TW200808819A - Use of adenosine A1 antagonists in radiocontrast media induced nephrophaty - Google Patents

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-cyclohexanol 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

200808819 5 IX. INSTRUCTIONS: [Technical Field of the Invention] The present invention relates to a pharmaceutical combination comprising a therapeutically effective amount of at least one selective adenosine A1 receptor antagonist and at least one radiographic medium (RM). The invention also relates to the use of said combination in the manufacture of a medicament for the treatment of radiocontrast media induced nephropathy. Furthermore, the invention relates to a kit comprising the combination. • [Prior Art 3 10 BACKGROUND OF THE INVENTION Interventional techniques, rapid multi-slice computed tomography, and new 3D reconstruction techniques have expanded the use of iodine intravascular radiography media (RM) over the past decade. Most inspections require iodized RM for accurate and safe diagnostic and interventional procedures. Today, the world uses about 60 million drugs a year (Andrew, 20041). ' 15 Radiographic mediators can cause a decline in renal excretory function, starting after dosing • soon. Renal dysfunction can be transient, long-lasting, or even irreversible. Therefore, the use of radiographic media has been associated with increased morbidity, mortality, and medical care and long-term hospitalization costs, especially in patients requiring dialysis. Radiographic contrast-induced nephropathy (CIN) is therefore an important issue on the bed. CIN is a structural damage to the kidneys. The definition of CIN is different. It can be defined as an acute deterioration of renal function after application of RM, for reasons similar to the exclusion of alternative causes. The most common definition of secondary effects is an increase in serum creatinine greater than 25% or 44 mmol/l (0.5 mg/dl) after administration in the RM tube. The main effect is defined as the increase in serum creatinine 5 200808819 More than 50% or 8811111〇 1 Sichuan 1 ah / call. The pathogenesis of 〇11\[ has not been fully understood. However, it is believed that there are two main factors involved, hemodynamics and small tube effects. The application of RM causes changes in renal hemodynamics, especially glomerular filtration rate (GFR). GFR is the ultrafiltration rate of plasma across the glomerular capillary wall, and measuring the total GFR of both kidneys will provide a sensitivity index for overall renal excretory function. Glomerular filtration rate was calculated by comparing urine creatinine levels with blood test results. The appropriate GFR value (see http://www.fpnotebook.com2) is 97-137 ml/min/1.73 m2 for men and 10 88-128 ml/min.73 m2 for women, while GFR is below 15 ml/ Min/1.73m2 can cause kidney failure. The decrease in GFR induced by the application of RM is considered to be the main cause of CIN formation. Along the renal tubule system, substances that are not resorbed (*RM) become more concentrated. Up to 99% of renal fluid is normally absorbed by the action of manifold cells and paracellular mechanisms. This means that the urine concentration of RM can be increased by a factor of 100 by a factor of 15. As the continuous concentration process progresses, the small tube fluid containing RM will become viscous and can cause tubule occlusion (Ueda, 19933). Inevitably, the intrarenal pressure also increases because the kidney cannot expand due to the presence of the surrounding envelope. As a result, the renal perfusion pressure of the renal medulla may no longer be sufficient to ensure adequate perfusion. In the kidney, the activation of A1AR in imported glomerular arterioles has been suggested to contribute to tubule glomerular feedback (TGF), a strategic feedback mechanism designed to control tubule flow and regional perfusion . An increase in [NaCl] in the macula densa region of the nephron causes vasoconstriction. The role of adenosine in the mediated TGF response is consistent with its effect on vasoconstriction. In addition to its vasoconstrictor effect, Al receptor stimulation shrinks mesangial cells in the glomerulus 6 200808819 (Olivera, 1989). Acute renal failure caused by RM injection has been considered for many years to be a syndrome in diagnostic and interventional procedures. The incidence of acute renal failure directly induced by RM is approximately one to 15%' and the rate of cin defined by clinically significant increases in serum creatinine is as high as 22% (Porter, 19895). Peak creatinine concentrations occur within 3 to 5 days of exposure to contrast media and are usually satisfactorily eliminated, but in up to 10% of dangerous patients, dialysis is required. Existing renal insufficiency, decreased vascular content, and other underlying diseases (eg, high blood, diabetes) are said to be • some of the leading risk factors for nephropathy induced by radiographic mediators. Weight gram 10 osmolality is a measure of the number of molecules and particles per kilogram of aqueous solution. The osmolality of RM is considered to be of great significance in the induction of renal disease by radiographic contrast media. The incidence of nephropathy induced by low-permeability RM is lower in the general population and is calculated to be less than 2% (Nikolsky, 20036). The production of adenosine is one of the CIN mechanisms already discussed. Adenosine is an endogenous 15-derived neuromodulator that is primarily responsible for the inhibitory effects of the CNS, heart, kidneys, and other organs. It is a naturally occurring nucleoside that exerts its biological effects by interacting with adenosine by a family of families known to have A1, A2a, A2b, and A3, all of which regulate important physiological processes. The selective A1 adenosine antagonist (AiAR) has a prominent renal effect and has been shown to be a powerful diuretic and natriuretic excretion with little effect on potassium excretion. Thus, they are renal protective and can be used to treat renal failure, renal dysfunction, nephritis, hypertension and edema. The kidneys constitutively produce adenosine to modulate glomerular filtration and electrolyte resorption mediated by the adenosine A1 receptor system. The A1 adenosine receptor has been found to innervate the blood vessels of the imported glomerular arterioles 7 200808819 Contraction response. Adenosine causes a decrease in blood flow to the kidney, resulting in a decrease in glomerular filtration rate and renal blood flow. Inhibition of the A1 receptor will increase glomerular filtration rate and correspondingly increase the rate of urine production. The use of adenosine receptor antagonists has been used to protect against acute renal failure. The adenosine receptor antagonist aminophylline (a combination of theophylline and ethylenediamine 2:15) and theophylline (which has been found to non-selectively antagonize adenosine receptors in the brain) were evaluated as protective radiographic mediators. Potential drug for inducing kidney disease (Shammas, 2001; Welch, 2002; Huber, 200727). Aminophylline appears to have no protective role in preventing radiation-induced contrast-induced nephropathy, and theophylline is effective in preventing radiation-induced contrast-induced nephropathy, renal excretion, endocrine and tubular dysfunction. These results suggest that adenosine may play a role in the pathogenesis of CIN and that the use of non-selective adenosine receptor antagonists has been used to protect acute renal failure associated with RM treatment. Erley (19948) studied the effect of non-selective adenosine antagonist theophylline on glomerular filtration rate after RM application and assigned an important role for adenosine in CIN. In addition, 15 Arakawa (19969) describes the role of adenosine in the renal response of the existing and non-renal insufficiency dogs to the contrast medium iohexol. Arakawa noted that in normal renal function, iohexol causes renal vasodilation, which primarily activates the adenosine A2 receptor. In diminished renal function, iohexol induces activation of A2 and A1. Arakawa suggested that the adenosine A2 receptor is involved in the initial renal vasodilation 20, which is responsible for the persistent deterioration of renal hemodynamics. Yao (20001()) studied the effect of selective adenosine A1 antagonist KW-3902 on radiographic contrast-induced nephropathy in rats with chronic hypoxic deficiency. Yao suggests that the activation of adenosine via the A1 receptor affects the onset of CIN. Greiner (2005u) studied theophylline and acetaminophen cysteine alone and in combination 8 200808819

The effect of radiographic contrast-induced nephropathy in patients with intensive care confirms the preventive properties of theophylline in CIN. Lee (2〇〇6i2) concluded that renal A1 adenosine receptors are only partially responsible for the onset of radiation contrast nephropathy. In experiments using kidney A1 adenosine receptor knockout mice, it was found that these mice 5 were protected from acute renal failure induced by RM injection. However, direct tubule toxicity does not appear to be regulated by the renal A1 adenosine receptor. Patent application EP 1 386 609 (CV Therapeutics 13) describes a method for restoring prosperous and renal function, including a combination of an adenosine A1 antagonist and a diuretic. Patent application WO 99/31101 (Univ. South Florida 14) discloses a xanthine derivative as an adenosine receptor antagonist. Further, methods for imaging radiolabeled derivatives and adenosine A1 receptor antagonists are mentioned for medical diagnostic purposes. I: SUMMARY OF THE INVENTION 3 SUMMARY OF THE INVENTION A! AR has previously been shown to have a protective effect in several nephrotoxicity models 15 of acute renal failure. Increased release of renal adenosine and stimulation of renal adenosine receptors have been proposed as the main cause of the formation of acute renal failure induced by radiographic media. We have now surprisingly found that administration of a selective I1 receptor antagonist of Formula I is particularly beneficial for preventing the risk of CIN formation and/or the need for dialysis in patients receiving radiographic mediators. We have now surprisingly found that administration of the selective 20 A1 receptor antagonist of Formula I is particularly beneficial for the prevention of the risk of side effects and end organ damage (e.g., CIN formation) and/or dialysis in patients receiving radiographic mediators. The field has used selective adenine A1 antagonists to treat a specific group of critically ill patients with certain long-term kidney disorders in order to cure or improve these kidney diseases (see, for example, Wo 200 Nacher 15). We have now surprisingly found that administration of a selective Α1 receptor antagonist of Formula I is particularly beneficial for preventing (10) the risk of formation and/or dialysis in all patients receiving a vehicle for delivery, including healthy patients and Patients who already have kidney disease, 5 such as kidney failure and other kidney disorders. Accordingly, a subject of the invention is the use of a therapeutically effective amount of at least one selective glandular A1 receptor antagonist for the preparation of a medicament for the treatment of renal disease induced by at least one radiographic medium in mammals and humans. It is used for the increase of creatinine liver level, for the reduction of renal blood flow, and for the dialysis demand caused by (4) angiography. A further object of the invention relates to a pharmaceutical combination comprising a therapeutically effective amount of at least one selective adenosine A1 receptor antagonist and a radiographic contrast medium. A further object of the invention relates to a kit comprising a therapeutically effective amount of at least one selective adenosine A1 receptor antagonist and a radiographic medium. At least one a ar antagonist that can be used in accordance with the present invention may be selected from the group consisting of compounds of formula I.

Wherein 2 〇 R 1 and R 2 are each independently selected from a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety, or a composition of from 200,808,819 is optionally substituted. a heterocyclic ring; ^ selected from a hydrogen atom or an optionally substituted alkyl group, an optionally substituted square group or an optionally substituted alkylaryl moiety; the substituted elR5 are each independently derived from a halogen atom or a hydrogen atom. Or optionally taking a carbonyl group, an optionally substituted aryl group or a (iv) substituted arylaryl moiety, or R4 and R5-, and optionally a substituted carbocyclic ring; and/or its pharmaceutically acceptable An acceptable salt and/or prodrug and/or solvate, 10 is used to prepare a medicament for the prevention of kidney disease induced by at least one RM in a mammal or human. And or a pharmaceutically acceptable salt and/or prodrug and/or solvate thereof. Specifically, the present invention relates to a pharmaceutical combination consisting of 4_[(2-phenyl-indole-15-[2,3-d]pyrimidinyl)aminol-trans-cyclohexanol mesylate or (4S) _4-Hydroxy-1(2-phenyl-711-pyrrolo[2,3-d]pyrimidinyl)indole-hydrazinamide methanesulfonate is composed of a fixed combination of at least one RM. The at least one RM which can be used according to the present invention may be an iodination or gadolinium-based radiography medium selected from the group consisting of bunaiod, biligram, and iodine. Promethic acid (biiimir〇), bilopaque, cholimil, ethi〇d〇l, diatrast, dionosil, Isoamylate (falignost), gadobutrol, gadodiamide, gadopentetate dimeglumine, glucagon 11 200808819

(gastrografin), hexabrix, hippodin, mangafodipir, amidotrizoate, ethiodized oil, imagopaque, Iodamide, iodipamide, iodixanol, iodophene, iophendylate, iomeron, iomeprol ), ipopamidol, iopanoic acid, iopiperidol, iophendylate, iopromide, iopydol, emipylon Alisomenol, iotalimamic acid, iotrolan, ioversol, ioxilan, ioxaglic acid, thioglycolic acid (isopaque), ipodate, meglumine iothalamate, meglumine acetrizoate, meglumine diatrizoate, meglumine (metrizamide), myelotrast, omnipaque, 15 osbil, mothol (optira) y), filled with oxysulfonate (optojod), acetocoronate (opacoron), all-I-propyl (perflutren), phenobutiodil, phentetiothalein sodium, 峨阿芬Acid (priodax), propyliodone, skiodan, sodium iodomethamate, sodium diatrizoate, triiodophenyl phenylethyl propionate (telepaque), teridax, tetrabrom, thorotrast, triognost, 1,3,5_tri-n-hexyl-2,4, 6. Triiodobenzene, tyropanoate, visipaque or sterol (xenetix), and/or pharmaceutically acceptable salts and/or prodrugs thereof and/or lysate 12 200808819 Formulation. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a hemodynamic measurement in a volume-limited rat to evaluate the TGF response. 5 Figure 2: Experimental setup 2 is used to collect urine. Determination of diuretic, urinary osmolality and urine viscosity. Figure 3: Effect of Vision Parker and Substance 1 on renal cortical blood flow, measured at 2 〇 min after injection of Vision Park or vehicle (control) at the time of sputum. Mean ± SEM (n = 9) is shown to represent the relative value of the cortical flow rate recorded before the Vision (or vector) attack. * : P< 0.05 Vision Parker vs. Control; +: Ρ<〇·〇5 Substance 1 + Vision Parker vs. Vision Parker. Figure 4: Effect of Vision Pike and Substance 1 on renal cortical vascular conductance, measured at 20 min after injection of Vision Park or vehicle (control). The mean ± 8 訄 (11 = 9) is shown as a relative numerical representation compared to the cortical flow rate recorded before the Vision (or vector) attack. * : Ρ<0·05 Vision Parker vs. Control; +: Ρ<〇.〇5 Substance 1 + Vision Parker vs. Vision Parker. Figure 5: The effect of Vision Parker and Substance 1 on renal cortical oxygenation (ρ02), measured at 20 min after injection of Vision Park or vehicle (control). The mean ± SEM (n = 9) is shown to be a relative numerical representation compared to the cortical flow rate recorded prior to the Vision Parker (or vector) attack 20. * : Ρ<0·05 Wei Shi Pike vs. Control; + : ρ<〇.〇5 Substance 1 + Vision Parker vs. Vision Parker. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relates to the use of a therapeutically effective amount of at least one selective adenosine 1 antagonist 13 200808819 for the preparation of a medicament for the prevention of at least one radiation in a mammal or human Nephropathy induced by contrast media. The invention thus relates to the use of a therapeutically effective amount of at least one selective adenosine A1 antagonist of formula I in the manufacture of a medicament:

Wherein R 1 and R 2 are each independently selected from a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety, or together form an optionally substituted heterocyclic ring; R3 is selected from a hydrogen atom or an optionally substituted indenyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety;

Substituted alkyl, optionally substituted green or substituted aryl moiety, or 114 and 115-constituting (iv) lion-ring or optionally substituted carbocycle; and/or pharmaceutically acceptable (d) And/or prodrug and/or solvated contrast media induced renal disease. The medicament is for preventing at least one radiation in a mammal or a human. In addition, the invention relates to a small amount of material (10) - selective adenine

14 200808819 Prevention of an increase in serum creatinine levels induced by at least one radiographic medium in humans. The invention thus relates to the use of a therapeutically effective amount of at least one selective adenosine A1 antagonist of the formula I as defined above for the preparation of a medicament for the prevention of induction of 5 by at least one radiographic medium in a mammal or human The level of creatinine is increased, preferably a transient, persistent or irreversible increase in serum creatinine levels. Furthermore, the invention relates to the use of a therapeutically effective amount of at least one selective adenosine A1 antagonist for the preparation of a medicament for preventing a decrease in renal blood flow induced by at least one radiographic medium. The invention thus relates to the use of a therapeutically effective amount of at least one selective adenosine A1 antagonist of the formula I as defined above for the preparation of a musical substance for use in the prevention of induction by at least one radiographic medium in a mammal or human. Renal blood flow is reduced, preferably a transient, persistent or irreversible decrease in renal blood flow induced by radiographic media. Further, the invention relates to the use of a therapeutically effective amount of at least one selective adenosine 15 A1 antagonist for the preparation of a medicament for preventing dialysis requirements caused by a radiographic contrast-induced nephropathy in a mammal or human, said CIN It is short-lived, long-lasting or irreversible. The invention thus relates to the use of a therapeutically effective amount of at least one selective adenosine A1 antagonist of the formula I as defined above for the manufacture of a medicament for the prevention of the risk or need for dialysis in a human or mammalian subject, preferably transient, persistent or Irreversible dialysis, the patient receives a radiographic medium. The invention further relates to a therapeutically effective amount of a pharmaceutical combination of at least one selective adenosine A1 antagonist and at least one radiographic medium, wherein the combination of drugs is suitable for simultaneous, separate or stepwise administration to a human or TJ milk animal. 15 200808819

Furthermore, the invention relates to a kit comprising at least an effective amount of at least one selective adenosine A1 antagonist and at least one radiographic contrast medium, wherein the combination of drugs is suitable for simultaneous, separate or progressive administration to a human mammal. Eight eight eight 11 that can be used in accordance with the present invention may be selected from Formula I

Wherein R 1 and R 2 are each independently selected from a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety, or together form an optionally substituted heterocyclic ring; R 3 is selected from a hydrogen atom or an alkyl group optionally substituted by 10, an optionally substituted aryl group or an optionally substituted alkylaryl moiety; R 4 and R 5 are each independently selected from a halogen atom, a hydrogen atom or optionally a substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety, or R4 and R5- form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring; Wherein R1 and R are independently selected from a hydrogen atom, an optionally substituted alkyl or a substituted heterocyclic ring; R3 from a hydrogen atom or an optionally substituted aryl; each of R4 and R5 Independently selected from "child or chlorine atom; more preferably, wherein hydrazine is a hydrogen atom and hydrazine is an optionally substituted cyclohexyl ring, or · and R2 constitutes a turn-by-turn substitution: phantom is a phenyl ring (10) 16 20 200808819 5 R5 are each a hydrogen atom; and/or a pharmaceutically acceptable salt and/or prodrug thereof / or solvate. In a preferred embodiment, the octagonal ruler according to the present invention may be selected from the group consisting of cockroaches - cockroaches - primordial - piroxime and ^ ^ 幻 ^ 密 - bit 丨 丨 丨 丨 - - Cyclohexanol methanesulfonate or (4S)-4-hydroxy-1 -(2-phenyl-7H-pyrrolo[2,3_d] shoutin-4-yl)-L_proline Acid salts and/or their prodrugs and/or solvates. • Suitable for use in the description herein are described in the following international patent applications: 10 WO 99/62518, WO 01/39777, WO 02/057267 and WO 2004 /094428 (Osi Pharmaceuticals and Solvay Pharmaceuticals) 15. The RM which can be used according to the invention may be a deuterated or 1-based radiographic medium selected from the group consisting of bimaiod, biligram, Imidoperoic acid (bilimiro), η than rop〇paque, iodine _ 15 • cholimil, ethiodol, diatrast, dionosil, Falignost, gadobutrol, gadodiamide, gadopentetate dimeglumine, gastrografin, sea safari (hexabrix), hippodin, mangafodipir, amidotrizoate, ethiodized oil, imagopaque, iodamide , iodipamide, iodixanol, iodophene, iophendylate, iomeron, iomeprol, ipopamidol , succinic acid (iopanoic 17 200808819

Acid), iopiperidol, iophendylate, iopromide, iopydol, iosimenol, iothalamic acid, moth Iotrolan, ioversol, ioxilan, ioxaglic acid, isopaque, ipodate, iodine Meglumine iothalamate, meglumine acetrizoate, meglumine diatrizoate, metrizamide, myelotrast, omnipaque ), osbil, optiray, optojod, opacoron, perflutren, phenobutiodil, adjacent four angstroms Phentetiothalein sodium, priodax, propyliodone, skiodan, sodium iodomethamate, sodium diatrizoate , triiodophenethyl propionic acid (telepaque), iodide 15 acid (teridax), tetrapene benzoate sodium (tetra Brom), thorotrast, triognost, 1,3,5-tri-n-hexyl 2,4,6-triiodobenzene, tyropanoate, vista Parker Visipaque) or iodietol (xenetix), and/or pharmaceutically acceptable salts and/or prodrugs and/or solvates thereof. 20 Preferred RMs include xenetix, omnipaque or visipaque. Some examples of RMs suitable for use herein (Schering, Bracco Industria Chimica, Univ. California, Nyegaard, Cook Imaging Corporation, Mallinckrodt, Eprova, Nycomed, and Savag) 16 described 18 200808819 are described in the following documents: European Patent Application Ep 〇 022 744, EP 0 023 992, ΕΡ 026 026 28 ΕΡ Ο 033 426, ΕΡ Ο 108 638 and ΕΡ 317 492, international application W0 87/00757 and W0 89/081 (Π, US Patent US 2,776, 24, US 3 , 29G, 366, US 3, 36G, 436 and US 5,349, 085, 5 British application TM 1 321 59 and German patents DE 2 547 789, DE 2 726 196 and DE 2 909 439, but are not limited to these rm. (2.Phenyl-7H-indolo[2,3-d]pyridin-4-yl)amino]-trans-cyclohexanol methanesulfonate will also be abbreviated as substance 1, (4S)- 4-Hydroxy-1-(2•phenyl-7H-indolo[2,3-d]-pyridin-4-yl)-L-prolinamide methanesulfonate 10 below 2.

In a preferred embodiment, the invention relates to the use of a combination of: substance 1 with bunaiod, or substance 1 with biligram, or substance 1 with iodoproxil (9) limbro, or Substance 1 and bilopaque, or substance 1 and oxicillin (ch〇limil), or 15 substances 1 and ethiodol, or substance 1 and diatrast, Or substance 1 and di〇nosil, or substance 1 and falignost, or substance 1 and gadobutrol, or substance 1 and gadodiamide, or substance 1 With gadopentetate dimeglumine, or substance 1 with gastrografin, or substance 1 with hexabrix, or substance 1 with hippodin, Or substance 1 and mangafodipir, or substance 1 and amidotrizoate, or substance 1 and ethiodized oil, or substance 1 and imagopaque, or substance 1 with iodamide, or substance 1 19 200808819

With iodipamide, or substance 1 with iodixanol, or substance 1 with iodophene, or substance 1 with iophendylate, or substance 1 with 硪 硪 伦 伦(i〇meron), or substance 1 with iomeprol, or substance 1 with iipamidol, or 5 substances with iagonoic acid, or substance 1 and moth Iopiperidol, or substance 1 and iophendylate, or substance 1 and iopromide, or substance 1 and iopydol, or substance 1 and iosimenol, Or substance 1 with iotalimamic acid, or substance 1 with iotrolan, or substance 10 1 with ioversol, or substance 1 with iodoxan, or substance 1 with ioxaglic acid, or substance 1 with isopaque, or substance 1 with ipodate, or substance 1 with mothamide (meglumine) Iothalamate), or substance 1 with meglumine acetrizoate, or substance 1 with ubiquinone 15 amine Meglumine diatrizoate), or substance 1 with metrizamide, or substance 1 with iodine acid (myelotrast), or substance 1 with omnipaque, or substance 1 with iodine (osbil), Or substance 1 and opiray, or substance 1 and optojod' or substance 1 and opacoron, or substance 1 20 and perflutren, or Substance 1 and phenobutiodil, or substance 1 and hentetiothalein sodium, or substance 1 and priodax, or substance 1 and propyliodone, or substance 1 with sodium iodosulfonate (skiodan), or substance 1 with sodium iodomethamate, or substances 1 and 20 200808819 sodium diatrizoate, or substance 1 and triiodophenyl phenylethyl propyl Acid (telepaque), or substance 1 with iodide (teridax), or substance 1 with tetrabrom, or substance 1 with thirart, or substance 1 with triognost ), or substance 1 and 5 1,3,5-tri-n-hexyl·2 , 4,6-triiodobenzene, or substance 1 and tyropanoate, or substance 1 and visipaque, or substance 1 and xenetix. In a preferred embodiment, the invention relates to the following pharmaceutical combinations: substance 1 with bunaiod, or substance 1 with biligram, or substance 1 with iopromole (bilimir〇) ), or substance 1 and bilopaque, or substance 1 and oxicillin (ch〇limil), or substance 1 and ethiodol, or substance 1 and diatrast, or Substance 1 and dion〇sii, or substance 1 and falignost, or substance 1 and gadobutrol, or 15 substance 1 and gadodiamide, or substance 1 And gadopentetate dimeglumine, or substance 1 and gastrografin ' or substance 1 and hexabrix, or substance 1 and hippodin, or substance 1 with mangafodipir 'or substance 1 and diatrizoate (丨加甘丨), or 20 substances 1 and ethiodized oil, or substance 1 with imagopaque ) 'Or substance 1 with edaconamine such as ^), or substance 1 with biliary acid (i Odipamide), or substance 1 with iodixanol, or substance 1 and iodophene, or substance 1 with iodophenylate, or substance 1 with iodamine (i〇mer〇n) ), or substance! 21 200808819 with memeprol, or substance 1 with iopamidol, or substance 1 with iopanoic acid, or substance 1 with iopiperidol, or substance 1 With i〇phendylate, or substance 1 with iopromide, or substance 1 with iopydol, or 5 substance 1 with iosimenol, or substance 1 with moth Otatalamic acid, or substance 1 and iotrolan, or substance 1 and ioversol, or substance 1 and ioxilan, or substance 1 and ioxaglic acid ), or substance 1 with isopaque acid, or substance 1 with amiodapine, or substance 1 10 with meglumine iothalamate, or substance 1 With meglumine acetrizoate, or substance 1 and meglumine diatrizoate, or substance 1 with metrizamide, or substance 1 with iodine acid (mydotrast), or Substance 1 with omnipaque, or substance 1 with iodobenzoic acid (0Sbil), or 15 Substance 1 with entropic (optiray), or substance 1 with iodine phenolic acid (optojod), or substance 1 with sodium oleate (0pac〇r〇n), or substance 1 with perfluoropropane (perflutren) , or substance 1 and phenobutiodil, or substance 1 and hentetiothalein sodium, or substance 1 and iodine acid (pri〇dax), or substance 1 and propyl 20 iodine ( Pmpyliodone), or substance 1 and sodium iodosulfonate (ski〇dan), or substance 1 and sodium iodomethamate, or substance 1 and sodium diatrizoate, or substances 1 and 3 Isoaminophenethylpropionic acid (telepaque), or substance 1 with iodide (teridax), or substance 1 with tetrabromyl tetrabromide (tetrabrom), or substance 1 with indane colloid 22 200808819 (th0rotrast), or Substance 1 and diatom sodium (tri〇gn〇st), or substance 1 and 1,3,5-tri-n-hexyl-2,4,6-triiodobenzene, or substance 1 and sodium strontanoate (tyropanoate) Or substance 1 and visjpUque, or substance 1 and xenetix. In a preferred embodiment, the invention relates to a kit comprising: substance 1 with bunaiod, or substance 1 with biligram, or substance 1 with iopromide for ilimir0 ), or substance 1 and bilopaque, or substance 1 and cholimil, or substance 1 and ethiodol, or substance 1 and iotrast, or Substance 1 and di〇nosil, or substance 1 and falignost, or substance 1 and gad〇butrol, or substance 1 and gadodiamide, or Substance 1 and gadopentetate dimeglumine, or substance 1 and gastrografin, or substance 1 and hexabrix, or substance 1 15 with iodine sodium (hippodin) , or substance 1 and mangafodipir, or substance 1 and amidotrizoate, or substance 1 and ethiodized oil, or substance 1 and imagopaque, or substance 1 with iodamide, or substance 1 with bilid acid (iodipami) De), or substance 1 with iodixanol, 20 or substance 1 with iodophene, or substance 1 with iophendylate, or substance 1 with iodamine (i〇) Meron), or substance 1 with iomeprol, or substance 1 with iopamidol (i〇pamid〇l), or substance 1 with ipanic acid, or substance 1 with indapamide ( Iopiperidol), or substance 1 with iophendylate, or substance 23 200808819 1 with iopromide, or substance 1 with iopydol, or substance 1 with iosimenol, or Substance 1 and iotatalic acid, or substance 1 and iotrolan, or substance 1 and ioversol, or substance 1 and ioxilan, or substance 5 Ioxaglic acid, or substance 1 and methyl ubiquinic acid > (isopaque), or substance 1 and ipodate, or substance 1 - with edetate Meglumine iothalamate), or substance 1 with meglumine acetrizoate, or substance 1 and diatrizoate Meglumine diatrizoate), or substance 1 with metrizamide, or substance 1 with myelotrast, or substance 1 with omnipaque, or substance 1 with bismuth (osbil) , or substance 1 and mothol (optiray), or substance 1 and optojod, or substance 1 and sodium oxacoronate (opacoron), or substance 1 and perfluorotrine (perflutren), Or substance 1 with phenobutiodil, or substance 1 with hentetiothalein ^ sodium, or substance 1 with priodax, or substance 1 with propyl ketone (propyliodone), or substance 1 with sodium iodide (skiodan), or substance 1 with sodium iodomethamate, or substance 1 with sodium diatrizoate, or substance 1 and three moths Aminophenethyl 20 propionic acid (telepaque), or substance 1 and emidin (teridax), or substance 1 with tetrabromtoate (tetrabrom), or substance 1 with indane colloid (thorotrast), or substance 1 With diatom sodium (triognost), or substance 1 with 1,3,5-tri-n-hexyl-2,4, 6-triiodobenzene, or substance 1 with sodium tyrosanoate, or substance 1 with visipaque, or substance 24 200808819 1 with xenetix. In a preferred embodiment, the invention relates to the use of a combination of: substance 2 with bunaiod, or substance 2 with biligram, or substance 2 with ipilide (bilimiro), Or substance 2 and 5 σ than bilopaque, or substance 2 with oclimate (cholimil), or substance 2 with ethiodol (ethiodol), or substance 2 with dionotene (diatrast) or substance 2 with dionosil, or substance 2 with falignost, or substance 2 with gadobutrol, or substance 2 with gadodiamide, or substance 2 with IL spray Gadopentetate dimeglumine, or substance 2 with gastrografin ' or substance 2 and hexabrix, or substance 2 with hippodin, or substance 2 Mangafodipir ' or substance 2 and amidotrizoate, or substance 2 and ethiodized oil, or substance 2 and iodopaque, or substance 2 and iodine I〇damide, or substance 2 - with biliary acid (iodipamide), or substance 2 with iodixanol, or substance 2 with iodophene, or substance 2 with iophendylate, or substance 2 with i〇meron, Or substance 2 with iomeprol, or substance 2 with iopamidoi, or 20 of substance 2 with iopanoic acid, or substance 2 with iopiperidol, or substance 2 with iodophenylate, or substance 2 with iopromide, or substance 2 with iodine π (i〇py(|〇i), or substance 2 with iodinol (iosimenol) , or substance 2 with iothalamic acid, or substance 2 with iodine (i〇tr〇ian), or substance 25 200808819

2 with mooverol (ioversol), or substance 2 with ioxilan, or substance 2 with ioxaglic acid, or substance 2 with isopaque, or substance 2 Ipodate, or substance 2 with meglumine iothalamate, or substance 2 and vinegar 5 meglumine acetrizoate, or substance 2 and diatrizoate (meglumine diatrizoate), or substance 2 with metrizamide, or substance 2 with ecamar (myelotrast), or substance 2 with omnipaque, or substance 2 with esbil (osbil) , or substance 2 with iohexol (optiray), or substance 2 with optojod, or substance 2 with sodium oxacobenzoate (opacoron), or substance 2 with all-IL perfutren, Or substance 2 and phenobutiodil, or substance 2 and hentetiothalein sodium, or substance 2 and priodax, or substance 2 and propyliodone, Or substance 2 and sodium sulphate (skiodan), or 15 substances 2 and sodium bismuth (sod) Io iodomethamate), or substance 2 with sodium diatrizoate, or substance 2 with tripaprofen (telepaque), or substance 2 with teridac (teridax), or substance 2 with four deserts Benzene (tetrabrom), or substance 2 and hydroquinone colloid (thorotrast), or substance 2 and triognost, or substance 2 and 20 1,3,5-tri-n-hexyl-2,4, 6-triiodobenzene, or substance 2 and tyropanoate, or substance 2 and visipaque, or substance 2 and xenetix. In a preferred embodiment, the invention relates to the following pharmaceutical combinations: substance 2 with bunaiod, or substance 2 with glucosinolate 26 200808819 (biligram), or substance 2 with iopromole (bilimiO) ), or substance 2 and bilopaque, or substance 2 and cholimil, or substance 2 and ethiodol, or substance 2 and diatrast, or substance 2 with dionosil, or substance 2 with iodine 5 melatic acid (falignost), or substance 2 with gadobutrol (§8 (1〇1311 plus 1), or substance 2 with gadodiamide) , or substance 2 with gadopent'etate dimeglumine, or substance 2 with gastrografin, or substance 2 with hexabrix, or substance 2 with iodine urate (hippodin), or substance 2 and mangaf〇dipir, or substance 2 and amidotrizoate, or substance 2 and ethiodized oil, or substance 2 and iodine (imagopaque), or substance 2 with iodamide, or substance 2 with gallbladder Acid (iodipamide), or substance 2 with exixanol, or substance 2 with iodophene, or substance 2 with iodophenylate, or substance 2 with iomeron, Or substance 2 with iomeprol, or substance 2 with iopamidol, or substance 2 with iopaanoic acid, or substance 2 with iopiperidol, or substance 2 Iophendylate, or substance 2 with iopromide, or substance 2 with iopydol, or 2, substance 2 with iosimenol, or substance 2 with iodine Acid (iothalamic acid), or substance 2 and iotrolan, or substance 2 and ioversol, or substance 2 and ioxilan, or substance 2 and ioxaglic acid , or substance 2 with isopaque acid, or substance 2 with ipodate, or substance 2 27 200808819

With meglumine iothalamate, or substance 2 with meglumine acetrizoate, or substance 2 with meglumine diatrizoate, or substance 2 with glucosinolate (metrizamide), or substance 2 with myelotrast, or substance 2 5 with omnipaque, or substance 2 with osbil, or substance 2 with entropic (optiray), Or substance 2 and dopophyrin (optojod), or substance 2 with sodium benzoate (〇pacoron), or substance 2 with perfluorotene (perflutren), or substance 2 with iodopropylbutyric acid (phenobutiodil) , or substance 2 with ortho-tetradophenol sodium (hentetiothalein 10 sodium), or substance 2 and iodofenac (pri〇dax), or substance 2 with propyl iodide (propyliodone), or substance 2 with sodium iodosulfonate (skiodan), or substance 2 with sodium iodomethamate, or substance 2 and sodium diatrizoate, or substance 2 with triiodophenylpropionic acid (telepaque), or substance 2 Iridine (teridax), or substance 2 15 with sodium tetrabromophenolate Tetrabrom), or substance 2 and hydroquinone colloid (thorotrast), or substance 2 and triognost, or substance 2 and 1,3,5-tri-n-hexyl-2,4,6-triphenyl, Or substance 2 and tyropanoate, or substance 2 and visipaqUe, or substance 2 and xenetix. In a preferred embodiment, the invention relates to a kit comprising: substance 2 with bunaiod, or substance 2 with biligram, or substance 2 with iopromide ( Bilimiro), or substance 2 with bilopaque, or substance 2 with cholimil, or substance 2 with ethiodol, or substance 2 with moth ketone 28 200808819 (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 釓Gadopentetate dimeglumine, or substance 2 with gastrografin, or substance 2 and hexabrix, or substance 2 with hippodin, or substance 2 With mangafodipir, or substance 2 and amidotrizoate, or substance 2 with ethiodized oil, or substance 2 with iagopaque, or substance 2 with iodine Iodamide, or substance 2 10 with cholestanic acid Odipami De), or substance 2 and iodixanol, or substance 2 and iodophene, or substance 2 and iophendylate, or substance 2 and iomeron, Or substance 2 with iomeprol, or substance 2 with iopamidol, or substance 2 with iopanoic acid, or substance 2 with iopiperidol, or substance 2 With iophendylate, or substance 2 with iopromide, or substance 2 with iopydol, or substance 2 with iosimenol, or substance 2 with edaravic acid (iothalamicacid), or substance 2 with iotrolan, or substance 2 with ioversol, or substance 2 with ioxilan, or substance 20 with ioxaglic acid ), or substance 2 and isopaque acid, or substance 2 and amiodapine, or substance 2 with meglumine iothalamate, or substance 2 Meglumine acetrizoate, or substance 2 and meglumine diatrizoate Or substance 2 with meglumine 29 200808819 (metrizamide), or substance 2 with myelotrast, or substance 2 with omnipaque, or substance 2 with osbil, or substance 2 with iohexol (optiray), or substance 2 with phenolphthalein (optojod), or substance 2 with sodium acetate (opacoron), or substance 2 5 with perfluoropropyl (perfluent), or substance 2 with phenobutiodil, or substance 2 and hentetiothalein sodium, or substance 2 with priodax, or substance 2 with propyliodone, or substance 2 With sodium iodosulfonate (skiodan), or substance 2 with sodium iodomethamate, or substance 2 and 10 sodium diatrizoate, or substance 2 with three ampamophene propionate (telepaque), or substance 2 with iodide (teridax), or substance 2 with tetrabrom, or substance 2 with tantotrast, or substance 2 with triognost , or substance 2 and 1,3,5·tri-n-hexyl-2,4,6-triterpene, or 2 Pan substance casein sodium acid 15 (tyroPanoate), or substance 2 and Visipaque (Visipqque), or substance 2 and the ratio of alcohol Bauer (xenetix). A therapeutically effective amount of a pharmaceutical or pharmacologically active ingredient, which is an amount that is non-toxic but sufficient to provide the desired effect of the drug or ingredient. In the combination therapies of the invention, a therapeutically effective amount of one component of the combination is an amount effective to provide the desired effect of the compound when used in combination with 20 other components of the combination. It varies depending on the subject, and depends on the age and general condition of the individual, the specific active ingredient, and the like. Thus, it is not always possible to specify an accurate, therapeutically effective amount. However, one of ordinary skill in the art can determine an appropriate, therapeutically effective amount in any individual case using routine experimentation. 30 200808819 At least one RM is not administered earlier until the plasma level of at least one selective adenosine A1 receptor antagonist has reached a concentration of 1〇5〇〇ng/ml. The invention also relates to any concentration or concentration range in the range of 10-500 ng/ml. In a preferred embodiment, the at least one selective adenosine A1 5 antagonist has the following concentrations: 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 10 500 ng/ml, and any concentration or concentration range located within any range defined by two of the above concentration values, wherein the lower limit of the range The upper limit of the range is defined by a smaller value, such as 11 〇 to 180 ng/ml, 370-390 ng/ml, 10-150 ng/ml, and the like. The invention thus relates to the use of at least one radiographic contrast medium not to be administered 15 earlier until a therapeutically effective amount of said at least one selective adenosine A1 receptor antagonist is sufficient to provide 10 - 500 ng/ml, preferably 20 - 400 ng A plasma level concentration of /ml, more preferably 30-30 ng/ml. The invention thus further relates to a pharmaceutical combination comprising at least one radiographic contrast medium that is not administered earlier until a therapeutically effective amount of said at least one selective adenosine A1 receptor antagonist is sufficient to provide 10 - 500 ng/ml, preferably 20 — a plasma level concentration of 4 〇〇 ng/ml, more preferably 30 〜 300 ng/ml. The invention further relates to the use of at least one radiographic contrast medium not to be administered earlier until a therapeutically effective amount of said at least one selective adenosine A1 receptor antagonist is sufficient to provide from 1 to 500 ng/m b, preferably from 20 to 400 ng. /m Bu is more preferably 30-300 ng / ml of blood stasis 31 200808819 horizontal concentration. The invention further relates to a pharmaceutical combination comprising at least one radiation & shirting medium which is not administered earlier until a therapeutically effective amount of said at least one selective adenosine A1 receptor antagonist is sufficient to provide 1〇5〇〇ng/m Preferably, the blood plasma level is 20-40 ng/ml, more preferably 3 〇 3 (10) ng/ml. The maintenance dose of the selective A1 adenine antagonist is applied for a period of time sufficient to maintain a plasma level of at least one selective A1 adenosine antagonist at a concentration of 1 〇 500 ng/ml. The amount of at least one selective adenosine antagonist to be administered to achieve and maintain a particular plasma level of at least one selective A1 adenosine antagonist corresponds to the particular dose to be administered to the patient. The technician 10 is able to select a dose that is appropriate for the particular patient. The invention also relates to any concentration or concentration range in the range of from 10 to 500 ng/ml. In a preferred embodiment, the at least one selective adenosine scorpion antagonist has the following concentrations: 10, 20, 30, 40, 50, 60, 70, 80, 90, 1 〇〇, 11 〇, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 15 230, 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/m and any concentration or concentration range located within any range defined by the two concentration values, wherein The lower limit of the range is defined by a smaller value, and the upper limit of the range 20 is defined by a larger value, such as a range of 10 - 18 〇 ng / ml, 320 ~ 390 ng / ml, 100 - 150 ng / ml, and the like. The maintenance dose of at least one selective A1 adenosine antagonist is applied between 0.1 and 48 hours to maintain a plasma level of at least one selective A1 adenosine antagonist at a concentration of 10 to 500 ng/ml. The invention further relates to 32 200808819 and any of the 〇. 1~48", U (four) 任(四) intervals. In a preferred formula, the administration period of the maintenance dose is 0.1, 03, 05, L5, 2, 25, 3, m U·5 1 · 5, 4, 4·5, 5, 5·5, 6 ,6·5,7,7·5,8,8·5,9,9·5, ι〇, 1G 5 5 1 11.5 12,12·5, η 5, 14, 14.5, 15, one, coffee , 17.5, 18, 185, 19, !9.5>20^ 20 5 ^?ι οι c •, 22, 22·5, 23, 23.5, 24, 24·5,

25,25·5,26,26·5,27,27·5,28,28.5,29,29·5,30,3〇·5,3b 31·5,32,32·5,33,33 ·5, 34, 34.5, 35, 35 5, 36, ·5, 37, 37·5, 38, 38 5, ι^^^ 10 41·5, 42, 42·5, 43, 43·5, 44 , 44·5, 45, 45·5, 46, 46·5, 47, and 48 Xiaori Temple, and any period of time within any range defined by two of the above hour values, wherein the range The lower limit is defined by a smaller value, and the upper limit of the range is defined by a larger value, such as a range of 2 hours, 0.1-10 hours, 〇2-6 hours, 2_45 hours, 9.3-35 hours 15 hours, and the like. The selective adenosine 1 receptor antagonist can be administered intravenously at a loading dose followed by a maintenance dose, and at least one selective adenosine is administered at a time of administration of the at least one radioactive sputum 'mussel's uranium for 5-25 minutes. A loading dose of an octahedral steroid antagonist and administration of at least one selective adenosine A1 receptor antagonist after administration of the at least one selective Al receptor 20 antagonist loading dose for a period of up to 48 hours The dosage, in a preferred embodiment, is as follows: up to 0.1, 0.3, 〇.5, 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, U.5, 12, 12.5, 13, Π.5, 14, 14·5, 15, 33 200808819 15.5 ^16 ^16.5 ^17 ^17.5 ^18 ^18.5^ 19 >19.5 ^20 > 20.5, 2 Bu 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, 5 37.5, 38, 38.5, 39 , 39.5, 40, 40.5, 4 Bu 41.5, 42, 45 5, 43, 43, 5'44'44·5'45, 45·5, 46, 46·5, 47, 47 5_ hours. The present invention relates to any time interval located within a W5-25 minute period of administration of said at least one radiographic medium, and wherein the at least one remote selective Α1 receptor antagonist loading dose is administered the longest A maintenance dose of at least one selective adenosine A1 receptor antagonist is administered after a period of 10 hours, in a preferred embodiment over the following periods of time: 长 1, 0.3, 0.5, 1, 1.5, 2, 2.5 , 3, 3.5, 4, 4.5, 5, 5·5, 6, 6 5, 7^7.5^8^8.5^9^9.5^10^10.5.11.1^5^2^25, 13, 13·5, 14, 14·5, 15, 15.5, 16, 16·5, 17, 17 5, 18, 15 18·5, 19, 19·5, 20, 20.5, 2, 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, 4, 41.5, 42, 42, 5, 43, 43, 5, 44, 44 5'45, 45·5, 20 46, 46.5, 47, 47·5 and 48 hours. In a preferred embodiment, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, before the administration of the at least one radiographic medium, Intravenous administration of at least one selective glandular Ai 34 200808819 5 • 10 receptor antagonist at 2, 21, 22, 23, 24, and 25 minutes, and any period of time within any range defined by two of the above minute values. Wherein the lower limit of the range is defined by a smaller value, the upper limit of which is defined by a larger value, for example, 1 〇 18 minutes, 2 〇 25 is known, 12-15 minutes, and After administration of at least one selective Ai receptor antagonist loading dose for a period of up to 48 hours, a maintenance dose of at least one selective adenosine A1 receptor antagonist is administered, in a preferred embodiment, following the following stages: 0.1, 〇.3, 〇.5, 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, 1 Bu 11.5, 12, 12.5, 13, 13 5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 1 9.5, 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 _ 15 and 48 hours. The invention thus relates to a use comprising intravenously administering a therapeutically effective amount of a loading dose of at least one selective adenosine 1 receptor antagonist, followed by administration of a maintenance dose, prior to administration of said at least one radiographic medium 5 - a loading dose of at least one selective gland: g:Al by a 20-body antagonist, and included in the at least one selection, for a period of 25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes, more preferably 15 minutes A maintenance dose of at least one selective adenosine A1 receptor antagonist is administered after administration of a loading dose of the A1 receptor antagonist for up to 48 hours. The invention thus further relates to a pharmaceutical combination comprising intravenously administering a therapeutically effective amount of a loading dose of at least one selective adenosine A1 receptor antagonist, followed by administration of a vitamin 35 200808819 dose, administration of said at least one radiographic medium A loading dose of at least one selective adenosine A1 receptor antagonist is administered for a period of 5 to 25 minutes, preferably 10 to 20 minutes, more preferably 13 to 17 minutes, more preferably 15 minutes, and is included in the at least one selectivity A maintenance dose of at least one selective adenosine A1 receptor antagonist is administered after administration of the A1 receptor antagonist loading agent for a period of up to 48 hours. The invention thus further relates to a kit comprising administering a therapeutically effective amount of a loading dose of at least one selective adenosine A1 receptor antagonist, followed by administration of a maintenance dose prior to administration of said at least one radiographic medium A loading dose of at least one selective adenosine A1 receptor antagonist is administered for a period of 5 to 25 minutes, preferably 1 to 20 minutes, more preferably 13 minutes, more preferably 15 minutes, and is included in the at least one selection A maintenance dose of at least one selective adenosine A1 receptor antagonist is administered after a period of up to 48 hours of administration of the A1 receptor antagonist loading dose. The present invention is not limited in its broadest scope to specific dosage forms, carriers, sizing agents, and the like, which may be different. It is also to be understood that the term H used herein is for the purpose of describing particular embodiments only and is not intended to be limited. It must be noted that the singular forms "a", "the" and "the" Thus, for example, reference to a therapeutically active ingredient, a single ingredient, and a combination of two or more different ingredients, for a carrier, includes a mixture of two or more carriers and a single carrier, and the like. The terms ''A1AR', 'selective adenosine A1 antagonists, and, &, selective adenosine A1 receptor antagonists' are used interchangeably herein to refer to a compound comprising the desired physiological and physiological effects of the drug 36 200808819. At least one selective adenosine A1 antagonist can be administered orally and/or intravenously. The invention thus relates to the use comprising administering a therapeutically-administered therapeutically in a delayed release formulation prior to administration of at least one radiocontrast agent An effective amount of said at least one selective adenosine A1 receptor antagonist. - The invention thus relates to a use comprising a loading dose of said at least one selective adenosine A1 receptor antagonist effective for intravenous administration, % ' Administering a maintenance dose, administering at least one selective adenosine A during a period of 5-25 minutes, preferably 10-20 minutes, more preferably 13-17 minutes, more k-domain 15 minutes prior to administration of the at least one radiographic medium a loading dose of the receptor antagonist, and comprising a dose of the at least one selective A1 receptor antagonist loading for up to 48 hours After the paragraph, a maintenance dose of at least one selective adenosine A1 receptor antagonist is administered. - The invention thus relates to a pharmaceutical combination comprising administering a treatment in an oral, preferably in a time release formulation, prior to administration of at least one radiocontrast agent. Attacking the at least one selective adenosine A1 receptor antagonist. The invention thus relates to a pharmaceutical combination comprising administering a therapeutically effective amount of a loading dose of said at least one selective adenosine A1 receptor antagonist intravenously, followed by administration Maintaining a dose, administering at least one selective adenosine during the administration of the at least one radiographic medium for 20 ^ ^, 5 - 25 minutes, preferably 10 - 20 minutes, more preferably 13 - 17 minutes, more preferably 15 minutes The A1 receptor antagonizes the loading dose of the sword and comprises administering at least one selective adenosine A1 receptor antagonist after a period of up to 48 hours of administration of the at least one selective A1 receptor orange antagonist loading dose Maintaining the dose. 37 200808819 The invention thus relates to a kit comprising oral, preferably extended, prior to administration of at least one radiocontrast agent A therapeutically effective amount of the at least one selective adenosine A1 receptor antagonist is administered to a release formulation. The invention thus relates to a kit comprising intravenously administering a therapeutically effective amount of 5 of said at least one selective adenosine A1 receptor antagonist. The loading dose, followed by administration of a maintenance dose, is administered at least 5 to 25 minutes, preferably 10 to 20 minutes, more preferably 13 to 17 minutes, more preferably 15 minutes before administration of the at least one radiographic medium A loading dose of a selective adenosine A1 receptor antagonist, and comprising administering at least one selective adenosine after a period of up to 48 hours of administration of the at least one selective A1 receptor antagonist loading dose Maintenance dose of the A1 receptor antagonist. The term "intravenous" relates to parenteral administration, including injection or infusion into the veins and arteries, but is not limited to the parenteral forms described above. The term "oral" relates to enteral administration, including oral administration such as tablets, "15 drops, pills, capsules, powders, granules and the like, but is not limited to the above-mentioned enteral-in-use forms. 0 “Delayed release” indicates the pharmaceutical dosage form. The term "delay" includes, for example, but not limited to, "extended", "delayed", "stagnant", and "delayed" dosage forms. The term "container" means a sealed medicinal storage case. It includes a storage case for liquid medication 20, such as Ampoules, vials, flasks, dispersers, syringes, etc., and storage containers for solid drugs, such as blister packs, capsules, etc., but are not limited to the above-described storage cartridges. The term "irreversible" as used herein may be used interchangeably with the term "permanent". 200808819 and "pharmaceutically acceptable", for example, pharmaceutically acceptable carrier, "pharmaceutical acceptable adjuvant" or "pharmaceutically acceptable salt," in the description of the expression or otherwise Unacceptable material 'that is, the material 5 to the drug combination administered to the patient does not cause any interaction with the physical activity or any combination of harmful activities in a harmful manner. . In the "Lion activity" derivative or metabolite, the drug / Table 7F has a street organism or metabolite with a parent compound and a large pharmacological activity. #词汇学上接接: 10 ^ in the table (four) «分的魅(10), this gamma lysis 化2 treatment has ^sheng, that is, for the treatment of radiographic contrast medium induced nephropathy as a drug _ text = used" carrier Or alternatively, a pharmaceutically acceptable adjuvant, means a conventional pharmaceutically acceptable excipient material suitable for known to be given to music, including 15 alpha, any such material in the art, which are non-toxic and not harmful. The disc drug combination or drug delivery system makes other sub-interactions. The terminology used herein, encompasses the meaning of "and", and the meaning of the phrase cup. 3 * 4 their open, 20, the term "prodrug" used to represent the derivative of the compound of the invention 2 Is a prodrug that releases a drug via chemical or bioinjection in vivo after administration to a patient. The term, prodrug, as used herein, includes metabolism y °, in fact, a prodrug is a derivative of a compound of the invention. The straight group carries additional components, traits, and traits that can be cleaved in vivo under physiological conditions (eg, 'prodrugs are converted to the desired drug form at physiological pH or by the action of an enzyme). Drugs are drugs 39 200808819 Bioreversible derivatives of molecules that overcome some of the barriers of maternal drug molecular applications. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism, and Light limit (Bundgaard, 1985) 17. Prodrugs (i.e., compounds that are metabolized to a compound of formula I when administered to a human by any known route 5) are within the scope of the invention. Pharmaceutically acceptable salt thereof ,, representation salts are pharmacologically acceptable, and the acceptance of administration of the compounds of the present invention are essentially non-toxic. Preferably, the pharmaceutically acceptable salt is a methylation salt. The term "solvate" relates to the association of a suitable organic solvent molecule with an Aiar molecule or ion. The term "solvate," means a stable solvate, as used herein, wherein the compound of formula I contains a fixed amount of solvent molecules per molecule; it also means that the inclusion complexes are less stable, per molecule. A1AR contains a variable amount of solvent molecules. The term "treatment" as used herein refers to a reduction in the severity and/or frequency of symptoms, a reduction in symptoms and/or underlying causes, symptoms and/or the occurrence of their underlying causes. Prevention, and improvement or remediation of the injury. Thus, for example, "treatment" of a patient involves prevention of a particular condition or adverse physiological event in a susceptible individual and treatment of a clinically symptomatic individual. Induced by radiographic mediators, serum creatinine levels Increase, may be 20 transient, long-lasting or irreversible, preferably transient. Reference value of serum creatinine level (see llttp: //www.mceus.com/renal/renalcreat.html)18, adult male is located approximately 〇.8-1.4mg / (H, adult female 0.6-l.lmg / (n, children 0.2-l. 〇mg / dl. serum creatinine level reference value increased by 25% - 50% or CIN is defined in any higher range. Serum creatinine levels are increased by 40 200808819 plus any random (arbitrary) values in the range of 25–70% define αΝ. Serum creatinine levels as measurable physiological parameters Increased, defines the extent of the condition, which is well understood by the skilled person. In a preferred embodiment, 25, 30, 35, 40, 45, 50, 55, 60, 65 and 70%, and 5 are added Any numerical value or range of values within any range defined by any two of the above values defines CIN, wherein the lower end of the range is defined by a smaller value, the upper limit of which is defined by a larger value, such as 25 25, 35%, 30-60%, etc. This definition can explain, to a partial extent, a transient, persistent or irreversible increase in serum creatinine levels. 10 Reduced renal blood flow induced by radiographic mediators, possibly It is transient, persistent or irreversible, preferably transient. The reference value of renal blood flow in healthy people is about 20% per minute of cardiac output, so it is located at i〇〇Qmi/min. The renal blood flow reference value is reduced by 20% —Any range between 80% or even higher defines CIN. Any value in the range of 20-80% reduction in renal blood flow or a range of values 15 defines CIN. As a measurable hemodynamic parameter, renal blood flow Reduced, defines the degree of disease, which is readily understood by the skilled person. In a preferred embodiment, the reduction is 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 7 〇, 75, 80 , 85 and 90%, and any numerical or numerical range located within any range defined by any two of the above numerical values defines CIN, the lower limit of the range stated in 20 being defined by a smaller value, the range of The upper limit is defined by a larger value, such as 25-30%, 20-35%, 30-60%, etc. This definition can explain, to some extent, the transient, prolonged and irreversible inhibition of renal blood flow. Renal blood flow can be measured using MRI (magnetic resonance imaging) techniques to determine renal 200808819 blood flow and renal vascular resistance, as well as PAH (p-aminopurine) infusion techniques. Any of the A1ARs described may be administered in the form of a salt, an ester, a guanamine, a prodrug, an active metabolite, an analog, a solvate, etc., as long as the salt, ester, guanamine, prodrug, active in the context Metabolites, analogs or solvates are pharmaceutically acceptable and pharmacologically active. Salts, esters, guanamines, prodrugs, metabolites, analogs, solvates and other derivatives of the active ingredient can be prepared by a 'quasi-process' known to those skilled in the art of synthetic organic chemistry, for example as J. March ( 1992) 19 described. In a specific embodiment, the present invention also relates to a kit comprising a single packaged pharmaceutical dosage form for use in combination in separate cereals, comprising a pharmaceutical dosage form comprising at least one A1AR in a knife-opening trough, A pharmaceutical dosage form comprising at least one of the first separate compartments. Kits are particularly advantageous, but not limited to, where separate components must be administered in different dosage forms - either at different dosing intervals. The selective adenosine form may advantageously be an injectable preparation such as a solution and a suspension. The kit may further include instructions, which will typically be written instructions on the package insert, label and/or other components of the kit, the intravenous dosage form being as described herein. Each dosage form can be stored separately. This kit will also typically include a device for packaging individual kit components, i.e., dosage form, container device, and written use. Preferably, a therapeutically effective amount of A1AR is administered in a manner as emphasized above. In some cases, however, patients may be administered a therapeutically effective amount of their own separate dosage forms of A1AR and RM, or a combination of individual, combined "dosage forms" containing two or more therapeutically effective A1ARs. In the open dosage form of 200808819, A1AR and RM can be administered at substantially the same time (in parallel) or at separate staggered times (sequential). When the active plasma level of the A1AR component is maintained while the anti-% is administered To achieve the best beneficial effect. These optimal 5 benefits can be achieved by applying a loading dose followed by a maintenance dose. The loading dose will increase the plasma level very quickly, while the maintenance dose will maintain the plasma level achieved. A form comprising all of a1Ar and RM is more preferred. Such a dosage form provides convenience and simplification for the patient, thereby increasing the likelihood of patient compliance. Since two or even more active ingredients are used together, each component The effectiveness and interaction achieved through the combination of 10 and they must also be considered. All within the scope of the permission of a general technical clinician, the purpose is to determine a therapeutically effective or prophylactically effective dose. The term "alkyl" denotes a radical of a saturated aliphatic group, including straight chain alkyl groups, branched alkyl groups. a cycloalkyl (alicyclic), alkyl substituted cycloalkyl, and cycloalkyl 15 alkyl substituted alkyl. The term alkyl also includes one or more of which may further include an oxygen, nitrogen, sulfur or phosphorus atom in place of the hydrocarbon backbone. a carbon alkyl group, such as an oxygen, nitrogen, sulfur or phosphorus atom. In a preferred embodiment, the linear or branched alkyl group has 30 or fewer carbon atoms in its backbone (eg, a linear CVC%, a branch) The chain is C3-C3G), more preferably 20 or less, for example, in one embodiment, the "20 alkyl" may be CrC6 or CrC4 in a further embodiment. Also, in one embodiment, the cycloalkyl group is Their ring structure has 4 to 10 carbon atoms, and in a further embodiment, the cycloalkyl group has 5 to 7 carbon atoms in their ring structure, for example 5, 6 or 7 carbons in the ring structure. And throughout the specification and claims The term "alkyl as used optionally substituted by 43 200808819" is intended to include "unsubstituted alkyl, and, substituted alkyl," which refers to one or more carbons having a substituent in place of the hydrocarbon backbone. The alkyl portion of hydrogen. Such substituents may, for example, include halogen, hydroxy, alkylcarbenyloxy, arylcarbenyloxy, alkoxycarbenyloxy, aryloxycarbenyloxy, 5carboxylate, alkylcarbonyl, alkane Oxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, I., phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, aromatic) Alkylamino, diarylamino and alkylarylamino), mercaptoamino (including alkylcarbamino, arylcarbenyl, carbamoyl and ureido), fluorenyl, sub-10 amino, fluorenyl , alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfonamide, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocycle a base, an alkyl aryl group or an aromatic L aromatic moiety. Those skilled in the art will appreciate that the moiety substituted on the hydrocarbon chain may itself be substituted, if appropriate. The cycloalkyl group may be further substituted, for example, by 15 substituents as described above. "Alkylaryl" is an alkyl group substituted with an aryl group (e.g., phenylmethyl (benzyl)). The term "alkyl" also includes unsaturated aliphatic groups which are similar in length and possible substitution to the above alkyl groups, but which contain at least one double or triple bond, respectively. . . The term "aryl," as used herein, denotes an aryl radical, including a 5-membered monocyclic aromatic group, which may include zero to four heteroatoms such as benzene, pyrrole, furan, thiophene, imidazole, benzoxazole. Azole, benzothiazole, triazole, tetra. ketone, hydrazine, hydrazine, hydrazine, pyridazine, hydrazine, etc. The aryl group also includes polycyclic conjugated aromatic groups, such as naphthyl, fluorene 1 fluorenyl, etc. Those aryl groups having a hetero atom in the ring structure 44 200808819 may also be referred to as a heterocyclic ring. The aromatic ring may be substituted at the one or more ring positions by the above substituents, for example, a tooth. , carpet base, alkoxy, alkyl carboxyoxy, arylcarbenyloxy, alkoxycarbenyloxy, aryloxycarbenyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl , cyanocarbonyl, alkylthiocarbonyl, phosphate, phosphonium, phosphonium, ^" amino (including anthracenylamino, diasterylamino, arylamino, diaryl 10 15 20 amino and fluorenyl) Arylamino), arginylamino (& calcined carbon si amino, aromatic sulfonylamino, carbamoyl and ureido), fluorenyl Imino, fluorenyl, pyridyl, arylthio, thiocarboxylate, sulfate, sulfonyl, sulfonamide, aminonitro, difluoromethyl, cyano, azide, heterocyclic An alkyl group or a % or heteroaromatic moiety. The aryl group may also be fused or bridged to an aromatic alicyclic or heterocyclic ring to form a polycyclic ring (e.g., tetrahydronaphthalene). The term "heteroatom" is used herein. An atom representing any element other than carbon or hydrogen, preferably a hetero atom is nitrogen. The main w to 'some structures of the compounds of the invention include asymmetric breaks', correspondingly understood, resulting from such asymmetry Isomers (e.g., "enantiomers" and "diastereomers" are included within the scope of the invention, and the separation techniques of the teeth, the external control, and the stereochemically controlled synthesis can be used to obtain such isomers. A substantially pure form of the body. The selected heterologous gland (4) antagonizes the low lipophilic nature and the south hydrophilic nature of the human, resulting in good water solubility. The data used in the present invention are used to distinguish the compounds from other known selective A1 antagonists; exemplary data are depicted in the sputum (the pro-Adenine properties of the selective adenosine A! antagonists). 45 200808819 Table 1: Lipophilic properties of selective adenosine A1 antagonists PGP-factor permeability (%) LogP (ACD v9.〇5) 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 enzymatic behavior of the substance 1 in a wide range of assays, it was concluded that the substance 1 exhibited a selective adenosine A1 receptor ligand with a certain phospho-acid monoester to PDE4 inhibitory activity. Substance 1 replacement of rolipram from the PDE4 site of the dihydrogenase is related to the relative potency of substance 1 to inhibit this enzyme; pKi inhibition of PDE4 is calculated to be 75〇nM; for other phosphodiesterases (PDE 1, 2, 3, 5 and 6) are at least 25 times less active. Diacidase PDE4 inhibitory activity can be used for titration of patients (also known as (10)). The glycerol diesterase PDE4 inhibitory activity of the compounds of the invention 10 prevents overdose of selective gossip antagonists by prompting the patient with a self-evident non-severity signal, for example, before serious events such as CNS convulsions may occur Headache signal. Experiment 1 · Substance 1 Acute (IV) In the anesthetized rats, the experimental protocol for the effect of diuretic and urinary excretion after radiographic contrast media (phagic acid) was induced by the use of Osswald 10, 20 small radiographic mediators. Sexual neonatal kidney failure. A male pretreatment with a body weight of approximately gg 5 mg/kg) was chronically pretreated. For experimental purposes, sexual sprague-Dawley rats were acclimated to h weeks and then started to oxidize with 20% enzyme inhibitor N-mercapto-L-arginine formazan (Uname 7_9 weeks, daily, will be fasted overnight) Rats (following 46 200808819 continued free access to water) were anesthetized with sodium sec- thiobarbital (80 mg/kg, ip., bolus). Place the catheter in (0 trachea, (ii) a jugular vein Medium (for radiographic mediation and background saline infusion; see below), (iii) in another jugular vein (for carrier or substance 1 administration), (iv) in the carotid artery (for blood sampling and 5 Part of the background saline infusion; see below), and (V) in the bladder (for urine collection). Keep the rats on a heated platform to maintain their body temperature at 37.0. Collect urine samples for 60-90 min. After baseline measurement, the animals received vehicle or substance 1 as follows: 0_15 or 1.5 mg substance Ι/kg of the bolus bolus, or vehicle 1 mL/kg 'intravenous administration, followed by continuous intravenous infusion at a rate of 15 1 〇 and 15#g substance 1kg/min, or carrier iivL/kg/min until the end of the experiment. Using these dosing regimens, substance 1 Steady state plasma levels were 59 ± 23 and 314 ± 36ng / mL. 1〇min material 1 after the start (or vector) disposal, over 3min i.v · infusion previously heated to the temperature of the acid diatrizoate (meglumine,

Urolux, 〇.61g phacoid acid/mL, equivalent to total strontium content of 29〇mg/mL, 15 Sanochemia Diagnostics, Neuss, Germany), dose of 2_55mL/kg, equivalent to 740mg angstroms/kg (time of contrast medium administration) The point is defined as tG). The background saline solution was infused from the beginning, and the rate was maintained at ~ 1.2 mL/h/100 g ' until the end of the experiment (〇 24 mL/h via the arterial catheter, 0.96 mL/h via the IV). This infusion is required to compensate for fluid loss due to surgery and subsequent blood sampling, but also to ensure that the arterial catheter is open between blood sampling points. Urine samples were collected according to the following schedule: baseline (60-90 min before substance carrier administration), t〇_ 30 min (〇.5h time point), 30 · 60 min (lh time point), 60 · 120 min (2h time point) and 120 _ 18〇min (3h time point). Plasma samples were taken at the end of each of the above stages. The diuretic and urinary sodium excretion rates over the above time intervals were calculated using the measured urine volume values of the amount of 200820088 and the Na+ level in the urine. As shown in Table 4, the substance 1 treatment produced a large and significant increase in urine production within the first 30 min after administration of the contrast medium compared to the vehicle control group; although the rate of diuresis in the 5 groups was then restored to a lower value. However, the irritating effect of substance 1 lasts for at least 3 hours. Since radiographic media is eliminated via urine, this diuretic effect of substance 1 is likely to strongly promote their elimination, thereby limiting their toxicity. 10 Table 2: Effect of substance 1 on diuresis after administration of diatrizoic acid in anesthetized rats CM post-time carrier control substance 1 low dose sputum, compared with vehicle 1 high dose sputum, compared with vehicle 0.5 h 17· 10 ± 1·42 27.31 ± 2.36 氺氺氺28.01 ± 2.02 氺氺氺1 h 3·76 ± 0·31 3.87 ± 0·40 ns 4·97 ± 0·30 ns 2 h 1·96 ± 0·15 3 · 34 ± 0,42 氺氺3·13 ± 0·27 氺氺3 h 2·14 ± 0.40 3·54 ± 0·50 ns 3·11 Soil 0·36 ns The value is expressed in mL/kg body weight/h. Represents the mean soil SEM (n = 14 - 24). Statistical significance was assessed by one-way analysis of variance followed by Bonferroni test. Comparison with vehicle control ' ns ·: not significant, * · P &lt; 0.05, **: p < 〇〇 1 ; *** · p &lt; 〇〇 Similarly, substance 1 caused prominent and sustained comparison with the vehicle control group Increased sodium excretion (Table 5). Gas excretion received stimulation of the substance sputum in a similar manner, while potassium excretion was not affected by the compound during the entire experiment (not shown). 48 20 200808819 Table 3: Effect of substance 1 on sodium excretion after administration of diatrizoic acid in anesthetized rats CM post-time vehicle control substance 1 low dose P, compared with vehicle 1 high dose p, compared with vehicle 0.5 h 1332 ± 184 3039 ± 354 氺氺氺3301 ± 306 氺氺氺1 h 185 ± 39 338 ± 81 ns 520 ± 77 氺氺2 h 153 ± 40 613 ± 121 氺氺591 ± 88 氺氺3 h 329 ± 72 842 ± 121 氺氺 830 ± 91 氺氺 Λ is expressed as # mol / kg body weight / h, representing the mean SEM (n 2 14 ^ 3⁄4). The factor variance analysis was followed by the Bonferroni test to evaluate the statistical significance. Compared with the vector control, n.s.: not significant; *: p &lt;〇.〇5; : p &lt;〇.〇1; *** ·· p &lt; 〇 . 5 Φ 2 · substance 1 acute drug in anesthetized rats for the effect of radiographic medium tidal acid on renal blood flow and oxygenation experimental protocol based on previously published method 2, 22 using adult male 3 to 4 months old Wistar rats were tested. The weight ranges from 25〇 to 4〇%. Rats received the standard feed. Eating and drinking were interrupted for approximately 12 hours prior to surgery. Animals were anesthetized with an intraperitoneal injection of urethane solution (2% aqueous solution, 6 ml/kg) and the animals were placed on a heated table to maintain body temperature at 37 throughout the surgery and subsequent experiments. C. After cutting the left groin, carefully prepare the femoral artery, insert the cannula, and average the arterial blood pressure with _ (four). The other branch f is placed in the vein for the administration of the 15 medium. Finally, the expandable tube head is placed around the abdominal aorta of the renal artery. The expansion of the hose head controlled by the servo device keeps the monthly irrigation/main pressure reduction V at a preset level. To the left side of the kidney's cortex and Bu Puibei implanted two straight! The 5GG&quot;m optical fiber was used to measure the total renal blood flow (clear) by placing the ultrasonic jet lag probe around the kidney 20 artery of the same kidney. Similarly, partial determination of renal oxygen levels (oxygen partial pressure = P〇2) (cortex and medulla P〇2, 〇XyLite, 0xford P, respectively) after planting mosquitoes, 'pass (four) amount of blood under baseline conditions 2008 200808819 Kinetics Start the experiment with the oxygenation parameters. The vehicle or substance l (5 mg/kg, intravenous bolus) is then administered. For the new measurement, flazasol (Wei Pike 320; l. 5 mL i.a.; Amersham Buchler, Braunschweig, Germany) or vehicle was applied 30 min after carrier or substance 1 administration. After another 2 〇 min, repeat the measurement (after 20 min, as shown in the attached figure below). The experimental group was thus: ι·carrier + vector (‘control'), vector + Vision Parker and substance 1 + Vision Park. Substance 1 did not alter the hemodynamic parameters (arterial blood pressure RBF) before the Vision Parker attack (not shown). After administration of Visioncap, a strong transient mean arterial blood pressure increase (~35 mmHg) was observed for approximately 1 〇 min, 10 was partially prevented by substance 1 (not shown). The renal cortical blood flow showed a transient initial increase in the vehicle + Vision Packer group, followed by a progressive and significant decrease (Fig. 1) compared to the vehicle control group. In contrast, cortical blood flow showed a sustained and significant increase in the presence of substance 1 in the presence of the substance + Visipaque group, and blood flow was consistently elevated until the end of the measurement phase (Fig. 1 15). Cortical vascular conduction was rapidly and steadily reduced by Visipaque, while substance 1 maintained this parameter at the level of the vehicle control group (Fig. 2). Similarly, medullary blood flow rises briefly (~3 min) after Visipaque injection, and then falls below the control level; medullary vascular conduction is rapidly and stably inhibited by Vision peek; Disposal only partially (but significantly) prevents these effects (not shown). Finally, substance 1 caused a significant increase in cortical p〇2 and continued until the end of the experiment (Fig. 3). In summary, these observations show that substance 1 improves renal hemodynamics and oxygenation, thereby at least partially antagonizing the potentially deleterious effects of radiographic contrast agent iodixanol. 50 200808819 Study protocol study 1 performed in 60 anesthetized rats Animal research. Assess renal hemodynamics' The oxygen tension in the kidney was measured after RM administration. Partial hemodynamics were quantified by laser-Doppler flux by means of time-quantization of total renal blood flow. In addition, the regional oxygen tension of the kidney is evaluated, and urine is collected to determine the osmolality, viscosity, and diuresis of the urine. Using a recently established technology (Wronski, 2003) 21, it is possible to assess TGF responses in this environment. Rm significantly reduces renal blood flow and disrupts regional renal oxygenation. This effect is most likely due to viscous properties, as seen in the increase in urinary viscosity. The prior administration of the A1AR antagonist alleviates or even reverses these RM effects on renal hemodynamics (renal blood flow and hypoxia). Two options were developed: Option 1: Fluid limitation occurred 24 h before the experiment. This causes an increase in the RM concentration in the tubule system. Implanted catheters, time-flow 15 gauges, laser Doppler probes and sound sources were used to evaluate absolute p〇2. Record the measurement results and give the ruler. Option 2: The measurement will then be repeated. Urine volume, osmolality and viscosity were measured in liquid-filled animals. The control measurements were recorded and then administered. "Evaluation of renal blood flow, oxygen tension, and regional blood flow in rats after water restriction. * TGF response. Plasma volume reduction is generally a recognized risk factor because CM is resistant During diuresis, it is concentrated in the small tube. Figure 1 depicts these schemes. In the top stop, RM (N = 15) is given after the control measurement. The bottom stop is drawn to the series of tA1Ar before the ruler ^(N 2 15) 〇 51 200808819 In order to collect sufficient urine, animals with bladder volume filling were used. The diuretic, urinary osmolality and viscosity of the control were evaluated, and the RM of the control was evaluated (N=15, top bar of Figure 2), A1A5 and A1AR. +RM (N = 15, bottom panel of Figure 2). All experiments were performed on adult male Wistar rats, 5 from the animal room of the college. Rats were housed in groups. All animals were randomly assigned to various protocols. Animals were numbered by cage number. The standard rat diet (Altromin 1324, Altromin GmbH, D-32791 Lage) served as a feed. For protocol 1, eating and drinking water was interrupted for approximately 12 hours prior to surgery. In protocol 2, water was allowed to drink freely. Drinking water is supplied ad libitum, except for 12 h before cm. Therefore, the animal is dehydrated. In scenario 2, water is supplied ad libitum, knowing that it is not long before the experiment. Use granular wood (Granulat A2, J. Brandenburg) , D-49424 Goldenstedt) as the bottom material of the gas. Replace and clean the cage between 6: 〇〇 and 8: 00 am. Every day, during the adaptation period, the animals are kept at 15 MAKR0L0N every 3-5 groups. In the cage (type 4), the room temperature is 22 °C ± 3 °C, the relative humidity is 6〇% soil, 20%. For example, it may cause deviation during the cleaning procedure. Anesthesia is introduced and maintained with urethane. The rats are placed on the heating platform. Above, the body temperature was maintained during the entire surgery at 37.0. The body temperature was controlled during the study. After the left groin was opened, the femoral artery was carefully prepared and cannulated with a polypropylene tube (PP 1〇) to measure 20 renal perfusion pressure ( RPP). Place another catheter (pp5〇) of the same material in the head = vein 3 to measure systemic blood pressure (BP) and heart rate (HR). Finally, place the expandable hose: the head in the abdominal aorta Surrounding; one above the origin of the renal artery, another Below, the servo-controlled proximal hose head expansion causes the monthly irrigation main c to decrease and maintain at a preset level. To the left kidney cortex and 52 200808819 medulla implant two optical fibers of 500 / zm diameter (Moore instruments, GB), placing ultrasound through a time-flow probe (1RB, Transonic Systems inc, USA) 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 a partial measurement 5 . Local blood flow was measured and evaluated by means of a misfire-Doppler flowmeter (Moore Instruments, GB). Connect the arterial catheter to a calibrated pressure sensor. Connect the expandable hose head to the external servo control system and connect the flow probe to the flow meter via an extension cable. The oxygen partial pressure sensing probe is fixed in a corresponding manner. After the analog signal is converted to a digital signal, all data (BP, RPP, RBF, 10 LFC, LFM, local oxygen tension) are stored online in a computer system (IBM compatible AT) in ASCII format. After implantation and stabilization, the experiment was started. Infusion The test solution. After 5 min of equilibration, measurements of RBF, local flux and local p〇2 were initiated. A 5 min step response was then obtained to assess TGF. Urine was collected for 35 min to evaluate diuretic, osmolality and viscosity. Modify the plan as needed. Total and regional RBF and oxygen tension in the renal medulla and cortex were assessed by measuring laser-Doppler flux and direct assessment according to previous studies (Flemming, 2000 and 2001)22. After calculating the individual mean for each number, the mean and standard error of each control/intervention group were calculated using these averages for each animal. The latter was used to test statistically significant differences, preferably levels less than 〇·〇5 were considered significant. The test method used for the selection of parameters for basic data. Study 2 The study was similar to that described by Yao (2-sided 1G) and selected for some changes in the protocol. Unlike Yao's research, chronic and acute experiments are performed. In addition to L-nameCNw-Shisuke-L-arginine A in this study, 53 200808819, indomethacin was also used. Experiment 1 · Substance 1 Acute administration in anesthetized rats for radiographic contrast media (pan 5 acid) The effects of post-diuretic and urinary sodium excretion were induced using radiographic contrast medium-dependent acute renal failure based on an experimental protocol published by the Osswald Groups 10 and 23. Male Sprague-Dawley rats weighing approximately 3 〇〇g were acclimated for at least 1 week and then started synthesizing with nitric oxide, the inhibitor N-Ph-L-arginine methyl vinegar (L-NAME 7-9 weeks, per曰 is j 10 amount 5 mg / kg) chronic pretreatment. For the experiment, rats that were fasted overnight (following free access to water) were anesthetized with sodium sec- thiobarbital (8 〇 mg/kg, i p., bolus). Place the catheter in (1) the trachea, (ii) in a jugular vein (for radiographic mediation and background saline infusion; see below), (m) in another jugular vein (for carrier or substance 1 Medicine), (iv) in the carotid artery (for blood sampling and 15 part of background saline infusion; see below), and (v) in the bladder (for urine collection). Rats were kept on a heating platform to maintain their body temperature at 37 gamma. After collecting the urine sample for 60-90 min for baseline measurement, the animal received the vehicle or substance 1 as follows: 0.15 or 1.5 mg substance Ι/kg for the bolus injection, or the carrier 1 mL/kg 'intravenous administration, followed by continuous vein For internal infusion, the rate is 15 20 and 15 #g substance &quot;kg/min, or carrier 丨丨# L/kg/min until the end of the experiment. Use these dosing regimens, substances! Steady-state plasma levels were 59 ± 23 and 314 ± 36 ng/mL, respectively. Substance or carrier) 10 minutes after the start of treatment, after 3 minutes ί·ν· infusion of phacoxic acid (glucanamine salt, Urolux, 〇.6lg phlebamine/mL, which is pre-warmed to body temperature, equivalent to a total broken content of 290 mg/mL, 54 200808819

Sanochemia Diagnostics, Neuss, Germany), dose 2.55 mL/kg, equivalent to 740 mg./kg (time point for contrast medium administration is defined as tG). The background saline solution was infused from the beginning, and the rate was maintained at ~1.2 mL/h/l〇〇g until the end of the experiment (〇24 mL/h via the arterial catheter, 5 〇.96 mL/h via the IV). This infusion is required to compensate for fluid loss due to surgery and subsequent blood sampling, but also to ensure that the arterial catheter is open between time points of blood sampling. Urine samples were collected according to the following schedule: baseline (60-90 min before substance administration), t〇-30 min (0.5 h time point), 30 60 min (lh time point), 6〇_ 12〇min (2h time point) And i2〇_ i80min (3h 1〇 time point). Plasma samples were taken at the end of each of the above stages. Diuresis and urinary sodium excretion over the above time interval were calculated using the measured urine volume value and urine Na+ level. Rate. As shown in Table 4, the substance 1 treatment produced a large and significant increase in urine production within the first 30 minutes after administration of the contrast medium compared to the vehicle control group; although the rate of diuresis in the 15 king group was then restored. Low values, but the irritating effect of substance 1 lasts for at least 3 h. Since the radiographic media is eliminated via urine, this diuretic effect of substance 1 is likely to strongly promote their elimination, thereby limiting their toxicity.

20 55 200808819 Similarly, substance 1 caused an increase in prominent and sustained sodium excretion compared to the vehicle control group (Table 2). Chlorine excretion received stimulation of Substance 1 in a similar manner, while potassium excretion was not affected by the compound during the entire experiment (not shown). 5 Table 5: Effect of substance 1 on sodium excretion after administration of diatrizoic acid in anesthetized rats CM post-time vehicle control substance 1 low dose p, compared with vehicle 1 high dose P, compared with vehicle 0.5 h 1332 ± 184 3039 ± 354 氺氺氺3301 ± 306 氺氺氺1 h 185 ± 39 338 ± 81 ns 520 ± 77 氺氺 2 h 153 Soil 40 613 ± 121 591 ± 88 *氺3 h 329 ± 72 842 ± 121 830 ± 91 The value of 氺氺^ is expressed as # mol/kg body weight/h, which represents the mean SEM (n = 14 _ 24). One-way analysis of variance was followed by a Bonferroni test to assess statistical significance. Compared with the vector, n.s. is not significant; *: P &lt;〇.〇5; : p &lt; 〇 〇1 ; *** : p &lt; 〇 . 10 2. The effect of substance 1 acute drug on renal blood flow and oxygenation in radiographic medium after iodixanol in anesthetized rats. Based on previously published methods 21, 22 using adult males 3 to 4 months old Wistar large The rats were tested. The weight ranges from 250 to 400g. Rats received the standard feed. Eating and drinking were interrupted for approximately 12 hours prior to surgery. The animals were anesthetized by intraperitoneal injection of urethane (2% water &gt; trough, 6 ml/kg) and the animals were placed on a heated platform to maintain body temperature at 37 throughout the surgery and subsequent experiments. C. After cutting the left groin, the femoral artery was carefully prepared and cannulated to measure the mean arterial blood pressure. Another catheter was placed in the carotid artery for administration of a photographic medium. Finally, the expandable tube head is placed around the abdominal aorta on the origin of the renal artery. The expansion of the hose head controlled by the servo device reduces and maintains the renal perfusion pressure at a preset level. Two fibers of 500/0.5 m diameter were implanted into the cortex of the left kidney and 56 200808819, to determine the local clock-multiple Jinle flux, and the ultrasound time-lapse flow probe was placed in the renal artery of the same kidney. Around to measure total renal blood flow (RBF). The renal oxygen level (oxygen knife pressure - p〇2) was also measured locally (pipigia and Zhao pQ2, 〇XyLite, 〇xf〇rd 5 Optronics, respectively). After implantation and stabilization, the experiment was started by measuring hemodynamic and oxygenation parameters under baseline conditions. The vehicle or substance - 1 (5 mg/kg, intravenous bolus) is then administered. For the new measurement, iodixanol (Wei Pike 320; 1.5 mL i.a.; Amersham _ Buchler, Braunschweig, Germany) or vehicle was applied 30 min after carrier or substance 1 administration. After another 2 〇 min, the measurement is repeated 10 times (after 20 minutes, as shown in the following figure). The experimental group was thus: ι·carrier + vector (‘control'), vector + Vision Parker and substance 1 + Vision Park. Substance 1 did not alter the hemodynamic parameters (arterial blood pressure RBF) before the Vision Parker attack (not shown). After administration of Visioncap, a strong transient mean arterial blood pressure increase (~35 mmHg) was observed, lasting approximately i〇min, and -15 was partially prevented by substance 1 (not shown). Renal cortical blood flow showed a brief initial increase in the Carrier-+ Vision Packer group, followed by a progressive and significant decrease in the Carrier-+ Vision Packer (Figure 3). In contrast, cortical blood flow showed a sustained and significant increase in the presence of substance 1 in the presence of the substance + Visipaque group, and blood flow was consistently elevated until the end of the measurement phase (Fig. 3 20). Cortical vascular conduction was rapidly and steadily reduced by Visipaque, while substance 1 maintained this parameter at the level of the vehicle control group (Fig. 4). Similarly, medullary blood flow rises briefly (~3 min) after Visipaque injection, and then falls below the control level; medullary vascular conduction is rapidly and stably inhibited by Vision peek; Disposal of only part (but 57 200808819) prevents these effects (not shown). Finally, substance 1 caused a significant increase in cortical P〇2 and continued until the end of the experiment (Fig. 5). Taken together, these observations show that Substance 1 improves renal hemodynamics and oxygenation, thereby at least partially antagonizing the potentially harmful effects of radiographic mediators. Brief description of t-pattern 3 Figure 1: Hemodynamic measurements were performed in volume-limited rats to assess TGF responses. Figure 2 · Experimental setup 2 is used to collect urine. Determination of diuretic, urinary osmolality and urine viscosity. Figure 3: Effect of Vision Parker and Substance 1 on renal cortical blood flow, measured at 20 mM η after injection of Vision Parker or vehicle (control) at time 0. Mean ± SEM (n = 9) is shown to represent the relative value of the cortical flow rate recorded prior to the Vision (or vector) challenge. * : P&lt; 〇.〇5威视派克 15 vs•Control;+·· Ρ&lt;〇·〇5 Substance 1 + Vision Parker vs. Vision Parker. Figure 4: Effect of Vision Parker and Substance 1 on renal cortical vascular conductance, measured at 2 min after injection of Vision Park or vehicle (control) at time 0. The mean ± SEM (n = 9) is shown as a relative numerical representation compared to the cortical flow rate recorded prior to the Vision Parker (or vector) challenge. * : p &lt; 〇.〇5 威视 20 Pike vs. Control; + : P&lt;〇_〇5 Substance 1 + Vision Parker vs. Vision Parker. Figure 5: The effect of Vision Pike and Substance 1 on renal cortical oxygenation (p〇2) was measured at 2 〇 min after injection of Vision Park or vehicle (control) at time 0. The mean ± SEM (n = 9) is shown as a relative numerical representation compared to the cortical flow rate recorded prior to the Vision Parker (or vector) challenge. * ·· P &lt; 0.05 58 200808819 Vision Pike vs. Control; + : P&lt; 0.05 Substance 1 + Vision Pike vs. Pike. [Main component symbol description] (none)

59 200808819 Citations ^drew E? Berg KJ? „ Nephrotoxic effects of X-my contrast media,,, J Toxicol Clin Toxicol· 2004 ; 42(3) ·· 325-32 2 http : //www^notebookxom/REN70 .htm and http · //\vww^notebookxom/REN3 8.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 401ivera A? Lamas S9 Rodriguez -Puyol D? Lop^-Novoa JM. "Adenosine induces mesangial cell contraction by an A1-type receptor^'· Kidney Int 1989 ; 35(6) : 1300-1305

5 Porter, "Contrast-associated nephropathy 5. Am J. Cardiol., (1989), 64 (9)? 22E-26E 6 Nikolsky E? Aymong ED, Dangas Q Mehran R. &quot;Radiocontrast nephropathy · identifying the high-risk patient And the implications of exacerbating renal fimction", Rev Cardiovasc Med 2003; 4 Suppl 1 : S7-S14 7a) Shammas et al·, uAminophylline does protect against radiocontrast nephropathy in patients undergoing percutaneous angiographic procedures59, J Invasive Cardiol (2001)? 13( 11), 738-40; b) Welch et al. &quot;Adenosine A1 receptor antagonists in tiie kicbiey ^ effects in fluid-retaining disorders^, Cmr Opin Phannacx)l (2002)? 2(2), 165-70; c Huber et al. &quot;Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency : controlled^ randomized, 60 200808819 double-blinded study55, Radiology(2002)? 223(3), 772-9 ^Erhy etal" uAdenosineantagonist theophylline prevents the reduction of glomemlarfiltration rate after contrast media applica Tion^, Kidney Int (1994), 45, 1425-31 9 K. Akawara et al, uRole of Adenosine in the renal responses to contrast medium’,, Kidney Int (1996), 49(3), 1199_206

_ 10 K· Yao et al·, “The selective Adenosine A1 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, 5? TU Munchen, 19.10.2005 H. Thomas Lee, Michael Jan, Soo Chan Bae, Jin Deok Joo, Farida R. Goubaeva, Jay Yang, and Mihwa Kim, uAi Adenosine receptor knockout mice are protected against acute radiocontrast nephropatiiy in vivo, 5? Am J Physiol Renal Physiol 290 · F1367-F1375, 2006 13EP1 386 609? filed by CV Therapeutics 14WO 99/31101, filed by Univ. South Florida 15WO 99/ 62518, WO 01/39777, WO 02/057267, all filed by Osi Pharmaceuticals and WO 2004/094428 filed by Solvay Pharniaceuticals 16EP 0 022 744 filed by Schering, EP 0 023 992 filed by Bracxx) Industria Chimica, EP 0 026 281 filed By Bracco Industria Chimica, EP 0 033 426 filed by Univ. Ca Lithuania, EP 0 108 638 filed by Nyegaard, EP 0 61 200808819 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

17Bundgaard, H. (editor), "Design of Prodrugs", Elsevier, 1985 18http ^ //\vww.mceusxom/renal/renalcreat.html(15-June-2006) 19Advanced Organic Chemistry : Reactions, Mechanisms and Structure, 4th Edition , New York: Wiley-Interscience, 1992 20 Wronski T? Seeliger E? Persson PB9 Fomer C? Fichtner C? Scheller J et al. The step response: a method to characterize mechanisms of renal blood flow autoregulation· Am J Physiol Renal Physiol 2003; 285(4): F758-F764 21a) Flemming B? Arenz N, Seeliger E5 Wronski X 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) 22Flemming B? Seeliger E? Wronski T9 Steer K, Arenz N? Persson PB. Oxygen and renal hemodynamics in the conscious rats. J Am Soc Nq^hrol 2000 ; 11(1) : 18-24 23Erley CM, Heyne N5 Burgert K, Langanke J5 Risler T? &amp; Osswald H (1997) ^ Prevention of RadiocontrasMnduced Nq)hropathy by Adenosine Antagonists in Rats with Chronic Nitric Oxide DeflBciency. J. Am. Soc. Nephrol, 8 · 1125-1132 62

Claims (1)

