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WO2016204169A1 - Agent thérapeutique et procédé thérapeutique pour mastite suraiguë ou aiguë pendant l'allaitement bovin - Google Patents

Agent thérapeutique et procédé thérapeutique pour mastite suraiguë ou aiguë pendant l'allaitement bovin Download PDF

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Publication number
WO2016204169A1
WO2016204169A1 PCT/JP2016/067748 JP2016067748W WO2016204169A1 WO 2016204169 A1 WO2016204169 A1 WO 2016204169A1 JP 2016067748 W JP2016067748 W JP 2016067748W WO 2016204169 A1 WO2016204169 A1 WO 2016204169A1
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lactoferrin
milk
mastitis
acute
days
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Japanese (ja)
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昌志 板垣
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Kyoritsu Seiyaku Corp
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Kyoritsu Seiyaku Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof

Definitions

  • the present invention is a bovine containing lactoferrin as an active ingredient, wherein 10 to 500 mg of lactoferrin per titer is used to inject directly into a diseased chamber from a teat canal several times at intervals of 2 days or more. It relates to a therapeutic agent for acute acute or acute mastitis during lactation, a therapeutic agent set of lactoferrin and glycyrrhizin or a salt thereof, a method for treating acute acute or acute mastitis during lactation of cattle, and the like.
  • Dairy farming is widely used as an industry, and many dairy cows are raised for the production of milk and dairy products. From the viewpoint of economic efficiency of milk production, dairy cows are generally bred in the following life cycle.
  • the first artificial insemination is performed around 14-16 months after birth, and after the pregnancy period of about 9 months, the baby is delivered and milking is started.
  • the next artificial insemination takes place about 2 months after childbirth, but milking continues.
  • milking for about 10 months from the previous delivery that is, 2-3 months before the next delivery
  • milking is stopped until delivery.
  • lactation period The period during which milking activity is carried out for about 10 months from parturition
  • the period during which milking is stopped for 2 to 3 months thereafter is called dry period.
  • artificial insemination is performed at an appropriate time to maintain the lactation and dry period cycles and continue milk production while conceiving and delivering.
  • Bovine mastitis is an inflammatory disease of the mammary gland tissue and duct system caused by infection with microorganisms that have entered one or more of the breasts. Inflammation increases the number of somatic cells in milk, and abnormal milk is secreted by inhibiting the milk synthesis mechanism.
  • the PL test is a modified method of CMT, and is a simple milk test method widely used for detecting mastitis in Japan.
  • a PL tester solution (PL test reagent) is added to the milk. This is a method of simultaneously detecting an increase in the number of somatic cells in milk due to mastitis and a change in milk quality based on the degree of aggregation and color tone.
  • the PL tester contains a surfactant and a pH indicator.
  • DNA in the somatic cells contained in the milk and the double-sided active agent react and coagulate. Therefore, the degree of aggregation when adding a PL tester to the milk is scored and determined. Increase in the number of somatic cells can be easily detected.
  • milk reacts with a pH indicator, it is possible to easily detect abnormal pH of milk and changes in milk quality by determining the degree of color tone when a PL tester is added to milk.
  • Mastitis is classified into clinical mastitis, subclinical mastitis, dry mastitis, mastitis in heifers, etc. based on pathological conditions and various modifying factors.
  • Clinical mastitis is mastitis in which systemic symptoms and gross findings of breast and milk are observed.
  • Latent mastitis does not show systemic symptoms or gross findings of breast and milk, but has increased somatic cell count or abnormal milk quality due to physical and chemical tests. It is a flame.
  • Mastitis during the dry period is mastitis that occurs immediately after dry milk and immediately before parturition, and is often due to the recurrence of chronic mastitis or latent mastitis during the lactation period.
  • mastitis are further classified into acute mastitis, acute mastitis and chronic mastitis.
  • Acute mastitis is a mastitis that shows serious symptoms and progresses very rapidly, and in severe cases it may die.
  • Escherichia coli (scientific name, hereinafter referred to as “E.coli”) and Klebsiella pneumoniae (scientific name, hereinafter referred to as “K.pneumoniae”), which are coliforms, and Staphylococcus aureus (scientific name), S.aureus ”)
  • E.coli Escherichia coli
  • Klebsiella pneumoniae scientific name, hereinafter referred to as “K.pneumoniae”
  • Staphylococcus aureus (scientific name), S.aureus ”).
