Applying (r)-ibuprofen methanesulfonamide and its salts for treatment and prophylaxis of rejection response of transplantable organs

FIELD: medicine, transplantology.

SUBSTANCE: method involves applying (R)-ibuprofen methanesulfonamide and its nontoxic salts for preparing medicinal agents used for prophylaxis or treatment of ischemic, reprefusion and functional damages of transplanted organs. Invention provides prophylaxis such complications as delayed function of transplant arising in transplantation of organs.

EFFECT: valuable medicinal properties of medicinal agent.

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The present invention relates to the use of (R)-ibuprofenonline and its non-toxic salts for the preparation of drugs intended for the treatment and prevention of functional damages resulting from the rejection of transplantable organs.

Background of the invention

Transplantation of organs, especially the type of kidney, took a significant step forward in the last few decades with the introduction of improved modes of immunosuppression, conservation bodies and pre - and post-operative care. However, there is a wide scope for improvement, particularly in relation to improving long-term results. The initial ischemic/reperfusion damage, which is secondary to organ removal, storage and transplantation, is associated with subsequent deterioration and failure of the transplant. When kidney transplantation is the lack of immediate allograft function is known as delayed graft function (oft), which in the most General sense can be defined as the need for dialysis within the first week after transplantation. Delayed graft function is the most frequent complication when allotransplantation directly in the post-transplantation period, affecting more than 50% of primary cadaveric tra is of plantation kidney (A.O. Ojo et al. Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63, 7:968-974, 1997; Koning O.H.J. et al. Risk factors for delayed graft function in three bands : cadaveric kidney transplantation. Transplantation 63, 11:1620-1628, 1997). Although oft allograft may have different etiology, collected experimental and clinical evidence that postischemic reperfusion injury to the allograft may be an important key event responsible for the manifestation of the oft. There is a General opinion that the combination oft and early rejection is a strong indicator of low survival rates of transplant, and that the manifestation of the oft leads to an increased risk of acute rejection (Carmellini M. et al. Delayed graft function adversely affects one-year graft survival of three bands : cadaveric renal transplants. Transplant Proc 28, 1:359-360, 1996). Currently it is generally accepted that the pathogenesis of ischemic/reperfusion injury involved cytokines and, in particular, surface adhesion molecules, the expression of which initiates the attachment of inflammatory cells. Data on experimental animals with acute renal ischemia showed that immediately after injury increases the factor intercellular adhesion-1 (ICAM-1) and that are consistently infiltration of neutrophils, T cells and macrophages. Interleukin-8 (IL-8), a cytokine with strong effect of chemotaxis of polymorphonuclear cells (PMA) can be generated by stimulation of endothelial the notches, followed by reperfusion, and can give a contribution to the complex processes, ultimately leading to delayed graft function due to ischemic/reperfusion injury. Recently discovered new drugs that selectively inhibit the biological activity of IL-8. Among them, R(-)-N-[2-(4-isobutylphenyl)propanol]methanesulfonamide, hereinafter referred to as (R)-ibuprofenonline, and its salt L-lysine (hereinafter referred to as DF V), have been described in the published international patent application WO 00/24710 as selective in vitro inhibitors of the chemotaxis of neutrophils, due to IL-8 and therefore extremely suitable for the treatment of neutralization pathologies.

Currently, it is shown that DF 1681B inhibits chemotaxis in vivo in mice and inhibits the infiltration PMA on various models of ischemic/reperfusion injury in mice and rats.

However, according to the current situation in the art, selective inhibition of chemotaxis due to IL-8, is not sufficient to protect the transplanted organ from functional damage. In fact, in the scientific literature describes numerous factors involved in the etiology of delayed functional recovery of transplanted kidneys, among which the factor IL-8 is not the C is definitely one of the most important: for example, it is reported (Kutukculer N. et al. Transplantation, 1995, 59(3), 333-40), IL-8, together with IL-3 and soluble CD-23, are not diagnostically significant for rejection, in any case, high levels of these markers is also present in patients, which was performed the transplant, and which was completely absent from the phenomenon of exclusion. Moreover, in addition to IL-3, IL-8, and CD-23, in the scientific literature describes numerous other Pro-inflammatory molecules as a possible pathogenic factors delay functional recovery of transplanted organ, such as, for example, IL-1 beta, IL-2, IL-10, IL-17, MIP-1 beta, MCP-1 and others. From literature data it follows that for inhibiting reperfusion injury in organ transplantation, especially, such as the kidneys, the necessary non-specific inhibitor of the inflammatory response or, at least, mobilization of leukocytes.

