Case-control studies on effects of drugs in pregnancy rely heavily on maternal recall. At the Motherisk Program in Toronto we counsel women during early pregnancy on the risk of drug and chemical exposure; subsequently, we follow up the outcome of pregnancy after birth. This cohort has given us an opportunity to assess the magnitude of recall of early pregnancy exposure and determinants likely to affect it in 145 consecutive cases. The mean recall of exposure identity was 62%, while accurate recall of timing of exposure was 37% and of dosage 24%. Exposures that prompted the clinic visit, chronic therapeutic exposures, environmental agents, and known teratogens were recalled significantly better than were other exposures. Accurate report of smoking was significantly higher than of alcohol use (79.4% vs. 59%, respectively, P = .0002). The number of agents consumed by the pregnant woman negatively correlated with her recall; mean recall of 1 agent was 85% vs. only 40% recall of 4 agents. Women greater than or equal to 30 years of age recalled significantly worse (mean +/- SEM, 52 +/- 4%) than women younger than 30 (70 +/- 4%), P = .002) despite a similar mean number of exposures. No difference in mean recall was found between women having normal (n = 112) or adverse pregnancy outcome (n = 33). There was a recall bias in reporting alcohol consumption; postnatally, women with adverse outcome tended to report significantly less than the amount initially reported by them.

Six classes of drug may be prescribed in the treatment of airway hyperreactivity and allergy. Use of the methylxanthine theophylline requires that plasma drug concentrations be monitored because of its pharmacokinetic properties and narrow therapeutic range. β2-Selective adrenergic agonists, glucocorticoids, sodium cromoglycate and the quaternary antimuscarinic ipratopium achieve specificity of drug action on the bronchi with minimal side effects by local delivery as aerosols or ‘microfine’ powders. Glucocorticoids, sodium cromoglycate and ipratropium bromide may also be applied locally to the nasal mucosa in allergic rhinitis, and sodium cromoglycate (cromolyn sodium) may be applied to the eye. The ‘antihistamines’ — H1-receptor antagonists — are not used to treat bronchial hyperreactivity but are frequently used systemically for treating allergic conditions. Two new agents, terfenadine and astemizole, appear to be specific for H1-receptors and represent a new ‘generation’ of antihistamines that produce sedation only infrequently. Terfenadine exhibits a bimodal elimination phase (slow component ± 22 hours) and astemizole has an active metabolite with a half-life of 12 days. The half-lives of most other antihistamines lie in the 4- to 8-hour range (except chlorpheniramine, which has a longer half-life). However, data reflecting disposition of these drugs in children are scanty. There is a need for more powerfully predictive pharmacokinetic approaches, which is discouraged by the widely used modelling approach combining patient and drug characteristics in single variables. Separation of these could improve extrapolation from drugs for which data are available to those for which they are not.

Using newborn and adult rats we tested the correlation between aminoglycoside dose, resultant serum and renal cortical concentrations and nephrotoxicity evidenced by creatinine in serum and urine, N-acetylglucosaminidase and beta 2 microglobulins in urine and sphingomyelinase in renal cortical tissue. Our data reveal that aminoglycoside nephrotoxicity is clearly more evident in adult rats despite significantly lower drug serum concentrations and in the presence of substantially higher renal cortical concentrations. These data indicate that high aminoglycoside serum concentrations are not causing nephrotoxicity but rather reflect secondary body accumulation of the drug associated renal damage.

We assessed the existence of endogenous digoxin-like substance(s) (EDLS) in mother-neonate pairs using a routine radioimmunoassay for digoxin. None of those studied had been treated with cardiac glycosides during or before pregnancy. In uneventful pregnancies, cord EDLS levels (0.31 +/- 0.02 ng/ml mean +/- SEM) were significantly higher (p less than 0.001) than both antepartum and postpartum maternal levels (0.14 +/- 0.02 and 0.17 +/- 0.02 mg/ml, respectively). This observation was in contrast with findings in high-risk pregnancies. In general, EDLS levels in the high-risk group were significantly higher than in normal pregnancies (cord 0.94 +/- 0.38 ng/ml; antepartum 1.63 +/- 0.54 ng/ml; postpartum 0.89 +/- 0.73 ng/ml). In the high-risk group there was a remarkably wide range of maternal and cord EDLS concentrations. The present studies suggest that following pregnancies of high risk for a variety of reasons, EDLS determination may be commonly high in the perinatal period and may affect the determination of 'true' digoxin. Consequently, digoxin dosing based on monitoring drug concentration may be futile.

