Developmental pharmacology and therapeutics最新文献

Serum vancomycin concentrations determined by fluorescence polarization immunoassay (FPIA) with a specific high-performance liquid chromatography (HPLC) method in preterm neonates were compared. Preterm neonates (< 38 weeks gestational age) requiring vancomycin therapy and serum vancomycin concentration monitoring were enrolled. Peak serum vancomycin concentration samples were collected and independently analyzed by FPIA and HPLC. Multivariate and stratified data analysis was done with mean absolute error and mean percent error as dependent variables and independent variables as postconceptional age, postnatal age, gestational age, weight, and duration of therapy to characterize the findings. A total of 15 paired vancomycin concentrations were analyzed from neonates with a mean gestational age of 30 +/- 4 weeks. The mean percentage error of FPIA versus HPLC vancomycin concentrations was 18.1 +/- 11.1% and the mean absolute error was 3.7 +/- 2.0 mg/l. Postconceptional age, weight, and time from initiation of therapy to sample collection were independent variables which best characterized the overestimation of FPIA vancomycin concentrations. The FPIA vancomycin assay method overestimated actual vancomycin concentrations in preterm neonates. Preterm neonates less than 30 weeks postconceptional age, less than 1,200 g body weight, and duration of therapy greater than 48 h prior to concentration determination had the greatest difference in FPIA and HPLC results. Significant error in pharmacokinetic parameter estimations and dosage adjustments is possible when vancomycin concentrations are determined by FPIA.

Yin Zhi Huang (YZH) is a decoction of four plants which is widely used in Asia to treat neonatal jaundice. This study compares the ability of phenobarbital and the individual herbs comprising YZH, Artemisia, Gardenia, Rheum, and Scutellaria baicalensis, to induce hepatic drug and bilirubin metabolizing enzymes in rats. Herbal decoctions (30 ml/kg/day) or phenobarbital (60 mg/kg/day) were administered for 5 days. Only phenobarbital increased cytochrome P-450 levels whereas Gardenia slightly decreased levels. Artemisia, Rheum and phenobarbital increased bilirubin glucuronyl transferase activity. Glucuronidation of alpha-naphthol was increased by Gardenia and phenobarbital, whereas Artemisia and Rheum were ineffective inducers. Phenobarbital was the most effective inducer of glutathione-S-transferase (GSHT) activity. Phenobarbital and Gardenia both induced delta 5-3-ketosteroid isomerase activity, a marker for the Ya subunit of GSHT responsible for intracellular bilirubin transport in liver. The selective patterns of enzyme induction suggest potential value for using specific plant decoctions to modify drug and bilirubin metabolic pathways.

The effects of a single dose of 5 mg.kg-1 of ketamine administered intravenously to 10 critically ill preterm infants prior to epicutaneo-caval catheterization were analyzed using pulsed-wave Doppler ultrasound. The infants weighed between 670 and 1,885 g and their gestational ages ranged from 26 to 33 weeks. Arterial pressure (MAP), cardiac output (CO), transcutaneous oxygen pressure (TcPO2), transcutaneous carbon dioxide pressure (TcPCO2), end-diastolic velocity (EDV), peak systolic velocity (PSV), mean arterial velocity (MAV) of the cerebral anterior artery as well as Pourcelot's resistance index (PRI) were measured before and after injection of the drug. We observed a significant decrease in arterial pressure at 2 min after injection while heart rate and CO did not vary significantly. TcPO2 and TcPCO2, also remained unchanged throughout the period of measurement. EDV, PSV, and MAV did not vary significantly nor did PRI. As this drug provides major comfort to the baby during painful procedures and considerably facilitates difficult thin vessel catheterization, we believe that it may be used in such conditions.

