Comparison of two screening methods for in-house genotyping in clinical pharmacology units.

Two genetic screening methods, the fluorescence resonance energy transfer (FRET) technique on the LightCycler and the real-time pyrophosphate detection technique on the Pyrosequencer have been compared with regard to their usefulness as screening methods for subject recruitment in clinical studies in pharmacology units. Two SNPs of possible clinical relevance were selected, namely the 118A>G SNP of the OPRM1 gene and the 3435C>T SNP of the ABCB1 gene. Genotypes diagnosed using conventional sequencing served as control. The allelic frequency of the mutated 118G allele of the OPRM1 gene was 12.7% and that of the mutated 3435T allele of the ABCB1 gene was 50.7%. All results obtained with the Pyrosequencer were in accord with those obtained using conventional sequencing. With the LightCycler, an incorrect genotype was assigned to 1 of the 130 DNA samples corresponding to an error rate of 0.8%. Although both methods were found suitable for rapid SNP detection, Pyrosequencing was the preferred method since it provides the nucleotide sequence directly thus facilitating interpretation.

Effects of the opioid remifentanil on olfactory function in healthy volunteers.

The effects of opioids on human subjective olfactory function have rarely been investigated. This is despite the fact that opioid receptors are widely distributed throughout the olfactory systems. Using an established validated test of subjective olfactory function, olfactory threshold, odor discrimination and odor identification performance were tested in 16 healthy volunteers before opioid administration and at steady state after 3 hours remifentanil infusion. Each one man and one women were assigned randomly to one out of eight predefined remifentanil target plasma concentrations: 0, 1.2, 1.8, 2.4, 3, 3.6, 4.8, and 6 ng/ml. In the thirteen subjects that had completed the tests, olfactory thresholds were elevated with increasing remifentanil dose, and this correlated statistically significant with the remifentanil dose. Remifentanil plasma concentrations were linearly related to changes in olfactory thresholds. In contrast, effects of remifentanil on odor discrimination and identification were not statistically significant. However, remifentanil target plasma concentrations were also significantly correlated with the subjects' ratings of tiredness and drowsiness, although only drowsiness was significantly correlated with the differences in odor thresholds. We conclude that opioid administration leads to impaired olfactory function expressed in raised olfactory thresholds. This is compatible with previously reported opioidergic effects at the level of the olfactory bulb.

[Intestinal flora in the neonate: impact on morbidity and therapeutic perspectives]. / Acquisition de la flore intestinale néonatale: rôle sur la morbidité et perspectives thérapeutiques.

Studies in recent years have focused on the role that intestinal flora plays in health and disease. At birth, infant gut colonization begins with bacteria which are derived from the mother during delivery. Environmental factors (hospital, hygiene, antibiotics administered to the mother or to the neonate) may contribute to modification of the type of primary colonizing germs. Afterwards, diet represents the most important variable by the end of the first postnatal week. Exclusive breast-feeding promotes growth of Bifidobacteria which have been associated with the healthy nature of stool flora in infants because of their potential role in resisting pathogen colonization. Clinical trials have been made to promote bifidobacteria growth in the feces of bottle-fed infants. In addition, administration of non-pathogenic micro-organisms (probiotics) has been claimed to exert a positive influence on host health or physiology, and is a new approach to the prevention or elimination of infection originating from gut.

Adaptation in neonatology of the once-daily concept of aminoglycoside administration: evaluation of a dosing chart for amikacin in an intensive care unit.

