WO2013051330A1 - Traitement de la fibrillation auriculaire à l'aide de vidarabine - Google Patents

Traitement de la fibrillation auriculaire à l'aide de vidarabine Download PDF

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Publication number
WO2013051330A1
WO2013051330A1 PCT/JP2012/069540 JP2012069540W WO2013051330A1 WO 2013051330 A1 WO2013051330 A1 WO 2013051330A1 JP 2012069540 W JP2012069540 W JP 2012069540W WO 2013051330 A1 WO2013051330 A1 WO 2013051330A1
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Prior art keywords
vidarabine
atrial fibrillation
day
administration
arrhythmia
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PCT/JP2012/069540
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English (en)
Japanese (ja)
Inventor
石川　義弘
敏 奥村
憲治 吹田
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公立大学法人横浜市立大学
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Priority to JP2013537448A priority Critical patent/JP6028983B2/ja
Publication of WO2013051330A1 publication Critical patent/WO2013051330A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates to the transient atrial fibrillation inhibitory action of vidarabine, which is an anti-herpes drug, and more particularly to the use of vidarabine as a therapeutic agent for arrhythmia.
  • Beta blockers that have been frequently used as treatments for ischemic heart disease and hypertension have been classified as Vaughan Williams group II drugs and have been known to have antiarrhythmic effects for a long time. Inhibitors have long been used frequently as first-line drugs.
  • Beta-adrenergic receptors regulate cardiac function and heart rate by activating adenylate cyclase enzyme present in cell membranes and increasing intracellular cyclic AMP (cAMP) concentration.
  • beta-blockers suppress excessive levels of L-type calcium channels, sarcoplasmic reticulum phospholamban, and ryanodine receptors by inhibiting adenylate cyclase enzyme activity and cAMP-PKA signal downstream of sympathetic overstimulation. It is thought that phosphorylation (activation) is suppressed, excessive increase of intracellular calcium is suppressed, and an antiarrhythmic effect is exhibited, but details are unknown.
  • beta blocker As a side effect when using a beta blocker as an antiarrhythmic drug, exercise tolerance is reduced, and respiratory depression is clinically significant, especially for administration to elderly arrhythmia patients.
  • Sodium channel blockers and beta-blockers have an inhibitory effect on cardiac function, and careful administration is required for arrhythmias that develop in patients with heart failure or after cardiovascular surgery.
  • Non-patent Document 1 Some drugs targeting cardiac adenylate cyclase have already been clinically applied (Non-patent Document 1). Although some compounds have already been reported as inhibitors of heart-type adenylate cyclase (Non-patent Documents 2 and 3), clinical application has not started, and no new compounds have been reported. In AC5 knockout mice, it has been reported that the calcium current in the L-type channel is decreased and the increase due to isoproterenol stimulation is suppressed (Non-patent Document 4), but an inhibitor of heart-type adenylate cyclase is reported. There is no report that it is useful as an antiarrhythmic drug.
  • An object of the present invention is to provide a novel therapeutic agent for arrhythmia.
  • the present inventors examined the preventive effect of vidarabine, which is a known heart-type adenylate cyclase inhibitor, on the occurrence of arrhythmia.
  • vidarabine is a known heart-type adenylate cyclase inhibitor
  • Vidarabine is blocked for the existing beta by administering a dose equivalent to the dose approved for herpes encephalitis or shingles (15 mg / kg / day) for 3 days (10 days for herpes simplex encephalitis). It was confirmed that there was an effect of preventing the occurrence of atrial fibrillation equivalent to metoprolol, which is a drug, and the present invention was completed.
  • the gist of the present invention is as follows. (1) An antiarrhythmic drug comprising vidarabine, a pharmaceutically acceptable salt or solvate thereof. (2) A method for preventing and / or treating arrhythmia, comprising administering to a subject a pharmaceutically effective amount of vidarabine, a pharmaceutically acceptable salt or solvate thereof. (3) Use of vidarabine, a pharmaceutically acceptable salt or solvate thereof for the prevention and / or treatment of arrhythmia. (4) Vidarabine, a pharmaceutically acceptable salt or solvate thereof for use in a method for preventing and / or treating arrhythmia.
  • the present invention provides an antiarrhythmic drug comprising vidarabine, a pharmaceutically acceptable salt or solvate thereof.
  • Vidarabine can be produced by a known method, and a commercially available product can also be used.
  • Examples of pharmaceutically acceptable salts of vidarabine include, but are not limited to, sodium phosphate, sodium salt, potassium salt, hydrochloride, sulfate, and the like.
  • solvates of vidarabine include, but are not limited to, solvates such as water, methanol, ethanol, dimethylformamide, and ethyl acetate.
  • Vidarabine pharmaceutically acceptable salts and solvates thereof have a transient atrial fibrillation inhibitory action and can be used as an antiarrhythmic drug.
