WO1995003057A1 - Neutralisant d'endotoxine - Google Patents
Neutralisant d'endotoxine Download PDFInfo
- Publication number
- WO1995003057A1 WO1995003057A1 PCT/JP1994/001159 JP9401159W WO9503057A1 WO 1995003057 A1 WO1995003057 A1 WO 1995003057A1 JP 9401159 W JP9401159 W JP 9401159W WO 9503057 A1 WO9503057 A1 WO 9503057A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tetracycline
- endotoxin
- agent
- derivative
- antibacterial
- Prior art date
Links
- 239000002158 endotoxin Substances 0.000 title claims abstract description 38
- 239000004098 Tetracycline Substances 0.000 claims abstract description 40
- 235000019364 tetracycline Nutrition 0.000 claims abstract description 40
- 229960002180 tetracycline Drugs 0.000 claims abstract description 39
- 229930101283 tetracycline Natural products 0.000 claims abstract description 39
- 150000003522 tetracyclines Chemical class 0.000 claims abstract description 32
- 206010040070 Septic Shock Diseases 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 claims abstract description 5
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 claims abstract description 5
- 239000004100 Oxytetracycline Substances 0.000 claims abstract description 5
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- 229960000625 oxytetracycline Drugs 0.000 claims abstract description 5
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 claims abstract description 5
- 235000019366 oxytetracycline Nutrition 0.000 claims abstract description 5
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 claims abstract description 5
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 claims abstract description 4
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 claims abstract description 4
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- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 claims abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 20
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- 238000011282 treatment Methods 0.000 description 3
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- 206010061598 Immunodeficiency Diseases 0.000 description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 2
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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
- A61K31/65—Tetracyclines
Definitions
- the present invention relates to an endotoxin neutralizing agent containing a tetracycline antibacterial agent or a derivative thereof as an active ingredient.
- the present invention is used as a preventive / therapeutic agent for various diseases caused by endotoxin and endotoxin shock.
- Endotoxin (bacterial endotoxin) is a component of the outer membrane structure of the cell wall of Gram-negative bacteria. Its major component, lipopolysaccharide (1S), is a complex of polysaccharide and lipid. And its toxicity has been shown to be localized to 1 ipidA.
- Endotoxin release in the body causes a variety of symptoms, including fever, chills, horror, and reduced blood pressure, and eventually multiple organ failure (MOF), including diffuse intravascular coagulation (DIC) and renal and hepatic failure
- MOF multiple organ failure
- DIC diffuse intravascular coagulation
- renal and hepatic failure It is a big problem that can cause shock and death in patients. It is thought that the pathology of these diseases progresses due to activation of the complement system and coagulation-fibrinolytic system by endotoxin stimulation and interaction with cytokines produced from monocytes, neutrophils, vascular endothelial cells, and the like.
- T NF cachectin tumor necrosis factor
- polymyxin B has been identified as a substance that blocks the harmful effects of endotoxin.
- its use is limited, for example, topical administration due to its high nephrotoxicity and neurotoxicity.
- large doses of dalcocorticoid have protective effects in experimental endotoxin shock models.
- combination treatment of antibiotics and methylprednisolone was attempted in patients with sepsis and septic shock.
- the usefulness of the combination is not recognized, and that the prevalence of secondary infection is increased by the administration of methylprednisolone.
- studies on anti-1ipid A antibody ⁇ anti-TNF antibody and the like have been attempted, but a reliable adjuvant therapy has not yet been established.
- tetracycline antibacterial agents have an extremely wide antibacterial spectrum and have been frequently used for various infectious diseases. Its antibacterial effect is to inhibit bacterial protein synthesis by inhibiting the binding of bacterial aminoacyl-tRNA to liposomes, and its effect on LPS, an outer membrane component of Gram-negative bacteria, is not known. Not. Today, Gram-positive bacteria such as Streptococcus pneumoniae and Streptococcus haemolyticus-Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, and Shigella have become resistant to tetracycline-based antibacterial agents. It has been limited to resistant Staphylococcus aureus.
- the present inventors have been studying methods for preventing or treating endotoxin shock and found that the ability of LPS to induce TNF is blocked by existing tetracycline antibacterial agents.
- the present invention has been completed by further studying this finding.
- the present invention provides: (1) a neutralizing agent for endotoxin containing a tetracycline antibacterial agent or a derivative thereof as an active ingredient; and (2) prevention of a disease caused by endotoxin containing a tetracycline antibacterial agent or a derivative thereof as an active ingredient. And therapeutic agents (except when used as antibacterial agents). And 3 a prophylactic or therapeutic agent for endotoxin shock containing a tetracycline antibacterial agent or a derivative thereof as an active ingredient.
- the tetracycline-based antibacterial agent is tetracycline (4-dimethy 1 amino-1,4,4a, 5, oa, 6,11,12a-oc t ahyd r o-3, 6, 10, 12, 12 ap en t ahy d r oxy-6 — me t hy 1— 1, 1 1 di oxo— 2—carboxami de) It refers to a group of antibiotics with four 6-membered rings as the basic skeleton and their derivatives. Specific examples include tetracycline, oxytetracycline, demethylchlorotetracycline, doxycycline, minocycline, quintetratetracycline, and salts or derivatives thereof.
