Ibuprofen concentrations in human mature milk--first data about pharmacokinetics study in breast milk with AOR-10127 "Antalait" study.

BACKGROUND: Analgesics are one of the most prescribed drugs during the postpartum period to prevent and treat pain and inflammatory disease. The focus on analgesics during breastfeeding has increased because of lack of information and fatal codeine intoxication in a breastfed neonate. Ibuprofen has an advantageous benefit-risk ratio profile compared with codeine. There is a lack of information on drug transfer into human milk, thus ibuprofen intake during breastfeeding may be debated. Consequently, there is a dilemma whether to terminate breastfeeding or drug therapy. The objective of this study was to determine the relative infant dose of ibuprofen. METHODS: The first week after the delivery, each woman received ibuprofen to treat pain or inflammatory disorders (mean dose, 1012 ± 96 mg/d). Just after the third dose of ibuprofen, 1 milk sample and 2 blood samples were obtained after 1 week of breastfeeding. Ibuprofen concentrations in breast milk and blood were measured by using high-performance liquid chromatography. RESULTS: Twenty women were included after written informed consent, and 13 gave their breast milk and blood samples. The mean ibuprofen milk concentration was 360 ± 160 mcg/L. The mean fat milk concentration was 3.23 ± 1.15 g per 100 mL, and the mean milk protein concentration 0.87 ± 0.27 g per 100 mL. The ibuprofen transfer infant dose (theoretical infant dose) was 68 mcg·kg-1·d-1 (8-262 mcg·kg-1·d-1), and the relative infant dose was <0.38% (0.04%-1.53%) of the weight-adjusted maternal daily dose, which equals 0.2% of the infant dose. CONCLUSIONS: The results confirm that the transfer of ibuprofen into breast milk decreases with the protein concentration and the duration of lactation. These results suggest that the use of ibuprofen is compatible with prolonged breastfeeding after the early postpartum stage.

Role of serotonin via 5-HT2B receptors in the reinforcing effects of MDMA in mice.

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT(2B) receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT(2B) receptors to the reinforcing properties of MDMA.We show here that 5-HT(2B) (-/-) mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT(2B) receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT(2B) receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT(2B) receptor-independent behavioral effects.These results underpin the importance of 5-HT(2B) receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions.

Reactivation of gammaHV68 induces neointimal lesions in pulmonary arteries of S100A4/Mts1-overexpressing mice in association with degradation of elastin.

S100A4/Mts-overexpressing mice have thick elastic laminae and mild pulmonary arterial hypertension (PAH), and the occasional older mouse develops occlusive neointimal lesions and perivascular inflammation. We hypothesized that a vasculotropic virus could induce neointimal lesions in the S100A4/Mts1 mouse by facilitating breakdown of elastin and migration and proliferation of smooth muscle cells. To test this hypothesis, we infected S100A4/Mts1 mice with gammaherpesvirus 68 (gammaHV68). We observed, 6 mo after gammaHV68 [4 x 10(3) plaque-forming units (PFU)], perivascular inflammation in 10/15 S100A4/Mts1 mice and occlusive neointimal formation in 3/10 mice, accompanied by striking degradation of elastin. We then compared the early response after high-dose gammaHV68 (4 x 10(6) PFU) in C57Bl/6 and S100A4/Mts1 mice. In S100A4/Mts1 mice only, significant PAH, muscularization of distal vessels, and elastase activity were observed 6 wk after gammaHV68. These features resolved by 3 mo without neointimal formation. We therefore infected mice with the M1-gammaHV68 strain that reactivates from latency with higher efficiency and observed neointimal lesions at 3 mo in 2/5 C57Bl/6 (5-9% of vessels) and in 5/5 S100A4/Mts1 mice (13-40% of vessels) accompanied by mild PAH, heightened lung elastase activity, and intravascular viral expression. This suggested that enhanced generation of elastin peptides in S100A4/Mts1 mice may promote increased viral entry in the vessel wall. Using S100A4/Mts1 PA organ culture, we showed, in response to elastase activity, heightened production of elastin peptides associated with invasion of inflammatory cells and intravascular viral antigen. We therefore propose that early viral access to the vessel wall may be a critical determinant of the extent of vascular pathology following reactivation.