Biomedical subjects

L E Mather

Publications and source records attributed to L E Mather.

At least 37 records · Page 2Linked to original sources

PubMed2000

Determination of defensin HNP-1, HNP-2, and HNP-3 in human saliva by using LC/MS.

The mass spectral profiling of saliva by liquid chromatography mass spectrometry in relation to particular types of pain is being examined. The aim is to develop a profile that could be useful for the assessment of patients and their treatment programs, as well as identifying unknown compounds observed in saliva. Defensin human neutrophil peptide-1 (HNP-1) and defensin HNP-2 were identified and confirmed, whereas defensin HNP-3 was tentatively identified. Linear calibration range of defensin HNP-1 and HNP-2 was 0.25 to 3 microg/ml with R(2) values of > 0.99 for both. The detection limit for defensin HNP-1 and HNP-2 was estimated at 0.1 microg/ml. The healthy subjects surveyed in this study had readily measurable salivary concentrations of defensin HNP-1 (8.6 +/- SD 8.0 microg/ml) and defensin HNP-2 (5.6 +/- SD 5.2 microg/ml).

Adult↗

PubMed2000

Pulmonary insulin administration using the AERx system: physiological and physicochemical factors influencing insulin effectiveness in healthy fasting subjects.

BACKGROUND: Orally inhaled insulin may provide a convenient and effective therapy for prandial glucose control in patients with diabetes. This study evaluated the influence of formulation pH and concentration and different respiratory maneuvers on pharmacokinetic and pharmacodynamic properties of inhaled insulin. METHODS: Three, open-label crossover studies in a total of 23 healthy subjects were conducted in which the safety, pharmacokinetics, and pharmacodynamics of insulin inhalation were compared to subcutaneous (SC) injection into the abdomen of commercially available regular insulin. A novel, aerosol generating system (AERx Diabetes Management System, Aradigm Corporation, Hayward, CA) was used to deliver aqueous insulin bolus aerosols to the lower respiratory tract from formulations at pH 3.5 or 7.4 and concentrations of U250 (250 U/mL) or U500 (500 U/mL). RESULTS: Time to maximum insulin concentration in serum (Tmax) after SC dosing occurred approximately 50-60 minutes with the time to minimum plasma glucose concentration (i.e., maximum hypoglycemic effect), (TGmin), occurring later, at around 100-120 minutes. In contrast, pulmonary delivery led to a significantly earlier Tmax (7-20 minutes) and TGmin (60-70 minutes), parameters that were shown to be largely unaffected by changing the pH or concentration of the insulin. However, investigation of changes in inhaled volume (achieved by different programming of the AERx system) for administration of the same sized aerosol bolus revealed significant effects. Significantly slower absorption and time to peak hypoglycemic activity occurred when aerosol delivery of insulin occurred during a shallow (approximately 40% vital capacity) as opposed to a deep (approximately 80% vital capacity) inspiration. In addition, it was shown that serum concentration of insulin increased immediately after a series of forced expiraratory maneuvers 30 minutes after inhaled delivery. CONCLUSIONS: Pulmonary delivery of aqueous bolus aerosols of insulin in healthy subjects resulted in rapid absorption with an associated hypoglycemic effect quicker than is achieved after subcutaneous dosing of regular insulin. Inhaled insulin pharmacokinetics and pharmacodynamics were independent of formulation variables (pH, concentration) but affected by certain respiratory maneuvers.

Administration, Inhalation↗

PubMed2000

Microdialysis study of the blood-brain equilibration of thiopental enantiomers.

Thiopental is a racemate of equimolar R- and S-thiopental enantiomers that have different potencies in laboratory experiments. We measured concentrations of R- and S-thiopental in plasma, tissues and brain microdialysate of rats after computer-controlled infusion of thiopental i.v. to a plasma concentration of 40 micrograms ml-1 for 20 min in two pharmacokinetic studies. In study 1, animals were found to maintain their target plasma concentrations, which then decayed biphasically after infusion. Brain microdialysate concentrations of both enantiomers increased from about 3% of corresponding plasma concentrations at 1 min to 9% at 20 min. In study 2, thiopental concentrations were found to be highest at 20 min in CNS tissue, at 30 min in muscle and at 60 min in fat. Tissue:plasma distribution coefficients of R-thiopental were greater than those of S-thiopental when calculated from total or unbound plasma concentrations. We found no pharmacokinetic evidence to support differences between the thiopental enantiomers in rates of equilibration across the blood-brain barrier after infusion of rac-thiopental.

