WO2010150836A1 - Amplificateur d'activité d'analogue d'acide nucléique - Google Patents

Amplificateur d'activité d'analogue d'acide nucléique Download PDF

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WO2010150836A1
WO2010150836A1 PCT/JP2010/060703 JP2010060703W WO2010150836A1 WO 2010150836 A1 WO2010150836 A1 WO 2010150836A1 JP 2010060703 W JP2010060703 W JP 2010060703W WO 2010150836 A1 WO2010150836 A1 WO 2010150836A1
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nucleic acid
acid analog
chain amino
antiviral activity
isoleucine
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PCT/JP2010/060703
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English (en)
Japanese (ja)
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一郎 惣中
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味の素株式会社
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Priority to CN201080027706.7A priority Critical patent/CN102458417B/zh
Priority to JP2011519930A priority patent/JP5720569B2/ja
Publication of WO2010150836A1 publication Critical patent/WO2010150836A1/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the present invention relates to a nucleic acid analog activity enhancer comprising a branched chain amino acid, a prophylactic or therapeutic agent for viral hepatitis comprising a combination of a branched chain amino acid and a nucleic acid analog, a drug for viral hepatitis, and the like.
  • Hepatitis B virus (hereinafter also referred to as “HBV”) is a causative virus of hepatitis B belonging to the genus Orthohepadnavirus belonging to the Hepadnaviridae family, mainly by blood mediated, mother-child (vertical), sexual activity (horizontal) Infect. Although this persistent infection is poor in subjective symptoms, it may cause chronic hepatitis and then gradually fibrosis of the liver, resulting in cirrhosis and liver cancer. On the other hand, in the case of infection with hepatitis B virus, in principle, it is difficult to completely eliminate the virus. However, reducing the virus by applying antiviral therapy maintains liver function and cirrhosis. It is very important to prevent progression to liver failure and to prevent the development of liver cancer.
  • Lamivudine is an active ingredient of an antiviral agent developed as a therapeutic agent for HBV, and is a typical ingredient of a nucleic acid analog preparation having a nucleoside-like structure. Lamivudine was initially shown to have antiviral activity against AIDS virus, but was found to show growth inhibitory effect on HBV. The mechanism of action of lamivudine on HBV is that lamivudine phosphorylated in the cell to a triphosphate derivative inhibits the reverse transcriptase of HBV, is incorporated into the viral DNA chain, and stops its elongation (non-patented). Reference 1). Nucleic acid analogs such as lamivudine are applicable as oral preparations, have few side effects, and have antiviral activity equivalent to or higher than that of interferon.
  • nucleic acid analog preparations have a problem that virus relapse occurs with high probability when the administration is stopped.
  • semi-permanent administration of nucleic acid analogs is necessary, but even if it is administered for a long period of time, the effect will reach an early stage, and resistant virus will develop due to long-term administration.
  • disadvantages such as increased medical costs.
  • hepatitis B carriers frequently experience decreased hepatic activity in the natural course, administering a nucleic acid analog at an early stage and a long-term administration, particularly in young people, may result in over-treatment. From such a viewpoint, combination therapy with other drugs has been actively studied as a treatment strategy aiming at long-term remission with drug-free (see Non-Patent Document 2).
  • Interferon is a drug that exerts its effects through two mechanisms: direct antiviral action and activation of host immunity. Interferon has many side effects such as fever, headache, joint pain and high medical costs (see Non-Patent Document 3), but seroconversion and calming down of viral DNA lasts for a long time (see Non-Patent Document 4). Therefore, it is a powerful option for long-term remission.
  • PEG interferon and a nucleic acid analog has an effect of preventing the production of resistant virus, it has been suggested that the therapeutic results are not different from those of interferon alone (see Non-Patent Documents 5 to 7). . Accordingly, there is a need for drugs that can be used in combination with nucleic acid analogs other than IFN and that improve therapeutic results.
  • Non-Patent Document 8 It has been reported that when branched chain amino acids are applied to IFN therapy, the blood concentration decreases (see Non-Patent Document 8). In addition, it has been reported that branched chain amino acids have an action of enhancing the effect of IFN and an action of reducing side effects of IFN (see Patent Document 1). However, it has not been clarified so far that branched-chain amino acids have a function of enhancing the antiviral action of nucleic acid analogs.
