Therapeutic combination containing human interferon, pharmaceutical drug interferon-based (options)

 

(57) Abstract:

The invention relates to the field of medicine and is intended for the treatment of hepatitis. The inventive developed a therapeutic combination comprising human interferon, as well as glutathione, or its predecessor, or the inductor. Developed pharmaceutical drugs interferon-based, suitable for the treatment of hepatitis, such as hepatitis b or C. the Technical result of the invention is the expansion of the means to combat viral infections. 3 S. and 12 C.p. f-crystals, 1 tab., 4 Il.

The invention relates to therapeutic combinations or, more specifically, to a combination therapy involving the use of human interferon.

The first and localized reaction of the animal to the virus - producing lymphokine-interferon. Earlier it was believed that the interferon is one molecule, now known that a large family of proteins that have undergone significant evolutionary path and widespread in the animal world. Although there may be some limited cross-reactivity, interferons are usually specific by species. Were initially identified three types of interferon, know the respectively.

Human interferon - can be produced by many different cell types and chromatography HPL C (IHVR) separates this type of interferon on more than 30 subtypes, each of which is encoded by its genome. With regard to human interferon-believe that it is one substance and is produced by fibroblasts. Human interferon - also represents one substance produced by subpopulations of T-lymphocytes stimulated by helper, under the influence of antigen or under the influence of mitogens on white blood cells, T-lymphocytes or T-lipoblastoma cells.

Human interferon - industrial scale is produced by stimulation of the human lymphoblastoid cell line Namalwa the Sendai virus with obtaining a natural mixture of at least 21 subtypes of interferon -, which is then purified by chromatography to a purity of 95% and a specific activity of about 100106IU/mg protein (IU - immunizing unit). Such a product is defined as human interferon - N1, sold under the name WELLFERON (Registered trademark Wellcome Foundation Limited). Natural human interferon - derived from human diploid fibroblasts, usually the Y. Human interferon - you can get a light layer of blood clots using a mitogen, such as enterotoxin A Staphylococcus as an inductor.

Human interferon-and - can also be obtained using recombinant DNA technology, although, if recombinant interferons are produced by expression of the corresponding gene in bacterial cells, they may not have the same tertiary structure as the natural molecule. Similarly, interferons produced in bacterial cells will not be glikozilirovanie, and although this does not affect the biological activity of the molecule when tested in-vitro, it may change the conformation and antigenicity and affect the distribution in the body. Such recombinant human interferon has more than 90% amino acid homology with the natural human interferon: preferably 95% homology, more preferably 97, 98, 99% homology, and most preferably 100% homology. Recombinant human interferons are commercially available, and examples are interferon --2a (ROFERON - a, Roche) and --2a interferon (INTRON - Schering). These molecules differ in one amino acid residue at position 23 (lysine in ROFERONe and argini the experiments in the mid 70-ies used human leukocyte interferon, obtained from cells light layer of blood clots, remaining after receiving plasma from blood, and this has considerably limited the received quantity. In the early 1980-ies progress in production technology led to the use of both natural and recombinant human interferon - for the treatment of chronic hepatitis B. Although this treatment can be considered successful in many cases, indicators of response to treatment only human - interferon, judging by the steady loss of viral markers are usually below 50%. Human interferon - and - were also analyzed for use in chronic hepatitis B, but has never established itself as a therapeutic agent.

All three types of human interferon was also investigated in the treatment of chronic hepatitis C, although the limited availability of interferon - kept work with this type of interferon. Very extensive studies were carried out with the use of interferons mentioned above (Interferon--2a, interferon-2b--and lymphoblastoid interferon) and the results were encouraging as complete response was observed in about 40% of patients. However, 6 months after the only 20-25% of patients.

For complete information on the use of interferons in the treatment of hepatitis, you can refer to the book "Interferons in the treatment of chronic viral infection of the liver "Eddleston and Dixon Pennine Press, 1990

In addition, interferons suggested be used to treat other conditions, including other viral diseases, in addition to hepatitis, and disorders of the immune system, including autoimmune conditions, and various cancers, including kidney cancer, breast cancer, colon cancer, Kaposi's sarcoma, glioma and malignant diseases of the blood.

There is some reason to suppose that, in particular, HIV, chronic viral infections may cause oxidative load in the infected organism. The increased oxidative load viruses obliged a number of mechanisms, including the activation of phagocytic cells by immunocomplexes, accelerate the formation of free radicals Pro-inflammatory cytokines (TNFa, ILG) and the formation of species with reactive oxygen direct interaction between the viral surface glycoproteins and cell membranes.

