WO2010038656A1 - Prophylactic and therapeutic agent for sepsis - Google Patents
Prophylactic and therapeutic agent for sepsis Download PDFInfo
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- WO2010038656A1 WO2010038656A1 PCT/JP2009/066593 JP2009066593W WO2010038656A1 WO 2010038656 A1 WO2010038656 A1 WO 2010038656A1 JP 2009066593 W JP2009066593 W JP 2009066593W WO 2010038656 A1 WO2010038656 A1 WO 2010038656A1
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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
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
Definitions
- the present invention relates to a preventive and therapeutic agent for sepsis and its use.
- Sepsis is caused by bacterial infections such as pneumonia and peritonitis, and bacterial infections caused when the immune system is reduced by chemotherapy for malignant tumors.
- bacterial infections such as pneumonia and peritonitis
- bacterial infections caused when the immune system is reduced by chemotherapy for malignant tumors.
- Symptoms such as fever, tachypnea, tachycardia, and leukocytosis appear, and if progressed, circulatory failure such as impaired consciousness and blood pressure decrease, and organ dysfunction such as renal / lung / liver / coagulation dysfunction. If severe, it leads to acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation syndrome (DIC), etc., leading to the worst results such as cardiac arrest and death due to septic shock.
- ARDS acute respiratory distress syndrome
- DIC disseminated intravascular coagulation syndrome
- Treatment methods for sepsis include fluid resuscitation, antibiotics intended to suppress lipopolysaccharide (LPS) production, and nonsteroidal anti-inflammatory drugs that suppress inflammatory reactions.
- LPS lipopolysaccharide
- nonsteroidal anti-inflammatory drugs that suppress inflammatory reactions.
- administration of vasopressors that improve hypotension, steroids that suppress inflammation, blood coagulation inhibitors, and the like are performed in clinical settings.
- Xigris (Digris Drotrecogin alfa, activated: Eli Lilly, USA), which is known as a therapeutic agent for sepsis, is an active protein C preparation and has an effect of suppressing cell apoptosis as well as an effect of inhibiting blood coagulation. It is ineffective for patients with sepsis and is restricted to use only for patients with severe sepsis.
- cyclic oligosaccharides mainly used as food additives include ⁇ -, ⁇ - and ⁇ - ⁇ cyclodextrins in which 6 to 8 molecules of glucose are linked by ⁇ -1,4 bonds to form a cyclic structure. It has been known. There is a report that these ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin have an effect on sepsis (see Patent Document 1 below). However, ⁇ - and ⁇ -cyclodextrins have a problem of hemolysis (see Non-Patent Document 1 and Non-Patent Document 2 below), and ⁇ -cyclodextrin has nephrotoxicity.
- ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin cannot be said to sufficiently satisfy the demand as a therapeutic agent for sepsis.
- the present invention has been made in view of the above-described problems of the prior art, and its main purpose is to provide a preventive and therapeutic agent for sepsis that has a sufficient therapeutic effect on sepsis and has no side effects. It is to be.
- the present inventor has intensively studied to achieve the above-mentioned purpose.
- cyclic tetrasaccharides composed of glucose, cyclic pentasaccharide and derivatives thereof which have not been used as a therapeutic agent for sepsis, have a sufficiently strong effect on sepsis from an early stage, Furthermore, it has been found that there are almost no side effects such as hemolysis and nephrotoxicity, and the present invention has been completed here.
- a prophylactic and therapeutic agent for sepsis comprising as an active ingredient at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof.
- Item 2. The preventive and therapeutic agent for sepsis according to Item 1, which is an injectable aqueous preparation or a solid agent for dissolution upon use. 4).
- Item 4. The prophylactic and therapeutic agent for sepsis according to Item 3, which is used for intravenous administration. 5).
- a prophylactic and therapeutic agent for sepsis containing at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof; Methods for preventing and treating sepsis. 8).
- the sepsis preventive and therapeutic agent of the present invention contains, as an active ingredient, at least one selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof. .
- a cyclic tetrasaccharide having glucose as a constituent sugar is a compound in which four glucoses are linked to form a ring
- a cyclic pentasaccharide having glucose as a constituent sugar is a compound in which five glucoses are connected in a ring. is there.
- CNN is a compound found by Gregory El Cote et al. (European Journal of Biochemistry, 226, 641 (1994)), and then Hayashibara Biochemical Research Institute Co., Ltd. As a result, a mass production method from starch was realized. CNN itself exhibits high solubility (dissolves 46.1 g in 100 g water at 20 ° C.), low sweetness (27% sweetness of sugar), and good pH stability and heat stability. As for the use of CNN, there are reports that some medical uses are expected, but the prevention and treatment effects of sepsis are not known at all.
- CMM is a compound found by Hayashibara Biochemical Laboratories Co., Ltd. and described in JP-A-2005-95148.
- CMM like CNN, is a compound that exhibits high solubility and stability, and its use is currently under investigation, but there is no report on the prevention and treatment effects of sepsis.
- ICG5 a cyclic pentasaccharide, is a compound found by Hayashibara Biochemical Laboratories Co., Ltd. and is described in WO2006 / 35725. ICG5 is a compound that has almost no sweetness and exhibits high solubility and stability, and its use is currently under investigation, but there is no report on the effect of preventing and treating sepsis.
- cyclic tetrasaccharide and cyclic pentasaccharide can also be used as derivatives in which hydrogen atoms of one or more hydroxyl groups in the glucose residues constituting these cyclic sugars are substituted with various substituents.
- a derivative is not particularly limited, and a derivative having an arbitrary substituent can be used. Examples thereof include acylated derivatives; etherified derivatives; sulfur-containing derivatives;
- acylated derivative a lower alkanoyl group having an alkyl group having about 1 to 6 carbon atoms such as an acetylated derivative, a propionylated derivative, a butyrylated derivative, a pentanoylated derivative, a hexanoylated derivative, a heptanoylated derivative, etc.
- etherified derivatives include lower alkyl ether derivatives having about 1 to 6 carbon atoms such as methyl ether, ethyl ether, propyl ether, butyl ether, pentyl ether, hexyl ether and the like.
- Examples of sulfur-containing derivatives include sulfonated derivatives.
- Examples of carbohydrate derivatives include those in which sugars such as glucose are ether-bonded to form a branched chain.
- carbohydrate derivatives of CNN are described in WO2002 / 72594, and carbohydrate derivatives of CMM are This is described in JP-A-2007-84462.
- cyclic tetrasaccharide cyclic pentasaccharide and derivatives thereof can be used singly or in combination of two or more.
- the agent for preventing and treating sepsis according to the present invention can be made into various preparation forms containing the above-mentioned active ingredients.
- a liquid agent in particular an aqueous preparation for injection
- a suitable example a liquid agent
- the aqueous medium in the injectable aqueous preparation include water or a medium containing water.
- water sterilized water, preferably sterilized water that does not contain a pyrogen, is usually used.
- the medium containing water may be a known solvent used in pharmaceutical preparations, and examples thereof include physiological saline, PBS (phosphate buffered physiological saline), and lactic acid-containing Ringer's solution.
- additives usually used in the art can be appropriately used.
- additives include isotonic agents, buffering agents, soothing agents, and the like.
- isotonic agent include sugars such as glucose, sorbitol and mannitol, sodium chloride, glycerin, propylene glycol, polyethylene glycol and the like.
- buffer include borate buffer, phosphate buffer, citrate buffer, tartaric acid buffer, and acetate buffer.
- soothing agents include polyhydric alcohols such as albumin, glycerin and propylene glycol, lidocaine hydrochloride, benzyl alcohol and the like.
- the agent for preventing and treating sepsis of the present invention may contain various pH adjusters that are usually used in the art in order to adjust the pH.
- the pH adjuster may be an acid or a base.
- the acids include ascorbic acid, hydrochloric acid, gluconic acid, acetic acid, lactic acid, boric acid, phosphoric acid, sulfuric acid, tartaric acid, and citric acid.
- the base include potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, monoethanolamine, diethanolamine, triethanolamine and the like.
- amino acids such as glycine, histidine, and ⁇ -aminocaproic acid can be used.
- the aqueous injection preparation of the present invention can be produced by a conventional method.
- a component contained in the injectable aqueous preparation according to the present invention (hereinafter referred to as a contained component) is dissolved in an aqueous medium.
- the order of mixing the components is not particularly limited. All the components may be mixed at the same time, or only some of the components may be dissolved in the aqueous medium first, and then the remaining components may be dissolved. Good.
- the total concentration of active ingredients in the injectable aqueous preparation of the present invention that is, the total concentration of cyclic tetrasaccharide, cyclic pentasaccharide, and derivatives thereof is, for example, 0.1 to 70 W / V% (mass / volume%) Degree.
- the obtained solution is usually subjected to sterilization such as filtration sterilization using a membrane filter, autoclaved autoclaving, heat sterilization such as intermittent sterilization.
- sterilization such as filtration sterilization using a membrane filter, autoclaved autoclaving, heat sterilization such as intermittent sterilization.
- the solution thus obtained preferably has a pH of about 6-8.
- the obtained aqueous preparation is sealed after filling in a container such as an infusion bag or ampoule.
- a commonly used additive may be used as necessary, and it may be processed into a solid agent that is dissolved and used in an aqueous medium, that is, a “solid agent for use when dissolved”.
- solid preparation for use at the time of use can be prepared, for example, by drying the above-mentioned aqueous preparation for injection in a solution state by a known drying method such as freeze-drying or drying under reduced pressure to form a powder or granules.
- the solid preparation includes, for example, sterilized water; physiological saline; infusion containing electrolytes, sugars, amino acids, vitamins, trace elements, and the like.
- the total concentration of the active ingredient of the present invention is, for example, 0.1 to 70 W / It can be dissolved at the time of use so as to be about V% (mass / volume%).
- the aqueous preparation for injection according to the present invention is filled with the above-described solid solution for use in one room of a multi-chamber container and sterilized water in another room; physiological saline; electrolyte, carbohydrate, amino acid, vitamin, trace element
- the preparation may be in the form of being filled with an infusion solution containing, etc. and mixed and dissolved before use.
- Administration Method There are no particular limitations on the administration method of the prophylactic and therapeutic agent for sepsis according to the present invention, and administration is performed according to the dosage form, patient age, sex, other conditions, disease severity, and the like.
- the dose varies depending on the patient's symptoms, age, etc., but it is desirable to administer the amount of the active ingredient in the range of usually about 0.001 to 1 g, preferably about 0.01 to 0.8 g per kg body weight per day.
- an administration method for example, in the case of an aqueous preparation for injection, it is administered alone, intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, intrathecally, intraperitoneally, or the like.
- the injectable aqueous preparation can be mixed with an infusion solution, and can be administered intravenously as a mixture of the injectable aqueous preparation and the infusion solution according to the present invention.
- the infusion to be mixed with the injectable aqueous preparation is not particularly limited, and generally commercially available or normal infusion is used.
- infusion examples include glucose injection, xylitol injection, D-mannitol injection, fructose injection, physiological saline, dextran 40 injection, dextran 70 injection, amino acid injection, Ringer's solution, lactated Ringer's solution Sugar, electrolytes, amino acids, and general vitamin solutions.
- sepsis preventive and therapeutic agent of the present invention sepsis can be prevented and treated without causing side effects such as hemolysis.
