Biomedical subjects

L E Mather

Publications and source records attributed to L E Mather.

At least 91 records · Page 5Linked to original sources

PubMed1991

An assessment of methods for sampling blood to characterize rapidly changing blood drug concentrations.

The accuracy of different blood sampling methods used to characterize rapidly changing blood drug concentrations was examined both in vitro and in vivo. It was shown in vitro that blood sampling methods based on the fraction collection principle failed to characterize a "square wave" change in drug concentration, and there was a 9-16-s delay before achieving 95% of the expected drug concentration. Varying the catheter size and length did not improve the response. This observation is consistent with laminar and/or turbulent flow producing dispersion and mixing of blood of different drug concentrations in the catheter. A sampling method (flush and withdrawal) was developed to minimize these effects. In vivo studies showed that peak blood drug concentrations obtained using this method after an iv bolus of a drug were approximately 25-28% higher than those simultaneously obtained by methods based on fraction collection principles. It is concluded that blood sampling methods based on fraction collection principles can produce significant errors in measured blood drug concentrations. The error is greater the greater the rate of change of the blood drug concentrations.

Animals↗

PubMed1991

Disposition of mepivacaine and bupivacaine enantiomers in sheep.

Mepivacaine and bupivacaine are used clinically as racemic mixtures of enantiomers. In these studies the enantiomers of each agent were administered separately to sheep by i.v. bolus injection on separate occasions. Enantioselective disposition was deemed if the R:S ratio of the relevant pharmacokinetic parameter differed significantly from unity. Both enantiomers of both agents were cleared principally by the liver; urinary excretion of unmetabolized agents accounted for less than 2% of the doses. For R(-)-and S(+)-mepivacaine, respective mean (SEM) values of parameters were: total body clearance 1.20 (0.29) litre min-1 and 0.97 (0.20) litre min-1 (ns); total volume of distribution 144 (39) litre and 80 (21) litre (P less than 0.05); slow half-life 120 (40) min and 84 (22) min (ns); mean hepatic extraction ratio 0.50 (0.14) and 0.52 (0.09) (ns); mean hepatic clearance 0.75 (0.23) litre min-1 and 0.75 (0.18) litre min-1 (ns). For R(+)- and S(-)-bupivacaine, respective values were: total body clearance 0.77 (0.33) litre min-1 and 0.53 (0.26) litre min-1 (P less than 0.05); total volume of distribution 40 (10) litre and 43 (10) litre (ns); slow half-life 57 (10) min and 104 (21) min (P less than 0.05); mean hepatic extraction ratio 0.46 (0.15) and 0.29 (0.13) (P less than 0.05); mean hepatic clearance 0.85 (0.31) litre min-1 and 0.54 (0.26) litre min-1 (P less than 0.05). Thus there was enantioselective distribution of mepivacaine and enantioselective clearance of bupivacaine, but the magnitude of the effect was relatively small.

Animals↗

PubMed1991

Cardiovascular effects and regional clearances of i.v. bupivacaine in sheep: enantiomeric analysis.

All currently available aminoacylaniline local anaesthetics, except lignocaine, contain a chiral centre but are used as racemates, a fact usually ignored in pharmacokinetic studies. This study reports the cardiovascular effects, and the regional and total body clearances of the enantiomers of bupivacaine determined at two steady state periods (3-4 h and 23-24 h) during continuous i.v. infusion to subtoxic concentrations in conscious sheep. Racemic (RS)-bupivacaine hydrochloride 1 mg min-1, was infused in five sheep that had been prepared at least 1 week previously with appropriate intravascular cannulae. The infusion of RS-bupivacaine produced constant arterial R(+)- and s(-)-bupivacaine concentrations of 0.20-0.68 mg litre-1 and 0.22-0.94 mg litre-1, respectively. This caused no appreciable cardiovascular effects. The hepatic clearance of R(+)- was greater than that of S(-)-bupivacaine (P less than 0.05) with mean (SD) clearance at the two respective time periods being 1.37 (0.78) and 1.47 (0.57) litre min-1 and 1.01 (0.72) and 1.29 (0.47) litre min-1. There was no significant clearance of either enantiomer by the lungs, brain, heart, gut, kidneys or hindquarters. It was concluded that, although the clearances of the enantiomers differed, the total body clearance of both enantiomers was accounted for by hepatic clearance exclusively. There was no evidence of time dependent kinetics.

