JPH04211613A - Oral administrative composition for preventing and treating opportunistic infectious disease - Google Patents

Abstract

PURPOSE:To obtain an oral composition useful for preventing and treating opportunistic infectious diseases caused by immunodeficiency, actinotherapeutics, administration of anti-cancer drug and acquired immunodeficiency. CONSTITUTION:An oral composition for preventing and treating opportunistic infectious diseases, comprising a milk containing an antibody against a bacterial antigen as an active ingredient. A bacterial antigen of Staphylococcus simulans is used as the bacterial antigen of this invention. A milk collected from a milch cow which is obtained by sensitizing a cow in a milk secretion period with such a bacterial antigen and continuously administering the bacterial antigen is used as the milk containing an antibody against the bacterial antigen.

Description

Detailed Description of the Invention [0001] [Industrial Application Field] The present invention is directed to the prevention and treatment of opportunistic infections that occur due to immunodeficiency, radiotherapy, anticancer drug administration, acquired immunodeficiency, etc. The present invention relates to an oral composition. [0002] Opportunistic infections are infections caused by bacteria, attenuated bacteria, protozoa, etc. that are normally considered harmless to hosts with weakened resistance to infection. In hosts with reduced resistance to such infections,
Patients with serious underlying diseases, such as those with diabetes or acquired immunodeficiency, those receiving treatment that may reduce their resistance to infection, such as high-dose steroid therapy during organ transplants, and patients with cancer. Some patients are receiving high-dose therapy with anti-cancer drugs, X-ray radiation therapy, or high-dose antibiotic therapy for infections, and these patients often develop opportunistic infections, and the number of these types of infections has increased rapidly in recent years. It is said that this has been the case. [0003] Moreover, malignant tumors, which are currently the leading cause of death in Japan, are increasing year by year. For this reason, various anticancer drugs have been developed, and radiotherapy is also used to treat lung cancer, uterine cancer, laryngeal cancer, and the like. Furthermore, combination therapy of anticancer drugs and radiation is widely used, and the therapeutic effects are increasing. However, these cancer treatments lower the patient's immune function and lead to frequent infections.Furthermore, the use of antibiotics leads to a decline in the immune system, and as mentioned above, the use of extremely low pathogenic attenuated bacteria and non-virulent bacteria. Opportunistic infections caused by resident bacteria such as pathogenic bacteria may occur. moreover,
In recent years, opportunistic infections that occur particularly with acquired immunodeficiency disease (AIDS) have become a problem, causing difficult-to-treat diseases such as mycoses and pneumonia. [0004] Treatments for these opportunistic infections include:
Antibiotics that are effective against resistant bacteria and intravenous administration of interferon, γ-globulin, etc. are being used. However, the current situation is that these treatments have not achieved significant effects. One of the major reasons that treatments for opportunistic infections are ineffective is thought to be that no screening system has been developed to search for effective drugs. [0005] Problems to be Solved by the Invention The present inventors were conducting research on model animals to develop a screening system for therapeutic agents for preventing opportunistic infections. We discovered that the immune system in the intestinal tract is damaged, causing opportunistic infections, and reported this (Abstracts from the 19th Annual Meeting of the Japanese Society of Immunology, p. 477). As a result of conducting research using this model animal, we found that it is possible to orally administer milk containing antibodies against bacterial antigens, such as colostrum or milk from cows immunized with the antigen after antigen sensitization. It has been found that even infections, especially serious opportunistic infections, can be treated. That is, the present invention
An object of the present invention is to provide a composition for preventing and treating opportunistic infections that can be administered orally. Conventionally, intravenous injection of immunoglobulin has been used in cases of opportunistic infections in which the causative pathogen has not been identified, or as immunoreplenishment therapy, but it has been administered orally and in the form contained in milk. There are no known examples so far. [Means for Solving the Problems] The present inventors have discovered that when milk containing antibodies against bacterial antigens is orally administered to patients with opportunistic infections as described above, even patients with severe opportunistic infections can This was based on the knowledge that it can be treated. As the bacterial antigen, one or more microorganisms selected from the groups shown in Tables 1 and 2 below are suitable for the present invention. [Table 1] Bacteria name
ATCC No. Staphylococcus simulans 11
631 Staphylococcus epidermidis
155 Streptococcus pyogenes type 1 8671 Streptococcus pyogenes type 3 103
89 Streptococcus pyogenes type 5
12347 Streptococcus pyogenes type 8 12349 Streptococcus pyogenes type 12 1143
4 Streptococcus pyogenes type 14
12972 Streptococcus pyogenes type 18 12357 Streptococcus pyogenes type 22 10403
Aerobacter aerogenes
884 Escherichia coli

