Biomedical subjects

L E Mather

Publications and source records attributed to L E Mather.

At least 55 records · Page 3Linked to original sources

PubMed1998

Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep.

UNLABELLED: Commercially available bupivacaine is an equimolar mixture of R(+)- and S(-)-bupivacaine. S(-)-bupivacaine (i.e., levobupivacaine) is currently undergoing preclinical evaluation. Cross-over studies with i.v. levobupivacaine and bupivacaine were conducted in two groups of seven conscious sheep. Doses were chosen to avoid convulsions (smaller dose 6.25-37.5 mg/min) or to be potentially toxic (larger dose 75-200 mg/3 min). In subconvulsive doses, both drugs produced similar time- and dose-dependent depression of left ventricular systolic contractility (dP/dt(max)). Convulsions occurred consistently with > or = 75 mg of bupivacaine and > or = 100 mg of levobupivacaine, producing an abrupt reversal of dP/dt(max) depression. Subconvulsive doses produced minor cardiovascular effects on heart rate and blood pressure, whereas both were increased by convulsions. Cardiac output and myocardial blood flow were decreased with larger doses of both drugs. Doses > 75 mg of bupivacaine or > 100 mg of levobupivacaine induced QRS widening and ventricular arrhythmias, but significantly fewer and less deleterious arrhythmias were induced by levobupivacaine. Three animals died after 150, 150, and 200 mg of bupivacaine from the sudden onset of ventricular fibrillation. These doses of levobupivacaine produced nonfatal arrhythmias that automatically returned to sinus rhythm. We conclude that levobupivacaine could offer a greater margin of clinical safety than bupivacaine. IMPLICATIONS: Levobupivacaine comprises 50% of commercially available bupivacaine and is being considered for use in its own right. Local anesthetics can cause toxicity to the cardiovascular and central nervous systems. As a part of a preclinical evaluation of levobupivacaine, this study compared the toxic effects of levobupivacaine and bupivacaine in sheep.

Anesthetics, Local↗

PubMed1998

Systemic and regional pharmacokinetics of levobupivacaine and bupivacaine enantiomers in sheep.

UNLABELLED: Commercially available bupivacaine is an equimolar mixture of R(+)- and S(-)-bupivacaine. S(-)-bupivacaine (levobupivacaine) is the subject of current clinical evaluation. We conducted partial cross-over systemic and regional pharmacokinetic studies of i.v. bupivacaine (12.5-200 mg) and levobupivacaine (6.25-200 mg) in ewes. Enantiospecific analysis of blood drug concentration-time data and of regional myocardial and brain drug mass balance data indicated that (a) there was a higher mean total body clearance of R(+)-bupivacaine than of S(-)-bupivacaine (as previously reported); (b) there were no differences in the systemic pharmacokinetics of S(-)-bupivacaine whether administered alone or as a component of bupivacaine; (c) there was no evidence of dose-dependent pharmacokinetics with either enantiomer; (d) for both enantiomers, mean calculated myocardial tissue concentrations of 1%-4% dose occurred between 3 and 5 min. Mean brain concentrations of 0.2%-1% dose occurred between 2 and 4 min after the administration of bupivacaine but between 4 and 5 min after the administration of levobupivacaine. There was no evidence that systemic toxicity induced by these local anesthetics significantly modified their pharmacokinetics, and there was no evidence of an enantiomer-enantiomer pharmacokinetic interaction for bupivacaine. IMPLICATIONS: Levobupivacaine comprises 50% of commercially available bupivacaine and is being considered for use in its own right. As a part of its preclinical evaluation, this study considered whether levobupivacaine behaved kinetically in the body in the same way as when administered as a component of bupivacaine.

Anesthetics, Local↗

PubMed1998

Arterial and pulmonary arterial concentrations of the enantiomers of bupivacaine after epidural injection in elderly patients.

