US 20140057832A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0057832 A1 Conrad et al. (43) Pub. Date: Feb. 27, 2014 (54) USE OF RELAXN TO INCREASE ARTERAL Publication Classification COMPLIANCE (51) Int. Cl. (71) Applicants: Kirk P. Conrad, Gainesville, FL (US); A638/22 (2006.01) Sanjeev G. Shroff, Pittsburg, PA (US) (52) U.S. Cl. CPC .................................. A61 K38/2221 (2013.01) (72) Inventors: Kirk P. Conrad, Gainesville, FL (US); USPC 514/1.9; 514/12.7: 514/7.3; 514/6.9; 514/7.4 Sanjeev G. Shroff, Pittsburg, PA (US) (73) Assignee: University of Pittsburgh - Of the (57) ABSTRACT Commonwealth System of Higher Education, Pittsburgh, PA (US) The present invention provides methods for increasing arte rial compliance. The methods generally involve administer (21) Appl. No.: 14/071,705 ing to an individual in need thereof an effective amount of relaxin. The present invention further provides methods of (22) Filed: Nov. 5, 2013 increasing arterial compliance in individuals who have Type 1 or Type 2 diabetes. The present invention further provides Related U.S. Application Data methods of increasing arterial compliance in perimeno (63) Continuation of application No. 12/985,714, filed on pausal, menopausal, and post-menopausal women. The Jan. 6, 2011, now Pat. No. 8,602,998, which is a con present invention further provides methods of increasing arte tinuation of application No. 11/084,670, filed on Mar. rial compliance in individuals who have or who are at risk of 18, 2005, now Pat. No. 7,878,978. developing age-associated arterial stiffness. 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S 9 S. s s s iet e 33 8 BS b is r d s (eueseguoy eBuelo afieueled) epuessa JejnoseA puests US 2014/0057.832 A1 Feb. 27, 2014 USE OF RELAXN TO INCREASE ARTERAL waveform using the area method. In another embodiment, COMPLIANCE global arterial compliance may be calculated as the stroke Volume-to-pulse pressure ratio, where the stroke Volume is CROSS-REFERENCE TO RELATED defined as the ratio of cardiac output to heart rate. APPLICATIONS 0008. In related embodiments, the local arterial compli ance or the regional arterial compliance of a Subject may be 0001. This application is a continuation of application Ser. measured in addition to or as an alternative to the global No. 12/985,714, filed on Jan. 6, 2011, that is a continuation arterial compliance measurement and, if the local or regional application of application Ser. No. 1 1/084,670, filed Mar. 18, arterial compliance is diminished relative to the local or 2005, which claims benefit of U.S. Provisional Application regional arterial compliance expected for a similarly situated No. 60/554,716, filed Mar. 19, 2004, the teachings of which healthy individual, relaxin may be administered to increase are hereby incorporated by reference in their entirety. arterial compliance in that individual. STATEMENT REGARDING FEDERALLY 0009. In further embodiments, the subject to whom relaxin is administered suffers from one or more of the fol SPONSORED RESEARCH lowing disorders: atherosclerosis, Type 1 diabetes, Type 2 0002 The US, government may have certain rights in this diabetes, coronary artery disease, Scleroderma, stroke, dias invention, pursuant to Grant No. ROI HL67937 awarded by tolic dysfunction, familial hypercholesterolemia, isolated the National Institutes of Health. systolic hypertension, primary hypertension, secondary hypertension, left ventricular hypertrophy, arterial stiffness FIELD OF THE INVENTION associated with long-term tobacco Smoking, arterial stiffness associated with obesity, arterial stiffness associated with age, 0003. The present invention is in the field of arterial com systemic lupus erythematosus, preeclampsia, and hypercho pliance, and in particular, the use of relaxinto increase arterial lesterolemia. In related embodiments, the invention provides compliance. methods of increasing arterial compliance in perimeno BACKGROUND OF THE INVENTION pausal, menopausal, and post-menopausal women and in individuals who are at risk of one of the aforementioned 0004 Arterial compliance declines with age even in disorders. healthy individuals with no overt cardiovascular disease. 0010. In an additional embodiment of the invention, With age, a decrease is seen in the ability of the large and administration of relaxin increases arterial compliance by at Small arteries to distendin response to an increase in pressure. least 10%, 15%, 20% or more, relative to the measured arte The age-associated reduction in arterial compliance is an rial compliance before administration. In still further embodi independent risk factor for the development of cardiovascular ments, the invention provide for the administration of relaxin disease, and is associated with a number of other pathological to individuals with diminished arterial compliance at a pre conditions. For example, reduced arterial compliance is also determined rate so as to maintain a serum concentration of associated with both Type 1 diabetes mellitus and Type 2 relaxin from 0.5 to 80 ng/ml. In one embodiment, the relaxin diabetes melitus. It has been reported that diabetic arteries is recombinant human relaxin. In yet another embodiment, appear to age at an accelerated rate compared to arteries of the relaxin is recombinant H2 relaxin. In related embodi nondiabetic individuals. See, e.g., Arnett et al. (1994) Am J ments, the relaxin may be administered daily, in an injectable Epidemiol. 140:669-682: Rowe (1987) Am J Cardid. 60:68 formulation, as a Sustained release formulation, or as a con G-71 G: Cameronet al. (2003) Diabetes Car-26(7):2133-8: tinuous infusion. Kass et al. (2001) Circulation 104: 1464-1470; Avolio of al. (1983) Circulation 68: 50-58; U.S. Pat. No. 6,251,863: U.S. BRIEF DESCRIPTION OF THE DRAWINGS Pat. No. 6,211,147. 0011 FIGS. 1A-C depict the percent change from base 0005. There is a need in the art for methods of increasing line for cardiac output (FIG. 1A), heart rate (FIG. 1B), and arterial compliance, and for treating disorders associated with stroke volume (FIG.1C) in female rats administered low dose or resulting from reduced arterial compliance. The present recombinant human relaxin (rhRLX; 4 Jug/h), high dose invention addresses these needs. rhRLX (25 g/h), or vehicle. 0012 FIGS. 2A-D depict percent change from baseline SUMMARY OF THE INVENTION for systemic vascular resistance (FIG. 2A), mean arterial 0006. The present invention provides methods of treating pressure (FIG.