- the antibacterial activity of the tetracycline used does not need to be particularly problematic, but only the neutralizing activity against endotoxin. This means that the use of this drug is not restricted even in the current clinical setting where many Gram-negative bacteria have become resistant to tetracycline antibiotics.
- a tetracycline derivative having no antibacterial activity can be used in the present invention.
- Such tetracyclines have the advantage that the problem of inducing resistance to bacteria does not occur.
- the present invention is a method using a tetracycline-based compound as an endotoxin neutralizing agent that inhibits a biological response to endotoxin stimulation. It can be used to ameliorate the pathology of temporary or persistent endotoxemia.
- endotoxemia in which the neutralizing agent for endotoxin of the present invention can be used include trauma, burn, peritonitis, biliary tract infection, liver abscess, urinary tract infection, infectious abortion, pneumonia, and sepsis associated with Gram-negative bacterial infection.
- endotoxemia due to mechanical manipulations for treatment and examination and endotoxin absorption from intestinal flora due to deterioration of the underlying disease include liver cirrhosis, fulminant hepatitis, surgical operations such as hepatectomy and digestive organs , Suture failure, ulcerative colitis, acute inflammation and the like.
- tetracycline antibiotics have already been indicated for sepsis, trauma, burns, postoperative secondary infections, pneumonia, urinary tract infections, and biliary tract infections.
- these were used according to the so-called antibacterial activity expressed by the minimum inhibitory concentration (MIC) of bacteria, and there is no known use as a neutralizing agent of endotoxin action.
- MIC minimum inhibitory concentration
- the present invention is further used as an agent for preventing and treating a disease caused by endotoxin.
- Endotoxin-induced diseases include sporadic intravascular coagulation (DIC), adult respiratory distress syndrome (ARDS), and multiple organ failure (MOF), including renal and hepatic failure And so on.
- endotoxin shock refers to an irreversible shock state exhibiting acute circulatory failure based on endotoxemia. These are more likely to occur due to severe gram-negative bacterial infections in cancer and immunocompromised patients, as well as contaminated blood transfusions, fluids, and long-term catheter placement.
- the administration of the tetracycline compound is appropriately selected from oral, injection (intramuscular, intravenous, intravenous drip), topical, and the like.
- the dose is appropriately selected depending on the route of administration, purpose of use (prevention or treatment), and symptoms, but is preferably 100 mg to 1 g (therapeutic agent) and 2 mg to 30 mg (the prophylactic agent). Generally, when used as a prophylactic agent, a relatively low dose is often required.
- the tetracycline compound of the present invention can be converted into a pharmaceutically acceptable salt with a suitable acid.
- suitable acids include hydrochloric acid, nitric acid, metaphosphoric acid and the like.
- oral administration it can be made into tablets, granules, powders, capsules, suspensions, emulsions, syrups, etc.Addition of excipients, binders, bulking agents, etc. commonly used in formulation Things may be included.
- it may be in the form of an aqueous solution, suspension, oily or water-soluble emulsion, but is usually prepared as an aqueous solution such as sterile water or physiological saline. If necessary, commonly used solubilizers, stabilizers, preservatives and the like may be added.
- ICR mice (5-week-old 25-28 g) were intraperitoneally injected with 100 r of LPS and 50 Or or 1000 r of tetracycline (TC), and TNF in the blood of the mice 4 hours later The amount was measured. After a mixture of LPS and TC was cultured at 4 ° C for 4 hours, the mixture was intraperitoneally administered. TNF was measured by cytotoxicity to L cells.
Landscapes
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU71948/94A AU7194894A (en) | 1993-07-20 | 1994-07-15 | Endotoxin neutralizer |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5/178893 | 1993-07-20 | ||
| JP17889393 | 1993-07-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995003057A1 true WO1995003057A1 (fr) | 1995-02-02 |
Family
ID=16056540
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1994/001159 WO1995003057A1 (fr) | 1993-07-20 | 1994-07-15 | Neutralisant d'endotoxine |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU7194894A (enrdf_load_stackoverflow) |
| TW (1) | TW264389B (enrdf_load_stackoverflow) |
| WO (1) | WO1995003057A1 (enrdf_load_stackoverflow) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004043228A3 (en) * | 2002-11-09 | 2005-04-07 | Univ New York State Res Found | Method of treating sepsis-induced ards |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991001755A1 (en) * | 1989-08-10 | 1991-02-21 | Celltech Limited | Pharmaceutical product for the treatment of sepsis |
-
1994
- 1994-07-15 WO PCT/JP1994/001159 patent/WO1995003057A1/ja active Application Filing
- 1994-07-15 AU AU71948/94A patent/AU7194894A/en not_active Abandoned
- 1994-07-20 TW TW83106648A patent/TW264389B/zh active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991001755A1 (en) * | 1989-08-10 | 1991-02-21 | Celltech Limited | Pharmaceutical product for the treatment of sepsis |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004043228A3 (en) * | 2002-11-09 | 2005-04-07 | Univ New York State Res Found | Method of treating sepsis-induced ards |
Also Published As
| Publication number | Publication date |
|---|---|
| TW264389B (enrdf_load_stackoverflow) | 1995-12-01 |
| AU7194894A (en) | 1995-02-20 |
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