Search PubMed⌕ Search

Biomedical subjects

D R Cook

Publications and source records attributed to D R Cook.

At least 73 records · Page 4Linked to original sources
PubMed1989

Clinical pharmacology of mivacurium chloride (BW B1090U) in children during nitrous oxide-halothane and nitrous oxide-narcotic anesthesia.

We determined the dose-response relationships of mivacurium (BW B1090U) in children (2-10 years) during nitrous oxide-halothane anesthesia (0.8% end-tidal) and during nitrous oxide-narcotic anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation at the ulnar nerve at 2 Hz for 2 seconds at 10-second intervals. To estimate dose-response relationships, for each anesthetic background four subgroups of nine patients received single bolus doses of 20-120 micrograms/kg mivacurium. The ED50 and ED95 (estimated from linear regression plots of log-dose vs. probit of effect) were 52 micrograms/kg and 89 micrograms/kg during halothane anesthesia and 62 micrograms/kg and 103 micrograms/kg during narcotic anesthesia. Nine additional patients in each anesthetic group received 250 micrograms/kg mivacurium. Three of the 18 patients given 250 micrograms/kg mivacurium developed cutaneous flushing; in one of these mean arterial pressure decreased 32% for less than 1 minute; no significant changes in heart rate occurred. With the increase in mivacurium dose from 120 micrograms/kg to 250 micrograms/kg the times to onset of 90% and maximum neuromuscular block decreased by 0.5 to 1 minute, and the times to recovery of neuromuscular transmission to 5% (T5) or 25% (T25) increased by 2-4 minutes. The recovery index (T25-75) in patients anesthetized with halothane was 4.3 +/- 1.5 minute (mean +/- SD); the time to complete recovery (T4:1 greater than or equal to 0.75) was 19.8 +/- 7.4 minutes.

Age Factors↗
PubMed1989

A method to increase recovery of fentanyl from urine.

Fentanyl, a highly lipophilic drug (pk(a) 7.7), is a common drug of abuse. The current standard techniques to detect fentanyl in urine have low recovery rates and poor sensitivity. We report a modified solvent extraction technique that can recover between 63 and 86% of the drug with a detection limit of 0.2 ng/10 ml of urine. In addition, we report the duration of urinary fentanyl excretion in 11 adolescent patients administered either low (less than 10 mg/kg) or high (20-40 mg/kg) doses of fentanyl as part of anesthesia. The mean duration of urinary fentanyl excretion was similar in the two groups, with duration ranging from 1 to 5 days, and urine fentanyl concentration ranging from 0.1 ng to 10.3 ng/10 ml of urine.

Adolescent↗
PubMed1989

Effects of cholestatic hepatic disease and chronic renal failure on alfentanil pharmacokinetics in children.

The role of the liver and the kidney in alfentanil metabolism has not been defined. The effects of cholestatic hepatic disease and chronic renal failure on the pharmacokinetics of alfentanil were evaluated in 9 children undergoing liver transplantation and 10 children undergoing kidney transplantation. These findings were compared with data from 10 children with normal hepatic and renal function undergoing other surgical procedures. There was no statistical difference among the 3 groups with respect to apparent volume of distribution, half-life, or clearance. In a subgroup of 3 patients undergoing liver transplantation alfentanil kinetics were determined both before and after the allograft was incorporated into the recipient's circulation. Though both volume of distribution and elimination half-life increased in the posttransplantation period, only the decrease in clearance was statistically significant. Thus, it appears that alfentanil may be a useful anesthetic agent in pediatric patients with cholestatic hepatic disease or chronic renal failure. The dose of alfentanil in these patients need not be altered except in the period immediately after liver transplantation.

Adolescent↗
PubMed1989

In vitro metabolism of mivacurium chloride (BW B1090U) and succinylcholine.

