Antihelminthic agent

 

(57) Abstract:

The invention relates to medicine and veterinary medicine, namely to medical and veterinary helminthology, and can be used for larval treatment of hydatid cysts and other castadot humans and animals. The essence of the invention lies in the fact that antihelminthic means includes active ingredient carbonitridation (nocodazole or mebendazole), lecithin and cholesterol in a ratio of components 1 : 9 : 1, respectively, and is applied by rectal injection or cutaneous applications. The claimed tool provides greater inhibition of growth darvocet alveococcosis (a 99.6 - 100%), the destruction of all germinal elements (protoscoleces and acetalized) in servicesto alveoli and death of the parasite in General 62,5 is 85.7%. table 2.

The invention relates to medicine and veterinary medicine, particularly to medical and veterinary helminthology, and can be used for larval treatment of hydatid cysts and other castadot humans and farm animals.

The larval hydatid cysts are heavy parasitic diseases of humans and farm animals caused by the larva of Echinococcus and leading the th echinococcosis - a disease of humans and farm animals.

For larval treatment of hydatid cysts using drugs group carbonitridation - albendazole (methyl-5-[propylthio]-2 - benzimidazolecarbamate) and mebendazole (methyl ester of 5-benzoyl-2-benzimidazole-carbamino acid). In experimental alveococcosis laboratory animals therapeutic activity showed nocodazole (methyl (5-[2-thienylboronic]-1H-benzimidazole-2-yl)carbamate). Alveococcosis amenable to treatment with these drugs is much worse than hydatidosis echinococcosis. The disadvantages of all of these drugs are high therapeutic doses and the absence of a radical therapeutic effect after multiple courses of treatment that does not guarantee the recovery of the patient throughout his life (p.M.Schantz et al., 1982; C. I., gaborova and others, 1983; D. H. Taylor et al., 1988).

Closest to the claimed technical solution is liposomal albendazole (LA), the efficiency of which is tested in experimental alveococcosis cotton rats (H. Wen et al., 1996). Prepared according to the method of the prototype LA includes active substance (albendazole) and phospholipid (egg phosphatidyl choline) in the ratio 1:2 appropriate; to the solution was added 50 mg of albendazole and stirred until complete dissolution of the latter; 3) to the resulting solution was added 9 ml of 2M sodium hydroxide, stirred until the formation of the neutralized suspension LA; 4) the resulting suspension LA cialiswhat with 5 l of 0.15 M phosphate buffer pH of 7.4 at 4oC for 1 day; 5) remove supernatant, the remaining suspension LA lead phosphate buffer to a concentration of albendazole equal to 10 mg/ml; 6) LA suspension is treated with ultrasound for 20-30 minutes to reduce the size of liposomes; 7) received ready-to-use LA stored at 4oC and used in experiments in the retention period not more than 3 months. Therapeutic activity of LA experienced late-stage experimental alveococcosis cotton rats. The duration of the invasion of animals at start of treatment was 3 months. The initial intensity of infection to the beginning of the treatment by the average mass of parasitic darvocet (PL), 1 animal was not determined. LA was administered to animals orally in a daily dose of the active substance (DV) 35 mg/kg over 8 5-day course with intervals between courses of 2 days. The control were infected untreated cotton rats. The effectiveness of LA was evaluated animals comparable groups. The index of inhibition of growth DPS (ICBL) in treated rats was calculated in percentage according to the formula

ITCL = (MK - Ml)/MK 100,

where MK and Ml - average weight SQUARE per 1 animal control and treated rats, respectively, opened in 7 months. after infection. The test results showed that LA only causes growth inhibition of DPS and has no significant impact on the viability of the parasite, as evidenced by indicators of invasion control animals (MK = 72.4 g, spontaneous death protoscoleces in PL at 13.5% of rats) and treated rats (Ml = 19,4 g, ITBL = 73,2% death protoscoleces SQUARE in 66.7% of rats). Susceptibility of cotton rats to infection with alveococcosis amounted to 84.3 percent.

