Biomedical subjects

S R Edwards

Publications and source records attributed to S R Edwards.

At least 19 recordsLinked to original sources

PubMed2002

Concurrent ketamine and alfentanil administration: pharmacokinetic considerations.

BACKGROUND: A ketamine-alfentanil combination has been suggested for total i.v. anaesthesia. We determined the pharmacokinetics of ketamine and alfentanil, alone and together, in three groups of adult male rats, to assess any pharmacokinetic interaction. METHODS: Group 1 animals were infused with i.v. ketamine for 5 min; in group 2, constant low plasma concentrations of alfentanil were maintained by computer-controlled infusion; in group 3, the treatments were combined. Serial plasma and terminal tissue concentrations were measured by high performance liquid chromatography or gas chromatography-mass spectrometry. RESULTS: In the presence of alfentanil, the mean plasma ketamine concentration-time area under the curve (AUC) value was significantly lower (by 13%, P<0.05), while clearance (CIT) and volume of distribution (Vss) were significantly higher (by 16 and 28%, respectively, both P<0.05). Tissue:plasma distribution coefficients for ketamine in the presence of alfentanil were significantly higher in forebrain (by 128%, P<0.005), hindbrain (by 207%, P<0.01), gut (by 254%, P<0.005), and fat (by 344%, P<0.0001). Mean AUC values for alfentanil did not differ significantly in the presence of ketamine, but alfentanil tissue concentrations were significantly lower in forebrain (by 77%, P<0.0001), hindbrain (by 28%, P<0.01), heart (by 33%, P<0.01), lung (30%, P<0.05), and gut (by 21%, P<0.05). Corresponding tissue:plasma distribution coefficients were significantly lower for forebrain (by 69%, P<0.0001) alone. CONCLUSIONS: The finding that the distribution of ketamine into the brain was increased by low plasma concentrations of alfentanil could have important clinical applications for pain management.

Alfentanil↗

PubMed2001

Tissue uptake of ketamine and norketamine enantiomers in the rat: indirect evidence for extrahepatic metabolic inversion.

Ketamine, used clinically as an intravenous analgetic and dissociative anaesthetic agent, is a racemate with both pharmacokinetic and pharmacodynamic enantioselectivity. S-ketamine has been found have a higher clearance and greater potency than R-ketamine as well as a greater therapeutic index. We performed a study in rats with two complementary paradigms: (i) constant rate "washin" infusion until fatal, (ii) brief infusion then "washout". These, respectively, allowed examination of ketamine and norketamine serial plasma enantiomer concentrations and tissue distribution at maximal and minimal drug effects. Both paradigms found plasma concentrations of R-ketamine>S-ketamine; however, tissue distribution coefficients for S-ketamine>R-ketamine. For paradigm (i), plasma concentrations of R-norketamine>S-norketamine; for paradigm (ii), R-norketamine>>S-norketamine initially, but S-norketamine>>R-norketamine later. Comparison of distribution coefficients of ketamine and norketamine enantiomers for the two paradigms provided indirect evidence for metabolic inversion. During washin, when circulating concentrations of ketamine enantiomers were high, uptake and metabolism occurred predominantly in the kidney and to a lesser extent in liver, lung and gut, with formation of R-norketamine by a (presumed) first-order process predominating. However, following washout, when circulating concentrations of ketamine enantiomers were low, uptake and metabolism was dominated by the kidney and gut. Under these conditions inversion of R- to S-ketamine appeared to predominate with subsequent metabolism to S-norketamine by (presumed) zero-order processes. In summary, different profiles for the uptake and metabolism of ketamine enantiomers were apparent following constant rate washin, and brief infusion washout, paradigms with i.v. rac-ketamine. Uptake into most tissues, and metabolism in some tissues, was enantioselective.

Animals↗

PubMed2001

Applying data mining techniques to the mapping of complex disease genes.

The simulated sequence data for the Genetic Analysis Workshop 12 were analyzed using data mining techniques provided by SAS ENTERPRISE MINER Release 4.0 in addition to traditional statistical tests for linkage and association of genetic markers with disease status. We examined two ways of combining these approaches to make use of the covariate data along with the genotypic data. The result of incorporating data mining techniques with more classical methods is an improvement in the analysis, both by correctly classifying the affection status of more individuals and by locating more single nucleotide polymorphisms related to the disease, relative to analyses that use classical methods alone.

