METHODS FOR TREATMENT OF ATHEROSCLEROSIS
Disclosed herein are methods and compositions for preventing or treating atherosclerosis in a mammalian subject. The methods comprise administering to the subject an effective amount of an aromatic-cationic peptide and, in some applications, a second active agent, to subjects in need thereof. The present technology relates to the treatment or prevention of atherosclerosis in mammals through the administration of a therapeutically effective amount of aromatic cationic peptides and, in some embodiments, a second active agent.
1 . A method for treating atherosclerosis in a mammalian subject in need thereof, the method comprising administering simultaneously, separately or sequentially an effective amount of (i) a peptide D-Arg-2′6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof and (ii) an antihyperlipidemic drug.
2 . The method of claim 1 , wherein the antihyperlipidemic drug is selected from the group consisting of: atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, clinofibrate, clofibrate, simfibrate, fenofibrate, bezafibrate, colestimide, colestyramine, ADVICOR® (niacin extended-release/lovastatin), ALTOPREV® (lovastatin extended-release), CADUET® (amlodipine and atorvastatin), CRESTOR® (rosuvastatin), JUVISYNC® (sitagliptin/simvastatin), LESCOL® (fluvastatin), LESCOL XL (fluvastatin extended-release), LIPITOR® (atorvastatin), LIVALO® (pitavastatin), MEVACOR® (lovastatin), PRAVACHOL® (pravastatin), SIMCOR® (niacin extended-release/simvastatin), VYTORIN® (ezetimibe/simvastatin), and ZOCOR® (simvastatin).
3 . The method of claim 1 , wherein the antihyperlipidemic drug is a statin.
4 . The method of claim 3 , wherein the statin is selected from the group consisting of: ADVICOR® (niacin extended-release/lovastatin), ALTOPREV® (lovastatin extended-release), CADUET® (amlodipine and atorvastatin), CRESTOR® (rosuvastatin), JUVISYNC® (sitagliptin/simvastatin), LESCOL® (fluvastatin), LESCOL XL (fluvastatin extended-release), LIPITOR® (atorvastatin), LIVALO® (pitavastatin), MEVACOR® (lovastatin), PRAVACHOL® (pravastatin), SIMCOR® (niacin extended-release/simvastatin), VYTORIN® (ezetimibe/simvastatin), and ZOCOR® (simvastatin).
5 . The method of claim 1 , wherein the peptide and the antihyperlipidemic drug are administered simultaneously.
6 . The method of claim 1 , wherein the peptide and the antihyperlipidemic drug are administered sequentially in either order.
7 . The method of claim 1 , wherein treatment includes decreasing the size or number of atherosclerotic plaques in the subject, and/or decreasing the cholesterol content of an atherosclerotic plaque in the subject.
8 . A method for preventing atherosclerosis in a mammalian subject in need thereof, the method comprising administering simultaneously, separately or sequentially an effective amount of (i) a peptide D-Arg-2′6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof and (ii) an antihyperlipidemic drug.
9 . The method of claim 8 , wherein the antihyperlipidemic drug is selected from the group consisting of: atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, clinofibrate, clofibrate, simfibrate, fenofibrate, bezafibrate, colestimide, colestyramine, ADVICOR® (niacin extended-release/lovastatin), ALTOPREV® (lovastatin extended-release), CADUET® (amlodipine and atorvastatin), CRESTOR® (rosuvastatin), JUVISYNC® (sitagliptin/simvastatin), LESCOL® (fluvastatin), LESCOL XL (fluvastatin extended-release), LIPITOR® (atorvastatin), LIVALO® (pitavastatin), MEVACOR® (lovastatin), PRAVACHOL® (pravastatin), SIMCOR® (niacin extended-release/simvastatin), VYTORIN® (ezetimibe/simvastatin), and ZOCOR® (simvastatin).
10 . The method of claim 8 , wherein the antihyperlipidemic drug is a statin.
11 . The method of claim 10 , wherein the statin is selected from the group consisting of: ADVICOR® (niacin extended-release/lovastatin), ALTOPREV® (lovastatin extended-release), CADUET® (amlodipine and atorvastatin), CRESTOR® (rosuvastatin), JUVISYNC® (sitagliptin/simvastatin), LESCOL® (fluvastatin), LESCOL XL (fluvastatin extended-release), LIPITOR® (atorvastatin), LIVALO® (pitavastatin), MEVACOR® (lovastatin), PRAVACHOL® (pravastatin), SIMCOR® (niacin extended-release/simvastatin), VYTORIN® (ezetimibe/simvastatin), and ZOCOR® (simvastatin).
12 . The method of claim 8 , wherein the peptide and the antihyperlipidemic drug are administered simultaneously.
13 . The method of claim 8 , wherein the peptide and the antihyperlipidemic drug are administered sequentially in either order.
