Anti-inflammatory

 

(57) Abstract:

The invention relates to medicine, namely to the use of new anti-inflammatory drugs from the class alkanolammonium salts hetarylthioacyl acids, specifically to indolyl-3-diacetate Tris/2-hydroxyethyl/ammonium. The substance has a high anti-inflammatory activity in acute aseptic inflammation and can be used in drug therapy for traumatic tissue damage, myocardial infarction in the postoperative period. 5 Il.

The invention relates to a new anti-inflammatory agent, representing Tris/2-hydroxyethyl/ammonium salt of 3-IntelliTouch acid, which can be used in medicine for treatment of inflammation in acute aseptic inflammation.

Anti-inflammatory properties of Tris/2-hydroxyethyl/ammonium salt of 3-IntelliTouch acid are not described in literature.

Currently used in clinical practice a wide range of anti-inflammatory drugs with different mechanisms of action. One of the most powerful anti-inflammatory drugs are considered glucocorticoid hormones. Their protivovospalitiona reduce vascular permeability, phagocytic activity of neutrophils and macrophages and inhibit all processes of reparative phase: the growth and division of fibroblasts, collagen synthesis, neovascularization and scarring. These effects of glucocorticoid hormones restrict their scope only aseptic inflammatory and only in that case if you want to suppress the process of scarring. For example, glucocorticoids are widely used in eye diseases, bursitis, or inflammation of the joints, etc., Despite a pronounced anti-inflammatory steroid drugs cannot be considered as optimal anti-inflammatory drugs, since their use is accompanied by a significant number of side effects and complications.

Of non-steroidal drugs that have anti-inflammatory effect, the most widely used indometacin, acetylsalicylic acid and other actions aimed at the suppression of prostaglandin synthetase. However, these drugs have side effects, caused by disturbance of the synthesis of prostaglandins in the body, causing damage to the gastric mucosa, gastric bleeding, exacerbation of chronic diseases of the stomach and intestines. In addition, Inga is The closest anti-inflammatory action and structure to the claimed drug is indomethacin /derived indole/, which we have chosen as a prototype. Indometacin highly effective drug and is widely used in clinical practice, however, noted a number of shortcomings: the drug is highly toxic, causes allergic reactions and dizziness, while long-term treatment it is observed damage of the gastric mucosa, gastric bleeding, exacerbation of chronic diseases of the stomach and intestines, etc. because the product is aimed at suppressing prostaglandines. In addition, this drug is not soluble in water, difficult to access, is not produced in Russia.

The aim of the invention is the creation of a drug having anti-inflammatory activity at a low dose, non-toxic to warm-blooded animals, water-soluble, which is aimed at optimizing the inflammatory process.

This goal is achieved by a new anti-inflammatory agent, representing Tris/2-hydroxyethyl/ammonium salt of 3-IntelliTouch acid, internal cipher VM-2-84.

Anti-inflammatory properties are not described in literature.

Tris/2-hydroxyethyl/ammonium salt of 3-IntelliTouch acid obtained 0oC and a 1:1 ratio when heated for 5 min according to the scheme:

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Connection VM-2-84 is a yellow color crystalline substance, with a weak odor, infinitely soluble in water, alcohol, aqueous acetone and dioxane, insoluble in ether and hydrocarbons. The composition and structure of its proven method of IR spectroscopy, elemental analysis. In the IR spectrum of VM-2-84 contains absorption bands in the region 1610/COO-/, 3220/NH hetaryl/, 3300 / / 2990/CH alkyl/, 3430/OH/ cm-1.

A method of producing a drug based on available industrial raw materials: large-capacity product triethanolamine and available indolyl-3-teoksessa acid. It is simple to implement, does not require the use of catalysts, special equipment, expensive and scarce solvents, selection of target products is carried out by known methods with a high output.

Study of anti-inflammatory activity of Tris/2-hydroxyethyl/ammonium salt of 3-IntelliTouch acid.

