Endotracheal tolazoline: pharmacokinetics and pharmacodynamics in dogs

Tolazoline is a potent vasodilator of both arteries and veins and has a powerful effect on the pulmonary vasculature, reducing hypoxic pulmonary vasoconstriction and lowering pulmonary artery pressure. Intravenous tolazoline lowers the mean pulmonary arterial pressure and resistance and increases the cardiac index when given to infants with persistent pulmonary hypertension of the newborn (PPHN). Endotracheally administered tolazoline decreases mean pulmonary arterial pressure and pulmonary vascular resistance, and improves oxygenation without the harmful decline in systemic arterial pressure. The purpose of our study was to examine the pharmacokinetic and pharmacodynamic characteristics of endotracheal tolazoline in order to determine the relationship between endotracheal tolazoline administration, plasma concentration and its effects on the cardiovascular and respiratory systems. Tolazoline was administered endotracheally to 7 newborn dogs, and its serum concentration and the haemodynamic parameters were monitored for 270 min post-delivery. Results are expressed as median and quartiles. It was found that 15 s after dosing, tolazoline plasma concentrations started to increase significantly above baseline levels, reaching a maximum of 2.64 (1.36; 13.16) microg/ml. The extent of tolazoline absorption was 305 (148;453) microg/ min/ml. The volume of distribution was 3.4 (1.6;7.4) 1/kg. The total body clearance was 12.1 (10.9;23.9) ml/min/kg and the elimination half-life was 225 (171;303) min. Endotracheal tolazoline produced an initial short-lived decrease in mean blood pressure in all the dogs, but thereafter the blood pressure increased gradually above baseline levels. Immediately following endotracheal tolazoline significant tachycardia developed, peaking at 90 min. Subsequently, the heart rate gradually decreased and stabilized at values above baseline for 200 min. A single endotracheal dose of tolazoline is effectively absorbed and produces measurable pharmacological effects. Determining the optimal endotracheal dose of tolazoline in the clinical setting requires additional evaluation.     

Dobutamine pharmacokinetics and cardiovascular responses in critically ill neonates.

The pharmacokinetics and pharmacodynamics of dobutamine were studied in 13 critically ill neonates requiring inotropic support. Dobutamine was administered as a constant infusion in increasing doses of 2.5, 5, and 7.5 micrograms/kg per minute. During dobutamine infusions, there were significant increases in cardiac output measurements above perinfusion values. There were no statistically significant changes in systolic or diastolic blood pressure or heart rate during the infusions. The mean calculated threshold value, or the minimum plasma concentration necessary for a change in cardiac output, was 39 +/- 8 ng/mL. The mean plasma clearance rate was 90 +/- 38 mL/min per kilogram and was most consistent with first-order kinetics over the range of dosages studied. Plasma catecholamine levels were unchanged during the dobutamine infusions. These data suggest that dobutamine is an effective but limited inotropic agent in the neonate. Dobutamine may be most beneficial when cardiogenic failure is presented.     

Pharmacokinetic profile of caffeine in the premature newborn infant with apnea.

The pharmacokinetic profile of caffeine was studied in 32 premature newborn infants with apnea: 12 following a single intravenous dose; 3 after a single oral dose; 7 during treatment with an initial empirical (high) maintenance dose schedule; and 10 during treatment with a revised (lower) dose schedule. Mean (+/- SE) AV d, t 1/2, ke1, and clearance following a single intravenous dose were 0.916 +/- 0.070 1/kg, 102.9 +/- 17.9 hours, 0.009 +/- 0.001/hours and 8.9 +/- 1.5 ml/kg/hour, respectively. Rapid absorption was noted with plasma concentrations of 6 to 10 mg/l achieved within 30 minutes to two hours following an oral dose of 10 mg/kg. Cpss of caffeine in infants given a high empirical dose (11.2 +/- 1.5 mg/kg/day) ranged from 22.5 to 84.2 mg/l (mean = 45.3) whereas a dose schedule based on kinetic data (2.5 mg/kg/day) yielded plasma concentrations ranging from 7.4 to 19.4 mg/l (mean = 13.7). We suggest a loading dose of 10 mg/kg intravenously or orally followed by a daily maintenance dose of 2.5 mg/kg/day administered as a single dose for the treatment and prevention of neonatal apnea.     