BACKGROUND: The bactericidal efficacy of aminoglycosides is directly related to peak serum concentration (Cmax), particularly the first one. Transitory high concentrations of aminoglycosides do not result in such a high drug uptake by renal and cochlear tissues because of the saturation of cell binding sites. These observations have led to the concept that less frequent administration of relatively larger doses of aminoglycosides would be of interest in treating infectious diseases. OBJECTIVE: Prospective evaluation of a dosing chart of amikacin (Ak) in high-risk neonates suspected of infection within the first 2 days of life. This dosing chart was based on a previous pharmacokinetic population study published elsewhere, treated accordingly to the new once-daily concept of aminoglycoside administration. STUDY DESIGN: One hundred and seventy-seven neonates (69 females and 108 males; mean gestational age (GA +/-SD: 33.6 +/- 4.1 weeks (W) received Ak regimen dosage according to the following dosing chart: Group (Gr) 1a GA <28 W: 20 mg/kg/42 h; Gr 1b GA 28 /= 37 W: 15.5 mg/kg/24 h. In case of asphyxia, hypoxic episode and intercourse treatment with indomethacin, the interval was systemically increased by 6 h whatever the GA groups. The mean duration time of Ak treatment (+/- 1 SD) was 5.00 +/- 2.01 days (range 2-13). Ak serum concentrations 1 h after completion of 30 min infusion (C1h), and successive Ak serum concentrations just before next administration depending on the difference of interval between each group (so defined minimum serum concentration (Cmin)), were determined in each neonate. Creatininemia during the fist postnatal weeks was used as an index of glomerular filtration rate; brainstem auditory evoked potentials (BEAPs) were used in 139 babies when reaching a postconceptional age of >/= 36 weeks to assess possible ototoxicity, and were compared to values from a group of term and a group of preterm babies, previously defined as our reference control groups. RESULTS: At day 1 of treatment, there was no correlation between the Ak C1hS and the GA at birth (mean 27.8 +/- 5.21 microgram/ml (+/- 1 SD); median 28; r = -0.003; range 10-40). In the same way, there was no correlation between the first Ak CminS and the GA at birth (mean 3.7 +/- 2.0 microgram/ml (+/- 1 SD); median 3.0; r = -0.33; range 0-10). The lack of correlation between these first observed C1hS and CminS and the GA at birth suggests the validity of our previous established dose regimen recommendations. Analyzing the data between groups, the mean value +/- 1 SD of Ak C1hS at day 1 of treatment was not significantly different (p > 0.05). Concerning the first Ak CminS, a significant difference (p < 0.01) was only observed when comparing groups 1a, 1b and 2 to group 4. However, this significant difference disappeared when comparing the successive next Ak CminS between groups while each interval remained the same, suggesting a positive postnatal maturation of the renal clearance. In the same way, creatininemia showed a significant and normal decrease (p < 0.01) in each group during the first postnatal weeks. Threshold values of BEAPs at 30 dB showed no significant difference (p > 0.05) between the treated groups (preterm group and term group) and the corresponding control groups. While the primary aim of the study was not to test the bactericidal efficacy of this new regimen, the recovery was excellent in 37 babies with proven or highly suspected infectious disease, except in 1 of them who died from septic shock (group B Streptococcus). After 5 years of using this kind of Ak administration in the unit, minimal inhibitory concentration profiles tested in 43 successive bacterial strains collected from inborn patients remained adequate. (ABSTRACT TRUNCATED)

Effect of a fermented infant formula containing viable bifidobacteria on the fecal flora composition and pH of healthy full-term infants.

We assessed the growth, tolerance, and acceptability as well as fecal flora composition and stool pH of 20 healthy full-term infants fed with a fermented whey-adapted infant formula containing viable bifidobacteria (10(6)/g of powder) during the first 2 months of life. This fermented infant formula, first biologically acidified by Streptococcus thermophilus and Lactobacillus helveticus, was compared to a whey-adapted, nonacidified, low-phosphate infant formula in a double-blind, randomized controlled study. The results were compared to a control group (n = 14) of fully breast-fed infants. The fermented whey-adapted formula containing viable bifidobacteria induced a prevalence of colonization with bifidobacteria at 1 month of age similar to that of breast-fed infants (12/20 versus 8/14) but significantly higher than in the group fed the standard infant formula (4/20). The mean bacterial count of bifidobacteria was similar in all colonized infants; however, fecal pH was significantly lower in the breast-fed infants than in the nonacidified bottle-fed infants. This kind of infant formula was well tolerated and promoted a normal growth during the first 2 months.

Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity.

Neonates, especially preterms, are known to have low glomerular filtration rates (GFR). This may result in elevated trough concentrations during multiple administration of aminoglycosides (AGs), potentially leading to nephro- and ototoxic reactions. The once-daily administration (q.d.) of AGs has been shown to be equally or better tolerated in adults and children than the conventional schedules (twice daily, b.i.d.; thrice daily, t.i.d.), while offering potential pharmacodynamic and nursing advantages. No data, however, are available for neonates. As a consequence, this pilot study was conducted in order to assess the tolerance of the once-a-day administration of amikacin in comparison with the twice daily dose regimen, in relation to the pharmacokinetics of the drug under these two schedules. 22 Male neonates (gestational age > or = 34 weeks; postnatal age < or = 2 days) were randomized to receive amikacin (AK) (15 mg/kg/day) q.d. (n = 10) or b.i.d. (n = 12) together with ampicillin (50 mg/kg/12 h). AK plasma levels were measured at days 1, 3, 5 and 7 of treatment just before the next dose (trough level) and 1 h after completion of infusion (peak level) and after 3 and 6 h only at day 1. Due to the small size of the samples, no difference in efficacy could be assessed and was not the aim per se. Glomerular dysfunction was assessed by creatinine clearance, and tubular injuries by the urinary excretion of proteins (retinol binding protein, beta 2-microglobulin, clara cell protein (P1) and microalbumin), enzymes (N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, alanine aminopeptidase, and gamma-glutamyltransferase), and total phospholipids (TPL) in urine. Ototoxicity was assessed by brainstem auditory evoked potentials (BAEPs) at days 0, 3 and 9 of therapy. Eight healthy neonates served as controls. All patients showed a normal and similar increase of GFR during the first postnatal days. Proteinuria did not increase, but enzymuria and TPL increased significantly during the treatment in both AK groups without significant difference between groups. BAEPs at day 9 were not significantly different between treated and untreated patients. We conclude from this pilot study that, in the absence of more toxicity, the q.d. administration of AK in neonates of > or = 34 weeks of gestational age may be recommended over its bid schedule in view of its potential advantages.