Neuroprotective and anticonvulsant effects of EGIS-8332, a non-competitive AMPA receptor antagonist, in a range of animal models.

BACKGROUND AND PURPOSE: Blockade of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors is a good treatment option for a variety of central nervous system disorders. The present study evaluated the neuroprotective and anticonvulsant effects of EGIS-8332, a non-competitive AMPA receptor antagonist, as a potential drug candidate. EXPERIMENTAL APPROACH: AMPA antagonist effects of EGIS-8332 were measured using patch-clamp techniques. Neuroprotective and anticonvulsant effects of EGIS-8332 were evaluated in various experimental models, relative to those of GYKI 53405. KEY RESULTS: EGIS-8332 inhibited AMPA currents in rat cerebellar Purkinje cells and inhibited the AMPA- and quisqualate-induced excitotoxicity in primary cultures of telencephalon neurons (IC(50)=5.1-9.0 microM), in vitro. Good anticonvulsant actions were obtained in maximal electroshock-, sound- and chemically-induced seizures (range of ED(50)=1.4-14.0 mg kg(-1) i.p.) in mice. Four days after transient global cerebral ischaemia, EGIS-8332 decreased neuronal loss in the hippocampal CA1 area in gerbils and rats. EGIS-8332 dose-dependently reduced cerebral infarct size after permanent middle cerebral artery occlusion in mice and rats (minimum effective dose=3 mg kg(-1) i.p.). Side effects of EGIS-8332 emerged much above its pharmacologically active doses. A tendency for better efficacy of GYKI 53405 than that of EGIS-8332 was observed in anticonvulsant tests that reached statistical significance in few cases, while the contrary was perceived in cerebral ischaemia tests. CONCLUSIONS AND IMPLICATIONS: EGIS-8332 seems suitable for further development for the treatment of epilepsy, ischaemia and stroke based on its efficacy in a variety of experimental disease models, and on its low side effect potential.

Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone.

The electrophysiological effects of dronedarone, a new nonionidated analogue of amiodarone were studied after chronic and acute administration in dog Purkinje fibres, papillary muscle and isolated ventricular myocytes, and compared with those of amiodarone by applying conventional microelectrode and patch-clamp techniques. Chronic treatment with dronedarone (2x25 mg(-1) kg(-1) day p.o. for 4 weeks), unlike chronic administration of amiodarone (50 mg(-1) kg(-1) day p.o. for 4 weeks), did not lengthen significantly the QTc interval of the electrocardiogram or the action potential duration (APD) in papillary muscle. After chronic oral treatment with dronedarone a small, but significant use-dependent V(max) block was noticed, while after chronic amiodarone administration a strong use-dependent V(max) depression was observed. Acute superfusion of dronedarone (10 microM), similar to that of amiodarone (10 microM), moderately lengthened APD in papillary muscle (at 1 Hz from 239.6+/-5.3 to 248.6+/-5.3 ms, n=13, P<0.05), but shortened it in Purkinje fibres (at 1 Hz from 309.6+/-11.8 to 287.1+/-10.8 ms, n=7, P<0.05). Both dronedarone (10 microM) and amiodarone (10 microM) superfusion reduced the incidence of early and delayed afterdepolarizations evoked by 1 microM dofetilide and 0.2 microM strophantidine in Purkinje fibres. In patch-clamp experiments 10 microM dronedarone markedly reduced the L-type calcium current (76.5+/-0.7 %, n=6, P<0.05) and the rapid component of the delayed rectifier potassium current (97+/-1.2 %, n=5, P<0.05) in ventricular myocytes. It is concluded that after acute administration dronedarone exhibits effects on cardiac electrical activity similar to those of amiodarone, but it lacks the 'amiodarone like' chronic electrophysiological characteristics.

The effect of amiodarone and/or antioxidant treatment on splenocyte blast transformation.

