The effect of postnatal age on gentamicin pharmacokinetics in neonates.

STUDY OBJECTIVE: To determine if gentamicin serum concentrations obtained from newborns on day 2 of life versus days 3-4 yield significantly different pharmacokinetic parameter values. DESIGN: Retrospective chart review. SETTING: Neonatal intensive care unit. PATIENTS: Two hundred and sixty-seven infants who had peak and trough gentamicin serum concentrations determined on days 2, 3, or 4 of life. INTERVENTION: Determination of peak and trough serum gentamicin concentrations on days 2, 3, or 4 of life. MEASUREMENTS AND MAIN RESULTS: The elimination rate constant, serum half-life, volume of distribution, and clearance of gentamicin were calculated using a one-compartment pharmacokinetic model. Gestational age, birthweight, gentamicin dosage, peak and trough gentamicin concentrations, and hours after birth at which serum concentrations were drawn were recorded for all infants. Infants were stratified into three groups based on gestational age: 28 weeks or younger, older than 28 weeks but younger than 37 weeks, and 37 weeks or older. Birthweight and calculated pharmacokinetic parameters were compared by 2-tailed Student t test to determine if significant differences existed between pharmacokinetics parameters determined on day 2 of life versus days 3 or 4 within each of the gestational age groups. These analyses revealed only one significant difference between parameters assessed on day 2 versus days 3 or 4: at day 2, the mean trough concentration of gentamicin in infants of gestational age between 28 and 37 weeks was 1.63 +/- 0.44 mg/L, whereas at days 3 or 4, the same parameter for patients of the same gestational age was 1.4 +/- 0.48 mg/L (p=0.005). CONCLUSIONS: With one exception--elevated trough concentrations in infants in the gestational age group between 28 and 37 weeks--pharmacokinetic parameters calculated using gentamicin serum concentrations determined on day 2 of life are not significantly different from those derived from gentamicin serum concentrations determined on days 3 or 4. This suggests that gentamicin serum concentrations and subsequent dosage adjustments can be determined on day 2 of life.

Release of prostaglandin E-2 in bovine brain endothelial cells after exposure to three unique forms of the antifungal drug amphotericin-B: role of COX-2 in amphotericin-B induced fever.

Common formulations of amphotericin-B include a deoxycholate colloidal suspension (d-Amph), an amphotericin-B lipid complex (Ablc), and a liposomal product (l-Amph). The clinical incidence of infusion related fever is highest with d-Amph, intermediate with Ablc, and lowest with l-Amph. In the present study, we measured the activation of cyclooxygenase-2 (COX-2) and subsequent release of prostaglandin E-2 (PgE-2) from brain microvessel endothelium treated with these three formulations of amphotericin-B. Primary cultured bovine brain microvessel endothelial cells (BBMEC) were exposed to d-Amph, Ablc and l-Amph at concentrations that can be achieved in the plasma of patients receiving the drug. Media samples from the cells were collected and analyzed for PgE-2. Release of PgE-2 from BBMEC monolayers treated with l-Amph was similar to cells receiving culture media alone. In contrast, Ablc and d-Amph caused significantly greater release of PgE-2 from BBMEC monolayers compared to controls receiving culture media alone. PgE-2 release after d-Amph treatment was similar in magnitude to that observed with bacterial lipopolysaccharide (LPS). Western blot analysis indicated significant induction of COX-2 expression in BBMEC following LPS, Ablc or d-Amph treatment. Furthermore, PgE-2 release following exposure of BBMEC monolayers to either LPS or the various amphotericin-B formulations was reduced by the addition of the selective COX-2 inhibitor, NS-398. These studies indicate that amphotericin-B induces COX-2 expression in brain microvessel endothelium resulting in release of fever producing PgE-2. The magnitude of PgE-2 release from BBMEC following exposure to various amphotericin-B formulations mirrors the clinical observations regarding amphotericin-B induced fever and serves as initial support for the clinical use of COX-2 inhibitors to reduce amphotericin-B fever.

The effect of hydroxyurea on the phosphorylation of zidovudine and lamivudine in human umbilical vein endothelial cells.

The purpose of this study was to characterize the activation of zidovudine (ZDV) and lamivudine (3TC) in human umbilical vein endothelial cells (HUVEC) with and without hydroxyurea (HU) pretreatment. HUVEC were pretreated with HU or control media for 24 h and then incubated for an additional 3 h with ZDV or 3TC. Intracellular concentrations of parent drugs and the phosphorylated forms were determined by high-performance liquid chromatography. Pretreatment with HU resulted in more than a threefold increase in intracellular concentrations of total ZDV, with the major intracellular form being the monophosphate (>80%). The relative percentage of each ZDV form was similar between control and HU-treated cells. On the other hand, intracellular concentrations of total 3TC increased only slightly (14%) with HU pretreatment. Although the parent drug remained the major intracellular form of 3TC, there was nearly a 400% increase in the 3TC triphosphate after HU pretreatment. These data demonstrate that HU causes a large increase in the intracellular accumulation of total ZDV, whereas it increases total 3TC only slightly but improves its triphosphorylation. Given the increase in intracellular concentrations of ZDV monophosphate after HU pretreatment and that the monophosphate has no antiviral activity but is associated with toxicity, the use of HU is not a good strategy to improve ZDV activation in human endothelium. There is improved production of the active antiviral 3TC triphosphate with HU pretreatment. The combination may be beneficial in treating potential sanctuary sites such as endothelium.

Repeated bowel perforations with Ibuprofen lysine: a case report.

Non-steroidal anti-inflammatory drugs (NSAID) have been used to close the patent ductus arteriosus in neonates for over two decades. Ibuprofen lysine, a parenteral NSAID, is labeled for the treatment of patent ductus arteriosus in neonates who do not respond to conventional medical management. While sharing many of the same adverse effects as indomethacin, spontaneous bowel perforation has not been reported. We describe a premature infant that experienced isolated bowel perforations after treatment with ibuprofen lysine for symptomatic patent ductus arteriosus.