  • Acute mastitis is mastitis in which symptoms and progress are milder than those of acute mastitis, but breast swelling, induration, fever, and pain-like symptoms suddenly appear.
  • Streptococcus uberis (scientific name, hereinafter referred to as “Str. Uberis”) and Streptococcus eqinus (scientific name, hereinafter referred to as “Str. Eqinus”), the aforementioned Escherichia coli group, and Staphylococcus aureus are involved.
  • antibiotics such as cefazolin
  • enteral administration intravenous administration
  • ointment direct injection into the affected area
  • mastitis sufficient therapeutic effects cannot be obtained even if antibiotics are administered.
  • bacteria of the coliform group are extremely fast growing, Gram-negative bacilli, and have LPS (lipopolysaccharide) as a constituent of the cell wall of the cell, which is an endotoxin when the bacteria grow and die.
  • LPS lipopolysaccharide
  • acute acute mastitis due to coliforms during lactation often fails to provide a sufficient therapeutic effect even when antibiotics are administered, and is prone to drowning and a marked reduction in milk yield.
  • it is difficult to heal and restore milk yield and quality there are many cases in which it is necessary to decide on the outcome of disuse, and economic losses in dairy farming are significant.
  • acute mastitis due to coliform bacteria there is a view that antibiotics should not be used because endotoxin is generated by the use of antibiotics and may induce endotoxin shock.
  • Lactoferrin is an iron-binding glycoprotein with a molecular weight of about 80 kDa that naturally exists in the secretions of the body such as milk, tears, mucus, blood, saliva, and contains 689 amino acids in cattle and 692 amino acids in humans.
  • Lactoferrin is known to chelate iron, thereby preventing the use of iron by microorganisms with high iron requirement and suppressing bacterial growth.
  • lactoferrin has a direct bactericidal action, an antiviral action, an immunomodulatory action, and the like.
  • an immunomodulating action by lactoferrin there is a finding that human lactoferrin prevents deregulation of the immune system by binding and neutralizing LPS released from bacteria as endotoxin.
  • Non-Patent Document 1 describes the effect of injecting bovine lactoferrin into the udder at the early stage of dry milk on cows with staphylococcal mastitis. The effects of lactoferrin hydrolyzate injected into the mammary gland on bovine latent mastitis are described respectively.
  • Patent Document 1 describes a method for treating mastitis in which lactoferrin and antibiotics are administered in combination in the dry cow cow.
  • Patent Document 2 treats mastitis by a combination of exogenous lactoferrin and an oxazolidinone antibacterial agent. Or each method of prevention is described.
  • Patent Document 3 describes a mastitis therapeutic agent for direct administration to the breast of a domestic animal, which is administered during lactation and containing glycyrrhizin or a pharmaceutically acceptable salt thereof as an active ingredient.
  • an object of the present invention is to provide a mastitis treatment means that is more effective and can quickly restore the milk yield and quality to the state before the disease.
  • lactoferrin has been considered to be ineffective for cattle during lactation mastitis, and particularly not effective against cattle lactation acute or acute mastitis.
  • the present inventor (1) shows that when an appropriate amount of lactoferrin is injected directly into the affected quarter several times, it is remarkably effective against cattle lactation acute or acute mastitis.
  • (2) administration of an appropriate amount of lactoferrin per administration can prevent the inflammatory state from becoming extremely worsening or protracted, and (3) administration of an appropriate amount of lactoferrin multiple times allows the cow to lactate.
  • lactoferrin at a titer per time is used as an active ingredient, which is used so as to be directly injected into the affected quarter from the papillary canal several times at intervals of 2 days or more.
  • a therapeutic agent for cattle lactation acute mastitis or acute mastitis further, the therapeutic agent and glycyrrhizin or a salt thereof having a titer of 100 to 1,000 mg after two or more days after the last infusion of lactoferrin.
  • a therapeutic agent for cattle's lactating acute or acute mastitis containing glycyrrhizin or a salt thereof as an active ingredient, used for direct injection into the affected quarter from the teat canal, A therapeutic agent set for lactating acute or acute mastitis is provided.
  • lactoferrin is a naturally occurring substance in milk and the like, and there is no concern about residual in the body like antibiotics. Therefore, milk production and shipping can be resumed in a short period after the illness, the amount of collected milk can be greatly reduced, and economic losses in the dairy industry can be greatly reduced.