The number of known substances, which act as trap free radicals at the cellular level or the entire organization is westwoodi in most mammalian cells, who is involved in numerous metabolic functions, including functions of detoxification against free radicals. Glutathione is the major intracellular defense mechanism against oxidative stress, and factors that increase the formation of free radicals that contribute to the inventory of intracellular glutathione. Glutathione also plays an important immunoregulatory role in modulating the activation of lymphocytes, T-cell cytotoxicity and interactions macrophage-lymphocyte.

N-Acetyl-cysteine known for many years as mucolytic, agent corneal healing and as an antidote for acetaminophen poisoning. The connection has a relatively soft recovery action and acts as mucolytic, splitting disulfide bond in mukoproteidov. In some publications, there are claims that the levels of reduced glutathione can be reduced in some chronic viral conditions, particularly HIV infection. N-Acetylcysteine is a precursor, and therefore inducer of glutathione and N-acetylcysteine has been proposed as a therapeutic agent for use in the case of HIV infection.

EP-A-0269017 (Cetus) refers to combined the ideological disorders of native mammals, caused by the production of free radicals. Although the description refers to interferon as lymphokine and mentions infection as a possible cause of biological impairments, it mainly affects of free radicals, which may be formed in the treatment of cancer. Biological data given in the description, fully relate to cancer and focused on the destination TNFa in fibrosarcoma in mice.

The present invention relates to the use of traps free radical or its predecessor or inductor as an aid in the treatment of human interferon.

Thus, in one aspect the invention provides a method of treating a patient suffering from the condition to be treated with interferon, which includes assigning the patient an effective amount of human interferon and in which trap free radical or its precursor or inducer is also assigned for the whole period or part of period of administration of human interferon.

In another aspect, the invention provides for the use of human interferon in the preparation of medicines for use in the treatment of a condition susceptible to cerapachys for the whole or part of a course assignment of the human interferon.

In accordance with another aspect of the invention involves the use of traps free radical or its predecessor or inductor for the preparation of drugs for the treatment of a condition susceptible to treatment with interferon, the method comprising the use of human interferon, and in which trap free radical or its precursor or inducer is also assigned for the entire course or part of a course assignment of the human interferon.

Condition susceptible to treatment with interferon, can be any of the States in which take the human interferons or designate them as effective drugs. Such conditions include viral infections, such as viral hepatitis, infection caused by the human papilloma virus (HPV, CMV and HIV, non-viral infections, such as tuberculosis and health conditions such as asthma.

The present invention is particularly applicable to the use of human interferon in the treatment of hepatitis. As already mentioned, although this treatment gives considerable success in many cases, indicators of response is relatively low, and in the case of hepatitis C, a significant percentage of recidivist these problems.

An example of human interferon used in the present invention, includes the interferons, mentioned above.

In accordance with another aspect, the present invention provides a method of treating viral infection by hepatitis purpose of human interferon, which trap free radical or its precursor or inducer is also assigned to the entire course or part of course assignments of human interferon.

In accordance with the following aspect, the invention provides the use of human interferon in the preparation of medicines for the treatment of infection with viral hepatitis by a method in which trap free radical or its precursor or inducer is also assigned to the entire course or part of course assignments of human interferon.

In another aspect, the invention provides a synergistic effect of the combination, also known as the synergistic combination of human interferon and trap free radical or its predecessor or inductor for use in the treatment of a condition susceptible to treatment with interferon. The active ingredients in a synergistic effect camby combined product. If the assignment is consistent, the delay in the appointment of the second of the active ingredients should not be large, in order not to lose the advantage potenzirovannogo therapeutic action of the combination of active ingredients.

The present invention is applicable to the treatment of viral hepatitis in all its forms, at present there are five such and they are respectively denoted by hepatitis A, B, C, D and E.

Hepatitis a is an acute viral infection with an incubation period of 40 days that are transmitted by the fecal-oral route. The virus is a member of the family picornavirus and consists of the spherical neobrazkove particles 27 nm. The sequence of the viral genome, and it includes a single chain of RNA, containing about 7480 grounds.

