WO2009123029A1 - Régulateur de niveau d’ammoniac dans le sang - Google Patents

Régulateur de niveau d’ammoniac dans le sang Download PDF

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Publication number
WO2009123029A1
WO2009123029A1 PCT/JP2009/056201 JP2009056201W WO2009123029A1 WO 2009123029 A1 WO2009123029 A1 WO 2009123029A1 JP 2009056201 W JP2009056201 W JP 2009056201W WO 2009123029 A1 WO2009123029 A1 WO 2009123029A1
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WO
WIPO (PCT)
Prior art keywords
blood ammonia
cyclodextrin
blood
regulator
adjusting agent
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PCT/JP2009/056201
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English (en)
Japanese (ja)
Inventor
雅子 土居
望 田村
益浩 西村
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株式会社 大塚製薬工場
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Publication of WO2009123029A1 publication Critical patent/WO2009123029A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the present invention relates to a blood ammonia adjusting agent used for lowering the blood ammonia concentration or for suppressing an increase in blood ammonia concentration. More specifically, the present invention relates to a blood ammonia adjusting agent which contains ⁇ -cyclodextrin as an active ingredient and is used, for example, by administration to hyperammonemia patients or hepatic encephalopathy patients.
  • ammonia in the blood is derived from ammonia generated in the intestine. Protein or amino acid taken orally ingests ammonia by being metabolized by the action of intestinal bacteria. Normally, ammonia generated in the intestinal tract is absorbed into the portal blood from the intestinal wall and transported to the liver. Ammonia carried to the liver is detoxified to urea in the urea cycle.
  • the liver function decreases due to liver disease such as cirrhosis, blood ammonia cannot be metabolized and blood ammonia increases.
  • a bypass portal vein-aortic shunt path, PC shunt
  • ammonia absorbed from the intestinal wall flows directly into the systemic circulation without being metabolized by the liver.
  • Hyperammonemia develops as a result of the increased ammonia concentration in the blood. Ammonia easily breaks through the cerebral blood barrier, and when it falls into hyperammonemia, it causes cerebral damage (hepatic encephalopathy) such as consciousness disorder, movement disorder and language disorder. Sometimes.
  • Ammonia is considered to be a typical encephalopathy-inducing factor together with lower fatty acids and mercaptans.
  • Examples of the treatment aimed at lowering the blood ammonia concentration include diet therapy centered on a low protein diet and medication treatment.
  • Examples of pharmaceuticals used in medication include pharmaceuticals intended to suppress the production of ammonia in the intestinal tract, such as antibiotics, lactulose (see Non-Patent Document 1) and lactitol, and pharmaceuticals intended to remove ammonia, such as Amino acid formulations are known.
  • lactulose and lactitol are often used as therapeutic agents for hyperammonemia.
  • Lactulose and lactitol When taken, lactulose and lactitol reach the large intestine without being absorbed in the stomach and small intestine, and are decomposed into organic acids such as acetic acid, propionic acid and butyric acid by intestinal bacteria. As a result, the pH in the intestine decreases, and ammonia changes to an ionic form that is difficult to be absorbed. Lactulose and lactitol also have an action of promoting intestinal transport ability and shortening the residence time of intestinal contents serving as an ammonia source.
  • lactulose has a problem that it frequently causes digestive symptoms such as diarrhea. In addition, there is a problem that discomfort and nausea are caused at the time of taking due to strong sweetness, and portability and storage are not good.
  • lactitol is easy to drink because it has a lower sweetness than lactulose, it has an insufficient effect of lowering the blood ammonia concentration, and diarrhea occurs not a little. Bircher J. et al., Lancet 1, 890-893, 1966
  • an object of the present invention is to provide a blood ammonia adjusting agent which is less likely to cause side effects and is useful for lowering the blood ammonia concentration.
  • the present inventors have sought a substance that has a high effect of reducing blood ammonia concentration and has few side effects.
  • ⁇ -cyclodextrin conventionally used as a food additive is excellent in the action of lowering the ammonia concentration in blood and has no side effects, thereby completing the present invention.
