WO2003055480A1 - Produits a utiliser dans une therapie immunosuppressive et renfermant de l'acide lipoique et un inhibiteur de la calcineurine - Google Patents

Produits a utiliser dans une therapie immunosuppressive et renfermant de l'acide lipoique et un inhibiteur de la calcineurine Download PDF

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Publication number
WO2003055480A1
WO2003055480A1 PCT/FI2002/000542 FI0200542W WO03055480A1 WO 2003055480 A1 WO2003055480 A1 WO 2003055480A1 FI 0200542 W FI0200542 W FI 0200542W WO 03055480 A1 WO03055480 A1 WO 03055480A1
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WO
WIPO (PCT)
Prior art keywords
lipoic acid
cyclosporine
calcineurin inhibitor
calcineurin
tacrolimus
Prior art date
Application number
PCT/FI2002/000542
Other languages
English (en)
Inventor
Eero Mervaala
Original Assignee
Pharmaconsult Oy
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
Application filed by Pharmaconsult Oy filed Critical Pharmaconsult Oy
Priority to AU2002345121A priority Critical patent/AU2002345121A1/en
Publication of WO2003055480A1 publication Critical patent/WO2003055480A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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

Definitions

  • the invention relates to products containing lipoic acid and a calcineurin inhibitor as a combined preparation for simultaneous, separate or sequential use in imrnunosuppressive therapy.
  • the invention also relates to the use of lipoic acid for the manufacture of a medicament for the prevention and treatment of the adverse effects of calcineurin inhibitors, such as cyclosporine and tacrolimus.
  • Further objects of the invention are pharmaceutical compositions comprising lipoic acid and a calcineurin inhibitor, and a method for the treatment and prevention of the adverse effects of calcineurin inhibitors.
  • Calcineurin inhibitors such as cyclosporine and tacrolimus
  • Calcineurin inhibitors have a selective inhibitory effect on T lymphocytes suppressing the early cellular response to antigenic and regulatory stimuli.
  • Both cyclosporine and tacrolimus bind to their cytoplasmic receptors, called cyclophilin and FKBP, respectively.
  • Cyclophilin-cyclosporine and FKBP-tacrolimus complexes associate with calcineurin at the endofacial surface of T cells and inhibit calcineurin catalytic activity (Liu et al, Cell 1991;66:807-815). As a consequence, the nuclear translocation of nuclear factor of activated T cells (NFAT) and the induction of several cytokine genes are not initiated.
  • NFAT nuclear factor of activated T cells
  • Calcineurin inhibitors have dramatically improved long-term survival after organ transplantations.
  • cyclosporine as well as tacrolimus have been shown to markedly increase blood pressure, deteriorate renal function, and induce lipid disorders (Paul, Transplant Proc 2001;33:2089-2091).
  • hypertension, nephrotoxicity, and hyperlipidemia are very common side effects during CsA and tacrolimus treatments, and these side effects may also contribute to the increased risk of cardiovascular morbidity and mortality after organ transplantation.
  • Alpha-lipoic acid (6,8-thioctic acid) is a sulfur-containing substance that is readily converted to and from its reduced form, dihydrolipoic acid. It acts as a coenzyme in 5 mitochondrial reactions that lead to ATP formation. More specifically, alpha-lipoic acid is involved in the decarboxylation of pyruvate and some other alpha-keto acids. Alpha-lipoic acid is considered to be extremely safe in the amounts utilized clinically. During more than three decades of scientific research and clinical usage no serious adverse effects have been reported as a consequence of alpha-lipoic acid 0 supplementation, when used at daily doses from 25 mg to 1800 mg.
  • alpha-lipoic acid Clinical applications for alpha-lipoic acid include, for example, the following conditions: diabetic polyneuropathy, cataracts, glaucoma, ischemia-reperfusion injury, and Amanita mushroom poisoning. Because of its unique characteristics alpha-lipoic acid is likely to have therapeutic application in a wide range of additional clinical 5 conditions and it has also shown great promise, for example, in the treatment of
