MX2008016255A

MX2008016255A - Use of adenosine a1 antagonist in radiocontrast media induced nephropathy.

Info

Publication number: MX2008016255A
Application number: MX2008016255A
Authority: MX
Inventors: Dieter Ziegler; Klaus Witte; Berthold Hocher; Yvan Fischer
Original assignee: Solvay Pharm Gmbh
Priority date: 2006-06-19
Filing date: 2007-06-18
Publication date: 2009-01-15
Also published as: JP2009541256A; KR20090029727A; EP2035007A1; AU2007263036A1; BRPI0713126A2; CA2655016A1; EA200802402A1; TW200808819A; IL195867A0; WO2007147809A1

Abstract

The present invention relates to pharmaceutical combinations comprising a therapeutically effective amount of at least one selective adenosine A1 antagonist and at least one radiocontrast media. In particular, the present invention relates to pharmaceutical combinations comprising 4-[(2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-trans-cyclo hexanol methanesulfonate and/or (4S)-4-hydroxy-1-(2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-L- prolinamide methanesulfonate as selective adenosine A1 antagonists and at least one radiocontrast media. The invention also relates to the use of said combinations in the manufacture of a medicament for the treatment of radiocontrast media induced nephropathy. Furthermore, the invention is relating to a kit comprising a therapeutically effective amount of said combination of at least one selective adenosine A1 antagonist and at least one radiocontrast media.

Description

USE OF ADENOSIN ANTAGONISTS TO IN INDUCED NEPHROPATHY THROUGH RADIOCONTRASTE FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one selective adenosine Al receptor antagonist and at least one (R) contrast medium. The invention also relates to the use of said combinations in the manufacture of a medicament for the treatment of nephropathy induced by radiocontrast means. In addition, the invention relates to a kit comprising said compositions.

BACKGROUND OF THE INVENTION Interventional techniques, computerized rapid multidetector tomography and new 3D reconstruction techniques, have increased the use of iodinated intravascular radiocontrast (MR) medium during the last decades. Most examinations require iodinated MRI for safe and accurate diagnosis and interventional procedures. Today, approximately 60 million doses are applied every year around the world (Andrew, 20041). The radiocontrast medium can lead to a decline in excretory renal function that starts soon after the administration. Renal dysfunction may be temporary, persistent or even irreversible. Therefore, the use of radiocontrast means has been associated with morbidity, increased hospital mortality, and costs of medical care and long admissions, especially in patients requiring dialysis. Nephropathy induced by radiocontrast (CIN) is, therefore, a clinically important problem. CIN is a structural damage of the kidney. The definition of CIN varies. It can be defined as the aggravation of renal functionality after the application of MRI, induced as a cause close to the exclusion of alternative etiologies. The most common definition of a minor effect is an increase in serum creatinine, greater than 25% or 44 mol / l (0.5 mg / dl) after intravascular administration of an MRI. A major effect is defined as an increase in serum creatinine greater than 50% or 88% mmol / 1 (1 mg / dl). The pathogenesis of CIN is not completely understood. It is believed that two main factors, hemodynamic as well as tubular effects, are involved. The application of MRI leads to a change in renal hemodynamics, especially to a decrease in the glomerular filtration rate (GFR). GFR is the ultrafiltration rate of plasma through the walls of the glomerular capillaries and the measurement of the total GFR of both kidneys, provides an index of sensitivity of total renal excretory function. The glomerular filtration rate is calculated by comparing creatinine levels in the urine with the results of blood tests. A GFR value (see http: //www.fpnotebook.com2), in the range of 97-137 ml / min / 1.73 m2, is suitable for a male human and 88- 128 ml / min / 1.73 m, is suitable for a female human, while a lower GFR of 15 ml / min / 1.73 m2 leads to renal failure. A decrease in GFR induced by the application of MRI is considered to be the main cause for the development of CIN. Along with the renal tubular system, substances such as RM that are not reabsorbed become increasingly concentrated. Up to 99 of renal fluids are usually taken by the action of multiple cellular and paracellular mechanisms. This means that the RM urine concentration can be increased by a factor of 100. Together with the continuous concentration process, the tubular fluid containing RM will become increasingly viscous and can lead to tubular obstruction (Ueda, 19933). Inevitably, the intrarenal pressure also increases, since the kidney can not expand due to the capsule that surrounds it. As a consequence, the renal perfusion pressure for the renal medulla may not be large enough to guarantee sufficient perfusion. In the kidney, the activation of A1AR in afferent glomerular arterioles, has been suggested for contributing to tubuloglomerular feedback (TGF), which is a strategic feedback mechanism, designed to control tubular flow and regional perfusion. Vasoconstriction stimulated by elevations in [NaCl] in the dense region of the macula of the nephron. An adenosine role in mediating the TGF response is consistent with its effect to cause vasoconstriction. An adenosine role in mediating the TGF response is consistent with its effect to cause vasoconstriction. In addition to its vasoconstrictor effect, the stimulation of the Ai receptor contracts the mesangial cells in the glomerulus (Olivera, 19894). Acute renal failure caused by MR injection has been recognized for many years as a complication in interventional and diagnostic procedures. The incidence of acute renal failure directly induced by MRI falls to approximately 10-15%, while the incidence of CIN defined by clinically significant, increases in serum creatinine as high as 22% (Porter, 19895). The maximum creatinine concentration occurs within 3-5 days of exposure to the contrast medium and usually resolves satisfactorily, but up to 10% of dialysis is required in at-risk patients. Intravascular volume reduces pre-existing renal insufficiency and additional fundamental diseases (for example, hypertension, diabetes mellitus), it is said, are some of the risk factors conducive to the nephropathy induced by means of radiocontrast. The osmolarity, the measurement of the number of molecules and particles in a solution per kilogram of water, of the RM, is considered to be of greater importance in the nephropathy induced by radiocontrast. The incidence of nephropathy induced by low osmolar MRI is low in the general population and has been calculated to be less than 2% (Nilolsky, 20036). The production of adenosine is one of the mechanisms discussed behind the CIN. Adenosine is an endogenous neuromodulator with predominantly inhibitory effects on the CNS, heart, kidneys and other organs. It is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as Al, A2a, A2b and A3, all of which modulate important physiological processes. Selective adenosine Al receptor antagonists (Ai, AR) have pronounced effects on the kidney, and have been shown to be potent diuretics and natriuretics with little effect on potassium excretion. In this way, they are renal protectors, used for the treatment of renal insufficiency, renal dysfunction, nephritis, hypertension and edema. The kidney produces constitutively adenosine to regulate glomerular filtration and electrolyte-mediated resorption by the adenosine Al receptor system. The adenosine Al receptor has been found to govern the vasoconstriction response of the afferent glomerular arteriole. Adenosine causes a reduction in blood flow to the kidney, and thus, a reduction in glomerular filtration rate and renal blood flow. Inhibition of Al receptor will increase the rate of glomerular filtration, and correspondingly, increase the rate of urine formation. The application of adenosine receptor antagonists has been implicated in the protection of acute renal failure. Antagonists of the adenosine receptor aminophylline (combination of theophylline and ethylenediamine 2: 1) and theophylline (which has been found to non-selectively antagonize adenosine receptors in the brain), were evaluated as potential agents to protect against medically induced nephropathy radiocontrast (Shammas, 2001; Welch, 2002; Huber, 20027). Aminophylline does not seem to add a protective role in the prevention of radiocontrast-induced nephropathy while theophylline was effective in the prevention of renal excretory, endocrine and tubular function impaired by radiocontrast-induced nephropathy. These results suggest that adenosine may play a role in the pathogenesis of CIN and such application of non-selective adenosine receptor antagonists has been implicated in the protection of acute renal failure associated with MR treatment. Erley (19948) investigated the influence of nonselective adenosine antagonist theophylline on glomerular filtration rate after the application of MRI and assigns adenosine a major role in CIN. In addition, Arakawa (19969) describes the role of adenosine in the renal response to iohexol contrast medium in dogs, with and without pre-existing renal insufficiency. Arakawa indicates that in normal renal function, iohexol stimulates renal vasodilation by activation mainly of A2 adenosine receptors. While in impaired renal function, iohexol induces activation of both Al and A2. Arakawa proposes the adenosine A2 receptors for being associated with the initial renal vasodilation, and the adenosine Al receptors for being responsible for the sustained aggravation of renal hemodynamics. Yao (200010) investigated the influence of the selective adenosine antagonist Al KW-3902 in radio contrast-induced nephropathy in rats with chronic nitric oxide deficiency. Yao suggests adenosine that influences the pathogenesis of CIN via the activation of Al receptors. Greiner (200511), studied the influence on theophylline and acetylcysteine separately and in combination, in nephropathy induced by contrast medium in intensive care patients, and corroborates the prophylactic properties of theophylline in CIN.

Lee (200612) concludes that renal adenosine Al receptors are only partially responsible for the pathogenesis of radiocontrast nephropathy. In experiments with agénic mice with renal adenosine Al receptors, it was found that these mice are protected from acute renal failure induced by MR injection. Direct tubular toxicity will, however, not be modulated by the renal adenosine Al receptors. Patent application EP 1 386 609 (CV Therapeutics13) describes methods for restoring diuretic and renal function comprising adenosine Al antagonists, in combination with a diuretic. Patent application WO 99/31101 (Univ. South Florida14), describes xanthine derivatives as adenosine Al receptor antagonists. In addition, radiolabeled derivatives and a method for imaging adenosine Al receptor antagonists are mentioned for the purposes of Medical diagnostic.

BRIEF DESCRIPTION OF THE INVENTION AiAR have previously been known to possess protective effects in several nephrotoxic models of acute renal failure. The increased release of renal adenosine and stimulation of renal adenosine receptors has been proposed as being among the main reasons in the development of acute renal failure induced by means of radiocontrast. It has now been surprisingly found that the administration of selective Al receptor antagonists of formula I, especially, is beneficial in the prevention of the risk of developing CIN and / or the need for dialysis in patients receiving radiocontrast medium. It has now been surprisingly found that the administration of selective Al receptor antagonists of formula I especially is beneficial in the prevention of the risk of side effects and development of CIN as damage to final organ and / or need for dialysis in patients who receive medium. radiocontrast. The treatment of a specific group of seriously ill patients suffering from certain long-term renal disorders with selective adenosine Al antagonists to cure or ameliorate these renal disorders is proposed by the state of the art (see, for example, WO 2004/09442815 ). It has now surprisingly been found that the administration of selective Al-receptor antagonists of formula I, especially, are beneficial in the prevention of the risk of developing CIN and / or the need for dialysis in all groups of patients who receive radiocontrast medium, which they include healthy patients, as well as patients who already suffer from kidney disorders, for example, kidney failure and other kidney disorders. It is therefore an object of the present invention, using a therapeutically effective amount of at least one selective adenosine Al receptor antagonist, for the manufacture of a medicament for the treatment of nephropathy induced by at least one radiocontrast medium, for the increase in serum creatinine levels, for the reduction in renal blood flow, as well as for the prevention of dialysis requirement caused by nephropathy induced by radiocontrast medium, in mammals and humans. A further object of the invention pertains to the pharmaceutical combination comprising a therapeutically effective amount of at least one selective adenosine Al receptor antagonist and a radiocontrast medium. A further object of the invention is that of a kit comprising a therapeutically effective amount of at least one selective adenosine Al receptor antagonist and a radiocontrast medium. At least one AiAR antagonist which can be used according to the present invention, can be selected from the group consisting of a compound of formula I I wherein R1 and R2 are each independently selected from a hydrogen atom, an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl or together form an optionally substituted heterocyclic ring; R3 is selected from a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl or optionally substituted alkylaryl; R4 and R5 are each independently selected from a halogen atom, a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl, or R4 and R5 together form an optionally substituted or carbocyclic heterocyclic ring optionally replaced; and / or a salt, and / or a prodrug, and / or a solvate thereof pharmaceutically acceptable, for the manufacture of a medicament for the prevention of nephropathy induced by at least one R in mammals or humans; and / or a pharmaceutically acceptable salt and / or prodrug and / or solvate thereof. In particular, the present invention relates to a methanesulfonate combination of 4- [(2-phenyl-7-pyrrolo [2,3-d] pyrimidin-4-yl) amino] -trans-cyclohexanol or methanesulfonate of (AS) 4-hydroxy ^ l- (2-phenyl-7tf-pyrrolo [2,3-d] pyrimidin-4-yl) -L-prolinamide with at least one MRI. At least one MRI which can be used according to the present invention, can be a gadolinium or iodine based radiocontrast medium, selected from the group consisting of bunaiod, biligram, bilimiro, bilopaque, colimil, etiodol, diatrast, dionosil , falignost, gadobutrol, gadodiamide, gadopentetate dimeglumine, gastrografin, hexabrix, hypodine, mangafodipir, amidotrizoate, ethiodized oil, imagopaque, yodamide, iodipamide, iodixanol, iodophene, yophenilate, iomeron, iomeprol, iopamidol, iopanoic acid, iopiperidol, yofendilate, iopromide, yopidol, iosimenol, iotalámico acid, iotrolan, ioversol, ioxilan, ioxáglico acid, isopaque, ipodato, meglumina iotalamato, meglumina acetriozato, meglumina diatrozato, metrizamida, mielotrast, omnipaque, osbil, optiray, optojod, opacoron, perflutren, fenobutiyodil, sodium fentatiotalein, priodax, propylodone, skiodan, sodium iodomethamate, diatrizoate sodium, telepaque, teridax, tetrabrom, torotrast, triognost, 1, 3, 5-Tri-n-hexyl-2,4,6-triiodobenzene, thyropanoate, visipaque or xenetix, and / or a salt, and / or a prodrug, and / or a pharmaceutically acceptable solvate thereof.