- the active ingredient has a short half-life, it can be administered to patients with rapidly-advanced sepsis as needed to avoid unnecessary exposure to the drug and prevent the transition to severe sepsis. Can do.
- Example 1 50 g of CNN (produced by Hayashibara Biochemical Laboratories), which is a cyclic tetrasaccharide composed of glucose, is injected with 0.1 g of calcium chloride, 0.15 g of potassium chloride, 3.0 g of sodium chloride and 1.55 g of sodium lactate. It melt
- CNN produced by Hayashibara Biochemical Laboratories
- Example 2 10 g of CNN (manufactured by Hayashibara Biochemical Laboratories) was dissolved in 100 mL of PBS (phosphate buffered saline). After aseptic filtration, it was dried by freeze-drying to form a powder, which was filled in 1-g glass vials, sealed, dissolved at the time of use, and used as an injection for prevention and treatment of sepsis.
- PBS phosphate buffered saline
- Example 3 10 g of CNN (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of water for injection, and this was sterilized by filtration and then dried by lyophilization to obtain a powder. This was pre-filled with 100 mL of physiological saline in the lower chamber and filled into the upper chamber of a plastic multi-chamber container sterilized by autoclaving according to a conventional method to prepare a sepsis prevention and treatment agent kit product.
- CNN manufactured by Hayashibara Biochemical Laboratories Co., Ltd.
- Example 4 5 g of CNN (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 50 mL of water for injection, and this was sterilized by filtration and then lyophilized to a powder. This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
- Example 5 Injection of 5 g of CMM (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.), a cyclic tetrasaccharide composed of glucose, 0.02 g of calcium chloride, 0.03 g of potassium chloride, 0.6 g of sodium chloride and 0.31 g of sodium lactate It melt
- CMM manufactured by Hayashibara Biochemical Laboratories Co., Ltd.
- Example 6 5 g of CMM (produced by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of PBS (phosphate buffered saline). After aseptic filtration, it was dried by freeze-drying to form a powder, which was filled in 1-g glass vials, sealed, dissolved at the time of use, and used as an injection for prevention and treatment of sepsis.
- PBS phosphate buffered saline
- Example 7 2 g of CMM (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of water for injection, and this was sterilized by filtration and dried by lyophilization to obtain a powder. This was prefilled in the lower chamber with 100 mL of physiological saline and filled into the upper chamber of a plastic multi-chamber container that was autoclaved in accordance with a conventional method to obtain a kit product for preventing and treating sepsis.
- CMM manufactured by Hayashibara Biochemical Laboratories Co., Ltd.
- Example 8 1 g of CMM (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 50 mL of water for injection, and this was sterilized by filtration and dried by lyophilization to obtain a powder.
- This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
- Example 9 Injection of 10 g of ICG5 (produced by Hayashibara Biochemical Laboratories Co., Ltd.), a cyclic pentasaccharide containing glucose as a constituent sugar, 0.02 g of calcium chloride, 0.03 g of potassium chloride, 0.6 g of sodium chloride and 0.31 g of sodium lactate It melt
- Example 10 ICG5 (produced by Hayashibara Biochemical Laboratories Co., Ltd.) 30 g, calcium chloride 0.01 g, potassium chloride 0.015 g, sodium chloride 0.3 g and sodium lactate 0.155 g were dissolved in 30 mL of water for injection, and water for injection was added. The total volume was 50 mL. This was sterilized by filtration to produce an injection solution.
- Example 11 25 g of ICG5 (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of water for injection, and this was sterilized by filtration and then lyophilized to a powder. This was prefilled in the lower chamber with 100 mL of physiological saline and filled into the upper chamber of a plastic multi-chamber container that was autoclaved in accordance with a conventional method to obtain a kit product for preventing and treating sepsis.
- ICG5 manufactured by Hayashibara Biochemical Laboratories Co., Ltd.
- Example 12 5 g of ICG5 (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 50 mL of water for injection, and this was sterilized by filtration and dried by lyophilization to obtain a powder.
- This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
- Example 13 5 g of CNN (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) and 5 g of ICG5 (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) were dissolved in 50 mL of water for injection. .
- This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
- control group was treated in the same manner as the CNN group except that 1 mL / kg of the injection solution having the composition of Example 1 containing no CNN was administered as a test solution.
- the survival rate (%) of each group every 4 hours after LPS administration is shown in Table 1 below.
- the CNN group administered with the sepsis prevention and treatment agent of Example 1 showed a higher survival rate than the comparative group administered with ⁇ -cyclodextrin. From this, it was confirmed that CNN, which is an active ingredient of the sepsis prevention and treatment agent of the present invention, has a preventive effect on sepsis, suggesting that it can be used effectively from the initial stage.
- Example 5 2 mL / kg of the injection solution obtained in Example 5 was administered as a test solution within the tail vein within 10 seconds after a fasting day and night (hereinafter referred to as fasting until the end of the experiment). Furthermore, in order to induce septic shock immediately after that, a physiological saline solution (20 mg / mL) of an endotoxin Escherichia coli 0111: B4-derived lipopolysaccharide (hereinafter “LPS”) was administered at a dose of 1 mL / kg. It was administered intraperitoneally within 10 seconds.
- LPS an endotoxin Escherichia coli 0111: B4-derived lipopolysaccharide
- the ICG5 group was treated in the same manner as the CMM group except that 1 mL / kg of the injection solution obtained in Example 9 was administered as a test solution.
- control group was treated in the same manner as the CMM group except that 1 mL / kg of the injection solution having the composition of Example 1 containing no CNN was administered as the test solution.
- the survival rate (%) of each group every 4 hours after LPS administration is shown in Table 2 below.
- the CNN group was intraperitoneally administered with a physiological saline solution of LPS (20 mg / mL) at a dose of 1 mL / kg within 10 seconds after fasting all day and night (hereinafter referred to as fasting until the end of the experiment). . Further 2 hours later, 1 mL / kg of the injection solution obtained in Example 1 as a test solution was administered into the tail vein within 10 seconds. Separately, inflammatory cytokines were measured to confirm that sepsis occurred at the time of administration of the test solution.
- control group was treated in the same manner as the CNN group except that 1 mL / kg of the injection solution having the composition of Example 1 containing no CNN was administered as the test solution.
- the survival rate (%) of each group every 4 hours after LPS administration is shown in Table 3 below.
- CNN group showed a higher survival rate than the control group. From this, it was confirmed that CNN which is an active ingredient of the sepsis prevention and treatment agent of the present invention has a therapeutic effect after infection of sepsis.
- Test example 4 Effect of CNN on erythrocyte hemolysis (comparison with ⁇ -cyclodextrin and effect of CNN concentration) Blood blood components and plasma were separated by centrifugation (2000 rpm ⁇ 15 min) of 25 mL of blood (cardiac blood sampling: heparin-treated) for 30 male and female 4 to 6 month old Syrian hamsters at room temperature. Further, the uppermost part of the blood cell layer (buffy coat; leukocyte layer) was removed with a Pasteur pipette.
- PBS (0.15 M NaCl + 10 mM phosphate buffer, pH 7.4) was added thereto, the blood cells were suspended and centrifuged again (2000 rpm ⁇ 15 min), and this operation was repeated three times to obtain erythrocytes. This was suspended in 25 mL of PBS to obtain a hamster erythrocyte suspension of 6.07 ⁇ 10 10 cells / mL.
- CNN does not show the strong erythrocyte hemolytic action seen in ⁇ -cyclodextrin.
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Abstract
Disclosed is a prophylactic and therapeutic agent for sepsis, which comprises at least one component selected from the group consisting of a cyclic tetrasaccharide of which a constituent saccharide is glucose, a cyclic pentasaccharide of which a constituent saccharide is glucose and derivatives of the cyclic tetrasaccharide and the cyclic pentasaccharide as an active ingredient.
The prophylactic and therapeutic agent for sepsis can prevent and treat sepsis without inducing any adverse side effect such as hemolysis.
Description
本発明は、敗血症の予防及び治療剤、並びにその用途に関する。
The present invention relates to a preventive and therapeutic agent for sepsis and its use.
敗血症は、肺炎や腹膜炎などの細菌感染症や、悪性腫瘍の化学療法によって免疫力が低下したときに生じた細菌感染症等が全身に波及したものである。発熱、頻呼吸、頻脈、白血球増加等の症状を現し、進行すれば意識障害、血圧低下などの循環不全、さらに、腎・肺・肝・凝固機能異常などの臓器機能障害をきたす。そして、重篤に至れば、急性呼吸窮迫症候群(ARDS)や播種性血管内凝固症候群(DIC)などを併発し、敗血症ショックによる心停止・死亡などの最悪の結果に至る。
Sepsis is caused by bacterial infections such as pneumonia and peritonitis, and bacterial infections caused when the immune system is reduced by chemotherapy for malignant tumors. Symptoms such as fever, tachypnea, tachycardia, and leukocytosis appear, and if progressed, circulatory failure such as impaired consciousness and blood pressure decrease, and organ dysfunction such as renal / lung / liver / coagulation dysfunction. If severe, it leads to acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation syndrome (DIC), etc., leading to the worst results such as cardiac arrest and death due to septic shock.
敗血症は、段階が進むにつれて予後が悪くなり、死亡率が高くなるので、可能な限り初期の段階で早期診断・早期治療を行う必要がある。
As sepsis progresses, the prognosis worsens and the mortality rate increases, so it is necessary to conduct early diagnosis and treatment at the earliest possible stage.
敗血症の治療法としては、輸液蘇生法や、リポポリサッカライド(LPS)の産生を抑制する目的の抗生物質や炎症性反応を抑える非ステロイド抗炎症薬の投与が行われており、重症の敗血症に対しては、低血圧症を改善する昇圧剤の投与や、炎症を抑えるステロイド、血液凝固阻害薬などの投与が臨床現場で行われている。
Treatment methods for sepsis include fluid resuscitation, antibiotics intended to suppress lipopolysaccharide (LPS) production, and nonsteroidal anti-inflammatory drugs that suppress inflammatory reactions. On the other hand, administration of vasopressors that improve hypotension, steroids that suppress inflammation, blood coagulation inhibitors, and the like are performed in clinical settings.
敗血症の治療薬として知られているXigris(ジグリスDrotrecogin alfa、activated:米国Eli Lilly社)は、活性型プロテインC製剤であり、血液凝固阻害効果とともに細胞のアポトーシスを抑制する効果があるが、初期の敗血症患者には無効であり、重症の敗血症患者のみに使用が制限されている。
Xigris (Digris Drotrecogin alfa, activated: Eli Lilly, USA), which is known as a therapeutic agent for sepsis, is an active protein C preparation and has an effect of suppressing cell apoptosis as well as an effect of inhibiting blood coagulation. It is ineffective for patients with sepsis and is restricted to use only for patients with severe sepsis.
また、輸液、抗生物質、抗炎症薬等の投与については、満足できる治療効果が得られず、重症の段階においては対症療法しかない。
In addition, for the administration of infusion solutions, antibiotics, anti-inflammatory drugs, etc., satisfactory therapeutic effects cannot be obtained, and there is only symptomatic treatment in severe stages.
