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Biomedical subjects

S M MacLeod

Publications and source records attributed to S M MacLeod.

At least 73 records · Page 4Linked to original sources
PubMed1984

Sequestration of fentanyl by the cardiopulmonary bypass (CPBP).

Immediately following the connection of pediatric patients to cardiopulmonary bypass we have consistently observed a steep decrease in fentanyl plasma concentration (74 +/- 8.7%) (mean +/- SD), much greater than would have been expected from hemodilution alone (50.6% +/- 12.0%) (p less than 0.0001). Priming of the pump with 20 ng/ml of fentanyl before connection to the patients did not prevent this phenomenon. In order to study the possibility that fentanyl is sequestered by the bypass, levels of the primed drug in the bypass were assessed before connecting the pump to the children and a steep fall from 20 ng/ml to zero was shown before initiation of bypass. Pharmacokinetic assessment of fentanyl in a closed pump circuit showed that levels of 120 ng/ml fall to 2 ng/ml within 3 min and remain stable at the lower concentration for at least 30 min. Further studies have identified the membrane oxygenator as the major site of fentanyl sequestration. Concentrations across the membrane fall from 120 ng/ml to 10 ng/ml. The attached siliconized tubing is associated with a minor binding effect sufficient to reduce concentrations from 110 to 84 ng/ml. The pvc tubing, aluminium heat exchanger and plastic reservoir had no binding effect on fentanyl. The possibility that a decrease in fentanyl protein binding caused the fall in serum concentration was checked in 5 patients undergoing open heart surgery. After initiation of the cardiopulmonary bypass, there was a significant decrease in albumin serum concentrations from 32.0 +/- 2.3 mM to 15.0 +/- 1.6 mM (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

Difficulty in achieving therapeutic serum concentrations of salicylate in Kawasaki disease.

We investigated 49 children (33 boys), mean (+/- SD) age 2.6 +/- 1.8 years (range 8 months to 8 years), who had Kawasaki disease treated with acetylsalicylic acid (ASA) 30 to 180 mg/kg. There was good correlation between salicylate doses and serum concentrations (r = 0.69, P less than 0.01); however, large variability existed. With doses less than 80 mg/kg/day there was not a single therapeutic salicylate serum concentration (greater than 20 mg/dl). In children receiving 100 to 110 mg/kg/day 55% of the serum concentrations were subtherapeutic. The same pattern persisted with doses greater than 120 mg/kg/day; however, 28% of levels were in the toxic range (greater than 30 mg/dl). There was no evidence of salicylate poisoning in the group; three children receiving greater than 100 mg/kg/day had aspirin-induced gastritis. An additional four children, studied prospectively, received ASA 80 to 180 mg/kg/day. The fraction absorbed was 14% to 60%, which may be compared to a normal 85% to 90% absorption. Salicylate renal clearance in these children (7.3 to 21 ml/kg/hr) was lower than in hyperthermic children. Their steady-state serum salicylate concentrations were subtherapeutic (7 to 11.5 mg/dl). The high ASA dose needed to overcome the impaired absorption should be accompanied by frequent monitoring of levels because of the unpredictable changes in absorption.

Aspirin↗
PubMed1984

Cloxacillin absorption and disposition in cystic fibrosis.

Because of reports of lowered antibiotic serum concentrations in patients with cystic fibrosis (CF), a bioavailability and pharmacokinetic study of cloxacillin was conducted in 12 control and 16 patients with CF after intravenously and orally administered doses of cloxacillin 25 mg/kg. The patients had mild to moderate CF and were in stable condition. Significantly lower serum concentrations in CF were a result of a 78% increase in total body clearance (P less than 0.005) and a 38% increase in the apparent volume of distribution (P less than 0.025). The bioavailability in CF (0.50) was not significantly different than in controls (0.38), but more variability was seen in the group with CF. After the intravenously given dose the fraction of cloxacillin excreted in the urine unchanged was similar in controls (0.644) and patients with CF (0.547). Compared with that in the control subjects, the mean renal clearance in patients with CF was 30% greater (P less than 0.10) and the nonrenal clearance was 144% greater (P less than 0.07). Enhanced nonrenal clearance explains most of the demonstrated difference between serum concentrations in controls and patients with CF after identical weight-adjusted doses. The data suggest enhanced cloxacillin biotransformation in CF.