Hepatitis B is an internationally widespread and serious viral disease with an estimated number of speakers of more than 200 million people. When it was known as serum hepatitis, the disease was diagnosed based on the symptoms 2-3 months after blood transfusion, injection of fractions of human plasma or use resterilizing needles with syringes. Identification of serum markers NY phase of the disease the majority of adult patients quickly recovered within a few weeks, but some of them does not get rid of the virus after many months and become chronic carriers. The hepatitis B virus belongs to the family of hepadnavirus, the genome of which consists of a small bulk double chain ring DNA fragment that reproduces by copying its DNA into RNA and then re-copying RNA into DNA using revertase.

Non-A, non-B hepatitis is recognized as an increasingly serious health problem internationally. At least 80% of cases of chronic post-transfusion non-A, non-B hepatitis can be attributed to the virus, certain now as hepatitis C, and possibly this virus is responsible for all cases of post-transfusion hepatitis in clinical conditions where blood products are tested for hepatitis B. If approximately half of cases of acute hepatitis C were resolved within months, the rest remained chronic, and in many, if not all cases, is accompanied by the risk of cirrhosis and hepatocellular carcinoma. The structure of the genome of the hepatitis C virus was recently identified, and the virus was characterized as a virus with a single chain of RNA, similar to flaviviruses.

Hepatitis D virus was first identified in 1 the Titus B as helper virus (or closely associated hepadna-virus), although replication is sufficiently effective, so that may be achieved in the serum of a higher titer than the virus-helper). The genome of hepatitis D consists of covalently closed circular RNA and has some structural similarity with some ring viroids or virus-like agents found in plants. Infection with hepatitis D is associated with exacerbation of liver disease and is more common in patients with serious acute illness or exacerbation of chronic hepatitis or cirrhosis) than in patients with persistent chronic hepatitis.

Hepatitis E refers to the virus that causes hepatitis A (Reyes and other Science 247, 1335-39 (1990)), and he gives acute hepatitis without chronic phase. The intestinal virus is transmitted by water and is transmitted by the fecal-oral route. It is particularly widespread in the Indian subcontinent and gives a high percentage of mortality in pregnant women.

The present invention is also applicable to the treatment of human papilloma virus (HPV, which is the agent responsible for nestrogannye warts, juvenile papilloma of the larynx, Condyloma accuminata, and which is involved in cervical cancer. The invention is also applicable to the treatment of other viral infections is red infections, such as tuberculosis, and conditions such as asthma.

Human interferon for use according to the invention can be any of the three types mentioned above, i.e., interferon -, interferon -, interferon -. Usually human interferon is interferon or interferon -. Preferably, if it is human interferon-better yet, if human interferon - obtained from human cell lines in culture or recombinant human interferon -. In accordance with a preferred variant of human interferon is a recombinant interferon --2a or IFN --2B, for example, one of the products under the brand name ROFERON and INTRON. In accordance with another preferred variant of human interferon is a human lymphoblastoid interferon (interferon --N1), for example, the product Wellcome Foundation Ltd under the brand name WELLFERON.

The term "human interferon" includes any interferon wild type, the sequence of which was determined from the person, and any allele, variant or mutant, which substantially retains the activity of the corresponding sequence on the corresponding wild-type.

Human interferons prepared in preparations for the appointment according to the invention as well as for use in pure form in the treatment of a specific condition, such as hepatitis. Thus, the interferon is usually administered parenterally, e.g. by injection, preferably subcutaneous injection. It is better to cook interferon in the form of an aqueous preparation or as a freeze-dried product designed to restore suitable media, for example, water for injections. The preparation can also contain a suitable carrier, diluent or stabilizer, for example, another human protein, such as human serum albumin.

Human interferon is usually administered in accordance with the scheme of treatment, already established in the practice for this product. For example, human interferon -, lymphoblastoid or recombinant may be administered in a dose of from 1 to 10 magaizines interferon per day. The dose may be administered for 3 days a week or more, preferably 3 times a week. The most appropriate dosage ranges from 2 to 6 magaizines interferon daily for three or more days per week, preferably 3 times a week, and specifically, the most acceptable is inost destination interferon is usually a period of several weeks, for example, 12 to 30 weeks, in particular, 24 weeks, although in some cases the treatment can last up to a year or more.

Here, the term "trap free radical or its precursor or inducer" refers to any material that is capable of assigning a carrier to reduce the level of free radicals (also known as oxidative stress) in the media. The material can achieve this reduction in the level of free radicals directly scavenge free radicals or induction as a biological precursor or the other role of the product material in the carrier, which has a utilitarian effect on free radicals. In another case, the material can reduce the level of free radicals implementation inhibitory actions in the processes that lead to the formation of free radicals.

