[go: up one dir, main page]

WO2018092911A1 - Agent augmentant l'atp intracellulaire - Google Patents

Agent augmentant l'atp intracellulaire Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
inosine
atp
febuxostat
administration
day
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2017/041733
Other languages
English (en)
Japanese (ja)
Inventor
鎌谷　直之
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
StaGen Co Ltd
Original Assignee
StaGen Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP2017031953A external-priority patent/JP6937134B2/ja
Application filed by StaGen Co Ltd filed Critical StaGen Co Ltd
Priority to EP17871969.6A priority Critical patent/EP3542823B1/fr
Priority to US16/462,345 priority patent/US10881662B2/en
Priority to CN201780083970.4A priority patent/CN110225767B/zh
Publication of WO2018092911A1 publication Critical patent/WO2018092911A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention cherche à résoudre le problème qui est de fournir un puissant agent augmentant l'ATP dont l'effet d'augmentation de l'ATP soit beaucoup plus important que celui d'une substance dont l'effet est d'augmenter l'ATP dans les cellules, en particulier l'inosine seul ou un inhibiteur de la xanthine oxydase/xanthine déshydrogénase seul. L'invention concerne un agent augmentant l'ATP intracellulaire chez l'être humain ou l'animal, comprenant une combinaison des composants suivants (A) et (B) : (A) un inhibiteur de la xanthine oxydase/xanthine déshydrogénase ; et (B) de l'hypoxanthine ou un composé qui peut être converti en hypoxanthine in vivo.
PCT/JP2017/041733 2016-11-21 2017-11-21 Agent augmentant l'atp intracellulaire Ceased WO2018092911A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP17871969.6A EP3542823B1 (fr) 2016-11-21 2017-11-21 Agent augmentant l'atp intracellulaire
US16/462,345 US10881662B2 (en) 2016-11-21 2017-11-21 Intracellular ATP enhancer
CN201780083970.4A CN110225767B (zh) 2016-11-21 2017-11-21 细胞内atp增强剂

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2016-225609 2016-11-21
JP2016225609 2016-11-21
JP2017-031953 2017-02-23
JP2017031953A JP6937134B2 (ja) 2016-11-21 2017-02-23 細胞内ａｔｐ増強剤

Publications (1)

Publication Number Publication Date
WO2018092911A1 true WO2018092911A1 (fr) 2018-05-24

Family

ID=62146421

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2017/041733 Ceased WO2018092911A1 (fr) 2016-11-21 2017-11-21 Agent augmentant l'atp intracellulaire

Country Status (1)

Country Link
WO (1) WO2018092911A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020149218A1 (fr) * 2019-01-18 2020-07-23 学校法人東京女子医科大学 Agent anti-âge ou agent de prolongement de la durée de vie
KR20220018512A (ko) 2019-06-07 2022-02-15 가부시키가이샤 스타젠 신경 변성 질환에 대한 atp 증강 요법의 효과를 예측하는 방법
WO2022124325A1 (fr) 2020-12-08 2022-06-16 国立大学法人東京大学 Activateur intracellulaire d'atp
WO2023135827A1 (fr) * 2022-01-13 2023-07-20 ＮｅＳＡ合同会社 Agent de protection contre les maladies neurodégénératives et de ralentissement de leur progression

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003038184A (ja) * 2001-07-06 2003-02-12 Tanabe Seiyaku Co Ltd 新規プリン受容体およびその遺伝子
EP2050467A1 (fr) 2006-07-19 2009-04-22 Nippon Medical School Foundation Agent thérapeutique destiné à la sclérose latérale amyotrophique
JP2012505925A (ja) * 2008-10-19 2012-03-08 リチャード ジェイ ジョンソン 代謝不均衡に関連付けられる慢性腎疾患を治療するための治療組成物及び方法
JP2015057436A (ja) * 2005-03-28 2015-03-26 ペリコー セラピューティクス， インコーポレイテッド 患者における副作用を予防または減少するための方法、組成物および処方物
WO2017033963A1 (fr) * 2015-08-26 2017-03-02 株式会社スタージェン Agent de renforcement de l'atp dans les cellules

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003038184A (ja) * 2001-07-06 2003-02-12 Tanabe Seiyaku Co Ltd 新規プリン受容体およびその遺伝子
JP2015057436A (ja) * 2005-03-28 2015-03-26 ペリコー セラピューティクス， インコーポレイテッド 患者における副作用を予防または減少するための方法、組成物および処方物
EP2050467A1 (fr) 2006-07-19 2009-04-22 Nippon Medical School Foundation Agent thérapeutique destiné à la sclérose latérale amyotrophique
US8318792B2 (en) 2006-07-19 2012-11-27 Nippon Medical School Foundation Therapeutic agent for amyotrophic lateral sclerosis
JP2012505925A (ja) * 2008-10-19 2012-03-08 リチャード ジェイ ジョンソン 代謝不均衡に関連付けられる慢性腎疾患を治療するための治療組成物及び方法
WO2017033963A1 (fr) * 2015-08-26 2017-03-02 株式会社スタージェン Agent de renforcement de l'atp dans les cellules