  • a blood ammonia adjusting agent containing ⁇ -cyclodextrin as an active ingredient is provided.
  • the above blood ammonia adjusting agent can be used as a therapeutic agent for hyperammonemia or hepatic encephalopathy.
  • the blood ammonia adjusting agent can also be used as a preventive agent for hyperammonemia or hepatic encephalopathy.
  • the blood ammonia adjusting agent is preferably formed as a preparation for oral administration or enteral administration.
  • the blood ammonia adjusting agent may be formed as a solid agent. In that case, the blood ammonia adjusting agent preferably contains ⁇ -cyclodextrin in an amount of 10 to 100% by mass.
  • the blood ammonia adjusting agent can be used as a food or drink for hyperammonemia patients or hepatic encephalopathy patients.
  • the blood ammonia regulator may be formed as a solid food, and in that case, it preferably contains ⁇ -cyclodextrin in an amount of 10 to 100% by mass.
  • the blood ammonia regulator of this embodiment contains ⁇ -cyclodextrin as an active ingredient.
  • Cyclodextrin is a cyclic oligosaccharide in which a plurality of glucose molecules are linked cyclically by ⁇ -1,4 glycosidic bonds, and is also present in nature. Cyclodextrin molecules are generally known to have an inclusion action of incorporating molecules into a central cavity (hole). Since the inside of the cavity of cyclodextrin is hydrophobic, cyclodextrin tends to include a hydrophobic substance. For this reason, for example, in the field of food additives, cyclodextrins are used for the purpose of enhancing the solubility of hydrophobic substances or protecting substances that easily react with water and oxygen.
  • the cyclodextrin formed by combining six glucose molecules is called ⁇ -cyclodextrin and is produced from starch by the action of ⁇ -cyclomaltodextrin glucanotransferase.
  • Cyclodextrin formed by combining seven glucose molecules is called ⁇ -cyclodextrin and is produced from starch by the action of ⁇ -cyclomaltodextrin glucanotransferase.
  • Cyclodextrin formed by combining eight glucose molecules is called ⁇ -cyclodextrin and is produced from starch by the action of ⁇ -cyclomaltodextrin glucanotransferase.
  • ⁇ -cyclodextrin specifically suppresses an increase in blood ammonia concentration.
  • ⁇ -Cyclodextrin is a water-soluble dextrin that dissolves in about 14 g in 100 mL of water at 25 ° C., and is also an indigestible dextrin that is not degraded by digestive enzymes.
  • the blood ammonia regulator exerts the action of reducing the ammonia concentration in the blood or the action of suppressing the increase in the blood ammonia concentration by the action of ⁇ -cyclodextrin when taken into the body.
  • the blood ammonia adjusting agent is preferably used as a therapeutic agent for hyperammonemia in patients with hyperammonemia, but is not limited thereto.
  • the blood ammonia adjusting agent may be used as a preventive agent for hyperammonemia.
  • it may be used for hepatic encephalopathy patients as a therapeutic agent for hepatic encephalopathy, which is a brain disorder caused by hyperammonemia, or as a prophylactic agent for hepatic encephalopathy.
  • the blood ammonia regulator can be used as a medicine or a food or drink. It is considered that the decrease in blood ammonia concentration or the suppression of increase in blood ammonia concentration by ⁇ -cyclodextrin is exhibited by the action of ⁇ -cyclodextrin in the intestinal tract. Therefore, the blood ammonia regulator is preferably formed as a preparation for oral administration or enteral administration if used as a pharmaceutical product. Since ⁇ -cyclodextrin is water-soluble and indigestible as described above, it reaches the intestine without being decomposed and absorbed in the stomach by ingestion.
  • the dosage form of the blood ammonia regulator is not particularly limited, and may be any of solid, liquid and gel.
  • the solid preparation include tablets, pills, powders, powders, granules, and fine granules.
  • Liquid agents include, for example, solutions, suspensions and emulsions.
  • the powder of ⁇ -cyclodextrin can also be used for administration as a blood ammonia adjusting agent.
  • the blood ammonia adjusting agent may be filled into a capsule and formed as a capsule.
