[go: up one dir, main page]

WO2006015546A1 - Utilisation de bicyclol pour produire un medicament capable de prevenir et/ou traiter l’alcoolisme aigu et une lesion d’intestin d’alcoolisme aigu ou chronique - Google Patents

Utilisation de bicyclol pour produire un medicament capable de prevenir et/ou traiter l’alcoolisme aigu et une lesion d’intestin d’alcoolisme aigu ou chronique Download PDF

Info

Publication number
WO2006015546A1
WO2006015546A1 PCT/CN2005/001236 CN2005001236W WO2006015546A1 WO 2006015546 A1 WO2006015546 A1 WO 2006015546A1 CN 2005001236 W CN2005001236 W CN 2005001236W WO 2006015546 A1 WO2006015546 A1 WO 2006015546A1
Authority
WO
WIPO (PCT)
Prior art keywords
bicyclol
ethanol
liver
mice
acute
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2005/001236
Other languages
English (en)
Chinese (zh)
Inventor
Yan Li
Chunzhen Zhang
Gengtao Liu
Ye Li
Huailing Wei
Wei Hu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Materia Medica of CAMS and PUMC
Original Assignee
Institute of Materia Medica of CAMS and PUMC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Materia Medica of CAMS and PUMC filed Critical Institute of Materia Medica of CAMS and PUMC
Publication of WO2006015546A1 publication Critical patent/WO2006015546A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • the present invention relates to the use of bicyclol for the preparation of a medicament for the prevention or treatment of acute alcoholism and acute or chronic alcoholic liver injury.
  • Alcoholic liver disease can be divided into alcoholic fatty liver, alcoholic hepatitis, alcoholic cirrhosis and alcoholic cirrhosis with liver cancer according to its pathological changes.
  • alcoholic liver disease has gradually increased in China, and it is currently the second largest liver disease after viral hepatitis.
  • the main clinical measure for the treatment of alcoholic liver disease is abstinence, and the types of drug treatment are very limited. Therefore, it is still necessary to find effective and safe drugs against alcoholic liver disease.
  • bicyclol in addition to the effect of lowering serum transaminase, bicyclol has both an effect of improving serum albumin/globulin ratio and liver proline content, ie, reducing liver The role of fibrosis.
  • Bicyclol has the effect of inhibiting the secretion of hepatitis B virus core antigen (HBeAg), hepatitis B virus ribonucleic acid (HBV-DNA) and hepatitis B virus surface antigen (HbsAg). No toxicity or no teratogenicity was observed in the long-term chronic toxicity test. The toxicity of the mutation.
  • bicyclol has a good effect on clinical symptoms and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in patients with chronic viral hepatitis B and hepatitis C, and can make HBeAg, HBV-DNA is negative. Significantly no significant side effects, good safety and tolerability. Bicyclol was awarded the new drug certificate by the State Drug Administration in 2001 under the trade name "Bai Sainuo 8" and was officially put on the market in October 2001.
  • the invention establishes a model of acute alcoholism and acute and chronic alcoholic liver injury, observes the protective effect of bicyclol on alcoholism and alcoholic liver injury and explores its mechanism of action. The results show that bicyclol has a good protective effect on experimental acute alcoholism and acute and chronic liver injury.
  • the present invention records the disappearance time and mortality of the righting reflex of the mouse by orally administering a toxic dose of ethanol (50%, 12-24 ml/kg) or a 5% Liber-Decarli feed to the mouse.
  • Alanine aminotransferase (ALT), triglyceride (TG), cholesterol (CHOL), high-density lipoprotein (HDL) and low-density lipoprotein LDL levels cholesterol (CHOL), high-density lipoprotein (HDL) and low-density lipoprotein LDL levels
  • liver lipid peroxidation product malondialdehyde (MDA) production and antioxidant Glutathione (GSH) content liver mitochondrial membrane fluidity and swelling
  • liver glutathione-thiol transferase (GST) activity serum alcohol dehydrogenase (ADH), acetaldehyde dehydrogenase (ALDH)
  • serum ethanol concentration liver NDMA-demethylase activity and pathological changes.
  • bicyclol 150-300mg/kg can significantly reduce serum ALT caused by ethanol, increase of liver MDA and TG, CHOL, LDL, reduce the decrease of liver GSH and GST, and inhibit the mitochondrial membrane flow induced by ethanol. Decreased sex and increased mitochondrial swelling, significantly induced HDL, ADH and ALDH, inhibited elevated NDMA-demethylase activity, and decreased blood ethanol concentration. In addition, bicyclol can shorten the disappearance of dysregulation caused by ethanol poisoning and reduce mortality.
