JPH06219957A - Agent for treatment of cryptostridium disease - Google Patents

Abstract

PURPOSE:To improve the excretion of ootid of the protozoon of Cryptostridium from human, other mammals and birds, improve the diarrhea and dehydration symptom and prevent the turning of the local symptom to constitutional symptom by orally administering Miyairi bacterium. CONSTITUTION:An agent for the treatment of cryptostridium disease containing Miyairi bacterium [Clostridium butyricum (FERM P-1467)] as main agent. The excretion of the ootid of cryptostridium can be promoted to minimize the parasitism of sporozoid by the administration of Miyairi bacterium. The shrunken or destructed intestinal villus can quickly be restored by the action of butyric acid generated by the proliferation of Miyairi bacteria in the intestines. The agent is effective for improving the diarrhetic symptom and preventing the turning of the diarrhetic symptom to the constitutional symptom occurring in infant animals and babies having incomplete immunological function and patient of immunological function insufficiency.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a therapeutic agent for cryptostridia.

[0002]

2. Description of the Related Art Cryptostridia is a small protozoa belonging to the genus Apicomplexa, sporozoa, subfamily Coccidia, order Coccidia, suborder Eimeria, subfamily Cryptostridia, and genus Cryptostridia. It is known as an infectious disease that parasitizes mammals, birds, reptiles, etc. as a common host and exhibits frequent diarrhea and associated severe dehydration.

The mechanism of Cryptostridium infection is that the life cycle of Cryptostridium ortis reaches the intestinal tract, and the microfilaments on the intestinal mucosa are atrophied and destroyed by parasitism of parasites (sporozoids). Therefore, it is considered that malabsorption diarrhea is caused.

In humans and mammals with normal immune functions, the infection is transiently terminated, but severe diarrhea for 1 to 2 weeks, although transient, causes severe dehydration and general weakness in patients and animals. Come on. 5 calves under 5 months with imperfect immune function
In infants under the age of age, patients with acquired immunodeficiency disorders such as AIDS, and patients receiving immunosuppressive drugs for organ transplantation, diarrhea is prolonged and the infected site does not remain in the intestinal tract, but the entire digestive tract from the esophagus to the stomach and gallbladder. -Many cases have been reported to reach the turning point of death, extending to the secretory organs such as the bile duct and the respiratory system.

Although many preventive / therapeutic treatments have been applied to cryptostridia disease to date, none of the drugs have any effect and it is said that there is no effective therapeutic agent at present.

[0006]

DISCLOSURE OF THE INVENTION The present invention aims at accelerating the excretion of Cryptosporidium oocysts by administering Mycobacterium leprae, minimizing parasitism of parasites (sporozoids), and proliferating the intestinal tract of Mycobacterium leprae. By the action of butyric acid produced by lactic acid, it promotes early recovery of atrophied and destroyed intestinal mucosa microvilli and improves diarrheal symptoms, and systemic symptoms observed in babies, infants and patients with immunodeficiency who have imperfect immune function. To prevent the turning point.

[0007]

[Means for Solving the Problems] As a means for developing the present invention, a test for administration of B. miyalii was carried out using male primal calves for dairy animals. Usually, when diarrhea occurs in calves, treatments such as stopping feeding (fasting), administration of antibiotics / antibacterial agents and other antidiarrheal agents, and oral administration of electrolyte solution for treatment of dehydration are performed. Since there is currently no effective therapeutic agent for cryptostridia, injection or oral administration of antibiotics / antibacterial agents and oral administration of electrolyte solution, on the contrary, accelerate the progress of diarrhea due to side effects and lead to death. Therefore, it is said that it is best to wait for the natural treatment by expressing the immune function of the calf by only continuing a small amount of feeding to maintain nutrition. However, diarrhea of calves in the lactating period has a great influence on the subsequent development, and the milk-producing ability and the fattening efficiency in the adult period are poor, and the discontinuation is accelerated.

