WO1993002679A1 - Methode pour traiter le syndrome premenstruel par administration d'un inhibiteur de l'enzyme de conversion de l'angiotensine - Google Patents

Methode pour traiter le syndrome premenstruel par administration d'un inhibiteur de l'enzyme de conversion de l'angiotensine Download PDF

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Publication number
WO1993002679A1
WO1993002679A1 PCT/US1992/006210 US9206210W WO9302679A1 WO 1993002679 A1 WO1993002679 A1 WO 1993002679A1 US 9206210 W US9206210 W US 9206210W WO 9302679 A1 WO9302679 A1 WO 9302679A1
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WO
WIPO (PCT)
Prior art keywords
ace inhibitor
angiotensin
quinapril
pharmaceutically acceptable
premenstrual syndrome
Prior art date
Application number
PCT/US1992/006210
Other languages
English (en)
Inventor
Anthony Salvator Depadova
Original Assignee
Warner-Lambert Company
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 Warner-Lambert Company filed Critical Warner-Lambert Company
Publication of WO1993002679A1 publication Critical patent/WO1993002679A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Definitions

  • the present invention relates to a new method of treating premenstrual syndrome (PMS) or symptoms arising therefrom by administering an effective amount of an angiotensin converting enzyme (ACE) inhibitor .
  • PMS premenstrual syndrome
  • ACE angiotensin converting enzyme
  • Premenstrual syndrome is a combination of physical and psychological symptoms usually occurring in the luteal phase of the cycle and disappearing with the onset of menses and of sufficient severity to interfere with interpersonal relationships or social activities .
  • Psychological symptoms include depression, irritability, tension, anger, and fatigue .
  • Physical symptoms include breast swelling and tenderness , abdominal bloating and variable degrees of edema of the extremities .
  • An increased appetite with craving for sweet or salty food is also common .
  • PMS can be associated with personality change, irrationality, hostility, physical aggression, and frank psychosis .
  • the symptoms of PMS occur to some degree in 70% of women in the reproductive age group and 5% to 10% of women report some degree of temporary mental or physical incapacitation because of this problem.
  • hypothalamus is a major controlling center of functions within the central nervous system (CNS) and to the periphery. It contains opioid and angiotensin II neurotransmitters and receptors. Cognition and behavior have hypothalamic interconnections.
  • CNS central nervous system
  • angiotensin II is a key mediator in PMS is suggested by its extensive presence in the hypothalamus and its interaction with peripheral hormonal and biochemical mediators which can evoke PMS symptomatology.
  • circulating angiotensin II can act on the subfornical organ, an area connected to the hypothalamus and lying outside the blood-brain barrier, by increasing neuronal activity on these nuclei. This increased activity has been shown to increase circulating levels of oxytocin and vasopressin.
  • Angiotensin II receptors are also involved in the release of GnRH and LH.
  • angiotensin II increases peripheral noradrenergic function and intraventricularly administered angiotensin II increases efferent sympathetic activity, with release of epinephrine, norepinephrine, ACTH, prolactin, and vasopressin into the circulation.
  • thala ⁇ us Parts of the brain in which receptors have been identified (mammalian species) are the midbrain, thala ⁇ us, hypothalamus, brain stem (nucleus tractus solitarius [NTS]) , dorsal motor nucleus of vagus, pineal gland, SFO, OVLT, and the anterior pituitary.
  • NTS nucleus tractus solitarius
  • the angiotensin II receptors in these brain areas and the effects produced by angiotensin II stimulation could produce the symptomatology of PMS.
  • the effects attributed to these areas are behavioral, endocrine, and cardiovascular. These include hormonal release from the anterior pituitary, pressor responses, and water drinking behavior.
  • Central angiotensin II also inhibits the release of renin from the juxtaglomerular cells of the kidney.
  • angiotensin II or its receptors may produce in some of the cognitive and behavioral symptoms of PMS.
  • angiotensin II stimulation is involved in the release of LH and FSH probably through activation of noradrenergic nerves in the hypothalamus which release GnRH.
  • the pulsatile release of LH is thought to precipitate the vasomotor instability and the phenomenon of "hot flashes”. It has also been shown that circulating angiotensin II levels vary with the menstrual cycle, increasing during the luteal phase.
  • Angiotensin converting enzyme (ACE) inhibitors intervene in the renin ⁇ angiotensin I —» angiotensin II sequence thereby reducing or eliminating the formation of the pressor substance angiotensin II.
  • Angiotensin II antagonist also can eliminate the effects of circulating angiotensin II. As such, the compounds have been described as useful in reducing or relieving hypertension but have never been described as being useful for the method of the present invention.
  • the present invention is a method of treating premenstrual syndrome in a female host suffering therefrom by administering to said host an effective amount of an angiotensin converting enzyme (ACE) inhibitor in a unit dosage form.
  • ACE angiotensin converting enzyme
  • the ACE inhibitors which can be used in the invention are any of a group of well— nown compounds previously described as being involved in reducing or eliminating the formation of the pressor substance angiotensin II in mammals.
  • One preferred group of compounds includes compounds conforming to the general formula