  • the therapeutic agent according to the present invention is caused by any one of coliform bacteria, Staphylococcus aureus, and streptococci, which have not necessarily obtained a sufficient therapeutic effect by conventional antibiotic administration. Even for cattle acute or acute mastitis in the lactation period of cattle, mastitis can be cured early, and the milk yield and quality can be restored to the pre-morbid state at an early stage.
  • the present invention treats without using antibiotics, and does not act directly on the causative bacteria, but improves the symptoms mainly by the phagocytosis of granulocytes, so that the appearance of resistant bacteria can be suppressed. . And since there is no concern about antibiotics remaining in the body, food safety can be ensured.
  • the present invention is a bovine containing lactoferrin as an active ingredient, wherein 10 to 500 mg of lactoferrin per titer is used to inject directly into a diseased chamber from a teat canal several times at intervals of 2 days or more. All therapeutic agents for lactating acute or acute mastitis are included.
  • the subject of application of the present invention is general mastitis in the lactation period of cattle, and in particular, the treatment of cattle during the lactation period or acute breast, which has not always obtained a sufficient therapeutic effect by administration of antibiotics. Useful for flames.
  • the causative bacteria of cattle's lactation acute or acute mastitis are not particularly limited.
  • the mastitis is caused by any one of coliform group, Staphylococcus aureus and streptococci Is also applicable. Since these bacteria have a high growth rate even in the affected area, mastitis caused by these bacteria is often relatively severe and progresses in pathological condition.
  • the present invention is also effective against relatively severe mastitis caused by these bacteria.
  • Lactoferrin can be widely used, including pharmaceutically acceptable salts and solvates thereof, and is not particularly limited. In principle, those derived from cow's milk are most suitable.
  • the dosage form is preferably liquid or ointment. Further, for example, powder, granules, tablets and the like may be dissolved at the time of use and used as a liquid.
  • solvent for the liquid agent known ones can be widely used and are not particularly limited.
  • water for injection alcohol such as methanol, ethanol, n-butanol, propylene glycol, polyethylene glycol, macrogol, sesame oil, corn oil and the like can be used.
  • a lipophilic ointment base or a hydrophilic ointment base can be used.
  • the lipophilic ointment base include white petrolatum, yellow petrolatum, liquid paraffin, olive oil, peanut oil, and soybean oil.
  • the hydrophilic ointment base include polyethylene glycol, sodium polyacrylate, stearic acid, aluminum stearate, glycerin, and carboxymethyl cellulose.
  • a pharmacologically acceptable carrier When formulating lactoferrin as a drug, a pharmacologically acceptable carrier may be used.
  • the carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials can be used.
  • liquid preparations such as excipients, lubricants, binders, disintegrants, etc.
  • Solubilizing agents, suspending agents, tonicity agents, buffers, soothing agents, and the like may be appropriately blended.
  • formulation additives such as antiseptic
  • excipients for example, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like can be used.
  • lubricant for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like can be used.
  • binder for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be used.
  • disintegrant for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like can be used.
  • solubilizer for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like can be used.
  • suspending agents include, for example, surfactants (stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.)
  • surfactants stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.
  • Molecules polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.
  • surfactants stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride,
  • tonicity agent for example, sodium chloride, glycerin, D-mannitol and the like can be used.
  • a buffer solution such as phosphate, acetate, carbonate, citrate and the like can be used.
  • benzyl alcohol can be used as a suitable example of the soothing agent.
  • preservative for example, p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like can be used.
  • antioxidant for example, sulfite, ascorbic acid and the like can be used.
  • this drug includes auxiliary ingredients such as light-absorbing dyes (riboflavin, adenine, adenosine, etc.) that serve as storage and efficacy aids, and chelating / reducing agents (vitamin C, citric acid, etc.) for stabilization. Etc. may be included.
  • auxiliary ingredients such as light-absorbing dyes (riboflavin, adenine, adenosine, etc.) that serve as storage and efficacy aids, and chelating / reducing agents (vitamin C, citric acid, etc.) for stabilization. Etc. may be included.
  • the dose of lactoferrin is preferably 10 to 500 mg, more preferably 50 to 400 mg, most preferably 100 to 300 mg as a titer per dose.
  • lactoferrin is administered multiple times at intervals of 2 days or more.
