WO1985000107A1 - Prophylaxis and therapy of coronary heart diseases by lowering the estrogen concentration - Google Patents

Prophylaxis and therapy of coronary heart diseases by lowering the estrogen concentration Download PDF

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Publication number
WO1985000107A1
WO1985000107A1 PCT/DE1984/000137 DE8400137W WO8500107A1 WO 1985000107 A1 WO1985000107 A1 WO 1985000107A1 DE 8400137 W DE8400137 W DE 8400137W WO 8500107 A1 WO8500107 A1 WO 8500107A1
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estrogen
therapy
prophylaxis
coronary heart
heart diseases
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PCT/DE1984/000137
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German (de)
French (fr)
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Paul Eberhard Schulze
Ulrich Kerb
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Schering Aktiengesellschaft
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol

Definitions

  • the invention relates to the prophylaxis and therapy of coronary heart diseases by lowering the estrogen level.
  • Coronary artery disease is one of the most common life-threatening vascular diseases.
  • several preparations are used, which have an expanding effect on the vascular system, which improve the disturbed oxygen supply to the heart muscle tissue (myocardium) and which are also intended to prevent the formation of blood clots (platelet aggregation).
  • the blood pressure is also lowered with medication.
  • Anti-estrogens such as tamoxifen and especially aromatase inhibitors such as testolactone can be used to lower estrogen levels. It has been found that serum estradiol levels are significantly higher in men with coronary artery disease than in healthy men (The American Journal of Medicine 74 (1983) 863-869). Serum estrogen levels are also increased in men with an acute heart attack (The American Journal of Medicine 73 (19 ⁇ 2) 872 - 881).
  • aromatase inhibitors reduce the estrogen content in plasma (J. Clin. And Met. 52 (1981) 897-902).
  • aromatase inhibitors can also reduce the estrogen content in the atrium (atrium cordis).
  • geriatric rat goats (age approx. 2 years) are treated subcutaneously for 8 days with an aromatase inhibitor, such as 6 mg 4-hydroxy-4-androsten-3.17-dione daily, and the estrogen content in the plasma is thus reduced, one finds after administration of (3H) -estradiol a surprising
  • angina pectoris symptoms subsided after taking 4 times 100 mg of testolactone twice a day for 4 weeks and finally disappeared completely.
  • the patient was no longer aware of the clinical picture, which was characterized by convulsions and anxiety. Therapy continued for 5 months. During this time, heart problems only occurred briefly, but did not reach the previous painful severity.
  • the dosage of the anti-estrogen or aromatase inhibitor depends on the type and severity of the heart disease. In general, a daily dose of an anti-estrogen equivalent to that of 10 to 200 mg tamoxifen or an aromatase inhibitor equivalent to that of 50 to 1000 mg testolactone will be sufficient.
  • an anti-estrogen equivalent to that of 10 to 200 mg tamoxifen or an aromatase inhibitor equivalent to that of 50 to 1000 mg testolactone will be sufficient.
  • all substances are suitable according to the invention which bring about a reduction in the estrogen level. These substances include all anti-estrogens, which can be both steroidal and non-steroidal.
  • the best-studied non-steroidal anti-estrogens include:
  • Tamoxifen ((Z) -2- / p- (1,2-diphenyl-1-butenyl) phenoxy7-
  • Cyclofenil bis (p-acetoxyphenyl) cyclohexylidene methane
  • aromatase inhibitors for lowering the estrogen level in men are special well suited.
  • the administration of aromatase inhibitors prevents or inhibits the formation of biologically active estrogens (estrogen biosynthesis).
  • all aromatase inhibitors are suitable which inhibit estrogen biosynthesis and which themselves have only little or no estrogenic or other hormonal action.
  • aromatase inhibitors are described, for example, in Endocrinology 92 (1973) 866-880, DE-OS 3 124 719 and US Pat. No. 4,289,762.
  • the invention also relates to agents for lowering the estrogen level for the prophylaxis and therapy of coronary heart diseases in men, anti-estrogens and in particular aromatase inhibitors being suitable for lowering the estrogen level.
  • the active ingredients can be processed with the additives, carrier substances and / or taste correctants customary in galenical pharmacy according to methods known per se to give the usual forms of administration, for example for oral, percutaneous or parenteral administration.
  • Tablets, coated tablets, capsules, pills, suspensions or solutions are particularly suitable for the preferred oral application.
  • the drugs formulated as above preferably contain
  • anti-estrogens or aromatase inhibitors can also be administered together with ⁇ -receptor blockers.