The effects of tolazoline on the distribution of cardiac output in normoxemic and hypoxemic lambs

We measured cardiac output and its distribution (microspheres), blood gases and pH, heart rate, and pulmonary and aortic pressures in three groups of 1- to 3-day-old lambs. Group I consisted of six animals who had these measurements made during both control (normoxemic) and hypoxemic (PaO2 25 +/- 3 mm Hg) periods. Hypoxemia increased the pulmonary artery pressure 70% (p less than 0.01). This elevation in pulmonary arterial pressure lasted as long as the animals were hypoxemic (90 min). Hypoxemia had no effect on cardiac output, mean systemic arterial pressure, heart rate, or the rate-pressure product of the left ventricle. Blood flow to the heart increased an average of 228% (p less than 0.05); flow to the brain increased 233% (p less than 0.05); flow to the skin decreased 35% (p less than 0.05) after 60 and 90 min of hypoxemia. Blood flow to the remaining organs was uneffected by hypoxemia. Group II consisted of four animals who were given 1, 5, and 10 mg/kg/h of tolazoline (Priscoline) intravenously while normoxemic. There was no effect on the pulmonary arterial pressures or blood gases and pH. Tolazoline (5 and 10 mg/kg/h) reduced systemic arterial pressures an average of 22% (p less than 0.05). Tolazoline (1 mg/kg/h) reduced blood flow to the spleen 48% and that to the brain by 20% and increased flow to the body 32% (p less than 0.05). Five mg/kg/h of tolazoline decreased renal and brain blood flow 35 and 20%, respectively (p less than 0.05) while that to the body and liver increased 26 and 48% (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of intravenously administered piperacillin in preadolescent children

We studied the pharmacokinetics of piperacillin in 37 preadolescent children (mean age 52 months, range 1 month to 11 years) after 50 mg/kg IV doses. Pharmacokinetic parameters were determined after the initial dose in 18 instances and after subsequent doses in 32 instances. There were no significant differences between the initial doses and the subsequent doses in the plasma piperacillin concentrations at comparable times, the elimination rate constants, the elimination-phase plasma half-lives, the total body clearances, the apparent volumes of distribution, or the areas under the concentration curves. At the end of a 30-minute infusion of the drug, the plasma concentration was 166.2 +/- 42.2 mg/L (mean +/- SD) and ranged from 91.6 to 268.3 mg/L. The mean half-life was 31.0 +/- 9.4 minutes. The half-life of piperacillin in children 1 to 6 months of age (47.2 minutes) was significantly longer than in older children (28.8 minutes) (P less than 0.05). Likewise, the total body clearance of the drug in the younger age group (71.7 ml/min/m2) was significantly lower than in the older children (130.8 ml/min/m2) (P less than 0.05). The mean renal clearance of the drug was only 63% (range 39% to 85%) of the total body clearance, suggesting a variable but substantial nonrenal route of elimination. The intravenous administration of 50 mg/kg piperacillin every four hours results in adequate plasma concentrations for the treatment of most infections caused by gram-negative and gram-positive organisms.     

Pharmacokinetic observations of phenytoin disposition in the newborn and young infant

The pharmacokinetic profile of phenytoin (DPH) was studied in 30 infants aged 2 days to 96 weeks. The plasma DPH half-life during the first week of life in term infants was prolonged and very variable (20-7 +/- 11-6 h, mean +/-SD). Thereafter the plasma half-life was much shorter (7-6 +/- 3-5 h). In preterm infants the half-life was much longer (75-4 +/- 64-5 h) and more variable. The mean apparent volume of distribution was similar in these groups of infants: preterm newborn 0-80 +/- 0-22 l/kg, term infants during the first week of life 0-80 +/- 0-26 l/kg, and term infants greater than 2 weeks of age 0-73 +/- 0-18 l/kg. Predictions of steady-state plasma DPH concentrations, based on these kinetic parameters, were confirmed. Very low "trough" plasma DPH concentrations were observed after the 14th postnatal day in 19 infants receiving 8 mg/kg per 24 h orally. On the other hand, infants of less than one week of age receiving the same dose, especially if preterm, frequently showed drug accumulation to toxic plasma DPH concentrations. The impaired binding of DPH to newborn plasma protein was confirmed but "normal adult values" were approached by the age of 3 months. An intravenous loading dose of 8 mg/kg (sodium phenytoin) can be expected to generate a mean plasma DPH concentration of 10 mg/l (40 micronmol/l) in the newborn. Loading doses of up to 12 mg/kg were given without untoward effects. During the first week or so of life plasma Dph half-life is so variable that no fixed dosage regimen can be derived from the available data. Beyond the second week of life, however, a dose of 8 mg/kg per 24 h is probably inadequate for most infants.     