  • the present invention can draw the following conclusions: Oral administration of bicyclol can significantly reduce mouse death and liver damage caused by ethanol poisoning, improve hepatic steatosis, protect and induce anti-oxidation GST and GSH in vivo, and improve hepatocyte resistance Oxidative capacity, protection against mitochondrial damage and function, regulation of drug metabolism enzymes involved in ethanol metabolism, and reduction of blood alcohol concentration are closely related.
  • the present invention finds the protective effect of bicyclol on acute ethanol poisoning mice.
  • the effect of bicyclol on the prolongation of sleep time in mice with acute alcoholism was examined.
  • Test animals After the administration of 50% ethanol at 16 ml/kg, the disappearance and recovery time of the righting reflex of the mice were observed, and the interval time was determined as the sleep time.
  • the results showed that after oral administration of ethanol, the sleep time of the mice was as long as 3.6 hours, and bicyclol can significantly shorten the sleep time caused by ethanol, and showed a good dose-effect relationship.
  • the average sleep time of the high-dose group was only the model group. 10%.
  • Bicyclol can reduce the effects of ethanol poisoning on mouse death.
  • the test animals were intragastrically administered with 50% ethanol 24 ml/kg, and the number of deaths of 8, 12, 24 small animals was recorded after ethanol administration.
  • Oral bicyclol can significantly reduce the mortality of mice poisoned by alcohol.
  • Bicyclol has a protective effect on acute liver injury induced by ethanol in mice.
  • Bicyclol has a protective effect on the pathological changes of acute alcoholic liver injury in mice. After 10 days of infusion of 56% liquor, animal liver cells, mainly 1-2 layers of hepatocytes around the central vein, showed swelling and rounding. Hepatocyte cytoplasm was loose, and some vacuoles were formed in the liver cytoplasm, but the liver cell nucleus was not obvious. change. Nearly half of the model group animals showed necrosis of small focal hepatocytes (3-5 hepatocytes) and small focal inflammatory cell infiltration. However, there was no obvious hepatocyte injury in bicyclol animals, and there was no significant difference compared with the normal control group.
  • bicyclol can reduce the elevated blood alcohol concentration by 31%.
  • bicyclol significantly induced liver ADH and ALDH activity, which were 215% and 122% of the normal control group, respectively, and inhibited DMA-demethylase activity with an inhibition rate of 21%.
  • Bicyclol significantly improves the increase in the degree of polarization and microviscosity of the mitochondrial membrane caused by alcohol.
  • the swelling of liver mitochondria is significantly increased under high calcium conditions, and bicyclol can significantly reduce mitochondrial swelling and maintain it at a normal level, thus ensuring the normal function of mitochondria.
  • mice After 4 weeks of feeding with alcohol-containing liquid diet, the mice showed not only a significant increase in liver TG content, but also a slight increase in serum CHOL, LDL, and HDL.
  • the liver TG, serum CHOL, LDL levels in the drug-administered group decreased significantly, and serum HDL levels increased significantly, suggesting that bicyclol can effectively prevent alcohol-induced fat accumulation, accelerating fat-transporting mice after long-term administration of alcohol-containing diet.
  • the GSH content in the liver decreased, but also the GST and glutathione reductase (GR) activities were significantly reduced.
  • the GSH level and GST activity in the liver of the mice returned to normal levels, and the GR activity increased to 1.2 in the control group. Times.
  • the above results suggest that bicyclol has the function of promoting GSH regeneration and enhancing liver free radical scavenging ability.
  • bicyclol can significantly inhibit the increase in P450 2E1 activity caused by long-term alcohol intake, keeping the enzyme at a normal level. Similar to the results of acute alcoholic liver injury, bicyclol significantly induced ALDH activity, especially in cytosolic ALDH activity (2.9 times that of the model group), accelerated acetaldehyde clearance, thereby alleviating liver damage caused by acetaldehyde. In addition, bicyclol has no effect on ADH.
