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The effect of Aligeron (1-benzhydril-4-allyl-piperazine dihydrochloride) on the cranial circulation was studied in dogs under chloralose-urethan anaesthesia. The parameters followed were: venous outflow from the confluence of the cerebral sinusses (CVO), cerebrospinal fluid pressure in cysterna magna (CSFP), systemic arterial blood pressure (BP) and pulse rate (PR). CVP was measured using the technique of Rapela and Green (1964). Aligeron was applied at doses of 5 and 10 mg/kg i.v. Papaverine hydrochloride was used as a reference compound. aligeron administration at a dose of 5 mg/kg led to quick increase of the CVO with a duration of the effect approximately 30 min. CSFP also increased in a similar way. BP and PR showed insignificant changes. The administration of 10 mg/kg did not lead to an increase of its effect on CVO. Papaverine (1 mg/kg i.v.) had a weaker effect than that of Aligeron. According to the classical concepts the changes observed in our experiments were due to the cerebral vasodilator effect of Aligeron which caused a fall in cerebrovascular resistance and an increase of the intracranial blood volume. Our experiments suggest that Aligeron influenced the resistance vessels more than the capacitance ones.

The effect of the cinnarizine analogue Aligeron on the resistance of cerebral and peripheral blood vessels was studied in acute experiments on cats and dogs. The resistance of the cerebral vessels was determined directly and indirectly. For direct determination the method of autoperfusion was used. The resistance was calculated indirectly as a quotient of mean arterial blood pressure and internal carotid blood flow. For evaluation of Aligeron effect on the resistance of the peripheral blood vessels and method of autoperfusion of the femoral artery was used. Aligeron was administered i. v. and i. a. In some of the experiments the compound was applied on the background of previously injected dihydroergotamine. Cinnarizine and papaverine were used as reference compounds. The results show that Aligeron decreases considerably the cerebral and peripheral resistance vessels tone, and its effect is higher than those of cinnarizine. For the realization of this effect most probably its direct myotropic action plays the main role. The reduction of its effect after alpha-adrenergic blockade suggests an involvement of some adrenergic blocking properties in its mechanism of vascular action.

The effect of the anti-hypoxic drugs piracetam, nicergoline, papaverine, cinnarizine and aligeron on the activity of bee venom phospholipase A2 was studied in experiments in vitro. The pH-stat titration method of Grossmann et al. was used. All the drugs studied inhibited to a various degree the activity of phospholipase A2 in vitro. The most potent drug was nicergoline and the least potent was papaverine. Taking into account that the activity of phospholipase A2 is stimulated in hypoxia, the results make us believe that the inhibition of phospholipase A2 might play a certain role in the anti-hypoxic effect of the drugs studied.

In view of the interesting problem of the correlation between the functional cerebral activity and cerebral blood circulation, as well as the controversy in the literature concerning the effects of tranquilizers on cerebral blood circulation, the effects of the daily tranquilizer Lonetyl on the spontaneous cerebral bioelectrical activity and cerebral haemodynamics have been studied. According to rheoencephalographic data, Lonetyl is found to reduce cerebral vascular tone, which is manifested by decreased values of the relative share and the dicrotic index, the maximum effect being observed between the 15th and 30th min. The changes in the EEG consist in significant increase of the alpha- and theta-activity, with maximum effect on the 15th min, increased mean frequency and decreased mean amplitude. Synchronization of the cerebral bioelectrical activity is observed after the 30th min.

The anti-hypoxic effect of drugs that inhibit different steps of arachidonic acid metabolism was studied using an experimental model of acute hypobaric hypoxia in mice. The drugs investigated were chloroquine, betamethasone, chlorpromazine (phospholipase A2 inhibitors), ketoprofen (cyclo-oxygenase inhibitor) and imidazole (TxA2 synthetase inhibitor). Prostacyclin (PGI2) and PGF2 alpha were also studied. The results show that all the inhibitors of arachidonic acid metabolism manifest an anti-hypoxic effect of a various degree. PGF2 alpha had a deleterious effect, and PGI2 showed a marked anti-hypoxic effect. The results suggest that it is advantageous to search for anti-hypoxic drugs among the blockers of arachidonic acid cascade.

The authors examined the analgetic and antiinflammatory action of glaucine. They used the following methods for evaluation the analgetic action: chemical irritation, heating plate, heat-ray irritation, mechanical irritation of the normal and inflammatory tissues, electrical irritation and analgetic test. The following methods were used for evaluation of antiinflammatory action: effect on the edema of the rat paw and granulation phases of the inflammation in rats. Codeine and acetysal were used as control drugs. The results from the experiments showed that glaucine successfully inhibited the granulation phase of inflammation and did not affect edema of the rat paw, induce by yeast beer. The analgetic action of glaucine was weak and without practical significance.

