WO2001056609A1 - Pharmaceutical composition for treating hyperhomocysteinaemia caused by medicaments - Google Patents

Pharmaceutical composition for treating hyperhomocysteinaemia caused by medicaments Download PDF

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WO2001056609A1
WO2001056609A1 PCT/EP2000/008801 EP0008801W WO0156609A1 WO 2001056609 A1 WO2001056609 A1 WO 2001056609A1 EP 0008801 W EP0008801 W EP 0008801W WO 0156609 A1 WO0156609 A1 WO 0156609A1
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acid
pharmaceutical
pharmaceutical composition
nicotinic acid
combination
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PCT/EP2000/008801
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German (de)
French (fr)
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Sabine Westphal
Jutta Dierkes
Klaus Luley
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Sabine Westphal
Jutta Dierkes
Klaus Luley
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Priority to AU2000272858A priority Critical patent/AU2000272858A1/en
Publication of WO2001056609A1 publication Critical patent/WO2001056609A1/en

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    • 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
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic 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
    • A61K31/185—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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • composition for the treatment of drug-induced hyperhomocysteinemia is provided.
  • the invention relates to a pharmaceutical composition for the therapy of hyperhomocysteinemia, which, for. B. induced by therapy with antihypertensive drugs, analgesics, antidepressants, immunosuppressants, H 2 -receptor blockers, antiepeleptics, methylxanthines, biguanides or lipid-lowering agents.
  • hyperhomocysteinemia increased levels of the amino acid homocysteine in the blood plasma
  • anti-hypertensive drugs diuretics, calcium antagonists, ACE inhibitors or angiotensin-II receptor antagonists
  • non-steroidal analgesics non-steroidal analgesics
  • antidepressants lithium
  • Immunosuppressants methylxanthines (theophylline)
  • biguanides metalformin
  • lipid-lowering agents foribrates, anion exchangers, nicotinic acid and nicotinic acid analogues.
  • Elevated homocysteine levels represent a risk factor for the development of coronary heart disease, apoplexy and peripheral occlusive disease. Treatment of these elevated homocysteine levels is therefore carried out as part of the prevention of coronary artery disease, apoplexy and peripheral occlusive disease. Congenital and acquired causes of hyperhomocysteinemia are known. Deficiency of the vitamins cobalamin (vitamin B12), folic acid or pyridoxine chloride (vitamin B6) are a common cause of hyperhomocysteinemia. B vitamins and folic acid have important coenzyme functions in the breakdown of homocysteine.
  • the therapy consists in the targeted vitamin substitution of folic acid, vitamin B6 or B12 (O. Stanger; metabolism, news about the risk factor homocysteine, medical journal Dr. Med. 06/99). It is therefore an object of the invention to prevent the development of drug-induced hyperhomocysteinemia by means of suitable active ingredient additions.
  • a pharmaceutical composition comprising a combination of a pharmaceutical active ingredient inducing hyperhomocysteinemia and at least one or more of the active ingredients cobalamin (cyano-, hydroxo-, methyl-), folic acid (pteroyiglutamic acid, methyltetrahydrofolate, folinic acid), vitamin B6 (pyridoxine chloride) , Betaine or N-acetylcysteine is suitable, can prevent an increase in the homocysteine concentration in the blood plasma, as has been observed with the administration of blood pressure-lowering drugs, analgesics, antidepressants, immunosuppressants, H 2 -receptors, antiepeleptics, methylxanthines, biguanides or lipid-lowering drugs ,
  • the following table shows the effect of antihypertensive therapy on parameters of homocysteine metabolism in patients with high blood pressure.
  • the median with the smallest and the largest value in brackets or the mean with simple standard deviation is given.
  • the probability of error (p-value values) was determined using the Wilcoxon test for connected samples.
  • Vitamin B6 (PLP) (ng / mL) 9.0 (5.0-39.4) 10.9 (5.2-39.3) 0.10
  • Vitamin B12 (cobalamin) 369 (217-1115) 358 (123-907) 0.75
  • Vitamin B6 (PLP) (ng / mL) 9.0 (5.1-36.4) 10.3 (4.7-25.9) 0.53
  • homocysteine-lowering active ingredients are used in combination with the pharmaceutical active ingredients inducing hyperhomocysteinemia in the following daily doses for the indicated indications:
  • N-acetylcysteine up to 5,000 mg
  • the combination of the active pharmaceutical ingredients with the vitamins mentioned can preferably be taken orally, e.g. B. in the form of capsules, dragees, tablets, tablets or film tablets.