The in vitro rates of metabolism of mivacurium chloride and succinylcholine in pooled human plasma were compared. In addition, the rate of metabolism of mivacurium in buffered solutions of butyrylcholinesterase (E.C. 3.1.1.8) and acetylcholinesterase (E.C. 3.1.1.7) was determined. Succinylcholine concentrations were measured spectrophotometrically, and mivacurium concentrations were determined with a high-pressure liquid chromatographic assay. The hydrolysis of mivacurium in plasma followed first-order kinetics, and the rate of hydrolysis decreased as plasma was serially diluted. The Michaelis-Menten constant (Km) for mivacurium metabolism in plasma was 245 mumol/L, and the maximum velocity (Vmax) was 50 U/L; the Km for succinylcholine was 37 mumol/L, and Vmax was 74 U/L. At comparable multiples of the Km the hydrolysis rate of mivacurium was 70% of that of succinylcholine. Mivacurium was metabolized significantly in solutions containing butyrylcholinesterase, but only minimally in solutions containing acetylcholinesterase.

Butyrylcholinesterase↗
PubMed1989

Intravenous ranitidine antagonizes intense atracurium-induced neuromuscular blockade in rats.

The neuromuscular action of ranitidine, an H2-receptor antagonist, was investigated by determining its effect on atracurium-induced neuromuscular blockade in urethane-anesthetized and mechanically ventilated male Sprague-Dawley rats. An intravenous bolus and an infusion of atracurium were administered to produce a stable 93 +/- 5% (n = 11) neuromuscular blockade as judged by tibialis anterior muscle twitch response. Ranitidine administered as a 1, 5, or 10 mg/kg normal body weight IV bolus during continuous atracurium infusion produced marked antagonism of neuromuscular paralysis. The percentage of antagonism (25 +/- 9%; n = 4; 53 +/- 19%, n = 4; and 79 +/- 9%, n = 3, respectively) was linearly related to the dose of ranitidine (r = 0.86, P less than 0.05). These results suggest that IV ranitidine has a significant anticholinesterase action against atracurium-induced neuromuscular blockade.

Animals↗
PubMed1988

Pharmacokinetics of sufentanil in adolescent patients with chronic renal failure.

The role of the kidney in sufentanil elimination or metabolism has not been defined. The effects of chronic renal failure (CRF) on the pharmacokinetic profile of sufentanil were evaluated in six adolescent patients undergoing renal transplantation, and these findings were compared with data from age-matched control patients with normal renal function who were undergoing other surgical procedures. Patients with CRF weighed significantly less than did the control patients (28.7 +/- 5.7 vs 44.7 +/- 12.9 kg [mean +/- SD]). Although there was no statistical difference in the rate of clearance or apparent volume of distribution and half-life between the two groups, clearance and half-life were more variable among patients with CRF. In these patients, therefore, sufentanil dose must be carefully administered based on responses elicited in individual patients.

Adolescent↗
PubMed1988

Clinical pharmacology of doxacurium chloride (BW A938U) in children.

The neuromuscular effects of doxacurium were studied in 26 children during halothane-nitrous oxide-oxygen anesthesia. Neuromuscular blockade was measured using electromyographic activity of the adductor pollicis muscle after supramaximal stimulation of the ulnar nerve at 2 Hz for 2 seconds at 10-second intervals. To estimate the cumulative dose-response relation, nine patients received incremental doses of doxacurium (2.5-10 micrograms/kg); nine patients received 27.5 micrograms/kg (the estimated ED95); eight patients received 50 micrograms/kg (1.8 X ED95). The ED25, ED50, ED75, and ED95 (estimated from linear regression plots of log dose vs probit of effect) were 11.5, 14.8, 19.0, and 27.3 micrograms/kg, respectively. Clinical duration (T25) was 27.8 +/- 10.3 (mean +/- SD) minutes at 1 X ED95 and 50.6 +/- 15.6 minutes at 1.8 X ED95. Time to recovery of the train-of-four ratio to 0.75 was 63.1 +/- 32.9 minutes at 1 X ED95 and 108.5 +/- 25.7 minutes at 1.8 X ED95. There were no significant changes in heart rate or mean arterial pressure after bolus administration of any dose of doxacurium.