  • Anti-estrogens and ⁇ -receptor blockers or aromatase inhibitors and ⁇ -receptor blockers are preferably administered simultaneously in separate or uniform dose units.
  • ß-receptor blockers are administered together with anti-estrogens or aromatase supporters in the same form and in the same amount or reduced by half compared to the treatment with ß-blockers alone.
  • the weight ratio of aromatase inhibitor to ⁇ -blocker for testolactone as an aromatase inhibitor and propranolol as a ⁇ -blocker is approximately 1: 1 to 15: 1. Depending on the potency of the active ingredients, the weight ratio of the combination can be adjusted accordingly.
  • ⁇ -blockers are also suitable as ⁇ -receptor blockers, such as oxprenolol, nadolol, pindolol, mepindolol, sotalol, etc.
  • composition of an oily solution Composition of an oily solution
  • the solution is filled into an ampoule and sterilized.
  • composition of a tablet is Composition of a tablet:

Abstract

Utilisation of antiestrogen and aromatase inhibitors, optionally in combination with $g(b)-receptor blockers for the prophylaxis and therapy of coronary heart diseases. Substances such as tamoxifen are considered to be used as antiestrogen, and such as testolactone to be used as aromatase inhibitors.

Description

Prophylaxe und Therapie von koronaren Herzkrankheiten durch Senkung des Östrogenspiegels Prophylaxis and therapy of coronary heart diseases by lowering the estrogen level
Die Erfindung betrifft die Prophylaxe und Therapie von koronaren Herzkrankheiten durch Senkung des Östrogenspiegels. Koronare Herzkrankheiten gehören zu den häufigsten lebensbedrohenden Gefäßerkrankungen. Zur Behandlung dieser Krankheiten verwendet man mehrere Präparate, die einmal auf das Gefäßsystem erweiternd wirken, die die gestörte Sauerstoffversorgung des Herzmuskelgewebes (Myocard) verbessern und die dazu noch die Bildung von Blutgerinseln (Thrombozytenaggregation) verhindern sollen. Darüber hinaus wird auch der Blutdruck medikamentös gesenkt.The invention relates to the prophylaxis and therapy of coronary heart diseases by lowering the estrogen level. Coronary artery disease is one of the most common life-threatening vascular diseases. For the treatment of these diseases, several preparations are used, which have an expanding effect on the vascular system, which improve the disturbed oxygen supply to the heart muscle tissue (myocardium) and which are also intended to prevent the formation of blood clots (platelet aggregation). In addition, the blood pressure is also lowered with medication.
Obwohl seit vielen Jahren bekannt ist, daß Männer mit koronaren Herzkrankheiten wie Angina pectoris, Koronarinsuffizienz, drohendem oder eingetretenem Herzinfarkt im Serum erhöhte Ostrogenspiegel aufweisen, hat man noch niemals versucht, eine Behandlung vorzunehmen, bei der der Ostrogenspiegel gesenkt wird.Although it has been known for many years that men with coronary heart diseases such as angina pectoris, coronary insufficiency, impending or occurring myocardial infarction have elevated estrogen levels, no attempt has ever been made to carry out a treatment in which the estrogen level is lowered.
Eine Behandlung durch Senkung des Östrogenspiegels wurde bisher nur bei Erkrankungen endokriner Drüsen vorgeschlagen, zum Beispiel bei Mammakarzinom (US-Patent 4.235.893, Endocrinology 100 (1977) 1684 - 1695), Prostatahyperplasie (DE-OS 2 817 157 und DE-OS 3 121 153) oder Oligospermie (J. Clin. End. and Met. 52 (1981) 897 - 902).Treatment by lowering the level of estrogen has hitherto been proposed only for diseases of endocrine glands, for example breast cancer (US Pat. No. 4,235,893, Endocrinology 100 (1977) 1684-1695), prostatic hyperplasia (DE-OS 2 817 157 and DE-OS 3 121 153) or oligospermia (J. Clin. End. And Met. 52 (1981) 897-902).
