RU2183957C1 - Preparation of antipain with activity and capacity to raise higher power of analgetics action - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: it is suggested to apply mexidole as antipain preparation raising to a higher power the action of narcotic-free analgetics, and premedication method to apply such a preparation. EFFECT: increased threshold of pain sensitivity. 2 cl, 4 tbl, 7 dwg

Description

 The invention relates to medicine, namely to the creation of a new pain medication and a new method of sedation of patients with conditions accompanied by pain.

 The new tool is intended to eliminate pain and sedation of patients before treatment, accompanied by pain, as well as to enhance the analgesic effect of analgesics without increasing their doses and side effects.

State of the art
Non-narcotic analgesic agents (analgin, pentalgin, etc.) that reduce pain are used to eliminate pain and sedation of patients before treatment accompanied by pain. However, their effectiveness is often insufficient to eliminate pain irritations and they do not have a positive effect on emotional stress that occurs before pain exposure. In addition, traditional analgesics have a significant number of side effects, especially with increasing doses (5, 12, 13).

 Tranquilizing agents (diazepam, phenazepam, medazepam, etc.) are used to eliminate anxiety and fear of the upcoming treatment in patients. However, these means of sedation cause general sedation, muscle relaxation, impaired memory, and with repeated use, there is a risk of drug dependence (5, 12, 13).

 The known antioxidant mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate), used in medical practice as a means of treating neurotic and neurosis-like disorders with manifestation of anxiety, fear, emotional stress (1, 2, 8, 9), alcohol withdrawal (1, 2), acute and chronic cerebrovascular insufficiency, including cerebral strokes, discirculatory encephalopathy, vegetovascular dystonia (7, 9-11), as well as in various diseases accompanied by memory, attention, mental disorders working capacity (1, 2).

 The ability of mexidol to increase pain sensitivity thresholds and its ability to potentiate the effect of analgesics has not been studied previously.

 Disclosure of the invention.

 The aim of the present invention was the creation of a highly active and non-toxic drug with analgesic activity and the ability to potentiate the effect of analgesics.

 This problem is solved by the use of succinate 2-ethyl-6-methyl-3-hydroxypyridine (Mexidol) as an analgesic that can increase the thresholds of pain sensitivity.

 The task of a new method for the premedication of patients with conditions accompanied by pain was solved by the combined use of mexidol and non-narcotic analgesics, as a result of which potentiation of the analgesic effect and elimination of emotional discomfort without increasing doses and enhancing the side effect of analgesics are achieved.

 Example 1. The analgesic effect of mexidol and its ability to potentiate the effect of non-narcotic analgesics in an experiment on rats with contact-pain, thermal irritation according to the hot plate test (table 1, Fig. 1).

The study was carried out in experiments on male outbred white rats (weight 200-220 g). The potentiating effect of mexidol on the analgesic effects of non-narcotic analgesics was evaluated by changing the pain response to contact-pain, thermal irritation according to the hot plate test - Hot-place-test (6, 14). Thermal irritation of the skin of the paws of rats was carried out when the animal was placed on a heated metal surface (55 ^o C) with registration of the latent period of the motor reaction. The pain sensitivity of rats was assessed by the threshold of pain response, which was assessed by the latent time of the beginning of licking and pulling of the hind legs after placing the animals on a hot plate. At the second stage, a day later, experimental animals were randomly divided into groups of 10 rats each and, after the administration of substances, they were re-placed on a hot plate and their effect on the thresholds of pain sensitivity was evaluated. The rats of the control group 30 minutes before the animals were re-placed on the hot plate were injected intramuscularly with water at a rate of 0.2 ml / 100 g weight. Mexidol was administered intramuscularly at doses of 100, 200, 400 mg / kg intramuscularly, or intramuscular analgin at a dose of 200 mg / kg, pentalgin ICN at a dose of 400 mg / kg orally. To study the potentiating effect of mexidol on the effects of analgesics, the combined use of mexidol at a dose of 100 and 200 mg / kg intramuscularly and analgin at a dose of 200 mg / kg intramuscularly and in the other group mexidol at a dose of 100 mg / kg intramuscularly and pentalgin ICN at a dose of 400 mg / kg inside.