  • the problem to be solved by the present invention is to provide a nucleic acid analog preparation activity enhancer and the like.
  • At least one branched-chain amino acid selected from isoleucine, leucine and valine enhances the activity of nucleic acid analog preparations and completes the present invention. did.
  • the present invention is as follows.
  • An activity enhancer for a nucleic acid analog having antiviral activity comprising at least one branched-chain amino acid selected from isoleucine, leucine and valine, or a salt thereof;
  • a prophylactic or therapeutic agent for viral hepatitis comprising a combination of at least one branched-chain amino acid selected from isoleucine, leucine and valine or a salt thereof and a nucleic acid analog having antiviral activity;
  • the activity of a nucleic acid analog preparation that bottoms out by continuous administration can be further enhanced.
  • the liver reserve ability is improved as compared with the case where the nucleic acid analog preparation is used alone, which is useful in that a treatment method for liver lesions including liver cancer can be selected more widely.
  • the present invention can provide a preventive or therapeutic agent for viral hepatitis, a pharmaceutical for treating viral hepatitis, and the like that are stronger than conventional nucleic acid analogs.
  • the virus growth inhibitory effect of the nucleic acid analog preparation can be stably maintained for a long period of time.
  • hepatitis B virus may proliferate rapidly when using anticancer drugs or immunosuppressants during chemotherapy, immunotherapy, or transplantation therapy. The invention is useful.
  • FIG. 1 shows the amount of change in the serum albumin level after the start of administration of the rebact granule.
  • a white circle indicates a group without lamivudine prescription history, and a black circle indicates a group with lamivudine prescription history.
  • FIG. 2 shows the amount of change in the AST value after the start of administration of the rebact granule.
  • a white circle indicates a group without lamivudine prescription history, and a black circle indicates a group with lamivudine prescription history.
  • FIG. 3 shows the amount of change in the ALT value since the start of administration of the rebact granule.
  • FIG. 4 is a diagram showing the effect of reducing the amount of hepatitis B virus DNA in serum when Leveract granules and a nucleic acid analog preparation are administered in combination.
  • the vertical axis shows the amount of decrease in the amount of hepatitis B virus DNA in each combination period compared with the time when the administration of the rebact granule and the nucleic acid analog preparation was started (logarithmic value).
  • the horizontal axis indicates the time from the start of (combination) administration.
  • horizontal bars indicate the single administration of the nucleic acid analog preparation (Group A)
  • black bars indicate the combined administration of the nucleic acid analog preparation (Group B) after administration of the rebact granules for one year
  • white bars indicate The combination administration (group C) of the rebact granule after administering a nucleic acid analog formulation for one year is shown.
  • Isoleucine, leucine and valine which are active ingredients (branched chain amino acids) in the “activity enhancer of nucleic acid analog having antiviral activity (hereinafter referred to as activity enhancer of the present invention)” of the present invention, are each in the L-form.
  • D-form and DL-form can be used, but L-form and DL-form are preferred, and L-form is more preferred.
  • Isoleucine, leucine and valine can be used not only in free form but also in salt form.
  • the salt form include acid addition salts and base addition salts, and any form can be adopted as long as it is a chemically acceptable salt, but from the viewpoint that the present invention is used for medical purposes, It is preferable to select pharmaceutically acceptable salts of isoleucine, leucine and valine.
  • Examples of the pharmaceutically acceptable salt to be added to isoleucine, leucine and valine include salts with acids and salts with bases.
  • Examples of the acid that forms a salt include inorganic acids such as hydrogen chloride, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid, and monomethyl sulfuric acid. Can be mentioned. These branched chain amino acids can also form salts with bases. Examples of such bases include metal hydroxides such as sodium and potassium, metal carbonates such as calcium, and ammonia. And inorganic bases such as ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, and triethanolamine.
  • nucleic acid analog having antiviral activity in which the activity enhancer of the present invention enhances the activity has a structure similar to that of a nucleic acid (nucleoside) in addition to substances known as active ingredients of nucleic acid analog preparations. As long as it has antiviral activity, it is not particularly limited.
