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INVENTION
Patent of the Russian Federation RU2083204
MEANS FOR BUILDING ABSTEINENT SYNDROME IN THE OPTICAL DRUGS
The name of the inventor: Yarygin Vladimir Nikitich; Sudakov Sergey Konstantinovich
The name of the patent holder: Yarygin Vladimir Nikitich; Sudakov Sergey Konstantinovich
Address for correspondence:
The effective date of the patent: 1993.03.30
The invention relates to the field of medicine, namely, to narcology. The method allows to increase the effectiveness of withdrawal of the withdrawal syndrome in opiate addictions. For this, lupeptin is used.
DESCRIPTION OF THE INVENTION
(EN) The invention relates to medicine and biology, in particular to narcology, to the means of arresting the withdrawal syndrome.
There are known funds for the treatment of drug addiction, having oligopeptidnuyu nature, for example cholecystokinin. However, this tool has not found wide application in medical practice, as relatively expensive and ineffective.
The aim of the invention is to find a means for arresting the withdrawal syndrome in opiate addictions.
This goal is achieved using the known substance in the practice of biological studies of lupeptin for the first time as a means for stopping the withdrawal syndrome in opiate addictions.
The drug lupeptin was known as an inhibitor of calcium-activated endoproteases (Kondo S. et al., Chem., Pharm., Bull., 17, 1869, 1969, Suda H. et al., J. Antibiot., 1972, 25, 263).
The lupeptin preparation is described in detail as an oligopeptide compound produced by microorganisms consisting of 3 amino acid residues and having the structural formula (Acetyl-Leu-Leu-Arg-al). The drug lupeptin was first used to stop the abstinence syndrome in opiate addictions. This application is fundamentally new and is the result of lengthy experimental and theoretical studies. It is not obvious for an experienced pharmacologist and unexpectedly for a doctor-expert in narcology.
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FIG. 1 shows the change in pain sensitivity threshold under the influence of morphine and lupeptin in tolerant rats (2) compared with intact (1). The abscissa is the dose of lupeptin. On the y-axis, the latent tail-pulling period as a percentage of the original; 2, the index of withdrawal syndrome in animals treated with lupeptin in a dose of 0.5 mg / kg (1) and saline (2) together with morphine.
The following are specific examples that prove the antinarcotic effect of lupeptin.
Example 1. Effect of lupeptin at a dose of 10 mg / kg on withdrawal cessation in morphine-dependent rats. The experiments were carried out on 20 male Wistar rats weighing about 200 g at the beginning of the experiment. The rats were kept under artificial illumination (12 hours a day), constant access to the standard combined feed and water in 6-7 animals. In rats, the dependence on morphine was developed and then the withdrawal syndrome was evaluated in the "open field" test. The essence of the procedure was that the animals were intraperitoneally injected with morphine for 12 days at doses increasing from 10 to 60 mg / kg twice a day at an interval of 8 hours. 36 hours after the last injection of morphine, the animals were placed in an "open" Field "for 3 minutes to record changes in general behavioral and the presence of specific abstinence reactions. Expressed in points the total index of changes in horizontal and vertical motor activity, the presence and frequency of grooming, shaking, changes in breathing and posture, ptosis, piloerection, vocalization, grinding of teeth, cramps, seizures, flight, rhinorrhea, shaking paws, diarrhea. 10 animals 1 hour prior to testing, lupeptin was administered at a dose of 10 mg / kg intraperitoneally, another 10 animals had an equal volume of saline.
The experimental data were processed statistically by means of Student's t test. It was found that the animals of the control group had signs of morphine withdrawal syndrome of varying degrees of severity. The average total index characterizing all the studied general behavioral and specific responses of animals in the control group was 10.325. The introduction of lupeptin at a dose of 10 mg / kg for 1 h before the test resulted in the fact that the manifestation of abstinence in these animals was less expressed than in the control ones. The average total score was 6.6, which is 36% less than in the control. The differences were significant with a probability of 0.005. Reduction of the total indicator of withdrawal was mainly due to a decrease in such indicators as diarrhea, gnashing of teeth, shaking with paws. The drug increased the level of vertical motor activity (the number of racks), decreased in dependent animals.
The results obtained show that intraperitoneal administration of lupeptin at a dose of 10 mg / kg leads to a decrease in the severity of the withdrawal syndrome in morphine-dependent rats.
EXAMPLE 2 Effect of Lupeptin at a dose of 0.5 mg / kg on withdrawal syndrome in morphine-dependent rats.