Administration, Oral↗
PubMed1984

Digoxin toxicity associated with amiodarone therapy in children.

The addition of amiodarone to digoxin therapy in nine children caused a sharp increase in digoxin serum concentrations (68% to 800%) in the presence of preserved serum creatinine and BUN concentrations. Digoxin half-life was prolonged. Digoxin accumulation could be attributed in part to the decrease in the renal clearance of digoxin resulting from inhibited tubular secretion of the drug and to the reduction in the distribution volume of digoxin caused by amiodarone. Creatinine clearance was not affected by amiodarone. This interaction appears to be more acute in children than in adults, presumably because of the more important role of the renal tubular secretion of digoxin in children. Whenever digoxin and amiodarone therapy are combined, the digoxin serum concentration should be monitored carefully, with appropriate reduction of the digoxin dose.

Adolescent↗
PubMed1984

Ceftazidime disposition in acute and stable cystic fibrosis.

Ceftazidime disposition after an intravenous dose of 50 mg/kg infused over 20 min was followed in 10 subjects with cystic fibrosis (CF) hospitalized with acute pulmonary exacerbations and in 10 healthy subjects. Serum ceftazidime elimination t 1/2 decreased from 105.3 +/- 12.4 min (mean +/- SD) in controls to 90.0 +/- 11.1 min in subjects with CF. Calculated distribution volumes were both larger in subjects with CF. When normalized for body surface area, total body clearance (Cl) was 41.9% greater in the CF group (142.4 +/- 16.9 and 100.5 +/- 10.3 ml/min/1.73 m2). Normalization for body weight revealed 64.8% greater Cl in subjects with CF. Fraction of dose recovered in urine was of the same order for each group, while renal clearance (ClR) was 40.9% greater in the subjects with CF (130.1 +/- 11.4 and 92.7 +/- 11.6 ml/min/1.73 m2). Five subjects with CF were restudied while infection-free 119 to 219 days after the original study day. With the exception of a 10% increase in the volume of distribution at steady state while infection-free, kinetic parameters were much the same. No changes in Cl or ClR were evident from one study day to the next. Acute pulmonary infection does not appear to alter ceftazidime clearance in CF. The mechanism underlying increased ceftazidime Cl and ClR in CF is not apparent from the present data.

Adolescent↗
PubMed1984

Pharmacokinetics of fentanyl in children with renal disease.

Two cases of fentanyl anesthesia in children with renal diseases are described. In a case of end stage renal failure, the pharmacokinetic parameters during cardiac surgery were similar to 18 children from the same age group with normal renal function. In a case of Wilm's tumor, there was an unusually prolonged elimination half-life of fentanyl and smaller distribution volume as compared to pediatric parameters during fentanyl anesthesia.

Anesthesia, Intravenous↗
PubMed1984

Characteristics of the digoxin-quinidine and digoxin-verapamil interactions in the rat kidney.

Recently quinidine and verapamil have been reported to cause toxic accumulation of digoxin due to mainly decrease in the renal secretion of the cardiac glycoside. Because these drugs do not alter GFR, it was assumed that the renal tubular secretion of digoxin is inhibited by them. We studied the characteristics of the renal cortical specific binding for digoxin in the rat kidney, and the antagonistic effects of quinidine and verapamil on digoxin uptake by the kidney slices. Specific binding of digoxin was documented in the renal slices with B max of 42.34 pmol/gr and Kd of 7.6 pmol/gr. The addition of quinidine in therapeutic concentrations (6.7 microM) caused a mean 23% reduction of digoxin uptake by the kidney slice (p less than 0.01). When quinidine concentrations were elevated above the therapeutic range there was additional reduction in digoxin uptake; 84 mM quinidine caused a mean 61% reduction (p less than 0.0001). A similar interaction was documented with verapamil; therapeutic concentrations (550 mM) of the drug caused 15% reduction in digoxin uptake. Further increase in verapamil concentration resulted in additional reduction in digoxin uptake; the maximal concentration used (42 microM) caused 60% decrease in uptake (p less than 0.0001). The inhibition of the renal uptake of digoxin caused by quinidine and verapamil in conjunction with the pharmacokinetic studies, which have shown that both drugs decrease the renal clearance of digoxin without changing GFR, support the suggestion that they inhibit the renal tubular secretion of digoxin.

