Vertebrata digestive tract detoxicant

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to veterinary science. A detoxicant of polysilicic acid derivatives is specified in a group of reversed-phase sorbents.

EFFECT: using the detoxicant enables practically eliminating toxic effects accompanying animal's poisoning.

2 dwg

 

The invention relates to the detoxification of the digestive tract of vertebrates acute and chronic poisoning caused by drugs and narcotic drugs, mycotoxins, polycyclic aromatic hydrocarbons (PAHs) and persistent organic pollutants (POPS)such as organochlorine pesticides, paigaldamine dibenzodioxins, dibenzofurans, biphenyls and other dangerous toxins.

In recent years increasingly used for detoxification of the digestive tract of vertebrates (humans and animals) chelators, such as "Polisorb" - silica gel (Bulletin HLS No. 4, 2005); "Smectite" - aluminosilicate company Beaufour Ipsen Pharma, France; series products "Mycofix" - silicate, zeolite, biological additives company Biomin Holding GmbH, Austria; "Mycosorb" modified glucomannan from the walls of yeast cells company Alltech Inc., USA; "Sorbitols" - composition of silicates and components of the yeast wall company, LLC "Lallemand, RF.; "Enterosgel" (CJSC "Selma", RF, RU # 2293743, CL C08G 77/16 (2006.01), 20. 02.2007, and RU # 2293744. CL C08G 77/16 (2006.01), 20. 02.2007,).

These drugs have high hydrophilicity and, therefore, low sorption capacity with respect to hydrophobic substances with a high distribution coefficient in the Octanol-Water designated logPowor Kow/sub> (R.Collander, Acta Chimica Scandinavica (1951) 5, 774-780). While many drugs and medicines, as well as the vast majority of PAHs, POPS and mycotoxins are compounds with very high hydrophobicity, i.e., high value of distribution coefficient in the system octanol/water logPow=3-8.

More suitable sorbents in this situation seem to be hydrophobic sorbents able to hold on its surface such connections. Moreover, in contrast to various grades of activated carbons used as chelators, hydrophobic sorbents on the basis of hydrophobized silica or aluminosilicates possess both surface and volume capacity, which is vertical relative to the surface location of the hydrocarbon substituents.

Hydrophobizated derivatives of silica gel (xerogel anhydride polysilicon acid), containing on the surface covalently attached hydrocarbon residues, for more than 40 years are used as sorbents for high-performance reversed-phase liquid chromatography for the separation of substances of different nature (..Unger. Porous Silica, its properties and use as support in column liquid chromatography. Elsevier, Amsterdam, 1979, p.p.187-236). As hydrophobic substituents typically use alkyl residues with the number is the number of carbon atoms from 1 to 18 (usually C 4C8and C18or phenyl group. These sorbents surface has a high hydrophobicity, and the free silanol groups (-OH)present on the surface, shielded and/or not available for the liquid phase.

The technical result of the invention is the expansion of the range of existing chelators with materials having higher hydrophobicity, efficiency and availability of admission.

To achieve the technical result of the proposed detoxifier of the digestive tract of vertebrates based on the derivatives of polysilicon acid selected from the group reversed-phase sorbents, representing gidrofobizirovannogo matrix gel polysilicon acid containing on the surface of particles and pores silanol groups (OH)yand hydrocarbon substituents (R)zwhere:

y is the concentration of silanol groups in the structure and on the surface of the gel;

z is the concentration of the hydrocarbon substituents;

the ratio z/y takes the value from 79/21 to 1/99, respectively;

R is a hydrocarbon radical, coupled with a silicate basis through a covalent bond Si-C, Si-O-C or Si-NX-C and presents a linear or branched alkyl or alkyl fluoride residues with the number of carbon atoms from 2 to 24, containing from one to 4 isol is skilled or conjugated double bonds, or cyclic substituents with the General formula Ar(CH2)n-, in which Ar is an aromatic or alicyclic mono - or polycyclic Deputy with the number of carbon atoms from 6 to 24, with values of n from zero to six, and when the moisture content of the matrix from 0.1 to 95%.