  • a pharmaceutical preparation eg, injection, capsule, tablet, powder, granule, etc.
  • a conventional method is used as a human.
  • it can be administered to animals.
  • a dose of about 5 to 50 mg / kg (body weight) per day, preferably about 5 to 15 mg / kg (body weight) per day, once or several times Oral or parenteral administration is preferable, but the dose and frequency of administration can be appropriately changed depending on symptoms, age, administration method and the like.
  • carriers such as distilled water and physiological saline may be used.
  • the active ingredient when taking the form of tablets, capsules, granules, powders, etc., it is preferable to contain 5 to 80% by weight of the active ingredient, and in the case of injections, it contains 1 to 10% by weight of the active ingredient. It is preferable to do so.
  • Example 1 Prevention of Atrial Fibrillation by Vidarabine Derivative Using Mouse Atrial Fibrillation Model After inhalation anesthesia with mice using isoflurane (Sigma), an intracardiac electrocardiogram was obtained from the oral cavity for the purpose of recording an intracardiac electrocardiogram The connected electrode catheter was slowly inserted into the esophagus, and the electrode catheter (Miller) was fixed at the site where the P wave was recorded most. The fixed electrode catheter was carefully connected to the electrical stimulator so that the position did not move, and at the same time, the electrocardiogram amplifier recorded the body surface electrocardiogram at the position of lead II. Next, atrial fibrillation was induced by applying a voltage 1.5 times the minimum voltage (threshold) required for atrial-ventricular pacing for 30 seconds at 60 msec (Circ Res 97, 62-69, 2005).
  • Vidarabine (Sigma; 7.5 mg / kg / day, 10 mg / kg / day, 15 mg / kg / day) and metoprolol diluted with DMSO in normal wild-type mice (C57BL / 6) using an osmotic minipump (Alzet 2001) (Sigma; 2mg / kg / day, 3mg / kg / day, 4mg / kg / day), and a control group administered with DMSO (Sigma) alone, induced atrial fibrillation under the above induction conditions and induced normal sinus The duration of atrial fibrillation until returning to rhythm was measured (Fig. 1).
  • the experiment was terminated when it was confirmed that normal sinus rhythm recovery continued for 5 minutes or more and no atrial fibrillation occurred.
  • the maximum dose of vidarabine approved for humans is 15 mg / kg / day for 10 days, and metoprolol is 240 mg / day.
  • mice normal wild-type mice (C57BL / 6) were administered vidarabine (15 mg / kg / day) and metoprolol (4 mg / kg / day) for 3 days, respectively, after atrial frequent stimulation
  • the actual electrocardiogram waveform is shown in FIG.
  • mice DMSO
  • transient atrial fibrillation is induced for 30-60 seconds, but transient atrial fibrillation is not induced in mice administered with vidarabine or metoprolol.
  • Example 2 Therapeutic effect of vidarabine on atrial fibrillation after post-opening surgery Administration protocol Subjects 1) Cases after open heart surgery 2) Ages 20 and over 3) Exclusion criteria (1) Patients using interactive drugs (pentostatin, allopurinol) (2) Renal dysfunction (eGFR ⁇ 50) (3) Patients with atrial fibrillation before surgery Evaluation items ⁇ br/> Primary evaluation item 1) Time from start of vidarabine administration to atrial fibrillation stop 2) Rate of atrial fibrillation stoppage by vidarabine administration Secondary endpoint 1) Atrial fibrillation recurrence (avoidance) rate in patients with effective vidarabine Administration method 1) Postoperative new onset of atrial fibrillation 2) Dissolve 1 vial (300 mg) of vidarabine in 250 ml of 5% glucose and administer over 3 hours 3) Evaluate effect 4 hours after start of administration (1 hour after end of administration) First effective case of vidarabine : Observation of recurrence of atrial fibrillation 1) When recurrence is observed
  • Case 2 80-year-old male diagnosis name: Aortic stenosis operation: Aortic valve replacement was performed on March 26, 2012. Postoperative course: Atrial fibrillation onset was confirmed at 13:00 on April 2, 2012. Administration of vidarabine started at 9:00:00 on April 4, 2012. The sinus rhythm did not recover at 13:00 on April 4. Invalid He was discharged on April 17.
  • Case 3 73-year-old male diagnosis name: Thoracic aortic aneurysm method: Stent graft endoscopy was performed on July 13, 2012. Postoperative course: Confirmed onset of atrial fibrillation at 1:30 on July 16, 2012. Administration started at 8:50 on July 16, 2012. It does not recover to sinus rhythm at 12:50. Invalid
  • the blood concentration of vidarabine when 15 mg / kg / day was administered to mice was measured. An indicator should be used.
  • the current protocol confirms the effect of stopping atrial fibrillation.
  • the usefulness of beta-blockers for atrial fibrillation after open heart surgery is highly recommended in the AHA Guidelines 2004 for the prevention of atrial fibrillation that occurs before or immediately after open heart surgery. If the effectiveness of the stop effect is not confirmed even if the number of cases is increased in the future, it may be considered to change the current protocol to confirm the preventive effect.
  • the present invention can be used for the treatment and / or prevention of arrhythmia.

