WO1998035665A1 - Antagonistes des endotoxines - Google Patents

Antagonistes des endotoxines Download PDF

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Publication number
WO1998035665A1
WO1998035665A1 PCT/JP1998/000598 JP9800598W WO9835665A1 WO 1998035665 A1 WO1998035665 A1 WO 1998035665A1 JP 9800598 W JP9800598 W JP 9800598W WO 9835665 A1 WO9835665 A1 WO 9835665A1
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WO
WIPO (PCT)
Prior art keywords
endotoxin
fatty acids
acid
neutralizing
solution
Prior art date
Application number
PCT/JP1998/000598
Other languages
English (en)
Japanese (ja)
Inventor
Yoshiyuki Fujishima
Naoto Koyama
Hisao Ito
Kenzo Yokozeki
Masahiko Oshimura
Hisamine Kobayashi
Tadashi Takemoto
Toshihiko Ando
Satoko Azumi
Ken-Ichi Tanamoto
Original Assignee
Ajinomoto Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ajinomoto Co., Inc. filed Critical Ajinomoto Co., Inc.
Publication of WO1998035665A1 publication Critical patent/WO1998035665A1/fr

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Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids

Definitions

  • the present invention relates to an endotoxin neutralizing agent, and more particularly, to an endoxin neutralizing agent containing a fatty acid as an active ingredient.
  • the endotoxin-neutralizing component (fatty acids) of the present invention can be injected or administered into a vein, intraperitoneal cavity, breast, rumen (ruminal ruminal of a reproductive animal), or the like, and then be administered.
  • Endotoxin (lipopolysaccharide), known as a cell wall component of Gram-negative bacteria, is mainly composed of sugars and fatty acids. Phosphorylated diglucosamine, in which multiple long-chain fatty acids are amide- and ester-linked, is particularly called lipid A and is a common active unit that expresses various physiological actions of endotokins. ing.
  • endotoxin Although the physiological actions of endotoxin are diverse and varied, it is well known that it produces lethal toxicity in susceptible animals, including humans. Endotoxin that has migrated into the blood by translocation of intestinal gram-negative bacteria, etc., is taken up by phagocytic cells such as macrophages when it is taken up by TNF and IL. It induces the production of inflammatory cytokines, such as eleven. As a result, a variety of eicanosides, such as vasodilator mediators such as nitric oxide, have been updated. As they are released into the blood one after another, they often trigger a systemic inflammatory response (sepsis).
  • metabolic diseases such as abomasum displacement, laminitis, and hepatic disorder have frequently occurred in ruminants such as stomachs that have been heavily fed with concentrated feed.
  • ruminants such as stomachs that have been heavily fed with concentrated feed.
  • endotoxin is released from gram-negative bacteria in the rumen that died due to metabolic abnormalities in the rumen.
  • Measures to reduce endotoxin concentration in body fluids include reducing the influx of endotoxin from the intestinal tract into the blood and neutralizing endotoxin in the blood. It has been devised. In fact, a method of reducing endotoxin influx from the intestinal tract into the bloodstream by orally administering a substance capable of absorbing endotoxin (B. Ditteretal. , G as troentero , Vol. 84, 1547, 1983), polymixin complex (JP-A-3-2201998) and aliphatic amine (JP-A-5-271710). Methods for neutralizing endotoxin in the blood have been reported so far.
  • Endotoxin (lipid A) neutralizing antibody developed by Centa Co., Ltd., Zoma of Amerika has finally proved clinically effective despite extensive clinical trials. There was no. Also, in patients who need to neutralize endotoxin in the intestine or blood, it is often necessary to administer the neutralizing agent for a certain period of time, for example, until the intestinal inflammation subsides. There is. With this in mind, synthetic drugs such as those described above always carry the risk of side effects, and long-term administration is not always appropriate. On the other hand, a horseshoe crab-derived peptide (Japanese Patent Application Laid-Open No.
  • Japanese Patent Publication No. 5-501416 discloses the prevention and treatment of the toxic effects of endotoxin by the combined use of iron-binding lactoferrin and IgG. A method for performing this is disclosed. This is thought to be mainly due to the bacteriostatic action of lactoferrin.
  • ⁇ ⁇ is related to the removal and inactivation of endotoxins derived from pathogenic bacteria in milk.
  • frequent milking is the only means and rarely uses such drugs for persistence, toxicity, or economics for such purposes.
  • livestock metabolic disease although there are attempts to prevent a decrease in pH in rumen, which is said to lead to the death of gram-negative bacteria in rumen, endotoxin in rumen fluid Very few attempts have been made to actively remove or inactivate these components.
  • the present invention is effective in the prevention and treatment of systemic inflammatory response syndrome (sepsis) in humans and animals caused by gram-negative bacteria and local inflammation such as mastitis and laminitis in the background of the prior art described in the preceding paragraph.
  • the aim is to develop and supply new and superior endoxin neutralizers.
