RU2249465C1 - Method for treatment and prevention immunodeficiency conditions and diseases associated with bacterial or viral aggression - Google Patents

Abstract

FIELD: medicine and immunology, in particular treatment and prevention immunodeficiency conditions and diseases associated with bacterial or viral aggression.

SUBSTANCE: claimed method includes administration to a patient immunoglobulin drug (e.g., pharmaceutical composition containing 6-12 % of specific heterologous secreted immunoglobulin A, isolated from milk or foremilk of immunized ungulates). Administration is performed parenterally wherein single dose is at least 10 IU/kg of patient weight for treatment or at least 5 IU/kg for prophylaxis; or perorally in dose of 0.2-0.5 g and/or topically one-two times per day for 1-5 days. Method of present invention makes it possible to decrease dose of administrating immunoglobulin due to prolonged retention of its high titers in body fluids.

EFFECT: enlarged range of application and assortment of immunoglobulin drugs.

4 cl, 5 ex

Description

The invention relates to medicine and immunology, in particular to the treatment and prevention of diseases associated with bacterial or viral aggression.

Immunoglobulin preparations are a highly effective treatment and prophylaxis of various infectious, viral diseases and immunodeficiency states, however, to date, only immunoglobulin preparations from human and animal blood serum have been developed and are widely used. This is entirely justified in cases where the disease is manifested by severe toxemia, viremia or bacteremia with toxic, bacterial or viral damage to internal organs. However, there is a wide range of diseases in which the primary localization of the infectious process is associated with the mucous membranes, and the state of local immunity, in particular, the content of secretory immunoglobulins in epithelial secrets, plays the greatest role in protecting the body.

Secretory immunoglobulins A and M are classes of immunoglobulins that protect the body from infectious agents directly at the gates of their penetration - in the skin and on the mucous membranes [1]. Moreover, under the conditions of the infectious process, the locally synthesized antigen-specific secretory immunoglobulin plays the main role in protecting the body. Antigen-specific secretory immunoglobulin A is capable of adsorbing microbial bodies, neutralizing toxins [2] and regulating the functional activity of immunocompetent cells in the focus of inflammation [3], preventing the generalization of the infectious process and the development of a systemic immune response. Specific secretory immunoglobulin A is produced both on bacterial [4] and viral [5, 6, 7] antigens. Moreover, on models of viral infections, it was shown that secretory immunoglobulin A is able not only to interact with virions on the surface of mucous membranes, but also to penetrate into infected cells, blocking viral replication there.

The difference between secretory immunoglobulins and serum immunoglobulins is the ability to penetrate from circulation through intact mucous membranes and skin integuments into epithelial secrets and persist for a long time in high titers in secreted fluids. This allows the use of drugs of specific secretory immunoglobulins for the prevention and treatment of diseases in which the primary localization of the infectious process is associated with the mucous membranes, and to achieve greater clinical effect due to wider possibilities for combining various methods and routes of administration of the immunoglobulin preparation - parenteral and various topical applications , which allows to achieve higher titers of specific antibodies in the pathological focus.

There is a method of treating staphylococcal infection and mixed infections with the presence of staphylococcus serum human antistaphylococcal immunoglobulin for intravenous administration with a specific activity of at least 20 IU / ml [8], which is used to treat patients with chronic obstructive pulmonary disease who have staphylococcus with high antibiotic resistance . Immunoglobulin is administered intravenously every other day, 4 times, in a single dose of 500-1000 ME.

The disadvantage of this method is the need for immunization with a staphylococcal vaccine and staphylococcal toxoid healthy donors, intravenous administration of the drug and the need to use relatively high doses of immunoglobulin.

Closest to the claimed method - the prototype - is a method for the treatment and prevention of smallpox by the use of sheep serum gamma globulin, in which anti-pox sheep gamma globulin is administered intramuscularly in doses of 6-12 ml several times depending on the severity and nature of the course of the disease [9] .

The disadvantages of this method are: the drug is active only in the viremia stage and the need for intramuscular administration of high doses of an immunoglobulin preparation, which increases the risk of anaphylactoid reactions.

An object of the invention is to increase the efficiency of the method, reduce the dose of immunoglobulin administered, expand the scope and expand the range of immunoglobulin preparations.

