Vol 14, No 3 (2023)

BACKGROUND: Levodopa therapy currently remains the clinical method of choice for patients with Parkinson’s disease. However, in the late stages of the disease, approximately 80% of patients receiving treatment developed levodopa-induced dyskinesia. The studied substances are derivatives of imidazole-4,5-dicarboxylic acid. Their pharmacological effect is produced due to interaction with the recognition site of NMDA receptor, which, together with their high efficiency, implies that they are safer than previously available drugs in this pharmacological group.

AIM: To study the antidyskinetic effect of IEM2295 and IEM2296 derivatives of imidazole-4,5-dicarboxylic acid.

MATERIALS AND METHODS: The model is based on the toxic effect of 6-hydroxydopamine on rat brain tissue. The first (control) group of rats received injections of only Levodopa and Benserazide, the second group received injections of Levodopa, Benserazide, and the test substance IEM2295, and the third group received injections of Levodopa, Benserazide and the test substance IEM2296. Each group was evaluated based on three criteria: motor function violations, limb dyskinesia, and axial and chewing dyskinesia. The severity of motor functions was graded on a scale of 0 to 4 points at 35, 70, 105, and 140 minutes after injection of the above substances, where 0 and 4 represent the absence and most pronounced degree of pathological movements, respectively.

RESULTS: The result analysis showed that the greatest effect on reducing the severity of limb dyskinesia, axial dyskinesia, and chewing dyskinesia in rats was observed at 105 and 140 minutes after injections of the studied substances. Statistically significant differences between the control group and rats receiving injections of the studied substances were revealed at all the time points for limb dyskinesia; i.e., at 35, 105, and 140 minutes for axial dyskinesia and at 105 and 140 minutes for chewing dyskinesia.

CONCLUSIONS: In the experimental model of parkinsonism, IEM2295 and IEM2296 show antiparkinsonian and antidyskinetic activity because they reduce the severity of motor function disorders in rats with levodopa-induced dyskinesia. The results indicate the prospects for continued development of these substances and further research for effective and safe antiparkinsonian agents among compounds of this class.

The Department of Pharmacology of the Institute of Experimental Medicine was established in the autumn of 1923 on the initiative of the institute’s leadership. Professor Nikolai Pavlovich Kravkov (1865–1924), the most respected domestic pharmacologist at that time and the head of the Department of Pharmacology of the Military Medical Academy, was invited as the alleged head of the department. However, N.P. Kravkov’s untimely death in April 1924 precluded the department from developing extensive research in Pharmacology. Professor Vladimir Vasilyevich Savich (1874–1936), a student of I.P. Pavlov who focused his main research on the effect of medicinal substances on the nervous regulation of the cardiovascular system, gastrointestinal tract, endocrine system, and water metabolism, led the department from 1924 to 1936. The mechanism of the direct impact of drugs and poisons on organs and tissues was studied using both isolated organs, notably endocrine glands, and classical conditioned reflex techniques. In 1936, the department was disbanded in connection with the death of the head (V.V. Savich) and the reorganization of the institute’s structure. Professor S.V. Anichkov (1892–1981), who later became the Hero of Socialist Labor, laureate of the Lenin and State Prizes of the USSR, and academician of the USSR Academy of Medical Sciences, revived the department in 1948 and remained its permanent head until his death (in July 1981). Along with him were well-known researchers Professors V.M. Karasik, N.V. Khromov-Borisov, I.S. Zavodskaya (who led the department from 1981 to 1984), Y.S. Borodkin (who led the department from 1984 to 1992), N.A. Kharauzov, V.E. Ryzhenkov, N.S. Sapronov (who led the department from 1992 to 2011), P.P. Denisenko, and N.A. Losev. The main focus of the department from 1948 to 1984 was the integration of fundamental pharmacological advancements with the introduction of drugs into healthcare practice. Currently, the Department of Neuropharmacology. S.V. Anichkova is one of the largest research centers in Russia, focusing on fundamental research in Pharmacology. Professor P.D. Shabanov has been the head of the department since 2011. The department divided into four laboratories: the Laboratory of Chemistry and Pharmacology of Medicinal Products (led by Doctor of Medical Sciences, E.R. Bychkov), the Laboratory of General Pharmacology (led by Doctor of Biological Sciences, Prof. A.A. Lebedev), the Laboratory of Biochemical Pharmacology (led by Doctor of Medical Sciences, Prof. P.D. Shabanov), and the Laboratory of Synthesis and Nanotechnology of Medicinal Substances (led by Doctor of Biological Sciences, Prof. L.B. Piotrovsky).

BACKGROUND: The V.V. Zakusov Research Institute of Pharmacology developed hybrid digital sensors for the first, second, and fourth BDNF patches (GSB-214, GTSB-201, and GSB-106, respectively). When tested in vitro, on an oxidative stress model, in the culture of hippocampal neurons NT-22, the compound GTS201 (hexamethylenediamide bis-hexanoyl-seryl-lys), a simulator of the 2^nd series of BDNF, activates the TrkB spy receptor and MAPK/Erk kinase pathway but does not affect the PI3K/Akt signature pathway and has neuroprotective activity similar to BDNF.

AIM: To study the effect of GTS-201 dipeptide on the behavior of laboratory white rats during the formation of their dependency state and morphine withdrawal syndrome.