従って、敗血症の疾患に対しては、予後を考慮して初期の段階から積極的に治療効力を発揮する薬剤の開発が望まれている。
Therefore, for sepsis diseases, it is desired to develop a drug that exerts a therapeutic effect positively from an early stage in consideration of the prognosis.
ところで、主に食品添加物として用いられている環状オリゴ糖としては、6~8分子のグルコースがα-1,4結合で結合して環状構造を形成したα-、β-及びγ- シクロデキストリンが知られている。これらのα-シクロデキストリン、β-シクロデキストリン及びγ-シクロデキストリンについて、敗血症に対する効果があるという報告がある(下記特許文献1参照)。しかしながら、α-及びβ-シクロデキストリンには溶血性という問題があり(下記非特許文献1、非特許文献2等参照)、更に、β-シクロデキストリンには腎毒性があり、γ-シクロデキストリンについては、効力が十分でないという様々な問題点がある。このため、α-シクロデキストリン、β-シクロデキストリン及びγ-シクロデキストリンについては、敗血症の治療剤として十分に要望を満たすものとはいえない。
By the way, cyclic oligosaccharides mainly used as food additives include α-, β- and γ-γ cyclodextrins in which 6 to 8 molecules of glucose are linked by α-1,4 bonds to form a cyclic structure. It has been known. There is a report that these α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin have an effect on sepsis (see Patent Document 1 below). However, α- and β-cyclodextrins have a problem of hemolysis (see Non-Patent Document 1 and Non-Patent Document 2 below), and β-cyclodextrin has nephrotoxicity. Have various problems that their efficacy is not sufficient. For this reason, α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin cannot be said to sufficiently satisfy the demand as a therapeutic agent for sepsis.
本発明は、上記した従来技術の問題点に鑑みてなされたものであり、その主な目的は、敗血症に対して十分な治療効果を有し、しかも副作用のない敗血症の予防及び治療剤を提供することである。
The present invention has been made in view of the above-described problems of the prior art, and its main purpose is to provide a preventive and therapeutic agent for sepsis that has a sufficient therapeutic effect on sepsis and has no side effects. It is to be.
本発明者は、上記した目的を達成すべく鋭意研究を重ねてきた。その結果、敗血症の治療剤としてこれまで使用されたことのない、グルコースを構成糖とする環状四糖、環状五糖やその誘導体が、敗血症に対して早い段階から十分に強い効力を発揮し、さらに溶血性や腎毒性等の副作用がほとんどないことを見出し、ここに本発明を完成するに至った。
The present inventor has intensively studied to achieve the above-mentioned purpose. As a result, cyclic tetrasaccharides composed of glucose, cyclic pentasaccharide and derivatives thereof, which have not been used as a therapeutic agent for sepsis, have a sufficiently strong effect on sepsis from an early stage, Furthermore, it has been found that there are almost no side effects such as hemolysis and nephrotoxicity, and the present invention has been completed here.
即ち、本発明は、下記の敗血症の予防及び治療剤、並びにその用途を提供するものである。
1.グルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を有効成分として含有する敗血症の予防及び治療剤。
2.シクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を有効成分として含有する敗血症の予防及び治療剤。
3.注射用水性製剤又は用時溶解用固形剤である上記項1に記載の敗血症の予防及び治療剤。
4. 静脈内投与用として用いられる上記項3に記載の敗血症の予防及び治療剤。
5. 敗血症の予防及び治療剤を製造するためのグルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分の使用。
6. 敗血症の予防及び治療剤を製造するためのシクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分の使用。
7. グルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を含有する敗血症の予防及び治療剤をヒトに投与して、敗血症を予防及び治療する方法。
8. シクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を含有する敗血症の予防及び治療剤をヒトに投与して、敗血症を予防及び治療する方法。
9. 敗血症の予防及び治療方法に使用のためのグルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分。
10.敗血症の予防及び治療方法に使用のためのシクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分。 That is, the present invention provides the following preventive and therapeutic agents for sepsis, and uses thereof.
1. A prophylactic and therapeutic agent for sepsis comprising as an active ingredient at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof.
2. Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl -(1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α- A prophylactic and therapeutic agent for sepsis comprising, as an active ingredient, at least one component selected from the group consisting of D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →} and derivatives thereof.
3. Item 2. The preventive and therapeutic agent for sepsis according to Item 1, which is an injectable aqueous preparation or a solid agent for dissolution upon use.
4). Item 4. The prophylactic and therapeutic agent for sepsis according to Item 3, which is used for intravenous administration.
5). Use of at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof for producing an agent for preventing and treating sepsis.
6). Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 →) for producing a preventive and therapeutic agent for sepsis 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D Use of at least one component selected from the group consisting of glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, and derivatives thereof.
7). Administering a prophylactic and therapeutic agent for sepsis containing at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof; Methods for preventing and treating sepsis.
8). Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl -(1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α- A prophylactic and therapeutic agent for sepsis containing at least one component selected from the group consisting of D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →} and derivatives thereof is administered to humans , Methods for preventing and treating sepsis
9. At least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof for use in a method for preventing and treating sepsis.
10. Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 →) for use in methods for preventing and treating sepsis 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D At least one component selected from the group consisting of glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, and derivatives thereof.
1.グルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を有効成分として含有する敗血症の予防及び治療剤。
2.シクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を有効成分として含有する敗血症の予防及び治療剤。
3.注射用水性製剤又は用時溶解用固形剤である上記項1に記載の敗血症の予防及び治療剤。
4. 静脈内投与用として用いられる上記項3に記載の敗血症の予防及び治療剤。
5. 敗血症の予防及び治療剤を製造するためのグルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分の使用。
6. 敗血症の予防及び治療剤を製造するためのシクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分の使用。
7. グルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を含有する敗血症の予防及び治療剤をヒトに投与して、敗血症を予防及び治療する方法。
8. シクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を含有する敗血症の予防及び治療剤をヒトに投与して、敗血症を予防及び治療する方法。
9. 敗血症の予防及び治療方法に使用のためのグルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分。
10.敗血症の予防及び治療方法に使用のためのシクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分。 That is, the present invention provides the following preventive and therapeutic agents for sepsis, and uses thereof.
1. A prophylactic and therapeutic agent for sepsis comprising as an active ingredient at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof.
2. Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl -(1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α- A prophylactic and therapeutic agent for sepsis comprising, as an active ingredient, at least one component selected from the group consisting of D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →} and derivatives thereof.
3. Item 2. The preventive and therapeutic agent for sepsis according to Item 1, which is an injectable aqueous preparation or a solid agent for dissolution upon use.
4). Item 4. The prophylactic and therapeutic agent for sepsis according to Item 3, which is used for intravenous administration.
5). Use of at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof for producing an agent for preventing and treating sepsis.
6). Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 →) for producing a preventive and therapeutic agent for sepsis 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D Use of at least one component selected from the group consisting of glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, and derivatives thereof.
7). Administering a prophylactic and therapeutic agent for sepsis containing at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof; Methods for preventing and treating sepsis.
8). Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl -(1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α- A prophylactic and therapeutic agent for sepsis containing at least one component selected from the group consisting of D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →} and derivatives thereof is administered to humans , Methods for preventing and treating sepsis
9. At least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof for use in a method for preventing and treating sepsis.
10. Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 →) for use in methods for preventing and treating sepsis 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D At least one component selected from the group consisting of glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, and derivatives thereof.
以下、本発明の敗血症の予防及び治療剤、並びにその用途について具体的に説明する。
Hereinafter, the agent for preventing and treating sepsis according to the present invention and its use will be described in detail.
有効成分
本発明の敗血症の予防及び治療剤は、グルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖及びこれらの誘導体からなる群から選ばれる少なくとも一種を有効成分として含むものである。 Active ingredient The sepsis preventive and therapeutic agent of the present invention contains, as an active ingredient, at least one selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof. .
本発明の敗血症の予防及び治療剤は、グルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖及びこれらの誘導体からなる群から選ばれる少なくとも一種を有効成分として含むものである。 Active ingredient The sepsis preventive and therapeutic agent of the present invention contains, as an active ingredient, at least one selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof. .
グルコースを構成糖とする環状四糖とは、4個のグルコースが結合して環状に連なった化合物であり、グルコースを構成糖とする環状五糖とは5個のグルコースが環状に連なった化合物である。環状四糖及び環状五糖については、それぞれの結合部位の違いにより、幾つかの種類があるが、本発明では、いずれの種類のものも用いることができる。
A cyclic tetrasaccharide having glucose as a constituent sugar is a compound in which four glucoses are linked to form a ring, and a cyclic pentasaccharide having glucose as a constituent sugar is a compound in which five glucoses are connected in a ring. is there. There are several types of cyclic tetrasaccharides and cyclic pentasaccharides depending on the difference of the respective binding sites. In the present invention, any type can be used.
本発明では、特に、以下の環状四糖及び環状五糖が、製造量、製造コスト、効力、体内動態、副作用(溶血など)のいずれかの点で好ましい。
・シクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}(別名:環状ニゲロシルニゲロース;以下「CNN」ということがある)
・シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}(別名:環状マルトシルマルトース;以下「CMM」ということがある)
・シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}(別名:イソサイクロマルトペンタオース;以下「ICG5」ということがある) In the present invention, the following cyclic tetrasaccharides and cyclic pentasaccharides are particularly preferable from the viewpoints of production amount, production cost, efficacy, pharmacokinetics, and side effects (such as hemolysis).
Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- ( 1 →} (also known as cyclic nigerosyl nigerose; hereinafter sometimes referred to as “CNN”)
Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- ( 1 →} (also known as: cyclic maltosyl maltose; hereinafter sometimes referred to as “CMM”)
Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- ( 1 → 4) -α-D-glucopyranosyl- (1 →} (also known as: isocyclomaltopentaose; hereinafter sometimes referred to as “ICG5”)
・シクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}(別名:環状ニゲロシルニゲロース;以下「CNN」ということがある)
・シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}(別名:環状マルトシルマルトース;以下「CMM」ということがある)
・シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}(別名:イソサイクロマルトペンタオース;以下「ICG5」ということがある) In the present invention, the following cyclic tetrasaccharides and cyclic pentasaccharides are particularly preferable from the viewpoints of production amount, production cost, efficacy, pharmacokinetics, and side effects (such as hemolysis).
Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- ( 1 →} (also known as cyclic nigerosyl nigerose; hereinafter sometimes referred to as “CNN”)
Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- ( 1 →} (also known as: cyclic maltosyl maltose; hereinafter sometimes referred to as “CMM”)
Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- ( 1 → 4) -α-D-glucopyranosyl- (1 →} (also known as: isocyclomaltopentaose; hereinafter sometimes referred to as “ICG5”)
上記した環状四糖のうちで、CNNは、グレゴリー・エル・コテ氏らによって見出された化合物であり(European Journal of Biochemistry,226,641(1994))、その後(株)林原生物化学研究所により澱粉からの大量製法が実現化された。CNNは、それ自体、高い溶解性(20℃で100gの水に46.1g溶ける。)を示し、低甘味(砂糖の27%の甘味度)であり、pH安定性・熱安定性がよい。CNNの用途としては、いくつかの医薬用途が期待されるとの報告があるが、敗血症の予防及び治療効果については全く知られていない。
Among the cyclic tetrasaccharides mentioned above, CNN is a compound found by Gregory El Cote et al. (European Journal of Biochemistry, 226, 641 (1994)), and then Hayashibara Biochemical Research Institute Co., Ltd. As a result, a mass production method from starch was realized. CNN itself exhibits high solubility (dissolves 46.1 g in 100 g water at 20 ° C.), low sweetness (27% sweetness of sugar), and good pH stability and heat stability. As for the use of CNN, there are reports that some medical uses are expected, but the prevention and treatment effects of sepsis are not known at all.