BRIEF DESCRIPTION OF THE FIGURES Figure 1: In rats restricted in volume, hemodynamic measurements were made and the TGF response was assessed. Figure 2: Experimental setting 2 was used to collect the urine. Diuresis, urine osmolarity and urine viscosity were determined. Figure 3: Effects of Visipaque and substance 1 on renal cortical blood flow, measurements during a period of 20 minutes after injection of Visipaque or vehicle (control) at time 0. Mean + SEM (n = 9) are shown, expressed as relative values compared to the cortical flow rates recorded before stimulation with Visipaque (or vehicle). *: P <; 0.05 Visipaque vs. Control; +: P < 0.05 substance 1 + Visipaque vs. Visipaque. Figure 4: Effects of Visipaque and substance 1 on renal cortical vascular conductance, measurements during a period of 20 minutes after the injection of Visipaque or vehicle (control) at the time. Mean ± SEM (n = 9), expressed as relative values compared to the cortical flow rates recorded before stimulation with Visipaque (or vehicle). *: P < 0.05 Visipaque vs. Control; +: P < 0.05 substance 1 + Visipaque vs. Visipaque. Figure 5: Effects of Visipaque and substance 1 on renal cortical oxygenation (p02), Measurements during a period of 20 minutes after injection of Visipaque or vehicle (control) at time 0. Mean values are shown ± SEM (n = 9) , expressed as relative values compared to the cortical flow velocities registered before the stimulation of Visipaque (or vehicle). *: P < 0.05 Visipaque vs. Control; +: P < 0.05 substance 1 + Visipaque vs. Visipaque.

DETAILED DESCRIPTION OF THE INVENTION The present invention pertains to the use of a therapeutically effective amount of at least one selective adenosine Al antagonist for the manufacture of a medicament for the prevention of nephropathy induced by at least one radiocontrast medium in mammals or humans. The invention pertains to the use of a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I wherein R1 and R2 are each independently selected from a hydrogen atom, an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl or together form an optionally substituted heterocyclic ring; R3 is selected from a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl or optionally substituted alkylaryl; R4 and R5 are each independently selected from a halogen atom, a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl, or R4 and R5 together form an optionally substituted or carbocyclic heterocyclic ring optionally replaced; and / or a salt, and / or a prodrug, and / or a solvate thereof pharmaceutically acceptable, for the manufacture of a medicament for the prevention of Nephropathy induced by at least one MRI in mammals or humans. In addition, the invention relates to the use of a therapeutically effective amount of at least one selective adenosine Al antagonist, for the manufacture of a medicament for the prevention of increase in serum creatinine levels, induced by at least one radiocontrast medium in mammals or humans. The invention thus pertains to the use of a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I, as defined above, for the manufacture of a medicament for the prevention of increase in serum creatinine levels, induced by at least one radiocontrast medium, preferably a temporary, persistent or irreversible increase in serum creatinine levels, induced by radiocontrast medium in mammals or humans. Furthermore, the invention relates to the use of a therapeutically effective amount of at least one selective adenosine Al antagonist for the manufacture of a medicament for the prevention of reduction in renal blood flow induced by at least one radiocontrast medium. The invention thus pertains to the use of a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I, as defined above, for the manufacture of a medicament for the prevention of reduction in renal blood flow induced by at least one radiocontrast medium, preferably a temporary, persistent or irreversible reduction in renal blood flow induced by radiocontrast medium in mammals or humans. Furthermore, the invention relates to the use of a therapeutically effective amount of at least one selective adenosine Al antagonist, for the manufacture of a medicament for the prevention of dialysis requirement caused by radiocontrast induced nephropathy., said CIN may be temporary, persistent or irreversible in mammals or humans. The invention thus pertains to the use of a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I, as defined above, for the manufacture of a medicament for the prevention of a need for dialysis risk in a human or mammalian patient, preferably of temporary, persistent or irreversible dialysis, said patient is subject to receive radiocontrast means. The present invention furthermore relates to a pharmaceutical combination of a therapeutically effective amount of at least one selective adenosine Al antagonist, and at least one radiocontrast medium, wherein the pharmaceutical combination is suitable for administration Simultaneously, separately or in stages to humans or mammals. Furthermore, the present invention relates to a kit comprising a therapeutically effective amount of at least one Al-selective antagonist, and at least one radiocontrast medium, wherein the pharmaceutical combination is suitable for simultaneous, separate or stepwise administration to humans or mammals. The A1AR which can be used according to the present invention can be selected from the formula I wherein R1 and R2 are each independently selected from a hydrogen atom, an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl or together form an optionally substituted heterocyclic ring; R3 is selected from a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl or optionally substituted alkylaryl; R4 and R5 are each independently selected from a halogen atom, an hydrogen or an optionally substituted alkyl, optionally substituted aryl, or optionally substituted alkylaryl moiety, or R4 and R5 together form an optionally substituted or optionally substituted carbocyclic heterocyclic ring; preferably wherein R1 and R2 are each independently selected from a hydrogen atom, an optionally substituted alkyl or together form an optionally substituted heterocyclic ring; R3 is a hydrogen atom or an optionally substituted aryl; R4 and R5 are each independently selected from a halogen atom or a hydrogen atom; more preferably wherein R 1 is a hydrogen and R 2 is an optionally substituted cyclohexyl ring, or R 1 and R 2 together form an optionally substituted pyrrolidine ring; R3 is a phenyl ring; R4 and R5 are each a hydrogen atom; and / or a pharmaceutically acceptable salt, and / or prodrug, and / or solvate thereof. In one embodiment, AlARs according to the present invention can be selected from 4- [(2-phenyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] -trans-cyclohexanol methanesulfonate or methanesulfonate. of (4S) -4-hydroxy-1- (2-phenyl-7'-pyrrolo [2,3-d] pyrimidin-4-yl) -L-prolinamide and / or a prodrug and / or a solvate thereof.

The AlARs suitable for use herein, are described in the international patent applications WO 99/62518, WO 01/39777, WO 02/057267 and WO 2004/094428 (Osi Pharmaceuticals and Solvay Pharmaceuticals1). The MRI which can be used according to the present invention, can be a gadolinium or iodine based radiocontrast medium, selected from the group consisting of bunaiod, biligram, bilimiro, bilopaque, colimil, etiodol, diatrast, dionosil, falignost gadobutrol, gadodiamide, gadopentetate dimeglumine, gastrografin, hexabrix, hypodine, mangafodipir, amidotrizoate, ethiodized oil, imagopaque, yodamide, iodipamide, iodixanol, iodophene, yofendilate, iomeron, iomeprol, iopamidol, iopanoic acid, iopiperidol, yofendilate, iopromide, yopidol, iosimenol, iotamic acid, iotrolan, ioversol, ioxilan, ioxáglico acid, isopaque, ipodato, meglumina iotalamato, meglumina acetriozato, meglumina diatrozato, metrizamida, mielotrast, omnipaque, osbil, optiray, optojod, opacoron, perflutren, phenobutiyodil, fentetiotalein sodium , priodax, propylodone, skiodan, sodium iodomethamate, diatrizoate sodium, telepaque, teridax, tetrabrom, torotrast, triognost, 1, 3, 5-Tri -n-hexyl-2,4,6-triiodobenzene, thyropanoate, visipaque or xenetix, and / or a salt, and / or a prodrug, and / or a pharmaceutically acceptable solvate thereof.

