WO2018092911A1 - Intracellular atp enhancer - Google Patents

Intracellular atp enhancer Download PDF

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Publication number
WO2018092911A1
WO2018092911A1 PCT/JP2017/041733 JP2017041733W WO2018092911A1 WO 2018092911 A1 WO2018092911 A1 WO 2018092911A1 JP 2017041733 W JP2017041733 W JP 2017041733W WO 2018092911 A1 WO2018092911 A1 WO 2018092911A1
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Prior art keywords
inosine
atp
febuxostat
administration
day
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PCT/JP2017/041733
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French (fr)
Japanese (ja)
Inventor
鎌谷　直之
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株式会社スタージェン
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Priority claimed from JP2017031953A external-priority patent/JP6937134B2/en
Application filed by 株式会社スタージェン filed Critical 株式会社スタージェン
Priority to CN201780083970.4A priority Critical patent/CN110225767B/en
Priority to EP17871969.6A priority patent/EP3542823B1/en
Priority to US16/462,345 priority patent/US10881662B2/en
Publication of WO2018092911A1 publication Critical patent/WO2018092911A1/en

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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • 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
    • A61K31/70—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
    • A61K31/7076—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 containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K31/7076—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 containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—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 containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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

Definitions

  • ATP adenosine triphosphate, sometimes referred to simply as ATP
  • ATP reduction is thought to be related to the pathology of various diseases. Yes. For example, as a cause of various hereditary hemolytic anemias, ATP reduction in erythrocytes is considered to be a mechanism of hemolysis.
  • Non-patent document 1 sickle cell disease
  • Non-patent document 2 pyruvate kinase deficiency
  • Non-patent document 3 spherocytosis
  • Non-patent document 3 elliptical erythrocytosis
  • Non-patent document 3 cleft erythrocytosis
  • Patent Document 4 Thalassemia
  • Non-Patent Document 5 Thalassemia
  • Non-patent Document 6 a decrease in intracellular ATP has been suggested as a mechanism of myocardial injury due to ischemic heart disease (Non-patent Document 6), and administration of allopurinol, a xanthine oxidase / xanthine dehydrogenase inhibitor, has prevented chronic stable angina. It has been reported that the symptoms were suppressed (Non-patent Document 7). The authors and others suggest that allopurinol had a positive effect on ischemic heart disease by increasing ATP (Non-patent Document 7). Furthermore, ATP augmentation therapy is likely to be effective for heart failure.
  • Non-patent Document 8 muscular genetic AMPD deficient patients have a long period of time from heart failure to heart transplantation.
  • Non-patent Document 9 it has been suggested that heart failure in mice is improved by an AMPD inhibitor.
  • Non-patent Document 10 AMP is not converted to IMP (inosine monophosphate, hereinafter sometimes referred to as IMP), AMP reduction can be prevented and ATP reduction does not occur (FIG. 6).
  • IMP inosine monophosphate
  • FIG. 6 it is considered that ATP deficiency of cardiomyocytes hardly occurs in the hereditary muscle AMPD deficiency and the progression of heart failure is suppressed.
  • Non-patent Document 12 Speculate that administration of febuxostat increases ATP in neurons to suppress disease progression.
  • Non-patent Document 12 knocking down Na / K-ATPase in ALS model mice suppresses neuronal degeneration.
  • Non-patent Document 13 Na / K-ATPase activity is renewed in ALS patients. That is, activation of Na / K-ATPase that decreases ATP promotes the onset or progression of ALS, and suppression of Na / K-ATPase that suppresses ATP decrease suppresses the progression of ALS.
  • Non-Patent Document 14 administration of inosine reduces the symptoms of Parkinson's disease
  • Non-Patent Document 15 multiple sclerosis
  • Clinical trials are being conducted with the aim of increasing the serum uric acid level by administering inosine and exerting a therapeutic effect.
  • the effectiveness of previous reports is not sufficient.
  • An object of the present invention is to provide a composition having an effect of enhancing intracellular ATP, and among them, an intracellular ATP enhancer that surpasses the enhancing effect of inosine alone or febuxostat alone.
  • a human or animal intracellular ATP enhancer comprising a combination of the following A) and B).
  • the compound that can be converted into hypoxanthine in B) is inosine, inosinic acid, adenine, adenosine, AMP, ADP, ATP, succinyladenosine, S-adenosylmethionine, S-adenosylhomocysteine, methylthioadenosine
  • the intracellular ATP enhancer according to [1] or [2] which is any one or more compounds selected from pharmaceutically acceptable salts thereof.
  • A) and B) combined effects of the present invention enhance intracellular ATP, and various diseases in which ATP decrease forms part of the disease state, and further, the progression of the disease state is suppressed by excessive supply of ATP. It is possible to provide therapeutic agents for various diseases.
  • 6 is a graph showing the transition of serum uric acid level when administration in groups A to E is performed.
  • the horizontal axis represents the measurement period (weeks), and the vertical axis represents the serum uric acid level (unit: mg / dL).
  • Group A febuxostat 20 mg, twice daily, 14 days
  • Group B inosine 500 mg, twice daily, 14 days
  • Group C febuxostat 20 mg + inosine 500 mg, twice daily, 14 days
  • Group D Febuxostat 20 mg + inosine 1000 mg, twice daily, 14 days
  • group E febuxostat 30 mg, twice daily, 14 days
  • 6 is a graph showing the transition of urinary uric acid concentration / creatinine concentration when administration in groups A to E is performed.
  • the horizontal axis represents the measurement period (weeks), and the vertical axis represents the urinary uric acid concentration / creatinine concentration (ratio).
  • 2 is a graph showing changes in ATP and ADP in blood when administration in groups A to E is performed.
  • the horizontal axis represents the measurement period (weeks), and the vertical axis represents the ATP or ADP concentration (unit: ⁇ M).
  • ATP solid line
  • ADP broken line.
  • 3 is a graph showing changes in Hx (hypoxanthine) and X (xanthine) in blood when administration in groups A to E is performed.
  • the horizontal axis represents the measurement period (weeks), and the vertical axis represents the Hx or X concentration (unit: ⁇ M).
  • 6 is a graph showing changes in the concentration ( ⁇ M) of various purines in urine when administration is performed in groups A to E. It is a figure which shows the path
  • One active ingredient of the present invention is A) a xanthine oxidase / xanthine dehydrogenase inhibitor.
  • Xanthine oxidase / xanthine dehydrogenase inhibitors include febuxostat (trade name Febrik (Teijin Pharma)), topiroxostat (trade name Uriadeck (Sanwa Chemical Research Laboratories), Topyrrolic (Fuji Pharmaceutical)), allopurinol (trade name Zyrolic) (GlaxoSmithKline)), hydroxyalkane, carprofen, Y-700 (Mitsubishi Tanabe Seiyaku), KUX-1151 (Kissei Pharmaceutical) and the like.
  • compositions of these compounds are also included in the active ingredient A) of the present invention.
  • Another active ingredient of the present invention is B) hypoxanthine, or a compound that can be converted into hypoxanthine in the body.
  • compounds that can be converted into hypoxanthine in the body include, for example, inosine, inosinic acid, adenine, adenosine, AMP, ADP, ATP, succinyladenosine, S-adenosylmethionine, S-adenosylhomocysteine, methylthioadenosine and their pharmaceuticals Any one or more compounds selected from pharmaceutically acceptable salts are included, but since these compounds are eventually decomposed into hypoxanthine, it is possible to use these substances instead of inosine ( FIG. 6). Of these, inosine is desirable.
  • the intracellular ATP enhancing action of the present invention refers to the effect that the active ingredient of the present invention increases the production of ATP in the cell.
  • the term “increase” is used to mean any of suppressing an increase or decrease from the steady state, or bringing the decreased state close to the steady state. Confirmation of the effect of the present invention can be measured indirectly by directly measuring the intracellular ATP concentration, or by measuring products of other metabolic pathways caused by the increase in ATP.
  • a mixture also referred to as a compounding agent in which the component A) and the component B) are mixed to form a composition, or is physically present without being mixed, but is administered. Any of the agents present together as being administered at the same time.
  • the mixture include those prepared by mixing. Examples of the preparation include oral preparations such as granules, powders, solid preparations, liquids, and inhalants.
  • kits agents and forms that are collected in one bag examples include so-called kit agents and forms that are collected in one bag.
  • the term “same time” does not necessarily mean the same time in the strict sense, and includes the case where an interval is set within a range in which the ATP enhancing effect of the present invention is exhibited. For example, the case where one is taken before a meal and the other is taken after a meal corresponds to the case of administration at the same time of the present invention.
  • the present invention can also be understood as an intracellular ATP enhancing method and an ATP increasing method including the step of coadministering A) and B).
  • the dosage of the ATP enhancer of the present invention is preferably about 50 mg to about 800 mg / day for allopurinol of A), 40 to 160 mg / day for topiroxostat, and 10 to 80 mg / day for febuxostat.
  • the inosine of B) is preferably 0.5 to 4.0 g / day, and the effective amount of B) hypoxanthine, or a compound that can be converted into hypoxanthine in the body, is an amount corresponding to the amount of inosine depending on the molecular weight. It can be obtained by conversion.
  • the administration method it is possible to divide and administer the above dose once or twice a day.
  • Inosine is also preferably administered twice a day rather than once a day. Therefore, it is more desirable to administer both inosine and febuxostat twice a day.
  • allopurinol and topiroxostat are preferably administered twice a day rather than once a day.
  • the dosage form of the medicament of the present invention is not particularly limited, and any oral or parenteral dosage form may be used.
  • it can be made into an appropriate dosage form according to the dosage form, for example, an injection, or an oral preparation such as a capsule, a tablet, a granule, a powder, a pill, and a fine granule, a rectal administration agent, and an oily seat.
  • various preparations such as suppositories and aqueous suppositories. Since the medicament of the present invention contains the active ingredients A) and B), the dosage form of the active ingredient A) and the dosage form of B) may be the same or different.
  • Examples of the same dosage form include the case where both are administered orally in tablets, the case where they are administered orally as a combination of both, and the case where they are administered as a mixed injection. Moreover, as an example of a different dosage form, the case where one is administered by an oral agent and the other is administered by an injection etc. is mentioned.
  • the administration target of the present invention is a human or animal, and is a human or animal in a state where ATP enhancement is necessary.
  • the following diseases are strongly suggested that ATP reduction is related to the pathological condition: (1) hemolytic anemia (2) ischemic heart disease (3) heart failure (4) amyotrophic lateral sclerosis (5) Parkinson's disease (6) ADSL deficiency. Among these, it is particularly effective for (2) ischemic heart disease (3) heart failure (4) amyotrophic lateral sclerosis.
  • the ATP enhancer of the present invention can be further combined with other drugs as long as the effects of the present invention are not impaired.
  • the present invention will be specifically described based on examples, but the present invention is not limited thereto.
  • Clinical trial (combination of febuxostat and inosine) 1.
  • Various measurement methods (1) Clinical examination The items other than the following items were measured by a conventional method.
  • Serum uric acid level The automatic clinical chemistry analyzer used a dry clinical chemistry analysis measurement unit manufactured by ARKRAY, Inc., and the uric acid peroxidase method was used to measure the serum uric acid level.
  • Urinary uric acid concentration / creatinine concentration Since the urinary uric acid concentration varies depending on the amount of urine, the value of urinary uric acid / creatinine divided by the urinary creatinine concentration was used to evaluate the urinary uric acid amount.
  • the method for measuring uric acid levels is the same as serum uric acid levels.
  • Purine concentration in blood The measurement of various purines in peripheral blood was based on literature. Briefly, peripheral blood was collected from EDTA, mixed with 500 ⁇ L + 500 ⁇ L ice cold 8% PCA, immediately centrifuged for 5 seconds at 4 ° C. at 12,000 ⁇ g for 5 seconds, and the supernatant was stored at ⁇ 80 degrees. In a state where the sample was collected, the sample was dissolved and 40 ⁇ L of 2MK 2 CO 3 in6MKOH was added to 650 ⁇ L of the solution to simultaneously precipitate and neutralize PCA.
  • Dosing test (1) Administration target The following administration test was conducted by dividing 16 healthy Japanese adult males, 1 in stage I and 15 in stage II into groups A to E, each divided into 3 groups. (2) Administration content and administration schedule (2-1) Phase I For one patient, febuxostat 20 mg and inosine 500 mg were co-administered twice daily for 14 days to confirm safety. (2) Phase II After completion of Phase I, administration was performed to 3 patients in each group with the following contents.
  • Phase I Adverse events (1-1) Physical findings There were no adverse events in the subject's subjective and physical findings. (1-2) Clinical examination The AST on the 8th day showed an abnormal value of 49 U / L (reference value 10 to 40), but on the 15th day, it returned to the reference value of 29 U / L. On the 8th day, creatinine showed an abnormal value of 1.09 mg / dL (reference value 0.61 to 1.04), but on the 15th day, it returned to the standard value of 0.98 mg / dL. The blood glucose level on the 8th day was 66 mg / dL, and the 15th day was 67 mg / dL (reference value 70 to 109), indicating abnormal values.
  • Phase II Phase II
  • Adverse events (1-1) Physical findings There were no significant differences between groups in age, height, weight, BMI, systolic blood pressure, diastolic blood pressure, pulse, body temperature. There was no significant change in systolic blood pressure, diastolic blood pressure, pulse, or body temperature, except for a significant increase in pulse rate in one subject.
  • FIG. 1 shows a graph for each of groups A to E.
  • a significant increase in serum uric acid levels was observed in group B administered only with inosine (maximum 8.1 mg / dL).
  • groups A and C to E a decrease in serum uric acid level was observed.
  • the serum uric acid level was not reduced to less than 2 mg / dL, but in the case of group E being febuxostat 60 mg / day administration, the serum uric acid level was less than 2 mg / dL. It was observed.
  • febuxostat 40 mg / dL decreased the serum uric acid level by 2.53 mg / dL (Group A), but in the case where 1 g of inosine was administered at the same time, decreased 2.23 mg / dL (Group C), 1 day. In the case of administration of 2 g, the dose decreased by 1.47 mg / dL (Group D).
  • Administration of febuxostat 60 mg / dL decreased the serum uric acid level by 3.93 mg / dL (Group E). Serum uric acid level increased by an average of 2.57 mg / dL with 1 g of inosine per day (Group B).
  • the serum uric acid level is 0.3 mg / dL by administration of inosine 1 g / day and serum by administration of 2 g / day under febuxostat 40 mg / day.
  • the uric acid value increased by 1.06 mg / dL.
  • the serum uric acid level increased by 2.57 mg / dL by administration of 1 g / day of inosine in the absence of febuxostat administration, so that the increase in serum uric acid by inosine is significantly suppressed in the administration of febuxostat. become.
  • FIG. 3 shows the concentration of ATP / ADP in blood for each of groups A to E.
  • the A and B groups did not change the ATP concentration, and the C and D groups suggested that ATP increased.
  • the E group does not show a certain tendency. That is, no increase in ATP was observed when febuxostat or inosine alone was administered, but an increase in ATP was observed in the combination examples, particularly febuxostat 40 mg / day and inosine 1-2 g / day. When febuxostat and inosine were used in excess of these amounts, a certain tendency was not observed.
  • FIG. 3 shows the concentration of ATP / ADP in blood for each of groups A to E.
  • the A and B groups did not change the ATP concentration, and the C and D groups suggested that ATP increased.
  • the E group does not show a certain tendency. That is, no increase in ATP was observed when febuxostat or inosine alone was administered, but an increase in
  • Hx hypoxanthine
  • X xanthine
  • FIG. 5 shows changes in urinary inosine, Hx, X, and uric acid concentrations from week 0 to week 2 for each group.
  • Urinary Hx increased moderately in the case of febuxostat alone, but markedly increased in the combination of febuxostat and inosine. In the case of using inosine alone, no increase in Hx and X was observed.
  • the concentration of X was also significantly increased in the case of single administration of febuxostat, but was further significantly increased in the case of combined use of febuxostat and inosine.
  • the maximum concentration of urinary X in each group was A group 556.0, B group 61.9, C group 2023.3, D group 1474.8, and E group 867.7 ⁇ M. That is, in the case where febuxostat 40 mg and inosine 1 and 2 g were used in combination, the maximum urinary X concentration was 3.64 and 2.65 times that of the febuxostat 40 mg single administration group.
  • Test Example 4 The combined use of febuxostat and inosine was safe at doses of febuxostat 40 mg / day and inosine 2 g / day or less in a 2-week continuous administration test. Moreover, although the increase of ATP in blood was seen in these combination groups, such a change was not observed in the other administration group other than that. (2) Serum uric acid levels decreased significantly with febuxostat alone, serum uric acid levels increased significantly with inosine alone, and moderate decreases were observed with combination therapy. (3) No increase in inosine was observed in any group, and it was considered that PNP was metabolized to Hx.
  • Test Example 2 Clinical trial (2) According to Test Example 1, an ATP enhancing action that was not observed in single administration by the combined use of febuxostat and inosine was observed. Therefore, a test for confirming whether or not allopurinol and topiroxostat, which are the same xanthine oxidase / xanthine dehydrogenase inhibitors as febuxostat, have the same effect was conducted. 1.
  • Dosing test (1) Administration target Fifteen Japanese healthy adult males were divided into groups A, B, and C, and the following administration test was conducted.
  • Hypoxanthine concentration Table 2 shows the average value of hypoxanthine concentration before and after the end of the tests for groups A to C. In any group, administration of the ATP enhancer of the present invention significantly increased blood hypoxanthine.
  • ATP concentration Table 3 shows the average value of the ATP concentration in blood before and after the start of the tests of groups A to C. In any group, ATP in blood increased by administration of the ATP enhancer of the present invention.
  • hypoxanthine and ATP is a phenomenon that occurs only when both supply from inosine and suppression of xanthine oxidase / xanthine dehydrogenase occur simultaneously. This is because hypoxanthine and ATP did not increase with administration of xanthine oxidase / xanthine dehydrogenase inhibitor alone or inosine alone (Test Example 1). That is, in Test Example 1, neither hypoxanthine nor ATP increased when febuxostat and inosine were administered alone (FIGS. 4A, B, and 3A, B), but when these were administered in combination Increased hypoxanthine and ATP (FIGS. 4C, D, 3C, D). Therefore, it can be said that the increase in hypoxanthine and ATP is a phenomenon that occurs only when a xanthine oxidase / xanthine dehydrogenase inhibitor and inosine are administered in combination.
  • Pregelatinized starch (disintegration bander) 70mg
  • Silicified microcrystalline cellulose (filler) 32.656 mg
  • Croscarmellose sodium (disintegrant) 10mg
  • Magnesium stearate (lubricant) 0.8mg
  • Kit Agents The following A. containing topiroxstat. The medicine of the composition of the following B containing the tablet of the composition of this and inosine was manufactured, and it put into the same bag divided
  • Pregelatinized starch (disintegration bander) 70mg
  • Silicified microcrystalline cellulose (filler) 32.656 mg
  • Croscarmellose sodium (disintegrant) 10mg
  • Magnesium stearate (lubricant) 0.8mg
  • Kit Agents The following A. containing febuxostat: The medicine of the composition of the following B containing the tablet of the composition of this and inosine was manufactured, and it put into the same bag divided
  • A. Febuxostat tablets Febuxostat 20mg Pregelatinized starch (disintegration bander) 70mg Silicified microcrystalline cellulose (filler) 32.656 mg Croscarmellose sodium (disintegrant) 10mg Magnesium stearate (lubricant) 0.8mg
  • Intracellular ATP could be enhanced by the combined administration of alpurinol, topiroxostat or febuxostat and inosine. This is a new pharmacological action not found in conventional drugs. Therefore, it is considered to be effective for diseases having various ATP reductions.
  • the action of inosine to increase the uric acid level was suppressed by the combined use with alpurinol, topiroxostat or febuxostat. Therefore, ATP can be increased without reducing the therapeutic effect of hyperuricemia in patients who receive alpurinol, topiroxostat or febuxostat for the treatment of hyperuricemia.