[0008] Mycobacterium leprae is Clostridium Butyricum MI
Special strain of butyric acid bacteria classified by scientific name of YAIRI: Microorganisms Research Institute: Microbial Accession No .: 1467, imbalance of intestinal flora, decrease in absorption / secretion function at the time of intestinal pathogenic bacterial infection,
It has the effect of restoring abnormalities of intestinal tract function such as the onset of diarrhea to normal. In addition, since it is a spore bacterium, side effects during administration of antibiotics / antibacterial agents, such as Clostridium Difficil
It is widely administered to humans as a prophylactic and suppressive agent for e-induced pseudomembranous colitis and abnormal absorption and secretion. The present invention provides the above-mentioned therapeutic agent for Cryptostridia using the Mycobacterium leprae.

Test 1-1 Ten male dairy calves were used to make 5 test groups and 5 control groups. Immediately after birth, the amount of colostrum fed was reduced to half the usual amount and the daily dose was 3 liters to limit the amount of colostrum immunity obtained, and cryopreserved Cryptostridium oocysts were orally administered to another male calf in advance with a catheter. Administration to cause infection
Purify excreted fecal orchest, 25 x per head
10 ^6/30 ml of the Ochisuto oral administration to infected develop experimentally by catheter during 5 days old, respectively. Oral administration of Cryptostridium oocyst is 5
From the age of 8 to 8 weeks. Five animals in the test group were mixed with milk substitute or electrolyte solution in a daily dose of 10 g of the Myxomycetes preparation (4 × 10 ⁷ / g), and the mixture was administered twice a day. Conventional antidiarrheal agents (berberine and creosote formulations) were administered orally at the indicated dose and usage.

When the diarrhea symptom was severe, feeding of the milk replacer was stopped (fasting), and as a preventive measure against dehydration, an electrolyte solution was orally administered at a daily dose of 2 liters × 2 times. When the diarrhea was relieved, the milk substitute was gradually increased from the prescribed 1/3 amount and fed.

The survey items were calculated by the number of fecal oocysts: modified Wisconsin method. Fecal characteristics: Hard stool ・ 1, normal stool ・ 2, soft stool ・ 3, mud stool ・ 4, watery stool ・ 5 stool scores, observed and recorded twice daily in the morning and evening . Feed intake: Calculated by subtracting the amount of residual food from the fed artificial milk before feeding in the morning. Weight: Recorded at 5 days of age and each week (excluding 7 days of age) before feeding in the evening. Appearance and vitality of test cows: Recorded with the naked eye. Death accident:
Record the date of death upon death, which is the 6 items.

Next, the results of the survey for each item are shown in a table.

[Table 1]

Appearance and vitality of the test cow. No abnormalities were found in the test plot from the time of introduction to the end of the test. In the control group, two dogs were found to have dry mouth, decreased vitality, and reduced luster of the hair due to dehydration. One of the three recuperated animals showed a slight decrease in vitality during the 3-4 week old period,
No abnormalities were found in the two animals.

A fatal accident. All animals recovered in the test area, but one in the control area was 26
The other one was 32 days old and died due to weakness.

Test 1-2 Feces of 2 females and 4 males who showed severe diarrhea during lactation under normal control and whose symptoms were not improved by administration of antibiotics and antibacterial agents were examined. Stridium oocysts were found, so antibiotics and
Focusing on the administration of antibacterial agents, the formulation of Miyali bacteria (4 × 10 ⁷ /
g) 5g was mixed with 2 liters of electrolyte solution and administered twice a day (10g as daily dose). One female and three males from the fifth day, one female and one male on the seventh day. Since the orchest was no longer recognized in the feces and the appetite was restored,
The Mycobacterium leprae preparation 10 g per day was continued until 2 weeks of age, 6 g until 6 weeks of age, and 2 g was administered until weaning at 8 weeks of age. Thereafter, diarrhea symptoms did not occur, and favorable growth results were obtained.

