The agent with analgesic activity and ability to potentiate the effects of analgesics

 

(57) Abstract:

The invention relates to medicine. The proposed use of Mexidol as potentiating the analgesic effect of non-narcotic analgesics means and method of sedation using it. The tool allows you to increase the pain threshold. 2 C. p. F.-ly, 4 tab., 7 Il.

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

The new tool is designed to alleviate pain and sedation of patients before treatment, followed by pain, as well as to enhance the analgesic action of analgesics without increasing their doses and side effects.

Prior art

For pain relief and sedation of patients before treatment, followed by pain, used non-narcotic analgesic agents (aspirin, Pentalgin, and others ), reducing pain. However, their effectiveness is often insufficient to eliminate the pain, irritation and they do not have affirmative action for emotional distress arising before the painful impact. In addition, 3).

To address patients ' anxiety and fear of the upcoming treatment applied tranquilizing agents (diazepam, phenazepam, medazepama and others ). However, these tools sedation common cause sedation, muscle relaxation, impaired memory, and when the second application occurs the risk of drug dependence (5, 12, 13).

Known antioxidant Mexidol (2-ethyl-6-methyl-3-oxypyridine succinate), used in medical practice as a means of treatment of neurotic and neurosis-like disorders with manifestations of anxiety, fear, emotional stress(1, 2, 8, 9), alcohol withdrawal symptoms (1, 2), acute and chronic insufficiency of cerebral circulation, including cerebral stroke, discirculatory encephalopathy, vascular dystonia (7, 9-11), as well as in various diseases involving disorders of memory, attention, impaired mental health (1, 2).

The ability of Mexidol to raise the threshold of pain sensitivity and its ability to potentiate the analgesic action of funds not previously been studied.

Disclosure of the invention.

The aim of the present invention was the creation of view to potentiate the effects of analgesics.

This problem is solved by applying succinate 2-ethyl-6-methyl-3-oksipiridina (Mexidol) as analgesic tools that can increase the threshold of pain sensitivity.

The goal of a new method of sedation of patients with conditions accompanied by pain, solved by the combined application of Mexidol and non-narcotic analgesics, which results in the potentiation of the analgesic effect and the elimination of emotional discomfort without increasing doses, and to strengthen the side effects of analgesics.

Example 1. Analgesic effect of Mexidol and its ability to potentiate the effect of non-narcotic analgesics in the experiment on rats with contact-painful thermal stimulation test hot plate (Hot-place-test) (table 1, Fig. 1).

The study was performed in experiments on male outbred albino rats (weighing 200-220 g). Potentiating effect of Mexidol on the analgesic effects of non-narcotic analgesics were evaluated according to the change of painful reaction on contact-painful thermal stimulation test hot plate - Hot-place-test (6, 14). Was carried out thermal stimulation of the skin of the paws of rats when placing the animal on the hot IU the activity of the rats was evaluated according to the threshold of pain reaction which was estimated by the latent time to begin licking and otdergivanija hind legs after placing the animals on a hot plate. In the second stage, through the day of the experimental animals were randomly divided into groups of 10 rats each, and after the introduction of substances again was placed on a hot plate and assessed their impact on the threshold of pain sensitivity. The rats 30 minutes before re-premise animal on the hot plate intramuscularly injected water at the rate of 0.2 ml/100 g mass. Experimental animals 30 minutes before the test was administered Mexidol in doses of 100, 200, 400 mg/kg intramuscularly or aspirin at a dose of 200 mg/kg intramuscularly, Pentalgin ICN at a dose of 400 mg/kg orally. For research potentiation of Mexidol on the effects of analgesics was carried out by combined use of Mexidol in the dose of 100 and 200 mg/kg intramuscularly and dipyrone in a dose of 200 mg/kg intramuscularly, and in the other group - Mexidol in the dose of 100 mg/kg intramuscularly and Pentalgin ICN at a dose of 400 mg/kg orally.

Studies have shown that Mexidol in doses of 200, 400 mg/kg intramuscularly has a strong statistically significant analgesic effect, raising the threshold of pain sensitivity. Meboy inactive dose of 100 mg/kg aspirin or Pentalgin caused a potentiation of their analgesic effect, which increased 1.5 times for dipyrone and 1.7 times for Pentalgin. The combined use of Mexidol in the dose of 200 mg/kg and aspirin at a dose of 200 mg/kg caused increased in 2 times. Side effects when using Mexidol with analgesics was not observed.

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

Effect on sensitivity to mechanical irritation was evaluated in the test dosed compression of the anterior limb of rats according to the traditional method of assessment of analgesic action (6) in a special device - analgesiometer firm Hugo Basil (Italy). The threshold of pain sensitivity in increasing pressure on the paw was recorded on squeak animal, and then, on a special scale was recorded and the pressure on the paw in conventional units. The increase in pain threshold reactions under the influence of the preparation is to increase the force of compression on the limb and characterizes the intensity of the analgesic effects of the drug.

