RU2367432C2 - Analgesic agent and therapy of pain syndrome of various aetiologies by using said agent - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: pain management agent contains comenic and benzylcomenic acids. The invention can be used for manufacturing of high-effective synthetic nonnarcotic analgesic agent to be applied in medicine and veterinary science for managing pain of various aetiologies. The analgesic agent represents an aqueous solution of comenic acid, benzylcomenic acid, and an adjuvant - sodium hydrocarbonate in the following ratio, wt %: comenic acid - 1-2, benzylcomenic acid to 0.025, sodium hydrocarbonate - 0.55-1.1, water for injection - to 100. Besides, there is disclosed therapy of pain syndrome of various aetiology, consisting that said agent is introduced to the patient intravenously in a dose to 350 mg (in equivalent of comenic acid) a day during 5-30 days.

EFFECT: analgesic agent does not cause dependence and addiction, and intoxication.

4 cl, 8 ex, 6 tbl

Description

The claimed invention relates to pharmaceuticals and medicine, specifically to an analgesic agent based on comenic acid and a method for treating pain with this agent.

The claimed invention can be used to produce highly effective synthetic non-narcotic analgesic drugs, which, in turn, can be used in medicine and veterinary medicine for the relief of pain syndromes of various etiologies, in the treatment of drug dependence and for poisoning by opiates during detoxification to restore the respiratory center in oncology.

Analgesics or analgesics (from the Greek algos - pain and an - without) are medicines that have a specific ability to weaken or eliminate the feeling of pain (MD Mashkovsky. Medicines. 14th ed. M.: New Wave, 2003. T .1. P.145).

An analgesic (analgesic) effect can be exerted not only by the analgesics themselves, but also by other substances belonging to different pharmacological groups. So, the drugs used for anesthesia (general anesthesia) may have an analgesic effect, and some of them in appropriate concentrations and doses (for example, trichlorethylene, nitrous oxide) are used specifically for analgesia. Essentially local anesthetics are also analgesic for pain associated with smooth muscle spasms. Antispasmodic and anticholinergic drugs can have an analgesic effect.

In the proper sense of the word, analgesic means drugs whose dominant effect is analgesia, which occurs as a result of resorptive action and is not accompanied in therapeutic doses by turning off consciousness and a pronounced violation of motor functions.

According to the chemical nature, nature and mechanisms of pharmacological activity, modern analgesic drugs are divided into two groups: small and large analgesics.

The main representatives of the group of small analgesics are salicylic acid derivatives (sodium salicylate, acetylsalicylic acid, salicylamide, etc.), pyrazolone derivatives (antipyrine, amidopyrine, analgin), para-aminophenol or aniline derivatives (phenacetin, paracetamol) (ibid., P. 1 ) These analgesics are synthetic drugs. The analgesic activity of the group of small analgesics is manifested in certain types of pain, mainly with neuralgic, muscle, joint pain, with headache and toothache. With severe pain associated with injuries, abdominal surgery, etc., they are practically ineffective. Known agents also exhibit antipyretic and anti-inflammatory effects in febrile conditions. The use of these drugs does not affect the respiratory and cough centers. In therapeutic doses, drugs belonging to this group do not cause phenomena of euphoria, mental and physical dependence. However, prolonged use, for example, analgin, is accompanied by an increase in the dose of the drug to achieve the desired analgesic effect. In addition, the most commonly used drugs from this group - analgin and acetylsalicylic acid (aspirin), have a number of negative side effects. Currently, analgin as a drug is prohibited for use in several countries around the world.

In the mechanism of action of the analgesics of the first group, a certain role is played by the effect on the thalamic centers, which leads to inhibition of the conduct of pain impulses to the cerebral cortex. An important role in the mechanism of action of salicylates is inhibition of prostaglandin biosynthesis, as well as the stimulating effect of these drugs on the pituitary axis — the adrenal glands, which promotes the release of corticosteroids. Of significant importance in the action of the analgesics of the first group is their effect on the kinin system (antagonism with the allergic effect of bradykinin, etc.).

Analgesics of the second group include natural compounds - morphine and related alkaloids (opiates) - and synthetic compounds with opiate-like properties (opioids). They are characterized by strong analgesic activity, providing the possibility of their use in injuries (surgical interventions, wounds, etc.) and in diseases accompanied by severe pain (malignant neoplasms, myocardial infarction, withdrawal symptoms in patients with drug and drug dependence, etc.) . Preparations of this group are called large analgesics.

According to the sources of production and chemical structure, the analgesics of the second group include natural alkaloids - morphine and codeine, contained in sleeping pills; semisynthetic compounds obtained by chemical modification of a morphine molecule (ethyl morphine); synthetic compounds (promedol, fentanyl, pentazocine, nalbuphine, butorphanol, tramadol, etc.). Most synthetic drugs are obtained by reproducing the simplified structure of morphine. By chemical modification of the morphine molecule, compounds are also obtained that are its pharmacological antagonists (naloxone, naltrexone). Morphine as an analgesic is prescribed for adults by mouth in a single dose of up to 0.02 g (daily dose of 0.05 g).

A single dose lasts 3-5 hours. For acute and chronic pain, morphine is prescribed epidurally. 0.2-0.5 ml of a 1% solution of morphine in isotonic sodium chloride solution is introduced. The action manifests itself after 10-15 minutes, after 1-2 hours a very pronounced analgesic effect is observed, lasting for 8-12 hours. To reduce side effects, atropine, metacin or other anticholinergics are often prescribed with morphine. Method of release: tablets of 0.01 g, 1% solution in ampoules and syringe tubes of 1 ml (ibid., P. 145). Morphine and its analogues in the order of the Ministry of Health of the Russian Federation No. 326 (1997) are not listed in lists A and B; they are included in the "List of narcotic drugs whose circulation in the Russian Federation is limited and in respect of which control measures are established in accordance with the legislation of the Russian Federation" (list No. 2).

Morphine and its analogues have a specific effect on the central nervous system of a person, which manifests itself in the development of euphoric states. With the repeated use of these drugs, syndromes of mental and physical dependence (drug dependence) arise, which limits the possibility of their long-term use. Long-term use of drugs of the group of large analgesics is accompanied by the need to increase the dose of the drug to achieve an analgesic effect. This is due to the addiction to the action of lower (therapeutic) concentrations of these agents in case of their long-term use. The action of these analgesics is not limited to the analgesic effect. To one degree or another, they have a negative effect on the cardiovascular and respiratory systems and have pronounced toxic effects. Exceeding the required dose of drugs can provoke respiratory arrest due to inhibition of the respiratory center, blocking the cough reflex. Toxic properties in relation to the central nervous system are manifested in sleeping pills; depressive states that replace euphoria, the occurrence of hallucinations. All representatives of the group of large analgesics have a negative effect on intestinal motility and tone of the bladder. Prolonged use of drugs of this group can provoke nausea, vomiting, diarrhea and is accompanied by a number of other negative side effects with respect to the digestive system.

In patients with a manifestation of physical dependence during deprivation of their analgesic drug, a painful condition may develop - withdrawal syndrome, which, as a rule, is accompanied by a powerful algic component.

In connection with the expressed narcogenic potential, the analgesics of the second group are subject to storage, prescription and release from pharmacies in accordance with special rules. In recent years, a number of large analgesics used that have a pronounced narcotic potential (tecodine, hydrocodone phosphate, phenadone, some finished dosage forms containing opium and codeine) are excluded from the list of medicines in the Russian Federation (ibid., P. 145).

The mechanism of action of large analgesics is not well understood.

Neurophysiological studies indicate inhibition of the thalamic centers of pain sensitivity by the indicated analgesics and blocking the transmission of pain impulses to the cerebral cortex. However, in their effect, these analgesics differ significantly from the representatives of the group of small analgesics, since they affect the ability of the central nervous system to summarize subthreshold impulses.

Recently, data have been obtained on the presence of specific opiate receptors in the brain and other organs. The endogenous ligands, i.e. specific binding to these receptors, physiologically active compounds formed in the body, are, as a rule, neuropeptides. These are enkephalins and endorphins, as well as prof. D. Zadina endomorphins (Zadina J.E., Hackler L., Ge L., Kastin A. A potent and selective endogenous agonist for the µ-opiate receptor // Nature. 1997. V.386. P.499-502). Endogenous ligands are released in large quantities into the systemic circulation when stressful reactions occur, both positively and negatively emotionally colored. The greatest number of endogenous morphines is released at the stage of a shock during the development of a general adaptation syndrome. They have an analgesic effect, which can often be accompanied by euphoric conditions (Selye G. Stress without distress: transl. From English / Ed. By E.M. Kreps; Foreword by Yu.M. Saarma. - M .: Progress, 1979 . 124 p.).

