Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to the use of (R)-ibuprofen methanesulfonamide and non- toxic salts thereof for the preparation of medicaments for the treatment and prevention of functional injury resulting from rejection reactions of transplanted organs.
• DGF delayed graft function
• Delayed graft function is the most common allograft complication in the immediate posttransplant period, affecting up to 50% of primary cadaveric renal transplants (Ojo AO et al. Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63, 7:968-974, 1997; Koning OHJ et al. Risk factors for delayed graft function in cadaveric kidney transplantation. Transplantation 63, 11:1620-1628, 1997). Although different etiologies may cause DGF of implanted allograft, there is accumulating experimental and clinical evidence suggesting that post-ischemic reperfusion injury to allograft may represent the major key event responsible for the occurrence of DGF.
• Interleukin-8 IL-8
• PMN polymorphonuclear cells
• R (-)-N-[2-(4-Isobutylphenyl)propionyl]- methanesulfonamide hereinafter referred to as (R)-ibuprofen methanesulfonamide
• DF 168 IB L-lysine salt
• DF 168 IB has now been shown to inhibit chemotaxis in vivo in a mouse model and to inhibit PMN infiltration in different models of ischemia/reperfusion injury in mice and rats.
• IL-8 does not certainly appear as one of the most important: for example, IL-8, together with IL-3 and soluble CD 23, (Kutukculer N. et al, Transplantation, 1995, 59(3), 333-40) is reported to be of no diagnostic use for organ rejection given that, in any case, high levels of these markers were also present in transplant patients who were wholly free from rejection phenomena.
• RT11 Male Lewis rats (Charles River, Calco Italia S.p.A, Italy) were used. All animals were allowed free access to food and water. The study was performed in a syngeneic kidney transplant model using such rats as donor and graft recipients. Donor animals were anaesthetized with leptofen. The left kidney was prepared by freeing the ureter from the attachments. The renal artery was separated from the renal vein by dissection. The donor kidney and ureter were removed "en bloc” and flushed with Belzer (UW) containing 1000 U/ml of heparin. Then the kidney was placed in an iced Belzer (UW) solution for 4 - 6 hours (cold ischemia) until transplant.
• UW Belzer
• Recipients were prepared by removal of the left kidney. Animal treatment with DF 168 IB is summarized below. Kidney grafts were washed with saline solution before transplant. An anastomosis was created between the recipient and the donor renal artery as well as renal vein with end-to-end anastomosis. Vascular clamps were released after 30 minutes (warm ischemia). Donor and recipient ureters were attached end-to-end. The native right kidney was then removed. Animals were placed in individual metabolic cages for measurements of daily urine output as an index of renal function recovery. After 16 and
• kidney transplantation Twenty-four hours after kidney transplantation, the animals were sacrificed. The kidney graft was removed, cut in slices and put in Dubosq-Brazil solution for the analysis of conventional histology by light microscopy. Moreover, additional kidney fragments were frozen in liquid nitrogen and used for immunohistochemical analysis of inflammatory cell infiltrate (polymorphonuclear cells, MHC class II positive cells).
• Group 1 rats recipients of a kidney graft exposed to 4 hours cold ischemia and treated with the IL-8 inhibitor DF 1681B.
• Group 2 rats recipients of a kidney graft exposed to 4 hours cold ischemia and treated with the vehicle.
• Group 3 rats recipients of a kidney graft exposed to 6 hours cold ischemia and treated with the IL-8 inhibitor DF 168 IB.
• Group 4 rats recipients of a kidney graft exposed to 6 hours cold ischemia and treated with the vehicle.
• the recipients were pretreated the day before the experiment (15mg/kg s.c).
• the animals received an intravenous injection of DF 1681B (15mg/kg) immediately before reperfusion of the transplanted kidney. Additional administration of the compound (15mg/kg s.c.) was performed 2 hours after transplantation. Control animals were given vehicle at the same time points and using the same administration method as for animals treated with DF 1681B.