Zur Senkung des Östrogenspiegels kommen Antiöstrogene wie Tamoxifen und insbesondere Aromatasehemmer wie Testolacton infrage. Man hat festgestellt, daß der Serumöstradiolspiegel bei Männern mit koronaren Herzkrankheiten signifikant höher liegt als bei gesunden Männern (The American Journal of Medicine 74 (1983) 863 - 869). Ebenso sind die Serumöstrogenspiegel bei Männern mit akutem Herzinfarkt erhöht (The American Journal of Medicine 73 (19Ö2) 872 - 881).Anti-estrogens such as tamoxifen and especially aromatase inhibitors such as testolactone can be used to lower estrogen levels. It has been found that serum estradiol levels are significantly higher in men with coronary artery disease than in healthy men (The American Journal of Medicine 74 (1983) 863-869). Serum estrogen levels are also increased in men with an acute heart attack (The American Journal of Medicine 73 (19Ö2) 872 - 881).
Ferner ist bekannt, daß Aromatasehemmer den Östrogengehalt im Plasma senken (J. Clin. and Met. 52 (1981) 897 - 902).It is also known that aromatase inhibitors reduce the estrogen content in plasma (J. Clin. And Met. 52 (1981) 897-902).
Es wurde nun gefunden, daß durch Verabreichung von Aromatasehemmern auch der Östrogengehalt im Herzvorhof (Atrium cordis) vermindert werden kann.It has now been found that the administration of aromatase inhibitors can also reduce the estrogen content in the atrium (atrium cordis).
Behandelt man geriatrische Rattenböcke (Alter ca. 2 Jahre) über 8 Tage subkutan mit einem Aromatasehemmer, wie zum Beispiel täglich 6 mg 4-Hydroxy-4-androsten-3.17-dion, und senkt damit den Östrogengehalt im Plasma, so findet man nach Gabe von ( 3H)-Östradiol einen überraschendenIf geriatric rat goats (age approx. 2 years) are treated subcutaneously for 8 days with an aromatase inhibitor, such as 6 mg 4-hydroxy-4-androsten-3.17-dione daily, and the estrogen content in the plasma is thus reduced, one finds after administration of (3H) -estradiol a surprising
Anstieg der Tritiumaufnähme im Atrium gegenüber einer nicht mit 4-Hydroxy-4-androsten-3, 17-dion behandelten Kontrollgruppe. Hieraus läßt sich schließen, daß der Aromatasehemmer den Östrogenspiegel insgesamt im Organismus senkt und damit auch den Einbau von Östrogenen im Atrium vermindert. Mit der dann folgenden Zugabe von spezifisch hoch Tritium-markiertem Östradiol (1 /ug 3,17-Dihydroxy-1, 3, 5( 10)-/2, 4, 6, 7, 16, 17-3H7-estratrien) findet eine bevorzugte Aufnahme in die an Östrogen verarmten Östrogenrezeptoren im Atrium statt. Der Faktor der Anreicherung gegenüber der Kontrollgruppe beträgt 3 und bestätigt damit die hohe Bedeutung, die im Zusammenhang zwischen Östrogenspiegel im Plasma, Östrogenauf- findung im Herzmuskel und koronaren Erkrankungen gegeben ist. Erste Ergebnisse einer Nacharbeitung einer in ScienceIncrease in tritium uptake in the atrium compared to a control group not treated with 4-hydroxy-4-androsten-3, 17-dione. From this it can be concluded that the aromatase inhibitor lowers the overall estrogen level in the organism and thus also reduces the incorporation of estrogens in the atrium. With the then following addition of specific high tritiated oestradiol (1 / ug 3,17-dihydroxy-1, 3, 5 (10) - / 2, 4, 6, 7, 16, 17- 3 H7-estratriene) is preferential inclusion in the estrogen-depleted estrogen receptors in the atrium instead. The enrichment factor compared to the control group is 3 and thus confirms the high importance given in connection with estrogen levels in plasma, estrogen detection in the heart muscle and coronary diseases. First results of a reworking in Science
196 (1977) 319 - 321 publizierten Arbeit von Stumpf et al. zeigen nach Applikation von ( 3H)-Ostradiol bei nicht vorbehandelten 2 Jahre alten Rattenböcken einen etwa 3fach höheren Östrogengehalt im Atrium als in anderen Teilen des Herzens oder im Plasma.196 (1977) 319-321 published work by Stumpf et al. show after application of (3H) -estradiol in untreated 2-year-old rat goats an approximately 3-fold higher estrogen content in the atrium than in other parts of the heart or in plasma.
