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Biomedical subjects

S M MacLeod

Publications and source records attributed to S M MacLeod.

At least 55 records · Page 3Linked to original sources
PubMed1986

Pharmacokinetics of cimetidine after subchronic administration.

The influence of cimetidine on its own pharmacokinetics after subchronic administration was assessed in 8 healthy volunteers, aged 26-29 years. On control Day 1, each subject received cimetidine 300 mg i.v., and serum and urine samples were obtained. Each subject was initiated on cimetidine 600 mg b.i.d. orally for 2 weeks. There were 3 further study days repeated after 1 and 2 weeks of cimetidine dosing and 1 week after stopping cimetidine. There was no significant difference in the mean total body clearance of cimetidine among the 4 study days. Mean elimination t1/2 beta and V beta were similarly unchanged. However mean renal clearance (CLR) and fe were significantly increased following 2 weeks of drug dosing (CLR 5.41 ml X min-1 X kg-1; fe 0.61) compared to control (CLR 4.00 ml X min-1 X kg-1; fe 0.48). Although the non renal clearance was reduced from control values of 4.29 to 3.51 ml X min-1 X kg-1 following 2 weeks of dosing the difference was not significant. Dosage adjustment of cimetidine appears unnecessary after short-term dosing in the presence of normal renal function.

Administration, Oral↗
PubMed1986

Determinants of drug disposition in man.

This article reviews some of the important determinants of variation in drug disposition such as age, gender, body weight, diet, environmental influences, drug - protein interactions, compliance, drug - drug interactions, endogenous substances, disease states, circadian variation and genetics.

Adult↗
PubMed1986

Unexpected alterations in fentanyl pharmacokinetics in children undergoing cardiac surgery: age related or disease related?

We assessed the pharmacokinetics of fentanyl in 19 infants and children undergoing cardiac surgery for correction of tetralogy of Fallot, A-V-canal and transposition of the great arteries. Distribution T1/2 (10.2 +/- 2.4 min) and total body clearance (13.3 +/- 6.5 ml/kg/min) were similar to adult values. An elimination t1/2 (102 +/- 85 min) shorter than in adults is readily explained by the significantly smaller distribution volume of the drug (1,203 +/- 777 ml/kg). Good correlation was found between distribution volume (Vss) and elimination t1/2 (r = 0.86, p less than 0.01) and between Vss and age of patients with tetralogy of Fallot (r = 0.85, p less than 0.01). However, older children with Fallot's had higher values of PO2 due to a milder condition (r = 0.89, p less than 0.01); consequently PO2 correlated positively with Vss (r = 0.76, p = 0.05). Fentanyl total body clearance (TBC) tends to decrease with age in these patients (r = 0.66, p = 0.05) similar to noncardiac children. Our studies suggest that the alterations in the distribution volume of fentanyl in these children may largely depend upon the severity of the hemodynamic disturbance whereas TBC of the drug may depend on their age.

Adolescent↗
PubMed1986

Intravenous paraldehyde for seizure control in newborn infants.

We studied 14 newborn infants with seizures after birth asphyxia or other causes. Paraldehyde was given as a 200 mg/kg IV bolus followed by an infusion of 16 mg/kg/h (10 cases), or as a 400 mg/kg bolus (4 cases). Serum concentrations of paraldehyde were higher in periods of adequate seizure control than in periods of little or no response. Paraldehyde serum concentrations above 10 mg/dl were associated with anticonvulsant effects and were achieved in most neonates with a 2-hour infusion of 200 mg/kg/h. If there is no effect, serum concentrations are probably below 10 mg/dl and an additional 200 mg/kg can be given safely over 1 hour.

Female↗
PubMed1986

Pharmacokinetics of intravenous clindamycin in newborn infants.

