Antihelminthic agent

 

(57) Abstract:

The invention relates to the field of medicine and veterinary medicine. The essence of the invention as the active substance use complex albendazole and copper optionally included in microcapsules of cellulose acetate in a ratio of albendazole, copper sulphate and acetate as the source of products to obtain the drug, which is 1:1:0,5 respectively. The introduction of the deworming drugs metal complex albendazole can improve its therapeutic activity, and the inclusion of the metal complex of albendazole in microcapsules of cellulose acetate provides extended target effect necessary for radical chemotherapy larval of hydatid cysts. The tool provides a complete inhibition of growth darvocet Echinococcus and death of the entire population of the parasite. 3 table.

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 and intestinal nematodes humans and farm animals.

The larval hydatid cysts are heavy parasite the death of patients. Alveolar echinococcosis (alveococcosis) is a human disease, and hydatidosis echinococcosis is a disease of humans and farm animals. The only radical method of treatment of hydatid cysts remains surgical, ineffective in advanced cases of the disease. Radical operation cannot be performed in the 11-15% of patients with alveococcosis and 25-58% of patients hydatidosis echinococcosis; the remaining patients in 93% of cases are doomed to die within 10 years after surgery. But even when successful operations, there are cases (3-54%) of recurrence of the disease. Relapses result in the need for re-operations up to 10 times (B. C. Petrovsky et al., 1985).

The first drug for the conservative treatment of larval hydatid cysts were identified in experimental models of diseases in 1974 (A. I. Krotov et al., 1974). Used since then for chemotherapy of larval hydatid cysts drugs group carbonitridation - albendazole (methyl-5-[propylthio] -2-benzimidazolecarbamate) and mebendazole (methyl ester of 5-benzoyl-2-benzimidazolecarbamic acid) are able to inhibit growth of the parasite without causing the death of all or ballrolling life of the patient, but does not guarantee recovery of the patient throughout his life. The most difficult chemotherapy alveococcosis humans and experimentally infected laboratory animals. The most resistant to chemotherapy was experimental alveococcosis cotton rats, characterized by rapid growth of the parasitic darvocet and rapid death of animals from infestation (A. I. Krotov et al., 1974; P. Schantz et al., 1982).

As a prototype elected work D. Taylor et al. (1988), who attempted treatment of experimental alveococcosis cotton rats is the most effective currently protevoanemicakim drug albendazole. Cotton rats with an initial duration of experimental infestations in 1 month. after intraperitoneal infection of germinal elements alveoli was injected into the gastric albendazole suspension in physiological solution at a daily dose of the active substance (DV) 50 mg/kg over 1 to 6-month courses (5 days of treatment with 2-day intervals during each week). The total course dose of the active ingredient was 1.0-6.0 g/kg After treatment at the opening of the treated and untreated control animals found that albendazole was caused only by reversible inhibition of p is ptx2">

The disadvantages of the prototype are:

1) low therapeutic activity of the drug (80,6-96,1% growth inhibition of the parasite, the lack of larvicide effect);

2) lack of reliability criterion to assess the impact of the drug on the growth of the parasite in treated animals (but was determined by the intensity of infestation of rats at start of treatment; not specified the exact date of opening of the animals after treatment).

The task of the invention to provide microcapsular form metal complex of albenzadole with high anthelmintic activity in larval and alveolar hydatidosis the hydatid cysts.

The invention consists in the fact that as DV deworming drugs use complex albendazole-substance (AU) and copper optionally included in microcapsules of cellulose acetate at a ratio of AU, copper sulphate (MK) and acetate as the source of products to obtain the drug, which is 1: 1: 0,5 respectively. The introduction of the deworming drugs metal complex of albendazole (ICA) as DV increases its therapeutic activity compared to the current speaker, and the inclusion of UA in microcapsules of cellulose acetate provides the="ptx2">