Anesthetics, Intravenous↗

PubMed2000

The effect of diclofenac on the expression of spinal cord c-fos-like immunoreactivity after ischemia-reperfusion-induced acute hyperalgesia in the rat tail.

Ischemia-reperfusion of the rat tail for 20 min induces local acute hyperalgesia of approximately 1-h duration. We studied how this stimulus affected the expression of c-fos-like immunoreactivity (c-fos-LI) labeling of neurons of the sacral spinal cord, and how diclofenac pretreatment influenced the outcome. After ischemia, the number of c-fos-LI-labeled neurons was significantly increased when assessed at 60, 90, and 120 min after reperfusion (to 183%, 283%, and 164% of control, respectively; all P < 0.01). At 90 min, the number of regional c-fos-LI-labeled neurons was increased to 585% in laminae I-II, 183% in laminae III-IV, 270% in laminae V-X, and 286% in total, compared with respective control values (all P < 0.01). After diclofenac pretreatment (subcutaneous 40 mg/Kg, 30 min before insult) the number of c-fos-LI-labeled neurons at 90 min was increased to 424% in laminae I-II, 150% in laminae III-IV, 142% in laminae V-X, and 183% in total (all P < 0.01). Thus diclofenac pretreatment partially prevented the insult-induced increase in total and regional neuronal c-fos-LI. This acute nociceptive model involves only natural algogens. However, the results were similar to acute chemically induced or chronic adjuvant induced arthritic inflammatory pain models in which increases in c-Fos were partially inhibited by nonsteroidal antiinflammatory drugs.

Acute Disease↗

PubMed2000

Tolerability of large-dose intravenous levobupivacaine in sheep.

UNLABELLED: In preclinical pharmacological studies of levobupivacaine (S-bupivacaine), we determined its tolerability, cardiovascular actions, and pharmacokinetics, and we estimated its margin of safety compared with bupivacaine in conscious sheep. Levobupivacaine HCl. H(2)O was infused IV for 3 min into 10 previously instrumented ewes (approximately 50 kg). On subsequent days, the doses were increased by 50 mg from 200 or 250 mg until fatality occurred. All doses produced convulsions, QRS widening, and cardiac arrhythmias. With incremental doses, 4 of 4 animals survived 200 mg, 7 of 10 survived 250 mg, 3 of 7 survived 300 mg, but 0 of 3 survived 350 mg. Death resulted from sudden onset ventricular fibrillation (n = 3, within 2-3 min), electromechanical dissociation-pump failure (n = 5, within 4-5 min), or ventricular tachycardia-induced cardiac insufficiency (n = 2, >10 min). The estimated fatal dose (mean +/- SD) was 277 +/- 51 mg for levobupivacaine (compared with 156 +/- 31 mg found previously for bupivacaine). Pharmacokinetic analysis indicated initial and total distribution volumes = 4.5 (+/-1.6) and 97 (+/-22) L, total clearance = 1.7 (+/-0.4) L/min, and slow half life = 70 (+/-29) min; these values did not differ from those found previously with smaller doses. Heart and brain tissue levobupivacaine concentrations were approximately 3 times those in arterial blood. The doses of levobupivacaine survived were larger than found previously for bupivacaine, indicating its greater margin of safety. IMPLICATIONS: Levobupivacaine produced fatal cardiac toxicity at doses significantly greater than those found in previous studies with bupivacaine. As the two drugs have similar potency for producing clinical nerve blocks, the data imply that levobupivacaine should provide a safer alternative to bupivacaine in practice.

Acid-Base Equilibrium↗

PubMed2000

The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury.

We performed a double-blinded, randomized, controlled trial in 15 patients to determine the efficacy of intrathecal morphine or clonidine, alone or combined, in the treatment of neuropathic pain after spinal cord injury. The combination of morphine and clonidine produced significantly more pain relief than placebo 4 h after administration; either morphine or clonidine alone did not produce as much pain relief. In addition, lumbar and cervical cerebrospinal fluid (CSF) concentrations, sampled at these levels at different times after administration were examined for a relationship between pain relief and CSF drug concentration. Lumbar CSF drug concentrations were initially several orders of magnitude larger than those in cervical CSF. After 1-2 h, the concentrations of morphine in cervical CSF markedly exceeded those of clonidine. The concentration of morphine in the cervical CSF and the degree of pain relief correlated significantly. We conclude that intrathecal administration of a mixture of clonidine and morphine is more effective than either drug administered alone and is related to the CSF-borne drug concentration above the level of spinal cord injury. If there is pathology that may restrict CSF flow, consideration should be given to intrathecal administration above the level of spinal cord damage to provide an adequate drug concentration in this region.