  • nucleic acid analog for example, a protein that has a nucleic acid (nucleoside) -like structure such as a purine ring or a pyrimidine ring and has a competitive intermolecular interaction with a natural nucleoside molecule, and finally constitutes a virus And substances that inhibit the synthesis of Specific examples of such substances include lamivudine (cytosine analogue), clevudine (pyrimidine analogue), entecavir (deoxyguanosine analogue), adefovir (adenine analogue), terbivudine (cytosine analogue), tenofovir (adenine analogue) Substance), emtricitabine (cytosine analog) and the like.
  • cytosine analogue cytosine analogue
  • clevudine pyrimidine analogue
  • entecavir deoxyguanosine analogue
  • adefovir adenine
  • lamivudine, clevudine, entecavir, and adefovir are preferable as the nucleic acid analog, and lamivudine, entecavir, and adefovir are more preferable.
  • treatment with IFN is basically aimed at drug free in patients under 35 years old, but in patients over 35 years old, the initial administration is aimed at continuous negativeization of HBV DNA.
  • Entecavir is particularly preferred as the nucleic acid analog preparation.
  • lamivudine and adefovir are preferably administered in combination.
  • the activity enhancer of the present invention is completed based on the discovery that at least one branched-chain amino acid selected from isoleucine, leucine and valine or a salt thereof enhances the activity of a nucleic acid analog having antiviral activity. is there. Therefore, the present invention also provides a method for enhancing the activity of a nucleic acid analog having antiviral activity, which comprises using an effective amount of at least one branched-chain amino acid selected from isoleucine, leucine and valine or a salt thereof. .
  • the “effective amount” is a dose of the branched chain amino acid in the activity enhancer of the nucleic acid analog of the present invention described later.
  • the activity enhancer of the present invention is only required to contain at least one kind selected from isoleucine, leucine and valine or a salt thereof as a branched chain amino acid.
  • isoleucine may be contained, but all of isoleucine, leucine and valine are contained. It is preferable.
  • the content ratio (weight ratio) of such branched chain amino acids can be appropriately adjusted by those skilled in the art according to the condition of the subject to be administered.
  • all of isoleucine, leucine, and valine are contained.
  • the weight ratio of isoleucine, leucine and valine is more preferably 1: 1 to 3: 0.5 to 2.0.
  • the weight ratio of isoleucine, leucine, and valine is particularly preferably 1: 1.5 to 2.5: 0.8 to 1.5, and the most preferred weight ratio is 1: 2: 1.2. .
  • the activity enhancer of the present invention may further contain a pharmaceutical carrier.
  • a pharmaceutical carrier examples include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, and carboxymethylcellulose calcium salt.
  • the compounding amount of the branched chain amino acid in the activity enhancer of the present invention can be appropriately adjusted by those skilled in the art in consideration of the disease in the subject to be administered, the age, sex, weight, etc. of the subject.
  • the activity enhancer of the present invention may further contain components other than branched chain amino acids, for example, components such as amino acids, sugars, fats, and trace elements, depending on applications.
  • branched chain amino acids weight ratio of isoleucine, leucine, valine 1: 0.9 to 1.5: 0.7 to 1.1
  • branched chain Ingredients other than amino acids for example, amino acids such as lysine may be contained, sugars such as dextrin, fats and vitamins such as rice oil and soybean oil, mineral ingredients such as calcium, sodium and potassium, zinc and iron Trace elements may be contained.
  • the activity enhancer for HBV positive patients with hepatic encephalopathy is preferably formulated so as to contain 3 to 6 g of branched chain amino acids per administration, and is preferably administered three times a day.
  • “enhancement of nucleic acid analog activity” means directly enhancing the antiviral action of nucleic acid analogs in nucleic acid analog therapy. This also includes a reduction in blood HBV RNA levels, improvement in serum albumin levels, improvement in ALT / AST levels, shortening of the treatment period, reduction in dosage of nucleic acid analog, This includes improving the efficiency of analog patients.
  • chemotherapy is performed on patients with malignant tumors among HBV positive patients, there is concern that severe and fulminant hepatitis may develop due to rapid proliferation and reactivation of the virus.