As options R or Ar may contain one or more functional substituents: -Cl, -OH, -CN, -CO2H, -NH2, -SO3H, -NR'2, -PO3H2.

The moisture content of from 0.1 to 95% determines the degree of gidratirovannoi xerogel or hydrogel.

The proposed detoxifier silicate-based, different from the known structures of chelators, in addition to the silanol groups (OH), R is a hydrocarbon radical connected with silicate basis through a covalent bond Si-C, Si-O-C or Si-NX-C and presents a linear or branched alkyl or alkyl fluoride residues with the number of carbon atoms from 2 to 24, containing from one to 4 isolated or conjugated double bonds, or cyclic Deputy General formula Ar(CH2)n-, in which Ar is an aromatic or alicyclic mono - or polycyclic Deputy, with the number of carbon atoms from 6 to 24, with values of n from 0 to 6, as well as with functional substituents previously for the purpose of detoxification vertebrates has not been used in this capacity, not about the Isan in scientific, technical, patent literature and in medical documentation.

As a detoxifier in the present invention can also be used a known or new hydrophobizated derivatives of natural or synthetic aluminosilicates represented by the bentonites, smectites, montmorillonite, zeolites, sodium-calcium hydrated aluminosilicates, etc. with the above substituents.

The detoxifier of the present invention apply:

1) by adding a detoxifier in food in the form of a dry powder or soaked in water detoxifier in the form of a xerogel in zootechnika and veterinary medicine for fattening and/or treatment of poultry, fish, pigs, horses, small and large cattle and other domestic animals;

2) in the form of aqueous suspensions or dry gel of detoxifier, or in the form of enteric capsules, or the retina of a suitable material, filled detoxifier dry or moistened with water in medicine - per os;

3) by adding it to the feed dry powder detoxifier or moistened with water detoxifier in the form of a gel in zootechnics when feeding wild animals that are of practical interest for hunting.

To confirm the declared technical result was a comparative evaluation of the sorption capacity of a typical reversed-F. the gas chromatographic sorbents "Lichrosorb RP-8" (cat. No. 9143, Merck, Germany) with a particle size of 7 μm, specific surface area 300 m2/g and pore diameter of 10 nm, which is a silica gel with the above parameters with covalently grafted through the connection of Si-C aktalnye residues (C8)containing 9.5% of carbon, and sorbent "Enterosgel" (CJSC "Selma", Russia), containing in its composition metal of the group (C1). For evaluation used a hydrophilic dye Congo red and hydrophobic PAHs naphthalene - household insecticide poison. The evaluation was conducted according to the method described in patent RU No. 2293744, CL C08G 77/16 (2006.01), 20, 02.2007, (Congo red) and chromatographic - based methods described below (naphthalene).

According to the patent RU №229374 sorption capacity declared gel against Congo red is 4.9±0.7 µmol/g According to the measurements of the sorption capacity of hydrophobic reversed-phase sorbent Lichrosorb RP-8" was 1.75±0.15 µmol/g

To evaluate the sorption capacity of the reversed-phase sorbent Lichrosorb RP-8 and enterosorbent "Enterosgel" in relation to hydrophobic compounds was used naphthalene, representing the class of simple hydrophobic PAHs, with the value of the distribution coefficient >3 (logPow=3.3V) and a solubility in water at 30 mg/L. All work with naphthalene were carried out in glass containers. In 100 ml of purified water was placed a portion naftalina 5 mg Suspension of naphthalene portions homogenized in a hand homogenizer of downs with a capacity of 15 ml to obtain a homogeneous suspension of naphthalene in water. The suspension was filtered through a syringe equipped with a filter with a pore diameter of 0.22 μm. The concentration of naphthalene was determined using liquid chromatography according to the method of external standard in the system acetonitrile: water (65:35) octadecylphenol column with detection at 275 nm. The concentration of naphthalene in the obtained filtrate was 24 µg/ml. To remove physically adsorbed water samples sorbents, "LiChrosorb RP-8", and "Enterosgel" before the experience was placed in an oven and kept at 110°C to constant weight.