  • blood ammonia regulators include excipients (bulking agents), binders, disintegrants, surfactants, disintegration inhibitors, adsorbents, lubricants, gelling agents, etc.
  • excipients include, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and potassium phosphate.
  • binders include, for example, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • Examples of the disintegrant include, for example, sodium carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, and calcium carbonate.
  • Examples of the surfactant include polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, and stearic acid monoglyceride.
  • disintegration inhibitors include, for example, sucrose, stearin, cocoa butter, and hydrogenated oil.
  • Examples of adsorbents include, for example, starch, lactose, kaolin, bentonite, and colloidal silicic acid.
  • lubricants include purified talc, stearate, boric acid powder, and polyethylene glycol.
  • gelling agents include agar, gelatin, carrageenan, gellan gum, xanthan gum, locust bean gum, pectin, sodium alginate, and potassium alginate.
  • Blood ammonia regulators are tablets coated with a known coating to mask the sweetness derived from ⁇ -cyclodextrin, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, and film-coated tablets. Also good.
  • the coating may be a single layer or a multilayer of two or more layers.
  • the blood ammonia adjusting agent having a capsule dosage form is filled in capsules such as hard gelatin capsules and soft capsules after mixing ⁇ -cyclodextrin with an arbitrary pharmaceutical carrier according to the usual method of capsule preparation. Manufactured.
  • Liquid dosage forms of blood ammonia such as liquids, emulsions, and suspensions, contain a diluent used as a solvent.
  • the diluent include water and alcohols. From the viewpoint of safety and solubility, a preferred diluent is water.
  • the liquid ammonia adjusting agent in the liquid dosage form may further contain at least one of a solubilizing agent and a buffer (pH adjusting agent). Moreover, you may further contain at least one chosen from a coloring agent, a preservative, a fragrance
  • the blood ammonia regulator can also be used by mixing with other drugs that do not inhibit the action of the blood ammonia regulator.
  • the blood ammonia regulator is used as a food or drink, it is prepared by mixing it with a food or drink material.
  • foods and drinks used as the blood ammonia regulator particularly preferred are foods and drinks for hyperammonemia patients or hepatic encephalopathy patients.
  • the form of the blood ammonia regulator used as a food or drink is not particularly limited. For example, it may be a jelly-like, cream-like, jam-like or gel-like semi-fluid food, solid food, or beverage. Good.
  • blood ammonia regulators used as semi-fluid foods or beverages include sugars, electrolytes, nutrients, amino acids (eg, branched chain amino acids), vitamins, minerals (eg, zinc and Serine), flavoring agents, coloring agents, and flavoring substances may be further contained.
  • amino acids eg, branched chain amino acids
  • vitamins eg, zinc and Serine
  • flavoring agents eg, coloring agents, and flavoring substances
  • branched chain amino acids include, for example, isoleucine, leucine and valine.
  • vitamins include, for example, retinol palmitate, tocopherol, thiamine, riboflavin, pyridoxine hydrochloride, cyanocobalamin, sodium ascorbate, cholecalciferol, nicotinamide, calcium pantothenate, folic acid, biotin, and choline bitartrate It is done.
  • blood ammonia adjusting agents used as semi-fluid foods are, for example, thickening polysaccharides such as agar, gelatin, carrageenan, gellan gum, xanthan gum, locust bean gum, pectin, sodium alginate, potassium alginate and the like as gelling agents. You may contain.
  • the amount of ⁇ -cyclodextrin contained in the blood ammonia regulator is not particularly limited. However, when formed as a solid agent or a solid food, the amount of ⁇ -cyclodextrin contained in the blood ammonia regulator is preferably 10 to 100% by mass, more preferably 50 to 100% by mass. When the blood ammonia regulator contains ⁇ -cyclodextrin in an amount of 10% by mass or more, the blood ammonia concentration can be sufficiently reduced by ingesting a relatively small amount of blood ammonia regulator, or blood An increase in the ammonia concentration can be sufficiently suppressed.