  • the activity enhancer of the present invention can be administered prophylactically.
  • the HBV-DNA can be continuously monitored by the PCR method or the TMA method. It is also effective for negative results.
  • nucleic acid analog therapy refers to treating viral diseases by exerting an antiviral effect with a nucleic acid analog having antiviral activity and consequently suppressing viral growth or reducing the virus.
  • the nucleic acid analog therapy for example, when the viral disease is viral hepatitis, not only the viral hepatitis is treated by suppressing the growth of the hepatitis virus or by reducing the hepatitis virus, but also the viral hepatitis It exhibits antiviral activity against the remaining virus even in cirrhosis and liver cancer caused by the disease, and can delay the progression from viral hepatitis to cirrhosis and liver cancer. Therefore, the “nucleic acid analog activity enhancer having antiviral activity” of the present invention should be used not only for viral hepatitis but also for applications such as prevention of cirrhosis and liver cancer caused by viral hepatitis. Can do.
  • the treatment options for liver cancer are determined by the liver reserve of the underlying liver lesion, so restore liver function as much as possible. This is important because it gives you a wide range of treatment options. Therefore, the activity enhancer of the present invention can be applied together with a nucleic acid analog as an agent for improving liver reserve.
  • Nucleic acid analog therapy includes not only treatment with a single nucleic acid analog but also treatment with a plurality of nucleic acid analogs, or treatment with a combination of nucleic acid analogs and other drugs. Cases are also included. Examples of such a combination include, for example, a combination of a nucleic acid analog and an IFN agonist described in International Publication WO2007 / 013677, or a combination of different nucleic acid analogs.
  • the activity enhancer of the present invention can be applied to a subject who has a history of administration of nucleic acid analogs. It is known that the hepatitis virus grows with high probability when the administration of the nucleic acid analog is stopped, and the effect of the nucleic acid analog preparation itself bottoms out at a certain value (for example, “Clinical and Drug Medicine” June 1999 issue, (See FIG. 6 on page 563). Even in such a case, the effect of the bottomed-out nucleic acid analog preparation can be further enhanced by applying the activity enhancer of the present invention in addition to the continuous administration of the nucleic acid analog.
  • the activity enhancer of the present invention can further enhance the effect of the nucleic acid analog preparation to be administered later by administering the nucleic acid analog preparation prior to the administration of the nucleic acid analog to the subject to which the nucleic acid analog preparation is to be administered.
  • the activity enhancer of the present invention when the nucleic acid analog preparation is administered alone, the effect bottoms out at a certain value, but the effect of the nucleic acid analog preparation is suppressed by administering the activity enhancer of the present invention first. Can be strengthened. At this time, it is desirable that the activity enhancer of the present invention is continuously administered even after administration of the nucleic acid analog.
  • the administration start timing of the activity enhancer of the present invention can appropriately select an appropriate timing for obtaining the desired effect of the nucleic acid analog preparation.
  • the activity enhancer of the present invention is administered to a subject to be administered at a dose of 12 g per day for 1 year, and then the nucleic acid analog preparation is administered, for example, entecavir hydrate, while administering the activity enhancer of the present invention. If administered, 0.5 mg (as entecavir) is administered daily.
  • the subject is not particularly limited, and any mammal can be the subject of administration, but is preferably a human.
  • the activity enhancer of the present invention can be administered as a pharmaceutical together with the nucleic acid analog preparation.
  • the said pharmaceutical is a pharmaceutical which has a nucleic acid analog therapeutic effect stronger than the conventional pharmaceutical which uses a nucleic acid analog formulation as an active ingredient.
  • the activity enhancer of the present invention can be given in various forms, for example, in the form of functional foods, health foods (including beverages), and foods for specified health use, as well as administration forms of the above agents and pharmaceuticals. is there.
  • the activity enhancer of the present invention can be produced by adding a branched chain amino acid to a food or beverage ingredient, and can be taken orally.
  • the activity enhancer of the present invention is administered as a functional food, health food, or food for specified health use, the food itself should be prepared in the same manner as a normal food and drink composition except that a branched chain amino acid is added. Can do.