CMMは、(株)林原生物化学研究所により見出された化合物であり、特開2005-95148号公報に記載されている。CMMは、CNNと同様に、高い溶解性と安定性を示す化合物であり、その用途については、現在検討が進められているが、敗血症の予防及び治療効果についての報告はない。
CMM is a compound found by Hayashibara Biochemical Laboratories Co., Ltd. and described in JP-A-2005-95148. CMM, like CNN, is a compound that exhibits high solubility and stability, and its use is currently under investigation, but there is no report on the prevention and treatment effects of sepsis.
環状五糖であるICG5は、(株)林原生物化学研究所により見出された化合物であり、WO2006/35725に記載されている。ICG5は、殆ど甘みがなく、高い溶解性と安定性を示す化合物であり、その用途についても、現在検討が進められているが、敗血症の予防及び治療効果についての報告はない。
ICG5, a cyclic pentasaccharide, is a compound found by Hayashibara Biochemical Laboratories Co., Ltd. and is described in WO2006 / 35725. ICG5 is a compound that has almost no sweetness and exhibits high solubility and stability, and its use is currently under investigation, but there is no report on the effect of preventing and treating sepsis.
上記した環状四糖及び環状五糖は、更に、これらの環状糖を構成するグルコース残基中の一個以上の水酸基の水素原子が各種の置換基で置換された誘導体としても用いることができる。この様な誘導体としては、特に限定的ではなく、任意の置換基を有する誘導体を用いることができ、例えば、アシル化誘導体;エーテル化誘導体;硫黄含有誘導体;糖質誘導体等を挙げることができる。
The above-mentioned cyclic tetrasaccharide and cyclic pentasaccharide can also be used as derivatives in which hydrogen atoms of one or more hydroxyl groups in the glucose residues constituting these cyclic sugars are substituted with various substituents. Such a derivative is not particularly limited, and a derivative having an arbitrary substituent can be used. Examples thereof include acylated derivatives; etherified derivatives; sulfur-containing derivatives;
これらの内で、アシル化誘導体としては、アセチル化誘導体、プロピオニル化誘導体、ブチリル化誘導体、ペンタノイル化誘導体、ヘキサノイル化誘導体、ヘプタノイル化誘導体等の炭素数1~6程度のアルキル基を有する低級アルカノイル基によって置換された低級アルカノイル化誘導体を挙げることができる。また、エーテル化誘導体としては、メチルエーテル、エチルエーテル、プロピルエーテル、ブチルエーテル、ペンチルエーテル、ヘキシルエーテル等の炭素数1~6程度の低級アルキルエーテル誘導体を挙げることができる。硫黄含有誘導体としては、スルホン化誘導体を挙げることができる。糖質誘導体としては、グルコースなどの糖がエーテル結合して分岐鎖を形成したものを挙げることができ、例えば、CNNの糖質誘導体についてはWO2002/72594に記載され、CMMの糖質誘導体については特開2007-84462号公報に記載されている。
Among these, as the acylated derivative, a lower alkanoyl group having an alkyl group having about 1 to 6 carbon atoms such as an acetylated derivative, a propionylated derivative, a butyrylated derivative, a pentanoylated derivative, a hexanoylated derivative, a heptanoylated derivative, etc. And lower alkanoylated derivatives substituted by. Examples of etherified derivatives include lower alkyl ether derivatives having about 1 to 6 carbon atoms such as methyl ether, ethyl ether, propyl ether, butyl ether, pentyl ether, hexyl ether and the like. Examples of sulfur-containing derivatives include sulfonated derivatives. Examples of carbohydrate derivatives include those in which sugars such as glucose are ether-bonded to form a branched chain. For example, carbohydrate derivatives of CNN are described in WO2002 / 72594, and carbohydrate derivatives of CMM are This is described in JP-A-2007-84462.
本発明では、上記した環状四糖、環状五糖及びこれらの誘導体を、一種単独又は二種以上混合して用いることができる。
In the present invention, the above-mentioned cyclic tetrasaccharide, cyclic pentasaccharide and derivatives thereof can be used singly or in combination of two or more.
本発明の敗血症予防及び治療剤
本発明の敗血症の予防及び治療剤は、上記した有効成分を含む種々の製剤形態とすることができる。特に、敗血症治療の必要な段階で充分な効果と即効性を得るためには、注射剤として、静脈内投与することが好ましい。 The agent for preventing and treating sepsis according to the present invention The agent for preventing and treating sepsis according to the present invention can be made into various preparation forms containing the above-mentioned active ingredients. In particular, it is preferable to administer intravenously as an injection in order to obtain a sufficient effect and immediate effect at the necessary stage of sepsis treatment.
本発明の敗血症の予防及び治療剤は、上記した有効成分を含む種々の製剤形態とすることができる。特に、敗血症治療の必要な段階で充分な効果と即効性を得るためには、注射剤として、静脈内投与することが好ましい。 The agent for preventing and treating sepsis according to the present invention The agent for preventing and treating sepsis according to the present invention can be made into various preparation forms containing the above-mentioned active ingredients. In particular, it is preferable to administer intravenously as an injection in order to obtain a sufficient effect and immediate effect at the necessary stage of sepsis treatment.
注射剤としては、液剤、特に注射用水性製剤が好適例として挙げられる。注射用水性製剤における水性媒体としては、水または水を含有する媒体が挙げられる。水としては、通常滅菌水、好ましくは発熱性物質が含有されていない滅菌水が使用される。水を含有する媒体としては、医薬製剤において用いられている公知の溶媒であればよく、例えば、生理食塩水、PBS(リン酸緩衝生理食塩水)、乳酸配合リンゲル液などが挙げられる。
As an injection, a liquid agent, in particular an aqueous preparation for injection, can be mentioned as a suitable example. Examples of the aqueous medium in the injectable aqueous preparation include water or a medium containing water. As the water, sterilized water, preferably sterilized water that does not contain a pyrogen, is usually used. The medium containing water may be a known solvent used in pharmaceutical preparations, and examples thereof include physiological saline, PBS (phosphate buffered physiological saline), and lactic acid-containing Ringer's solution.
本発明の敗血症予防及び治療剤では、当技術分野で通常使用されている添加剤を適宜用いることができる。この様な添加剤としては、例えば、等張化剤、緩衝剤、無痛化剤などが挙げられる。等張化剤としては、例えば、ブドウ糖、ソルビトール、マンニトール等の糖類、塩化ナトリウム、グリセリン、プロピレングリコール、ポリエチレングリコール等が挙げられる。緩衝剤としては、例えば、ホウ酸緩衝剤、リン酸緩衝剤、クエン酸緩衝剤、酒石酸緩衝剤、酢酸緩衝剤などが挙げられる。無痛化剤としては、例えばアルブミン、グリセリン、プロピレングリコール等の多価アルコール、リドカイン塩酸塩、ベンジルアルコールなどが挙げられる。
In the sepsis prevention and treatment agent of the present invention, additives usually used in the art can be appropriately used. Examples of such additives include isotonic agents, buffering agents, soothing agents, and the like. Examples of the isotonic agent include sugars such as glucose, sorbitol and mannitol, sodium chloride, glycerin, propylene glycol, polyethylene glycol and the like. Examples of the buffer include borate buffer, phosphate buffer, citrate buffer, tartaric acid buffer, and acetate buffer. Examples of soothing agents include polyhydric alcohols such as albumin, glycerin and propylene glycol, lidocaine hydrochloride, benzyl alcohol and the like.
本発明の敗血症予防及び治療剤には、pHを調整するために、当技術分野で通常用いられている種々のpH調整剤が含有されていても良い。pH調整剤は、酸類であっても塩基類であってもよい。具体的には、酸類としては、例えば、アスコルビン酸、塩酸、グルコン酸、酢酸、乳酸、ホウ酸、リン酸、硫酸、酒石酸、クエン酸などが挙げられる。塩基類としては、例えば、水酸化カリウム、水酸化カルシウム、水酸化ナトリウム、水酸化マグネシウム、モノエタノールアミン、ジエタノールアミン、トリエタノールアミンなどが挙げられる。その他のpH調整剤として、グリシン、ヒスチジン、ε-アミノカプロン酸などのアミノ酸類なども用いることができる。
The agent for preventing and treating sepsis of the present invention may contain various pH adjusters that are usually used in the art in order to adjust the pH. The pH adjuster may be an acid or a base. Specifically, examples of the acids include ascorbic acid, hydrochloric acid, gluconic acid, acetic acid, lactic acid, boric acid, phosphoric acid, sulfuric acid, tartaric acid, and citric acid. Examples of the base include potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, monoethanolamine, diethanolamine, triethanolamine and the like. As other pH adjusting agents, amino acids such as glycine, histidine, and ε-aminocaproic acid can be used.
本発明の注射用水性製剤は、常法により製造できる。例えば、まず、水性媒体に、本発明に係る注射用水性製剤に含有される成分(以下、含有成分という)を溶解させる。含有成分の混合順序は特に問わず、全ての含有成分を同時に混合してもよいし、一部の含有成分のみを先に上記水性媒体に溶解し、その後、残りの含有成分を溶解させてもよい。本発明の注射用水性製剤中の有効成分の総濃度、即ち、環状四糖、環状五糖、及びこれらの誘導体の合計濃度は、例えば、0.1~70W/V%(質量/体積%)程度である。
The aqueous injection preparation of the present invention can be produced by a conventional method. For example, first, a component contained in the injectable aqueous preparation according to the present invention (hereinafter referred to as a contained component) is dissolved in an aqueous medium. The order of mixing the components is not particularly limited. All the components may be mixed at the same time, or only some of the components may be dissolved in the aqueous medium first, and then the remaining components may be dissolved. Good. The total concentration of active ingredients in the injectable aqueous preparation of the present invention, that is, the total concentration of cyclic tetrasaccharide, cyclic pentasaccharide, and derivatives thereof is, for example, 0.1 to 70 W / V% (mass / volume%) Degree.
ついで、得られた溶液について、通常、例えばメンブランフィルターによるろ過滅菌、オートクレーブによる加圧熱滅菌、間欠滅菌法等による熱滅菌処理等の滅菌処理を施す。このようにして得られる溶液は、pHが約6~8程度とするのが好適である。
Next, the obtained solution is usually subjected to sterilization such as filtration sterilization using a membrane filter, autoclaved autoclaving, heat sterilization such as intermittent sterilization. The solution thus obtained preferably has a pH of about 6-8.
得られた水性製剤は、例えば輸液バッグやアンプルなどの容器に充填後密封する。
The obtained aqueous preparation is sealed after filling in a container such as an infusion bag or ampoule.
一方、通常用いられる添加剤を必要に応じて使用し、水性媒体に用時溶解して使用する固形剤、即ち、「用時溶解用固形剤」に加工することもできる。
On the other hand, a commonly used additive may be used as necessary, and it may be processed into a solid agent that is dissolved and used in an aqueous medium, that is, a “solid agent for use when dissolved”.