  • Bicyclol has a protective effect on pathological changes of chronic alcoholic liver injury.
  • the mice were fed with 5% alcoholic liquid feed for 4 weeks, which caused hepatic steatosis, and the hepatic steatosis of the central lobular lobule was the most severe. Hepatocytes around some central lobular veins are swollen and the cytoplasm is loose. In addition, hepatic venous congestion and other phenomena were observed. After administration of bicyclol, hepatic cell steatosis was significantly alleviated, and hepatocyte swelling did not occur.
  • compositions of the invention further relates to pharmaceutical compositions comprising bicyclic alcohol conventional pharmaceutical excipients or adjuvants as an active ingredient of a pharmaceutical composition
  • P compositions of the invention generally comprises 0.5 95% by weight of bicyclic alcohols.
  • compositions containing the compounds of the invention can be prepared according to methods well known in the art.
  • the compounds of the invention may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants, if desired, in a suitable form or dosage for use as a human or veterinary drug. form.
  • the compound of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as orally, muscle, nasal cavity, oral mucosa, skin, transdermal, subcutaneous, intradermal, peritoneal. , rectal, intravenous, intramuscular, intrathecal, epidural, intraocular, intracranial, vaginal administration, etc.
  • injections include intravenous, intramuscular, subcutaneous, intradermal, acupoint, intrathecal, and intraperitoneal injections.
  • the dosage form can be a liquid dosage form or a solid dosage form.
  • the solution properties of the liquid dosage form may be true solutions, colloids, microparticulate forms, emulsion dosage forms, suspension dosage forms.
  • the liquid dosage form may be a syrup, an elixir, an injection solution, a non-aqueous solution, a suspension or an emulsion; a solid dosage form such as a tablet, a lozenge, a capsule, a dropping pill, a pill, a granule, a powder, a cream, a solution Liquid, suppository, dispersible powder such as lyophilized powder injection, aerosol, and the like.
  • the compounds of the present invention can be formulated into common preparations, sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • the carrier include, excipients such as calcium carbonate, lactose, calcium phosphate, sodium phosphate; diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, Calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, dextran, colloidal silica, gum arabic, gelatin, magnesium trisilicate, keratin, etc.; wetting agent and binder such as water, glycerin, Polyethylene glycol, ethanol, propanol, starch syrup, dextrin, syrup, honey, glucose solution, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyethylene Pyrrolidone or the like; a disintegrating agent such as dried starch, alginate,
  • Tablets may also be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets to delay disintegration and absorption in the gastrointestinal tract. And thus provide a lasting effect over a longer period of time.
  • a carrier for example, a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc.; binders such as acacia, tragacanth, Gelatin, ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, and the like.
  • a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc.
  • binders such as acacia, tragacanth, Gelatin, ethanol, honey, liquid sugar, rice paste or batter
  • disintegrating agents such as agar powder, dried starch, alginate, sodium dodecy
  • the active ingredient compound of the present invention is mixed with the above various carriers, and the mixture thus obtained is placed in a hard gelatin capsule or soft capsule.
  • the active ingredient of the compound of the present invention can also be formulated into a microcapsule, suspended in an aqueous medium to form a suspension, or can be incorporated into a hard capsule or used as an injection.
  • the administration unit in order to prepare the administration unit into an oral liquid preparation, it includes an emulsion, a solution, a suspension, a syrup, and the like.
  • Suitable carriers include solutions, suspensions, syrups and the like, and optionally contain additives such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfumes.
