The means and method of increasing resistance to infection
(57) Abstract:The invention relates to medicine, namely to Virology, immunology, pharmacology, concerns the creation tools and development methods for increasing resistance to infection. The essence of the invention lies in the fact that developed a new drug interferon (IFN), which use sublingual pellets containing low-dose IFN or realtion or inhibitor of IFN (Radostin, lorivan, Poludan, Amiksin, and so on). Another aspect of the invention is a method of increasing resistance to infection by viruses and other infectious agents (viruses, influenza, parainfluenza, adenoviruses, herpes simplex, Epstein-Barr, coronaviruses, enteroviruses, rhinoviruses, respiratory intitially virus, chlamydia, Mycoplasma). The technical result - the expansion of the means of stimulating the immune system. 3 S. and 4 C.p. f-crystals, 4 PL. The invention relates to medicine, namely to Virology, immunology, pharmacology, concerns the creation tools and development methods to increase nonspecific resistance of the organism, which can be used to prevent infection by viruses and other infectious agents (viruses giratina-intitially virus chlamydia, Mycoplasma), and treatment of disease they cause. In addition, the proposed tool and method can be used in the treatment of autoimmune, cancer and other diseases and conditions associated with the development of secondary immunodeficiency.In the prevention and treatment of the above infections along with traditional chemotherapy drugs and antibiotics are the drugs interferon (IFN) and various inducers of interferons (IIRR), combined with nonspecific antiviral, immunomodulatory and antiproliferative action.The technical purpose of this invention is the rapid and effective enhancement of nonspecific resistance of the mucosa and underlying tissues of the oral cavity and nasopharynx to infection by various viruses and other infectious agents or their recovery is already occurring infection and disease.To solve the problem in the oral cavity is injected the drug interferon, which uses sublingual pellets containing low-dose IFN or realigion (recombinant human IFNa) or IIFN (Radostin, lorivan, Poludan, Amiksin, cycloferon, kagocel, the IFN, which, on the one hand, ensure the immunity of oral mucosa to infection, on the other stimulate immunocompetent cells of the lymphoid formations of the oral cavity and nasopharynx to the additional production of other Pro - and anti-inflammatory cytokines in the gate potential infection. In the case of sublingual pellets containing low dose IIFN, their interaction with cells of the mucosa and lymphoid tissue of the oral cavity and nasopharynx causes the synthesis of a mixture of different ,,- endogenous Itnov and other cytokines in the gate potential infection. Effect of non-specific nature of the antiviral action Ifny and Yerrow contained in sublingual pellets, increase nonspecific resistance of treated their tissues to the effects of different viruses and other infectious agents or their associations, preventing their reproduction in the gate infection, further penetration and distribution in the body.Thus, sublingual pellets containing low-dose IFN or IIFN, create a kind of nonspecific interferon cytokine barrier preventing the spread of infections. Along with local nonspecific antiviral Dec its systemic effects through the gastro-intestinal tract (GIT).Preparations of recombinant human (and natural) of Itnow traditionally used in high doses (106ME to 3-5106ME and more than once) parenteral (V/m, p/or/) in the treatment of hepatitis b and C, multiple sclerosis and various cancers. Moreover, it is known that parenteral administration of drugs of Itnow (recombinant and natural) in high doses is associated, generally, with the development of flu-like syndrome: fever, malaise, arthralgia, catarrhal phenomena, headache.Oral route of administration of drugs of Itnow does not apply because it is believed that under the action of proteolytic enzymes GCG interferons are destroyed (inactivated) and are not absorbed in the native form. However, in the foreign scientific publications of the last years, there have been several reports on the antiviral, antitumor efficacy of oral administration of low doses of recombinant IFN (mouse and human) in mice (1-5) and positive immunological and clinical changes in patients with AIDS, multiple sclerosis and type I diabetes with long-term use of low doses of recombinant human IFNa(104-3104ME) (6-9). In Russia to prevent p is ME in liposomes (DGUP Vector-Pharm", Novosibirsk, Russia), which have been tested in the treatment of acute hepatitis C. also Created tablets reaferona at a dose of 105ME with protease inhibitor that can be used in children and often suffer from various respiratory viral infections.The prototype of the present invention can be applied preparations and IIFN in the form of suppositories for the prevention and treatment of sexually transmitted infections (described in the patent of the Russian Federation 2147873 from 27.04.2000 year ). The present invention differs from the prototype in that it is a sublingual pellets containing low-dose reaferona (realigion) or IIFN and are intended for local dissolution in the oral cavity, i.e., exogenous and endogenous interfrontal and stimulate local nonspecific antiviral immunity. Moreover, the use of sublingual pellets does not exclude exposure of the mixture injected and induced Itnov and cytokines, which creates an additional advantage of their nonspecific antiviral and immunomodulatory effect on the organism as a whole.It should be noted that in the mechanism of action of low oral doses CLASS="ptx2">As a means to stimulate the nonspecific resistance of the organism include:
1. Sublingual pellets containing as IFN - IFN (or realigion) (recombinant human IFNa) at a dose of from 2000 to 4000 ME each.2. Sublingual pellets-minitablets containing IIFN in a dose of from 0.01 to 5 mg depending on the inductor.Sublingual pellets weighing 0.05 g were prepared from sucrose or lactose. For diabetics you can use drops.Interferon - (IFN, realigion) - recombinant human IFNa (DGUP Vector-Pharm", Novosibirsk) lyophilized powder in vials 1000.000 - 3000.000 ME for I/m injection at various viral diseases and cancer.Amiksin - derived fluorenone. Available in tablets of 0.125 in bottles of 10 tablets ("LANCE-Pharma, Moscow). Synthetic low-molecular oral of IIFN induces education-IFN in the blood, liver, lungs, spleen, etc. Has a wide range of antiviral and immunomodulating action. Used in the prevention of influenza and other acute respiratory viral infections, treatment of hepatitis b and C, multiple sclerosis, papillomatosis of the larynx and otherThe results of the COI is culture of fibroblast cells of a human embryo M-19 infection of reference to determine the antiviral actions of IFN by vesicular stomatitis virus (air force) immediately after preparation and after 24 hours of treatment, presented in table 1, indicate that contamination of the air force immediately after processing culture the greatest effect of antiviral protection reaferona average concentrations from 10000-250 IU/ml 50% after 48 hours is reduced to 10% at doses 10000-8000 IU/ml and completely disappears in the other (4000-250 IU/ml). However, 24 hours after treatment culture IFN doses 10000-2000 IU/ml provides 100% protective effect within 24 hours, which is stored on the achieved maximum level within 48 hours in doses 10000-8000 IU/ml With the lowest dose reaferona that provides 100% antivirus protection within 24 hours is 2000 IU/ml, and within 48 hours - 8000-10000 ME.These data are experimental substantiation of expediency of inclusion reaferona in the proposed tool in the minimum dose of 2000 ME and use the most effective - 8000-10000 ME (4-5 pellets).The effectiveness of local application of low doses of IIFN was established in experimental studies in mice on the comparative example internalnode (h) the introduction of low-molecular IIFN - Amiksin and traditional oral method of application and/h infection with the influenza virus (Aichi 68/H3N2/).The data presented show that/h introduction of IIFN in low doses provides preferential synthesis of IFN in the gate infection and creates in them and in target organs more effective interferon barrier (the oral administration of large doses), which inhibits replication of influenza virus. In addition, they point to the leading role of the security entrance gate and target organs in achieving sustainable nonspecific antiviral resistance.The total results of experimental studies in cell cultures and animals were the basis for testing and evaluating the effectiveness of prophylactic use of the proposed sublingual pellets containing low-dose reaferona (n=12) and low dose of one of IIFN of Dibazol (n= 7) in humans during an outbreak of influenza caused by virosta (50-77 years), are at risk for the incidence of influenza and SARS, with a characteristic lack of production-IFN. Test sublingual pellets of Dibazol conducted in a limited contingent of males aged 18-20 years, with a characteristic low-IFN-producing ability of white blood cells. Granules containing 2000 ME reaferona, was used according to the scheme: 5 granules (10000 ME) under the tongue 1 time a day 30 minutes before meals for 10 days.Granules containing Dibazol of 0.01 mg was used according to the scheme: 5 granules (0.5 mg) under the tongue 1 time a day 30 minutes before meals for 10 days.Evaluation of the effectiveness of such prevention was conducted on the results of the monitoring of main indicators of IFN status before and after administration of prophylactic courses reaferona or Dibazol, and 1 month after graduation.From the data of tables 3 and 4 shows that the 10-day course of sublingual pellets 10000 ME reaferona in the course dose of 100000 ME and Dibazol 0.5 mg in the course dose of 5 mg causes stimulation and normalization as characteristic