Description of the invention

Currently, it has been unexpectedly found that, contrary to expectations based on the previously discussed level of this technology, (R)-ibuprofenonline and its salt lysine (L-lysine or DL-lysine) is effective in protection against functional damage by transplantation of an organ, especially of such as the kidneys. Moreover, it was shown that the same active drugs to prevent ischemic/reperf the precise damage.

This activity was demonstrated in an experimental model of kidney transplantation in rats, which is discussed in more detail below, and in which DF1681B demonstrated activity in preserving renal function immediately after ischemic/reperfusion damage, which followed syngeneic transplantation of kidney, also preventing the infiltration of leukocytes in the transplant occurring after postischemic reperfusion.

Were used adult male rats Lewis (RT11) (Charles River, Caico Italia S.p.A, Italy). All animals had free access to food and water. The study was conducted on the model of syngeneic transplantation of kidneys with the use of these rats as donors and recipients of transplants. Animals donors were shot by leptotene. The left kidney was prepared by separation of the ureter from the ligaments. The renal artery was separated from the honorary Vienna by dissection. Kidney donor and the ureter were removed "en bloc" and washed Belzer (UW)containing 1000 u/ml heparin. Then the kidney was placed in an ice Belzer solution (UW) for 4-6 hours (cold ischemia) before transplantation. The recipients were prepared by removal of the left kidney. Therapy animals using DF V described below. Transplants of kidneys before transplantation were washed with saline solution. Was imposed anastomosis con the t in the end, as between the renal arteries and between the veins of the recipient and donor. The clamps on the vessels were removed after 30 minutes (heat ischemia). The ureter of the donor and recipient were connected end to end. Then right native kidney was removed. Animals were placed in individual metabolic chambers for measurement of the daily output of urine as an indicator of recovery of renal function. Kidney function was assessed after 16 and 24 hours by measuring the concentration of creatinine in plasma. Animals were euthanized 24 hours after transplantation. The transplant kidney was removed, divided into thin slices and placed in a solution Dubosq-Brazil for standard histological analysis by light microscopy. In addition, the remaining fragments of the kidneys were frozen in liquid nitrogen and used for immunohistochemical analysis of infiltration of inflammatory cells (polymorphonuclear cells, MHC II positive cells). Addressed the following experimental groups:

Group 1 (n=3) rats-recipients of transplant kidneys subjected to 4-hour cold ischemia, and received as a therapy DF V inhibitor of IL-8.

Group 2 (n=3) rats-recipients of transplant kidneys subjected to 4-hour cold ischemia, and received as a therapy medium.

Group 3 (n=3) rats-recipients of the graft is the kidney, subjected to 6 hours of cold ischemia, and received as a therapy DF V inhibitor of IL-8.

Group 4 (n=3) rats-recipients of transplant kidneys subjected to 6 hours of cold ischemia, and received as a therapy medium.

The recipients were prepared the day prior to the experiment (15 mg/kg subcutaneously). Animals received an intravenous injection DF V (15 mg/kg) immediately prior to reperfusion of the transplanted kidney. Additional use of the drug (15 mg/kg subcutaneously) was made 2 hours after transplantation. The control group of animals was introduced to the media at the same time, using the same methods apply as for animals that received therapy DF W.

In addition, DF 1681B demonstrated activity in maintaining the functions of the kidney immediately after ischemic/reperfusion damage following allotransplantation kidney.

Addressed the following experimental groups:

Group 1 (n=9) rats Brown Norway, the recipient of the transplant kidney Lewis rats subjected to 6-hour cold ischemia, received as a therapy medium.

Group 2 (n=5) rat, Brown Norway, the recipient of the transplant kidney Lewis rats subjected to 6-hour cold ischemia who received therapy DF V inhibitor of IL-8.

The recipients were prepared the day before ek is periment (20 mg/kg subcutaneously). Animals received an intravenous injection DF V (20 mg/kg) immediately before reperfusion transplanted kidney. Additional use of drugs (20 mg/kg subcutaneously) was made 2 hours after transplantation. The control group of animals was introduced to the media at the same time, using the same methods apply as for animals that received therapy DF W.

Data were analyzed using non-parametric test of Kruskal-Wallis (Well-Wallis) for multiple comparisons, or test Tukey-Cicchetti.