Aus in vitro-Untersuchungen zur Aromatasehemmwirkung mit ß-Receptoren-Blockern in Sertoli-Zellen (Molecular and Cellular Endocrinology, 13 (1979) 241 - 253) ist bekannt, daß eine durch Inkubation mit Testosteron und Stimulation mit Epinephrin um den Faktor 9 verstärkte Bildung von Östradiol durch Zusatz von Propranolol auf das 2fache der Östradiolbildung gegenüber der Kontrollgruppe abfällt.It is known from in vitro investigations of the aromatase inhibitory effect with β-receptor blockers in Sertoli cells (Molecular and Cellular Endocrinology, 13 (1979) 241-253) that the formation is increased by a factor of 9 by incubation with testosterone and stimulation with epinephrine of estradiol drops by the addition of propranolol to twice the estradiol formation compared to the control group.
In neuen von V. Hansson, Oslo, durchgeführten in vitro- Studien wurde nun gefunden, daß sowohl ß-Receptoren- blocker, wie Propranolol und Mepindolol, als auch Aromatasehemmer, wie Testolacton und 4-Hydroxy-4- androsten-3, 17-dion, in Sertoli-Zellkulturen eine durch Isoproterenol induzierte Aromatisierung zu hemmen vermögen. Hier bietet sich eine Parallele in der Wirkungsweise von ß-Blockern und Aromatasehemmern an. Wenn auch der biochemische Angriffspunkt im Ablauf der Ereignisse, die zur Aromatisierung führen, ein anderer ist, so bleibt letztlich beiden Stoffklassen gemeinsam eine Minderung des endogenen Östrogengehalts.In new in vitro studies carried out by V. Hansson, Oslo, it has now been found that both β-receptor blockers, such as propranolol and mepindolol, and aromatase inhibitors, such as testolactone and 4-hydroxy-4-androsten-3, 17- dion, are able to inhibit aromatization induced by isoproterenol in Sertoli cell cultures. Here there is a parallel in the mode of action of ß-blockers and aromatase inhibitors. Even if the biochemical point of attack in the course of the events leading to the aromatization is different, both substance classes ultimately have a reduction in the endogenous estrogen content.
Aus den Ergebnissen der Studien von Hansson läßt sich folgern, daß die Aromatasehemmwirkung - mit ihrer Konsequenz einer verminderten Östrogenbildung - auch das Wirkprofil der ß-Blocker prägt. So wie Isoproterenol sollte auch Adrenalin (Epinephrin) die Aromatisierung induzieren. ß-Blocker greifen zweimal in den Östrogenbildungsregelmechanismus ein. Einmal über eine verminderte Adrenalinausschüttung per se und Blockierung des Angriffspunktes von Adrenalin (ß-Receptoren) und der damit geringeren Stimulierung einer Aromatisierung und zum anderen über die nachgewiesene sekundäre Hemmwirkung auf die als Folge der Stimulierung anlaufende Aromatisierung.It can be concluded from the results of Hansson's studies that the aromatase inhibitory effect - with its consequence of a reduced estrogen formation - also shapes the activity profile of the β-blockers. Like isoproterenol, adrenaline (epinephrine) should induce aromatization. β-blockers intervene twice in the estrogen regulation mechanism. Once over a diminished one Adrenaline release per se and blocking the point of attack of adrenaline (ß-receptors) and the consequent less stimulation of aromatization and secondly via the proven secondary inhibitory effect on the aromatization which starts as a result of the stimulation.
Erste klinische Versuche mit dem Aromatasehemmer Testolacton bei Patienten mit koronaren Herzkrankheiten sind vielversprechend.Initial clinical trials with the aromatase inhibitor testolactone in patients with coronary artery disease are promising.
In einem Fall ließen Angina-pectoris-Beschwerden schon nach 4wöchiger Einnahme von täglich je 2 mal 100 mg Testolacton nach und verschwanden schließlich völlig. Das durch Krampf- und Angstzustände gekennzeichnete Krankheitsbild wurde vom Patienten nicht mehr empfunden. Die Therapie wurde 5 Monate fortgesetzt. In dieser Zeit traten nur noch einmal kurzfristig Herzbeschwerden auf, die jedoch den früheren schmerzhaften Schweregrad nicht erreichten.In one case, angina pectoris symptoms subsided after taking 4 times 100 mg of testolactone twice a day for 4 weeks and finally disappeared completely. The patient was no longer aware of the clinical picture, which was characterized by convulsions and anxiety. Therapy continued for 5 months. During this time, heart problems only occurred briefly, but did not reach the previous painful severity.