for the elderly is reduced IFN-producing ability of blood leukocytes, and IFN-producing ability of leukocytes in young people.Sublingual apolitically change products or-IFN at their normal values before administration of the drug and stimulates the production or IFN moreover, the stronger is determined by their oppression to the drug. Moreover, the corrective effect on the functional activity of the IFN system low doses as reaferona and Dibazol in the proposed tool has the aftereffect of up to 1 month (time of observation), and the reception of Dibazol stimulates the production of serum IFN up to 16-32 IU/mlThe effectiveness index (EI) of the proposed granules low doses reaferona and Dibazol considering morbidity in the main and control groups in relation to influenza and SARS amounted to an average of 2.2 and 2.0, and the coefficient of efficiency (CE) - 55,1 and 57.4%, respectively.Granules of low doses reaferona and Dibazol have been used for therapeutic purposes in individuals of the control group, patients with influenza (n=12) according to the scheme: 5 pellets under the tongue 2-3 times a day 30 minutes before meals for 10-15 days. therapeutic effect of the proposed remedies in cases of influenza were expressed in mild disease, the absence of complications and reduce the duration of disability. In the control group it was 11.6 days, treated with IFN - 6.9 days, and treated Dibazol - 8.6 days, i.e., the use of Reaper the practical course reaferona granules in the elderly during 6 months of follow-up, there was increased resistance to a variety of respiratory viral infections.Thus, the results of applying the proposed funds were expressed in a fast, effective and lasting immunorehabilitation, mediating the enhancement of nonspecific antiviral resistance of the organism. Moreover, in experimental infection in vitro peripheral blood leukocytes of individuals who received the proposed granules reaferona or Dibazol, virus of the air force, the reproduction of the virus was suppressed by 2.5 and 2.3 Lg PFU/ml, respectively, compared with those not receiving these funds.LITERATURE
1. Tovey, M. G., Maury, S., Eid P. - Marked antiviral and antitumoral activity of Interferon administered by the intranasal/ oral route. European Cytokine Network. 1996, v.7, 3, R. 506.2. Brod, S. A., I. Nelson, J. S. Wolinsky - Ingested IFN - has biological effects in humans. - J. of Interferon &Cytokine Research. 1997, supp.2, p. 63.3 Tovey, M. G., Meritet J. F., Baonz S. et al. - Identification of genes induced by oral Interferon therapy.- J. of Interferon &Cytokine Research. 1999, v. 19, supp. 1, p.92.4. Tovey, M. G. , Meritet J. F., Dron M. et al. - Oromucosal interferon therapy: mechanism (s) of action. European Cytokine Network. 2000, v. 11, p. 154.5. Beilharz, M., Cluning C., Bosio E. - Low dose oral Interferon therapy: Towards mechanism of action. European Cytokine Network. 2000, v.11, p. 154.6. Satoh Y., Kasama K, Yimin et al. - Involvement of hypothalamic pituitary adrenal (HPA) axis in an induction of 2-5 OAS by low dose oral administration of interferon in mice. -J. of Interferon &Cytokine Research. 1999, v.19, p. 125.7. Brod, S. A., T. Phan, S. Katz et al. - Ingest IFN delays i" period in newly diagnosed IDDM. - J. of Interferon & Cetokine Research. 1999, v. 19, p. 124.9. Brod , S., Vriesendorp F. J., C. Ahn et al. - Ingested IFN decreases new brain MRI lesions in relapsing-remiting multiple sclerosis (RRMS). European Cetokine Network. 2000, v. 11, p. 154.10. Brod , S., Henniger E., Brosnan, P. et al. - Ingested IFN maintains residual cell function in newly diagnosed IDDM. European Cytokine Network. 2000, v.11, p. 156. 1. Means for increasing the resistance to infection of the mucous membranes of the oral cavity, nasopharynx and underlying tissue, characterized in that it is made in the form of sublingual pellets, each containing interferon (IFN) at a dose of 2000 - 4000 ME and the canvas.2. Means under item 1, characterized in that as IFN contains IFN or realigion.3. Means under item 1, characterized in that as the Foundation it contains sucrose or lactose.4. Means for increasing the resistance to infection of the mucous membranes of the oral cavity, nasopharynx and underlying tissue, characterized in that it is made in the form of sublingual pellets, each of which contains an interferon inducer (IIFN) at a dose of 0.01-5 mg basis.5. Means on p. 4, characterized in that as an interferon inducer, it provides a means selected from the group: Amiksin, cycloferon, neovir, Radostin, Poludan, lorivan, kagocel, as well as the games it contains sucrose or lactose.7. The method of increasing the resistance to infection of the mucous membranes of the oral cavity, nasopharynx and underlying tissue, characterized by the fact that administered sublingually tool under item 1 at a dose of 2000 - 4000 ME active substances according to the scheme 5 pellets under the tongue 1 to 3 times a day 30 minutes before meals for 10-15 days.