上記した「用時溶解用固形剤」は、例えば、上記した溶液状態の注射用水性製剤を凍結乾燥、減圧乾燥など公知の乾燥方法により乾燥して粉末状または顆粒状にすることによって調製できる。
The above-mentioned “solid preparation for use at the time of use” can be prepared, for example, by drying the above-mentioned aqueous preparation for injection in a solution state by a known drying method such as freeze-drying or drying under reduced pressure to form a powder or granules.
該固形剤は、例えば、滅菌水;生理食塩液;電解質、糖質、アミノ酸、ビタミン、微量元素等を含む輸液等に、本発明の有効成分の総濃度が、例えば、0.1~70W/V%(質量/体積%)程度となるように用時溶解して使用できる。
The solid preparation includes, for example, sterilized water; physiological saline; infusion containing electrolytes, sugars, amino acids, vitamins, trace elements, and the like. The total concentration of the active ingredient of the present invention is, for example, 0.1 to 70 W / It can be dissolved at the time of use so as to be about V% (mass / volume%).
本発明に係る注射用水性製剤は、上記した用時溶解用固形剤を複室容器の一室に充填し、他室に滅菌水;生理食塩液;電解質、糖質、アミノ酸、ビタミン、微量元素等を含む輸液等を充填し、用時に混合・溶解して使用する形態の製剤であってもよい。
The aqueous preparation for injection according to the present invention is filled with the above-described solid solution for use in one room of a multi-chamber container and sterilized water in another room; physiological saline; electrolyte, carbohydrate, amino acid, vitamin, trace element The preparation may be in the form of being filled with an infusion solution containing, etc. and mixed and dissolved before use.
投与方法
本発明の敗血症の予防及び治療剤の投与方法については、特に制限はなく、剤形、患者の年令、性別、その他の条件、疾患の程度などに応じた方法で投与される。 Administration Method There are no particular limitations on the administration method of the prophylactic and therapeutic agent for sepsis according to the present invention, and administration is performed according to the dosage form, patient age, sex, other conditions, disease severity, and the like.
本発明の敗血症の予防及び治療剤の投与方法については、特に制限はなく、剤形、患者の年令、性別、その他の条件、疾患の程度などに応じた方法で投与される。 Administration Method There are no particular limitations on the administration method of the prophylactic and therapeutic agent for sepsis according to the present invention, and administration is performed according to the dosage form, patient age, sex, other conditions, disease severity, and the like.
投与量は患者の症状、年齢等により異なるが、1日体重1kgあたり、有効成分量として通常0.001~1g程度、好ましくは0.01~0.8g程度の範囲で投与することが望ましい。
The dose varies depending on the patient's symptoms, age, etc., but it is desirable to administer the amount of the active ingredient in the range of usually about 0.001 to 1 g, preferably about 0.01 to 0.8 g per kg body weight per day.
投与方法としては、例えば、注射用水性製剤の場合には、単独で静脈内、動脈内、筋肉内、皮内、皮下、脊髄腔内、腹腔内などに投与される。また、注射用水性製剤は、輸液と混和でき、本発明に係る注射用水性製剤と輸液との混合物として、特に静脈内に投与することもできる。注射用水性製剤と混和される輸液については特に限定されず、一般的には、商業的に入手可能なまたは通常の輸液が使用される。この様な輸液の具体例としては、ブドウ糖注射液、キシリトール注射液、D-マンニトール注射液、フルクトース注射液、生理食塩液、デキストラン40注射液、デキストラン70注射液、アミノ酸注射液、リンゲル液、乳酸リンゲル液、糖・電解質・アミノ酸・総合ビタミン液などが挙げられる。
As an administration method, for example, in the case of an aqueous preparation for injection, it is administered alone, intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, intrathecally, intraperitoneally, or the like. In addition, the injectable aqueous preparation can be mixed with an infusion solution, and can be administered intravenously as a mixture of the injectable aqueous preparation and the infusion solution according to the present invention. The infusion to be mixed with the injectable aqueous preparation is not particularly limited, and generally commercially available or normal infusion is used. Specific examples of such infusion include glucose injection, xylitol injection, D-mannitol injection, fructose injection, physiological saline, dextran 40 injection, dextran 70 injection, amino acid injection, Ringer's solution, lactated Ringer's solution Sugar, electrolytes, amino acids, and general vitamin solutions.
本発明の敗血症の予防及び治療剤によれば、溶血等の副作用を惹起することなく、敗血症の予防及び治療を行うことができる。しかも、有効成分の半減期が短いので、進行が速い敗血症に対して、必要時に投与し、薬剤への不必要な暴露を回避することができ、重症敗血症に移行することを防いで治療することができる。
According to the sepsis preventive and therapeutic agent of the present invention, sepsis can be prevented and treated without causing side effects such as hemolysis. In addition, because the active ingredient has a short half-life, it can be administered to patients with rapidly-advanced sepsis as needed to avoid unnecessary exposure to the drug and prevent the transition to severe sepsis. Can do.
以下、実施例及び試験例を挙げて本発明を更に詳細に説明する。
Hereinafter, the present invention will be described in more detail with reference to examples and test examples.
実施例1
グルコースを構成糖とする環状四糖であるCNN((株)林原生物化学研究所製)50g、塩化カルシウム0.1g、塩化カリウム0.15g、塩化ナトリウム3.0g及び乳酸ナトリウム1.55gを注射用水350mLに溶解し、注射用水を加えて全量を500mLとした。これを、ろ過滅菌後100mLずつバッグに充填、密封して注射液を製造した。この注射液を有効成分濃度が10%(W/V%)である実施例1の敗血症予防及び治療剤とした。 Example 1
50 g of CNN (produced by Hayashibara Biochemical Laboratories), which is a cyclic tetrasaccharide composed of glucose, is injected with 0.1 g of calcium chloride, 0.15 g of potassium chloride, 3.0 g of sodium chloride and 1.55 g of sodium lactate. It melt | dissolved in 350 mL of irrigation water, and the water for injection was added, and the whole quantity was set to 500 mL. This was filled into a bag 100 mL after filtration sterilization and sealed to produce an injection solution. This injection solution was used as an agent for preventing and treating sepsis of Example 1 having an active ingredient concentration of 10% (W / V%).
グルコースを構成糖とする環状四糖であるCNN((株)林原生物化学研究所製)50g、塩化カルシウム0.1g、塩化カリウム0.15g、塩化ナトリウム3.0g及び乳酸ナトリウム1.55gを注射用水350mLに溶解し、注射用水を加えて全量を500mLとした。これを、ろ過滅菌後100mLずつバッグに充填、密封して注射液を製造した。この注射液を有効成分濃度が10%(W/V%)である実施例1の敗血症予防及び治療剤とした。 Example 1
50 g of CNN (produced by Hayashibara Biochemical Laboratories), which is a cyclic tetrasaccharide composed of glucose, is injected with 0.1 g of calcium chloride, 0.15 g of potassium chloride, 3.0 g of sodium chloride and 1.55 g of sodium lactate. It melt | dissolved in 350 mL of irrigation water, and the water for injection was added, and the whole quantity was set to 500 mL. This was filled into a bag 100 mL after filtration sterilization and sealed to produce an injection solution. This injection solution was used as an agent for preventing and treating sepsis of Example 1 having an active ingredient concentration of 10% (W / V%).
実施例2
CNN((株)林原生物化学研究所製)10gをPBS(リン酸緩衝生理食塩水)100mLに溶解した。無菌濾過後凍結乾燥により乾燥して粉末状にし、これを1gずつガラスバイアル瓶に充填、密封して、用時溶解して使用する敗血症予防及び治療用注射剤とした。 Example 2
10 g of CNN (manufactured by Hayashibara Biochemical Laboratories) was dissolved in 100 mL of PBS (phosphate buffered saline). After aseptic filtration, it was dried by freeze-drying to form a powder, which was filled in 1-g glass vials, sealed, dissolved at the time of use, and used as an injection for prevention and treatment of sepsis.
CNN((株)林原生物化学研究所製)10gをPBS(リン酸緩衝生理食塩水)100mLに溶解した。無菌濾過後凍結乾燥により乾燥して粉末状にし、これを1gずつガラスバイアル瓶に充填、密封して、用時溶解して使用する敗血症予防及び治療用注射剤とした。 Example 2
10 g of CNN (manufactured by Hayashibara Biochemical Laboratories) was dissolved in 100 mL of PBS (phosphate buffered saline). After aseptic filtration, it was dried by freeze-drying to form a powder, which was filled in 1-g glass vials, sealed, dissolved at the time of use, and used as an injection for prevention and treatment of sepsis.
実施例3
CNN((株)林原生物化学研究所製)10gを注射用水100mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め下室に生理食塩水100mLを充填し、常法に従い高圧蒸気滅菌されたプラスチック製複室容器の上室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 3
10 g of CNN (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of water for injection, and this was sterilized by filtration and then dried by lyophilization to obtain a powder. This was pre-filled with 100 mL of physiological saline in the lower chamber and filled into the upper chamber of a plastic multi-chamber container sterilized by autoclaving according to a conventional method to prepare a sepsis prevention and treatment agent kit product.
CNN((株)林原生物化学研究所製)10gを注射用水100mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め下室に生理食塩水100mLを充填し、常法に従い高圧蒸気滅菌されたプラスチック製複室容器の上室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 3
10 g of CNN (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of water for injection, and this was sterilized by filtration and then dried by lyophilization to obtain a powder. This was pre-filled with 100 mL of physiological saline in the lower chamber and filled into the upper chamber of a plastic multi-chamber container sterilized by autoclaving according to a conventional method to prepare a sepsis prevention and treatment agent kit product.
実施例4
CNN((株)林原生物化学研究所製)5gを注射用水50mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め上室にアミノ酸輸液300mL、下室に糖・電解質輸液600mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の小室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 4
5 g of CNN (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 50 mL of water for injection, and this was sterilized by filtration and then lyophilized to a powder. This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
CNN((株)林原生物化学研究所製)5gを注射用水50mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め上室にアミノ酸輸液300mL、下室に糖・電解質輸液600mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の小室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 4
5 g of CNN (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 50 mL of water for injection, and this was sterilized by filtration and then lyophilized to a powder. This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
実施例5
グルコースを構成糖とする環状四糖であるCMM((株)林原生物化学研究所製)5g、塩化カルシウム0.02g、塩化カリウム0.03g、塩化ナトリウム0.6g及び乳酸ナトリウム0.31gを注射用水85mLに溶解し、注射用水を加えて全量を100mLとした。これを、ろ過滅菌して注射液を製造した。この注射液を有効成分濃度が5%(W/V%)である実施例5の敗血症予防及び治療剤とした。 Example 5
Injection of 5 g of CMM (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.), a cyclic tetrasaccharide composed of glucose, 0.02 g of calcium chloride, 0.03 g of potassium chloride, 0.6 g of sodium chloride and 0.31 g of sodium lactate It melt | dissolved in 85 mL of water, and the water for injection was added and made the whole quantity to 100 mL. This was sterilized by filtration to produce an injection solution. This injection solution was used as an agent for preventing and treating sepsis of Example 5 having an active ingredient concentration of 5% (W / V%).
