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Biomedical subjects

L E Mather

Publications and source records attributed to L E Mather.

At least 127 records · Page 7Linked to original sources
PubMed1986

Hepatic and renal clearances of lidocaine in conscious and anesthetized sheep.

Sheep were implanted with cannulae to study blood flow through, and drug extraction by, the lungs, kidneys, liver, and gut. Lidocaine, infused to a steady state in conscious sheep, caused no significant changes in cardiac output or regional blood flow, and was cleared principally by the liver, where the extraction ratio usually exceeded 0.9, and by the kidneys, where the extraction ratio was 0.1-0.2. There was no detectable clearance by lungs or gut. Under general anesthesia with 1.5% halothane, the cardiac output and renal and hepatic blood flows were decreased to means of 77, 44, and 79% of mean control values, respectively, but hepatic and renal extraction ratios of lidocaine were not systematically altered, so that regional clearances of lidocaine were not significantly different from those in conscious animals. There was evidence that the total body clearance of lidocaine exceeded the sum of the directly measured regional clearances in both control and general anesthesia studies. These equivocal findings of the effects of general anesthesia on lidocaine clearance are at variance with unequivocal findings of reduced regional clearances of other drugs tested in this preparation.

Anesthesia, General↗
PubMed1985

A sheep preparation for studying interactions between blood flow and drug disposition. IV: The effects of general and spinal anaesthesia on blood flow and cefoxitin disposition.

Control measurements of blood flow through and cefoxitin extraction ratios across heart and lungs, liver, kidneys and gut were made under steady-state conditions in awake unrestrained sheep. The studies then were repeated with the same animals anaesthetized with 1.5% halothane or whilst undergoing high thoracic (to approximately T4) subarachnoid blockade with amethocaine. In the control-drug studies, it was shown that cefoxitin was cleared by the kidneys and that the cefoxitin infusion produced no significant changes in haemodynamics or in the kinetics of iodohippurate (the marker substance used for determining renal blood flow). Under general anaesthesia, there were significant reductions in renal blood flow (to 61% of the mean control value), in iodohippurate renal extraction ratio and clearance (to, respectively, 64 and 38% of the mean control values) and in cefoxitin renal extraction ratio and clearance (to, respectively, 48 and 23% of the mean control values). Under spinal anaesthesia there were no significant changes in haemodynamics or in cefoxitin or iodohippurate extraction ratios or clearances.

Anesthesia, General↗
PubMed1985

Comparison of the efficacy of chlormethiazole and diazepam as i.v. sedatives for supplementation of extradural anaesthesia.

The clinical efficacy of two sedative agents was compared in 21 young healthy patients undergoing surgery under extradural blockade. A state of sedation and amnesia in which patients lapsed into a sleep-like state when left undisturbed, yet spontaneously opened their eyes to make comments and co-operate with verbal commands, was sought. This was achieved readily by careful titration of responses and required a diazepam loading dose of 20 (+/- 15) mg given at a rate of 1 mg min-1 or 0.8% chlormethiazole edisylate infusion 10 ml min-1 given over 16 (+/- 6) min. Control of this state was easier with chlormethiazole (by varying the rate of infusion) than by giving repeated doses of diazepam. Both agents provided good anterograde amnesia; there was no retrograde amnesia. Considerable postoperative somnolence with a high incidence of relapse into amnesic and sedated states were noted with both agents. However, if the total volume of chlormethiazole infused was less than 300 ml, then a distinct advantage of abrupt and lucid recovery was apparent. Blood concentrations producing the desired clinical state were more variable for diazepam than for chlormethiazole.

Adjuvants, Anesthesia↗
PubMed1984

A sheep preparation for studying interactions between blood flow and drug disposition. II: Experimental applications.

A sheep preparation has been developed which allows systematic direct studies into the sites and rates of distribution, formation and elimination of both endogenous and exogenous substances and their metabolites. Examples of some experimental applications are presented which provide information not usually available using traditional methods. Substantial metabolism at sites not usually regarded as important (e.g. limbs, lungs) was shown both for exogenous substances (procainamide and chlormethiazole) and for an endogenous substance (choline). Studies on drug clearance by kidney (cefoxitin), liver (chlormethiazole, pethidine and the optical isomers of mepivacaine) and lung (chlormethiazole) demonstrate that simple first-order elimination should not routinely be assumed to occur, as multiple sites and pathways may be involved, and kinetics may be non-linear as a result of characteristics of both organ flow and organ function. It was also shown that large changes (up to three-fold) in arterial blood drug concentrations may occur because of exogenous (anaesthesia) and endogenous (gastric recycling) perturbations, and that simple compartmental kinetics should not be assumed for either the whole body or individual organs. This preparation may be used in conjunction with traditional pharmacokinetic methods to resolve complex problems relating to interactions between drugs and the body, to establish a data base for physiological models of drug disposition, and to gain practical insights for drug treatment in patients.