An important role in processing this kind of information is assigned to the so-called “pleasure center” of the lateral hypothalamus. The model of self-stimulation with irritation of this center is currently testing most of the known analgesic and psychotropic drugs (Zvartau E.E. Effect of chronic administration of morphine on the reward system in rats. Pharmacology and Toxicology. 1978. No. 3. P. 529-535 ; Zvartau EE The effect of naloxone on the emotionally positive and antinociceptive effects of stimulation of the hypothalamus in rats, Bull. Expert biol. And medical 1979. V.88. No. 11. P.43-45; Zvartau E.E., Patkina N.A. Motivational components and self-stimulation during behavioral reactions, in called electric stimulation of the hypothalamus, Journal of Higher Nervous Worker 1974. No. 3. P.529-535; Bespalov A., Lebedev A., Panchenko G., Zvartau E. Effects of abused drugs on thresholds and breaking points of intracranial self-stimulation in rats. Eur. Neuropsychopharmacol. 1999. V.9. N 5. P.377-383).

The binding of morphine to the receptors of endogenous opiates is ensured by the fact that a certain part of its molecule has structural, including conformational similarity with the tyrosine residue of enkephalins and endorphins. Thus, exogenous analgesic morphine (like other opiates and opioids similar in structure to it), when introduced into the body, interacts with the same receptors that are designed to bind endogenous ligands. Chronic administration of exogenous substances of opioid nature by the feedback mechanism blocks the synthesis of their own endogenous. When you stop taking exogenous drugs, the pain syndrome also develops due to the lack of intrinsic endogenous compounds.

Opiate receptors are isolated in a separate population that is heterogeneous. It was shown that opiate receptors exist in the form of different subpopulations (subgroups): μ (mu) (or OP ₃ according to the IUPHAR system), æ (kappa) (OP ₂ ), σ (sigma), δ (delta) (OP ₁ ), having different physiological significance. It is believed that mu receptors mediate supraspinal analgesia, euphoria, respiratory depression and physical dependence, kappa receptors mediate spinal analgesia, miosis, sedation. Various endogenous ligands and large analgesics can bind predominantly to one or another subgroup of receptors, which can determine the characteristics of their pharmacological action.

A variety of large analgesics differ in the nature of binding to opiate receptors. Some of them (morphine, promedol, fentanyl, etc.) are “pure” complete agonists; binding to receptors, they exert a physiological (pharmacological) effect characteristic of endogenous ligands. Others are “pure” antagonists (naloxone, naltrexone). Contacting the receptors, they seem to close them, thus blocking the action of exogenous opiates. The third group includes drugs of a mixed type of action (antagonist agonists) that bind differently to different subgroups of opiate receptors and therefore have an agonistic effect on one type of action and an antagonistic effect on the other (tramadol, nalorphine, pentazocine, nalbuphine, etc. .).

The latest generation synthetic analgesic, belonging to the group of large analgesics, tramadol, is ± trans-2 - [(dimethylamino) methyl] -1- (m-methoxyphenyl) cyclohexanol hydrochloride (ibid., P. 157). Tramadol (dosage form in the form of a solution for injection) is selected as a prototype of the proposed synthetic non-narcotic analgesic agent. The prototype drug has a high analgesic activity, gives a quick and lasting effect. Tramadol is inferior in activity to morphine, therefore it is used, respectively, in large doses. Unlike other opioids in equianalgetic doses, tramadol does not cause constipation, does not inhibit blood circulation and respiration, which is why the drug is chosen as a prototype. Tramadol is a centrally acting analgesic, non-selective agonist for mu, delta and kappa receptors. Tramadol is known to inhibit the reuptake of norepinephrine by stimulating the norepinephrine system. The drug is effective for intravenous, intramuscular, oral and rectal administration. The drug is produced in the form of the following dosage forms: capsules of 0.05 g in a package of 10-20 pieces; drops (with a content of 1 ml of 0.1 g of the drug) in vials in a package of 10 pieces; 5% solution in ampoules of 1 and 2 ml in a package of 5 and 50 ampoules; rectal suppositories of 0.1 g in a package of 5 pieces. The analgesic effect of tramadol when administered intravenously occurs after 5-10 minutes, the effect persists for 3-5 hours. After oral administration, about 90% of the drug is rapidly absorbed from the gastrointestinal tract. The maximum plasma concentration is reached 2 hours after ingestion. The bioavailability of tramadol with a single dose is 68% and increases with repeated use of the drug. Plasma protein binding is 20%. Tramadol is widely distributed in tissues, penetrates the placental barrier in a concentration equal to the concentration of the active substance in the plasma. When taking the drug in women during lactation, 0.1% of the dose is excreted in breast milk. Tramadol is metabolized by demethylation and conjugation of up to 11 metabolites, of which only 1 is active. 90% of the drug is excreted by the kidneys, 10% - through the intestines. The treatment method using tramadol (dosage form in the form of a 5% solution in ampoules of 1 and 2 ml) was selected as a prototype for the method of treatment with the drug.

Tramadol is used for severe acute and chronic pain, in preparation for operations, in the postoperative period, with injuries, in cancer patients. It is possible to use the drug to relieve acute and tonic pain, as well as to stop the algic component of the withdrawal syndrome that develops after refusing to take drugs.

Adults and children over 14 years of age are administered intravenously (slowly dropwise), intramuscularly or subcutaneously, 0.05-0.1 g (1-2 ampoules), up to 0.4 g (400 mg) per day. For children under 14 years of age, the drug is not prescribed due to lack of knowledge (the drug is relatively recently introduced into medical practice). The drug tramadol is undesirable to use for a long time (to avoid addiction). Of the possible side effects, the development of nausea, dizziness, and in rare cases, vomiting should be noted. In general, tramadol has proven itself in clinical practice. According to various sources, the effectiveness of tramadol in traumatology, orthopedics, surgery and oncology varies from 66 to 94%. In addition to the use of tramadol as an analgesic, it has been used since 1989 (although the mechanism of this action is still unclear) for the relief of muscle tremor in the immediate post-narcotic and postoperative periods. Storage: tramadol is included in List No. 1 of potent substances of the Standing Committee on Drug Control of the Ministry of Health of the Russian Federation (1998). Tramadol is not a “pure” agonist, therefore, it is objectively inferior in effectiveness to morphine. Like morphine, with repeated doses it causes addiction and intoxication in most patients. To achieve an analgesic effect with prolonged use, it is necessary to increase the dose of the drug.

It should be noted that the comparison of the claimed invention is carried out by the inventors with drugs approved in the Russian Federation: tramadol (prototype), morphine hydrochloride and analgin.

A separate area of application of drugs of the group of large analgesics is the use in the treatment of drug and drug dependence. Symptoms of drug and drug dependence are manifested primarily in the form of depression, neurosis, anxiety, frequent changes in mood and, as a result, in increased irritability, insomnia. Patients experience pain. It is known that there are many patients who have become drug or drug dependent for both medical and non-medical (social) reasons. Drug dependence is a state of periodic or chronic intoxication that is harmful to the patient and is obtained due to the prescribed repeated administration of the appropriate medication. A drug-dependent patient and drug addict show a constant desire to use a medicine (drug) and fall into a painful condition - withdrawal syndrome - when the drug is withdrawn or the drug is unavailable (BES, M .: BDT, 1997. P.8).

For the treatment of drug and drug addiction, various pharmacological approaches are used. Such approaches typically involve attempting to cure the drug for "asking" or alleviating the concomitant symptoms. So, in US patent No. 4786653 describes the use of drugs with phenylzine or its equivalent phenylalkylhydrazine as an active principle, which are physiologically incompatible with addictive drugs such as amphitamine and cocaine. US patent No. 4696818 relates to a method of prescribing herbal infusions for the treatment of drug and drug-dependent patients. US Pat. No. 3,308,631 describes a method for treating addiction to different types of drugs using 2-imino-5-phenyl-4-oxazolidinone. US Pat. Nos. 4,117,161 and 4,124,715 disclose methods and compositions for treating drug and amphetamine cravings associated with the administration of alpha-methyl-para-tyrosine. A common drawback of these drugs is, as a rule, their selective effectiveness in relation to a particular drug and side effects in the form of relapses and negative effects on the liver.

