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Biomedical subjects

L E Mather

Publications and source records attributed to L E Mather.

At least 73 records · Page 4Linked to original sources
PubMed1996

The systemic and cerebral kinetics of thiopental in sheep: enantiomeric analysis.

Thiopental is used as a racemate (rac-thiopental). Enantiomeric pharmacokinetic differences could therefore influence the onset and duration of anesthesia of rac-thiopental. We studied the systemic and cerebral kinetics of R(+)- and S(-)-thiopental in five adult ewes after a 2-min intravenous infusion of 500 mg rac-thiopental sodium. Systemic kinetic values were determined from the time course of concentrations in arterial plasma; cerebral kinetic values were deduced from the time course of the concentration differences between arterial and superior sagittal sinus blood plasma. Enantiomeric differences were found in both sites, with the (R:S) ratio of thiopental enantiomer blood concentrations initially being > or = 1 then decreasing to < 1 after approximately 60 min. This is consistent with the finding of the mean total body clearance of R(+)-thiopental being 17% (SD 12%) greater than that of S(-)-thiopental (P = .04). Sagittal sinus plasma concentrations of both enantiomers followed closely behind those in arterial plasma and this is consistent with facile bidirectional exchange of thiopental between plasma and brain. No significant differences were found between enantiomers in the rates of brain influx or efflux. Onset and regression of anesthesia occurred while the enantiomer blood concentrations were similar. Hence published pharmacokinetic-pharmacodynamic models of the onset of thiopental effects probably are not significantly compromised by neglecting the enantiomeric duality of thiopental, but models based on its elimination kinetics could be compromised if enantiomeric differences are neglected.

Anesthetics, Intravenous↗
PubMed1995

High-performance liquid chromatographic determination of thiopentone enantiomers in sheep plasma.

An HPLC method was developed to determine the plasma concentrations of R(+)- and S(-)-thiopentone for pharmacokinetic studies in sheep. The method required separation of the thiopentone enantiomers from the corresponding pentobarbitone enantiomers which are usually present as metabolites of thiopentone. Phenylbutazone was used as an internal standard. After acidification, the plasma sample were extracted with a mixture of ether and hexane (2:8). The solvent was evaporated to dryness and the residues were reconstituted with sodium hydroxide solution (pH 10). The samples were chromatographed on a 100 mm x 4 mm I.D. Chiral AGP-CSP column. The mobile phase was 4.5% 2-propanol in 0.1 M phosphate buffer (pH 6.2) with a flow-rate of 0.9 ml/min. This gave k' values of 1.92, 2.92, 5.71, 9.30 and 11.98 for R(+)-pentobarbitone, S(-)-pentobarbitone, R(+)-thiopentone, S(-)-thiopentone, and phenylbutazone, respectively. At detection wavelength of 287 nm, the limit of quantitation was 5 ng/ml for R(+)-thiopentone and 6 ng/ml for S(-)-thiopentone. The inter-day coefficients of variation at concentrations of 0.02, 0.1 and 8 micrograms/ml were, respectively, 4.8, 4.4 and 3.5% for R(+)-thiopentone and, respectively, 5.0, 4.3 and 3.9% for S(-)-thiopentone (n = 6 each enantiomer). At the same concentrations, the intra-day coefficients of variation from six sets of replicates (measured over six days) were, respectively, 8.0, 8.0 and 8.8% for R(+)-thiopentone and 8.8, 7.4 and 9.6% for S(-)-thiopentone. Linearity over the standard range, 0.01-40 micrograms/ml, was shown by correlation coefficients > 0.998. This method has proven suitable for pharmacokinetic studies of thiopentone enantiomers after administration of rac-thiopentone in human plasma also and would be suitable for pharmacokinetic studies of the pentobarbitone enantiomers.

Animals↗
PubMed1995

Bupivacaine enantiomer pharmacokinetics after intercostal neural blockade in liver transplantation patients.