Intranasal Ketamine for Procedural Sedation in Pediatric Laceration Repair: A Preliminary Report

OBJECTIVE: The objective of this study was to compare the efficacy of 3 doses of intranasal ketamine (INK) for sedation of children from 1 to 7 years old requiring laceration repair. METHODS: This was a randomized, prospective, double-blind trial of children requiring sedation for laceration repair. Patients with simple lacerations were randomized by age to receive 3, 6, or 9 mg/kg INK. Adequacy and efficacy of sedation were measured with the Ramsay sedation score and the Observational Scale of Behavioral Distress-Revised. Serum ketamine and norketamine levels were drawn during the procedure. Sedation duration and adverse events were recorded. RESULTS: Of the 12 patients enrolled, 3 patients achieved adequate sedation, all at the 9-mg/kg dose. The study was suspended at that time as per predetermined criteria. CONCLUSIONS: Nine milligrams of INK per kilogram produced a significantly higher proportion of successful sedations than the 3- and 6-mg/kg doses.     

Pharmacokinetic observations of phenytoin disposition in the newborn and young infant.

The pharmacokinetic profile of phenytoin (DPH) was studied in 30 infants aged 2 days to 96 weeks. The plasma DPH half-life during the first week of life in term infants was prolonged and very variable (20-7 +/- 11-6 h, mean +/-SD). Thereafter the plasma half-life was much shorter (7-6 +/- 3-5 h). In preterm infants the half-life was much longer (75-4 +/- 64-5 h) and more variable. The mean apparent volume of distribution was similar in these groups of infants: preterm newborn 0-80 +/- 0-22 l/kg, term infants during the first week of life 0-80 +/- 0-26 l/kg, and term infants greater than 2 weeks of age 0-73 +/- 0-18 l/kg. Predictions of steady-state plasma DPH concentrations, based on these kinetic parameters, were confirmed. Very low "trough" plasma DPH concentrations were observed after the 14th postnatal day in 19 infants receiving 8 mg/kg per 24 h orally. On the other hand, infants of less than one week of age receiving the same dose, especially if preterm, frequently showed drug accumulation to toxic plasma DPH concentrations. The impaired binding of DPH to newborn plasma protein was confirmed but "normal adult values" were approached by the age of 3 months. An intravenous loading dose of 8 mg/kg (sodium phenytoin) can be expected to generate a mean plasma DPH concentration of 10 mg/l (40 micronmol/l) in the newborn. Loading doses of up to 12 mg/kg were given without untoward effects. During the first week or so of life plasma Dph half-life is so variable that no fixed dosage regimen can be derived from the available data. Beyond the second week of life, however, a dose of 8 mg/kg per 24 h is probably inadequate for most infants.     

Response of the fetal and newborn lamb to glucose and tolbutamide infusions

Tolbutamide infused into the chronically catheterized sheep fetus produced significant secretion of insulin. An optimal dose range of 100-200 mg/kg estimated fetal weight was demonstrated. Paired tolbutamide and glucose infusions using a square wave technique demonstrated that although early phase insulin secretion is dimished in the fetus, this is not due to an absolute deficiency of stored insulin. Tolbutamide produced peak insulin concentrations of 51.6 +/- 9.0 muu/ml by 20 min postinfusion in the fetus. When similar tolbutamide infusions were performed in neonatal lambs, qualitatively similar insulin response curves were demonstrated although peak insulin levels were much greater (260 +/- 70 muu/ml at 20 min). A fall in plasma glucose was demonstrated in both fetal and neonatal lambs (to 75 and 39% of control values, respectively) by 60 min after tolbutamide infusion. In the fetus, this fall was not associated with changes in maternal glucose concentration.     