  • A is absent, a fused five-, six-, or seven—membered cycloaliphatic ring or a fused benzene ring which is unsubstituted or substituted by one or two alkoxy groups having one to four carbon atoms; n is zero or one, and R is hydrogen or alkyl having one to five carbon atoms.
  • A is absent, a fused five- or six-membered cycloaliphatic ring or a fused benzene ring which is unsubstituted or substituted by two methoxy groups? n is zero or one, and R is hydrogen or ethyl.
  • ACE inhibitors are alacepril, benzapril, captopril, cilazapril, delapril, enalapril, fosinopril, indolapril, libenzapril, lisinopril, pentopril, perindopril, quinoxipril, quinapril, ramipril, spirapril, or zofenopril, their corresponding free acids or pharmaceutically acceptable acid addition or base salts thereof.
  • Especially valuable as an ACE inhibitor is quinapril or quinaprilat (the free acid form) or a pharmaceutically acceptable acid addition or base salt thereof.
  • the total drug content of the final composition unit dosage form will be about 1% to about 70%, preferably from about 1% to about 25%.
  • the daily dosages of the pharmaceutical preparations of the invention depend upon the nature of the dosage form, the nature of the drug(s), and the type and extent of any interactive(s) , in drug combinations.
  • the therapeutic needs of the individual patient and the desires of the prescribing physician dictate the dosage levels to be employed.
  • the manufacturer's specifications for any drug or drug combinations are useful guides to administration.
  • the Physicians Desk Reference or other suitable publication can be consulted to ascertain appropriate dosage levels.
  • typical dosage levels for quinapril and enalapril are from about 1 g to about 80 mg per dosage.
  • Preferable daily doses of quinapril are from about 20 to about 40 mg.
  • the pharmaceutical compositions prepared in unit dosage form preferably contain additives and stabilizers as described in U.S. Patent 4,743,450 which disclosure is incorporated herein by reference.
  • the final form of the pharmaceutical preparations can vary greatly.
  • tablets, capsules, sachets, sprinklers, pomades, transdermal compositions, nasal formulations, ocular compositions, and the like are contemplated.
  • Orally administrable forms i.e., tablets, caplets, and capsules, are preferred.
  • Solid, semi-solid, and liquid formulations can be made. However, solids are highly preferred.
  • the drug preparations can be adapted for immediate, slow, or sustained release profiles, or any combination of these. Thus, a formulation adapted to give an initial loading dosage within 30 minutes followed by sustained release of the remaining drug over 4 to 12 hours is contemplated. Sustained and immediate release formulations are preferred.
  • EXAMPLE B The following materials were processed by wet granulation for 40-mg tablets.
  • the method of treating PMS is accomplished by administering to a female host capable of having a menstrual cycle, preferably nonpregnant females about the age 18 to about 45, a unit dosage form of an ACE inhibitor at least once a day and continuously, or preferably from about the 16th day of the menstrual cycle to onset of menses.
  • the dose can range from 20 to 80 mg per day, preferably 40 mg per day, preferably taken orally, once a day, in the morning, in preferably, two 20-mg tablets.
  • angiotensin II By inhibiting the production of angiotensin II, the ACE " inhibitor reduces or eliminates the symptoms of PMS.
  • the responsibility of angiotensin II in causing PMS can be postulated as follows:
  • the circulating estrogen and progesterone modulate angiotensin II receptor activity in the CNS, subfornical organ, OVLT, and peripherally.
  • Angiotensin II modulates gonadotrophic hormone release by inhibiting opioid pathways. There is a difference in sensitivity of areas of the brain to circulating angiotensin II, in patients with premenstrual syndrome, possibly with more variable facilitation or suppression of the neural pathways. An increased activity of angiotensin II may also be the result of increased converting enzyme activity, thus producing more angiotensin II. This can further suppress the activity of opioid receptors because the converting enzyme also breaks down opioid peptides and alters luteinizing hormone (LH) release and the release of other implicated hormonal mediators. Additionally, the activation of central angiotensin II pathways may produce other effects due to the wealth of interconnecting neurons.
  • LH luteinizing hormone
  • angiotensin pathways would be to activate ACTH release or increase autonomic nervous system activity.
  • Increased sympathetic activity can produce the symptoms of nervousness or agitation, while increased aldosterone levels and activation of the RAA system in the luteal phase may be responsible for fluid retention and other symptoms.
  • LH pulse frequency in the follicular phase of the menstrual cycle is approximately one pulse every 60 minutes.
  • LH pulse frequency slows to one pulse every 3 to 12 hours. This slowing of LH pulse frequency is mediated by increased central endogenous opioid peptide (EOP) tone as indicated by the ability of the opiate receptor blocker, naloxone, increase pulse frequency to one per hour.
  • EOP central endogenous opioid peptide
  • LH pulse frequencies are measured by placing an intravenous line in the antecubital vein. Blood samples (5 mL) are obtained every 15 minutes over a 24-hour period. Screen obtained is separated by centrifugation and stored at —20°C until assayed for LH by the known i munoluminescence technique. LH pulse frequency is determined by a computerized pulse analysis system. The administration of an effective amount of an ACE inhibitor, e.g., quinapril, increases LH pulse f equency.
  • an ACE inhibitor e.g., quinapril