UNLABELLED: Bupivacaine HCl is a 50:50 racemic mixture of the levo [S(-)] and dex [R(+)] enantiomers. The R(+) enantiomer exhibits greater cardiac tissue binding and toxicity. To determine whether the lung exhibits selective uptake of one of the enantiomers of bupivacaine, we measured pulmonary artery and radial artery blood concentrations of the two enantiomers after a lumbar epidural injection of 20 mL of 0.75% bupivacaine in 10 elderly patients undergoing one-stage bilateral total knee arthroplasty. Significantly lower concentrations of R(+) than S(-) were noted in both pulmonary artery and arterial blood. Both enantiomers were absorbed by the lung to a similar extent within the first 5 min after epidural injection (extraction ratio approximately equal to 0.1 or 10%). Mean time of maximal concentration (Tmax) was 6 min. In 3 of the 10 patients, Tmax occurred in 1-3 min. We conclude that the lung absorbs both the R(+) and S(-) enantiomers of bupivacaine to a similar extent after epidural injection and that this is of doubtful clinical significance. This study also suggests that peak concentrations of bupivacaine may occur earlier after epidural injection in certain elderly patients than previously believed. IMPLICATIONS: In the first 5 min after epidural injection, approximately 10% of the local anesthetic bupivacaine was absorbed by the lung. Absorption of the two enantiomers (mirror images) of bupivacaine were similar. Lung absorption of bupivacaine is unlikely to influence local anesthetic toxicity.

Absorption↗

PubMed1998

Factors influencing ketorolac-associated perioperative renal dysfunction.

UNLABELLED: Nonsteroidal antiinflammatory drugs (NSAIDs) are useful for the treatment of postoperative pain, but there is continuing concern about adverse effects on renal function. We studied the renal effects of ketorolac in an animal model using Fischer 344 rats undergoing isoflurane anesthesia and laparotomy. Treatment groups--control (C), ketorolac (5 mg x kg(-1) x d(-1)) (K), large-dose ketorolac (15 mg x kg(-1) x d(-1)) (KH), dehydration-ketorolac (5 mg x kg(-1) x d(-1)) (DK), gentamicin (20 mg x kg(-1) x d(-1)) (G), and gentamicin (20 mg x kg(-1) x d(-1)) with ketorolac (5 mg x kg(-1) x d(-1)) (GK)--each comprised 10 animals. Renal function was assessed before laparotomy and after 3 treatment days using concurrent paraaminohippurate and iothalamate clearances, respectively, to estimate renal plasma flow and glomerular filtration rate, and by measuring serum and urine electrolytes, osmolality, urea, and creatinine. A significant increase in serum potassium was found in the GK and DK groups. There were no major changes in renal function in the C, K, KH, and DK groups. Mild renal dysfunction was found in the G group. We found severe and consistent changes in renal function, accompanied by severe, widespread histological changes of acute tubular necrosis, in the GK group. In this postoperative rat model, the combination of ketorolac and gentamicin was deleterious to renal function. IMPLICATIONS: We examined the renal effects of the nonsteroidal antiinflammatory drug ketorolac. Renal function was measured in rats before and after surgery and 3 days' drug administration; the kidneys studied by using microscopy. Only ketorolac plus the antibiotic gentamicin produced marked changes in kidney function and structure.

Animals↗

PubMed1998

Chirality in anaesthesia--ropivacaine, ketamine and thiopentone.

Drug chirality (molecular handedness) is a source of pharmacological differences between otherwise chemically identical molecules. Specific applications to the pharmacology of ropivacaine (single enantiomer), ketamine and thiopentone (both racemates) are discussed. Ropivacaine is produced as a single S-enantiomer homologue of the more toxic bupivacaine to preclude the higher central nervous system and heart toxicity found in the R-enantiomer. S-ketamine is presently undergoing trials as a potential replacement for the racemate, on the grounds that it optimizes anaesthesia and minimizes psychotomimetic phenomena. Thiopentone, previously known to have quantitative differences in the pharmacology of its enantiomers, has recently also been shown to have pharmacokinetic differences. The evidence for these claims is discussed in this review.

Journal Article↗

PubMed1998

Central nervous system toxicity attributable to epidural ropivacaine hydrochloride.

Ropivacaine, a new local anaesthetic agent, has been demonstrated to have less potential than bupivacaine for central nervous system toxicity on the basis of human and animal studies. We report a case of a convulsion secondary to presumed inadvertent intravascular injection of 20 mg of ropivacaine in a 44 kg patient during an epidural for chronic pain. There were minimal signs of cardiovascular toxicity.