  • Alpha-lipoic acid has recently gained considerable attention as an endogenous and universal antioxidant that is readily absorbed from an oral dose.
  • Alpha-lipoic acid o and its reduced form, dihydrolipoate are potent natural antioxidants both in fat and water-soluble media.
  • Lipoic acid reacts with superoxide, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen, and thereby protects against increased oxidative stress. Lipoic acid also effectively strengthens the antioxidant network of the human body by recycling vitamin C, vitamin E, and by increasing intracellular glutathione concentrations.
  • 'lipoic acid' is intended to mean alpha-lipoic acid, which is a chiral molecule known also as thioctic acid; 1,2- dithiolane-3-pentanoic acid; l,2-dithiolane-3 -valeric acid; 6,8-thioctic acid.
  • the term covers the racemic mixture as well as any other (non 50/50) mixture of the enantiomers including substantially pure forms of either the R-(+) or the S-(-) enantiomer.
  • pharmaceutically acceptable salts e.g.
  • Lipoic acid Na and K salts
  • amides, esters, and metabolites of the acid the reduced form of lipoic acid (dihydrolipoic acid) and naturally occuring forms of lipoic acid, such as lipoamide and lipoyllysine.
  • Lipoic acid prevents the development of cyclosporme-induced renal damage.
  • Lipoic acid prevents the development of cyclosporine-induced hypertension.
  • Lipoic acid prevents the development of cyclosporine-induced increase in serum total cholesterol concentration.
  • Lipoic acid prevents the development of cyclosporine-induced increase in serum LDL-cholesterol concentration.
  • Lipoic acid prevents the development of cyclosporine-induced increase in serum triglyceride concentration.
  • the invention is directed to products containing lipoic acid and a calcineurin inhibitor as a combined preparation for simultaneous, separate or sequential use in immunosuppressive therapy.
  • a further object of the invention is the use of lipoic acid for the manufacture of a medicament for the prevention and treatment of the adverse effects of calcineurin inhibitors.
  • Another object of the invention is the use of lipoic acid and a calcineurin inhibitor as a combination for the manufacture of a medicament for therapeutic application as an immunosuppressant.
  • a still further object of the invention is a pharmaceutical composition comprising lipoic acid and a calcineurin inhibitor, preferably together with pharmaceutically acceptable carriers and adjuvants.
  • the invention is also directed to a method for the treatment and prevention of the adverse effects of calcineurin inhibitors in a mammal, said method comprising administering to said mammal lipoic acid in an amount ranging preferably from 25 mg to 1800 mg per day, even more preferably in an amount ranging from 600 to l o 800 mg per day, and preferably in an amount not exceeding the level of 350 mg/kg or 5% of the dry weight of the diet.
  • the calcineurin inhibitor is cyclosporine or tacrolimus, preferably cyclosporine, such as cyclosporine A, or a biologically 15 active metabolite of cyclosporine or tacrolimus.
  • Preferred pharmaceutical compositions according to the invention may be for example in the form of pharmaceutical tablets, capsules, injection solutions, eye drops or ointments.
  • the pharmaceutically acceptable carriers and adjuvants and 2 o their amounts can easily be selected by a person skilled in the art.
  • Lipoic acid may be administered together with the calcineurin inhibitor in a single dosage form, for instance in a capsule containing both agents, or lipoic acid and the calcineurin inhibitor may be administered in separate dosage forms.
  • a single dosage form for instance in a capsule containing both agents, or lipoic acid and the calcineurin inhibitor may be administered in separate dosage forms.
  • the calcineurin inhibitor may be administered intravenously, orally, transdermally, or topically, while lipoic acid is administered orally, intravenously, transdermally or topically.
  • lipoic acid is administered simultaneously with the calcineurin