  • the present inventors can inactivate endotoxin directly, or localize endotoxin in addition to the original endotoxin target cells (inflammatory cells) to achieve systemic activity. If the release of these cells from the media, which triggers the inflammatory response, could be suppressed, the survival rate of sepsis could be improved, or the livestock could be prevented or reduced by local inflammation. Being able to contribute to the improvement of productivity, we conducted intensive studies to find a neutralizing agent for endotoxin, and as a result, various fatty acids showed a neutralizing effect on endotoxin activity. Have Were newly found, and the present invention was completed based on such knowledge. That is, the present invention relates to an endotoxin neutralizer characterized by comprising one or more fatty acids as an active ingredient.
  • fatty acids which are the active ingredients of the endotoxin neutralizer of the present invention include free fatty acids, salts thereof and derivatives thereof.
  • Fatty acids are preferably fatty acids having 9 or more carbon atoms, more preferably saturated or unsaturated fatty acids having 9 to 22 carbon atoms.
  • These fatty acids can be obtained by ordinary methods such as hydrolysis of natural fats and oils or isolation from natural products, and can be easily and inexpensively obtained.
  • Examples of the salt of the fatty acid include pharmaceutically acceptable salts thereof, for example, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt and the like. it can.
  • Derivatives of fatty acids include derivatives that do not lose endotoxin neutralizing activity, such as amides and esters (monoglycerides, diglycerides, triglycerides). , Etc.), phospholipids (L- ⁇ -phosphatidylcolindilaurol, L_ ⁇ -phosphatidylcolindimyristyl, L- ⁇ -phosphatidylcolindioleyl, soy lecithin, Egg yolk lecithin, etc.), glycolipids, protein-bound fatty acids, polyoxyethylene, Examples include steles, acid anhydrides, pyridine compounds, halides, sulfonates, sulfides, thiocyanates, etherates, acylates, azides, thiols, and the like.
  • One of these fatty acids may be used alone or two or more of them may be used in combination as an active ingredient of an endotoxin neutralizing agent. Can also.
  • the findings regarding the neutralizing action of endotoxin by the endotoxin neutralizing agent of the present invention are as follows. That is, first, the above-mentioned fatty acids used in the present invention are mixed with endotoxin in advance and kept at room temperature to inhibit the limulus reaction by endotoxin (test example). 1). In addition, the above fatty acids and endotoxin are mixed in advance, and then injected into mice whose sensitivity has been increased by administration of galactosamine, or by injection of endotoxin. Later administration of the above fatty acids suppresses the lethal effects of endotoxin injection, which would normally cause endotoxin shock and die (Test Examples 2 and 3) See).
  • fatty acids when ingested, do not undergo degradation in the gastrointestinal tract (including the stomach) from the oral cavity to the stomach, and reach the intestinal tract without being broken down. Can also be expected to act as an endotoxin neutralizer in the gastrointestinal tract.
  • the endotoxin neutralizing agent of the present invention is administered to animals such as humans and livestock as a sterile injection solution intravenously, intraperitoneally, intramuscularly, in the breast, etc., or as an enteral infusion. You can do it. It can also be applied topically to the skin, eyes, ears, nose, anus, breast, vagina, etc. as a powder, solution, suspension, cream, ointment, spray, etc.
  • doxoxine neutralizing agent can be administered in combination with an existing antibiotic.
  • the preparation can be prepared by appropriately using excipients, stabilizers, and the like that are used in usual preparations.
  • known and suitable pharmacologically acceptable solvents eg, water, ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc.
  • flavors, sweeteners, binders, isotonic Formulations can also be made with appropriate use of active substances, liniments, surfactants (such as bile acids), absorption delaying agents, PH regulators (such as triethanolamine), and the like.
  • fatty acids may be used in addition to other components effective in alleviating the symptoms of endotoxin (eg, corticosteroids (methylprednisolone, dexamethasone, etc.), antibiotics, etc. (Ampicillin, methicillin, noncomicin, etc.) and antibodies (anti-endotoxin antibody, anti-interleukin-16 antibody, anti-TNF antibody, etc.) and the like. It is also possible to prepare an endotoxin neutralizing agent.
  • corticosteroids methylprednisolone, dexamethasone, etc.
  • antibiotics etc.
  • anti-endotoxin antibody anti-interleukin-16 antibody, anti-TNF antibody, etc.
  • anti-TNF antibody anti-TNF antibody
  • Prevention and treatment of local inflammation such as sepsis and mastitis in humans and animals by the endotoxin neutralizing agent of the present invention include, for example, direct injection, It can be mixed with food and drink in advance and administered orally.
  • oral administration, injection, suppositories, and the application of a matrix containing fatty acids to mucous membranes can be used. It can be administered by control release.