Test 1-3 In a cow house contaminated with cryptostridia, from a day of birth, a daily dose of 2 g of a Mycobacterium leprae preparation (4 × 10 ⁷ / g) was divided into morning and evening and mixed with colostrum, and administered after 5 days of age. Was mixed with normal milk and administered at a dose of 1 g per day from 3 weeks to 8 weeks, and there was no initial symptom, and the preventive effect was remarkable.

Immediately after the birth of mammals including humans, the structure of the intestinal epithelial tissue is extremely specific, that is, the development of microcilia on mucosal cells is sparse and short, and an invaginated image is observed.
The tubular structure penetrates intricately, forming large and small vacuoles. Due to such a structure, uptake of a high molecular substance in the intestinal tract is observed, and not only the uptake of gamma-globulin (antibody transfer protein) in colostrum but also the non-selective passage of bacteria is possible. To investigate whether Clostridium Butyricum MIYAIRI, a spore-bearing obligate anaerobic bacterium, is incorporated into the small intestinal mucosal tissue of newborn animals to investigate whether it has an unexpected effect on the growth in the tissue 1 In carrying out -3, 6 male calves for dairy cows were used in advance, and within 6 hours after birth, the colostrum was mixed with 1 g of the Mycobacterium spp. When the dose of 2 g, 1 g per day was continued until weaning at the age of 8 weeks, no abnormality was observed. Tests 1-3 were performed after this preliminary test.

(Clinical Example in Human) During the above-mentioned Test 1-1, one staff member who happened to be involved in the test accidentally presented with severe abdominal pain accompanied by slight fever and frequent diarrhea and was hospitalized. It was Immediately after fecal examination, Cryptostridium oocysts were detected in the feces, and the patient was diagnosed with cryptostridia. From the afternoon of the 2nd day of hospitalization (the 3rd day after the onset of illness), the daily dose of 12g of the Miyali bacterium preparation (4 × 10 ⁷ / g)
Oral administration of (divided three times a day), no oocysts were detected in the stool test from the 4th day after administration, watery diarrhea improved to normal diarrhea, and loose stools from the 9th day onwards. I was able to be discharged from the hospital on the 17th day (18th day after the illness). Fortunately, it was an infection of a person with a normal immune function, but the drug administered after detection of Cryptostridium oocyst was:
Except for fluid replacement (drip administration until 10th day after hospitalization), only Miyariiri preparations were used, and even in cases of normal immune function patients, oocysts were excreted in a very short time. Also, the effectiveness of Miyairi bacteria is recognized.

It is also effective against cryptostridia in birds such as chickens. In that case, for example, it is administered by a method in which 0.5% (by weight) of B. millet powder is mixed in the feed.

No acute, subacute, or chronic toxicity is observed. (Applied Pharmacology Vol. 34, No. 2 215-221.
Pp. 223-237, Vol. 33, No. 4, 683-69.
(See page 4)

[0021]

EFFECTS OF THE INVENTION In domestic animals, the potential prevalence of cryptostridia is reported to be 81% in calves aged 2-3 weeks (Ohio, USA). Infection has a common host from animals to humans and from polluted environments to humans. Not only raw water and raw vegetables, but chlorine disinfection does not kill Cryptosporidium oocysts, and the oocysts are extremely small. Therefore, there is a possibility of airborne infection as a mist.

According to the AIDS surveillance survey conducted in FY 1990, the number of AIDS patients in Japan was less than 600. However, the worldwide epidemic situation and the future of medical treatment in the medical community are likely to cause surgery. Administration of immunosuppressive drugs to patients with organ transplantation, and in developed countries, cryptostridia is becoming a problem as a nosocomial infection for infants under the age of 5 and an infection in nursery schools. Has been done. Cryptostridia is a problem in immunocompromised patients, and its countermeasures are regarded as important. Parasitism of Cryptostridium parasites (sporozoids) in immunodeficient patients does not stop in the digestive tract, but also causes the turning points from the secretory organs to the respiratory organs and to death. The early excretion of erythrocytes and the improvement of symptoms due to the early recovery of small intestinal microvilli due to butyric acid produced in the intestinal tract of Mycobacterium leprae are extremely effective in medical and veterinary medicine.