Testing anti-inflammatory activity conducted on 100 white rats-males. Aseptic inflammation modeled by the introduction into the skin of the lower leg sterile celloidin plates standard size animal for each time of observation. The dynamics of inflammation were studied in histological preparations stained with hemotoxin-eosin. In inflammation measured the thickness of the cell shaft around the foreign body, calculated density of cells /number of cells per 1000 µm2/, as well as the number of layers of fibroblast fibroblast capsule. In the peripheral area of inflammation was calculated the number of undifferentiated fibroblast 5000 μm2reflecting from proliferative activity. In preparations stained with pikrofusin by van gieson, morphometric /using an ocular grid was determined by the amount of collagen in fibroblast capsule /gg of Avtandil. Medical morphometry. M. 1990/. The research results are statistically processed and presented in the form of a test report and graphs.

In Fig. 1 shows the dynamics of the concentration of cellular elements in the cell shaft and the number of layers of fibroblast in the capsule in the control group, where 1 is the concentration of neutrophils, 2 the concentration of macrophages, 3 the concentration of fibroblast, 4 the number of layers of fibroblast in the capsule of Fig. 2 the dynamics of the density of cells in the cell shaft in the development of aseptic inflammation, occurring against the background of the introduction of VM-2-84 in the dose of 10 mg/kg; about the infusion of BM-2-84 at a dose of 2 mg/kg; in Fig. 4 - the dynamics of the concentration of undifferentiated fibroblast in the peripheral zone of inflammation in the control group animals /1/, in the conditions of introduction VM-2-84 at a dose of 2 mg/kg /2/ and 10 mg/kg /3/ of Fig. 5 trends in the number of collagen and fibroblast in fibroblastic capsule in the control and experimental groups of animals.

The effect of the substance VM-2-84 depends on the dose. With the introduction of money in the dose of 10 and 2 mg/kg every 2 h after the onset of inflammation marked anti-inflammatory effect. In the dose of 2 mg/kg anti-inflammatory action of the claimed compounds aimed at optimizing the course of the inflammatory process, which is manifested in the following:

reducing the intensity of leukocyte infiltration, means at a dose of 2 mg/kg limits the alteration of tissue in inflammation caused by proteolytic enzymes and peroxide radicals, sekretiruemyi by leukocytes;

keeping the phagocytic activity of neutrophils and macrophages at a high level, makes it possible phagocytosis of debris smaller number of phagocytes;

suppressing proliferative processes that hinder the transition of acute inflammation in the chronic form;

stimulating the differentiation of fibroblast and kleemola compounds at a dose of 2 mg/kg is the limit of the acute phase and stimulation of reparative process.

At a higher dose of 10 mg/kg single administration of the drug after 2 h after the onset of inflammation anti-inflammatory effect of VM-2-84 is expressed in a significant suppression of all cellular reactions of the inflammatory process, including a decrease in phagocytic activity of neutrophils and macrophages and the inhibition of the process of fibrosis and is complicated by the excessive redness of inflammation with impaired integrity of the microvascular bed.

Side processes using substances VM-2-84 at a dose of 2-10 mg/kg were found.

Thus, the claimed substance VM-2-84 has a pronounced anti-inflammatory action, aimed at the optimization of the inflammatory process, and has a wider scope, because in a dose of 2 mg/kg did not reduce the phagocytic activity of cells, but reduces the intensity of the acute phase, did not inhibit the reparative phase, but rather stimulates it.

The study of toxicity. Carried out on outbred white mice weighing 20-22 g intraperitoneal, reg. 3. the introduction of the drug. Studied resorptive action of the drug and chronic toxicity. Intraperitoneal injection LD503000 mg/kg, with the introduction through the mouth LD504466 /3937-5001/ mg/kg. m drug use VM-2-84 for 5 months.at doses of 40 and 70 mg/kg noted certain changes in the tissues of the heart, liver, lungs, kidneys, which are less noticeable in the structures of the cerebral cortex and spleen of mice when compared to control.

In the chronic experience with the drug in a dose of 10 mg/kg not detected abnormalities in the tissues of animals.

Thus, the claimed connection refers to practically non-toxic substances.

The data obtained indicate that it is possible to consider the claimed connection is promising for the creation of drugs anti-inflammatory agents for the treatment of traumatic tissue damage, myocardial infarction and other aseptic inflammations.

Anti-inflammatory agent, characterized in that it is a Tris(2-hydroxyethyl)ammonium salt of 3-IntelliTouch acid.

 

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