JP2712000B2 - Hepatitis C treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a therapeutic agent for hepatitis C, comprising a lactic acid bacterium or a processed product thereof as an active ingredient.

[0002]

2. Description of the Related Art In 1989, hepatitis C virus (HC)
V) A method for measuring gene antibodies has been developed,
95% of about 200,000 patients annually who are said to have non-B hepatitis
Was found to have hepatitis C, and about 70,000 C
Hepatitis patients are increasing.

[0003] Hepatitis C is most commonly transmitted by blood, such as transfusion of blood or blood products, or infection of patients or HCV carriers by instruments contaminated with the blood of HCV, but unlike hepatitis B, it is caused by sexual activity. Infection, family transmission, and mother-to-child transmission are low.

[0004] The natural cure rate of hepatitis C is low, and after the onset of acute hepatitis, persistent infection occurs, and about 60% of cases shift to chronic hepatitis, and some progress to cirrhosis and hepatocellular carcinoma. In addition, even in the case of primary infection in adults, about 70% of the people become carriers and shift to chronic hepatitis. Therefore, the number of chronic patients with hepatitis C is currently 1
It is estimated that over half a million people and careers will exceed two million.

[0005] At present, as a drug for treating chronic active hepatitis C, an antiviral agent, interferon (IF) is used.
N) and two types of strong neo-minophagen C (SNMC), which is a glycyrrhizin preparation, are mainly used.

[0006] INF has an action of destroying HCV-RNA, but requires long-term administration, and about half of the group with normal GPT levels have recurred hepatitis after discontinuing INF administration. In addition, side effects are large, such as influenza-like symptoms (headache, fever, joint pain, muscle pain, anorexia, general malaise, nausea, vomiting, etc.), loss of effect due to induction of INF antibodies, autoimmune diseases, depression symptoms ( Insomnia, irritability, etc.), hair loss, thyroid dysfunction, blurring, etc. In particular, the sudden increase in suicides due to depression is a major problem.

[0007] SNMC has an anti-inflammatory effect, and a lower transamylase effect has been confirmed. In chronic hepatitis, 20
４０40 ml / day intravenous injection or 5% glucose 200-50
0 ml and 4 weeks or more by intravenous drip. If liver damage is strong and GPT value is more than 200 IU / dl, 100 ml / day is mixed with 200-500 ml of 5% glucose and 4 to 8 weeks by intravenous drip. Long-term large dose administration. SNM
Glycyrrhetinic acid, which is produced by the conversion of glycyrrhizin, which is the main component of C, has the effect of suppressing the inactivation of corticosteroids in the liver, so no side effects have been reported with small doses of SNMC. It has been reported that glycyrrhetinic acid causes pseudoaldosterone symptoms such as hypertension and edema, and hypokalemia during the administration period has also been observed.

[0008] Although there are oral preparations containing glycyrrhizin, the active ingredient glycyrrhizin is converted to glycyrrhetinic acid in the stomach and loses its original activity. The usage is low because it can be seen.

Although currently limited to hepatitis B, immunomodulators have also been used. This drug has the effect of stimulating immune cells and enhancing immunity against chronic hepatitis whose immunity is mildly reduced. Examples of immunomodulators include Sho-saiko-to, OK-432 (Picibanil), Lentinus edodes
mycelia (LEM), recombinant interleukin 2 (r
IL-2).

When liver damage occurs, GOT (glutamate oxaloacetate transaminase) in the blood
The abnormalities of the liver can be known by remarkably increasing the values and GPT (glutamate pyruvate transamylase) values. Γ-G for alcohol overdose
TP (gamma glutamyl transpeptidase) shows a high value. In acute hepatitis, GOT value is several hundred to several thousand IU / dl
To go to chronic hepatitis.
The T value is less than 1000 IU / dl, and the GPT value is rather high. Also, with appropriate treatment, these values can be reduced to the normal range. Thus, these test values are important as indices indicating liver damage or liver function status.

[0011]

At present, most of the above-mentioned drugs used for treatment are injections. Moreover, in the case of long-term parenteral administration, antibodies to the administered drug are likely to be generated, in which case the effects are diminished and sometimes serious side effects are caused. Therefore, for chronic hepatitis that requires long-term treatment, it is impossible to treat only outpatients.
Or they are forced to stay inside and outside the hospital for long periods of time with daily visits. Such treatments are particularly time consuming, physically and mentally and economically burdensome for patients, limiting their range of activity and quality of life (QOL). It will take time to reintegrate into society by imposing a decline.