26 Salmonella enteritidis
13076 Pseudomonas
Erginosa 77
00 Klebsiella pneumoniae
9590 Salmonella Typhimurium 133
11 Haemophilus influenzae
9333 Streptococcus
Mitis 62
49 [Table 2] Bacteria name
ATCC No Proteus
vulgaris
13315 Shigella disenteriae
11835 Propiobacterium acnes
11827 Streptococcus sanguis 10556 Streptococcus salivarius 1
3419 Streptococcus mutans
25175 Streptococcus
Agalactie 13813
Streptococcus pneumoniae
Moreover, according to the present invention, milk containing an effective form of γ-globulin can be obtained. This is because adding serum-derived γ-globulin to milk is inadequate in terms of stability and activity maintenance, and it is necessary to use a product that contains the natural form of γ-globulin that is secreted into milk. . An example of such a product is so-called colostrum, which is milked from a mother's body immediately after production. Also, JP-A-54-113425, JP-A-57-
Milk obtained from a cow injected with a booster of the antigen disclosed in Publication No. 188523 has a similar effect. Such milk is preferably obtained by sensitizing a cow by administering a bacterial vaccine, then administering a sufficient amount of the same antigen as the sensitizing bacteria, and then milking the cow. The milk thus obtained is dried at a low temperature to form milk powder after the amount of specific antibodies or γ-globulin is measured by a conventional method. For drying, methods such as freeze drying and continuous vacuum drying are preferred to avoid deactivation of the antibody. [0011] Dried milk can be dissolved as needed for oral administration to form liquid milk or administered in the form of dairy products such as yogurt or ice cream, or in the form of tablets with excipients. can. When administered, in the form of an aqueous solution or milk, 50 ml per person per day.
Have the patient drink 0 ml or more. Furthermore, the dosage of dry milk may be 1 g or more per 1 kg of body weight. Depending on the symptoms, the solution may be continuously injected through a tube as a meal replacement. In this case, by taking into account the nutritional composition and administering an amount equivalent to the daily required calorie amount, it is possible to achieve both the purpose of treatment and nutritional supplementation. [0012] The present invention will be explained in detail by showing Examples and Experimental Examples below. [Example 1] Production of immunized milk with mixed bacterial antigen
Antibody milk was obtained according to the method for producing immune milk disclosed in Japanese Patent No. 188523. Five cows were immunized against a multivalent vaccine consisting of the bacterial strains shown in Tables 1 and 2 above. 4 x 108 cells of each heat-sterilized bacteria were used as the primary immunization.
The vaccine containing 5 ml of the vaccine was administered once a week for 4 consecutive times. After confirming the antibody titer of each cow by the agglutination method, the cows were milked every day while administering the same dose of killed bacteria at 14-day intervals. The milk thus obtained was cream-separated by centrifugation, sterilized at low temperature, and then freeze-dried to obtain powdered milk. This milk powder was dissolved in water at a concentration of 10%, and the amount of γ-globulin contained was determined to be 0.8 mg/ml. In addition, when the reaction to the antigen was measured using a microagglutination method, it was found that the dilution rate was 30.
00 showed positive. [Example 2] Production of immunized milk with mixed bacterial antigen Five cows were immunized with a multivalent vaccine consisting of the bacterial strains shown in Tables 1 and 2 above in the same manner as in Example 1. Processed milking was performed in the same manner. Thereafter, skimmed milk powder was prepared in the same manner. The amount of γ-globulin in the 10% aqueous solution of the obtained milk powder was determined to be 0.8 mg/ml. In addition, when the reaction against the mixed antigen was measured using a microagglutination method, positive results were obtained up to a dilution of 300 times. The skimmed milk obtained in this example had the same effect of preventing opportunistic infections caused by X-ray irradiation as in the experimental example shown below. [Example] This experimental example shows the therapeutic effect of the skim milk powder obtained in Example 1 on opportunistic infections. A group of 10 7-week-old female ICR mice were each irradiated with 700 rad of X-rays, thereby creating a model animal in which gastrointestinal immune function is reduced, thereby causing opportunistic infections. The therapeutic agent to be administered was skim milk powder (FZ-
09), a water bottle was filled with a 12.5% concentration of ordinary commercially available skim milk powder (GZ-08) dissolved in sterilized water, and the subjects were given ad libitum instead of water. Administration began 8 days before X-ray irradiation, and 7 days after irradiation. Each individual was bred and observed, and observations were continued for 30 days while recording the number of days the animals survived when they died. Separately, 3 mice per group were prepared, and after administering the therapeutic agent for 8 days, Peyer's patches of the small intestine were collected. Peyer's patches from three animals were crushed together to prepare a cell suspension. After culturing, the IgA concentration in the culture supernatant was measured. The average survival days for each sample administration group are shown in Table 3, and the changes in mortality rate for each group are shown in Figure 1. Furthermore, the IgA concentration in the Peyer's patch cell culture supernatant of each sample administration group was as shown in FIG. 2. [Table 3] 1: Observation period is 30 days 2: Calculated based on survival days of 31 days for surviving individuals (mean ± standard deviation) 3: Wilcoxon rank test (*: significant at 5%) for each dead animal Dissection was performed and liver homogenates were prepared. A large amount of E. coli was detected in this homogenate, confirming that an opportunistic infection of intestinal bacteria had occurred. Furthermore, it was confirmed from the autopsy findings that each animal's cause of death was due to an infectious disease. The survival rate was significantly higher when the sample according to the present invention was administered, and the number of days of survival was significantly higher when the sample according to the present invention was administered. Since the production of IgA, which plays a role, was high in those administered with the sample according to the present invention, it was confirmed that the therapeutic composition of the present invention has therapeutic and preventive effects on opportunistic infections. Effects of the Invention The composition for preventing and treating opportunistic infections of the present invention is effective in treating and preventing opportunistic infections. Moreover, the therapeutic agent of the present invention can be administered orally and has not only a therapeutic effect but also a nutritional effect, so it is suitable for administering to patients with serious opportunistic infections. .