The preferred trap free radicals or its predecessors or inducers include glutathione and its precursors, such as a derivative of the naturally available amino acid cysteine. One of the most preferred precursor of glutathione is N-acetylcysteine. As mentioned above, N-acetylcysteine finds pharmaceutical use in chakalov or its predecessors or inducers include vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, buthionine sulfoxime, diethylacetamide, superoxide dismutase and methionine. Materials that inhibit the formation of free radicals, include inhibitors of xanthine oxidase, such as allopurinol.

Trap free radical or its predecessor or the inductor should be administered in such form and dosage, which could reduce free radical formation and/or to remove the action of free radicals (oxidative stress) in the media. The appointment may be in any convenient way, for example, oral or parenteral, depending on the nature of the material. When possible, is preferred oral assignment.

N-Acetylcysteine is prepared for oral assignments in the form of tablets or granules or as a liquid preparation such as syrup. The appropriate dose of N-acetylcysteine is in the range of 200 mg to 4 g per dose assigned to 4 times a day, for example, 400 - 800 mg 4 times daily, best 600 mg 4 times a day.

Although the treatment according to the invention, for example, viral hepatitis is the combined use of human interferon and traps free radical or her presistence to appoint two components in the form of a combined preparation, and the invention includes such a combination of drugs.

Thus, another aspect of the invention provides a pharmaceutical composition comprising human interferon together with trap free radicals or its precursor or inducer.

Typically, this combination drug is in the form intended for parenteral purposes, such as injection. Such a combined preparation may be in liquid or solid form, in which the human interferon dried and recovered in liquid form.

Two drugs in suitable form may be issued for separate purposes. Therefore, another aspect of the invention provides double pack for the separate purpose of human interferon and traps free radical or its precursor or inducer.

The present invention is particularly applicable to the treatment of hepatitis B or hepatitis C. As mentioned above, the purpose of human interferon, in particular, recombinant or lymphoblastoid interferon -- already established therapy of hepatitis B. in Addition, a number of studies have shown that the same therapy brings significant pulsation B or hepatitis C will be conducted in accordance with established treatment regimens with the addition of the treatment trap free radical or its precursor or inducer during part or the entire course of therapy of human interferon.

The levels of serum alanine aminotransferase (ALT) are highly sensitive marker of liver dysfunction. Of hepatitis B and hepatitis C are both characterized by a high content of ALT, and the progress of the disease is usually controlled by determination of serum ALT. As mentioned above, only about 50% of patients or less with hepatitis B or hepatitis C respond to treatment of the human interferon -, as shown by a significant excretion of viral markers or reduction of ALT levels.

According to one variant of the invention, which is particularly applicable to the treatment of hepatitis B or hepatitis C, particularly hepatitis C, treatment of human interferon, in particular interferon -, is conducted in a conventional way in a few weeks, for example, 12 to 30 weeks, exactly 24 weeks. For patients who do not respond to this initial course of treatment of the human interferon, as shown by significantly reduced levels of serum ALT, treatment continued the com or inductor, preferably glutathione or its precursor or inducer, preferably N-acetylcysteine. Treatment of human interferon and a trap free radical or its precursor or inducer may continue for several weeks, for example, 12 to 30 weeks, specifically around 24 weeks. In accordance with a preferred variant of the invention, this treatment is applied to the treatment of hepatitis C human lymphoblastoid interferon (human interferon --N1).

How did above, some patients with hepatitis B or C may initially respond to treatment of the human interferon, especially interferon -, but there may be relapses. Such patients may be better in the combined treatment of human interferon and a trap free radical or its precursor or inducer, as indicated above.

Dose of human interferon and traps free radical may vary depending on the patient and his condition. Ultimately, the treatment is carried out under the control and responsibility of the treating physician.