Results

In the drawing and table 1 shows the concentration of creatinine in the plasma of rats Lewis after 16 and 24 hours after receiving syngeneic transplant kidneys subjected to 4 - and 6-hour cold ischemia. In animals that have received a kidney from a 4-hour ischemia, creatinine plasma increased after surgery, reaching values that after 16 and 24 hours were significantly higher than the values observed in the control group of animals that received syngeneic transplant kidney, not subjected to ischemia. Therapy with DF V protected animals from damaging the kidney functions, values of plasma creatinine after 24 hours is comparable with the same values in animals that received syngeneic transplant kidney, not subjected to ischemia (table 2). As expected, the 6-hour ish is MIA caused more severe damage to the kidney functions, as evidenced by significantly higher levels of creatinine in the plasma than in animals that received syngeneic transplant kidney after 4 hours of ischemia (drawing and table 1). DF 1681B significantly reduced the concentration of plasma creatinine levels, which, however, were still significantly higher than that measured in animals that received syngeneic transplant kidney, not subjected to ischemia.

More detailed immunohistological evaluation of infiltration of cells in the transplanted kidney, produced 24 hours after transplantation are summarized in table 2. In kidneys subjected to 4-hour cold ischemia, was found a large number of granulocytes in interstitium, and, to a lesser extent, intra - and periglomerular areas. The drug reduces PMN infiltration and reduces changes in tubules caused by ischemia/reperfusion. The use of an inhibitor of IL-8 significantly, but not significantly, reduced the number of granulocytes in intraglomerular areas. After 6 hours of ischemia cellular infiltrates increased in comparison with the values after 4 hours of ischemia is not everywhere. At the same time, the number of interstitial inflammatory cells was significantly reduced (p<0,01) with DF 1681B. As for neutrophils, the number of MHC II was lower in kidney transplanted after 4 - and 6-hour ischemia. Cells on which the detected mainly in interstitium (table 3), and the inhibitor of IL-8 did not affect their number.

Histological evaluation of glomerular, interstitial and tubular damage observed in slices of kidney, transplanted after 4 - and 6-hour cold ischemia and investigated within 24 hours after transplantation, presented in table 4. Using the method of light microscopy, the transplanted kidneys were characterized by degenerative changes in the tubular epithelial cells, mainly in the proximal tubules, manifested in the form of swelling of the cells, vacuolization and necrosis (table 4). DF V weakened, but not normalized changes in tubules after 4 hours of ischemia. In addition, all kidneys were found tubular cylinders. Focal ischemic changes in the glomeruli were registered only in the kidney subjected to 6-hour ischemia, and they were prevented when using DF 1681B.

Thus, DF 1681B capable of preventing renal dysfunction, secondary to cold ischemia. Connection reduces the number of cellular infiltrates and weakens changes tubules caused by ischemia. Data were confirmed by other animals. 6-hour ischemia causes a sharp deterioration of renal function.

Effect DF 1681B on the concentration of serum creatinine in rats Brown Norway after 16 and 24 hours after receiving the Oia allogeneic transplant kidneys from Lewis rats are presented in table 5. Significant prevention of increase of level of serum creatinine was observed equally in all rats that received therapy with 20 mg/kg

The data presented above clearly show that (R)-ibuprofenonline or its salt lysine (L-lysine or DL-lysine) can be successfully used in medical practice.

For this purpose, (R)-ibuprofenonline or its salt of lysine can be appropriately included in the pharmaceutical preparations, which can be used for oral, parenteral, rectal, or local way, before or after transplantation. Examples of acceptable dosage forms include capsules, tablets, suppositories, syrups, drops, suspensions, emulsions, sterile solutions for injection, vials containing sterile lyophilized powder for injection dosage form with controlled release of drugs, transdermal dosage forms, ointments and the like. Methods and media used for the preparation of such dosage forms is fairly standard, as described in Remington''s Pharmaceutical Sciences Handbook, Mack Pub. Co.,New York, USA, XVII Ed.

The pharmaceutical compositions are preferably applied in the form containing a unit dosage of 1 to 500 mg, more preferably from 10 to 100 mg of (R)-ibuprofenonline or equivalent to the number of its lysine salt. Can also be considered a higher dose depending on the circumstances. The application can be single or separated into many techniques, distributed within a suitable period of time, usually several days before the operation to several weeks after. (R)-ibuprofenonline or a suitable salt, such as salt lysine, can, if necessary, to be used in combination with other drugs with additional information, or, in any case, a useful effect, for example, anti-inflammatory drugs, immunosuppressants, analgesics, anti-thrombotic agents.

Example 1

Obtaining (R)-ibuprofenonline.

A suspension of R (-)-2-(4-isobutylphenyl)propionic acid (R-ibuprofen, 4 g, 0.019 mol) in thionyl chloride (7,4 ml) is boiled in a flask with reflux for 4 hours, then leave to cool at room temperature.

The excess thionyl chloride is evaporated in vacuum.

Trace amounts of thionyl chloride is removed by washing the precipitate twice with a few drops of dry dioxane and viparita the solvent in vacuo. of 4.66 g (0.019 mol) R(-)-2-(4-isobutylphenyl)Propionaldehyde receive in the form of a yellow oily liquid, which was dissolved in a few ml of anhydrous tetrahydrofuran (THF).

Separately, methanesulfonamide (2.3 g, 0,0243 mol) relax the Ute to a suspension of tert-butoxide potassium (2,73 g, 0,0244 mol) in anhydrous THF (28 ml) and the mixture is stirred for 30 minutes at room temperature. Then add with stirring a solution of R(-)-2-(4-subutility)propionitrile (of 4.66 g, 0.019 mol), the receipt of which is described above, the content of the reaction mixture is stirred over night at room temperature.

Selected inorganic salt is filtered off, the solvent is evaporated in vacuum and the oily residue is divided between CH2Cl2(30 ml) and a saturated solution of monopotassium phosphate. The organic phase is washed with water (2×10 ml) and the aqueous phase extracted with CH2Cl2(2×10 ml). The combined organic extracts are dried over Na2SO4and the solvent is evaporated, then the solution of the oily residue in anhydrous Meon (10 ml) add two droplets of concentrated sulfuric acid for the esterification to the methyl ether of trace amounts of unreacted R(-)-2-(4-isobutylphenyl)propionic acid. The mixture was incubated over night at room temperature, the solvent is carefully evaporated in vacuo, the residue is divided between water (10 ml) and methylene chloride (25 ml). The aqueous phase is removed, and the organic phase is extracted with a saturated solution of NaHCO3(2×20 ml). The main phases are combined acidified with conc. HCl and extracted with CH2Cl23× 15 ml). After the usual washing to neutrality combined organic extracts are dried over Na2SO4and the solvent is evaporated in vacuum to obtain 1.86 g (0,0066 mol) R (-)-N-[2-(4-isobutylphenyl)propionyl]methanesulfonamide: melting point 103-105°C (decomp.); [α]D=-68 (C=1; CH3OH);1H-NMR (DMSO-d6) δ and 7.3 (d, 2H, J=8 Hz); to 7.09 (d, 2H, J=7 Hz); 3.42 points (kV, 1H, J=8 Hz); 2,8 (s, 3H); of 2.45 (d, 2H, J=7 Hz); of 1.55 (m, 1H); 1,3 (d, 3H, J=8 Hz), of 0.95 (d, 6N, J=7 Hz).

Example 2

Preparation of (R)-ibuprofenonline salt of L(+)-lysine (DF V).

A solution of L(+)-lysine (129 mg; 0.88 mmol) in water (1/3 ml) was added to a solution of R(-)-N-[2-(4-isobutylphenyl)propionyl]methanesulfonamide (250 mg; 0.88 mmol) in 1 ml of methanol. The solvent is evaporated, and the residue is treated with ethyl ether (5 ml) and stirred over night at room temperature. Selected crystalline product, highly hygroscopic, rapidly filtered under nitrogen atmosphere, washed on the filter with anhydrous ethyl ether and dried in vacuum at 50°C for 2 hours to obtain 360 mg of R(-)-N-[2-(4-isobutylphenyl)propionyl]methanesulfonamide salt of L(+)-lysine in the form of a pale yellow powder. [α]D=- 17, 3C° (C=1,15; CH3HE);1H-NMR (D2O) δ 7.30 (DD, 4H, J=8 Hz); of 3.77 (t, 1H, J=7 Hz); the 3.65 (q, 1H, J=7 Hz); 3,05 (m, 5H); 2,52 (d, 2H, J=7 Hz); of 1.92 (m, 2H); to 1.75 (m, 2H); 1,50 (m, 3H); of 1.40 (d, 3H, J=7 Hz); 0,90 (6N, d, J=7 G IS).

1. The use of (R)-ibuprofenonline or its non-toxic salts for the preparation of drugs for the prevention or treatment of ischemic/reperfusion injury of transplanted organs.

2. The use of (R)-ibuprofenonline or its non-toxic salts for the preparation of drugs for the prevention or treatment of functional damage resulting from reactions of rejection of transplanted organs.

3. The use according to claim 1 or 2, in which a non-toxic salt is a salt of L-lysine or DL-lysine.

4. The use according to claim 3, in which a non-toxic salt is a salt of L-lysine.

5. The use according to any one of claims 1 to 4, in which these transplanted organs are transplanted kidneys.



 

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