MXPA97002207A - Combination of prostaciclin with an oprogestin estrogen for the prevention and treatment of vascular ateroesclerotic diseases, including re-clampsia and for the treatment of hypertension and for therapy of stroke replacement - Google Patents

Abstract

Cardiovascular diseases, which include pre-eclampsia in pregnant women and hypertension in women and men, are prevented or treated by administering protacycline or a prostacyclin analogue in combination with an estrogen and a progestin, which combination is also useful for HRT (hormone replacement therapy) in peri and postmenopausal women

Description

COMBINATION OF PROSTACICLIN WITH AN ESTROGEN OR PROGESTINE FOR THE PREVENTION AND TREATMENT OF VASCULAR ATEROSCLEROTIC DISEASES INCLUDING PRECLAMPSIA AND FOR THE TREATMENT OF HYPERTENSION AND FOR THERAPY OF HORMONE REPLACEMENT.

D E S C R I P C I O N Background of the Invention., - This invention relates to a method for the prevention and treatment of vascular atherosclerotic diseases (cardiovascular diseases); for the prevention and treatment of pre-psia in pregnant women and for hormone replacement therapy in peri and postmenopausal women and for the treatment of hypertension in men and women.

Epidemiological data indicate that approximately half of deaths in economically developed countries are attributable to a single major cause, namely, cardiovascular diseases, including coronary heart disease, stroke and other forms of vascular disease (Green A. Bain. , C 1993). The most common and most lethal form of cardiovascular disease is coronary heart disease. In men, there is a continuous increase in the prevalence of cardiovascular diseases after 30-40 years of age. On the other hand, the cardiovascular disease regimen, especially coronary heart disease, is relatively low in premenopausal women but rises markedly with increasing age, suggesting that sex steroids (estrogen and progesterone) have a protective effect on women. The increased risk of coronary heart disease among women with bilateral oophorectomy also supports the view that steroid hormones may play a protective role in relation to cardiovascular diseases.

Cardiovascular diseases can be prevented in postmenopausal women by hormone replacement therapy (HRT) with estrogen. The meta-analysis recently conducted in 29 studies demonstrated a risk of reduced cardiovascular disease among estrogen users in 23 of these studies (Sta pfer et al., 1991). On the other hand, there are no effective methods for the prevention of cardiovascular diseases in man, since estrogen can not be used because of its side effects.

The mechanism of the protective effect of female hormones is not fully understood. An impact on the lipid profile may be possible. Among postmenopausal women, estrogen reverses atherogenic changes in the lipid profile that is associated with early menopause, such as the increase in LDL cholesterol and triglyceride levels in the serum and the decrease in HDL cholesterol. However, new data suggests that both estrogen and progesterone may have a direct effect on blood vessels. The presence of progesterone and estrogen receptors in artery and smooth muscle endothelial cells supports the view that sex steroids can have a direct effect on blood vessels (Lin et al., 1986). Estrogen therapy has also been shown to result in the redistribution of arterial estrogen receptors and in the increase in arterial progesterone receptors in mandrels (Lin. Et al., 1986). The study in monkeys suggests that estrogens can prevent atherosclerosis induced ovariectomy by inhibiting the uptake and degradation of LDL in the wall of the artery (Adams, et al., 1992). The effects of estrogen and / or progesterone on the arterial appearance may also explain some of the beneficial effects of HRT on the risk of arterial disease. From animal models it is known that estrogens increase uterine blood flow by regulating the arterial appearance (Greiss &Anderson,., 1970, Ganger et al., 1993). The effects of a sex steroid on the vascular aspect suggest that sex steroids may play a role in the pathogenesis of hypertension.

The effects of steroids on the vessels can be mediated by several locally produced hormones including citric oxide, prostacyclin and endothelin. Both nitric oxide and prostacyclin induce vascular relaxation and inhibit platelet aggregation. On the other hand, endothelin has a strong vasoconstrictor effect. Nitric oxide is produced by endothelial cells and is involved in the regulation of vascular appearance, platelet aggregation, neurotransmission and immunoactivation (Furchgott and Za adz i, 1980., Moneada, Palmer and Higgs, 1991). Nitric oxide, formally known as FRDE (relaxation factor derived from endothelin) (Furchgott and Zawadzki, 1980., Moneada, Palmer and Higgs, 1991), is synthesized by the oxidative deamination of a guanidino nitrogen of L-arginine by at least three different isoforms of an enzyme containing flavin, nitric oxide synthase (Moneada, Palmer and Higgs., 1991). Nitric oxide increases the levels of c-GMP (guanosine monophosphate 1, 3, 5-cyclic) within vascular smooth muscle to produce relaxation and reduce the appearance of blood vessels (Moneada, Palmer and Higgs., 1991).

