US 2008.0027082A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0027082 A1 Hocher et al. (43) Pub. Date: Jan. 31, 2008 (54) USE OF ADENOSINE A1 ANTAGONISTS IN Publication Classification RADIOCONTRAST MEDIA NDUCED NEPHROPATHY (51) Int. Cl. A 6LX 3/59 (2006.01) (76) Inventors: Berthold Hocher, Hannover (DE): A6IP I3/2 (2006.01) Yvan Fischer, Barsinghausen (DE); (52) U.S. Cl. .......................................................... 51.4/265.1 Klaus Witte, Hannover (DE); Dieter Ziegler, Hemmingen (DE) (57) ABSTRACT Correspondence Address: MLAYER BROWN LLP Described herein are pharmaceutical combinations compris P.O. BOX2828 ing a therapeutically effective amount of a first selective CHICAGO, IL 60690 (US) adenosine A1 antagonist and a first radiocontrast media. In one embodiment the selective adenosine A1 antagonist (21) Appl. No.: 11/765,290 comprises 4-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4- yl)amino-trans-cyclohexanol methanesulfonate and/or (22) Filed: Jun. 19, 2007 (4S)-4-hydroxy-1-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4- Related U.S. Application Data yl)-L-prolinamide methanesulfonate. Also described are the use of a first selective adenosine A1 antagonist in the (60) Provisional application No. 60/805,173, filed on Jun. treatment of radiocontrast media induced nephropathy. Fur 19, 2006. Provisional application No. 60/805,168, thermore, a kit comprising a therapeutically effective filed on Jun. 19, 2006. Provisional application No. amount of a first selective adenosine A1 antagonist and a 60/871,062, filed on Dec. 20, 2006. first radiocontrast media is also described herein. Patent Application Publication Jan. 31, 2008 Sheet 1 of 4 US 2008/0027082 A1 Figure 1 implantation lines implantation Figure 2 air its 3' i collection -- colletion its. 3' Sir fier Patent Application Publication Jan. 31, 2008 Sheet 2 of 4 US 2008/0027082 A1 Figure 3 l P --Tit am Cit -- Subst. 1 + Wisipaque -o- Wisipaque 2O 4 OO SOO 8OO 1 OOO 12 times Patent Application Publication Jan. 31, 2008 Sheet 3 of 4 US 2008/0027082 A1 Figure 4 - Control -- SubSt. 1 + Wisipaque -O-Wispaque O 2OO 400 600 8OO OOO 12OO times Patent Application Publication Jan. 31, 2008 Sheet 4 of 4 US 2008/0027082 A1 Figure 5 - Control -- SubSt. 1 + Wiisipaque -o- Wispaque O 2OO 400 6OO 8OO 1OOO 12OO times US 2008/0027082 A1 Jan. 31, 2008 USE OF ADENOSINE A1 ANTAGONSTS IN of CIN. Along the renal tubular system, substances like RM RADIOCONTRAST MEDIA NDUCED that are not reabsorbed become increasingly concentrated. NEPHROPATHY Up to 99% of renal fluids are usually taken up by the action of manifold cellular and paracellular mechanisms. This CROSS REFERENCE TO RELATED means that the urine concentration of RM can increase by a APPLICATIONS factor of 100. Along with the continuous concentration process, tubular fluid containing RM will become increas 0001) This application claims the benefit of U.S. Provi ingly viscous and can lead to tubular obstruction (Ueda, sional Application Nos. 60/805,168 and 60/805,173 filed on 1993). Inevitably, intrarenal pressure increases as well, as Jun. 19, 2006 and U.S. Provisional Application No. 60/871, the kidney cannot expand due to the Surrounding capsule. As 062 filed on Dec. 20, 2006 and all three are hereby incor a consequence, renal perfusion pressure for the renal porated by reference in their entirety to the extent permitted medulla may no longer be sufficient to allow for sufficient by law. perfusion. FIELD 0006. In the kidney, activation of A1AR in afferent glom erular arterioles has been Suggested to contribute to tubulo 0002 Pharmaceutical combinations comprising a thera glomerular feedback (TGF) which is a strategic feedback peutically effective amount of a first selective adenosine A1 mechanism designed to control tubular flow and regional receptor antagonist and a first radiocontrast media (RM) are perfusion. The vasoconstriction elicited by elevations in described herein. Also described is the use of said combi NaCl) in the macula densa region of the nephron. A role of nations for the treatment of radiocontrast media induced adenosine in TGF response mediation is consistent with its nephropathy as well as kits comprising said combinations. effect to cause vasoconstriction. In addition to its vasocon strictor effect. A receptor stimulation contracts mesangial BACKGROUND cells in the glomerulus (Olivera, 1989). Acute renal failure 0003 Interventional techniques, fast multislice computer caused by the injection of RM has been recognized for many tomographies and new 3D reconstruction techniques have years as a complication in diagnostic and interventional increased the use of iodinated intravascular radiocontrast procedures. The incidence of acute renal failure directly media (RM). The majority of examinations require iodinated induced by RM lies at approximately 10-15%, while the RM for accurate and safe diagnosis and interventional incidence of CIN defined by clinically significant increases procedures. Today approximately 60 million doses are given in serum creatinine is as high as 22% (Porter, 1989). The every year world