Animals↗
PubMed1984

Influence of bioavailability on the calculated Michaelis-Menten parameters of phenytoin in children.

In spite of the fact that therapeutic and toxic ranges of phenytoin are well defined, it is still often difficult to calculate an optimal dosage regimen because of the nonlinear saturable kinetics of the drug. Predictions are much more complicated when impaired bioavailability exists. We estimated individual Michaelis-Menten pharmacokinetic parameters from two reliable steady-state serum concentrations of phenytoin following two different drug dosages in 13 epileptic children treated with a preparation that has been shown to be poorly absorbed. Their calculated average Vmax (the maximal rate of elimination) was significantly higher than the average for their age (12.21 and 9.28 mg/kg/day, respectively) (p less than 0.05). The impaired bioavailability did not affect the values of Km. In the six children who needed a third adjustment of dosage, the observed steady-state serum levels of phenytoin with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with the predicted levels (r = 0.97, p less than 0.01). Our data suggest that Michaelis-Menten kinetics can be used to predict phenytoin levels even when impaired bioavailability exists, providing that the fraction of absorption is constant.

Absorption↗
PubMed1984

Pediatric fentanyl dosing based on pharmacokinetics during cardiac surgery.

The pharmacokinetics of fentanyl (F) were studied in 10 children, age 5 months-4.5 yr (mean 19 months) undergoing cardiac surgery with cardiopulmonary bypass ( CPBP ). They suffered from transposition of the great arteries (6), tetralogy of Fallot (2), and atrio-ventricular (A-V) canal (2). Induction of anesthesia included a bolus of 50 micrograms X kg-1 X min-1 F followed by a continuous F infusion of either 0.15 micrograms X kg-1 X min-1 (4 patients) or 0.3 micrograms X kg-1 X min-1 (6 patients). The F infusion was discontinued when cardiopulmonary bypass was started, 81-141 min (mean 112 min) along with deep hypothermia. Blood was collected throughout surgery from an indwelling radial arterial catheter and plasma concentration of F was assayed by GLC. F plasma concentrations after 30 min were 2-3-fold higher than reported with the same regimen in adults. The calculated values for t1/2 alpha (12 +/- 9 min) (mean +/- SD), t1/2 beta (141 +/- 98 min) and total body clearance (12.8 +/- 7.3 ml X min-1 X kg-1) were similar to adult values. The significantly lower steady-state volume of distribution observed in children with intracardiac shunts (1385 +/- 875 ml X kg-1) compared to reported values for adults (3200-6000 ml X kg-1) explains the higher F plasma concentrations achieved in these children. Cardiopulmonary bypass produced a mean 70% (range, 56-89%) decrease in plasma F, significantly higher than would be expected from hemodilution alone. Studies of F disposition in the CPBP demonstrated that F is bound to the pump.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiopulmonary Bypass↗
PubMed1984

Effects of indomethacin on digoxin pharmacokinetics in preterm infants.

