RU2160603C1 - Method for treating viral hepatitis - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves applying etiotropic therapy with cytotoxins and antiviral preparations is carried out on the background of synthetic polypeptide preparation of bis- glutathione belonging to thiopoietins class of drugs. The preparation is administered predefined mode taking into account the mode of etiotropic therapy application. EFFECT: accelerated treatment course; reduced frequency and severity of side effects. 3 cl, 2 dwg, 1 tbl

Description

 The invention relates to medicine and can be used to treat hepatitis caused by viruses.

 Known drugs for the treatment of viral hepatitis, such as α-interferon, derivatives of nucleosides and nucleotides, pyrophosphate analogues.

 The closest analogue of the proposed method for the treatment of viral hepatitis is cytokine therapy, for example interferon and nucleoside analogues, in particular lamivudine, according to the scheme: 8 weeks - 100 mg per day lamivudine monotherapy, then 16 weeks - a combination of drugs - 100 mg per day lamivudine with interferon α 2c at 10 million ME per day (J. Heathcote, SW Schalm et al. - Lamivudine and Intron. A combination treatment in patients with chronic Hepatitis B infection - J. Hepatology 1998, 28 (Suppl. 1): 43.) .

 However, the introduction of drugs according to this scheme throughout the course of treatment is accompanied by adverse events. For example, 86.5% of patients report general malaise and increased fatigue, 93.4% report headaches, almost half (44.5%) suffer from muscle pain, and 42% are nausea and vomit. Such therapy is effective only for 24% of patients. Thus, 4.5 months of treatment are accompanied by a variety of unpleasant sensations, and cure is achieved only in 24% who have undergone treatment.

 The aim of the invention is to increase the effectiveness of treatment, reducing the duration of therapy, reducing the frequency and severity of side effects.

 This goal is achieved by the fact that patients are administered bis- (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt or preparations containing this compound in a dose of 10-30 mg intramuscularly 5-7 days before, in course, and 5-7 days after etiotropic therapy for 30-90 days.

 Reverse transcriptase inhibitors, protease inhibitors or pyrophosphate analogues are used as the antiviral drug.

 In particular, α-interferon is used at a dose of 1–3 million ME per day for 30–90 days, and as antiviral drugs, lamivudine at a dose of 300–900 mg per day for 30–60 days, cricivan at a dose of 0, 5 - 2.0 per day for 30 - 60 days or foscamet in a dose of 0.4 - 5 mg per day for 5-15 days.

 Bis- (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt (RF patent 2089179 from 12/14/1995) has a differentiated effect on liver cells and the immune system: it initiates apoptosis of cells containing the virus at the same time stimulating the proliferation and differentiation of unchanged cells of the immune system and liver.

 According to the invention, bis- (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt is administered 5 to 7 days before the start of the use of cytokines and antiviral drugs and stopped 5 to 7 days after its completion, at doses of 10- 30 mg per day intramuscularly for 30-90 days. A dosage form of interferon is used as a cytokine, reverse transcriptase inhibitors, such as lamivudine at a dose of 300-900 mg per day, lasting 30-60 days, are used as an antiviral drug; protease inhibitors, such as crixivan, at a dose of 0.5-2 mg per day for 30-60 days; or pyrophosphate analogues.

 In particular, α-interferon is used at a dose of 1–3 million ME per day for 30–90 days, and as antiviral drugs, lamivudine at a dose of 300–900 mg per day for 30–60 days, cricivan at a dose of 0, 5-2.0 per day for 30-60 days or foscamet in a dose of 0.4-5 mg per day for 5-15 days.

 In FIG. 1 shows the content of alanine aminotransferase (AlAT) of the patient’s blood before and after treatment; in FIG. 2 - change in titer of antibodies to hepatitis C virus during treatment.

The invention is illustrated by the following examples:
Example 1

 Patient N., 39 years old, in April 1999 with a diagnosis of hepatitis C, a chronic course, the stage of virus replication, sought help with complaints of general weakness, decreased performance, and a feeling of heaviness in the liver after errors in the diet.

 On examination: the correct physique, sclera of normal color, skin and visible mucous membranes are pale, no rashes. In the right iliac region, there is a scar after appendectomy. The abdomen on palpation is soft, painless. The liver is enlarged, protrudes from the edge of the costal arch by 1 cm. The edge of the liver on palpation is soft, painless, rounded. A slight swelling of the legs is noted. No pathology was detected in the cardiopulmonary system. A laboratory blood test revealed an increase in the level of alanine aminotransferase (AlAT) to 44.9 units / L, aspartic aminotransferase (AsAT) to 36.7 units / L.

 Patient complaints, enlargement of the liver, swelling, increased levels of ALAT indicate liver damage. Detection of hepatitis C virus RNA in the blood indicates the circulation of the virus in the body, which is an etiological factor in liver damage.

Appointed course of treatment:
bis- (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt - intramuscularly, 20 mg each - 100 days.