  • the administration interval is preferably 2 to 5 days, and the administration frequency is preferably 2 to 4 times.
  • the initial administration and 2 to 5 days after that may be administered twice, or the initial administration, 2 to 5 days after that, and then 2 to 5 days later, 3 times in total.
  • the initial administration is preferably performed immediately after the onset, for example, within 30 hours from the onset, more preferably within 24 hours, and most preferably within 18 hours.
  • milking is usually performed every 6-12 hours during lactation, and the amount of milk is greatly reduced when clinical mastitis develops, so the onset can be estimated with an error range of 6-12 hours.
  • the administration method is not particularly limited as long as it can be directly injected into the affected quarter, and for example, a cylindrical member for intramammary administration, a cannula, a non-sharp injection needle, etc. is inserted into the papillary canal, and a lactoferrin solution or ointment May be performed by injecting directly into the affected quarter from the teat canal.
  • the present invention is such that, after two or more days have passed since the last injection of the above-mentioned therapeutic agent and the aforementioned lactoferrin, 100 to 1,000 mg of glycyrrhizin or a salt thereof is directly injected into the affected compartment from the teat canal.
  • a therapeutic agent for cattle lactation acute or acute mastitis comprising a therapeutic agent for cattle lactation acute or acute mastitis containing glycyrrhizin or a salt thereof as an active ingredient. Includes all.
  • Applicable object is the same as above.
  • Glycyrrhizin can be widely used, including pharmaceutically acceptable salts, solvates, derivatives starting from glycyrrhizin, and the like, and is not particularly limited.
  • Examples of pharmaceutically acceptable salts thereof include alkali metal salts (sodium salt, potassium salt, lithium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, lithium salt, etc.), metal salts (aluminum salt, Iron salt, zinc salt, copper salt, nickel salt), inorganic salt (phosphate, sulfate, hydrobromide, ammonium salt, etc.), organic acid salt (methanesulfonate, p-toluenesulfonate, Lactate, acetate, trifluoroacetate, citrate, succinate, fumarate, maleate, salicylate, etc., organic amine salts (methylamine, dimethylamine, trimethylamine, ethylenediamine, Diethylamine salt, triethylamine salt, ethanolamine salt, diethanolamine salt, dibenzylamine salt, glucosamine salt, dicyclohexane Silamine salts, tetramethylammonium salts, etc.), amino acid salts (
  • Glycyrrhizin can be obtained by a known method, for example, by extracting roots or strons of licorice (genus Glycyrrhiza) with a solvent such as water, methanol, ethanol, or n-butanol.
  • the dosage form of glycyrrhizin or a salt thereof is preferably a liquid or an ointment.
  • a known solvent can be widely used as the solvent or ointment in the case of liquid, and is not particularly limited. For example, the same ones as described above can be widely adopted.
  • carriers, solubilizers, suspending agents, tonicity agents, buffers, soothing agents, and preparation additives such as preservatives, antioxidants, coloring agents, etc. You may mix
  • the dosage of glycyrrhizin or a salt thereof is preferably 100 to 1,000 mg in titer, more preferably 300 to 900 mg, and most preferably 400 to 800 mg.
  • glycyrrhizin or a salt thereof is administered 2 days or more after the last infusion of lactoferrin, for example, 2 to 7 days after the last infusion of lactoferrin.
  • the administration method is not particularly limited as long as it can be directly injected into the affected quarter.
  • a cylindrical member for intramammary administration, a cannula, a non-sharp injection needle or the like is inserted into the nipple tube, and lactoferrin is introduced.
  • the solution or ointment may be injected directly into the affected compartment from the teat canal.
  • the present invention is directed to cattle lactation acute or acute mastitis, in which 10 to 500 mg of lactoferrin at a titer per injection is directly injected into the affected quarter from the teat canal multiple times at intervals of 2 days or more.
  • the method of treatment, and cattle during lactation in the lactation period in which 100 to 1,000 mg of glycyrrhizin or a salt thereof is injected directly into the affected quarter from the teat canal after 2 days from the last infusion of lactoferrin
  • a wide range of treatment methods for acute mastitis and the like are included.
  • the application target of this treatment method is the same as above.
  • By injecting the appropriate amount of lactoferrin multiple times directly into the affected quarter it is effective even for relatively severe and rapidly developing mastitis, such as cattle lactation acute or acute mastitis Can be treated.