  • the combination of the active pharmaceutical ingredients with betaine or N-acetylcysteine can preferably be administered orally, e.g. B. in the form of an effervescent tablet.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, which contain the compounds according to the invention, and processes for the preparation of these preparations.
  • suitable pharmaceutical preparations are as follows:
  • the pharmaceutical preparations listed can also contain other active pharmaceutical ingredients.
  • the pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active ingredient (s) with the excipient (s).
  • diuretics calcium antagonists, ACE inhibitors and angiotensin-II receptor antagonists
  • Active substances that belong to the class of diuretics, calcium antagonists, ACE inhibitors or angiotensin-II receptor antagonists are listed in Table 1.
  • Other side effects than the newly found hyperhomocysteinemia when taking these antihypertensive agents are already known.
  • the patient was given a pharmaceutical preparation according to the invention as

Abstract

The invention relates to a pharmaceutical composition for producing H2-receptor blockers (cimetidin), non-steroidal analgesics (ibuprofen, indometacin), antidepressants (lithium), anti-epileptic agents (phenytoin, carbamazepin), immunosupressants (cyclosporin, methotrexate), methylxanthine (theophyllin), biguanides (metformin) and lipid reducers (fibrates, anion exchangers, nicotinic acid and nicotinic acid analogues) or medicaments for treating hypertension, containing a combination of a pharmaceutical active agent which causes hyperhomocysteinaemia and at least one of the following active agents: cobalamine (cyano-, hydroxo-, methyl-), folic acid (pteroylglutamic acid, methyltetrahydrofolate, folinic acid), vitamin B6 (pyridoxine chloride), betain or N-acetylcysteine. According to a novel observation, hyperhomocysteinaemia (a high level of the amino acid homocysteine in the blood plasma) is caused by the intake of medicaments for lowering blood pressure (diuretics, calcium antagonists, ACE inhibitors or angiotensin-II receptor antagonists), non-steroidal analgesics, antidepressants (lithium), immunosupressants, methylxanthine (theophyllin), biguanides (metformin) or lipid reducers (fibrates, anion exchangers, nicotinic acid and nicotinic acid analogues).

Description

Beschreibungdescription
Pharmazeutische Zusammensetzung für die Behandlung einer durch Arzneimittel induzierten HyperhomocysteinämiePharmaceutical composition for the treatment of drug-induced hyperhomocysteinemia
Die Erfindung betrifft eine pharmazeutische Zusammensetzung zur Therapie einer Hyperhomocysteinämie, die z. B. durch Therapie mit blutdrucksenkenden Arznei- mittein, Analgetika, Antidepressiva, Immunsuppressiva, H2-Rezeptorenblockern, Antiepeleptika, Methylxanthinen, Biguaniden oder Lipidsenkern induziert wird.The invention relates to a pharmaceutical composition for the therapy of hyperhomocysteinemia, which, for. B. induced by therapy with antihypertensive drugs, analgesics, antidepressants, immunosuppressants, H 2 -receptor blockers, antiepeleptics, methylxanthines, biguanides or lipid-lowering agents.
Es ist eine neue Beobachtung, dass eine Hyperhomocysteinämie (erhöhte Spiegel der Aminosäure Homocystein im Blutplasma) durch die Einnahme von blutdruck- senkenden Arzneimitteln (Diuretika, Calciumantagonisten, ACE-Hemmern oder Angiotensin-Il Rezeptorantagonisten), nicht-steroidale Analgetika, Antidepressiva (Lithium), Immunsupressiva, Methylxanthine (Theophyllin), Biguanide (Metformin) oder Lipidsenkern (Fibrate, Anionenaustauscher, Nikotinsäure und Nikotinsaureanaloga) entsteht. Die Entwicklung einer Hyperhomocysteinämie stellt eine bisher nicht bekannte Nebenwirkung dieser Wirkstoffe dar. Diese beobachtete Nebenwirkung tritt bei Einnahme der vorgenannten Arzneimittel regelmäßig und häufig auf. Die biochemische Ursache dieser Hyperhomocysteinämie ist nicht bekannt.It is a new observation that hyperhomocysteinemia (increased levels of the amino acid homocysteine in the blood plasma) through the taking of anti-hypertensive drugs (diuretics, calcium antagonists, ACE inhibitors or angiotensin-II receptor antagonists), non-steroidal analgesics, antidepressants (lithium) , Immunosuppressants, methylxanthines (theophylline), biguanides (metformin) or lipid-lowering agents (fibrates, anion exchangers, nicotinic acid and nicotinic acid analogues). The development of hyperhomocysteinemia is a hitherto unknown side effect of these active substances. This observed side effect occurs regularly and frequently when the aforementioned medicines are taken. The biochemical cause of this hyperhomocysteinemia is unknown.