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Abstract

The present invention addresses the problem of providing a potent ATP increasing agent which has a much higher ATP-increasing effect than that of a substance having an effect to increase ATP in cells, particularly inosine alone or a xanthine oxidase/xanthine dehydrogenase inhibitor alone. An intracellular ATP increasing agent for human or an animal, comprising a combination of the following components (A) and (B): (A) a xanthine oxidase/xanthine dehydrogenase inhibitor; and (B) hypoxanthine or a compound that can be converted to hypoxanthine in vivo.

Description

細胞内ＡＴＰ増強剤Intracellular ATP enhancer



　本発明は、Ａ）キサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害剤と、Ｂ）ヒポキサンチンまたは体内でヒポキサンチンに変換され得る化合物と、を組み合わせてなるヒト又は動物の細胞内ＡＴＰ増強剤に関する。さらに詳しくは、Ａ）がアロプリノール又はトピロキソスタットである場合の前記細胞内ＡＴＰ増強剤に関する。


The present invention relates to a human or animal intracellular ATP enhancer comprising a combination of A) a xanthine oxidase / xanthine dehydrogenase inhibitor and B) hypoxanthine or a compound that can be converted into hypoxanthine in the body. More specifically, the present invention relates to the intracellular ATP enhancer when A) is allopurinol or topiroxostat.