The only officially approved treatment method in Europe and the USA is to prescribe one of the drugs belonging to the group of large analgesics (differing in the nature of binding to opiate receptors), in the form of substitution therapy: naltrexone, naloxone, nalmefine and antaxone (naltrexone, naloxone, nalmephine, and antaxone) - bind to receptors, close them, thereby blocking the action of exogenous opiates; pentazocine (pentazocine), butorphanol (butorphanol), nalbuphine (nalbuphine), buprenorphine (buprenorphine), tramadol (tramadole) - bind differently to different subgroups of opiate receptors, exerting an agonistic effect in one case and an antagonistic effect in the other; methadone and other drugs are more weakly bound to opioid receptors.

Each of the above medicines has its own disadvantages. A common drawback of these drugs is that they do not fully stop the algic component of opiate withdrawal syndrome. Drugs have a number of side effects, there is a high risk of death. The use of methadone, according to drug-addicted patients, published in the US open press, leads to the formation of drug dependence, which turns out to be stronger than drug addiction, in particular from heroin. Regarding the algic component, the data open in print are not available.

The appropriate drug is prescribed depending on the history of the patient’s pathology - whether he was a drug addict, who took the drug or received drug (drug) dependence as a result of taking a specific drug during the treatment of the underlying disease. Therefore, the method of replacement therapy is selected individually. The daily dose usually does not exceed 0.5 g, otherwise it will quickly become addictive already to a replacement drug.

A common drawback of the known methods is that the duration of this kind of replacement therapy is quite long, it is 3-6 months, and during this time, due to their physiological instability and general weakening of the body and psychological state, patients often refuse treatment.

All of the above funds in themselves are addictive, have side effects in relation to the cardiovascular, respiratory, reproductive systems and adversely affect the liver of patients. Despite the obvious shortcomings, the method of replacement therapy is widely used in world practice, since at present there is no effective alternative to it.

In the Russian Federation, due to the reasons mentioned above, the method of substitution therapy, as well as the means (in particular methadone) used for its implementation, are prohibited (Law of the Russian Federation “On Narcotic Drugs and Psychotropic Substances”).

For the treatment of drug and drug dependence, drugs are used that remove the patient from intoxication and depression - antidepressants (e.g., imitriptyline) and antipsychotics (aminosine, azaleptin) in large doses, then a long-term rehabilitation is carried out with the help of psychotherapy. The known technique is objectively ineffective, as it is the precursor of replacement therapy. High doses of drugs are toxic, cause new intoxication of the body. However, with persistent dosed use of appropriate drugs in combination with individual psychotherapy and rehabilitation under the supervision of a psychologist in special groups and, most importantly, with a strong desire to recover from the patient himself and the attention of relatives in some cases, especially if treatment is started at the beginning of the manifestation of addiction, relapse can be avoided .

Preparations belonging to the group of large analgesics are also used in the complex treatment of patients with cancer. This is necessary, first of all, to maintain and improve the quality of life of patients. Despite the presence of all the side effects and disadvantages listed above, morphine and morphine-like compounds in this case have the main advantage - they provide a relatively stable relief of pain. The use of drugs of this series in patients with cancer is ethically and socially justified. However, there are publications in which it is proved that morphine and its analogues, with prolonged use even in small doses, can irreversibly inhibit the work of Na / K-ATPase of the nerve cell membrane (Krylov B.V., Derbenev A.V., Podzorova S.A. , Lyudino M.I., Kuzmin A.V., Izvarina N.L. Morphine reduces the potential sensitivity of slow sodium channels // Russian Physiol. Zh. 1999. V.85, No. 2. P.225-236). When the pump function is turned off, sodium ions begin to accumulate inside the cell, and potassium ions begin to accumulate on the outside of the cytoplasmic membrane. As a result, the transmembrane potential difference drops and, ultimately, the cell dies. With prolonged use of morphine and its analogues, the cause of death is not the main disease, for example, oncological pathology, but cell death provoked by negative side effects of opiates.

Thus, from the above analysis of the known practice of using analgesics, it follows that the problem of developing universal synthetic drugs from the group of large analgesics remains relevant.

The objective of the present invention is to provide a highly effective synthetic non-narcotic analgesic agent that does not have the negative side pharmacological effects inherent in known analogues and a method for treating pain syndrome of various etiologies using this analgesic.

This problem is solved by the claimed group of two inventions, united by a single inventive concept, an analgesic agent based on comenic acid and a method for treating pain with this agent.

The inventive composition is characterized by the following set of essential features:

1. An analgesic agent, which is an aqueous solution of the active principle - comenic acid and excipients - sodium bicarbonate, in the following ratio, in wt.%:

Comenic acid 1-2, mainly 1 and 2,

sodium bicarbonate 0.55-1.1,

water for injection up to 100.

2. The analgesic agent according to claim 1, characterized in that it additionally contains an admixture of comenic acid - benzylcomenic acid - in an amount of not more than 2.5% in terms of comenic acid.

The set of essential features of the claimed invention provides a technical result: the created synthetic non-narcotic analgesic agent is capable of stopping pain syndrome of various origins (including in the postoperative period, in cancer patients, patients with opiate withdrawal syndrome, accompanied by an allergic component, as well as with opiate poisoning), and according to preclinical studies and expert judgment, he has no negative side effects. The claimed agent in therapeutic doses does not affect the cardiovascular system, blood count, respiratory system, embryogenesis, does not stimulate terratogenesis, does not cause allergies, does not affect reproductive function, exhibits tranquilizing properties in conditions of emotional stress, and stops the toxic effects of drugs related to a group of large analgesics. Neurotoxic effects of the claimed drug are absent. A study of acute and subacute toxicity showed that the drug (dosage form in the form of 1 and 2% injection solutions in ampoules of 1, 2, 5 ml) belongs to the V class of practically non-toxic compounds, which compares favorably with its existing analogues - tramadol (prototype) and comparison drugs - analgin and morphine hydrochloride. The inventive tool is not addictive and addictive, crosses the blood-brain barrier, blocks the toxic effects of opiates and does not provoke tumor growth.

The inventive tool is stable. When stored under natural conditions, its decomposition is about 1% per year. Based on these data, the expiration date is set to 2 years.

The creation of the claimed drug was made possible by the study of the elements of the subtle mechanism of the effects of narcotic and non-narcotic substances on the central and autonomic nervous systems and a thorough study of the membrane signaling pathway, including the membrane receptor, Na / K-ATPase of the neuronal membrane and slow tetrodotoxin-resistant (TTXg) sodium channel ( ibid., p. 225-236).

The inventors have obtained convincing evidence that the analgesic effect of the claimed drug (dosage form in the form of 1 and 2% solution for injection) is realized in a different, non-opioid way of coding and modulation of nociceptive information.

According to the invention, the active substance of the analgesic agent - comenic acid - interacts with one of the subtypes of opioid membrane receptors discovered by the authors, forming stronger bonds than hydrogen bonds, namely, realizing ion-ion interactions during ligand-receptor binding. Further, the signal activates the Na / K-ATPase (and not G-proteins, as in the case of opiates), starts its transduction function (the signal is amplified). An analgesic effect at the cellular level is realized by reducing the potential sensitivity (excitability) of tetrodotoxin-resistant sodium channels.

The inventive composition differs from the prototype preparation by a number of essential features: a qualitative composition, primarily the use of another active substance - comenic acid, and the corresponding quantitative characteristics.

Analysis of the prior art did not allow to find a solution that completely coincides in the totality of essential features with the claimed. Previously, the inventors have shown that kamenovo acid has a sedative effect, in doses exceeding the values of the claimed invention (RF patent No. 2209062 "A substance with a sedative effect" from 03.19.02, publ. 07.27.03), which does not discredit the novelty of the claimed invention . Thus, we can assume that the claimed tool has novelty.

Only the combination of essential features of the claimed analgesic means allows to achieve the specified technical result. The ability of the composition of the substances that form the basis of the claimed funds to exhibit stable analgesic activity was discovered by the inventors by chance. A unique mechanism of their action, which, in fact, denies addiction to the drug, is also disclosed by the inventors.

It should be emphasized that analgesics that do not have negative side effects and are comparable in degree of analgesia with drugs belonging to the group of large analgesics have not yet been created.

Thus, the proposed analgesic agent may meet the eligibility condition "inventive step" ("non-obviousness").

The inventive method of treatment is the following set of essential features:

13). A method of treating pain syndrome of various etiologies, which consists in the fact that the patient is administered intravenously the claimed analgesic agent (according to claims 1-2) in a dose of up to 350 mg (in terms of comenic acid) per day for 5-30 days, mainly in the form 1% or 2% solution for 7-10 days.

The duration of the course of treatment and the dose of the drug depend on the severity of the pain syndrome, the condition of the patient, the main diagnosis and concomitant diseases.

The introduction of the inventive analgesic in a dose greater than 350 mg per day (5 mg / kg) (in terms of the active substance - comenic acid) is impractical, since the analgesic effect does not increase.