Bupivacaine, being a racemic local anesthetic, exists as an equal mixture of its component enantiomers R(+)- and S(-)-bupivacaine, which behave pharmacokinetically as independent drugs after injection into the body. Intercostal neural blockade using bupivacaine was performed for postoperative analgesia in 12 patients after orthotopic liver transplantation. Arterial blood, sampled serially, was assayed by enantioselective high-performance liquid chromatography for R(+)- and S(-)-bupivacaine. The average of the simultaneous R(+):S(-) ratios of blood bupivacaine concentrations in the 12 patients was 0.74 (SD 0.11); however, the use of a population mean value or a mean value for any patient denies the time-dependence of this entity. The blood enantiomer concentration difference was reflected in the maximum measured concentrations which, after the first dose, were, respectively, 0.38 (SD 0.19) and 0.52 (SD 0.28) mg.L-1.100 mg-1 RS-bupivacaine administered (P = 0.0003). The difference in blood concentrations between the enantiomers, reflected by the R(+):S(-) ratio being less than unity, could be explained by a greater mean total body clearance and a larger apparent volume distribution of R(+)-bupivacaine. Elimination of both enantiomers was prolonged in these patients after liver transplantation compared to data from the literature, but there was no tendency for either enantiomer to accumulate selectively, even upon repeated dosing. We conclude that this demonstration of differences in pharmacokinetics (and, in laboratory studies, also in pharmacodynamics) between the bupivacaine enantiomers points to the need for future studies to recognize the enantiomeric duality of this local anesthetic.

Bupivacaine↗
PubMed1995

Opioids: a pharmacologist's delight!

1. Opioids, in one form or another, have been used for their pain-relieving properties from prehistoric times: they are still the first line medication for the treatment of severe nociceptive pain and are likely to remain so for the foreseeable future. 2. The therapeutic index of opioids used for pain management is low: opioid side effects are essentially extensions of therapeutic effects and no available agent has a marked advantage over the others. When used for opioid 'anaesthesia', differences in therapeutic index are more obvious due to differences in non-opioid effects. 3. Opioid receptors in brain and spinal cord periphery are the main 'therapeutic targets' and clinical dosage strategies have been derived using a variety of systemic (indirect or blood-borne) methods as well as intraspinal and intracerebroventricular (direct) methods: no method, however, is without potential side effects. Peripheral opioid effects are now being exploited with intra-articular injection. 4. Opioid pharmacokinetics and pharmacodynamics are characterized by high inter-subject variability: accordingly, patient-controlled dosage strategies are found to be more successful for pain control than deterministic recipes.

Analgesia↗
PubMed1995

Comparative disposition of morphine-3-glucuronide during separate intravenous infusions of morphine and morphine-3-glucuronide in sheep. Importance of the kidney.

The disposition of morphine-3-glucuronide (M3G) in sheep was compared during separate constant infusions of morphine and M3G. Five ewes received a 15-min loading dose, followed by a constant infusion of morphine sulfate (10 mg/hr) or M3G (4 mg/hr for 4 sheep, 7.5 mg/hr for 1 sheep) for a further 5.75 hr. During the 5th-6th hr of infusion, blood was collected simultaneously from the aorta, pulmonary artery, hepatic vein, hepatic portal vein, renal vein, and posterior vena cava. Additional samples were collected from the aorta from 0 to 5 hr and from 6 to 48 hr. Urine was collected via an indwelling catheter from 0 to 6 hr, with further free-flowing urine up to 48 hr. An HPLC assay was used to determine simultaneously morphine, M3G, and morphine-6-glucuronide (M6G) in plasma and urine. Constant concentrations of morphine, M3G, and M6G in plasma were achieved during the 5- to 6-hr period of infusion with morphine, as were the concentrations of M3G while M3G was infused. Regional net extraction ratios and total and regional clearances were calculated during the 5- to 6-hr period. After the infusions were ceased, there was prolonged elimination of M3G formed in situ from morphine compared to when infused as M3G. No morphine or M6G was detected in the plasma during and after infusion with M3G, nor were they found in urine collected up to 6 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Determination of ketorolac enantiomers in plasma using enantioselective liquid chromatography on an alpha 1-acid glycoprotein chiral stationary phase and ultraviolet detection.