Prostacyclin is a potent inhibitor of endogenous platelets and antithrombogenic substance that acts as a local regulator of cell wall interaction (Willis and Smith., 1989). The pharmacological effects of prostacyclin are similar to those of nitric oxide. It is a powerful vasodilator that depending on the dose lowers the peripheral arterial resistance and the blood pressure. The clinical use of prostacyclin is limited due to its chemical instability. Therefore, a prostacyclin analog, ie, a prostaglandin derivative with a structure related to the prostaglandin which exhibits an effect on the cardiovascular system, for example, inhibitions of platelet aggregation, is preferred. Iloprost and Cicaprost are stable analogs of prostacyclin. Iloprost was the first synthesized compound that combined the biological profile of prostacyclin with chemical stability (Skuballa et al., 1985). Cicaprost is a metabolically stable and chemically stable prostacyclin analogue that shows high bioavailability and long duration of action (Skuballa et al., 1986). It is a highly specific prostacyclin mimic, which exhibits only minor if there are effects on organic systems sensitive to other prostaglandins.

There is evidence that prostacyclin analogs exert protective effects on the endothelium. The beneficial effects of Iloprost and Cicaprost on atherosclerosis have been described in animal models. Oral treatment of rabbits fed cholesterol with Cicaprost reduced the formation of aortic atheromatous plaques and partially prevented the damage induced by hypercholesterolenia of endothelium-dependent relaxation (Braun, M. et al., 1992). In addition, Cicaprost reduced platelets induced by hypercholesterolemia and neutrophil hyperactivity in rabbits (Hohfeld et al., 1992). Platelets and leukocytes are believed to contribute to atherogenesis. In addition, studies in rabbits showed that oral Cicaprost has a beneficial effect on the damage induced by coronary vasodilation hypercholesterolemia (Woditsch I, et al., 1992). Iloprost has been found to protect the microvascular arteriolar endothelium from damage by cyclosporin (Burton GA et al., 1992).

These animal studies suggest that prostacyclin analogs alone may be protective against atherosclerosis. There are no experimental or clinical studies with a combination of prostacyclin analogues with a progestin or an estrogen.

Preeclampsia is a specific disease of pregnancy classically defined as the triad of hypertension, pathological edema and proteinuria normally associated with fetal hypotrophy. The etiology and pathogenesis of this common disease (approximately 10% of all pregnant women) has been poorly studied. It is generally believed that preeclampsia is linked to prostacyclin deficiency and increased production of thromboxane A2. Current therapy is restricted to bed rest (benign form), symptomatic medication with antihypertensive drugs and early delivery with risks of operative delivery care and iatrogenic prematurity. In pre-eclampsia, there is a reduced preload, a low cardiac output and a high posterior load that is consistent with a decreased intravascular volume and increased peripheral vascular resistance. The increased peripheral resistance has been explained by (1) the increased vascular sensitivity to oppressive agents and (2) the presence of a vasoactive substance.

There is considerable evidence that preeclampsia is associated with an increased sensitivity of the oppressive effects of angiotensin 11 and other vasoactive agents (Abdul-Karim 1961, Gant 1973, Gant 1974) platelet activation, (Bonner 1971, Perkins 1979, Giles 1981) , and endothelial cell damage (Roberts 1989, Shanklin 1989). The prominent clinical features of preeclampsia, edema and proteinuria are consistent with the loss of endothelial transport function.

Often, pre-eclampsia is considered an acute form of atherosclerosis. The spiral arteries that perfuse the interbilious space of the normal placenta undergo extensive morphological changes during normal pregnancy, ie a fourfold increase in diameter and a loss of its muscular and elastic components (Robertson., 1986). These changes allow an approximate 10-fold increase in uterine blood flow that occurs during normal pregnancy. These changes are absent in preclampsia (Robertson, 1986) so that the intramiometrial segments of the spiral arteries are unable to dilate. In addition, the basal arteries and myometrial segments of spiral arteries in the preclampic placenta show characteristic lesions that have been called "acute atherosis" (Roberts, 1989). In acute atherosis of the preclampic uterus there is a damage of endothelial cells, a focal interruption of the basement membrane, lipoid necrosis with platelet deposition of muscle cells (foam cells), (a result of chronic hypoxia and / or cytotoxins), thrombomural and fibrinoid necrosis (Robertson., 1967, DeWolf., 1980 and Roberts, 1989), effects very similar to those seen in atherosclerotic vascular disease.