The preferred RM includes xenetix, omnipaque or visipaque. Some examples (Schering, Braceo Industria Chimica, Univ. California, Nyegaard, Cook Imaging Corporation, Mallinckrodt, Eprova, Nycomed and Savag11) of RM suitable for use herein, are described within the European patent applications EP 0 022 744, EP 0 023 992, EP 0026 281, EP 0 033 426, EP 0 108 638 and EP 0 317 492, International applications WO 87/00757 and WO 89/08101, US patents US 2,776,241, US 3,290,366, US 3,360,436, and US 5,349,085, the British application GB 1 321 591, as well as within the German patents DE 2 547 789, DE 2 726 196 and DE 2 909 439, without limiting the RM group. The methanesulfonate of 4- [(2-phenyl-7tf-pyrrolo [2,3-d] pyrimidin-4-yl) amino] -trans-cyclohexanol will subsequently also be abbreviated as substance 1 and the methanesulfonate of (4S) -4- hydroxy-1- (2-phenyl-7-pyrrolo [2,3-d] pyrimidin-4-yl) -L-prolinamide will also be subsequently abbreviated as substance 2. In a preferred embodiment, the invention pertains to the use of the substance 1 and bunaiod, or substance 1 and biligram, or substance 1 and bilimiro, or substance 1 and bilopaque, or substance 1 and colimil, or substance 1 and etiodol, or substance 1 and diatrast, or substance 1 and dionosil, or substance 1 and falignost,. substance 1 and gadobutrol, or substance 1 and gadodiamide, or substance 1 and gadopentetate dimeglumine, or substance 1 and gastrografin, or substance 1 and hexabrix, or substance 1 and hypodine, or substance 1 and mangafodipir, or substance 1 and amidotrizoate, or substance 1 and ethiodized oil, or substance 1 and imagopaque, or substance 1 and iodide, or substance 1 and iodipamide, or substance 1 and iodixanol, or substance 1 and iodophene, or substance 1 and yofendylate, or substance 1 and ionomer, or substance 1 and iomeprol, or substance 1 and iopamidol, or substance 1 and iopanoic acid, or substance 1 and iopiperidol, or substance 1 and yofendilate, or substance 1 and iopromide, or substance 1 and yopidol, or substance 1 and iosimenol, or substance 1 and isothalamic acid, or substance 1 and iotrolan, or substance 1 and ioversol, or substance 1 and ioxilan, or substance 1 and ioxáglico acid, or substance 1 and isopaque, or substance 1 and ipodato, or substance 1 and iotalamato of meglumina, or substance 1 and meglumine acetrizoate, or substance 1 and diatriz o of meglumine, or substance 1 and metrizamide, or substance 1 and mielotrast, or substance 1 and omnipaque, or substance 1 and osbil, 0 substance 1 and optiray, or substance 1 and optojod, or substance 1 and opacoron, or substance 1 and perflutren, or substance 1 and phenobutiyodil, or substance 1 and sodium fentatiotalein, or substance 1 and priodax, or substance 1 and propylodone, or substance 1 and skiodan, or substance 1 and sodium iodomethamate, or substance 1 and diatrizoate sodium, or substance 1 and telepaque, or substance 1 and teridax, or substance 1 and tetrabrom, or substance 1 and torotrast, or substance 1 and triognost, or substance 1 and 1, 3, 5-Tri-n -hexyl-2, 4,6-triiodobenzene, or substance 1 and thyropanoate, or substance 1 and visipaque, or substance 1 and xenetix. In a preferred embodiment, the invention pertains to a pharmaceutical combination of substance 1 and bunaiod, or substance 1 and biligram, or substance 1 and bilimiro, or substance 1 and bilopaque, or substance 1 and colimil, or substance 1 and etiodol, or substance 1 and diatrast, or substance 1 and dionosil, or substance 1 and falignost, or substance 1 and gadobutrol, or substance 1 and gadodiamide, or substance 1 and gadopentetate dimeglumine, or substance 1 and gastrografin, or substance 1 and hexabrix, or substance 1 and hypodine, or substance 1 and mangafodipir, or substance 1 and amidotrizoate, or substance 1 and ethiodized oil, or substance 1 and imagopaque, or substance 1 and iodide, or substance 1 and iodipamide, or substance 1 and iodixanol, or substance 1 and iodophene, or substance 1 and yofendylate, or substance 1 and iomeron, or substance 1 and iomeprol, or substance 1 and iopamidol, or substance 1 and iopanoic acid, or substance 1 and iopiperidol, or substance 1 and yofendylate, or substance 1 and iopromide, or substance 1 and yopidol, or substance a 1 and iosimenol, or substance 1 and iothalamic acid, or substance 1 and iotrolan, or substance 1 ioversol, or substance 1 and ioxilan, or substance 1 and ioxáglico acid, or substance 1 and isopaque, or substance 1 and ipodato, or substance 1 and iotalamato of meglumina, or substance 1 and meglumina acetrizoato, or substance 1 and diaglizoate of meglumina , or substance 1 and metrizamide, or substance 1 and mielotrast, or substance 1 and omnipaque, or substance 1 and osbil, 0 substance 1 and optiray, or substance 1 and optojod, or substance 1 and opacoron, or substance 1 and perflutren, or substance 1 and phenobutyodil, or substance 1 and sodium fentatiotalein, or substance 1 and priodax, or substance 1 and propylodone, or substance 1 and skiodan, or substance 1 and sodium iodomethamate, or substance 1 and diatrizoate sodium, or substance 1 and telepaque, or substance 1 and teridax, or substance 1 and tetrabrom, or substance 1 and torotrast, or substance 1 and triognost, or substance 1 and 1, 3, 5-Tri-n -hexyl-2,4,6-triiodobenzene, or substance 1 and thyropanoate, or substance 1 and visipaque, or substance 1 and xenetix. In a preferred embodiment, the invention pertains to a kit comprising, substance 1 and bunaiod, or substance 1 and biligram, or substance 1 and bilimiro, or substance 1 and bilopaque, or substance 1 and colimil, or substance 1 and etiodol, or substance 1 and diatrast, or substance 1 and dionosil, or substance 1 and falignost, or substance 1 and gadobutrol, or substance 1 and gadodiamide, or substance 1 and gadopentetate dimeglumine, or substance 1 and gastrografin, or substance 1 and hexabrix, or substance 1 e hypodine, or substance 1 and mangafodipir, or substance 1 and amidotrizoate, or substance 1 and ethiodized oil, or substance 1 and imagopaque, or substance 1 and iodide, or substance 1 and iodipamide, or substance 1 and iodixanol, or substance 1 and iodofen , or substance 1 and yofendylate, or substance 1 and iomeron, or substance 1 and iomeprol, or substance 1 and iopamidol, or substance 1 and iopanoic acid, or substance 1 and iopiperidol, or substance 1 and yofendylate, or substance 1 and iopromide, or substance 1 and yopidol, or substance 1 and iosimenol, or substance 1 and iothalamic acid, or substance 1 and iotrolan, or substance 1 and ioversol, or substance 1 and ioxylan, or substance 1 and ioxáglico acid, or substance 1 and isopaque, or substance 1 and iodate, or substance 1 and iotalamate of meglumine, or substance 1 and meglumine acetrizoate, or substance 1 and diatrizoate of meglumine, or substance 1 and metrizamide, or substance 1 and mielotrast, or substance 1 and omnipaque, or substance 1 and osbil, 0 substance 1 and optiray, or substance 1 and optojod, or substance 1 and opacoron, or substance 1 and perflutren, or substance 1 and phenobutyodil, or substance 1 and sodium fentatiotalein, or substance 1 and priodax, or substance 1 and propylodone, or substance 1 and skiodan, or substance 1 and sodium iodomethamate, or substance 1 and diatrizoate sodium, or substance 1 and telepaque, or substance 1 and teridax, or substance 1 and tetrabrom, or substance 1 and torotrast, or substance 1 and triognost, or substance 1 and 1, 3, 5-Tri-n -hexyl-2, 4, 6- triiodobenzene, or substance 1 and thyropanoate, substance 1 and visipaque, or substance 1 and xenetix. In a preferred embodiment, the invention pertains to a use of substance 2 and bunaiod, or substance 2 and biligram, or substance 2 and bilimiro, or substance 2 and bilopaque, or substance 2 and colimil, or substance 2 and etiodol, or substance 2 and diatrast, or substance 2 and dionosil, or substance 2 and falignost, or substance 2 and gadobutrol, or substance 2 and gadodiamide, or substance 2 and gadopentetate dimeglumine, or substance 2 and gastrografin, or substance 2 and hexabrix, or substance 2 and hypodine, or substance 2 and mangafodipir, or substance 2 and amidotrizoate, or substance 2 and ethiodized oil, or substance 2 and imagopaque, or substance 2 and iodide, or substance 2 and iodipamide, or substance 2 and iodixanol, or substance 2 and iodophene, or substance 2 and yofendylate, or substance 2 and iomeron, or substance 2 and iomeprol, or substance 2 and iopamidol, or substance 2 and iopanoic acid, or substance 2 and iopiperidol, or substance 2 and yofendylate, or substance 2 e iopromide, or substance 2 and yopidol, or substance 2 and iosimenol, or susta nia 2 and iothalamic acid, or substance 2 and iotrolan, or substance 2 and ioversol, or substance 2 and ioxilan, or substance 2 and ioxáglico acid, or substance 2 and isopaque, or substance 2 and ipodato, or substance 2 and iotalamato of meglumina , or substance 2 and meglumine acetrizoate, or substance 2 and diatrizoate meglumine, or substance 2 and metrizamide, or substance 2 and mielotrast, or substance 2 and omnipaque, or substance 2 and osbil, or substance 2 and optiray, or substance 2 and optojod, or substance 2 and opacoron, or substance 2 and perflutren, or substance 2 and phenobutyodil, or substance 2 and sodium fentetiotalein, or substance 2 and priodax, or substance 2 and propylodone, or substance 2 and skiodan, or substance 2 and sodium iodomethamate, or substance 2 and sodium diatrizoate, or substance 2 and telepaque, or substance 2 and teridax, or substance 2 and tetrabrom, or substance 2 and torotrast, or substance 2 and triognost, or substance 2 and 1, 3, 5-Tri-n-hexyl-2,4,6-triiodobenzene , or substance 2 and thyropanoate, or substance 2 and visipaque, or substance 2 and xenetix. In a preferred embodiment, the invention pertains to a pharmaceutical combination of substance 2 and bunaiod, or substance 2 and biligram, or substance 2 and bilimiro, or substance 2 and bilopaque, or substance 2 and colimil, or substance 2 and etiodol, or substance 2 and diatrast, or substance 2 and dionosil, or substance 2 and falignost, or substance 2 and gadobutrol, or substance 2 and gadodiamide, or substance 2 and gadopentetate dimeglumine, or substance 2 and gastrografin, or substance 2 and hexabrix, or substance 2 and hypodine, or substance 2 and mangafodipir, or substance 2 and amidotrizoate, or substance 2 and ethiodized oil, or substance 2 and imagopaque, or substance 2 and iodide, or substance 2 and iodipamide, or substance 2 and Iodixanol, or substance 2 and Iodofen, or substance 2 and yofendylate, or substance 2 and Iomeron, or substance 2 and Iomeprol, or substance 2 and Iopamidol, or substance 2 and Iopanoic acid, or substance 2 and Ioperoperidol, or substance 2 and Yofendylate , or substance 2 and iopromide, or substance 2 and yopidol, or substance 2 and iosimenol, or substance 2 and iotalámico acid, or substance 2 and iotrolan, or substance 2 and ioversol, or substance 2 and ioxilan, or substance 2 and ioxáglico acid , or substance 2 and isopaque, or substance 2 and ipodate, or substance 2 and iotalamato of meglumine, or substance 2 and meglumine acetrizoate, or substance 2 and diatrizoate of meglumine, or substance 2 and metrizamide, or substance 2 and mielotrast, or substance 2 and omnipaque, or substance 2 and osbil, or substance 2 and optiray, or substance 2 and optojod, or substance 2 and opacoron, or substance 2 and perflutren, or substance 2 and phenobutyodil, or substance 2 and fentatiotalein sodium, or substance 2 and priodax, or substance 2 and propylodone, or substance 2 and skioda n, or substance 2 and sodium iodomethamate, or substance 2 and diatrizoate sodium, or substance 2 and telepaque, or substance 2 and teridax, or substance 2 and tetrabrom, or substance 2 and torotrast, or substance 2 and triognost, or substance 2 and 1, 3, 5-Tri-n-hexyl-2,4,6-triiodobenzene, or substance 2 and thyropanoate, or substance 2 and visipaque, or substance 2 and xenetix. In a preferred embodiment, the invention pertains to a kit comprising the substance 2 and bunaiod ,. or substance 2 and biligram, or substance 2 and bilimiro, or substance 2 and bilopaque, or substance 2 and colimil, or substance 2 and etiodol, or substance 2 and diatrast, or substance 2 and dionosil, or substance 2 and falignost, or substance 2 and gadobutrol, or substance 2 and gadodiamide, or substance 2 and gadopentetate dimeglumine, or substance 2 and gastrografin, or substance 2 and hexabrix, or substance 2 and hypodine, or substance 2 and mangafodipir, or substance 2 and amidotrizoate, or substance 2 and ethiodized oil, or substance 2 and imagopaque, or substance 2 and iodide, or substance 2 and iodipamide, or substance 2 and iodixanol, or substance 2 and iodofen, or substance 2 and yofendylate, or substance 2 and iomeron, or substance 2 and iomeprol, or substance 2 and iopamidol, or substance 2 and iopanoic acid, or substance 2 and iopiperidol, or substance 2 and yofendylate, or substance 2 and iopromide, or substance 2 and yopidol, or substance 2 and iosimenol, or substance 2 and iothalamic acid, or substance 2 and iotrolan, or substance 2 and ioversol, or substance ia 2 and ioxilan, or substance 2 and ioxáglico acid, or substance 2 and isopaque, or substance 2 and ipodato, or substance 2 and iotalaraato of meglumina, or substance 2 and meglumina acetrizoato, or substance 2 and diaglizoate of meglumina, or substance 2 and metrizamide, or substance 2 and mielotrast, or substance 2 and omnipaque, or substance 2 and osbil, or substance 2 and optiray, or substance 2 and optojod, or substance 2 and opacoron, or substance 2 and perflutren, or substance 2 and phenobutyodil ,. or substance 2 and sodium fentatiotalein, or substance 2 and priodax, or substance 2 and propylodone, or substance 2 and skiodan, or substance 2 and sodium iodometamate, or substance 2 and diatrizoate sodium, or substance 2 and telepaque, or substance 2 and teridax, or substance 2 and tetrabrom, or substance 2 and torotrast, or substance 2 and triognost, or substance 2 and 1, 3, 5-Tri-n-hexyl-2,4,6-triiodobenzene, or substance 2 and thyropanoate , or substance 2 and visipaque, or substance 2 and xenetix. By a "therapeutically effective amount" of a pharmacologically active drug or agent, it means a sufficient but non-toxic amount of the drug or agent, to provide the desired effect. In the combination therapy of the present invention, "a therapeutically effective amount" of a component of the combination, is the amount of such a compound that is effective to provide the desired effect when used in combination with the other components of the combination. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents and the like. Thus, it is not always possible to specify an exact "therapeutically effective amount". However, an appropriate "therapeutically effective amount" in any individual case can be determined by an expert of ordinary skill using experimentation routine. At least one MRI is not promptly administered until the plasma level of at least one selective adenosine Al receptor antagonist has reached a concentration of 10-500 ng / ml. The invention also pertains to any arbitrary concentration or concentration ranges, which fall within the range of 0-500 ng / ml. In a preferred embodiment, at least one selective adenosine Al antagonist has a concentration of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, and 500 ng / ml, and any arbitrary concentration or concentration ranges, which fall in any of the ranges defined by two of the concentration values mentioned above, wherein the lower limit of said range is defined by the lower value and the upper limit of said range by the upper value, for example, a range of lO-180 ng / ml, 370-390 ng / mg, 10-150 ng / ml, etc. The invention thus belongs to the use comprising at least one radiocontrast medium for not being promptly administered until the therapeutically effective amount of at least one selective adenosine Al receptor antagonist is sufficient to provide a concentration level of plasma of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml. The invention thus further pertains to a pharmaceutical combination comprising at least one radiocontrast medium so as not to be promptly administered until the therapeutically effective amount of at least one selective adenosine Al receptor antagonist is sufficient to provide a level of plasma concentration of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml. The invention further pertains to a use comprising at least one radiocontrast medium so as not to be promptly administered until the therapeutically effective amount of at least one selective adenosine Al receptor antagonist is sufficient to provide a plasma concentration level. of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml. The invention further pertains to a pharmaceutical combination comprising at least one radiocontrast medium so as not to be promptly administered until the therapeutically effective amount of at least one selective adenosine Al receptor antagonist is sufficient to provide a plasma concentration level. of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml. The time period of application of the maintenance dosage of at least one antagonist selective adenosine Al, is sufficient to maintain the plasma level of at least one selective adenosine Al antagonist, at a concentration of 10-500 ng / ml. The amount of at least one selective adenosine Al antagonist to be administered to achieve and maintain a specific plasma level of at least one selective adenosine Al antagonist, corresponds to specific dosages to be administered to a patient. The person skilled in the art is able to select an appropriate dosage for a specific patient. The invention also pertains to any arbitrary concentration or concentration range, which falls within the range of 10-500 ng / ml. In a preferred embodiment, at least one selective adenosine Al antagonist has a concentration of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, and 500 ng / ml, and any arbitrary concentration or concentration range, which falls in any of the ranges defined by two of the concentration values mentioned above, wherein the lower limit of said range is defined by the lower value and the upper limit of said range by the upper value, for example, a range of 10-180 ng / ml, 320-390 ng / ml, 100-150 ng / ml, etc.

