Disease relevance of Progabide

• Progabide in Parkinson's disease [1].
• The GABA-agonist progabide for spasticity in multiple sclerosis [2].
• This appears to be the basis for the clinical action of progabide in neuroleptic-induced dyskinesia, L-dopa-induced involuntary movements, and possibly mania [3].
• A trend was observed for lower seizure frequency of secondary generalized seizures during treatment with progabide [4].
• Double-blind crossover trial of progabide versus placebo in severe epilepsies [5].

Psychiatry related information on Progabide

• Combinations of progabide and pentobarbital or progabide and phenobarbital interacted additively by the maximal electroshock seizure (MES) test [6].
• The mixed GABAA/ GABAB agonist progabide reduced exploratory behaviors and receptivity without producing motor impairment at a dose of 400 mg/kg [7].
• The effects of progabide (SL 76002) on locomotor activity and conditioned place preference induced by d-amphetamine [8].
• In clinical trials in depressed patients progabide produces a significant reduction in depressive symptoms, an action similar to that of imipramine both for the global clinical rating and the HRSD [9].
• This antidepressant activity is reflected by the action of progabide in behavioural models of depression such as olfactory bulbectomy, learned helplessness and the sleep-wake cycle [9].

High impact information on Progabide

• Progabide was investigated as a potential inhibitor of microsomal epoxide hydrolase as a result of reports of elevated levels of carbamazepine-10,11-epoxide after coadministration of progabide and carbamazepine to patients with epilepsy [10].
• A mixed competitive and noncompetitive mechanism of inhibition best described the effect of progabide on microsomal epoxide hydrolase; the most potent inhibition was competitive [10].
• On repeated treatment, progabide prevents or reverses the neuroleptic-induced up-regulation of dopamine receptors in the rat striatum and antagonizes the concomitant supersensitivity to dopaminomimetics [11].
• Finally, the behavioral effects of diazepam, of the mixed GABAA/GABAB receptor agonist progabide, and of the selective GABAB receptor agonist baclofen have been assessed in adult qk mutants [12].
• The GABAA antagonist bicuculline, at a dose of 1 mg/kg, blocked the effects of progabide on sex behavior [13].

Chemical compound and disease context of Progabide

• In order to investigate this hypothesis in relation to the hyperphagia produced by benzodiazepines, the effects of chlordiazepoxide were compared with those of the GABA agonists progabide and muscimol and the GABA antagonists picrotoxin and bicuculline [14].
• Analysis of efficacy showed progabide to be inferior to valproate against all seizure types, particularly against tonic-clonic seizures [15].
• Combinations of pentobarbital and progabide or phenobarbital and progabide interacted additively when subjected to the pentylenetetrazol (PTZ) minimal threshold seizure (clonic) test [6].
• Like repeated electroconvulsive shock (ECS), progabide altered the head-twitch response, clonidine-induced sedation response and 5-HT2 receptor number [16].
• L-5-hydroxytryptophan and progabide also blocked type B myoclonus, but the blockade was only transiently effective and was always accompanied by slight drowsiness [17].

Biological context of Progabide

• Therapeutic concentrations of progabide inhibited S (+)-styrene oxide hydrolysis in human liver microsomes (inhibition constant [Ki] = 1.9 mumol/L) and purified human liver microsomal epoxide hydrolase (Ki = 4.4 mumol/L) [10].
• Several issues pertaining to the bioavailability of progabide were addressed: first-pass effect, incomplete dissolution, and dose and time dependency [18].
• A decrease in severity of motor seizures was found only after 200 mg/kg progabide which, however, gave rise to marked sedation and muscle relaxation [19].
• Effect of erythrocytes and plasma protein binding on the transport of progabide and SL 75102 through the rat blood-brain barrier [20].
• The data obtained indicate that the gastric pH and gastric emptying rate will have a profound effect on the oral bioavailability of Progabide [21].

Anatomical context of Progabide

• Similarly, the brain extraction of the drugs in the presence of either albumin, or red blood cells for progabide was inversely related to their respective concentrations [20].
• Thus, after i.p. administration of 100 mg/kg progabide, a significant increase in seizure latency and significant decreases in duration of motor seizures and amygdala afterdischarges were determined [19].
• Repeated progabide and valproate (but not diazepam) administration attenuated the sedation response to the alpha 2-adrenoceptor agonist, clonidine (0.15 mg kg-1) but neither drug altered beta-adrenoceptor number in the cerebral cortex [16].
• Furthermore, since systemically administered progabide still increased hypothalamic DOPEG levels after ibotenate-induced destruction of the hypothalamic neuronal cell bodies, a presynaptic modulation of noradrenergic neurons by local GABAergic interneurons is excluded [22].
• Determination of progabide and its main acid metabolite in biological fluids using high-performance liquid chromatography and electrochemical detection. Application to the measurement of blood/plasma partition ratio [23].

Associations of Progabide with other chemical compounds

• Disposition of progabide and valproic acid following intraperitoneal administration in rhesus monkey [18].
• Oral administration (dose in mg/kg in parentheses) of flunitrazepam (0.1), lorazepam (1.0), nitrazepam (3.0), diazepam (10), flurazepam (10) and chlordiazepoxide (30), all prevented retention whereas progabide (100-800) and PPK 9084 (10-100) were ineffective [24].
• The progabide metabolite, 4-[( (4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino)butyric acid (SL75.102) (1 microM) inhibited the K+-evoked release of 5-HT by 61% [25].
• There was a moderate inhibition by progabide of the rise in prolactin after domperidone [26].
• In a proposed rat model for anxiety (electrical stimulation of the periaqueductal grey region), progabide (a GABA agonist) and diazepam both increased the latency to escape to a safe compartment and also the current needed to induce the escape response (escape threshold) [27].

Gene context of Progabide

• Neuroleptic-induced oral dyskinesias: effects of progabide and lack of correlation with regional changes in glutamic acid decarboxylase and choline acetyltransferase activities [28].
• Progabide for refractory partial epilepsy: a controlled add-on trial [29].
• It was concluded that the GABAA but not the GABAB receptor is important for the inhibitory effects of progabide on that behavior [13].
• Repeated progabide administration (400 mg kg-1, i.p. twice daily for 14 days) enhanced the head-twitch response the effect lasting for over 8 days after the last dose, and also increased 5-HT2 receptor number in frontal cortex [16].
• Progabide infusion also diminished or abolished circulating gastrin, somatostatin, and pancreatic polypeptide responses during insulin-induced hypoglycemia (P less than 0.05) [30].

Analytical, diagnostic and therapeutic context of Progabide

• Progabide does not seem to be the drug urgently needed for failures of previous high-dose drug therapy [29].
• The monoaminergic changes induced by progabide, though dissimilar from those induced by tricyclics, are probably connected with the antidepressant action on the compound observed in double-blind clinical trials [3].
• These data confirm the anticonvulsant properties of progabide in another animal model [31].
• At the same time intervals, safety was assessed by means of reports of adverse events, clinical and neurological examination, laboratory tests, and measurement of plasma concentrations of progabide and associated AEDs [32].
• Intravenous injection of various doses (30 to 100 mg/kg) of progabide induced a protective effect against intermittent light stimulation (25 Hz) in both test situations [31].

References