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United States Patent (19) 11 Patent Number: 5,902,831 Holland Et Al USOO5902831A United States Patent (19) 11 Patent Number: 5,902,831 Holland et al. (45) Date of Patent: May 11, 1999 54 PREVENTION OF ATHEROSCLEROSIS Wasielewski “Lovastatin verzogert Athersklerose . " A. USING NADPH OXIDASE INHIBITORS Allg. Med. 68,987 (1993). Aviram et al. “Lovastatin Inhibits Low-Density Lipoprotein 75 Inventors: James Arthur Holland, Bath; David Oxidation and Alters. Its Fluidity . " Metabolism 41, K. Johnson, Genesco, both of N.Y. 229-235 (1992). 73 Assignee: The Research Foundation of State Weber et al. “Antioxidants inhibit monocyte adhesion by University of New York, Albany, N.Y. suppressing nuclear . ' Arterioscler. Thromb. 14, 1665–1673 (1994). 21 Appl. No.: 08/862,515 BorS et al. "Antioxidants: their function and mechanism as radical scavengers' Proc. Int. Conf. Superoxide 1, 38-43 22 Filed: May 23, 1997 (1982). Related U.S. Application Data Keaney et al. "AtherOSclerosis, Oxidative StreSS, and Anti oxidant Protection . .” Prog. Cardivasc. Dis. 38, 129-154 63 Continuation-in-part of application No. 08/562,767, Nov. 27, 1995, Pat. No. 5,763,496. (1995). Day et al. “Hypercholesterolemia and Simvastatin therapy: 51 Int. CI. ... A61K 31/12, A61K 31/11 Effects on cell membrane...” Clin. Chem. 21, S137 (1995). 52 U.S. Cl. .......................... 514/685; 514/689; 514/699; 514/824 Pschyrembel “Klinisches Worterbuch” 132 (1994). 58 Field of Search ..................................... 514/685, 689, 514/699, 824 Primary Examiner Kimberly Jordan Attorney, Agent, or Firm-Heslin & Rothenberg, P.C. 56) References Cited 57 ABSTRACT FOREIGN PATENT DOCUMENTS A method for the prevention and treatment of atherOSclerosis 4109627 3/1991 Germany. and its related diseases in mammals, in which an NADPH 6135880 5/1994 Japan. 06145040 5/1994 Japan. oxidase inhibitor is administered, is provided. The NADPH 06227977 8/1994 Japan. oxidase inhibitor prevents the production of reactive oxygen 07165575 6/1995 Japan. Species upon exposure of endothelial cells to atherogenic 07179853 7/1995 Japan. LDL levels, thus resulting in decreased endocytosis and WO9513063 5/1995 WIPO. vascular hyperpermeability. Preferred NADPH oxidase inhibitors are of the formula: OTHER PUBLICATIONS O Miikki, V. et al., Characterization of the humic material R3 formed by composting of domestic and industrial biowastes. Part 1 HPLC of the cupric oxide oxidation products from humic acids; Chemosphere 29(12), 2609-18 (1994). re Van der Hage, Erik R.E. et al., Ammonia chemical ionization OH mass spectrometry of Substituted phenylpropanoids and phe nylalkyl phenyl ethers; J. Mass. Spectrom. 30(4), 541-8 OR1 (1995). Senaratne et al. "Lovastatin prevents the impairment of Additionally, there is provided a diagnostic method for endothelium dependent . " Cardivasc. Res. 25, 568-578 predicting risk of a human patient to atherOSclerotic-related (1991). Goldstein et al. “Regulation of low-density lipoprotein diseases. receptors: implications . " Circulation 76, 504-507 (1987). 20 Claims, 4 Drawing Sheets U.S. Patent May 11, 1999 Sheet 1 of 4 5,902,831 HIGH LDL & ECH2O2 APOCYNIN EFFECT 0.35 k = p <0.01 O.30 0.25 0.2O (-) APOCYNIN 0.15 x (+) APOCYNN O.10 0.05 XXXXXXX XXXXXXXXXXXXX & xx's O OO s &S CONTROL LDL 240 mg/d FIG. 1 HIGH LDL & ECENDOCYTOSIS APOCYNIN EFFECT 3.50 k = p < 0.01 2.80 2.10 (-) APOCYNIN 1.40 x (+) APOCYNN O.O CXXXXXXX XXXXXXX& O OO &RSSSSSSS 2XXXXXXXX CONTROL LDL 240 mg/d FIG. 2 U.S. Patent May 11, 1999 Sheet 2 of 4 5,902,831 ARACHIDONIC ACID & ECH2O2 APOCYNIN EFFECT 0.30 k = p <0.01 0.25 0.20 Ž (-) APOCYNN is is x (+) APOCYNIN F 0.10 0.05 0.00 2& 2& CONTROL 10 ARACHIDONIC ACID (uM) FIG. 3 PMN NADPHOXIDASE ACTIVITY ATHEROSCLEROSIS (22 HUMAN SUBJECTS) 200 150 100- S.33 S. P. C. P. s: 50- : ;: FIG. 6 U.S. Patent May 11, 1999 Sheet 3 of 4 5,902,831 U.S. Patent May 11, 1999 Sheet 4 of 4 5,902,831 3. 5,902,831 1 2 PREVENTION OF ATHEROSCLEROSIS blood Subsequently pass through this endothelial tissue and USING NADPH OXIDASE INHIBITORS accumulate in the intima of the arterial wall. Even a mod erate in crease in end othelial permeability CROSS-REFERENCE TO RELATED (hyperpermeability) is accompanied by a significant APPLICATION increase in the incidence of atherosclerotic events. This application is a continuation-in-part of U.S. patent One mechanism by which vascular hyperpermeability can application Ser. No. 08/562,767 filed Nov. 27, 1995, now occur in the presence of an intact endothelium is increased U.S. Pat. No. 5,763,496. endothelial endocytosis due to perturbation of the endothe lium. The endothelium can be perturbed by various STATEMENT AS TO RIGHTS UNDER conditions, including high levels of low density lipoprotein FEDERALLY SPONSORED RESEARCH (LDL) in the bloodstream and shear stress, as occurs in hypertension. Diabetes mellitus and Smoking can also give This invention was made with support from the Depart rise to perturbation of the endothelium. In Studies in Support ment of Veterans Affairs (Merit Review 0002) and from the of the instant invention, human vascular endothelial cells National Institutes of Health (Grant No. 5R01 HL49573). 