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[Procedure amendment]

[Submission date] May 20, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] Full text

[Correction method] Change

[Correction content]

[Document name] Statement

Patent application title: Cryptostridia treatment agent

[Claims]

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a therapeutic agent for cryptostridia.

[0002]

2. Description of the Related Art Cryptostridia is a small protozoa belonging to the genus Apicomplexa, sporozoa, subfamily Coccidia, order Coccidia, suborder Eimeria, subfamily Cryptostridia, and genus Cryptostridia. It is known as an infectious disease that parasitizes mammals, birds, reptiles, etc. as a common host and exhibits frequent diarrhea and associated severe dehydration.

[0003] The mechanism of Cryptostridium infection is that the life cycle begins when Cryptosporidium ortis reaches the intestinal tract, and microvilli on the intestinal mucosa are atrophied and destroyed by parasitism of the parasite (sporozoid). Therefore, it is considered that malabsorption diarrhea is caused.

In humans and mammals with normal immune functions, the infection is transiently terminated, but severe diarrhea for 1 to 2 weeks, although transient, causes severe dehydration and general weakness in patients and animals. Come on. 5 calves under 5 months with imperfect immune function
In infants under the age of age, patients with acquired immunodeficiency disorders such as AIDS, and patients receiving immunosuppressive drugs for organ transplantation, diarrhea is prolonged and the infected site does not remain in the intestinal tract, but the entire digestive tract from the esophagus to the stomach and gallbladder. -Many cases have been reported to reach the turning point of death, extending to the secretory organs such as the bile duct and the respiratory system.

Although many preventive / therapeutic treatments have been applied to cryptostridia disease to date, none of the drugs have any effect and it is said that there is no effective therapeutic agent at present.

[0006]

DISCLOSURE OF THE INVENTION The present invention aims at accelerating the excretion of Cryptosporidium oocysts by administering Mycobacterium leprae, minimizing parasitism of parasites (sporozoids), and proliferating the intestinal tract of Mycobacterium leprae. By the action of butyric acid produced by lactic acid, it promotes early recovery of atrophied and destroyed intestinal mucosa microvilli to improve diarrheal symptoms, and systemic symptoms observed in babies, infants and patients with immunodeficient imperfect immune function. To prevent the turning point.

[0007]

[Means for Solving the Problems] As a means for developing the present invention, a test for administration of B. miyalii was carried out using male primal calves for dairy animals. Usually, when diarrhea occurs in calves, treatments such as stopping feeding (fasting), administration of antibiotics / antibacterial agents and other antidiarrheal agents, and oral administration of electrolyte solution for treatment of dehydration are performed. Since there is currently no effective therapeutic agent for cryptostridia, injection or oral administration of antibiotics / antibacterial agents and oral administration of electrolyte solution, on the contrary, accelerate the progress of diarrhea due to side effects and lead to death. Therefore, it is said that it is best to wait for the natural treatment by expressing the immune function of the calf by only continuing a small amount of feeding to maintain nutrition. However, diarrhea of calves in the lactating period has a great influence on the subsequent development, and the milk-producing ability and the fattening efficiency in the adult period are poor, and the discontinuation is accelerated.

[0008] Mycobacterium leprae is Clostridium Butyricum MI
Special strain of butyric acid bacteria classified by scientific name of YAIRI: Microorganisms Research Institute: Microbial Accession No .: 1467, imbalance of intestinal flora, decrease in absorption / secretion function at the time of intestinal pathogenic bacterial infection,
It has the effect of restoring abnormalities of intestinal tract function such as the onset of diarrhea to normal. In addition, since it is a spore bacterium, side effects during administration of antibiotics / antibacterial agents, such as Clostridium Difficil
It is widely administered to humans as a prophylactic and suppressive agent for e-induced pseudomembranous colitis and abnormal absorption and secretion. The present invention provides the above-mentioned therapeutic agent for Cryptostridia using the Mycobacterium leprae.