Chromosome Mapping↗

PubMed2001

Effects of diclofenac in the rat tail ischaemia--reperfusion injury model of acute hyperalgesia.

The rat tail ischaemia--reperfusion model of acute hyperalgesia described by Gelgor et al. (Pain 24 (1986) 251) has been investigated pharmacologically and electrophysiologically. Despite the advantages of this reusable animal model, biochemical changes associated with the behavioural response have not been determined. After injury+/-subcutaneous diclofenac pretreatment, we investigated the behavioural response (changes to thermally-induced tail flick latency) and measured diclofenac, prostaglandin E(2), 6-keto-prostaglandin F(1 alpha) and thromboxane B(2) concentrations in the tail, spinal cord and brain. Subcutaneous injection of 40 mg kg(-1) diclofenac sodium abolished the hyperalgesic response, suppressed the increased eicosanoid production in the tail, inhibited eicosanoid synthesis in the brain, but gave equivocal effects on eicosanoid concentrations in the spinal cord. Injection of 10 and 20 mg kg(-1) diclofenac reduced the duration of hyperalgesia but did not abolish the behavioural response. Diclofenac concentrations in all three tissues were similar, being approximately 5--10% of the corresponding plasma concentrations. We propose that both central and peripheral mechanisms are associated with the hyperalgesia and that the findings lend indirect support to a central action for non-steroidal anti-inflammatory drugs.

6-Ketoprostaglandin F1 alpha↗

PubMed2001

The elimination of the yeast [PSI+] prion by guanidine hydrochloride is the result of Hsp104 inactivation.

In the yeast Saccharomyces cerevisiae, Sup35p (eRF3), a subunit of the translation termination complex, can take up a prion-like, self-propagating conformation giving rise to the non-Mendelian [PSI+] determinant. The replication of [PSI+] prion seeds can be readily blocked by growth in the presence of low concentrations of guanidine hydrochloride (GdnHCl), leading to the generation of prion-free [psi-] cells. Here, we provide evidence that GdnHCl blocks seed replication in vivo by inactivation of the molecular chaperone Hsp104. Although growth in the presence of GdnHCl causes a modest increase in HSP104 expression (20-90%), this is not sufficient to explain prion curing. Rather, we show that GdnHCl inhibits two different Hsp104-dependent cellular processes, namely the acquisition of thermotolerance and the refolding of thermally denatured luciferase. The inhibitory effects of GdnHCl protein refolding are partially suppressed by elevating the endogenous cellular levels of Hsp104 using a constitutive promoter. The kinetics of GdnHCl-induced [PSI+] curing could be mimicked by co-expression of an ATPase-negative dominant HSP104 mutant in an otherwise wild-type [PSI+] strain. We suggest that GdnHCl inactivates the ATPase activity of Hsp104, leading to a block in the replication of [PSI+] seeds.

Fungal Proteins↗

PubMed2000

Electroencephalographic effects of thiopentone and its enantiomers in the rat.

Electrophysiological studies with some chiral barbiturates have shown that one enantiomer can be excitant while the other is depressant. Thiopentone, a chiral barbiturate, has both differences in potency between enantiomers and biphasic effects on the electroencephalogram (EEG). This study investigated whether a differential EEG activity between the enantiomers of thiopentone could account for the biphasic effects. Rats were administered rac-, R- or S-thiopentone to determine the nature and time course of quantitative EEG effects. Two studies using computer-controlled i.v. infusions of the three drugs were performed in groups of animals previously prepared with EEG electrodes and/or arterial blood sampling cannulae. Study 1 used several stepwise increments in plasma drug concentration over 35 min, followed by washout. Study 2 used a 4 min period of constant plasma drug concentration, followed by washout. In both studies, both enantiomers and racemate caused an initial EEG activation followed by deactivation. Quantitative enantioselectivity was found for depression. The extent of depression was significantly less for R-thiopentone (P=0.008) and racthiopentone (P=0.038) than for S-thiopentone; recovery from depression appeared to be faster for R-thiopentone than either rac- or S-thiopentone. Fatality was only found with S-thiopentone (3/7 animals in Study 2). R-thiopentone plasma concentrations were approximately 8% less than those of S-thiopentone in rats treated with racthiopentone. Although small differences in clearance between enantiomers were found that may influence recovery, they were not large enough to account for the reported differences in potency between the two enantiomers.

Animals↗

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

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

Enolase is present in the cell wall of Saccharomyces cerevisiae.