Adult↗

PubMed2000

Lack of whole-body pharmacokinetic differences of halothane enantiomers in the rat.

BACKGROUND: Halothane is made and used as a racemate (an equimolar mixture of R- and S- enantiomers). This study was initiated to determine whether there were demonstrable enantiomeric differences in the whole-body pharmacokinetics of halothane that might have significance for studies in which racemate is used. METHODS: Adult male Wistar rats were exposed to halothane vaporized in the atmosphere of a closed constant volume chamber supplied with O2 commensurate with CO2 production. Concentrations of halothane enantiomers were measured by a specific gas chromatography-mass spectrometry method. Experiments were performed at four initial concentrations of halothane (0.1%, 0.5%, 1.0%, and 1.5% vol/vol). Enantiomeric differences in whole-body pharmacokinetics were assessed indirectly from the relative chamber atmosphere concentrations of halothane enantiomers. RESULTS: Concentrations of halothane decreased biphasically. The initial more rapid decrease was interpreted as incorporating absorption, distribution, and clearance; the slower decrease was interpreted as principally incorporating metabolic clearance. The ratio of concentrations of the two halothane enantiomers and of the ratios of the respective areas under the concentration-time curves remained constant without differing from unity at any time at any concentration of halothane. The dose-normalized areas under the concentration-time curves for the concentrations 0.1%, 0.5%, and 1.0% did not differ; that for 1.5% was significantly greater, suggesting nonlinear clearance, but the values did not differ significantly between enantiomers at any concentration. CONCLUSIONS: As there were no significant differences in concentrations of the two enantiomers in the chamber atmosphere, enantioselectivity was not demonstrated in the whole-body pharmacokinetics of halothane.

Anesthetics, Inhalation↗

PubMed2000

Glutamate and kynurenate in the rat central nervous system following treatments with tail ischaemia or diclofenac.

Kynurenate is an endogenous antagonist at the allosteric glycine site on the N-methyl-D-aspartate (NMDA) receptor, and may have a role in ameliorating nociceptive processes through modulation of NMDA receptor function. While antinociceptive effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are mediated peripherally and possibly centrally through inhibition of prostaglandin synthesis, there is also evidence for centrally mediated prostaglandin-independent antinociceptive effects that may result from increased central nervous system (CNS) concentrations of kynurenate. We have investigated the effects of the NSAID diclofenac, (40 mg kg(-1), s.c.; administered to rats 1 h before killing) or the exposure of rats to noxious stimulation (tail ischaemia for 20 min before killing), on the concentrations of glutamate and kynurenate in discrete CNS regions. Regional CNS tissue concentrations of diclofenac were between 3.0-3.8 nmolg(-1). The corresponding regional glutamate concentrations ranged between 4.8-10.6 micromol g(-1), and were significantly lower in the ischaemia group when compared with both control (15%, P < 0.05) and diclofenac-treated (19%, P < 0.002) groups. Kynurenate concentrations in these CNS regions ranged between 3.3-45.8 pmol g(-1). Pairwise comparisons between the control and diclofenac-treated groups found significant increases in kynurenate concentrations in the diencephalon and lumbo-sacral regions of the CNS (P = 0.05). Noxious stimulation from tail ischaemia appeared to be associated with increased release of glutamate. Additionally, NSAIDs appeared to increase kynurenate concentrations in the spinal cord and diencephalon. Antagonism by kynurenate of glutamate effects at NMDA receptors may contribute to the antinociceptive effects of NSAIDs.

Animals↗

PubMed1999

Stereoselective interaction of thiopentone enantiomers with the GABA(A) receptor.

