RU2077326C1 - Analgetic preparation - Google Patents

Abstract

FIELD: medicine, pharmacology. SUBSTANCE: preparation has an inhibitor of Ca⁺⁺-activated endopeptidases - antipain and lupeptin at ratio to morphine 1: 20. Its analgetic effect exceeds that of morphine but tolerance and physical dependence are much weaker as compared with morphine. Also, addition of inhibitors of Ca⁺⁺-activated endopeptidases to morphine solution decreases positive-fortifying properties of the latter sharply. So, this preparation is an effective agent for analgesia and it can be used at low doses, for example, in oncology for arresting the strong lasting pain syndromes. EFFECT: enhanced analgetic action, decreased dependence and tolerance. 3 cl, 5 dwg

Description

 The present invention relates to the field of pharmacology of narcotic substances, in particular to solving the issue of increasing the effectiveness of the analgesic effects of morphine with a decrease in the risk of dependence and tolerance.

 The purpose of morphine along with atropine, metacin and other anticholinergic substances is already known (M.D. Mashkovsky. Medicines. I. Medicine, 1987, T. 1, p. 170).

 However, these drugs are used to reduce the side effects that occur when using large doses of morphine (nausea, vomiting, respiratory depression), and not to enhance the analgesic effect of the latter. In addition, the use of a combination of morphine with anticholinergics does not reduce the formation of tolerance and dependence during prolonged, repeated use of the drug.

 The aim of the present invention is to enhance the analgesic effect of morphine and to reduce the formation of dependence and tolerance.

This goal is achieved by the fact that the preparation contains an inhibitor of Ca ⁺⁺ -activated endopeptidases.

As an inhibitor of Ca ⁺⁺ -activated endopeptidases, antipain ([(S) -1-Carboxy-2-phenylenthyl] -carbamoyl-Arg-Val-Arg-al) in the ratio with morphine 1:20 is used.

 Also, as an endopeptidase inhibitor, the drug lupeptin (Acethy-Leu-Leu-Arg-al) is used in a ratio with morphine of 1:20.

Figure 1 presents the change in the latent period of tail withdrawal in rats when antipain is added to the morphine solution. The abscissa axis is the dose of antipain. On the ordinate axis, the latent period of tail tail removal as a percentage of the latent period with the introduction of morphine;
figure 2 presents the change in the latent period of tail tail withdrawal in rats when lupeptin is added to the solution of morphine. The abscissa axis is the dose of lupeptin. On the ordinate axis, the latent period of tail tail removal as a percentage of the latent period with the introduction of morphine;
figure 3 shows the change in the threshold of pain sensitivity under the influence of morphine and lupeptin in tolerant rats (2) compared with intact (1). The abscissa axis is the dose of lupeptin. On the ordinate axis, the latent period of tail tail removal as a percentage of the initial one;
in FIG. Figure 4 shows the index of withdrawal symptoms in animals, which, together with morphine, were administered antipain at a dose of 0.5 mg / kg (1), lupeptin at a dose of 0.5 mg / kg (2), and physical. solution (3);
figure 5 presents the time spent in the undesirable compartment during testing in control animals (1), as well as in rats that were injected with antipain at a dose of 10 mg / kg (2) and 50 mg / kg (3) once before testing and 10 mg / kg (4) and 25 mg / kg (5) daily before administration of morphine.

The invention is illustrated by the following specific examples of its implementation:
Example 1

Strengthening the analgesic activity of morphine when antipain is added to its solution
The experiments were conducted on 7 groups of Wistar rats, males, weighing about 200 g, 8 rats in each group. The analgesic effect was evaluated using a tail flick test. Before testing, animals were placed in individual houses for 15 minutes, after which the tip of the tail of each animal was lowered into hot water (56 ^o C). The analgesic effect was evaluated by changing the time of the latent period of tail withdrawal.

 The first group of animals was injected intraperitoneally with 10 mg / kg morphine before testing. The second group contains a solution containing 10 mg / kg of morphine and 0.05 mg / kg of antipain. The third group contains a solution containing 10 mg / kg of morphine and 0.1 mg / kg of antipain. The fourth group contains a solution containing 10 mg / kg of morphine and 0.5 mg / kg of antipain. The fifth group 30 minutes before the introduction of a solution containing 10 mg / kg of morphine, was administered 1.0 mg / kg of antipain. The sixth group 30 minutes before administration of a solution containing 10 mg / kg of morphine, was administered 10 mg / kg of antipain. The seventh group 30 minutes before the introduction of a solution containing 10 mg / kg of morphine, was administered 50 mg / kg of antipain.

