Anti-allergic drug

 

(57) Abstract:

The invention relates to the field of medicine and relates to a drug for treatment of allergic diseases. The invention lies in the fact that the anti-allergic drug based on Hinkley-3-diphenylcarbinol hydrochloride further comprises 1,3-dimethylxanthine at a certain ratio of components. The invention provides a reduction in toxicity of the substances and combined drug has a pre-emptive therapeutic effect in comparison with the known available antiallergic means, including agents on the basis of individual substances. 3 table.

The invention relates to medicine and can be used as a drug for the treatment of allergic diseases.

The most numerous and long-used antiallergic therapy H1-antihistamines (1): diphenhydramine, suprastin, pyrilamine, pipolphen, ketotifen, and others. Possessing a sufficiently high therapeutic efficiency of these antagonists of H1-histamine receptors cause a number of unwanted side effects that often limit their use. In addition, the PR is using.

It is known in medical practice, the use of drugs (2) providing an inhibitory effect on allergic activation of cells and the secretion of these mediators of Allergy by affecting intracellular processes the regulation of cellular functions due to changes in the level of intracellular accumulation of "messengers" (transmitters). Examples of such drugs are derivatives of xanthine, which have antitotalitarianism effect, causing a rise in intracellular cyclic 3,5-adenosine monophosphate (camp), which leads to inhibition of mediators of Allergy. However, these drugs do not have noticeable effects on the activation of histamine, which plays a critical role in the development of all known external manifestations of allergic process, and therefore not effective for the treatment of some allergic diseases. In addition, preparations based on xanthine derivatives have a relatively high toxicity, which is also not conducive to their mass use in the treatment of allergies.

Because the allergic reaction is a complex cellular organization process involving many mechanisms activate the secretion of various mediators of Allergy, obespecheniya methods of treatment of allergic diseases including improving the effectiveness of pharmacological treatment through the creation of multifunctional drugs.

Directed search in this direction and creation of new chemical compounds with polyfunctional action (3) is most desirable, but is a process long, complex and costly, and therefore the solution to this problem based on combinations economically acceptable, affordable and highly effective medications the most feasible in these terms.

Known H1-antihistaminics funds to the technical nature and provided the action closest to the present invention is fenkarol - antiallergic drug (4), including Hinkley-3-diphenylcarbinol hydrochloride-C20H23NO MODEL HC1 (HDFC). Well-known medication has expressed antihistaminic activity due to the high selectivity of the blockade of H1-histamine receptors and has no undesirable side effects (sedative, hypnotic effects, actions on the cardiovascular system, gastrointestinal tract, eye, urinary system, etc), characteristic for the above H1-antihistaminics drugs preparatoires, is limited by its ability to inhibit only the action of histamine. In addition, HDFC has implications not only for allergic reactions, but also induces antiproliferative effect, which greatly reduces its anti-allergic effect.

Thus, the technical result from implementation of the described invention to provide on the basis of available and low cost of the starting component of the new, multifunctional, high-performance anti-allergic drug.

This technical result is achieved by the fact that the anti-allergic drug, including Hinkley-3-diphenylcarbinol hydrochloride, further comprises 1,3-dimethylxanthine when the mass ratio of the components:

Hinkley-3-diphenylcarbinol hydrochloride: 1,3-dimethylxanthine 12:4.

1,3-dimethylxanthine - C7H8N4O2(DMK) belongs to a group of methylxanthines in standalone application as a medicinal product "theophylline", has a vasodilator, bronchodilator and anti-allergic effect, which is explained by the diversity of its pharmacological activities, manifested at the cellular and molecular UB is the influence of adenosine, enhances apoptosis (including cells involved in allergic inflammation). In the anti-allergic effect DMK may be associated with the complex effects: inhibition of the secretion of histamine from mast cells and basophils, with the inhibition of respiratory burst in eosinophils, with some inhibition of prostaglandin synthesis and degranulation of eosinophiles, inhibition of proliferation of T-lymphocytes and the production of interleukin-2.

Combined preparation according to the present invention is superior in antianaphylactic activity, bronchodilators and antiexudative action every single substance, and has lower toxicity. This drug has advantages in the ability of inhibition of secretion of mediators from cells-targets allergies - basophils. In addition, first discovered the ability DMK significantly reduce the antiproliferative effect HDFC, which further demonstrates the advantages of the combined drug.

The combined action of the drug due to the impact of the allergic process as by blocking H1-histamine receptors, and by inhibition of the function of target cells and pre is the drug (teufen) according to the invention can be prepared by mixing powdered HDFC and DMK in the ratio 12:4 with the addition, depending on the type of dosage form, excipients, which are selected from the group of carriers, preservatives and/or flavorings. For example, for preparation of the drug in pill form, you can use such excipients as starch, various sugars, phosphates of calcium.

Tablets get white or white with a yellowish tint.

The drug is not soluble in water and can be dissolved in solutions of acids, such as hydrochloric acid, and alkalis.

An example of the application of the described product are tablets in the composition, g:

1,3-Dimethylxanthine - 0,1

Hinkley-3-diphenylcarbinol hydrochloride - 0,025

Corn starch - 0,111

Milk sugar - 0,0621

Calcium stearate - 0.003

The biological activity of the described drug was studied in comparison with drugs fenkarol and theophylline.

The following examples illustrate the methodology and results of tests of the properties anti-allergic drug.

Example 1. Study of the anti-allergic action of the drug.

A. Model of active anaphylaxis in vivo.

Study of wire is 2 hours prior to the introduction of the resolving dose of antigen. Assessment of the effectiveness of anaphylactic reactions was carried out by plethysmometry registration pryroxene volume of the foot, the hind paws of rats.

Antigen-induced swelling of the paws of rats selected as the primary model, as more fully reflected the stages of development of allergic reactions in the whole organism.

It is established that the average effective antiexudative dose of the combined preparation according to the invention, i.e. the dose that inhibits swelling of the paws in rats by 50% (ED50), significantly lower than each of its components in a separate application, which demonstrates its predominant anti-allergic activity.

The results are shown in table 1(1).

B. Model of passive anaphylaxis in vivo.

Studies were conducted on sensitized intradermally rats male weight 300350 g by oral administration "teofane" at a rate of 30, 60 and 90 mg/kg for 11.5 hours before permitting injection of the allergen. Evaluation of the effectiveness of the drug was carried out by determining the severity of passive cutaneous anaphylaxis (PKA) comparison of average values of the logarithms of reciprocal titers in intensity PKA under criterion Fox.< the with the introduction of the drug "tefen" compared to control.

Example 2. The study of the bronchodilator activity.

The studies were conducted in anesthetized Guinea pigs by intravenous injection of histamine (10 mg/kg). Increased bronchial tone muscles were recorded according to the method of Konzett, Rossler in the modification of the M. E. Kaminky. The study drugs were injected for 3 minutes before the injection of histamine. About bronchodilatory activity of preparations were judged on their ability to reduce the magnitude of bronchoconstriction induced by histamine.

The results obtained indicate potentsiirovannye bronchodilatory action of the described drug.

The results are shown in table 1 (II).

Example 3. The study antiexudative activity.

The studies were conducted according to the method of estimation-induced histamine of oftalmologii in outbred Guinea pigs of both sexes weighing 250350, Swelling of the conjunctiva was performed by instillation of two drops of 2% solution of histamine dihydrochloride. The study drugs were administered orally in the form of an aqueous suspension for 1 hour prior to the installation of histamine.

About the effect of the drug is to be judged by the condition of hyperemia of the mucous membrane of the century.

Table 1 (III), R is th drug "tefen".

Example 4.

Assessment of the impact of the drug on the level of intracellular content of camp.

A comparative study of the effect of the described drug-stimulated adenosine increase in the level of camp in lymphocytes. The final concentration of adenosine in the samples was 0.1 μm, which corresponds to physiological concentrations of purine in the blood. The assessment of the content of camp in lymphocytes was carried out by radioligand method. The concentration of cells in suspension was 3 million/ml of medium 199 containing 10 mm HEPES. Cells were incubated at temperature 37oC. Investigational drugs made in the volume not exceeding 50 ml. After the cells were destroyed by heating at a temperature of 90oC for 2 minutes, centrifuged at 3000 g for 5 minutes and selected 200 µl of the supernatant for analysis of the content of camp. The concentration of cyclic nucleotide expressed in pmol/107cells reliable error of the mean at a significance level of p<0.05 78 results of independent experiments.

The research results are summarized in table 1(IV).

Studies on the action of the described drug showed a significant increase caused by adenosine level rise nutrici the Oia of the drug on the effector phase of allergic reactions.

Studies on the action of the drug was carried out by the reaction of the release of histamine from basophils in human peripheral blood in vitro.

We used the samples of peripheral blood of healthy donors and patients aged from 18 to 47 years with a heightened sensitivity to the pollen of grasses and trees.

To determine the effect of drug-induced allergen reaction release of histamine suspended cells were incubated without or in the presence of the tested agents in over 40 min at a temperature of 37oC. Next, the samples were added to the allergen and the incubation was prolonged for another 40 minutes the Content of histamine was determined microspectrophotometric method in sedimentary portions of cells without prior extraction of histamine. To exclude the influence of individual differences in the degree of allergic release of histamine from basophils, the results of the experiments were expressed in percents of the maximum release of histamine in this test the basophils of the patient.

Studies have shown that HDFC at a concentration of 10 μm and DMK in concentrations up to 100 μm, there was no statistically significant effect on the secretion of histamine caused by allergen in kanchana braking allergic release of histamine approximately twice the braking control group, and to achieve the same effect when applied separately required five times greater concentration HDFC.

The test results presented in table 3, which shows a pronounced potentiation of inhibition submaximal allergic release of histamine when tested in vitro.

Example 6. Study of the effect of the drug on the proliferation.

Research conducted by assessing the proliferative activity of peripheral blood lymphocytes of patients with atopy. With this purpose from the peripheral blood of patients with atopy were isolated mononuclear cells by centrifugation at one stage the density gradient finalversion (1080 g/cm). As the coagulant used is 2.7% solution of ethylenediaminetetraacetate sodium in the ratio of 1 ml per 10 ml of blood. Isolated and washed with buffer solution mononuclear cells were cultured in medium RPMI 1640 containing 10% serum embryo cow, 5 mm HEPES, 20 mm glutamine and 100 U/ml of gentamicin. To the cells was added phytohemagglutinin (PHA, Sigma) at a final concentration of 1,5x10 μg/ml and tested preparations. The cultivation was carried out in an atmosphere with high humidity and airborne CO2during the course the SS="ptx2">

The study investigated the influence of drugs induced mitogen proliferative response found that:

the level of proliferation of mononuclear cells in action HDFC at concentrations of 10-3M, 10-M and DMK in concentrations of 10-4M, respectively 2680 pulse/min, 4750 pulse/min and 4950 pulse/min, which indicates almost complete suppression of the proliferative response of immune cells,

in concentrations of 10-5M connection HDFC and DMK had no significant effect on proliferation,

the level of proliferation when combined drug action "tefen" was 29570+3200 imp/min, which indicates a weakening of the antiproliferative effect independently applied HDFC and DMK.

Example 7. Test acute toxicity.

Acute combined drug toxicity was evaluated in 4 groups of outbred white mice weighing 18-20, the Drug was administered Per os to 0.3 ml aqueous suspension of the calculation of the drug 100, 200, 400, 800 mg/kg per dose of the drug had 5 animals. Observation on animals and their destruction was carried out for 14 days. The death of animals occurred within the first two days after the introduction of the prep is Riverina re similarly conducted with intelecom 10 days experiment on outbred white mice-males at a dose of teofane - 200, 300, 600, and 900 mg/kg

LD50was calculated by the formula Cerberus.

The results obtained are presented in table 1 (IV).

It is established that the combined toxicity of the drug is reduced in comparison with each individual substance and 455 mg/kg, which can be attributed to his class of mild or low-toxic drugs. Moreover, in combination with HDFC a sharp decrease of toxicity DMK.

Thus, the described combination drug, having a polyfunctional action exceeds the main factors that contribute to anti-allergic properties of the drug, its components at independent application and is thus less toxic, which can be recommended for treatment more efficiently to a wide range of allergic diseases.

Sources of information

1. Saudi F. C., Histamine and antihistaminics funds, Ufa, s.

2. ER, the application 344586, CL MKI And 61 To 31/71, op. 1989.

3. USSR author's certificate 1100875, MKI 07 D 473/08, op. 1986

4. Mashkovsky and others, "Fenkarol and its application in the treatment of allergic diseases", J. Clinical medicine, 1978, 11, S. 22-28.

 

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