Age Factors↗
PubMed1988

Mivacurium chloride (BW B1090U)-induced neuromuscular blockade during nitrous oxide-isoflurane and nitrous oxide-narcotic anesthesia in adult surgical patients.

The neuromuscular and cardiovascular effects of mivacurium were studied in 90 adult patients during nitrous oxide-oxygen-isoflurane (n = 45, ISO group) and nitrous oxide-oxygen-narcotic (n = 45, BAL group) anesthesia. Neuromuscular blockade was measured using electromyographic activity of the adductor pollicis muscle after supramaximal stimulation of the ulnar nerve at 2 Hz for 2 seconds at 10-second intervals. To estimate dose-response relations, three subgroups of nine patients in the ISO group received mivacurium doses of 0.025, 0.03, and 0.04 mg/kg, respectively. Similarly, three subgroups of nine patients in the BAL group received mivacurium doses of 0.03, 0.04, and 0.05 mg/kg, respectively. The ED50 and ED95 of mivacurium in each group were estimated from linear regression plots of log dose vs probit of maximum percentage depression of neuromuscular function. The estimated ED50 values for the ISO and BAL groups were 0.029 and 0.041 mg/kg, respectively. The estimated ED95 values for the ISO and BAL groups were 0.045 and 0.058 mg/kg, respectively. Recovery indexes were measured in 26 patients who received ED95 or greater doses of mivacurium in either the ISO or BAL groups. The recovery index was shorter in the BAL group (5.5 +/- 1.6 minutes [n = 10]), than in the ISO group (7.4 +/- 3.0 minutes [n = 16]). The addition of isoflurane (0.5-0.75% end-tidal concentration) to nitrous oxide-narcotic anesthesia augments the degree of neuromuscular blockade from a given dose of mivacurium and also prolongs the recovery index.

Adult↗
PubMed1988

Cimetidine does not inhibit plasma cholinesterase activity.

Cimetidine increases the duration of action of succinylcholine several-fold by an unknown mechanism. The hydrolysis rate of succinylcholine by human plasma was measured with a modified spectrophotometric assay. At a concentration of 1-50 micrograms/ml cimetidine did not inhibit the hydrolysis of succinylcholine. It is concluded that cimetidine may have an effect at the neuromuscular junction but does not inhibit plasma cholinesterase.

Cholinesterase Inhibitors↗
PubMed1987

Pharmacodynamics and pharmacokinetics of high-dose sufentanil in infants and children undergoing cardiac surgery.

The pharmacodynamic and pharmacokinetic profiles of high-dose sufentanil (15 micrograms/kg) and oxygen were determined in 20 infants and children undergoing repair of congenital heart defects. Sufentanil provided marked hemodynamic stability after an infusion and during the stress periods of incision and sternotomy. Two patients required supplemental nitrous oxide because of an increase in blood pressure greater than 20% of baseline. Mean plasma catecholamine concentrations varied widely among patients and increased, although not significantly, during intraoperative stress. Pharmacokinetic data best fit a two-compartment model. In infants younger than 10 months (group 1) and children older than 10 months (group 2) who were not surface-cooled, elimination half-lives were similar (mean +/- SD, 53 +/- 15 min vs 55 +/- 10 min) as were clearance values (27.5 +/- 9.3 vs 18.1 +/- 10.7 ml X kg-1 X min-1). However, the volumes of distribution were significantly smaller in group 1 compared with group 2 (1.6 +/- 0.46 vs 3.0 +/- 1.3 L/kg). In infants younger than 10 months who were surface-cooled (group 3) elimination half-life was longer (120 +/- 36 min) and volume of distribution larger (3.7 +/- 1.1 L/kg), but clearance rate was similar (21.5 +/- 5.0 ml X kg-1 X min-1) compared with age- and weight-matched infants (group 1).