The experiments were carried out on 20 male Wistar rats weighing about 200 g at the beginning of the experiment. The rats were kept under artificial lighting conditions (12 hours a day), constant access to the standard combined feed and water in 6-7 animals. In rats, the dependence on morphine was developed and then the withdrawal syndrome was evaluated in the "open field" test. The essence of the procedure was that the animals were intraperitoneally injected with morphine for 12 days at doses increasing from 10 to 60 mg / kg twice a day at an interval of 8 hours. 36 hours after the last injection of morphine, the animals were placed in an "open" Field "for 3 minutes to record changes in general behavioral and the presence of specific abstinence reactions. The total index of changes in horizontal and vertical motor activity, the presence and frequency of grooming, shaking, changes in breathing and posture, ptosis, piloerection, vocalization, gnashing of teeth, cramps, convulsions, flight, rhinorrhea, shaking of paws, diarrhea expressed in scores. 10 animals received lupeptin 0.5 mg / kg intraperitoneally for 1 h before the test, another equal volume of physiological saline to another 10 animals.
The experimental data were processed statistically by means of Student's t test. It was found that the animals of the control group had signs of morphine withdrawal syndrome of varying degrees of severity. The average total index characterizing all the studied general behavioral and specific responses of animals in the control group was 10.325. The introduction of lupeptin at a dose of 0.5 mg / kg for 1 h before the test resulted in the fact that the manifestation of abstinence in these animals was much less pronounced than in the control ones. The average total score was 5.1, which is almost two times less than in the control. The differences were significant with a probability of 0.0001. Reduction of the total indicator of withdrawal was due to a decrease in the majority of the studied indicators.
The results obtained show that intraperitoneal administration of lupeptin at a dose of 0.5 mg / kg leads to a sharp decrease in the severity of the withdrawal syndrome in morphine-dependent rats.
EXAMPLE 3 Reduction of the development of tolerance according to the analgesic effect of morphine when administered to animals with lupeptin
The experiments were carried out on 64 Fischer-344 rats, males, weighing 180-200 g. All animals were divided into groups of 8 rats in each, depending on the substances injected subsequently. 1-st group isotonic sodium chloride solution; 2nd group morphine, 3rd group isotonic sodium chloride solution + 1 mg / kg lupeptin; 4th group isotonic sodium chloride solution + 10 mg / kg of lupeptin; Group 5 isotonic sodium chloride solution + 50 mg / kg of lupeptin; 6th group of morphine + 1 mg / kg of lupeptin; 7th group - morphine + 10 mg / kg of lupeptin; The 8th group of morphine + 50 mg / kg of lupeptin.
At the first stage of the experiments, all animals were tested on a "hot platform" in order to study the latency period of the pain reaction. Before testing, for 10 minutes intraperitoneally injected morphine or saline, and for 1 hour before testing, lupeptin. In the second stage, rats were tolerated for morphine by daily injections twice (9 and 19 hours) of morphine at doses rising from 10 to 50 mg / kg for 8 days. Control animals were injected with physiological saline. On the 8th day, 0.5 h before the last injection of morphine, rats were administered a corresponding dose of lupeptin or saline. Then the pain sensitivity on the "hot platform" was determined.
It was shown that multiple injections of morphine in increasing doses caused the formation of tolerance to the analgesic effect of morphine - the effect of morphine at a dose of 50 mg / kg was almost completely absent. The administration of lupeptin in doses of 10 and 50 mg / kg in tolerant animals led to the appearance of a significant analgesic effect of morphine (FIG. 1).
Thus, the injection of lupeptin into morphine-dependent rats results in a decrease in morphine tolerance by the analgesic effect.
Example 4. Reducing the formation of physical dependence on morphine when adding lupeptin to its solution.
The experiments were carried out on 32 Wistar rats, males weighing 180-200 g. All animals were divided into groups of 8 rats in each, depending on the substances injected subsequently. 1-st group isotonic sodium chloride solution; 2-nd group morphine, 3rd group isotonic sodium chloride solution + 0.5 mg / kg lupeptin; The 4th group of morphine + 0.5 mg / kg of lupeptin. In rats, morphine dependence was formed by daily injections twice (9 and 19 hours) of morphine at doses increasing from 10 to 50 mg / kg with the addition of lupeptin or saline for 8 days. Control animals received saline (group 3 with the addition of lupeptin). 35 hours after the last injection, the behavioral symptoms of withdrawal syndrome in the "open field" were determined. The presence of such signs as ptosis, cramps, convulsions, jumping out of the field, shaking the "wet dog", gnashing of teeth, dyspnoea, piloerection, violation of the posture, rhinorrhea, shaking of the front paws, diarrhea were recorded. The total abstinence index was calculated.
It was shown that multiple injections of morphine in increasing doses caused the formation of a physical dependence on morphine in animals showed a marked withdrawal syndrome. Adding to the morphine solution of lupeptin at a dose of 0.5 mg / kg resulted in a decrease in the signs of withdrawal syndrome (Fig. 2).
Thus, the addition of lupeptin to the morphine solution leads to a decrease in the formation of the physical dependence on morphine.
Thus, the drug lupeptin is an effective means of arresting the withdrawal syndrome in opiate addictions. Low effective doses with insignificant taxicity of the drug cause wide prospects for the use of lupeptin in narcological practice for relief of withdrawal symptoms in opiate addictions.
CLAIM
The use of the drug lupeptin as a means for stopping the withdrawal syndrome in opiate addictions.
print version
Date of publication 06.01.2007gg
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