• DF 168 IB proved active in the preservation of renal function immediately after ischemia/reperfusion injury which follows kidney allotransplantation.
• the following experimental group of animals were considered:
• Results Figure 1 and table 1 show plasma creatinine concentrations in Lewis rats at 16 and 24 hours after receiving a syngeneic kidney transplant, pre-exposed to 4 and 6 hour cold ischemia.
• plasma creatinine increased after surgery reaching values that at 16 and 24 hours were significantly higher than values observed in a control group of animals receiving a non-ischemic syngeneic kidney transplant.
• Treatment with DF 1681B protected animals from renal function deterioration, the values of plasma creatinine at 24 hours being fairly comparable to those of animals receiving a non-ischemic syngeneic kidney transplant (table 2).
• the compound decreases the PMN infiltrate and attenuates the tubular variations induced by ischemia/reperfusion.
• Granulocyte count in the intraglomerular area was numerically but not significantly lowered by the IL-8 inhibitor.
• the cellular infiltrates did not consistently increase after 6 hour ischemia compared to values after 4 hour ischemia.
• interstitial inflammatory cells were significantly lowered (p ⁇ 0.01) by DF 1681B.
• neutrophils With respect to neutrophils, the number of MHC class II cells was lower in kidneys transplanted following 4 and 6 hour ischemia. Cells were detected mainly in the interstitium (table 3) and their number was not affected by the IL-8 inhibitor.
• DF 168 IB is thus able of preventing renal function impairment secondary to cold ischemia.
• the compound reduces the number of cellular infiltrates and attenuates tubular changes induced by ischemia. Data have been confirmed in other animals. 6 hour ischemia induces a very severe renal function impairment.
• the effect of DF 168 IB on serum creatinine concentrations in Brown Norway rats at 16 and 24 hours after receiving an allogeneic kidney transplant from Lewis rats is shown in Table 5. A significant prevention of increased serum creatinine levels was observed consistently in all rats receiving 20 mg/kg of the treatment.
• the above data clearly show how (R)-ibuprofen methanesulfonamide or its lysine salt (L-lysine or DL-lysine) can be advantageously used in medical practice.
• (R)-ibuprofen methanesulfonamide or its lysine salt will be suitably formulated in pharmaceutical compositions which may be administered in oral, parenteral, rectal or topic route, before and after transplantation surgery.
• suitable formulations include capsules, tablets, suppositories, syrups, drops, suspensions, emulsions, injectable sterile solutions, vials of sterile lyophilized powders for injection, controlled release formulations, transdermal formulations, ointments and the like.
• the techniques and carriers used for the preparation of such formulations are wholly conventional, as described for example in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., New York, USA, XVII Ed.
• the pharmaceutical formulations are to be preferably administered in unit dosage forms containing from 1 to 500 mg, more preferably from 10 to 100 mg, of (R)-ibuprofen methanesulfonamide or the equivalent of its lysine salt. Higher doses can also be considered, depending on the circumstances.
• the administration can be a single one or divided into more administrations spread over a suitable time period, normally from some day before surgery until some weeks afterwards.
• (R)-Ibuprofene methanesulfonamide or an acceptable salt thereof, such as lysine salt can, if necessary, be administered in combination with others drugs of complementary or, in any case, useful action, for instance anti-inflammatory agents, immunosuppressants, analgesics, antithrombotic agents.
• Example 1 Example 1

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• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Immunology (AREA)
• Urology & Nephrology (AREA)
• Cardiology (AREA)
• Emergency Medicine (AREA)
• Heart & Thoracic Surgery (AREA)
• Vascular Medicine (AREA)
• Transplantation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicinal Preparation (AREA)

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• 2001
  • 2001-02-02 IT IT2001MI000206A patent/ITMI20010206A1/it unknown
• 2002
  • 2002-01-30 EP EP02719742A patent/EP1355641B1/en not_active Expired - Lifetime
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  • 2002-01-30 DK DK02719742T patent/DK1355641T3/da active
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• 2003
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