　ＡＴＰ（adenosine triphosphate、以下単にＡＴＰということがある）は生物のエネルギーを蓄え、必要なときに供給する最も重要な化合物であり、ＡＴＰ減少は様々な疾患の病態に関連していると考えられている。例えば、各種の遺伝性溶血性貧血の原因として、赤血球内のＡＴＰ減少が溶血のメカニズムであると考えられている。例えば、鎌形赤血球症（非特許文献１）、ピルベートキナーゼ欠損症（非特許文献２）、球状赤血球症（非特許文献３）、楕円赤血球症（非特許文献３）、***状赤血球症（非特許文献４）、サラセミア（非特許文献５）などである。



　また、虚血性心疾患による心筋障害のメカニズムとして細胞内ＡＴＰ低下が示唆されており（非特許文献６）、キサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害薬であるアロプリノールの高用量投与により慢性安定性狭心症の症状が抑えられたと報告されている（非特許文献７）。著者他は、アロプリノールがＡＴＰを増加させたことにより虚血性心疾患に良好な影響があったと示唆している（非特許文献７）。



　更に、ＡＴＰ増強療法は心不全に効果がある可能性が高い。米国では心不全患者にしばしば心臓移植が行われており、心不全の発生から死亡に至る期間ではなく、心不全の発生から心臓移植に至る期間が心不全進行の早さの目安になる。心臓移植に至る期間が短いことは心不全の進行が早いことを示す。欧米では遺伝性筋ＡＭＰ　deaminase（ＡＭＰＤ）欠損症の頻度が極めて高く、約２０％の一般人がヘテロ接合体欠損症である。研究により筋肉の遺伝的ＡＭＰＤ欠損者は、心不全発生から心臓移植に至る期間が長いことが知られている（非特許文献８）。また、ＡＭＰＤ阻害薬によりマウスの心不全が改善することが示唆されている（非特許文献９）。一般に運動をすると筋肉のＡＴＰは減少する。しかし、遺伝性筋ＡＭＰＤ欠損者は運動後も筋肉内ＡＴＰが減少しない、あるいは減少が抑制されていると報告されている（非特許文献１０）。即ち、ＡＭＰがＩＭＰ（inosine monophosphate、以下単にＩＭＰということがある）に変換されないためＡＭＰ減少が防止でき、ＡＴＰ減少も起きないのである（図６）。これより考えると、遺伝的筋ＡＭＰＤ欠損症では心筋細胞のＡＴＰ減少が起きにくく心不全の進行が抑えられたと考えられる。



　このようにＡＴＰを増強することにより、ＡＴＰ低下が病態に関係する疾患の病態を改善することが期待できる。


ATP (adenosine triphosphate, sometimes referred to simply as ATP) is the most important compound that stores the energy of living organisms and supplies it when needed. ATP reduction is thought to be related to the pathology of various diseases. Yes. For example, as a cause of various hereditary hemolytic anemias, ATP reduction in erythrocytes is considered to be a mechanism of hemolysis. For example, sickle cell disease (Non-patent document 1), pyruvate kinase deficiency (Non-patent document 2), spherocytosis (Non-patent document 3), elliptical erythrocytosis (Non-patent document 3), cleft erythrocytosis (non-patent document 3) Patent Document 4), Thalassemia (Non-Patent Document 5), and the like.



In addition, a decrease in intracellular ATP has been suggested as a mechanism of myocardial injury due to ischemic heart disease (Non-patent Document 6), and administration of allopurinol, a xanthine oxidase / xanthine dehydrogenase inhibitor, has prevented chronic stable angina. It has been reported that the symptoms were suppressed (Non-patent Document 7). The authors and others suggest that allopurinol had a positive effect on ischemic heart disease by increasing ATP (Non-patent Document 7).



Furthermore, ATP augmentation therapy is likely to be effective for heart failure. In the United States, heart transplantation is often performed for heart failure patients, and the period from the occurrence of heart failure to heart transplantation is a measure of the speed of progression of heart failure rather than the period from the occurrence of heart failure to death. A short period leading to heart transplantation indicates that heart failure progresses rapidly. In Europe and America, the frequency of hereditary muscle AMP deaminase (AMPD) deficiency is extremely high, and about 20% of ordinary people have heterozygote deficiency. Studies have shown that muscular genetic AMPD deficient patients have a long period of time from heart failure to heart transplantation (Non-patent Document 8). In addition, it has been suggested that heart failure in mice is improved by an AMPD inhibitor (Non-patent Document 9). In general, muscle ATP decreases with exercise. However, it has been reported that hereditary muscle AMPD deficient patients do not decrease intramuscular ATP even after exercise or suppress the decrease (Non-patent Document 10). That is, since AMP is not converted to IMP (inosine monophosphate, hereinafter sometimes referred to as IMP), AMP reduction can be prevented and ATP reduction does not occur (FIG. 6). In view of this, it is considered that ATP deficiency of cardiomyocytes hardly occurs in the hereditary muscle AMPD deficiency and the progression of heart failure is suppressed.



By enhancing ATP in this way, it can be expected that the reduction in ATP improves the pathology of diseases related to the pathology.





　また、イノシン投与によりＡＴＰ増加により筋肉運動の増強作用が起きることを期待し、イノシンが筋肉運動を増強するという報告があるが、最近はその効果を否定する報告もある（非特許文献１１）。しかし、イノシンによる筋運動増強作用が証明されない原因は、イノシンのみではＡＴＰ増強作用が不完全なためである可能性がある。



　西野他は、筋萎縮性側索硬化症（以下、単にＡＬＳということがある）モデルマウスにフェブキソスタットなどのキサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害薬を投与し、疾患進行を抑制することを見出している（非特許文献１２）。西野他はフェブキソスタットの投与により神経細胞のＡＴＰが増加することが疾患進行を抑制させると推測している　（非特許文献１２）。実際に、ＡＬＳモデルマウスのＮａ／Ｋ－ＡＴＰａｓｅをknock-downすることにより神経細胞の変性が抑制されると報告されている（非特許文献１２）。また、ＡＬＳ患者ではＮａ／Ｋ－ＡＴＰａｓｅ活性が更新していると報告されている（非特許文献１３）。即ち、ＡＴＰを減少させるＮａ／Ｋ－ＡＴＰａｓｅの活性化がＡＬＳの発症あるいは進行を促進し、ＡＴＰ減少を抑えるＮａ／Ｋ－ＡＴＰａｓｅの抑制がＡＬＳの進行を抑えると考えられる。



　更に、イノシン投与によりパーキンソン病（非特許文献１４）、多発性硬化症（非特許文献１５）の症状が軽減するという報告がある。著者他はいずれも血清尿酸値の低下が疾患に関係しているのではないかと考えている。イノシンを投与することにより血清尿酸値を上昇させ、治療効果を発揮することを目的として臨床試験を行っている。しかし、これまでの報告では効果は十分ではない。


In addition, there is a report that inosine enhances muscle movement in anticipation of an increase in ATP by administration of inosine, but recently there is also a report that denies the effect (Non-patent Document 11). However, the reason why inosine does not prove the muscle movement enhancing action may be due to the incomplete ATP enhancing action of inosine alone.



Nishino et al. Found that administration of xanthine oxidase / xanthine dehydrogenase inhibitors such as febuxostat to model mice with amyotrophic lateral sclerosis (hereinafter sometimes referred to as ALS) suppresses disease progression. (Non-patent document 12). Nishino et al. Speculate that administration of febuxostat increases ATP in neurons to suppress disease progression (Non-patent Document 12). In fact, it has been reported that knocking down Na / K-ATPase in ALS model mice suppresses neuronal degeneration (Non-patent Document 12). In addition, it has been reported that Na / K-ATPase activity is renewed in ALS patients (Non-patent Document 13). That is, activation of Na / K-ATPase that decreases ATP promotes the onset or progression of ALS, and suppression of Na / K-ATPase that suppresses ATP decrease suppresses the progression of ALS.



Furthermore, there is a report that administration of inosine reduces the symptoms of Parkinson's disease (Non-Patent Document 14) and multiple sclerosis (Non-Patent Document 15). The authors and others believe that a decrease in serum uric acid levels may be related to the disease. Clinical trials are being conducted with the aim of increasing the serum uric acid level by administering inosine and exerting a therapeutic effect. However, the effectiveness of previous reports is not sufficient.








　イノシンの単独投与によっても細胞内ＡＴＰは多少増加すると報告されている。実際に、Ogasawara他は２０－３０日低温で放置し、ＡＴＰが低下した赤血球にイノシンを加え１時間放置した後、ＡＴＰが上昇したことを報告している（非特許文献１６）。しかし、ヒト体内ではイノシンはヒポキサンチン、キサンチンを経て尿酸へと速やかに代謝される（図６）。従ってイノシンだけで十分なＡＴＰ増強作用を発揮するには不十分であった。また、フェブキソスタットの単独投与でも多少の細胞内ＡＴＰの増強は期待できるが、これだけでは不十分の可能性がある。



　本発明は、細胞内のＡＴＰを増強させる効果を有する組成物、そのうちでもイノシン単独、又はフェブキソスタット単独による増強効果を凌ぐような細胞内ＡＴＰ増強剤の提供を課題とする。


It has been reported that intracellular ATP is somewhat increased by administration of inosine alone. In fact, Ogasawara et al. Reported that ATP increased after standing at low temperature for 20-30 days, adding inosine to erythrocytes with reduced ATP, and leaving it for 1 hour (Non-patent Document 16). However, inosine is rapidly metabolized into uric acid via hypoxanthine and xanthine in the human body (FIG. 6). Therefore, inosine alone is insufficient to exert a sufficient ATP enhancing action. In addition, even a single administration of febuxostat can be expected to slightly enhance intracellular ATP, but this alone may be insufficient.



An object of the present invention is to provide a composition having an effect of enhancing intracellular ATP, and among them, an intracellular ATP enhancer that surpasses the enhancing effect of inosine alone or febuxostat alone.





　本発明は、上記課題を解決するためのものであって、以下の構成を有する。



〔１〕以下のＡ）及びＢ）を組み合わせてなる、ヒト又は動物の細胞内ＡＴＰ増強剤。



Ａ）キサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害剤



Ｂ）ヒポキサンチン、又は体内でヒポキサンチンに変換され得る化合物



〔２〕Ａ）が、フェブキソスタット、トピロキソスタット、アロプリノール、ヒドロキシアルカン、カルプロフェン、Ｙ－７００およびＫＵＸ－１１５１からなる群から選ばれるいずれか１以上である〔１〕に記載の細胞内ＡＴＰ増強剤。



〔３〕Ｂ）の体内でヒポキサンチンに変換され得る化合物が、イノシン、イノシン酸、アデニン、アデノシン、ＡＭＰ、ＡＤＰ、ＡＴＰ、サクシニルアデノシン、Ｓ－アデノシルメチオニン、Ｓ－アデノシルホモシステイン、メチルチオアデノシンおよびそれらの薬学的に許容される塩から選ばれるいずれか１以上の化合物である〔１〕又は〔２〕に記載の細胞内ＡＴＰ増強剤。



〔４〕Ａ）及びＢ）の組み合わせが、Ａ）及びＢ）を含む合剤又はキット剤である、〔１〕～〔３〕のいずれかに記載のＡＴＰ増強剤。



〔５〕細胞内ＡＴＰ増強剤としてイノシンと組み合わせて使用される、アロプリノール又はトピロキソスタット。


The present invention is for solving the above-described problems and has the following configuration.



[1] A human or animal intracellular ATP enhancer comprising a combination of the following A) and B).



A) Xanthine oxidase / xanthine dehydrogenase inhibitor



B) Hypoxanthine or a compound that can be converted into hypoxanthine in the body



[2] Intracellular ATP according to [1], wherein A) is any one or more selected from the group consisting of febuxostat, topiroxostat, allopurinol, hydroxyalkane, carprofen, Y-700 and KUX-1151 Enhancer.



[3] The compound that can be converted into hypoxanthine in B) is inosine, inosinic acid, adenine, adenosine, AMP, ADP, ATP, succinyladenosine, S-adenosylmethionine, S-adenosylhomocysteine, methylthioadenosine And the intracellular ATP enhancer according to [1] or [2], which is any one or more compounds selected from pharmaceutically acceptable salts thereof.