Animals↗

PubMed1991

Physiological disposition of i.v. morphine in sheep.

In a crossover design study we have measured the total body and regional clearances of morphine. Thirteen experiments were performed in four conscious sheep that had been prepared previously with appropriate intravascular cannulae. Morphine (as sulphate pentahydrate) was infused i.v. at 2.5, 5, 10 and 20 mg h-1 to produce constant blood concentrations. Morphine (base) concentrations were measured in blood, urine and tissues with a specific HPLC method. The mean (SEM) total body clearance of morphine was 1.63 (0.21) litre min-1; this comprised 1.01 (0.10) litre min-1 clearance by the liver and 0.55 (0.06) litre min-1 by the kidneys. There was no evidence of dose-dependent clearance or significant extraction of morphine by the lungs, brain, heart, gut or hindquarters at any dose. The kidney clearance of morphine was greater than the 0.21 (0.06) litre min-1 renal clearance determined from the product of the mean total body clearance and the 12.3 (2.4%) of the administered dose recovered as unmetabolized morphine from 48 h urine collection (P less than 0.05). It was concluded that the liver and kidneys account for the majority of morphine clearance, and that the kidneys both excrete and metabolize morphine.

Animals↗

PubMed1991

Failure of the Kety-Schmidt nitrous oxide method for determination of myocardial blood flow.

1. The reliability of the Kety-Schmidt nitrous oxide (N2O) blood-tissue equilibration method was examined in 50 studies of myocardial blood flow in seven conscious, unrestrained sheep using a newly developed carefully validated gas chromatographic assay for N2O. 2. In 10 studies the arterial and coronary sinus N2O blood concentration-time curves converged as expected at the end of the 10 min sampling period. In 14 studies they crossed over, and in 26 studies, the curves failed to converge. 3. A survey of the literature revealed that such results have been encountered previously but have not been accorded particular significance. An ultimate matching equilibrium between arterial and venous blood N2O concentration-time curves is, however, fundamental to the validity of the method. 4. The results indicate that the use of the Kety-Schmidt method with N2O as the indicator gas is invalid as applied to the measurement of myocardial blood flow in this preparation.

Animals↗

PubMed1991

The in vitro uptake and metabolism of lignocaine, procainamide and pethidine by tissues of the hindquarters of sheep.

1. In vitro studies using tissue slices or tissue homogenates of liver, skeletal muscle, fat skin and blood were conducted to determine whether the uptake of procainamide, lignocaine and pethidine into the hindquarters of sheep was due to distribution or metabolism. Both homogenates and slice preparations of liver showed significant metabolism or uptake, confirming the viability of the preparations. 2. None of the drugs was metabolized in blood and there was minimal uptake of the drugs into the skin. 3. There was metabolism of pethidine in skeletal muscle and substantial uptake of pethidine into fat, indicating that the rapid rate of uptake and prolonged elution of pethidine in the hindquarters was due to both distribution and metabolism. 4. No metabolism of lignocaine in muscle was found, but there was substantial uptake into fat, indicating that the rapid rate of uptake and prolonged elution of lignocaine in the hindquarters was due to its distribution into fat. 5. There was negligible uptake of procainamide into either muscle or fat, presumably due to its relatively low lipophilicity.

Adipose Tissue↗

PubMed1991

The in vivo blood, fat and muscle concentrations of lignocaine and bupivacaine in the hindquarters of sheep.