The stated technical problem is achieved in that for the treatment and prevention of immunodeficiency conditions, bacterial and viral infections of humans and animals, a preparation is used that contains immunoelectrophoretically pure heterologous antigen-specific secretory immunoglobulin A as an active substance in an effective amount that is administered to the patient parenterally, orally and / or locally once or twice a day in a course of 1-5 days, depending on the nature and severity of the disease.

The basic preparation (substance) contains 6-12% of secretory immunoglobulin A, has a pH value of 4-8, anticomplementary activity of at least 10 mg of protein that does not activate 2 CH ₅₀ , protects in> 70% from the corresponding infections when the macroorganism is infected in doses of ≥10 ID ₅₀ ), isreactogenic when administered intravenously, may contain stabilizing additives in a total concentration of not more than 4%. The drug is isolated from the serum of milk and / or colostrum of immunized ungulates.

The proposed method is as follows

A freeze-dried sterile preparation containing immunoelectrophoretically pure heterologous secretory immunoglobulin A is dissolved in a sterile 0.9% aqueous solution of sodium chloride in accordance with the instructions for use and is administered intravenously, intramuscularly, subcutaneously, subcutaneously, during puncture, probing or endoscopy of various organs and body cavities affected by a particular pathological process, intranasally, inhalation, in the form of endotracheal and endobronchial fillings, microclysters, are used To irrigation mouth, nasopharynx, trachea, bronchus, colon, buried in the nose and ears. In this case, the optimal prophylactic single dose of the injection form of the drug is at least 5 IU / kg, and the therapeutic dose is at least 10 IU / kg of the patient's weight, depending on the nature and severity of the disease.

The tabletted or encapsulated form of the drug is taken orally on an empty stomach 0.2-0.5 g twice a day for at least 3 days, with a preventive purpose the dose is reduced by 2 times.

The ointment form of the drug, containing 6-12% of secretory immunoglobulin A, is applied in a thin layer to the area of the pathological process and gently rubbed until completely absorbed.

Rectal and vaginal suppositories containing 0.2-1.5 g of secretory immunoglobulin A are injected into the appropriate organs for at least 5 days.

The introduction of secretory immunoglobulin A is mainly carried out in combination, for example, parenterally and topically, orally and topically, depending on the type of pathology, which allows to achieve a higher titer of specific antibodies in the pathological focus.

The defining difference of the proposed method from the prototype is that an immunoelectrophoretically specific specific heterologous secretory immunoglobulin A is used in an experimentally selected optimal mode, which allows to increase the effectiveness of treatment, expand the scope of the method and reduce the dose of immunoglobulin administered.

Due to the fact that in the known patent and scientific and technical sources of a similar method of treatment using secretory immunoglobulin A isolated from milk and / or colostrum of immunized ungulates, it can be concluded that the claimed technical solution meets the criteria of “novelty” and “ inventive step ”.

The invention is illustrated by the following specific examples of the treatment of diseases associated with bacterial or viral aggression.

Example 1

Patient V., 37 years old, was admitted with complaints of cough with difficult to separate purulent sputum, shortness of breath at rest, NPV up to 24 per minute, elevated temperature - 37.8 ° C. Auscultatory - vesicular breathing, exhalation phase is difficult, multiple dry scattered rales of various timbres, single moist rales in the interscapular region. Percussion - “boxed” sound.

Radiological: the pulmonary pattern is strengthened, deformed, the roots of the lungs are expanded, pulled up to the diaphragm, the sinuses are free. The transparency of the pulmonary fields is enhanced. Determined bilateral peribronchial pulmonary tissue infiltration.

The diagnosis of the underlying disease: bilateral bronchopneumonia.

Concomitant diseases: chronic deforming purulent-obstructive bronchitis, pulmonary emphysema II tbsp.

Laboratory data: blood test - Er. - 4.8 × 10 ¹² / L, Lake. - 8.8 × 10 ⁹ / L, B - 0%, E - 2%, P - 18%, C - 60%, L - 15%, M - 5%.

Pseudomonas aeruginosa in association with St. Aureus resistant to penicillins, gentamicin, lincomycin, tetracycline, chloramphenicol.