グルコースを構成糖とする環状四糖であるCMM((株)林原生物化学研究所製)5g、塩化カルシウム0.02g、塩化カリウム0.03g、塩化ナトリウム0.6g及び乳酸ナトリウム0.31gを注射用水85mLに溶解し、注射用水を加えて全量を100mLとした。これを、ろ過滅菌して注射液を製造した。この注射液を有効成分濃度が5%(W/V%)である実施例5の敗血症予防及び治療剤とした。 Example 5
Injection of 5 g of CMM (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.), a cyclic tetrasaccharide composed of glucose, 0.02 g of calcium chloride, 0.03 g of potassium chloride, 0.6 g of sodium chloride and 0.31 g of sodium lactate It melt | dissolved in 85 mL of water, and the water for injection was added and made the whole quantity to 100 mL. This was sterilized by filtration to produce an injection solution. This injection solution was used as an agent for preventing and treating sepsis of Example 5 having an active ingredient concentration of 5% (W / V%).
実施例6
CMM((株)林原生物化学研究所製)5gをPBS(リン酸緩衝生理食塩水)100mLに溶解した。無菌濾過後凍結乾燥により乾燥して粉末状にし、これを1gずつガラスバイアル瓶に充填、密封して、用時溶解して使用する敗血症予防及び治療用注射剤とした。 Example 6
5 g of CMM (produced by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of PBS (phosphate buffered saline). After aseptic filtration, it was dried by freeze-drying to form a powder, which was filled in 1-g glass vials, sealed, dissolved at the time of use, and used as an injection for prevention and treatment of sepsis.
CMM((株)林原生物化学研究所製)5gをPBS(リン酸緩衝生理食塩水)100mLに溶解した。無菌濾過後凍結乾燥により乾燥して粉末状にし、これを1gずつガラスバイアル瓶に充填、密封して、用時溶解して使用する敗血症予防及び治療用注射剤とした。 Example 6
5 g of CMM (produced by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of PBS (phosphate buffered saline). After aseptic filtration, it was dried by freeze-drying to form a powder, which was filled in 1-g glass vials, sealed, dissolved at the time of use, and used as an injection for prevention and treatment of sepsis.
実施例7
CMM((株)林原生物化学研究所製)2gを注射用水100mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め下室に生理食塩水100mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の上室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 7
2 g of CMM (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of water for injection, and this was sterilized by filtration and dried by lyophilization to obtain a powder. This was prefilled in the lower chamber with 100 mL of physiological saline and filled into the upper chamber of a plastic multi-chamber container that was autoclaved in accordance with a conventional method to obtain a kit product for preventing and treating sepsis.
CMM((株)林原生物化学研究所製)2gを注射用水100mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め下室に生理食塩水100mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の上室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 7
2 g of CMM (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of water for injection, and this was sterilized by filtration and dried by lyophilization to obtain a powder. This was prefilled in the lower chamber with 100 mL of physiological saline and filled into the upper chamber of a plastic multi-chamber container that was autoclaved in accordance with a conventional method to obtain a kit product for preventing and treating sepsis.
実施例8
CMM((株)林原生物化学研究所製)1gを注射用水50mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め上室にアミノ酸輸液300mL、下室に糖・電解質輸液600mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の小室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 8
1 g of CMM (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 50 mL of water for injection, and this was sterilized by filtration and dried by lyophilization to obtain a powder. This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
CMM((株)林原生物化学研究所製)1gを注射用水50mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め上室にアミノ酸輸液300mL、下室に糖・電解質輸液600mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の小室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 8
1 g of CMM (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 50 mL of water for injection, and this was sterilized by filtration and dried by lyophilization to obtain a powder. This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
実施例9
グルコースを構成糖とする環状五糖であるICG5((株)林原生物化学研究所製)10g、塩化カルシウム0.02g、塩化カリウム0.03g、塩化ナトリウム0.6g及び乳酸ナトリウム0.31gを注射用水70mLに溶解し、注射用水を加えて全量を100mLとした。これを、ろ過滅菌して注射液を製造した。この注射液を有効成分濃度が10%(W/V%)である実施例9の敗血症予防及び治療剤とした。 Example 9
Injection of 10 g of ICG5 (produced by Hayashibara Biochemical Laboratories Co., Ltd.), a cyclic pentasaccharide containing glucose as a constituent sugar, 0.02 g of calcium chloride, 0.03 g of potassium chloride, 0.6 g of sodium chloride and 0.31 g of sodium lactate It melt | dissolved in 70 mL of water, and the water for injection was added, and the whole quantity was set to 100 mL. This was sterilized by filtration to produce an injection solution. This injection solution was used as an agent for preventing and treating sepsis of Example 9 having an active ingredient concentration of 10% (W / V%).
グルコースを構成糖とする環状五糖であるICG5((株)林原生物化学研究所製)10g、塩化カルシウム0.02g、塩化カリウム0.03g、塩化ナトリウム0.6g及び乳酸ナトリウム0.31gを注射用水70mLに溶解し、注射用水を加えて全量を100mLとした。これを、ろ過滅菌して注射液を製造した。この注射液を有効成分濃度が10%(W/V%)である実施例9の敗血症予防及び治療剤とした。 Example 9
Injection of 10 g of ICG5 (produced by Hayashibara Biochemical Laboratories Co., Ltd.), a cyclic pentasaccharide containing glucose as a constituent sugar, 0.02 g of calcium chloride, 0.03 g of potassium chloride, 0.6 g of sodium chloride and 0.31 g of sodium lactate It melt | dissolved in 70 mL of water, and the water for injection was added, and the whole quantity was set to 100 mL. This was sterilized by filtration to produce an injection solution. This injection solution was used as an agent for preventing and treating sepsis of Example 9 having an active ingredient concentration of 10% (W / V%).
実施例10
ICG5((株)林原生物化学研究所製)30g、塩化カルシウム0.01g、塩化カリウム0.015g、塩化ナトリウム0.3g及び乳酸ナトリウム0.155gを注射用水30mLに溶解し、注射用水を加えて全量を50mLとした。これを、ろ過滅菌して注射液を製造した。 Example 10
ICG5 (produced by Hayashibara Biochemical Laboratories Co., Ltd.) 30 g, calcium chloride 0.01 g, potassium chloride 0.015 g, sodium chloride 0.3 g and sodium lactate 0.155 g were dissolved in 30 mL of water for injection, and water for injection was added. The total volume was 50 mL. This was sterilized by filtration to produce an injection solution.
ICG5((株)林原生物化学研究所製)30g、塩化カルシウム0.01g、塩化カリウム0.015g、塩化ナトリウム0.3g及び乳酸ナトリウム0.155gを注射用水30mLに溶解し、注射用水を加えて全量を50mLとした。これを、ろ過滅菌して注射液を製造した。 Example 10
ICG5 (produced by Hayashibara Biochemical Laboratories Co., Ltd.) 30 g, calcium chloride 0.01 g, potassium chloride 0.015 g, sodium chloride 0.3 g and sodium lactate 0.155 g were dissolved in 30 mL of water for injection, and water for injection was added. The total volume was 50 mL. This was sterilized by filtration to produce an injection solution.
実施例11
ICG5((株)林原生物化学研究所製)25gを注射用水100mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め下室に生理食塩水100mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の上室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 11
25 g of ICG5 (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of water for injection, and this was sterilized by filtration and then lyophilized to a powder. This was prefilled in the lower chamber with 100 mL of physiological saline and filled into the upper chamber of a plastic multi-chamber container that was autoclaved in accordance with a conventional method to obtain a kit product for preventing and treating sepsis.
ICG5((株)林原生物化学研究所製)25gを注射用水100mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め下室に生理食塩水100mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の上室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 11
25 g of ICG5 (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 100 mL of water for injection, and this was sterilized by filtration and then lyophilized to a powder. This was prefilled in the lower chamber with 100 mL of physiological saline and filled into the upper chamber of a plastic multi-chamber container that was autoclaved in accordance with a conventional method to obtain a kit product for preventing and treating sepsis.
実施例12
ICG5((株)林原生物化学研究所製)5gを注射用水50mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め上室にアミノ酸輸液300mL、下室に糖・電解質輸液600mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の小室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 12
5 g of ICG5 (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 50 mL of water for injection, and this was sterilized by filtration and dried by lyophilization to obtain a powder. This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
ICG5((株)林原生物化学研究所製)5gを注射用水50mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め上室にアミノ酸輸液300mL、下室に糖・電解質輸液600mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の小室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 12
5 g of ICG5 (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in 50 mL of water for injection, and this was sterilized by filtration and dried by lyophilization to obtain a powder. This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
実施例13
CNN((株)林原生物化学研究所製)5g及びICG5((株)林原生物化学研究所製)5gを注射用水50mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め上室にアミノ酸輸液300mL、下室に糖・電解質輸液600mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の小室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 13
5 g of CNN (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) and 5 g of ICG5 (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) were dissolved in 50 mL of water for injection. . This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
CNN((株)林原生物化学研究所製)5g及びICG5((株)林原生物化学研究所製)5gを注射用水50mLに溶解し、これをろ過滅菌後凍結乾燥により乾燥して粉末状にした。これを、予め上室にアミノ酸輸液300mL、下室に糖・電解質輸液600mLを充填し常法に従い高圧蒸気滅菌されたプラスチック製複室容器の小室に充填して、敗血症予防及び治療剤のキット製品とした。 Example 13
5 g of CNN (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) and 5 g of ICG5 (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) were dissolved in 50 mL of water for injection. . This product is filled with 300 mL of amino acid infusion in the upper chamber and 600 mL of sugar / electrolyte in the lower chamber and filled into a small chamber of a plastic multi-chamber container sterilized by high-pressure steam according to a conventional method. It was.
試験例1
LPSモデルラットを用いたCNNの敗血症予防効果の検証
6週齢のSD系雄性ラット(日本チャールス・リバー株式会社から購入)を7日以上の馴化期間(標準飼料AIN-93G:日本農産工業株式会社を自由摂餌)を設けた後、実施例1の敗血症予防及び治療剤を投与する群(CNN群)、比較群並びにコントロール群の3群に群分けした(n=15)。 Test example 1
Verification of sepsis prevention effect of CNN using LPS model rats 6 weeks old SD male rats (purchased from Charles River Japan Co., Ltd.) acclimatization period of 7 days or longer (standard feed AIN-93G: Nippon Agricultural Industrial Co., Ltd.) Were provided, and then divided into three groups (n = 15): a group (CNN group) to which the agent for preventing and treating sepsis of Example 1 was administered (CNN group), a comparative group, and a control group.
LPSモデルラットを用いたCNNの敗血症予防効果の検証
6週齢のSD系雄性ラット(日本チャールス・リバー株式会社から購入)を7日以上の馴化期間(標準飼料AIN-93G:日本農産工業株式会社を自由摂餌)を設けた後、実施例1の敗血症予防及び治療剤を投与する群(CNN群)、比較群並びにコントロール群の3群に群分けした(n=15)。 Test example 1
Verification of sepsis prevention effect of CNN using LPS model rats 6 weeks old SD male rats (purchased from Charles River Japan Co., Ltd.) acclimatization period of 7 days or longer (standard feed AIN-93G: Nippon Agricultural Industrial Co., Ltd.) Were provided, and then divided into three groups (n = 15): a group (CNN group) to which the agent for preventing and treating sepsis of Example 1 was administered (CNN group), a comparative group, and a control group.