 α-interferon - intravenously, at a dose of 3 million ME per day - 90 days.

 lamivudine - orally, 300 mg / day - 90 days, from the 6th to the 95th.

 Selective tissue specialization allows AlAT to be considered a marker enzyme for the liver, therefore, to control the functional activity of the organ and the adequacy of therapy, a change in its quantity was recorded (Fig. 1). By the end of the 9th week of treatment, the level of AlAT becomes normal, which demonstrates the restoration of the functional activity of the liver, the cessation of the destructive effect of the virus on cells.

 During treatment, the patient noted an increase in working capacity, an increase in the duration of sleep, and an improvement in complexion. They stopped worrying about pain in the liver. She does not notice any unpleasant sensations.

 On examination: the correct physique, sclera of normal color, skin and visible mucous pink, no rashes. The abdomen on palpation is soft, painless. The liver does not protrude from the edge of the costal arch. The edge of the liver is not palpable. No swelling. In the cardiopulmonary system without pathology. In the blood - normalization of the level of AlAT, the disappearance of hepatitis C virus RNA, which indicates a clinical and laboratory recovery.

 During the control examination one month after the end of the course in the blood: AlAT 23.9; AsAT 25.1, hepatitis C virus RNA was not detected. Thus, as a result of the treatment, there is a persistent remission.

 Example 2

 Patient G., 17 years old, diagnosed with hepatitis C, chronic course, stage of virus replication, sought advice with complaints of general weakness, insomnia, fatigue, irritability.

 On examination: the correct physique, sclera of normal color, skin and visible mucous membranes are pale, no rashes. The abdomen on palpation is soft, painful in the right hypochondrium. The liver protrudes 1.5 cm from the edge of the costal arch. There is no swelling.

 In a laboratory study, biochemical blood parameters within normal values, hepatitis C virus RNA was detected. The titer of antibodies to hepatitis C virus is 2.054, exceeding the norm by 6.8 times.

 The patient revealed astheno-neurotic and astheno-vegetative syndromes, which, combined with soreness and enlargement of the liver, are a manifestation of its dysfunction.

 The detection of hepatitis C virus RNA indicates the circulation of the virus in the body as a cause of liver damage. The titer of antibodies to hepatitis C virus confirms the viral etiology of liver damage and allows you to judge the dynamics of the infectious process.

Appointed course of treatment:
The complex bis (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt with inosine is intramuscular, 30 mg each for 90 days.

α-interferon - intravenously, at a dose of 1 million ME per day - 90 days
Crixivan - orally, 2 mg / day - 80 days, from the 6th to the 85th.

 During treatment, the patient noted an increase in working capacity, an increase in the duration of sleep, pain in the liver area ceased to bother. According to others, the complexion improved. She does not note any unpleasant reactions during the administration of drugs.

 By the end of the course of treatment (Fig. 2), a decrease in antibody titer occurs.

 On examination: the correct physique, sclera of normal color, skin and visible mucous pink, no rashes. The abdomen on palpation is soft, painless. The liver does not protrude from the edge of the costal arch. The edge of the liver is not palpable. No swelling. In the cardiopulmonary system without pathology. In the blood - a normal amount of AlAT, the disappearance of hepatitis C virus RNA, which indicates a clinical and laboratory recovery.

 During the follow-up examination one month after the end of the course of therapy in the blood, a normal level of enzymes was detected; hepatitis C virus RNA was not detected.

 Example 3

 Patient S., 32 years old, applied for a consultation in June 1999 with a previously established diagnosis of hepatitis "B". Complaints of weakness, loss of appetite, decreased performance, irritability, pain in the liver.

 On examination: the correct physique, sclera is icteric, the skin and visible mucous membranes are pale, there are no rashes. The abdomen on palpation is soft, painless. The liver is enlarged, protrudes from the edge of the costal arch by 1 cm, painful on palpation. The edge of the liver is soft, painful, rounded. No swelling. No pathology was detected in the cardiopulmonary system. A laboratory blood test revealed an increase in the level of AlAT to 50.4 units / L, AsAT to 33.7 units / L. The level of HBs antigen increased by 12.4 times.

 Patient complaints, an increase in liver in size, an increase in ALAT levels indicate liver damage. Hepatitis B virus was detected in the blood of DNA, which indicates the circulation of the virus in the body, which is an etiological factor in liver damage.

Appointed course of treatment:
bis- (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt - intramuscularly, 20 mg each - 90 days.

α-interferon - intravenously, at a dose of 3 million ME per day - 90 days
lamivudine - orally, at 600 mg / day - 70 days.

 During the treatment, the patient noted an increase in working capacity, normalization of the color of the sclera, improvement in complexion, ceased to disturb pain in the liver. I did not notice any discomfort with the introduction of drugs.

 On examination: the correct physique, sclera of normal color, skin and visible mucous pink, no rashes. The abdomen on palpation is soft, painless. The liver does not protrude from the edge of the costal arch. The edge of the liver is not palpable. No swelling. In the cardiopulmonary system without pathology. In the blood - normalization of the level of AlAT, disappearance of hepatitis B virus DNA, a decrease in antibody titer by 4.4 times, which indicates a clinical and laboratory recovery.