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Une méthode pour traiter le syndrome prémenstruel consiste à administrer à un hôte femelle d'age menstruel une dose quotidienne d'une quantité efficace d'un inhibiteur de l'enzyme de conversion de l'angiotensine, par ex. le quinapril.
PCT/US1992/006210 1991-08-05 1992-08-03 Methode pour traiter le syndrome premenstruel par administration d'un inhibiteur de l'enzyme de conversion de l'angiotensine WO1993002679A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US74055791A 1991-08-05 1991-08-05
US740,557 1991-08-05

Publications (1)

Publication Number Publication Date
WO1993002679A1 true WO1993002679A1 (fr) 1993-02-18

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/006210 WO1993002679A1 (fr) 1991-08-05 1992-08-03 Methode pour traiter le syndrome premenstruel par administration d'un inhibiteur de l'enzyme de conversion de l'angiotensine

Country Status (4)

Country Link
AU (1) AU2413992A (fr)
MX (1) MX9204528A (fr)
PT (1) PT100759A (fr)
WO (1) WO1993002679A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0759754A1 (fr) * 1994-04-29 1997-03-05 DePadova, Anthony S. Methode de modification de l'activite du recepteur de l'angiotensine pour le traitement du syndrome premenstruel et de la douleur
US6469024B2 (en) 2000-05-11 2002-10-22 Bristol-Myers Squibb Company Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
US6649606B1 (en) 2001-11-09 2003-11-18 Bristol-Myers Squibb Co. Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity
US20100119482A1 (en) * 2004-05-13 2010-05-13 Anthony Joonkyoo Yun Treatment of Conditions Through Modulation of the Autonomic Nervous System During at Least One Predetermined Menstrual Cycle Phase

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AM J PHYSIOL, VOL. 245, NO. 6, PAGES R805-R810, December 1983, US M.K. STEELE ET AL. 'A possible role for the brain renin-angiotensin system in the regulation of LH secretion.' *
J CARDIOVASC PHARMACOL, VOL. 18, NO. 3, PAGES 462-467, 1991, NEW YORK, US C. TROFFA ET AL. 'Effect of angiotensin converting enzyme inhibition on the menstrual cycle of hypertensive women.' *
J. CARDIOVASC. PHARMACOL., VOL. 15, SUPPLEMENT 2, PAGES S6-S13, 1990, NEW YORK, US B. FABRIS ET AL. 'Inhibition of angiotensin-converting enzyme (ACE) in plasma and tissue' *
J. HYPERTENS., VOL. 7, SUPPLEMENT 5, PAGES S11-S16, 5 September 1989, GB C.I. JOHNSTON ET AL. 'Comparative studies of tissue inhibition by angiotensin converting enzyme inhibitors' *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0759754A1 (fr) * 1994-04-29 1997-03-05 DePadova, Anthony S. Methode de modification de l'activite du recepteur de l'angiotensine pour le traitement du syndrome premenstruel et de la douleur
EP0759754A4 (fr) * 1994-04-29 2000-07-05 Anthony S Depadova Methode de modification de l'activite du recepteur de l'angiotensine pour le traitement du syndrome premenstruel et de la douleur
EP1393722A2 (fr) * 1994-04-29 2004-03-03 DePadova, Anthony S. Utilisation d'antagonistes de l'angiotensine de type II (AT1) dans la fabrication d'un médicament pour le traitement du syndrome prémenstruel
EP1393722A3 (fr) * 1994-04-29 2004-06-23 DePadova, Anthony S. Utilisation d'antagonistes de l'angiotensine de type II (AT1) dans la fabrication d'un médicament pour le traitement du syndrome prémenstruel
US6469024B2 (en) 2000-05-11 2002-10-22 Bristol-Myers Squibb Company Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
US6649606B1 (en) 2001-11-09 2003-11-18 Bristol-Myers Squibb Co. Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity
US20100119482A1 (en) * 2004-05-13 2010-05-13 Anthony Joonkyoo Yun Treatment of Conditions Through Modulation of the Autonomic Nervous System During at Least One Predetermined Menstrual Cycle Phase

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Publication number Publication date
MX9204528A (es) 1993-02-01
AU2413992A (en) 1993-03-02
PT100759A (pt) 1993-09-30

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