CNN群には、一昼夜絶食後(以後、実験終了まで絶食とする。)に、被験液として実施例1で得られた注射液1mL/kgを、投与時間10秒間以内で尾静脈内投与した。さらにその直後に敗血症ショックを誘発させるために、エンドトキシンであるEscherichia coli 0111:B4由来のリポポリサッカライド(以下「LPS」)の生理食塩溶液(20mg/mL)を、1mL/kgの投与量で投与時間10秒間以内にて腹腔内投与した。
In the CNN group, 1 mL / kg of the injection solution obtained in Example 1 as a test solution was administered into the tail vein within 10 seconds after administration, after fasting all day and night (hereinafter referred to as fasting until the end of the experiment). Furthermore, in order to induce septic shock immediately after that, a physiological saline solution (20 mg / mL) of an endotoxin Escherichia coli 0111: B4-derived lipopolysaccharide (hereinafter “LPS”) was administered at a dose of 1 mL / kg. It was administered intraperitoneally within 10 seconds.
一方、コントロール群については、被験液としてCNNを含まない実施例1の組成の注射液を1mL/kg投与した以外は、CNN群と同様に処理した。
On the other hand, the control group was treated in the same manner as the CNN group except that 1 mL / kg of the injection solution having the composition of Example 1 containing no CNN was administered as a test solution.
また、比較群については、CNNに代えてα-シクロデキストリン(株式会社林原生物化学研究所)を同濃度となるように溶かした注射液を被験液として、同様に実験を行った。
For the comparative group, an experiment was similarly performed using an injection solution in which α-cyclodextrin (Hayashibara Biochemical Laboratories Co., Ltd.) was dissolved in the same concentration instead of CNN as a test solution.
各群について、LPS投与後4時間毎に死亡例数を測定し、24時間まで生存率をみた。LPS投与後4時間毎における各群の生存率(%)を下記表1に示す。
For each group, the number of deaths was measured every 4 hours after LPS administration, and the survival rate was observed up to 24 hours. The survival rate (%) of each group every 4 hours after LPS administration is shown in Table 1 below.
以上の結果から明らかなように、実施例1の敗血症予防及び治療剤を投与したCNN群は、α-シクロデキストリンを投与した比較群に比べて高い生存率を示した。このことから、本発明の敗血症予防及び治療剤の有効成分であるCNNが、敗血症に対する予防効果を有することが確認され、初期の段階から有効に使用できることが示唆された。
As is clear from the above results, the CNN group administered with the sepsis prevention and treatment agent of Example 1 showed a higher survival rate than the comparative group administered with α-cyclodextrin. From this, it was confirmed that CNN, which is an active ingredient of the sepsis prevention and treatment agent of the present invention, has a preventive effect on sepsis, suggesting that it can be used effectively from the initial stage.
試験例2
LPSモデルラットを用いたCMM及びICG5の敗血症予防効果の検証
6週齢のSD系雄性ラット(日本チャールス・リバー株式会社から購入)を7日以上の馴化期間(標準飼料AIN-93G:日本農産工業株式会社を自由摂餌)を設けた後、実施例5の注射液を投与する群(CMM群)、実施例9の注射液を投与する群(ICG5群)及びコントロール群の3群に群分けした(n=15)。 Test example 2
Verification of sepsis prevention effect of CMM and ICG5 using LPS model rats 6 weeks old SD male rats (purchased from Japan Charles River Co., Ltd.) acclimatization period of 7 days or more (standard feed AIN-93G: Nippon Agricultural Industry) After the corporation was given free feeding), the group was divided into 3 groups: the group administered with the injection solution of Example 5 (CMM group), the group administered with the injection solution of Example 9 (ICG group 5), and the control group. (N = 15).
LPSモデルラットを用いたCMM及びICG5の敗血症予防効果の検証
6週齢のSD系雄性ラット(日本チャールス・リバー株式会社から購入)を7日以上の馴化期間(標準飼料AIN-93G:日本農産工業株式会社を自由摂餌)を設けた後、実施例5の注射液を投与する群(CMM群)、実施例9の注射液を投与する群(ICG5群)及びコントロール群の3群に群分けした(n=15)。 Test example 2
Verification of sepsis prevention effect of CMM and ICG5 using LPS model rats 6 weeks old SD male rats (purchased from Japan Charles River Co., Ltd.) acclimatization period of 7 days or more (standard feed AIN-93G: Nippon Agricultural Industry) After the corporation was given free feeding), the group was divided into 3 groups: the group administered with the injection solution of Example 5 (CMM group), the group administered with the injection solution of Example 9 (ICG group 5), and the control group. (N = 15).
CMM群には、一昼夜絶食後(以後、実験終了まで絶食とする。)に、被験液として実施例5で得られた注射液2mL/kgを、投与時間10秒間以内で尾静脈内投与した。さらにその直後に敗血症ショックを誘発させるために、エンドトキシンであるEscherichia coli 0111:B4由来のリポポリサッカライド(以下「LPS」)の生理食塩溶液(20mg/mL)を、1mL/kgの投与量で投与時間10秒間以内にて腹腔内投与した。
In the CMM group, 2 mL / kg of the injection solution obtained in Example 5 was administered as a test solution within the tail vein within 10 seconds after a fasting day and night (hereinafter referred to as fasting until the end of the experiment). Furthermore, in order to induce septic shock immediately after that, a physiological saline solution (20 mg / mL) of an endotoxin Escherichia coli 0111: B4-derived lipopolysaccharide (hereinafter “LPS”) was administered at a dose of 1 mL / kg. It was administered intraperitoneally within 10 seconds.
ICG5群には、被験液として実施例9で得られた注射液1mL/kgを投与した以外は、CMM群と同様に処理した。
The ICG5 group was treated in the same manner as the CMM group except that 1 mL / kg of the injection solution obtained in Example 9 was administered as a test solution.
一方、コントロール群については、被験液としてCNNを含まない実施例1の組成の注射液1mL/kgを投与した以外は、CMM群と同様に処理した。
On the other hand, the control group was treated in the same manner as the CMM group except that 1 mL / kg of the injection solution having the composition of Example 1 containing no CNN was administered as the test solution. *
各群について、LPS投与後4時間毎に死亡例数を測定し、24時間まで生存率をみた。LPS投与後4時間毎における各群の生存率(%)を下記表2に示す。
For each group, the number of deaths was measured every 4 hours after LPS administration, and the survival rate was observed up to 24 hours. The survival rate (%) of each group every 4 hours after LPS administration is shown in Table 2 below.
以上の結果から明らかなように、実施例5又は実施例9の敗血症予防及び治療剤を投与したCMM群とICG5群は、コントロール群に比べて生存率の改善効果がみられた。このことから、本発明の敗血症予防及び治療剤の有効成分であるCMMとICG5については、いずれも敗血症に対する予防効果を有することが確認され、初期の段階から有効に使用できることが示唆された。
As is clear from the above results, the CMM group and the ICG5 group to which the sepsis prevention and treatment agent of Example 5 or Example 9 was administered showed an improvement effect on the survival rate compared to the control group. From these results, it was confirmed that CMM and ICG5, which are active ingredients of the sepsis prevention and treatment agent of the present invention, both have a preventive effect on sepsis, suggesting that they can be used effectively from the initial stage.
試験例3
LPSモデルラットを用いたCNNの敗血症治療効果の検証
6週齢のSD系雄性ラット(日本チャールス・リバー株式会社から購入)を7日以上の馴化期間(標準飼料AIN-93G:日本農産工業株式会社を自由摂餌)を設けた後、実施例1の敗血症予防及び治療剤を投与する群(CNN群)およびコントロール群の2群に群分けした(n=15)。 Test example 3
Verification of sepsis treatment effect of CNN using LPS model rats 6-week-old SD male rats (purchased from Charles River Japan Co., Ltd.) acclimatization period of 7 days or longer (standard feed AIN-93G: Nippon Agricultural Industrial Co., Ltd.) Were provided (free feeding), and then divided into two groups (n = 15): a group (CNN group) to which the agent for preventing and treating sepsis of Example 1 was administered and a control group.
LPSモデルラットを用いたCNNの敗血症治療効果の検証
6週齢のSD系雄性ラット(日本チャールス・リバー株式会社から購入)を7日以上の馴化期間(標準飼料AIN-93G:日本農産工業株式会社を自由摂餌)を設けた後、実施例1の敗血症予防及び治療剤を投与する群(CNN群)およびコントロール群の2群に群分けした(n=15)。 Test example 3
Verification of sepsis treatment effect of CNN using LPS model rats 6-week-old SD male rats (purchased from Charles River Japan Co., Ltd.) acclimatization period of 7 days or longer (standard feed AIN-93G: Nippon Agricultural Industrial Co., Ltd.) Were provided (free feeding), and then divided into two groups (n = 15): a group (CNN group) to which the agent for preventing and treating sepsis of Example 1 was administered and a control group.
CNN群には、一昼夜絶食後(以後、実験終了まで絶食とする。)に、LPSの生理食塩溶液(20mg/mL)を1mL/kgの投与量で投与時間10秒間以内にて腹腔内投与した。更にその2時間後、被験液として実施例1で得られた注射液1mL/kgを、投与時間10秒間以内で尾静脈内投与した。なお別に炎症性サイトカインを測定し、被験液投与時点において敗血症が起こっていることを確認した。
The CNN group was intraperitoneally administered with a physiological saline solution of LPS (20 mg / mL) at a dose of 1 mL / kg within 10 seconds after fasting all day and night (hereinafter referred to as fasting until the end of the experiment). . Further 2 hours later, 1 mL / kg of the injection solution obtained in Example 1 as a test solution was administered into the tail vein within 10 seconds. Separately, inflammatory cytokines were measured to confirm that sepsis occurred at the time of administration of the test solution.
一方、コントロール群は、被験液としてCNNを含まない実施例1の組成の注射液1mL/kgを投与した以外は、CNN群と同様に処理した。
On the other hand, the control group was treated in the same manner as the CNN group except that 1 mL / kg of the injection solution having the composition of Example 1 containing no CNN was administered as the test solution.
各群について、LPS投与後4時間毎に死亡例数を測定し、24時間まで生存率をみた。LPS投与後4時間毎における各群の生存率(%)を下記表3に示す。
For each group, the number of deaths was measured every 4 hours after LPS administration, and the survival rate was observed up to 24 hours. The survival rate (%) of each group every 4 hours after LPS administration is shown in Table 3 below.
上記結果から明らかなように、CNN群は、コントロール群に比べて高い生存率を示した。このことから、本発明の敗血症予防及び治療剤の有効成分であるCNNが、敗血症に感染後の治療効果を有することが確認された。
As is clear from the above results, the CNN group showed a higher survival rate than the control group. From this, it was confirmed that CNN which is an active ingredient of the sepsis prevention and treatment agent of the present invention has a therapeutic effect after infection of sepsis.