Test 1-1 Ten male dairy calves were used to make 5 test groups and 5 control groups. Immediately after birth, the amount of colostrum fed was reduced to half the usual amount and the daily dose was 3 liters to limit the amount of colostrum immunity obtained, and cryopreserved Cryptostridium oocysts were orally administered to another male calf in advance with a catheter. Administration to cause infection
Purify excreted fecal orchest, 25 x per head
10 ^6/30 ml of the Ochisuto oral administration to infected develop experimentally by catheter during 5 days old, respectively. Oral administration of Cryptostridium oocyst is 5
From the age of 8 to 8 weeks. For 5 animals in the test group, the bacillus miyali preparation (4 × 10 ⁷ / g) was mixed with milk substitute or electrolyte solution at a daily dose of 10 g, and the mixture was administered twice a day. Conventional antidiarrheal agents (berberine and creosote formulations) were administered orally at the indicated dose and usage.

When the diarrhea symptom was severe, feeding of the milk replacer was stopped (fasting), and as a preventive measure against dehydration, an electrolyte solution was orally administered at a daily dose of 2 liters × 2 times. When the diarrhea was relieved, the milk substitute was gradually increased from the prescribed 1/3 amount and fed.

The survey items were calculated by the number of fecal oocysts: modified Wisconsin method. Fecal characteristics: Hard stool ・ 1, normal stool ・ 2, soft stool ・ 3, mud stool ・ 4, watery stool ・ 5 stool scores, observed and recorded twice daily in the morning and evening . Feed intake: Calculated by subtracting the amount of residual food from the fed artificial milk before feeding in the morning. Weight: Recorded at 5 days of age and each week (excluding 7 days of age) before feeding in the evening. Appearance and vitality of test cows: Recorded with the naked eye. Death accident:
Record the date of death upon death, which is the 6 items.

Next, the results of the survey for each item are shown in a table.

[Table 1]

Appearance and vitality of the test cow. No abnormalities were found in the test plot from the time of introduction to the end of the test. In the control group, two dogs were found to have dry mouth, decreased vitality, and reduced luster of the hair due to dehydration. One of the three recuperated animals showed a slight decrease in vitality during the 3-4 week old period,
No abnormalities were found in the two animals.

A fatal accident. All animals recovered in the test area, but one in the control area was 26
The other one was 32 days old and died due to weakness.

Test 1-2 Feces of 2 females and 4 males who showed severe diarrhea during lactation under normal control and whose symptoms were not improved by administration of antibiotics and antibacterial agents were examined. Stridium oocysts were found, so antibiotics and
The administration of the antibacterial agent was stopped, and the Miyali bacterium preparation (4 × 10 ⁷ /
g) 5g was mixed with 2 liters of electrolyte solution and administered twice a day (10g as daily dose). One female and three males from the fifth day, one female and one male on the seventh day. Since the orchest was no longer recognized in the feces and the appetite was restored,
The Mycobacterium leprae preparation 10 g per day was continued until 2 weeks of age, 6 g until 6 weeks of age, and 2 g was administered until weaning at 8 weeks of age. Thereafter, diarrhea symptoms did not occur, and favorable growth results were obtained.

Test 1-3 In a cow house contaminated with cryptostridia, from a day of birth, a daily dose of 2 g of a Mycobacterium leprae preparation (4 × 10 ⁷ / g) was divided into morning and evening and mixed with colostrum, and administered after 5 days of age. Was mixed with normal milk and was administered at a dose of 1 g per day from 3 weeks old to 8 weeks old, and there was no onset, and the preventive effect was remarkable.