  • the amount of ⁇ -cyclodextrin contained in the blood ammonia regulator is appropriately within the range where ⁇ -cyclodextrin is dissolved in the blood ammonia regulator. Is set.
  • the dosage of the blood ammonia regulator is appropriately set according to, for example, the dosage form, patient age, sex, disease severity, and administration method, and is usually 0.01 to 7 in terms of ⁇ -cyclodextrin. 5 g / kg (body weight) / day, preferably 0.05 to 3 g / kg (body weight) / day, more preferably 0.05 to 2 g / kg (body weight) / day.
  • the blood ammonia regulator may be administered either by single dose or once or several doses per day.
  • the blood ammonia regulator of this embodiment containing ⁇ -cyclodextrin as an active ingredient sufficiently reduces the blood ammonia concentration or sufficiently suppresses the blood ammonia concentration from rising without side effects.
  • the blood ammonia adjusting agent is useful as a therapeutic or prophylactic agent for hyperammonemia, and is also useful as a therapeutic or prophylactic agent for hepatic encephalopathy.
  • ⁇ -cyclodextrin which is an active ingredient of a blood ammonia regulator, has a weaker sweetness than lactulose and lactitol. Therefore, the blood ammonia regulator is less likely to cause disgust or nausea when taken.
  • the blood ammonia regulator is preferably formed as a preparation for oral administration or enteral administration.
  • the ⁇ -cyclodextrin in the blood ammonia adjusting agent acts reliably in the intestinal tract, so that the blood ammonia concentration is efficiently reduced or efficiently suppressed.
  • ⁇ -Cyclodextrin is safe enough to be evaluated by the World Food Additives Joint Expert Meeting (JECFA) as it is not necessary to specify an acceptable daily intake (ADI). Therefore, the blood ammonia adjusting agent can be used as a food and drink with high biological safety, and can be safely and continuously ingested.
  • JECFA World Food Additives Joint Expert Meeting
  • the blood ammonia regulator is preferably used as a food or drink for hyperammonemia patients or hepatic encephalopathy patients. In this case, daily intake of the blood ammonia regulator is useful for the treatment of hyperammonemia patients or hepatic encephalopathy patients.
  • the blood ammonia adjusting agent formed as a solid agent or a solid food contains ⁇ -cyclodextrin in an amount of preferably 10 to 100% by mass, more preferably 50 to 100% by mass.
  • the intake of a relatively small amount of blood ammonia regulator can sufficiently reduce the blood ammonia concentration or sufficiently suppress the blood ammonia concentration from rising.
  • the blood ammonia regulator is not limited to human administration, and may be administered to non-human animals.
  • domestic animals such as horses, cows and pigs, and domestic animals such as chickens, dogs and cats. It may be administered to pets such as rats and mice.
  • Production Example 1 10 g of ⁇ -cyclodextrin (product name W6 manufactured by Cyclochem) was dissolved in purified water to prepare a blood ammonia adjusting agent in a liquid dosage form with a total volume of 100 mL.
  • Production Example 2 500 g of ⁇ -cyclodextrin, 25 g of anhydrous citric acid (Japanese pharmacopoeia product), and 15 g of hydroxypropylcellulose (Japanese pharmacopoeia product) were uniformly mixed, and 70 mL of distilled water was added and granulated. The obtained granules were dried at 60 ° C. for 2 hours and then passed through a 24-mesh sieve, and the granules passed through the sieve were collected to prepare a solid dosage form of a blood ammonia regulator. The obtained blood ammonia adjusting agent was filled and sealed in an aluminum laminated stick bag in an amount of 3.5 g.
  • Production Example 4 5 g of ⁇ -cyclodextrin (product name W6 manufactured by Cyclochem) was dissolved in purified water to prepare a blood ammonia adjusting agent in a liquid dosage form with a total volume of 100 mL.