The set of essential features of the proposed method of treatment allows to achieve a technical result consisting in the long-term relief of pain syndrome of various etiologies, which allows high-quality therapy to treat the underlying disease (for example, in cancer patients) and significantly improve the quality of life of patients. The analgesic effect occurs 5-7 minutes after administration of the drug and lasts up to 24 hours.

The inventive tool and method of treatment are characterized by the absence of physical and mental dependence on the drug, addiction to the action of the drug, the analgesic effect persists for a whole day (in the prototype - tramadol - 3-5 hours), with prolonged treatment it is not necessary to increase the dose of the drug to achieve an analgesic effect. In contrast to the method of treating pain syndrome of various etiologies with the help of tramadol, the proposed treatment method has no side effects accompanying treatment with drugs related to opiate receptor antagonists, namely the development of nausea, dizziness, and in rare cases, vomiting.

The inventive method of treating pain of various etiologies is gentle, since the drug used has no negative side effects, and the mechanism of its effect is purely selective. Treatment proceeds much faster (from 5 days to 1 month, depending on the severity and cause of the underlying disease) than with known analogues (from 14 days to 6 months). The treatment is not addictive, physical and mental dependence and, therefore, the need for a constant increase in the dose of the drug.

The claimed method of treatment differs from the prototype method using tramadol by a number of essential features: using another active substance - the claimed analgesic agent based on comenic acid in a certain dose and duration of treatment.

Completely coinciding with the claimed in the aggregate of essential features of the method of treatment of pain is not found, this can serve as proof of the novelty of the proposed method.

Only the set of essential features of the proposed method of treatment allows to achieve the above technical result. Indeed, the method of stopping the pain syndrome is not yet known, during the implementation of which there is a subtle selective effect on the activation portal device of tetrodotoxin-resistant sodium channels. This happens in the case of the claimed invention due to activation of the receptor-mediated signaling pathway, in which the sodium pump plays the role of the signal transducer. As a result, the pain syndrome is stopped without intoxication, addiction and relapse. The latter indicates the non-obviousness of the proposed method.

Thus, based on the foregoing, the claimed group of inventions as a whole can claim to meet the eligibility criteria of “novelty” and “non-obviousness”.

To confirm the compliance of the proposed solution to the requirement of "industrial applicability", as well as to better understand the essence of the invention, we give examples of its specific implementation.

Prototype

Analgesic drug tramadol (prototype), dosage forms: capsules of 0.05 g in a package of 10-20 pcs.; drops (with a content of 1 ml of 0.01 g of the drug) in bottles in a package of 10 pcs .; 5% solution in ampoules of 1 and 2 ml in a package of 5 and 50 ampoules; rectal suppositories of 0.1 g in a package of 5 pcs. Used a commercial drug (company Hemofarm JSC).

Reagents used for the preparation of the claimed non-narcotic synthetic analgesic:

The active principle of the drug is comenic acid (5-hydroxy-4-oxopyrone-2-carboxylic acid) synthesized according to the procedure (Garkusha, J.A. Zh. General chemistry. 1961. V.31. S.2573). The melting point (261-267 ° C) and spectral analysis are consistent with published data. In an analgesic, as an impurity of comenic acid, benzylcomenic acid may be present in an amount of not more than 2.5% in terms of comenic acid.

As an auxiliary substance, sodium bicarbonate (GOST 4201-79; FS 42-0324-4716-03) is included in the composition of the claimed analgesic agent in order to create an optimal pH value that promotes the dissociation of comenic acid and increases its solubility.

Water for injection corresponded to the requirements of FS 42-2620-97. Sterilization of the agent is carried out by membrane filtration under aseptic conditions. The filtrate is poured into neutral glass ampoules and sealed.

The composition of the claimed funds

The positive claimed effect of the drug is manifested for a 1-2% aqueous solution. The preferred form of the claimed analgesic agent (dosage form) is a 1% or 2% aqueous solution for injection in ampoules of 1, 2 and 5 ml. The active substance is comenic acid, the concentration of which is 10 mg in 1 ml (1% solution of an analgesic) or 20 mg in 1 ml (2% solution). The composition of the dosage form of the claimed drug in terms of 100% substance includes sodium bicarbonate 5.5 g (1% solution) or 11 g (2% solution), water for injection up to 1 l (or 1-2 g of comenic acid, 055- 1.1 g of sodium bicarbonate and water to 100 ml). The inventive analgesic is a clear liquid from yellowish to yellow (10 mg / ml), yellowish-greenish to yellow-green (20 mg / ml) odorless, pH 4.1 to 5.6 (potentiometric). Among foreign impurities, benzylcomenic acid, which is an intermediate product of the synthesis of comenic acid, has been identified. The standard for the total content of foreign impurities is established on the basis of storage data and taking into account the admissible level of impurities in the substance of comenic acid: not more than 5% (benzylcomenic acid content not more than 2.5%) in terms of comenic acid. The inventive analgesic agent is a stable compound. When stored under natural conditions: the degree of decomposition is about 1% per year. Shelf life of a sterile preparation in a dark place at a temperature of no higher than + 25 ° C for 2 years. The tool is pyrogen-free. A test dose of 10 mg per kg of animal weight in a volume of 0.5 ml and 1 ml, respectively, for preparations with a concentration of 20 mg / ml and 10 mg / ml. The tool is non-toxic, belongs to the V class of practically non-toxic medicinal substances (according to comenic acid) (H. Lodge et al., Clinical Toxicology of Commercial Products. Acute Poisoning. Ed. IV, Baltimore, 1975, 427 p.). A dosage form in the form of a solution for injection is a non-narcotic analgesic and can be used to relieve pain of various etiologies of both peripheral and central origin.

Example 1. The proposed mechanism of action of the claimed analgesic funds (dosage form in the form of a solution for injection)

The proposed analgesic agent and method of treatment are based on an in-depth understanding of the physiological role of the molecular mechanism for modulating a nociceptive signal discovered by the inventors when it is transmitted from the membrane receptor to the Na / K-ATPase of a nociceptive neuron and further to tetrodotoxin-resistant Na channels (Krylov B.V. et al. Russian Physiological Journal. 1999. T. 85, No. 2. S.225-236).

The claimed analgesic agent was tested in vitro, taking into account the new mechanism discovered by the inventors for the transduction of nociceptive signals by Na / K-ATPase on the way from the membrane receptor to the tetrodotoxin-resistant Na channel. Opiates, in particular morphine, inhibit the work of Na / K-ATPase neurons (Biser PS, Thayne KA, Fleming WW, Taylor DA Na, K-ATPase alpha-subunit isoform distribution and abundance in guinea-pig longitudinal muscle / mienteric plexus after exposure to morphine. Brain Res. 2002 Mar. 29; 931 (2): 186-93), while the absolute value of the resting potential of the cell drops sharply, then irreversible morphological changes in cells, tissues and organs occur, leading to death.

The delicate mechanism of the effect of the claimed agent on the central nervous system and its differences from the action of morphine and its analogues are described below.

As mentioned above, morphine is one of the 20 alkaloids that make up opium. He is the most studied opioid receptor agonist, triggering a sequence of intracellular signaling processes, the first step of which is the emergence of ligand-receptor binding. At the same time, morphine binds to receptors from a well-studied class of cell membrane receptors. Morphine activation of opioid receptors associated with potassium and calcium ion channels leads to analgesic and sedative effects. In this case, G-proteins act as a transducer of a nociceptive signal. Opioids (and opiates) reduce pain sensitivity by reducing calcium-dependent release of neurotransmitters from presynaptic terminals, delaying signal transmission between neurons.

The authors of this invention have shown that there is an unknown interaction before them (a new signaling pathway in the membrane of a sensory neuron) between the membrane receptor, Na / K-ATPase and the activation portal system of the tetrodotoxin-resistant sodium channel. G-proteins are not involved in this mechanism (that is why the claimed drug, the active substance of which is comenic acid, is not addictive already at the molecular and cellular levels). Comenic acid interacts with one of the subtypes of opioid membrane receptors discovered by the authors, forming not weak hydrogen bonds (as in the case of opiates), but stronger ion-ion interactions during ligand-receptor binding. Further, the signal activates the Na / K-ATPase (and not G-proteins, as in the case of opiates), starts its transduction function (the signal is amplified). An analgesic effect at the cellular level is realized by reducing the potential sensitivity (excitability) of tetrodotoxin-resistant sodium channels. As noted above, morphine inhibits the activity of Na / K-ATPase, blocks its pumping function (Biser PS, Thayne KA, Fleming WW, Taylor DA Na, K-ATPase alpha-subunit isoform distribution and abundance in guinea-pig longitudinal muscle / mienteric plexus after exposure to morphine. Brain Res. 2002 Mar. 29; 931 (2): 186-93), thereby causing negative side effects. Therefore, the known analogues from the group of large analgesics (tramadol, morphine hydrochloride, butorphanol, omnopon) are objectively unable to exhibit the properties of the claimed invention.