  • the effective amount of the fatty acids for the prevention and treatment of local inflammation such as sepsis and mastitis is about 1 to 100 mg / kg of human or animal body weight per day. It is presumed that
  • Inspection example 1 (Best mode for carrying out the invention) Hereinafter, the present invention will be further described with reference to inspection examples. Inspection example 1
  • fatty acids were preliminarily mixed with endotoxin, and the concentration of residual endotoxin after a certain period of time was determined by Limulus test. Then, the endotoxin neutralizing ability of those fatty acids was evaluated.
  • Lipopolysaccharide prepared from Salmonel la minnesota (S. minnesota) was used as the enodotocin (Wes tpha 1 et a 1 .. Z. Naturforsch., Vol. 76, 148-155, 1952).
  • Fatty acids include radium, myristate, palmitate, oleic, linoleic, ⁇ -linolenic, r— Linoleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid (all manufactured by Nacalai Tesque, reagent grade), L- ⁇ -phosphatidylco-lindilaurol, L_ ⁇ — Those listed in Table 1 below were inspected, such as phosphatidylcolindi millistoil (above, manufactured by Sigma). That is, each of these fatty acids was dissolved in 99.5% ethanol to prepare a stock solution having a concentration of 20 mg Zml.
  • the lipopolysaccharide was dissolved in distilled water for injection to give a solution having a concentration of 20 ⁇ g Zml.
  • the evaluation by Limulustest was performed by diluting the above fatty acid stock solution with ethanol to a concentration of 10, 2.5, and 0.SSS mg Zml.
  • Glycine sodium hydroxide buffer (0.2 M, pH 10.6 (1992 published by Hirokawa Shoten)
  • Reagent preparation method (Reagent preparation method”)) and endotoxin solution are added in a ratio of 1: 1: 2, and these mixtures are each pre-plated at room temperature for 1 hour and 30 minutes, and then added to distilled water for injection.
  • LPS Lipopolli Saccharide
  • Fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, ⁇ -linolenic acid, arachidonic acid, and docosahexane. The acid was checked. That is, each of these fatty acids was dissolved in 99.5% ethanol to give a stock solution having a concentration of 25 mg Zm1. The endotoxin was a solution having a concentration of 200 g Zm1.
  • mice, endotoxin and fatty acids were all the same as those in Test Example 2.
  • Endotoxin prepared a solution with a concentration of 200 ⁇ g Zml from this, Mix with the lactosamine solution so that the concentration of endotoxin is 0.2 ⁇ g Zm1 and the concentration of galactosamine is 24 mg Zml. It was adjusted.
  • the oleic acid was dissolved in 99.5% ethanol to form a stock solution with a concentration of 25 mg Zm1, which was then added to a sodium glycine hydroxide buffer. (Same as in Test Example 1) were mixed in the ratios of 2: 3 and 1: 4.
  • fatty acids or phospholipids were premixed with endotoxin in milk to determine the residual endotoxin content and activity in milk after a certain period of time.
  • the endotoxin neutralizing ability of these fatty acids in milk was evaluated by measuring them in the test of administration to limulustest and mice, respectively.
  • the endotoxins were lipopolysaccharide (LPS) extracted from S. Minnesota and Escherichia coli (E. coil) 011 and E. col1 purchased from Sigma. LPS of i 0 128 was used.
  • the free fatty acids are oleic acid (manufactured by Nakara Itesque), and the phospholipids are L- ⁇ -phosphatidylcholine dilauroyl and L- ⁇ -phosphatidylcholine.
  • Myristoil L- ⁇ -phosphatidylcolindioleoleyl (all manufactured by Sigma), egg yolk lecithin PC-98NJ (manufactured by Kyupie Co., Ltd.) and soybean lecithin (Tsurichi Lecithin Industrial ( Was inspected.
  • Oleic acid was dissolved in 99.5% ethanol and mixed with triethanolamine to form a solution having a concentration of 50 mg Zml.
  • oleic acid or phospholipids include sodium cholate (manufactured by Nakara Itesque), sodium taurocholate (manufactured by DFCO), and sodium deoxycholate.
  • sodium salt manufactured by Nacala Itesque
  • sodium salt of taurodeoxycholic acid manufactured by Nacala Itesque
  • PBS Phosphate-buffered saline
  • Composition (* 1) S, y-Calide Neutralizing substance / LPS / Milk Neutralization rate (%) Oleic acid
  • Fatty acids which are the active ingredients of the neutralizing agent of the present invention, neutralize endotoxin and suppress the lethal effect of endotoxin, so that humans at the time of infection with Gram-negative bacteria can be used. And prevent harmful effects on the body due to local inflammation such as sepsis and mastitis in animals, and thus are effective in preventing and treating it. Further, an advantage of the present invention is that many such fatty acids are readily and inexpensively available. Therefore, according to the present invention, an excellent preventive and therapeutic agent for local inflammation such as sepsis and mastitis can be easily and inexpensively supplied.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur un excellent antagoniste des endotoxines comportant comme principes actifs un ou plusieurs acides gras, et servant à traiter la septicémie et les inflammations locales.
PCT/JP1998/000598 1997-02-14 1998-02-13 Antagonistes des endotoxines WO1998035665A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/30573 1997-02-14
JP3057397 1997-02-14