1. A method was developed for sampling muscle and fat from the hindquarters of sheep undergoing spinal anaesthesia. The method was used to measure the concentrations of lignocaine and bupivacaine in the blood, muscle and fat of the hindquarters of sheep during and after 180 min constant-rate infusions of the drugs. 2. For both drugs the muscle drug concentrations were a relatively constant ratio of the simultaneous arterial blood drug concentrations during and after the infusion. 3. There was uptake of both lignocaine and bupivacaine into subcutaneous fat during the infusions. At the end of the infusion the ratio of the fat: arterial blood drug concentrations were 1.54 (SD = 0.57, n = 4) and 3.1 (SD = 1.4, n = 4) for lignocaine and bupivacaine, respectively. 4. The drug concentrations in fat declined relatively slowly after the infusion. The ratio of the fat: arterial blood drug concentrations 180 min after the end of the infusion was 21.5 (SD 4.0, n = 3) and for lignocaine, and 120 min after the end of the infusion was 9.54 (SD 5.2, n = 3) for bupivacaine. 5. It was concluded that the concentrations of lignocaine and bupivacaine in muscle were essentially in equilibrium with the arterial concentrations during and after the infusion. However, the concentrations of lignocaine and bupivacaine in fat were not in equilibrium with the arterial concentrations in the post-infusion period.

Adipose Tissue↗

PubMed1991

Insight into interstitial drug disposition: lymph concentrations of lidocaine, procainamide and meperidine in the hindquarters of unanesthetized and anesthetized sheep.

Drug concentrations in the lymph of the hindquarters of sheep were used to gain insight into drug disposition within the interstitial space. Lidocaine, procainamide and meperidine were each infused into the right atrium of adult merino ewes for 220 min. The time courses of drug concentrations in arterial and inferior vena caval (IVC, draining the hindquarters) blood and hindquarter lymph were determined. It was found that in unanesthetized sheep the mean (+/- S.D., n = 3) lidocaine, procainamide and meperidine concentrations in the hindquarter lymph, were 74 +/- 11, 107 +/- 25 and 94 +/- 17%, respectively, of the arterial and 92 +/- 15, 113 +/- 27 and 134 +/- 28%, respectively, of the IVC blood drug concentrations. Drug binding in lymph, determined by equilibrium dialysis, was not significantly higher than that in blood, except for lidocaine at an initial buffer concentration of 5 micrograms/ml. When the studies were repeated with different animals under halothane anesthesia, the lymph/arterial and lymph/IVC blood drug concentration ratios of the three drugs decreased to 66 +/- 9, 73 +/- 13 and 71 +/- 13% and 77 +/- 8, 88 +/- 19 and 85 +/- 10%, respectively. These values were all significantly lower than those in unanesthetized animals. The results suggest that drug protein binding in interstitial fluid and the status of the microcirculation are important determinants of drug distribution in the interstitial and intracellular spaces. The data also confirm the assumption made in pharmacokinetic studies based upon mass balance principles that the rate of drug removal from organs by lymph is negligible.

Anesthesia↗

PubMed1990

Regional pharmacokinetics. II. Experimental methods.

Regional pharmacokinetics is the study of the drug concentrations in specific regions of the body. It allows greater insight into the mechanisms of drug disposition than the study of systemic blood concentrations. Experimental methods in regional pharmacokinetics and their applications and limitations are reviewed. Post-mortem tissue biopsies give the drug concentrations in highly specific regions of the body, but require a large number of animals. Serial tissue biopsies yield the time-course of drug concentrations in individual animals, but have limited applications. Regional blood sampling in vivo requires catheterization of blood vessels and a measure of regional blood flow, but allows repeated measurements of the time-course of regional drug concentrations in an individual. In contrast, artificially perfused regions allow greater control of perfusate flow and composition, but are less representative of the in vivo situation. These factors can be retained in some animals by surgically transplanting organs to another location to increase access. Tissues slices and cell cultures can examine drug uptake in the absence of perfusion, and tissue homogenates can be used to study the in vitro rates of drug metabolism and tissue drug binding.

Autoradiography↗

PubMed1990

PCA or PAA?

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Analgesics↗

PubMed1990

Plasma concentrations of the stereoisomers of prilocaine after administration of the racemate: implications for toxicity?

A chiral high pressure liquid chromatography method was developed to measure the separate isomers of prilocaine in plasma after administration of the racemate. The concentrations of the isomers in six patients were similar (S(+)/R(-) = 1.06 (SD 0.06)) after brachial plexus block with 1.5% (RS)-prilocaine hydrochloride 35 ml, suggesting that a higher systemic safety margin may not be achieved by substituting racemic prilocaine by one of its isomers. Much higher plasma concentrations of the S(+)- than the R(-)-form after oral administration of 300 mg of the racemate (n = 4) indicated a large difference in intrinsic metabolic clearance of the isomers on first pass through gut, liver or both organs.