  • the compound of the present invention is formulated into an injectable preparation such as a solution, a suspension solution, an emulsion, or a lyophilized powder injection, which may be aqueous or non-aqueous, and may contain one and/or more drugs.
  • a pharmaceutically acceptable carrier, diluent, binder, lubricant, preservative, surfactant or dispersing agent may be aqueous or non-aqueous, and may contain one and/or more drugs.
  • the diluent may be selected from the group consisting of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, vegetable oils such as olive oil and corn oil, gelatin, and Injectable organic esters such as ethyl oleate, polyoxyethylene sorbitol, fatty acid esters and the like.
  • Such dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional cosolvent, a buffer, a pH adjuster or the like may be added. These excipients are commonly used in the art.
  • a coloring agent a preservative, a flavoring agent, a flavoring agent such as peppermint, wintergreen oil or the like, a sweetener such as sucrose, lactose, saccharin or the like or other materials may be added to the pharmaceutical preparation.
  • the sterile medium used in the present invention can be prepared by standard techniques well known to those skilled in the art. They may be sterilized, for example, by filtration through a bacterial filter, by adding a sterilizing agent to the composition, by radiation treatment of the composition, or by heating the composition. They can also be made into sterile injectable media before use.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of enhancing the therapeutic effect for the purpose of administration.
  • the route of administration of the compounds used in the practice of the invention will depend on the disease and the site in need of treatment. Because the pharmacokinetic and pharmacodynamic characteristics of the compounds of the invention will vary to some extent, the most preferred method of obtaining therapeutic concentrations in tissues is to gradually increase the dose and monitor the clinical effect. For such a gradual increase in therapeutic dose, the initial dose will depend on the route of administration.
  • the particular therapeutically effective dose level of a pharmaceutical composition of a compound of the invention will depend on a number of factors, such as the nature of the disease to be prevented or treated, the severity of the route of administration, the number of administrations, the purpose of treatment, the clearance of the compound, for any particular patient. Speed, duration of treatment, specific drugs in combination with or in combination with the specific compound, patient or animal gender, age, weight, personality, diet, individual response, and general health status, etc., are well known factors in the field of medical science, and thus the treatment of the present invention
  • the dosage can vary widely. Depending on the condition of the patient being treated, certain changes in dosage may be necessary, and in any event, the physician will determine the appropriate dosage for the individual patient.
  • the dose administered refers to the weight of the compound excluding the weight of the carrier (when the carrier is used).
  • the dosages of the pharmaceutical ingredients employed in the present invention are well known to those skilled in the art.
  • the prophylactic or therapeutic effect of the present invention can be accomplished by appropriately adjusting the amount of the actual drug contained in the final formulation of the compound composition of the present invention to achieve its therapeutically effective amount. It may be administered in a single dosage form or divided into several, for example two, three or four dosage forms; this is limited by the clinical experience of the administering physician and the dosing regimen including the use of other therapeutic means.
  • the compounds or compositions of this invention may be administered alone or in combination with other therapeutic or symptomatic agents and adjusted in dosage.
  • ALT alanine aminotransferase
  • HDL high density lipoprotein
  • DL low density lipoprotein
  • MDA malondialdehyde
  • GSH glutathione
  • ADH alcohol dechlorination enzyme
  • NDMA-DH dimethyl nitrosamine-demethylase
  • GR Glutathione Reductase Figure 1 Figure 1. Effect of bicyclol on ethanol-induced sleep in mice