[4] The ATP enhancer according to any one of [1] to [3], wherein the combination of A) and B) is a mixture or a kit containing A) and B).



[5] Allopurinol or topiroxostat used in combination with inosine as an intracellular ATP enhancer.





　本発明の以下の、Ａ）及びＢ）の併用投与による細胞内ＡＴＰ増強効果により、ＡＴＰ減少が病態の一部を形成する様々な疾患、更にはＡＴＰの過剰供給により病態の進行が抑制される様々な疾患の治療薬を提供することが可能である。



Ａ）キサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害剤



Ｂ）ヒポキサンチン、又は体内でヒポキサンチンに変換され得る化合物


The following A) and B) combined effects of the present invention enhance intracellular ATP, and various diseases in which ATP decrease forms part of the disease state, and further, the progression of the disease state is suppressed by excessive supply of ATP. It is possible to provide therapeutic agents for various diseases.



A) Xanthine oxidase / xanthine dehydrogenase inhibitor



B) Hypoxanthine or a compound that can be converted into hypoxanthine in the body





Ａ～Ｅ群の投与を行った場合の血清尿酸値の推移を示すグラフである。横軸は測定期間（週）、縦軸は血清尿酸値（単位ｍｇ／ｄＬ）を示す。Ａ群：フェブキソスタット２０ｍｇ、１日２回、１４日間，Ｂ群：イノシン５００ｍｇ、１日２回、１４日間，Ｃ群：フェブキソスタット２０ｍｇ＋イノシン５００ｍｇ、１日２回、１４日間，Ｄ群：フェブキソスタット２０ｍｇ＋イノシン１０００ｍｇ、１日２回、１４日間，Ｅ群：フェブキソスタット３０ｍｇ、１日２回、１４日間（以下の図でも同様）6 is a graph showing the transition of serum uric acid level when administration in groups A to E is performed. The horizontal axis represents the measurement period (weeks), and the vertical axis represents the serum uric acid level (unit: mg / dL). Group A: febuxostat 20 mg, twice daily, 14 days, Group B: inosine 500 mg, twice daily, 14 days, Group C: febuxostat 20 mg + inosine 500 mg, twice daily, 14 days, Group D : Febuxostat 20 mg + inosine 1000 mg, twice daily, 14 days, group E: febuxostat 30 mg, twice daily, 14 days (the same applies to the following figures) Ａ～Ｅ群の投与を行った場合の尿中尿酸濃度／クレアチニン濃度の推移を示すグラフである。横軸は測定期間（週）、縦軸は尿中尿酸濃度／クレアチニン濃度（比）を示す。6 is a graph showing the transition of urinary uric acid concentration / creatinine concentration when administration in groups A to E is performed. The horizontal axis represents the measurement period (weeks), and the vertical axis represents the urinary uric acid concentration / creatinine concentration (ratio). Ａ～Ｅ群の投与を行った場合の血液中ＡＴＰ及びＡＤＰの推移を示すグラフである。横軸は測定期間（週）、縦軸はＡＴＰ又はＡＤＰ濃度（単位μＭ）を示す。ＡＴＰ：実線、ＡＤＰ：破線。2 is a graph showing changes in ATP and ADP in blood when administration in groups A to E is performed. The horizontal axis represents the measurement period (weeks), and the vertical axis represents the ATP or ADP concentration (unit: μM). ATP: solid line, ADP: broken line. Ａ～Ｅ群の投与を行った場合の血液中Ｈｘ（ヒポキサンチン）、Ｘ（キサンチン）の推移を示すグラフである。横軸は測定期間（週）、縦軸はＨｘ又はＸ濃度（単位μＭ）を示す。Ｈｘ：実線、Ｘ：破線。3 is a graph showing changes in Hx (hypoxanthine) and X (xanthine) in blood when administration in groups A to E is performed. The horizontal axis represents the measurement period (weeks), and the vertical axis represents the Hx or X concentration (unit: μM). Hx: solid line, X: broken line. Ａ～Ｅ群の投与を行った場合の尿中の各種プリン体の濃度（μＭ）の推移を示すグラフである。6 is a graph showing changes in the concentration (μM) of various purines in urine when administration is performed in groups A to E. ＡＴＰ合成に関する経路を示す図である。It is a figure which shows the path | route regarding ATP synthesis | combination.



　本発明の１つの有効成分は、Ａ）キサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害剤である。キサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害剤としては、フェブキソスタット（商品名フェブリク（帝人ファーマ））、トピロキソスタット（商品名ウリアデック（三和化学研究所）、トピロリック（富士薬品））、アロプリノール（商品名ザイロリック（グラクソ・スミスクライン））、ヒドロキシアルカン、カルプロフェン、Ｙ－７００（田辺三菱製薬）、及びＫＵＸ－１１５１（キッセイ薬品）などが挙げられる。また、これらの化合物の薬学的に許容される塩も本発明のＡ）の有効成分に含まれる。



　本発明のもう１つの有効成分は、Ｂ）ヒポキサンチン、又は体内でヒポキサンチンに変換され得る化合物である。体内でヒポキサンチンに変換され得る化合物としては、例えばイノシン、イノシン酸、アデニン、アデノシン、ＡＭＰ、ＡＤＰ、ＡＴＰ、サクシニルアデノシン、Ｓ－アデノシルメチオニン、Ｓ－アデノシルホモシステイン、メチルチオアデノシン及びそれらの薬学的に許容される塩から選ばれるいずれか１以上の化合物が挙げられるが、これらの化合物も結局はヒポキサンチンに分解されるため、イノシンの代わりにこれらの物質を使用することが可能である（図６）。このうちでもイノシンが望ましい。


One active ingredient of the present invention is A) a xanthine oxidase / xanthine dehydrogenase inhibitor. Xanthine oxidase / xanthine dehydrogenase inhibitors include febuxostat (trade name Febrik (Teijin Pharma)), topiroxostat (trade name Uriadeck (Sanwa Chemical Research Laboratories), Topyrrolic (Fuji Pharmaceutical)), allopurinol (trade name Zyrolic) (GlaxoSmithKline)), hydroxyalkane, carprofen, Y-700 (Mitsubishi Tanabe Seiyaku), KUX-1151 (Kissei Pharmaceutical) and the like. Further, pharmaceutically acceptable salts of these compounds are also included in the active ingredient A) of the present invention.



Another active ingredient of the present invention is B) hypoxanthine, or a compound that can be converted into hypoxanthine in the body. Examples of compounds that can be converted into hypoxanthine in the body include, for example, inosine, inosinic acid, adenine, adenosine, AMP, ADP, ATP, succinyladenosine, S-adenosylmethionine, S-adenosylhomocysteine, methylthioadenosine and their pharmaceuticals Any one or more compounds selected from pharmaceutically acceptable salts are included, but since these compounds are eventually decomposed into hypoxanthine, it is possible to use these substances instead of inosine ( FIG. 6). Of these, inosine is desirable.





　本発明の細胞内ＡＴＰ増強作用とは、本発明の有効成分が細胞内でＡＴＰの生成を増加させる効果をいう。増加には、定常からの増加、又は減少を抑制すること、あるいは減少した状態から定常に近づけること、のいずれをも含む意味で用いられる。本発明の効果の確認は、細胞内ＡＴＰ濃度の直接の測定の他、ＡＴＰ増加によってもたらされる他の代謝経路の産物の測定によって間接的に測定することもできる。


The intracellular ATP enhancing action of the present invention refers to the effect that the active ingredient of the present invention increases the production of ATP in the cell. The term “increase” is used to mean any of suppressing an increase or decrease from the steady state, or bringing the decreased state close to the steady state. Confirmation of the effect of the present invention can be measured indirectly by directly measuring the intracellular ATP concentration, or by measuring products of other metabolic pathways caused by the increase in ATP.





　本発明の「Ａ）及びＢ）を組み合わせてなる」とは、Ａ）の成分とＢ）の成分が投与対象の体内でＡＴＰ増強作用を発揮するように組み合わされた態様をすべて含む意味で用いられる。したがって、Ａ）の成分とＢ）の成分が混合されて組成物を形成している合剤（配合剤ともいう）、あるいは混合されることなく、物理的に別々に存在するが、投与される際に同時期に投与されるようにまとめられて存在する薬剤のいずれをも含む。



　合剤（配合剤）の例としては、混合されて製剤化されたものが挙げられる。製剤化の例としては、顆粒、粉体、固形剤、液体などの経口剤、吸入剤などが挙げられる。



　物理的に別々に存在するが、投与される際に同時期に投与されるようにまとめられて存在する薬剤としては、いわゆるキット剤や、１つの袋に取りまとめられる形態が挙げられる。



　同時期とは、必ずしも厳密な意味での同時を意味せず、本発明のＡＴＰ増強作用効果が発揮される範囲で間隔を置く場合も本発明の同時期に含むものとする。例えば、一方を食前、一方を食後に飲むような場合は本発明の同時期に投与される場合に相当する。



　また、本発明は、Ａ）及びＢ）を併用投与する工程を含む細胞内ＡＴＰ増強方法、ＡＴＰ増加方法ともとらえることができる。


The term “combined with A) and B) of the present invention is used in the meaning of including all aspects in which the component A) and the component B) are combined so as to exert an ATP enhancing action in the body of the administration subject. It is done. Therefore, a mixture (also referred to as a compounding agent) in which the component A) and the component B) are mixed to form a composition, or is physically present without being mixed, but is administered. Any of the agents present together as being administered at the same time.



Examples of the mixture (compounding agent) include those prepared by mixing. Examples of the preparation include oral preparations such as granules, powders, solid preparations, liquids, and inhalants.



Examples of the drugs that exist physically separately but are combined to be administered at the same time when administered include so-called kit agents and forms that are collected in one bag.



The term “same time” does not necessarily mean the same time in the strict sense, and includes the case where an interval is set within a range in which the ATP enhancing effect of the present invention is exhibited. For example, the case where one is taken before a meal and the other is taken after a meal corresponds to the case of administration at the same time of the present invention.



The present invention can also be understood as an intracellular ATP enhancing method and an ATP increasing method including the step of coadministering A) and B).





　本発明のＡＴＰ増強剤の投与量は、例えば、Ａ）のアロプリノールは、約５０ｍｇ～約８００ｍｇ／日、トピロキソスタットは、４０～１６０ｍｇ／日、フェブキソスタットは、１０～８０ｍｇ／日が望ましい。また、Ｂ）のイノシンは、０．５～４．０ｇ／日が望ましく、Ｂ）ヒポキサンチン、または体内でヒポキサンチンに変換され得る化合物の有効量も前記イノシンの量に相当する量を分子量により換算して求めることができる。


The dosage of the ATP enhancer of the present invention is preferably about 50 mg to about 800 mg / day for allopurinol of A), 40 to 160 mg / day for topiroxostat, and 10 to 80 mg / day for febuxostat. . In addition, the inosine of B) is preferably 0.5 to 4.0 g / day, and the effective amount of B) hypoxanthine, or a compound that can be converted into hypoxanthine in the body, is an amount corresponding to the amount of inosine depending on the molecular weight. It can be obtained by conversion.