Theophylline disposition (5.5 mg/kg administered intravenously) was studied in 12 patients with cystic fibrosis (CF) and 16 healthy control volunteers. Dietary controls and logs were used to minimize the influence of food on theophylline metabolism. Control subjects were restudied in random order on two subsequent occasions after 2 weeks of either pancreatic enzymes or placebo. Theophylline and its three main metabolites, 1-methyluric acid, 3-methylxanthine, and 1,3-dimethyluric acid, were analyzed in serum and urine by HPLC. The total body clearance, renal clearance, nonrenal clearance, and volume of distribution of theophylline were significantly greater (p less than 0.05) in patients with CF than in control subjects. The increased nonrenal clearance was the result of increased biotransformation to each of the three main metabolites. Patients with CF exhibited enhanced N-demethylation and 8-hydroxylation of theophylline, pathways that appear to be mediated by two different families of P-450 enzymes. Theophylline clearance after 2 weeks of pancreatic enzyme administration in the control subjects was the same as with placebo. Possible reasons for enhanced theophylline biotransformation in CF are discussed.

The pharmacokinetics and safety of amphotericin B infusion were studied in 13 infants and children (age range 3 weeks to 18 years; median age 11 years) treated with the drug for proved (n = 11) or suspected (n = 2) fungal infections. The dose during the first day was 0.5 mg/kg, followed by a daily dose of 1 mg/kg for the rest of the treatment period in most patients. The drug was infused over 4 to 6 hours. During the first day, serum concentrations were above the target therapeutic level of 0.3 microgram/ml in all patients at 2 and 6 hours from the start of the infusion, in 12 of 13 patients at 12 hours, but in only 6 of 13 patients at 24 hours. On the third day, all concentrations were greater than 0.3 microgram/ml throughout the 24-hour period, and in 12 of 13 patients were greater than 0.5 microgram/ml. The same kinetic profile prevailed on days 7 to 10 of therapy, with a tendency for increasing concentrations. Elimination half-life was 9.93 +/- 1.5 hours (mean +/- SEM), clearance rate 26 +/- 5 ml/kg.hr, and distribution volume 378 +/- 25 ml/kg. The half-life inversely correlated with patient's age. Pharmacokinetic values calculated during the first day were not different from those calculated on day 3. Significant decreases in hemoglobin, platelets, and serum potassium concentration were recorded along with significant increases in serum creatinine, urea, and aspartate transaminase values. Because of the large pharmacokinetic variability and the high rate of serious adverse effects, individualized dosing of amphotericin B based on therapeutic drug monitoring should be considered.

The effect of hypothermia on the disposition of fentanyl was evaluated in 18 children undergoing corrective cardiac surgery. They received a bolus of fentanyl followed by a continuous infusion which was stopped when cardiopulmonary bypass was established and profound hypothermia was achieved (18 °C–25 °C). Fentanyl plasma concentration remained essentially unchanged during hypothermia (6.45 ng/ml 5 min into hypothermia and 5.26 ng/ml 100–140 min later; p>0.1).

The absorption characteristics of 3 sustained release quinidine formulations were assessed in 12 healthy male volunteers in a randomised 3-way crossover trial. Each formulation (‘Quinidex’ 300mg, ‘Biquin Durules’ 250mg and ‘Quinaglute Dura-Tabs’ 324mg) was administered as a single tablet every 12 hours for 5 days. Peak quinidine serum concentrations of 2.7 ± 0.8 mg/L occurred 2.5 ± 1.1 hour after ‘Quinaglute’ administration, significantly higher (p < 0.01) than concentrations of 1.6 ± 0.4 mg/L achieved 4.2 ± 1.1 hours following ‘Biquin’ dosing and 1.7 ± 0.6 mg/L attained 3.9 ± 2.7 hours after ‘Quinidex’ ingestion. The extent of absorption based on AUC∞ and normalised for the anhydrous quinidine content was similar for the 3 products. Following multiple dosing, the mean steady-state trough concentration of quinidine was 2.06 ± 0.56 mg/L for ‘Quinidex’, significantly greater (p < 0.05) than that of ‘Biquin’ (1.18 ± 0.67 mg/L) or ‘Quinaglute’ (1.58 ± 0.58 mg/L).