MATERIALS AND METHODS: Morphine dependence in rats was developed due to administration of morphine in a doses escalation manner ranging from 10 to 20 mg/kg twice daily at 8-h intervals for 5 days. GTS-201 was given in 1- or 5-mg/kg doses for once in 30 minutes before morphine on the 5^th day of the experiment or daily (in one of the groups) for 5 days in the morning 30 minutes before morphine administration. On the 5^th day of the experiment, animals were tested for the presence of specific signs of morphine withdrawal syndrome in an “open field” for 5 minutes. Four experimental groups were formed: group 1 “morphine hr. + naloxone” (“active control” group); group 2 “morphine hr. + GTS-201 (1) + naloxone”; group 3 “morphine hr. + GTS-201 (5) + naloxone”; and group 4 “morphine hr. + GTS-201 (1 × 5) + naloxone.” Designations: hr. — morphine administration within 5 days; (1) and (5) — doses of substances in mg/kg, (1 × 5) — chronic administration of the peptide for 5 days.

RESULTS: When studying the effect of GTS-201 dipeptide on behavioral, somatic, and neurological markers of animal behavior after morphine withdrawal, significant changes in the severity of individual signs of withdrawal syndrome were noted. Manifestations of diarrhea were significantly decreased in all groups of animals injected with the peptide. In animals from group 3, “morphine hr. + GTS201 (5) + naloxone showed the maximum effect: diarrhea was decreased by 71.0% (p < 0.001), convulsions were decreased by 83.3 % (p < 0.05), running was decreased by 71.4% (p < 0.01), and vocalization was decreased by 62.5% (p < 0.05). GTS-201, administered at a dose of 1 mg/kg once, eliminated the appearance of escape attempts in group 2, but the peptide at the same dose completely blocked convulsive reactions in rats in group 4. Despite significant changes in individual indicators, the total index (of morphine withdrawal syndrome for groups chronically injected with morphine) did not change statistically significantly compared with group 1 of “active control.” In the control group, its value in points was 7.3 ± 0.36 (100%), whereas in groups 2–4, it ranged from 6.2 (84.9%) to 6.5 (89.0%; p > 0.05).

CONCLUSIONS: It is assumed that the antiaddictive dipeptide activity of GTS-201 is mediated by activation of these receptors and markers/the Erk-kinase signaling pathway, which does not exclude the involvement of opioid receptor mechanisms in the implementation of the observed behavioral phenomena.

BACKGROUND: The issues of therapy of dependence on psychoactive substances remain relevant at present, focusing on the prevention, treatment, and rehabilitation of these patients in the first place.

AIM: To evaluate the effectiveness of a course of Cytoflavin in patients with alcohol dependency during the post-abstinence period.

MATERIALS AND METHODS: An open, double-blind, placebo-controlled clinical study of the antioxidant Cytoflavin (10 mL/day, 5 days) effectiveness to correct emotional and motivational disorders after the treatment of alcohol withdrawal syndrome was performed in 30 patients with alcohol dependency. Anamnestic information, the clinical picture of the disease, and psychological tests — the Holmes and Rage method (the degree of stress tolerance and social adaptation) and alcohol consumption motivation test (ACMT) — were used to verify alcohol dependency. Before and after Cytoflavin treatment, the psychological indicators and complaints were recorded. According to the alcohol intake questionnaire, the psychological state of the patients was assessed based on a package of standard psychological tests, including the Wasserman test (level of neuroticism), Spielberger test (level of anxiety), Hamilton test (level of depression), SAN test (self-assessment of well-being, activity, and mood), and degree of craving for alcohol. For pairwise conjugated variants, the significance of differences was determined using the Student’s t-test; statistical analysis was performed using the standard Statistica for Windows software package.

RESULTS: In general, the course use of Cytoflavin treatment improved clinical and psychological parameters in patients with alcohol dependency in the post-abstinence period.

CONCLUSION: It is concluded that the use of the drug as a component of a comprehensive therapeutic program for alcohol dependency is highly promising.

Controlled local hyperthermia and hypothermia are important factors in drug pharmacodynamics and pharmacokinetics because changing the temperature of drugs changes their physicochemical properties. In this regard, a controlled change in the temperature of the drug and/or the body part with which the drug interacts, relative to the level of human body temperature (hyperthermia or hypothermia) forms the basis of temperature pharmacology. To analyze the author’s publications on the problem of methodology and technology for repurposing drugs based on changes in the physicochemical properties of dosage forms. A controlled change in the temperature of the drug and/or the part of the body with which the drug interacts; a change in acid (alkaline), osmotic activity, and the degree and quality of carbonation and/or oxygen-forming activity of medicinal solutions; and a change in the concentration of medicinal solution ingredients. On the basis of the used methods, the reprofiling of a number of drugs has been achieved. The author proposed reprofiling a 4% potassium chloride solution from the group of macroelements and microelements used to regulate acid-base balance with a resorptive effect (when administered intravenously to the whole body) into a group of vasoconstrictive drugs used to stop bleeding when applied to by a single irrigation of the bleeding surface. Cooling certain drugs and tissues at their interaction sites to 18°C–20°C (via an ice pack or its substitute) inhibits metabolism and function, ensuring the conversion of many drugs into anti-ischemic drugs by reducing the need for tissues in oxygen. A targeted change in the physicochemical properties of known drugs combined with local hyperthermia allows them to be converted into expectorant, pyrolytic (astringent), hemolytic, thrombolytic (hemostatic), detergent, bleaching, cleaning, and other drugs, including antiseptic and cauterizing (necrotizing) drugs, very reliably, quickly, and inexpensively. Thus, 40 years ago, pharmacologists of the Russian Federation established the foundation for a novel method of drug development known today as repurposing of existing drugs. Today, it is evident that reprofiling may rapidly, inexpensively, and effectively give existing drugs a new purpose.