Administration, Oral↗

PubMed1990

Cardiovascular effects of propofol and of thiopentone anaesthesia in the sheep.

We have examined the effects on the cardiovascular system and on regional blood flow of propofol and thiopentone when administered with IPPV (FIO2 0.4). A longitudinal study design was used in which 16 studies were performed in eight sheep for 30 min before, during the last 30 min of 70 min anaesthesia, and for 6 h after anaesthesia. During anaesthesia with propofol and thiopentone, mean total body oxygen consumption decreased, respectively, by 47% (P less than 0.001) and 24% (P less than 0.01) of pre-anaesthesia baseline values, mean heart rate increased by approximately 50% (P less than 0.05) with both agents, mean arterial pressures increased by approximately 50% (P less than 0.05) with both agents and the mean cardiac output was unaltered with propofol anaesthesia but was decreased by 20% (P less than 0.05) with thiopentone anaesthesia. The changes in arterial pressure and heart rate were unexpected and may have been a result of a species-specific effect. Mean hepatic blood flow decreased consistently by a mean of 17% (P less than 0.01) during propofol anaesthesia, and inconsistently during thiopentone anaesthesia so that it was not significantly different from baseline values. Mean renal blood flow decreased during propofol anaesthesia by 7% (P less than 0.05) and by 27% (P less than 0.001) during thiopentone anaesthesia. Whereas most variables returned to baseline values within 2 h after propofol anaesthesia, this took 5 h after thiopentone anaesthesia.

Anesthesia, Intravenous↗

PubMed1990

Effects of propofol and of thiopentone anaesthesia on the renal clearance of cefoxitin in the sheep.

We have examined the renal extraction ratios and clearances of cefoxitin in three groups of adult merino ewes. One group (n = 3) was studied for 12 h without perturbation; these were designated control studies. The other two groups (n = 4 each) were studied before (baseline values), during and after the induction and 70-min maintenance of anaesthesia with propofol or thiopentone. In the control studies, mean renal extraction ratio and clearance for cefoxitin were, respectively, 0.67-0.92 and 0.66-0.91 litre min-1 and were consistent throughout the entire study period in individual animals. Comparable values were obtained as baseline values in the anaesthesia groups. Compared with individual baseline values, blood concentrations of cefoxitin doubled during anaesthesia with each agent. At the same time, renal extraction ratio and clearance for cefoxitin each decreased significantly to about 50-60% of their control values. Recovery to control values of arterial blood concentrations and renal extraction ratio of cefoxitin took at least 5 h, but recovery of renal clearance was more rapid. The results indicate that renal elimination of an organic anion such as cefoxitin may be affected by changes in renal blood flow and in renal function produced by propofol and thiopentone; these effects may last for several hours after recovery of renal blood flow.

Anesthesia, Intravenous↗

PubMed1990

Effects of propofol and of thiopentone anaesthesia on the regional kinetics of pethidine in the sheep.

We have examined the extraction ratios, net fluxes and clearances of pethidine by the liver, kidneys and hindquarters in sheep before, during and after continuous anaesthesia (70 min) with propofol or thiopentone. Before anaesthesia, the overall mean respective regional pethidine extraction ratios were 0.98 (SD 0.01), 0.20 (0.06) and 0.44 (0.13), the corresponding net fluxes were 47 (7), 5 (2) and 20 (10)% dose min-1 and the clearances 1.44 (0.22), 0.17 (0.07) and 0.80 (0.39) litre min-1. During propofol anaesthesia, arterial blood concentrations of pethidine approximately doubled (P less than 0.05), mean pethidine hepatic extraction ratio was unchanged, flux was increased to 145 (20)% and clearance decreased to 79 (10)% (P less than 0.05) of baseline values; mean pethidine renal extraction ratio, flux and clearance were 73 (34), 112 (43) and 69 (31)% of baseline values; mean hindquarter pethidine extraction ratio decreased to 65 (25)% (P less than 0.05) of baseline values. During thiopentone anaesthesia, arterial blood concentrations of pethidine approximately doubled (P less than 0.01), mean pethidine hepatic extraction ratio was 97 (2)% of baseline values and flux and clearance were unchanged, mean pethidine renal extraction ratios, flux and clearance decreased to 37 (21), 54 (18) and 27 (19)% (all P less than 0.05) of baseline values and mean pethidine hindquarter extraction ratio was 81 (20)% of baseline values. In spite of only modest changes in hepatic and renal blood flow during anaesthesia, blood concentrations of pethidine doubled and pethidine kinetics were disturbed for several hours after anaesthesia. Overall, however, the changes were of smaller magnitude and shorter duration than those that have been described for anaesthesia with the volatile anaesthetic agents.

