RU2411944C1 - Immunometabolic anthelmintic medication - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to immunometabolic anthelmintic drug. Immunometabolic anthelmintic drug, including levamisole, succinic acid and water, taken in specified ratio.

EFFECT: medication possesses efficient immunometabolic, hepatoprotecting and anti-nematode action, without toxic effect.

5 tbl, 4 ex

Description

The invention relates to veterinary medicine, in particular, to veterinary immunology, helminthology and hepatology.

Currently acquired immunodeficiencies and metabolic disorders are the most urgent problems of veterinary and humane medicine. These pathologies are closely related and are often caused by toxicosis of alimentary, infectious and invasive origin.

Recently, an intensive search has been carried out for means to stimulate the immune system and metabolic processes in different genesis of pathophysiological conditions. These are, as a rule, complex preparations.

The objective of the present invention is to develop a comprehensive drug with immunometabolic and anti-nematological effects, the introduction of which would cause a systemic therapeutic effect, aimed at normalizing metabolic and immune processes, as well as hepatoprotective and anthelmintic activity.

As the closest analogue, we took a comprehensive preparation for the treatment of animal hepatosis (RF patent No. 2200547, 2003). This preparation contains the amino acid L-arginine, sodium nucleinate and Hanks solution. The drug has a pronounced immunostimulating effect on the T-system of immunity and ensures the restoration of reparative processes in the liver with invasive hepatosis. However, the drug does not have anthelmintic activity and is not effective enough for toxicosis and hepatosis.

An anthelmintic complex preparation against animal nematodoses was taken as a prototype (RF patent No. 2200548, 2003). This drug includes anthelmintic nilverm (based on levamisole), sodium nucleinate - immunomodulator, amino acid L-arginine and, as a solvent, Hanks solution.

This drug provides high anthelmintic activity. However, according to observations, it is not effective enough for toxicosis, hepatosis and has a side effect on the animal organism.

Succinic acid was included in the composition of the claimed preparation to enhance hepatoprotective activity.

Succinic acid (UC) is a powerful stimulator of the metabolism of living cells. The object of its action is cells and tissues that are in a state of excitement or pathologically altered. In almost all pathophysiological conditions, UC and its salts give an atypically high therapeutic effect. A positive effect of UC on the body is found at relatively low doses - 0.5-1 mg / kg body weight.

Currently, UC is actively used to obtain drugs with improved pharmacological properties in the clinic for the surgical treatment of toxicosis and hepatitis of various origins.

As an anthelmintic and immunomodulator, levamisole is included in the complex preparation.

Levamisole is a highly effective anthelmintic and immunomodulator mainly of the cellular immune system. However, it has a pronounced side effect, mainly convulsive, on the body, and therefore it is reluctant to use it in the clinic for treating sick animals.

The proposed immunometabolic anti-nematode drug contains levamisole as an anthelmintic and immunostimulant, and succinic acid at pH 4-4.5 as a metabolite, while the components included in it are taken in the following ratio, wt.%:

Levamisole - 7.5

Succinic acid - 1.0

Water - Else

Received a complex preparation by adding to the standard solution of levamisole (75 mg / ml - the active substance), succinic acid powder - 10 mg / ml. When heated to 38-40 ° C and constant stirring, succinic acid was dissolved without changing the physicochemical properties of the standard solution. By adding a 10% sodium hydroxide solution, the pH was adjusted to an initial value of 4-4.5. The resulting preparation was packaged in 50.0 ml vials and sterilized by autoclaving in a 1-1.1 atm mode. for 20 minutes. Autoclaving sterilization did not change the physicochemical and anthelmintic properties of the complex preparation.

The resulting complex immunometabolic preparation is a clear, colorless sterile solution. The qualitative and quantitative composition of the proposed drug, in comparison with the standard solution of levamisole and the prototype, can significantly reduce the toxicity of the anthelmintic - the immunostimulant levamisole, provide a high hepatoprotective, immunometabolic and anti-nematous effect. The qualitative and quantitative composition of the proposed drug provides a synergistic effect, as illustrated by examples of its experimental testing.

Using a standard solution of levamisole with an activity of 75 mg / ml, succinic acid was introduced into its composition in the amount of 10, 20 and 30 mg / ml. After that, experimental solutions were prepared with a concentration of 5, 7.5 and 10.0 maximum therapeutic doses for mice weighing 20 g. Similarly, dilutions of levamisole without succinic acid were prepared (control).