Against the background of antibiotic therapy, means aimed at restoring the function of external respiration, detoxification and symptomatic therapy, a specific preparation of bovine secretory immunoglobulin A against Pseudomonas aeruginosa was treated. The lyophilized dried preparation was dissolved in a 0.9% sterile sodium chloride solution and was administered 3 times at a dose of 500 ME intranasally for 3 days, as well as 1 time at a dose of 250 ME endotracheally with bronchoscopy. On the 4th day, the symptoms of intoxication were stopped, the temperature returned to normal. Restoration of the function of external respiration - on day 9. Discharged for 21 days with recovery.

Example 2

Child I., 5 years old, was admitted with complaints of fever up to 39.5 ° C, lethargy, decreased appetite, pain when swallowing, shortness of breath. On examination, the skin is pale, moist, acrocyanosis, sublingual, submandibular lymph nodes are enlarged, they are dense and painful to the touch. Nasal breathing is difficult, the oropharynx is hyperemic, swollen, the back of the pharynx and tonsils are covered with dense, poorly removable plaque, ulcerated, and bleeding of the mucous membrane was found when trying to remove plaque.

The lungs have hard breathing, no wheezing, heart sounds are rhythmic, single extrasystoles, the first tone at the apex is weakened, deaf, blood pressure 90/60 mm Hg, heart rate 110 beats / min. The abdomen is soft, painless. No swelling.

ECG - a rare irregular supraventricular extrasystole, degree I av block

Diagnosis: diphtheria, toxic form of the III degree. Toxic myocarditis.

Against the background of conventional therapy, anti-diphtheria bovine secretory immunoglobulin was administered for intravenous administration at a dose of 500 IU intravenously once and 20 IU intranasally and inhalation using a dosing aerosol balloon three times with an interval of 12 hours.

The fever stopped at the end of 1 day, the symptoms of intoxication - on the second, after 2 days the plaque from the throat mucosa began to leave, after 3 days the changes in the lymph nodes disappeared. On the 7th - normalization of the ECG picture. Discharged after 14 days with recovery.

Example 3

Patient Z., 24 years old, was admitted with complaints of itching in the external genital area, scanty mucous discharge, pain when urinating, sensations of “sand in the eyes”, profuse tearing, and pain in the eyes.

On examination: the conjunctiva of the eyes is swollen, hyperemic, single erosion, vesicles on the edges of the eyelids, injection of sclera.

The external genitalia are hyperemic, edematous, vesicles on the labia minora, single erosion, the vaginal mucosa is hyperemic, the external opening of the urethra is edematous.

No pathogenic flora was found in smears and tear fluid. PCR diagnostics - HSV-1, HSV-2.

The diagnosis of herpes simplex, herpetic keratoconjunctivitis, genital herpes

Against the background of traditional therapy, treatment was carried out with antiherpetic equine secretory immunoglobulin. An ophthalmic ointment containing 6% of antiherpetic secretory immunoglobulin daily for 5 days was placed in the eyes. The external genitalia were smeared with an ointment containing 12% antiherpetic secretory immunoglobulin according to the same scheme. According to the same scheme, vaginal suppositories containing 0.5 g of antiherpetic secretory immunoglobulin were introduced into the vagina. Discharged after 10 days with recovery.

Example 4

Child D., 1.5 years old, was admitted with complaints of lethargy, shortness of breath, nausea, vomiting once, lack of appetite, a liquid, watery stool with a pungent odor, whitish flakes in the stool.

Upon examination, the child is lethargic, inhibited, the skin is pale, temperature 37.1 ° C. Chair - 5 times a day.

When sowing in the stool, pathogenic flora was not found. In the blood, leukocytosis is 10 × 10 ⁹ / L. In urine, protein is 0.5 g / l, leached red blood cells and white blood cells.

PCR diagnosis - rotavirus infection.

The diagnosis of rotavirus gastroenteritis, degree II exicosis

Against the background of rehydration therapy, a tablet preparation of a specific bovine secretory immunoglobulin was administered at a dose of 0.5 g 2 times a day for 3 days. On the second day, diarrheal syndrome stopped, the symptoms of intoxication disappeared. Discharged on the 7th day with recovery.