Auch nach Absetzen des Testolactons blieben die Beschwerden aus, und der Patient ist weiterhin - nach Ablauf von weiteren 8 Monaten - beschwerdefrei. Da ein lebensbedrohender Zustand nicht vorlag, kann mit der Medikation so lange ausgesetzt werden, bis erneut Beschwerden eintreten, die dann nach Einsatz einer Erhaltungsdosis wieder zum Verschwinden gebracht werden können.Even after stopping the testolactone, the symptoms remained absent and the patient is still symptom-free after a further 8 months. Since there was no life-threatening condition, the medication can be suspended until symptoms arise again, which can then be resolved after the maintenance dose has been used.
Die Dosierung des Antiöstrogens bzw. des Aromatasehemmers richtet sich nach der Art und Schwere der Herzkrankheit. Im allgemeinen wird man mit einer täglichen Dosis eines Antiöstrogens, die der von 10 bis 200 mg Tamoxifen entspricht, oder eines Aromatasehemmers, die der von 50 bis 1000 mg Testolacton entspricht, auskommen. Zur Prophylaxe und Therapie von koronaren Herzkrankheiten sind erfindungsgemäß alle Stoffe geeignet, die eine Senkung des Östrogenspiegels bewirken. Zu diesen Stoffen zählen alle Antiöstrogene, die sowohl steroidal als auch nicht-steroidal sein können. Zu den am besten untersuchten nicht-steroidalen Antiöstrogenen zählen:The dosage of the anti-estrogen or aromatase inhibitor depends on the type and severity of the heart disease. In general, a daily dose of an anti-estrogen equivalent to that of 10 to 200 mg tamoxifen or an aromatase inhibitor equivalent to that of 50 to 1000 mg testolactone will be sufficient. For the prophylaxis and therapy of coronary heart diseases, all substances are suitable according to the invention which bring about a reduction in the estrogen level. These substances include all anti-estrogens, which can be both steroidal and non-steroidal. The best-studied non-steroidal anti-estrogens include:
Tamoxifen ((Z) -2-/p-(1, 2-Diphenyl-1-butenyl)-phenoxy7-Tamoxifen ((Z) -2- / p- (1,2-diphenyl-1-butenyl) phenoxy7-
N,N-dimethylethylamin) und dessen Salze,N, N-dimethylethylamine) and its salts,
Clomifen (1-/p-(ß-diethylaminoethoxy)pheny17-1, 2- diphenylchlorethylen,Clomiphene (1- / p- (ß-diethylaminoethoxy) pheny17-1, 2-diphenylchlorethylene,
Cyclofenil (Bis(p-acetoxyphenyl) cyclohexylidenmethan,Cyclofenil (bis (p-acetoxyphenyl) cyclohexylidene methane,
Nafoxidin ( 1 -( 2-/4-( 6-Methoxy-2-phenyl-3, 4-dihydro-1 - naphthyl)phenoxy7-ethyl)-pyrrolidin, hydrochlorid u.a.Nafoxidin (1 - (2- / 4- (6-methoxy-2-phenyl-3, 4-dihydro-1 - naphthyl) phenoxy7-ethyl) pyrrolidine, hydrochloride, etc.
Als Beispiele für steroidale Antiöstrogene seienExamples are steroidal anti-estrogens
11α-Methoxy-17α-ethinyl-östradiol und 16ß-Ethylöstradiol genannt.11α-methoxy-17α-ethinyl-estradiol and 16ß-ethyl estradiol called.
Ein Übersichtsreferat über die "Pharmalogie der Antiöstrogene", in dem noch weitere Antiöstrogene abgehandelt werden, ist publiziert in "Gynäkologe" 12 (1979) 199 - 211, Springer-Verlag.A review of the "Pharmalogy of Anti-Estrogens", in which other anti-estrogens are dealt with, is published in "Gynecologist" 12 (1979) 199-211, Springer-Verlag.
