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WO2000067731A2 - Utilisation de medicaments pour eviter la tolerance aux nitrates - Google Patents

Utilisation de medicaments pour eviter la tolerance aux nitrates Download PDF

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Publication number
WO2000067731A2
WO2000067731A2 PCT/DE2000/001413 DE0001413W WO0067731A2 WO 2000067731 A2 WO2000067731 A2 WO 2000067731A2 DE 0001413 W DE0001413 W DE 0001413W WO 0067731 A2 WO0067731 A2 WO 0067731A2
Authority
WO
WIPO (PCT)
Prior art keywords
nitrate
xanthine oxidase
inhibitor
tolerance
pathological phenomena
Prior art date
Application number
PCT/DE2000/001413
Other languages
German (de)
English (en)
Other versions
WO2000067731A3 (fr
Inventor
Michael Stoeter
Gerd König
Eberhard Bassenge
Original Assignee
Alpharma-Isis Gmbh & Co.Kg
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 Alpharma-Isis Gmbh & Co.Kg filed Critical Alpharma-Isis Gmbh & Co.Kg
Priority to EP00943550A priority Critical patent/EP1173214A2/fr
Priority to AU58020/00A priority patent/AU5802000A/en
Publication of WO2000067731A2 publication Critical patent/WO2000067731A2/fr
Publication of WO2000067731A3 publication Critical patent/WO2000067731A3/fr
Priority to BG105955A priority patent/BG105955A/bg