  • lipoic acid as part of the diet at the level of ranging from 0.005% to 5% of the dry weight of the diet, preferably at the level of 0.1% to 0.5% of the dry weight of the diet, while the calcineurin inhibitor is administered in separate usual dosage forms.
  • Lipoic acid may also be administered in the form of a dietary supplement or as a food ingredient. It may also be administered in separate doses several hours (for example up to 6 hours) 5 before or after the administration of the calcineurin inhibitor.
  • lipoic acid in amounts such as 25-1800 mg/d, corresponding in a 70-kg adult a daily dose of ranging from 0 0.3 to 25 mg/kg.
  • the upper limit of the amount of lipoic acid is of minor importance, and based on data from the experimental studies may be as high as 350 mg/kg per day.
  • Cyclosporine and tacrolimus are typically used at doses ranging from 2 to 15 mg/kg, and 0.05 to 0.3 mg/kg, respectively.
  • the preferred ratio of cyclosporine to lipoic acid is thus 5 from about 2:350 to 15:0.3, more preferably from about 2:25 to about 15:3.
  • the preferred ratio of tacrolimus to lipoic acid is from about 0.05:350 to 0.3:0.3, more preferably from about 0.05:25 to about 0.3:3.
  • Lipoic acid proposed for use in accordance with the present invention allows to o avoid the undesired side effects induced by calcineurin inhibitors, when administered before the administration of the calcineurin inhibitor, simultaneously therewith or thereafter. Even more surprising is that lipoic acid produces this effect upon administration spread over a prolonged period of time before and after administration the calcineurin inhibitor. 5
  • the spontaneously hypertensive rat provides a suitable model for examining the effects of various dietary factors or drugs on, among other things, on blood o pressure and renal function and/or morphology.
  • SHR spontaneously hypertensive rat
  • Group 1 SHR control group. During the 6-week experimental period these rats received a commercially available rodent diet (R36, Finnewos, Finland) containing all the essential nutrients, also including adequate levels of the mineral elements and vitamins to maintain normal body function. Systolic blood pressure increased in this group to the level of 180 ⁇ 6 mm Hg during the 6-week experimental period. The degree of cardiac hypertrophy, i.e. the pathological increase of the weight of the heart, was estimated by the heart weight-to-body weight ratio (mg/g). In the
  • SHR control group the average cardiac hypertrophy index was 3.795 ⁇ 0.232 mg/g.
  • the degree of renal damage was assessed by analyzing the 24-hour urinary excretion of albumin by a commercially available rat albumin ELISA kit (Celltrend, Germany). This technique has generally considered as extremely reliable and sensitive method for detection of renal dysfunction.
  • albumin measurements urinary samples were collected in rats kept for 24 hours in metabolic cages. Urine volumes were measured gravimetrically, and the urine samples were stored at -80°C before assayed.
  • the 24-hour albuminuria in SHR control group was 557 ⁇ 170 ⁇ g/d.
  • Serum lipids from the samples taken at the end of the experiment were analyzed by an accredited laboratory, United Laboratories Ltd., Helsinki, Finland (Hitachi 912 Automatic Analyzer, Hitachi Ltd., Tokyo, Japan). Serum total cholesterol was determined with an enzymatic method (Boehringer Mannheim GPO-PAP-method), serum LDL-cholesterol with an enzymatic direct method (Boehringer Mannheim
  • Systolic blood pressure increased markedly in this group to the level of 243 ⁇ 6 mm Hg (p ⁇ 0.05 compared to SHR control group).
  • Table 1 Effects of alpha-lipoic acid on blood pressure, cardiac hypertrophy, albuminuria, and concentrations of serum total cholesterol, LDL-cholesterol and triglycerides in cyclosporine-treated SHR on high sodium for 6 weeks. Data are presented as means ⁇ SEM. Statistically significant differences in mean values were tested by ANONA and the Tukey's test. The differences were considered significant when p ⁇ 0.05. The data were analyzed using SYSTAT statistical software (SYSTAT Inc, Evanston, IL, USA). * denotes p ⁇ 0.05 between CsA group and Control group; ⁇ denotes p ⁇ 0.05 between CsA group and CsA+LA group.
  • Serum triglycerides 0.92 + 0.097 1.24 ⁇ 0.18 * ⁇ 0.59 + 0.072 0.01