  • Figure 4 Effect of bicyclol on serum ALT elevation in mice with chronic alcoholic liver injury. The results are expressed as mean SD.
  • M ethanol group
  • T2/3 bicyclol (200/300 mg/kg) treatment group
  • Y2/3 Bicyclol (200/300 mg/kg) prevention group.
  • Figure 5 Effect of bicyclol on liver TG elevation in mice with chronic alcoholic liver injury. The result is the average value of SD.
  • M Ethanol T2/3: (200/300 mg/kg) bicyclol treatment
  • Y2/3 bicyclol (200/300 mg/kg) prevention.
  • P ⁇ 0.01 Compared with the control group, *P ⁇ 0.05, **P ⁇ 0.01 compared with the model group.
  • Figure 6 Effect of bicyclol on the decline of liver GSH in mice with chronic alcoholic liver injury. The result is the average value of SD.
  • M ethanol T2/3: (200/300 mg/kg) bicyclol treatment, Y2/3: bicyclol (200/300 mg/kg) prevention, Herp PO.01 compared with the control group, *P ⁇ 0.05, ** P ⁇ 0.01 compared to the model group.
  • Figure 8 Effect of bicyclol on liver GR decline in mice with chronic alcoholic liver injury. The result is the mean soil SD.
  • M ethanol T2/3: (200/300 mg/kg) bicyclol treatment, Y2/3: bicyclol (200/300 mg/kg) prevention, ## P ⁇ 0.01 compared with the control group, * P ⁇ 0.05 , ** P ⁇ 0.01 compared to the model group.
  • Figure 9 Effect of bicyclol on the activity of hepatic cytosolic NDMA-DH in mice with chronic alcoholic liver injury. The result is the average value of SD.
  • M Ethanol T2/3: (200/300 mg/kg) bicyclol treatment
  • Y2/3 bicyclol (200/300 mg/kg) prevention.
  • P ⁇ 0.01 compared with the control group *P ⁇ 0.05, **P ⁇ 0.01 compared with the model group.
  • mice Male Kunming mice, weighing 22-24 g, were randomly divided into 4 groups, 10 in each group, 3 of which were given oral bicyclol 75, 150, 300 mg/kg o in the afternoon of the first day of the experiment and the next day. Give the same volume of excipients. After fasting overnight, the animals in each group were intragastrically administered with 50% ethanol and 16 ml/kg. The disappearance of the righting reflex and the recovery time of the mice after oral ethanol were observed, and the interval was determined as the sleep time.
  • mice Male Kunming mice, weighing 22-24 g, were randomly divided into 4 groups, 10 in each group, 3 of which were given oral bicyclol 100, 200 in the afternoon of the first day of the experiment and the afternoon of the next day.
  • mice As shown in Figure 1, after oral administration of alcohol, the mortality rate of mice at 8, 12, 24 hours was 60%, 80%, respectively.
  • Oral bicyclol (200, 300 mg/kg) significantly reduced mortality in mice poisoned with alcohol.
  • mice Male Kunming mice, weighing 22-24 g, were randomly divided into 5 groups, 10 in each group, 3 of which were given oral bicyclol 75, 150, 300 mg/kg on the afternoon of the first day of the experiment and the next day. Give the same volume of excipients. After fasting overnight in each group of animals, except for the normal control group, the other groups were given 50% ethanol 12 ml/kg, and the control group was given 20% glucose solution of the same energy. Animals were sacrificed 6 hours after ethanol administration, serum was taken for ALT determination, and liver was taken for determination of TG, MDA and GSH and GST content.
  • liver TG increased to 1.3 times that of normal controls, serum ALT was also significantly increased (1.8 times), and MDA production reflecting lipid peroxidation damage increased, while liver antioxidants GSH and GST fell to 87% and 77%, respectively.
  • Bicyclol 75, 150, 30 s0 mg/kg significantly inhibited the increase in sALT caused by ethanol and the decrease in liver GSH.
  • bicyclol 150, 300 mg/kg can also reduce elevated liver TG and MDA
  • bicyclol can induce liver GST and increase the body's antioxidant energy S.
  • Bicyclol 150 226.6 soil 30.70 soil 41.30 soil 6.41 ⁇ 0.84
  • mice Male Kunming mice, weighing 22-24 grams, were randomly divided into 3 groups, 7 in each group.
  • the drug-administered group was orally administered bicyclol 300 mg/kg on the afternoon of the first day of the experiment and the next day, and the control group was given the same volume of excipients. Animals in each group were fasted overnight after the last dose. The next day, except for the normal control group, the other animals received oral 50% ethanol 16ml/kg. The animals were sacrificed 1 hour after the ethanol was given, and blood was taken to determine the ethanol content. The results showed that after oral administration of ethanol, the blood ethanol increased rapidly, which is 35 times that of normal control. Bicyclol can reduce elevated blood ethanol concentrations by 31%.
