JPH08176000A - Agent for treating c type hepatitis - Google Patents

Abstract

PURPOSE: To obtain a preparation containing the cells (their treated products) of a lactic acid bacterium as an active ingredient, free from a side effect and toxicity, and enabling the rapid therapy of chronic active C type hepatitis by the oral administration of the preparation. CONSTITUTION: The preparation contains the cells of a lactic acid bacterium or their treated products, preferably comprising the cells of a microorganism [e.g. Enterococcus faecalis NF-1011 (FERM P-12564)] belonging to the genus Enterococcus, as an active ingredient. For the production of the preparation, a carrier such as starch, lactose or soybean protein, and additives such as an excipient, a binder, a disintegrator, a lubricant, a stabilizer and a flavor are used. The preparation is usually administered at a dose of 2-100mg/kg body weight/day as the active ingredient in one to several portions. The preparation can be used together with other medicines, and is effective also for a patient not exhibiting an effect on an INF therapeutic method.

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, which comprises a lactic acid bacterium or a treated product thereof as an active ingredient.

[0002]

2. Description of the Related Art Hepatitis C virus (HC
V) method for measuring gene antibody was developed,
95% of about 200,000 patients with non-B hepatitis per year
Has been found to be hepatitis C, and currently approximately 70,000 C
The number of hepatitis patients is increasing.

Most of the infection routes of hepatitis C are blood infections such as blood transfusions of blood and blood products, infections by devices contaminated with blood of patients and HCV carriers, but unlike hepatitis B, they are caused by sexual activity. Infection, family infection, and mother-to-child transmission are low.

The spontaneous cure rate of hepatitis C is low, persistent infection occurs after the onset of acute hepatitis, and about 60% of cases shift to chronic hepatitis, and some progress to cirrhosis and hepatocellular carcinoma. In addition, about 70% of adults will become carriers and become chronic hepatitis even after the first infection of adults. Therefore, the number of chronic hepatitis C patients is currently 1
It is estimated that over 500,000 people and over 2 million carriers.

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

[0006] INF has an action of destroying HCV-RNA, but it requires long-term administration, and about half of the groups in which the GPT value became normal have recurrent hepatitis after the discontinuation of INF administration. In addition, side effects are large, such as influenza-like symptoms (headache, fever, arthralgia, myalgia, loss of appetite, general malaise, nausea, vomiting, etc.), loss of effect due to induction of INF antibody, autoimmune disease, and depression ( Insomnia, irritability, etc.), hair loss, thyroid dysfunction, blurring, etc. In particular, the rapid increase in suicides due to depression is a big problem.

[0007] SNMC has an anti-inflammatory action, and its descending transamylase action has been confirmed. 20 for chronic hepatitis
~ 40 ml / day IV or 5% glucose 200-50
Mix with 0 ml for 4 weeks or more by intravenous drip, and if liver damage is strong and the GPT value is 200 IU / dl or more, mix 100 ml / day with 5% glucose 200-500 ml and drip intravenously for 4-8 weeks. Long-term high-dose administration. SNM
Glycyrrhetinic acid produced by conversion of glycyrrhizin, which is the main component of C, has an action of suppressing the inactivation of adrenocortical hormones in the liver. Therefore, no side effects have been reported with small doses of SNMC at present, but with large doses. , Glycyrrhetinic acid-induced hypertension, edema and other pseudo-aldosterone symptoms have been reported, and hypokalemia during administration has also been observed.

There is also an oral preparation containing glycyrrhizin, but glycyrrhizin, which is a medicinal component, is converted into glycyrrhetinic acid in the stomach and loses its original activity. Therefore, the effect is lower than that of SNMC, and side effects due to glycyrrhetinic acid produced are also caused. Since it can be seen, it has low utilization.

Although currently limited to hepatitis B, immunomodulators are also used. This drug has an action of stimulating immune cells to enhance the immune capacity for chronic hepatitis in which the immune capacity is slightly reduced. Immune regulators include Shosaikoto, OK-432 (picibanil), Lentinus edodes
mycelia (LEM), recombinant interleukin 2 (r
IL-2).