wide (Andrew, 2004). The use of radio peak creatinine concentration occurs within 3-5 days of contrast media can lead to a decline of excretory renal exposure to the contrast media and usually resolves satis function that starts soon after administration. The renal factorily. However, in about 10% of at-risk patients, dialysis dysfunction can be transient, persistent or even irreversible. is required. Preexisting renal insufficiency, reduced intra Hence, the use of radiocontrast media has been associated vascular volume and additional underlying diseases (e.g. with increased in-hospital morbidity, mortality, and cost of hypertension, diabetes mellitus) are thought to be some of medical care and long admissions, especially in patients the leading risk factors for radiocontrast media induced requiring dialysis. Radiocontrast media induced nephropa nephropathy. The osmolality, the measurement of the num thy (CIN) is therefore a clinically important problem. ber of molecules and particles in a solution per kilogram of water, of the RM is regarded to be of great importance in 0004 CIN is the structural damage of the kidney. The radiocontrast induced nephropathy. The incidence of neph definition of CIN varies. It can be defined as acute aggra ropathy induced by low-osmolar RM is low in the general vation of renal functionality after application of RM, population and has been calculated to be less than 2% induced as proximate cause to the exclusion of alternative (Nikolsky, 2003). etiologies. The most common definition of a minor effect is 0007 Adenosine production is one of the discussed an increase in serum creatinine greater than 25% or 44 mol/l mechanisms behind CIN. Adenosine is an endogenous neu (0.5 mg/dl) after the intravascular administration of a RM. A romodulator with predominantly inhibitory effects on the major effect is defined as increase in serum creatinine greater CNS, heart, kidneys and other organs. It is a naturally than 50% or 88 mmol/l (1 mg/dl). The pathogenesis of CIN occurring nucleoside, which exerts its biological effects by is not fully understood. It is believed that two main factors, interacting with a family of adenosine receptors known as hemodynamic as well as tubular effects, are involved. Appli A1, A2a, A2b, and A3, all of which modulate important cation of RM leads to a change in renal hemodynamics, physiological processes. Selective A1 adenosine receptor manifesting itself as a decrease in the glomerular filtration antagonists (AAR) have pronounced effects on the kidney rate (GFR). GFR is the rate of ultra filtration of plasma and have shown to be potent diuretics and natriuretics with across the walls of the glomerular capillaries and measure little effect on potassium excretion. Thus, they are renal ment of total GFR of both kidneys provides a sensitive index protective and useful for the treatment of renal failure, renal of overall renal excretory function. dysfunction, nephritis, hypertension, and edema. The kid 0005 The glomerular filtration rate is calculated by com neys produce adenosine constitutively to regulate glomeru paring urine creatinine levels with the blood test results. A lar filtration and electrolyte reabsorption mediated by the GFR value (see http://www.fpnotebook.com) in a range of adenosine A1 receptor system. The A1 adenosine receptor 97-137 ml/min/1.73 m is adequate for a male human and of has been found to govern the vasoconstriction response of 88-128 ml/min/1.73 m is adequate for a female human, the afferent glomerular arteriole. Adenosine causes a reduc whereas a GFR lower than 15 ml/min/1.73 m leads to tion in the blood flow to the kidney, and thus a reduction in kidney failure. A decrease in GFR induced by application of the glomerular filtration rate and the renal blood flow. RM is considered to be the main cause for the development Inhibition of the A1 receptor will heighten the glomerular US 2008/0027082 A1 Jan. 31, 2008 filtration rate and correspondingly increase the rate of urine effective amount of a first selective adenosine A1 receptor formation. The application of adenosine receptor antagonists antagonist and a radiocontrast media. has been implicated in protection from acute renal failure. The adenosine receptor antagonists aminophylline (combi 0011. A further embodiment described herein relates to a nation of theophylline and ethylenediamine 2:1) and theo kit comprising a therapeutically effective amount of a first phylline (which has been found to non-selectively antago selective adenosine A1 receptor antagonist and a radiocon nize adenosine receptors in the brain) were evaluated as trast media. potential agents to protect against radiocontrast media 0012. In an additional embodiment, the first AAR induced nephropathy (Shammas, 2001; Welch, 2002; Huber, antagonist may be selected from the compounds represented 2002). Aminophylline does not appear to add a protective by formula I role in preventing radiocontrast media induced nephropathy while theophylline was effective in preventing radiocontrast media induced nephropathy impaired renal excretory, endo crine and tubular function.