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Item does not contain fulltext, Background The metabolism of the short-acting anaesthetic agent propofol has been described over the first 24 h. However, the long-term disposition of propofol and its metabolites is unclear. We describe the pharmacokinetics (renal excretion rates and renal clearance) of propofol and its metabolites over 60 h. Methods Ten patients undergoing lung surgery were included in the study. They received anaesthesia with continuous i.v. propofol at an average rate of 10 mg min−1. During surgery and 60 h thereafter, we sampled blood and urine. Propofol and its metabolites were measured using gradient high performance liquid chromatography (HPLC). Results In nine patients, propofol and its glucuronides were found in the plasma over the first 15 h. In the urine, however, even after 60 h, propofol and its quinol glucuronides were still detectable. One patient had a markedly different pharmacokinetic profile, showing a limited renal excretion or absorption of 12% of the dose. Conclusions After an infusion of propofol, patients excrete propofol and its metabolites in the urine over a period in excess of 60 h. We hypothesize that (re)absorption of propofol and its metabolites by the kidney is a major process in elimination and that the reabsorbed compounds are gradually conjugated in the kidney and excreted in the urine. One patient showed a different pharmacokinetic profile for which we currently have no explanation.

Contains fulltext : 54749.pdf (publisher's version ) (Closed access), We examined the expression and function of group-II metabotropic glutamate (mGlu) receptors in an animal model of absence seizures using genetically epileptic WAG/Rij rats, which develop spontaneous non-convulsive seizures after 2-3 months of age. Six-month-old WAG/Rij rats showed an increased expression of mGlu2/3 receptors in the ventrolateral regions of the somatosensory cortex, ventrobasal thalamic nuclei, and hippocampus, but not in the reticular thalamic nucleus and in the corpus striatum, as assessed by immunohistochemistry and Western blotting. In contrast, mGlu2/3 receptor signalling was reduced in slices prepared from the somatosensory cortex of 6-month-old WAG/Rij rats, as assessed by the ability of the agonist, LY379268, to inhibit forskolin-stimulated cAMP formation. None of these changes was found in "pre-symptomatic" 2-month-old WAG/Rij rats. To examine whether pharmacological activation or inhibition of mGlu2/3 receptors affects absence seizures, we recorded spontaneous spike-wave discharges (SWDs) in 6-month-old WAG/Rij rats systemically injected with saline, the mGlu2/3 receptor agonist LY379268 (0.33 or 1 mg/kg, i.p.), or with the preferential mGlu2/3 receptor antagonist, LY341495 (0.33, 1 or 5 mg/kg, i.p.). Injection of 1 mg/kg of LY379268 (1 mg/kg, i.p.) increased the number of SWDs during 3-7 h post-treatment, whereas injection with LY341495 reduced the number of seizures in a dose-dependent manner. It can be concluded that mGlu2/3 receptors are involved in the generation of SWDs and that an upregulation of these receptors in the somatosensory cortex might be involved in the pathogenesis of absence epilepsy.

Contains fulltext : 64701.pdf (publisher's version ) (Closed access), The aim of this study was to investigate the couplings between various binding sites on the GABAA receptor complex. We investigated combinations of three test compounds: (1) GABA ( -aminobutyric acid), (2) Org 20549 [(2 3 5 )-21hydroxy-3Hydroxy-2(4morpholinyl)pregnan-20one methane-sulphonate)], a neuroactive steroid and (3) retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester), a new antiepileptic drug. Receptor-binding assays were conducted using rat brain membranes. [3H]TBOB ([3H]-t-butyl-bicyclo-ortho-benzoate) was the tracer ligand. All three test compounds inhibited the binding of [3H]TBOB with EC50's of 4.0, 98 and 23 μM, respectively. Isobolic analysis of the combination data showed that the three compounds act in synergy in displacing [3H]TBOB. These interactions could be described and quantified by a hypercube model in which each of the three test compounds and [3H]TBOB bind to different, allosterically coupled sites such that each of the test compounds allosterically displaces the tracer [3H]TBOB and allosterically enhances the affinity of any other test compound by a factor 4.4. The simultaneous binding of any two ligands enhances the affinity of the third by a factor 9. These results may contribute to the understanding of individual variability in drug responses and to the discussion about rational polytherapy.

Contains fulltext : 63317.pdf (publisher's version ) (Closed access), Effects of vigibatrin (saline, 125, 250, or 500 mg/kg i.p.) on spontaneous locomotor activity in Wistar rats were investigated. There was a dose dependent decrease in amount of locomotion for doses up to 250 mg/kg. This decrease was measurable 2-4 hours after injection and still became more pronounced in the following hours. The mean velocity during the movements 2-6 hours after injection remained intact and was higher in the 500 mg/kg group. In this high dose group an abnormal posture with a hunched back and pilo-erection was observed. The decrease of the amount of motor activity with the preservation of the mean velocity in this non-stimulating procedure, suggests that the level in which the experimental procedure imposes motor activity might be an important factor when measuring effects of vigabatrin. Postscript: Immediate post injection effects were observed, equivalent to those seen in the writhing test, a pain test using hyperosmolar saline injections. These observations stress the importance of controlling the osmolarity of the injection fluids.

Contains fulltext : 63645.pdf (Publisher’s version ) (Closed access), The molecular mechanism underlying the activity of the novel antiepileptic drug retigabine is not yet fully understood. The aim of this study was to investigate whether retigabine interacts directly with the GABAA receptor complex (-aminobutyric acid). Receptor-binding assays were conducted using rat brain membranes. [3H]-t-Butyl-bicyclo-orthobenzoate ([3H]TBOB) was used as a tracer ligand. We determined the effects of GABA and retigabine in the presence of several concentrations of GABA on the binding of [3H]TBOB. GABA inhibited [3H]TBOB binding with an EC50 of 4.8 M. In the absence of GABA, retigabine inhibited [3H]TBOB with an EC50 of 124 M and an EC50 of 42 M in the presence of 2.5 M GABA. Isobolic analysis revealed that retigabine acts in synergy with GABA in displacing [3H]TBOB. This synergy could be quantified by a molecular model in which GABA and retigabine both allosterically displace [3H]TBOB, and retigabine allosterically enhances the binding of GABA and vice versa with a factor of 4. In summary, we found that retigabine does indeed interact with a site on the GABAA receptor complex, and this site is positively allosterically coupled with the GABA site. This GABA-positive effect may well contribute to the clinical anticonvulsive effects of retigabine.

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