In rats with streptozotocin-induced diabetes antioxidant protection of diabetic angiopathy was performed by flunarizine (10 mg/kg/day) and aligeron (10 mg/kg/day), applied intraperitoneally during 2.5 months of diabetes. Diabetic vascular complications were assessed by morphologic determination of PAS-positive mucopolysaccharides and measurement of vascular wall thickness in addition to quantitative estimation of lipid hydroperoxides, thromboxane A2/prostacyclin disbalance and plasma beta-thromboglobulin changes. Both drugs prevented development of diabetic angiopathy in rats by inhibition of lipid peroxidation, prostanoid synthesis and platelet activity, but the effect of flunarizine was more pronounced, which could be explained by its additional blocking effect of abnormal calcium flux into vascular cells. The free radical scavenging action of flunarizine and aligeron was investigated.

The anti-amnestic action of nicergoline was studied using the following experimental methods for learning and memory impairment, based on passive avoidance response: amnesia induced by maximal electroshock in mice, scopolamine-induced amnesia in mice and amnesia by paradoxical sleep deprivation in rats. Piracetam, meclofenoxate, pyritinol, deanol and phenazepam were used as reference drugs. The results show that nicergoline demonstrates well-expressed anti-amnestic effect manifested by reducing the amnestic effect of maximal electroshock, scopolamine or paradoxical sleep deprivation, its effect being equal to or more pronounced than piracetam, meclofenoxate, pyritinol, deanol and phenazepam.

The effect of piracetam (2-oxo-1-pyrrolidine-acetamide, Pyramem) on the local cortical cerebral blood flow (CBF) and oxygen balance in the brain was studied on cats anesthetized with ether-chloralose. The changes in local CBF were registered by means of the thermistor thermoclearance technique. pO2 and pCO2 were determined in blood samples from the femoral artery and superior sagittal sinus and arterio-venous differences of O2 and CO2 partial pressures (AVD-O2 and AVD-CO2) were calculated. The experiments were made on normoxic animals and on animals with slight hypoxia. Piracetam administration (100 mg/kg i.v.) leads to an increase in local cortical CBF corresponding to a change in the specific thermoconductivity of the brain of 0.6 . 10(-4) cal . cm-1 . sec-1 . degrees C-1. This effect is observed in 84% of the experiments with normoxia (arterial pO2 96.0 +/- 21.0 mm Hg) and in 40% of the experiments with slight hypoxia (arterial pO2 59.9 +/- 6.0 mm Hg). Changes in AVD-O2 and AVD-CO2 are not observed. Most probably the increase in CBF does not participate in the mechanism of the protective action of piracetam in hypoxia.

Muscle strips isolated in longitudinal and circular directions from the fundus, corpus and antrum, and from the pyloric sphincter of the guinea-pig stomach were placed in organ baths for recording their spontaneous contractility. Concentrations of the order of 10(-9) to 10(-6) M of prostacyclin (PGI2) were tested and compared with the effect of PGE1, PGE2, PGF2 alpha and acetylcholine. Furthermore, a modification of PGI2 effect was studied in the presence of adrenergic and cholinergic blocking agents, tetrodotoxin, indomethacin and the PG antagonist SC-19220. Like PGE1, PGE2, PGF2 alpha and acetylcholine, PGI2 increased the tone of the longitudinal strips from fundus, corpus and antrum, its effect being less potent than the effects of PGE1 and PGE2 and more potent than the effects of PGF2 alpha and acetylcholine. All the PGs inhibited the phasic contractions of the circular muscle of antrum and pyloric sphincter in a dose-dependent manner. These effects were not significantly changed in the presence of adrenergic and cholinergic blocking agents, nor in the presence of tetrodotoxin, and could therefore be interpreted as being myogenic in nature. Indomethacin exerted effects opposite to those of PGI2. It shifted the log concentration-effect curve for PGI2 to the right suppressing the maximum response of PGI2 by about 50%. SC-19220 reversibly inhibited the spontaneous tone and the excitatory responses of the gastric muscle to PGI2. The concentration-effect curves for PGI2 were shifted to the right in the presence of SC-19220. Analysis of the data gave the pA2 value for PGI2 5.3, the slope of Schild plot being 1.23, which suggests that SC-19220 is a competitive antagonist.