　投与方法は、上記投与量をそれぞれ１日１回又は２回以上に分けて投与することが可能である。このうちでも、フエブキソスタットは、従来のフェブキソスタットの用法のように１日１回投与ではなく、１日２回の投与を行うことが望ましい。また、イノシンも１日１回よりも２回の投与が望ましい。したがって、イノシン、フェブキソスタットともに１日２回にわけて投与することがさらに望ましい。また、アロプリノール、トピロキソスタットも同様に１日１回よりも２回の投与が望ましい。



　合剤とする場合は、１日の投与量、投与方法を考慮して調整すればよく、アロプリノール１００ｍ、トピロキソスタット８０ｍｇ、フェブキソスタット２０ｍｇ、又は４０ｍｇにイノシン０．５ｇ、１ｇ、１．５ｇ、又は２ｇを加えたものなどが望ましい。


As for the administration method, it is possible to divide and administer the above dose once or twice a day. Among these, it is desirable to administer febuxostat twice a day instead of once a day as in the conventional use of febuxostat. Inosine is also preferably administered twice a day rather than once a day. Therefore, it is more desirable to administer both inosine and febuxostat twice a day. Similarly, allopurinol and topiroxostat are preferably administered twice a day rather than once a day.



In the case of a mixture, it may be adjusted in consideration of the daily dose and administration method, and allopurinol 100 m, topiroxostat 80 mg, febuxostat 20 mg, or 40 mg inosine 0.5 g, 1 g, 1.5 g Or 2 g added is desirable.





　本発明医薬の投与形態は特に限定されず、経口又は非経口のいずれの投与形態でもよい。また、投与形態に応じて適当な剤形とすることができ、例えば注射剤、あるいはカプセル剤、錠剤、顆粒剤、散剤、丸剤、細粒剤などの経口剤、直腸投与剤、油脂性坐剤、水性坐剤などの各種製剤に調製することができる。



　本発明医薬は、有効成分Ａ）及びＢ）を含むことから、有効成分Ａ）の投与形態とＢ）の投与形態は同じであってもよいし、異なってもよい。同じ投与形態の例としては、両方を錠剤で経口投与する場合、両者を合わせた合剤として経口投与する場合、両者を混合した注射剤で投与する場合などが挙げられる。また、異なる投与形態の例としては、一方を経口剤、一方を注射剤などで投与する場合が挙げられる。


The dosage form of the medicament of the present invention is not particularly limited, and any oral or parenteral dosage form may be used. In addition, it can be made into an appropriate dosage form according to the dosage form, for example, an injection, or an oral preparation such as a capsule, a tablet, a granule, a powder, a pill, and a fine granule, a rectal administration agent, and an oily seat. And various preparations such as suppositories and aqueous suppositories.



Since the medicament of the present invention contains the active ingredients A) and B), the dosage form of the active ingredient A) and the dosage form of B) may be the same or different. Examples of the same dosage form include the case where both are administered orally in tablets, the case where they are administered orally as a combination of both, and the case where they are administered as a mixed injection. Moreover, as an example of a different dosage form, the case where one is administered by an oral agent and the other is administered by an injection etc. is mentioned.





　本発明の投与対象は、ヒト又は動物であり、ＡＴＰの増強が必要な状態にあるヒト又は動物である。



　対象疾患としては、ＡＴＰ減少が病態に関連していることが強く示唆される、以下の疾患（１）溶血性貧血（２）虚血性心疾患（３）心不全（４）筋萎縮性側索硬化症（５）パーキンソン病（６）ＡＤＳＬ欠損症が挙げられる。このうちでも特に、（２）虚血性心疾患（３）心不全（４）筋萎縮性側索硬化症に効果的である。


The administration target of the present invention is a human or animal, and is a human or animal in a state where ATP enhancement is necessary.



The following diseases are strongly suggested that ATP reduction is related to the pathological condition: (1) hemolytic anemia (2) ischemic heart disease (3) heart failure (4) amyotrophic lateral sclerosis (5) Parkinson's disease (6) ADSL deficiency. Among these, it is particularly effective for (2) ischemic heart disease (3) heart failure (4) amyotrophic lateral sclerosis.





　本発明のＡＴＰ増強剤は、本発明の作用を損なわない範囲で他の医薬とさらに組み合わせることも可能である。



　以下、本発明を実施例をもとに具体的に説明するが、本発明はこれらに限定されるものではない。


The ATP enhancer of the present invention can be further combined with other drugs as long as the effects of the present invention are not impaired.



Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited thereto.





〔試験例１〕臨床試験（フェブキソスタットとイノシンの併用投与）



１．各種測定方法



（１）臨床検査



　下記項目以外は定法により測定した。



（２）血清尿酸値



　臨床化学自動分析装置はアークレイ株式会社製の乾式臨床化学分析測定ユニットを用い、血清尿酸値の測定はウリカーゼーペルオキシダーゼ法を用いた。



（３）尿中尿酸濃度／クレアチニン濃度



　尿中尿酸濃度は尿量により変化するため、尿中クレアチニン濃度で除した、尿中尿酸／クレアチニンの値を用い、尿中尿酸量を評価した。尿酸値の測定方法は血清尿酸値と同じ。



（４）血液中プリン体濃度



　末梢血中の各種プリン体の測定は、文献によった。簡単に述べると、末梢血をＥＤＴＡ採血し、５００μＬ＋５００μＬ　ice cold ８％ＰＣＡと混合し、直ちに５秒Ｖｏｒｔｅｘ、１２，０００ｘ ｇで４℃で１０分間遠心、上清を－８０度で保存した。サンプルが集まった状態で、溶解し、溶解液６５０μＬに４０μＬの２ＭＫ２ＣＯ３ｉｎ６ＭＫＯＨを加え、ＰＣＡの沈殿と中性化を同時に行った。これを、１２，０００ｘ　ｇで摂氏４度で１０分間遠心後、上清４０μＬに移動相１６０μＬを加えＨＰＬＣにかけた。ＨＰＬＣの条件も下記文献によった。プリン体の量は全血１Ｌ中に含まれるモル量で表した。



　文献



　Coolen EJ, Arts IC, Swennen EL, Bast A, Stuart MA,Dagnelie PC. Simultaneous determination of adenosine triphosphate and itsmetabolites in human whole blood by RP-HPLC and UV-detection. J Chromatogr BAnalyt Technol Biomed Life Sci. 2008 Mar 15;864(1-2):43-51.



（５）尿中プリン体濃度



　上記（４）と同じ方法によりプリン体濃度を測定した。


[Test Example 1] Clinical trial (combination of febuxostat and inosine)



1. Various measurement methods



(1) Clinical examination



The items other than the following items were measured by a conventional method.



(2) Serum uric acid level



The automatic clinical chemistry analyzer used a dry clinical chemistry analysis measurement unit manufactured by ARKRAY, Inc., and the uric acid peroxidase method was used to measure the serum uric acid level.



(3) Urinary uric acid concentration / creatinine concentration



Since the urinary uric acid concentration varies depending on the amount of urine, the value of urinary uric acid / creatinine divided by the urinary creatinine concentration was used to evaluate the urinary uric acid amount. The method for measuring uric acid levels is the same as serum uric acid levels.



(4) Purine concentration in blood



The measurement of various purines in peripheral blood was based on literature. Briefly, peripheral blood was collected from EDTA, mixed with 500 μL + 500 μL ice cold 8% PCA, immediately centrifuged for 5 seconds at 4 ° C. at 12,000 × g for 5 seconds, and the supernatant was stored at −80 degrees. In a state where the sample was collected, the sample was dissolved and 40 μL of 2MK 2 CO 3 in6MKOH was added to 650 μL of the solution to simultaneously precipitate and neutralize PCA. This was centrifuged at 12,000 × g for 10 minutes at 4 ° C., and 160 μL of the mobile phase was added to 40 μL of the supernatant and subjected to HPLC. The conditions of HPLC were also based on the following literature. The amount of purine was expressed as the molar amount contained in 1 L of whole blood.



Literature



Coolen EJ, Arts IC, Swennen EL, Bast A, Stuart MA, Dagnelie PC. Simultaneous determination of adenosine triphosphate and itsmetabolites in human whole blood by RP-HPLC and UV-detection. J Chromatogr BAnalyt Technol Biomed Life Sci. 2008 Mar 15; 864 (1-2): 43-51.



(5) Purine concentration in urine



Purine concentration was measured by the same method as in (4) above.





２．投与試験



（１）投与対象



　日本人の健康成人男性１６名を、I期は１名、第II期は１５名をＡ群～Ｅ群に各群３名ずつに分けて下記投与試験を行った。



（２）投与内容及び投与スケジュール



（２－１）第Ｉ期



　１名に対し、フェブキソスタット２０ｍｇとイノシン５００ｍｇ、１日２回の同時投与を１４日間行い、安全性を確認した。



（２）第ＩＩ期



第Ｉ期終了後、下記に示す内容で、各群３名に投与を行った。



　　　Ａ群　フェブキソスタット２０ｍｇ、１日２回、１４日間



　　　Ｂ群　イノシン５００ｍｇ、１日２回、１４日間



　　　Ｃ群　フェブキソスタット２０ｍｇとイノシン５００ｍｇ、１日２回、１４日間



　　　Ｄ群　フェブキソスタット２０ｍｇとイノシン１０００ｍｇ、１日２回、１４日間



　　　Ｅ群　フェブキソスタット３０ｍｇ、１日２回、１４日間


2. Dosing test



(1) Administration target



The following administration test was conducted by dividing 16 healthy Japanese adult males, 1 in stage I and 15 in stage II into groups A to E, each divided into 3 groups.



(2) Administration content and administration schedule



(2-1) Phase I



For one patient, febuxostat 20 mg and inosine 500 mg were co-administered twice daily for 14 days to confirm safety.



(2) Phase II



After completion of Phase I, administration was performed to 3 patients in each group with the following contents.



Group A febuxostat 20mg, 2 times a day, 14 days



Group B Inosine 500 mg, 2 times a day, 14 days



Group C febuxostat 20 mg and inosine 500 mg twice a day for 14 days



Group D febuxostat 20 mg and inosine 1000 mg, twice a day for 14 days



Group E febuxostat 30 mg, 2 times a day, 14 days





３．結果



３－１．第Ｉ期



（１）有害事象



（１－１）身体所見等



　被検者は自覚所見、及び身体所見で有害事象はなかった。



（１－２）臨床検査



　８日目のＡＳＴが４９Ｕ／Ｌ（基準値１０～４０）と異常値を示したが、１５日目に２９Ｕ／Ｌと基準値に復した。８日目のクレアチニンが１．０９ｍｇ／ｄＬ（基準値０．６１～１．０４）と異常値を示したが、１５日目に０．９８ｍｇ／ｄＬと基準値に復した。８日目の血糖値が６６ｍｇ／ｄＬ、１５日目が６７ｍｇ／ｄＬ（基準値７０～１０９）と異常値を示した。



（２）血清尿酸値の変化



　血清尿酸値は、１日目４．９ｍｇ／ｄＬ、８日目２．５ｍｇ／ｄＬ、１５日目２．９ｍｇ／ｄＬであった。フェブキソスタット４０ｍｇ、イノシン１ｇの服用により、平均２．２ｍｇ／ｄＬ低下したことになる。


3. result



3-1. Phase I



(1) Adverse events



(1-1) Physical findings



There were no adverse events in the subject's subjective and physical findings.