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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 medicaments for avoiding nitrate and / or nitrate cross tolerance as well as pathological phenomena associated therewith.
  • GTN glycerol trinitrate
  • PETN pentaerythrityl tetranitrate
  • ISMN isosorbide-5-mononitrate
  • ISMN isosorbide-5-mononitrate
  • ISMN isosorbide-5-mononitrate
  • DE-OS-2221080 DE-OS-2751934, DE-OS-3028873, DE-PS-2903927, DE-OS-3102947, DE-OS-3124410
  • EP- A1- 045076 EP-A1-057847, EP-A1-059664, EP-A1-064194, EP-A1-067964, EP-A1-143507
  • US-PS-3886186 US-PS-4065488, US-PS- 4417065, US-PS-4431829
  • Isosorbide Dinitrate ISDN
  • L. Goldberg Acta Physiolog. Scand. 15, 173 (1948)
  • Propatyl Nitrate Medard, Mem.
  • Preparations for the treatment of angina pectoris or ischemic heart disease are generally known. It is carried out in accordance with the working methods and rules which are generally familiar to the pharmaceutical expert, the choice of the technologies to be used and the pharmaceutical auxiliaries used being based primarily on the active ingredient to be processed. Questions of its chemical-physical properties, in particular the explosive properties known to be attached to the organic nitrates, which require attention to special safety precautions and special processing technologies, the chosen form of application, the desired duration of action and the avoidance of drug-auxiliary incompatibilities are of particular importance.
  • Substances are their use for the treatment and prevention of diseases described, which are caused by pathologically increased concentrations of sulfur-containing amino acids in body fluids. These disease states, caused by congenital or acquired defects in the metabolism of these amino acids and which are characterized by increased blood and urine concentrations of said amino acids (homocystinuria), are summarized under the term homocysteinemia (WO-A1 -92/18002).
  • homocysteinemia WO-A1 -92/18002
  • the use of certain organic nitric acid esters as endothelial protective agents (DE-A1 -4410997) and as agents for the treatment of erectile dysfunction (WO-A1 -96/32118) have recently been described.
  • the known organic nitrates (nitric acid esters) have a number of therapeutic disadvantages.
  • nitrate tolerance can be observed, ie the decrease in the nitrate effect at high doses or when long-acting nitrates are applied.
  • Side effects such as headache, dizziness, nausea, weakness, reddening of the skin and the risk of a greater drop in blood pressure with reflex tachycardia are also documented (Mutschier, drug effects,ticianliche Verlagsgesellschaft mbH, Stuttgart, 1991).
  • the metabolism of GTN and other organic nitrates has been extensively investigated (Taylor et al., Moscow. Drug Metab., 10 (1987), 207).
  • organic nitrates have a pronounced oxidative effect on compounds carrying thiol groups (Boschan et al., Chem. Rev. 55, 485 (1955); Taylor et al., Progress in drug metabolism, Vol. 10, 207 ( 1987); Feelisch et al., Methods in Nitric Oxide Research, John Wiley & Sons, Chichester, 1996)). Furthermore, it is generally accepted and scientifically well documented that organic nitrates inevitably trigger counter-regulatory processes via the NO mechanism, for example the formation of angiotensin II in the vascular wall, which form large amounts of superoxide radicals when the endothelial enzyme NADH synthase is activated.
  • nitrate tolerance is determined by a massive accumulation of superoxide radicals, which lead to the formation of peroxynitrite and thus inactivation of NO according to the reaction scheme ON ' + 0 2 ' ⁇ ONOO.
  • antioxidants such as ascorbic acid (vitamin C) or vitamin E (Münzel et al., The physiology and pathophysiology of the nitric oxide / superoxide System, Vascular Endothelium (GVR Born, CJ Schwartz edt., P.
  • peroxynitrite itself breaks down again into superoxide and NO radicals and thus serves independently as a source of NO (Moro et al., Proc. Natl. Acad. Sei. 91 (1994), 6702; Moro et al., Br. J Pharmacol 116 (1995), 1999).
  • the xanthine oxidase in turn can release NO from organic nitrates under hypoxic conditions (Millar et al., FEBS Lett. 427 (2) (1998), 225; Millar et al., Biochem. Biophys. Res. Commun. 249 (1998), 767).
  • NO itself inhibits xanthine oxidase (Fukahori et al., Free Rad. Res. 21 (4) (1994), 203; Cote et al., Am. J. Physiol. 271 (1996), L869).
  • xanthine oxidase also called xanthine oxidoreductase in more recent literature, have been extensively investigated (Fridovich, J. Biol. Chem. 245 (1970), 4053; Battelli et al., FEBS Lett. 113 (1980), 47; Parks et al ., Acta Physiol. Scand. Suppl. 1986; 548: 87-99; Parks et al., Am. J. Physiol. 254 (Gastrointes. Liver Physiol. 17) (1988), G768; Kooij, Histochem. J. 26 (1994), 889; Hille, Chem. Rev.
  • the object of the invention is to counteract nitrate and / or nitrate cross tolerance as well as pathological phenomena associated with this by using suitable medicinal substances.
  • the object of the invention is achieved by the use of antagonists of purine derivative metabolizing enzymes to prevent or reduce nitrate and / or nitrate cross tolerance and of pathological phenomena associated with them.
  • An antagonist for the purposes of the present invention is a substrate which competes with purine derivatives or an inhibitor of the enzyme.
  • the terms competitive or non-competitive inhibitor are also suitable for describing the term antagonist.
  • a particular and preferred embodiment of the invention is the use of antagonists of xanthine oxidase to prevent or reduce nitrate and / or nitrate cross-tolerance and of pathological phenomena associated therewith, wherein the antagonist can have the meaning described above. Allopurinol or oxipurinol are e.g. B.
  • nitrate tolerance by the procedure according to the invention for. B. by inhibition of xanthine oxidase by means of allopurinol or its active metabolite oxipurinol (alloxanthin) can be antagonized and the reactivity of the considered vessels, which no longer adequately react to NO in the state of nitrate tolerance, could be restored to nitrogen monoxide. It was unexpected for the person skilled in the art that the state of the extinct (not present) NO effect can be eliminated and the effect of exogenously supplied NO can be restored with continuous administration of nitrate.
  • Tablets containing 20 mg, 40 mg or prolonged-release tablets containing 40 mg or 60 mg isosorbide mononitrate and at the same time 100 mg allopurinol are blistered, provided with instructions for use and spatially combined in a packaging unit.
  • Tablets containing 20 mg pentaerythrityl tetranitrate and 100 mg allopurinol are blistered, provided with instructions for use and spatially combined in a packaging unit.
  • Tablets containing 50 mg of pentaerythrityl tetranitrate and 300 mg of allopurinol are blistered, provided with instructions for use and spatially combined in a packaging unit.
  • Tablets containing 80 mg of pentaerythrityl tetranitrate and 100 mg of allopurinol are blistered, provided with instructions for use and spatially combined in a packaging unit.
  • Tablets containing a coronary therapeutic and tablets containing a xanthine oxidase inhibitor are blistered separately, provided with instructions for use and combined in a packaging unit in a spatially separate manner.
  • Tablets containing 40 mg of pentaerythrityl tetranitrate and at the same time 40 mg of propranolol hydrochloride are blistered, provided with instructions for use and spatially combined in a packaging unit.
  • ROS reactive oxygen species