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

Abstract

La présente invention concerne un nouvel agent anti-arythmique. Ledit agent anti-arythmique contient de la vidarabine, et un sel ou un solvate pharmaceutiquement acceptable de celui-ci.
PCT/JP2012/069540 2011-10-07 2012-08-01 Traitement de la fibrillation auriculaire à l'aide de vidarabine WO2013051330A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2013537448A JP6028983B2 (ja) 2011-10-07 2012-08-01 ビダラビンによる心房細動治療

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JP2011-222421 2011-10-07
JP2011222421 2011-10-07

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WO2013051330A1 true WO2013051330A1 (fr) 2013-04-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019131308A1 (fr) * 2017-12-27 2019-07-04 公立大学法人横浜市立大学 TRAITEMENT D'UNE ARYTHMIE EN FAISANT APPEL À LA 9-β-D-ARABINOFURANOSYLHYPOXANTINE

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002338467A (ja) * 2001-05-23 2002-11-27 Nippon Kayaku Co Ltd アデニル酸シクラーゼ５型阻害剤
WO2012056976A1 (fr) * 2010-10-27 2012-05-03 公立大学法人横浜市立大学 Modulateur de l'activité de l'adénylate cyclase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002338467A (ja) * 2001-05-23 2002-11-27 Nippon Kayaku Co Ltd アデニル酸シクラーゼ５型阻害剤
WO2012056976A1 (fr) * 2010-10-27 2012-05-03 公立大学法人横浜市立大学 Modulateur de l'activité de l'adénylate cyclase

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
IWATSUBO,K. ET AL.: "Direct inhibition of type 5 adenylyl cyclase prevents myocardial apoptosis without functional deterioration", J BIOL CHEM, vol. 279, 2004, pages 40938 - 45, XP002525724, DOI: doi:10.1074/JBC.M314238200 *
IWATSUBO,K. ET AL.: "Drug therapy aimed at adenylyl cyclase to regulate cyclic nucleotide signaling", ENDOCR METAB IMMUNE DISORD DRUG TARGETS, vol. 6, 2006, pages 239 - 47 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019131308A1 (fr) * 2017-12-27 2019-07-04 公立大学法人横浜市立大学 TRAITEMENT D'UNE ARYTHMIE EN FAISANT APPEL À LA 9-β-D-ARABINOFURANOSYLHYPOXANTINE
JPWO2019131308A1 (ja) * 2017-12-27 2020-12-10 公立大学法人横浜市立大学 ９‐β‐Ｄ‐アラビノフラノシルヒポキサンチンによる不整脈治療
JP7137852B2 (ja) 2017-12-27 2022-09-15 学校法人福岡大学 ９‐β‐Ｄ‐アラビノフラノシルヒポキサンチンによる不整脈治療

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JP6028983B2 (ja) 2016-11-24

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