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Biomedical subjects

J M Treluyer

Publications and source records attributed to J M Treluyer.

At least 19 recordsLinked to original sources
PubMed2005

Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method.

OBJECTIVE: Intravenous ibuprofen (IBU) has been found to be as effective as indomethacin for the treatment of patent ductus arteriosus (PDA) in preterm infants and has been associated with fewer adverse effects in comparative phase III studies. The dose regimen used (10-5-5 mg/kg/day) was based on limited pharmacokinetic data and no phase II study was available to determine the optimal dose of IBU for this indication. The present study was designed to determine the minimum effective dose regimen (MEDR) of IBU (one course) required to close ductus arteriosus in preterm infants. METHOD: A double-blind dose-finding study was conducted using the continual reassessment method, a Bayesian sequential design. Two distinct target closure rates were initially chosen according to postmenstrual age (PMA) at birth: 80% in infants with a PMA of 27-29 weeks, and 50% in infants with a PMA < 27 weeks. Forty neonates (20 in each PMA group) with PDA were treated between days 3 and 5 of life. Four different dose regimens were tested: loading doses of 5, 10, 15 or 20 mg/kg, followed by two doses (1/2 loading dose) at 24-h intervals. Efficacy was evaluated by echocardiography 24 h after the third infusion. RESULTS: In infants with a PMA of 27-29 weeks, the estimated MEDR was 10-5-5 mg/kg with a final estimated probability of success of 77% (95% credibility interval: 56-92%). The 15-7.5-7.5 mg/kg dose regimen had a better estimated probability of success (88%, 95% credibility interval: 68-97%), but resulted in more minor renal adverse effects. In contrast, in infants with a PMA < 27 weeks, the estimated MEDR was 20-10-10 mg/kg with an estimated probability of success of 54.8% (95% credibility interval: 22-84%), whereas the conventional dose regimen resulted in a low estimated probability of success (30.6%, 95% credibility interval: 13-56%). In these infants, compared with those with a PMA of 27-29 weeks, minor renal adverse effects were more frequent from the 10-5-5 mg/kg/day dose regimen and did not appear to be clearly dose related. CONCLUSION: This study confirms that the currently recommended dose regimen (10-5-5 mg/kg) of IBU is associated with a high closure rate (80%) and few adverse effects in premature infants with a PMA of 27-29 weeks. The failure rate was much higher below 27 weeks. A higher dose regimen (20-10-10 mg/kg) might achieve a higher closure rate. However, tolerability and safety of this dose regimen should be assessed in a larger population before considering the use of these doses for ductus arteriosus closure.

Bayes Theorem↗
PubMed2003

Inhibitory effect of stiripentol on carbamazepine and saquinavir metabolism in human.

AIMS: To characterize the in vitro and in vivo inhibitory effect of stiripentol, a new anticonvulsant, on the metabolism of carbamazepine and saquinavir, which are substrates of CYP3A4. METHODS: Human liver microsomes and cDNA-expressed CYP enzymes were used for the in vitro experiments. Pharmacokinetic data from epileptic children and healthy adults were used for the carbamazepine and saquinavir in vivo studies, respectively. RESULTS: Carbamazepine biotransformation to its 10,11-epoxide by human liver microsomes (Vmax = 10.3 nmol min(-1) nmol(-1) P450, apparent Km = 362 microm), cDNA-expressed CYP3A4 (Vmax = 1.17 nmol min(-1) nmol(-1) P450, apparent Km = 119 microm) and CYP2C8 (Vmax = 0.669 nmol min(-1) nmol(-1) P450, apparent Km = 757 microm) was inhibited by stiripentol (IC50 14, 5.1, 37 microM and apparent Ki 3.7, 2.5, 35 microm, respectively). Saquinavir biotransformation to its major metabolite M7 by human liver microsomes (Vmax = 5.7 nmol min(-1) nmol(-1) P450, apparent Km = 0.79 microm) was inhibited by stiripentol (IC50 163 microM, apparent Ki 86 microm). In epileptic children treated with carbamazepine and stiripentol, the plasma concentration ratio of carbamazepine epoxide/carbamazepine was decreased by 65%. The in vivo apparent Ki for stiripentol ranged from 10.5 to 41.4 microm. The pharmacokinetics of saquinavir was not modified by stiripentol in healthy adults. The 95% confidence intervals for the difference for Cmax and AUC of saquinavir between the placebo and stiripentol phase were (-39.8, 39.8) and (-33.2, 112), respectively. CONCLUSIONS: These results showed that stiripentol was a weak inhibitor of saquinavir metabolism both in vitro and in vivo. In contrast, stiripentol is a potent inhibitor of carbamazepine 10,11-epoxide formation in vitro and in vivo in epileptic patients.

