US 2006OOO9534A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0009534 A1 Cooper et al. (43) Pub. Date: Jan. 12, 2006 (54) PREVENTING AND/OR TREATING Publication Classification CARDIOVASCULAR DISEASE AND/OR ASSOCATED HEART FAILURE (51) Int. Cl. A6IK 3III.3 (2006.01) (76) Inventors: Garth J.S. Cooper, Auckland (NZ); (52) U.S. Cl. .............................................................. 514/673 John R. Baker, Auckland (NZ) (57) ABSTRACT Correspondence Address: Methods are provided for reducing copper values for, by DUANE MORRIS LLP way of example, treating, preventing or ameliorating tissue 101 WEST BROADWAY damage Such as, for example, tissue damage that may be SUTE 900 caused by (i) disorders of the heart muscle (for example, SAN DIEGO, CA 92101-8285 (US) cardiomyopathy or myocarditis) Such as idiopathic cardi omyopathy, metabolic cardiomyopathy which includes dia Appl. No.: 11/221,298 betic cardiomyopathy, alcoholic cardiomyopathy, drug-in (21) duced cardiomyopathy, ischemic cardiomyopathy, and (22) Filed: Sep. 7, 2005 hypertensive cardiomyopathy, (ii) atheromatous disorders of the major blood vessels (macrovascular disease) Such as the Related U.S. Application Data aorta, the coronary arteries, the carotid arteries, the cere brovascular arteries, the renal arteries, the iliac arteries, the (63) Continuation of application No. 10/388,213, filed on femoral arteries, and the popliteal arteries, (iii) toxic, drug Mar. 12, 2003, now Pat. No. 6,951,890, and which is induced, and metabolic (including hypertensive and/or dia a continuation of application No. PCT/NZ03/00042, betic disorders of small blood vessels (microvascular dis filed on Mar. 10, 2003. ease) Such as the retinal arterioles, the glomerular arterioles, the Vasa nervorum, cardiac arterioles, and associated capil (60) Provisional application No. 60/364,382, filed on Mar. lary beds of the eye, the kidney, the heart, and the central and 12, 2002. peripheral nervous Systems, (iv) plaque rupture of athero matous lesions of major blood vessels Such as the aorta, the (30) Foreign Application Priority Data coronary arteries, the carotid arteries, the cerebrovascular arteries, the renal arteries, the iliac arteries, the fermoral Mar. 11, 2002 (NZ). 517725 arteries and the popliteal arteries, (v) diabetes or the com Mar. 8, 2002 (NZ)................................................ 517721 plications of diabetes. Patent Application Publication Jan. 12, 2006 Sheet 1 of 27 US 2006/0009534 A1 Normal Myocardium Reducing Substance & Free Copper S tem Cell Free Radicals Tissue Mediated D Repair amage Cardiomyopathy F G U R E 1 Patent Application Publication Jan. 12, 2006 Sheet 2 of 27 US 2006/0009534 A1 Hypothesis 1. Glyco-oxidation production (AGE" formation) Lipid or Protein + glucose - {Protein - AGE {Lipid - AGE Cu-AGE Protein or Cu-AGE Lipid -> Protein + 02 2. Superoxide dismutase 202 -- 2H' -) H202 -H 02 3. Haber-Weiss Reaction (Copper salt catalyst) H202 + 20, - 0 + OH- + OH *AGE = Advance Glycation Endproduct FIGURE 2 Patent Application Publication Jan. 12, 2006 Sheet 3 of 27 US 2006/0009534 A1 sn?e?sberpuessisessy :3uauue6w FGURE3 Patent Application Publication Jan. 12, 2006 Sheet 4 of 27 US 2006/0009534 A1 uue6uw:33 e?34snu,Iwa?epodelaousi elH FIGURE 4 Patent Application Publication Jan. 12, 2006 Sheet 5 of 27 US 2006/0009534 A1 200 -- STZ -be-Sham 150 -- STZ/D7 - -o-Sham D7 50 O O 1 2 3 4 5 6 7 8 9. 1 0 1 1 12 13 14 Time (weeks) FIGURES Patent Application Publication Jan. 12, 2006 Sheet 6 of 27 US 2006/0009534 A1 40 -- STZ -be - Sham 3 O Aa’YKA2-fiS --- slavorSTZ/D7 -2 O 10 y O O 1 2 3 4 5 6 7 8 9 10 1 1 12 13 14 Time (weeks) FIGURE 6 Patent Application Publication Jan. 12, 2006 Sheet 7 of 27 US 2006/0009534 A1 100 -- STZ -- Sham 75 -H STZ/D7 -o-Sham/D7 5 O 2 5 O 5 10 15 20 Preload (cmH2O) *p-0.05:STZ v STZ/D7 FIGURE 7 Patent Application Publication Jan. 12, 2006 Sheet 8 of 27 US 2006/0009534 A1 30 1S -- STZ S -%-Sham 5, 20 -- STZ/D7 -o-Sham/D7 s 10 9 O O O O 5 10 15 20 25 Preload (cmH2O) * p-0.05: STZ v STZ/D7, "p-0.05: STZ/D7 v Sham/D7. FIGURE 8 Patent Application Publication Jan. 12, 2006 Sheet 9 of 27 US 2006/0009534 A1 2 o E -- STZ e -- Sham S -- STZ/D7 N-1 S-s -o-Sham/D7 on 10 s C. C 9 O O O O 5 10 15 20 25 Preload (cmH2O) FIGURE 9 Patent Application Publication Jan. 12, 2006 Sheet 10 of 27 US 2006/0009534 A1 75 es -- STZ E -- Sham s 50 -- STZ/D7 s -- Sham/D7 O o 25 5 O O 5. 10 15 2O 25 Preload (cmH2O) * p-0.05:STZ v STZ/D7 FIGURE 10 Patent Application Publication Jan. 12, 2006 Sheet 11 of 27 US 2006/0009534 A1 -A-STZ -- Sham --STZ/D7 -o-Sham/D7 O 5 10 15 2O Preload (cmH2O) p<0.05: STZ v STZ/D7 FIGURE 11 Patent Application Publication Jan. 12, 2006 Sheet 12 of 27 US 2006/0009534 A1 -A-STZ -e-Sham -- STZ/D7 -o-Sham D7 O 5 10 15 20 Preload (cmH2O) p-0.05: STZ v STZ/D7, #p-0.05: STZ/D7 v Shan/D7. FIGURE 12 Patent Application Publication Jan. 12, 2006 Sheet 13 of 27 US 2006/0009534 A1 2 125 3 -o-Sham/D7 C 2 100 -e- Sham E -- STZ O5 75 -- STZ/D7 C 2 O-e 50 CD O St. 25 9 ? O ---- 60 80 100 120 Afterload (mmHg) Wilcoxon p<0.05 for STZ v STZ/D7 FIGURE 13 Patent Application Publication Jan. 12, 2006 Sheet 14 of 27 US 2006/0009534 A1 Flow-probe Afterload |Poona 95% O2 5% CO2 Pressure transducers FIGURE 14 Patent Application Publication Jan. 12, 2006 Sheet 15 of 27 US 2006/0009534 A1 FIGURE 1S Patent Application Publication Jan. 12, 2006 Sheet 16 of 27 US 2006/0009534 A1 -- nondiabetic: saline infused -a-diabetic: saline infused 1000 PF0.003 E. 750 PC0.0001 PC0.0001 P<0.000 E ? Y Y Y so 3. 