Erhöhte Homocysteinspiegel stellen einen Risikofaktor für die Entstehung der koronaren Herzkrankheit, des Apoplex sowie der peripheren Verschlusskrankheit dar. Eine Behandlung dieser erhöhten Homocysteinspiegel wird daher im Rahmen der Prävention der koronaren Herzkrankheit, des Apoplexes und der peripheren Verschlusskrankheit durchgeführt. Es sind angeborene und erworbene Ursachen der Hyperhomocysteinämie bekannt. Mangelzustände der Vitamine Cobalamin (Vitamin B12), Folsäure oder Pyridoxinchlorid (Vitamin B6) stellen eine häufige Ursache einer Hyperhomocysteinämie dar. B-Vitamine und Folsäure haben wichtige Coenzym- Funktionen im Abbau von Homocystein. Zur Senkung erhöhter Homocysteinwerte besteht die Therapie in der gezielten Vitaminsubstitution von Folsäure, Vitamin B6 oder B12 (O. Stanger; Stoffwechsel, Neues zum Risikofaktor Homocystein, Medizinische Fachzeitschrift Dr. Med. 06/99). Es ist deshalb Aufgabe der Erfindung, die Entstehung einer durch Arzneimittel induzierten Hyperhomocysteinämie mittels geeigneter Wirkstoffzugaben zu verhindern.Elevated homocysteine levels represent a risk factor for the development of coronary heart disease, apoplexy and peripheral occlusive disease. Treatment of these elevated homocysteine levels is therefore carried out as part of the prevention of coronary artery disease, apoplexy and peripheral occlusive disease. Congenital and acquired causes of hyperhomocysteinemia are known. Deficiency of the vitamins cobalamin (vitamin B12), folic acid or pyridoxine chloride (vitamin B6) are a common cause of hyperhomocysteinemia. B vitamins and folic acid have important coenzyme functions in the breakdown of homocysteine. To lower elevated homocysteine levels, the therapy consists in the targeted vitamin substitution of folic acid, vitamin B6 or B12 (O. Stanger; metabolism, news about the risk factor homocysteine, medical journal Dr. Med. 06/99). It is therefore an object of the invention to prevent the development of drug-induced hyperhomocysteinemia by means of suitable active ingredient additions.
Überraschend wurde gefunden, dass eine pharmazeutische Zusammensetzung aus einer Kombination eines eine Hyperhomocysteinämie induzierenden pharmazeutischen Wirkstoffes und mindestens eines oder mehrerer der Wirkstoffe Cobalamin (Cyano-, Hydroxo-, Methyl-), Folsäure (Pteroyiglutaminsäure, Methyltetrahydrofolat, Folinsäure), Vitamin B6 (Pyridoxinchlorid), Betain oder N-Acetylcystein geeignet ist, einen Anstieg der Homocysteinkonzentration im Blutplasma, wie sie bei alleiniger Gabe blutdrucksenkender Arzneimittel, Analgetika, Antidepressiva, Immunsup- pressiva, H2-Rezeptoren blockern, Antiepeleptika, Methylxanthinen, Biguaniden oder Lipidsenkern beobachtet wurde, verhindern kann.Surprisingly, it was found that a pharmaceutical composition comprising a combination of a pharmaceutical active ingredient inducing hyperhomocysteinemia and at least one or more of the active ingredients cobalamin (cyano-, hydroxo-, methyl-), folic acid (pteroyiglutamic acid, methyltetrahydrofolate, folinic acid), vitamin B6 (pyridoxine chloride) , Betaine or N-acetylcysteine is suitable, can prevent an increase in the homocysteine concentration in the blood plasma, as has been observed with the administration of blood pressure-lowering drugs, analgesics, antidepressants, immunosuppressants, H 2 -receptors, antiepeleptics, methylxanthines, biguanides or lipid-lowering drugs ,
Es war erstaunlich und nicht vorhersehbar, dass sich durch Kombination von einem, eine Hyperhomocysteinämie induzierenden pharmazeutischen Wirkstoff mit den vorgenannten Verbindungen eine Senkung der Homocysteinwerte erreichen ließ, obwohl durch die Einnahme dieser pharmazeutischen Wirkstoffe kein Vitaminmangel erzeugt wurde.It was astonishing and unpredictable that a combination of a pharmaceutical active substance that induces hyperhomocysteinemia and the above-mentioned compounds could bring about a reduction in homocysteine values, although the intake of these pharmaceutical active substances did not produce a vitamin deficiency.