 Studies have shown that mexidol in doses of 200, 400 mg / kg intramuscularly has a pronounced statistically significant analgesic effect, increasing thresholds of pain sensitivity. Mexidol at a dose of 100 mg / kg does not have an analgesic effect. The combined use of mexidol in a subthreshold inactive dose of 100 mg / kg with analgin or pentalgin caused a potentiation of their analgesic effect, which increased by 1.5 times for analgin and 1.7 times for pentalgin. The combined use of Mexidol at a dose of 200 mg / kg and Analgin at a dose of 200 mg / kg caused an increase in the effect by 2 times. Side effects when using Mexidol with analgesics were not observed.

 Example 2. The analgesic effect of Mexidol and its ability to potentiate the effect of non-narcotic analgesics in an experiment on rats with dosed mechanical irritation (table 2, Fig. 2).

 The effect of the drugs on sensitivity to mechanical irritation was evaluated in a test with metered compression of the front extremity of rats according to the traditional method for assessing the analgesic effect (6) in a special device - an analgesimeter from Hugo Basil (Italy). The threshold of pain sensitivity with increasing pressure on the paw was recorded according to the squeak of the animal, after which the pressure on the paw was recorded on a special scale in arbitrary units. An increase in the threshold of a painful reaction under the influence of the drug is expressed in an increase in the compression force of the limb and characterizes the severity of the analgesic effect of the drug.

 To the rats of the control group 30 minutes prior to placement in the analgesimeter, intramuscularly injected water at the rate of 0.2 ml / 100 g of mass. Mexidol at doses of 100, 200, 400 mg / kg intramuscularly or analgin at a dose of 200 mg / kg intramuscularly was administered to animals of the experimental groups 30 minutes before testing. To study the potentiating effect of mexidol on the effects of analgesics, the combined use of mexidol at a dose of 100 and 200 mg / kg intramuscularly and analgin at a dose of 200 mg / kg intramuscularly was carried out.

 It was found that mexidol in doses of 200 and 400 mg / kg statistically significantly increased the thresholds of pain sensitivity of rats for mechanical irritation.

 With the combined use of Mexidol in a subthreshold inactive dose of 100 mg / kg and, especially, 200 mg / kg and dipyrone at a dose of 200 mg / kg, a significant potentiation of the analgesic effects of dipyrone was observed without side effects. So, Mexidol at a dose of 100 mg / kg increased the thresholds of pain sensitivity of dipyrone by 1.4 times, and at a dose of 200 mg / kg - by 2.24 times.

 Example 3. The study of the effect of Mexidol in combination with non-narcotic analgesics on the emotional reactions of rats with stress waiting for pain when animals are re-placed on a hot plate (Fig. 3).

 The study was conducted on the same animals on which thresholds of pain sensitivity were studied during thermal irritation of the skin of the paws. Rats were re-placed on a metal plate, where they previously received pain irritation, and the animals experienced severe emotional stress, which was associated with the expectation of pain irritation, because the animals were placed in an aversive situation on the plate. A manifestation of stress was a violation of behavior, which was evaluated in an alternative form by a change in motor parameters. Rats that did not move around the chamber were recorded as inhibited rats with a fading reaction ("freezing"); animals with an active reaction attempting to get out of the experimental chamber were evaluated as active rats. In addition, animals with calm behavior were isolated in which the response to repeated placement in the chamber did not differ from the tentative research behavior when the rat was placed in the chamber in a situation of painless irritation.

 To the rats of the control group 30 minutes before the animals were re-placed on the plate, water was intramuscularly administered at a rate of 0.2 ml / 100 g weight. Mexidol was administered intramuscularly at doses of 100, 200, 400 mg / kg intramuscularly or intramuscular analgin at a dose of 200 mg / kg, ICN pentalgin at a dose of 400 mg / kg, and combinations of Mexidol at a dose of 100 and 200 30 minutes before testing. mg / kg and analgin or pentalgin.

 It was found that mexidol in all doses used reduced the percentage of animals with emotional reactions to stress expectations of pain and increased the percentage of animals with calm behavior. Analgin and pentalgin did not affect stress, and after their administration, the animals remained in a state of emotional stress. With a combination of Mexidol at a dose of 100 mg / kg and especially 200 mg / kg with analgin or pentalgin, the antistress effect of Mexidol remained at a high level. The number of rats with a calm behavior with a combination of mexidol at a dose of 200 mg / kg and analgin at a dose of 200 mg / kg in a situation of stress increased compared to the administration of one analgesic by 6 times, and with the combined use of pentalgin with mexidol, by 3.5 times.