  • Test Example 1 Verification of blood ammonia lowering effect by ⁇ -cyclodextrin in normal rats (Part 1) (1) Administration of blood ammonia regulator 6 weeks old SD male rats (purchased from Japan SLC) were acclimated for 3 days or more, and then into three administration groups: experimental group, comparative group, and control group. Separately, it was used for the administration experiment. The number of individuals in each group was 6-7. For rats in the experimental group, once between 8 am and 10 pm in the morning and once between 15 pm and 18 pm in the free drinking with the standard purified diet AIN-93G Twice per day, the blood ammonia adjusting agent obtained in Production Example 1 was orally administered using a rat oral sonde at a dose of 1.5 g / kg (body weight) per administration.
  • distilled water was administered in the same manner as in the experimental group at a dose of 15 mL / kg (body weight) per administration instead of the blood ammonia adjusting agent.
  • a distilled aqueous solution containing 10% lactitol product name: Poltrac manufactured by Nippon Shinyaku Co., Ltd.
  • blood ammonia regulator was added at 15 mL / kg (body weight) per administration. The dose was administered as in the experimental group.
  • the ammonia concentration in portal vein plasma measured in the experimental group was lower than the ammonia concentration in portal vein plasma measured in the control group and the comparison group.
  • the ammonia concentration in the jugular vein plasma measured in the experimental group was not different from the ammonia concentration in the jugular vein plasma measured in the control group and the comparative group. From the above, it was confirmed that the blood ammonia regulator has a function of selectively lowering the ammonia concentration in the portal vein plasma even when administered for a relatively short period of 3.5 days. Therefore, the blood ammonia regulator is expected to be effective for the treatment and prevention of hyperammonemia.
  • Test Example 2 Verification of blood ammonia lowering effect by ⁇ -cyclodextrin in normal rats (Part 2) (1) Administration of blood ammonia regulator 9 weeks old SD male rats (purchased from Charles River Japan) after an acclimatization period of 3 days or more, experimental group, first comparative group, second comparative group, The administration experiment was divided into four administration groups of the control group. The number of individuals in each group was 7. For rats in the experimental group, once between 8 am and 10 am in the morning and 15:00 in the evening under free drinking with the mouse, rat and hamster feed CRF-1 manufactured by Oriental Yeast Co., Ltd.
  • the ammonia concentration in the portal vein plasma measured in the experimental group was lower than the ammonia concentration in the portal vein plasma measured in the control group, the first comparison group and the second comparison group. It was. On the other hand, the ammonia concentration in the jugular vein plasma measured in the experimental group was not different from the ammonia concentration in the jugular vein plasma measured in the control group, the first comparison group and the second comparison group. Based on the above, methylated ⁇ -cyclodextrin and ⁇ -cyclodextrin belonging to the same cyclodextrin as ⁇ -cyclodextrin contained in the blood ammonia regulator have the function of reducing the ammonia concentration in portal vein plasma. Not confirmed.
  • Test Example 3 Verification of blood ammonia lowering effect by ⁇ -cyclodextrin in rats with porto-caval shunt (PCS) (Part 1) (1) Preparation of PCS rats 6-week-old Crl: CD (SD) male rats (purchased from Charles River Japan) were fasted overnight after 3 days of acclimatization period, and the day after ether anesthesia An incision was made in the abdomen to the sphenoid process. A part of the liver was turned over and taken out on the chest, and the gastrointestinal tract was taken out on the left ventral side.
  • PCS porto-caval shunt
  • the abdominal vena cava was peeled from the upper branch of the right renal vein to the lower branch of the left renal vein, and a suture for cigarette suture (drawstring suture) was put on the anastomosis near the portal vein.
  • the portal vein portion of about 2 cm was completely peeled from the liver inflow side.
  • the part of the detached portal vein and the splenic vein were clipped, and the portal vein on the liver side was ligated.
  • the site of the portal vein 1 to 2 mm away from the ligation part toward the digestive tract was lightly ligated.
  • the portal vein was blocked between the two ligatures, and the intestinal portal vein was passed through the anastomosis button.
  • the portal vein that came out on the groove side of the anastomosis button was fixed to the groove of the button with a suture.
  • Arterial clips were applied between the abdominal vena cava and the right renal vein, and between the abdominal vena cava and the left renal vein, respectively, and the central part of the tobacco suture was incised to insert an anastomosis button.