Further, the invention is illustrated by examples, which should not be considered as limiting the amount of isabetta post-transfusion and sporadic non-A, non-B hepatitis. Transfer of the infection into a chronic condition is normal, which leads to chronic hepatitis, cirrhosis and eventually to malignant transformation. Several studies have shown that interferon (INF) useful in the treatment of chronic hepatitis C (CHC), but the percentage of responses on average is 50% and the relapse rate after discontinuation of treatment INF can reach 30 - 40%. Accordingly, the proportion of patients with CHC maintaining normal levels of transferase after removing the INF is only about 20 - 40% of all treated cases. Restored glutathione (GSH) is an important antioxidant in mammalian cells, is involved in many cellular functions and depletion of GSH may play a pathogenic role in some chronic viral diseases such as AIDS. In this study, GSH levels were measured in plasma and peripheral blood mononuclear cells (PBMC) from patients with CHC who did not respond to treatment with INF after at least 4 months of treatment. Effect of N-acetylcysteine, a precursor thiol, also was determined according to CH levels and clinical and virological response to treatment.

2. Patients and methods

2.1. Patients

The study involved 14 pitches and serologically, two patients had cirrhosis. All patients were treatment - lymphoblastoid interferon (Wellferon) minimum 4 months (USD 151.6 IU per week, 9 - 21 IU / week); all patients had abnormal ALT values (above 30 IU/L) before the study. The majority of patients with CHC, reacting to INF, normalized transaminase levels in the first 3 months of treatment, and those who have remained high ALT levels after 4 months of treatment, was considered not responsive to treatment. Accordingly, in this study all patients were considered not responsive to INF. Patients continued appointment INF according to the same scheme, but added oral N-acetylcysteine (NAC), 600 mg every 8 hours daily. No patient had increased the dosage of interferon after adding oral NAC, although in 3 cases, the number of interferon slightly decreased (to 151.8 IU) per week to NAC compared with 11.5 1.3 IU/week after NAC/.

In addition, 10 patients (8 men and 2 women, mean age 32 years, from 24 to 63 years) who was recently diagnosed with chronic hepatitis C and who had not received antiviral treatment, took the same number of oral NAC, but without interferon for one month.

26 healthy subjects (14 men and 12 women, mean age 43 years, from 25 to 7 the local ethics Committee.

2.2. Determination of GSH in RVS and plasma

Each patient took blood tests for the simultaneous determination of GSH in VRMS (L - GSH) and depleted platelet plasma (P - GSH). RVMS were isolated by centrifugation on Lymphoprep (Nycomed Pharma AS, Oslo, Norway) and washed 5 times. Isolated cells were killed 20% perchloric acid (2% final concentration), and after centrifugation (1200 g x 10 min at 4oC), and supernatant was stored at -40oC before use. 20% perchloric acid was added to the depleted platelet plasma (2% final concentration), and after centrifugation the supernatant was stored at -40oC to determine GSH.

The samples were thawed, and GSH was determined by the enzymatic method described Brigellus and other Biochem Pharmacol 32, 2529-34 (1983) with modifications Ferrer and others Biochem 264, 532-34 (1990). CH in the presence of CH-transferase was conjugatively with 1-chloro-2,4-benzene (CDNB) (Sigma) and the absorbance of the complex was measured at 340 nm using a spectrophotometer Perkin-Elmer Lambda 2. The absolute value of CH were obtained using the molar extinction coefficient in 9,6103.

2.3. Extraction of RNA and RT-PCR

Polymerase chain reaction reverse transcription (RT described in Ruig and other Hepatology 16, 637-643 (1992) and Cheng and others J. Hepat. in press (1992). Strict procedures were used, recommended Kwoks and Higuchi, Nature, 339, 237-238 (1989) to reduce the risk of contamination (contamination). All extraction and reaction was conducted simultaneously in both positive and negative controls. Also included an aliquot of the final rinse, and in these samples PCR was always negative.

2.4 Statistical analysis

All data are presented as mean values standard error of the mean values (SEM). Comparison for paired and unpaired data was performed using tests Wann Whitney u Wilcoxon.

3. Chart

The results described with reference to the accompanying diagrams, in which:

Fig. 1 - the effect of INF (from 4 to 0 months) and INF plus NAC (0 to 6 months) on the levels of ALT in 14 patients participating in the study;

Fig. 2 - detection in RVMS positive and negative circuits HCV - RNA at treatment of INF and INF plus NAC;

Fig. 3 - detection of HCV - RNA in serum at the serum dilution of 1: 10 both before and after addition of NAC to the treatment of INF; and

Fig. 4 - mean levels of ALT in the same patient population, is shown in Fig. 1, for up to 11 months after the introduction of NAC in the treatment of INF.

4. Results

Srval L-GSH and P-GSH.