 Example 4. Evaluation of the analgesic effect of Mexidol and its combination with non-narcotic analgesics in patients at the dental appointment in terms of sensory thresholds of the fingers (Table 4).

 The effectiveness of the action of a 5% solution of Mexidol (2 ml i / m) in isolation and in combination with a 50% solution (2 ml i / m) of analgin or one pentalgin tablet was studied by sensometry on a Phase-2 instrument that we designed for this purpose (3, 4), intended for the quantitative determination of pain sensitivity by the values of sensory thresholds, i.e. thresholds of tactile sensitivity (PM), pain sensitivity (CP), and also the threshold of pain endurance limit (PPV) were measured. Using the described premedication option, 40 patients (12 men and 28 women) aged 18 to 55 years were treated and examined.

 There were six groups in total. In the first group (10 people), the effect of mexidol was studied; in the second - analgin, in the third - pentalgin; in the fourth, a mixture of mexidol with analgin; in the fifth, a mixture of mexidol with pentalgin; the sixth group is the control. The last five groups consisted of six people each.

 The sensory threshold measurements are given in summary table 4 and in FIG. 4. Analysis of these materials showed that in the first group, where sedation was carried out by applying a 5% solution of Mexidol 2 ml / m, all sensory thresholds significantly increased. It was found that Mexidol 2 ml of a 5% solution statistically significantly increased all thresholds: the threshold of tactile sensitivity (PTC) - by 38%, the threshold of pain (PB) - by 41% and the most important indicator - the threshold of endurance to pain PPV - by 109% . The maximum increase in thresholds was observed after 60 minutes. 60% of patients noted dullness of pain, 30% showed a complete absence of pain during dissection of the carious cavity. The threshold of endurance limit (PPV) for pain increased most of all and the thresholds of tactile sensitivity (PM) and pain sensitivity (CU) changed to a slightly lesser extent.

 Thus, an increase in pain sensitivity thresholds after treatment with Mexidol was observed in 90% of patients. An increase in pain sensory thresholds indicates a pronounced analgesic effect of mexidol.

 For clarity, as an example, we give a sensogram of patient K. (Fig. 5). As can be seen from FIG. 5, by the nature of the ratio of sensory thresholds, the patient can be attributed to type II. Initial thresholds are control. In all subsequent examples, we will take patients of this type so that, having approximately equal initial thresholds, it is possible to compare different sensograms of each group. In this sensogram, in the control, the tactile-pain interval is low (0.2 mA), and the endurance to a pain stimulus - the endurance interval corresponds to 0.7 mA. After taking Mexidol, the tactile-pain interval increased by a factor of 2 due to an increase in CBP from 0.4 mA to 0.8mA. PPV increased to 1.8 mA. These data were obtained by increasing all sensory thresholds. After premedication, already at 10-15 minutes, the patient noted a dullness of pain during the preparation of tooth tissues for secondary caries, sedation and willingly finished the treatment.

 The following two groups of patients received analgesics. Analysis of the results obtained in the study of groups of patients after taking one tablet of pentalgin or dipyrone (2 ml IM) showed the presence of relatively small shifts. In contrast to the first group, PB increased here more (by 84% in patients receiving pentalgin and by 74% in those receiving analgin), IF increased by 44% and 48%, respectively (the results are reliable). The PPV increased less - by 19% and 24% (the results are not reliable).

 For an example we give a sensogram of patient D. (Fig. 6). As can be seen from FIG. 6, an increase in PB by 0.3 mA was not accompanied by an increase in the interval of endurance to pain. The PM threshold increased by 0.2 mA. The patient was anxious, reacted to any intervention by a doctor, and noted soreness when preparing a tooth for secondary caries.

