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WO1997037649A1 - Technique de diminution de la nephrotoxicite - Google Patents

Technique de diminution de la nephrotoxicite Download PDF

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Publication number
WO1997037649A1
WO1997037649A1 PCT/US1997/005292 US9705292W WO9737649A1 WO 1997037649 A1 WO1997037649 A1 WO 1997037649A1 US 9705292 W US9705292 W US 9705292W WO 9737649 A1 WO9737649 A1 WO 9737649A1
Authority
WO
WIPO (PCT)
Prior art keywords
accordance
reducing nephrotoxicity
nephrotoxicity
reducing
therapeutic agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1997/005292
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English (en)
Inventor
Helmut Kropp
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9612059.7A external-priority patent/GB9612059D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU25565/97A priority Critical patent/AU2556597A/en
Publication of WO1997037649A1 publication Critical patent/WO1997037649A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine

Definitions

  • a method of reducing nephrotoxicity in a mammalian patient receiving a primary therapeutic agent comprises administering to said patient a dehydropeptidase inhibitor in an amount which is effective for reducing nephrotoxicity.
  • the present invention relates to a method of reducing the nephrotoxicity of drugs in patients.
  • Numerous drugs are known to cause nephrotoxic side effects when administered to patients. This serious side effect is a limiting factor in the use of these potent medications, so much so that the use of nephrotoxic medications is usually restricted by clinicians to those patients where withholding the drug is more serious than the risk of nephrotoxicity or harm which accompanies the reaction or adverse effect.
  • the present invention thus serves to shift the balance toward facilitating the use of these potent medications, while reducing the incidence and severity of nephrotoxicity.
  • Nephrotoxicity is typically seen clinically as a decrease in renal function, causing a rise in serum creatinine (SC) and/or blood urea nitrogen (BUN) levels. Ordinarily a clinician upon noting a rise in SC or BUN will reduce the dosage or eliminate altogether any drugs from the regimen used which are known to cause nephrotoxicity. This may significantly worsen the primary condition of the patient, since limited secondary treatments for the underlying disease may be available. Reducing nephrotoxicity of primary therapeutic agents includes the treatment of patients before or after a nephrotoxic reaction is observed.
  • Administration of the DHP inhibitor can be undertaken with or without the nephrotoxic agent, i.e., the separate or combined administration of the DHP inhibitor and primary therapeutic agent in the same or different pharmaceutical compositions, at the same or different times.
  • the same or different modes of administration for the nephrotoxic drug and the DHP inhibitor are also contemplated.
  • the nephrotoxic drug may be one which is administered intravenously, and the DHP inhibitor may be administered by injection (IM or IV) or orally by mouth. All such combined methods of administration are included in the present invention.
  • the primary therapeutic agent is a drug which causes a reduction in renal function in some patients, which can ordinarily be identified and measured by conventional means, e.g., rise in serum creatinine or blood urea nitrogen (BUN). Examples of primary therapeutic agents which fall within this category are numerous.
  • Primary therapeutic agents are drugs which are recognized to be common causes of nephrotoxicity, when used in therapeutic or higher doses, and include immunosuppressants, antiinfectives and chemotherapeutics used to treat cancer.
  • immunosuppressants known to cause nephro ⁇ toxicity are cyclosporine, mycophenolate and related compounds. Cyclosporine is the preferred immunosuppressant which is used in combination with a DHP inhibitor. Dosages of the immunosuppressant are conventional or increased slightly as determined by the clinician in view of the patient's overall tolerance of these medications.
  • a primary indication for the present method of treatment involves immunosuppression in conjunction with organ or tissue trans ⁇ plantation.
  • Immunosuppressants are regularly used in these procedures to reduce the likelihood of transplant rejection, and a primary limiting factor in the use of the immunosuppressants in the past has been the incidence and severity of nephrotoxicity of the immunosuppressant compounds.
  • the present invention thus serves to facilitate the use of immunosuppressants in these patients.
  • the antiinfectives known to cause nephrotoxicity can be broadly categorized as antibacterials, anti-fungal/pneumocystis compounds, anti-tubercular compounds and anti-virals. These categories are descriptive only, since many of the compounds have activity in more than one area.
  • antibacterials include the aminoglycoside antibiotics, for example, gentamicin, kanamycin, tobramycin, amikacin and netilmycin. Such antibiotics are used routinely in hospitalized patients with susceptible infections, and a primary limiting factor in using these antibiotics has been the incidence and severity of nephrotoxicity.
  • Nephrotoxicity is a factor which is considered by the clinician when these drugs are used, particularly when prolonged administration is necessary.
  • antifungal/pneumocystis drugs which are used in connection with the present invention include amphotericin B, pentamidine, pentamidine isoethionate and atavaquone.
  • antiviral compounds which are used in connection with the present invention include acyclovir, AZT, 3TC, vidarabine, cidofovir (Vistide®), lamivudine, saquinavir and valacyclovir.
  • the antiinfective is a non-beta lactam.
  • Non-beta lactams include antiinfectives which do not contain a beta lactam ring, such as the penicillins, carbapenems, cephalosporins and the like. Beta lactam antibiotics are not generally associated with nephrotoxic reactions.
  • non-beta lactams include all of the antiinfectives recited above, and in particular, the following: gentamycin, tobramycin, amikacin, netilmycin, streptomycin, spectinomycin, vancomycin, polymixin B, lincomycin, metronidazole, neomycin, chloramphenicol and trimethoprim/sulfamethoxazole.