The disadvantages of the prototype are:

1) low therapeutic activity of the drug (73% growth inhibition of the parasite, the lack of larvicide effect);

2) lack of reliability models of invasion (84% garagemate animals alveococcosis) and criteria to assess the impact of the drug on the growth of the parasite (not was determined by the intensity of infection at start of treatment) and viability (spontaneous death protoscoleces in PL at 13.5% of animals; does not take into account the effect of the drug on more resistant to its destructive action of detailed drug (oral), coupled with the premature destruction of liposomes in the gastrointestinal tract of animals and therapeutic effect of the active ingredient released from the destroyed liposomes, which eliminates objective evaluation of anthelmintic activity applied liposomal drug.

The task of the invention is obtaining a liposomal preparation based on carbonitridation with high anthelmintic activity and optimization of the method of its application.

The essence of the invention lies in the fact that antihelminthic means includes DV - carbonitridation (nocodazole or mebendazole), lecithin and cholesterol in a ratio of components 1:9:1, respectively, and is applied by rectal injection or cutaneous applications. The introduction of the proposed deworming drugs cholesterol as a stabilizer and high content of lecithin as a carrier allows you to increase the effectiveness of the drug, and parenteral application provides optimal conditions for the fuller realization of the target biological activity.

We offer an antihelminthic agent was prepared as follows. part 1 DV (nocodazole or mebendazole) and 1 part of cholesterol t is ethanol. The solvents are evaporated from the composition to dryness to obtain a dry lipid film. To the lipid film add saline solution, air phase is replaced by nitrogen and the resulting mixture is sealed and suspended before the formation of the finished product is a homogeneous liquid milky color. Received deworming tool used by rectal injection or cutaneous applications.

Obtaining and effectiveness of the proposed deworming drugs are illustrated by the following examples.

Example 1. Liposomal drug nocodazole was prepared as follows. 100 mg nocodazole and 100 mg of cholesterol were dissolved in 250 ml of a mixture of chloroform-methanol (2:1). To the resulting solution was added 900 mg of lecithin dissolved in 100 ml of 10% ethanol. The solvent was evaporated from the composition to dryness on a rotary evaporator at a temperature of 35oC to obtain a dry lipid film. In the flask with the lipid film was placed glass beads (or porcelain jar by using boiling stones), were added to the physiological solution in the volume 11-15 ml in accordance with a given concentration of the active ingredient in liposomal drug (6,7-9.1 mg/ml). The flask was purged with nitrogen and was closed with a glass stopper and a paraffin film. The contents of the flask which was stvovala the appearance of staining fluid milk color. Ready-to-use liposomal nocodazole representing a homogeneous microemulsion white with low specific smell, poured into tanks or capsules. The tanks were covered with a lid and a paraffin film, the ampoule was sealed after blowing with nitrogen and placed in a refrigerator at +4oC and use within 3 months. storage.

Therapeutic activity of liposomal nocodazole studied in experimental larval alveococcosis cotton rats at a late stage of invasion after rectal injection of the drug. In the same experimental conditions tested the efficiency obtained by the above method samples liposomal nocodazole, in which the ratio LW:lecithin:cholesterol were respectively 1:3:0.3 and 1:4,5:0,5.

In the experience used 35 cotton rats (males), infected at the age of 1 month. intraperitoneally microscopic cefaloridine alveoli with a diameter of 100-300 μm. Each animal received 20 acetalized. By the beginning of treatment the duration of experimental infestation was 60 days, and the average weight of DPS, according to the autopsy to this term of 6 rats was equal to 10.4. The remaining 29 rats were divided into 4 groups of 7-8 goals in cardonnel ratio DV, lecithin and cholesterol: 1:3:0,3 (the first group), 1:4,5:0,5 (the second group) and 1:9:1 (the third group). The drug was injected with a syringe connected to the cannula with a removable flexible transparent polyethylene catheter with a length of 5 cm, 3 times a day for 46 days without interruption (61st in 106 days after infection) in a daily dose of the active ingredient 0.05 g/kg (total dose of the active ingredient was 2.3 g/kg). Untreated rats of the fourth group served as control. All animal experimental and control groups were exposed on the 121st day after infection and were determined in each rat mass of all identified SQ. The contents of the SQUARE were subjected to microscopic examination for the presence and severity of destructive changes embryonic elements (protoscoleces and acetalized) Echinococcus. Therapeutic activity LFN was assessed using the index of chemotherapeutic activity (IHT), which is considered in percentage according to the formula