The rats 30 minutes prior to placement in analgesiometer Mexidol in doses of 100, 200, 400 mg/kg intramuscularly or aspirin at a dose of 200 mg/kg intramuscularly. For research potentiation of Mexidol on the effects of analgesic was carried out by combined use of Mexidol in the dose of 100 and 200 mg/kg intramuscularly and dipyrone in a dose of 200 mg/kg intramuscularly.

It is established that Mexidol in doses of 200 and 400 mg/kg statistically significantly increased the threshold of pain sensitivity of rats to mechanical irritation.

When combined application of Mexidol in the subthreshold inactive dose of 100 mg/kg and especially 200 mg/kg and aspirin at a dose of 200 mg/kg there was a significant potentiation of analgesic effects of aspirin without the side effects. So, Mexidol in the dose of 100 mg/kg increased the threshold of pain sensitivity analgin 1.4 times, and at a dose of 200 mg/kg - 2.24 times.

Example 3. Study of the effect of Mexidol in combination with non-narcotic analgesics on the emotional reactions of rats under stress, the anticipation of pain when you re-location of animals on a hot plate (Fig. 3).

The study was performed on the same animals, which carried out the study of the threshold of pain sensitivity during thermal stimulation of the skin of the paws. Rats re-foam emotional stress, which was associated with the expectation of receiving painful stimuli, as the animals were placed in aversive situation on the plate. The manifestation of stress was a breach of conduct, which was estimated in an alternative form by changing the movement of the indicators. Rats without movement on the camera, were recorded as rats inhibited, with the reaction of awe ("frisina"); animals with active reaction, attempt to get out of the experimental chamber was estimated as rats are active. In addition, provided the animals with a calm behavior, in which the reaction for a second location in the camera did not differ from the orienting-exploratory behavior when placing the rat in the chamber in the situation painless irritation.

The rats 30 minutes prior to re-space the animals on the plate intramuscularly injected water at the rate of 0.2 ml/100 g mass. Experimental animals 30 minutes before the test was administered Mexidol in doses of 100, 200, 400 mg/kg intramuscularly or aspirin at a dose of 200 mg/kg intramuscularly, Pentalgin ICN at a dose of 400 mg/kg orally, as well as combinations of Mexidol in the dose of 100 and 200 mg/kg and dipyrone or Pentalgin.

It is established that Mexidol in usual the percentage of animals with a calm demeanor. Analgin and Pentalgin did not affect the stress and after the introduction of the animals remained in a state of emotional tension. When the combination of Mexidol in the dose of 100 mg/kg and especially 200 mg/kg aspirin or Pentalgin antistress effect of Mexidol remained at a high level. The number of rats with a calm behavior with a combination of Mexidol in the dose of 200 mg/kg and aspirin at a dose of 200 mg/kg in a situation of stress was increased in comparison with the introduction of a single analgesic in 6 times, and the combined application of Pentalgin with Mexidol - 3.5 times.

Example 4. Evaluation of the analgesic action of Mexidol and its combination with non-narcotic analgesics in patients on dental reception indicators sensory thresholds fingers (table 4).

The effectiveness of a 5% solution of Mexidol (2 ml/m) in isolation and in combination with a 50% solution (2 ml/m) dipyrone or one tablet of Pentalgin were examined by the method of tensometry on our custom-designed for this purpose, the device "Phase - 2" (3, 4) intended for the quantitative determination of pain sensitivity by the values of the sensory thresholds, i.e., the measured thresholds of tactile sensitivity (PM), pain sensitivity (BSC), and the study 40 patients (12 men and 28 women) aged 18 to 55 years.

Just had six groups. In the first group (10 persons) studied the effect of Mexidol; second - analgin, in the third - Pentalgin; in the fourth, a mixture of Mexidol with dipyrone; in the fifth, a mixture of Mexidol with Pentalgin; the sixth group control. The last five groups consisted of six people each.

The results of the measurement of sensory thresholds are given in the summary table 4 and Fig. 4. The analysis of these materials showed that in the first group, where the treatment was conducted by applying a 5% solution of Mexidol 2 ml/m, significantly increased all sensory thresholds. It is established that Mexidol 2 ml of 5% solution statistically significantly increased all thresholds: the threshold of tactile sensitivity (PTC) - 38%, the threshold of pain (PB) - 41%, and the most important indicator is the threshold limit of endurance to pain FFC - 109%. The maximum increase in threshold was observed after 60 minutes. 60% of patients reported dulling pain, 30% were observed complete absence of pain in the carious cavity preparation. More than just increased the threshold limit of endurance (FFC) to pain and to a lesser extent changed the thresholds of tactile sensitivity (PM), pain sensitivity (BSC).

Thus, the increase of thresholds bol indicates a pronounced volutrauma the effect of Mexidol.