The time period of application of the maintenance dosage of at least one selective adenosine Al antagonist, falls between 0.1-48 hours, to maintain the plasma level of at least one Al selective adenosine, at a concentration of 10-500 ng / ml. The invention also pertains to a period of any arbitrary time interval, which falls within the time period of 0.1-48 hours. In a preferred embodiment, the time period of administration of the maintenance dosage is 0.1, 0.3, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 , 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20 , 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 31.5, 32, 32.5 , 33, 33.5, 34, 34.5, 35, 35.5, 36, 36.5, 37, 37.5, 38, 38.5, 39, 39.5, 40, 40.5, 41, 41.5, 42, 42.5, 43, 43.5, 44, 44.5, 45 , 45.5, 46, 46.5, 47, 47.5 and 48 hours, and any arbitrary period which falls in any of the intervals defined by two of the hour values mentioned above, where the lower limit of said interval is defined by the value lower and the upper limit of said interval by the higher value, for example, a range of 1-2 hours, 0.1-10 hours, 0.2-6 hours, 2-45 hours, 9.5-35 hours, etc. At least one selective receptor antagonist Al adenosine can be administered intravenously in a charged dosage followed by a maintenance dosage, and the amount of at least one loading dose of the selective adenosine Al receptor antagonist is administered at a time for a period of 5-25 minutes, before of the administration of at least one radiocontrast medium, and the maintenance dosage of at least one selective adenosine Al receptor antagonist is administered over a period of up to 48 hours subsequent to the administration of the loading dosage of at least one antagonist selective of the Al receptor, in a preferred embodiment over a period of up to 0.1, 0.3, 0.5, 1, 1.5, 2, 2. 5, 3, 3. 5, 4, 4 • 5, 5, 5.5, 6, 6. 5, 7, 7.5, 8, 8. 5, 9, 9. 5, 10, 10. 5, 11, 11. 5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15. 5, 16, 16. 5, 17, 17. 5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21. 5, 22, 22. 5, 23, 23. 5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27. 5, 28, 28. 5, 29, 29. 5, 30, 30.5, 31, 31.5, 32, 32.5, 33, 33. 5, 34, 34. 5, 35, 35. 5, 36, 36.5, 37, 37.5, 38, 38.5, 39, 39. 5, 40, 40. 5, 41, 41. 5, 42, 42.5, 43, 43.5, 44, 44.5, 45, 45. 5, 46, 46. 5, 47, 47. 5 and 48 hours The invention belongs to a period of any arbitrary time interval which is within the time period of 5-25 minutes before the administration of at least one medium radiocontrast, and maintenance dosing of at least one selective adenosine receptor agonist Al administered for a period of up to 48 hours subsequent to the administration of the loading dosage of at least one selective Al receptor antagonist, in a preferred embodiment for a period up to: 0.1, 0.3, 0.5, 1, 1.5, 2, 2.5 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15 , 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5 , 28, 28.5, 29, 29.5, 30, 30.5, 31, 31.5, 32, 32.5, 33, 33.5, 34, 34.5, 35, 35.5, 36, 36.5, 37, 37.5, 38, 38.5, 39, 39.5, 40 , 40.5, 41, 41.5, 42, 42.5, 43, 43.5, 44, 44.5, 45, 45.5, 46, 46.5, 47, 47.5 and 48 hours. In a preferred embodiment, at least one selective adenosine Al receptor antagonist can be administered intravenously at 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21, 22, 23, 24 and 25 minutes, and any arbitrary period which is in any interval defined by two of the minutes values mentioned above, where the lower limit of the interval is defined by the lower value and the limit upper of the range by the upper value, for example, a range of 10-18 minutes, 20-25 minutes, 12-15 minutes, etc., before the administration of at least one radiocontrast medium, and the maintenance dosage of at least one selective adenosine Al receptor antagonist is administered for a period of up to 48 hours subsequent to the administration of the loading dosage of at least one selective Al receptor agonist, in a preferred embodiment over a period of up to 0.1, 0.3, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 , 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17 , 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5 , 30, 30.5, 31, 31.5, 32, 32.5, 33, 33.5, 34, 34.5, 35, 35.5, 36, 36.5, 37, 37.5, 38, 38.5, 39, 39.5, 40, 40.5, 41, 41.5, 42 , 42.5, 43, 43.5, 44, 44.5, 45, 45.5, 46, 46.5, 47, 47.5 and 48 hours. The invention thus belongs to a use comprising the therapeutically effective amount of at least one selective adenosine Al receptor antagonist in a loading dosage to be administered intravenously, followed by a maintenance dosage, and the amount of at least one loading dosage of the selective adenosine Al receptor antagonist to be administered over a period of time of 5-25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes, more preferably 15 minutes before administration of at least a radiocontrast means, and comprising the maintenance dosage of at least one selective adenosine Al receptor antagonist to be administered for a period of up to 48 hours subsequent to the administration of the dosage of the at least one selective Al receptor antagonist. The invention thus belongs to a pharmaceutical combination comprising the therapeutically effective amount of at least one selective adenosine Al receptor antagonist in a loading dose to be administered intravenously followed by a maintenance dosage, and the amount of at least one loading dose of selective adenosine Al receptor antagonist to be administered over a period of time of 5-25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes , more preferably 15 minutes before the administration of at least one radiocontrast medium, and comprising the maintenance dosage of at least one selective adenosine Al receptor antagonist to be administered for a period of up to 48 hours subsequent to the administration of loading dosage of at least one selective Al receptor antagonist. The in Thus, the composition thus belongs to a kit comprising the therapeutically effective amount of at least one selective adenosine Al receptor antagonist in a loading dosage to be administered intravenously, followed by a maintenance dosage, and the amount of at least one loading dosage of the selective adenosine Al receptor antagonist to be administered over a period of time of 5-25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes, more preferably 15 minutes before the administration of at least one radiocontrast medium, and comprising the maintenance dosage of at least one selective antagonist of the Al adenosine receptor to be administered for a period of up to 48 hours subsequent to the administration of the loading dosage of at least one selective Al receptor antagonist. This invention in its broad scope is not limited to specific dosage forms, carriers, excipients or the like, as such may vary. It will also be understood that the terminology used in this document is for the purpose of describing only particular modalities, and is not intended to be limiting. It can be noted that as use in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, the reference to "a therapeutically effective agent" includes a single agent, as well as two or more different agents in combination, and the reference to "one carrier" includes mixtures of two or more carriers, as well as well as a single carrier, and the like.

The terms "A1AR", "selective adenosine Al antagonist" and "selective adenosine Al receptor antagonist" are used interchangeably herein to refer to a chemical compound that induces a desired pharmacological, physiological effect. At least one selective adenosine Al antagonist can be administered orally and / or intravenously. The invention of this form pertains to the use comprising the therapeutically effective amount of at least one selective adenosine Al receptor antagonist to be administered orally, preferably in an extended release formulation, prior to the administration of at least one radiocontrast agent. The invention of this form pertains to the corresponding use of the therapeutically effective amount of at least one selective adenosine Al receptor antagonist in a loading dosage to be administered intravenously followed by a maintenance dosage, and the amount of at least one dosage of loading of the selective adenosine Al receptor antagonist to be administered over a period of time of 5-25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes, more preferably 15 minutes before the administration of at least one medium radiocontrast, and comprising the maintenance dosage of at least one selective antagonist. Al adenosine receptor to be administered for a period of up to 48 hours subsequent to the administration of the loading dosage of at least one selective Al receptor antagonist. The invention thus belongs to a pharmaceutical combination comprising the therapeutically effective amount of at least one selective adenosine Al receptor antagonist to be administered orally, preferably in an extended release formulation, prior to the administration of at least one radiocontrast agent. The invention thus belongs to a pharmaceutical combination comprising the therapeutically effective amount of at least one selective adenosine Al receptor antagonist in a loading dosage to be administered intravenously followed by a maintenance dosage, and the amount of at least a loading dose of the selective adenosine Al receptor antagonist to be administered over a period of time of 5-25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes, more preferably 15 minutes prior to administration of minus a radiocontrast medium, and comprising the maintenance dosage of at least one selective adenosine Al receptor antagonist to be administered during a period of up to 48 hours subsequent to the administration of the loading dosage of at least one selective Al receptor antagonist. The invention thus belongs to a kit comprising the therapeutically effective amount of at least one selective receptor antagonist of Al adenosine to be administered orally, preferably in an extended release formulation, prior to the administration of at least one radiocontrast agent. The invention thus belongs to a kit comprising the therapeutically effective amount of at least one selective adenosine Al receptor antagonist in a loading dosage to be administered intravenously followed by a maintenance dosage, and the amount of at least one loading dosage of the selective adenosine Al receptor antagonist to be administered over a period of time of 5-25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes, more preferably 15 minutes before administration of at least a radiocontrast medium, and comprising the maintenance dosage of at least one selective adenosine Al receptor antagonist to be administered for a period of up to 48 hours subsequent to the administration of the loading dosage of at least one selective receptor antagonist. To the.