Publications (1)

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WO1998035665A1 true WO1998035665A1 (fr) 1998-08-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011037906A (ja) * 2004-03-30 2011-02-24 Soda Aromatic Co Ltd アラキドン酸代謝抑制剤

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435386A (en) * 1982-05-26 1984-03-06 Ribi Immunochem Research, Inc. Refined detoxified endotoxin product
WO1993014115A1 (fr) * 1992-01-16 1993-07-22 Massimo Porro Peptides synthetiques pour la detoxication des endotoxines bacteriennes et pour le traitement des chocs septiques
JPH05320043A (ja) * 1992-05-20 1993-12-03 Terumo Corp リポポリサッカライド捕捉剤
JPH08119917A (ja) * 1994-09-02 1996-05-14 Sankyo Co Ltd アミノ酸含有リピド化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435386A (en) * 1982-05-26 1984-03-06 Ribi Immunochem Research, Inc. Refined detoxified endotoxin product
WO1993014115A1 (fr) * 1992-01-16 1993-07-22 Massimo Porro Peptides synthetiques pour la detoxication des endotoxines bacteriennes et pour le traitement des chocs septiques
JPH05320043A (ja) * 1992-05-20 1993-12-03 Terumo Corp リポポリサッカライド捕捉剤
JPH08119917A (ja) * 1994-09-02 1996-05-14 Sankyo Co Ltd アミノ酸含有リピド化合物

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
EMANCIPATOR K., CSAKO G., ELIN R. J.: "IN VITRO INACTIVATION OF BACTERIAL ENDOTOXIN BY HUMAN LIPOPROTEINS AND APOLIPOPROTEINS.", INFECTION AND IMMUNITY, AMERICAN SOCIETY FOR MICROBIOLOGY., US, vol. 60., no. 02., 1 February 1992 (1992-02-01), US, pages 596 - 601., XP002912839, ISSN: 0019-9567 *
MATHISON J., ET AL.: "REGULATORY MECHANISMS OF HOST RESPONSIVENESS TO ENDOTOXIN (LIPOPOLYSACCHARIDE).", PATHOBIOLOGY., KARGER, BASEL, CH, vol. 59., no. 03., 1 January 1991 (1991-01-01), CH, pages 185 - 188., XP002912838, ISSN: 1015-2008 *
TOSHIAKI I B A , ET AL.: "THE CHANGES IN LIPOPROTEIN LEVELS AFTER ADMINISTRATION OF MEDIUM CHAIN TRIGLYCERIDE - A PRELIMINARY STUDY ON NEUTRALIZATION OF ENDOTOXIN IN RATS", PRELIMINARY STUDY ON NEUTRALIZATION OF ENDOTOXIN IN RATS, XX, XX, vol. 31, no. 04, 1 January 1997 (1997-01-01), XX, pages 233 - 238, XP002912837 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011037906A (ja) * 2004-03-30 2011-02-24 Soda Aromatic Co Ltd アラキドン酸代謝抑制剤

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