[Brief explanation of the drawing]

FIG. 1 shows a survival rate curve of animals to which the composition for preventing and treating opportunistic infections of the present invention was orally administered. ↑ indicates that the therapeutic agent for preventing opportunistic infections of the present invention was administered. X-ra
The arrow above y indicates the day of X-ray (700 rad) irradiation.

[Explanation of symbols]

─○─ (GZ-08) shows the survival rate curve when a sterile aqueous solution of commercially available skim milk powder is orally administered. ─●─ (FZ-09) shows a survival rate curve when the aqueous solution of skim milk powder according to Example 1 was orally administered.

FIG. 2 shows the IgA concentration in the culture supernatant of Peyer's patch cells collected from animals to which the therapeutic composition for preventing opportunistic infections of the present invention was orally administered.

[Explanation of symbols]

[I] (GZ-08) shows the IgA concentration in the culture supernatant of Peyer's patch cells when a sterile aqueous solution of commercially available skim milk powder was orally administered. [II] (FZ-09) shows the IgA concentration in the culture supernatant of Peyer's patch cells when the aqueous solution of skim milk powder according to Example 1 was orally administered.

Claims (3)

[Claims] 1. A composition for preventing or treating opportunistic infections, which contains milk containing antibodies against bacterial antigens as an active ingredient. 2. A therapeutic composition for oral opportunistic infection prevention, comprising continuously administering a bacterial antigen to a lactating cow sensitized by the bacterial antigen, and containing milk extracted from the cow as an active ingredient. [Claim 3] Claim 1 or 2, wherein the bacterial antigen is one or more selected from the following microorganism groups:
Oral opportunistic infection prevention therapeutic compositions as described. Bacteria name
ATCC No. Staphylococcus simulans 11
631 Staphylococcus epidermidis
155 Streptococcus pyogenes type 1 8671 Streptococcus pyogenes type 3 103
89 Streptococcus pyogenes type 5
12347 Streptococcus pyogenes type 8 12349 Streptococcus pyogenes type 12 1143
4 Streptococcus pyogenes type 14
12972 Streptococcus pyogenes type 18 12357 Streptococcus pyogenes type 22 10403
Aerobacter aerogenes
884 Escherichia coli

26 Salmonella enteritidis
13076 Pseudomonas
Erginosa 77
00 Klebsiella pneumoniae
9590 Salmonella Typhimurium 133
11 Haemophilus influenzae
9333 Bacteria name

ATCC No. Streptococcus mitis
6249 Proteus vulgaris
13315 Shigella disenteriae
11835
Propiobacterium acnes
11827 Streptococcus sanguis 10556 Streptococcus salivarius
13419 Streptococcus mutans 25175 Streptococcus agalactiae 138
13 Streptococcus pneumoniae
6303