14 . The method of any one of claims 8 - 13 , wherein the subject is predisposed to atherosclerosis.
15 . A method for ameliorating the signs, symptoms or complications of atherosclerosis, the method comprising administering simultaneously, separately or sequentially an effective amount of (i) a peptide D-Arg-2′6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof and (ii) an antihyperlipidemic drug.
16 . The method of claim 15 , wherein the signs, symptoms or complications of atherosclerosis include one or more selected from the group consisting of: elevated levels total cholesterol, VLDL cholesterol, LDL cholesterol, free cholesterol, cholesterol ester, phospholipids, triglycerides, and atherosclerotic lesions.
17 . The method of claim 15 , wherein the antihyperlipidemic drug is selected from the group consisting of: atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, clinofibrate, clofibrate, simfibrate, fenofibrate, bezafibrate, colestimide, colestyramine, ADVICOR® (niacin extended-release/lovastatin), ALTOPREV® (lovastatin extended-release), CADUET® (amlodipine and atorvastatin), CRESTOR® (rosuvastatin), JUVISYNC® (sitagliptin/simvastatin), LESCOL® (fluvastatin), LESCOL XL (fluvastatin extended-release), LIPITOR® (atorvastatin), LIVALO® (pitavastatin), MEVACOR® (lovastatin), PRAVACHOL® (pravastatin), SIMCOR® (niacin extended-release/simvastatin), VYTORIN® (ezetimibe/simvastatin), and ZOCOR® (simvastatin).
18 . The method of claim 15 , wherein the antihyperlipidemic drug is a statin.
19 . The method of claim 18 , wherein the statin is selected from the group consisting of: ADVICOR® (niacin extended-release/lovastatin), ALTOPREV® (lovastatin extended-release), CADUET® (amlodipine and atorvastatin), CRESTOR® (rosuvastatin), JUVISYNC® (sitagliptin/simvastatin), LESCOL® (fluvastatin), LESCOL XL (fluvastatin extended-release), LIPITOR® (atorvastatin), LIVALO® (pitavastatin), MEVACOR® (lovastatin), PRAVACHOL® (pravastatin), SIMCOR® (niacin extended-release/simvastatin), VYTORIN® (ezetimibe/simvastatin), and ZOCOR® (simvastatin).
20 . The method of claim 15 , wherein the peptide and the antihyperlipidemic drug are administered simultaneously.
21 . The method of claim 15 , wherein the peptide and the antihyperlipidemic drug are administered sequentially in either order.
22 . The method of claim 15 , wherein ameliorating the signs, symptoms or complications of atherosclerosis includes decreasing the size or number of atherosclerotic plaques in the subject, and/or decreasing the cholesterol content of an atherosclerotic plaque in the subject.
23 . A method for delaying onset, ameliorating or eliminating statin side effects in a subject in need thereof, the method comprising administering simultaneously, separately or sequentially with the statin, an effective amount of a peptide D-Arg-2′6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof.
24 . The method of claim 23 , wherein the statin side effect includes one or more of myopathy, rhabdomyolysis, kidney failure, diabetes, memory loss, decreased coenzyme Q10 levels and mitochondrial dysfunction.
25 . The method of claim 23 , wherein the statin is selected from the group consisting of: atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, ADVICOR® (niacin extended-release/lovastatin), ALTOPREV® (lovastatin extended-release), CADUET® (amlodipine and atorvastatin), CRESTOR® (rosuvastatin), JUVISYNC® (sitagliptin/simvastatin), LESCOL® (fluvastatin), LESCOL XL (fluvastatin extended-release), LIPITOR® (atorvastatin), LIVALO® (pitavastatin), MEVACOR® (lovastatin), PRAVACHOL® (pravastatin), SIMCOR® (niacin extended-release/simvastatin), VYTORIN® (ezetimibe/simvastatin), and ZOCOR® (simvastatin).
26 . A method for increasing statin dosage in a subject in need thereof comprising: administering an effective amount of a statin at a first dosage level, and an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof;
evaluating the subject for side-effects characteristic of the statin, wherein the side-effects in the subject are reduced or absent as compared to a control subject administered the statin and not the aromatic cationic peptide;
administering a statin at a second dosage level, wherein the second dosage level is higher than the first statin dosage level.
27 . The method of claim 26 , wherein the peptide is D-Arg-2′6′-Dmt-Lys-Phe-NH 2 .
28 . The method of claim 26 , wherein the statin comprises LIPITOR® or CRESTOR®.
29 . The method of claim 26 , wherein the side effect characteristic of the statin includes one or more of myopathy, rhabdomyolysis, kidney failure, diabetes, memory loss, decreased coenzyme Q10 levels and mitochondrial dysfunction.
30 . The method of any one of claims 1 - 29 , wherein the pharmaceutically acceptable salt comprises acetate salt or trifluoroacetate salt.