Nachfolgende Tabelle beinhaltet die Auswirkung einer blutdrucksenkenden Therapie auf Parameter des Homocysteinstoffwechsels bei Patienten mit Bluthochdruck. Angegeben ist jeweils der Mediän mit dem kleinsten und dem größten Wert in Klammern oder der Mittelwert mit einfacher Standardabweichung. Die Irrtumswahr- scheinlichkeit (p-Value-Werte) wurden mittels des Wilcoxon-Tests für verbundene Stichproben ermittelt.The following table shows the effect of antihypertensive therapy on parameters of homocysteine metabolism in patients with high blood pressure. The median with the smallest and the largest value in brackets or the mean with simple standard deviation is given. The probability of error (p-value values) was determined using the Wilcoxon test for connected samples.
vor Behandlung nach 4-6 Wochen Behandlung p-Value mit Hydrochlorothiazid 25-50 mg/d (n=10) Alter in Jahren 60 (57-73)before treatment after 4-6 weeks of treatment p-Value with hydrochlorothiazide 25-50 mg / d (n = 10) age in years 60 (57-73)
syst. Blutdruck (mmHg) 169 ± 8 142 ± 11 0,001systemic blood pressure (mmHg) 169 ± 8 142 ± 11 0.001
diast. Blutdruck (mmHg) 95 + 5 82 ± 9 0,002diast. Blood pressure (mmHg) 95 + 5 82 ± 9 0.002
Homocystein (μmol/L) 10,8 (8,0-20,2) 13,9 (8,6-23,8) 0,008Homocysteine (µmol / L) 10.8 (8.0-20.2) 13.9 (8.6-23.8) 0.008
Folat (ngtmL) 8,4 (5,1-15,1) 7,4 (5,0-14,0) 0,11 Vitamin B12 (Cobalamin) 381 (191-652) 412 (221-613) 0,50Folate (ngtmL) 8.4 (5.1-15.1) 7.4 (5.0-14.0) 0.11 Vitamin B12 (cobalamin) 381 (191-652) 412 (221-613) 0.50
(pg/mL)(Pg / mL)
Vitamin B6 (PLP) (ng/mL) 9,0 (5,0-39,4) 10,9 (5,2-39,3) 0,10Vitamin B6 (PLP) (ng / mL) 9.0 (5.0-39.4) 10.9 (5.2-39.3) 0.10
vor Behandlung nach 4-6 Wochen Behandlung p-Value mit Captoprii 25 mg/d (n=12) Alter in Jahren 69 (46-85)before treatment after 4-6 weeks of treatment p-Value with Captoprii 25 mg / d (n = 12) age in years 69 (46-85)
syst. Blutdruck (mmHg) 177 + 21 149 ± 23 0,002systemic blood pressure (mmHg) 177 + 21 149 ± 23 0.002
diast. Blutdruck (mmHg) 91 ± 12 86 + 12 0,28diast. Blood pressure (mmHg) 91 ± 12 86 + 12 0.28
Homocystein (μmol/L) 12,8 (7,3-25,5) 14,2 (9,0-28,0) 0,05Homocysteine (µmol / L) 12.8 (7.3-25.5) 14.2 (9.0-28.0) 0.05
Folat (ng/mL) 6,7 (3,4-16,1) 7,9 (3,6-15,1) 0,56Folate (ng / mL) 6.7 (3.4-16.1) 7.9 (3.6-15.1) 0.56
Vitamin B12 (Cobalamin) 369 (217-1115) 358 (123-907) 0,75Vitamin B12 (cobalamin) 369 (217-1115) 358 (123-907) 0.75
(pg/mL)(Pg / mL)
Vitamin B6 (PLP) (ng/mL) 9,0 (5,1-36,4) 10,3 (4,7-25,9) 0,53Vitamin B6 (PLP) (ng / mL) 9.0 (5.1-36.4) 10.3 (4.7-25.9) 0.53
Deutlich ersichtlich ist, dass sich die Homocysteinspiegel bei Gabe von Hydro- chlorothiazid oder Captoprii signifikant erhöhen, obwohl kein Vitaminmangel eintritt.It is clearly evident that homocysteine levels increase significantly when hydrochlorothiazide or Captoprii are administered, even though there is no vitamin deficiency.