 It was found that only the addition of 0.5 mg / kg of antipain to the morphine solution sharply enhances its analgesic effect (Fig. 1). The use of a combination of morphine with other doses of antipain did not cause an increase in analgesia.

 Thus, adding to a solution containing 10 mg / kg morphine, 0.5 mg / kg antipain (20: 1 ratio) enhances the analgesic effect of morphine.

 Example 2

Strengthening the analgesic activity of morphine when lupeptin is added to its solution
The experiments were conducted on 7 groups of Wistar rats, males, weighing about 200 g, 8 rats in each group. The analgesic effect was evaluated using a tail flick test. Before testing, animals were placed in individual houses for 15 min, after which the tip of the tail of each animal was lowered into a hot hearth (56 ^o C). The analgesic effect was evaluated by changing the time of the latent period of tail withdrawal.

 The first group of animals was injected intraperitoneally with 10 mg / kg morphine before testing. The second group contains a solution containing 10 mg / kg of morphine and 0.05 mg / kg of lupeptin. The third group contains a solution containing 10 mg / kg of morphine and 0.1 mg / kg of lupeptin. The fourth group is a solution containing 10 mg / kg of morphine and 0.5 mg / kg of lupeptin. The fifth group 30 minutes before the introduction of a solution containing 10 mg / kg of morphine, was administered 1.0 mg / kg of luteptin. To the sixth group, 30 mg prior to administration of a solution containing 10 mg / kg of morphine was administered 10 mg / kg of luteptin. The seventh group 30 minutes before the introduction of a solution containing 10 mg / kg of morphine, was administered 50 mg / kg of luteptin.

 It was found that only the addition of 0.5 mg / kg of lupeptin to the morphine solution sharply enhances its analgesic effect (Fig. 2). The use of a combination of morphine with other doses of luteptin did not cause an increase in analgesia.

 Thus, adding to a solution containing 10 mg / kg of morphine, 0.5 mg / kg of lupeptin (ratio 20: 1), enhances the analgesic effect of morphine.

 Example 3

Reducing the development of tolerance for the analgesic effect of morphine when animals are injected with lupeptin
The experiments were performed on 64 Fuscher-344 rats, males weighing 180-200 g. All animals were divided into groups of 8 rats each, depending on the substances injected in the subsequent ones. 1 group isotonic sodium chloride solution; 2 group morphine, 3 group isotonic sodium chloride solution + 1 mg / kg lupeptin; 4 group isotonic sodium chloride solution <10 mg / kg of lupeptin; 5 group isotonic sodium chloride solution + 50 mg / kg of lupeptin; 6 group morphine + 1 mg / kg of lupeptin; 7 group morphine + 10 mg / kg of lupeptin; 8 group 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 latent period of the pain reaction. Before testing for 30 minutes, morphine or nat. solution, and 1 hour before testing lupeptin. At the second stage, morphine tolerance was formed in rats by daily two injections (at 9 and 19 hours) of morphine in doses increasing from 10 to 50 mg / kg for 8 days. Control animals were injected with physical. solution. On day 8, 0.5 hour before the last injection of morphine, the rats were given the appropriate dose of lupeptin or physical. solution. After that, pain sensitivity was determined on a "hot platform".

 It was shown that repeated 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 introduction of lupeptin in doses of 10 and 50 mg / kg in tolerant animals led to the appearance of a reliable analgesic effect of morphine (Fig. 3).

 Thus, the injection of luteptin to rats with a developed tolerance to morphine by the analgesic effect leads to a decrease in tolerance.