A chirally selective high-performance liquid chromatographic assay was developed to measure the R(+) and S(-) enantiomers of ketorolac in plasma for pharmacokinetic studies. Naproxen sodium [S(+) enantiomer] (10 micrograms) was used as an internal standard. Plasma samples (0.5 ml) were acidified (50 microliters of 4 M H3PO4 to pH 1.5), extracted into 0.4 ml of 10% pentan-2-ol in hexane and back-extracted into 0.15 ml of base (20 mM NaOH pH to 7-8), of which samples (5 microliters) were chromatographed on a 100 x 4 mm I.D. column packed with an HPLC chiral stationary phase based upon immobilized alpha 1-acid glycoprotein (Chiral AGP-CSP) with 4% propan-2-ol in 0.1 M NaH2PO4 pH 5.5, at 0.9 ml/min. Detection was at 325 nm and run time was 10 min. Retention times of R- and S-ketorolac and of S(+)-naproxen were 3.3, 4.8 and 6.4 min, respectively. The metabolite p-hydroxyketorolac was not resolved enantiomerically and had a retention time of 2.2 min. The assay was linear over the range 0.5-10 mg/l, with precisions < 5% C.V. Good separations (alpha > 1.35) and resolutions (Rs > 3.23) between peaks were achieved. The sensitivity could be extended to 35 micrograms/l with less precision by increasing the injection volume to 100 microliters.

Chromatography, High Pressure Liquid↗
PubMed1994

Pharmacokinetics of bupivacaine enantiomers in sheep: influence of dosage regimen and study design.

Bupivacaine is used as a racemate. In previous studies the mean total body clearance of R(+)-bupivacaine was found to be greater than S(-)-bupivacaine by 65% after iv bolus dose of separate enantiomers and by 20% after iv infusion to steady state of racemate. The present studies were performed to determine whether different study designs using different iv dosage regimens could influence the pharmacokinetic parameters determined for either bupivacaine enantiomer. rac-Bupivacaine.HCl was administered iv to 6 adult Merino ewes by bolus, brief infusion, and prolonged infusion. Arterial blood concentrations of R(+)- and S(-)-bupivacaine were measured by enantioselective HPLC. These regimens consistently produced lower arterial blood concentrations of R(+)-bupivacaine than S(-)-bupivacaine due to R(+)-bupivacaine having a greater initial dilution volume by 16 (95% CI = 3-29)%, volume of distribution at steady state equilibrium by 32 (95% CI = 17-32)% and mean total body clearance by 28 (95% CI = 21-35)%. The slow half-life of R(+)-bupivacaine, however, was found to be 15 (95% CI = 0-31)% longer than that of S(-)-bupivacaine. The difference between enantiomers in mean total body clearance thus was similar to the previous study based upon infusion to steady state of rac-bupivacaine. Differences in pharmacokinetics attributable to the dosage regimen consisted of a greater mean total body clearance for R(+)-bupivacaine along with a smaller terminal half life with the bolus regimen and a longer half-life of S(-)-bupivacaine after prolonged infusion. Differences in pharmacokinetics between the bupivacaine enantiomers occurred consistently in both distribution and clearance but the magnitude of the effect was less than 50% in each case. Systematic differences in pharmacokinetics associated with the dosage regimen were found mainly in terminal half-life. Dosage regimen, thus, was found to influence the pharmacokinetic results found experimentally and is therefore a significant variable in its own right.

Anesthetics, Local↗
PubMed1994

The hemodynamic effects of intravenous bolus doses of meperidine in conscious sheep.

The hemodynamic effects of 100, 200, and 300 mg of meperidine injected intravenously were studied in five chronically instrumented adult ewes. The maximum rate of increase of left ventricular pressure was decreased, respectively, by 27.4% +/- 3.9%, 37.5% +/- 5.6%, and 31.9% +/- 13.0%, and recovery occurred by 5, 8, and 0.5 min, respectively. Mild central nervous system stimulatory effects (agitation) were observed in three of five sheep at 200 mg and moderate effects (rigor and jumping movements) were observed in four of five sheep at 300 mg. These doses also produced increases in heart rate (43%-64%) and mean arterial blood pressure (17%-27%). At these doses, cardiac output was increased for 0.5 min by approximately 25% without changes in stroke volume and left ventricular stroke work. Coronary blood flow was increased by 44%-81% for 0.5 min. We conclude that, in unpremedicated sheep, meperidine has a brief direct negative inotropic effect on the myocardium, but that at larger doses this is overridden by stimulatory central nervous system (CNS) and indirect hemodynamic effects.