  • milk production and shipping can be resumed in a short period of time after the illness, the amount of collected milk can be greatly reduced, and economic losses in the dairy industry can be greatly reduced.
  • milk can be improved / recovered to a pre-morbid state in a shorter period of time by administering an appropriate amount of glycyrrhizin or a salt thereof two or more days after the last infusion of lactoferrin.
  • the initial administration of lactoferrin is first performed immediately after onset, for example, within 30 hours, more preferably within 24 hours, and most preferably within 18 hours from onset.
  • milking is usually performed every 6-12 hours during lactation, and the amount of milk is greatly reduced when clinical mastitis develops, so the onset can be estimated with an error range of 6-12 hours.
  • lactoferrin is administered multiple times at intervals of 2 days or more, including the first administration.
  • the administration interval is preferably 2 to 5 days, and the administration frequency is preferably 2 to 4 times.
  • the initial administration and 2 to 5 days after that may be administered twice, or the initial administration, 2 to 5 days after that, and then 2 to 5 days later, 3 times in total.
  • the dose per lactoferrin is the same as described above.
  • glycyrrhizin or a salt thereof may be administered after 2 days or more have passed since the last infusion of lactoferrin (for example, after 2 to 7 days have passed since the last infusion of lactoferrin).
  • the dosage of glycyrrhizin or a salt thereof is the same as described above.
  • the method for administering lactoferrin and glycyrrhizin or a salt thereof is not particularly limited as long as it can be directly injected into the affected quarter.
  • a cylindrical member for intramammary administration, a cannula, a non-sharp injection needle, etc. are inserted into the nipple tube.
  • a lactoferrin solution or ointment may be injected directly into the affected compartment from the nipple tube.
  • Example 1 it was verified whether lactoferrin or a combination of lactoferrin and glycyrrhizin was effective against cattle acute mastitis during lactation caused by coliform bacteria.
  • the first day of onset (within 24 hours from the onset, within about 18 hours from discovery) and 3 times after the onset, a total of 2 times, 10 mL of lactoferrin solution per quarter each ( Lactoferrin (200 mg, manufactured by Kyoritsu Pharmaceutical Co., Ltd.) was injected directly into the affected quarter from the nipple tube.
  • cefazolin sodium solution (every 4 times in total) from the first day of onset (within 24 hours from the onset, within about 18 hours from discovery) to 3 days after the onset (each 4 times in total)
  • Intravenous administration of cefazolin sodium (3 g) and cefazolin oily breast infusion (containing cefazolin 150 mg) were injected directly into the affected quarters, and benzylpenicillin procaine on days 7 and 10 ⁇ Kanamycin sulfate oily breast injection (PC / G 300,000 units, containing KM300 mg titer) was injected directly into the affected quarter.
  • cefazolin sodium solution was intravenously administered to one of the three animals. It was.
  • Table 1 The results are shown in Table 1.
  • the “LF alone” column shows the score of the first group (Lactoferrin alone administration group)
  • the “LF / GL combination” column shows the score of the second group (Lactoferrin and glycyrrhizin combination group)
  • the milk yield recovered with the passage of days, and almost 30 days after the onset
  • the third group antibiotic-administered group
  • Milk findings were determined according to the following criteria. Determination of milk properties: score 0 (normal; milky white), score 1 (mild; watery), score 2 (moderate; bloody), score 3 (severe; pus-like). Determination of coagulum: score 0 (normal; no coagulum), score 1 (mild; less than 10 coagulum in 5 mL milk), score 2 (moderate; 10 or more coagulum in 5 mL milk), Score 3 (severe; huge mass). The total value of the determination score of the milk properties and the determination score of the coagulum was taken as the milk score.
  • the collected milk was applied to a flow cytometer (“Somacount150”, Fujihira Kogyo Co., Ltd.), and the number of cells in the milk was counted.
  • the milk mainly contains epithelial cells and white blood cells, and the number of white blood cells rapidly increases during inflammation. Therefore, normal milk has a low number of somatic cells, and abnormal milk has a large number of somatic cells.
  • the number of somatic cells in milk decreased significantly after 7 days of onset, and mastitis
  • the number of somatic cells in milk remained high even after 10 days from the onset.
  • the lactoferrin / glycyrrhizin combination group the number of somatic cells in the milk could be reduced to the same level as that of normal milk 10 days after the onset.
