears to inhibit several CYP450 enzymes in vitro and in vivo. In vivo inhibition constants show that stiripentol inhibition of CYP3A4 is linearly related to plasma concentration in patients with epilepsy.

Endothelial cells are known to participate in angiogenesis, adaptation of vascular tonus and maintenance of blood fluidity in the microcirculation. To investigate these functions in the placenta, we devised a method of isolation and culture of endothelial cells from villous microvessels. In primary culture, these intraplacental endothelial cells exhibited many features observed in microvascular endothelium from other organs: spindle-shape, rosette associations, circular arrangements and confluence. In contrast to the confluent endothelial cells derived from the umbilical vein, cells from microvessels did not form a cobblestone network. After trypsin digestion of microvessels, magnetic microbeads coated with S-Endol immunoglobulin, antithrombomodulin and Ulex europaeus-I lectins were tested for sorting endothelial cells. Only the microbeads coated with antithrombomodulin allowed a suitable magnetic cell separation after trypsinization. By contrast, the microbeads coated with each of these antibodies or with lectins attached to confluent cells from the second passage. The microbeads detached from the cells at different rates. Their examination by scanning microscopy indicates that a portion of these microbeads was phagocytosed. Microvascular endothelial cells from the second passage were intensively stained by the anti-von Willebrand reaction and only weakly by the anti-smooth muscle -actin reaction. They incorporated acetylated-low density lipoproteins coupled to a fluorescent probe. The positive reactions against the anti-von Willebrand factor and the uptake of the fluorescent acetylated-low density lipoproteins were modified after eight passages.

The maturation of the different pathways of caffeine metabolism was studied during infancy. The group of children (n = 14) consisted of four premature newborn infants and 10 older infants who received caffeine citrate solution. Caffeine and 11 of its metabolites were measured by HPLC. Total demethylation and N3- and N7-demethylation increase exponentially with postnatal age; the plateau is reached by 120 days and accounts for 58.6%, 90.5%, and 79.3%, respectively. N1-demethylation shows no variation with postnatal age. It is suggested that N3-demethylation is more important in young infants than in adults and that maturation of N1-demethylation occurs later than 19 months of age. 8-Hydroxylation is mature as early as 1 month of age and may be higher in infants than in adults. Acetylation is not mature before at least 1 year of age. Differences in maturation rate of acetylation may be related in part to genetic acetylator status.