Adolescent↗

PubMed1998

Preoperative dextromethorphan reduces intraoperative but not postoperative morphine requirements after laparotomy.

UNLABELLED: N-methyl-D-aspartate (NMDA) antagonists combined with opioids are thought to be effective in the control of pain states. We evaluated morphine use and analgesia in 37 patients postlaparotomy. Patients received 60 mg of oral dextromethorphan or placebo the night before and again 1 h before surgery. Morphine was titrated intraoperatively to maintain blood pressure and heart rate within 20% of baseline and postoperatively via patient-controlled analgesia (PCA). The dextromethorphan and placebo groups were compared for morphine use intraoperatively, in recovery, via PCA in the first 4 and 24 h, and total use over the study period. Pain scores at rest and on activity for the first 4 and 24 h were also compared. Intraoperatively, the dextromethorphan group required less morphine: 13.1+/-4.3 vs 17.6+/-6.0 mg (P = 0.012). Postoperatively, there was no significant difference between the dextromethorphan and placebo groups for morphine use: in the recovery room 10.9+/-7.7 vs 12.1+/-7.7 mg; the first 4 h of PCA 15.9+/-9.3 vs 12.7+/-5.1 mg; the first 24 h of PCA 76.4+/-44.7 vs 61.8+/-27.5 mg; or in total morphine use 100.4+/-49.5 vs 91.5+/-3.1 mg. Pain scores for the two groups were not statistically different throughout the study period. We conclude that 60 mg of oral dextromethorphan given the night before and repeated an hour before surgery does not provide a postoperative morphine-sparing effect or improve analgesia after laparotomy. IMPLICATIONS: Patients given dextromethorphan before surgery had significantly reduced intraoperative morphine requirements. However, postoperative morphine requirements were unaltered. Dextromethorphan may need to be continued postoperatively to improve postoperative analgesia.

Abdomen↗

PubMed1997

Highly sensitive gas chromatographic-mass spectrometric method for morphine determination in plasma that is suitable for pharmacokinetic studies.

A sensitive method was devised to determine morphine plasma concentrations by gas chromatography-mass spectrometry (GC-MS) using selected ion monitoring (SIM) with nalorphine as the internal standard. This method was rugged, reliable, selective and sensitive and was used to determine the morphine content of over 2000 samples. Sample preparation involved extraction of basified sample using n-butyl chloride-chloroform (5:1) and evaporation of the extract to dryness. The residue was derivatised with pentafluoropropionic anhydride, evaporated to dryness, reconstituted in 40 microl toluene and injected onto the GC-MS. For a sample size of 1 ml, the limit of quantitation was 0.75 ng/ml (S/N ratio 10:1) and the estimated limit of detection was calculated to be 0.2 ng/ml (S/N ratio 3:1), expressed as morphine base. Precision (n=5) was 4.9% at 0.75 ng/ml, 6.8% at 1.5 ng/ml, 3.0% at 37.5 ng/ml and 2.3% at 150 ng/ml. Standard curves for the range of 0-750 ng/ml morphine in plasma were linear with all r2 values greater than 0.99. No interfering peaks were seen for either morphine or internal standard in the blank samples. The method is suitable for pharmacokinetic studies after subclinical doses of morphine where it has been used to study morphine plasma concentrations for 6 h after a dose of only 2 mg.

Administration, Inhalation↗

PubMed1997

Determination of subnanogram concentrations of fentanyl in plasma by gas chromatography-mass spectrometry: comparison with standard radioimmunoassay.

A method was devised to determine fentanyl plasma concentrations by GC-MS using selected-ion monitoring (SIM) with sufentanil as internal standard. This was compared with a commonly used commercial radioimmunoassay (RIA). Sample preparation for GC-MS involved basification of plasma then extraction using n-butyl chloride followed by concentration to dryness and reconstitution in toluene for chromatography. Using 1-ml plasma samples, the estimated limit of detection of fentanyl was 20 pg/ml. Blood samples for pharmacokinetic studies were split and assayed by GC-MS and RIA which had a limit of detection of 200 pg/ml. Pearson's r (r - 0.80, p < 0.0001) indicated the methods were highly correlated at all plasma concentrations. Owing to the greater sensitivity of the method, GC-MS is recommended over RIA for subnanogram determination of fentanyl in plasma.

