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Biomedical subjects

W B Runciman

Publications and source records attributed to W B Runciman.

At least 109 records · Page 6Linked to original sources
PubMed1989

Propofol: assay and regional mass balance in the sheep.

1. Pharmacokinetic data for propofol, a new intravenous anaesthetic agent, indicate that there may be extensive extrahepatic clearance. This was investigated during intravenous infusions of propofol in adult merino ewes with chronic intravascular cannulae using a newly developed simple and rapid assay for propofol in blood and other biological samples. 2. The assay was based on organic solvent extraction of pH 4.5 buffered blood, urine or tissue homogenate, followed by reverse-phase h.p.l.c. with fluorescence detection. 3. A mean total body clearance of propofol of 3.15 l/min, (SD 0.87 l/min; n = 8) was found, consistent with a high hepatic extraction ratio (overall mean 0.87, SD 0.19; n = 8) and clearance (overall mean 1.12, SD 0.25 l/min; n = 7). The difference between total and hepatic clearances consisted principally of pulmonary clearance, but its extent was variable. 4. Other regional pharmacokinetic data were consistent with propofol distribution into muscle and brain tissues and propofol 'production' by the kidney, probably from a propofol metabolite formed elsewhere. 5. If these data are confirmed in humans then clinical pharmacokinetic data so far derived from peripheral venous blood sampling will require re-evaluation.

Animals↗
PubMed1989

Myocardial and cerebral drug concentrations and the mechanisms of death after fatal intravenous doses of lidocaine, bupivacaine, and ropivacaine in the sheep.

This paper reports the cardiovascular effects of intentionally toxic intravenous doses of lidocaine, bupivacaine, and ropivacaine and the mechanisms of death. Fatal doses of lidocaine, bupivacaine, and ropivacaine were established in sheep treated with successive daily dose increments of each drug. The mean fatal dose of lidocaine (+/- SD) was 1450 +/- 191 mg (30.8 +/- 5.8 mg/kg), that of bupivacaine was 156 +/- 31 mg (3.7 +/- 1.1 mg/kg), and that of ropivacaine was 325 +/- 108 mg (7.3 +/- 1.0 mg/kg); thus the ratio of fatal doses was approximately 9:1:2. In four out of four lidocaine-treated animals, respiratory depression with bradycardia and hypotension without arrhythmias were the causes of death. Three out of four bupivacaine-treated animals died after the sudden onset of ventricular tachycardia/fibrillation without hypoxia or acidosis; the fourth died in a similar manner to the lidocaine-treated animals. Three out of five animals given ropivacaine died in a manner resembling the fatal effects of lidocaine-treated animals, but unlike the lidocaine-treated animals, in all three sheep there were also periods of ventricular arrhythmias. The remaining two ropivacaine-treated sheep died as a result of the sudden onset of ventricular tachycardia/fibrillation. The mean percentages of the fatal dose found in the myocardium was 2.8 +/- 0.7 for lidocaine-treated animals, 3.3 +/- 0.9 for bupivacaine-treated animals, and 2.2 +/- 1.4 for ropivacaine-treated animals; the corresponding percentages in whole brain were, respectively, 0.71 +/- 0.01, 0.71 +/- 0.21, and 0.89 +/- 0.27.

Amides↗
PubMed1989

Hemodynamic and central nervous system effects of intravenous bolus doses of lidocaine, bupivacaine, and ropivacaine in sheep.

Lidocaine hydrochloride (HCl) (80-320 mg), bupivacaine HCl (20-80 mg), and ropivacaine HCl (30-120 mg) were administered as intravenous bolus doses to conscious sheep (n = 18; average body weight 45 kg) that had previously placed intravascular cannulae for hemodynamic monitoring and for obtaining blood samples. The mean convulsive doses and arterial blood concentrations were approximately 110 mg and 40 mg/L, respectively, for lidocaine HCl, 45 mg and 14 mg/L for bupivacaine HCl, and 60 mg and 20 mg/L for ropivacaine HCl. After subconvulsive doses of each agent, there were minimal cardiovascular effects. After convulsive doses, there were marked increases in heart rate, mean arterial pressure, pulmonary artery pressure, cardiac output, systemic vascular resistance, left ventricular end diastolic pressure, and myocardial contractility. Ventricular fibrillation caused death in two sheep after bupivacaine (80 mg) and in two sheep after ropivacaine (90 and 120 mg) administration. With sublethal doses, the hemodynamic responses to these agents were qualitatively and quantitatively similar when compared with their local anesthetic potencies.

Acid-Base Equilibrium↗
PubMed1988

The use of mass balance principles to describe regional drug distribution and elimination.