(1-2) Clinical examination



The AST on the 8th day showed an abnormal value of 49 U / L (reference value 10 to 40), but on the 15th day, it returned to the reference value of 29 U / L. On the 8th day, creatinine showed an abnormal value of 1.09 mg / dL (reference value 0.61 to 1.04), but on the 15th day, it returned to the standard value of 0.98 mg / dL. The blood glucose level on the 8th day was 66 mg / dL, and the 15th day was 67 mg / dL (reference value 70 to 109), indicating abnormal values.



(2) Changes in serum uric acid levels



Serum uric acid levels were 4.9 mg / dL on day 1, 2.5 mg / dL on day 8, and 2.9 mg / dL on day 15. By taking febuxostat 40 mg and inosine 1 g, the average decreased by 2.2 mg / dL.





３－２．第ＩＩ期



（１）有害事象



（１－１）身体所見



　年齢、身長、体重、ＢＭＩ、最高血圧、最低血圧、脈拍、体温に群間の著明な差はなかった。最高血圧、最低血圧、脈拍、体温も、被検者１名において脈拍数の著明な増加が見られた以外は、著明な変化は見られなかった。



（１－２）各検査値の有害事象（尿酸値を除く）



　総蛋白、アルブミン、総ビリルビン、ＡＳＴ、ＡＬＴ、ＡＬ－Ｐ、ＬＤ、γ－ＧＴ、総コレステロ－ル、中性脂肪、ＨＤＬコレステロ－ル、ＬＤＬコレステロール定量、尿酸、尿素窒素、クレアチニン、ナトリウム、クロ－ル、カリウム、カルシウム、血糖検査、ＨｂＡ１ｃ（ＮＧＳＰ）、白血球数ＷＢＣ、赤血球数ＲＢＣ、血色素量Ｈｂ、ヘマトクリツトＨｔ、血小板数ＰＬＴ、ＢＡＳＯ、ＥＯＳＩＮＯ、ＮＥＵＴＲＯ、ＬＹＭＰＨ、ＭＯＮＯについて測定した。



　特に各群の背景に差は見られなかった。また、血清尿酸値以外は特に著明な変化は認められなかった。


3-2. Phase II



(1) Adverse events



(1-1) Physical findings



There were no significant differences between groups in age, height, weight, BMI, systolic blood pressure, diastolic blood pressure, pulse, body temperature. There was no significant change in systolic blood pressure, diastolic blood pressure, pulse, or body temperature, except for a significant increase in pulse rate in one subject.



(1-2) Adverse events of each test value (excluding uric acid level)



Total protein, albumin, total bilirubin, AST, ALT, AL-P, LD, γ-GT, total cholesterol, neutral fat, HDL cholesterol, LDL cholesterol determination, uric acid, urea nitrogen, creatinine, sodium, black -Lead, potassium, calcium, blood glucose test, HbA1c (NGSP), white blood cell count WBC, red blood cell count RBC, hemoglobin amount Hb, hematocrit Ht, platelet count PLT, BASO, EOSINO, NEUTRO, LYMPH, MONO.



In particular, there was no difference in the background of each group. In addition, no significant changes were observed except for serum uric acid levels.





（２）血清尿酸値の変化



　図１にＡ～Ｅの群ごとのグラフを示す。イノシンのみを投与したＢ群では血清尿酸値の著増が見られた（最高８．１ｍｇ／ｄＬ）。Ａ、Ｃ～Ｅ群では血清尿酸値の低下が見られた。フェブキソスタット４０ｍｇ／日投与例では血清尿酸値が２ｍｇ／ｄＬ未満に低下した例は無かったが、フェブキソスタット６０ｍｇ／日投与群であるＥ群では血清尿酸値が２ｍｇ／ｄＬ未満になる例が見られた。



　フェブキソスタット４０ｍｇ／ｄＬの投与により、血清尿酸値は２．５３ｍｇ／ｄＬ低下したが（Ａ群）、同時にイノシンを１日１ｇ投与した例では２．２３ｍｇ／ｄＬ低下（Ｃ群）、１日２ｇ投与した例では１．４７ｍｇ／ｄＬ低下（Ｄ群）した。



　フェブキソスタット６０ｍｇ／ｄＬの投与により、血清尿酸値は３．９３ｍｇ／ｄＬ低下した（Ｅ群）。一日１ｇのイノシンにより血清尿酸値は平均２．５７ｍｇ／ｄＬ上昇した（Ｂ群）。これをフェブキソスタット投与下におけるイノシンの血清尿酸値増加効果から検討すると、フェブキソスタット４０ｍｇ／日の下ではイノシン１ｇ／日投与により血清尿酸値は０．３ｍｇ／ｄＬ、２ｇ／日投与により血清尿酸値は１．０６ｍｇ／ｄＬ増加したことになる。前述のように、フェブキソスタット非投与下では１ｇ／日のイノシン投与により血清尿酸値は２．５７ｍｇ／ｄＬ増加したのでフェブキソスタット投与下ではイノシンによる血清尿酸上昇作用が大幅に抑制されることになる。


(2) Changes in serum uric acid levels



FIG. 1 shows a graph for each of groups A to E. A significant increase in serum uric acid levels was observed in group B administered only with inosine (maximum 8.1 mg / dL). In groups A and C to E, a decrease in serum uric acid level was observed. In the case of febuxostat 40 mg / day administration, the serum uric acid level was not reduced to less than 2 mg / dL, but in the case of group E being febuxostat 60 mg / day administration, the serum uric acid level was less than 2 mg / dL. It was observed.



The administration of febuxostat 40 mg / dL decreased the serum uric acid level by 2.53 mg / dL (Group A), but in the case where 1 g of inosine was administered at the same time, decreased 2.23 mg / dL (Group C), 1 day. In the case of administration of 2 g, the dose decreased by 1.47 mg / dL (Group D).



Administration of febuxostat 60 mg / dL decreased the serum uric acid level by 3.93 mg / dL (Group E). Serum uric acid level increased by an average of 2.57 mg / dL with 1 g of inosine per day (Group B). When this is examined from the effect of increasing the serum uric acid level of inosine under febuxostat administration, the serum uric acid level is 0.3 mg / dL by administration of inosine 1 g / day and serum by administration of 2 g / day under febuxostat 40 mg / day. The uric acid value increased by 1.06 mg / dL. As described above, the serum uric acid level increased by 2.57 mg / dL by administration of 1 g / day of inosine in the absence of febuxostat administration, so that the increase in serum uric acid by inosine is significantly suppressed in the administration of febuxostat. become.





（３）尿中尿酸濃度／クレアチニン濃度



　各群ごとの尿中尿酸濃度／クレアチニン濃度の第０週から第２週までの変化を図２に示した。尿中尿酸／クレアチニンはＢ群のみがイノシン投与により著明に増加した。Ａ、Ｃ－Ｇ群はすべて尿中尿酸／クレアチニンが低下した。これらの尿中尿酸濃度／クレアチニン濃度の変化は、血清尿酸値の変化のパターンとほぼ同じであった。


(3) Urinary uric acid concentration / creatinine concentration



Changes in urine uric acid concentration / creatinine concentration for each group from week 0 to week 2 are shown in FIG. Urinary uric acid / creatinine was markedly increased only in group B by inosine administration. In groups A and CG, urinary uric acid / creatinine decreased. These changes in urinary uric acid concentration / creatinine concentration were almost the same as the pattern of changes in serum uric acid levels.





（４）血液中プリン体濃度



　各群ごとの血液中のプリン体の濃度の第０週から第２週までの変化を図３～４に示した。



　図３はＡ～Ｅ群ごとの血液中ＡＴＰ／ＡＤＰの濃度を示す。Ａ、Ｂ群はＡＴＰ濃度は変化なし、Ｃ、Ｄ群ではＡＴＰが上昇した事を示唆している。Ｅ群は一定の傾向が見られない。即ち、フェブキソスタット、イノシン単独投与ではＡＴＰの上昇は見られないが、併用例、特にフェブキソスタット４０ｍｇ／日、イノシン１～２ｇ／日の例ではＡＴＰの上昇が見られた。それらの量を超えたフェブキソスタット、イノシンの併用では一定の傾向が見られなかった。



　図４はＡ～Ｅ群ごとの血液中ヒポキサンチン（Ｈｘ）とキサンチン（Ｘ）の濃度を示す。フェブキソスタット４０ｍｇ／日のみの投与群（Ａ群）ではＨｘ濃度は不変であるが、Ｘは著明に増加した。イノシン１ｇ／日のみの投与群（Ｂ群）ではＨｘ、Ｘともに不変であった。なお、血液中イノシン濃度も測定したが、イノシン単独投与群を含め、イノシンの濃度の上昇は見られなかった（Ａ－Ｅ群）。これはイノシンをＨｘに変換する酵素、Purine nucleoside phosphorylase（ＰＮＰ）の濃度が血液中で極めて高く、イノシンは速やかにＨｘに分解され、更にはＨｘ、Ｘへと分解されると考えられる。フェブキソスタット４０ｍｇ／日にイノシンを１～２ｇ／日併用した例ではＨｘとＸの両方の著明な上昇が認められた。即ち、フェブキソスタット単独でもイノシン単独でも見られなかった「血液中のＨｘの上昇」という効果が併用により見られた（図４）。



　フェブキソスタット６０ｍｇ／日の単独投与例ではＸの上昇とともにＨｘの軽微な上昇が見られた（図４Ｅ）。


(4) Purine concentration in blood



Changes in blood purine concentrations in each group from week 0 to week 2 are shown in FIGS.



FIG. 3 shows the concentration of ATP / ADP in blood for each of groups A to E. The A and B groups did not change the ATP concentration, and the C and D groups suggested that ATP increased. The E group does not show a certain tendency. That is, no increase in ATP was observed when febuxostat or inosine alone was administered, but an increase in ATP was observed in the combination examples, particularly febuxostat 40 mg / day and inosine 1-2 g / day. When febuxostat and inosine were used in excess of these amounts, a certain tendency was not observed.



FIG. 4 shows the concentrations of hypoxanthine (Hx) and xanthine (X) in blood for groups A to E. In the group administered only with febuxostat 40 mg / day (Group A), the Hx concentration was unchanged, but X was significantly increased. In the inosin 1 g / day only administration group (Group B), both Hx and X were unchanged. The inosine concentration in the blood was also measured, but no increase in inosine concentration was observed including the inosine alone administration group (AE group). This is thought to be because the concentration of purine nucleoside phosphorylase (PNP), an enzyme that converts inosine to Hx, is extremely high in blood, and inosine is rapidly decomposed into Hx and further decomposed into Hx and X. In the case where febrxostat 40 mg / day and inosine were combined at 1 to 2 g / day, both Hx and X were markedly increased. That is, the effect of “increase in Hx in blood”, which was not observed with febuxostat alone or inosine alone, was seen with the combination (FIG. 4).



In the case of febuxostat 60 mg / day alone, a slight increase in Hx was observed with an increase in X (FIG. 4E).