The pharmacological activity of four new groups of isoquino [2,1-d] ((1,4]benzodiazepines, i.e. the 6-oxo-12,13-dimethoxy-5H-7H--9,10-dihydroisoquino [2,1-d] [1,4]benzodiazepinium bromides (I); 5,9,10,14b--tetrahydroisoquino [2,1-d] [1,4]benzodiazepin-7H-6-ones (II); 6-phenyl-12,13--dimethoxy-7,9,10,14b-tetrahydroisoquino [2,1-d] [1,4]benzodiazepines (III) and 6-phenyl-12,13-dimethoxy-7H-9,10-dihydroisoquino [2,1-d] [1,4]benzodiazepinium bromides (IV) was studied. All the compounds studied are biologically active. They show a depressive effect on the central nervous system, which is most pronounced in (II). It was established that the presence of alkyl substituents in the position-7 of the structure (II) as well as the chlorine atom in position-2 resulted in an increase of activity. Most of these compounds possess a mild or strong antinociceptive effect. Some of them exhibited an antireserpine activity as well. The spasmolytic effect of (IV) was strong while the rest of the compounds exerted a very weak spasmolytic effect. All the compounds tested on the autonomous nervous system possess the characteristics of weak sympathomimetics.

The influence of orotic acid on cortical excitability processes and cerebral circulation was studied in acute experiments in cats. The effect on CNS excitability was assessed by examination of the cortical visual-evoked potentials and the recovery cycles. The flash-evoked responses were recorded from visual cortex (VC), associative cortex (AsC) and auditory cortex (AuC). The recovery cycles were determined as the ratio of the average response to the test stimulus and those to the conditioning stimulus depending on the interstimulus interval duration. For investigation of cerebral circulation the method of local cerebral rheoencephalography (REG) was used. The following REG parameters were assessed: amplitude, anacrotic sections of the curve and its relative part, and duration of the wave. The arterial blood pressure was monitored continuously. Orotic acid administration (50 mg/kg i.v.) induced a significant increase in the amplitude of the primary response from VC and AsC. Significant shortening of the peak latency of the second wave of the response in the VC was also observed. The recovery cycles examination showed a facilitation of the test response. The changes observed indicate an increase of excitability processes in the CNS. The REG changes after orotic acid indicate a cerebrovascular resistance decrease and increase in cerebral blood volume. It is assumed that increased cortical activity by orotic acid may lead to an improvement of cerebral circulation.

The effect of piracetam on the excitability of the brain has been examined in cats by electrophysiological approaches: spontaneous electrocorticogram (ECoG), visual evoked potentials (VEPs) and their recovery cycles in some brain structures (visual and associative cortex, lateral geniculate body, centrum medianum thalami and mesencephalic reticular formation). Piracetam (100 mg/kg i.v.) increased the spectral power of ECoG and particularly in the associative cortex for the frequency bands of 10-12 and 19-22 Hz. Piracetam decreased the early components and facilitated the late components of VEPs predominantly in the associative cortex. Changes were found in the recovery cycles too, namely, facilitation and shortening of recovery in all structures studied except in lateral geniculate body. The data suggest that piracetam acts as a non-specific activator on the excitability thus optimizing the functional state of the brain.

The influence of piracetam (2-oxo-1-pyrrolidine-acetamide, Pyramem) on the cerebral circulation and brain bioelectrical activity of cortex and mesencephalic reticular formation (RF) was studied in acute experiments on cats which were encéphale isolé preparations. The methods of local cerebral rheoencephalography (REG) and electroencephalography (EEG) were used. The following REG parameters were assayed: anacrotic section of the curve and its relative part, amplitude and duration of the wave. The arterial blood pressure was followed continuously. The results show that upon piracetam administration (150 mg/kg i.v.) an improvement of the REG parameters of the cortex and RF is observed-an increase of the amplitude and decrease of the values of the anacrotic section of the curve and its relative part. The changes observed indicate a cerebro-vascular resistance decrease and give indirect evidence of cerebral blood volume increase. EEG data are characterized mainly by an increase of alpha-waves, both of cortex and RF. Suggestions for possible mechanism of action of piracetam are made.

The following methods were used: neuropharmacologic study according to the a modified method of Nikolova, Daleva, orientation reaction according to Boissier and Simon, "open field" according to Fontenay et al. and actographic study. The data from "the free" observation suggested clearly a manifested central stimulating effect of aligeron. The data from the actographic study were similar, which showed an increased motor activity in mice and rats, given doses of 1/100-1/4 of LD50. The stimulating action of the preparation was observed in doses of 1/8-1/6 of LD50 during the experimental procedure "open field". The preparation inhibited orientation reaction in mice. Cinnarizine inhibited the examined indices, obtained by all tests. The complex of the used methods allowed to make an inference that aligeron had central stimulating effect, weaker in smaller therapeutic doses and more manifested in higher doses. Cinnarizine had weak depressive effect.