В результате направленного синтеза из доступного 3-метилксантина получена новая группа производных 1- и 7-[ω-(бензгидрил-1)алкил]-3-метилксантина, обладающих свойствами блокаторов гистаминовых рецепторов. Наиболее активное, длительно действующее и малотоксичное соединение 7-[4-(4-бензгидрилпиперазинил-1)бутил]-3-метилксантина сукцинат отобрано для клинических испытаний.

Обнаружена способность янтарной кислоты потенцировать (синергизм) антигипоксическую активность производных 3-оксипиридина: сукцината (Iа) и гидрохлорида (Iб) 3-(N,N-диметилкарбамоилокси)-2-этил-6-метилпиридина, что определило целесообразность создания новых комбинированных лекарственных средств, обладающих наряду с высокой антигипоксической активностью антиамнестическим и противосудорожным действием. Установлено, что антигипоксическая активность препаратов группы 3-оксипиридина повышается в ряду эмоксипин < мексидол < проксипин < Iа + янтарная кислота < Iб + янтарная кислота.

Обнаружена способность янтарной кислоты потенцировать антигипоксическую активность винпоцетина. Это свойство (потенцирование) явилось основанием для создания нового комбинированного препарата, содержащего винпоцетин и янтарную кислоту, обладающего более выраженной антигипоксической активностью, чем исходный монопрепарат - винпоцетин, а также антиамнестическим и противосудорожным действием.

A series of new piperidyl-4-ethane derivatives possessing antiarrhythmic activity has been synthesized and studied. The most active compound, hydrochloride 1-(4-fluorophenyl)-1-(4-nitrobenzoylamino)-2-(N-ethyl-4-piperidyl)-ethane (niferidyl), was selected for clinical trials as a potential class III antiarrhythmic drug.

Working hypotheses for the creation of new potential drugs, including Class III antiarrhythmic (nibentan, niferidyl), antiallegic (theoritin), and antituberculosis (hixozid) agents are formulated and experimental data on the activity of obtained compounds are presented.

The effects of proxodolol--new beta-blocker with alpha-blocking activity--on system hemodynamics, heart function and morphology of rats with ischemia-induced congestive heart failure were studied and compared with those of carvedilol. It was shown that both drugs administered during 3 weeks after ligation of coronary artery inhibit heart remodeling and development of myocardial hypertrophy. Proxodolol was more effective than carvedilol in prevention of heart dysfunctions typical for congestive heart failure, that was especially evident during the pharmacological overload tests.

В работе приведены данные о синтезе и результатах изучения противовоспалительной, анальгетической и жаропонижающей активности 11 производных N-ариламидинов. Установлено, что по указанным выше видам активности изученные соединения не имеют преимуществ перед ибупрофеном и парацетамолом.

The comparative investigation of the action of the aminostigmine and its combination with pyrlindol on the learning and memory in the rats and mice demonstrated the advantage of this combination that may be useful in the treatment of the dementia

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.

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.

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.

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 effect of the new hybrid (beta-, alpha-) adrenoceptor blocking drug proxodolol on cardiac output and its distribution between 16 vascular regions, by using the microsphere method on anesthesized normotensive rats and rats with persistent renovascular hypertension. Proxodolol given in beta-adreno-blocking doses similar to those of labetalol was shown to exert vasodilating effects in normotensive rats. Renal, adrenal, splenic, and skeletal muscle vessels were most sensitive to labetalol, whereas cardiac and pulmonary vessels were responsive to proxodolol. In rats with persistent renovascular hypertension, proxodolol had a vasodilating effect only when it was used in doses inducing alpha-adrenoceptor blockade.

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.

In experiments on anesthetized rats it was found that some derivatives of 2-(3-isopropylamino-2-hydroxypropoxy) phenoxymethyl isoxazole possess marked beta-adrenoblocking activity associated with alpha-adrenoblocking properties. The most active compound is 3-methyl-4-chloro-5-(3-isopropylamino-2-hydroxypropoxy) phenoxymethyl isoxazole hydrochloride (compound II) which by its beta-adrenoblocking activity is superior to propranolol, oxprenolol and especially labetalol. By its alpha-adrenoblocking activity the compound does not differ significantly from labetalol but it is inferior to phentolamine. Compound II has partial agonistic activity, exerts nonspecific membrane-stabilizing action and exhibits antifibrillatory and antiarrhythmic activity.

Some derivatives of 2-(3-amino-2-hydroxypropoxy)phenoxymethyl isoxazole possess beta- and alpha-adrenoblocking activity. 3-Methyl-4-chlor-5-(3-isopropylamino-2-hydroxypropoxy)phenoxymethyl isoxazole hydrochloride (compound OF-4452) is the most active of the compounds studied. As to the beta-adrenoblocking activity, this compound given in vivo and in vitro compares very favourably with propranolol, oxprenolol and labetalol, in particular; as regards the alpha-adrenoblocking action, it is not inferior to the latter drug. Compound OF-4452 has a partial agonist activity and nonspecific membrane-stabilizing action. It displays antifibrillatory and antiarrhythmic activity as well.

It has been demonstrated in experiments on rats that atenolol in a dose of 10 mg/kg exerts an antiischemic action in transitory coronary occlusion lasting 30 minutes followed by reperfusion for 23h and 30 min. The effect manifested in the diminution of the relative area and mass of myocardial necrosis zone and in the dilatation of the left ventricle. Atenolol also produced an antiischemic action in permanent coronary occlusion for 24 h. However, the effect in the latter case was less marked than in transitory occlusion. When injected for permanent occlusion, atenolol (10 mg/kg i. v.) led to a 1.59-fold decrease in the necrosis area and a 2.1-fold decrease (p less than 0.001) when administered for transitory occlusion. The mass of the myocardial necrosis zone also dropped (by 1.65-fold and 2.3-fold, respectively), whereas the degree of dilatation by 2.1- and 2.3-fold, respectively.