We studied the effect of acetylcholine (ACh), 1 x 10(-8) to 5 x 10(-7) M, on electrophysiologic characteristics of the isolated (Langendorf), perfused fetal canine heart. ACh induced concentration-dependent decreases in sinoatrial (SA) rate and recovery from overdrive pacing and in atrioventricular (A-V) conduction. These effects of ACh were greater in mid-gestation than late-gestation hearts. The effects of ACh were potentiated by inhibition of acetylcholinesterase by neostigmine, 1 x 10(-7) M, in the late- but not the mid-gestation fetal heart. Decreasing the pH of the perfusion solution from 7.3 to 6.8 potentiated the response to ACh of SA rate and A-V conduction more in mid- than in late-gestation hearts. The response to ACh of the late-gestation fetal canine heart is more sensitive to cholinesterase inhibition whereas the response of the mid-gestation heart is more sensitive to the action of ACh in the presence of acidosis.

The pharmacokinetic parameters of paracetamol were studied after 15 min intravenous infusion of 15 mg/kg of propacetamol (Prodafalgan) in 5 neonates aged less than 10 days and 7 infants aged between 1 and 12 months. Blood was sampled at 0, 0.5, 2 and 6 h after the first intravenous infusion of propacetamol. The infants aged less than 10 days had higher plasma concentrations of paracetamol, a longer half-life (3.5 vs. 2.1 h) and a lower plasma clearance (0.149 vs. 0.365 l/h/kg) than the older children. Dose simulations were performed on the basis of individual data of each child in order to obtain steady-state plasma concentrations between 4 and 18 mg/l permitting the best antipyretic effect for each child. In infants aged less than 10 days a 15 mg/kg dose of propacetamol four times a day (i.e. 30 mg/kg/day paracetamol) is sufficient, corresponding to the dosage recommended by the French pharmacopoeia. On the other hand, double the dosage, nearer to the American dosage, is necessary for children aged over 10 days.

A total of 20 newborn piglets age 11.5 +/- 0.3 days and weighing 3.7 +/- 0.1 kg were studied under pentobarbital anesthesia. After stabilization following surgical procedures, baseline values for blood gases, base excess (BE), heart rate (HR), aortic pressure (AoP), left-ventricular contractility (LV dP/dtmax), carotid artery flow (CarF) and renal artery flow (RenF) were measured and normal lactic acid 0.2 ml/kg was infused over 1 h and the same parameters repeated. Then sodium bicarbonate (BC, n = 8), Tris-(hydroxymethyl)aminomethane (THAM, n = 6) or dichloroacetate (DCA, n = 6) were infused over 1 h. The doses of BC and THAM were calculated from the standard formula: Mmol = Base deficit x kg x 0.3. DCA was given at a dose of 300 mg/kg. Following lactic acid infusion, pH was 7.00 +/- 0.4 and BE was -20.6 +/- 1.2. Acidosis was associated with a significant (p < 0.05) increase in AoP (+18.6 +/- 7.4%) and decreases in HR (-13.9 +/- 2.7%) and RenF (-43.8 +/- 10.4%). Values of dP/dtmax and CarF were higher during acidosis in all but 3 animals. Following infusion of alkalizing agents pH and BE values were highest with BC and lowest with DCA and the differences were statistically significant (p < or = 0.05). In general, all three alkalizing agents reversed, in part or completely, the changes in cardiovascular parameters associated with acidosis so that following alkali infusion the changes were not statistically significant when compared to baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study investigated the effect of cocaine (COC) on cerebral circulation (CBF) and oxidative metabolism (CMRO2) in the newborn piglet and aimed to relate pharmacokinetics of cocaine to cerebrovascular effects. COC decreased CBF and CMRO2 from 75 to 64 and 4.27 to 3.91 ml/min/100 g, respectively, at 4 min with reduced flow to all brain regions (p < 0.05) which returned to baseline by 10 min. COC was rapidly metabolized with a t1/2 of 43 min and peak plasma concentration of 1,172 ng/ml. Norcocaine (NOR) appeared in plasma and CSF within 3 min of cocaine administration and remained elevated for the duration of the study along with COC in the CSF. These data show that the timing of the peak plasma COC level is associated with maximal decreased CBF. Further, the stable elevated level of COC and NOR in the CSF suggests that biotransformation does not occur in the brain. As a result, accumulation of these drugs may occur in the brain with successive COC use and affect the developing CNS in a deleterious manner.