  • chemotherapeutic drugs which can be considered in connection with the present invention for use in the treatment of cancer include: doxorubicin, dauonrubicin, carmustine, cisplatnin, methotrexate, plicamycin, streptazocin, 5-fluorouracil, Novantrone®, mechlorethamine, melphelan, mercaptopurine, L-asparaginase, bicalutamide, taxol and anastrozole.
  • DHP inhibitors as a class are typified by cilastatin.
  • Cilastatin and related DHP inhibitors are disclosed, for example in U. S. Patent No. 4,668,504 issued to Kahan, et al. on May 26, 1987, which is incorporated herein by reference.
  • the nephroprotective dose of the DHP inhibitor used to decrease the incidence and severity of nephrotoxicity experienced upon the administration of primary therapeutic agents can be varied within wide limits, depending upon the severity of the nephrotoxic reaction, judged by the clinician in view of the recommended dosage range, the overall condition of the patient and other factors.
  • Representative (nephroprotective) dosages of the DHP inhibitor range from about 0.1 mg. per kg. to about 100 mg. per kg.
  • the DHP inhibitor can be given separate from the primary therapeutic agent which is implicated in the nephrotoxic reaction, or the drugs can be given in combination.
  • the compounds are formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • This invention also relates to a pharmaceutical composition which is comprised of a DHP inhibitor, alone or with a drug which is suspected of causing nephrotoxic reactions, and a pharmaceutically acceptable carrier.
  • Formulating these compositions typically involves mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the pharmaceutical carrier employed may be, for example, a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known in the art, such as glyceryl mono-stearate or glyceryl distearate, alone or with a wax.
  • the preparation can be in the form of a tablet, hard gelatin capsule, a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 0.025 mg to as high as about 1 g.
  • the preparation is typically in the form of a syrup, emulsion, soft gelatin capsule or nonaqueous liquid suspension.
  • Injectable aqueous or oil solutions or suspensions are prepared by dissolving the active ingredient in a suitable aqueous solution, optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including other agents.
  • a suitable aqueous solution optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including other agents.
  • the resulting solution may be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01 %).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • the method of treatment described herein is typically practiced by administering the DHP inhibitor orally or parenterally, preferably orally.
  • the term 'parenteral' as used herein includes intravenous, intramuscular and intraperitoneal administration.
  • the DHP inhibiting compound used in the present invention is useful in various pharmaceutically acceptable salt forms.
  • pharmaceutically acceptable salt refers to those salt forms which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.
  • Anions derived from inorganic or organic acids may be suitable for the preparation of salt forms of the DHP inhibitor.
  • Representative examples are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, bromide, citrate, camphorate, camphorsulfonate, chloride, digluconate, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolate, hydroxynaphthoate, 2- hydroxyethanesulfonate, iodide, lactate, lactobionate, malate, maleate, mandelate, methylenebis(salicylate), mucate, methanesulfonate, napadisylate, napsylate, pa
  • compositions for injection may be prepared in unit dosage form in ampoules or in multidose containers.
  • the compositions may take such forms as suspensions, solutions or emulsions, oily or aqueous in nature, and may contain various formulating agents, such as diluents, buffers, preservatives and the like. Hence, the compound is present in combination with these pharmaceutically acceptable carriers.
  • the active ingredient may be in the form of a powder, which can be reconstituted with a suitable carrier such as sterile water, normal saline and the like at the time of administration.
  • a suitable carrier such as sterile water, normal saline and the like at the time of administration.
  • the powder can be in lyophillized or non-lyophillized form.
  • Oral compositions are typically in the form of tablets, capsules, solutions or suspensions. Such compositions may likewise be packaged in unit dose or multidose containers.
  • the pharmaceutically acceptable carriers may be comprised of diluents, tabletting and granulating aids, lubricants, disintegrants, buffers, sweeteners, preservatives and the like.
  • compositions for human delivery per unit dosage may contain from about 0.01 % to about 99% of active material, the preferred range being from about 10-60%.
  • the composition will generally contain from about 15 mg to about 2000 mg of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of from about 250 mg to 1000 mg.
  • the unit dosage is usually the compound in a sterile water or saline solution or in the form of a soluble powder intended for solution.
  • a preferred weight ratio of the primary compound : DHP inhibitor in the combination compositions is about 1 :1.
  • the most preferred DHP inhibitor used in the present invention is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclo- propanecarboxamide)-2-heptenoic acid, (cilastatin) or a useful salt thereof.
  • the compound used in the present invention provide su ⁇ rising and unexpected safety benefits in that the nephrotoxicity of primary therapeutic agents is reduced upon administration of the DHP inhibitor. This not only renders normal dosages of these nephrotoxic drugs safer to use in the majority of seriously ill patients, but facilitates the use of higher dosages of these important drugs in patients that are critically ill.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur une technique visant à diminuer la néphrotoxicité consistant dans l'administration d'un inhibiteur de le déhydropeptidase (DHP).
PCT/US1997/005292 1996-04-04 1997-03-31 Technique de diminution de la nephrotoxicite Ceased WO1997037649A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU25565/97A AU2556597A (en) 1996-04-04 1997-03-31 Method of reducing nephrotoxicity