We offer an antihelminthic agent was prepared as follows. 0.5 parts of cellulose acetate dissolved in 30 parts of acetone with heating and constant stirring. To the resulting solution was added 1 part AC. The mixture is stirred under heating for 1.5 hours. The reaction product was added 1 part dissolved MK. The resulting mixture was stirred under heating for 1 hour. Then to the mixture is added 150 parts of mineral oil, which is stirred for 30 minutes without heating. The resulting mixture is distilled acetone when heated, shallow vacuum and stirring. The formed microcapsules are placed on paper or glass filter under vacuum filtered liquid paraffin. Remaining on the filter is washed microcapsules 4-5 portions 30 parts in each of hexane or petroleum ether. The obtained microcapsules are dried by heating for 4-5 hours. The finished product represents granules are spherical or oval in shape with a diameter of 100-200 μm greenish color without smell and taste. The output of the microcapsules is 90-95%. The content of the active ingredient, calculated according to the associated speaker is about 40%. The finished product is used as a deworming drugs e and growth darvocet Echinococcus and not with larvicide effect, microencapsulated µa (MKMK) not only fully and consistently inhibits the growth darvocet Echinococcus the hosts of the parasite, but also cause the death of the entire population of Echinococcus in treated animals, providing a radical cure them from invasion.

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

Example 1. MKMK was prepared as follows. 0.5 g of cellulose acetate was dissolved in 30 ml of acetone in a three-neck reaction flask with a capacity of 0.5 l at 40-50oWith and constant stirring on a magnetic stirrer with a speed of 300-350 rpm for 30 minutes in a flask were placed 1 g of the AU and the mixture was stirred at 40-45oC for 1.5 hours. Separately in a beaker with a capacity of 50 ml was dissolved 1 g MK in 5 ml of water at 40oC. After cooling the solution MK to 18-20oSince it was placed in a separating funnel with a capacity of 25 ml and Then a solution of MK bury into the reaction flask and the resulting mixture was stirred for 1 hour at 40-50oC. By the end of the exposure to the flask was added 150 ml of paraffin oil. The mixture was stirred for 30 minutes without heating. To the flask was connected to the water-jet pump, and when heated to 40-50oWith shallow vacuum and constant peremeci the Goy or glass filter 1-2 and under vacuum was filtered liquid paraffin. Remaining on the filter microcapsules were washed 4-5 portions of hexane or petroleum ether 30 ml in each portion. Vaseline oil and hexane leaching fraction after distillation was collected for reuse. The obtained microcapsules were dried at 50oC for 4-5 hours. The dried microcapsules were used as deworming drugs in a mixture with vegetable oil.

Therapeutic activity MKMK studied in experimental larval alveococcosis cotton rats. As Comparators used AC and UA (prepared as described above without the addition of acetate). In the same experimental conditions was evaluated the efficiency obtained by the above method two samples MKMK, upon receipt of which the ratio of initial products AC:MK:cellulose acetate were respectively 1:1:0.4 and 1:1:0,6.

In the experiment of cotton rats-males infected at the age of 1-1,5 months. intraperitoneally with protocolectomy and microscopic cefaloridine alveoli Kamchatka isolate (500 protoscoleces and 100 acephalism 1 animal) from experimentally infected cotton rats donor. 23 days after infection W is intensively invasion (at start of treatment). The average weight they developed in the abdominal cavity darvocet alveoli (LA) by this time was 2,44 g 1 rat. Rats 6 experimental groups were treated MKMK and Comparators. In the control group were infected untreated animals.

The drugs were injected animals mixed with refined sunflower oil or 1% starch gel in the stomach with a syringe and metal cannula 1 times a day, gradually increasing the daily dose of the active ingredient from 0.05 to 0.30 g/kg for 42 days without interruption. Mode changes daily doses of the active ingredient during the course of treatment was as follows: week I - 0.05 g/kg, II week - 0.10 g/kg, III and IV of the week - 0.20 g/kg, V and VI of the week - 0,30 g/kg All animals of the experimental and control groups were exposed through 74 days after infection and were determined in each mass and viability of the identified AIRCRAFT. Therapeutic activity of the tested drugs was determined by the index of chemotherapeutic activity (IHTA) and data microscopic studies of native drugs LA on the presence and severity of destructive changes of the embryonic elements of the parasite (protoscoleces and acetalized). IHTA was calculated in percentage using the formula: ATA=(MK-Ml)/(MK-Mi)100,