FIELD: medicine, anesthesiology-resuscitation, infectology, detoxication.
SUBSTANCE: the innovation suggested interrupts infectious-toxic shock, moreover, after that it is necessary to prescribe peroral intake of Reaferon-EC-Lipint at the dosage of 10000 - 15000 U/kg. Then one should sample patient's blood to obtain leukocytes to be washed and diluted in 0.9%-NaCl solution, activated due to incubation with immunophan and intravenously injected for a patient. Then comes peroral intake of Reaferon-EC-Lipint at the dosage of 10000 - 15000 U/kg once daily for 5 d. The innovation enables to decrease the number of complications and lethality due to decreasing immunodeficiency.
EFFECT: higher efficiency of therapy.
3 ex, 1 tbl
FIELD: medicine, obstetrics.
SUBSTANCE: at the first stage of pregravidic training one should introduce leukinferon per 10000 IU intramuscularly every other day 10 times, at the second stage it is necessary to perform 3 seances of discrete plasmapheresis. The present innovation enables to decrease the frequency in developing gestosis and the risk for abortion due to normalized activity of female immune system, that in its turn, enables to stop virusemia and virusuria, prevent fetoplacental failure and intrauterine fetal infectioning.
EFFECT: higher efficiency of training.
3 ex, 1 tbl
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to an agent with broad spectrum of biological effect. Agent based on natural interferon and/or recombinant interferon of α- and/or β- and/or γ-types. Agent is made in the form of different medicinal formulations and elicits immunomodulating, antibacterial, antioxidant and regenerating effect and designated for both internal using and external applying on skin and mucosa tissues. Invention provides the development of medicinal agent with broad spectrum of biological action. The prolonged administration of preparation doesn't effect on morphological composition of peripheral blood and has no effect on blood coagulation. The preparation doesn't show topical irritation and pyrogenic effect.
EFFECT: valuable medicinal properties of agent.
22 cl, 8 ex
FIELD: medicine, immunology.
SUBSTANCE: method involves inhalation administration of combination of immunocorrecting agents wherein recombinant interleukin-2 is used or its combination with genetic engineering α2-interferon and with the complex immunoglobulin preparation in the daily doses for 5 days depending on age of patient. Before sanitation with an immunocorrecting agent the method involves assay of carrying type by anti-lysozyme activity of microorganisms (resident or transitory) and repeated examination after sanitation course is carried out. Carriers are subjected for additional sanitation with anti-bacterial preparations in change of carrying type from resident to transitory and with taking into account antibiotic-resistance property of the carrier strain. Method allows carrying out the effective sanitation and immune reablement of germ carriers due to recovery of the adequate natural resistance and complex of nonspecific factor of regional and systemic immunity.
EFFECT: improved and effective method for sanitation.
2 cl, 2 tbl, 5 ex
FIELD: oncological diseases.
SUBSTANCE: invention is designed for use in complex treatment of urinary bladder cancer in case of propagation of tumor to sub-epithelium connective tissue. Method comprises transurethral resection and introduction of immune preparations and furacillin solution. Once transurethral resection completed, three-way Foli catheter is transurethrally introduced to patient, through which mixture of standard furacillin solution with 10·106 ME interferon α-2β is injected from the first postoperative day and over following 3-5 postoperative days bringing summary dose of interferon to 50·106 ME.