Da die beim Manne vorhandenen Ostrogene vorwiegend aus der peripheren Aromatisierung von androgenen Hormonen stammen (Excerpta Medica 1979, 42 - 50 und J. Clin. Endocrinol. Metab. 27 (1967) 1103 - 1111), sind Aromatasehemmer zur Senkung des Östrogenspiegels beim Manne besonders gut geeignet. Durch Verabreichung von Aromatasehemmern wird die Bildung von biologisch wirksamen Östrogenen (Östrogenbiosynthese) verhindert bzw. gehemmt. Erfindungsgemäß sind alle Aromatasehemmer geeignet, die die Östrogenbiosynthese hemmen und selbst nur geringe oder keine ostrogene oder andere hormonelle Wirkung entfalten. Aromatasehemmer gemäß vorliegender Erfindung sind zum BeispielSince the estrogens present in men mainly come from the peripheral aromatization of androgenic hormones (Excerpta Medica 1979, 42 - 50 and J. Clin. Endocrinol. Metab. 27 (1967) 1103 - 1111), aromatase inhibitors for lowering the estrogen level in men are special well suited. The administration of aromatase inhibitors prevents or inhibits the formation of biologically active estrogens (estrogen biosynthesis). According to the invention, all aromatase inhibitors are suitable which inhibit estrogen biosynthesis and which themselves have only little or no estrogenic or other hormonal action. Aromatase inhibitor according to For example, the present invention
Testolacton ( 17a-Oxa-D-homo-androsta-1, 4-dien-3.17-dion,Testolactone (17a-oxa-D-homo-androsta-1, 4-diene-3.17-dione,
Androst-4-en-4-ol-3, 17-dion (Endocrinology 100 (1977)Androst-4-en-4-ol-3, 17-dione (Endocrinology 100 (1977)
1684 - 1695),1684 - 1695),
Ester des Androst-4-en-4-ol-3, 17-dions (US-Patent 4 235 893)Esters of androst-4-en-4-ol-3, 17-dione (U.S. Patent 4,235,893)
Weitere geeignete Aromatasehemmer werden beschrieben beispielsweise in Endocrinology 92 (1973) 866 - 880, DE-OS 3 124 719 und US-Patent 4 289 762.Other suitable aromatase inhibitors are described, for example, in Endocrinology 92 (1973) 866-880, DE-OS 3 124 719 and US Pat. No. 4,289,762.
Die Erfindung betrifft auch Mittel zur Senkung des Östrogenspiegels für die Prophylaxe und Therapie von koronaren Herzkrankheiten bei Männern, wobei Antiöstrogene und insbesondere Aromatasehemmer zur Senkung des Östrogenspiegels geeignet sind.The invention also relates to agents for lowering the estrogen level for the prophylaxis and therapy of coronary heart diseases in men, anti-estrogens and in particular aromatase inhibitors being suitable for lowering the estrogen level.
Die Wirkstoffe (Ostrogenspiegelsenker) können mit den in der galenischen Pharmazie üblichen Zusätzen, Trägersubstanzen und/oder Geschmackskorrigentien nach an sich bekannten Methoden zu den üblichen Applikationsformen verarbeitet werden, beispielsweise für die orale, perkutane oder parenterale Applikation.The active ingredients (estrogen countersink) can be processed with the additives, carrier substances and / or taste correctants customary in galenical pharmacy according to methods known per se to give the usual forms of administration, for example for oral, percutaneous or parenteral administration.
Für die bevorzugte orale Applikation kommen insbesondere Tabletten, Dragees, Kapseln, Pillen, Suspensionen oder Lösungen infrage.Tablets, coated tablets, capsules, pills, suspensions or solutions are particularly suitable for the preferred oral application.
Die wie oben angegeben formulierten Arzneimittel enthalten vorzugsweiseThe drugs formulated as above preferably contain
10 - 100 mg Tamoxifen oder biologisch äquivalente Mengen eines anderen Antiöstrogens oder10 - 100 mg tamoxifen or biologically equivalent amounts of another anti-estrogen or
50 - 200 mg Testolacton oder biologisch äquivalente Mengen eines anderen Aromatasehemmers. Darüber hinaus können zur Behandlung von Herzkrankheiten gemäß vorliegender Erfindung auch Antiöstrogene oder Aromatasehemmer mit ß-Receptorenblockern gemeinsam verabreicht werden. Antiöstrogene und ß-Receptorenblocker oder Aromatasehemmer und ß-Receptorenblocker werden vorzugsweise gleichzeitig in getrennten oder einheitlichen Dosiseinheiten appliziert.50-200 mg testolactone or biologically equivalent amounts of another aromatase inhibitor. In addition, for the treatment of heart diseases according to the present invention, anti-estrogens or aromatase inhibitors can also be administered together with β-receptor blockers. Anti-estrogens and β-receptor blockers or aromatase inhibitors and β-receptor blockers are preferably administered simultaneously in separate or uniform dose units.
ß-Receptorenblocker werden zusammen mit Antiöstrogenen oder Aromatasehmmern in gleicher Form und gleicher oder bis auf die Hälfte herabgesetzter Menge im Vergleich zu der Behandlung mit ß-Blockern allein appliziert.ß-receptor blockers are administered together with anti-estrogens or aromatase supporters in the same form and in the same amount or reduced by half compared to the treatment with ß-blockers alone.