The term "intravenously" belongs to the parenteral application, which includes injection or infusion into the vein and the artery, without limiting the group of parenteral application forms. The term "orally" refers to enteric application, which includes application of for example, tablets, drops, pills, capsules, pellets, granules, etc., by mouth, without limiting the group of forms of enteric application. "Extended release" refers to a pharmaceutical dosage form. The term "extended" includes for example, "prolonged", "delayed", "retentive" and "delayed" dosage forms, without limitation. The term "container" refers to a hermetically sealed storage box for pharmacists. It includes storage boxes for pharmacists in fluid such as, for example, ampoules, vials, bottles, dispensers, syringes, etc., as well as storage boxes for solid pharmaceuticals such as, for example, ampoules, capsules, etc., without limiting the group of storage boxes. The term "irreversible" as used herein may be used interchangeably with the term "permanent." By "pharmaceutically acceptable" as such in the declaration of a "pharmaceutically acceptable carrier", a "Pharmaceutically acceptable auxiliary" or a "pharmaceutically acceptable salt" herein means a material that is not biologically or otherwise undesirable, i.e., the material can be incorporated into a pharmaceutical combination administered to a patient without causing any of the effects biological undesirable or interacting in a harmful way with any of the other components of the combination in which it is contained. "Pharmacologically active", as in a "pharmacologically active" derivative or metabolite, refers to a derivative or metabolite having the same type of pharmacological activity as the original compound and approximately equivalent in degree. When the term "pharmaceutically acceptable" is used to refer to a derivative of an active agent, it will be understood that the compound is pharmacologically active, as well as, that is to say, therapeutically effective for the treatment of nephropathy induced by radiocontrast means. "Carrier" or "pharmaceutically acceptable auxiliary" as used herein, refer to conventional pharmaceutically acceptable excipient materials suitable for drug administration, and including any material known in the art to be non-toxic and not interacting with other components of a pharmaceutical combination or drug delivery system in a harmful way. As used herein, the terms "comprising" and "including" are used in this document in an open, non-limiting sense. The term "prodrug" as used herein, represents derivatives of the compounds of the invention which are drug precursors which, after administration to a patient, release the drug in vivo via a chemical or physiological process. As used herein, the term "prodrug" includes metabolic precursors. In particular, the pro-drugs are derivatives of the compounds of the invention in which the functional groups carry additional constituents, which can be split under physiological conditions in vivo and therefore release the active principle of the compound (for example, a prodrug is brought to a physiological pH or through an enzymatic action is converted to the desired drug form). Prodrugs are bio-reversible derivatives of the drug molecules used to overcome some barriers to the usefulness of the original drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and objective limitations (Bundgaard, 198517). Prodrugs, that is, compounds that when administered to humans by any known route, are metabolized to compounds having formula I, which belong to the invention. The term "pharmaceutically acceptable salts" refers to salt forms that are pharmacologically acceptable and substantially non-toxic to the subject to which the compounds of the invention are administered. Preferably, the pharmaceutically acceptable salts is a methanesulfonate salt. The term "solvate" belongs to the association of suitable organic solvent molecules with molecules or ions of an A1AR. As used herein, the term "solvates" refers to both solvates containing a defined number of pro molecules of solvent molecules of a compound of formula I, and inclusion complexes, which are less stable and contain a number variable of molecule of solvent molecules of an A1AR. The term "treatment" as used herein, refers to reduction in severity and / or frequency of symptoms, elimination of symptoms and / or underlying cause, prevention of the incidence of symptoms and / or its underlying cause, and improvement or healing of the damage. Thus, for example, "treatment" of a patient involves prevention of a particular disorder or adverse physiological event in a susceptible individual, as well as treatment of a clinically symptomatic individual.

The increase in serum creatinine level induced by radiocontrast may be temporary, persistent or irreversible, preferably temporary Reference values for serum creatinine levels (see, http://www.rnceus.com/renal /renalcreat.html18) in a male adult is approximately 0.8-1.4 mg / dl, in adult female at 0.6-1.1 mg / dl, and in children at 0.2-1.0 mg / dl, an arbitrary range of values between 25% -50% or even greater increase in serum creatinine levels from the reference values defines the CIN An increase of any arbitrary value within the range of 25-70% in serum creatinine levels defines the CIN. increase in serum creatinine level "as a measurable physiological parameter defines a disease condition well understood by the skilled artisan.In a preferred embodiment, an increase of 25, 30, 35, 40, 45, 50, 55, 60, 65 and 70% and any arbitrary interval which is in any of the ranges defined by two of the values mentioned above, wherein the lower limit of the range is defined by the lower value and the upper limit of the range by the upper value, for example, a range of 25-30%, 25- 35%, 30-60%, etc., defines the CIN. This definition can in part count for the temporary, persistent or irreversible elevations of serum creatinine levels.

The "decrease in renal blood flow" induced by radiocontrast means may be temporary, persistent or irreversible, preferably temporary. The reference value for the blood flow in the kidney is approximately 20% of the cardiac output per minute, thus it is found at 1000 ml / min in a healthy human. An arbitrary range of values between 20% -80% or even greater decrease in a renal blood flow from reference values defines the CIN. A decrease in any arbitrary value or range of value within the 20-80% range in renal blood flow defines the CIN. A "decrease in renal blood flow" as a parameter of measurable hemodynamics defines a disease condition well understood by the person skilled in the art. In a preferred embodiment, a decrease of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 and 90%, and any arbitrary value or range of value which is finds in any of the intervals defined by two of the values mentioned above, where the lower limit of the interval is defined by the lower value and the upper limit of the interval by the upper value, for example, a range of 25-30%, 20-35%, 30-60%, etc., defines the CIN. This definition can in part count for temporary, persistent and irreversible depressions of renal blood flow values. The renal blood flow can be measured usingMRI (magnetic resonance imaging) techniques to determine renal blood flow and renal vascular resistance, as well as infusion techniques PAH (acid for hippuric amino). Any of the described A1AR can be determined in the form of a salt, ester, amide, prodrug, active metabolite, analogue, solvate or the like, it being provided that the salt, ester, amide, prodrug, active metabolite, analogue or solvate is pharmaceutically acceptable and pharmacologically active in the present context. The salts, esters, amides, prodrugs, metabolites, analogues, solvates and other derivatives of the active agents can be prepared using standard procedures known to those skilled in the synthetic organic chemistry art and described, for example, by J. March (199219 ). In a specific embodiment, the invention also relates to a kit comprising in separate containers in a single packaged pharmaceutical dosage forms for use in combination, comprising, in a separate container a pharmaceutical dosage form comprising at least one A1AR and in a second separate container a pharmaceutical dosage form comprising at least one RM. The shape of the kit is particularly advantageous, but is not limited to the case when the separate components can be administered in different dosage forms or are administered at different dosage intervals. The selective adenosine Al dosage forms may favorably be injectable formulations similar to solutions and suspensions. The kit may further comprise instructions which are typically instructions written on a package insert, a label and / or other components of the kit, and the intravenous dosage forms are as described herein. Each dosage form can be housed individually. The present kits may also typically include means for packaging the individual components of the kit, i.e., dosage forms, container means and instructions written for use. It is preferred that the therapeutically effective amount of AlAR be administered in a form, as emphasized above. However, in some cases, a patient may be provided by each, the therapeutically effective amount of AlAR and the RM, in its separate dosage form, or a combination of individual "combination" dosage forms containing two or more of therapeutically effective AlAR present. When using separate dosage forms, the AlAR and the RM can be administered at essentially the same time (concurrently), or at separately staggered times (sequentially). Optimal beneficial effects are achieved when the concentrations of the active blood plasma level of the AlAR agent are maintained while the MR is administered. These optimal beneficial effects can be achieved by application of a loading dose followed by a maintenance dose. The loading dose can increase the plasma level in the blood very fast, while the maintenance dose can then maintain the plasma level achieved. A form that includes all AlAr and RM is, however, more preferred. Such a dosage form provides convenience and simplicity for the patient, thereby increasing the changes for patient compliance. Since two or even more of the active agents are to be used together in combination, the potency of each of the agents and the interactive effects achieved by combining them together can also be taken into account. A consideration of these factors is within the scope of the ordinarily experienced physician for the purpose of determining the therapeutically effective and prophylactically effective dosage amounts. The term "alkyl" refers to the radical of saturated aliphatic groups, which include straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, substituted cycloalkyl alkyl groups and substituted alkyl cycloalkyl groups. The term alkyl also includes alkyl groups, which they may further include oxygen, nitrogen, sulfur or phosphorus atoms which replace one or more carbons of the hydrocarbon structure, for example oxygen, nitrogen, sulfur or phosphorus atoms. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its structure (eg, C1-C50 for straight chain, C3-C30 for branched chain), and more preferably 20 or less, for example , in an "alkyl" embodiment can be C1-C6 or in an additional modality C1-C4. Similarly, in one embodiment the cycloalkyls have 4-10 carbon atoms in their ring structure, and in a further embodiment the cycloalkyls have 5-7 carbon atoms in their ring structure, for example, 5, 6 or 7 carbons in the structure of the ring. However, the term "optionally substituted alkyl" as used throughout the specification and claims, is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl portions having substitute substituents a hydrogen or one or more carbons of the hydrocarbon structure. Such substituents may include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonate, sulfamoyl , sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, and an aromatic or heteroaromatic portion. It will be understood by those skilled in the art that the portions substituted in the hydrocarbon chain by themselves are replaced, if appropriate. Cycloalkyls can also be substituted, for example, with the substituents described above. An "alkylaryl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). The term "alkyl" also includes analogs of unsaturated aliphatic groups in length and possible substitution to the alkyls described above, but containing at least one double or triple bond respectively. The term "aryl" as used herein, refers to the radical of aryl groups, which include 5- and 6-membered single ring aromatic groups which may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, prazol, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Arilo groups also they include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. These aryl groups having heteroatoms in the ring structure can also be referred to as "heterocyclic ring". The aromatic ring can be substituted at one or more positions with such substituents as described above, such as, for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate , phosphinate, cyano, amino (including amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonate , sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic to form a polycycle (e.g., tetralin). The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen, the preferred hetero atom is nitrogen.

It was noted that the structure of some compounds of this invention includes asymmetric carbon atoms. It will also be understood, therefore, that isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless otherwise indicated. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. The selective adenosine Al antagonists described in the present invention have low lipophilic properties and also high hydrophilic properties resulting in good water solubility. The significantly low lipophilic properties of the compounds used in the present invention distinguish the compounds over other known Al selective antagonists; Exemplary data are described in the following table (Table 1: lipophilic properties of selective adenosine Al antagonists).

