[The creation of original Russian beta-adrenoblockers]. / Sozdanie otechestvennykh original'nykh beta-adrenoblokatorov.

Results of search for new beta-adrenoreceptor blocking agents of different effects are summarized. Derivatives of 4-hydroxyindolyl-3-acetic acid are characterized by a prolonged beta-adrenoblocking effect, cardioselective beta-adrenoblockers were found among derivatives of N,N-bis(2-hydroxy-3-phenoxypropanol)amine, and highly effective "hybrid" beta-,a-adrenoblockers were detected among derivatives of 3(5)-phenoxymethylisoxazolines and 5-phenoxymethyl-1,2,4,-oxadiasoles. Clinical studies of one of the most promising compounds of the latter series named proxodolol showed it to be a highly effective antihypertensive, antianginal, and antiglaucoma drug. Proxodolol is permitted for clinical application. At present it is manufactured as eye drops for decreasing intraocular pressure in glaucoma; its production as a solution for injections for arresting hypertensive crises is starting.

[The first original Russian class-III antiarrhythmic nibentan]. / Pervyi original'nyi otechestvennyi antiaritmik III klassa nibentan.

The paper presents experimental and clinical findings of the new antiarrhythmic drug nibentan. The agent was found to be a class-III antiarrhythmic agent in terms of its electrophysiological effects and an inhibitor of the delayed rectifier potassium current in terms of its effects on the ionic channels of cardiomyocytes. The clinical trial of nibentan shows that the drug is highly effective (in 70-100% of cases) in patients with atrial flutter and fibrillation and in those with supraventricular tachycardia and it is less effective in suppressing ventricular premature contractions and tachycardia. The rate of arrhythmogenic effects produced by the drug was inversely related to its antiarrhythmic action. Nibentan has been approved for clinical use.

[A comparative pharmacological study of the serotoninergic antidepressants tetrindole and fluoxetin]. / Sravnitel'noe farmakologicheskoe izuchenie serotoninergicheskikh antidepressantov tetrindola i fluoksetina.

Tetrindol, a selective inhibitor of MAOA (predominantly of serotonin oxidase) and fluoxetine, an inhibitor of serotonin neuronal uptake, were studied in psychotropic tests on mice and rats. Both drugs significantly intensified 5-hydroxytriptophan-induced head twitching, reduced the effect of reserpine and the destructive action of maximal electroshock and the scopalamine-induced transient disruption of memory in a test for conditioned response of passive avoidance in rats and mice. In a behavioral swimming test the drugs were less active. In potentiation of 5-HT activity both drugs were approximately equal.

[Proxodolol, a new domestic preparation for lowering intraocular pressure in glaucoma]. / Proksodolol--novyi otechestvennyi preparat dlia snizheniia vnutriglaznogo davleniia pri glaukome.

Effects of a Russian b-a-adrenoblocker proxodolol on the intraocular pressure, ocular hemodynamics, pupil diameter, ocular functions, arterial pressure, and heart rate were studied in 105 patients (163 eyes) with primary open-angle glaucoma. A manifest hypotensive effect of proxodolol was due to depression of aqueous humor production and improvement of its outflow. Comparative study of the efficacies of proxodolol and timolol maleate by the blind test and randomization demonstrated the identity of these drugs. A synergic effect on intraocular pressure was observed when proxodolol was combined with pilocarpine and/or klofelin.

[An experimental study of the antisecretory and antiulcer activities of kviditen]. / Eksperimental'noe issledovanie antisekretornoi i protivoiazvennoi aktivnosti kviditena.

Quiditene-(qunuclidyl-3)-di-(thyenel-2)carbinole hydrochloride was studied by using various experimental models. The agent was compared with H2-blockers. When gastrically used, quiditene in doses of 5-50 mg/kg dose-dependently decreased gastric acid secretion and prevented acute gastric mucosal lesions. As cimetidine and ranitidine, the agent accelerated chronic gastric ulcer healing. Quiditene has been allowed for clinical studies in Russia.

[A search for new beta-adrenoblockaders in the series of 5-phenoxymethyl-1,2,4-oxadiazole derivatives]. / Poisk novykh beta-adrenoblokatorov v riade proizvodnykh 5-fenoksimetil-1,2,4-oksadiazola.

The experiments on anesthesized rats have revealed that some derivatives of (3-amino-2-hydroxypropoxy)phenomethyl-1,2,4-oxadiazole with the oxadiazole cycle at the o-position of the aromatic ring possess a significant beta-adrenoceptor blocking activity associated with alpha-adrenoceptor blocking properties. The most potent compound is 3-methyl-5-[2-(3-tret.butylamino-2-hydroxypropoxy) phenoxymethyl]-1,2,4-oxadiazole (Compound 1, prodolol) which is superior to propranolol, oxprenolol, and particularly labetalol in its beta-adrenoceptor blocking activity. The agent does not greatly differ from labetalol in its alpha-adrenoblocking activity. Proxodolol has been chosen for preclinical and clinical studies.