500 GD . E 250 O m 30 90 time (min) 150 210 0.1 mg. kg 1.0 mg.kg 10 mg. kg' 100 mgkg' -- nondiabetic: drug infused -o- diabetic: drug infused 750 P-002 500 P<0.0001 PC00001 P=0.0003 E -- o ... 250 . - O 30 90 time (min) 150 210 0. mg kg." 1.0 mgkg' 10 mg.kg 100 mg.kg FIGURE 16 Patent Application Publication Jan. 12, 2006 Sheet 17 of 27 US 2006/0009534 A1 1000 -A-Saline infused -o- drug infused 750 r =0.044 P=0.0055 . 500 3t E 250 --saline infised -s-drug in?ised 500 P<0.0001 FIGURE 17 Patent Application Publication Jan. 12, 2006 Sheet 18 of 27 US 2006/0009534 A1 O.O4 -a-saline infused -g- drug infused P<0.0001 O.O3 PC0.0001 P<0.0001 Pa0.0001 -- 0.02 O 30 90 time (min) 150 210 0.1 mgkg' 1.0 mg.kg 10 mg.kg 100 mg.kg .04 -- Saline infused -- drug infused P<0.0001 0.03 P=0.005.5 P<0.0001 P<0.0001 0.02 0.01 O 3O 90 time (min) 150 210 f -1 - -1 f - 0.1 mg.kg 1.0 mg.kg 10 mg.kg 100 mg.kg FIGURE 18 Patent Application Publication Jan. 12, 2006 Sheet 19 of 27 US 2006/0009534 A1 -A - nondiabetic. Saline infused -a- diabetic. Saline infused O.OOOO12 - PeO.01.07 0.000009 P=0.0268 O.OOOOO6 OOOOOO3 O 30 90 time 150 210 t (min) t O. 1 mg.kg' 1.0 mg.kg' 1O mg.kg 100 mg.kg -H nondiabetic: drug infused -- diabetic: drug infused E 0.00012 P=0.0001 e 2, 000009 P=0.0001 =OOOO1 PEO.0002 c E O.OOOO6 PO.0318 9 s 5 0.00003 O O 30 90 time 150 0.1 mg.kg 1.0 mg.kg (min) 10 mg.kg 100 mg.kg FIGURE 19 Patent Application Publication Jan. 12, 2006 Sheet 20 of 27 US 2006/0009534 A1 nondiabetic: saline infused a nondiabetic: drug infused diabetic: Saline infused O diabetic: drug infused O.OO1 O.OOO75 0.0005 0.00025 FIGURE 20 Patent Application Publication Jan. 12, 2006 Sheet 21 of 27 US 2006/0009534 A1 a nondiabetic: drug infused O diabetic: drug infused a nondiabetic: saline infused a diabetic: saline infused P=0.003 0.0008 N 0.0001 0.0006 0.000075 0.0004 0.00005 0.0002 0.000025 FIGURE 21 Patent Application Publication Jan. 12, 2006 Sheet 22 of 27 US 2006/0009534 A1 0.01 -a-saline infused -- drug infused P=0.0035 0.0075 0.005 P=0. 00.15 P=0.0001 P-0.0293 0.0025 0.002 0.0015 0.001 5 0.0005 FIGURE 22 Patent Application Publication Jan. 12, 2006 Sheet 23 of 27 US 2006/0009534 A1 O.01 -a-saline infused -- drug infused P=0.0035 0.0075 O.005 P=0. 00.15 P=0.0001 P=0.0293 O.0025 0.002 -A-Saline infused -- drug infused 0.0015 O.001 0.0005 FIGURE 23 Patent Application Publication Jan. 12, 2006 Sheet 24 of 27 US 2006/0009534 A1 nondiabetic: saline infused a nondiabetic: drug infused diabetic: Saline infused O diabetic: drug infused 0.04 0.03 0.02 0.01 FIGURE 24 Patent Application Publication Jan. 12, 2006 Sheet 25 of 27 US 2006/0009534 A1 a nondiabetic: drug infused odiabetic: drug infused nondiabetic: saline infused a diabetic: Safine infused 0.00006 5 0.00015 s 0.0001.25 g a 0.00004 0.0001 G 5is O.OOOO75 s O.OOOO2 0.00005 C 0.000025 O FIGURE 25 Patent Application Publication Jan.