EFFECT: prevented traumatism of urinary bladder due to single introduction of catheter and assured continuous action of drugs without development of immune complications.
FIELD: agriculture, veterinary science.
SUBSTANCE: during the 1st d after forming raising groups one should once inject intramuscularly a solution of "Complex A" preparation at the dosage of 0.30-0.32 mg/kg body weight for 45-60-d-aged piglets and simultaneously with fodder one should introduce "Lactobifadol" preparation at the quantity of 0.50-0.52 g/kg body weight during the first 1-5 d. The present innovation enables to activate immune system, increase total protein and hemoglobin in blood that in its turn, prevents bronchopneumonia and remove stress in piglets after forming special raising groups.
EFFECT: higher efficiency of prophylaxis.
1 ex, 1 tbl
SUBSTANCE: method involves administering inmmunotherapy with recombinant interferon-α2b in daily dose of 3x106 MU. It is incubated in thermostat during 1 h at 37°C with 100 ml of autoblood and then it is intravenously introduced to a patient during 1-1.5h daily under blood formula control to reach leukocyte content of>4*109 /l, granulocytes >2*109 /l.
EFFECT: eliminated leukopenia and dose-limiting toxicity risk; accelerated treatment course; reduced risk of infectious complications.
FIELD: genetic engineering, proteins, medicine, pharmacy.
SUBSTANCE: invention relates to a method for preparing a fused protein representing immunoglobulin Fc-fragment and interferon-alpha and can be used in treatment of hepatitis. Method involves construction of a fused protein comprising immunoglobulin Fc-fragment prepared from Ig G1 or Ig G3 in direction from N-end to C-end and the end protein comprising at least one interferon-alpha. Fc-fragment and the end protein are joined directly or by a polypeptide bridge. The fused protein is used for preparing a pharmaceutical composition used in treatment of liver diseases and in a method for targeting interferon-alpha into liver tissues. Invention provides preparing the fused protein eliciting with biological activity of interferon-alpha providing its concentrating in liver and showing enhanced solubility, prolonged half-time life in serum blood and enhanced binding with specific receptors.
EFFECT: improved targeting method, valuable biological properties of fused protein.
10 cl, 5 dwg, 9 ex
FIELD: medicine, oncology.
SUBSTANCE: after removing malignant cerebral tumor one should conduct successive course of: cytokinotherapy consisting of 3 intramuscular injections of leukineferon at 48-h-long interval, adaptive immunotherapy with lymphokine-activated killer cells (LAKC) generated in the presence of recombinant interleukin-2 (IL-2). Moreover, LAKC should be introduced into the channel of removed tumor in combination with IL-2 as 2 procedures at 24-h-long interval. Then comes the course of adaptive immunotherapy with cytotoxic lymphocytes (CTL) generated due to cultivating patient's mononuclear blood cells together with dendritic cells loaded with a tumor antigen, in the presence of recombinant IL-2 to be introduced in combination with it into the channel of removed tumor as 2 procedures at 48-h-long interval. For obtaining dendritic cells in patients before operation it is necessary to isolate monocytes to cultivate with granulocytic-macrophageal colony-stimulating factor and interferon-α at maturating dendritic cells in the presence of monocytic conditioned medium and incubation of dendritic cells in the presence of tumor antigenic material for their loading with a tumor antigen. After immunotherapy with CTL on should conduct the course of vaccinotherapy with dendritic cells loaded with a tumor antigen in combination with subcutaneous injections of IL-2. The method enables to induce high specific anti-tumor immune response along with improved quality of life and prolonged duration of relapse-free period.
EFFECT: higher efficiency of immunotherapy.
2 cl, 2 ex
FIELD: medicine, infectology.
SUBSTANCE: one should introduce rhoncoleukin in standard dosages and standard mode in combination with corbiculin for internal intake per 2 g once daily after meals, being pre-dissolved in 50 ml water, at 8-wk-long course. The present innovation enables to decrease the size of liver, favors regression of disease clinical manifestations in shorter period of time and normalization of detoxicational, protein-synthetic, pigment functions of liver and prolonged remission of the disease mentioned due to corbiculin and rhoncoleukin synergism.
EFFECT: higher efficiency of therapy.
3 dwg, 2 ex, 3 tbl