Effect of continuous tolazoline infusion on cardiopulmonary response to dopamine in unanesthetized newborn lambs

We evaluated the cardiopulmonary interaction of tolazoline and low-, medium-, and high-dose dopamine infusion (2.7, 27, and 270 micrograms/kg/min) in 11 normal, chronically instrumented, unsedated neonatal lambs. Concomitant tolazoline and dopamine infusions caused tachycardia at all dopamine doses and blocked alpha-adrenergic-mediated increases in systemic resistance and left atrial pressure caused by medium and high doses of dopamine. Moderate doses of dopamine alone increased cardiac output. During simultaneous tolazoline infusion, dopamine increased cardiac output at both moderate and high doses. The effect of dopamine on pulmonary artery pressure was not modified by tolazoline; pulmonary pressure increased similarly with dopamine alone and with dopamine plus tolazoline. Calculated pulmonary vascular resistance rose with dopamine alone, but not with infusion of tolazoline and dopamine, because pulmonary blood flow rose in proportion to pulmonary artery pressure.     

Feasibility of using the stable isotope 25Mg to study Mg metabolism in infants

The feasibility of using isotopic techniques to study Mg absorption and metabolism was explored in three full-term human infants. 25Mg (98.8 atom %) was administered orally as an in vivo tracer. Fractional 25Mg absorption, isotope retention, endogenous fecal Mg losses, and apparent Mg exchangeable pool size were then determined under three conditions of isotope administration: 1) 20 mg 25Mg, with single feeding; 2) 20 mg 25Mg, distributed over a 24-h period; and 3) 60 mg 25Mg, over a 24-h period. Mg isotope ratios were determined by inductively coupled plasma mass spectrometry. Fractional absorption was increased in all three infants after distributed versus bolus administration at the 20 mg dose; mean (+/- SD) fractional absorption was 64.0 +/- 3.9 versus 54.3 +/- 5.9%, respectively. 25Mg retention was also more in all three infants after distributed administration (55.8 +/- 3.0 versus 44.3 +/- 1.3% of dose). At the 60-mg 25Mg dose, compared to 20 mg, fractional absorption was reduced but absolute isotope absorption more than doubled in all infants; urine isotope losses represented a similar fraction of the absorbed dose, thus, 25Mg retention also more than doubled. Compared to the results of the isotope studies, net Mg absorption and balance were uninfluenced by total Mg intake. Isotope retention with distributed isotope administration resulted in measurable isotopic enrichment of plasma and erythrocytes at 72 h (i.e. plasma isotope enrichment was 6.3-10.2 and 19.2-23.5% for the 20- and 60-mg dose, respectively). With these doses, apparent Mg exchangeable pool size ranged from 5.5 to 7.6 mmol/kg body wt; these values showed a decrease with age both within and between infants.(ABSTRACT TRUNCATED AT 250 WORDS)     

The use of short-acting nifedipine in pediatric patients with hypertension.

OBJECTIVE: To evaluate the use of short-acting nifedipine for treatment of severe hypertension in children. STUDY DESIGN: A retrospective chart review of 520 nifedipine doses given for severe hypertension in 117 pediatric patients was completed. Nifedipine dose, systolic and diastolic blood pressures before and within 2 hours of the dose, and side effects were recorded. Pre- and post-dose mean arterial pressure (MAP) and percent reductions in MAP and systolic and diastolic blood pressure were calculated. Age, dose, primary diagnosis, and use of other antihypertensive agents were examined with respect to blood pressure reduction. RESULTS: Of the doses received, 35% were associated with > or =25% reduction in MAP, a degree of MAP reduction previously associated with hypertension treatment complications. MAP percent reduction was correlated with nifedipine dose adjusted for weight (r = 0.24, P<.001). Mean nifedipine doses per kilogram were larger in patients who had > or =25% MAP reduction compared with those who had <25% MAP reduction (0.26 +/- 0.12 mg/kg vs. 0.21 +/- 0.11 mg/kg, F = 29.01, P <.001). Adolescents received lower nifedipine doses per kilogram and had lower percent reduction in blood pressure compared with younger children. No clinically significant side effects were noted after administration of nifedipine. CONCLUSION: Precipitous reductions in blood pressure are ameliorated by decreasing the initial nifedipine dose to < or =0.25 mg/kg in pediatric patients. Short-acting nifedipine use in pediatric patients with hypertension in a hospital setting is safe.     

