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L Landais

Publications and source records attributed to L Landais.

6 recordsLinked to original sources
PubMed2006

BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology.

Histamine H3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H3 receptor. On the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity approximately 50% higher than that of ciproxifan. Its in vitro potency was approximately 6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.

Acetylcholine↗
PubMed1996

Combined potassium and calcium channel blocking activities as a basis for antiarrhythmic efficacy with low proarrhythmic risk: experimental profile of BRL-32872.

In the search for novel antiarrhythmic agents, compounds with a diversity of electrophysiological actions have been suggested to result in treatments with potentially improved efficacy but with reduced proarrhythmic risk. To test this hypothesis, the antiarrhythmic versus proarrhythmic profile of BRL-32872, a novel agent with combined potassium and calcium channel blocking activity, was assessed in two different in vivo models of ventricular arrhythmia. Furthermore, the effects of potassium and calcium channel antagonists given either alone or in combination were assessed in the same models. Dogs with myocardial infarction received intravenously either vehicle, BRL-32872, the class III antiarrhythmic agent, E-4031, verapamil or a combination of E-4031 with verapamil (n = 8 per group). Ventricular tachyarrhythmias were induced by programmed electrical stimulation (PES). BRL-32872 (0.1, 0.3, 1.0 mg/kg) significantly increased QTc interval (from 387 +/- 10 to 462 +/- 19 msec.sec-1/2 at 1.0 mg/kg, P < .01). Ventricular effective refractory periods were increased in normal and infarcted areas (P < .01). Similar effects were observed with E-4031 (0.1, 0.3, 1.0 mg/kg). Verapamil (0.03, 0.1, 0.3 mg/kg) reduced heart rate, mean arterial pressure and, to a lesser extent, (+)dP/dtmax. Verapamil did not change QTc interval and ventricular effective refractory periods, but increased PR interval (P < .001). PES-induced tachyarrhythmias were not changed by vehicle or increasing doses of verapamil. E-4031 reduced the severity of arrhythmias from sustained ventricular tachycardia (VT) to nonsustained VT (7 dogs at 1.0 mg/kg, P = .013 vs. vehicle). BRL-32872 (0.1 and 0.3 mg/kg) suppressed the induction of sustained VT in six dogs (P = .02 vs. vehicle). In the presence of BRL-32872, 1.0 mg/kg, five dogs became noninducible to PES (P = .013 vs. vehicle). Combination of E-4031 (0.1 mg/kg) with verapamil provided a degree of protection that was similar to that observed with BRL-32872. In a second model, the proarrhythmic potential of BRL-32872 was assessed in anesthetized rabbits sensitized to develop torsades de pointes (TdP). BRL-32872 was compared with the class III antiarrhythmic agents, E-4031, dofetilide, clofilium and RP-58866. The pure class III antiarrhythmic agents induced TdP in 50 to 90% of the rabbits, and prolonged QT interval by 20 to 50%. BRL-32872 (10 micrograms/kg/min) increased QT interval by 35 +/- 5%, but did not promote TdP. In additional experiments, verapamil reduced the incidence of TdP induced by E-4031. These results show that BRL-32872 is a potent antiarrhythmic compound in a model of PES-induced arrhythmias and induces fewer proarrhythmic events than typical class III antiarrhythmic agents. The effects observed with BRL-32872 suggest that a compound with a combination of potassium (class III) and calcium (class IV) channel antagonistic properties might constitute a novel antiarrhythmic agent with reduced proarrhythmic risk.

Animals↗
PubMed1994

Effect of zatebradine, a specific bradycardic agent, on ischemia-induced arrhythmias in anesthetized rabbits.

The effects of the specific bradycardic agent, zatebradine (UL-FS 49), on ventricular arrhythmias occurring during an acute ischemia were compared to those of verapamil. Anesthetized rabbits were submitted to a ligation of the left circumflex coronary artery for 20 min. Zatebradine (150 and 750 micrograms/kg, i.v.) dose-dependently reduced heart rate, but changed neither the left ventricular pressure nor the (+)dp/dtmax. In comparison, verapamil (150 and 750 micrograms/kg, i.v.) reduced heart rate, systemic blood pressure, left ventricular pressure and (+)dp/dtmax. The incidence of ventricular premature beats occurring during acute ischemia was changed neither by zatebradine nor by verapamil. Ventricular fibrillation, occurring in 36% of the saline-treated rabbits, was reduced to 18% in the presence of 750 micrograms/kg of zatebradine and 0% with verapamil (750 micrograms/kg, p < 0.05). The action of zatebradine on ischemia-induced ventricular fibrillation, albeit limited, was completely reversed by atrial pacing to the predrug heart rate. To further investigate the mechanisms involved in the antiarrhythmic potential of both zatebradine and verapamil, their electrophysiological actions were compared in canine Purkinje fibers. Both zatebradine and verapamil induced a dose-dependent increase in action potential duration (APD) measured at 90% repolarization. The APDs measured during the plateau level (APD30) and at 50% of the repolarization (APD50) were shortened by verapamil and increased by zatebradine showing that at the concentrations used, zatebradine did not exhibit any calcium antagonistic activity when compared to verapamil. The results of the present study suggest that the specific bradycardic agent zatebradine showed a beneficial action mainly because of its anti-ischemic properties. However, the present studies performed in anesthetized rabbits suggest that in this species pure reduction in heart rate is not sufficient to entirely prevent ischemic arrhythmias.

Action Potentials↗
PubMed1993

Actions and interactions of E-4031 and tedisamil on reperfusion-induced arrhythmias and QT interval in rat in vivo.

The effects of the Ito blocker, tedisamil (0.1, 1.0, and 3.0 mg/kg, IV), and the IK blocker, E-4031 (0.1, 1.0, and 3.0 mg/kg, IV), on the incidence and duration of reperfusion-induced arrhythmias were compared in the anesthetized rat (n = 12 per group). Reperfusion arrhythmias were evaluated after a 5 minute occlusion period of the left main coronary artery. In the absence of any pronounced effect on blood pressure, tedisamil and E-4031 reduced heart rate in a dose-dependent manner. During the preischemic period, QTc interval was increased by tedisamil but was not changed by E-4031. Both compounds increased the QTc interval during the ischemic period and also during the reperfusion. E-4031 was unable to reduce the incidence and duration of reperfusion-induced ventricular arrhythmias after 5 minutes of coronary artery occlusion. Tedisamil dose-dependently reduced the duration of reperfusion arrhythmias and their incidence. In a second set of experiments, the combination of tedisamil (1.0 mg/kg) with E-4031 (1.0 mg/kg) was administered. The electrocardiographic action of this combination was similar to that observed with tedisamil given alone. However, with the combination the incidence of fibrillation was reduced from 83% in the control group to 8% in the treated group (p < 0.001), and the mortality was reduced from 67% to 0% (p < 0.001), that is, to a greater extent than with tedisamil (1.0 mg/kg) alone. The results show that the blockade of Ito by tedisamil allows a reduction of reperfusion-induced mortality and that a specific IK blocker (E-4031) is devoid of antifibrillatory action in the anesthetized rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