The standardized model of alcoholic anesthesia for the purposeful screening of analeptics

Abstract

The analysis of pathogenetic mechanisms of development of urgent conditions (anesthesia, asphyxia, hypoxia, shock, collapse, bacterial intoxication, poisoning by chemical compounds or drugs suppressing the function of the central nervous system) suggests that among urgent therapies analeptic drugs (AD) are of a paramount importance. At the same time, their assortment has not only been updated in the last 50 years, but reduced to 6 drugs. This situation is conditioned by the absence of the standard for selecting AD. Aim. To create a standard for selecting AD which can quantitatively (statistically reliable) evaluate both the level of the awakening effect in general and its mechanism (namely its analeptic action); compare and determine the priorities of further study of substances; create theoretical foundations for the purposeful search of AD and optimize the scientific research. Materials and methods. During the research the procedure of AD selection was developed experimentally. It consists in intraperitoneal introduction of the narcotic agent (ethanol) in the optimal dose; introduction of a classical analeptic sulfocamphocaine (SCC) in the standard dose at the peak of anesthesia to one group of mice, while the second group received the substance studied (Heterocide-31) with the subsequent recording of the anesthesia duration, dynamics of the frequency of respiratory movements, assessment of the psychomotor state and physiological functions of animals during anesthesia and after awakening assuming that in the course of the experiment the specific dose-time conditions for introduction of substances are observed. Results. The results of the study show that the maximum efficacy (18.2 %) was achieved by Heteroсide-31 in the dose of 1 mg / kg, while the optimal dose of SCC (20 mg / kg) accelerated awakening of animals by 19.5 %. Thus, Heterocide-31 showed almost identical activity in the concentration of 20 times lower than SCC. The fact that after introduction of Heterocide-31 the respiratory rate (RR4) significantly increases (p <0.05) by 1.6 times already within the first minute compared to the control group, and the maximum (125) respiratory movements / min in the reference drug group is achieved only in 6 min (RR5) indicates the 6-fold advantage of Heterocide-31 by the rate of the respiratory center stimulation and allows referring the latter to a number of promising analeptics. Conclusions. The model of pharmacological screening proposed accelerates the purposeful search of original AD, has a complete novelty, originality, easy in repeatability, economic, environmental and humanistic advantages, namely it reduces time and the number of laboratory animals, the cost of experiments, increases the information value of the experiments. The method has been tested on heterosides and suggests that derivatives of sulfur and nitrogen-containing heterocycles are promising for the search of original AD having a significant advantage over classical analeptics. Key words: alcohol; anesthesia; heterocide; analeptic; awakenin...

Mechanisms of Analeptic and Antigipoxic Effects of Heterosides – (Derivatives for Sulfur and Nitrogen Containing Heterocycles)

“…The animals of the control group remained stagnant and disoriented for a long time (they frozed or moved slowly, rolled over from one side to the other, carried out circular motions, they completely lost their interest in water and food). After some time, they also fell into a long sleep (1-2 hours), which fully coincides with the classic symptoms of TPA intoxication [2][3][4][5][6][9][10][11].…”

“…For comparison, classic drugs were chosen -combined analeptic Sulfocamphocaine (SCC) (Darnitsa), stimulating the respiratory (RC) and vasomotor (VMC) brain centers [1], as well as antihypoxant Piracetam (Halychpharm), prescribed during hypoxia of the central nervous system (CNS) [12]. Optimal doses of TPA (42 mg/kg), SCC (20 mg/kg), Heterosides-21 and Heterosides-31 (2 mg/kg), Piracetam (300 mg/kg) were established experimentally [2][3][4][5][6][9][10][11]12].…”

“…The test substances and comparison preparations were also administered intraperitoneally after the animals entered the third phase of anesthesia (immobilized lateral position with uniform slow breathing), i.e. at the peak of anesthetic sleep (30 -40 minutes) [2][3][4][5][6][9][10][11]. The second and third groups received the studied substances, namely, Heterosides-21, Heterosides-31 [4][5][6], the fourth group -SCC [2-6,9-11], the fifth -Piracetam [1,6,12].…”

“…The effect on RC was determined by the frequency of respiratory movements per minute (FRM/min) in different phases of anesthesia before and after the administration of the awakening drugs. Indicators DA and FRM/min in mice of the 1st group were considered control, and all other experimental groups were compared with them [2][3][4][5][6][9][10][11]. The FRM were counted for 60 seconds, starting immediately with the animals adopting a lateral position (LP) after the introduction of the TPA (FRM 1), and the counts were repeated at intervals of ten minutes (respectively, the FRM 2 -FRM 9).…”

“…The introduction of Heterosides-21, Heterosides-31 and SCC in the respective groups was carried out at the peak of anesthesia (thirty-first minute) immediately after counting of FRM 4. The last FRM measurement was performed after complete awakening of the mice (taking position on four legs) [2][3][4][5][6][9][10][11]. From that moment, their psychomotor state was evaluated (disorientation in space or purposefulness of movement); the level of their adaptation after anesthesia (lethargy or hyperactivity, interest in food and water); physiological reactions (urination, defecation) and other behavioral reactions [4][5][6][7].…”