Indomethacin is commonly coadministered with digoxin for the treatment of patent ductus arteriosus (PDA) in preterm infants. The combination of digoxin that is eliminated almost exclusively by the kidney and indomethacin, which tends to reduce renal function, has potential hazards. We report 11 preterm infants (gestational age 25-33 week) treated with digoxin for PDA in whom a standard indomethacin therapy (mean of total dose = 0.32 mg/kg) resulted in a significant elevation of serum digoxin to potentially toxic levels (from 2.2 +/- 0.7 ng/ml to 3.2 +/- 0.7) (P less than 0.001). This phenomenon correlated well with decreased urine output (from 86 +/- 34 ml to 43 +/- 24 per 24 hour) (P less than 0.001) following indomethacin. No significant change was found in serum creatinine concentration pre- and post-indomethacin. Digoxin half-life was significantly prolonged (mean 97 +/- 17 hour) following indomethacin therapy as compared with an age matched control group (mean half-life 43 +/- 19 hour) (P less than 0.05). Our data suggest that when indomethacin is added to digoxin therapy, the digoxin dosage should be reduced by 50% until urine output and digoxin serum levels can be better assessed.

Digoxin↗
PubMed1983

Measurement of amphotericin B in serum or plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the analysis of amphotericin B in 25 microliters of serum or plasma is described. The procedure involves the addition of the internal standard, p-nitrobenzyloxyamine, to the sample followed by a precipitation of protein with acetonitrile. The supernatant is directly injected into a chromatograph attached to a reversed-phase mu Bondapak (Waters) column containing C18 packing. The mobile phase is a 60 : 40 mixture of a sodium acetate buffer (10 mM, pH 7.0)--acetonitrile, and we employ a flow-rate of 1.5 ml/min and a detection wavelength of 405 nm. Total analysis time per sample is 10 min. Coefficients of variation were found to be less than 4% for concentrations less than 2 mg/l. Analytical recoveries were between 75 and 80%. No drug or drug metabolite interference was found. The method will be used to study pharmacokinetic and pharmacodynamic data in a pediatric population.

Amphotericin B↗
PubMed1983

Corticosteroid treatment of laryngotracheitis v spasmodic croup in children.

We compared the efficacy of high-dose dexamethasone sodium phosphate (0.6 mg/kg) in laryngotracheitis (LT) v spasmodic croup (SC) in 72 children (age range, 8 months to 8 years) using a double-blind randomized protocol that measured the individual change in respirations as an objective variable to evaluate the outcome. Administration of dexamethasone did not change the respirations in the patients with LT and significantly decreased the respirations in the patients with SC, compared with the placebo group. Since, in most cases, the pediatrician will be able to differentiate between LT and SC at admission by history and clinical signs, it seems that steroid treatment should be avoided in cases of LT and may be of benefit in some cases of SC.

Acute Disease↗
PubMed1983

Kinetics of CSF phenytoin in children.

The efficacy of intravenous phenytoin for the treatment of status epilepticus is related to the rapid entry of phenytoin into brain parenchyma. There is no information concerning the correlation between phenytoin serum and CSF concentrations in children, and the application of CSF data to clinical use. We report 7 children (2-11 yrs) who were treated or exposed to phenytoin in doses between 10.5-230 mg/kg. Lumbar puncture was performed 9 times in 6 of the patients. In one patient, an intraventricular catheter permitted successive assessment of CSF phenytoin concentrations. The ratio of CSF/serum phenytoin concentrations was 0.16 +/- 0.08, with gradual increase over the first 8 hours as the serum phenytoin concentration decreased. There was good correlation between therapeutic outcome and CSF phenytoin levels higher than 2 mcg/ml. In one patient the coma state secondary to phenytoin intoxication was associated with high CSF concentration (6 mcg/ml).

Age Factors↗
PubMed1983

High-pressure liquid chromatographic analysis of ceftazidime in serum and urine.

A rapid and sensitive high-pressure liquid chromatographic procedure was developed for quantitative analysis of a new semisynthetic cephalosporin, ceftazidime, in serum and urine. A good linear relationship was established between peak height and the amount of ceftazidime injected over a concentration range of 1.9 to 30 micrograms/ml. Recovery was approximately 90% at concentrations of 3, 15, and 30 micrograms/ml. The method is specific for ceftazidime, with no interference noted from 11 other beta-lactam antibiotics tested. The assay is accurate, reproducible, and useful for pharmacokinetic studies in humans as demonstrated in two subjects.

Ceftazidime↗