  • Examples of such food and beverage composition include beverages such as soft drinks, carbonated drinks, nutrient drinks, fruit juice drinks, and lactic acid bacteria drinks (including concentrated concentrates and powders for adjustment of these drinks); ice cream, sherbet, shaved ice Ice confectionery such as candy; chewing gum, candy, gum, chocolate, tablet confectionery, snack confectionery, biscuits, jelly, jam, cream, baked confectionery, etc .; Dairy products such as processed milk, milk drinks, fermented milk, butter; bread Enteral nutritional foods, liquid foods, milk for childcare, sports drinks; and other functional foods. Examples of the shape of the food and drink include tablets and granular supplements.
  • Examples of such foods include 3.2 g of a branched chain amino acid having a weight ratio of isoleucine, leucine, and valine of 1: 2: 1 as an activity enhancer, and further containing trace elements such as vitamins and zinc. Examples include granular foods with a dose of 4 g per dose. It is also possible to prepare a nutritional composition such as a liquid food that contains only 0.5 to 3 g of isoleucine as a branched chain amino acid.
  • the present invention also includes the following step (1): a step of administering a nucleic acid analog having antiviral activity to a subject; (2) A step of administering to a subject an effective amount of at least one branched-chain amino acid selected from isoleucine, leucine and valine or a salt thereof;
  • the present invention also provides a method capable of enhancing the activity of a nucleic acid analog having antiviral activity. At this time, it is desirable to perform step (2) while continuing step (1). Even if the nucleic acid analog is continuously administered in the step (1), the effect reaches a peak, so that the nucleic acid administered in the step (1) is performed by performing the step (2) while continuing the step (1).
  • the activity of analogs can be further enhanced, and viruses (eg, hepatitis virus) can be reduced more effectively.
  • step (1) it is desirable to perform step (1) while continuing the above step (2). Even if the nucleic acid analog is continuously administered simply by performing the step (1), the effect reaches a peak, so the step (2) is performed first, and the step (1) is performed while continuing this. As a result, the activity of the nucleic acid analog administered in step (1) can be further enhanced, and viruses (eg, hepatitis virus) can be reduced more effectively.
  • viruses eg, hepatitis virus
  • nucleic acid analogs eg, red blood cell reduction, white blood cell reduction, thrombocytopenia, depression, consciousness disorder, aplastic anemia, dyspnea, arrhythmia, retina Sickness, fever, malaise, headache, loss of appetite, hair loss, joint pain, etc.
  • the activity enhancer of the present invention by applying the activity enhancer of the present invention, an equivalent effect as a nucleic acid analog can be obtained in a smaller amount than when used alone, and as a result, the relative nucleic acid analog itself in the whole preparation Dosage can be reduced. Therefore, when the activity enhancer of the present invention is used in combination with a nucleic acid analog, it can also be applied as a side effect reducing agent for the nucleic acid analog.
  • nucleic acid analogs can be administered for a long time, and thus the possibility of appearance of resistant viruses is reduced. Therefore, the activity enhancer of the present invention can be applied as an inhibitor of the emergence of resistant viruses in combination with nucleic acid analogs.
  • hepatitis virus to be treated by the nucleic acid analog of the present invention all known hepatitis viruses can be exemplified, and among them, hepatitis B virus is preferable.
  • the activity enhancer of the present invention contains at least one branched chain amino acid selected from isoleucine, leucine, and valine, and the activity enhancer of the present invention uses these branched chain amino acids as the activity of nucleic acid analogs. It has been completed based on the discovery that it has been enhanced. That is, the combination of at least one branched chain amino acid selected from isoleucine, leucine and valine and a nucleic acid analog having antiviral activity has a stronger activity against viral hepatitis than the nucleic acid analog alone. It can be applied as a preventive or therapeutic agent for viral hepatitis.
  • the present invention relates to a prophylactic or therapeutic agent for viral hepatitis (hereinafter referred to as “this”) comprising a combination of at least one branched-chain amino acid selected from isoleucine, leucine and valine or a salt thereof and a nucleic acid analog having antiviral activity. Also referred to as “a prophylactic or therapeutic agent of the invention”).