Anesthesia, Intravenous↗

PubMed1990

Variables of patient-controlled analgesia. 3: Test of an infusion-demand system using alfentanil.

Patient-controlled infusion-demand analgesia was studied using alfentanil. We were unable to identify an optimal dose and administration rate; doses required range from 100 to 900 micrograms alfentanil. The mean concentration of alfentanil in blood associated with return of pain (i.e. immediately before demand) was 58 ng/ml on day 1 and 37 ng/ml on day 2. This difference was despite similar drug consumption on both days.

Adolescent↗

PubMed1990

Physiological and biochemical consequences of electroimobilisation in conscious sheep.

An electroimmobilisation device has been developed to facilitate the automated shearing of sheep, but there is little information on its effects on the body. We have studied its effects on the cardiovascular system and on intermediary metabolism in sheep. Electroimmobilisation caused statistically significant increases in mean arterial pressure, heart rate, cardiac output, renal and hepatic and hindquarter glucose and lactate flux, organ and whole body oxygen flux, hindquarter blood flow and core temperature and decreases in arterial and posterior vena cava blood pH, renal and hepatic blood flow and PaCO2. Notably, no change occurred in PaO2. The metabolic changes demonstrated the capacity of sheep to respond to the increased muscular and cardiovascular work induced by electroimmobilisation. Pulmonary function was not compromised during electroimmobilisation as judged from blood gas changes, and the acid/base changes were rapidly reversed after electroimmobilisation. The recovery to control conditions for all perturbations generally took no longer than 30 min, consistent with a rapid and physiologically adequate reversal by the animal's homeostatic mechanisms.

Acid-Base Equilibrium↗

PubMed1990

Improved method for morphine determination in biological fluids and tissues: rapid, sensitive and selective.

Morphine was assayed using a simple two step solvent extraction--acid back extraction sample preparation method, coupled with normal phase high-performance liquid chromatography (HPLC) and dual electrode coulometric detection. HPLC is performed with a 1.0 M Tris-methanol (5:95) mobile phase with subtle pH adjustments to separate morphine and internal standard from any interfering compounds. The use of normal phase HPLC (silica column) substantially reduces problems from interfering lipophilic substances sometimes encountered with reverse phase HPLC following solvent extraction and which would otherwise require more time-consuming sample preparation. Dual electrode detection further improves the selectivity for morphine and gives excellent sensitivity (0.5 ng mL-1), reproducibility and stability for automated sample injection. This method has proven suitable for pharmacokinetic studies of morphine.

Animals↗

PubMed1990

Cardiovascular effects and regional clearances of intravenous ropivacaine in sheep.

The purpose of this study was to determine the cardiovascular effects and the total body and regional clearances of ropivacaine during its continuous intravenous infusion to subtoxic levels in five conscious unrestrained sheep that had been previously prepared with appropriate intravascular cannulas. Ropivacaine HCl.H2O, 1 mg/min, produced constant arterial blood concentrations which ranged from 0.70 to 1.84 mg/L. This caused no appreciable cardiovascular effects. The mean total body clearance (+/- SD) of ropivacaine was 1.00 +/- 0.27 L/min. There was significant clearance of ropivacaine by the liver (0.85 +/- 0.32 L/min), gut (0.09 +/- 0.07 L/min), and kidneys (0.04 +/- 0.03 L/min). There was no significant clearance of ropivacaine by the lungs, brain, heart, or hindquarters. It was concluded that the liver accounts for the majority of ropivacaine clearance.

Amides↗