Erfindungsgemäß werden bei den angegebenen Indikationen die homocystein- senkenden Wirkstoffe in Kombination mit den eine Hyperhomocysteinämie induzierenden pharmazeutischen Wirkstoffen in folgenden Tagesdosierungen eingesetzt:According to the invention, the homocysteine-lowering active ingredients are used in combination with the pharmaceutical active ingredients inducing hyperhomocysteinemia in the following daily doses for the indicated indications:
Cobalamin bis 10 000 μgCobalamin up to 10,000 μg
Folsäure bis 15 mgFolic acid up to 15 mg
Pyridoxin bis 500 mgPyridoxine up to 500 mg
Betain bis 20 gBetaine up to 20 g
N-Acetylcystein bis 5 000 mg Die Kombination der pharmazeutischen Wirkstoffe mit den genannten Vitaminen kann vorzugsweise peroral, z. B. in Form von Kapseln, Dragees, Compretten, Tabletten oder Filmtabletten, verabreicht werden. Die Kombination der pharmazeutischen Wirkstoffe mit Betain oder N-Acetylcystein kann vorzugsweise peroral, z. B. in Form einer Brausetablette verabreicht werden.N-acetylcysteine up to 5,000 mg The combination of the active pharmaceutical ingredients with the vitamins mentioned can preferably be taken orally, e.g. B. in the form of capsules, dragees, tablets, tablets or film tablets. The combination of the active pharmaceutical ingredients with betaine or N-acetylcysteine can preferably be administered orally, e.g. B. in the form of an effervescent tablet.
Zur vorliegenden Erfindung gehören pharmazeutische Zubereitungen, die neben nichttoxischen, inerten pharmazeutisch geeigneten Trägerstoffen, die erfindungsgemäßen Verbindungen enthalten, sowie Verfahren zur Herstellung dieser Zubereitungen. Beispiele für geeignete pharmazeutische Zubereitungen sind folgende:The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, which contain the compounds according to the invention, and processes for the preparation of these preparations. Examples of suitable pharmaceutical preparations are as follows:
Beispiel 1 DrageeExample 1 Dragee
Hydrochlorothiazid 25 mgHydrochlorothiazide 25 mg
Cyanocobalamin 1 000 μgCyanocobalamin 1 000 μg
Pteroylglutaminsäure 100 μgPteroylglutamic acid 100 μg
Pyridoxinchlorid 2 mgPyridoxine chloride 2 mg
Hilfs- und FüllstoffeAuxiliaries and fillers
Beispiel 2Example 2
Gelatinekapselgelatin capsule
Furosemid 20 gFurosemide 20 g
Betain 2 gBetaine 2 g
Hilfs- und FüllstoffeAuxiliaries and fillers
Beispiel 3Example 3
Brausetabletteeffervescent tablet
Amilorid 2,5 mgAmiloride 2.5 mg
Trichlormethiazid 2 mgTrichloromethiazide 2 mg
N-Acetylcystein 600 mgN-acetylcysteine 600 mg
Hilfs- und Füllstoffe Beispiel 4Auxiliaries and fillers Example 4
Filmtablettetablet
Captoprii 25 mgCaptoprii 25 mg
Cyanocobalamin 1 000 μgCyanocobalamin 1 000 μg
Pteroylglutaminsäure 100 μgPteroylglutamic acid 100 μg
Hilfs- und FüllstoffeAuxiliaries and fillers
Beispiel 5Example 5
Filmtablettetablet
Losartan 50 mgLosartan 50 mg
Cyanocobalamin 1 000 μgCyanocobalamin 1 000 μg
Pteroylglutaminsäure 100 μgPteroylglutamic acid 100 μg
Hilfs- und FüllstoffeAuxiliaries and fillers
Die aufgeführten pharmazeutischen Zubereitungen können außer den erfindungsgemäßen Verbindungen auch weitere pharmazeutische Wirkstoffe enthalten.In addition to the compounds according to the invention, the pharmaceutical preparations listed can also contain other active pharmaceutical ingredients.
Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher weise nach bekannten Methoden, z.B. durch Mischen des oder der Wirkstoffe mit dem oder den Trägerstoffen.The pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active ingredient (s) with the excipient (s).
Die Verwendung von Diuretika, Calciumantagonisten, ACE-Hemmern und Angiotensin- II Rezeptorantagonisten in pharmazeutischen Zubereitungen zur Therapie des Bluthochdruckes ist bereits bekannt. Wirkstoffe, die zur Stoffklasse der Diuretika, Calciumantagonisten, ACE-Hemmer oder Angiotensin-Il Rezeptorantagonisten zählen, sind in Tabelle 1 aufgeführt. Es sind bereits andere Nebenwirkungen als die neu gefundene Hyperhomocysteinämie bei der Einnahme dieser blutdrucksenkenden Wirkstoffe bekannt.The use of diuretics, calcium antagonists, ACE inhibitors and angiotensin-II receptor antagonists in pharmaceutical preparations for the treatment of high blood pressure is already known. Active substances that belong to the class of diuretics, calcium antagonists, ACE inhibitors or angiotensin-II receptor antagonists are listed in Table 1. Other side effects than the newly found hyperhomocysteinemia when taking these antihypertensive agents are already known.
Wirkstoffe, die zu den Stoffklassen der Lipidsenker und der Nicht-steroidalen Analgetika gehören, sind in Tabelle 2 aufgeführt.Active substances that belong to the classes of lipid-lowering drugs and non-steroidal analgesics are listed in Table 2.
Wirkstoffe, die zu den Stoffklassen der Methylxanthine, H2-Rezeptorenblocker, Antidepressiva, Antiepileptika, Immunsupressiva und Biguanide gehören, sind in Tabelle 3 aufgeführt. Tabelle 1Active substances that belong to the classes of methylxanthines, H 2 -receptor blockers, antidepressants, antiepileptics, immunosuppressants and biguanides are listed in Table 3. Table 1
Figure imgf000007_0001
Figure imgf000007_0001
Figure imgf000007_0002
Tabelle 2
Figure imgf000007_0002
Table 2
Figure imgf000008_0001
Figure imgf000008_0001
Tabelle 3Table 3
Figure imgf000008_0002
Figure imgf000008_0002
Die Erfindung wird nachstehend an einem weiteren Beispiel erläutert.The invention is explained below using a further example.
25 Patienten mit Hyperlipidämie wurden im Rahmen einer klinischen cross-over-Studie mit einer Fenofibrat-Placebo-Kombination und mit einer erfindungsgemäßen Kombination jeweils über einen Zeitraum von 6 Wochen behandelt, wobei zwischen den beiden Behandlungsphasen eine Auswaschphase von 8 Wochen eingehalten wurde.25 patients with hyperlipidemia were treated in a clinical cross-over study with a fenofibrate-placebo combination and with a combination according to the invention each over a period of 6 weeks, with a washout phase of 8 weeks being observed between the two treatment phases.
erste Behandlungsphase A:first treatment phase A:
Den Patienten wurde eine Fenofibrat-Placebo-Kombination folgender Zusammensetzung verabreicht in einer einmaligen Gabe pro Tag: Fenofibrat 200 mgThe patients were given a fenofibrate-placebo combination of the following composition in one single dose per day: fenofibrate 200 mg
Placebo 1 Kapsel Vor Beginn und nach Abschluss der 6-wöchigen Behandlung wurden die in der Tabelle 4 angegebenen Werte ermittelt.Placebo 1 capsule Before the start and after completion of the 6-week treatment, the values given in Table 4 were determined.
zweite Behandlungsphase B:second treatment phase B:
Diese erfolgte 8 Wochen nach Abschluss der Behandlungsphase A.This took place 8 weeks after the end of treatment phase A.