As a result, the basis of the present invention is the idea of activating a fundamentally different way from the classic opiate way of encoding nociceptive information. The existence of this mechanism only confirms the theory of the polymodality of nociceptors and the presence in the human and animal body of several parallel ways of protecting their integrity from superpowerful nociceptive stimuli. Pain reduction occurs when the Na / K-ATPase realizes the transducer function when coding a nociceptive signal with the participation of tetrodotoxin-resistant sodium channels, the excitability of which decreases.

Addiction to the claimed drug at the molecular level is absent.

In vitro experiments have shown a decrease in the excitability of slow (TTXr) sodium channels resulting from the action of an active substance - comenic acid. The application of the claimed means to the outer side of the membrane of the sensory neuron had a significant effect on the currents of slow TTX _r sodium channels, which was manifested in a decrease in their potential sensitivity and shift to the right, towards higher potentials, depending on the potential of their activation portal characteristic. The registered changes depended on the concentration of the active substance of the preparation - comenic acid - and were most pronounced when the studied substance was introduced into the extracellular medium at a concentration of 1 mM (in terms of the active substance).

The registered decrease in the excitability of slow (TTXr) sodium channels occurs, firstly, due to a decrease in the potential sensitivity of the activation gate device of these channels and, secondly, due to a shift of the activation curve to the right. The experiments proved that comenic acid is indeed a specific agent, a receptor-indirectly reducing the excitability of precisely the slow sodium channels (according to the international classification, these are Na _v 1.8 channels), and this is due to its analgesic properties. A specific “shutdown” of precisely these channels is promising in the search for new ways to solve the problem of relief of chronic pain of peripheral origin. The results of the studies conducted by the authors indicate that the claimed tool activates a fundamentally different from the classical opiate mechanism of membrane signaling. Endomorphins, the most potent agonists of opioid receptors of endogenous origin (Katina I.E., Schegolev B.F., Zadina D.E., Mackey M.L., Krylov B.V. Inhibitory effect of endomorphins on the temperature-dependent sodium currents of sensory neurons // Sensory systems. 2003. 17. No. 1. P.1-17; Zadina JE, Hackler L., Ge L., Kastin A. A potent and selective endogenous agonist for the µ-opiate receptor // Nature. 1997. V. 386. P.499-502), can inhibit slow sodium channels, but only with intracellular and not extracellular supplementation, unlike the claimed drug. The concentration of endomorphins required to affect the channel is orders of magnitude higher than the effective concentration of the drug developed by the authors, which indicates that endomorphins bind exclusively to opioid receptors. The introduction of ouabain into the extracellular medium during the intracellular application of endomorphine had no effect. With extracellular supplementation (namely, in this way, the authors found the “analgesic” effect of the claimed drug) endomorphins do not affect the responses of the nociceptive neuron. Thus, at the cellular level, results have been obtained that suggest that the effect of the claimed drug is significantly different from the action of morphine-like compounds, including endogenous origin. The authors experimentally proved that the "analgesic effect" of the claimed drug is not associated with the activation of a new subtype of µ-opioid receptors that are activated by endomorphins (Wu H.-E., Thompson J., Sun H.-S., Leitermann RJ, Fujimoto JM, Tseng LF Nonopioidergic mechanism mediating morphine-induced antianalgesia in the mouce spinal cord. // J. Pharmacol. And Experim. Therapeutics 2004. V.310. 240-246). The analgesic effect of the claimed drug is realized due to the effect on the molecular mechanism of membrane signaling, including Na / K-ATPase (its alpha three isoform) and slow TTX _r sodium channels.

Example 2. Pharmacokinetics

With the intravenous administration of the claimed drug to dogs, the pharmacokinetics of the active substance of the drug - comenic acid - in the blood plasma is described by a 3-part dependence.

The first phase of the distribution proceeds rapidly - the characteristic time in this section is 1.5 minutes. In the first 10 minutes, about 95% of comenic acid (active substance) leaves the blood plasma, while its concentration decreases from 50-60 μg / kg to 3 μg / kg, i.e. almost 20 times. The next phase lasts from the 10th minute until the beginning of the 2nd hour; the typical time here is about 30 minutes, and the concentration of comenic acid decreases from 3 to 0.6 μg / ml, i.e. 5 times. Finally, after the 2nd hour, the phase of true elimination apparently begins with a time T _{1/2 of the} order of 5.5 hours.

In general, the average time of the presence of the claimed drug in the body - an indicator of MRT - is 5.5-6.0 hours.

High values of such indicators as clearance (450-500 ml / kg / h) and stationary volume of distribution (2.5 l / kg) indicate that the drug is very actively distributed from the systemic circulation. This fact is unexpected since comenic acid belongs to a number of hydrophilic compounds. It follows that most of the drug is probably not excreted, but is metabolized and utilized in the body itself. The latter makes it possible to recommend the use of the claimed drug in patients with renal and hepatic insufficiency. Considering the chemical nature of comenic acid (i.e., the presence of hydroxyl and carboxyl groups in its structure), glucuronide conjugates or complex compounds with metal cations may be its metabolites.

The analgesic effect after intravenous administration of the claimed drug occurs in 5-7 minutes and lasts up to 24 hours. The claimed drug does not cause dependence and addiction, therefore, the dose of the drug necessary to achieve the analgesic effect remains unchanged during treatment even with prolonged use (on recommendation doctor, depending on the severity of the underlying disease, as in the case of patients with cancer). In a therapeutic dose, the drug does not affect the blood formula, cardiovascular and respiratory systems, does not cause allergic reactions, does not provoke terratogenesis, does not affect reproductive function and embryogenesis. It has been experimentally proven that the claimed drug blocks the toxic effects of opiates.

Example 3. The safety study of the use of the inventive analgesic

The pyrogenic effect was studied in rabbits weighing 2.0-3.5 kg in accordance with the requirements of Global Fund XI, issue 2, p. 183. With the introduction of the inventive analgesic in a dose of 10 mg per 1 kg of animal body weight, an increase in temperature in animals of more than 0.3 ° C was not observed. Based on the studies, it was concluded that it is pyrogen-free.

To determine the indicators of acute toxicity, the claimed drug was administered to white mice and rats of both sexes intravenously (iv) in the tail vein in increasing doses according to Litchfield-Wilcoxon. Calculations of average lethal doses were carried out according to VB Prozorovsky. To achieve large doses of the drug, administration was repeated at intervals of 20-30 minutes for 4 hours. The control animals were injected with the same volumes of sodium bicarbonate solution.

Experimental studies have shown that with acute administration of the inventive tool has almost no toxic effects. The lethal dose levels for outbred white mice and rats of both sexes with iv administration exceed 1000 mg / kg, which is hundreds of times more than the maximum daily therapeutic dose for humans - 5 mg / kg (with an average weight of 70 kg, the maximum daily therapeutic dose is 350 mg per day). In acute experiments, there were no signs indicating an irritating effect of the drug at the injection site.

The results of toxicometry, observations of experimental animals in the period after acute use, as well as data of pathomorphological studies allow us to classify the claimed drug in class V of practically non-toxic drugs (N. Hodge et al., Clinical Toxicology of Commercial Products. Acute Poisoning. Ed. IV , Baltimore, 1975, 427 p .; K.K. Sidorov, 1973).

Preclinical studies of the claimed drug (dosage form in the form of a solution for injection) in mice, rats, dogs, guinea pigs showed that the drug does not cause allergic reactions, does not affect reproductive function, embryogenesis, does not stimulate mutagenesis and terratogenesis, does not negatively affect cardiovascular and nervous systems.

Example 4. Specific pharmacological activity

4.1. Assessment of analgesic effect

The analgesic effect of the claimed drug was determined on mice by the method of "hot plate" at a temperature of 52 ° C. The latent period of the appearance of jerking of the legs in animals, motor anxiety, and hopping activity using a stopwatch was measured.

The experiments were carried out after 30, 60 and 120 minutes after administration of the drug for a group of 20 animals. In this case, the analgesic activity of the claimed drug was compared with the most commonly used and effective drugs for the relief of pain, including cancer. Comparators were analgin and morphine hydrochloride. The results of the experiments are presented in table 1.