There is also evidence that prostacyclin production is decreased in pre-eclampsia. In a normal pregnancy there is a 5- to 10-fold increase in the production of prostacyclin compared to the non-pregnancy state (Goodman 1982, Walsh 1985, Fitzgerald, 1987). In contrast, there is a decrease in the production of prostacyclin in the maternal cord blood vessels and placenta and in the cotyledons of the placenta (Remuzzi 1980, Makila 1984, Walsh 1985) in preclampsia. An imbalance in the ratio of thromboxane A2 to prostacyclin in preeclampsia has been proposed as a major pathological mechanism in preeclampsia (Walsh 1988, Fitzgerald 1987, Friedman 1988). Other experimental studies (unreported) in pregnant rats and guinea pigs indicate that nitric oxide deficiency is the main event in preeclampsia. The inhibition of nitric oxide synthesis during pregnancy with "L-NAME" caused the classic symptoms of hypertension, proteinuria and retardation in the development of the fetus.

Prostacyclin is available as a stable lyophilized preparation, for example, epoprostenol, for intravenous administration to man. A major limitation of epoprostenol is the need to administer it parenterally, the ratio of excessive dose response to both platelet inhibition and the occurrence of side effects and its short duration of action (Moran and Fitzgerald 1994; Vane 1993). The marked drop in systemic blood pressure, especially associated with the use of epoprostenol, or intravenous Iloprost, is why the use of prostacyclin and its analogs has not been widely used in the management of cardiovascular diseases (Vane, 1993).

Attempts have been made to treat pre-eclampsia with prostacyclin. Prostacyclin consistently relaxes the blood vessels of the placenta when they have been tested in vitro (Glance 1986, Howard 1986, Maigaard 1986). However, when tested in vivo, the infusion of prostacyclin did not result in increased placental perfusion in sheep (Phernetton, 1979, Rankin 1979, Landauer 1985) and humans (Husslein 1985).

In addition, studies in the sheep model also showed that the infusion of prostacyclin leads to a decrease in perfusion of the placenta with results of detrimental effects on the fetus.

When it becomes evident that there is an imbalance in the production of increased thromboxane and decreased prostacyclin in pre-eclampsia, some researchers tried to treat this disease by means of an infusion of constant intravenous prostacyclin. There are three reports of 7 women with severe preclampsia who were treated with prostacyclin (4-8 ng / kg / min, 5 hours to 11 days) after the failure of conventional medications (Fidler 1980, Lewis 1981, Belch 1985). In all women there was a rapid decrease in blood pressure during the infusion of prostacyclin. The clinical result of these studies was scarce. All the children were born prematurely by caesarean section and only 4/7 survived. Fetal bradycardia was observed during the treatment and two fetuses died during the prostacyclin infusion. The treatment with prostacyclin caused a stabilizing phenomenon in those studies and uterine-placental blood flow really decreased. This explanation is supported by a study of the effects of prostacyclin in two cases of several delays in premature fetal development. Intravenous prostacyclin was administered in an attempt to promote fetal development and thus prolong pregnancy. This attempt failed and resulted in an intrauterine death in each case. In this report, the infusion rate of 4 ng / kg / min. was limited by maternal side effects (Steel and Pearce 1988).

These observations indicated that the treatment of pre-eclampsia already established with high doses of prostacyclin is a risky and ineffective strategy. On the other hand, there are no effective methods for the prevention of pre-eclampsia. Aspirin, when given to inhibit the synthesis of prostaglandins at relatively low doses, is thought to suppress predominantly the production of thromboxane A2 platelets with little inhibition of vascular prostacyclin production (Massoti 1979). Therefore, a low dose of aspirin was proposed for the prevention of pre-eclampsia. The results of the recently published multicenter studies are discouraging and low-dose aspirin is not usually recommended for the prevention of pre-eclampsia (CLASP Collaborative Group, 1994). Therefore, there is a need for an effective and safe method to prevent and treat pre-eclampsia.

The unexpected results of the studies described below indicate that the blood vessel response to prostacyclines and the effect of lowering blood pressure in the subsequent blood is controlled by progesterone. Treatment of pregnant rats with the nitric oxide inhibitor (L-NAME) produces signs and symptoms of pre-eclampsia (eg, hypertension, fetal retardation, and proteinurea, the classic pre-eclampsia triad). These symptoms are related to the decrease in vascular resistance and placental perfusion. In the rat model of preeclampsia (inhibition of nitric oxide synthesis with L-NAME), the blood pressure lowering effects of Cicaprost and Iloprost are greater in later pregnancy when progesterone levels are elevated in the Pregnant rats After delivery, when blood levels of progesterone decrease, there is a rapid increase in blood pressure in animals treated with L-NAME and Cicaprost or Iloprost. Injection of an R5020 progesterone receptor agonist (promegestone) restores the efficacy of Iloprost / Cicaprost to lower blood pressure. In addition, progesterone partially lowers blood pressure in male rats treated with L-NAME and the antiprogestin RU486 raises the blood pressure in this model. Therefore, the pregnancy condition and the progestin treatment greatly increase the responses of the blood vessels to exogenous prostacyclin. The increased response of blood vessels results in the decrease of the effective dose of prostacyclin analogues and subsequently in the reduction of side effects. The treatment of preclampic rats with a combination of prostacyclin and a progestin is therefore widely effective in lowering blood pressure and fetal mortality and in reversing the delay in fetal development.