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Food Science & Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Transplantation (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des produits renfermant de l'acide lipoïque et un inhibiteur de la calcineurine présentés sous la forme d'une préparation combinée destinée à une utilisation simultanée, distincte ou séquentielle dans une thérapie immunosuppressive. L'invention concerne également l'utilisation d'acide lipoïque dans la fabrication d'un médicament destiné à la prévention et au traitement d'effets indésirables induits par des inhibiteurs de la calcineurine. L'invention concerne enfin des compositions pharmaceutiques renfermant de l'acide lipoïque et un inhibiteur de la calcineurine, ainsi qu'un procédé de traitement et de prévention d'effets indésirables induits par des inhibiteurs de la calcineurine.
PCT/FI2002/000542 2001-12-21 2002-06-19 Produits a utiliser dans une therapie immunosuppressive et renfermant de l'acide lipoique et un inhibiteur de la calcineurine WO2003055480A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002345121A AU2002345121A1 (en) 2001-12-21 2002-06-19 Products for use in immunosuppressive therapy containing lipoic acid and a calcineurin inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI20012565A FI20012565A (fi) 2001-12-21 2001-12-21 Immunosuppressiivisessa terapiassa käytettäviä tuotteita
FI20012565 2001-12-21

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WO2003055480A1 true WO2003055480A1 (fr) 2003-07-10

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0712626A2 (fr) * 1994-11-08 1996-05-22 ASTA Medica Aktiengesellschaft Utilisation de l'acide R,S-(+/-)-alpha-lipoique, R-(+)-alpha-lipoique, S-(-)-alpha-lipoique en forme réducée ou oxidée ou des métabolites ainsi que leurs sels, esters, amides pour la manufacture des agents rhéologiques
US5990153A (en) * 1997-05-05 1999-11-23 Wood; John G. Ultrasonicated α-lipoic acid solutions for attenuating microvascular injury
WO2001085206A2 (fr) * 2000-05-08 2001-11-15 David Haines Compositions immunosuppressives
WO2001097774A2 (fr) * 2000-06-21 2001-12-27 Audit Institute For Medical Services And Quality Assurance Gmbh Nouvelle composition pharmaceutique destinee a l'application topique d'agents actifs insolubles dans l'eau et/ou difficilement solubles dans l'eau
WO2001097832A1 (fr) * 2000-06-21 2001-12-27 Audit Institute For Medical Services And Quality Assurance Gmbh Preparations pharmaceutiques contenant des cylosporines et des huiles neutres
WO2002017959A2 (fr) * 2000-08-28 2002-03-07 Wisconsin Alumni Research Foundation Immunosuppression par utilisation du piceatannol et d'un inhibiteur de la calcineurine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0712626A2 (fr) * 1994-11-08 1996-05-22 ASTA Medica Aktiengesellschaft Utilisation de l'acide R,S-(+/-)-alpha-lipoique, R-(+)-alpha-lipoique, S-(-)-alpha-lipoique en forme réducée ou oxidée ou des métabolites ainsi que leurs sels, esters, amides pour la manufacture des agents rhéologiques
US5990153A (en) * 1997-05-05 1999-11-23 Wood; John G. Ultrasonicated α-lipoic acid solutions for attenuating microvascular injury
WO2001085206A2 (fr) * 2000-05-08 2001-11-15 David Haines Compositions immunosuppressives
WO2001097774A2 (fr) * 2000-06-21 2001-12-27 Audit Institute For Medical Services And Quality Assurance Gmbh Nouvelle composition pharmaceutique destinee a l'application topique d'agents actifs insolubles dans l'eau et/ou difficilement solubles dans l'eau
WO2001097832A1 (fr) * 2000-06-21 2001-12-27 Audit Institute For Medical Services And Quality Assurance Gmbh Preparations pharmaceutiques contenant des cylosporines et des huiles neutres
WO2002017959A2 (fr) * 2000-08-28 2002-03-07 Wisconsin Alumni Research Foundation Immunosuppression par utilisation du piceatannol et d'un inhibiteur de la calcineurine

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BEER ANDRE-MICHAEL ET AL.: "Johanniskraut interaktion mit cyclosporin gefaehrdet nierentransplantat und erhoeht die taeglichen medikationskosten", MEDIZINISCHE KLINIK, vol. 96, no. 8, 2001, pages 480 - 484, XP002957919 *
BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL, vol. 44, no. 1, 1998, pages 127 - 134 *
DATABASE CAPLUS [online] MORKUNAITE SARUNE ET AL.: "Mechanism of dihydrolipoate stimulation of the mitochondrial permeability transition: effect of different respiratory substrates", XP002957921, accession no. STN Database accession no. 2000:379643 *
DATABASE CAPLUS [online] SARIS NILS-ERIK ET AL.: "The stimulation of the mitochondrial permeability transition by dihydrolipoate and alpha-lipoate", XP002957922, accession no. STN Database accession no. 1998:123687 *
IUBMB LIFE, vol. 49, no. 3, 2000, pages 211 - 216 *
SCHWEIZER MATTHIAS ET AL.: "Stimulation of Ca2+ release from rat liver mitochondria by the dithiol reagent alpha-lipoic acid", BIOCHEMICAL PHARMACOLOGY, vol. 52, no. 12, 1996, pages 1815 - 1820, XP002957920 *

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AU2002345121A1 (en) 2003-07-15
FI20012565A0 (fi) 2001-12-21
FI20012565A (fi) 2003-06-22

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