200808819 X. Patent application scope: Use in the preparation of a medicament i A therapeutically effective amount of at least an alternative sex agonist (10) antagonist and/or a pharmaceutically acceptable salt thereof and/or a prodrug and/or solvate thereof R1 and R2 are each independently selected from a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety, or together form an optionally substituted heterocyclic ring; R3 An alkyl group selected from a hydrogen atom or an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety; # R4 and R5 are each independently selected from a halogen atom, a hydrogen atom or optionally a substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety, or R4 and R5 together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring; For the prevention of kidney disease induced by at least one radiographic medium in a mammal or human. 2. A therapeutically effective amount of at least one of the selective adenine A1 antagonists of formula I as defined in claim 1 and/or pharmaceutically acceptable _ and/or prodrugs and/or solvents thereof Use of the compound in the preparation of a medicament, 63 200808819 The medicament is for preventing a transient, persistent or irreversible increase in serum creatinine levels, preferably serum creatinine levels, induced by at least one radiographic medium in a mammal or human. 3. A therapeutically effective amount of at least one selective adenosine A1 antagonist of formula I as defined in claim 1 and/or pharmaceutically acceptable salts and/or prodrugs and/or solvates thereof, The use in the preparation of a medicament, The medicament is for preventing a transient, persistent or irreversible reduction in renal blood flow induced by at least one radiographic medium, preferably in a mammal or human, preferably by radiographic contrast media. 4. A therapeutically effective amount of at least one selective adenosine A1 antagonist of the formula I as defined in claim 1 and/or pharmaceutically acceptable salts and/or prodrugs and/or solvates thereof, in the preparation Use in medicine, 64 200808819 The medicament is for the prevention of the risk or need for dialysis in a human or mammalian patient, preferably transient, persistent or irreversible dialysis, which receives a radiographic medium. 5. The use of any one of claims 1, 2, 3 or 4, wherein 5 therapeutically effective amount of said at least one selective A1 adenine antagonistic sword is applied for a period of time sufficient to maintain at least one selective A1 gland The plasma level of the glycoside antagonist is at a concentration of from 10 to 500 ng/ml, preferably from 20 to 400 ng/ml, more preferably from 30 to 300 ng/ml. 6. The use of any one of claims 1, 2, 3, 4 or 5, 10 comprising administering a therapeutically effective amount of the at least one selective adenosine A1 receptor antagonist at a loading dose, and comprising Maintaining a dose, administering a load of at least one selective adensin A1 receptor antagonist 5 to 25 minutes, preferably 10 to 20 minutes, more preferably 13 to 17 minutes, more preferably 15 minutes prior to administration of the at least one radiographic medium Dosage, and comprising a maintenance dose of at least one selective adenosine A1 receptor antagonist administered after administration of the at least one selective A1 receptor antagonist loading dose for up to 48 hours. 7. The use according to any one of claims 1, 2, 3, 4 or 5, wherein the treatment is administered orally, preferably in a 20 time release formulation, prior to administration of the at least one radiographic agent&gt; An effective amount of the at least one selective adenosine A1 receptor antagonist. 8. The use of any one of claims 1, 2, 3, 4, 5, 6 or 7 wherein the at least one radiographic medium is not administered earlier until the therapeutically effective amount of the at least one option Gonadal A1 receptor antagonist 65 200808819 /ml, choose 3 ° 5 10 9·Application time of the maintenance dose of the at least “selective Α1 glandular ridge” for the use of the patent scope 1 cn, ΜΑ 4, 5 or 8 arbitrary-term L 3 /α therapeutically effective amount The segment is sufficient to maintain at least one selection of 隹A1, and the blood level of the bitter antagonist is at an enthalpy of t 〇 5 ng/mi, preferably 2G-4 GGng/mh, more preferably 3 卜 3 (10). The use of any of the items of claim 2, 3, 4, 5, 6, 7, 8 or 9 wherein the therapeutically effective amount of the at least one selective adenoid A1 morph antagonist is selected from the group consisting of The formula is defined as a piroxi[2,H]-initiating derivative, and/or a pharmaceutically acceptable salt thereof and/or a prodrug and/or a solvate thereof. U. The use of the term of the invention, wherein the at least one of the therapeutically effective amounts is at least 15 Gonadal bitterness A1 receptor antagonism_from 4_[(2_phenyl_7H•(tetra)[2,3d] 咕.-4-yl)amino]trans-cyclohexanol-methyl-refenate or state·4 -Hydroxy-1 -(2-styl-7-pyrrolo[2,3-d]pyrimidin-4-yl)-L-prolinamide mesylate and/or its prodrugs and/or solvates. 12. The use of any of clauses i, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 20, wherein the at least one radiographic medium is transported from the following: Or milk-based radiographic media · bunaiod, biligmm, bilimir (bilimir), bilopaque, oxacylic acid (ch〇limil) ), ethiodol, diatrast, di〇n〇sil, iodine 66 200808819 5 10 15 20 falignost, gadobutrol, gadodiamide, gadopentetate dimeglumine, gastrografin, hexabrix, 峨Hippodin, mangafodipir, amidotrizoate, ethiodized oil, imag0paqiie, iodamide, iodipamide ), iodixanol, iodophene, iophendylate, iomeron, iomeprom (i〇mepr〇i), iopamidol (i〇pamid〇l) ), iopanoic acid, iopiperidol, iophendylate, iopromide, iopydol, iosimenol, mothala Iothalamic acid, iotrolan, ioversol, ioxilan, ioxaglic acid, isopaque, amphetamine (ipodate), meglumine ioAalamate, meglumine acetrizoate, ubiquitin (meglumine diatrizoate), metrizamide, myelotrast, omnipaque, osbil, optiray, optojod, acetophenone Sodium (opacoron), perflutren, phenobutiodil, phentetiothalein sodium, priodax, propyliodone, sputum Sodium sulphate, sodium iodomethamate, sodium diatrizoate, amphibious phenylethyl propionate 67 200808819 (telepaque), teridac (teridax), four deserts Sodium tetrabrom, thorotrast, triognost, 1,3,5-tri-n-hexyl-2,4,6-triphenyl, sodium tyropanoate , visipaque or xenetix, and/or its pharmaceutically acceptable 5 salts and/or prodrugs and/or solvates. 1.3. The use of any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein the medicament is a fixed combination. 14. A pharmaceutical combination comprising a) a therapeutically effective amount of at least one selective adenosine A1 antagonist, 10 and b) at least one radiographic medium, wherein the pharmaceutical combination is suitable for simultaneous, separate or stepwise administration to a human or mammal . 15. A pharmaceutical combination according to claim 14, comprising a therapeutically effective amount of said at least one selective adenosine A1 receptor antagonist administered intravenously, and comprising a maintenance dose, said at least one radiation A loading dose of at least one selective adenosine A1 receptor antagonist is administered 5 to 25 minutes, preferably 10 to 21 minutes, more preferably 13 to 17 minutes, more preferably 15 minutes before administration of the contrast medium, and is included in the at least A maintenance dose of at least one selective adenosine A1 receptor antagonist administered for up to 48 hours after administration of a selective dose of a selective A1 morphogen antagonist. 16. A pharmaceutical combination according to claim 14, comprising administering a therapeutically effective amount of said at least one selective adenosine arsenic in an oral, preferably in a time release formulation, prior to administration of at least one radioactive spectroscopy drug. Body Antagonism 68 200808819 agent. 17. A pharmaceutical combination according to any one of claims 14, 15 or 16, comprising at least one radiographic medium not administered earlier until a therapeutically effective amount of said at least one selective adenosine 1 receptor antagonist It is sufficient to provide a plasma level concentration of 10 - 500 ng / ml, preferably 20 - 400 ng / ml, more preferably 30 - 300 ng / ml. 18. The pharmaceutical combination according to any one of claims 14, 15, 16 or 17, wherein the at least one selective A1 adenosine antagonist is applied for a period of time sufficient to maintain plasma levels of at least one selective A1 adenosine antagonist A pharmaceutical composition according to any one of claims 14, 15, 16, 17 or 18, wherein the concentration is from 10 10 to 500 ng/ml, preferably from 20 to 400 ng/ml, more preferably from 30 to 300 ng/ml. A therapeutically effective amount of the at least one selective adenosine A1 receptor antagonist is selected from the group consisting of a pyridyl[2,3-d]pyrimidine derivative of formula I Wherein R1 and R2 are each independently selected from a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety, or together form an optionally substituted heterocyclic ring. R 3 is selected from a hydrogen atom or an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety; 69 20 200808819 R 4 and R 5 are each independently selected from a — atom, a hydrogen atom. Or optionally substituted silk, any (iv) substituted base or (d) substituted alkyl "Rent 4" R4 and R5 together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring; ί / or its pharmaceutically Acceptable salts and/or prodrugs and/or solvates. 2 〇 如 申请 申请 “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ 药物 药物 药物 药物The sessile bitter 1 receptor antagonist is selected from the group consisting of the formula ρ, and the R1 and R2 are each independently selected from a hydrogen atom, an optionally substituted alkyl group or together constitute an optional substitution. Heterocyclic ring; R3 is selected from a hydrogen atom or an optionally substituted aryl group; R4 R5 is each independently selected from a halogen atom or a hydrogen atom; preferably, wherein R1 is a ruthenium atom, and R2 is an optionally substituted cyclohexene 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 pharmaceutically acceptable salt thereof and/or a prodrug and/or a solvate. The pharmaceutical combination according to any one of claims 14, 15, 16, 17, 18, 19 or 2, wherein the therapeutically effective amount of the at least one selective adenosine 1 receptor antagonist is selected from the group consisting of 4 -[(2-phenyl-71^ ratio. each [2 3_d] 70 200808819 when pyridine-4-yl)amino]-trans-cyclohexanol methanesulfonate or (4S)_4_hydroxy_H2_ Stupid-pyrolo[2,3-d]pyrimidinyl)-L_prolylamine mephate and/or its prodrugs and/or solvates. 22. A pharmaceutical combination according to claim 14, wherein the at least one radiographic medium is selected from the group consisting of: a disruption or a radiographic contrast medium: Bunaiod, biligram, bilimiro...bilopaque, cholimil, ethiodol, diatrast , Dionysil (Exit 11 (^1), align美拉酸10 (falignost), gadobutrol (gadobutrol), gadodiamide, gadopentetate dimeglumine, stomach Gastrografin, hexabrix, hippodin, mangafodipir, amidotrizoate, ethiodized oil, Epto 15 (imagopaque), iodamide, iodipamide, iodixanol, iodophene, iophendylate, iomeron, amerop (iomeprol), mopamidol, ipananoic acid, iopiperidol, moth Benzene S (iophendylate), iopromide, iopydol, iosimenol, iothalamic acid, iotrolan, mothol ( Ioversol), ioxilan, ioxaglic acid, isopaque, ipodate, meglumine iothalamate, vinegar Megluminate 71 200808819 (meglumine acetrizoate), meglumine diatrizoate, metrizamide, myelotrast, omnipaque, ebene (osbil) ), optiray, optojod, opacoron, 5 perflutren, fenbufen ^1^11〇1)111^〇(1丨1) , phentetiothalein sodium, priodax, propyliodone, skiodan, sodium iodomethamate, sodium diatrizoate S〇dium diatrizoate), telepaque, teridax, tetrabrom, tetrabrom Throstrast, diatom sodium (1:1^〇§11(^), 1,3,5-tri-n-hexyl-2,4,6-triiodobenzene, sodium tyrosanoate, Visipaqiie or xenetix, and/or pharmaceutically acceptable salts and/or prodrugs and/or solvates thereof. 15 23. A kit comprising: a) a therapeutically effective amount of at least one selective adenosine A1 antagonist, and b) at least one radiographic contrast medium, wherein the pharmaceutical combination is suitable for simultaneous, separate or stepwise administration to a human or mammal medicine. 20 24. The kit of claim 23, comprising: a) a therapeutically effective amount of said at least one selective adenine A1 receptor antagonist dose container, b) the desired intravenous administration An effective amount of the at least one selective adenosine A1 receptor antagonist maintenance dose container, 72 200808819 C) at least one radiographic medium comprising intravenously administering a therapeutically effective amount of the at least one selective adenosine A1 receptor antagonist Loading dose, and comprising a maintenance dose, administering at least one selective adenosine 5 to 25 minutes, 5 preferably 10 to 20 minutes, more preferably 13 to 17 minutes, more preferably 15 minutes before administration of the at least one radiographic medium A loading dose of the A1 receptor antagonist, and comprising a maintenance dose of at least one selective adenosine A1 receptor antagonist administered after administration of the at least one selective A1 receptor antagonist loading dose for up to 48 hours. 10 25. The kit of claim 23, comprising a) a container comprising the therapeutically effective amount of the at least one selective adenosine A1 receptor antagonist to be orally administered, b) at least one radiographic medium, comprising The therapeutically effective amount of the at least one selective adenosine A1 receptor antagonist is administered orally, prior to administration of the at least one radiographic agent, in a time release formulation. 26. The kit of any of claims 23, 24 or 25, comprising at least one radiographic medium that is not administered earlier until a therapeutically effective amount of said at least one selective adenosine A1 receptor antagonist Sufficient to provide a plasma level concentration of from 1 to 2 500 ng/ml, preferably from 20 to 400 ng/ml, more preferably from 30 to 300 ng/ml. The kit of any one of claims 23, 24, 25 or 26, wherein the therapeutically effective amount of the at least one selective A1 adenosine antagonist is applied for a period of time sufficient to maintain at least one selective A1 gland The plasma level of the glycoside antagonist 73 200808819 is at a concentration of 10 to 50 ng/ml, preferably 2 to 400 ng/m, more preferably 30 to 30 ng/mb. 28, as claimed in claims 23, 24, 25, 26 Or a kit of any one of the 27, wherein the therapeutically effective amount of the at least one selective adenosine A1 receptor antagonist is selected from the group consisting of pyrrolo[2,3-d] biting derivatives of formula I Wherein R 1 and R 2 are each independently selected from the group consisting of a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety, 10 or together forming an optionally substituted group. a heterocyclic ring; R 3 is selected from a hydrogen atom or an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted alkylaryl moiety; R 4 and R 5 are each independently selected from a halogen atom, a hydrogen atom or An optionally substituted alkyl 'optionally substituted aryl or an optionally substituted alkyl 15 aryl moiety, or quaternary 4 and R 5 together form an optionally substituted heterocyclic ring or an optionally substituted carbon And/or a pharmaceutically acceptable salt and/or prodrug and/or solvate thereof. 29. The kit of any one of claims 23, 24, 25, 26, 27 or 28 wherein the therapeutically effective amount of the at least one selective adenosine Aj receptor antagonist is selected from Formula I Pyrrolo[2,3-d]pyrimidine derivatives, 74 200808819 wherein R1 and R2 are each independently selected from a hydrogen atom, an optionally substituted alkyl group or together form an optionally substituted heterocyclic ring; R3 is selected from a hydrogen atom Or an optionally substituted aryl; 5 R4 and R5 are each independently selected from a halogen atom or a hydrogen atom; preferably, wherein R1 is a hydrogen atom, R2 is an optionally substituted cyclohexyl ring, or R1 and R2 are together An optionally substituted pyrrolidine ring is formed; R3 is a phenyl ring; 10 R4 and R5 are each a hydrogen atom; and/or a pharmaceutically acceptable salt thereof and/or a prodrug and/or a solvate thereof. 30. The kit of any one of claims 23, 24, 25, 26, 27, 28 or 29, wherein the therapeutically effective amount of the at least one selective adenosine A1 receptor antagonist is selected from the group consisting of 4- [(2-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-trans-cyclohexanol methanesulfonate or (4S)-4-hydroxy-1-(2 -Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-L-prolinamide mesylate and/or its prodrugs and/or solvates. The kit of any one of claims 23, 24, 25, 26, 27, 28, 29 or 30, wherein the at least one radiographic medium is selected from the group consisting of iodine or sulfhydryl radiation as follows Contrast medium: bxmaiod, biligram, bilimiro, bilobaque, cholimil, ethiodol, Diatrast, dionosil, 埃75 200808819 10 15 20 falignost, gadobutrol, gadodiamide, gadopentetate dimeglumine, gastrografin, hexabrix, iodine Hipp〇din, mangafodipir, amid〇trizoate, ethiodized oil, imagopaque, iodamide, Iodipamide, iodixanol, iodophene, iophendylate, iomeron, iomeprol, mopamidol ), iopanoic acid, iopiperidol, iophendylate, iopromide, iopydol, iosimenol, mothala Iothalamic acid, iotrolan, ioversol, ioxilan, ioxaglic acid, isopaque, amphetamine (ipodate), mothalladine meglumine (!11611111^1^1〇1:11&amp;13111&amp;16), glucosinolate (meglumine ace) Trizoate), meglumine diatrizoate, metrizamide, myelotrast, omnipaque, osbil, optiray, broken acid ( Optojod), opacoron, perflutren, phenobutiodil, phentetiothalein sodium, priodax, propyl Propionol (propyliodone), sodium sulphate (8^0 (1&amp;11), 峨° acid sodium (80 (101111丨0 (1〇11^1:1^11^{6), phacoxime Sodium diatrizoate, triammonium acetophenone propionate 76 200808819 (telepaque), teridinic acid (teridax), tetrabromotetralin (tetrabrom), dioxosite (throtrast), diatom sodium ( Triognost), 1,3,5-tri-n-hexyl-2,4,6-triphenylene, tyropanoate, visipaque or xenetix, and/or its pharmacy Acceptable 5 salts and/or prodrugs and/or solvates. 77