  • mice Male Kunming mice, weighing 22-24 grams, were randomly divided into 2 groups, 10 in each group.
  • the drug-administered group was orally administered bicyclol 300 mg/kg on the afternoon of the first day of the experiment and the next day, and the control group was given the same volume of excipients. Animals in each group were fasted overnight after the last dose. The animals were decapitated the next morning and the liver was assayed for ADH, ALDH and NDMA demethylase activity.
  • the results showed that bicyclol significantly induced ADH and ALDH activity in the liver, which were 215% and 122% of the normal control group, respectively, and inhibited NDMA-demethylase activity with an inhibition rate of 21%.
  • Table 3 Effect of bicyclol on ADH, ALDH and NDMA-demethylase activity in mouse liver
  • mice Male Kunming mice, weighing 22-24 grams, were randomly divided into four groups of 10 animals each. After mice were intragastrically administered with 56° liquor 10ml/kg for 10 days, the swelling of liver mitochondria was significantly increased under high calcium conditions, while bicyclol (200, 300mg/kg) significantly reduced mitochondrial swelling, which was basically maintained at normal levels. Thereby ensuring the normal function of the mitochondria.
  • the results are shown in Figure 3. III. Protective effect of bicyclol on chronic alcoholic liver injury in mice.
  • Example 7 Effect of bicyclol on serum ALT elevation in mice with chronic alcoholic liver injury
  • Male Kunming mice weighing 22-24 g They were randomly divided into six groups of 10 each. After 4 weeks of feeding in a 5% alcoholic liquid diet, serum ALT levels increased significantly.
  • mice After 4 weeks of feeding with alcohol-containing liquid diet, the mice showed not only a significant increase in liver TG content, but also a slight increase in serum CHOL, LDL, and HDL. Compared with the model group, liver TG, serum CHOL, LDL levels were significantly decreased, and serum HDL levels were significantly increased, suggesting that bicyclol can effectively prevent alcohol-induced fat accumulation and accelerate fat transport. See Figure 5
  • the superoxide anion produced by this metabolic process can form hydroxyl groups under the catalysis of magnesium ions. It has been confirmed that the MEOS metabolic alcohol process relies on cytochrome P450 2 E1. The long-term word of experimental animals with ethanol, induced the expression of P450 2E1 enhanced, which can further lead to lipid peroxidation and aggravate liver damage. .
  • P450 2E1 activity was indirectly determined by measuring NDMA-DH. Studies have found that bicyclol can significantly inhibit the increase in P450 2E1 activity caused by long-term alcohol intake, keeping the enzyme at a normal level.
  • bicyclol significantly induced ALDH activity, especially in cytosolic ALDH activity (2.9 times that of the model group), accelerated acetaldehyde clearance, thereby alleviating liver damage caused by acetaldehyde.
  • bicyclol has no effect on ADH. Effects of bicyclol on serum ADH and ALDH levels in mice with chronic alcoholic liver injury
  • mice After 4 weeks of feeding 5% alcoholic liquid diet, the mice can cause hepatic steatosis, and the hepatic cells in the central lobular veins are most severely fatty. Although the liver cells around the central vein of some small leaves did not undergo steatosis, the hepatocytes were swollen and the cells were loose. In addition, liver was also observed Dirty venous congestion and other phenomena. After administration of bicyclol, hepatic steatosis was significantly alleviated, and hepatocyte swelling did not occur.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Addiction (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention divulgue l’utilisation de bicyclol de formule (I) pour fabriquer un médicament pour prévenir ou traiter l’alcoolisme aigu et une blessure intestinale d’alcoolisme aigu ou chronique.
PCT/CN2005/001236 2004-08-11 2005-08-11 Utilisation de bicyclol pour produire un medicament capable de prevenir et/ou traiter l’alcoolisme aigu et une lesion d’intestin d’alcoolisme aigu ou chronique Ceased WO2006015546A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200410058309.2 2004-08-11
CNB2004100583092A CN100364526C (zh) 2004-08-11 2004-08-11 双环醇在制备预防和/或治疗急性酒精中毒和急慢性酒精性肝损伤药物中的应用