Table 1 The effect of the claimed analgesic agent (1), analgin and morphine on the pain sensitivity of mice by the method of "hot plate", M ± m Drug dose Latent period, s 30 minutes 60 min 120 min Control (1.1% soda solution) 10.5 ± 0.9 10.8 ± 0.6 11.1 ± 0.8 (1), 5 mg / kg 22.0 ± 1.1 * 21.7 ± 0.7 * 22.3 ± 0.8 * (1), 10 mg / kg 31.8 ± 0.7 * 32.5 ± 1.4 * 33.7 ± 1.2 * (1), 50 mg / kg 37.0 ± 1.6 * 37.2 ± 1.9 * 38.2 ± 1.8 * Analgin 50 mg / kg 20.1 ± 0.6 * 22.1 ± 1.8 * 22.5 ± 0.9 * Morphine hydrochloride, 10 mg / kg 35.8 ± 0.6 * 30.5 ± 1.7 * 27.8 ± 1.2 * • - significant differences with control, P <0.05

The inventive tool in all doses exhibits a pronounced analgesic effect, not inferior in effectiveness to morphine and exceeding the analgesic activity of analgin. Its effectiveness was dose-dependent in the range from 5 to 50 mg / kg.

The authors investigated the analgesic effect of comenic acid at a dose of 40 mg / kg under the conditions of a formalin test. A convincing result was obtained about the powerful analgesic effect of comenic acid both at the peripheral and central levels. Since this test is a convincing and rather rigid model for the formation of pain syndrome of various origins, it was not practical to test the claimed drug, the active substance of which is comenic acid, under the same standard conditions (Helsinki Convention). A comparative analysis of the results obtained under the formalin test and in the “hot plate” test made it possible to prove that the analgesic properties of the claimed drug (in the form of 1–2% solution for injection) at the periphery level are realized in a dose of 5 mg / kg (in terms of the active substance is comenic acid), and at a dose of 50 mg / kg (in terms of the active substance - comenic acid), the drug relieves pain in general - on the periphery and in the center. Thus, in vivo experiments obtained experimental evidence confirming the ability of derivatives of gamma-pyrone to penetrate the blood-brain barrier. The latter also found confirmation in experiments on the influence of comenic acid on the pleasure center of the lateral hypothalamus (ibid.).

In experiments with the study of the influence of comenic acid at a dose of 40 mg / kg on the self-stimulation zone of the lateral hypothalamus, it was found that comenic acid opens the positive feedback formed in the experiment. The animal, after applying comenic acid, moved away from the pedal. The latter favorably distinguishes the studied drug from drugs belonging to the group of large analgesics.

4.2. Assessment of the emotional manifestations of a pain reaction

Emotional reactions in mice were evaluated by the method of electric pain stimulation. To do this, a pair of mice were planted in a 10 × 10 cm chamber, the floor of which was a rosette of rods. An alternating current from 1 to 50 V was passed through the grating of the chamber and the voltage was increased by 2 V until the current caused a squeak or a fight in two tests in a row. Each voltage was tested twice in 5 s and at intervals of 15-30 s. Thresholds for inducing a squeak (emotional reactivity) and aggressiveness in volts were taken into account. Testing of drugs was carried out on the same day in control and experimental groups of animals. Each group included 20 animals.

After 1 h after iv administration of the claimed drug, analgin or morphine, the thresholds of attention and squeak in mice were increased (Table 2). This effect of the claimed drug was manifested in rather small doses of 5-10 mg / kg. Thresholds for inducing aggressiveness after administration of the claimed agent and morphine also had a significant upward trend. Analgin, in contrast, enhanced the emotional responses of mice.

Based on these data, it can be assumed that the inhibitory effect of the claimed drug on the emotional reactions caused by electric pain irritation and its tranquilizing effect in a conflict situation is associated with the analgesic effect of the drug.

table 2 The effect of the claimed means (1), morphine and analgin 1 hour after the introduction of the emotional reactions of mice caused by electric pain irritation (M ± m) for a group of 20 animals Drug dose Thresholds of emotional reactions (volts) Sensitivity threshold Squeak threshold Threshold of aggressiveness Control (1.1% soda solution) 12.1 ± 0.7 25.0 ± 0.2 42.3 ± 1.9 (1), 5 mg / kg 21.0 ± 0.9 * 45.0 ± 1.9 * 66.0 ± 2.1 * (1), 10 mg / kg 30.0 ± 1.1 * 64.0 ± 1.2 * 74.0 ± 2.3 * Analgin, 50 mg / kg 20.8 ± 0.7 * 41.3 ± 1.6 * 50.0 ± 4.2 * Morphine hydrochloride, 10 mg / kg 33.0 ± 1.4 * 66.0 ± 1.5 * 78.0 ± 2.6 * • - significant differences with control, P <0.05

In a separate series of experiments on rats, the effect of the claimed drug on the aggressiveness of animals caused by electric pain irritation was studied. In this case, the animals received an iv preparation at a dose of 10 mg / kg per day for 5 days. The number of fights for 5 min, which were provoked by an electric current passing through the electrode floor of the chamber, was determined. The results are presented in table.3.

Table 3 The effect of re-introduction of the claimed funds (1) and analgin on the aggressiveness of rats caused by electric pain irritation Drug dose Introduction day Number of fights Reliability indicator, P Control (1.1% soda solution) one 20.8 ± 2.5 - (1), 10 mg / kg one 10.5 ± 1.5 0.05 Analgin, 50 mg / kg one 19.2 ± 1.6 - Control (1.1% soda solution) 3 18.6 ± 2.2 - (1), 10 mg / kg 3 7.3 ± 0.6 0.05 Analgin, 50 mg / kg 3 16.4 ± 1.2 - Control (1.1% soda solution) 5 19.3 ± 2.4 - (1), 10 mg / kg 5 6.4 ± 1.1 0.05 Analgin, 50 mg / kg 5 17.1 ± 0.8 -

It turned out that the claimed tool in the studied dose depressed the aggressiveness of animals, which was manifested in a sharp decrease in the number of fights. Based on the data obtained, we can conclude that the claimed tool with a single and repeated injections has a depressing effect on the emotional-pain reactions caused by stress and pain.

4.3. Assessment of the severity of a conflict situation provoked by an electric pain impulse

The conflict situation in animals was caused on the basis of strong drinking deprivation. For this, the mice were deprived of water for 48 h, then the animals were individually placed for 5 min in the experimental chamber, where there was a drinking bowl with water. At the time of taking water, the animal received an electric shock (2 mA, 0.5 seconds), which was recorded on the counter. The number of pulses was calculated (the number of water taken) and the number of times the animal rose in 5 minutes of observation.

As shown by the results of experiments, the claimed drug in small doses reduces the period between the first and second water intake and increases the number of water intake (Table 4), which indicates the tranquilizing effect of the drug associated with the relief of pain and an increase in the threshold of pain sensitivity.

Table 4 The influence of the claimed means (1) on the behavior of mice in a conflict situation, M ± m A drug Time between the first and second water intake, s R The amount of water taken in 3 minutes R Control (1.1% soda solution) 12.1 ± 4.1 - 28.7 ± 10.3 - (1), 5 mg / kg 5.2 ± 0.9 0.05 49.5 ± 14.8 0.05 (1), 10 mg / kg 4.9 ± 1.8 0.05 47.6 ± 12.9 0.01 Analgin, 50 mg / kg 19.6 ± 4.3 0.1 10.3 ± 1.9 0.1 Analgin, 100 mg / kg 18.9 ± 3.4 0.1 7.2 ± 2.9 0.1

Thus, the claimed tool in the study of pharmacological activity exhibits pronounced analgesic properties, which were combined with the relief of emotional reactions to pain.

However, it should be noted that the introduction of the drug had a mild tranquilizing and antidepressant effect, which did not have the nature of an excessive side effect. This is evidenced by the results of experiments to study the chronic administration of the claimed drug in doses 60-100 times the therapeutic dose. The data obtained in almost all experimental groups of animals during the 90 days of the experiment revealed a tendency to an increase in the latent period, as well as a decrease in activity, estimated by the number of uprights, intersections, and peeps compared to background data and control. At the maximum dose (300 mg / kg), these changes were reliable in all groups, but after discontinuation of the drug, the revealed changes took place within a week.

Phenomenon of addiction, dependence and similar to withdrawal were absent.

In addition, with the introduction of the claimed funds for 90 days, the threshold of excitability of the nervous system had a physiological level.

The results indicate a pronounced analgesic activity and the absence of negative side effects in relation to the central nervous system.