（５）尿中プリン体濃度



　各群ごとの尿中イノシン、Ｈｘ、Ｘ、尿酸の濃度の第０週から第２週までの変化を図５に示す。尿中Ｈｘはフェブキソスタット単独投与例では中程度の上昇を示すが、フェブキソスタットとイノシンの併用例では著明な上昇を示した。イノシン単独使用例ではＨｘとＸの上昇は認められなかった。Ｘの濃度はフェブキソスタットの単独投与例でも著明に上昇したが、フェブキソスタットとイノシンの併用例では更に著明に上昇した。



　尿中Ｘの各群での最大の濃度は、Ａ群５５６．０、Ｂ群６１．９、Ｃ群２０２３．３、Ｄ群１４７４．８、Ｅ群８６７．７μＭであった。即ち、フェブキソスタット４０ｍｇとイノシン１、２ｇを併用した例では、フェブキソスタット４０ｍｇ単独投与群に比較して最大尿中Ｘ濃度が３．６４、２．６５倍であった。


(5) Purine concentration in urine



FIG. 5 shows changes in urinary inosine, Hx, X, and uric acid concentrations from week 0 to week 2 for each group. Urinary Hx increased moderately in the case of febuxostat alone, but markedly increased in the combination of febuxostat and inosine. In the case of using inosine alone, no increase in Hx and X was observed. The concentration of X was also significantly increased in the case of single administration of febuxostat, but was further significantly increased in the case of combined use of febuxostat and inosine.



The maximum concentration of urinary X in each group was A group 556.0, B group 61.9, C group 2023.3, D group 1474.8, and E group 867.7 μM. That is, in the case where febuxostat 40 mg and inosine 1 and 2 g were used in combination, the maximum urinary X concentration was 3.64 and 2.65 times that of the febuxostat 40 mg single administration group.





４．試験例４の考察



（１）フェブキソスタットとイノシンの併用は、２週間連続服用試験において、フェブキソスタット４０ｍｇ／日、イノシン２ｇ／日以下の用量で安全であった。また、これらの併用群で血液中ＡＴＰの増加が見られたが、それ以外の単独投与群ではそのような変化は観察されなかった。



（２）フェブキソスタット単独投与では血清尿酸値の著減、イノシンの単独投与では血清尿酸値の著増が見られ、併用療法では中程度の低下が見られた。



（３）どの群でもイノシンの増加は見られず、ＰＮＰによりＨｘに代謝されたと考えられた。



（４）イノシンの単独投与群では血液中も尿中もＨｘもＸも増加せず、尿酸に変化したと考えられた。



（５）フェブキソスタット単独投与群ではＸが中程度増加したが、Ｈｘは血液中、尿中を含め軽度－中程度増加した。



（６）フェブキソスタットとイノシンの併用ではＨｘ、Ｘが血液中、尿中ともに著明に増加した。血液中のＨｘの増加がＡＴＰの増加の原因であると考えられる。



（７）上記臨床試験により、イノシン、フェブキソスタットの単独投与では不可能な薬理作用がこれらの併用により認められた。本発明は、これまでには存在しなかった新規の薬理作用である血液中ヒポキサンチンとＡＴＰの増強を可能にするものである。


4). Consideration of Test Example 4



(1) The combined use of febuxostat and inosine was safe at doses of febuxostat 40 mg / day and inosine 2 g / day or less in a 2-week continuous administration test. Moreover, although the increase of ATP in blood was seen in these combination groups, such a change was not observed in the other administration group other than that.



(2) Serum uric acid levels decreased significantly with febuxostat alone, serum uric acid levels increased significantly with inosine alone, and moderate decreases were observed with combination therapy.



(3) No increase in inosine was observed in any group, and it was considered that PNP was metabolized to Hx.



(4) In the inosine single administration group, blood, urine, Hx and X did not increase, and it was considered that the inosine was changed to uric acid.



(5) X increased moderately in the febuxostat group alone, but Hx increased slightly to moderately in blood and urine.



(6) In the combined use of febuxostat and inosine, Hx and X markedly increased in blood and urine. An increase in Hx in the blood is thought to be responsible for the increase in ATP.



(7) According to the above clinical studies, pharmacological actions that were impossible with the administration of inosine and febuxostat alone were observed with these combinations. The present invention makes it possible to enhance hypoxanthine and ATP in blood, which is a novel pharmacological action that has not existed before.





〔試験例２〕臨床試験（２）



　上記試験例１により、フェブキソスタットとイノシンの併用により単独投与には認められないほどのＡＴＰ増強作用が認められた。そこで、フェブキソスタットと同じキサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害剤であるアロプリノール、トピロキソスタットについても同様の作用効果があるか確認するための試験を行った。



１．投与試験



（１）投与対象



　日本人の健康成人男性１５名を５名ずつ、グループＡ，Ｂ，Ｃに分けて下記投与試験を行った。



（２）投与内容及び投与スケジュール



グループＡ



アロプリノール１００ｍｇとイノシン５００ｍｇを１日２回、１４日間



グループＢ



トピロキソスタット８０ｍｇとイノシン５００ｍｇを１日２回、１４日間



グループＣ



フェブキソスタット２０ｍｇとイノシン５００ｍｇを１日２回、１４日間


[Test Example 2] Clinical trial (2)



According to Test Example 1, an ATP enhancing action that was not observed in single administration by the combined use of febuxostat and inosine was observed. Therefore, a test for confirming whether or not allopurinol and topiroxostat, which are the same xanthine oxidase / xanthine dehydrogenase inhibitors as febuxostat, have the same effect was conducted.



1. Dosing test



(1) Administration target



Fifteen Japanese healthy adult males were divided into groups A, B, and C, and the following administration test was conducted.



(2) Administration content and administration schedule



Group A



Allopurinol 100mg and Inosine 500mg twice a day for 14 days



Group B



Topiroxostat 80mg and inosine 500mg twice a day for 14 days



Group C



Febuxostat 20mg and inosine 500mg twice a day for 14 days





２．結果



（１）血清尿酸値の変化



　グループＡ～Ｃの試験開始前、試験終了後の血清尿酸値の平均値を下記表１に示す。いずれのグループにおいても本発明のＡＴＰ増強剤の投与により血清尿酸値は低下した。


2. result



(1) Change in serum uric acid level



Table 1 below shows the average value of serum uric acid levels before and after the end of the tests for Groups A to C. In any group, the serum uric acid level decreased by administration of the ATP enhancer of the present invention.





Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001








（２）ヒポキサンチン濃度



　グループＡ～Ｃの試験開始前、試験終了後のヒポキサンチン濃度の平均値を下記表２に示す。いずれのグループにおいても本発明のＡＴＰ増強剤の投与により血液中ヒポキサンチンは大幅に増加した。


(2) Hypoxanthine concentration



Table 2 below shows the average value of hypoxanthine concentration before and after the end of the tests for groups A to C. In any group, administration of the ATP enhancer of the present invention significantly increased blood hypoxanthine.





Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002








（３）ＡＴＰ濃度



　グループＡ～Ｃの試験開始前、試験終了後の血液中ＡＴＰ濃度の平均値を下記表３に示す。いずれのグループにおいても本発明のＡＴＰ増強剤の投与により血液中ＡＴＰは増加した。


(3) ATP concentration



Table 3 below shows the average value of the ATP concentration in blood before and after the start of the tests of groups A to C. In any group, ATP in blood increased by administration of the ATP enhancer of the present invention.





Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003








３．考察



　フェブキソスタットとイノシンの併用、トピロキソスタットとイノシンの併用、及び、アロプリノールとイノシンの併用により、血液中ヒポキサンチンの増加、ＡＴＰの増加が確認された。これらはすべて、フェブキソスタット、トピロキソスタット、アロプリノールがキサンチンオキシダーゼ／キサンチンデヒドロゲナーゼを抑制し、そこにイノシンがプリンヌクレオシドホスホリラーゼにより分解されて出来たヒポキサンチンが体内に蓄積することにより、細胞内ＡＴＰが増加したと考えられる。このようなヒポキサンチンとＡＴＰの増加は、イノシンからの供給と、キサンチンオキシダーゼ／キサンチンデヒドロゲナーゼの抑制の両方が同時に起きたときのみ起こる現象である。



　なぜなら、ヒポキサンチンとＡＴＰの増加はキサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害剤単独の投与、あるいはイノシン単独の投与では起きなかったからである（試験例１）。すなわち、試験例１では、フェブキソスタット、イノシンのそれぞれの単独投与ではヒポキサンチンの増加も、ＡＴＰの増加も起きなかったが（図４Ａ、Ｂ、図３Ａ、Ｂ）、これらを併用投与したときは、ヒポキサンチンとＡＴＰの増加が起きたのである（図４Ｃ、Ｄ、図３Ｃ、Ｄ）。



　従って、ヒポキサンチン及びＡＴＰの増加は、キサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害剤とイノシンを併用投与したときのみに起きる現象であるといえる。


3. Consideration



Increased hypoxanthine in the blood and increased ATP were confirmed by the combined use of febuxostat and inosine, the combined use of topiroxostat and inosine, and the combined use of allopurinol and inosine. In all of these, febuxostat, topiroxostat, and allopurinol inhibit xanthine oxidase / xanthine dehydrogenase, and inoxin accumulates in the body due to the accumulation of hypoxanthine produced by degradation of purine nucleoside phosphorylase. It is thought that it increased. Such increase in hypoxanthine and ATP is a phenomenon that occurs only when both supply from inosine and suppression of xanthine oxidase / xanthine dehydrogenase occur simultaneously.



This is because hypoxanthine and ATP did not increase with administration of xanthine oxidase / xanthine dehydrogenase inhibitor alone or inosine alone (Test Example 1). That is, in Test Example 1, neither hypoxanthine nor ATP increased when febuxostat and inosine were administered alone (FIGS. 4A, B, and 3A, B), but when these were administered in combination Increased hypoxanthine and ATP (FIGS. 4C, D, 3C, D).



Therefore, it can be said that the increase in hypoxanthine and ATP is a phenomenon that occurs only when a xanthine oxidase / xanthine dehydrogenase inhibitor and inosine are administered in combination.


〔製剤例１〕合剤の例　１錠あたり下記を含む経口投与用の合剤（錠剤タイプ）を製造した。



　アロプリノール　　　　　　　　　　　　　　　１００ｍｇ



　イノシン　　　　　　　　　　　　　　　　　　　　０．５ｇ



　アルファ化デンプン（崩壊バンダー）　　　　　　７０ｍｇ



　ケイ化微結晶セルロース（充填剤）　　　　　　　３２．６５６ｍｇ



　クロスカルメロースナトリウム（崩壊剤）　　　　１０ｍｇ



　ステアリン酸マグネシウム（潤滑剤）　　　　　　　０．８ｍｇ


[Formulation Example 1] Example of Combination A combination (tablet type) for oral administration containing the following was prepared per tablet.