When liver damage occurs, GOT (glutamate oxaloacetate transaminase) in blood
The abnormal value of the liver can be known by the fact that the value or GPT (glutamate / pyruvate / transamylase) value is significantly increased. Γ-G if overdose of alcohol
TP (gamma glutamyl transpeptidase) shows a high value. Acute hepatitis has a GOT value of several hundred to several thousand IU / dl
It may increase to
The T value is 1000 IU / dl or less, and the GPT value is rather high. In addition, these values can be reduced to the normal range by proper treatment. As described above, these test values are important as indicators of liver damage or liver function status.

[0011]

Most of the above-mentioned drugs currently used for treatment are injections. Moreover, in the case of long-term parenteral administration, antibodies against the administered drug are likely to be produced, in which case the effect is diminished, and sometimes serious side effects occur. Therefore, for chronic hepatitis that requires long-term treatment, it is not possible to treat it only as an outpatient.
Or, they have to be held in and out of the hospital for a long time due to daily hospital visits. Such a treatment method imposes a heavy burden on the patient in terms of time, physical and mental as well as economically, and limits the range of behavior of the patient and quality of life (QOL). It takes time to return to society by mimicking the decrease in

[0012] In order to achieve early rehabilitation of patients, it is preferable to use the drug as an oral drug which can be easily used at home. Moreover, there are no side effects as described above,
A drug having a strong pharmacological action is required.

[0013]

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

Since the agent of the present invention is a lactic acid bacterium or a treated product thereof, it is not toxic and has no fear of side effects. In addition, it can be used in combination with other drugs and is effective even when administered to patients who are ineffective in IFN therapy.

To prepare the lactic acid bacterial cells or treated products thereof used in the present invention, carriers such as starch, lactose, soybean protein,
Tablets and granules can be prepared by a known method using additives such as an excipient, a binder, a disintegrant, a lubricant, a stabilizer, and a flavoring agent.

The amount used depends 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 a day or in several divided doses.

[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 also be used for patients who are ineffective in IFN therapy. Further, since it is orally administered, it is not necessary to go to the hospital every day, and it can be easily used at home, so that it is possible for patients to return to society early.

[0018]

EXAMPLES Examples will be shown below, but the present invention is not limited to the description of these Examples.

Example 1. (Cultivation of Enterococcus faecalis)
s) NF-1011 (NIKKO Microbiology No. 12564) was inoculated into a Rogosa liquid medium having the composition shown below (the number of bacteria: 10 ⁶
Cells / ml) and cultured at 37 ° C. for 10 to 16 hours to obtain a culture solution containing about 10 ⁹ viable cells / ml. 1 of the obtained culture solution
The cells were collected by centrifugation at 2,000 xg 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.
Then, the cells were dried by an appropriate method such as a hot air drying method or a freeze drying method to obtain dried dead cells.

The composition of the 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 in 1) 5 ml Distilled water 1000 ml (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 was pointed out in 1979 and he was diagnosed with chronic active hepatitis C. I was treated with SNMC, but GOT value 100 IU / dl, GPT value 120 IU / dl
Since it does not decrease to a normal value and has no effect simply by changing the neighborhood, from June 1993, the agent of the present invention containing the Enterococcus faecalis dried bacterial cells obtained in Example 1 is added as a bacterial cell amount of 10 mg / I took it once a day every day. About half a year later, the blood test value in January 1994 has a GOT value of 45 IU / d.
1, the GPT value was 61 IU / dl, which was only a slight increase compared to the normal value, the γ-GPT value was 28 IU / dl, and the serum amylase value was 104 IU / dl, which were decreased to the normal range.
When a liver biopsy was performed in February of the same year, there was almost no tissue moistening, and there was no tendency for lobular reconstruction. Therefore, IF
There was no need for N adaptation, and it was diagnosed that regular follow-up was sufficient.