We studied 12 newborn infants (gestational ages 26-39 wk [mean +/- SD, 30.6 +/- 4.7]; birth weight 640-2700 g, [mean, 1,322 +/- 688]; postnatal age 1-24 days [mean, 9.6 +/- 8.5]) who received clindamycin phosphate for suspected or proven necrotizing enterocolitis (ten patients) or suspected anaerobic septicemia (two patients) in doses of 3.2-11 mg/kg every six hours. Range of mean serum concentration of clindamycin at steady state was between 12.7 and 40 micrograms/ml (therapeutic range = 2-10 micrograms/ml). High concentrations could be attributed to elimination T1/2 (6.3 +/- 2.1 hr) 100% longer than in older children or adults. Clindamycin clearance (61.6 +/- 31.6 hr ml/kg/hr) was lower than in older children or adults. Because of the observed prolongation in T1/2 and correspondingly lower clearance, the IV dose of clindamycin in newborn infants should be reduced to 15-20 mg/kg/day given in four daily doses.

Clindamycin↗
PubMed1985

Altered PABA pharmacokinetics in cystic fibrosis. Implications for bentiromide test.

The bentiromide test has been proposed as a useful noninvasive method for assessing exocrine pancreatic function in cystic fibrosis (CF) patients. Following oral administration, this peptide is selectively cleaved by pancreatic chymotrypsin liberating PABA which is passively absorbed. Recent studies have suggested that PABA measured in plasma is superior to the more established method of estimating urinary recovery of this marker. However, in using the plasma test in CF patients, one makes the assumption that the PABA marker has similar distribution and elimination patterns in normal and CF subjects. Since many drugs display altered pharmacokinetics in CF patients, we studied the disposition of PABA following ingestion of free PABA in six controls (age 19-28 years) and 18 CF patients (13-18 years; seven steatorrheic and 11 nonsteatorrheic). Elimination of T1/2 of PABA was significantly shorter in CF patients (58 +/- 21 min) compared to controls (93.5 +/- 28) (P less than 0.005). PABA clearance was similar in the control and CF patients (2.99 +/- 1.21 and 3.27 +/- 1.02 ml/min/kg, respectively). PABA distribution volume was smaller, although not significantly so, than in the controls (268 +/- 107 vs 376 +/- 140 ml/kg). Good correlation was found between PABA distribution volume and T1/2 (r = 0.51 P less than 0.02). Our simulation data suggest that altered pharmacokinetics of PABA in CF patients would cause their PABA levels to be 7% lower than controls at 90 min, 18% at 120 min, 29% at 150 min, and 38% at 180 min.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminobenzoic Acid↗
PubMed1985

Assessment of glomerular filtration rate and effective renal plasma flow in cystic fibrosis.

A study was conducted to examine renal function in 10 healthy control subjects and eight patients with cystic fibrosis in stable condition. Sequential bolus injections of 99mTc-DTPA and 125I-OIH were administered to assess glomerular filtration rate and effective renal plasma flow, respectively. Blood was subsequently collected for 3 hours, and urine for 24 hours. Renal clearances of both radioisotope markers were virtually identical in patients and controls. Inasmuch as neither glomerular filtration rate nor effective renal plasma flow was enhanced in patients with cystic fibrosis, increased clearance of drugs in these patients is unlikely to be the result of enhanced glomerular filtration or tubular secretion.

Adolescent↗
PubMed1985

Temporal variation in the disposition of theophylline and its metabolites.

The temporal aspects of theophylline disposition are of interest, as there are predictable time-dependent fluctuations in the pulmonary function of patients with asthma and theophylline serum concentrations may vary throughout a 24-hour period. We studied the extent to which there are significant temporal changes in theophylline kinetics and the relative contribution of distribution, metabolism, and excretion to this phenomenon. Eight healthy men received an intravenous dose (6 mg/kg) of theophylline at 8 AM and 8 PM at 1-week intervals. Serum and urine were analyzed for theophylline and its three major metabolites by HPLC. Distribution volumes and total body and nonrenal clearances showed no differences between morning and evening dosing. The elimination rate was 12% greater after morning dosing. Renal clearance was 24% greater after morning dosing and was accompanied by an increased excretion fraction of unchanged theophylline. Based on total urinary metabolite excretion and the metabolite serum AUCs, there was no evidence of time-dependent variation in theophylline biotransformation. Although theophylline renal clearance is greater after morning dosing, it is only a small fraction of the overall drug elimination and does not change the total body clearance after morning or evening dosing.

