PDE III INHIBITORS FOR TREATMENT OF ASYMPTOMATIC HEART FAILURE

• US 20130203690A1
• Filed: 03/15/2013
• Published: 08/08/2013
• Est. Priority Date: 03/25/2004
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim Vetmedica GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Vetmedica GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Daemmgen, Juergen, Joens, Olaf, Troetschel, Christian, Vollmar, Andrea, Kleeman, Rainer
• Granted Patent: US 10,117,869 B2
• Time in Patent Office: Days
• US Class Current: 514/26
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Abstract

Phosphodiesterase type III (PDE III) inhibitor or a “Ca²⁺-sensitizing agent” or a pharmaceutically acceptable derivative thereof is used in the preparation of a medication for the reduction of the heart size of a patient suffering from heart failure, and as a medication for the reverse remodeling of the heart of a patient with asymptomatic (occult) heart failure and their delayed onset of clinical symptoms.

Claims

1. An article of manufacture including:

packaging material;

a pharmaceutical composition contained in the packaging material, the pharmaceutical composition comprising a therapeutically effective amount of a phosphodiesterase type III (PDE III) inhibitor, wherein said therapeutically effective amount is effective to prolong time until onset of clinical symptoms of the heart disease and of the reduction of the heart size of a patient having clinical symptoms of ISACHC Class II or Class III heart failure.

2. The article according to claim 1 wherein the PDE III inhibitor prevents breakdown of cAMP to 5′

AMP and thus maintain the effect of cAMP on protein kinase and other secondary messenger activation.

3. The article of claim 1, wherein the PDE III inhibitor is a Ca²⁺sensitizing agent effective to increase the Ca²⁺ sensitivity of cardiac contractile proteins.

4. The article according to claim 3, wherein the PDE III inhibitor is selected from the group consisting of pimobendan, milrinone, levosimendan, aminone, enoximone, piroximone, and pharmaceutically acceptable salts thereof.

5. The article according to claim 4, wherein the PDE III inhibitor is selected from the group consisting pimobendan and levosimendan.

6. The article according to claim 1 further comprising a label a indicating that the composition can be used to prolong the time until onset of symptoms and to reduce heart size of a patient having an asymptomatic heart failure.

7. The article according to claim 1, wherein reduction of the heart size is expressed in the relative change of the vertebral heart size.

8. The article according to claim 1, wherein the asymptomatic heart failure is asymptomatic dilated cardiomyopathy (DCM).

9. The article according to claim 1, wherein prolongation until onset of clinical symptoms relates to the time from diagnosing the changes of the heart until the beginning of clinical symptoms of heart failure

10. The article according to claim 1, wherein the pharmaceutical composition further includes a second active therapeutic agent selected from the group consisting of a calcium channel blocker, an ACE inhibitor, a diuretic, a platelet inhibitor, a beta blocker, an angiotensin II antagonist, an aldosterone antagonist, a digitalis glycoside, and an anti-arrhythmic agents.

11. The article according to claim 10, wherein:

the calcium channel blocker inhibitor is selected from the group consisting of diltiazem, verapamil and felodipine or a pharmaceutically acceptable derivative thereof;

the ACE inhibitor is selected from the group consisting of omapatrilat, MDL100240, alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, saralasin acetate, temocapril, trandolapril, trandolaprilat, ceranapril, moexipril, quinaprilat and spirapril or a pharmaceutically acceptable derivative thereof;

the beta blocker is selected from the group consisting of bisoprolol, carvediol, metoprolol, propranolol and timolol or a pharmaceutically acceptable derivative thereof;

the angiotensin II antagonist is selected from the group consisting of saralasin acetate, candesartan, cilexetil, valsartan, candesartan, losartan potassium, eprosartan, irbesartan, tasosartan, pomisartan and telmisartan or a pharmaceutically acceptable derivative thereof;

the aldosterone antagonist is selected from the group consisting of spironolactone, eplerenone, canrenone, potassium canrenone or a pharmaceutically acceptable derivative thereof;

the anti-arrhythmic agents are selected from the group consisting of amiodarone, betrylium, disopyramide, dofetilide, flecamide, ibutilide, mexiletine, tocamide, procainamide, propafenone, quinidine, sotalol or a pharmaceutically acceptable derivative thereof;

the diuretic is selected from the group consisting of furosemide, torasemide, bumetanide, etacrynic acid, azosemide, muzolimine, piretanide, trip amide, bendroflumethazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methychlothiazide, polythiazide, trichlormethiazide, chlorthialidone, indapamide, metolazone, quinethazone, etozolin, triamteren, amiloride, or a pharmaceutically acceptable derivative thereof; and

the digitalis glycosides is selected from the group consisting of digoxin, digitoxin, g-strophantin, β