Clinical example 2. 50-year-old man In November 1990, hepatitis C was diagnosed, and Shosaikoto and SM
IFN administration was continued for 1 year (3 million units / day) at the same time as the NC combination therapy was continued, but when the administration was discontinued after the symptom resolved, GOT and GPT levels re-elevated, and IFN was again administered. Administration (10 million units / day) was started. Since GOT and GPT levels decreased after administration for 3 months, both values increased again when the drug was discontinued, and liver function deteriorated. As described above, since the blood test value is unfavorable and the therapeutic effect cannot be obtained, from November 1993, the agent of the present invention containing the dried Enterococcus faecalis bacterial cells obtained in Example 1 was added as a bacterial cell amount of 45 mg. / Kg
The body weight was taken once every day. Four months later, the blood test value in March 1994 showed that the GOT value was 130 IU / dl to 80 IU / dl,
GPT value decreased from 265 IU / dl to 139 IU / dl,
The γ-GTP value decreased to the normal value of 56 IU / dl.

Clinical example 3. A 48-year-old man was pointed out to have high GOT and GPT levels in a medical examination 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 1 year, both GOT and GPT levels fell to the normal range of 25-45 IU / dl and became stable, so when administration was discontinued, GOT level was 90 IU / dl,
Since the GPT value rose again to 145 IU / dl, 1992 10
She was hospitalized monthly and re-administered IFN (10 million units / day). 2 months after re-administration, GOT value 30 IU / dl, GPT
The value was 45 IU / dl, so when the operation was stopped again, the GOT value was 70 IU / dl and the GPT value was 140 IU / dl again.
The IFN therapy was tried again and again, but the same course was shown.
Although the IFN therapy showed improvement in this way, the IFN therapy was discontinued in January 1994 because of relapse due to discontinuation of administration and strong side effects during administration.

From February 1994, the above-mentioned patient was orally administered with the agent of the present invention containing the dried Enterococcus faecalis cells obtained in Example 1 at a dose of 45 mg / kg body weight once a day. Blood test value of July, 1994 four months later is 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, GOT suddenly became 1500 IU / dl, and she was discharged from hospital one month after she was hospitalized urgently. After that, he was diagnosed with hepatitis C at another hospital. When I was a nurse, I accidentally inserted a needle with hepatitis C patient's blood attached to it, which is considered to be the cause. I couldn't physically receive IFN, I was around GOT90IU / dl, GPT120I
The numbers around U / dl remained the same, but there was no light answer. From July 1994, this patient was orally administered with the agent of the present invention containing Enterococcus faecalis dried bacterial cells obtained in Example 1 at a cell amount of 45 mg / kg body weight every day. One month later, the blood test value in August 1994 showed a GOT value of 86 IU / dl to 55 IU / dl, G compared with the value tested in January of the same year.
The PT value decreased from 120 IU / dl to 64 IU / dl.

Clinical example 5. A 58-year-old woman I was ill in 1983 after I accidentally inserted a needle with blood attached to a patient with hepatitis C while I was a nurse.
FN therapy was performed. When the first time was performed, side effects such as fever strongly appeared, but the blood biochemical liver function values did not decrease so much, and the type of IFN was changed and administration was performed again. A few days after administration, visual field loss due to fundus hemorrhage occurred, and IFN administration was discontinued. From June 1994, this patient was orally administered with the agent of the present invention containing the dried Enterococcus faecalis bacterial cells obtained in Example 1 at a dose of 45 mg / kg body weight every day. The values before and after ingestion of the agent of the present invention are shown in Table 1.

[0027] The units for GOT, GPT, LDH are IU / dl

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

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

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication C12R 1:01)

Claims (2)

[Claims] 1. A therapeutic agent for hepatitis C, which comprises a lactic acid bacterium or a treated product thereof as an active ingredient. 2. A lactic acid bacterium belonging to the genus Enterococcu
A microbial cell belonging to s) or a processed product thereof.
Hepatitis C therapeutic agent described