Table 1: Lipophilic Properties of Selective Adenosine Antagonists Al PGP Factor Permeability (%) LogP (ACD v9.05) Substance 1 1.5 37.4 1.6 substance 2 10.1 27.0 -1.4 KW3902 1.4 31.1 4.2 From the receptor binding and enzyme profile of substance 1 over a broad range of the assay, it is concluded that substance 1 acts as a ligand of the adenosine Al selective receptor with some activity that inhibits phosphodiesterase PDE4. The displacement of rolipram by substance 1 from PDE4 phosphodiesterase sites correlated with the relative potency of the substance to inhibit this enzyme; the calculated pKi of PDE4 inhibition is 750 nM; the activities in other phosphodiesterases (PDE 1, 2, 3, 5 and 6) are at least 25 times lower. The PDE4 phosphodiesterase inhibition activity can be used for purposes of titration of patients. The PDE4 phosphodiesterase inhibition activity of the compounds used in the present invention prevents overdose of the selective antagonist by alarming patients with the same evidence, not serious similar signals, for example, headache before similar series events, for example , CNS seizures may occur.

EXPERIMENTAL 1. Effects of the acute application of substance 1 on diuresis and natriuresis after the radiocontrast medium (diatrizoate) in anesthetized rats. Acute kidney failure is induced dependent on the radiocontrast medium using an experimental protocol in based on what was published by the Osswald group. Male 10, 20 Sprague-Dawley rats of approximately 300 g of body weight were acclimated for at least 1 week before the start of chronic pretreatment with the nitric oxide synthase synthase of N-nitro-L-arginine methyl ester (L-NA E for 7-9 weeks at a daily dose of 5 mg / kg). For the experiments, the rats were fasted overnight (which have continuous free access to drink water) were anesthetized with Inactin (80 mg / kg, providing i.p. as a bolus). Catheters (i) were placed in the trachea, (ii) in the jugular vein (for administration of the radiocontrast medium, and antecedent saline infusion, see below), (iii) in the other jugular vein for administration of vehicles or substance 1, (iv) in the carotid artery to take samples of blood and part of the antecedent saline infusion; see below) and (v) in the bladder for urine collection. The rats are kept on a hot table to maintain their body temperature at 37 ° C. After collecting the urine sample for 60-90 minutes for baseline measurements, the animals received the vehicle or substance 1 as follows: a loading bolus of 0.15, or 1.5 mg of substance 1 per kg, or vehicle, in a volume of 1 ml / kg, was applied intravenously, followed by a continuous intravenous infusion at a ratio of 1.5 and 15 g of substance 1 per kg per minute, or vehicle, in a volume of 11 1 / kg.min until the end of the experiment. With these plasma levels remained stable the dose regimens of substance 1 are 59 ± 23, and 314 ± 36 ng / ml, respectively. 10 minutes later, treatment of substance 1 (or vehicle), diatriazole (meglutin salt, Urolux, 0.61 g diatrizoate / ml, corresponding to a total iodine content of 290 mg / ml, Sanochemia Diagnostics, Neuss, Germany) was initiated. ), preheated to body temperature, was subjected to iv infusion for 3 minutes at a dose of 2.55 mg / kg, which corresponds to 740 mg of iodine / kg (the time point of administration of the contrast medium was defined as t0). An antecedent saline solution was subjected to right infusion of the start and maintenance at a rate of ~ 1.2 ml / h per 100 g until the end of the experiments (0.24 ml / h via the arterial catheter, and 0.96 ml / h via the venous line ). This infusion is required to compensate for volume loss due to the operation, and subsequent blood sampling, but also to ensure evidence of the arterial catheter between the time points of blood sampling. The urine samples were collected according to the following scheme: baseline (60-90 minutes preceding the start of substance 1, or vehicle, administration), t0 - 30 minutes (time point 0.5 hours), 30 - 60 minutes (time point 1 hour), 60 - 120 minutes (time point 2 hours) and 120 - 180 minutes (point of time 2 hours) 3 hours time). Plasma samples are taken at the end of each of the previous periods. The measured values of urine volume and urine levels of Na + are used to calculate the proportions of diuresis and natriuresis over the aforementioned time intervals. The treatment of substance 1 produces a large and significant increase in urine production in the first 30 minutes after administration of the contrast medium, compared to the vehicle control group; despite the fact that the proportion of diuresis then returns to the lower values in all groups, a stimulant effect of substance 1 persists for at least 3 hours. Because the radiocontrast medium is eliminated via urine, this diuretic effect of substance 1 is prone to strongly promote its elimination and thus limit its toxicity.

Table 2: Effects of substance 1 on diuresis after administration of diatrizoate in anesthetized rats, the values are expressed in me per kg of body weight per h, and represents means ± SE (n = 14-24). Statistical significance was evaluated using one-way analysis of variance followed by a Bonferroni test. n.s .: not significant; *: P < 0.05; **: P < 0.01 and ***: P < 0.001 against control vehicles.

Time Vehicle Substance 1 P against Substance 1 P against after control at low dose vehicle at high vehicle dose CM 0.5 h 17.10 ± 1.42 27.31 ± 2.36 *** 28.01 ± 2.02 *** 1 h 3.76 ± 0.31 3.87 ± 0.40 no. 4.97 ± 0.30 n.s. 2 h 1.96 ± 0.15 3.34 ± 0.42 ** 3.13 ± 0.27 ** 3 h 2.14 ± 0.40 3.54 ± 0.50 no. 3.11 ± 0.36 n.s.

Similarly, substance 1 causes a sharp and sustained increase in sodium excretion over the values observed in the control vehicle group. The excretion of chloride was stimulated by the substance 1 in a similar manner, while the excretion of potassium was not relatively affected by the compound through the experiment (not shown).

Table 3. Effects of substance 1 on sodium excretion after diatrizoate administration in anesthetized rats. Values are expressed in mol per kg of body weight per h, and represent means ± SEM (n = 14-24). Statistical significance was evaluated using one-way analysis of variance followed by the Bonferroni test. n.s .: not significant; *: P < 0.05; **: P < 0.01 and ***: P < 0.001 against control vehicles.

Time Vehicle Substance 1 P against Substance 1 to P against after control at low dose vehicle high vehicle dose CM 0.5 h 1332 ± 184 3039 ± 354 *** 3301 ± 306 *** 1 h 185 ± 39 338 ± 81 n.s. 520 ± 77 ** 2 h 153 ± 40 613 ± 121 ** 591 ± 88 ** 3 h 329 ± 72 842 ± 121 ** 830 ± 91 ** 2. Effect of acute application of substance 1 on renal blood flow and oxygenation after radiocontrast medium (iodoxanol) in anesthetized rats The experimental protocol is based on a previously published methodology. 21'22 The experiments are performed using Wistar rats of 3-4 months old adult males. The body weight varies from 250 to 400 g. Rats receive standard feed. Food and drink were discontinued approximately 12 hours before surgery. The animals were anesthetized by intraperitoneal injection of urethane solution (2% in water, 6 ml per kg) and placed on a hot table to maintain body temperature at 37 ° C throughout the surgery and subsequent experiments. An incision was then carefully made in the left groin of the femoral artery and cannulated to measure blood pressure in the artery. Another catheter was placed in the carotid artery for administration of the contrast medium. Finally an inflatable cloth was placed around the abdominal aorta below the origin of the renal arteries. A servo-controlled inflation of the cloth was left to reduce and maintain the renal perfusion pressure at a current level. Two optical fibers 500 m in diameter were implanted in the cortex and the expert medulla of the left kidney, to determine the local Doppler laser fluxes, and an ultrasound transit time-flow probe was placed around the renal artery of the same. Kidney to determine the total blood flow of the kidney (RBF). The levels of renal oxygen (oxygen partial pressure = p02) were also determined locally (cortical and medullary p02, respectively; OxyLife, Oxford Optronics). After implantation and stabilization, the experiment was started by measuring parameters of hemodynamics and oxygenation under the conditions of the baseline. The vehicle or substance 1 (5 mg / kg as an intravenous bolus) was then administered. Further measurements were made, and 30 minutes after administration of the vehicle or substance 1, iodixanol (Visipaque 320; 1.5 ml, i.a, Amersham Buchler, Braunschweig, Germany), or vehicle was applied. After another 20 minutes, the measurements were repeated (over a period of 20 min, shown in the following figures). The experimental groups are in this way: 1. Vehicle + Vehicle (control), Vehicle + Visipaque, and substance 1 + Visipaque.

Substance 1 does not modify the parameters of hemodynamics (arterial blood pressure, RBF) before the loading of Visipaque (not shown). After administration of Visipaque, a strong, temporary increase in mean arterial blood pressure was observed (by ~ 35 mm Hg), which lasted for approximately 10 minutes, and was partially prevented by substance 1 (not shown). In the vehicle + Visipaque group, the renal cortical blood flow showed a short initial increase, which was followed by a progressive and significant reduction, compared with the vehicle control group (Figure 3). In contrast, in the presence of substance 1, the cortical blood flow exhibits a negligible and sustained increase in blood flow remaining significantly high until the end of the measurement period, compared to the Vehicle + Visipaque group (Figure 3). Cortical vascular conductance was rapidly and stably reduced by Visipaque, while substance 1 maintained this parameter at levels seen in the vehicle control group (Figure 4). Similarly, the medullary blood flow is temporarily raised (by ~ 3 min), after the injection of Visipaque, and then falls below the control levels; concomitantly, the medullar vascular conductance was rapidly and stably depressed by the Visipaque; the treatment of substance 1 only partially (but significantly), prevents these effects (not shown). Finally, substance 1 causes a significant increase in cortical p02, which persists until the end of the experiment (Figure 5). In total, these observations show that substance 1 improves hemodynamics and renal oxygenation, thus, at least partially antagonizing the potentially deleterious effects of iodixanol from radiocontrast medium.

STUDY PROTOCOL Study 1 Animal studies were conducted in 60 anesthetized rats. The renal hemodynamics was assessed, and the oxygen tension within the kidney is measured after the application of MRI. The total blood flow to the kidney, is quantified by the method of transit time, local hemodynamics by laser Doppler flow. In addition, the regional oxygen tension of the kidney is assessed and the urine is collected to determine urine osmolarity, viscosity and diuresis. Using a recently established technique (Wronski, 200321), it is possible to assess the TGF response in this setting. MRI significantly reduces renal blood flow and alters the regional oxygenation of the kidney. This effect is more likely due to the viscous properties, as observed by an increase in viscosity of urine. These effects of MR in renal hemodynamics (blood flow and renal hypoxia) are relieved or even reversed prior to the administration of A1AR antagonists. Two protocols are made: Protocol 1: The fluid restriction takes place 24 hours before the experiments. This leads to increased concentration of RM in the tubular system. The catheters, transit time flow meters, Doppler laser probes and probes to assess the? (Absolute ½, are implanted.) Control measurements are recorded, and then the RM is given Protocol 2: The measurements will then be repeated. the animal fluid is full, the volume of urine, osmolarity and viscosity are determined, the control measurements are recorded, then the MRI is given, the evaluation of renal blood flow, oxygen tension and renal blood flow and the TGF response in rats. After the water restriction, they take place.The reduced volume of plasma is a generally recognized risk factor, since the CM is concentrated in the tubules during antidiuresis.Figure 1 represents the protocols.In the upper panel, the RM is given after the control measurements (N = 15) The lower panel dictates the series in which the AlARis is given prior to the MRI (N = 15) To collect enough urine, the rats full of volume are used. Diuresis, urine osmolarity and viscosity are evaluated for the control and the MRI (N = 15, figure 2, upper panel), and for the control, the A1AR and the A1AR + the MRI (N = 15, figure 2 lower panel ). All the experiments were carried out in male, adult rats, obtained from the animal facility of the institute. The rats are housed in groups. All animals are randomly distributed to protocols. The animals are identified by the cage number. A standard rat diet (Altromin 1324, Altromin GmbH, D-32791 Lage), serves as food. Feeding and drinking is discontinued approximately 12 hours before surgery for protocol 1. In protocol 2, the drink is left at will. Drinking water is offered at will, except for a period of 12 hours before CM application. In this way, the animals are deprived of water. In protocol 2, water is offered at will until immediately before the experiment. Textured granulated wood (Granulat A2, J. Brandenburg, D-49424 Goldenstedt), is used as a bed material for the cages. The cages are changed and cleaned every day between 6:00 and 8:00 a.m. During acclimation, the animals are kept in groups of 3-5 animals in MAKROLON cages, each one (type 4) at room temperature of 22 ° C + 3 ° C and at a relative humidity of 60% + 20%. The deviation could be caused, for example, during cleaning procedures.

Anesthesia is introduced and maintained by urethane. The rats are placed on a hot board to maintain body temperature at 37 ° C through surgery. Body temperature is controlled during the study. After an incision in the left groin, the femoral artery is carefully prepared and cannulated with a polypropylene catheter (PP 10), to measure the renal perfusion pressure (RPP). Another catheter (PP 50) of the same material is placed in the carotid artery to measure systemic blood pressure (BP) and heart rate (HR). Finally, an inflatable cuff is placed around the abdominal aorta; one above and the other below the origin of the renal arteries. A controlled servo inflating of the proximal fist allows to reduce and maintain the renal perfusion pressure at a pre-adjusted level. Two optical fibers 500 μt in diameter (Moore instruments, GB), are implanted in the cortex and medulla of the left kidney, and the ultrasound transit time flow probe (1RB, Transonic Systems Inc. USA) is placed around the renal artery of the same kidney, to determine local blood flow (LFC and LFM respectively), and total renal blood flow (RBF), p02, is also locally determined. The local blood flow is measured and processed by a Doppler laser flow meter (Moore Instruments, GB). The arterial catheter is connected to the calibrated pressure transducer. The fist inflatable It is connected to an extracorporeal servo control system and the flow probes are connected via extension cables to the flow meters. The oxygen partial pressure sensing probes are positioned in a corresponding manner. After the analog-to-digital conversion, all the data (BP, RPP, RBF, LFC, LFM, local oxygen voltage) are stored online in an ASCII format by a computer system (AT compatible with IBM). After implantation and stabilization, the experiment is initiated. The test solutions are infused. After 5 minutes of equilibrium, measurements of RBF, local flows and local p02 begin. Then, a step response of 5 minutes is obtained to assess the TGF. The urine is collected 35 minutes to evaluate diuresis, osmolarity and viscosity. When required, modifications are made to the protocols. The regional and total RBF and oxygen tension in the renal medulla and cortex are assessed in accordance with the previous studies (Flemming, 2000 and 2000122), by measurement of Doppler laser fluxes and direct evaluation of p02-After calculation of mean values individual values of each parameter, these average values of each animal are used to calculate the group averages and standard errors of each control / intervention group. The latter are used to prove differences by statistical significance, preferably levels of less than 0.05 are considered by indicate significance, The test methods used are chosen with respect to the parameters of the fundamental data.

Study 2 A study analogous to one described by Yao (200010) was carried out, with selected variations in the protocol. Contrary to Yao's study, chronic as well as acute experiments were carried out. Indomethacin was used in addition to L-name (? -? - nitro-L-arginine methyl ester) in this study. DOCUMENTS CITED 1 Andrew E, Berg KJ, "Nephrotoxic effects of X-ray contrast media", J Toxicol Clin Toxicol 200; 2 (3): 325-32 2 http://www.fpnotebook.com/REN70.htm and http: // www. fpnotebook.com / REN38. htm (15-June-2006) 3 Ueda J, Nygren A, Hansell P, Ulfendahl HR. "Effect of intravenous contrast media on proximal and distal tubular hydrostatic pressure in the rat kidney "Acta Radiol 1993; 34 (1): 83-87 4 Olivera A, Lamas S, Rodriguez-Puyol D, Lopez-Novoa JM." Adenosine induces mesangial cell contraction by an Al-type receptor. "Kidney Int 1989; 35 (6): 1300-1305 5 Porter, "Contrast-associated nephropathy" Am. J. Cardiol., (1989), 64 (9), 22E-26E 6 Nikolsky E, Aymong ED,. Dangas G, ehran R. "Radiocontrast nephropathy: identifying the high-risk patient and the implications of renal function exacerbation", Rev Cardiovasc Med 2003; 4 Suppl 1: S7-S14 7 a) Shammas et al., "Aminophylline does protect against radiocontrast nephropathy in patients undergoing percutaneous angiographic procedures," J Invasive Cardiol (2001), 13 (11), 738-40; b) Welch et al. "Adenosine to receptor antagonists in the kidney: effects in fluid-retaining disorders", Curr Opin Pharmacol (2002), 2 (2), 165-70; c) Huber et al. "Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency: controlled, randomized, double-blinded study", Radiology (2002), 223 (3), 772-9 8 Erley et.al., "Adenosineantagonist theophylline prevents the reduction of glomerularfiltration rate after contrast media application ", Kidney Int. (1994), 45, 1425-31 9 K. Akawara et al.," Role of adenosine in the renal responses to contrast medium ", Kidney Int. (1996) , 49 (5), 1199-206 10 K. Yao et al., "The selective adenosine to receptor antagonist KW-3902 prevents radiocontrast media-induced nephropathy in rats with chronic nitric oxide deficiency", Europ J of Pharmacology (2001) 414, 99-104 11 Greiner, Dissertation " Prophylaxis of Contrast Induced Nephropathy with Theophylline and Acetylcysteine in ICU-Patients ", TU München, 19.10.2005 H. Thomas Lee, Michael Jan, Soo Chan Bae, Jin Deok Joo, Farida R. Goubaeva, Jay Yang, and Mihwa Kim, "Ai adenosine receptor knockout mice are protected against acute radiocontrast nephropathy in vivo", Am J Physiol Renal Physiol 290 : F1367-F1375, 2006 13 EP 1 386 609, filed by CV Therapeutics 14 WO 99/31101, filed by Univ. South Florida 15 WO 99/62518, WO 01/39777, WO 02/057267, all filed by Osi Pharmaceuticals and WO 2004/094428 filed by Solvay Pharmaceuticals 16 EP 0 022 744 filed by Schering, EP 0 023 992 filed by Braceo Industria Chimica, EP 0 026 281 filed by Braceo Industria Chimica, EP 0 033 426 filed by Univ. California, EP 0 108 638 filed by Nyegaard, EP 0 317 492 filed by Schering, WO 87/00757 filed by Cook Imaging Corporation, WO 89/08101 filed by Mallinckrodt, US 2, 776.241 filed by Schering, US 3,290,366 filed by Mallinckrodt, US 3,360,436 filed by Eprova , US 5,349,085 filed by Nycomed, GB 1 321 591 filed by Nyegaard, DE 2 547 789 filed by Savag, DE 2 726 196 filed by Nyegaard, DE 2 909 439 filed by Schering 17 Bundgaard, H. (editor), "Design of Prodrugs", Elsevier, 1985 18 http://www.rnceus.com/renal/renalcreat.html (15-June-2006) 19 Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Edition, New York: iley-Interscience, 1992 Erley C, Heyne N, Burgert K, Langanke J, Risler T, & Osswald H (1997): Prevention of Radiocontrast-Induced Nephropathy by Adenosine Antagonists in Rats with Chronic Nitric Oxide Deficiency. J. Am. Soc. Nephrol., 8: 1125-1132 1 Wronski T, Seeliger E, Persson PB, Forner C, Fichtner C, Scheller J et al. The step response: a method to characterize raechanisras of renal blood flow autoregulation. Am J Physiol Renal Physiol 2003; 285 (4): F758-F764 22 a) Flemming B, Arenz N, Seeliger E, Wronski T, Steer K, Persson PB. Time-dependent autoregulation of renal blood flow in conscious rats. J Am Soc Nephrol 2001; 12 (11): 2253-2262 and b) Flemming B, Seeliger E, Wronski T, Steer K, Arenz N, Persson PB. Oxygen and renal hemodynamics in the rat conscious. J Am Soc Nephrol 2000; 11 (1): 18-24

Claims

1. Use of a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I I wherein R1 and R2 are each independently selected from a hydrogen atom, an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl or together form an optionally substituted heterocyclic ring; R3 is selected from a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl or optionally substituted alkylaryl; R4 and R5 are each independently selected from a halogen atom, a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl, or R4 and R5 together form an optionally substituted or carbocyclic heterocyclic ring optionally replaced; and / or a salt, and / or a prodrug, and / or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the prevention of nephropathy induced by at least one radiocontrast medium, in mammals or humans.

2. Use of a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I as defined according to claim 1, and / or a pharmaceutically acceptable salt, and / or a prodrug, and / or a solvate thereof, for the manufacture of a medicament for the prevention of increase in serum creatinine levels, induced by at least one radiocontrast medium, preferably a temporary, persistent or irreversible increase in serum creatinine levels, induced by radiocontrast medium in mammals or humans.

3. Use of a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I I as defined in accordance with claim 1, and / or a pharmaceutically acceptable salt, and / or a prodrug, and / or a solvate thereof, for the manufacture of a medicament for the prevention of reduction in renal-induced blood flow. at least one means of radiocontrast, preferably a temporary, persistent or irreversible decrease in renal blood flow by means of contrast, in mammals or humans.

4. Use of a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I I as defined in accordance with claim 1, and / or a pharmaceutically acceptable salt, and / or a prodrug, and / or a solvate thereof, for the manufacture of a medicament for the prevention of a risk or need for dialysis in. a human or animal patient, preferably of temporary, persistent or irreversible dialysis, said patient is subject to receiving radiocontrast means.

5. Use according to any of claims 1, 2, 3 or 4, wherein the time period of application of the therapeutically effective amount of at least one selective adenosine Al antagonist is sufficient to maintain the plasma level of at least one Al selective adenosine, at a concentration of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml.