Previous studies have shown that free radical reactions may play an important role in the pathogenesis of the adverse effects of the antiarrhythmic agent amiodarone. The aim of this study was to investigate the role of free radical reactions in amiodarone-induced changes in the cell-mediated immune response. Therefore, we investigated the effects of amiodarone alone and in combination with either vitamin E or silymarin on (a) spontaneous blast transformation of splenocytes, (b) concanavalin A (con A)-induced proliferation of splenocytes at three different lectin concentrations, and (c) the content of conjugated dienes in liver homogenate. Forty-eight male Fischer 344 rats were randomized to one of the following groups: 1, control; 2, amiodarone; 3, vitamin E; 4, amiodarone+vitamin E; 5, silymarin; 6, amiodarone+silymarin. The con A-induced splenocyte proliferation was significantly decreased in amiodarone-treated rats at all three lectin concentrations. In the amiodarone-treated group, the change of spontaneous blast transformation was not significantly different from the control. In groups treated with amiodarone plus either antioxidant, both the spontaneous and con A-induced splenocyte proliferation were significantly increased compared with the amiodarone-treated group, and were similar to those in the control group. Amiodarone treatment significantly increased, and both silymarin and vitamin E combined with amiodarone significantly decreased, the conjugated diene content of liver homogenate compared with amiodarone treatment alone. In conclusion, free radicals generated by amiodarone may be implicated in the adverse effects of amiodarone on cell-mediated immune response, and antioxidants applied together with amiodarone may protect against or reduce both the unfavorable immunological effects of amiodarone and amiodarone toxicity.

Modern method and instrument for measuring psychic performance.

This paper shows that cortical processing of information quantity can be given in bits, while speed of information processing can be given in bit/sec; therefore the information processing ability can be denoted in algebraical expression. Changes of emotional tension can be objectified by galvanic skin reflex and pulse reaction. This method and device is suitable to measure psychic state of space station personnel and to predict psychic activity.

Silymarin and vitamin E do not attenuate and vitamin E might even enhance the antiarrhythmic activity of amiodarone in a rat reperfusion arrhythmia model.

Oxidative stress and lysosomal phospholipoidosis, which also might be partly attributed to free radicals induced by amiodarone (AM), may be involved in AM toxicity, which can be prevented by antioxidants. Our aim was to study if vitamin E (E) or silymarin (S), a lipid and a water-soluble antioxidant, modified the antiarrhythmic efficacy of AM in a rat reperfusion arrhythmia test. The following groups of male Sprague-Dawley rats (15 rats/group) were treated by gavage once a day for 4 weeks: 1. methylcellulose (MC, 0.4%), 2. sunflower seed oil (SSO), 3. AM, suspended in MC (30 mg/kg), 4. E, dissolved in SSO (100 mg/kg), 5. AM + E, 6. S, suspended in MC (80 mg/kg), 7. AM + S. The mean duration of ventricular tachycardia + fibrillation (MDVT + VF) and sinus rhythm (MDSR) the incidence of ventricular fibrillation (VF) and ventricular tachycardia (VT) and mortality were measured during a 10-min reperfusion after a 5-min coronary artery occlusion in anaesthetized rats. An arrhythmia score, representing the combined incidence and duration of different types of ventricular arrhythmia, was calculated. Compared with the MC group, MDSR was longer and MDVT + VF was shorter in all drug treated groups and in the SSO group. In the AM + E treated group MDSR was prolonged more and MDVT + VF was shortened more than in the AM, E or SSO groups. Compared with the MC group, the incidence of VF and mortality was similarly decreased in the SSO group and in most drug treated groups. No significant difference in the incidence of VT was found among all groups. The arrhythmia score was reduced by all drug treatments. Combined treatment with AM + E decreased arrhythmia score more than treatment with AM or SSO alone, but arrhythmia score was similar in the AM + E and E groups. In conclusion, both AM and antioxidant treatments alone or together resulted in a marked reduction of reperfusion arrhythmias in this model. SSO also exerted a moderate antiarrhythmic effect. Antioxidants administered together with AM did not attenuate and E might have even enhanced the antiarrhythmic effect of AM, therefore the combination of antioxidants with AM may be advantageous to reduce AM toxicity.