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne l'utilisation de médicaments pour éviter la tolérance aux nitrates et/ou la tolérance croisée aux nitrates, ainsi que les phénomènes pathologiques résultant de celles-ci.
PCT/DE2000/001413 1999-05-05 2000-05-05 Utilisation de medicaments pour eviter la tolerance aux nitrates WO2000067731A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP00943550A EP1173214A2 (fr) 1999-05-05 2000-05-05 Utilisation de medicaments pour eviter la tolerance aux nitrates
AU58020/00A AU5802000A (en) 1999-05-05 2000-05-05 Medicinal substance utilization for preventing nitrate tolerance
BG105955A BG105955A (bg) 1999-05-05 2001-09-26 Използване на лекарствени вещества за избягване на нитратния толеранс

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19920775.5 1999-05-05
DE19920775A DE19920775A1 (de) 1999-05-05 1999-05-05 Arzneistoffverwendung zur Vermeidung von Nitrattoleranz

Publications (2)

Publication Number Publication Date
WO2000067731A2 true WO2000067731A2 (fr) 2000-11-16
WO2000067731A3 WO2000067731A3 (fr) 2001-01-25

Family

ID=7907118

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE2000/001413 WO2000067731A2 (fr) 1999-05-05 2000-05-05 Utilisation de medicaments pour eviter la tolerance aux nitrates

Country Status (6)

Country Link
EP (1) EP1173214A2 (fr)
AU (1) AU5802000A (fr)
BG (1) BG105955A (fr)
DE (1) DE19920775A1 (fr)
PL (1) PL352024A1 (fr)
WO (1) WO2000067731A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6537992B2 (en) 2001-01-05 2003-03-25 John D. Parker Regulation of organic nitrate tolerance
GB0909243D0 (en) * 2009-05-29 2009-07-15 Univ Dundee Angina treatment

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3839826A1 (de) * 1988-11-25 1990-05-31 Henning Berlin Gmbh Alkali- und erdalkalisalze des oxipurinols in amorpher oder kristalliner form als mittel zur behandlung von hyperurikaemie und gicht

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
C.G.SOBEY E.A.: "Allopurinol and amlodipine improve coronary vasodilatation after myocardial ischaemia and reperfusion in anaesthetized dogs" BRITISH JOURNAL OF PHARMACOLOGY, Bd. 108, Nr. 2, 1993, Seiten 342-347, XP000953125 *
T.M.MILLAR E.A.: "Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitric oxide under hypoxic conditions" FEBS LETTERS, Bd. 427, 1998, Seiten 225-228, XP002133526 in der Anmeldung erw{hnt *

Also Published As

Publication number Publication date
BG105955A (bg) 2002-06-28
EP1173214A2 (fr) 2002-01-23
AU5802000A (en) 2000-11-21
WO2000067731A3 (fr) 2001-01-25
PL352024A1 (en) 2003-07-14
DE19920775A1 (de) 2000-11-16

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