Immediately after the birth of mammals including humans, the structure of the intestinal epithelial tissue is extremely specific, that is, the development of microcilia on mucosal cells is sparse and short, and an invaginated image is observed.
The tubular structure penetrates intricately, forming large and small vacuoles. Due to such a structure, uptake of a high molecular substance in the intestinal tract is observed, and not only the uptake of gamma-globulin (antibody transfer protein) in colostrum but also the non-selective passage of bacteria is possible. To investigate whether Clostridium Butyricum MIYAIRI, a spore-bearing obligate anaerobic bacterium, is incorporated into the small intestinal mucosal tissue of newborn animals to investigate whether it has an unexpected effect on the growth in the tissue 1 In carrying out -3, 6 male calves for dairy cows were used in advance, and within 6 hours after birth, the colostrum was mixed with 1 g of the Mycobacterium spp. When the dose of 2 g, 1 g per day was continued until weaning at the age of 8 weeks, no abnormality was observed. Tests 1-3 were performed after this preliminary test.

(Clinical Example in Human) During the above-mentioned Test 1-1, one staff member who happened to be involved in the test accidentally presented with severe abdominal pain accompanied by slight fever and frequent diarrhea and was hospitalized. It was Immediately after fecal examination, Cryptostridium oocysts were detected in the feces, and the patient was diagnosed with cryptostridia. From the afternoon of the 2nd day of hospitalization (the 3rd day after the onset of illness), the daily dose of 12g of the Miyali bacterium preparation (4 × 10 ⁷ / g)
Oral administration of (divided three times a day), no oocysts were detected in the stool test from the 4th day after administration, watery diarrhea improved to normal diarrhea, and loose stools began on day 9 and later. I was able to be discharged from the hospital on the 17th day (18th day after the illness). Fortunately, it was an infection of a person with a normal immune function, but the drug administered after detection of Cryptostridium oocyst was:
Except for fluid replacement (drip administration until 10th day after hospitalization), only Miyariiri preparations were used, and even in cases of normal immune function patients, oocysts were excreted in a very short time. Also, the effectiveness of Miyairi bacteria is recognized.

It is also effective against cryptostridia in birds such as chickens. In that case, for example, it is administered by a method in which 0.5% (by weight) of B. millet powder is mixed in the feed.

No acute, subacute, or chronic toxicity is observed. (Applied Pharmacology Vol. 34, No. 2 215-221.
Pp. 223-237, Vol. 33, No. 4, 683-69.
(See page 4)

[0021]

EFFECTS OF THE INVENTION In domestic animals, the potential prevalence of cryptostridia is reported to be 81% in calves aged 2-3 weeks (Ohio, USA). Infection has a common host from animals to humans and from polluted environments to humans. Not only raw water and raw vegetables, but chlorine disinfection does not kill Cryptosporidium oocysts, and the oocysts are extremely small. Therefore, there is a possibility of airborne infection as a mist.

According to the AIDS surveillance survey conducted in FY 1990, the number of AIDS patients in Japan was less than 600. However, the worldwide epidemic situation and the future of medical treatment in the medical community are likely to cause surgery. Administration of immunosuppressive drugs to patients with organ transplantation, and in developed countries, cryptostridia is becoming a problem as a nosocomial infection for infants under the age of 5 and an infection in nursery schools. Has been done. In cryptosporidiosis in immunodeficient patients, the parasitism of Cryptostridium parasites (sporozoids) is not limited to the digestive tract, and the secretory organs are distributed to the respiratory organs and to the death. Improving symptoms due to early excretion of Stridium oocysts and early recovery of microvilli of the small intestine due to butyric acid produced in the intestinal tract of Mycobacterium leprae are extremely significant in terms of medical and veterinary medicine.

Claims (1)

[Claims] 1. A therapeutic agent for Cryptostridium disease, which comprises Miyairi bacteria as a main ingredient.