where Mi, MK

The results of the experiment showed (table.1) that the greatest efficiency had a sample MKMK, upon receipt of which the ratio AC : MK : cellulose acetate were respectively 1:1:0,5 (IHT=100,3%; severe destruction of the germinal elements in all LA all treated animals). Samples MKMK obtained when the ratio AC : MK : cellulose acetate 1:1:0.4 and 1:1: 0,6 were less effective (IHT=95,9 and 93.1%, respectively) and did not cause the death of all germinal elements in LA in treated rats. Next in the row reduction efficiency was located µa (IHT=84,3%), AU (IHT=72,0%), tested under identical conditions in a mixture with vegetable oil. The lowest therapeutic activity was observed in the AC input in starch gel (IHT= 48,4%). While in rats treated with AC with vegetable oil and starch gel, the majority of germinal elements in LA remains viable.

Example 2. MKMK was obtained as in example 1 at a ratio AC:MK: cellulose acetate = 1:1:0,5 respectively. Therapeutic activity MKMK studied in larval alveococcosis white mice at a late stage of invasion.

In the experiment outbred mouse-males infected at the age of 1.5 months. intraperitoneally FR the ez 121 days after infection were dissected 5 mice to determine the initial intensity of infection. By this time the index Mi was equal to the 7.65 g per 1 mouse. 8 mice of the experimental group were injected MKMK mixed with refined sunflower oil in the stomach of 1 times a day for two 10-day courses in gradually increasing daily doses of the active ingredient from 0.05 to 0.24 g/kg with an interval between courses of 15 days. Total treatment duration was 35 days (from 122 of 157 th days after infection). The total dose of the active ingredient was the equal of 2.45 g/kg 12 infected untreated mice served as control. Mice of the experimental group was exposed through 198 days after infection (42 days after treatment). Mice in the control group were exposed as their natural mortality from alveococcosis, and surviving animals on the same day as the mice of the experimental group. Therapeutic activity MKMK was evaluated as in example 1.

The results of the experiment showed (table. 2) that MKMK showed high therapeutic activity, as evidenced by the complete inhibition of the growth and collapse of the LA (IHT= 183,5%), and the death of all LA. At autopsy, the treated mice conglomerates LA were presented structureless amorphous formations yellow, fragmentariness when you try to extract them from the abdominal cavity of the animals. is strain or destroyed protoscoleces and acetalized with advanced destructive changes. Data microscopy testified that the death of LA in treated animals occurred much earlier period dissection of animals. Mass of necrotic LA in treated animals ranged from 3.04 to 7,13 g and averaged 4,16 g per 1 mouse. Reliability radical therapeutic effect MKMK confirmed distant date of opening of the treated animals after treatment (about 1.5 months. ). Of 12 control mice 10 animals fell from alveococcosis through 146-187 days after infection. LA in animals of the control group were mostly Mature, intensely budding forms containing many living protoscoleces and acetalized. The LA weight in control mice averaged 11,83 g for 1 animal.

Example 3. MKMK was obtained as in example 1 at a ratio AC : MK : cellulose acetate = 1:1:0,5 respectively. Therapeutic activity MKMK studied in larval hydatigena the echinococcosis white rats at a late stage of invasion.

The model of invasion reproduced in young outbred rats of both sexes weighing 140-180 g by operative intraperitoneal implantation darvocet hydatidosis Echinococcus (LGA) from outbred mice donor, saragani-mi rats-recipients, marked individual label, implanted intraperitoneally Mature LGA (containing visually distinct brood capsules with protocolectomy on the inner surface of the layered shell). The operation was performed under ether anesthesia; the anterior abdominal wall of rats was cut in layers in the midline from the xiphoid process (the length of the incision of 3-4 cm), donor LGA was injected into the abdominal cavity and the layers were sutured to the abdominal wall. For the prevention of peritonitis, the animals were injected intraperitoneally a single dose of 5 ml of saline solution with antibiotics (2000 U/ml penicillin and 0.3 mg/ml gentamicin. 4 rats of the experimental group through 119 days after surgical implantation 1-4 LGA diameter 11-18 mm was introduced MKMK mixed with sunflower oil in the stomach of 1 times a day for one 6-day course in gradually increasing daily doses of the active ingredient from 0.05 to 0.15 g/kg (total dose rate DV - 0.6 g/kg). 3 untreated rats, which were implanted into the abdominal cavity through 1-3 LGA diameter 11-21 mm, were used as control. The treatment efficiency was evaluated by ultrasound (ultrasound) of each rat experimental and control groups using ultrasonic scanner Acuson-512 (USA) through 119 and 156 days after infected the hinnon through 182 days after infection.