  • the prophylactic or therapeutic agent of the present invention only needs to contain at least one of isoleucine, leucine, and valine as a branched chain amino acid.
  • isoleucine, leucine, and valine are contained. It is preferable.
  • the content ratio (weight ratio) of such branched chain amino acids can be appropriately adjusted by those skilled in the art according to the condition of the subject to be administered, but the weight ratio of isoleucine, leucine, and valine is 1: It is more preferably 1 to 3: 0.5 to 2.0.
  • the weight ratio of isoleucine, leucine, and valine is particularly preferably 1: 1.5 to 2.5: 0.8 to 1.5, and the most preferred weight ratio is 1: 2: 1.2.
  • the preventive or therapeutic agent of the present invention may further contain a general pharmaceutical carrier described in the activity enhancer of the present invention. The content of these pharmaceutical carriers can be adjusted as appropriate by those skilled in the art.
  • the hepatitis virus targeted by the prophylactic or therapeutic agent of the present invention is not particularly limited, and any known hepatitis virus can be mentioned as a target, but hepatitis B virus is particularly preferable.
  • hepatitis B virus is particularly preferable.
  • the preventive or therapeutic agent of the present invention may contain a known antiviral component in addition to the branched chain amino acid and the nucleic acid analog having antiviral activity.
  • a known antiviral component is IFN.
  • the content of the antiviral component can be appropriately adjusted by those skilled in the art.
  • the preventive or therapeutic agent of the present invention can suppress viral hepatitis by enhancing the activity of a nucleic acid analog having antiviral activity.
  • the preventive or therapeutic agent of the present invention can suppress the growth of hepatitis virus and reduce the hepatitis virus. Therefore, the prophylactic or therapeutic agent of the present invention is mixed with a pharmacologically acceptable carrier and a pharmaceutical composition for viral hepatitis (eg, injection, tablet, granule, fine granule, powder, capsule, cream) Suppositories, suppositories, etc.).
  • the pharmaceutical or pharmaceutical composition can be administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.), but is preferably administered by oral administration.
  • Examples of the pharmacologically acceptable carrier used include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose.
  • These carriers are used in a form blended with the medicament or pharmaceutical composition of the present invention, depending on the form of the preparation. The content of these carriers can be appropriately adjusted by those skilled in the art.
  • the agent, pharmaceutical and pharmaceutical composition of the present invention branched chain amino acids
  • the dose (intake) varies depending on the patient's condition, age, method of administration, etc., but is usually 0.5 to 30.0 g isoleucine, 1.0 to 60.0 g leucine, 0 to valine per day. .5 to 30.0 g.
  • the daily dose for adults is usually 2. It is preferably about 0 to 50.0 g, and this is administered 1 to 6 times, preferably 1 to 3 times as necessary.
  • the dose of nucleic acid analog varies depending on various requirements such as the type of nucleic acid analog to be administered, patient's pathology, age, and administration method, but the daily dose for an adult is usually about 0.01 mg to 100 mg, preferably It is about 0.1 mg to 100 mg. Particularly in the case of patients with renal dysfunction (such as patients undergoing hemodialysis), it is necessary to reduce the dose, and the daily dose for adults is about 0.01 mg to 10 mg.
  • entecavir hydrate 0.5 mg is given once a day on an empty stomach (and all three types of branched chain amino acids). It is preferable to administer the amino acid preparation containing (the amount of branched chain amino acids 3 to 4 g at a time 3 times a day).
  • the branched chain amino acid and the nucleic acid analog may be administered in the same or different dosage forms as separate formulations, or the branched chain amino acid and the nucleic acid analog may be the same. You may administer as a compounding agent contained in a formulation. Whether the branched-chain amino acid and the nucleic acid analog are separate preparations or mixed in the same preparation, branching per administration in the above-mentioned agent, medicament and pharmaceutical composition of the present invention
  • the amount of chain amino acid is usually about 0.5 to 50.0 g, preferably about 1.0 to 20.0 g, and more preferably about 2.0 to 6.0 g.
  • the compounding quantity of the nucleic acid analog per administration is set for every medicine.
