RU2571543C1 - Drugs for treatment of helminthiasis of animals - Google Patents

Abstract

FIELD: veterinary medicine.

SUBSTANCE: drug for treatment of helminthiasis of animals comprises albendazole sulphoxide, butafosfan and water for injections with the following mass ratio of components, %: albendazole sulphoxide (n-[6-(propan-1-sulphinyl)-1H-1,3-benzodiazole-2-yl] methoxy carboximide acid) 5.0-10.0; butafosfan (1-butylamino-1-methyl) ethylphosphonic acid) 10.0-20.0; water for injections - the rest.

EFFECT: enhanced therapeutic efficacy in treatment of helminthic invasion while reduction of side effects and reduction of the drug toxicity.

7 tbl, 5 ex

Description

FIELD OF THE INVENTION

The invention relates to veterinary medicine, in particular to preparations for the treatment of animal helminthiases.

State of the art

A number of drugs have been developed for the prevention and treatment of parasitic diseases caused by nematodes, cestodes, and trematodes. The drugs based on benzimidazole carbamate derivatives are widely known: thiabendazole, mebendazole, flubendazole, oxfendazole, oxybendazole, cambendazole, fluorobendazole, albendazole, ricobendazole and fenbendazoline Venetinolum (1982). pp. 250-292; U.S. Patent No. 5,538,990, A61K 31/415, 1996).

The most deeply and comprehensively studied albendazole (Demidov N.V. Anthelmintics in veterinary medicine. M: Kolos, 1982, S. 279-283; German patent N 3315607, A61K 31/415, 1983).

Numerous clinical trials have confirmed the high efficacy and good tolerance of albendazole (NI Tumolskaya and others. New drugs: No. 4/2003). The drug causes the death of nematodes, cestodes and trematodes (only during the mature stage). In doses active against trematodes, it has an embryotoxic effect. Albendazole is a colorless crystal with _mp = 208-210 ° C, insoluble in water, soluble in dimethyl sulfoxide and dimethylformamide. Its main advantage is that it acts on helminths that are resistant to many other drugs. In mammals, albendazole is rapidly converted in the liver to an active metabolite - sulfoxide (known as ricobendazole) and sulfone (an inactive metabolite); moreover, sulfoxide exists in two enantiomeric forms and their ratio is different in different animals. When administered orally, albendazole is not completely absorbed (about 50%) and, after being converted into active metabolites, passively diffuses into the gastrointestinal tract. As a rule, albendazole has a better effect on the helminths of the gastrointestinal tract than in other places of localization (V.A. Sidorkin Terrible weapon against helminths // Veterinary of the Volga region. - 2002, No. 1).

Albendazole-based antiparasitic drugs are known, such as alvet, Alben C, valbazen, browalsen, atazole, vermitan 20% granulate, clozalbene, albendazole ultra 10%.

The closest in technical essence is the drug Alvet suspension, containing as an active substance albendazole 25 or 100 mg per 1 ml (2.5 or 10%, respectively), thickeners, preservatives and water. This drug is a wide spectrum of activity, is active against adults and larvae of nematodes, trematodes, as well as imago cestodes. The mechanism of action of the drug is to disrupt the processes of glucose transport, microtubular function and reduce the activity of fumarate reductase in helminths, which leads to their death. Alvet suspension, when administered orally, is absorbed in the gastrointestinal tract and penetrates into organs and tissues; it is rapidly excreted from the body mainly with urine and feces. The drug belongs to low toxicity for warm-blooded animals: LD ₅₀ when orally administered to white mice is more than 3000 mg / kg, at recommended doses it is well tolerated by animals, does not have hepatotoxic and sensitizing effects. (Sidorkin V.A., Nefedova N.S., Panfilova M.N. Experience in the use of alveta suspension for the treatment of feline helminthiases // Russian Parasitological Journal. - 2013. - No. 1. - P. 92-94).

The disadvantage of this drug is the relatively narrow scope, due to the inability to conduct complex therapy of complications on the background of helminth infections, as well as the oral route of administration of the drug.