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1480696P 1996-04-04 1996-04-04
US60/014,806 1996-04-04
GB9612059.7 1996-06-10
GBGB9612059.7A GB9612059D0 (en) 1996-06-10 1996-06-10 A method of reducing nephrotoxicity

Publications (1)

Publication Number Publication Date
WO1997037649A1 true WO1997037649A1 (fr) 1997-10-16

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PCT/US1997/005292 Ceased WO1997037649A1 (fr) 1996-04-04 1997-03-31 Technique de diminution de la nephrotoxicite

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AU (1) AU2556597A (fr)
WO (1) WO1997037649A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2143429A1 (fr) * 2008-07-11 2010-01-13 Fundacion para la Investigacion Biomedica Del Hospital Gregorio Marañon Utilisation de cilastatine pour réduire la néphrotoxicité de différents composés
WO2015111666A1 (fr) * 2014-01-24 2015-07-30 味の素株式会社 Antagoniste de la mégaline
WO2017220810A1 (fr) 2016-06-24 2017-12-28 Fundación Para La Investigación Biomédica Del Hospital Gregorio Marañón Cilastatine pour une utilisation dans le traitement de la sepsie
WO2025093926A1 (fr) * 2023-11-02 2025-05-08 Saito Akihiko Procédé de minimisation ou d'élimination de la néphrotoxicité chez des patients subissant une chimiothérapie à base de cisplatine par administration séquentielle d'un agent protecteur suivi d'un agent toxique
EP4574146A1 (fr) 2023-12-18 2025-06-25 Telara Pharma S.L. Inhibiteurs de dhp-i destinés à être utilisés en tant que neuroprotecteurs et dans le traitement de maladies neuro-inflammatoires

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4668504A (en) * 1970-11-18 1987-05-26 Merck & Co., Inc. Use of substituted propenoates to prevent nephrotoxicity of certain antibiotics