 Example 4

Reducing the formation of physical dependence on morphine when antipain and lupeptin are added to its solution
The experiments were performed on 64 Wistar rats, males, weighing 180-200 g. All animals were divided into groups of 8 rats each, depending on the substances injected in the future. 1 group isotonic sodium chloride solution; 2 group morphine; 3 group isotonic sodium chloride solution + 0.5 mg / kg antipain; 4 group isotonic sodium chloride solution + 0.5 mg / kg of lupeptin; 5 group morphine + 0.5 mg / kg antipain; 6 group morphine + 0.5 mg / kg of lupeptin. In rats, morphine dependence was formed by daily two injections (at 9 and 19 hours) of morphine in doses increasing from 10 to 50 mg / kg with the addition of an appropriate protease inhibitor or physical. solution for 8 days. Control animals were injected with physical. solution (the third and fourth group with the addition of antipain or lupeptin). 35 hours after the last injection, the behavioral signs of withdrawal syndrome in the open field were determined. The presence of signs such as ptosis, cramps, cramps, jumping out of the field, shaking off the “wet dog”, grinding teeth, dyspnoea, sawing, violation of the posture, rhinorrhea, shaking of the front paws, diarrhea were recorded. The total abstinence index was calculated.

 It was shown that repeated injections of morphine in increasing doses caused the formation of a physical dependence on morphine in animals, a pronounced withdrawal syndrome was observed. The addition of antipain or lupeptin to a solution of morphine at a dose of 0.5 mg / kg reduced the signs of withdrawal (Fig. 4).

 Thus, the addition of antipain or lupeptin to the morphine solution leads to a decrease in the formation of physical dependence on morphine.

 Example 5

Decreased narcogenic potential of morphine when antipain is added to it
The experiments were performed on 5 groups of Wistar rats with 8 animals in each group. At the first stage, rats were placed in an experimental chamber having dark and illuminated compartments. All animals chose a dark compartment for their stay. Then the animals were injected with morphine and placed in a light (undesirable) compartment, while access to the dark compartment was blocked. Animals of groups 1, 2 and 3 0.5 hours before the administration of morphine were injected with physical. solution. Group 4 and 5 animals were injected with 10 or 25 mg / kg of antipain, respectively. The procedure was repeated daily for 5 days. On day 6, animals of groups 1, 4, and 5 were injected with physical. solution, and for animals of groups 2 and 3 10 or 25 mg / kg of antipain, respectively, and after 1 hour, were placed in an experimental setup with free access to both compartments. The time spent in the original unreadable compartment was recorded.

 as a result, it was found that the presence of rats in the initially undesirable compartment after administration of morphine increases sharply (up to 70%). This time was significantly reduced in all animals that were given antipain at one time or another. To a greater extent in animals that were injected with 10 mg / kg of antipain before each injection of morphine, and to a lesser extent in animals that were injected with antipain at a dose of 25 mg / kg once before the last test (Fig. 5).

 Thus, antipain, when co-administered with morphine, reduces the drug's potential for narcotics, and also reduces the “memories” of pleasant sensations caused by morphine.

 The developed morphine-based analgesia drug has not only novelty, but also pronounced significant differences. This is expressed in the fact that with the same amount of the active principle of morphine, the analgesic activity increases many times, and the formation of dependence and tolerance decreases significantly. Such properties of the claimed drug are unexpected for specialists, many of whom are convinced of the impossibility of such an effect.

Thus, the developed drug is a creative solution to the problem posed as a result of a painstaking study of the mechanisms of action of morphine in combination with various biologically active substances, in particular, inhibitors of Ca ⁺⁺ -activated endopeptidases. As a result of a careful analysis of this group of substances, antipain and lupeptin are presented for protection, as they have shown the most stable results in terms of efficacy and dose ratio with the main active principle of morphine.

 the invention allows you to change existing ideas about the use of narcotic analgesics in various fields of clinical medicine, in particular oncology, etc. where they are usually widely used. A sharp increase in the analgesic activity of morphine and a decrease in tolerance can reduce the cost of treating patients. At the same time, the risk of drug abuse is reduced, which can be of great social importance for solving the problem of combating drug addiction.

Claims (1)

 1 1. A morphine-based analgesia preparation, characterized in that, in order to enhance the analgesic effect and reduce the formation of tolerance and dependence, it additionally contains inhibitors of Ca <M ^> + <D> <M ^> + <D> activated endopeptidases .2 2. The drug according to claim 1, characterized in that as an inhibitor of Ca <M ^> + <D> <M ^> + <D> of activated endopeptidases, antipain ([(S) -1-Carboxy-2- phenylethyl] -carbamoyl-Arg-Val-Arg-al) in relation to morphine 1 20.2 3. The drug according to claim 1, characterized in that, as an inhibitor, Ca <M ^> + <D> <M ^> + <D > activated endopeptidases use lupept n (Acethyl-Leu-Leu-Agr-al) in the ratio with morphine 20 January.

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