  • entecavir hydrate 0.5 mg (as entecavir) is administered once a day on an empty stomach
  • three types of branched chain amino acids The amount of branched chain amino acid per administration of an amino acid preparation containing all of is 3 to 4 g (preferably administered three times a day).
  • the order of the combined administration is not particularly limited, For example, an appropriate order and time difference can be selected depending on the dosage form, administration method and the like in order to obtain a preferable administration effect of the nucleic acid analog.
  • an appropriate order and time difference for example, when a branched chain amino acid is administered first, a method of administering a nucleic acid analog within 5 minutes to 2 years after the branched chain amino acid is administered can be mentioned.
  • the nucleic acid analog when the nucleic acid analog is administered first, there can be mentioned a method of administering the branched chain amino acid within 5 minutes to 2 years after the nucleic acid analog is administered.
  • the branched chain amino acid when the branched chain amino acid is administered first, it is desirable to continue the administration of the branched chain amino acid even after the start of the administration of the nucleic acid analog.
  • the nucleic acid analog when the nucleic acid analog is administered first, it is desirable to continuously administer the nucleic acid analog according to the prescription described in the package insert of each preparation, and also after the start of administration of the branched chain amino acid. It is desirable to continue administration.
  • the dosage (intake amount) of the branched chain amino acid which is an active ingredient in the agent, medicine and pharmaceutical composition of the present invention a drug used for the purpose of prevention and treatment of the disease targeted by the present invention, etc.
  • the range of the compounding amount for each administration is determined as described above, for the purpose different from the purpose of the present invention, for example, from the necessity of normal eating habits, or for other diseases
  • the present invention can be used to enhance the activity of at least one branched chain amino acid selected from isoleucine, leucine and valine or a salt thereof, and a nucleic acid analog having the antiviral activity.
  • a commercial package is provided that includes a statement that describes what the branched chain amino acid or salt thereof is that states what can or should be used.
  • Example 1 Combined effect of nucleic acid analog preparation and activity enhancer of the present invention (1) (Method) In patients with decompensated cirrhosis who are hypoalbuminemia despite sufficient food intake and who are positive for hepatitis B virus, the weight ratio of isoleucine, leucine and valine was 1: 2: 1.2 (isoleucine: 0 .952 g, leucine: 1.904 g, valine: 1.144 g) Changes in AST and ALT values were measured daily.
  • results were divided into two groups according to the presence or absence of prescription history of lamivudine (product name: ZEFIX (registered trademark) tablets, manufacturing and sales company GlaxoSmithKline Co., Ltd.), an antiviral chemotherapeutic agent.
  • Table 1 shows the patient background of both groups.
  • FIG. 1 shows changes in serum albumin levels of both patient groups shown in Table 1 after 6, 12, 18, and 24 months (values after each course) on the basis of the values before the start of administration of Levact granule. -Values plotted before the start of administration) are shown.
  • FIG. 2 shows the amount of change in AST.
  • FIG. 3 shows a plot of the amount of change in ALT.
  • Example 2 Combined effect of the nucleic acid analog preparation and the activity enhancer of the present invention (2) As Lievact granules and / or antiviral agents, lamivudine (“Zefix®” GlaxoSmithKline), Entecavir hydrate (“Baraclude®” Bristol Meyer) and Adefovir pivoxil (“Hepsera®”) The amount of hepatitis B virus in the serum was measured by nucleic acid amplification test for 20 patients with cirrhosis B who were administered a nucleic acid analog preparation selected from “Trademark” “GlaxoSmithKline” for 3 to 12 months. The 20 patients are cirrhotic patients and have not developed liver cancer.
  • the nucleic acid amplification test was performed by either the PCR method or the TMA method according to the amount of virus in the patient (measurement range: 2.6-7.6 log. Copies / mL (PCR method), 3.7-8.7 LGE). / ML (TMA method)). LGE means Logarithm genome equivalence, and the substantial meaning is log. Same as copies.
  • the viral load is reduced by administering the preparation for 3 months, but the effect does not increase significantly even if it is administered continuously for 1 year.
  • group B in which a nucleic acid analog preparation was administered to a patient who had been administered Leveract granules for one year, the viral load tended to be lower than in the case of nucleic acid analog preparation alone, and when the combined administration period was 1 year There is a tendency for the amount of reduction to be maintained or rather the amount of virus to decrease.