Adolescent↗
PubMed2003

Parasitic diarrhea in normal and malnourished children.

Diarrhea is only one of the many manifestations of intestinal parasites. Environmental influences are inescapable, regardless of an individual's state of health: in a highly endemic region, intestinal parasitic colonization is almost the rule. The clinical expression of the parasitoses, however, is largely determined by host defenses; and when they are weakened, parasitic diarrhea is frequent and severe. Protein-energy malnutrition is by far the most important cause of immune deficiency in developing countries. Diarrhea caused by Strongyloides or Giardia is common and severe in malnourished children, while well-nourished children remain healthy carriers. These parasites require specific treatment in the malnourished; and the well-nourished should have preventive treatment when they are to receive corticosteroids or immunosuppressive agents. Diarrhea caused by Cryptosporidium spp. may be severe in malnourished or immunodeficient children, and recovery is achieved only after renutrition or treatment of the immunodeficiency.

Antinematodal Agents↗
PubMed2001

Tolerance of efavirenz in children.

OBJECTIVE: To extend the limited knowledge of efavirenz tolerance in children. METHOD: An observational study of 33 children given efavirenz combined with various others agents and followed in a single institution. RESULTS: Fifteen (42%) of the children presented at least one clinically discernable side effect, cutaneous (n = 5), nervous system (n = 10), or both (n = 2). Intolerance led to treatment interruption in seven children but the main symptom was transitory dizziness or other signs similar to those observed in adults. CONCLUSION: Early, often transient nervous system side effects require careful preparation with the child and his family to avoid premature and inadequate withdrawal from treatment.

Adolescent↗
PubMed2001

[Cardiac rhythm disturbances and prolonged QT interval with halofantrine].

OBJECTIVE: To determine the importance of prolonged QT interval and electrocardiographic changes in children treated with halofantrin for an acute malaria attack. RESULTS: Out of 25 children treated with halofantrin, nine had an increase of QTc interval < 440 ms and ten a QTc > 440 ms on control 24 h after the first dose. A 9-year-old girl, treated with halofantrin, had bradycardia and increase of QTc interval for six days, with a normal halofantrin blood level. CONCLUSION: These data show that cardiac monitoring during halofantrin treatment is mandatory in children as in adults. Contraindications of halofantrin treatment must be respected, particularly a long congenital QT interval.

Adolescent↗
PubMed2001

Isoniazid pharmacokinetics in children according to acetylator phenotype.

The pharmacokinetics of isoniazid (INH) was studied in children (0-196 months old) according to their acetylator phenotype, estimated from the metabolic acetyl INH/INH molar plasma concentration ratio (MR) measured 3 h after INH oral administration. There were 17 slow (MR < 0.48) and 17 fast acetylators (MR > or = 0.48). The mean apparent plasma clearance was significantly lower, the mean apparent volume of distribution higher and the half-life longer in the slow acetylator group (C1, 0.298 +/- 0.099 L/h/kg; Vd, 1.56 +/- 0.65 L/kg; t1/2, 3.88 +/- 01.89 h) than in the fast acetylator group (Cl, 0.528 +/- 0.234 L/h/kg; Vd, 1.06 +/- 0.45; t1/2, 1.64 +/- 1.1 h). The half-life decreased with age. An impaired isoniazid elimination was suggested in children less than three months old, which may be in favour of an individual dose adjustment in this population.

Acetylation↗
PubMed1997

Developmental expression of CYP2C and CYP2C-dependent activities in the human liver: in-vivo/in-vitro correlation and inducibility.

Experiments were performed in vivo and in vitro to date the onset of hepatic CYP2C isoforms and CYP2C-dependent activities during the perinatal period in humans. Proteins were not detected by immunoblotting in fetal livers and developed in the first few weeks after birth, irrespective of the gestational age at birth. Similarly, the hydroxylation of tolbutamide, a marker for CYP2C9 was undetected in fetal liver microsomes and rose in the first month after birth. In adult liver preparations, the hydroxylation of diazepam correlated well with the CYP3 A content of microsomes (r = 0.858, p < 0.01) and with the 6 beta hydroxylation of testosterone (r = 0.830, p < 0.005), whereas demethylation was related to the bulk of CYP2C proteins (r = 0.865, p < 0.005). In fetal liver microsomes, hydroxylation and demethylation activities accounted for less than 5% of the adult activities and both increased immediately after birth to reach adult activities at 1 year of age. When diazepam was given for sedative purpose in neonates and infants, the in-vivo urinary excretion of desmethyl diazepam, temazepam and oxazepam was extremely low in 1-2 day newborns (less than 5 nmol metabolites excreted in 24 h per kg body weight) and developed in the first week after birth. In newborns, barbiturates and to a lesser extent steroids, acted as inducers of CYP2C isoforms and increased tolbutamide hydroxylation, diazepam demethylation and diazepam hydroxylation by 2 to 10-fold. The surge of CYP2C proteins was caused by an accumulation of RNAs occurring in the first week after birth. The hepatic content in CYP2C8, 2C9 and 2C18 RNA displayed the same profile of evolution, which suggested a coregulation of their synthesis during the neonatal period. Taken together, these biochemical and clinical data enable dating of the onset of CYP2C proteins to the first weeks after birth, which is of considerable clinical importance in pediatric pharmacology.

Adult↗
PubMed1996

Cytochrome P-450 expression in sudden infant death syndrome.

In the human liver, the major rise of the cytochrome P-450 isoform content occurs during the first months following birth (e.g., the high vulnerability period to sudden infant death syndrome (SIDS), a syndrome frequently associated with viral infection and drug hypersensitivity. We examined the expression of individual P-450 isoforms in liver samples collected postmortem from SIDS infants and compared values with those of control adults and children of the same age suffering from various pathologies. Hepatic microsomes were prepared and examined for their content in total P-450, the level of individual isoforms (CYP1A2, CYP2E1, CYP4A, CYP3A, and CYP2C) determined with specific antibodies and for their enzymatic activities. Total RNA was extracted and probed with several CYP cDNAs and oligomers. The overall hepatic P-450 content was not modified in SIDS infants. Among cytochrome P-450 isoforms, only CYP2C was markedly increased. This rise resulted from an accumulation of RNA encoding CYP2C and was associated with a stimulation of diazepam demethylation. The precocious expression of CYP2C in SIDS could result in a higher production of epoxyeicosatrienoic acids in the neonate, believed to act as relaxant of pulmonary smooth muscles. Its consequence might be the induction of fatal apnea in SIDS.

Base Sequence↗
PubMed1994

Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults.

1. Caffeine metabolism was studied in human liver microsomes from foetuses (n = 10), neonates (n = 10), infants (n = 9) and adults (n = 5). Caffeine and its metabolites, 1-3-7-trimethyluric acid, paraxanthine, theophylline and theobromine, were assayed by h.p.l.c. Methoxyresorufin-O-demethylase activity (MEROD) was determined and immunoquantifiable levels of CYP1A2 were measured. 2. The formation of the dimethylxanthines by N-3, N-7 or N-1-demethylation was significantly less in foetuses, neonates and infants than in adults, as shown previously in vivo. The formation of 1-3-7-trimethyluric acid (C-8-hydroxylation) was not significantly different between age groups. The production of total dimethylxanthines, paraxanthine and theophylline increased significantly with age within the neonate-infant group over at least the 0-300 day range (rs = 0.739, 0.667, 0.682, respectively). These data differ from those reported in vivo which suggested that N-3 and N-7-demethylations matured at about 120 days. The difference in maturational profiles of each metabolic pathway suggests that the reactions depend on different isoenzymes. The delay in the maturation of N-1 compared with N-3 and N-7-demethylation is in agreement with previous in vivo data. 3. In the neonate-infant group, only N-3-demethylation correlated with both MEROD activity (rs = 0.681; P < 0.05) and CYP1A2 microsomal concentration (rs = 0.454; P approximately 0.05), suggesting that, as in adults, this reaction depends on CYP1A2. 4. In the foetal samples, the production of total dimethylxanthines, paraxanthine and theobromine decreased significantly (rs = -0.879, -0.767, -0.708, respectively) with increasing gestational age.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Intravenous nicardipine in hypertensive children.

Fourteen hypertensive patients hospitalized in a paediatric intensive care unit were studied to evaluate safety and hypotensive efficacy of intravenous nicardipine. Systolic and diastolic blood pressure significantly decreased 1 h after the beginning of the treatment (1 microgram/kg per minute). Mean decrease in systolic blood pressure during the first 24 h was between 9.9% and 13.4% of the initial value. Mean lowering of diastolic blood pressure was between 16.7% and 25.6%. Nicardipine did not significantly affect heart rate with dose of 1 microgram/kg per minute. No clinical side-effects were observed. Nicardipine could be a first line drug for the treatment of hypertension in paediatric intensive care units.

Blood Pressure↗
PubMed1991

Expression of CYP2D6 in developing human liver.

The CYP2D6 protein is a polymorphic isoenzyme involved in the biotransformation of several drugs including the probe drug dextromethorphan. The rise in the protein concentration, immunochemically determined with a specific antibody, was shown to occur within the first week following birth, whatever the gestational age at birth. In fetuses, the concentration of hepatic CYP2D6 protein was very low or undetectable in 70% of samples tested. In the remaining 30%, its concentration was comparable to that of newborns aged 1-7 days. This early rise was associated with spontaneous abortion in 70% of positive samples, whereas in fetuses with an intermediate CYP2D6 protein concentration, 80% were from induced abortions. The rise in CYP2D6 protein was associated with the developmental onset of dextromethorphan O-demethylation, but not N-demethylation, even if activity was lower in fetal than in neonatal and in adult liver microsomes. Lastly, the CYP2D6 RNA is detectable earlier than the protein and exhibits a peak of hepatic accumulation in newborns, before declining in adulthood. A positive correlation between RNA accumulation and protein concentration can be demonstrated only in the adult. This suggest that regulation is primarily at the transcriptional level, but cannot rule out the participation of post-transcriptional events in the regulation process throughout ontogenesis.

Adult↗
PubMed1991

[Neonatal septicemias: biological diagnosis and antibiotherapy. Apropos of a series of 46 cases].

The records of 46 neonates with proven septicaemia were retrospectively studied. Patients could be divided in 2 groups: in group 1 (21 infants) a positive blood culture was obtained before one day of life; in group 2 (25 infants) a positive blood culture was obtained between days 1 and 28. The sensitivity of 9 chemical and bacteriological tests and the efficacy of the initial antibiotic treatment were examined in both groups. Of the 21 germs isolated in patients from group 1, 86% were Gram positive bacteria and 95% were susceptible to ampicillin. Of the 26 germs isolated in patients from group 2, 80% were Gram negative enteric bacteria and 86% were susceptible to cefotaxime. Bacterial tests (gastric aspiration, antigen detection, feces culture) had a better sensibility than biochemical tests (C reactive protein, orosomucoid, fibrinogen).

Aminoglycosides↗