  • the anastomosis button was anastomosed and fixed to the abdominal vena cava with a suture thread that had been put in advance.
  • the blood in the abdominal cavity was washed and removed, ampicillin solution was dropped into the anastomosis, the digestive tract and the liver were returned to the abdominal cavity, and then the abdominal muscle and skin were sutured back to the original.
  • ampicillin (titer 50 mg) was injected intramuscularly for the purpose of preventing infection.
  • PCS rats prepared as described above were subjected to administration experiments in 2 to 4 days after the operation, divided into two administration groups, an experimental group and a control group.
  • the number of individuals in each group was 3.
  • the blood ammonia adjusting agent obtained in Production Example 4 was used as drinking water under free feeding of the mouse / rat / hamster feed CRF-1 manufactured by Oriental Yeast Co., Ltd. It was given in a drinking bottle with a nozzle set.
  • distilled water was given as drinking water instead of the blood ammonia regulator.
  • the ammonia concentration in the jugular vein plasma measured in the control group increased with time.
  • the ammonia concentration in the jugular vein plasma measured in the experimental group hardly changed over time. From the above, it is expected that the blood ammonia regulator is effective for the treatment and prevention of hyperammonemia.
  • Test Example 4 Verification of blood ammonia lowering effect of ⁇ -cyclodextrin in the portal vein cava (porto-caval shunt (PCS)) rat (Part 2) (1) Preparation of PCS rat In the same manner as in Test Example 3, except that a 6-week-old SD male rat purchased from Japan SLC was used instead of a rat purchased from Charles River Japan. PCS rats were created.
  • PCS portal vein cava
  • the PCS rat prepared as described above was subjected to administration experiments 14 days after the operation, divided into two administration groups, a first experimental group and a second experimental group.
  • the number of individuals in each group was 3.
  • rats in the first experimental group distilled water was used until 11 am on the 6th day after the start of the administration experiment under free feeding with the mouse / rat / hamster feed CRF-1 manufactured by Oriental Yeast Co., Ltd. Thereafter, the blood ammonia adjusting agent obtained in Production Example 4 was given as drinking water in a drinking bottle with a nozzle set in a breeding cage.
  • the rats in the second experimental group were given the blood ammonia adjusting agent obtained in Production Example 4 until 11 am on the sixth day after the start of the administration experiment, and thereafter distilled water as drinking water.
  • the ammonia concentration in the jugular vein plasma measured in the first experimental group was at a relatively high level during the period when the first distilled water was administered. It decreased immediately after the start of administration of the conditioning agent.
  • the ammonia concentration in the jugular vein plasma measured in the second experimental group was kept at a relatively low level during the period when the first blood ammonia adjusting agent was administered. After finishing the administration of the drug, it started to increase after a while. From the above, it is expected that the blood ammonia regulator is effective for the treatment and prevention of hyperammonemia.

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Abstract

La présente invention concerne un régulateur de niveau d’ammoniac dans le sang comportant une α-cyclodextrine en tant que principe actif. Le régulateur de niveau d’ammoniac dans le sang peut être utilisé comme un agent thérapeutique pour l’hyperammonémie ou l’encéphalopathie hépatique. Le régulateur de niveau d’ammoniac dans le sang peut également être utilisé comme agent prophylactique l’hyperammonémie ou l’encéphalopathie hépatique. Le régulateur de niveau d’ammoniac dans le sang peut être préparé sous la forme d’une formulation pour l’administration orale ou entérale.
PCT/JP2009/056201 2008-03-31 2009-03-26 Régulateur de niveau d’ammoniac dans le sang WO2009123029A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011103822A (ja) * 2009-11-18 2011-06-02 Fujifilm Corp コラーゲンペプチド含有飲料
JP2018523978A (ja) * 2015-06-10 2018-08-30 シンロジック オペレーティング カンパニー インコーポレイテッド 高アンモニア血症に関連する疾患を治療するために操作された細菌
US11160826B1 (en) 2017-03-03 2021-11-02 United States Government As Represented By The Department Of Veterans Affairs Cholesterol lowering drugs for the treatment of hepatic encephalopathy

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