 During the control examination one month after the end of the course in the blood: AlAT 21.2; AsAT 20.1, DNA of hepatitis B virus - not found, which is evidence of persistent remission.

 Example 4

 Patient L., 27 years old, in March 1999 with a diagnosis of hepatitis C, a chronic course, the stage of virus replication, sought help with complaints of general weakness, decreased performance, and a feeling of heaviness in the liver area after errors in the diet.

 On examination: the correct physique, sclera of normal color, skin and visible mucous membranes are pale, no rashes. The abdomen on palpation is soft, painless. The liver is enlarged, protrudes from the edge of the costal arch by 2 cm. The edge of the liver on palpation is soft, painless, rounded. No pathology was detected in the cardiopulmonary system. A laboratory blood test revealed an increase in the level of alanine aminotransferase (AlAT) to 84.9 units / L, aspartic aminotransferase (AsAT) to 66.7 units / L.

 Patient complaints, an increase in liver in size, an increase in the level of AlAT and AsAT indicates liver damage. Detection of hepatitis C virus RNA in the blood indicates the circulation of the virus in the body, which is an etiological factor in liver damage.

Appointed course of treatment:
bis- (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt - intramuscularly, 10 mg each - 100 days once a day.

α-interferon - intravenously, at a dose of 3 million ME per day - 90 days
lamivudine - orally, 300 mg / day - 90 days, from the 6th to the 95th.

 By the end of the 7th week of treatment, the level of AlAT and AsAT became normal, which demonstrates the restoration of the functional activity of the liver, the cessation of the destructive effect of the virus on the cells.

 During treatment, the patient noted an increase in efficiency, increased sleep, improved complexion. They stopped worrying about pain in the liver. She does not notice any unpleasant sensations.

 On examination: the correct physique, sclera of normal color, skin and visible mucous pink, no rashes. The abdomen on palpation is soft, painless. The liver does not protrude from the edge of the costal arch. The edge of the liver is not palpable. In the cardiopulmonary system without pathology. In the blood - normalization of the level of AlAT and AsAT, the disappearance of hepatitis C virus RNA, which indicates a clinical and laboratory recovery.

 During the control examination one month after the end of the course in the blood: AlAT 24.8; AsAT 23.0, RNA of hepatitis C virus - not detected. Thus, as a result of the treatment, there is a persistent remission.

 The treatment of viral hepatitis by the claimed method is not obvious to a wide range of specialists. Traditionally, for the treatment of viral hepatitis, it is customary to prescribe cytokines, for example, interferon preparations in monotherapy or in combination with antiviral agents, for example lamivudine. It is believed that interferon blocks the replication of the RNA of the virus by binding to specific receptors on the cell surface, while lamivudine inhibits the synthesis of the RNA of the virus, penetrating into the infected cell.

 The claimed method uses a compound that implements a different mechanism for influencing hepatitis virus, namely, it initiates the death of virus-containing cells and ensures the availability of the virus to the action of specific drugs.

 No one has ever used this effect in the treatment of viral hepatitis. The combination of these drugs and the scheme of their use, i.e. the sequence of their administration in certain doses, which is defined by the term "method".

 The total decrease in the course dose of cytokines (interferon) and antiviral drugs with high toxicity, combined with the hepatoprotective effect of bis (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt leads to a decrease in the frequency and severity of side effects (see tab.).

 This was revealed during long-term clinical and experimental observations and allows using the optimal and sufficient doses of all drugs used in the proposed scheme for effective virus control. You can be firmly convinced that the claimed method will find wide application in practical medicine in the near future, since it is based on the use of manufactured drugs and can be carried out directly according to the description of the present invention. The inventive method is highly effective and affordable for use by a wide range of hepatologists and clinicians with experience in the treatment of viral hepatitis.

 The claimed invention has important socio-economic importance, since it largely allows to solve the problem of increasing liver diseases of viral etiology and reducing the number of infected people in the population.

Claims (3)

 1. A method of treating viral hepatitis with cytokines and antiviral drugs, characterized in that the patients are administered bis- (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt, or preparations containing this compound, in a dose of 10-30 mg intramuscularly 5 to 7 days before, during and 5 to 7 days after etiotropic therapy for 30 to 90 days.  2. The method according to claim 1, characterized in that the dosage form of interferon is used as a cytokine, reverse transcriptase inhibitors, protease inhibitors, or pyrophosphate analogues are used as an antiviral drug.  3. The method according to claims 1 and 2, characterized in that α-interferon is used at a dose of 1 to 3 million IU per day for 30 to 90 days, and as antiviral drugs, lamivudine at a dose of 300 to 900 mg per day for 30-60 days, Crixivan at a dose of 0.5 - 2 mg per day 30-60 days or foscamet at a dose of 0.4 - 5 mg per day for 5-15 days.

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