During parasitization, helminths have a negative effect on the host organism. In the body of nonspecific hosts, including humans, animals, and birds, the nematode larvae undergo somatic migration and cause pathological changes along the migration and localization pathway that are characteristic of larva migrans syndrome. More often, helminth larvae enter the liver and lungs, but can affect the tissues of the eyes, muscles, and brain, causing inflammatory and allergic reactions. Some larvae are destroyed, others are repeatedly activated and move throughout the body. (Esaulova N.V. Helminthiases of dogs and cats, dangerous for humans, and their diagnosis // Veterinary medicine, 2000. - No. 6. - P. 22-29. Tokmalaev A.K. Clinical parasitology: protozoa and helminthiases / A.K. Tokmalev, G. M. Kozhevnikova. - M.: Medical News Agency, 2009. - 432 p.). It is also known that helminths also have an immunosuppressive effect on the host organism, and the use of anthelmintics in most cases synergizes their negative effect on non-specific resistance factors, thereby increasing the risk of re-invasion of animals, possibly with a higher intensity. (Daugalieva E.X., Filippov V.V. Immune status and ways of its correction in case of helminthiases of farm animals. - M.: Agropromizdat, 1991. - 188 p .; Yakubovsky M.V., Chistenko G.N., Gorbacheva V .N., Vedenkov A.L. Modern problems of the immunology of helminthiases // Medical News. - 1997. - No. 4. - P. 11-15.)

Disclosure of invention

The objective of the invention is to develop a new dosage form of albendazole, with the possibility of complex specific effects on helminths and concomitant helminth infections, side effects and diseases, as well as low toxicity and high therapeutic efficacy.

The technical result is an increase in therapeutic efficacy due to the complex effect on helminths and concomitant helminth infections, side effects and diseases, reduction of toxicity of the drug.

The specified technical result is achieved by the fact that the preparation for the treatment of animal helminthiases contains,%: albendazole sulfoxide (n- [6- (propan-1-sulfinyl) -1H-1,3-benzodiazol-2-yl] methoxycarboxylic acid) - 5, 0-10.0; butafosfan (1-butylamino-1-methyl) ethylphosphonic acid - 10.0-20.0; water for injection - the rest.

The complex drug, having high anthelmintic effectiveness, normalizes metabolic processes, has a stimulating effect on protein, carbohydrate and fat metabolism, increases the body's resistance to adverse environmental factors, promotes the growth and development of animals. Butafosfan is an organic phosphorus compound that affects many assimilation processes in the body. Butafosfan improves the utilization of glucose in the blood, which helps to stimulate energy metabolism; accelerates metabolic processes due to stimulation of the ADP - ATP cycle; activates all functions of the liver; increases nonspecific resistance of the body; stimulates smooth muscles and increases its motor activity; restores the myocardium; stimulates the formation of bone tissue; normalizes the level of cortisol in the blood; It stimulates protein synthesis, accelerating the growth and development of the animal, as well as the reparative properties of organs and tissues. Organic phosphorus compounds do not accumulate in the body and do not have the side effects characteristic of stimulants and inorganic phosphorus. The therapeutic dose of the drug is in the range of 50-500 mg per dog, depending on live weight (http://www.animalhealth.bayerhealthcare.com).

The implementation of the invention

Albendazole sulfoxide (n- [6- (propan-1-sulfinyl) -1H-1,3-benzodiazol-2-yl] methoxycarboxylic acid) is obtained by oxidation from albendazole [5- (propylthio) -1H-benzimidazol-2-yl] carbamic acid methyl ester in the presence of dibenzoyl peroxide. The resulting compound is water soluble. Butaphosphane was used to stabilize albendazole sulfoxide. Butafosfan is an organic compound that is suitable as a stimulant of metabolism and a tonic, in particular for farm and domestic animals. The drug is obtained by the fact that these components are dissolved in water for injection in certain proportions.

Examples of specific preparation

To select the optimal ratio of active substances in the preparation, 4 dosage forms with different contents were used

active substances,%.

Example 1. Albendazole sulfoxide (n- [6- (propan-1-sulfinyl) -1H-1,3-benzodiazol-2-yl] methoxycarboxylic acid) - 2.0; butafosfan (1-butylamino-1-methyl) ethylphosphonic acid - 5.0; water for injection - the rest.