Animals↗
PubMed1994

The pharmacokinetics of meperidine in the myocardium of conscious sheep.

The pharmacokinetics of meperidine in blood and myocardium were studied in five conscious sheep. After an intravenous (i.v.) bolus of 100, 200, or 300 mg meperidine HCl, the maximum arterial blood concentrations (mean +/- SD) were 27.8 +/- 4.6, 66.8 +/- 13.3, and 114.5 +/- 23.1 micrograms/mL, respectively, and coronary sinus blood concentrations were 2.7 +/- 1.0, 7 +/- 1.5, and 13.7 +/- 2.5 micrograms/mL, respectively. These were linearly related to dose. Net uptake of meperidine into the myocardium occurred during the first minute and the maximum rates of uptake (influxes) were 5.1 +/- 2.6, 15.1 +/- 4.6, and 27.5 +/- 8.7 mg/min. Myocardial meperidine concentrations, calculated using mass balance principles for the 100-, 200-, and 300-mg doses, respectively, were 9.0 +/- 1.8, 20.5 +/- 8.6, and 34.1 +/- 7.4 micrograms/g at peak and had decreased to 57% +/- 11% of peak 5 min after injection. No pseudoequilibrium between blood and myocardial meperidine concentrations had been reached within the 15-min study period. Myocardial perfusion and blood-myocardial concentration gradients were both important determinants of meperidine myocardial pharmacokinetics. The fast uptake and brief sojourn of meperidine in the myocardium agreed with its rapid but transient negative inotropic effect reported previously.

Animals↗
PubMed1993

Tissue distribution of bupivacaine enantiomers in sheep.

rac-Bupivacaine HCl was infused intravenously to constant arterial blood drug concentrations in sheep using a regimen of 4 mg/min for 15 min followed by 1 mg/min to 24 h. At 24 h, arterial blood was sampled, the animal was killed with a bolus of KCl solution, then rapidly dissected and samples were obtained from heart, brain, lung, kidney, liver, muscle, fat, gut, and rumen. Tissue:blood distribution coefficients for (+)-(R)-bupivacaine exceeded those of (-)-(S)-bupivacaine (P < 0.05) for heart, brain, lung, fat, gut, and rumen by an overall mean of 43%. Blood:plasma distribution coefficients of (-)-(S)-bupivacaine exceeded those of (+)-(R)-bupivacaine by a mean of 29% and this offset the tissue:blood distribution coefficients so that the previously significant enantioselective differences disappeared. It is concluded that although enantioselectivity of bupivacaine distribution is shown by the measured tissue:blood distribution coefficients, it is not shown when tissue:plasma water distribution coefficients are calculated, suggesting that there is no intrinsic difference between the bupivacaine enantiomers in tissue affinity. Sheep given fatal intravenous bolus doses of rac-bupivacaine had significantly greater concentrations of (+)-(R)-bupivacaine than (-)-(S)-bupivacaine in brain (P = 0.028) and ventricle (P = 0.036); these could augment the greater myocardial toxicity of this enantiomer found in vitro.

Animals↗
PubMed1993

Patient-controlled analgesia. Pharmacokinetic and therapeutic considerations.

