US 20050113314A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0113314 A1 Fong et al. (43) Pub. Date: May 26, 2005 (54) CICLETANINE IN COMBINATION WITH Publication Classification ORAL ANTIDIABETIC AND/OR BLOOD LIPID-LOWERING AGENTS ASA COMBINATION THERAPY FOR DIABETES (51) Int. Cl." ..................... A61K 31/70; A61K 31/4741; AND METABOLIC SYNDROME A61K 31/426; A61K 31/155; A61K 31/175 (76) Inventors: Benson M. Fong, San Francisco, CA (52) U.S. Cl. ............................ 514/25; 514/302; 514/369; (US); Glenn V. Cornett, Palo Alto, CA 514/592; 514/635 (US) Correspondence Address: KNOBBE MARTENS OLSON & BEAR LLP 2040 MAIN STREET (57) ABSTRACT FOURTEENTH FLOOR IRVINE, CA 92614 (US) Preferred embodiments of the present invention are related to novel therapeutic drug combinations and methods for (21) Appl. No.: 10/929,108 treating and/or preventing complications in patients with (22) Filed: Aug. 27, 2004 diabetes and/or metabolic Syndrome. More particularly, aspects of the present invention are related to using a Related U.S. Application Data combination of cicletanine and an oral antidiabetic agent for treating and/or preventing complications (including microal (60) Provisional application No. 60/498,916, filed on Aug. buminuria, nephropathies, retinopathies and other compli 29, 2003. cations) in patients with diabetes or metabolic Syndrome. US 2005/0113314 A1 May 26, 2005 CICLETANNE IN COMBINATION WITH ORAL women >0.85) and/or Body Mass Index >30 kg/M); 6) ANTIDIABETIC AND/OR BLOOD micro albuminuria (urine albumin excretion: 220 ugmin' LIPID-LOWERING AGENTS ASA COMBINATION or albumin/creatinine ratio22.0 mg/mmol. THERAPY FOR DIABETES AND METABOLIC 0007. In the chronological sequence of impaired glucose SYNDROME tolerance, followed by early and late phases of type 2 diabetes, it is essential to Start early with nonpharmacologic RELATED APPLICATIONS therapy, including physical activity, diet, and weight reduc 0001) This application claims the benefit of UA Provi tion. In addition, to reduce the incidence of macrovascular sional Patent Application No. 60/498,916 filed Aug. 29, complications of diabetes, pharmacotherapy for distur 2003, which is expressly incorporated herein by reference in bances in lipid metabolism and for hypertension is war its entirety. ranted (Goldberg, R. et al. 1998 Circulation 98:2513-2519; Pyorala, K. et al. 1997 Diabetes Care 20:614-620). There FIELD OF THE INVENTION fore, it has become increasingly evident that the treatment should aim at Simultaneously normalizing blood glucose, 0002 Preferred embodiments of the present invention are blood preSSure, lipids and body weight to reduce the mor related to using a combination of cicletanine and an oral bidity and mortality. Unfortunately, until today no single antidiabetic agent and/or a blood-lipid-lowering agent for drug that Simultaneously attackS hyperglycemia, hyperten treating and/or preventing complications (including microal Sion and dyslipidemia is available for patients with meta buminuria, nephropathies, retinopathies and other compli bolic Syndrome. cations) in patients with diabetes or metabolic Syndrome, for controlling blood glucose, and a combination of cicletanine 0008. In general, there are three pharmacotherapeutic and a lipid-lowering agent for controlling blood lipids and approaches typically relevant to the management of meta treating metabolic Syndrome. bolic Syndrome (insulin resistance Syndrome, Syndrome X): 0009 1) Hypoglycemic agents: A) Oral antidiabet BACKGROUND OF THE INVENTION ics (OADS); B) Insulin; 0.003 Diabetes is a chronic metabolic disorder which 0010) 2) Antihypertensive agents; afflicts 14 million people in the United States, over two 0011 3) Lipid-lowering agents. million of whom have its most severe form, childhood diabetes (also called juvenile, Type I or insulin-dependent 0012 Drug toxicity is an important consideration in the diabetes). Type II Diabetes (DM II) makes up more than treatment of humans and animals. Toxic side effects result 85-90% of all diabetics, and is likely to be the next epidemic. ing from the administration of drugs include a variety of 0004 Patients with diabetes of all types have consider conditions that range from low-grade fever to death. Drug able morbidity and mortality from microvascular (retinopa therapy is justified only when the benefits of the treatment thy, neuropathy, nephropathy) and macrovascular (heart protocol outweigh the potential risks associated with the attacks, Stroke, peripheral vascular disease) pathology, all of treatment. The factors balanced by the practitioner include which carry an enormous cost. For example: a) Proliferative the qualitative and quantitative impact of the drug to be used retinopathy (the leading cause of