6. Use according to any of claims 1, 2, 3, 4 or 5, comprising the therapeutically effective amount of at least one selective adenosine Al receptor antagonist, in a loading dosage to be administered intravenously and comprising a maintenance dosage, and the amount of at least one loading dose of the selective adenosine Al receptor antagonist, to be administered over a period of time of 5-25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes, more preferably 15 minutes, before the administration of at least one radiocontrast medium, and comprising the maintenance dosage of at least one selective adenosine Al receptor antagonist, to be administered for a period of up to 48 hours, subsequent to the administration of the loading dosage of at least one selective Al receptor antagonist. Use according to any one of claims 1, 2, 3, 4 or 5, comprising a Therapeutically effective amount of at least one selective adenosine Al receptor antagonist, orally, preferably in an extended release formulation, to be administered prior to the administration of at least one radiocontrast agent. 8. Use according to any one of claims 1, 2, 3, 4, 5, 6 or 7, comprising at least one radiocontrast means so as not to be promptly administered until the therapeutically effective amount of at least one selective antagonist of the Al adenosine receptor is sufficient to provide a plasma level concentration of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml. 9. Use according to any of claims 1, 2, 3, 4, 5, 6, 7 or 8, comprising a period of time of application of the maintenance dosage of a therapeutically effective amount of at least one selective antagonist of adenosine Al, to be sufficient to maintain the plasma level of at least one Al selective adenosine at a concentration of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml. 10. Use according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the therapeutically effective amount of at least one selective adenosine Al receptor antagonist is selected from derivatives of pyrrolo [2,3d] pyrimidine of formula I, as defined according to claim 1, and / or a pharmaceutically acceptable salt, and / or a prodrug, and / or a solvate thereof. 11. Use according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein the therapeutically effective amount of at least one selective adenosine Al receptor antagonist is selected. of 4- [(2-phenyl-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino] -trans-cyclohexanol or (4S) -4-hydroxy-1- (2-phenyl) methanesulfonate -7 # -pyrrolo [2, 3-d] pyrimidin-4-yl) -L-prolinamide, and / or a prodrug, and / or a solvate thereof. 12. Use according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, wherein at least one radiocontrast means is a gadolinium-based radio contrast medium or iodine, selected from the group consisting of bunaiod, biligram, bilimiro, bilopaque, colimil, etiodol, diatrast, dionosil, falignost, gadobutrol, gadodiamide, gadopentetate dimeglumine, gastrografin, hexabrix, hypodine, mangafodipir, amidotrizoate, ethiodized oil, imagopaque, iodamide, iodipamide, iodide, iodophen, yofendylate, iomeron, iomeprol, iopamidol, iopanoic acid, iopiperidol, yofendilate, iopromide, yopidol, iosimenol, acid iotrolan, ioversol, ioxilan, ioxáglico acid, isopaque, ipodato, iotalamato of meglumina, acetriozato of meglumina, diatrozato of meglumina, metrizamida, mielotrast, omnipaque, osbil, optiray, optojod, opacoron, perflutren, fenobutiyodil, fentetiotalein sodium, priodax, propylodone, skiodan, sodium iodomethamate, diatrizoate sodium, telepaque, teridax, tetrabrom, torotrast, triognost, 1, 3, 5-Tri-n-hexyl-2,4,6-triiodobenzene, tiropanoate, visipaque or xenetix, and / or a salt, and / or a prodrug, and / or a pharmaceutically acceptable solvate thereof. 13. Use according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein the medicament is a fine combination. 14. A pharmaceutical combination, characterized in that it comprises: a) a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I, I wherein R1 and R2 are each independently selected from a hydrogen atom, an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl or together form an optionally substituted heterocyclic ring; R3 is selected from a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl; R4 and R5 are each independently selected from a halogen atom, a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl, or R4 and R5 together form an optionally substituted or carbocyclic heterocyclic ring optionally replaced; and / or a salt, and / or a prodrug, and / or a pharmaceutically acceptable solvate thereof, and b) at least one radiocontrast medium, wherein the pharmaceutical composition is suitable for simultaneous, separate or stepwise administration, to humans or mammals 15. Pharmaceutical combination in accordance with claim 14, characterized in that it comprises: a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I, wherein R 1 and R 2 are each independently selected from a hydrogen atom, an optionally substituted alkyl, or together form a optionally substituted heterocyclic ring; R3 is a hydrogen atom or an optionally substituted aryl; R4 and R5 are each independently selected from a halogen atom or a hydrogen atom; preferably when R1 is a hydrogen and R2 is an optionally substituted cyclohexyl ring, or R1 and R2 together form an optionally substituted pyrrolidine ring; R3 is a phenyl ring; R4 and R5 are each a hydrogen atom; and / or a salt, and / or a prodrug, and / or a pharmaceutically acceptable solvate thereof, and a) at least one radiocontrast medium, wherein the pharmaceutical combination is suitable for simultaneous, separate or stepwise administration to humans or mammals . 16. A pharmaceutical combination according to claim 15, characterized in that it comprises: a) a therapeutically effective amount of at least one selective adenosine Al antagonist selected from 4- [(2-phenyl-H-pyrrolo [2, 3-] methanesulfonate] d] pyrimidin-4-yl) amino] -trans-cyclohexanol or (4S) -4-hydroxy-l- (2-phenyl-7-pyrrolo [2,3-d] pyrimidin-4-yl) methanesulfonate - L-prolinamide, and / or a prodrug, and / or a solvate thereof and, b) at least one radiocontrast medium, wherein the pharmaceutical combination is suitable for simultaneous, separate or stepwise administration to humans or mammals. 1

7. A pharmaceutical combination according to any one of claims 14, 15 or 16, characterized in that it comprises a therapeutically effective amount of at least one selective adenosine Al receptor antagonist, to be administered intravenously in a loading dosage and comprising a dosage of maintenance, and the amount of at least one loading dose of the selective adenosine Al receptor antagonist to be administered at a time period of 5-25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes, more preferably 15 minutes, before the administration of at least one radiocontrast medium, and comprising the maintenance dosage of at least one selective adenosine Al receptor antagonist, to be administered for a period of up to 48 hours, subsequent to the administration of the loading dosage of at least one selective Al receptor antagonist. 1

8. Comp pharmaceutical composition according to any of claims 14, 15, 16 or 17, characterized in that it comprises a therapeutically effective amount of at least one selective receptor antagonist of Al adenosine, orally, preferably in an extended release formulation, to be administered prior to the administration of at least one radiocontrast agent. 1

9. Pharmaceutical composition according to any of claims 14, 15, 16, 17 or 18, characterized in that it comprises at least one means of radiocontrast not to be promptly administered until the therapeutically effective amount of at least one selective receptor antagonist of Al adenosine, is sufficient to provide a plasma level concentration of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml. 20. Pharmaceutical composition according to any of claims 14, 15, 16, 17, 18 or 19, characterized in that it comprises a period of time of application of at least one selective adenosine Al antagonist, sufficient to maintain the plasma level of at least one selective adenosine Al antagonist at a concentration of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml. 21. A pharmaceutical combination according to any of claims 14, 15, 16, 17, 18, 19 or 20, characterized in that at least one radiocontrast means is a radiocontrast medium based on gadolinium or iodine, selected from the group consisting of from bunaiod, biligram, bilimiro, bilopaque, colimil, etiodol, diatrast, dionosil, falignost, gadobutrol, gadodiamida, gadopentetato dimeglumina, gastrografina, hexabrix, hypodina, mangafodipir, amidotrizoato, ethiodized oil, imagopaque, yodamida, yodipamida, iodixanol, iodophen, yofendilato, iomeron, iomeprol, iopamidol, iopanoic acid, iopiperidol, yofendilate, iopromide, yopidol, iosimenol, iotamic acid, iotrolan, ioversol, ioxilan, ioxáglico acid, isopaque, ipodato, megluraine iotalamato, meglumine acetriozate, meglumine diatrozate, metrizamide, mielotrast, omnipaque, osbil , optiray, optojod, opacoron, perflutren, phenobutiyodil, fentatiotalein sodium, priodax, propylodone, skiodan, sodium iodometamate, diatrizoate sodium, telepaque, teridax, tetrabrom, torotrast, triognost, 1, 3, 5-Tri-n-hexyl-2, 4,6-triiodobenzene, thyropanoate, visipaque or xenetix, and / or a salt, and / or a prodrug, and / or a pharmaceutically acceptable solvate thereof. 22. Kit, characterized in that it comprises: a) a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I, I where Rl and R2 are each selected independently of a hydrogen atom, an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl or together form an optionally substituted heterocyclic ring; R3 is selected from a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl or optionally substituted alkylaryl; R4 and R5 are each independently selected from a halogen atom, a hydrogen atom or an optionally substituted alkyl portion, optionally substituted aryl, or optionally substituted alkylaryl, or R4 and R5 together form an optionally substituted or carbocyclic heterocyclic ring optionally replaced; and / or a salt, and / or a prodrug, and / or a pharmaceutically acceptable solvate thereof, and b) at least one radiocontrast medium, wherein the pharmaceutical composition is suitable for simultaneous, separate or stepwise administration, to humans or mammals 23. Kit according to claim 22, characterized in that it comprises: a) a therapeutically effective amount of at least one selective adenosine Al antagonist of formula I, wherein R1 and R2 are each independently selected from a hydrogen atom, optionally substituted alkyl, or together form an optionally substituted heterocyclic ring; R3 is a hydrogen atom or an optionally substituted aryl; R4 and R5 are each independently selected from a halogen atom or a hydrogen atom; preferably when R1 is a hydrogen and R2 is an optionally substituted cyclohexyl ring, or R1 and R2 together form an optionally substituted pyrrolidine ring; R3 is a phenyl ring; R4 and R5 are each a hydrogen atom; and / or a salt, and / or a prodrug, and / or a pharmaceutically acceptable solvate thereof, and a) at least one radiocontrast medium, wherein the pharmaceutical combination is suitable for simultaneous, separate or stepwise administration to humans or mammals . 24. Kit, according to claim 23, characterized in that it comprises: a) a therapeutically effective amount of at least one adenosine Al selective antagonist selected from 4- [(2-phenyl-7 # -pyrrolo [2, 3] -d] pyrimidin-4-yl) amino] -trans-cyclohexanol or (4S) -4-hydroxy-l- (2-phenyl-7-pyrrolo [2,3-d] pyrimidin-4-yl) methanesulfonate - L-prolinamide, and / or a prodrug, and / or a solvate thereof and, b) at least one radiocontrast medium, wherein the pharmaceutical combination is suitable for simultaneous, separate or stepwise administration to humans or mammals. 25. Kit according to any of claims 22, 23 or 24, characterized in that it comprises, a) a cargo dosing container of the therapeutically effective amount of at least one selective adenosine Al receptor antagonist, to be administered intravenously, b) a maintenance dosage container of the therapeutically effective amount of at least one selective adenosine Al receptor antagonist to be administered intravenously, c) at least one radiocontrast medium, comprising at least one antagonist A selective adenosine Al receptor, to be administered intravenously at a loading dose and comprising a maintenance dosage, and the amount of at least one loading dose of the selective adenosine Al receptor antagonist, to be administered over a period of time of 5-25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes, more preferably 15 minutes prior to the administration of at least one radiocontrast medium, and comprising the maintenance dosage of at least one selective antagonist of the adenosine Al receptor, to be administered for a period of up to 48 hours, count the administration of the loading dosage of at least one selective Al receptor antagonist. 26. Kit according to any of claims 22, 23 or 24, characterized in that it comprises, a) a container with the therapeutically effective amount of at least one selective adenosine Al receptor antagonist to be orally administered, b) at least one radiocontrast medium comprising at least one selective adenosine Al receptor antagonist orally, preferably in an extended release formulation, to be administered prior to the administration of at least one radiocontrast agent. 27. Kit according to any one of claims 22, 23, 24, 25 or 26, characterized in that it comprises the therapeutically effective amount of at least one radiocontrast medium so as not to be promptly administered until the therapeutically effective amount of at least one antagonist A selective adenosine receptor Al is sufficient to provide a plasma level of a concentration of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml. 28. Kit according to any of claims 22, 23, 24, 25, 26 or 27, characterized in that the period of time of application of the therapeutically effective amount of at least one selective adenosine Al antagonist is sufficient to maintain the plasma level of at least one Al selective adenosine at a concentration of 10-500 ng / ml, preferably 20-400 ng / ml, more preferably 30-300 ng / ml. 29. Kit in accordance with any of the claims 22, 23, 24, 25, 26, 27 or 28, characterized in that at least one radiocontrast means is a gadolinium based radiocontrast medium, selected from the group consisting of bunaiod, biligram, bilimiro, bilopaque, colimil, etiodol , diatrast, dionosil, falignost, gadobutrol, gadodiamide, gadopentetate dimeglumine, gastrografin, hexabrix, hypodine, mangafodipir, amidotrizoate, ethiodized oil, imagopaque, iodamide, iodipamide, iodixanol, iodophene, yofendylate, iomeron, iomeprol, iopamidol, iopanoic acid, iopiperidol, yofendilato, iopromuro, yopidol, iosimenol, iotalámico acid, iotrolan, ioversol, ioxilan, ioxáglico acid, isopaque, ipodato, iotalamato of meglumina, acetriozato of meglumina, diatrozato of meglumina, metrizamida, mielotrast, omnipaque, osbil, optiray, optojod, opacoron, perflutren, fenobutiyodil, fentetiotalein sodium, priodax, propilyodone, skiodan, sodium iodometamate, diatrizoate sodium, telepaque, teridax, tetrabrom, torotrast, triognos t, 1, 3, 5-Tri-n-hexyl-2,4,6-triiodobenzene, thyropanoate, visipaque or xenetix, and / or a salt, and / or a prodrug, and / or a pharmaceutically acceptable solvate thereof.