Lavage administration of dilute recombinant surfactant in acute lung injury in piglets

In an acute lung injury model, we previously observed reversal of pulmonary dysfunction with natural surfactant administered by lavage (dose = 18 mg/kg phospholipid). The present study questioned whether a lower dose of phospholipid would be effective if a recombinant preparation rather than natural surfactant were used. Acute lung injury was induced by repeated saline lung lavage in ventilated, sedated, and paralyzed piglets. Three concentrations of recombinant surfactant were studied (low phospholipid, 1 mg/mL; medium phospholipid, 4 mg/mL; high phospholipid, 13.5 mg/mL). Control piglets received no surfactant. Thirty-five milliliters per kilogram of surfactant was administered by gravity, followed by passive drainage of excess fluid. All treatment groups retained similar volumes (4.7+/-0.3 mL/ kg), corresponding to phospholipid doses of 4+/-0.4, 22+/-3, and 67+/-4 mg/kg in low, medium, and high-dose groups, respectively. Treatment groups showed significant improvement in Pao2 compared with controls. Other parameters different from controls were found in only the medium and high-dose groups. All surfactant-treated groups showed improvement over time in Pao2, Paco2, lung resistance mean airway pressure, functional residual capacity, and dynamic compliance. These data support the statement that whereas there is a dose response to exogenous surfactant, the effective dose of recombinant surfactant in acute lung injury may be as low as 4 mg/kg phospholipid when administered by lavage.     

Pharmacokinetic and pharmacodynamic study of midazolam in children during esophagogastroduodenoscopy

We undertook a prospective study to evaluate the relationship between the onset and degree of sedation and the midazolam plasma concentration in children between 6 and 18 years of age during esophagogastroduodenoscopy. Thirteen boys and seven girls (median age 13.5 years) were studied. Midazolam was injected intravenously for 5 minutes, and the dose was titrated to sedation or a maximum dose of 0.1 mg/kg was given. Plasma midazolam concentration was determined just before and at 5, 10, 15, 30, 45, and 60 minutes after the start of midazolam injection. The patient's level of sedation was evaluated by an assistant at each blood sampling time. Clearance, volume of distribution, and terminal elimination (beta) half-life were estimated from a biexponential fit of the serial plasma midazolam concentrations. Mean beta half-life of midazolam was 47 +/- 26 minutes and mean clearance was 10.0 +/- 5.0 ml/min per kilogram of body weight. Maximum level of sedation occurred at 5 minutes after initiation of the injection and corresponded to a mean peak midazolam serum concentration of 229 +/- 39 micrograms/L. Thereafter, a decline of mean sedation scores paralleled the decrease in midazolam concentration. Mean oxygen saturation remained greater than 94% during the study. We conclude that children metabolize and excrete midazolam more rapidly than adults do and that sedation adequate for endoscopy is safely achieved in the majority of children with a midazolam dose of 0.05 to 0.1 mg/kg and a mean peak midazolam concentration greater than 200 microgram/L.     

Metoclopramide pharmacokinetics and pharmacodynamics in infants with gastroesophageal reflux

The pharmacokinetics and pharmacodynamics of metoclopramide oral solution were evaluated in six infants (0.9-5.4 months) with gastroesophageal reflux (GER) following the initial and 10th dose of 0.15 mg/kg administered every 6 h. Metoclopramide pharmacodynamics were assessed by pre- and post-dose comparison of esophageal pH monitoring data and clinical evaluation of improvement in GER symptoms. A significant reduction in the number of episodes of pH less than 4 for greater than 5 min and the longest episode of GER was seen between the predose and 10th dose (steady-state) evaluation periods. Four of the 6 patients had a 75% reduction in reflux time and demonstrated improvement in clinical symptoms by the 10th dose. Metoclopramide pharmacokinetics were best characterized by a one-compartment open model following the first and 10th doses. Metoclopramide serum concentrations (mean +/- SD) ranged from 56.2 +/- 23.5 to 32.7 +/- 13.2 ng/ml within a 6-h dosing interval at steady state. There were no significant differences between the first versus tenth dose values for Tmax (2.0 +/- 0.5 versus 2.2 +/- 0.4 h), Kel (0.14 +/- 0.03 versus 0.17 +/- 0.04 h-1), Vdarea (4.9 +/- 0.4 versus 4.4 +/- 0.6 L/kg), or clearance (0.66 +/- 0.16 versus 0.67 +/- 0.13 L/h/kg). The youngest subject (3.5 weeks) had a metoclopramide t 1/2 of 23.1 h following initial dose, which decreased to 10.3 h at steady-state. Care should be exercised in using the 0.15 mg/kg dose in infants less than 1 month of age as prolonged clearance may produce excessive serum concentrations.     

