BY ADMINISTRATION OF AN ANGIOTENSIN

CONVERTING ENZYME INHIBITOR

BACKGROUND OF THE INVENTION

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 .

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 . In its severest form, 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.

Numerous etiologies and therapies have been suggested for PMS , but to date no convincing evidence exists to support any particular theory . Assessments of estrogen or progesterone levels , the elimination ,

or the ratios of these hormones during the different phases of the cycle have been studied without any conclusive result.

The 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. The hypothesis that 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.

For example, 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. In addition, 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.

The various components of the renin angiotensin system, have been localized in the CNS as follows:

Converting: Enzyme

This has been localized to various cerebral blood vessels (choroid plexus, ependyma, subfornical organ (SFO) , organum vasculosum of the lamina

terminalis (OVLT) , neurosecretory nuclei of hypothalamus, median eminence, and posterior pituitary. It has been found in both synapses and neuronal cell bodies.

Angiotensin II Receptors

Parts of the brain in which receptors have been identified (mammalian species) are the midbrain, thalaπus, hypothalamus, brain stem (nucleus tractus solitarius [NTS]) , dorsal motor nucleus of vagus, pineal gland, SFO, OVLT, and the anterior pituitary.

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.

Many studies have detailed behavioral effects of angiotensin II in animals. Memory and learning in a passive avoidance paradigm were disturbed. In addition, there are changes in grooming and exploratory behavior as well as increase in the seizure threshold. However, there is a difficulty in ascribing complex behaviors such as grooming or drinking to one mediator such as angiotensin II since the number of programmed circuits in the brain and their interactions are so numerous.

Studies in patients utilizing converting enzyme inhibitors have demonstrated effects on mood, attention, and alertness. This is due to a postulated interaction with opioid receptors within

the CNS, and partly by the fact that converting enzyme inhibitors also inhibit enkephalinase which increases opioid receptor activity.

The above suggests that angiotensin II or its receptors may produce in some of the cognitive and behavioral symptoms of PMS.

As mentioned, 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 INVENTION

Accordingly, 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.

DETAILED DESCRIPTION

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

wherein 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. Preferably 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.

Other valuable 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.

Compounds of the above type and methods of manufacture are described in the following U.S. patents: 4,248,883, 4,410,520, 4,105,776, 4,512,924, 4,385,051, 4,374,829, 4,337,201, 4,425,355, 4,473,575, 4,374,847, 4,508,729, 4,344,949,

4,587,258, 4,470,972, and 4,316,906, the disclosures of which are incorporated herein by reference.

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%.

All percentages stated herein are weight percentages based on total composition weight, unless otherwise stated.

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. Thus, the therapeutic needs of the individual patient and the desires of the prescribing physician dictate the dosage levels to be employed. In general, however, 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.

Nonetheless, typical dosage levels for quinapril and enalapril, for example, 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. Thus, 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.

Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.

EXAMPLE A The following materials were combined by the wet granulation method for the manufacture of 5—mg tablets.

Quinapril Hydrochloride 21.7 mg

Magnesium Carbonate 125.0 mg

Lactose 38.0 mg

Gelatin 10.0 mg

Polyplasdone 8.0 mg

Magnesium Stearate 20 mg

EXAMPLE B The following materials were processed by wet granulation for 40-mg tablets.

Quinapril Hydrochloride 43.4 mg

Magnesium Carbonate 250.0 mg Lactose 66.6 mg

Gelatin 20.0 mg

Polyplasdone 16.0 mg

Magnesium Stearate 40 mg

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.

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. Other effects of the 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.

The patients' self evaluation following the administration of an ACE inhibitor, e.g., quinapril, over several cycles demonstrates its effectiveness by the reduction of symptoms attributed to PMS. In addition, measurement of LH pulse frequency can assess the possible mechanisms of drug action. For

example, LH pulse frequency in the follicular phase of the menstrual cycle is approximately one pulse every 60 minutes. In the luteal phase of the cycle, 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. An increase in ACE activity, or in the hypothalamic concentration of angiotensin II should also reduce EOP activity. This hypothesis and effects of ACE inhibition is evaluated by measuring patient responses with and without ACE inhibition in PMS patients. 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.