Example 5. The study of the presence of drug potential

The experiment was performed on 96 sexually mature Wistar rats weighing 190-210 g for 50 days. 32 animals were included in the experimental group, 32 in the first control, 32 in the second control. The animals were kept in cells in groups of 4 individuals with free access to water and food and a constant light-dark regime of 12:12 hours.

The drug dependence of the experimental and first control rats was formed by a single intraperitoneal administration of 1% morphine hydrochloride in increasing doses from 20 to 100 mg / kg per injection for 18 days.

From the evening of the 19th and 36th day of the experiment (and sometimes 43 days) instead of morphine, the rats of the experimental group were administered the claimed drug intraperitoneally once a day. In this case, the rats of the experimental group were divided into 4 subgroups of 8 animals each. For the first subgroup, a single dose of the claimed drug was 34 mg / kg, for the second - 50 mg / kg, for the third - 68 mg / kg, for the fourth - 84 mg / kg (doses are given in terms of the active component of the drug - comenic acid).

The animals of the first control group, starting from 19 days, were injected daily with equivalent volumes of isotonic sodium chloride solution. Animals of the second control group from 1 to 18 days were injected with isotonic sodium chloride solution. On the 19th day of the experiment, this group was divided into 4 subgroups and the inventive agent was administered daily. Its dose in each of the subgroups, as well as in the experimental group, was 34, 50, 68 84 mg / kg (doses are given in terms of the active component of the drug - comenic acid).

All injections were carried out in a special chamber consisting of two compartments: a large brightly lit one and a small dark one. The compartments were interconnected by a passage with doors. Rats were landed in a bright compartment and the reaction of animals was observed.

Within 2 days before the start of the experiment, rats were landed in the bright compartment of the chamber. All animals behaved the same. In the first landing, they examined the light compartment, very quickly discovered an open passage into the dark compartment and quickly hid in it. Subsequent landings in the light compartment immediately ended with the animals moving to the dark. The preference for a dark small compartment is a natural reaction for rats (Sudakov S.K., Borisova E.V., Rusakov D.Yu. Method for the quantitative assessment of withdrawal syndrome in morphine-dependent rats "Experiment. And wedge. Pharmacol. 1994. No. 2. C .60-621).

On the third day, animals were landed in the bright compartment, after closing the transition to the dark. Without taking the rat out of the chamber, just lifting it slightly from the floor, grabbing it with its fingers on its back, they made injections with an insulin syringe with a very thin needle. The animals of the experimental and first control groups were injected with morphine, and the second control group was treated with saline. Subsequently, the injection procedure always took place in the bright compartment of the chamber. The first 7-12 days, the rats were forcibly kept in the bright compartment by keeping the door closed in the dark compartment until morphine was introduced. After the injection, the door was opened, and after a while (almost immediately) the rats went into the dark compartment. But by the 8-15th day, all 32 rats of the first control group and 30 experimental rats had developed a positive conditioned reflex to the administration of morphine in the bright compartment, reinforced by receiving positive emotions and eliminating unpleasant withdrawal symptoms. The reflex manifested itself in the fact that when they were placed in the light compartment of the chamber, the rats did not leave it, despite the open door to the dark compartment, until they received an injection of morphine, after which they nevertheless left the dark compartment, immediately or through some time. Morphization of rats lasted 18 days. In two rats of the experimental group, the described conditioned reflex could not be developed. None of the 32 rats of the second control group receiving saline did not develop a reflex either.

Then, for another 18 days, instead of morphine, the rats of the experimental group were injected with the claimed drug. Previously, these rats were divided into 4 subgroups (see above). Two rats that did not develop a conditioned reflex entered the fourth subgroup.

On the 5-14th day of administration of the claimed drug, 27 rats stopped waiting for the next injection in the bright compartment, they quickly ran into the dark after landing. These were all animals of the first and second subgroups, 6 animals from the third subgroup, and 5 from the fourth. In the 5 remaining animals, the positive conditioned reflex to the introduction was no longer of morphine, and the claimed drug in the light compartment did not die out, and the rats were still waiting for this procedure in the light compartment. Of these 5 rats, 3 animals were from the fourth subgroup (the dose of the effective substance was 42 mg / kg) and 2 from the third (the dose of the effective substance was 34 mg / kg). It was decided to extend the introduction of the claimed funds to these 5 animals, but at the same time reduce the dose. On days 16-25, 3 rats from the fourth subgroup were reduced the dose of Anoceptin to 34 mg / kg, and 2 rats from the third subgroup were reduced to 25 mg / kg. By 21 days, the conditioned reflex faded in all 5 rats. After 25 days of administration of the claimed drug (43 days of the total experiment time), these 5 rats stopped receiving the substance. Signs of "withdrawal syndrome" in animals were absent.

At the same time (from 19 to 50 days of the total experiment time), the following changes occurred with rats of the first control group. With the abolition of morphine and the developed withdrawal syndrome, 6 rats died in the period from 3 to 7 days of withdrawal. The fading of the positive reflex to voluntary stay in the bright compartment of the chamber in the remaining 26 rats under the conditions of cancellation of morphine occurred in the period from 15 to 25 days.

None of the animals of the second control group, received from 19 to 36 days of the experiment the claimed drug in various doses (34, 50, 68 and 86 mg / kg), the conditioned reflex of voluntary stay in the bright compartment of the chamber did not work out.

The data obtained allow us to conclude that the claimed drug is not addictive and even less dependent, does not have a morphine-like euphoric effect on the emotional state of rats, that is, the drug has no narcogenic potential. The conditional reflex of voluntary stay in the bright compartment before receiving the injection could not be developed in any of the 32 animals of the second control group that received only the claimed drug. Thus, it was found that the drug of the claimed tool does not cause the development of positive emotional states (state of euphoria).

The reflex to voluntary stay in the bright compartment of the chamber faded away both in rats of the first control group who did not receive the claimed drug at the stage of discontinuation of morphine, and in animals that received this drug. Apparently, an unconditional inhibition of the conditioned reflex developed as a result of non-reinforcement by positive emotion (Shabanov P.D., Shtakelberg O.Yu. Addiction. Pathopsychology, clinic, rehabilitation. St. Petersburg: Lan, 2001, 460 pp.). It was found that this reflex faster and easier faded away in rats that received the claimed drug at the stage of discontinuation of morphine than in animals that did not receive this substance (5-14 and 15-25 days of extinction of the reflex, respectively).

Example 6. The effect of the drug on respiration

It is known that opiates inhibit the respiratory rhythm by reducing the sensitivity to carbon dioxide of the respiratory centers located in the brain stem. Moreover, inhibition of the bridge centers and medullary centers changes the rhythm of breathing. Respiratory depression is the most common cause of death with an overdose of opiates and can develop 5-10 minutes after intravenous administration of morphine and within 30-90 minutes with subcutaneous administration. Compared to morphine, butorphanol depresses respiration to a lesser extent, but this phenomenon is also noted with increasing doses.

The results of a series of experiments to study the effect of the claimed means on breathing are presented in table.5. It should be noted that for a long time the respiration rates in mice during immobilization did not significantly change. Butorphanol at a dose of 10 mg / kg caused marked respiratory depression, which was recorded after 30 minutes.

The inventive tool in doses of 5 mg / kg and 50 mg / kg, injected 1 hour before butorphanol, statistically significantly normalized the number of respiratory movements in experimental animals. This effect of the studied drug persisted for 2 weeks (dose 5 mg / kg) and 3 weeks (dose 50 mg / kg).

Table 5 The effect of a single injection of the claimed drug (1) on the respiratory rate for 10 s when exposed to butorphanol Experiment group Dose mg / kg Respiratory rate after injection, 24 hours one 7 fourteen 21 Control (1.1% soda solution) 36 ± 2.6 33 ± 2.1 32 ± 1.8 38 ± 1.8 Butorphanol 10 28 ± 1.4 * 27 ± 1.1 * 26 ± 1.4 * 28 ± 1.0 * Butorphanol + (1) 5 35 ± 1.5 35 ± 1.2 33 ± 2.5 28 ± 2.4 * fifty 34 ± 1.8 35 ± 1.7 31 ± 1.8 34 ± 1.8 * - statistically significant difference with the control group (n = 6 in all experimental groups)

The data obtained indicate a prolonged leveling of the claimed means of respiratory depression in experimental animals caused by butorphanol, and additionally confirm the ability of the drug "Anoceptin" to penetrate the blood-brain barrier.

The proposed experimental design is standard for testing drugs used in resuscitation during opiate poisoning. The latter allows us to argue the possibility of using the drug “Anoceptin" in clinical practice for poisoning with drugs of the group of large analgesics.