The results of the experiment showed (table. 3) that MKMK caused the death and the subsequent collapse of all LGA all treated animals. Indicators abdominal ultrasound rats of the experimental group on the first day of treatment and after 37 days after the end of treatment testified in violation of the Express structure LGA (volume reduction, reshaping, the blurring of LGA, the emergence of dense inclusions in their cavity, peeling parenchymal layer from the cuticular membrane). One treated animal (rat 4) ultrasound did not reveal one of the 4 implanted LGA through 37 days after treatment, whereas in the first day of treatment by this method detected all of the implanted LGA (characteristic total loss gidridnoi the liquid resulting from the collapse of LGA). Ultrasound control rats showed no destructive changes in all the implanted LGA. Highly informative ultrasound confirmed the results of macro - and microscopic examination of LGE in treated and control rats at necropsy of animals over 6 months. after infection. In rats of the experimental group opened 2 months. after the end of treatment, all LGA were completely spauskite and contained lost and destroyed protogalaxy. The control vividly by protocolectomy (2-16 protoscoleces in each brood capsule).

Thus, the microencapsulated metal complex albendazole ratio albendazole: copper sulphate: cellulose acetate as the source of products to obtain the drug, which is 1:1:0.5, and accordingly has a high efficacy against not amenable to radical chemotherapy larval of hydatid cysts (complete inhibition of growth darvocet Echinococcus, a devastating effect on the whole population of the parasite has infested host) compared with that of the most effective to date protivorechivogo drug albendazole (81-96% growth inhibition of the parasite, the lack of larvicide effect), indicating a greater bioavailability of the proposed drug. It is known that albendazole and other drugs, representing a group of carbonitridation, are used in the treatment not only of hydatid cysts, and other larval of castadot, being primarily effective means for intestinal nematodes humans and farm animals. However, along with the larval Zestaponi, some intestinal nematodes (trichocephalosis clinical, and especially in experimental conditions) not respond well to chemotherapy with these drugs. Because this is in General castadot and intestinal nematodes humans and farm animals.

Sources of information taken into account in the preparation of the application:

1. Taylor, D. H., D. L. Morris, K. S. Richards, Reffin D. Echinococcus multilocularis: in vivo results with albendazole and praziquantel. Trans. Roy. Soc. Trop. Med. and Hyg., 1988, v. 82, 4, R. 611-615 (prototype).

2. Krotov, A. I., Chernyaev, A. I., Kovalenko, F. P., baiandina, D., Budanov I. S., Kuznetsova O. E., Voskoboynik L. C. Experimental therapy alveococcosis. Message II. Efficiency in alveococcosis laboratory animals some struggle with it tools. The honey. parasitol. and parasiten. diseases, 1974, 3, S. 314-319.

3. Petrovsky B. C., Milonov O. B., Denikin P., Surgery echinococcosis, 1985), 216 S.

4. Schantz, P. M., Van den Bosche H., Eckert J. Chemotherapy for larval echinococcosis in animals and humans. Report of a workshop. Z. Parasitenkd., 1982, v. 67, p. 5-26.

Antihelminthic agent, including benzimidazolecarbamate, characterized in that the active substance it contains a complex of albendazole and copper, which is optionally included in the microcapsules of cellulose acetate in a ratio of albendazole, copper sulphate and acetate 1: 1: 0,5 respectively as initial products for its receipt.

 

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< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
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