Publications (1)

Publication Number Publication Date
WO2006015546A1 true WO2006015546A1 (fr) 2006-02-16

Family

ID=35839140

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2005/001236 Ceased WO2006015546A1 (fr) 2004-08-11 2005-08-11 Utilisation de bicyclol pour produire un medicament capable de prevenir et/ou traiter l’alcoolisme aigu et une lesion d’intestin d’alcoolisme aigu ou chronique

Country Status (2)

Country Link
CN (1) CN100364526C (fr)
WO (1) WO2006015546A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112755192A (zh) * 2019-10-21 2021-05-07 北京协和药厂 双环醇类化合物在制备用于预防或治疗动脉粥样硬化疾病的药物中的应用和药物组合物
CN114869901A (zh) * 2022-05-06 2022-08-09 安徽医科大学 马鞭草苷在治疗酒精性肝损伤药物中的应用
CN116178494A (zh) * 2023-03-30 2023-05-30 郑州大学 一种解酒多肽

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101524329B (zh) * 2007-09-20 2014-09-03 中国医学科学院药物研究所 双环醇亚微乳及其制备方法
CN103923077B (zh) * 2013-07-05 2016-03-02 高尔医药科技(上海)有限公司 两种乙醛脱氢酶激动剂、其制备方法及用途
CN109106711A (zh) * 2017-06-23 2019-01-01 北京协和药厂 双环醇及其可药用衍生物用于预防或治疗药物性肝损伤的用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4868207A (en) * 1988-07-28 1989-09-19 Taisho Pharmaceutical Co., Ltd. Bis (methylenedioxy) biphenyl compounds useful for the treatment of liver diseases
CN1506363A (zh) * 2002-12-12 2004-06-23 中国医学科学院药物研究所 光活双环醇及其制备方法和其药物组合物与用途
CN1608620A (zh) * 2003-10-23 2005-04-27 中国医学科学院药物研究所 双环醇固体分散体
CN1608621A (zh) * 2003-10-23 2005-04-27 中国医学科学院药物研究所 双环醇微粉化及口服控释制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4868207A (en) * 1988-07-28 1989-09-19 Taisho Pharmaceutical Co., Ltd. Bis (methylenedioxy) biphenyl compounds useful for the treatment of liver diseases
CN1506363A (zh) * 2002-12-12 2004-06-23 中国医学科学院药物研究所 光活双环醇及其制备方法和其药物组合物与用途
CN1608620A (zh) * 2003-10-23 2005-04-27 中国医学科学院药物研究所 双环醇固体分散体
CN1608621A (zh) * 2003-10-23 2005-04-27 中国医学科学院药物研究所 双环醇微粉化及口服控释制剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIU G.-T.: "The anti-virus and hepatoprotective effect of bicyclol and its mechanism of action", CHINESE JOURNAL OF NEW DRUGS, vol. 10, no. 5, 2001, pages 325 - 327 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112755192A (zh) * 2019-10-21 2021-05-07 北京协和药厂 双环醇类化合物在制备用于预防或治疗动脉粥样硬化疾病的药物中的应用和药物组合物
CN114869901A (zh) * 2022-05-06 2022-08-09 安徽医科大学 马鞭草苷在治疗酒精性肝损伤药物中的应用
CN114869901B (zh) * 2022-05-06 2023-10-27 安徽医科大学 马鞭草苷在治疗酒精性肝损伤药物中的应用
CN116178494A (zh) * 2023-03-30 2023-05-30 郑州大学 一种解酒多肽