1. As pharmacokinetic differences between the thiopentone enantiomers seem insufficient to explain the approximately 2 fold greater potency for CNS effects of (-)-S- over (+)-R-thiopentone, this study was performed to determine any enantioselectivity of thiopentone at the GABA(A) receptor, the primary receptor for barbiturate hypnotic effects. 2. Two electrode voltage clamp recording was performed on Xenopus laevis oocytes expressing human GABA(A) receptor subtype alpha1beta2gamma2 to determine relative differences in potentiation of the GABA response by rac-, (+)-R- and (-)-S-thiopentone, and rac-pentobarbitone. Changes in the cellular environment pH and in GABA concentrations were also evaluated. 3. With 3 microM GABA, the EC50 values were (-)-S-thiopentone (mean 26.0+/-s.e.mean 3.2 microM, n=9 cells) >rac-thiopentone (35.9+/-4.2 microM, n=6, P=0.1) >(+)-R-thiopentone (52.5+/-5.0 microM, n=8, P<0.02) >rac-pentobarbitone (97.0+/-11.2 microM, n=11, P<0.01). Adjustment of environment pH to 7.0 or 8.0 did not alter the EC50 values for (+)-R- or (-)-S-thiopentone. 4 Uninjected oocytes responded to >100 microM (-)-S- and R-thiopentone. This direct response was abolished by intracellular oocyte injection of 1,2-bis(2-aminophenoxy)ethane-N, N,N1,N1-tetraacetic acid (BAPTA), a Ca2+ chelating agent. With BAPTA, the EC50 values were (-)-S-thiopentone (20.6+/-3.2 microM, n=8) <(+)-R-thiopentone (36.2+/-3.2 microM, n=9, P<0.005). 5 (-)-S-thiopentone was found to be approximately 2 fold more potent than (+)-R-thiopentone in the potentiation of GABA at GABA(A) receptors expressed on Xenopus oocytes. This is consistent with the differences in potency for CNS depressant effects found in vivo.

Animals↗

PubMed1999

Electroencephalographic effects of thiopentone and its enantiomers in the rat: correlation with drug tissue distribution.

1. To better understand the pharmacology of the thiopentone enantiomers, we studied their quantitative electroencephalographic effects and their distribution into vital tissues. 2. Adult Wistar rats were infused with rac-, R- or S-thiopentone at 4 mg kg(-1)min(-1) until death ensued. The EEG signal was acquired continuously; serial arterial plasma and terminal tissue thiopentone concentrations were measured enantiospecifically. Relevant drug tissue : plasma distribution coefficients and plasma concentration-EEG effect relationships were determined. 3. Doses (mg kg(-1)) (mean+/-s.e.mean) for anaesthesia (toe pinch) and lethality (respiratory failure), respectively, decreased in the order R-thiopentone (55.8+/-2.4 and 176.2+/-11.2)> rac-thiopentone (39.3+/-2.1 and 97.5+/-3.9)> S-thiopentone (35.6+/-1.9 and 74.2+/-5.2); plasma drug concentrations (microg ml(-1)) decreased in the order R-thiopentone (66.3+/-4.5 and 89.8+/-5.2)> rac-thiopentone (56.7+/-2.0 and 77. 8+/-2.8)> S-thiopentone (55.0+/-1.9 and 64.1+/-2.8). 4. Initial EEG activation was similar for all thiopentone forms. Plasma drug concentrations for the same extent of EEG deactivation reflected the potency order. 5. After infusion of rac-thiopentone, tissue : plasma distribution coefficients were higher for R- than for S-thiopentone in brain and visceral regions, but not in fat or muscle. After infusion of the separate enantiomers, the relative heart : brain distribution ratio was for S-thiopentone was double that for R-thiopentone. 6. The therapeutic index of R-thiopentone (3.16+/-0. 14) was more advantageous than either rac-thiopentone (2.52+/-0.13) or S-thiopentone (2.10+/-0.14), possibly due to the relatively greater distribution into CNS tissues than heart. The data suggest that R-thiopentone could make a satisfactory single enantiomer substitute for rac-thiopentone.

Anesthetics, Intravenous↗

PubMed1999

Enantioselectivity of thiopental distribution into the central neural tissue of rats: an interaction with halothane.