Analgesics, Opioid↗

PubMed1997

Morphine pharmacokinetics after pulmonary administration from a novel aerosol delivery system.

BACKGROUND: Successful pharmacotherapy of pain often depends on the mode of drug delivery. A novel, unit dose, aqueous aerosol delivery system (AERx Pulmonary Drug Delivery System) was used to examine the feasibility of the pulmonary route for the noninvasive systemic administration of morphine. METHODS: The study had two parts: (1) a dose-ranging study in four subjects with three consecutive aerosolized doses of 2.2, 4.4, and 8.8 mg (nominal) morphine sulfate pentahydrate at 40-minute intervals, and (2) a crossover study, on separate days, in six subjects with 4.4 mg (nominal) aerosolized morphine sulfate administered over 2.1 minutes on three occasions and intravenous infusions of 2 and 4 mg over 3 minutes. Subjects were healthy volunteers from 19 to 34 years old. Arterial blood was sampled for a total of 6 hours and plasma morphine concentrations were measured by gas chromatography-mass spectrometry. RESULTS: In part 1, plasma morphine concentrations were proportional to dose. In part 2, the mean +/- SD peak plasma concentration (Cmax) occurred at 2.7 +/- 0.8 minutes after the aerosol dose, with mean values for Cmax of 109 +/- 85, 165 +/- 22, and 273 +/- 114 ng/ml for the aerosol and 2 and 4 mg intravenous doses, respectively. The bioavailability [AUC(0-360 min)] of aerosol-delivered morphine was approximately 100% relative to intravenous infusion, with similar intersubject variability in AUC for both routes (coefficient of variation < 30%). CONCLUSION: The time courses of plasma morphine concentrations after pulmonary delivery by the AERx system and by intravenous infusions were similar. This shows the utility of the pulmonary route in providing a noninvasive method for the rapid and reproducible systemic administration of morphine if an appropriate aerosol drug delivery system is used.

Administration, Inhalation↗

PubMed1997

Pharmacokinetics of thiopentone enantiomers following intravenous injection or prolonged infusion of rac-thiopentone.

AIMS: Thiopentone is administered as a racemate (rac-thiopentone) for induction of anaesthesia as well as for neurological and neurosurgical emergencies. The pharmacokinetics and pharmacodynamics of rac-thiopentone have been extensively studied but the component R-(+)- and S-(-)- enantiomers, until very recently, have been largely ignored. METHODS: The present study analyses the pharmacokinetics of R-(+)- and S-(-)-thiopentone in 12 patients given rac-thiopentone intravenously for induction of anaesthesia and five patients given a prolonged infusion of rac-thiopentone used for treatment of intracranial hypertension. RESULTS: The mean total body clearance (CLT) and apparent volume of distribution at steady-state (Vss) showed trends towards higher values for R-(+)- than for S-(-)-thiopentone in both patient groups; CLT and Vss of unbound fractions of R-(+)- and S-(-)-thiopentone, however, did not show these trends. The time courses of R-(+)- and S-(-)- thiopentone serum concentrations were so similar that EEG effect could not be attributed to one or other enantiomer. Serum protein binding for S-(-)-thiopentone was greater than for R-(+)-thiopentone (P = 0.02) and 24 h urinary excretion of R-(+)-thiopentone was greater than for S-(-)-thiopentone (P = 0.03). In one patient, concomitant measurement of CSF and serum thiopentone concentrations found that serum: CSF equilibration of unbound fractions of both enantiomers was essentially complete. CONCLUSIONS: The study was unable to determine any pharmacokinetic difference of clinical significance between the R-(+)- and S-(-)-thiopentone enantiomers and concludes that minor differences in CLT and Vss could be explained by enantioselective difference found in serum protein binding.

Adult↗

PubMed1997

Nausea and vomiting in the postoperative patient-controlled analgesia environment.