  • Group C the virus reduction effect of nucleic acid analogs has not been observed, and even when combined with Levact Granule, no significant viral load reduction effect has been observed. In comparison with, the viral load tends to decrease.
  • the activity of a nucleic acid analog preparation that bottoms out by continuous administration can be further enhanced.
  • the liver reserve ability is improved as compared with the case where the nucleic acid analog preparation is used alone, which is useful in that a treatment method for liver lesions including liver cancer can be selected more widely.
  • the present invention can provide a preventive or therapeutic agent for viral hepatitis, a pharmaceutical for treating viral hepatitis, and the like that are stronger than conventional nucleic acid analogs.
  • the virus growth inhibitory effect of the nucleic acid analog preparation can be stably maintained for a long time.
  • hepatitis B virus may proliferate rapidly when using anticancer drugs or immunosuppressants during chemotherapy, immunotherapy, or transplantation therapy.
  • the invention is useful. This application is based on Japanese Patent Application No. 2009-150296 (filing date: June 24, 2009) and Japanese Patent Application No. 2010-040423 (filing date: February 25, 2010) filed in Japan. Are all encompassed herein.

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Abstract

La présente invention concerne un amplificateur d'activité d'une préparation d'analogue d'acide nucléique et d'autres éléments. Plus spécifiquement, la présente invention concerne un amplificateur d'activité d'un analogue d'acide nucléique, qui se caractérise en ce qu'il comprend au moins un acide aminé ramifié sélectionné parmi l'isoleucine, la leucine et la valine ou un sel de celles-ci, et en ce qu'il possède une activité antivirale.
PCT/JP2010/060703 2009-06-24 2010-06-24 Amplificateur d'activité d'analogue d'acide nucléique WO2010150836A1 (fr)

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CN201080027706.7A CN102458417B (zh) 2009-06-24 2010-06-24 核酸类似物的活性增强剂
JP2011519930A JP5720569B2 (ja) 2009-06-24 2010-06-24 核酸アナログの活性増強剤

Applications Claiming Priority (4)

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JP2009-150296 2009-06-24
JP2009150296 2009-06-24
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JP2010040423 2010-02-25

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WO2012147901A1 (fr) * 2011-04-28 2012-11-01 味の素株式会社 Composition pour atténuer les effets secondaires d'un médicament anticancer
JP2016523261A (ja) * 2013-06-25 2016-08-08 ザ・ウォルター・アンド・エリザ・ホール・インスティテュート・オブ・メディカル・リサーチ 細胞内感染の処置方法

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CN103734716A (zh) * 2013-12-16 2014-04-23 无锡金维氨生物科技有限公司 一种支链氨基酸
CN108260788A (zh) * 2017-12-29 2018-07-10 陕西思尔生物科技有限公司 一种有效改善支链氨基酸苦味的果酱及其制备方法

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JP2003095938A (ja) * 2001-09-21 2003-04-03 Masami Moriyama 抗菌ペプチド分泌誘発剤
WO2004019928A1 (fr) * 2002-08-30 2004-03-11 Ajinomoto Co., Inc. Agent pour le traitement des maladies hepatiques
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WO2012147901A1 (fr) * 2011-04-28 2012-11-01 味の素株式会社 Composition pour atténuer les effets secondaires d'un médicament anticancer
JP2016523261A (ja) * 2013-06-25 2016-08-08 ザ・ウォルター・アンド・エリザ・ホール・インスティテュート・オブ・メディカル・リサーチ 細胞内感染の処置方法
JP2019147823A (ja) * 2013-06-25 2019-09-05 ザ・ウォルター・アンド・エリザ・ホール・インスティテュート・オブ・メディカル・リサーチ 細胞内感染の処置方法
US10500252B2 (en) 2013-06-25 2019-12-10 Walter And Eliza Hall Institute Of Medical Research Method of treating intracellular infection
JP7203682B2 (ja) 2013-06-25 2023-01-13 ザ・ウォルター・アンド・エリザ・ホール・インスティテュート・オブ・メディカル・リサーチ 細胞内感染の処置方法

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