Non-covalently attached or soluble cell wall proteins of Saccharomyces cerevisiae were extracted using a high pH/2-mercaptoethanol procedure and were separated for peptide sequencing using 2D-PAGE. A partial N-terminal sequence of a major protein spot was obtained and showed high identity with enolase gene products. Western blotting with an anti-enolase antibody confirmed that enolase was present in the cell wall extract. Biotinylation of cells prior to protein extraction with a membrane impermeable biotinylating agent confirmed that the detection was not owing to cell lysis during extraction. Transmission immunoelectron microscopy showed enolase to be present in the cell wall. Enolase contains no known secretion signal that would localize it to the cell wall. Thus S. cerevisiae must have further mechanisms for targeting proteins to the cell wall.

Amino Acid Sequence↗

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

Specific immunoglobulin E to peanut, hazelnut and brazil nut in 731 patients: similar patterns found at all ages.

BACKGROUND: Previous studies have reported reactions to an increasing range of nuts as patients with nut allergy grow older. Most patients with symptoms suggesting nut allergy have specific IgE to more than one nut. Furthermore, fatal reactions have followed eating nuts different from any causing the deceased's previous reactions. OBJECTIVE: To explore the pattern of specific IgE to three distantly related nuts in patients of all ages with nut allergy. METHODS: This study includes all patients referred to our laboratory for nut allergy testing from January 1994 to August 1998 who were tested for peanut, hazelnut and brazil nut, and had specific IgE to at least one of these nuts. All tests were performed using the Pharmacia Unicap system. RESULTS: Seven hundred and thirty-one patients (age 7 months to 65 years, median 6.6 years) had specific IgE >0.35 kU(A)/L to at least one of these three nuts: 282 had IgE to one nut, 130 to two nuts, and 319 to all three nuts. When analysed by gender and age quartile, very similar patterns were found in all subgroups though significant age trends and age interactions were found for IgE to individual nuts and combinations of nuts. CONCLUSIONS: The probability of a patient with nut allergy having specific IgE to a particular combination of peanut, hazelnut and brazil nut is similar, whatever their age or sex. The apparent increase in multiple nut reactivity with increasing age may therefore be due to exposure of previously unchallenged sensitivity. The frequency of multiple-nut specificity is sufficiently high that patients should always be tested for allergy to a range on nuts if they have a history of reacting to any nut.

Adolescent↗

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↗

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↗

PubMed1994

Humane destruction of horses with a mixture of quinalbarbitone and cinchocaine.

One hundred and-two horses requiring to be euthanased for a variety of reasons were killed by the intravenous injection of a mixture of quinalbarbitone sodium (400 mg/ml) and cinchocaine hydrochloride (25 mg/ml). The dose rates used were 1 ml/10, 15, 20 and 30 kg bodyweight, and the time of injection was varied between 5 and 25 seconds. The average time to collapse from the start of the injection was 34 seconds and the average time to clinical death was 230 seconds. Slow injection (particularly of the low dose rates) and premedication with detomidine resulted in a longer time to collapse (median 46 seconds). Premedication with xylazine and low dose rates of the mixture resulted in an unacceptable degree of muscular activity and agonal gasping and death was delayed. Premedication with romifidine and butorphanol resulted in an apparent (but insignificant) reduction in the time to collapse and death but was also accompanied by significant agonal gasping. Without premedication quinalbarbitone and cinchocaine resulted in a smooth and quiet collapse with the cessation of cardiac and respiratory functions within three minutes in all cases, but the palpebral reflex of the horses was prolonged significantly beyond the time when all other reflex activity was lost. Occasional gasping and muscular tremors, particularly of the upper forelimb, occurred particularly when lower dose rates and either very slow or very fast rates of injection were used. One horse which was premedicated with xylazine and received a very low dose at a slow rate showed unacceptably violent muscular activity. At no other time was the procedure regarded as violent or unacceptable.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Welfare↗

PubMed1992

Humoral responses to a multivalent vaccine in age-matched lambs of different bodyweight and nutrition.

K-agglutination, pilus-enzyme-linked immunosorbent assay (ELISA) and outer membrane protein-ELISAs were used to assess humoral responses after vaccination with a commercial, multivalent, ovine foot rot vaccine (Dichelobacter nodosus whole cells) in three groups of nine-month-old lambs of markedly different bodyweight, nutritional history and dietary protein supply. Mean bodyweights of lambs in low (L), medium (M) and high (H) bodyweight/nutrition groups were 22, 32 and 48 kg, respectively, at the time of vaccination. Few significant differences in humoral responses to vaccine antigens were found between groups. However, lambs in group H tended to have lower levels of antibody to a greater number of component antigens than did lambs in the other groups. These results suggest that low bodyweight due to poor nutrition is unlikely to affect the response of sheep to multivalent foot rot vaccines.

Agglutination Tests↗

PubMed1992

Suppression of central noradrenergic neuronal activity inhibits hyperglycemia.

Hypothalamic noradrenergic neuronal activity (NNA) and hepatic glucose output are stimulated by stress. The aim of the present investigation was to examine whether the blockade of noradrenergic responses to stress might suppress the associated hyperglycemia. Mass spectrometry was used for analysis of norepinephrine (NE) and its neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) in rat hypothalamus, and the ratio DHPG/NE was used as an index of NNA. Treatment of rats with 2-deoxy-D-glucose (500 mg/kg ip, -30 min), yohimbine (10 mg/kg ip, -20 min), or neostigmine (2 micrograms icv, -60 min) increased both NNA and serum glucose (P < 0.05). When rats were additionally pretreated with pentobarbital (60 mg/kg ip; -60 min), the NNA responses were blocked (P < 0.01). At the same time the hyperglycemic responses were also inhibited (P < 0.01). In rats that had reduced NNA due to 7 days "gentling," serum glucose levels were also significantly reduced (P < 0.001) compared with naive controls. The data demonstrate that inhibition of central noradrenergic activity is also associated with an inhibition of hyperglycemia, raising the concept that therapies aimed at reducing central NNA may have a role in the management of diseases with excessive hepatic glucose output such as non-insulin-dependent diabetes mellitus.

Animals↗

PubMed1991

A role for central postsynaptic alpha 2-adrenoceptors in glucoregulation.

Central or peripheral administration of the alpha 2-adrenoceptor agonist clonidine causes marked hyperglycemia in the rat. It is not clear whether this effect is mediated within the brain at either pre- or postsynaptic alpha 2-adrenoceptors or whether it is due to peripheral alpha 2-agonist actions. We employed computerized mass spectrometry to measure noradrenaline (NA) and its primary neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) in the medial basal hypothalamus of rats treated acutely with clonidine, the alpha 2-antagonist yohimbine, the postganglionic noradrenergic blocker guanethidine and the neuroglycopenic agent 2-deoxy-D-glucose (2-DG). That clonidine's hyperglycemic effect was due, in part, to an action at central alpha 2-adrenoceptors was indicated by the ability of guanethidine to significantly inhibit the glucose response. Because of clonidine's inhibition of hypothalamic NA release (assessed by the DHPG/NA ratio), presumably by presynaptic agonism, these data indicated that postsynaptic receptor stimulation by clonidine was involved in activating glucose release. Yohimbine markedly increased the hypothalamic DHPG/NA ratio, reflecting presynaptic stimulation of NA release, but at the same time inhibited the hyperglycemic response due to 2-DG administration. This latter effect to block hyperglycemia is consistent with antagonism of postsynaptic alpha 2-adrenoceptors involved in mediating hepatic glucose output. These data indicate a major role for postsynaptic alpha 2-adrenoceptors in glucoregulation.

Animals↗

PubMed1989

Dopamine D2 agonist-induced behavioural depression is reversed by dopamine D1 agonists.

The dopamine (DA) D2 agonist bromocriptine produced dose-dependent locomotor depression in mice with intact stores of DA, as measured in automated activity cages. The DA D1 agonist CY208-243, reversed the bromocriptine-induced depression. Using direct observational analysis, another selective DA D2 agonist, quinpirole, induced dose-dependent depression and this was reversed by the D1 agonist SKF38393. The effect of SKF38393 could be blocked by prior pretreatment with SCH23390. It is concluded that DA D2 agonist-induced locomotor depression is mediated via a DA D2 autoreceptor-mediated inhibition of DA release onto postsynaptic DA receptors. This reduction in release probably deprives postsynaptic D1 and D2 receptors of endogenous DA. However, since bromocriptine (and probably quinpirole) in all likelihood occupies both pre- and postsynaptic D2 receptors immediately on injection, and since CY208-243 and SKF38393 (respectively) could reverse the depression, the depression seems to be due specifically to a deprivation of DA at postsynaptic D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