In accordance with the methodology below in three test tubes with ground stoppers were placed in 5 ml of a solution of naphthalene (accurately weighed). To a solution of naphthalene in the second and third tubes added accurate sample sorbents "LiChrosorb RP-8" and "Enterosgel". The first sample was used as control. All three tubes for 2 hours was placed into the rotating device of the planetary type speed turn 120 rpm Then the tubes were centrifuged in a basket rotor at 4000 rpm for 30 minutes. The liquid phase was analyzed for content of naphthalene. The sorption capacity reversed-phase sorbent LiChrosorb RP-8 in this experiment amounted to 55 is 2.5 µmol/g, while the concentration of naphthalene in the liquid phase of the third tube ("Enterosgel") was not significantly different from the control, i.e. unlike used reversed-phase sorbent, the medicine is not able to adsorb hydrophobic compounds of the type of PAH. These data confirm the possibility of using reversed-phase sorbents brand "LiChrosorb RP-8 for detoxification of hydrophobic toxic compounds, which include most of the PAHs, POPS.

To confirm the detoxifying properties of the sorbent LiChrosorb RP-8 in vivo was carried out the following experiment. To this end used male mice inbred lines C57B L/6J at the age of three weeks with an average weight of groups from 10 to 11, Were selected 4 groups of 10 animals each. Two experimental groups were injected typical POPS Arochlor 1254 (Supelco Inc., USA) in sunflower oil per os at a dose of 25 mg/kg for 10 days from the first to the 12th day (5 days + 2 days break + 5 days). Both the control group received only the vehicle (sunflower oil) in the same volume. The second control (No. 2) and the second experimental group (No. 4) from the first day of the experiment received pellets containing 0.075% (V/V) sorbent "LiChrosorb RP-8". The first prototype, and the first control group received conventional pellets. All animals in groups weighed every 5 days.

The results of exp is rimental to confirm the claimed technical result is shown in Fig.1 and Fig.2.

Figure 1 illustrates the impact of POPS Arochlor 1254 and reversed-phase sorbent LiChrosorb RP-8 on the body weight of male mice, where the axis is specified observation period in days on the y-axis of an average body weight of animals in grams. Curve 1 is the first control group, curve 2 - the second control group, curve 3 is the first experimental group, curve 4 is the second experimental group.

The curves in figure 1 show that the weight of the animals in both control groups were not significantly different, whereas in the experimental groups, the weight of animals differs between these groups and the values in the control, especially in 1-the first experimental group (No. 3).

It is known that Arochlor 1254 leads to an increase in the relative size of the liver, slows weight gain in growing mice, and in large repeated doses (>100 mg/kg) leads to a fall in weight, exhaustion and death of animals (Safe S. Crit. Rev. Toxicol. (1984) 13(4), 319-395). At the same time, the slowdown in the growth of the body in the second experimental group (No. 4) is much smaller than in the first experimental group (No. 3), and already by the second half of the experiment the weight of the animals in this group did not differ significantly from the control.

Figure 2 illustrates the impact of POPS Arochlor 1254 and reversed-phase sorbent LiChrosorb RP-8" on the relative weight of the liver of mice, where the abscissa axis is indicated the experimental group of animals on the y - axis relative liver weight in %. 100% take the Ali relative weight of the liver in the first control group.

The data in figure 2 show that significant differences are observed only in the first experimental group (No. 3), in which the animals did not receive enterosorbent.

Thus, it is proved that a typical reversed-phase sorbent brand "LiChrosorb RP-8 effectively Sorb hydrophobic PAHs (for example, naphthalene), and its application in the stern as a detoxifier in a concentration of 0.075% allows when used doses typical of the POPS (for example, Arochlor 1254) significantly reduce practically to eliminate the toxic effects of toxicant in the organism of experimental animals.

The detoxifier for the digestive tract of vertebrates based on the derivatives of polysilicon acid, wherein selected from the group reversed-phase sorbents.



 

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35 cl, 5 tbl, 4 ex

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3 ex, 3 tbl

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