Example 2. Albendazole sulfoxide (n-6- (propan-1-sulfinyl) -1H-1,3-benzodiazol-2-yl] methoxycarboxylic acid) - 5.0; butafosfan (1-butylamino-1-methyl) ethylphosphonic acid - 10.0; water for injection - the rest.

Example 3. Albendazole sulfoxide (n- [6- (propan-1-sulfinyl) -1H-1,3-benzodiazol-2-yl] methoxycarboxylic acid) - 10.0; butafosfan (1-butylamino-1-methyl) ethylphosphonic acid - 20.0; water for injection - the rest.

Example 4. Albendazole sulfoxide (n- [6- (propan-1-sulfinyl) -1H-1,3-benzodiazol-2-yl] methoxycarboxylic acid) - 15.0; butafosfan (1-butylamino-1-methyl) ethylphosphonic acid - 30.0; water for injection - the rest.

In the experiment used 20 clinically healthy white mice, divided into 4 groups. The animals of the first group were administered dosage form No. 1, the second group No. 2, the third - No. 3 and the fourth No. 4, respectively. Prior to administration and after 10 days, the mass of mice was measured and blood was collected for hematological studies (Table 1).

From the data of table 1 it is seen that the indicators of live weight, the number of red blood cells and hemoglobin in groups 2 and 3 10 days after the administration of dosage forms have a moderate increase, and in groups 1 and 4 they remain without visible changes. The indicators of the number of leukocytes in 1, 2, 3 groups before and after administration fluctuate within the reference values, while in group 4 a slight increase is noticeable.

Thus, the optimal ratio of active substances correspond to 2 and 3 dosage forms. Therefore, these concentrations are taken as a basis: Albendazole sulfoxide (n- [6- (propan-1-sulfinyl) -1H-1,3-benzodiazol-2-yl] methoxycarboxylic acid) - 5.0-10.0; butafosfan (1-butylamino-1-methyl) ethylphosphonic acid - 10.0-20.0; water for injection - the rest.

Examples of a specific test of the drug for the treatment of animal helminthiasis.

Example 1

To determine the indicators of acute toxicity, the studied drug was administered to mice of both sexes intragastrically at doses from 200 mg / kg to 7480.1 mg / kg for the active substance (table 2).

Below are data on the effect of the drug on the body weight of experimental animals (table 3).

As can be seen from the data in table 2, animals from the experimental groups gained weight during the entire observation period. Differences in weight gain compared with the control group were not detected.

As a result of studying the acute toxicity of the drug, it was found that in the acute experiment, with the intragastric administration of the studied drug in doses up to 1170.9 mg / kg, lethal effects were not achieved. The general condition and behavior of animals were normal and did not differ from those in animals from the control groups.

The results of the study of acute toxicity make it possible to classify the drug as class IV — low-hazard substances (GOST 12.1.007-76).

Example 2

The effect of the drug on the hematological parameters of white mice (table 4).

When analyzing the data obtained, no negative effect of the drug on the main hematological parameters was established. The hemoglobin concentration, the number of red blood cells, the color index, and the erythrocyte sedimentation rate in the groups that received the drug in a therapeutic and tenfold increased dose did not have statistically significant differences with the animals of the control group.

Example 3

The effect of the drug on biochemical blood parameters. The study of the main biochemical parameters of blood serum did not reveal negative changes under the action of the drug on liver, kidney, protein metabolism and enzyme activity (table 5).

Example 4

The aim of the test was to determine the therapeutic dose and anthelmintic efficacy of a new dosage form based on albendazole in intestinal nematodoses of dogs.

To determine the therapeutic dose, 20 dogs of different breeds aged 1-2 years, spontaneously infested with Toxocara canis, were selected. The diagnosis of toxocariasis was made in a comprehensive manner: the clinical data and the results of laboratory helminthovoscopic examination of feces according to the McMaster method were taken into account.

The calculation of the effectiveness of the preparations was carried out by the "Control Test" method according to the Guide for the Assessment of Anthelmintics, approved by the World Association for the Progress of Veterinary Parasitology.