Absorption↗
PubMed1985

Organization and efficacy of a therapeutic drug monitoring consultation service in a pediatric hospital.

On July 1, 1982, a therapeutic drug monitoring (TDM) consultation service was instituted in the hope of improving the decision-making of clinicians with respect to drug therapy. Thirteen different drugs are monitored daily, with an average load of 1,600 inpatient samples per month. The team consists of clinical pharmacology fellows and staff who are available 7 days a week to monitor all drug levels that are outside the putative therapeutic range. In order to evaluate the efficacy of this service in preventing development of potentially toxic drug concentrations, the TDM data from July 1982 to December 1983 have been reviewed. The percentage of toxic levels from the total sample load was significantly lower in the period of July-December 1983 compared with July-December 1982 at the beginning of the service (2.25% vs. 4.25%, p less than 0.01). Since January 1983, the percentage has been maintained at less than 3%. A TDM consultation service can help to optimize the use of drug monitoring data by physicians and may lead to improved prescribing in a hospital setting.

Adolescent↗
PubMed1985

Fentanyl pharmacokinetics and hemodynamic effects in preterm infants during ligation of patent ductus arteriosus.

A bolus of 30 micrograms X kg-1 fentanyl was given to nine preterm infants (gestational age 31.8 +/- 4.7 weeks, weight 1100 +/- 309 g) for induction of anesthesia for ligation of a patent ductus arteriosus. Thirty minutes after the injection, fentanyl plasma concentrations were between 7.7 and 13.6 ng X ml-1. Elimination half-life was 6-32 hr (mean +/- SD, 17.7 +/- 9.3). Systolic blood pressure remained stable throughout surgery. There was a gradual increase in heart rate from 159 +/- 12 min-1 at the time of skin incision to 173 +/- 15 min-1 at the time of skin closure (P less than 0.05). Fentanyl plasma concentrations remained virtually unchanged between 30 min (10.6 +/- 1.9 ng X ml-1) and 120 min (9.6 +/- 1.6 ng X ml-1); whereas at the end of surgery most infants moved and breathed spontaneously. This phenomenon can be explained by redistribution of fentanyl from brain into pharmacodynamically inert tissues.

Anesthesia, Intravenous↗
PubMed1985

Evaluating a filter device used for intermittent intravenous drug delivery to newborn infants.

Injection of aminoglycosides into a filter chamber was compared with retrograde injection into i.v. tubing for delivery of intermittent drug dosages at low infusion rates in neonates. In 50 infants receiving gentamicin sulfate and 21 receiving amikacin sulfate for at least two days by retrograde i.v. infusion, peak and trough concentrations of the drugs were obtained. A subsequent dose was administered using the filter device, and peak and trough concentrations were obtained. For each infant, the difference between trough and peak concentration (delta C) was compared for the two methods. In vitro testing for gentamicin concentration was performed using the same infusion systems (10 trials for each system). For both in vivo and in vitro testing, the infusion flow rate was 10 mL/hr. For infants receiving gentamicin, delta C was greater for the filter device in 32, greater for retrograde infusion in 13, and equal in 5. The mean gentamicin delta C was significantly greater for the filter chamber method than for retrograde infusion. The in vitro studies showed significantly better gentamicin recovery with the filter device than with retrograde infusion. For amikacin, delta C was greater for the filter device in 15 infants, but the mean amikacin delta C was not significantly different for the two methods. At low flow rates commonly used in infants, the infusion system using the filter device was equal to or superior to retrograde infusion for ensuring complete delivery of intermittent drug doses.

Amikacin↗
PubMed1985

Postmortem redistribution of digoxin in rats.