In order to achieve early rehabilitation of patients, it is preferable to use internal medicine that can be used easily even at home. Moreover, there are no side effects as described above,
There is a need for drugs that have strong pharmacological effects.

[0013]

Means for Solving the Problems In order to solve this problem, the present inventors have found that a method of enhancing immunity in the body and promoting the elimination of virus is effective in treating hepatitis and preventing recurrence of viral antigens. As a result of repeated studies based on the fact that there is, it is found that oral administration of killed cells of lactic acid bacteria having immunostimulatory effects has a remarkable therapeutic effect on chronic active hepatitis C or an effect that completely cures it. Thus, the present invention has been completed.

Since the agent of the present invention is a lactic acid bacterium cell or a processed product thereof, it has no toxicity and has no concern about side effects. It can also be used in combination with other drugs, and is effective even when administered to patients who are ineffective with IFN therapy.

The lactic acid bacterium cells or processed products thereof used in the present invention are formulated by using a carrier such as starch, lactose, soy protein, etc.
Tablets and granules can be prepared by known methods using additives such as excipients, binders, disintegrants, lubricants, stabilizers, and corrigents.

The amount used varies depending on symptoms, age, etc.
As an active ingredient, 2 to 100 mg / kg body weight per day can be usually administered to an adult once or several times a day.

[0017]

Industrial Applicability The therapeutic agent for hepatitis C of the present invention has no side effects and toxicity and can promptly treat chronic active hepatitis C. Since this drug can be used regardless of the subtype of hepatitis virus, it can be used in patients who are not effective by IFN therapy. In addition, since it is not necessary to go to the hospital every day for oral administration and can be used easily even at home, it is possible for the patient to return to society early.

[0018]

EXAMPLES Examples will be shown below, but the present invention is not limited by the descriptions of these examples.

Embodiment 1 FIG. (Culture of Enterococcus) Enterococcus faecali
s) Inoculation of NF-1011 (Microtechnical Laboratories No. 12564) into Rogosa liquid medium having the following composition, followed by the number of bacteria: 10 ⁶
Cells / ml) at 37 ° C. for 10 to 16 hours to obtain a culture solution with about 10 ⁹ viable cells / ml. The obtained culture solution is
The cells were collected by centrifugation at 2,000 × g for 20 minutes and washed twice with distilled water to obtain cells. The cells were suspended in distilled water and heated at 110 ° C. for 10 minutes to obtain a dead cell suspension.
Next, the cells were dried by a suitable method such as hot air drying or freeze drying to obtain dried dead cells.

The composition of Rogosa liquid medium is shown below. Trypticase 10 g Yeast extract 5 g Tryptose 3 g Monopotassium phosphate 3 g Dipotassium phosphate 3 g Triammonium citrate 2 g Tween 80 (surfactant) 1 g Glucose 20 g Cysteine hydrochloride 0.2 g Salt solution (as per 1) 5 ml Distilled water 1000ml (pH
Adjusted to 7.0, 15 minutes heat sterilized at 121 ℃) (1) saline: MgSO ₄ · 7H ₂ O 11.5
_{g FeSO 4 · 7H 2 O 0.68g} MnSO 4 · 2H 2 O 2.4g distilled water 100ml

Clinical Example 1 54-year-old man Hepatitis (Hepatitis) was pointed out in 1979, and he was diagnosed with chronic active hepatitis C. He had been treated with SNMC, but had a GOT value of 100 IU / dl and a GPT value of 120 IU / dl.
Since the effect of the present invention containing the dried Enterococcus faecalis cells obtained in Example 1 was obtained from June 1993, the amount of the present invention was reduced to 10 mg / day from June 1993 because there was no effect because the concentration of the cells did not decrease to the normal value. The patient was taken once a day at a daily weight of kg. About half a year later, the blood test value in January 1994 was a GOT value of 45 IU / d.
1. The GPT value was only 61 IU / dl, a slight increase from the normal value, the γ-GPT value was 28 IU / dl, and the serum amylase value was 104 IU / dl, each of which fell to the normal range.
When a liver biopsy was performed in February of the same year, there was almost no tissue wetting and no tendency to reconstruct lobules was observed. Therefore, IF
There was no need for N adaptation, and periodic follow-up was diagnosed as good.