Allopurinol 100mg



Inosine 0.5g



Pregelatinized starch (disintegration bander) 70mg



Silicified microcrystalline cellulose (filler) 32.656 mg



Croscarmellose sodium (disintegrant) 10mg



Magnesium stearate (lubricant) 0.8mg


〔製剤例２〕キット剤の例　アロプリノールを含む下記Ａ．の組成の錠剤とイノシンを含む下記Ｂの組成の医薬を製造し、それぞれ混ざらないように区切った同一袋に入れ、１回分を調整した。これを２回分すなわち１日分を同一の箱に梱包しキット剤を製造した。



　Ａ．アロプリノール錠



　アロプリノール　　　　　　　　　　　　　　　１００ｍｇ



　アルファ化デンプン（崩壊バンダー）　　　　　　７０ｍｇ



　ケイ化微結晶セルロース（充填剤）　　　　　　　３２．６５６ｍｇ



　クロスカルメロースナトリウム（崩壊剤）　　　　１０ｍｇ



　ステアリン酸マグネシウム（潤滑剤）　　　　　　　０．８ｍｇ



　Ｂ．イノシン



　イノシン　　　　　　　　　　　　　　　　　　　　０．５ｇ


[Formulation Example 2] Example of Kit Agent The following A.1 containing allopurinol. The medicine of the composition of the following B containing the tablet of the composition of this and inosine was manufactured, and it put into the same bag divided | segmented so that it might not mix, respectively, and prepared 1 time. This was packed twice in a single box, ie, one day, to produce a kit.



A. Allopurinol tablets



Allopurinol 100mg



Pregelatinized starch (disintegration bander) 70mg



Silicified microcrystalline cellulose (filler) 32.656 mg



Croscarmellose sodium (disintegrant) 10mg



Magnesium stearate (lubricant) 0.8mg



B. Inosine



Inosine 0.5g


〔製剤例３〕合剤の例　１錠あたり下記を含む経口投与用の合剤（錠剤タイプ）を製造した。



　トピロキソスタット　　　　　　　　　　　　　　８０ｍｇ



　イノシン　　　　　　　　　　　　　　　　　　　　０．５ｇ



　アルファ化デンプン（崩壊バンダー）　　　　　　７０ｍｇ



　ケイ化微結晶セルロース（充填剤）　　　　　　　３２．６５６ｍｇ



　クロスカルメロースナトリウム（崩壊剤）　　　　１０ｍｇ



　ステアリン酸マグネシウム（潤滑剤）　　　　　　　０．８ｍｇ


[Formulation Example 3] Example of Combination A combination (tablet type) for oral administration containing the following was prepared per tablet.



Topiroxostat 80mg



Inosine 0.5g



Pregelatinized starch (disintegration bander) 70mg



Silicified microcrystalline cellulose (filler) 32.656 mg



Croscarmellose sodium (disintegrant) 10mg



Magnesium stearate (lubricant) 0.8mg


〔製剤例４〕キット剤の例　トピロキソスタットを含む下記Ａ．の組成の錠剤とイノシンを含む下記Ｂの組成の医薬を製造し、それぞれ混ざらないように区切った同一袋に入れ、１回分を調整した。これを２回分すなわち１日分を同一の箱に梱包しキット剤を製造した。



　Ａ．トピロキソスタット錠



　トピロキソスタット　　　　　　　　　　　　　　８０ｍｇ



　アルファ化デンプン（崩壊バンダー）　　　　　　７０ｍｇ



　ケイ化微結晶セルロース（充填剤）　　　　　　　３２．６５６ｍｇ



　クロスカルメロースナトリウム（崩壊剤）　　　　１０ｍｇ



　ステアリン酸マグネシウム（潤滑剤）　　　　　　　０．８ｍｇ



　Ｂ．イノシン



　イノシン　　　　　　　　　　　　　　　　　　　　０．５ｇ


[Formulation Example 4] Examples of Kit Agents The following A. containing topiroxstat. The medicine of the composition of the following B containing the tablet of the composition of this and inosine was manufactured, and it put into the same bag divided | segmented so that it might not mix, respectively, and prepared 1 time. This was packed twice in a single box, ie, one day, to produce a kit.



A. Topiroxostat tablets



Topiroxostat 80mg



Pregelatinized starch (disintegration bander) 70mg



Silicified microcrystalline cellulose (filler) 32.656 mg



Croscarmellose sodium (disintegrant) 10mg



Magnesium stearate (lubricant) 0.8mg



B. Inosine



Inosine 0.5g


〔製剤例５〕合剤の例　１錠あたり下記を含む経口投与用の合剤（錠剤タイプ）を製造した。



　フェブキソスタット　　　　　　　　　　　　　　２０ｍｇ



　イノシン　　　　　　　　　　　　　　　　　　　　０．５ｇ



　アルファ化デンプン（崩壊バンダー）　　　　　　７０ｍｇ



　ケイ化微結晶セルロース（充填剤）　　　　　　　３２．６５６ｍｇ



　クロスカルメロースナトリウム（崩壊剤）　　　　１０ｍｇ



　ステアリン酸マグネシウム（潤滑剤）　　　　　　　０．８ｍｇ


[Formulation Example 5] Example of Combination A combination (tablet type) for oral administration containing the following was prepared per tablet.



Febuxostat 20mg



Inosine 0.5g



Pregelatinized starch (disintegration bander) 70mg



Silicified microcrystalline cellulose (filler) 32.656 mg



Croscarmellose sodium (disintegrant) 10mg



Magnesium stearate (lubricant) 0.8mg


〔製剤例６〕キット剤の例　フェブキソスタットを含む下記Ａ．の組成の錠剤とイノシンを含む下記Ｂの組成の医薬を製造し、それぞれ混ざらないように区切った同一袋に入れ、１回分を調整した。これを２回分すなわち１日分を同一の箱に梱包しキット剤を製造した。



　Ａ．フェブキソスタット錠



　フェブキソスタット　　　　　　　　　　　　　　２０ｍｇ



　アルファ化デンプン（崩壊バンダー）　　　　　　７０ｍｇ



　ケイ化微結晶セルロース（充填剤）　　　　　　　３２．６５６ｍｇ



　クロスカルメロースナトリウム（崩壊剤）　　　　１０ｍｇ



　ステアリン酸マグネシウム（潤滑剤）　　　　　　　０．８ｍｇ



　Ｂ．イノシン



　イノシン　　　　　　　　　　　　　　　　　　　　０．５ｇ


[Formulation Example 6] Examples of Kit Agents The following A. containing febuxostat: The medicine of the composition of the following B containing the tablet of the composition of this and inosine was manufactured, and it put into the same bag divided | segmented so that it might not mix, respectively, and prepared 1 time. This was packed twice in a single box, ie, one day, to produce a kit.



A. Febuxostat tablets



Febuxostat 20mg



Pregelatinized starch (disintegration bander) 70mg



Silicified microcrystalline cellulose (filler) 32.656 mg



Croscarmellose sodium (disintegrant) 10mg



Magnesium stearate (lubricant) 0.8mg



B. Inosine



Inosine 0.5g





　アルプリノール、トピロキソスタット又はフェブキソスタットとイノシンの併用投与により細胞内ＡＴＰの増強が可能であった。これは、これまでの薬剤に無い、新たな薬理作用である。したがって、様々なＡＴＰ減少を病態とする疾患に効果があると考えられる。



　また、イノシンが有する尿酸値上昇作用が、アルプリノール、トピロキソスタット又はフェブキソスタットとの併用により抑制された。したがって、高尿酸血症の治療のためにアルプリノール、トピロキソスタット又はフェブキソスタットを投与する患者に対して、高尿酸血症の治療効果を減じることなく、ＡＴＰの増加をすることができる。


Intracellular ATP could be enhanced by the combined administration of alpurinol, topiroxostat or febuxostat and inosine. This is a new pharmacological action not found in conventional drugs. Therefore, it is considered to be effective for diseases having various ATP reductions.



In addition, the action of inosine to increase the uric acid level was suppressed by the combined use with alpurinol, topiroxostat or febuxostat. Therefore, ATP can be increased without reducing the therapeutic effect of hyperuricemia in patients who receive alpurinol, topiroxostat or febuxostat for the treatment of hyperuricemia.

Claims (5)




  1. 以下のＡ）及びＢ）を組み合わせてなる、ヒト又は動物の細胞内ＡＴＰ増強剤。



    Ａ）キサンチンオキシダーゼ／キサンチンデヒドロゲナーゼ阻害剤



    Ｂ）ヒポキサンチン、又は体内でヒポキサンチンに変換され得る化合物


    A human or animal intracellular ATP enhancer comprising a combination of the following A) and B).



    A) Xanthine oxidase / xanthine dehydrogenase inhibitor



    B) Hypoxanthine or a compound that can be converted into hypoxanthine in the body





  2. Ａ）が、フェブキソスタット、トピロキソスタット、アロプリノール、ヒドロキシアルカン、カルプロフェン、Ｙ－７００およびＫＵＸ－１１５１からなる群から選ばれるいずれか１以上である請求項１に記載の細胞内ＡＴＰ増強剤。


    2. The intracellular ATP enhancer according to claim 1, wherein A) is at least one selected from the group consisting of febuxostat, topiroxostat, allopurinol, hydroxyalkane, carprofen, Y-700 and KUX-1151.





  3. Ｂ）の体内でヒポキサンチンに変換され得る化合物が、イノシン、イノシン酸、アデニン、アデノシン、ＡＭＰ、ＡＤＰ、ＡＴＰ、サクシニルアデノシン、Ｓ－アデノシルメチオニン、Ｓ－アデノシルホモシステイン、メチルチオアデノシンおよびそれらの薬学的に許容される塩から選ばれるいずれか１以上の化合物である請求項１又は２に記載の細胞内ＡＴＰ増強剤。


    B) compounds that can be converted into hypoxanthine in the body are inosine, inosinic acid, adenine, adenosine, AMP, ADP, ATP, succinyladenosine, S-adenosylmethionine, S-adenosylhomocysteine, methylthioadenosine and their The intracellular ATP enhancer according to claim 1 or 2, which is any one or more compounds selected from pharmaceutically acceptable salts.





  4. Ａ）及びＢ）の組み合わせが、Ａ）及びＢ）を含む合剤又はキット剤である、請求項１～３のいずれかに記載のＡＴＰ増強剤。


    The ATP enhancer according to any one of claims 1 to 3, wherein the combination of A) and B) is a combination or kit comprising A) and B).





  5. 細胞内ＡＴＰ増強剤としてイノシンと組み合わせて使用される、アロプリノール又はトピロキソスタット。


    Allopurinol or topiroxostat used in combination with inosine as an intracellular ATP enhancer.
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WO2022124325A1 (en) 2020-12-08 2022-06-16 国立大学法人東京大学 Intracellular atp enhancer
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020149218A1 (en) * 2019-01-18 2020-07-23 学校法人東京女子医科大学 Anti-aging agent or life-extending agent
KR20220018512A (en) 2019-06-07 2022-02-15 가부시키가이샤 스타젠 How to predict the effectiveness of ATP-enhancing therapy for neurodegenerative diseases
WO2022124325A1 (en) 2020-12-08 2022-06-16 国立大学法人東京大学 Intracellular atp enhancer
KR20230118083A (en) 2020-12-08 2023-08-10 학교법인 히가시-니뽄-가쿠엔 intracellular ATP enhancer
WO2023135827A1 (en) * 2022-01-13 2023-07-20 ＮｅＳＡ合同会社 Agent for protecting against and decelerating progression of neurodegenerative disease

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