Example 5

In the children's infectious diseases ward, 42 patients with intestinal infections aged 3 to 12 years were under observation. At the time of the observation, the department was quarantined for the flu epidemic. For the purpose of passive specific prophylaxis, 20 children without signs of manifest influenza infection were intranasally injected with polyvalent anti-influenza equine secretory immunoglobulin at a dose of 5 IU / kg of weight 1 time per day with an interval of 3 days. As a control group, 20 children of the same department were used, who also had no signs of flu at the time of observation.

After 3 weeks of observation in the experimental group, 1 child fell ill, in the control group - 4, the diagnosis of influenza in all patients was verified virologically and serologically by the dynamics of the increase in titer of specific serum antibodies.

It was also noted that in the control group the disease was more severe, the sick child in the experimental group had practically no symptoms of intoxication, catarrhal symptoms in the pharynx were less pronounced, the febrile period lasted 2 days and the body temperature did not rise above subfebrile values.

Using the present invention will increase the effectiveness of the treatment of diseases associated with bacterial and viral aggression, expand the scope, reduce doses and expand the range of immunoglobulin preparations used.

SOURCES OF INFORMATION

1. Kerr MA. The structure and function of human IgA. Biochem. J., 1990, 271, 1553-1559.

2. Jarvis G.A., Griffis J.M., Human IgA1 blockade of IgG-initiated lysis of Neisseria meningitides is a function of antigen-binding fragment binding to polessaccharide capsule. J. Immmunol., 1991, 147, 1962-1967.

3. Kaetzel C.S., Robinson J.K., Chintalacharuvu K.R. et al. The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complex across epithelial cells: a local defense function for IgA. Proc. Natl. Acad. Sci, USA, 1991, 88, 8796-8800.

4. Glass RI, Svennerholm A.M., Stoll BJ et al. Protection against cholera in breast-fed children by antibodies in breast milk. N. Engl. J. Med., 1983, 108, 1389-1392.

5. Mazanec MB, Nedrud JG, Lamm ME. Immunoglobulin A monoclonal antibodies protect against Sendai Virus. J. Virol., 1987, 61, 2624-2626.

6. Turner RB, Kelsey DK. Passive immunization for prevention of rotavirus illness in healthy infants. J. Infect Dis., 1987, 156, 158-166.

7. Renegar KB, Small PA. Immunoglobulin A mediation of murine nasal anti-influenza virus immunity. J. Virol., 1991, 65, 2146-2146.

8. Sharygin S.L., Sinitsyna G.M., Kardovsky A.G. et al. The use of anti-staphylacoccal immunoglobulin for intravenous administration in the treatment of bronchopulmonary diseases // in Sat. “Clinical use of immunoglobulins for intravenous administration”, ed. V.V. Anastasieva, issue 2 (ext.), Nizhny Novgorod: NGMA, 1999, pp. 91-95.

9. Guidelines for the use of gamma globulins for the prevention and treatment of infectious diseases. - Tomsk Research Institute of Vaccines and Serums of the Ministry of Health of the USSR. Issue 23. - Ed. Tomsk University, 1964.

Claims (4)

.1. A method for the treatment and prevention of immunodeficiency states and diseases associated with bacterial or viral aggression, comprising administering an immunoglobulin preparation to a patient, characterized in that a preparation containing 6-12% of a specific heterologous secretory immunoglobulin A isolated from milk or colostrum immunized is used as an immunoglobulin preparation ungulates, while the introduction is carried out parenterally in a single dose of at least 10 IU / kg of the patient’s weight for therapeutic purposes and in a dose not m it is 5 IU / kg body weight in order to prevent, or orally in a dose of 0.2-0.5 g, and / or topically once or twice daily, a course of 1-5 days. 2. The method according to claim 1, characterized in that the drug is used in liquid, tablet, capsule or ointment form. 3. The method according to claim 1, characterized in that the preparation containing a specific heterologous secretory immunoglobulin A is used topically to treat mucous membranes in the form of drops, spray, inhalations, microclysters and irrigation at a dose of 20-500 ME, in the form of rectal and vaginal suppositories containing 0.2-1.5 g of the active substance, as well as for treating the skin - in the form of an ointment containing 6-12% of the active substance. 4. The method according to claim 1, characterized in that the specific heterologous secretory immunoglobulin A is used in combination by simultaneous parenteral and local administration or oral and local administration.