[Proxodolol--a new beta- and alpha-adrenoblockader]. / Proksodolol--novyi (beta-, al'fa-)adrenoblokator.

The beta- and alpha-adrenoceptor blocking activity, the specificity of its beta-adrenoceptor blocking action, partial agonistic and membrane-stabilizing properties, as well as antihypertensive, antiarrhythmic, and anti-ischemic effects were studied. Proxodolol was shown to be superior to labetalol in its beta-adrenoceptor blocking action and similar to it in its alpha-adrenoceptor blocking agent. The drug has no a partial agonistic activity and produces a moderate membrane-stabilizing action. Proxodolol proved to be effective in treating experimental hypertension and arrhythmias. It exhibits anti-ischemic activity.

[The new antidepressant tetrindole]. / Novyi antidepressant tetrindol.

The antidepressive effects of tetrindole versus pyrazidole (pirlindole) and imipramine were studied in animal experiments. Tetrindole was found to be more active than pyrazidole and imipramine in a behavioral model of Porsolt, in antagonism with reserpine, in potentiation with 5-hydroxytryptophan, L-dopa and clonidine. The action of terindole is related to its ability to exert reversible inhibitory effects on MAO A activity. Tetrindole is less toxic than pyrazidole and imipramine.

[The effect of antihistaminic preparations on the binding of labelled mepyramine, ketanserin and quinuclidinyl benzilate in the rat brain]. / Vliianie antigistaminnykh preparatov na sviazyvanie mechennykh mepiramina, ketanserina i khinuklidinilbenzilata v mozge krysy.

The effects of some antiallergic drugs on H1-histamine, 5-HT2-serotonin, and M-cholinoreceptors ligand binding in the rat brain were studied in vitro. Dimedrol, dimebon, and phencarol bonded to H1-receptors: IC50 were 76 +/- 10, 153 +/- 15, 320 +/- 60 nM, respectively. Diazoline and dimebon had some affinity for 5-HT2-receptors, its IC50 was 880 +/- 90 nM. Dimedrol, phencarol and diazoline were found to be active against M-cholinoceptors, but when given in the maximal concentration (10 microM) it acted nonspecifically. In contrast to the other drugs, bicarphen had no effects on the binding of [3H]-mepyramine, [3H]-ketanserine, and [3H]-quinuclidinyl benzylate in the rat brain.

[Anticalcium activity of several antidepressive agents]. / Issledovanie antikal'tsievogo deistviia nekotorykh antidepressantov.

In experiments in white mice and rats the antidepressants pyrazidol (pirlindole), moclobemide and especially tetrindole possess anticalcium activity in tests of calcium chloride-induced lethality in mice and arrhythmia in rats. Tetrindole is as active as verapamil. Imipramine, azaphen and incazane were not active in these experiments. In vitro on isolated intestinal segments of guinea-pigs tetrindole exerts anticalcium action, but in less degree than verapamil. In all probability the anticalcium activity of tetrindole may play some role in the mechanism of action of this compound on the central nervous system.

[The antiamnesic properties of antidepressants]. / Antiamnesticheskie svoistva nekotorykh antidepressantov.

The experiments on albino rats demonstrated that antidepressants pyrazidol, imipramine, incazane, moclobemide and to a lesser degree azaphen reduce the amnesic effects of electroshock and scopolamine in the rats with the acquired conditioned reaction of passive avoidance. The studied antidepressants decrease also the disturbing action of alcohol on the learning of rats of the conditioned reaction of active avoidance.

[Effects of antidepressive agents on tolerance of hypoxia and physical exercise]. / Vliianie antidepressantov na vynoslivost' k gipoksii i fizicheskoi nagruzke.

In experiments on mice and rats we studied the influence of antidepressants on hypoxic and physical tolerance. The antidepressants pyrazidol, azaphen, imipramine and moclobemide as well as the nootropic drug piracetam prolonged the life of animals in conditions of hypoxic and hemic hypoxia and increased the survival rate of rats in circulatory hypoxia. In experiments on mice antidepressants increased also the time of swimming.

[The comparative influence of pyrazidol, inkazan and other antidepressant monoamine oxidase inhibitors on the pressor effect of tyramine]. / Sravnitel'noe vliianie pirazidola, inkazana i drugikh antidepressantov--ingibitorov monoaminoksidazy na pressornyi éffekt tiramina.

In experiments on conscious normotensive male Wistar rats the new antidepressants, reversible MAO-A inhibitors, pyrazidole and incazane, as well as moclobemid increased the pressor effect of orally administered tyramine. The drugs potentiated also the pressor effect of intravenous tyramine. More prolonged potentiation of tyramine action was produced by moclobemid, less prolonged by incazane. The potentiation by the studied MAO-A inhibitors of the pressor effect of tyramine reflects the inhibition of the activity of MAO-A and the first-pass metabolism of tyramine in the gut and liver, as well as the inhibition of intraneuronal MAO activity in noradrenergic nerve endings and the potentiation of sympathetic activity.