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
BORKOWSKI TSLOMINSKA EMORLEWSKA CCHLOPICKI SSIONDALSKI PYACOUB MHSMOLENSKI RT: "Protection of mouse heart against hypoxic damage by AMP deaminase inhibition", NUCLEOSIDES NUCLEOTIDES NUCLEIC ACIDS, vol. 29, no. 4-6, June 2010 (2010-06-01), pages 449 - 52
COOLEN EJARTS ICSWENNEN ELBAST ASTUART MADAGNELIE PC: "Simultaneous determination of adenosine triphosphate and its metabolites in human whole blood by RP-HPLC and UV-detection", J CHROMATOGR B ANALYT TECHNOL BIOMED LIFE SCI., vol. 864, no. 1-2, 15 March 2008 (2008-03-15), pages 43 - 51, XP022521731
DE JONG KLARKIN SKEBER SFRANCK PFROELOFSEN BKUYPERS FA: "Hereditary spherocytosis and elliptocytosis erythrocytes show a normal transbilayer phospholipid distribution", BLOOD, vol. 94, no. 1, 1 July 1999 (1999-07-01), pages 319 - 25
GALLARDO GBAROWSKI JRAVITS JSIDDIQUE TLINGREL JBROBERTSON JSTEEN HBONNI A: "An a2-Na/K ATPase/a-adducin complex in astrocytes triggers non-cell autonomous neurodegeneration", NAT NEUROSCI., vol. 17, no. 12, December 2014 (2014-12-01), pages 1710 - 9, XP055218129
GLADER BE: "Salicylate-induced injury of pyruvate-kinase-deficient erythrocytes", N ENGL J MED., vol. 294, no. 17, 22 April 1976 (1976-04-22), pages 916 - 8
HARMSEN, EEF ET AL: " ENHANCED ATP AND GTP SYNTHESIS FROM HYPOXANTHINE OR INOSINE AFTER MYOCARDIAL ISCHEMIA", AMERICAN JOURNAL OF PHYSIOLOGY, vol. 246, no. 1 pt.2, 1984, pages H37 - H43, XP002045699, ISSN: 0002-9513, DOI: 10.1152/ajpheart.1984.246.1.H37 *
ICHIDA, KUMI: "Febuxostat (TMX-67), Puricase (PEG-uricase), etc.", JAPANESE JOURNAL OF CLINICAL MEDICINE, vol. 66, no. 4, 2008, pages 759 - 765, XP009507050, ISSN: 0047-1852 *
LOH EREBBECK TRMAHONEY PDDENOFRIO DSWAIN JLHOLMES EW: "Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure", CIRCULATION, vol. 99, no. 11, 23 March 1999 (1999-03-23), pages 1422 - 5
MARKOWITZ CESPITSIN SZIMMERMAN VJACOBSDUDUPA JKHOOPER DCKOPROWSKI H: "The treatment of multiple sclerosis with inosine", J ALTERN COMPLEMENT MED., vol. 15, no. 6, June 2009 (2009-06-01), pages 619 - 25
MCNAUGHTON LDALTON BTARR J.: "Inosine supplementation has no effect on aerobic or anaerobic cycling performance", INT J SPORT NUTR., vol. 9, no. 4, December 1999 (1999-12-01), pages 333 - 44
MENTZER WC JRSMITH WBGOLDSTONE J: "Shohet SB. Hereditary stomatocytosis: membrane and metabolism studies", BLOOD, vol. 46, no. 5, November 1975 (1975-11-01), pages 659 - 69
NOMAN AANG DSOGSTON SLANG CCSTRUTHERS AD: "Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial", LANCET, vol. 375, no. 9732, 19 June 2010 (2010-06-19), pages 2161 - 7, XP027545138
NORMAN BSABINA RLJANSSON E: "Regulation of skeletal muscle ATP catabolism by AMPD1 genotype during sprint exercise in asymptomatic subjects", J APPL PHYSIOL, vol. 91, no. 1, 1985, pages 258 - 64
OGASAWARA NGOTO HYAMADA YNISHIGAKI IITOH THASEGAWA IPARK KS: "Deficiency of AMP deaminase in erythrocytes", HUM GENET., vol. 75, no. 1, January 1987 (1987-01-01), pages 15 - 8
OHTAKE, YOSHIO ET AL.: "The Efficacy of ATP and Allopurinol (AL) pretreatment against hypothermic ischemia-reperfusion injury of liver", THE JAPAN SOCIETY OF HEPATOLOGY, vol. 30, no. 4, 1 January 1989 (1989-01-01), pages 444 - 449, XP055602239, ISSN: 0451-4203, DOI: 10.2957/kanzo.30.444 *
OPIE, LIONEL H.: "Allopurinol for heart failure", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 59, no. 9, 2012, pages 809 - 812, XP055601258, ISSN: 0735-1097, DOI: 10.1016/j.jacc.2011.09.072 *
OTAKE, YOSHIO ET AL.: "(non-official translation) Effect of combined used of ATP and allopurinol for ischemic and reperfusion cellular injury", CYTO-PROTECTION BIOL., vol. 6, 1988, pages 393 - 399, ISSN: 0289-3681 *
PALEK JLIU SCLIU PA: "Crosslinking of the nearest membrane protein neighbors in ATP depleted, calcium enriched and irreversibly sickled red cells", PROG CLIN BIOL RES., vol. 20, 1978, pages 75 - 91
PARKINSON STUDY GROUP SURE-PD INVESTIGATORSSCHWARZSCHILD MAASCHERIO ABEAL MFCUDKOWICZ MECURHAN GCHARE JMHOOPER DCKIEBURTZ KDMACKLI: "Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial", JAMA NEUROL, vol. 71, no. 2, February 2014 (2014-02-01), pages 141 - 50
SATTUI, E. SEBASTIAN ET AL.: "Treatment of Hyperuricemia in gout: current therapeutic opinions, latest developments and clinical implications", THERAPEUTIC ADVANCES IN MUSCULOSKELETAL DISEASE, vol. 8, no. 4, May 2016 (2016-05-01), pages 145 - 159, XP055371250, ISSN: 1759-720x, DOI: 10.1177/1759720X16646703 *
See also references of EP3542823A4 *
SETTLE, T. ET AL: " Effect of Allopurinol and Inosine Administration on Xanthine Oxidoreductase Gene Expression in Selected Tissues of Broiler Chickens", INTERNATIONAL JOURNAL OF POULTRY SCIENCE, vol. 14, no. 1, January 2015 (2015-01-01), pages 37 - 43, XP055369487, ISSN: 1682-8356, DOI: 10.3923/ijps.2015.37.43 *
VOGT AMACKERMANN CYILDIZ MSCHOELS WKUBLER W: "Lactate accumulation rather than ATP depletion predicts ischemic myocardial necrosis: implications for the development of lethal myocardial injury", BIOCHIM BIOPHYS ACTA, vol. 1586, no. 2, 16 March 2002 (2002-03-16), pages 219 - 26, XP004349028
WANG, ZHENZHEN ET AL.: "Allopurinol preserves myocardial energy metabolism in chronic heart failure rats", JOURNAL OF CLINICAL CARDIOLOGY, vol. 31, no. 1, 1 January 2015 (2015-01-01), pages 89 - 93, XP009508859, ISSN: 1001-1439 *
WILEY JS: "Increased erythrocyte cation permeability in thalassemia and conditions of marrow stress", J CLIN INVEST., vol. 67, no. 4, April 1981 (1981-04-01), pages 917 - 22
YASUKO ABESHINSUKE KATOTAKESHI NISHINO, THERAPEUTIC AGENT FOR AMYOTROPHIC LATERAL SCLEROSIS