Anesthesia, Intravenous↗
PubMed1986

Pharmacokinetics of atracurium in anaesthetized infants and children.

The pharmacokinetics of atracurium were studied in infants and children anaesthetized with isoflurane and nitrous oxide in oxygen. There were no significant differences in volume of distribution (area) (139 v. 152 ml kg-1), clearance (5.1 v. 5.3 ml kg-1 min-1), T1/2 alpha (2.1 v. 2.0 min), or T1/2 beta (19.1 v. 20.3 min) between children with normal hepatic and renal function and those with moderately impaired hepatic function presenting for hepatic transplantation. There were significant differences in volume of distribution (area) (176 v. 139 ml kg-1) and in clearance of atracurium (9.1 v. 5.1 ml kg-1 min-1) between infants and children with normal excretory function. In infants the clearance of atracurium in ml m-2 min-1 (153 v. 133) tended to be greater and the T1/2 alpha and T1/2 beta tended to be shorter (1.0 v. 2.0 and 13.6 v. 19.1) than in children with normal excretory function; however, these trends did not reach statistical significance. Plasma laudanosine concentration was around 100 ng ml-1 greater in patients with liver disease than in normal children from 15-45 min following a bolus of atracurium 0.5 mg kg-1.

Anesthesia, Inhalation↗
PubMed1986

Cardiovascular and electroencephalographic effects of laudanosine in "nephrectomized" cats.

We studied a cat model simulating laudanosine accumulation in the "anephric" patient. Cardiovascular effects were seen only with the bolus doses of laudanosine 2 mg kg-1, and at plasma laudanosine concentrations unlikely to be achieved clinically. Similarly, EEG and power spectra analysis showed no evidence of epileptiform activity at all plasma laudanosine concentrations achieved. The non-specific EEG/power spectra changes observed may reflect a direct CNS activity with neurodepression, since laudanosine was shown by its presence in CSF to cross the blood-brain barrier. These EEG changes were observed at plasma concentrations eight to 10 times those observed in humans during infusion of atracurium. Thus, laudanosine accumulation and related CNS or cardiovascular toxicity seem unlikely following atracurium administration in the anephric patient.

Animals↗
PubMed1986

Hemodynamic effects of isoflurane in the newborn piglet: comparison with halothane.

To better understand the mechanism of hypotension and bradycardia that may occur in newborn infants during isoflurane anesthesia, we studied the hemodynamic changes in the major determinants of cardiac output in 15 newborn piglets given 0.5, 1.0, and 1.3 minimal alveolar concentrations (MAC) of isoflurane and in nine sham-instrumented, age-matched control animals. Cardiac output did not differ from the baseline reading or the control group at any isoflurane dose. Mean aortic pressure (MAP) decreased 23-45% in a dose-related manner. Total peripheral resistance index (TPRI) decreased 29% at 0.5 MAC, but did not decline further at higher concentrations. Because the decrease in MAP was offset by a similar reduction in TPRI, cardiac output did not change. Heart rate decreased significantly at 1.3 MAC (-19%). Contractility was depressed at all concentrations: left ventricular dP/dT decreased progressively at 0.5 and 1.0 MAC, and echocardiographic shortening fraction decreased significantly at 1.0 MAC. Left ventricular end-diastolic pressure was not affected. Eight of twelve animals who had bradycardia while breathing isoflurane were atrially paced at their baseline heart rate. Because pacing did not restore MAP, TPRI, and LV dP/dT/DP40 (a contractile index independent of preload and afterload) to control values, bradycardia was not primarily responsible for depression of these variables. At equipotent concentrations, isoflurane reduced MAP and TPRI more than, and cardiac output less than, halothane did in previous studies in this laboratory. Heart rate and dP/dT were decreased to a similar extent by both agents. Blood, heart, and brainstem isoflurane LD:MAC ratios were 2.04, 2.00, and 2.84, respectively, indicating a relatively low margin of safety for isoflurane in young piglets.

Animals↗