Indomethacin lowers neonatal cerebral perfusion immediately after intravenous administration. It is important to elucidate whether this reduction is mediated by inhibition of production of prostaglandins, especially prostacyclin, which plays an important role in the autoregulation of the neonatal cerebral vascular bed. We studied changes in cerebral blood flow by serial measurements of temporal mean flow velocity in the anterior cerebral artery (TMFV-ACA), relative cerebral vascular resistance (R-cer), and prostaglandins (measured as changes in thiobarbituric acid reactive substances concentration; TBARS) after a therapeutic dose of 0.1 mg/kg indomethacin administered intravenously for noninvasive closure of patent ductus arteriosus. TMFV-ACA decreased and R-cer increased immediately after the indomethacin administration with a sustained recovery to pre-indomethacin values. The TBARS concentrations, however, did not change during the study period. We conclude that the present study suggests that a therapeutic dose of 0.1 mg/kg of indomethacin has no impact on prostaglandin metabolism.

Heart muscle is dependent on the entry of calcium from the extracellular fluid to support contraction, and neonatal hearts are particularly sensitive to reductions in transsarcolemmal entry of calcium. Accordingly, this study evaluated the ability of the calcium channel agonist BAY K8644 to prevent or reverse the myocardial depressant effects of halothane or isoflurane in right ventricular papillary muscles from neonatal rabbits. The ability of BAY K8644 to reverse reductions in force (F) and dF/dt (halothane and isoflurane) or prevent reduction (halothane) was studied. Halothane decreased F to 24 +/- 2% of baseline values (p = 0.001). The addition of BAY K8644 reversed F to only 54 +/- 3% of baseline (p = 0.001 vs. baseline and p = 0.002 vs. halothane alone). Isoflurane decreased F to 20 +/- 2% of baseline (p = 0.001) with a return to 45 +/- 4% of baseline with the addition of BAY K8644 (p = 0.0001 vs. baseline and p = 0.0025 vs. isoflurane alone). With BAY K8644 in the bath prior to the addition of halothane, halothane decreased F to 38 +/- 4% of baseline (p = 0.001). dF/dt mirrored changes in F in all studies. These data show that a calcium channel agonist is only partially effective in modulating volatile anesthetic-induced depression in neonatal rabbit ventricular papillary muscle.

Endothelins (ETs), recently discovered and highly vasoactive substances, have been implicated in the pathogenesis of various perinatal problems, such as preeclampsia, intrauterine growth retardation, intraventricular hemorrhage, pulmonary hypertension and necrotizing enterocolitis. Although fetal ET levels have been measured at birth, reference ET values for healthy newborns in the first days of life have not been established. The purpose of this study was to determine in normal healthy neonates ET 1-21 plasma values on day 1 and 4 postpartum and to investigate possible changes after adaptation of the newborn to extrauterine life. The study comprised 20 healthy full-term neonates, born after vaginal delivery (n = 10), or cesarean section (CS; n = 10) because of a previous CS. Venous blood was drawn on day 1 and 4 from all neonates and ET 1-21 levels were determined in the plasma by radioimmunoassay (Amersham kit RPA 5559). ET 1-21 values were on day 1 11.83 +/- 2.39 pmol/l (n = 20) and on day 4 9.45 +/- 1.88 pmol/l (n = 20). The statistical analysis showed a significant reduction of plasma ET levels on day 4 (p = 0.004), but no influence of the mode of delivery on plasma ET levels. In conclusion irrespective of the mode of delivery the high ET 1-21 plasma levels on day 1 postpartum are significantly reduced on day 4 of life.