IHT = (MK - Ml)/(MK - Mi) 100.

where Mi, MK, and Ml is the average weight of PD on 1 animal: source control and treated animals, respectively.

The results of tests of therapeutic activity LFN showed (table 1) that the greatest efficiency has sample LPN, in which the ratio of nakedest all SQUARE at 6 of the 7 treated animals). Lower were indicators of therapeutic activity of samples LFN, in which the ratio of nocodazole, lecithin and cholesterol were respectively 1:4,5:0,5 (IHTA is 107.5%; destruction of all germinal elements in SQ in 2 of the 7 treated animals) and 1:3:0,3 (IHT = 98,6%; all treated animals in PL revealed live areality alveoli).

Example 2. Samples of liposomal forms of mebendazole (LFM), in which the ratio of mebendazole, lecithin and cholesterol, respectively 1:9:1, 1; 4,5: 0,5 and 1:3:0,3, prepared by the method described in example 1. Therapeutic activity LFN studied in experimental alveococcosis white mice at the early stage of invasion after cutaneous applications of the drug.

In the experience used 37 outbred mice of both sexes weighing 18-24 g, infected at the age of 1 month. intraperitoneally with cefaloridine alveolate on 20 acephalism 1 pet. Treatment of animals was started 10 days after infection, with an average initial weight of DPS, equal to 0.01 g (according to the autopsy 6 mice). LFM were applied to the shaved skin of the back of the animals with an area of about 15 cm21 time per day every day for 42 days without interruption in a daily dose of the active ingredient 0.05 g/kg Other parameters examu high efficiency showed a sample LFM, in which the ratio of mebendazole, lecithin and cholesterol corresponded to a 1:9:1 (IHT = 99,6%; the death of all DPS in 5 of the 8 treated animals). Lower efficiency had samples LFM, in which the ratio of mebendazole, lecithin and cholesterol corresponded to a 1:4,5:0,5 (IHT = 98,7%; the death of all SQUARE at one of the 8 treated mice) and 1:3:0,3 (IHT = 96,7%; all treated animals in PL revealed live areality alveoli).

According to the literature (H. Wen et al., 1996), liposomal form of albendazole (prototype) introduced experimentally infected alveococcosis cotton rats within 8 5-day course with intervals between courses of 2 days at a daily dose of the active ingredient of 35 mg/kg, causes growth inhibition darvocet alveoli at 73.2 per cent, the destruction of only the most sensitive to the drug embryonic elements of the parasite (protoscoleces) 52,3% of the animals and has no detrimental action on areality alveoli and parasite in General.

Thus, liposomal forms of nocodazole and mebendazole are improving the efficiency of the drug, which consists of carbonitridation, lecithin and cholesterol at a ratio of 1:9:1, and parenteral application which is optimal for i.e. monitoring) reference the OST darvocet alveoli (a 99.6-100%), the destruction of all germinal elements alveoli (protoscoleces and acetalized) and cure 62,5-85.7% of experimentally infected laboratory animals (cotton rats, white mice), compared with the prototype. In addition to improving efficiency, the optimal path of the application, as well as good tolerability of liposomal forms of nocodazole and mebendazole, which may justify their high efficiency in larval hydatid cysts in humans and animals.

Antihelminthic agent, including benzimidazolecarbamate and lecithin, characterized in that it has a high content of lecithin, further comprises cholesterol at a ratio of benzimidazolecarbamate, lecithin and cholesterol 1 : 9 : 1, respectively, and applied rectal or transdermal.

 

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