Adult male Wistar rats were treated with either 0.1 or 3 mg/kg body weight X day of digoxin for five days, then killed and stored at 4 degrees C for 12 h in an attempt to mimic the normal preautopsy procedures in our hospital. In rats treated with 0.1 mg/kg body weight X day, the antemortem serum digoxin concentrations (SDC) were 1.1 +/- 0.4 ng/mL while the 12-h postmortem concentration was markedly increased (16.3 +/- 5.9 ng/mL) (P less than 0.01). In rats treated with 3 mg/kg body weight X day, SDC was not changed significantly (11.2 +/- 4.8 ng/mL antemortem and 13.3 +/- 6 ng/mL postmortem). Postmortem redistribution of digoxin was assessed by injection of 125I-labelled digoxin with or without pretreatment with the unlabelled drug. The results indicate that after death passive redistribution of digoxin may take place. When the SDC are within the therapeutic or low toxic range, digoxin may reenter the blood. High antemortem serum concentrations of digoxin may prevent such passive redistribution. Therefore, antemortem digoxin intoxication cannot be reliably inferred on the basis of high postmortem levels of the drug. Digoxin intoxication can be ruled out when postmortem SDC remain within the therapeutic range. The above changes cast doubt on some of the forensic and cardiologic literature, which has in the past been based on incorrect assumptions concerning postmortem behavior of digoxin.

Animals↗
PubMed1985

Optimization of gentamicin therapy in very low birth weight infants.

In order to optimize gentamicin (G) therapy we studied G pharmacokinetics in 48 preterm infants (gest. age 31.6 +/- 3.4, range 25-37 wk; birth weight 1.5 +/- 0.5 kg, range 0.7-2.5 kg). They received IV G twice daily (5.2 +/- 0.6 mg/kg/day). After at least 2 days of treatment trough and peak levels were measured for 2 successive doses. Trough levels were significantly higher in infants less than 1 kg receiving 5 mg/kg/day than in other infants (1-2.5 kg) who received the same dose (3.1 +/- 1.0 vs. 2.3 +/- 0.5 micrograms/ml; p less than 0.01). Mean G t 1/2 was significantly longer in infants under 1 kg than in those weighing 1-2.5 kg (7.9 +/- 1.9 and 6.5 +/- 1.6 hr, respectively; p less than 0.01). These differences could be attributed to lower G clearance in infants less than 1 kg (31 +/- 6 vs. 39 +/- 8 ml/kg/hr; p less than 0.005). There was no difference in G distribution volume between less than 1 kg and 1-2.5 kg infants (0.35 +/- 0.07 and 0.38 +/- 0.13 L/kg, respectively). A correlation was found between clearance and t 1/2 for the total group (r = 0.57, p less than 0.01). No correlation was detected between BUN and clearance or between gestational age and clearance. Our data suggest that G dose in infants less than 1 kg should be reduced to 3.5-4 mg/kg/day in order to avoid excessive levels associated with nephrotoxicity.

Birth Weight↗
PubMed1985

Theophylline pharmacokinetics in adolescent females following coadministration of oral contraceptives.

The influence of 3-9 months of combined low dose oral contraceptives on theophylline pharmacokinetics was studied in 10 adolescent females (age 15-18 years, mean +/- SD 17 +/- 1) and compared to 10 age-matched control subjects (age 13.8-19 years, mean +/- SD 16.5 +/- 1.6). The distribution volume (0.44 +/- 0.06 L/kg in control vs. 0.44 +/- 0.09 L/kg oral contraceptive group), total body clearance (0.78 +/- 0.13 ml/kg/min vs 0.78 +/- 0.18 ml/kg/min) and elimination T 1/2 (402 +/- 78 min vs. 409 +/- 126 min) were identical in the two groups. It appears that during the first 3-9 months of low dose oral contraceptive treatment, these steroids do not alter the pharmacokinetic behaviour of theophylline in adolescent females.

Adolescent↗