Despite common clinical opinion that patient-controlled analgesia should be renamed 'patient-controlled nausea', there is little evidence in support of the notion that postoperative nausea and vomiting are exacerbated by the method. Indeed, data indicate that opioid-sparing techniques are not associated with less postoperative nausea and vomiting. Although some evidence suggests that certain opioids are less emetogenic than others, this too does not stand scrutiny when compared across patients, although research is still required to find whether individual patients are better treated with a particular opioid. Similarly, the emerging practice of combining anti-emetics with patient-controlled analgesia needs wider study before it can be supported.

Analgesia, Patient-Controlled↗

PubMed1997

The influence of age upon opioid analgesic use in the patient-controlled analgesia (PCA) environment.

It is often asserted that older patients are more sensitive to opioid analgesics than younger patients but experimental evidence for this assertion remains sparse. Two studies were conducted investigating the relationship between age and opioid analgesic use in the patient-controlled analgesia environment. In study I, the relationship was analysed subsequent to our publication of a study investigating patients' responses to opioid use with patient-controlled analgesia. Fifty-five postoperative patients, stratified into 'older' and 'younger' patients by median age, received morphine or pethidine or fentanyl patient-controlled analgesia. A strong inverse relationship was found between age and fentanyl and morphine use but not between age and pethidine use. Study II was a retrospective study of the medical records of 199 patient-controlled analgesia patients who had received morphine or pethidine patient-controlled analgesia; there were insufficient patients who had used fentanyl for a reasonable sample. There was a difference in morphine use with the younger patients using significantly more morphine than the older patients (< 60 years). Findings were less clear for patients receiving pethidine but there was an inverse correlation between age and pethidine use as well. Overall, the findings of these two studies supported the common clinical belief that older patients require less opioids than younger patients.

Adult↗

PubMed1997

Morphine blood concentrations in elderly postoperative patients following administration via an indwelling subcutaneous cannula.

The pharmacokinetics of morphine in venous blood after a 5 mg bolus dose via an indwelling subcutaneous cannula were characterised in 22 elderly patients undergoing elective major surgery. In a subgroup of seven patients, the kinetics were also characterised after a second 5 mg dose of morphine administered 180 min after the first dose. Blood morphine concentrations following the single dose were highly variable--the coefficients of variation of Cmax, Tmax and the AUC up to 180 min (AUC180) were 54, 37 and 39%, respectively, with mean values of 86.6 ng.ml-1, 15.9 min and 3954 ng.ml-1, respectively. These mean values for the second dose were not statistically different to those of the first dose but were more variable. It was concluded that the injection of morphine via an indwelling subcutaneous cannula results in blood concentrations that are comparable to, and as variable as, those arising from intramuscular injection.

Abdomen↗

PubMed1997

Lack of effect of high doses of inhaled morphine on exercise endurance in chronic obstructive pulmonary disease.

Systemic opiates may relieve dyspnoea and improve exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). Small doses of inhaled opiates may have similar effects; however, recent studies have shown no benefit. We studied higher doses of inhaled morphine and measured systemic absorption to determine whether any beneficial actions are local or systemic. Twenty and 40 mg doses and 0.9% saline were nebulized in a randomized, double-blind study of 16 patients with stable COPD. Patients performed 6 min walk tests immediately after the nebulized test solution (Walk 1) and again 60 min later (Walk 2). Arterial oxygen saturation (Sa,O2), modified Borg dyspnoea score and cardiac frequency were recorded during each walk. There was no difference between placebo and either dose of nebulized morphine on these measurements. The higher dose of nebulized morphine achieved a higher plasma concentration. The highest plasma concentration was measured immediately after nebulization, and this decreased steadily in the hour thereafter (p<0.002). There was no correlation between the change in walk distance and the change in plasma morphine concentration after either dose of nebulized morphine. We conclude that higher doses of nebulized morphine do not improve exercise endurance or relieve dyspnoea in patients with chronic obstructive pulmonary disease, and that morphine is rapidly absorbed systemically after inhalation.