Mass balance principles were used to derive a number of terms that are helpful in describing the rate and extent of regional drug uptake. Regional drug uptake was defined as the net movement of drug from the blood perfusing a region into the extravascular space of the region due to the distribution and/or elimination of the drug. By analogy with the traditional physiological definition of flux, net drug flux was defined as the difference in mass per unit time of drug respectively entering and leaving a region via the arterial and venous blood vessels. The time-integral of net drug flux, net drug mass, was defined as the mass of drug that has entered a region via the arterial blood vessels but has not left the region via the venous blood vessels. For regions in which no drug elimination occurs, the mean regional drug concentration was defined as the net drug mass divided by the mass of the region. When a number of criteria are satisfied, the net drug flux is approximately the rate of drug uptake and the net drug mass is approximately the extent of drug uptake. Several examples are given to demonstrate the broad range of applications of mass balance principles. First, the method was used to characterize the differences between drug distribution and elimination in a hypothetical region using drug concentrations simulated from compartmental models of either distribution alone or distribution with elimination. Second, the whole body distribution net flux was described during a constant rate infusion of iodohippurate (IOH) into a sheep from the difference between the whole body net flux and renal net flux of IOH. Third, the time course of the mean myocardial lignocaine (lidocaine) concentrations in a sheep after an intravenous bolus of lignocaine were described. The time course of the lignocaine-induced depression of myocardial contractility followed more closely the mean myocardial lignocaine concentrations than that of either the arterial or coronary sinus blood concentrations. It is concluded that the use of mass balance principles provides a simple, empirical, and physiologically based method for the determination of the rate and extent of both drug distribution and elimination in regions as simple as single organs or as complex as the whole body.

Lidocaine↗
PubMed1988

The uptake and elution of lignocaine and procainamide in the hindquarters of the sheep described using mass balance principles.

Mass balance principles were used to describe the uptake and elution of lignocaine (lidocaine) and procainamide in the hindquarters of the sheep. Each of four sheep received a right atrial infusion of either lignocaine.HCl (2.7 mg/min) or procainamide.HCl (5.5 mg/min) for 180 min. Paired arterial and inferior vena cava (draining the hindquarters) blood samples were taken at 20-min intervals during the infusion and for 180 min after the infusion. Lignocaine and procainamide mean total body clearances were 2.9 L/min (SD 1.1) and 1.3 L/min (SD 0.2), respectively. An index of the uptake and elution of these drugs in the hindquarters was estimated from the net drug mass per unit hindquarter blood flow; indirect evidence suggested that hindquarter blood flow was constant. All the net mass/flow of procainamide that was taken into the hindquarters during the infusion also eluted after the infusion, demonstrating reversible distribution into the tissues. However, uptake of procainamide was still occurring when blood concentrations were constant, indicating that the concentrations of procainamide in the hindquarters were not in equilibrium with the inferior vena cava concentrations. Lignocaine did not reach constant blood concentrations during the infusion and showed no tendency to reach arterio-venous equilibration; an arterio-venous difference of 22% (SD 5%) across the hindquarters was measured during the last 60 min of the infusion. By 180 min after the lignocaine infusions, 79% (SD 8%) of the lignocaine net mass/flow had not eluted from the hindquarters when arterial and venous lignocaine concentrations were not significantly different. This drug could remain uneluted due to metabolism and/or avid tissue binding, and presents difficulties in the interpretation of pharmacokinetic data whether based on arterial or venous blood sampling.

Animals↗
PubMed1988

Effects of lignocaine and bupivacaine on regional myocardial function and coronary blood flow in anaesthetized dogs.

Empirical i.v. doses of lignocaine or bupivacaine of equal local anaesthetic potency were administered to halothane-anaesthetized dogs. Both local anaesthetics caused the expected depression of global haemodynamic function. Regional myocardial systolic shortening was depressed similarly by both agents. Regional myocardial dysfunction, seen as post-systolic shortening, occurred to a similar extent with both lignocaine and bupivacaine. Coronary blood flow and coronary perfusion pressure were significantly correlated during the administration of lignocaine; bupivacaine had erratic effects on coronary blood flow and no correlation between coronary blood flow and coronary perfusion pressure was seen. These results suggest that regional myocardial dysfunction occurs with both local anaesthetics and does not account for the apparent increased cardiotoxicity of bupivacaine. Bupivacaine did, however, cause wider individual variations compared with lignocaine with respect to coronary blood flow.

Anesthesia, General↗
PubMed1987

Choline biosynthesis in sheep. Evidence for extrahepatic synthesis.

1. Choline production by various tissues of the sheep was measured by determining venous and arterial free choline concentrations in blood samples taken from various vessels in conscious multicannulated sheep. 2. Significant production of free choline occurred in the upper and lower body regions, and specifically in the heart, brain and hind-limb muscles of sheep, but there was no significant uptake or output of phosphatidylcholine across these tissues, as determined by arterio-venous differences. 3. In contrast, in the rat there were no significant arterio-venous differences in the concentrations of free choline or phosphatidylcholine across the hind-body. 4. Synthesis of phosphatidylcholine from endogenous phosphatidylethanolamine and S-adenosyl-L-[methyl-14C]methionine was measured in experiments in vitro using microsomal preparations from a variety of sheep and rat tissues. 5. The biosynthetic activity was highest in liver from sheep and rats, although the activity in sheep microsomal preparations was about one-quarter of that in rat microsomal preparations. 6. Microsomal preparations from sheep lung, kidney, gut epithelium, brain, heart and skeletal muscles also showed considerable biosynthetic activity, but in the rat the activity was virtually confined to the liver. 7. Overall, the results show a significant production of choline in extrahepatic tissues of the sheep, with skeletal muscle contributing some 60% of this extrahepatic activity. Thus the extrahepatic production of choline in the sheep, together with the extensive reutilization of bile choline, can explain the maintenance of the large endogenous body pool of choline in this species.

Animals↗