blindness for people under as well as the resulting outcome if the drug is not provided 65 years of age in the United States) and/or macular edema to the individual. Other factors considered include the physi occur in about 50% of patients with type 2 diabetes, as do cal condition of the patient, the disease Stage and its history peripheral and/or autonomic neuropathy. b) The incidence of of progression, and any known adverse effects associated diabetic renal disease is 10% to 50% depending on ethnicity. with a drug. c) Diabetics have heart attacks, Strokes and peripheral vas 0013. It is known that, for example, Sulfonylureas can cular disease at about triple the rate of non-diabetics. The cause Severe and lifethreatening hypoglycemia, due to their cost of treating diabetes and its complications exceeds S100 continuous action as long as they are present in the blood billion annually. (Holman, R. R. & Turner, R. C., 1991 In: Textbook of Diabetes, Pickup, J. C., Williams, G., Eds; Blackwell Sci 0005 Non-insulin dependent diabetes mellitus develops entific Publ. London, pp. 462-476). Such an action may especially in Subjects with insulin resistance and a cluster of affect the myocytes in the heart increasing the risk of cardiac cardiovascular risk factorS Such as obesity, hypertension and arrhythmias. On the other hand, metformin is known to dyslipidemia, a Syndrome which first recently has been cause Stomach-malfunction and toxicity which can cause recognized and is named “The metabolic Syndrome' death by excessive dose of administration to a patient for a (Alberti K. G., & Zimmet P. Z. 1998 Diabet Med 7:539-53). prolonged time (Innerfield, R. J. 1996 New Engl J Med 0006. In accordance with the WHO definition, a patient 334:1611-1613). Glitazones (e.g., Actos(R), Avandia(R), Rezu has metabolic Syndrome if insulin resistance and/or glucose lin(E); also known as the thiazolidinediones) tend to increase intolerance is present together with two or more of the lipids. TroglitaZone is known to have side effects, Such as following conditions: 1) reduced glucose tolerance or dia anemia, nausea, and hepatic toxicity (Eung-Jin Lee et al. betes; 2) insulin Sensitivity (under hyperinsulinemic, eugly 1998 Diabetes Science, Korea Medicine, 345-359; Ishii, S. cemic conditions corresponding to a glucose uptake below et al. 1996 Diabetes 45: (Suppl. 2), 141A (abstracts) Wat the lower quartile for the background population); 3) king, P. B. et al. 1998 N Engl J Med 338:916-917). Other increased blood pressure (2140/90 mmHg); 4) increased reported adverse events include dyspnea, headache, thirst, plasma triglyceride (21.7 mmol/l) and/or low HDL choles gastrointestinal distreSS, insomnia, dizziness, incoordina terol (<0.9 mmol/l for men; <1.0 mmol/l for women); 5) tion, confusion, fatigue, pruritus, rash, alterations in blood central adipositas (waist/hip ratio for men: >0.90 and for cell counts, changes in Serum lipids, acute renal insuffi US 2005/0113314 A1 May 26, 2005 ciency, and dryneSS of the mouth. Additional Symptoms that mitigate a Side effect of Said Second agent. In another have been reported, for which the relationship to troglita variation, the therapeutically effective amount of cicletanine Zone is unknown, include palpitations, Sensations of hot and is Sufficient to enhance tissue Sensitivity to insulin. Alterna cold, Swelling of body parts, skin eruption, Stroke, and tively, the therapeutically effective amount of cicletanine hyperglycemia. and the blood glucose lowering amount of the Second agent are preferably Sufficient to produce a Synergistic glucose 0.014 Consequently there is a long felt need for a new and lowering effect. combined medicament for the treatment of diabetes, and pre-diabetic, metabolic Syndrome, that has fewer, or no, 0023. In another embodiment, a method is disclosed for adverse effects (i.e., less toxicity) and favorable profile in treating and/or preventing a condition associated with terms of blood glucose and lipids. elevated cholesterol in a mammal. The method comprises administering an oral formulation comprising a therapeuti SUMMARY OF THE INVENTION cally effective amount of cicletanine and a lipid lowering 0.015. In accordance with one preferred embodiment of amount of a Second agent. the present invention, an oral formulation is disclosed, 0024 Preferably, the second agent is selected from the comprising a therapeutically effective amount of cicletanine group consisting of cholestyramine, colestipol, lovastatin, in combination with a Second agent that lowers blood pravastatin, Simvastatin, gemfibrozil, clofibrate, nicotinic glucose. acid and probucol. Alternatively, the Second agent is an 0016. In one preferred variation, the cicletanine com HMG-CoA reductase inhibitor. prises