The opioid analgesic agents exhibit relatively large pharmacokinetic differences between drugs, and there is substantial pharmacokinetic and pharmacodynamic variability across subjects or patients with each agent. The advent of patient-controlled analgesic administration techniques and their widespread use in contemporary pain management, especially in postsurgical and cancer patients, has decreased the unfortunate impact of interpatient variability on achieving the optimal balance between pain relief and opioid adverse effect intensity. The improvements in pain management provided by patient-controlled analgesia do not, however, decrease the importance of knowledge of opioid pharmacokinetics towards enlightened use of these drugs and attainment of maximal benefits from them in any patient. Future improvements in patient-controlled analgesia technology will probably be based on the pharmacokinetic behaviour of different opioid analgesic agents in specific receptor-containing regions. Finally, physicochemical and pharmacokinetic characteristics of these agents are important determinants of the speed of onset of effects, duration of action and spinal selectivity of epidurally and intrathecally administered analgesics. Thus, effective patient-controlled analgesia depends on an understanding of the differential pharmacokinetics of opioids self-administered by a variety of possible modes.

Analgesia, Patient-Controlled↗
PubMed1992

The pharmacological relief of pain--contemporary issues.

OBJECTIVE: To provide a general description of the pharmacological principles of pain management particularly the management of severe pain with opioid analgetic agents. DATA SOURCES: Literature updating previous reviews by the authors in this Journal and the Proceedings of the VIth World Congress on Pain, Adelaide, 1-6 April 1990. STUDY SELECTION: Studies were selected under the subheadings: opioid receptors; endogenous opioids; development of new agents; recognition of the need to improve analgesia; pharmacokinetics and pharmacodynamics of opioids; and novel drug delivery methods. DATA EXTRACTION: The extracted information was more descriptive than quantitative. DATA SYNTHESIS: The pharmacological relief of pain involves treatment of patients with drugs characterised by extremely large interpatient variability in pharmacokinetics and pharmacodynamics by way of an extremely complex interaction with endogenous control mechanisms. It is not surprising that management of pain in many patients is less than adequate. CONCLUSIONS: Although much vigorous interdisciplinary research is being undertaken to develop a scientific basis for understanding pain and analgesia, improvements in the clinical management of pain can only occur if practitioners recognise the need for individualised methods of pain relief and treat their patients accordingly.

Acute Disease↗
PubMed1992

Failure of the nitrous oxide tissue equilibration method for the determination of brain and myocardial blood flow under controlled conditions.

1. Two adult merino ewes were prepared with intravascular cannule for sampling aortic root blood, sagittal sinus blood and coronary sinus blood. 2. One week after preparation the animals were anaesthetized then ventilated with a gas mixture containing 10% nitrous oxide (N2O) for 60 min. Serial measurements of brain and myocardial blood flow were made using the N2O tissue equilibration method of Kety and Schmidt. 3. N2O failed to achieve matching arteriovenous blood concentration equality and saturation of the relevant tissues. Valid use of the Kety-Schmidt method, therefore, could not be confirmed. 4. Because of the failure of the arteriovenous equilibration, serially determined brain and myocardial blood flows were found to decrease with time. 5. The use of this method in circumstances where tissue saturation with the indicator gas cannot be ascertained is arbitrary.

Animals↗
PubMed1992

Postoperative course of plasma protein binding of lignocaine, ropivacaine and bupivacaine in sheep.

The plasma protein binding of the 2,6-xylidide local anaesthetic agents lignocaine, ropivacaine and bupivacaine enantiomers was determined by equilibrium dialysis in plasma obtained from chronically catheterized sheep before and up to 21 days after surgery. Three concentrations (1, 5 and 10 mg L-1), were used for each agent. Concentration-dependent binding was evident for each agent throughout the study period. R(+)-Bupivacaine was more extensively bound than S(-)-bupivacaine at the higher concentrations. Compared with pre-surgery, binding of each agent was less on the first postoperative day but did not differ significantly from days 8 to 21.

Amides↗
PubMed1992

Do the pharmacodynamics of the nonsteroidal anti-inflammatory drugs suggest a role in the management of postoperative pain?