Clinical Example 2 50-year-old male In November 1990, hepatitis C was diagnosed, and Sho-saiko-to and SM
Although the combination therapy of NC was continued and the administration of IFN was continued for one year (3 million units / day) at the same time, when the administration was stopped with remission of the symptoms, the GOT and GPT values were increased again. Dosing (10 million units / day) was started. Because the GOT and GPT values decreased after 3 months of administration, when the treatment was interrupted again, both values increased again, and deterioration of liver function was observed. As described above, since the blood test values are not good and the therapeutic effect cannot be obtained, the agent of the present invention including the dried Enterococcus faecalis cells obtained in Example 1 obtained in November 1993 as a cell mass of 45 mg from November 1993. / Kg
Body weight was taken once daily. Four months later, the blood test values in March 1994 were as follows: GOT value was 130 IU / dl to 80 IU / dl.
GPT value decreases from 265 IU / dl to 139 IU / dl,
The γ-GTP value dropped to the normal value of 56 IU / dl.

Clinical Example 3 A 48-year-old male was found to have high GOT and GPT levels at a health checkup in 1990, and became HCV antibody-positive in September 1991, and was diagnosed with hepatitis C. After that, IFN administration (3 million units /
Day), and after one year, the GOT value and the GPT value both decreased to a normal range of 25 to 45 IU / dl and became stable. When the administration was stopped, the GOT value was 90 IU / dl.
The GPT value rose again to 145 IU / dl.
In the month, she was hospitalized and re-administered IFN (10 million units / day). GOT value 30 IU / dl, GPT 2 months after re-administration
Since the value was 45 IU / dl, when the operation was stopped again, the GOT value was 70 IU / dl and the GPT value was 140 IU / dl again.
Repeated attempts at IFN therapy showed a similar course.
As described above, despite improvement by IFN therapy, relapse occurred after discontinuation of administration, and side effects during administration were strong. Therefore, IFN therapy was discontinued in January 1994.

From February 1994, the above-mentioned patient was orally administered once daily with 45 mg / kg body weight of the agent of the present invention containing the dried cells of Enterococcus faecalis obtained in Example 1 as the amount of cells. Four months later, the blood test value in July 1994 was G
OT value from 80 IU / dl to 41 IU / dl, GPT value 180
It decreased from IU / dl to 54 IU / dl. No side effects were observed during administration.

Clinical Example 4 52-year-old woman In 1986, the GOT suddenly became 1500 IU / dl, and she was discharged one month after emergency hospitalization. Later, another hospital pointed out hepatitis C. He accidentally inserted a needle to which hepatitis C patient's blood adhered while he was working as a nurse, which is considered to be the cause. Unable to receive IFN physically, around GOT90IU / dl, GPT120I
With the figures around U / dl, I didn't make any mistakes. From July 1994, the patient was administered the agent of the present invention containing the dried cells of Enterococcus faecalis obtained in Example 1 at a dose of 45 mg / kg body weight daily. One month later, the blood test value in August 1994 was compared to the value tested in January of the same year, and the GOT value was 86 IU / dl to 55 IU / dl.
The PT value dropped from 120 IU / dl to 64 IU / dl.

Clinical Example 5 A 58-year-old female was diagnosed with a disease in 1983 when she was a nurse and accidentally inserted a needle to which hepatitis C blood had adhered.
FN therapy was given. When the first test was performed, side effects such as fever were strongly exhibited, but the liver function values on blood biochemistry did not decrease so much. The administration was repeated with different types of IFN. A few days after administration, visual field loss due to fundus bleeding occurred, and IFN administration was stopped. From June 1994, the patient was administered the agent of the present invention containing the dried cells of Enterococcus faecalis obtained in Example 1 at a dose of 45 mg / kg body weight daily. Table 1 shows the values before and after drinking the agent of the present invention.

[0027] The unit is IU / dl for GOT, GPT and LDH.

Embodiment 2 FIG. (Preparation Example) (1) 50 mg of the dried cells obtained in Example 1 were mixed with 50 mg of purified starch powder and 200 mg of lactose,
Make into tablets or granules.

(2) 10 cells of the dried cells obtained in Example 1
0 mg, soy protein 100 mg and lactose 200 m
g) to make tablets or granules.

Claims (2)

(57) [Claims] 1. A therapeutic agent for hepatitis C, which comprises a lactic acid bacterium or a processed product thereof as an active ingredient. 2. The method according to claim 1, wherein the lactic acid bacterium is of the genus Enterococcus.
2. The cell of the microorganism belonging to s) or a processed product thereof.
Hepatitis C therapeutic agent as described above