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.

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.

A sustained-release theophylline preparation (Theo-Dur Sprinkle) was evaluated in young asthmatic patients aged 1 to 6 years and receiving a daily dose of 23.4 +/- 2.0 mg/kg (mean +/- SD) to determine, on the basis of serial serum concentrations obtained over a 12-hour dosing interval at steady state, the suitability of such a product in patients likely to metabolize the drug very rapidly. Peak theophylline concentrations of 15.1 +/- 4.1 mg/L were achieved 5.5 +/- 1.5 hours after dosing. The mean maximum to minimum concentration difference was 6.9 +/- 2.2 mg/L for the dosing interval studied. Fluctuations in theophylline concentration less than 100% were achieved in nine of the 12 study patients. Use of the "sprinkle-technique" with Theo-Dur Sprinkle appears to be a simple and effective method of maintaining acceptable fluctuations in serum theophylline concentrations in preschool asthmatic children.

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 t1/2β and Vβ were similarly unchanged. However mean renal clearance (CLR) and fe were significantly increased following 2 weeks of drug dosing (CLR 5.41 ml·min−1 kg−1; fe 0.61) compared to control (CLR 4.00 ml·min−1·kg−1; fe 0.48). Although the non renal clearance was reduced from control values of 4.29 to 3.51 ml·min−1·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.

We measured digoxin serum concentrations by RIA in 30 neonates not receiving digoxin (gestational age 33.5 ± 4.8 wk, range 25-40). Values ranged from 0.17 to 1.64 nM (mean 0.64 ± 0.27 nM). Gestational age and concentration of EDLS were negatively correlated (r=-0.62, P < 0.01). In an additional 6 critically ill newborn babies and infants receiving digoxin in adequate doses, excessive values of digoxin (> 6 nM) could be explained in part by circulating EDLS. In 4 of them digoxin concentrations continued to rise after cessation of therapy to concentrations as high as 14 nM. In the 2 remaining babies digoxin concentrations fell appropriately but stabilized at values of 1.5 - 2 nM suggesting that this concentration represents EDLS. Cross-reactivity studies comparing RIA and fluorescent polarization immunoassay show that cortisone is the most immuno-reactive substance in cord serum. EDLS was successfully extracted and concentrated from cord serum and placentas and was separated into several immunoreactive fractions by reverse phase HPLC. A potent inhibitor of Na+/K+ - ATPase has been identified in a progesterone-containing fraction. Simulation pharmaco-kinetics suggest that the presence of 0.6 nM EDLS would lengthen digoxin T½ by 64%, reduce Vd by 23%, and lessen clearance, by 53% if “true” peak digoxin level was 2 nM and “true” T½ = 28 hr. It appears likely that currently accepted digoxin kinetic parameters for infants are approximations only and distortion of pharmacokinetic behaviour by EDLS may lead to inappropriate dosing.

The pharmacokinetic behaviour of pemoline was studied in 28 children, aged 5 to 12 years, diagnosed as having the attention deficit disorder with hyperactivity. The mean elimination half-life of pemoline in these children was approximately 7 hours, which is considerably shorter than the half-life of 11 to 13 hours previously reported in adults. The tendency of the half-life to increase with age may be explained by the statistically significant decrease in total body clearance with age. The increasing half-life of pemoline with age should be considered during long term drug therapy. In this study no tolerance to the beneficial effects of pemoline was observed over 6 months. The apparent therapeutic serum concentration range for these children was attained after doses of 37.5 to 131.25 mg pemoline daily. Since the optimum serum concentration shows wide variation, the dosing regimen must be determined individually. Routine monitoring of the pemoline serum concentrations is not useful because of this apparent variation in optimum serum concentration and because of the linear relationship between dose and concentration.

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.

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.