Example 1. Evaluation of anticonvulsant and lethal effects. The experiments were carried out on white mice weighing 19-21 g. In the first series of experiments, the experimental group of mice (n = 5) was injected intraperitoneally in a volume of 0.25 ml with the complex composition of levamisole with succinic acid, the control group of mice (n = 5) similarly introduced a standard solution levamisole in a volume of 0, 24 ml. After 2-3 minutes, vigorous seizures were observed in all control mice. All control mice died within 3-5 minutes after administration of levamisole. On the contrary, in mice of the experimental group, the development of seizures and death of mice was observed after 10-15 minutes.

Almost the same data were obtained on groups of mice that were injected with a solution of levamisole with activity of 7.5 and 5 therapeutic doses. The results of a comparative test of the complex composition of levamisole with succinic acid and a standard solution of levamisole are presented in table 1.

Thus, the introduction of 1% succinic acid into the standard solution of levamisole provided a pronounced decrease in anticonvulsant activity. It should be noted that in a series of experiments on white mice, the inclusion of 20 and 30 mg / ml of succinic acid in the standard solution of levamisole did not provide an improvement in the pharmacological properties of the drug. Thus, the inclusion in the composition of a standard solution of levamisole UC in an amount of 1% (10 mg / ml) is the most rational, allowing for a pronounced effect of reducing the toxicity of levamisole.

Example 2. The study of the immunostimulating and metabolic effects of the complex drug was carried out on pigs-hypotrophy 25-30 days of age. The experimental group of piglets (n = 5) was intramuscularly injected with a complex preparation (levamisole + UC) in a volume of 1.0 ml. The control group (n = 5) was similarly injected with a standard solution of levamisole. After 10-15 minutes, all piglets in the control group showed marked signs of nervous excitement, vomiting and vomiting. Signs of arousal appeared within an hour. Pigs of the experimental group well tolerated the injection of the drug. Side effects are not marked.

Control studies of the effect of drugs on the immunobiochemical status of piglets were carried out on days 5 and 14. The results of immunobiochemical studies are presented in table 2.

Example 3. A study of the hepatoprotective activity of the proposed complex preparation was carried out on cows during the period of registration of biochemical disorders characteristic of hepatitis. As a comparison, a standard solution of levamisole and an experimental sample of a preparation prepared as described in the invention No. 2200547 (a preparation for treating animal hepatosis) were used.

According to the results of biochemical and clinical studies, 20 cows with a symptom complex of hepatodystrophy were selected, of which 4 experimental groups were formed, 5 animals each. The cows of the first group were injected intramuscularly with levamisole + UC once in a volume of 10 ml; animals of the second group - in the same volume of levamisole, cows of the third group - a drug for the treatment of hepatosis (analog), cows of the fourth group - saline - 10.0 ml.