Until recently, nonsteroidal anti-inflammatory drugs (NSAIDs) were regarded as weak analgesic agents with a potent antiplatelet effect that severely limited their perioperative usefulness. However, the recent development of injectable NSAIDs has stimulated a re-evaluation of the potential role of this class of drugs in postoperative pain management. In general surgery, NSAIDs have been shown to be effective analgesics when administered after surgery, as judged by either a reduction in pain scores and/or by an opioid sparing effect. Parenteral NSAIDs alone, notably ketorolac and diclofenac, may be adequate or even preferred analgesic agents after minor surgery. In dental surgery, NSAIDs produce greater initial analgesia than steroids, although the latter produce greater suppression of swelling and less functional loss. NSAID pretreatment results in only modest suppression of swelling compared with placebo. These data suggest that the acute analgesic effects of NSAIDs in oral surgery and probably other models result from suppression of a nociceptive process, rather than a generalised anti-inflammatory effect. This view challenges the traditional association between inhibition of prostaglandin synthesis and the therapeutic effects of these drugs. The variety of NSAIDs leads to a range in half-lives from short, e.g. diclofenac (1 h), intermediate, e.g. ketorolac (5h), to long, e.g. tenoxicam (60h), which has implications for both convenience of the dosage regimen and drug accumulation. For some racemic NSAIDs (e.g. ibuprofen), metabolic 'activation' of the inactive R-enantiomer to the active S-enantiomer occurs. Renal dysfunction may increase both the plasma concentration and body residence time of NSAIDs, thereby increasing the risk of adverse effects. The concomitant effects of anaesthesia have not yet been studied. The principal concern regarding the use of perioperative NSAIDs is the risk of decreased haemostasis and wound healing. Although it has been found that NSAIDs prolong bleeding times in patients, values generally remain below the upper limits of those in generally healthy patients. Healing of gastrointestinal anastomoses may be compromised by NSAID administration but corneal healing and bone remodelling are not. There is a need for further research into the potential for renal side effects with NSAIDs in the perioperative setting, where the effects of anaesthesia and surgery may increase the risk of side effects, particularly in elderly patients. The main benefits of NSAIDs derive from opioid sparing (e.g. reduction in perioperative nausea and vomiting and improvement in ventilation), although some studies allude to an enhanced quality of analgesia from the combination compared with either NSAID or opioid alone. The question of pre- vs postinjury treatment with NSAIDs remains unresolved.

Analgesics↗
PubMed1992

Pharmacokinetics and patient-controlled analgesia.

With patient control over dosage regimens as in PCA, the pharmacodynamic properties of the opioid analgesic agents emerge as being of greater importance than the pharmacokinetic properties in obtaining a salutary result. However, the prescription of opioid analgesic agents for PCA is more complex than for the same drugs under conventional control. There are major differences in the physicochemical, receptor selectivity and pharmacokinetic properties among opioid analgesic agents. Improved understanding of these differences, it is contended, can lead to more optimized strategies for the clinical management of pain whether under conventional or patient control. The impact of these properties on the components of the PCA prescription is discussed.

Analgesia, Patient-Controlled↗
PubMed1991

Uptake and elution of chlormethiazole, meperidine, and minaxolone in the hindquarters of sheep: implications for clearance calculations.

Mass balance principles were used to describe the uptake and elution of chlormethiazole, meperidine, and minaxolone in the hindquarters of sheep. Sheep received a right atrial infusion of either chlormethiazole (3.71 mg/min) or meperidine (2.70 mg/min) for 180 min, or minaxolone (0.37 mg/min) for 120 min. Paired arterial and inferior vena cava (draining the hindquarters) blood samples were taken during and after the infusion. The mean and SD (n = 4) of the time-averaged extraction ratios across the hindquarters (determined from the relevant arterio-venous area under blood concentration--time curves) were 0.12 (0.10), 0.36 (0.13), and 0.27 (0.05) for chlormethiazole, meperidine, and minaxolone, respectively. The rank order of the rate of uptake of the drugs into the hindquarters was the same as the rank order of their lipophilicity, and uptake still continued when both the arterial and inferior vena cava drug concentrations were essentially constant. For chlormethiazole, meperidine, and minaxolone, 48% (44), 4% (6), and 35% (17), respectively, of the drug taken into the hindquarters eluted from the hindquarters after the infusion. Drug uptake and retention in extravisceral tissues, represented here by the hindquarters, can result in the mean total body drug clearance being overestimated when determined by traditional systemic pharmacokinetic methods.

Anesthetics↗