Example 7. The effect on motility of the gastrointestinal tract

Opiates weaken peristalsis of smooth muscles and at the same time increase its tone. As a result, the rate of bile secretion, pancreatic and intestinal secretion, propulsive motor contractions decrease and non-propulsive intestinal contractions increase. The effect of the proposed drug on intestinal motility was studied in dynamics: indicators were recorded 1 hour, 14 and 21 days after its introduction. The experiments were carried out on white mice of both sexes, weighing 20-26 g. The activity of peristaltic contractions of the intestine was judged by the degree of advancement of 10% suspension of activated carbon prepared on 2% starch mucus. Coal suspension was injected into animals 0.5 ml per mouse 20 minutes after intravenous injection of butorphanol at a dose of 10 mg / kg. 10 minutes after this, the mice were euthanized by decapitation, their abdominal cavity was opened, and the stomach and intestines were carefully removed. Then measured the total length of the intestine and the length of the plot filled with contrast mass. The ratio of the length of the filled part of the intestine to the total length was expressed in%.

The inventive tool for animals was administered iv in doses of 5 and 50 mg / kg The control was an intact group of animals. The effect of the drug was judged by the difference in the promotion of coal suspension in the intestines of animals in the experimental and control groups. According to the results of different series of the experiment, in intact animals, coal suspension is promoted on average by 40% of the intestinal length (Table 6). The inventive tool (doses of 5 and 50 mg / kg) does not have a statistically significant effect on this indicator.

Table 6 The effect of the claimed funds (1) on intestinal motility in experiments on mice when exposed to butorphanol Experimental groups Dose mg / kg Bowel length, cm Promotion of coal suspension, cm % After 1 h The control - 58.3 ± 1.58 23.2 ± 1.22 40 (one) 5 59.3 ± 1.65 27.0 ± 1.46 46 fifty 58.2 ± 0.75 26.2 ± 1.78 45 Butorphanol 10 60.2 ± 1.30 14.4 ± 0.54 * 24 Butorphanol + (1) 5 59.3 ± 1.24 25.4 ± 1.33 43 fifty 55.0 ± 1.15 24.5 ± 1.26 45 14 days The control - 59.7 ± 1.09 25.7 ± 1.36 43 Butorphanol 10 57.2 ± 0.97 12.0 ± 1.14 * 21 Butorphanol + (1) 5 58.6 ± 1.12 22.3 ± 1.62 38 fifty 59.5 ± 1.55 20.0 ± 1.47 37 21 days The control - 58.5 ± 2.08 23.2 ± 2.10 39 Butorphanol 10 59.3 ± 1.14 15.4 ± 0.88 * 26 Butorphanol + (1) 5 59.2 ± 0.48 21.9 ± 0.90 37 fifty 59.3 ± 1.62 24.3 ± 1.17 41 * - statistically significant difference with the control group (n = 6 in all experimental groups)

The use of butorphanol at a dose of 10 mg / kg leads to a weakening of peristaltic contractions - in experimental animals the passage of 21-26% of the length of the intestine is recorded.

The inventive tool in this model has a pronounced and lasting antagonistic effect with respect to the effects of butorphanol morphinan: no statistically significant changes from intact animals were recorded in groups of mice that received the study drug.

Example 8. The use of the claimed means and method of treating pain of various etiologies

A study on the safety and pharmacokinetics of the claimed drug was conducted on 32 healthy volunteers who signed an informed consent. The results of a clinical study showed that the claimed drug in all the studied doses (10 mg, 20 mg and 60 mg per day) is absolutely safe. Next, a clinical study was conducted of the pharmacological activity of the drug in patients with pain syndrome of various origins. The studied dose and course were prescribed depending on the pathogenesis and etiology of the disease.

20 patients who had previously signed the informed consent form with a diagnosis of radiculopathy, discopathy took part in a study of the effectiveness of the claimed drug at a dose of 10 mg per day in terms of the active substance - comenic acid. To achieve an analgesic effect, patients received an intravenous injection of the drug daily. The effectiveness of analgesia was evaluated on a visually analogue scale (VAS). Before treatment, the patient assessed the severity of pain on a 10-point scale. He was further asked to evaluate the strength of the pain syndrome in points 10 minutes after the injection. It was proposed to evaluate the duration of analgesia. The results of the study showed that the effectiveness of the drug is more pronounced in the presence of severe pain. If the patient before the injection evaluated the pain syndrome by YOUR by 10 points, then after taking the drug only by 5. The effect persisted for 8-10 hours. Further administration of the drug reduced the severity of the pain syndrome until it was completely eliminated after 5 injections. In parallel, the restoration of the neurological status of patients, a decrease in the inflammatory response were observed.

20 patients who had previously signed an informed consent form with postoperative pain syndrome received injections of the claimed drug at a dose of 20 mg per day in terms of the active substance - comenic acid. The intensity of the pain response was evaluated according to YOUR, with a maximum of 10 points. As in the first case, the maximum analgesic effect was observed in patients with more severe pain syndrome. In the first day after the injection, the pain syndrome decreased by 40-50%. From 10 to 6-5 points according to YOUR, respectively. The effect of analgesia was stably maintained for 8-10 hours. A good combination of the claimed drug with antibiotics, a rapid decrease in the inflammatory response at the site of surgery was noted. Depending on the type of surgical intervention, a course of 7-10 injections of the drug was required to stop the pain syndrome. The severity of pain decreased most clearly in the first three days of therapy. Phenomena of addiction and dependence and negative side effects were not observed.

2 patients, operated on for oncological pathology of the reproductive organs, were administered the claimed drug once a day intravenously at a dose of 60 mg in terms of the active substance - comenic acid. Both patients received a serious course of drug treatment for the underlying disease, which was accompanied by pathology from the liver and kidneys. Tramadol was not possible due to individual intolerance. A single evening injection of the claimed drug allowed patients to improve the quality of life. No adverse reactions to the drug were observed. The analgesic effect was accompanied by mild antidepressant and sedative effects. During the night, repeated injections were not required. According to preclinical studies, the drug showed mild tranquilizing and antidepressant properties when taken against a background of emotional stress. There was no need to increase the dose of the drug to achieve an analgesic effect for 30 days.

Intravenously, the patient is administered the claimed analgesic in a dose of up to 350 mg (in terms of comenic acid) per day for 5-30 days, mainly in the form of a 1% or 2% solution for 7-10 days. The duration of the course of treatment and the dose of the drug depend on the severity of the pain syndrome, the condition of the patient, the main diagnosis and concomitant diseases.

The introduction of the claimed analgesic agent in a dose greater than 350 mg per day (5 mg / kg with an average weight of 70 kg) (in terms of the active substance - comenic acid) is impractical, since the analgesic effect does not increase.

According to preclinical studies, the drug restores the activity of the respiratory center after poisoning by opiates, the latter allows us to recommend the claimed drug for use in resuscitation in cases of poisoning with opiates or overdose.

The implementation of the claimed invention is not limited to the above examples.

Thus, the experimental results shown in the examples indicate the following advantages of the claimed tool in comparison with the known analogues and prototype (tramadol). The inventive tool has a pronounced analgesic effect, selectively blocking the slow sodium channels responsible for encoding the nociceptive signal, triggers the membrane signaling mechanism, which includes Na / K-ATPase as a signal transducer. The mechanism of action of the claimed funds is fundamentally different from the known analogues. The inventive tool can be used to relieve pain of various etiologies, it does not cause dependence and addiction, intoxication, because A method of stopping the pain syndrome is implemented, in which a subtle selective effect on the activation portal device of tetrodotoxin-resistant sodium channels occurs due to activation of the receptor-mediated signaling pathway, in which the sodium pump plays the role of signal transducer.

Going beyond the stated interval parameters in the lower boundary makes it impossible to implement the invention, in the upper boundary it is impractical, because does not increase analgesic activity.

Claims (4)

1. An analgesic agent, which is an aqueous solution of the active principle - comenic acid, impurities of comenic acid - benzylcomenic acid, excipients - sodium bicarbonate in the following ratio of components:
comenic acid 1-2 sodium bicarbonate 0.55-1.1 benzylcomenic acid up to 0.025 water for injections up to 100 2. The analgesic agent according to claim 1, characterized in that it mainly contains 1 or 2 wt.% Comenic acid. 3. A method of treating pain syndrome of various etiologies, which consists in the fact that the patient is intravenously administered an analgesic agent according to claims 1 and 2 at a dose of up to 350 mg (in terms of comenic acid) per day for 5-30 days. 4. A method of treating a pain syndrome of various etiologies according to claim 3, characterized in that the patient is intravenously administered an analgesic agent according to claims 1 and 2, mainly in the form of a 1% or 2% solution for 7-10 days.