Den Patienten wurde eine erfindungsgemäße pharmazeutische Zubereitung alsThe patient was given a pharmaceutical preparation according to the invention as
Kombination pro Tag verabreicht:Combination administered per day:
Fenofibrat 200 mgFenofibrate 200 mg
1 Kapsel enthaltendContaining 1 capsule
Folsäure 650 μgFolic acid 650 μg
Vitamin B12 50 μgVitamin B12 50 μg
Vitamin B6 6 mgVitamin B6 6 mg
Vor der Behandlung und nach Abschluss der Behandlung wurden die in der Tabelle 4 angegebenen Werte ermittelt. The values given in Table 4 were determined before the treatment and after the end of the treatment.
Tabelle:Table:
Auswirkung einer lipidsenkenden Therapie mit Fenofibrat oder mit Fenofibrat und Vitaminen auf Parameter des Lipid- und des Homocysteinstoffwechsels bei 25 hyperiipidämischen Männern. Angegeben ist jeweils der Mediän mit der 5. und 95. Perzentiie in Klammern. Die p-Werte wurden mittels des Wilcoxon-Tests für verbundene Stichproben ermittelt.Effect of lipid-lowering therapy with fenofibrate or with fenofibrate and vitamins on parameters of lipid and homocysteine metabolism in 25 hyperiipidemic men. The median is given with the 5th and 95th percentile in brackets. The p-values were determined using the Wilcoxon test for connected samples.
Figure imgf000010_0001
tHcy = Gesamthomocystein PLP = Pyridoxal 5-phosphat
Figure imgf000010_0001
tHcy = total homocysteine PLP = pyridoxal 5-phosphate
Ersichtlich ist, dass nach Kombinationsbehandlung mit Fenofibrat und Placebo- präparat die Homocysteinkonzentration um 3,3 μmol/l ansteigt. Demgegenüber ist bei Gabe der pharmazeutischen Zubereitung aus Fenofibrat und Folsäure, Vitamin B12 und B6 kein statistisch signifikanter Anstieg zu verzeichnen. It can be seen that after combination treatment with fenofibrate and placebo preparation, the homocysteine concentration increases by 3.3 μmol / l. In contrast, there was no statistically significant increase when the pharmaceutical preparation of fenofibrate and folic acid, vitamins B12 and B6 was administered.

Claims

Patentansprüche claims
1. Pharmazeutische Zusammensetzung zur Herstellung von H2-Rezeptoren- blockern (Cimetidin), Nicht-steroidalen Analgetika (Ibuprofen, Indometacin), Antidepressiva (Lithium), Antiepileptika (Phenytoin, Carbamazepin), Immunsupressiva (Cyclosporin, Methotrexat), Methylxanthine (Theophyllin), Biguanide (Metformin) und Lipidsenker (Fibrate, Anionenaustauscher, Nikotinsäure und Nikotinsaureanaloga) oder Arzneimitteln für die Behandlung von Bluthochdruck, enthaltend eine Kombination eines eine Hyperhomocystein- ämie induzierenden pharmazeutischen Wirkstoffes und mindestens eines oder mehrerer der Wirkstoffe Cobalamin (Cyano-, Hydroxo-, Methyl-), Folsäure (Pteroylglutaminsäure, Methyltetrahydrofolat, Folinsäure), Vitamin B6 (Pyridoxinchlorid), Betain oder N-Acetylcystein.1. Pharmaceutical composition for the production of H 2 -receptor blockers (cimetidine), non-steroidal analgesics (ibuprofen, indomethacin), antidepressants (lithium), antiepileptics (phenytoin, carbamazepine), immunosuppressants (cyclosporin, methotrexate), methylxanthine (theophylline) , Biguanides (metformin) and lipid-lowering agents (fibrates, anion exchangers, nicotinic acid and nicotinic acid analogues) or medicaments for the treatment of hypertension, containing a combination of a pharmaceutical active ingredient inducing hyperhomocysteineemia and at least one or more of the active ingredients cobalamin (cyano-, hydroxo-, Methyl-), folic acid (pteroylglutamic acid, methyltetrahydrofolate, folinic acid), vitamin B6 (pyridoxine chloride), betaine or N-acetylcysteine.