Table 3 Comparative evaluation of the effect of the complex drug levamisole + succinic acid, levamisole and the drug for the treatment of hepatosis on some biochemical parameters of blood of cows with hepatosis indicators preparations levamisole + UC levamisole hepatosis drug saline Protein, g / l before introduction 9.75 ± 0.53 9.52 ± 0.84 9.28 ± 1.22 9.27 ± 0.48 in 7 days 8.12 ± 0.75 9.96 ± 1.12 8.74 ± 0.82 9.15 ± 0.62 after 14 days 8.10 ± 0.84 9.84 ± 0.64 8.96 ± 1.15 9.28 ± 0.56 Reserve alkalinity, mg% before introduction 32.62 ± 7.14 33.63 ± 5.72 32.28 ± 6.14 38.74 ± 6.21 in 7 days 49.32 ± 5.41 32.92 ± 6.14 39.12 ± 5.38 39.62 ± 7.14 after 14 days 46.23 ± 4.35 31.78 ± 5.46 36.21 ± 4.68 37.39 ± 5.12 Ketone bodies, mg% before introduction 15.22 ± 1.75 14.37 ± 2.14 15.63 ± 1.24 14.38 ± 1.76 in 7 days 7.45 ± 1.52 15.14 ± 1.28 10.46 ± 1.32 14.52 ± 1.84 after 14 days 8.14 ± 2.37 15.26 ± 1.36 13.64 ± 1.56 14.75 ± 1.82 Calcium, mg% before introduction 7.52 ± 0.36 7.48 ± 0.32 7.22 ± 0.54 7.17 ± 0.22 in 7 days 9.88 ± 0.14 7.44 ± 0.27 7.36 ± 0.22 7.19 ± 0.17 after 14 days 9.54 ± 0.28 7.32 ± 0.18 7.26 ± 0.31 7.14 ± 0.36 Phosphorus, mg% before introduction 7.46 ± 0.52 7.35 ± 0.68 7.28 ± 0.44 7.52 ± 0.22 in 7 days 5.34 ± 0.48 7.42 ± 0.36 7.25 ± 0.37 7.49 ± 0.48 after 14 days 5.32 ± 0.76 7.84 ± 0.22 7.37 ± 0.23 7.48 ± 0.56 Total lipids, g / l before introduction 2.34 ± 0.12 2.36 ± 0.04 2,52 ± 0,06 2.68 ± 0.08 in 7 days 4.48 ± 0.10 2.33 ± 0.06 3.88 ± 0.05 2.46 ± 0.07 after 14 days 4.29 ± 0.08 2.35 ± 0.07 3.62 ± 0.04 2.45 ± 0.04 Cholesterol, mol / l before introduction 1.48 ± 0.12 1.52 ± 0.10 1.46 ± 0.15 1.52 ± 0.14 in 7 days 3.06 ± 0.14 1.44 ± 0.06 2.85 ± 0.22 1.48 ± 0.16 after 14 days 3.02 ± 0.18 1.45 ± 0.11 2.78 ± 0.18 1.52 ± 0.12 Glucose, mg% before introduction 32.36 ± 5.18 32.48 ± 6.02 34.27 ± 5.94 34.26 ± 5.07 in 7 days 48.54 ± 4.37 31.74 ± 5.96 39.82 ± 5.78 35.18 ± 4.76 after 14 days 46.28 ± 4.29 32.12 ± 5.48 40.15 ± 4.84 35.22 ± 5.84

Thus, the use of levamisole + UC had a more pronounced increase in the functional activity of the liver, which led to: - a decrease in the level of cotonic bodies (elimination of ketosis); - increase in reserve alkalinity (elimination of acidosis); - normalization of the content of calcium and phosphorus (transfer of antagonistic to the synergistic interaction of trace elements); - normalization of protein metabolism and stimulation of carbohydrate metabolism.

Normalization of biochemical parameters had a positive effect on the clinical status of animals (pain on palpation of the liver disappeared, appetite improved and milk production increased).

Example 4. The study of anthelmintic activity. The experiment was conducted on pigs of 2-2.5 months of age, spontaneously infested with roundworms and trichocephalus. From experimental piglets, three experimental groups were formed. The animals of the first group were injected intramuscularly with the proposed drug at a dose of 1 ml per 10 kg of body weight (this dose is recommended for the standard solution of levamisole). Piglets of the second group were injected with a standard solution of levamisole in a similar dose. The animals of the third group used an anthelmintic drug based on nilverm (levamisole), made according to the description of the invention No. 2200548 (prototype).

During clinical observation of experimental animals, it was found that in response to the introduction of a standard solution of levamisole, after 20-30 minutes, all animals began to manifest pronounced symptoms of nervous excitement and vomiting. In piglets of 3 groups, which were administered an anthelmintic drug (prototype), signs of arousal were also noted, and in some, vomiting was also noted. Piglets of the first group showed no signs of arousal. This testified to the fact that the inclusion of UC in the composition of the drug made it possible to expressly reduce the toxic effect of levamisole on the nervous system of animals.

Evaluation of anthelmintic activity was carried out according to the results of a coprological study on the 18th day after the administration of drugs, the results of which are shown in tables 4 and 5.

Thus, based on the experimental studies, it follows that a complex preparation based on the anthelmintic-immunomodulator levamisole and succinic acid metabolism clearly reduces the toxic effect on animals and provides a higher immunometabolic, hepatoprotective, anthelmintic activity with respect to the standard solution of levamisole, an analogue and prototype. Parenteral administration at a dose of 1 ml per 10 kg of animal body weight is recommended.

Claims (1)

Immunometabolic anthelmintic drug, including immunomodulator anthelmintic levamisole, succinic acid and water in the following ratio, wt.%:
levamisole 7.5 succinic acid 1,0 water rest,
while the drug is administered parenterally, at a dose of 1 ml per 10 kg of animal weight.