UNLABELLED: Thiopental is a racemate. In this study, we examined whether thiopental total body clearance and its distribution into central nervous system (CNS) tissue of rats was enantioselective. Rats, either anesthetized with halothane or conscious and restrained, were infused to stepwise steady-state targets of 5, 10, and 20 microg/mL thiopental by computer-controlled infusions. Serial arterial plasma and steady-state samples of brain and spinal cord were assayed enantiospecifically for thiopental. In both groups, concurrent total and unbound plasma concentrations of S-thiopental were approximately 10%-20% higher than those of R-thiopental, corresponding to its higher clearance. CNS tissue concentrations of S-thiopental were approximately 20% higher than those of R-thiopental. Spinal cord to plasma distribution coefficients were approximately 2 x those in the brain, with relative distribution coefficients approximately 10% greater for R-thiopental in both tissues. Plasma concentrations and distribution coefficients of both enantiomers were approximately 10%-20% lower in the halothane-anesthetized group, with a slightly greater effect on R-thiopental distribution. We conclude that the total body clearance of R-thiopental > S-thiopental, that halothane enantioselectively reduces the relative uptake of R-thiopental into brain tissue, and that composition is important in determining the CNS tissue concentrations of thiopental. The reported higher potency of S-thiopental did not seem to be due to its greater distribution into CNS tissues. IMPLICATIONS: Because thiopental is a mixture of two forms (termed R-and S-enantiomers), correct interpretation of its distribution into, and clearance from, the body requires knowledge about both enantiomers. In this study, performed in rats, we showed that the two enantiomers of thiopental differed significantly, with the R-enantiomer having the preferred profile.

Anesthetics, Inhalation↗

PubMed1999

Renal dysfunction associated with the perioperative use of diclofenac.

UNLABELLED: Postoperative renal dysfunction in rats is induced by ketorolac dosed concurrently with gentamicin. Herein, we report the renal effects of diclofenac in four groups of rats: control (C = anesthesia, surgery); diclofenac (D = anesthesia, surgery, diclofenac 18 mg x kg(-1) x d(-1)); gentamicin (G = anesthesia, surgery, gentamicin 20 mg x kg(-1) x d(-1)); and diclofenac and gentamicin (DG = anesthesia, surgery, diclofenac, gentamicin). Renal function, after three treatment days, was assessed using histology, p-aminohippurate (PAH), and iothalamate (IOT) clearances, serum and urine electrolytes, osmolality, urea, and creatinine. Urine output was increased (from 5.2 to 12.5 mL/24 h), and urine osmolality was decreased (from 2121 to 883 mOsm/kg) in the DG group. PAH and IOT clearances were decreased in the G and DG groups (PAH by 18%, IOT by 22%; PAH by 38%, IOT by 43%, respectively); there were no changes in the C and D groups. Urea and creatinine clearances were decreased by 61% and 43%, respectively, in the DG group. Kidney sections showed the most severe pathologic changes in the DG group. Our data indicate that the perioperative combination of diclofenac and gentamicin was deleterious to renal function. IMPLICATIONS: Diclofenac alone does not result in significant perioperative renal dysfunction, but the combination of gentamicin and diclofenac is deleterious to renal function. Considering this and previous findings, the evidence suggests that treatment with aminoglycosides may be a significant risk factor for inducing perioperative renal failure during treatment with nonsteroidal antiinflammatory drugs.

Animals↗

PubMed1999

Pharmacokinetics of thiopental enantiomers during and following prolonged high-dose therapy.

BACKGROUND: Thiopental is used as a racemate; however, this is not generally recognized. During conditions of prolonged high-dose therapy, the pharmacokinetics of thiopental may become nonlinear, but whether this derives from one or both enantiomers has not been evaluated. The authors determined the pharmacokinetics of R- and S-thiopental and serum concentrations of R- and S-pentobarbital from prolonged high-dose infusion of thiopental for neuroprotection. METHODS: Twenty patients received a mean thiopental dose of 41.2 g over a mean duration of 95 h. R- and S-thiopental enantiomer serum concentration-time data from 18 patients were fitted with two models: a linear one-compartment model with first-order output, and a nonlinear one-compartment model with Michaelis-Menten output. RESULTS: Nonlinear models were preferred in 16 of 18 patients. Paired analysis indicated that steady state clearance (Clss) and volume of distribution (Vd) were higher for R-thiopental (0.108 vs. 0.096 l/min, P < 0.0001; and 313 vs. 273 l, P < 0.0005, respectively); maximal rate of metabolism (Vm) was higher for S- than for R-thiopental (1.01 vs. 0.86 mg x l(-1) x h(-1), P = 0.02); elimination half-lives did not differ (14.6 vs. 14.7 h, P = 0.8); unbound fractions (f(u)) of R- and S-thiopental were 0.20 and 0.18, respectively, P < 0.0001). The differences in mean Clss, Vd and Vm were not significant when adjusted by f(u). Plasma concentrations of R- and S-pentobarbital were relatively small and unlikely to be of clinical significance. CONCLUSION: The pharmacokinetics of R- and S-thiopental became nonlinear at these doses. The pharmacokinetic differences between R- and S-thiopental, although small, were statistically significant and were influenced by the higher f(u) of R-thiopental.