Also Published As

Publication number Publication date
CN1732919A (zh) 2006-02-15
CN100364526C (zh) 2008-01-30

Similar Documents

Publication Publication Date Title
RU2498795C2 (ru) Способы лечения неалкогольного стеатогепатита (nash) с применением цистеаминовых продуктов
JP5214628B2 (ja) メタドキシンとニンニク油を含有するアルコール性脂肪肝並びに脂肪肝性肝炎の予防及び治療用薬学組成物
US20080249168A1 (en) Pharmaceutical composition for gout
KR102000332B1 (ko) 간내 담즙정체성 질환의 치료
US20210322407A1 (en) Use of Trimetazidine in Preparation of Drugs for Preventing and Treating Liver Diseases
WO2012000377A1 (fr) Composition pharmaceutique contenant de la lévocarnitine et du dobésilate
JP2022514152A (ja) Ｉｖ型コラーゲン疾患の処置のためのビフェニルスルホンアミド化合物
KR20010091012A (ko) 올티프라즈의 간섬유화 및 간경화 진행의 예방 및치료제로서의 용도 및 올티프라즈를 주성분으로 함유하는제약 조성물
WO2006015546A1 (fr) Utilisation de bicyclol pour produire un medicament capable de prevenir et/ou traiter l’alcoolisme aigu et une lesion d’intestin d’alcoolisme aigu ou chronique
TW200534852A (en) 4-methylpyrazole formulations for inhibiting ethanol intolerance
US20120277318A1 (en) Non-steroidal anti-inflammatory drugs for cough
CN116509841B (zh) 一种抗肿瘤组合物、脂质体、制备方法和用途
CN115607545B (zh) 依达拉奉在自闭症谱系障碍治疗中的应用
JP2010083871A (ja) 抗アデノウイルス剤を含有する医薬組成物
CN104490876A (zh) 盐酸小檗碱在制备预防和/或治疗急性肝衰竭药物中的应用
WO2017084631A9 (fr) Composition pharmaceutique et méthode destinées à prévenir ou traiter le foie gras, à améliorer les pathologies provoquées par un foie gras, le diabète sucré ou d'autres maladies associées
CN113244208A (zh) Hpa在制备治疗非酒精性脂肪性肝病药物中的应用
US20060166957A1 (en) Methods of treating obesity and related disorders using tellurium selenium compounds
TWI466676B (zh) 一種大和當歸萃取物之用途
JP7418502B2 (ja) 非常に速い皮膚及び膜浸透速度を有するｎｓａｉａプロドラッグ及びその新規医薬使用
CN114767665B (zh) 5-十四烷氧基-2-呋喃甲酸在制备用于治疗银屑病样皮炎的药物中的用途
WO2019232740A1 (fr) Composition pharmaceutique destinée à prévenir le diabète et utilisation correspondante
RU2356555C2 (ru) Антинейтрофильное средство
WO2025112027A1 (fr) Utilisation de l'inhibition ciblée de p300/cbp en traitement de maladies liées à une lésion hépatique
WO2024249509A1 (fr) Sparsentan destiné à être utilisé dans une méthode de traitement de maladies médiées par iga

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase