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Biomedical subjects

G G Thompson

Publications and source records attributed to G G Thompson.

At least 19 recordsLinked to original sources

Water relations of the burrowing sandhill frog, Arenophryne rotunda (Myobatrachidae).

Arenophryne rotunda is a small (2-8 g) terrestrial frog that inhabits the coastal sand dunes of central Western Australia. While sand burrowing is a strategy employed by many frog species inhabiting Australia's semi-arid and arid zones, A. rotunda is unique among burrowing species because it lives independently of free water and can be found nocturnally active on the dune surface for relatively extended periods. Consequently, we examined the physiological factors that enable this unique frog to maintain water balance. A. rotunda was not found to have any special adaptation to reduce EWL (being equivalent to a free water surface) or rehydrate from water (having the lowest rehydration rate measured for 15 Western Australian frog species), but it was able to maintain water balance in sand of very low moisture (1-2%). Frogs excavated in the field were in dune sand of 4.4% moisture content, as a consequence of recent rain, which was more than adequate for these frogs to maintain water balance as reflected by their low plasma and urine osmotic concentrations. We suggest that in dry periods of the year, A. rotunda can achieve positive water balance by cutaneous water uptake by burrowing deeper into the substrate to where the percent water content is greater than 1.5%.

Animals↗

A neurochemical study of the novel antiepileptic drug retigabine in mouse brain.

The novel antiepileptic drug, retigabine, has been reported to have multiple mechanisms of action, including potentiation of gamma -aminobutyric acid (GABA) and glutamate synthesis. We have investigated its effects on several GABA- and glutamate-related neurochemical parameters in mouse brain. Mice were administered retigabine either as a single dose or daily for 5 days. At 4 h after dosing, brains were removed and analysed for GABA, glutamate, and glutamine concentrations and for the activities of GABA-transaminase and glutamic acid decarboxylase. Single doses of retigabine significantly lowered brain concentrations of glutamate and glutamine. Repeated treatment significantly reduced the activity of GABA-transaminase. The drug was essentially without effect on all other parameters investigated. These results suggest that retigabine blocks GABA metabolism rather than enhancing GABA synthesis. In addition, the drug may also lower brain concentrations of the excitatory neurotransmitter glutamate and its precursor, glutamine. These effects may contribute to the antiepileptic action of retigabine.

4-Aminobutyrate Transaminase↗

Planning for cardiac surgical services: advice from an Ontario consensus panel. For the Consensus Panel on Cardiac Surgical Services in Ontario and the Steering Committee of the Cardiac Care Network of Ontario.

The Cardiac Care Network of Ontario (CCN) Consensus Panel on Cardiac Surgical Services drew on the literature and its own expertise to recommend guidelines for expanding services. This report, which is not an official position paper of the Canadian Cardiovascular Society, presents these recommendations. Rates of surgery are linked to diagnostic capacity, requiring increases in interventional therapies to match increases in invasive diagnostic activity. For quality and efficiency, panel members recommend an annual minimum of 150 procedures per surgeon and 500 per centre; a centre should serve a minimum population of 500,000. Services should be as close to patients' homes as possible while maintaining recommended volumes. Expanding the CCN's cardiac surgery database to include other cardiac modalities will yield a more accurate assessment of waiting times. The panel recommends collaborative regional planning associations, mentorship arrangements between new and existing centres, prompt action on human resource shortages and exploration of alternative funding models.

Cardiac Surgical Procedures↗

Neurochemical studies with the anticonvulsant felbamate in mouse brain.

Felbamate (FBM) is a relatively novel anticonvulsant agent which has been reported to exert its antiepileptic effects by blockade of the glycine recognition site on the N-methyl-D-aspartate subtype of glutamate receptor and potentiation at the gamma-aminobutyric acid (GABA) type A receptor. An increasing number of antiepileptic drugs have, however, additional, neurochemical actions on the GABA and glutamate systems which may contribute to their anticonvulsant activity. As a result, we have investigated the effects of FBM on several GABA- and glutamate-related neurochemical parameters in mouse brain. Adult male ICR mice were randomised into two groups and administered FBM (0-100 mg kg(-1)) intraperitoneally either as a single dose or twice daily for 5 days. Four hours after the final dose, animals were killed and their brains removed for analysis of GABA, glutamate and glutamine concentrations and activities of GABA-transaminase and glutamic acid decarboxylase. Single and repeated doses of FBM were without effect on all of the parameters investigated. These results appear to exclude the possibility that FBM, in addition to its known effects on GABA and glutamate receptors, exerts its antiepileptic effects via an action on the GABA- and glutamate-related neurochemical parameters chosen for investigation.

4-Aminobutyrate Transaminase↗

Effects of anti-epileptic drugs on glutamine synthetase activity in mouse brain.

1. Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate neurotransmission in the central nervous system. It is responsible for the conversion of glutamate to glutamine, and for the detoxification of ammonia. 2. We have investigated the effects of single and repeated intraperitoneal administration of a range of established and new anti-epileptic drugs on GS activity in mouse brain. 3. Four hours after the final dose, animals were sacrificed and the brains removed for analysis of GS activity. 4. Both single and repeated doses of phenytoin and carbamazepine were found to reduce enzyme activity (P<0.05). 5. Single doses of phenobarbitone, felbamate and topiramate were without effect, however repeated administration of these drugs dose-dependently reduced GS activity (P<0.05). 6. Single and repeated doses of sodium valproate, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam and desglycinyl-remacemide were found to have no effect on GS activity. 7. The reduction in enzyme activity demonstrated is unlikely to be related to the anti-epileptic actions of these drugs, but may contribute to their toxicity.

Ammonia↗

Vigabatrin and tiagabine are pharmacologically different drugs. A pre-clinical study.

In light of theirclosely related mechanisms of action, and preliminary clinical evidence suggesting that they possess similar efficacies, it has been anecdotally suggested that vigabatrin and tiagabine may prove to be therapeutically indistinguishable. As a result, we have conducted a preclinical comparison of their anticonvulsant profile and mechanism of action. Pentylenetetrazol and maximal electroshock seizures were employed to determine the experimental anticonvulsant profile. Mechanisms of action were investigated using assays of gamma -aminobutyric acid (GABA), GABA-transaminase and glutamic acid decarboxylase in mouse brain and GABA uptake and GABA-transaminase in rat astrocyte cultures. Vigabatrin was without effect on either pentylenetetrazol- or maximal electroshock-induced seizures, whereas tiagabine increased the latency to pentylenetetrazol seizures and reduced the incidence of maximal electroshock seizures. In mouse brain assays, tiagabine was without effect, while vigabatrin increased GABA concentrations and reduced GABA-transaminase and glutamic acid decarboxylase activities. In cortical astrocyte cultures, vigabatrin reduced the activities of both GABA uptake and GABA-transaminase, whereas tiagabine blocked GABA uptake alone. These results suggest that vigabatrin and tiagabine have differing efficacy in experimental seizure models and distinct neurochemical effects. It is possible, then, that these drugs will have different spectra of activity and toxicity profiles in human epilepsy.

Animals↗

Effects of valproate, vigabatrin and tiagabine on GABA uptake into human astrocytes cultured from foetal and adult brain tissue.

The antiepileptic agents sodium valproate (VPA), vigabatrin (VGB) and tiagabine (TGB) have been proposed to exert their effects, at least in part, by an action on the transport of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This information has, however, been gleaned from studies employing experimental systems derived from animal tissues. We have conducted preliminary studies of the effects of VPA, VGB and TGB on the transport of GABA into primary cultures of human astrocytes, derived from both adult and foetal tissues. Astrocytes were prepared from cerebral cortical tissue obtained from patients undergoing surgery for intractable epilepsy, and from spontaneously aborted foetuses (16-24 weeks gestation). The cells were isolated via a series of enzymatic digestions, grown under standard culture conditions for around 21 days and then assayed for GABA uptake activity. VPA (1,000 microM), VGB (100 microM) and TGB (200 nM) all significantly (p < 0.05) reduced the uptake of GABA into primary cultures of human adult astrocytes following a one hour exposure. VPA (1,000 microM) and VGB (100 microM) similarly reduced GABA uptake into astrocytes derived from human foetal tissue, while TGB (200 and 500 nM) was without effect. The results of these preliminary studies suggest that VPA and VGB reduce GABA transport into both adult- and foetally-derived human astrocytes, whereas TGB appears active only in cells cultured from adult brain. Delayed development of the GAT-1 transporter in foetal tissue could explain this observation.

Adult↗

Redesigning services to meet client needs: the Gage Transition to Independent Living.

The Gage Transition to Independent Living, offered by Toronto's West Park Hospital, helps physically disabled adults acquire the skills necessary for living independently in the community. Although the program's goal has remained constant, its structure has changed considerably. In response to client feedback and community trends, the program has replaced its original institutional framework with a community-based one. This article traces how those involved changed the program to meet client needs, and describes what they learned in the process.

Activities of Daily Living↗

Neurochemical actions of vigabatrin and tiagabine alone and in combination in mouse cortex.

1. The effects of repeated administration of the anticonvulsant compounds, vigabatrin (VGB) and tiagabine (TGB), on gamma-aminobutyric acid (GABA) concentration and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD) were investigated in mouse cortex. 2. VGB alone increased GABA levels and decreased GABA-T and GAD activities. 3. TGB alone was essentially without effect. 4. Low doses of VGB and TGB in combination increased GABA levels when neither drug had such an effect alone. 5. Despite this observation, this study failed to establish any conclusive evidence for an interaction between VGB and TGB that might help to explain their reported clinical synergism.

4-Aminobutyrate Transaminase↗

Neurochemical actions of gabapentin in mouse brain.

Gabapentin (GBP) is a recently licensed antiepileptic, drug whose mode of action remains to be fully elucidated. The following studies were designed to investigate the effects of GBP on several gamma-aminobutyric acid (GABA) related neurochemical parameters in mouse brain. GBP (0-75 mg/kg) was administered by intraperitoneal injection either as a single dose or twice daily for 8 days. Animals were sacrificed 4 h after the final administration and their brains removed and analysed for concentrations of GABA, glutamate and glutamine and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD). Single dose GBP increased brain GABA-T activity and glutamine concentration but was without effect on GAD activity or the concentrations of GABA and glutamate. Following repeated treatment with GBP, brain GABA-T activity was consistently decreased and there was also a decrease in brain glutamate concentration. Repeated drug treatment was without effect on the activity of GAD or on the concentrations of GABA and glutamine. These results suggest that GBP has effects on the GABAergic system which may contribute to its antiepileptic and/or neuroprotective actions.

Acetates↗

Neurochemical actions of the desglycinyl metabolite of remacemide hydrochloride (ARL 12495AA) in mouse brain.

1. Remacemide hydrochloride, a recently developed antiepileptic drug, is believed to exert its effects, at least in part, via its desglycinyl metabolite, ARL 12495AA. 2. We have investigated the effects of ARL 12495AA on several neurochemical parameters in mouse brain. Adult male ICR mice were randomized into two groups and administered ARL 12495AA (0-75 mg kg-1) intraperitoneally, either as a single dose or once daily for 5 days. 3. Six hours after the final dose, animals were killed and their brains removed. Brain tissues were analysed for concentrations of gamma-aminobutyric acid (GABA), glutamine and glutamate and for the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD). 4. Single dose ARL 12495AA was without effect on any of the parameters investigated. 5. Repeated ARL 12495AA treatment did not alter brain concentrations of GABA and glutamine, but at a high dose there was a trend toward reduced brain glutamate concentrations (P = 0.10). 6. Repeated administration of ARL 12495AA at a high dose significantly increased GABA-T activity (P < 0.05) and decreased that of GAD (P < 0.05). 7. These findings may have relevance to the clinical use of remacemide hydrochloride in human epilepsy.

4-Aminobutyrate Transaminase↗

Hormones and the control of porphyrin biosynthesis and structure in the hamster harderian gland.

The hamster Harderian gland seems to present both an excellent model for the control of porphyrin biosynthesis and an unusually robust example of the interrelationship between structure and function. It has been known for some time that 1) the capacity for manufacturing and storing porphyrins and 2) gland histology and ultrastructure are controlled by androgens. Thus, in intact males as well as in gonadectomised animals of either sex treated with androgens, porphyrin synthesis by the Harderian gland is suppressed and the gland tubules characteristically possess two cell types, the cytoplasm of both containing polytubular complexes. By contrast, the Harderian glands of intact females and castrated males synthesise and store large amounts of protoporphyrin, while their tubules possess only one cell type which lacks a polytubular complexes. So overarching is the effect of androgens that they have been described as a "coarse tuning" effect on the gland. By contrast, the role of the ovary is both less dramatic and less well understood. In female hamsters, ovariectomy leads to degenerative changes in Harderian gland tubules and (probably) a release of stored porphyrin; at the same time there is a reduction in enzyme levels and new synthesis. The causative hormone in this "fine tuning" is unclear at present. There is now clear evidence that the Harderian gland is also controlled directly by pituitary hormones. In particular, the use of continuous infusion osmotic minipumps has allowed us to demonstrate not only 1) that the expected rise in porphyrins and feminisation of gland morphology does not occur in castrated males receiving the dopamine agonist bromocriptine, but that 2) the simultaneous administration of prolactin does permit these changes; furthermore, 3) the administration of prolactin alone increases porphyrin synthesis above the levels found in untreated castrates. Similarly, bromocriptine administration to ovariectomised females markedly reduces porphyrin synthesis and masculinises gland structure; again, this is reversed by the simultaneous administration of prolactin. Prolactin must therefore be seen as equipotent with androgens in determining gland structure and activity.

Androgens↗

Effects of tiagabine and vigabatrin on GABA uptake into primary cultures of rat cortical astrocytes.

Tiagabine (TGB) and vigabatrin (VGB) are two novel anticonvulsant compounds reported to exert their pharmacological effects via an action on the gamma-aminobutyric acid (GABA) system. We have investigated the effects of acute exposure of these drugs on the uptake of GABA into rat cortical astrocytes in primary culture. Astrocytes were prepared from the cerebral cortices of one day-old rat pups by a mechanical dissociation technique and were assayed for GABA uptake activity after 21 days in culture. Tiagabine (100-300 nM) and VGB (100 microM) reduced GABA uptake when compared to control at four hours post-exposure. GABA uptake was also reduced following eight and 24 hour exposures to 200 nM TGB. A combination of TGB (200 nM) and VGB (100 microM) treatments reduced GABA uptake when compared to both control and VGB treated cultures. These results support the efficacy of TGB as a GABA uptake inhibitor and suggest that VGB may also exert an effect by this mechanism.

Animals↗

Peripheral benzodiazepine receptors in platelets of epileptic patients.

Tolerance to the anticonvulsant effect of benzodiazepines is likely to involve changes at the central benzodiazepine-GABA receptor complex. Peripheral benzodiazepine receptors (pBZRs), which can be measured in platelets, may also be involved. Using a binding assay with [3H]-PK 11195 as radioligand, pBZRs were assayed in platelets of patients taking a variety of antiepileptic drugs (AEDs). Comparisons were made with untreated patients. pBZR receptor density (mean +/- s.e. mean) was increased vs controls (8083 +/- 557 fmol mg-1 protein) in the platelets of patients taking a polypharmacy regime including the benzodiazepine clobazam (12661 +/- 1011 fmol mg-1 protein, P < 0.005) and also in those receiving sodium valproate as monotherapy (15003 +/- 1756 fmol mg-1 protein, P < 0.01). The significance of these findings is unclear, but the use of a specific pBZR antagonist may be a promising avenue for investigating the mechanism of BZ tolerance and its prevention.

Adolescent↗

Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity.

1. Nicotinylalanine is an analogue of kynurenine which has been reported to inhibit the enzymes kynurenine hydroxylase and kynureninase. 2. In the present study rats were given a tryptophan load together with nicotinylalanine two hours before killing, and the brain, liver and kidneys analysed by HPLC for their kynurenic acid content. 3. Tryptophan alone produced a significant elevation of kynurenate but with the additional administration of nicotinylalanine, levels rose dramatically, including a 19-fold increase in brain. 4. In mice the same dose of nicotinylalanine reduced the incidence of seizures induced by leptazol or electroshock treatment. 5. Since kynurenic acid is an antagonist at excitatory amino acid receptors the results may herald a new approach to producing a pharmacological blockade of amino acid receptors in the brain.

Alanine↗

Central and peripheral benzodiazepine receptors in rat brain and platelets: effects of treatment with diazepam and clobazam.

Tolerance to the effects of benzodiazepines (BZ) may be mediated by changes in benzodiazepine receptors (BZRs). Peripheral BZRs (in brain and platelets) and central BZRs (in brain) were measured in rats following intraperitoneal administration of diazepam and clobazam each for 4 and 12 days. BZRs were measured by binding assays using [3H] PK 11195 (peripheral) and [3H] flunitrazepam (central) as radioligands. Diazepam, but not clobazam, increased peripheral BZR numbers in platelets (both P < 0.005), but not in brain, after 4 and 12 days' treatment compared with appropriate controls. Neither drug altered central BZR affinities or numbers in rat brain. BZ effects on peripheral BZRs in platelets cannot be extrapolated to predict changes in brain receptors, either peripheral or central.

Animals↗