  • the milk agglomeration and color tone were judged by the PL tester according to the following criteria. Determination of aggregation: score 0 (normal; negative (-, ⁇ )), score 1 (mild; false positive (+)), score 2 (moderate; positive (++)), score 3 (severe; positive (+++ or higher) )). Judgment of color tone: score 0 (normal; negative (-)), score 1 (mild; false positive ( ⁇ )), score 2 (moderate; positive (+)), score 3 (severe; positive (++)). The sum of the determination score of the milk aggregation and the determination score of the color tone was used as the PL test score.
  • the score of the PL test was significantly lowered 7 days after the onset, and the symptoms of mastitis improved.
  • the PL test score remained high 7 days and 10 days after onset.
  • the PL test score was 0 10 days after onset.
  • Example 1 it was found that lactoferrin or the combined use of lactoferrin and glycyrrhizin was effective against cattle acute mastitis during lactation in which the coliform group was the causative agent. Therefore, in Example 2, it was verified whether lactoferrin was effective against acute mastitis during lactation in cattle caused by Staphylococcus aureus or Streptococcus based on the knowledge of Example 1.
  • Example 1 In the test group (Lactoferrin / Glycyrrhizin combination group), as in Example 1, the first day of onset (within 24 hours from the onset, within about 18 hours from the onset), and 3 days after onset, once per quarter 10 mL of lactoferrin solution (containing 200 mg of lactoferrin as a titer, manufactured by Kyoritsu Pharmaceutical Co., Ltd.) is directly injected into the affected quarter from the teat canal.
  • lactoferrin solution containing 200 mg of lactoferrin as a titer, manufactured by Kyoritsu Pharmaceutical Co., Ltd.
  • cefazolin oily breast infusions were made every day from the first day of onset (within 24 hours from onset, within about 18 hours from discovery) to 3 days after onset and 7 days after onset, respectively.
  • the drug (containing cefazolin 150 mg) was injected directly into the affected quarter.
  • cefazoline sodium solution 300 ⁇ L was intravenously administered in addition to direct injection into the affected quarter of cefazolin on the first day of onset and one day after the onset.
  • Example 2 In the same manner as in Example 1, on the day of onset, 1 day, 3 days, 7 days, and 10 days after the onset, each affected cow is observed for breasts, and the degree of breast swelling and induration is determined and scored Turned into. On the same day, milk was collected and the amount of milk was measured, and the properties of the milk and the presence or absence of coagulum were determined and scored. Furthermore, the number of somatic cells in the milk was measured, and the aggregation and color tone of the milk were comprehensively determined using a PL tester and scored.
  • Table 7 shows the clinical scores of breast findings when lactoferrin and glycyrrhizin were directly injected into affected quarters of cattle affected by acute mastitis in cattle caused by S. aureus or streptococci. ), Table 9 shows the recovery rate of milk yield, Table 10 shows the milk score, Table 11 shows the number of somatic cells in the milk, and Table 12 shows the score of the PL test.
  • the column “Test group” represents the result of the test group (Lactoferrin / Glycyrrhizin combination group), and the column “Control group” represents the result of the control group (antibiotic group). The notation is the same as above.
  • Example 1 As in Example 1, 4 days after the last infusion of lactoferrin, 600 mg of glycyrrhizin salt with a titer was directly injected into the affected quarter from the papillary canal for a shorter period of time. Thus, the quality of the milk was restored to that of normal milk. This is because, in the case of acute mastitis during lactation of cattle caused by Staphylococcus aureus or streptococci, just as in the case of cattle acute mastitis caused by coliform bacteria, Not only can it be cured in a short period of time, it also suggests that milk production and shipping can be resumed in a short period of time after illness, suggesting that economic losses on the dairy industry can be significantly reduced.
  • Example 3 the change with time of the white blood cell count in the milk was examined.
  • lactoferrin solution 200 mg of lactoferrin in titer, manufactured by Kyoritsu Pharmaceutical Co., Ltd.
  • milk was collected immediately before lactoferrin injection, 1 hour, 6 hours, 24 hours, and 48 hours after lactoferrin injection, and the number of T cells and granulocytes in each milk sample were measured.
  • cefazolin oily breast injection containing 150 mg of cefazolin
  • the FITC-conjugated anti-CD-3 antibody to the milk sample and react with the T cells in the sample. This was done by counting the number of cells.