Anesthesia, General↗
PubMed1984

A sheep preparation for studying interactions between blood flow and drug disposition. III: Effects of general and spinal anaesthesia on regional blood flow and oxygen tensions.

In awake unrestrained sheep the infusions i.v. of five drugs (cefoxitin, pethidine, chlormethiazole, tocainide and lignocaine) with potentially flow-limited clearance were shown to have no significant haemodynamic effects of their own, nor to have any effects on arterial or venous oxygen tensions. Under general anaesthesia (1.5% end-tidal halothane), haemodynamic changes similar to those previously documented in man occurred. Cardiac output and hepatic blood flow were decreased to 70%, and renal blood flow to 50% of control values; heart rate was unchanged and mean arterial pressure decreased by an average of 10%. Hepatic and renal vein oxygen tensions were decreased significantly. Under spinal anaesthesia, apart from a 10% decrease in hepatic blood flow, there were no significant changes in any haemodynamic variables or in the arterial or in any of the venous oxygen tensions. The i.v. infusion of adequate volumes of saline at the time of blockade probably contributed to the maintenance of these indices at their baseline values.

Anesthesia, General↗
PubMed1984

A sheep preparation for studying interactions between blood flow and drug disposition. I: Physiological profile.

A sheep preparation has been developed which allows repeated measurements of regional blood flow, oxygen consumption and drug disposition in awake, unrestrained animals. This allows systematic studies of both acute changes, such as haemodynamic disturbances, and of chronic changes, such as enzyme induction, to be carried out. Good agreement was shown between the values for cardiac output and regional blood flow obtained by the Fick and indicator dilution methods, and those obtained by others using microspheres. Significant day-to-day fluctuations in haemodynamic indices were shown to occur; assumptions that hepatic or renal blood flows are constant fractions of cardiac output, or that renal or hepatic flow indicator extraction ratios remain unchanged from day-to-day, will lead to significant errors. Thus, control measurements for each experiment are necessary. It is proposed that physiological models for studying drug disposition based on data from awake, unrestrained animals may provide insight into some mechanisms of changes in drug disposition that cannot be obtained using the traditional compartmental method.

Animals↗
PubMed1984

Pethidine binding in whole blood: methodology and clinical significance.

A three-compartment equilibrium dialysis method was developed for the simultaneous and direct determination of drug binding in whole blood and in plasma and of the blood to plasma concentration ratio (b/p). The unbound fraction of pethidine in the blood of six healthy volunteers (0.63, s.d. 0.09, n = 23 determinations) was significantly different from that in the blood of six patients (0.72, s.d. 0.08, n = 24 determinations). There was no significant difference in the b/p of six patients (0.84, s.d. 0.09, n = 24 determinations) and six volunteers (0.90, s.d. 0.14, n = 23 determinations). The observed unbound fraction of pethidine in blood (0.6 to 0.7) was considerably lower than previously reported. As this value for the unbound fraction (0.6 to 0.7) is similar to the reported estimated hepatic extraction ratio of the drug in man, it is proposed that pethidine elimination should be described as 'capacity limited, binding sensitive' rather than 'flow-limited'.

Adult↗
PubMed1984

Pethidine binding in plasma: effects of methodological variables.

Several methodological variables potentially influencing the plasma protein binding of [14C]-pethidine in vitro were investigated using equilibrium dialysis and rigorous pH control. Ionic strength of buffer, pethidine concentration and 21 days of plasma samples frozen to -8 degrees C did not affect the outcome of the binding experiments. Unbound fraction decreased with increasing temperatures between 25 degrees C and 37 degrees C. Unbound fraction decreased with increased pH between pH 7.0 and 8.0; the mean unbound fraction at an equilibrium pH of 7.4 and at 37 degrees C was 0.58 (s.d. 0.03, n = 58). It is likely that previous reports of pethidine unbound fraction as being between 0.2 and 0.4 represent artefacts caused by inadequate pH control during dialysis.

Blood Proteins↗
PubMed1984

Failure of IV atropine to abolish nasal irritation caused by chlormethiazole infusion in elderly patients undergoing spinal anaesthesia.

The efficacy of intravenous atropine in abolishing the nasal irritation of chlormethiazole was assessed. Forty elderly patients undergoing transurethral resection of prostate under spinal anaesthesia were studied. One ml of either atropine sulphate (0.6 mg) or normal saline was administered intravenously in a double-blind fashion 10 minutes prior to infusion of 0.8% chlormethiazole edisylate. A loading infusion of 5 ml X min-1 of the chlormethiazole solution was followed by a variable rate of infusion in order to maintain a predetermined state of sedation--i.e. where the patient lapsed into sleep but was easily awakened to obey commands. Sneezing was the commonest side-effect occurring in 45% and 70% of patients in atropine and saline groups respectively. This was not effectively abolished by IV atropine in incremental doses of 0.6 mg up to 1.8 mg. Because of the sneezing and restlessness, four patients in the atropine group required general anaesthesia to improve operating conditions. These side-effects of chlormethiazole may limit its use as a sedative for surgery in this elderly age group.

Aged↗
PubMed1983

Pharmacokinetics in renal failure.

A knowledge of pharmacokinetic principles is essential to understand dosage modification for drugs used in patients in renal failure. Dosage modification is indicated either where drugs have a low therapeutic index, or where renal mechanisms play a major role in drug elimination. Drug renal clearance can be indexed to creatinine clearance in order to gauge the degree of drug elimination impairment. Two schemes of dosage modification have been proposed; dosage interval extension or dosage size reduction. In addition to effects on drug elimination, renal failure may also alter drug absorption, distribution, protein binding and metabolism. Dialysis regimens, by eliminating drugs to a greater or lesser degree, have implications for drug therapy.

Absorption↗
PubMed1982

Determination of pharmacokinetic constants after multiple infusions of drugs.

Techniques for determining pharmacokinetic constants after single doses of drugs, or after different doses at fixed intervals or fixed doses at different intervals have been published previously. A generalised algorithm for determining pharmacokinetic constants has been developed for use where irregular intravenous doses given by bolus and/or infusion and irregular dosing intervals are used. The algorithm is robust and, based on data from simulation studies, will give good estimates of pharmacokinetic constants even with irregularly space data having up to 30% random error or as few as 1 degree of freedom. The use of the algorithm provides a way of obtaining pharmacokinetic constants from situations which may have been regarded previously as "too complex".

Humans↗
PubMed1982

Lidocaine and bupivacaine mixtures for epidural blockade.

In a prospective double-blind clinical study, single-dose lumbar epidural blockade was instituted in 60 healthy patients undergoing lower abdominal surgery. Patients were randomly assigned to one of five groups. Each group received treatment with a different local anesthetic solution containing 1:200,000 epinephrine. Local anesthetic solutions used were 0.5 per cent bupivacaine HCl, 2 per cent lidocaine HCl, and lidocaine-bupivacaine mixtures in the ratios of 1:3, 1:1 or 3:1 by volume. Onset and complete spread of sensory blockade were similar in all five groups. Time to regression to two segments of partial and complete sensory blockade was positively correlated (P less than 0.05) with increasing dose of bupivacaine in the solutions and ranged from 84 min (partial) and 70 min (complete) for lidocaine, to 128 min (partial) and 101 min (complete) for bupivacaine. Using skin temperature as a criterion of sympathetic blockade, all three mixtures demonstrated a duration of action intermediate between the two single drugs, lidocaine (124 +/- 13 min) and bupivacaine (286 +/- 32 min). Onset of complete motor blockade was fastest and the degree of motor blockade was most profound with the mixture containing equal proportions of lidocaine and bupivacaine. Pharmacokinetics of individual drugs were unaltered in any of the mixtures.

Adult↗
PubMed1982

The minimum effective analgetic blood concentration of pethidine in patients with intractable pain.

1 Pethidine infusions were performed in 16 patients with intractable pain in order to define a minimum effective analgetic blood concentration (MEAC) range. 2 Pethidine blood concentrations at the return of pain following a period of analgesia were considered to provide a more useful estimation of the MEAC than that at the onset of analgesia. 3. The MEAC range found in 15 of the 16 patients was 0.10 mg/l to 0.82 mg/l (median 0.25 mg/l). The intravenous dose of pethidine used in this study did not provide analgesia in one patient. 4 If the MEAC was greater than 0.40 mg/l in any patient, then additional techniques were required to provide adequate long term analgesia, e.g. destructive neurolytic techniques or antidepressant therapy. 5 The pharmacokinetic properties of pethidine found in the majority of these patients were in the range considered to be normal. 6 The clinical pharmacokinetic properties of pethidine found in the majority of these patients were in the range considered to be normal. 6 The clinical pharmacokineticist has in important role to play in the investigation, diagnosis and treatment of patients with intractable pain by detecting those patients with atypical pharmacokinetic and/or pharmacodynamic characteristics towards analgesic drugs.

Adult↗