試験例4
CNNの赤血球溶血に及ぼす影響(β-シクロデキストリンとの比較およびCNN濃度の影響)
シリアンハムスター4~6箇月齢の雄・雌計30匹分の血液(心臓採血:ヘパリン処理済)25mLを室温下で遠心分離(2000rpm×15min)して血球成分と血漿を分離した。さらにパスツールピペットで血球層の最上部(buffy coat;白血球層)を除去した。これにPBS(0.15M NaCl+10mMリン酸緩衝液、pH7.4)を加え、血球を懸濁し再度遠心分離し(2000rpm×15min)、この操作を3回繰り返して赤血球を得た。これをPBS25mLに懸濁し、6.07×1010個/mLのハムスター赤血球懸濁液とした。 Test example 4
Effect of CNN on erythrocyte hemolysis (comparison with β-cyclodextrin and effect of CNN concentration)
Blood blood components and plasma were separated by centrifugation (2000 rpm × 15 min) of 25 mL of blood (cardiac blood sampling: heparin-treated) for 30 male and female 4 to 6 month old Syrian hamsters at room temperature. Further, the uppermost part of the blood cell layer (buffy coat; leukocyte layer) was removed with a Pasteur pipette. PBS (0.15 M NaCl + 10 mM phosphate buffer, pH 7.4) was added thereto, the blood cells were suspended and centrifuged again (2000 rpm × 15 min), and this operation was repeated three times to obtain erythrocytes. This was suspended in 25 mL of PBS to obtain a hamster erythrocyte suspension of 6.07 × 10 10 cells / mL.
CNNの赤血球溶血に及ぼす影響(β-シクロデキストリンとの比較およびCNN濃度の影響)
シリアンハムスター4~6箇月齢の雄・雌計30匹分の血液(心臓採血:ヘパリン処理済)25mLを室温下で遠心分離(2000rpm×15min)して血球成分と血漿を分離した。さらにパスツールピペットで血球層の最上部(buffy coat;白血球層)を除去した。これにPBS(0.15M NaCl+10mMリン酸緩衝液、pH7.4)を加え、血球を懸濁し再度遠心分離し(2000rpm×15min)、この操作を3回繰り返して赤血球を得た。これをPBS25mLに懸濁し、6.07×1010個/mLのハムスター赤血球懸濁液とした。 Test example 4
Effect of CNN on erythrocyte hemolysis (comparison with β-cyclodextrin and effect of CNN concentration)
Blood blood components and plasma were separated by centrifugation (2000 rpm × 15 min) of 25 mL of blood (cardiac blood sampling: heparin-treated) for 30 male and female 4 to 6 month old Syrian hamsters at room temperature. Further, the uppermost part of the blood cell layer (buffy coat; leukocyte layer) was removed with a Pasteur pipette. PBS (0.15 M NaCl + 10 mM phosphate buffer, pH 7.4) was added thereto, the blood cells were suspended and centrifuged again (2000 rpm × 15 min), and this operation was repeated three times to obtain erythrocytes. This was suspended in 25 mL of PBS to obtain a hamster erythrocyte suspension of 6.07 × 10 10 cells / mL.
上記方法で調製したハムスター赤血球懸濁液1mLに、CNNの濃度が0mM,1mM,5mMまたは10mMとなるようにPBSに溶かした溶液5mLと、4mLのPBSを添加混合し、37℃で30分間反応させた。そして、反応後の反応液の遠心上清(12,000rpm×15min)について、577nmにおける吸光度を測定し、完全溶血液の577nmにおける吸光度を100とした相対値を求め、これを溶血率(%)とした。
To 1 mL of the hamster erythrocyte suspension prepared as described above, 5 mL of a solution dissolved in PBS so that the CNN concentration is 0 mM, 1 mM, 5 mM, or 10 mM and 4 mL of PBS are added and mixed, and the reaction is performed at 37 ° C. for 30 minutes. I let you. Then, the absorbance at 777 nm was measured for the centrifugal supernatant (12,000 rpm × 15 min) of the reaction solution after the reaction, and the relative value was determined with the absorbance at 577 nm of complete hemolysis as 100, and this was determined as the hemolysis rate (%). did.
また比較群として、CNNに代えてβ-シクロデキストリンを5mMまたは10mMとなるように溶かしたPBS溶液を調製し、CNNの代わりに添加して、上記方法と同様にして吸光度を測定し、溶血率を求めた。
As a comparison group, a PBS solution in which β-cyclodextrin was dissolved to 5 mM or 10 mM instead of CNN was prepared, added instead of CNN, and the absorbance was measured in the same manner as described above. Asked.
反応液の遠心上清の577nmにおける吸光度及び溶血率(%)を下記表4に示す。
The absorbance and hemolysis rate (%) at 577 nm of the centrifugal supernatant of the reaction solution are shown in Table 4 below.
上記結果から明らかなように、反応上清の吸光度から求めた溶血率(%:完全溶血を100とした相対値)について、CNNを添加した場合には、β-シクロデキストリンを添加した場合と比較して低い値を示した。
As is clear from the above results, with respect to the hemolysis rate (%: relative value with respect to complete hemolysis as 100) obtained from the absorbance of the reaction supernatant, when CNN is added, it is compared with the case where β-cyclodextrin is added. Showed a low value.
このことからCNNは、β-シクロデキストリンに見られる強い赤血球溶血作用を示さないことが判った。
From this, it was found that CNN does not show the strong erythrocyte hemolytic action seen in β-cyclodextrin.
Claims (10)
- グルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を有効成分として含有する敗血症の予防及び治療剤。 A prophylactic and therapeutic agent for sepsis comprising as an active ingredient at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof.
- シクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を有効成分として含有する敗血症の予防及び治療剤。 Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl -(1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α- A prophylactic and therapeutic agent for sepsis comprising, as an active ingredient, at least one component selected from the group consisting of D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →} and derivatives thereof.
- 注射用水性製剤又は用時溶解用固形剤である請求項1に記載の敗血症の予防及び治療剤。 The prophylactic and therapeutic agent for sepsis according to claim 1, which is an aqueous preparation for injection or a solid preparation for dissolution at the time of use.
- 静脈内投与用として用いられる請求項3に記載の敗血症の予防及び治療剤。 The prophylactic and therapeutic agent for sepsis according to claim 3, which is used for intravenous administration.
- 敗血症の予防及び治療剤を製造するためのグルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分の使用。 Use of at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof for producing an agent for preventing and treating sepsis.
- 敗血症の予防及び治療剤を製造するためのシクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分の使用。 Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 →) for producing a preventive and therapeutic agent for sepsis 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D Use of at least one component selected from the group consisting of glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, and derivatives thereof.
- グルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を含有する敗血症の予防及び治療剤をヒトに投与して、敗血症を予防及び治療する方法。 Administering a prophylactic and therapeutic agent for sepsis containing at least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof; Methods for preventing and treating sepsis.
- シクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分を含有する敗血症の予防及び治療剤をヒトに投与して、敗血症を予防及び治療する方法。 Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl -(1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α- A prophylactic and therapeutic agent for sepsis containing at least one component selected from the group consisting of D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →} and derivatives thereof is administered to humans , Methods for preventing and treating sepsis
- 敗血症の予防及び治療方法に使用のためのグルコースを構成糖とする環状四糖、グルコースを構成糖とする環状五糖、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分。 At least one component selected from the group consisting of a cyclic tetrasaccharide having glucose as a constituent sugar, a cyclic pentasaccharide having glucose as a constituent sugar, and derivatives thereof for use in a method for preventing and treating sepsis.
- 敗血症の予防及び治療方法に使用のためのシクロ{→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→3)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、シクロ{→6)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→4)-α-D-グルコピラノシル-(1→}、及びこれらの誘導体からなる群から選ばれる少なくとも一種の成分。 Cyclo {→ 6) -α-D-glucopyranosyl- (1 → 3) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 →) for use in methods for preventing and treating sepsis 3) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, cyclo {→ 6) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D -Gluopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 → 4) -α-D-glucopyranosyl- (1 →}, and at least one component selected from the group consisting of these derivatives.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03133931A (en) * | 1989-10-18 | 1991-06-07 | Ueno Seiyaku Oyo Kenkyusho:Kk | Antishock agent |
JP2005095148A (en) * | 2003-08-28 | 2005-04-14 | Hayashibara Biochem Lab Inc | Cyclic maltosylmalthose, cyclic maltosylmaltose-forming enzyme, method for forming them and use of them |
WO2006035725A1 (en) * | 2004-09-27 | 2006-04-06 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Isocyclomaltooligosaccharide, isocyclomaltooligosaccharide synthase, process for producing them and use thereof |
WO2006115067A1 (en) * | 2005-04-20 | 2006-11-02 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Peritoneal dialysis fluid |
WO2007013122A1 (en) * | 2005-07-28 | 2007-02-01 | Humanitas Mirasole S.P.A. | Haemofilters for blood detoxification |
JP2008056631A (en) * | 2006-09-01 | 2008-03-13 | Chisso Corp | Sulfated cyclic tetrasaccharide or salt thereof |
-
2008
- 2008-10-03 JP JP2008258709A patent/JP2011256111A/en active Pending
-
2009
- 2009-09-25 WO PCT/JP2009/066593 patent/WO2010038656A1/en active Application Filing
- 2009-09-29 TW TW098132910A patent/TW201018469A/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03133931A (en) * | 1989-10-18 | 1991-06-07 | Ueno Seiyaku Oyo Kenkyusho:Kk | Antishock agent |
JP2005095148A (en) * | 2003-08-28 | 2005-04-14 | Hayashibara Biochem Lab Inc | Cyclic maltosylmalthose, cyclic maltosylmaltose-forming enzyme, method for forming them and use of them |
WO2006035725A1 (en) * | 2004-09-27 | 2006-04-06 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Isocyclomaltooligosaccharide, isocyclomaltooligosaccharide synthase, process for producing them and use thereof |
WO2006115067A1 (en) * | 2005-04-20 | 2006-11-02 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Peritoneal dialysis fluid |
WO2007013122A1 (en) * | 2005-07-28 | 2007-02-01 | Humanitas Mirasole S.P.A. | Haemofilters for blood detoxification |
JP2008056631A (en) * | 2006-09-01 | 2008-03-13 | Chisso Corp | Sulfated cyclic tetrasaccharide or salt thereof |
Non-Patent Citations (4)
Title |
---|
GREGORY L. C. ET AL.: "Enzymically Produced Cyclic a-1,3-Linked and a-1,6-Linked Oligosaccharides of d-Glucose.", EUROPEAN JOURNAL OF BIOCHEMISTRY, vol. 226, no. 2, 1994, pages 641 - 648 * |
HIDETOSHI ARIMA: "Cyclodextrin no Saranaru Kanosei o Motomete", JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, vol. 63, no. 3, 2003, JAPAN, pages 125 - 128 * |
HIROSHI NISHIMOTO ET AL.: "Cyclodextrin Yudotai ni yoru Macrophage kara no NO Sansei no Yokusei", ABSTRACTS OF ANNUAL MEETING OF PHARMACEUTICAL SOCIETY OF JAPAN, vol. 120, no. 4, 2000, pages 21 * |
KEIICHI MOTOYAMA: "Endotoxin Shock Yokuseizai toshite no Dimethyl Acetyl-§-Cyclodextrin no Yuko Riyo", JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, vol. 68, no. 3, May 2008 (2008-05-01), JAPAN, pages 196 - 201 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016193917A (en) * | 2010-12-01 | 2016-11-17 | ジ オーストラリアン ナショナル ユニバーシティ | Histone Inhibition |
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