For illustration, as an example, here is sensogram patient K. (Fig. 5). As can be seen from Fig. 5, the correlation between sensory thresholds sick can be attributed to type II. Source thresholds are controlling. In all subsequent examples, we will take patients of this type, that, having approximately equal to the source thresholds, you can compare different sensogram each group. In this sensogram in control of the tactile-painful interval low (0,2 mA), and the endurance to pain stimulus - interval endurance corresponds to 0.7 mA. After taking Mexidol tactile and painful interval increased 2-fold by increasing PBC from 0.4 mA to 0.8 mA. PPV increased to 1.8 mA. These data were obtained by increasing all sensory thresholds. After sedation is already 10-15 minutes the patient was noted dulling pain during dissection of the tissues of the tooth about the middle of caries, calm and willingly completed treatment.

These two groups of patients received analgesics. Analysis of the results obtained in the study of groups of patients after administration of one tablet Pentalgin or dipyrone (2 ml/m), showed the presence of relatively small shifts. Unlike the first group there are more regards to 44% and 48% (the results are reliable). Less increased PPV 19% and 24% (the results are not reliable).

For example, sensogram sick Days (Fig. 6). As can be seen from the Fig. 6, the increase in PB 0.3 mA was not accompanied by an increase of the interval endurance to pain. The threshold increased PM 0.2 mA. The patient was concerned, to respond to any intervention of the doctor and noted pain during tooth preparation regarding secondary caries.

In other groups of patients we have performed pretreatment, using a combination of antioxidant Mexidol Pentalgin (one tablet) and Mexidol with dipyrone (2 ml/m). Of the above combinations of substances, the most effective combination of Mexidol with Pentalgin. This combination PTC increased by 125%, PB - 128%, PPV - 135%. In the group of patients treated as medical training combination of Mexidol with dipyrone, FC was increased by 60%, PB - 111%, FFC - 110%. Thus is established a significant potentiation of analgesic effects of Pentalgin and dipyrone.

For example, sensogram patient C. (Fig. 7). BP and PPV, respectively, equal to 0.8 and 1.0 mA. After sedation intervals increased to 1.8 and 1.9 mA. The patient before treatment was excited vzdohnuti, and at the time of preparation of carious cavity is not noted pain. Treatment was successful in comfort for the patient and doctor.

Side effects when using Mexidol and its combination with non-narcotic analgesics have not been observed.

Conclusion

Thus, Mexidol has a pronounced analgesic effect as in the experiment on animals and in patients whose treatment was accompanied by pain. The use of Mexidol in combination with non-narcotic analgesics (aspirin and Pentalgin) when sedation causes a significant increase in analgesic action of these drugs without any side effects and eliminates symptoms of emotional stress, pain caused by the expected impact.

Literature

1. Voronina T. A. Antioxidant Mexidol. Basic drugs is got with the effects and mechanism of action. - Psychopharmacology and biological narcology. - 2001. - N 1. - S. 2-13

2. Djumaev K. M., Voronina T. A., Smirnov, L. D. Antioxidants in the prevention and treatment of pathologies of the Central nervous system. M. 1995. - 271 S.

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

4. Lorencova L. I. Quantitative characterization of the effectiveness of nekotek. M., 1971.

5. Lorencova L. I. , Golabki N. To. Some questions instrumental evaluation of anaesthesia in dentistry. J. Dentistry, 1971, 4, S. 13-15.

6. Methodical recommendations. Experimental study of the drugs proposed for clinical trials as painkillers mainly Central action and their antagonists. - Sheets Pharm. Committee of the Russian Federation, - 1998, N 3, S. 30-31.

7. Mironov N. In., Rudnev centuries, Goryainova And. And. New domestic drug Mexidol in complex treatment of patients with ischemic stroke in the recovery period. The Kremlin medicine, 2001. - N 2. - S. 56-59.

8. Neznamov,,, Teleshova E. C., Sudakov S. A., Safarov, Etc., Clinical and pharmacological study of the anxiolytic properties of antioxidant Mexidol. "Medicine and health. Medical and Pharmacy". Tyumen. - 1997. - S. 85-87.

9. RF patent N 2145855, 1999, Anxiolytic, protivoallergennoy, cerebroprotective drug.

10. Spasennikov B. A. encephalopathy. - ed. Petah-Tikva. - Israel. 1996. - 278 S.

11. Fedin, A. I. , Rumyantsev, S. A., Mironov, O. P., Evseev Century. N. Methodical recommendations. Application Antioch">

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

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

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

1. The use of 2-ethyl-6-methyl-3-oxypyridine succinate as a means possessing analgesic activity and ability to potentiate the effect of non-narcotic analgesics.

2. How sedation of patients during treatment, followed by pain, including the use of non-narcotic analgesics, characterized in that it further in the complex therapy included antioxidant 2-ethyl-6-methyl-3-oxypyridine succinate, which is increased analgesic action of analgesics and eliminate emotional stress without side effects.

 

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