Das Gewichtsverhältnis von Aromatasehemmer zu ß-Blocker liegt für Testolacton als Aromatasehemmer und Propranolol als ß-Blocker etwa bei 1 : 1 bis 15 : 1. Je nach der Wirkungsstärke der Wirkstoffe kann das Gewichtsverhältnis der Kombination entsprechend angepaßt werden.The weight ratio of aromatase inhibitor to β-blocker for testolactone as an aromatase inhibitor and propranolol as a β-blocker is approximately 1: 1 to 15: 1. Depending on the potency of the active ingredients, the weight ratio of the combination can be adjusted accordingly.
Als ß-Receptorenblocker sind außer Propranolol auch alle anderen bekannten ß-Blocker geeignet, wie zum Beispiel Oxprenolol, Nadolol, Pindolol, Mepindolol, Sotalol usw. In addition to propranolol, all other known β-blockers are also suitable as β-receptor blockers, such as oxprenolol, nadolol, pindolol, mepindolol, sotalol, etc.
Beispiel 1example 1
100,0 mg 17a-0xa-D-homoandrosta-1, 4-dien-3, 17-dion (Testolacton)100.0 mg 17a-0xa-D-homoandrosta-1, 4-diene-3, 17-dione (testolactone)
80,5 mg Lactose80.5 mg lactose
39,5 mg Maisstärke39.5 mg corn starch
2,5 mg Poly-N-Vinylpyrrolidon 252.5 mg poly-N-vinylpyrrolidone 25
2,0 mg Aerosil2.0 mg Aerosil
0, 5 mg Magnesiumstearat0.5 mg magnesium stearate
225,0 mg Gesamtgewicht der Tablette, die in üblicher Weise auf einer Tablettenpresse hergestellt wird.225.0 mg total weight of the tablet, which is manufactured in the usual way on a tablet press.
Beispiel 2Example 2
50,0 mg 17a-0xa-D-homoandrosta-1, 4-dien-3, 17-dion (Testolacton)50.0 mg 17a-0xa-D-homoandrosta-1, 4-diene-3, 17-dione (testolactone)
115.5 mg Lactose115.5 mg lactose
54,5 mg Maisstärke54.5 mg corn starch
2,5 mg Poly-N-Vinylpyrrolidon 252.5 mg poly-N-vinylpyrrolidone 25
2,0 mg Aerosil2.0 mg Aerosil
0, 5 mg Magnesiumstearat0.5 mg magnesium stearate
225,0 mg Gesamtgewicht der Tablette , die in üblicher Weise auf einer Tablettenpresse hergestellt wird. 225.0 mg total weight of the tablet, which is manufactured in the usual way on a tablet press.
Beispiel 3Example 3
Zusammensetzung einer öligen Lösung;Composition of an oily solution;
50,0 mg 17a-Oxa-D-homoandrosta-1, 4-dien-3 , 17-dion (Testolacton) 378,4 mg Rizinusöl 64316 mg Benzylbenzoat50.0 mg 17a-Oxa-D-homoandrosta-1, 4-diene-3, 17-dione (testolactone) 378.4 mg castor oil 64316 mg benzyl benzoate
1072,0 mg = 1 ml Lösung1072.0 mg = 1 ml solution
Die Lösung wird in eine Ampulle gefüllt und sterilisiert.The solution is filled into an ampoule and sterilized.
Beispiel 4Example 4
Zusammensetzung einer Tablette:Composition of a tablet:
20,0 mg (Z)-2-/p-(1, 2-Diphenyl-1-butenyl) -phenoxy7- N,N-dimethyläthylamin (Tamoxifen) 120,5 mg Lactose20.0 mg (Z) -2- / p- (1, 2-diphenyl-1-butenyl) phenoxy7- N, N-dimethylethylamine (tamoxifen) 120.5 mg lactose
59 5 mg Maisstärke 2 5 mg Poly-N-Vinylpyrrolidon 25 2 0 mg Aerosil 0 5 mg Magnesiumstearat59 5 mg corn starch 2 5 mg poly-N-vinylpyrrolidone 25 2 0 mg Aerosil 0 5 mg magnesium stearate
205,0 mg Gesamtgewicht der Tablette, die in üblicher Weise auf einer Tablettenpresse hergestellt wird. 205.0 mg total weight of the tablet, which is manufactured in the usual way on a tablet press.

Claims

Patentansprüche Claims
1.) Mittel zur Senkung des Östrogenspiegels für die Prophylaxe und Therapie von koronaren Herzkrankheiten bei Männern.1.) Means for lowering the estrogen level for the prophylaxis and therapy of coronary heart diseases in men.
