Abstract— The Na+channel blocking activity and the antiarrhythmic effects of riluzole, and established anticonvulsants (lamotrigine and lifarizine) and class 1 antiarrhythmics (lidocaine, flecainide and disopyramide) were studied under in vitro and in vivo conditions. Guinea‐pig cardiac Purkinje fibres were superfused with Tyrode solution and electrically driven for recording action potentials with intracellular microelectrodes. In these preparations paced at 1 Hz, all compounds tested produced concentration‐dependent (0.3–100 μM) reductions in the maximum rate of depolarization of the action potential (Vmax). For riluzole, phenytoin and carbamazepine this effect was frequency‐independent (0.5–6 Hz) but for lamotrigine, lifarizine, lidocaine, flecainide and disopyramide it was frequency‐dependent. In anaesthetized rats, riluzole, in contrast to flecainide, did not delay the appearance of aconitine‐induced arrhythmias. Riluzole (0.3‐3.9 mg/kg, i.v.) also lacked notable cardiac electrophysiological effects in anaesthetized dogs. At an i.v. dose of 3.0 mg/kg riluzole failed to restore a normal sinus rhythm in conscious dogs with polymorphic arrhythmias produced by ligation of the left anterior descending coronary artery 24 h earlier. These results indicate that riluzole, phenytoin and carbamazepine, unlike lamotrigine, lifarizine and flecainide, block cardiac Na+channels in a frequency‐independent manner. This property may account for the lack of antiarrhythmic activity of riluzole, phenytoin and carbamazepine in animal models of arrhythmias that respond to class I antiarrhythmic drugs. It may also account for the clinical observation that riluzole does not seem to cause the unfavourable electrocardiographic changes characteristic of drugs that block cardiac Na+channels in a frequency‐dependent manner.

1998-02-01·General Pharmacology: The Vascular System

Focal cerebral ischemia in the mouse: Hypothermia and rapid screening of drugs

Article

作者: Willy C.M. Cramer ; G. Paul Toorop

1. We have investigated the ability of several compounds to diminish both infarct area and volume induced by middle cerebral artery occlusion in the mouse. 2. Lifarizine, ipsapirone and N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE) all reduced both infarct area and volume. Ifenprodil diminished the infarct area, but the effect on total infarct volume was much less pronounced. 3. In addition, we tested the protective effects of some other drugs on infarct area only. Nimodipine, verapamil, diltiazem, N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazo lamine (R56865) and sabeluzole had no effect on infarct area. (S)-Emopamil significantly diminished infarct area. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) also diminished infarct area significantly. 4. In some brain ischemia models hypothermia protects against ischemic damage. Mild hypothermia had no effect on infarct area in the present mouse model of focal ischemia.

1997-11-01·Neurology1区 · 医学

Cerestat and other NMDA antagonists in ischemic stroke

1区 · 医学

Review

作者: Lees, K R

A wealth of experimental evidence demonstrates that cerebral ischemia causes excessive release of glutamate and that glutamate contributes to ischemic injury. Glutamate antagonism by any of several mechanisms can ameliorate the extent of infarction. These antagonists comprise noncompetitive blockers of the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor [e.g., aptiganel (Cerestat)], competitive antagonists of the glutamate recognition site of the NMDA receptor (e.g., selfotel) or of the glycine recognition site (e.g., ACEA 1021, GV150526), antagonists at the polyamine site (e.g., eliprodil), and drugs that may interfere with glutamate release by sodium channel blockade as well as having other actions (e.g., lubeluzole, 619C89). Clinical experience suggests that although some NMDA antagonists are poorly tolerated at putative neuroprotective doses (e.g., selfotel), potentially neuroprotective plasma concentrations can be achieved in humans with others (e.g., aptiganel), though tolerable adverse effects are frequently observed. These clinical effects include hypertension (which is probably preferable to the hypotension seen with nimodipine and lifarizine), sedation, confusion or hallucinations and, at high doses, catatonia. Glycine antagonists may be associated with fewer adverse effects, but preclinical studies suggest that brain penetration may be low. Although recent studies with selfotel and eliprodil have been discontinued because of insufficient evidence for a satisfactory risk/benefit ratio, encouraging experience with aptiganel, magnesium, and glycine antagonists has prompted continued clinical trials with these agents. To be of sufficient size to detect a clinically useful improvement in outcome, these trials need to be large (600-1,000 patients). Present trials with aptiganel (Cerestat) are comparing the efficacy and tolerability of two doses vs. placebo in patients treated within 6 hours of ischemic stroke. Outcome is assessed by the modified Rankin Scale at 3 months.

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