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020149218A1 (fr) * 2019-01-18 2020-07-23 学校法人東京女子医科大学 Agent anti-âge ou agent de prolongement de la durée de vie
JPWO2020149218A1 (ja) * 2019-01-18 2021-12-02 学校法人東京女子医科大学 老化防止剤または寿命延長剤
KR20220018512A (ko) 2019-06-07 2022-02-15 가부시키가이샤 스타젠 신경 변성 질환에 대한 atp 증강 요법의 효과를 예측하는 방법
WO2022124325A1 (fr) 2020-12-08 2022-06-16 国立大学法人東京大学 Activateur intracellulaire d'atp
KR20230118083A (ko) 2020-12-08 2023-08-10 학교법인 히가시-니뽄-가쿠엔 세포 내 atp 증강제
WO2023135827A1 (fr) * 2022-01-13 2023-07-20 ＮｅＳＡ合同会社 Agent de protection contre les maladies neurodégénératives et de ralentissement de leur progression

Similar Documents

Publication Publication Date Title
JP6153281B1 (ja) 細胞内ａｔｐ増強剤
RU2394580C2 (ru) Способы лечения митохондриальных нарушений
WO2018092911A1 (fr) Agent augmentant l'atp intracellulaire
JP6990934B2 (ja) 異所性脂肪蓄積治療用ａ３アデノシン受容体リガンド
US10881662B2 (en) Intracellular ATP enhancer
KR20250034995A (ko) 뉴클레오시드 의약품의 생체이용률을 증가시키는 방법
JP2020176071A (ja) 血液がんの新規治療法及び新規治療剤
HK40007559B (zh) 细胞内atp增强剂
HK40007559A (en) Intracellular atp enhancer
HK1246165B (zh) 细胞内atp增强剂
EP1933823B1 (fr) Composition pharmaceutique basée sur l'inhibiteur de transcriptase inversée et le meldonium
Osswald Articles in PresS. Am J Physiol Renal Physiol (April 26, 2005). doi: 10.1152/ajprenal. 00465.2004
Bottiglieri S-Adenosylmethionine (SAMe): Preclinical and Clinical Studies in Depression
Igel et al. Effect of acute hyperhomocysteinemia on methylation
JP2008133271A (ja) 生活習慣病の予防および／または治療用組成物
HK1261991B (en) An a3 adenosine receptor ligand for use in treating ectopic fat accumulation
HK1261991A1 (en) An a3 adenosine receptor ligand for use in treating ectopic fat accumulation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17871969

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017871969

Country of ref document: EP

Effective date: 20190621