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4668504A (en) * 1970-11-18 1987-05-26 Merck & Co., Inc. Use of substituted propenoates to prevent nephrotoxicity of certain antibiotics

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BONE MARROW TRANSPLANTATION, Volume 18, issued 28 March 1996, GRUSS et al., "Nephroprotective Effect of Cilastatin in Allogeneic Bone Marrow Transplantation. Results from a Retrospective Analysis", pages 761-765. *
CANCER RESEARCH, Volume 54, issued 15 November 1994, HANIGAN et al., "Inhibition of Gammaglytamyl Transpeptidase Activity by Acivicin in Vivo Protects the Kidney from Cisplatin-Induced Toxicity", pages 5925-5929. *
JAPANESE JOURNAL OF PHARMACOLOGY, Volume 66, issued 1994, HIROUCHI et al., "Preventive Effect of Betamipron on Nephrotoxicity and Uptake of Carbapenems in Rabbit Renal Cortex", pages 1-6. *
JOURNAL OF MEDICINAL CHEMISTRY, Volume 34, issued 1991, WU et al., "Targeting Renal Dipeptidase (Dehydropeptidase I) for Inactivation by Mechanism Based Inactivators", pages 1914-1916. *
TRANSPLANTATION PROCEEDINGS, Volume 21, Number 1, issued February 1989, HAMMER et al., "Reduction of Cyclosporin (CSA) Nephrotoxicity by Imipenem/Cilastatin After Kidney Transplantation in Rats", page 931. *
TRANSPLANTATION, Volume 57, Number 6, issued March 1994, MARKEWITZ et al., "Reduction of Cyclosporin-Induced Nephrotoxicity by Cilastatin Following Clinical Heart Transplantation", pages 865-870. *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2143429A1 (fr) * 2008-07-11 2010-01-13 Fundacion para la Investigacion Biomedica Del Hospital Gregorio Marañon Utilisation de cilastatine pour réduire la néphrotoxicité de différents composés
US20110165264A1 (en) * 2008-07-11 2011-07-07 Alberto Tejedor Jorge Use of cilastatin to reduce nephrotatoxicity of various compounds
US9216185B2 (en) * 2008-07-11 2015-12-22 Fundacion Para La Investigacion Biomedica Del Hospital Gregorio Maranon Use of cilastatin to reduce nephrotatoxicity of various compounds
US9522128B2 (en) 2008-07-11 2016-12-20 Fundacion Para La Investigacion Biomedica Del Hospital Gregorio Maranon Use of cilastatin to reduce the nephrotoxicity of different compounds
US9757349B2 (en) 2008-07-11 2017-09-12 Fundacion Para La Investigacion Biomedica Del Hospital Gregorio Maranon Use of cilastatin to reduce the nephrotoxicity of different compounds
WO2015111666A1 (fr) * 2014-01-24 2015-07-30 味の素株式会社 Antagoniste de la mégaline
JPWO2015111666A1 (ja) * 2014-01-24 2017-03-23 Ｅａファーマ株式会社 メガリン拮抗剤
US10420741B2 (en) 2014-01-24 2019-09-24 Ea Pharma Co., Ltd. Megalin antagonist
WO2017220810A1 (fr) 2016-06-24 2017-12-28 Fundación Para La Investigación Biomédica Del Hospital Gregorio Marañón Cilastatine pour une utilisation dans le traitement de la sepsie
WO2025093926A1 (fr) * 2023-11-02 2025-05-08 Saito Akihiko Procédé de minimisation ou d'élimination de la néphrotoxicité chez des patients subissant une chimiothérapie à base de cisplatine par administration séquentielle d'un agent protecteur suivi d'un agent toxique
EP4574146A1 (fr) 2023-12-18 2025-06-25 Telara Pharma S.L. Inhibiteurs de dhp-i destinés à être utilisés en tant que neuroprotecteurs et dans le traitement de maladies neuro-inflammatoires
WO2025132723A1 (fr) 2023-12-18 2025-06-26 Telara Pharma S.L. Inhibiteurs de dhp-i destinés à être utilisés en tant que neuroprotecteurs et dans le traitement de lésions neuro-inflammatoires de la voie visuelle

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Publication number Publication date
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