 In the remaining groups of patients, we performed sedation using both the antioxidant Mexidol with Pentalgin (one tablet) and Mexidol with Analgin (2 ml IM). Of the above combinations of substances, the combination of mexidol with pentalgin is most effective. With this combination, the PTL increased by 125%, the PB - by 128%, the PPV - by 135%. In the group of patients who received a combination of Mexidol with analginum as a drug preparation, the IF increased by 60%, PB - by 111%, PPV - by 110%. Thus, a significant potentiation of the analgesic effects of pentalgin and analgin was established.

 For an example we give a sensogram of patient S. (Fig. 7). BP and PPV are respectively 0.8 and 1.0 mA. After premedication, the intervals increased to 1.8 and 1.9 mA. Before treatment, the patient was excited, trembling from the touch of the tool to the tooth. 20 minutes after taking Mexidol and Pentalgin, the patient calmed down, and during the preparation of the carious cavity did not notice pain. The treatment was successful in comfort for the patient and the doctor.

 Side effects when using Mexidol and its combinations with non-narcotic analgesics were not observed.

Conclusion
Thus, Mexidol has a pronounced analgesic effect both in an experiment on animals and in patients whose treatment was accompanied by pain. The use of mexidol in combination with non-narcotic analgesics (analgin and pentalgin) with premedication causes a significant increase in the analgesic effect of these drugs without side effects and eliminates the manifestations of emotional stress caused by the expected pain effect.

Literature
1. Voronina T.A. Antioxidant Mexidol. The main neuropsychotropic effects and mechanism of action. - Psychopharmacology and biological narcology. - 2001. - N 1. - p. 2-13
2. Dumayev K.M., Voronina T.A., Smirnov L.D. Antioxidants in the prevention and treatment of CNS pathologies. M. 1995 .-- 271 p.

 3. Mashkovsky M.D. Medicines, M, Medicine, 1993.

 4. Larencova L.I. A quantitative characteristic of the effectiveness of some options for drug preparation of patients in the clinic of therapeutic dentistry. Diss. Candidate of Medical Sciences. M., 1971.

 5. Larentsova L. I., Goloboky N.K. Some issues of instrumental assessment of analgesia in therapeutic dentistry. J. Dentistry, 1971, 4, p. 13-15.

 6. Methodical recommendations. An experimental study of drugs proposed for clinical trials as painkillers of predominantly central action and their antagonists. - Vedomosti Farm. Committee of the Ministry of Health of the Russian Federation, - 1998, N 3, p. 30-31.

 7. Mironov N.V., Rudneva V.V., Goryainova I.I. Mexidol, a new domestic drug in the complex treatment of patients with ischemic stroke in the recovery period. - Kremlin medicine, 2001. - N 2. - p. 56-59.

 8. Neznamov G. G., Teleshova E. S., Syunyakov S. A., Safarova T. P. Clinical and pharmacological study of the anxiolytic properties of the antioxidant Mexidol. - "Medicine and health protection. Medical equipment and Pharmacy." Tyumen. - 1997. - p. 85-87.

 9. RF patent N 2145855, 1999 - anxiolytic, anti-alcohol, cerebroprotective drug.

 10. Spasennikov B.A. Encephalopathy. - ed. Petah-Tikva. - Israel. 1996 .-- 278 p.

 11. Fedin A.I., Rumyantseva S.A., Mironova O.P., Evseev V.N. - Guidelines. The use of the antioxidant Mexidol in patients with acute cerebrovascular accident. - Ministry of Health of the Russian Federation.- Moscow. - 2000 - 16 p.

 12. Kharkevich D.A. - Pharmacology, 1999.

 13. Encyclopedia of drugs - Register Lek. funds of Russia, 1999.

 14. Woolfe G., Macdonald A.D. - The evaluation of the analgesic action of pethidine hydrochloride (demedrol) // J. Pharmacol Exp. Ther. - 1944. - v.80. - p. 300-307.

Claims (2)

 1. The use of 2-ethyl-6-methyl-3-hydroxypyridine succinate as an agent with analgesic activity and the ability to potentiate the effects of non-narcotic analgesics.  2. A method for the premedication of patients with treatment accompanied by pain, including the use of non-narcotic analgesics, characterized in that the complex therapy also includes the antioxidant 2-ethyl-6-methyl-3-hydroxypyridine succinate, which causes an increase in the analgesic effect of analgesics and the elimination of emotional stress without side effects.

Images