15 (EC) were exposed to high LDL concentrations (up to 330 The United States government may have certain rights in the mg/dL cholesterol) for prolonged periods. The results, as invention. demonstrated by Stability of cell count for instance, indicate that EC death and loSS do not occur in humans during the FIELD OF THE INVENTION promotion of atherosclerotic plaque formation by LDL. The present invention relates to therapeutic methods for When endothelial hyperpermeability is referred to herein, the prevention and treatment of atherosclerosis and diseases the proceSS is primarily one of increased transcytosis rather resulting from endothelial hyperpermeability. More than loSS of physical integrity of the cell membrane or particularly, the present invention relates to the prevention Separation between formerly adherent cells. and treatment of these diseases through the administration of Initially, endothelial perturbation occurs, resulting in an NADPH oxidase inhibitor. 25 increased endocytosis and LDL accumulation in the Suben dothelial Space. Thus, exposure to high LDL levels induces BACKGROUND OF THE INVENTION heightened EC endocytosis. Studies indicate that exposure AtherOSclerosis with its Sequelae of heart attack, Strokes, to LDL, in concentration ranges that are considered from and peripheral vascular disease is the leading cause of death epidemiologic Studies to be atherogenic (endothelial cells in the United States with over 800,000 deaths per year. exposed to >140 mg/dL LDL cholesterol, for example), is Excluding accidents, Suicide S, and homicides, necessary for exaggerated endocytosis. Another key finding atherosclerotic-related diseases account for nearly 50% of is that once heightened endocytosis develops, it persists. all deaths. Epidemiologic Studies Show that a large percent Such a persistent change in EC functional State is consistent with the end othelial perturbation, or Vascular age of those afflicted have an elevation in blood low density 35 lipoprotein (LDL) levels. LDL carries cholesterol from the hyperpermeability, concept. liver to body tissues. An elevated cholesterol level Endocytosis is a fundamental, apparently ubiquitous, cel (hypercholesterolemia) is commonly associated with an lular event. During endocytosis, a Segment of plasma mem elevation in LDL levels. High blood cholesterol levels, brane is interiorized to form a vesicle that migrates into the Specifically LDL-cholesterol, increase risk for coronary 40 cytoplasm. This vesicle may participate in transcellular heart disease (CHD), whereas lowering total cholesterol and transport via transcytosis. The endocytosis regulatory LDL-cholesterol levels reduces CHD risk. mechanism is not well understood, but Studies related to the Many pharmaceutical agents have been developed to treat instant invention demonstrate that reactive oxygen Species, or prevent atherosclerosis and its complications by control Such as H2O and O, enhance EC endocytosis. Cells ling abnormally high blood LDL levels or lowering choles 45 generate reactive oxygen species (ROS) as byproducts of terol levels. The most widely known of these agents include normal cellular metabolism. Perturbed endothelial cells nicotinic acid, clofibrate, dextrothyroxine Sodium, increase reactive oxygen Species production via the activa neomycin, beta-sitosterol, probucol, cholestyramine and tion of nicotinamide adenine dinucleotide phosphate HMG-CoA reductase inhibitors, Such as lovastatin and sim (NADPH) oxidase. vastatin. However, the usefulness of these agents is limited 50 NADPH oxidase is an enzyme that has been well char by the frequent occurrence of acute Side effects. Such side acterized in leukocytes, but leukocyte-type NADPH oxidase effects may include intense cutaneous flush, pruritus, gas has not been previously identified in endothelial cells. Stud trointestinal irritation, hepatotoxicity, cardiac arrhythmias, ies undertaken in Support of the instant application have nausea, Weight gain, alopecia, impotence, abdominal pain, demonstrated that it occurs in endothelial cells. Activation of diarrhea, eosinophilia, Skin rash, musculoskeletal pain, 55 NADPH oxidase results in the transfer of electrons from blurred vision, mild anemia, leukopenia, the enhancement of NADPH to oxygen, resulting in the generation of O. The gallstones, constipation, and impaction. Moreover, there is active form of the oxidase is a complex assembled from only a partial correlation between lowering
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