2.) Mittel nach Anspruch 1 auf Basis eines Antiöstrogens, gegebenenfalls in Kombination mit einem ß-Receptorenblocker.2.) Agent according to claim 1 based on an anti-estrogen, optionally in combination with a β-receptor blocker.
3.) Mittel nach Anspruch 1 auf Basis eines Aromatasehemmers, gegebenenfalls in Kombination mit einem ß-Receptorenblocker.3.) Composition according to claim 1 based on an aromatase inhibitor, optionally in combination with a β-receptor blocker.
4.) Mittel nach Anspruch 1 in einer oralen Applikationsform.4.) Composition according to claim 1 in an oral application form.
5.) Mittel nach Anspruch 1 für die perkutane oder parenterale Applikation.5.) Agent according to claim 1 for percutaneous or parenteral administration.
6.) Mittel nach Anspruch 1, enthaltend 10 - 100 mg6.) Composition according to claim 1, containing 10 - 100 mg
Tamoxifen oder biologisch äquivalente Mengen eines anderen Antiöstrogens.Tamoxifen or biologically equivalent amounts of another anti-estrogen.
7.) Mittel nach Anspruch 1, enthaltend 50 - 200 mg Testolacton oder biologisch äquivalente Mengen eines anderen Aromatasehemmers.7.) Composition according to claim 1, containing 50-200 mg testolactone or biologically equivalent amounts of another aromatase inhibitor.
8.) Prophylaxe und Therapie von koronaren Herzkrankheiten bei Männern durch Senkung des Östrogenspiegels.8.) Prophylaxis and therapy of coronary heart diseases in men by lowering the estrogen level.
9.) Verwendung von Antiöstrogenen, gegebenenfalls in9.) Use of anti-estrogens, possibly in
Kombination mit ß-Blockern zur Prophylaxe und Therapie von koronaren Herzkrankheiten nach Anspruch 8. Combination with β-blockers for the prophylaxis and therapy of coronary heart diseases according to claim 8.
10.) Verwendung von Tamoxifen gemäß Anspruch 9.10.) Use of tamoxifen according to claim 9.
11.) Verwendung von täglich 10 - 200 mg Tamoxifen bzw. biologisch äquivalente Mengen eines anderen Antiöstrogens nach Anspruch 9.11.) Use of daily 10-200 mg tamoxifen or biologically equivalent amounts of another anti-estrogen according to claim 9.
12.) Verwendung von Aromatasehemmern, gegebenenfalls in Kombination mit ß-Blockern, zur Prophylaxe und Therapie von koronaren Herzkrankheiten nach Anspruch 8.12.) Use of aromatase inhibitors, optionally in combination with β-blockers, for the prophylaxis and therapy of coronary heart diseases according to claim 8.
13.) Verwendung von Testolacton gemäß Anspruch 12.13.) Use of testolactone according to claim 12.
14.) Verwendung von täglich 50 - 1000 mg Testolacton bzw. biologisch äquivalente Mengen eines anderen Aromatasehemmers nach Anspruch 12. 14.) Use of daily 50-1000 mg testolactone or biologically equivalent amounts of another aromatase inhibitor according to claim 12.
PCT/DE1984/000137 1983-06-24 1984-06-19 Prophylaxis and therapy of coronary heart diseases by lowering the estrogen concentration WO1985000107A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19833323321 DE3323321A1 (en) 1983-06-24 1983-06-24 PROPHYLAXIS AND THERAPY OF CORONARY HEART DISEASES BY LOWERING THE OESTROGEN LEVEL
DEP3323321.7 1983-06-24

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WO1985000107A1 true WO1985000107A1 (en) 1985-01-17

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WO (1) WO1985000107A1 (en)

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US5595985A (en) 1989-03-10 1997-01-21 Endorecherche Inc. Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia
EP0943328B1 (en) * 1989-07-07 2004-06-16 Endorecherche Inc. Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia
US5441986A (en) * 1994-07-19 1995-08-15 Pfizer Inc. Estrogen agonists as remedies for prostate and cardiovascular diseases
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US6268390B1 (en) * 1991-09-27 2001-07-31 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US5472985A (en) * 1993-05-13 1995-12-05 Neorx Corporation Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells
US5599844A (en) * 1993-05-13 1997-02-04 Neorx Corporation Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells
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DE3323321A1 (en) 1985-01-03
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