Values for L - GSH and P-GSH in the control group were as follows:

L-GSH 3,43 0,89 nmol/106cells

P-GSH 18,1 4,08 nm.

In patients with chronic hepatitis C who have not received antiviral treatment (n = 10), the levels of GSH in plasma (0,63 0,07 lm and RVMS 1,02 0,09 nmol/106cells) is significantly reduced compared with healthy control groups (18,14,08 lm and 3,43 + 0,89 nmol/106cells, respectively, P < 0,01). The purpose of NAC for 1 month significantly increased the levels of GSH in RWMS (2,22 0,38 nmol/106cells, P < 0,05), but the levels of GSH in plasma were not significantly changed (0,99 0,22 lm, n.s). In addition, the levels of serum ALT (128 32 IU/L compared with 110 29 IU/L after one month of treatment NAC) has also changed slightly.

In patients who do not respond to interferon, the levels of GSH in RWMS (1,45 0,27 nmol/106cells) and plasma (0,7 0,21 lm) were also significantly reduced in comparison with the control values (p < 0,01). In these patients the purpose of NAC together with interferon for 3-4 months gave a significant increase in GSH in managernew cells (3,32 0,18 nmol/106cells, p < 0.05) and plasma (2,40 0,20 lm p < 0,05/.

Fig. 1 and the above table show that patients participating in the experiment (not responding to inter is the addition of oral NAC gave a sharp and significant decrease in ALT; even after months of combined treatment ALT values decreased significantly (87 9 IU/L, p < 0,05). Moreover, the continuing appointment of INF and NAC for 5 to 6 months provided further decrease of ALT values in all cases (37 4 IU/L), with normal values in 41% of cases and close to normal values (maximum 56 IU/L in one case) the rest. The addition of NAC to the treatment regimen INF clearly improves response to INF in the case of patients previously classified as not responding to INF therapy.

Reduced levels of ALT combinations INF and NAC was accompanied by a concomitant effect on viral replication. In the case of patients classified as not responding to INF, RVMS were analyzed for the presence of both genomic chain HCV (positive RNA chain) and replicative broker virus (negative RNA chain), before and after addition of NAC to the treatment regimen. As shown in Fig. 2, when patients were treated only INF, genomic chain could be detected in 7 cases (77%), and replicative mediator was detected in 3 patients (33%). However, after 4-6 months of combination therapy INF and NAC positive chain was detected in only 2 cases (22%) and negative circuit HCV - RNA was not detected in any of the cases.

To the 3, after adding the VAC treatment was required higher concentration of serum for detection of HCV: so, before adding NAC HCV - RNA could be detected in 100% of cases, using a serum dilution of 1:10, while after adding NAC to therapy in the same serum dilution, the virus was detected only in 70% of patients.

1. Potentiated by the combination of human - interferon and glutathione, or its predecessor, or the inductor.

2. Combination in p. 1, characterized in that the human - interferon is recombinant.

3. Combination in p. 1, characterized in that the human - interferon is a natural.

4. Combination in p. 3, characterized in that the natural human interferon is human lymphoblastoid interferon.

5. Combination according to any one of paragraphs.1 to 4, characterized in that a precursor or inducer of glutathione is N - acetylcysteine.

6. Combination according to any one of paragraphs.1 - 5 for the treatment of hepatitis.

7. Combination in p. 6, wherein the hepatitis is hepatitis A or hepatitis C.

8. Pharmaceutical drug interferon-based, characterized in that sod is the media.

9. Pharmaceutical drug under item 8, characterized in that it is used for the treatment of a patient suffering from hepatitis.

10. Pharmaceutical preparation comprising glutathione, or its predecessor, or inductor, characterized in that the preparation contains an effective amount of interferon and glutathione or its predecessor, and a pharmaceutically acceptable carrier.

11. The pharmaceutical preparation according to any one of paragraphs.8 to 10, characterized in that the human-interferon is recombinant.

12. The pharmaceutical preparation according to any one of paragraphs.8 to 10, characterized in that the human-interferon is a natural.

13. Pharmaceutical drug under item 12, characterized in that the natural human interferon is human lymphoblastoid interferon.

14. The pharmaceutical preparation according to any one of paragraphs.8 to 13, characterized in that a precursor or inducer of glutathione is N-acetylcysteine.

15. The pharmaceutical preparation according to any one of paragraphs.9 to 14, characterized in that the hepatitis is hepatitis B or hepatitis C.

 

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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

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