Single dose pharmacokinetics of pleconaril in neonates. Pediatric Pharmacology Research Unit Network

BACKGROUND: Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection. METHODS: Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years). RESULTS: Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (Cmax 686.7 vs. 617.1 ng/ml), elimination half-life (t 1/2; 4.6 vs. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V(dss)/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg). In addition, no correlation was observed between postconceptional age and AUC, V(dss)/F, t 1/2 or Cl/F for pleconaril. Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V(dss)/F (9.3 vs. 4.7 liters/kg), dose-normalized Cmax, (686.7 vs. 1272.5 ng(ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t 1/2 between neonates and children was not appreciably different. CONCLUSIONS: The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates. Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection.     

Gentamicin in the newborn

Serum gentamlcin assays were performed on 116 paired samples of sera from 99 infants, whose birthweights ranged from 740 g to 4400 g.
The gentamicin levels obtained were then studied in relation to the dosage used, the time interval between doses and the birthweight.
Peak serum levels obtained were related to the dosage per kilogram, but not to either birthweight or interval between doses.
A comparison of trough levels between infants over 2500 g, and under 2500 g, on a 12th hourly regime, showed me smaller infants had statistically significant higher trough levels (p<0.001).
In the infants under 2500 g there was a statistically significant difference in trough levels between 12th hourly and daily single dose regimes (p<0.001), showing evidence of retention of drug with a 12th hourly interval.
In order to obtain optimal drug levels in the immediate neonatal period, results of this study suggest infants under 2000 g receive a single daily dose of approximately 3 mg/kg whereas those over 2500 g have 2.5–3 mg/kg/dose, given 12th hourly.     

Single dose pharmacokinetics of linezolid in infants and children

BACKGROUND: Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. METHODS: Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. RESULTS: Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+/- SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 +/- 1.1 h, 0.34 +/- 0.15 liter/h/kg and 0.73 +/- 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. CONCLUSION: Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.     

Interactive ventilatory effects of two respiratory stimulants, caffeine and doxapram, in newborn lambs.

Caffeine and doxapram are two respiratory stimulants used in the treatment of apnea in newborns. When used concurrently, these drugs may produce interactive effects on the control of breathing in the newborn. The ventilatory effects of these drugs, given alone or together, were measured during 150 min of drug infusion in two groups of awake lambs 2-5 days old. The first group (n = 5) received a caffeine loading dose of 10 mg/kg followed by a maintenance dose of 0.1 mg/kg/h and incremental doses of doxapram: 0.25, 0.5, 1.25 and 2.5 mg/kg/30 min. The second group (n = 5) received a doxapram loading dose of 5.5 mg/kg followed by a maintenance dose of 1 mg/kg/h and incremental doses of caffeine: 2.5, 5.0, 7.5 and 10.0 mg/kg/30 min. In the first group, ventilation increased after the caffeine loading dose from 566 +/- 55 to 680 +/- 74 ml/kg/min (plasma caffeine = 14.7 +/- 1.6 mg/l) and progressively increased with the addition of incremental doses of doxapram up to 1,000 +/- 108 ml/kg/min at 2.5 mg/kg of doxapram (p less than 0.001 compared to baseline and caffeine loading dose). In contrast, in the second group, the doxapram loading dose markedly increased ventilation from 582 +/- 50 to 936 +/- 75 (p less than 0.002 and p less than 0.04 compared to caffeine loading dose) at plasma doxapram of 5.3 +/- 0.8 mg/l, but incremental doses of caffeine had no effects. We conclude that doxapram exerts a brisk and powerful respiratory stimulant effect and produces an additional dose-dependent ventilatory response when added to caffeine.     

Cardiovascular effects of tolazoline and ranitidine.

The cardiovascular effects of ranitidine were studied in 12 children with congenital heart disease who had been given tolazoline as a pulmonary vasodilator. Ranitidine was given as prophylaxis against gastrointestinal haemorrhage induced by tolazoline. Tolazoline 1-2 mg/kg caused significant falls in pulmonary and systemic vascular resistances and a rise in heart rate. After intravenous administration of ranitidine 3 mg/kg both resistances rose again and neither resistance then differed significantly from baseline levels. Heart rate also fell and the final heart rate was significantly below baseline levels. We conclude that there may be H2 receptors within the pulmonary and systemic circulations and that tolazoline may mediate some of its effects through these H2 receptors rather than by alpha adrenergic receptor blockade. The safety of H2 blockade in children, particularly those with pulmonary hypertension, needs further investigation.