-methyldigoxin, β

-acetyldigoxin or a pharmaceutically acceptable derivative thereof.

12. A pharmaceutical composition comprising:

a therapeutically effective amount of a phosphodiesterase type III (PDE III) inhibitor effective to prolong time until onset of clinical symptoms of the heart disease and of the reduction of the heart size of a patient having clinical symptoms of ISACHC Class II or Class III heart failure; and

a second active therapeutic agent.

13. The pharmaceutical composition according to claim 12, wherein the second active therapeutic agent is selected from the group consisting of a calcium channel blocker, an ACE inhibitor, a diuretic, a platelet inhibitor, a beta blocker, an angiotensin II antagonist, an aldosterone antagonist, a digitalis glycoside, and an anti-arrhythmic agent.

14. The pharmaceutical composition according to claim 13, wherein:

the calcium channel blocker inhibitor is selected from the group consisting of diltiazem, verapamil and felodipine or a pharmaceutically acceptable derivative thereof;

the ACE inhibitor is selected from the group consisting of omapatrilat, alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, saralasin acetate, temocapril, trandolapril, trandolaprilat, ceranapril, moexipril, quinaprilat and spirapril or a pharmaceutically acceptable derivative thereof;

the beta blocker is selected from the group consisting of bisoprolol, carvediol, metoprolol, propranolol and timolol or a pharmaceutically acceptable derivative thereof;

the angiotensin II antagonist is selected from the group consisting of saralasin acetate, candesartan, cilexetil, valsartan, candesartan, losartan potassium, eprosartan, irbesartan, tasosartan, pomisartan and telmisartan or a pharmaceutically acceptable derivative thereof;

the aldosterone antagonist is selected from the group consisting of spironolactone, eplerenone, canrenone, potassium canrenone or a pharmaceutically acceptable derivative thereof;

the anti-arrhythmic agents are selected from the group consisting of amiodarone, betrylium, disopyramide, dofetilide, flecamide, ibutilide, mexiletine, tocamide, procainamide, propafenone, quinidine, sotalol or a pharmaceutically acceptable derivative thereof;

the diuretic is selected from the group consisting of furosemide, torasemide, bumetanide, etacrynic acid, azosemide, muzolimine, piretanide, trip amide, bendroflumethazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methychlothiazide, polythiazide, trichlormethiazide, chlorthialidone, indapamide, metolazone, quinethazone, etozolin, triamteren, amiloride, or a pharmaceutically acceptable derivative thereof; and

the digitalis glycosides is selected from the group consisting of digoxin, digitoxin, g-strophantin, β

-methyldigoxin, β

-acetyldigoxin or a pharmaceutically acceptable derivative thereof.

15. The pharmaceutical composition according to claim 12, wherein the PDE III inhibitor prevents breakdown of cAMP to 5′

AMP and thus maintain the effect of cAMP on protein kinase and other secondary messenger activation.

16. The pharmaceutical composition according to claim 12, wherein the PDE III inhibitor is a Ca²⁺sensitizing agent effective to increase the Ca²⁺ sensitivity of cardiac contractile proteins.

17. The pharmaceutical composition according to claim 12, wherein the PDE III inhibitor is selected from the group consisting of pimobendan, milrinone, levosimendan, aminone, enoximone, piroximone, and pharmaceutically acceptable salts thereof.

18. The pharmaceutical composition according to claim 17, wherein the PDE III inhibitor is selected from the group consisting pimobendan and levosimendan.

19. The pharmaceutical composition according to claim 12, wherein the asymptomatic heart failure is asymptomatic dilated cardiomyopathy (DCM).