Administration, Inhalation↗

PubMed1997

Influence of renal failure on the disposition of morphine, morphine-3-glucuronide and morphine-6-glucuronide in sheep during intravenous infusion with morphine.

The influence of experimentally induced renal failure on the disposition of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was examined in seven sheep infused intravenously with morphine for 6 hr. Between 5 and 6 hr, blood was collected from the aorta, pulmonary artery, hepatic, hepatic portal and renal veins and posterior vena cava. Additional samples from the aorta and urine were collected up to 144 hr. Morphine, M3G and M6G were determined in plasma and urine by high-performance liquid chromatography. Constant concentrations of morphine, but not of M3G and M6G, were achieved in plasma between 5 and 6 hr. Significant (P < .001) extraction of morphine by the liver (0.72 +/- 0.05) and kidney (0.42 +/- 0.15) occurred. Compared with sheep with normal kidneys (Milne et al., 1995), renal failure did not alter (P = .11) the mean total clearance of morphine (1.5 +/- 0.3 liters/min); clearance by the kidney was less (P < .001). However, a paired comparison using sheep common to this study and from the study when their kidneys were normal revealed a significant reduction in mean total clearance of 25%. The renal extraction of M3G and M6G and urinary recovery of the dose as summed morphine, M3G and M6G were reduced by renal failure. The kidney metabolized morphine to M3G. The data suggest that nonrenal elimination of M3G becomes more important during renal failure.

Animals↗

PubMed1996

Urineless estimation of glomerular filtration rate and renal plasma flow in the rat.

A simple method to perform serial renal clearance studies without urine collection in rats is described. This was applied to nonradiolabelled para-aminohippurate sodium (PAH) and iothalamate sodium (IOT) which were used respectively to estimate renal plasma flow (RPF) and glomerular filtration rate (GFR). Under isoflurane-anesthesia the jugular vein and carotid artery of Fischer 344 rats were cannulated, and a loading dose followed by a continuous infusion of PAH and IOT was administered. Steady state was reached after 30 min, and four arterial blood samples were collected over the next 30 min for analysis by HPLC (day 0). The clearances of PAH and IOT were calculated according to Fick's principle as estimates of RPF and GFR from the ratio of the infusion rates to the median solute concentrations. Three days later the femoral artery and vein were cannulated, and the same study was repeated (day 3). There was no significant difference in renal clearances of PAH and IOT between days 0 and 3. The described method gives values that compare well with others in the literature based on other methods and presents an accurate and simple way of detecting changes in renal function before and after a potentially nephrotoxic treatment regimen.

Animals↗

PubMed1996

Comparison of the respiratory and systemic kinetics of nitrous oxide in the sheep.

BACKGROUND: To determine whether discrepancies in views on the kinetics of nitrous oxide (N2O) may have a methodological basis, we compared its kinetics, simultaneously, in the respiratory system and systemic circulation. METHODS: Six merino ewes (40-50 Kg) were previously prepared with catheters in the pulmonary artery and aorta. The animals were anaesthetised with thiopentone then ventilated on a mixture of 70% N2O, 1% halothane in oxygen for 4 h. Simultaneous serial arterial and pulmonary arterial blood samples were assayed for N2O by gas chromatography and respiratory gases were monitored continuously by mass spectrometry. RESULTS: Marked differences were observed between the respiratory and systemic kinetics of N2O uptake. While the expired/inspired N2O concentration ratio rose within 30 min to a value close to unity, the pulmonary arterial/arterial blood N2O concentration ratio did not reach unity during the 4 h of each study, but approached a constant rate of uptake shown by the mean ratio of 0.94 (SD 0.01) from about 2 h onward. CONCLUSIONS: Discrepancies in fluid flow between respiratory gas and the cardiovascular systems, a concentration effect of N2O in the lungs, the relative solubility of N2O in blood and tissues, and ventilation/perfusion inequalities all may contribute to the observed differences. The ongoing uptake is consistent with persistent extrapulmonary losses. There remains a need for experimental data on the pharmacokinetics of N2O. Unequivocal studies on the disposition of N2O can be undertaken only by using direct measurement of fluxes of N2O across relevant organs or tissues.

Anesthetics, Inhalation↗