All animals were divided into 4 groups of 5 dogs each. The animals of the first group were injected intramuscularly with a once-developed drug in a dose of 150 mg / kg of mass according to (0.75 ml / 10 kg body weight). The second group of dogs similarly injected the drug at a dose of 200.0 mg / kg a.a. (1.0 ml / 10 kg of body weight) once, the third - at a dose of 250.0 mg / kg a.a. (1.25 ml / 10 kg of body weight) according to a similar scheme. The fourth group served as an infected control and did not receive any drugs. After the introduction of drugs for 4 hours and then daily observed the clinical condition of the animals in order to identify possible side effects.

As a result of the studies, it was found that the developed drug has high therapeutic efficacy (table 6).

The use of the drug in a dose of 150 mg / kg ensured a decrease in helminth egg production by 84.5%, and the average group number of toxocar eggs was 25.2 ± 2.3 specimens. The introduction of anthelmintic in doses of 200 and 250 mg / kg provides intensification, respectively, 98.0-98.2%.

Thus, a therapeutic dose based on coprological studies can be considered a dose starting from 200.0 mg / kg a.a.

Example 5

For comparative testing of the new dosage form of anthelmintic using helminthovoscopy, dogs of different breeds and different ages were selected, spontaneously infested with Toxocara canis (38 goals), Toxascaris leonina (27 goals) and Uncinaria stenocephala (12 goals).

The effectiveness of the preparations was taken into account on the basis of the results of studies of dog feces samples by flotation and a McMaster chamber to account for the number of helminth eggs in g feces before and 15 days after application of anthelmintics.

The following anthelmintics were used as comparison preparations: Caniquantel Plus (Maramed Pharma GmbH, Germany) at a dose of 50 mg praziquantel and 500 mg fenbendazole per 10 kg of body weight; Polyvercan (SANOFI, France) at a dose of 40 mg of oxybendazole, 200 mg of niclosamide per 10 kg of body weight; Dirofen (LLC NPF Api-San, Russia) at a dose of 50 mg of fenbendazole and 15 mg of pyrantel pamoate per 1 kg of body weight. All of these comparison preparations were administered orally once. The developed drug was administered at a dose of 200 mg / kg d.v. intramuscularly once. The animals of the control group were not dewormed (table 7).

As a result of the studies, it was found that all tested drugs showed a fairly high anthelmintic effectiveness. The intensity of deworming deworming therapy for toxocariasis and toxascariasis was 100%, for uncinariosis - 98.9%. The lowest rates were noted when using dirofen.

The intensity of the use of dirofen in toxocariasis, toxascariasis, and uncinariosis was 92.7, 91.6, and 91.7%, respectively. The use of polyvercanum contributed to a decrease in the intensity of toxocar egg production by 97.1%, toxocariasis eggs by 98.3% and uncinarium by 97.5%. The effectiveness of the use of the developed drug with

toxocariasis was 98.2%, with toxascariasis - 98.8% and with uncinariasis - 98.1%.

Thus, according to the results of a comparative test, it was found that the developed preparation is not inferior in effectiveness to the anthelmintics widely used in veterinary practice for deworming of dogs infested with Toxocara canis, Toxascaris leonina and Uncinaria stenocephala.

In accordance with the recommendations of the World Association for the Progress of Veterinary Parasitology, the developed drug can be classified as a highly effective anthelmintic (Jacobs DE, Arakowa A., Courtney C.N. et al. // Vet. Parasitol. - 1994. - V. 52, No. 1. - P. 179-202).

The invention in comparison with the prototype and other technical solutions has the following advantages:

1. Complex therapy of side effects of helminth infections, due to the use of butafosfan in the preparation.

2. Low toxicity.

3. A convenient way of dosing and administration.

Claims (1)

A drug for the treatment of helminthiases in animals, containing albendazole sulfoxide, related substances, characterized in that it additionally contains butafosfan in the following mass ratio of components,%:
Albendazole sulfoxide (n- [6- (propane-1-sulfinyl) - 1H-1,3-benzodiazol-2-yl] methoxycarboxylic acid) 5.0-10.0 Butaphosphane (1-butylamino-1-methyl) ethylphosphonic acid) 10.0-20.0 Water for injections rest