The substance that causes the induction of microsomal liver enzymes

 

(57) Abstract:

The invention relates to medicine, namely to substances that cause the induction of microsomal liver enzymes. The technical result is an improved ability to induce microsomal liver enzymes. The inventive use of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo [2,3-f]xanthine as a substance which causes the induction of microsomal liver enzymes. 3 table.

The invention relates to medicine, namely to substances that cause the induction of microsomal liver enzymes.

As a prototype of the selected benzonal (1-benzoyl-5-ethyl-5 - fenilbarbiturovaya acid), which, along with phenobarbital is the reference inducer of microsomal enzymes, but significantly exceeds its ability to induce microsomal liver enzymes, and has a less pronounced effect gipnosedativny [Navajeevan, Etc., Means the activation of detoxication systems among cyclic and linear derivatives of urea (Experimental study).- Abstract of Diss. D. B. N., Tomsk, 1998. - 48 S.].

The technical result is an improved ability to induce microsomal liver enzymes,

This technical repulican, 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo [2, 3-f] xanthine of the formula I

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described previously [Khaliullin F. A., Mironenkov J. C., Gilmanov A. J. and other Synthesis and study of hypoglycemic activity of derivatives of 2,3-dihydrothiazolo[2,3-f]xanthine/Chem.-Pharm. journal.- 1994.- N 9.- S. 33-34].

Example 1. Acute toxicity was determined after intragastric administration of Mature weinbrenner mice-males according to the method of J. Litchfield and F. Wilcoxon modification Prozorovsky C. B., 1962. Survival of animals was observed during the first day. DL50X-68 = 816 (734-892) mg/kg, which corresponds to the 3rd class of hazard (moderately hazardous). Benzonal belongs to the same class of hazardous chemical substances DL50= 192 (162-223) mg/kg

Example 2. The effect of compound I (X-68) on the microsomal activity of the liver was studied in experiments on weinbrenner Mature mice-males using conventional test "geksenalovy sleep", which allows to indirectly estimate the functional activity of the mixed oxidase [Navajeevan Etc., Saratikov A. C. Methodological approaches to the creation of new garmentindustry tools/Siberian journal of gastroenterology and weapologize.- 1999.- N 8.- C. 55-60]. To avoid the Central influences on the duration of sleep (psi is, is Artikov A. S. Pharmacological agents in experimental medicine and biology. - Tomsk, 1977. - 45 S.].

The connection I and benzonal were diluted in 2% starch suspension was injected 2-fold intragastrically with an interval of 24 h, a day after the last injection tested. Control animals received 2% starch suspension in equianharmonic quantities.

X-68 in a wide range of doses caused a statistically significant reduction in the duration of geksenalovy sleep, a clear effect was observed even at a dose of 0.0005 mg/kg, which is 1/16324000 part from DL50the studied compounds (table. 1). As can be seen from the table. 1, the dependence of the effect of the dose of X-68 was not observed, which is not possible using conventional methods, to calculate the average effective dose and, consequently, therapeutic index of the compound.

Shortening geksenalovy sleep observed after 2 injections X-68, is not associated with effects on the Central nervous system, because the duration baritovogo sleep (barbitala - trudnootdelyaemoy inert compound, almost entirely, to 95%, output by the kidney in unchanged form) when a similar scheme and the doses did not differ from the values of the control group.

Introduction equivalent is carouse the effect was more pronounced and was superior to any of benzonal. So, in 1/100 of DL50benzonal had no significant effect, whereas X-68 caused shortening the duration geksenalovy sleep 70%; and in 1/20 from DL50the stimulation index of benzonal was 42%, X-68 - 89% (table.2).

We studied the connection unlike benzonal has a significantly longer inducing effect (table. 2). Shortening geksenalovy sleep in a dose of 1/100 DL50(8 mg/kg) and a dose of 1/20 DL50(41 mg/kg) significantly and 8 days after injection, whereas the duration of the effect of benzene (1/20 DL50) no more than two days, and the dose of 1/100 DL50without being inducing, at 4-6 days after the last injection causes inhibition of liver microsomal enzymes (table. 3). When using benzonal in the dose that causes a clear induction of microsomal enzymes, and according to literature data, the most frequently used (35 mg/kg) [Navajeevan, Etc., Means the activation of detoxication systems among cyclic and linear derivatives of urea (Experimental study).- Abstract of Diss. D. B. N., Tomsk, 1998. - 48 S.], the effect is observed only 4 days (table. 3).

Induction of microsomal enzymes under the influence of X-68 confirmed in the experiments, the direct quantitative determination of the level C is edenia X-68 (35 mg/kg) was significantly increased by 32% (X-68 - 657.36 38.22 mm/g tissue; control - 499.17 39.99 mm/g tissue; P < 0.05).

Thus, X-68 has a pronounced long-inducing effect, significantly exceeds benzonal therapeutic breadth, duration of action and more favorably low toxicity.

The use of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo [2,3-f}xanthine of the formula

< / BR>
as a substance which causes the induction of microsomal liver enzymes.

 

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SUBSTANCE: the present innovation deals with antiviral preparations that contain aliphatic alcohol C21-C28 in combination with either nucleoside or nucleotide analog or phosphoformic acid in pharmaceutically acceptable carrier. It is necessary to mention that n-docosanol is considered to be a preferable aliphatic alcohol. Concentration of aliphatic alcohol C21-C28 corresponds to 0.05% to 40% by weight. Concentration of either nucleoside or nucleotide analog or phosphoformic acid corresponds to 0.1% to 10% by weight. The innovation, also, deals with the ways to treat viral infections due to applying such compositions. Aliphatic alcohols C21-C28 synergistically intensify antiviral activity of nucleoside analogs directed against replication of several herpetic viruses and that of cow's pox.

EFFECT: higher efficiency of inhibition.

28 cl, 13 dwg, 21 ex, 6 tbl

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