2. Pharmazeutische Zusammensetzung nach Anspruch 1, dadurch gekennzeichnet, dass die Tagesdosierungen der homocysteinsenkenden Wirkstoffe in Kombination mit den eine Hyperhomocysteinämie induzierenden pharmazeutischen Wirkstoffen für Cobalamin bis 10 000 μg, für Folsäure bis 15 mg, für Pyridoxin bis 500 mg, für Betain bis 20g und für N-Acetylcystein bis 5 000 mg betragen.2. Pharmaceutical composition according to claim 1, characterized in that the daily doses of the homocysteine-lowering active ingredients in combination with the hyperhomocysteinemia-inducing pharmaceutical active ingredients for cobalamin up to 10,000 μg, for folic acid up to 15 mg, for pyridoxine up to 500 mg, for betaine up to 20g and for N-acetylcysteine up to 5,000 mg.
3. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, dass die homocysteinsenkenden Wirkstoffe mit den pharmazeutischen Wirkstoffen zusammen in peroraler Darreichungsform vorliegen.3. Pharmaceutical composition according to one of claims 1 or 2, characterized in that the homocysteine-lowering active ingredients together with the pharmaceutical active ingredients are present in oral dosage form.
4. Pharmazeutische Zusammensetzung nach Anspruch 3, dadurch gekennzeichnet, dass die Darreichungsform für die Kombination der pharmazeutischen Wirkstoffe mit den Vitaminen Kapseln, Dragees, Compretten, Tabletten oder Filmtabletten sind.4. Pharmaceutical composition according to claim 3, characterized in that the dosage form for the combination of the active pharmaceutical ingredients with the vitamins are capsules, dragees, compresses, tablets or film-coated tablets.
5. Pharmazeutische Zusammensetzung nach Anspruch 3, dadurch gekennzeichnet, dass die Darreichungsform für die Kombination der pharmazeutischen Wirkstoffe mit Betain oder N-Acetylcystein Brausetabletten sind. 5. Pharmaceutical composition according to claim 3, characterized in that the dosage form for the combination of the active pharmaceutical ingredients with betaine or N-acetylcysteine are effervescent tablets.
6. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass diese in nichttoxischen, inerten Trägerstoffen enthalten sind.6. Pharmaceutical composition according to one of claims 1 to 5, characterized in that these are contained in non-toxic, inert carriers.
7. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass diese weitere pharmazeutische Wirkstoffe und/oder Hilfs- und Füllstoffe enthält.7. Pharmaceutical composition according to one of claims 1 to 6, characterized in that it contains further active pharmaceutical ingredients and / or auxiliaries and fillers.
8. Verwendung einer Kombination eines eine Hyperhomocysteinämie induzieren- den pharmazeutischen Wirkstoffes und mindestens eines oder mehrerer der8. Use of a combination of a pharmaceutical active ingredient inducing hyperhomocysteinemia and at least one or more of the
Wirkstoffe Cobalamin (Cyano-, Hydroxo-, Methyl-), Folsäure (Pteroylglutaminsäure, Methyltetrahydrofolat, Folinsäure), Vitamin B6 (Pyridoxinchlorid), Betain oder N-Acetylcystein zur Herstellung von H2-Rezeptorenblockern (Cimetidin), nicht-steroidale Analgetika (Ibuprofen, Indometacin), Antidepressiva (Lithium), Antiepileptika (Phenytoin, Carbamazepin), Immunsupressiva (Cyclosporin,Active ingredients cobalamin (cyano-, hydroxo-, methyl-), folic acid (pteroylglutamic acid, methyltetrahydrofolate, folinic acid), vitamin B6 (pyridoxine chloride), betaine or N-acetylcysteine for the production of H 2 -receptor blockers (cimetidine), non-steroidal analgesics (ibuprofen , Indomethacin), antidepressants (lithium), antiepileptics (phenytoin, carbamazepine), immunosuppressants (cyclosporin,
Methotrexat), Methylxanthine (Theophyllin), Biguanide (Metformin) und Lipid- senker (Fibrate, Anionenaustauscher, Niktotinsäure und Nikotinsaureanaloga) oder Arzneimitteln für die Behandlung von Bluthochdruck. Methotrexate), methylxanthine (theophylline), biguanide (metformin) and lipid-lowering agents (fibrates, anion exchangers, nicotinic acid and nicotinic acid analogues) or medicines for the treatment of high blood pressure.
PCT/EP2000/008801 2000-02-03 2000-09-08 Pharmaceutical composition for treating hyperhomocysteinaemia caused by medicaments WO2001056609A1 (en)

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