  • the number of granulocytes in the milk sample is measured by adding FITC-conjugated anti-granulocyte antibody to the milk sample and reacting with the granulocytes in the sample. This was done by counting the number of cells produced.
  • FIG. 1A is a graph showing the change over time in the number of T cells at the time of lactoferrin injection
  • FIG. 1B is a graph showing the change over time in the number of granulocytes.
  • the horizontal axis in both figures represents the elapsed time (unit: hour) after injecting lactoferrin and the like
  • the vertical axis represents the number of cells ( ⁇ 10 6 ).
  • the “LF” line represents the time-dependent change in the number of cells in milk in cows injected with lactoferrin inside the affected quarter
  • “Control” shows the control in cows injected with antibiotics inside the affected quarter. The change over time of the number of cells in the milk is shown respectively.
  • lactoferrin when directly injected into the affected area as in the present invention, it can be presumed that symptom and prognosis due to endotoxin or prolongation of the unhealed state can be suppressed.
  • the ability to avoid the occurrence of endotoxin may be one of the reasons why it was possible to restore the bovine individual to the pre-mastitis situation in a relatively short time in Example 1 etc. .
  • Example 3 the graph showing the time-dependent change of the T cell number at the time of lactoferrin infusion. In Example 3, the graph showing the time-dependent change of the granulocyte count at the time of lactoferrin injection.

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Abstract

L'invention concerne un agent thérapeutique pour traiter la mastite suraiguë ou aiguë pendant l'allaitement bovin qui contient de la lactoferrine en tant que principe actif, et qui est utilisé par injection directe dans le pis affecté à travers le canal du trayon, plusieurs fois, à des intervalles d'au moins deux jours, le titre de la lactoferrine étant de 10 à 500 mg à chaque fois. L'invention concerne en outre un ensemble d'agents thérapeutiques pour traiter la mastite suraiguë ou aiguë pendant l'allaitement bovin constitué de l'agent thérapeutique et d'un agent thérapeutique pour traiter la mastite suraiguë ou aiguë pendant l'allaitement bovin, qui contient de la glycyrrhizine ou un sel de celle-ci en tant que principe actif, et qui est utilisé par injection directe dans le pis affecté à travers le canal du trayon, le titre de la glycyrrhizine ou du sel de celle-ci étant de 100 à 1 000 mg au moins deux jours après la dernière injection de la lactoferrine; et similaire.
PCT/JP2016/067748 2015-06-17 2016-06-15 Agent thérapeutique et procédé thérapeutique pour mastite suraiguë ou aiguë pendant l'allaitement bovin Ceased WO2016204169A1 (fr)

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WO2020043700A3 (fr) * 2018-08-27 2020-04-09 Société des Produits Nestlé S.A. Compositions et méthodes pour le traitement de la mastite
WO2021105345A1 (fr) * 2019-11-29 2021-06-03 Société des Produits Nestlé S.A. Compositions et procédés pour le traitement de la mastite
CN114945285A (zh) * 2020-01-16 2022-08-26 雀巢产品有限公司 用于治疗乳腺炎的组合物和方法
CN114945380A (zh) * 2019-11-29 2022-08-26 雀巢产品有限公司 用于预防或治疗乳腺炎的具有益生菌和营养物质和/或矿物质的组合物和方法

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Publication number Priority date Publication date Assignee Title
WO2020043700A3 (fr) * 2018-08-27 2020-04-09 Société des Produits Nestlé S.A. Compositions et méthodes pour le traitement de la mastite
CN112601530A (zh) * 2018-08-27 2021-04-02 雀巢产品有限公司 用于治疗乳腺炎的包含矿物质、蛋白质和脂肪酸的组合物
WO2021105345A1 (fr) * 2019-11-29 2021-06-03 Société des Produits Nestlé S.A. Compositions et procédés pour le traitement de la mastite
CN114745971A (zh) * 2019-11-29 2022-07-12 雀巢产品有限公司 用于治疗乳腺炎的组合物和方法
CN114945380A (zh) * 2019-11-29 2022-08-26 雀巢产品有限公司 用于预防或治疗乳腺炎的具有益生菌和营养物质和/或矿物质的组合物和方法
CN114945285A (zh) * 2020-01-16 2022-08-26 雀巢产品有限公司 用于治疗乳腺炎的组合物和方法

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