Adolescent↗

PubMed1999

Epidural analgesia reduces the release of amino acids from peripheral tissues in the ebb phase of the metabolic response to major upper abdominal surgery.

The purpose of this prospective cohort study was to compare metabolic effects of epidural or patient controlled analgesia (PCA) in patients undergoing major upper abdominal surgery. Seventeen patients undergoing major upper abdominal surgery were included: 10 received perioperative epidural analgesia (Group I) and the remainder received morphine via a PCA device for postoperative analgesia (Group II). A number of measures compared between one day preoperatively (day 1) and day 2 postoperatively included femoral arterial and venous blood concentrations of glucose, lactate, pyruvate and amino acids. In addition, the relevant flux values were measured from the products of the respective arteriovenous substrate concentration differences and calf blood flow. The efflux of lactate from peripheral tissues was greater in Group II than in Group I (P < 0.01): glucose and pyruvate efflux did not differ between groups. There was no difference between groups in mean individual and total flux of amino acids on day-1. However increased efflux between day-1 and day 2 was found for alanine, valine, isoleucine, leucine, phenylalanine, lysine, arginine in both groups, and for serine, glycine, tyrosine and histidine in Group II (P < 0.05). The efflux of glycine, methionine, amino benzoic acid, alanine, and lysine was less in Group I than Group II on day 2 (P < 0.05). There was a significant difference in the total amino acid flux on day 2 (Group I = -1.2 mumol. (100 ml tissue)-1.min-1 cf Group II = -2.5 mumol. (100 ml tissue)-1.min-1; P = 0.04). In conclusion, perioperative epidural analgesia was associated with a reduced postoperative amino acid efflux two days following major upper abdominal surgery.

Amino Acids↗

PubMed1999

The relationship between the myocardial kinetics of meperidine and its effect on myocardial contractility: model-independent analysis and optimal regional model.

The myocardial kinetics of meperidine and the relationship between these kinetics and the effect of meperidine on myocardial contractility (maximum positive rate of change of left ventricular pressure) were examined by analysis of previously published data collected in sheep after the i.v. injection of 100 mg of meperidine over 1 s. There was significant hysteresis between reductions in myocardial contractility and the arterial concentrations of meperidine, but not the coronary sinus blood (effluent from the heart) or calculated myocardial concentrations. The peak reduction in contractility occurred after the peak arterial concentration, at the time of the peak myocardial concentration, but before the peak coronary sinus concentration, suggesting that the site of drug action in the heart was not in equilibrium with either arterial blood or effluent blood from the heart. The most appropriate form of a dynamic model (a linear model with a threshold) was determined, without the need to assume a kinetic model, by directly fitting the observed reductions in myocardial contractility to the calculated myocardial concentrations. To determine the optimal kinetic and combined kinetic-dynamic models, a variety of one-, two-, and three-compartment models of the myocardium were fitted to the coronary sinus concentrations by using hybrid modeling. These included "tank in series" models that accounted well for drug dispersion and "peripheral compartment" models that accounted well for deep distribution. The most appropriate model was a "compilation" model, which incorporated features of both these extremes and was a better fit to the observed data than either a traditional single flow-limited compartment or a traditional membrane-limited model.

Algorithms↗

PubMed1998

High-performance liquid chromatographic separation and nanogram quantitation of bupivacaine enantiomers in blood.

Chiral separation of rac-bupivacaine extracted from blood was achieved with similar limits of detection but using a much simpler sample preparation than reported previously. The simple one-step sample preparation devised was highly robust and efficient and allowed a very high throughput of samples. The high-performance liquid chromatography (HPLC) conditions used gave baseline separation of the enantiomers with high sensitivity. R-(+)-bupivacaine and S-(-)-bupivacaine blood concentrations were determined using a chiral stationary phase (AGP, ChromTech) with diode array detection at 220 nm; this wavelength produced a stable baseline allowing semi-automated analysis. Sample preparation involved addition of internal standard (diphenhydramine), basification of blood, extraction with n-hexane, concentration of the extract to dryness and reconstitution in 0.002 M phosphoric acid. At rac-bupivacaine concentrations of 0.5, 5 and 50 microg/ml in blood, assay accuracy as estimated by coefficients of variation (C.V.s), were 3.3, 1.4, and 1.6%, respectively, for R-(+)-bupivacaine and 3.7, 2.0 and 1.5%, respectively, for S-(-)-bupivacaine. Using 0.6-ml samples, the estimated limits of detection for R-(+)-bupivacaine and S-(-)-bupivacaine were both 15 ng/ml of blood. Calibration curves (n=188) were linear from 0.1 to 50 microg/ml with all correlation coefficients being greater than 0.99. This semi-automated method was applied to studies involving whole body pharmacokinetics with intravenous doses ranging from 12.5 to 350 mg and regional myocardial pharmacokinetics with coronary arterial doses ranging from 2.5 to 12.5 mg. These studies generated approximately 12000 blood samples.

Anesthetics, Local↗

PubMed1998

Pulmonary administration of aerosolised fentanyl: pharmacokinetic analysis of systemic delivery.

AIMS: Pulmonary drug delivery is a promising noninvasive method of systemic administration. Our aim was to determine whether a novel breath-actuated, microprocessor-controlled metered dose oral inhaler (SmartMist, Aradigm Corporation) could deliver fentanyl in a way suitable for control of severe pain. METHODS: Aersolised pulmonary fentanyl base 100-300 microg was administered to healthy volunteers using SmartMist and the resultant plasma concentration-time data were compared with those from the same doses administered by intravenous (i.v.) injection in the same subjects. RESULTS: Plasma concentrations from SmartMist were similar to those from i.v. injection. Time-averaged bioavailability based upon nominal doses averaged approximately 100%, and was > 50% within 5 min of delivery. Fentanyl systemic pharmacokinetics were similar to those previously reported with no trends to dose-dependence from either route. Side-effects (e.g. sedation, lightheadedness) were the same from both routes. CONCLUSIONS: Fentanyl delivery using SmartMist can provide analgetically relevant plasma drug concentrations. This, combined with its ease of noninvasive use and transportability, suggests a strong potential for field and domicilliary use, and for patient controlled analgesia without the need for i.v. cannulae.

Administration, Inhalation↗

PubMed1998

The effect of duration of dose delivery with patient-controlled analgesia on the incidence of nausea and vomiting after hysterectomy.

AIMS: Postoperative nausea and vomiting (PONV) may be exacerbated by postoperative opioid analgesics and may limit patients' successful use of these medications when used with patient controlled analgesia (PCA). We tested the hypothesis that the rapid change in blood morphine concentration associated with PCA bolus delivery contributed to PONV, and that prolonging its delivery to a brief infusion would result in decreased PONV. METHODS: Patients, who were receiving morphine for pain relief via patient-controlled analgesia (PCA) after total abdominal hysterectomy, received 1 mg morphine sulphate incremental doses either over 40 s with a 5 min lockout interval or over 5 min delivery with a 1 min lockout interval. Episodes of nausea, retching and vomiting, along with the use of morphine and the pain relief obtained, were recorded. RESULTS: Data from 20 patients in each group were analysed. Contrary to expectations, most patients in both groups reported nausea postoperatively. Those patients receiving morphine over 5 min experienced more episodes of emesis (36) than those receiving the dose over 40 s (17). Most patients receiving the 40 s doses vomited in the first 12 h (median time 8 h), while those receiving the 5 min doses vomited between 12 and 24 h (median time 19 h) (P = 0.01). There were no differences between groups in the visual analogue pain scores or use of morphine between groups. CONCLUSIONS: Reasons for these unexpected findings remain speculative. The high incidence of PONV appears to be inherently high in gynaecological surgery patients and standard antiemetic medication regimens appear to be poorly efficacious. Reasons for the differences in the time-course of emetic episodes between the two groups may be related to differences in the time-course of central opioid receptor occupancy.

Adult↗