A prostacyclin analog in combination with a progestational agent reverses the increase in blood pressure induced by the inhibition of nitric oxide. Therefore, prostacyclin in combination with progesterone can completely compensate for nitric oxide deficiency. These observations indicate that both prostacyclin and nitric oxide systems are complementary (and interchangeable) in relation to blood pressure control.

Preeclampsia is a well-known model of atherosclerosis when the decrease in the placenta is accompanied by increased fibrin deposition in the placental vessels and increased thrombosis formation. Therefore, this regimen is also effective in preventing and treating atherosclerotic diseases in female and male mammals.

It is well known that estrogen regulates progesterone receptors in a variety of target organs. Therefore, administration of estrogen concurrent with a progestin is preferred.

OBJECTS OF THE INVENTION It is an object of the invention to provide a method for preventing and treating atherosclerotic vascular diseases (cardiovascular diseases) in female and male mammals, with a combination of prostacyclin or one of its stable analogues, for example Iloprost and Cicaprost, with a progestogen and / or estrogen It is a further object to provide a method for hormone replacement therapy (HRT) in the peri and post-menopausal female using an estrogenic agent in combination with prostacyclin or one of its stable analogues.

It is another object to provide a method for hormone replacement therapy (HRT) in the peri and post menopausal female using a combination of an estrogenic agent and a progestin agent with prostacyclin or one of its stable analogues.

It is another object to provide a method in which a progestin and / or estrogen is used in combination with prostacyclin or one of its stable analogues to prevent and treat pre-eclampsia in pregnant mammals.

It is another object to provide a method in which progestin and / or estrogen is used in combination with prostacyclin or one of its stable analogues, for example Iloprost and Cicaprost, for the treatment of hypertension, both in female and male mammals.

A further object is to provide pharmaceutical compositions useful for practicing the methods of this invention.

Other objects will be apparent to those skilled in the art to which this invention pertains.

THE INVENTION In one aspect of the method, this invention relates to a method for preventing and treating atherosclerotic vascular diseases (cardiovascular diseases) in female and male mammals, including the treatment of pre-eclampsia in pregnant female mammals and treating hypertension in female and male mammals, which it comprises administering to a subject exhibiting such symptoms (a) a prostacyclin or a prostacyclin analog, for example in a bioequivalent amount at 0.1-10 ng / kg / min. of prostacyclin intravenously and (b) one or both of a progestin and an estrogen, for example, an amount of estrogen bioequivalent to about 2 mg per day of estradiol and an amount of progestin bioequivalent to 50-300 mg of progesterone injected.

Other aspects will be apparent to those skilled in the art to which this invention pertains.

DETAILED DESCRIPTION The compositions of this invention can be used to prevent and treat atherosclerotic vascular disease (cardiovascular disease) and treat hypertension in female and male mammals, preferably humans and use for hormone replacement therapy in peri and post menopausal women. The methods of this invention can prevent and treat pre-eclampsia in pregnant mammals, for example, a human who manifests such symptoms or who is a high-risk candidate for that to happen, for example, as determined by the progress of a present pregnancy or previous.

Since female steroids (progesterone and estrogen) act synergistically with prostacyclin and its analogs, a combination of prostacyclin analogs with a progestin, an estrogen or both estrogen and progestin is used. A synergistic effect is achieved when progestational and / or estrogenic people are concurrently administered with prostacyclin or prostacyclin analogue.

Therefore, the aspect of the method of this invention and the aspect of the pharmaceutical composition of this invention employ prostacyclin or a prostacyclin analog and one or more of an estrogen (eg, estradiol valerate, conjugated equine estrogens, 17beta-estradiol). , estriol or ethinylestradiol such as "Pyrigynova R", Schering AG) and a progestin (for example progesterone, dydrogesterone, medroxyprogesterone, norethisterone, levonogestrel, norgestrel or gestoden).

Examples of combinations of prostacyclin analogs that are administered concurrently with a progestin and / or an estrogen are: prostacyclin (epoprostenol), Iloprost, Cicaprost. The following are typical oral dosing regimens of active agents of estrogen and progestin with a prostacyclin analog: Prostacyclin: Iloprost, 10-1000 mg / patient; 2 times a day orally; Cicaprost, 1-100 pg / patient; 2 times a day orally.

Estrogens: a daily dose bioequivalent to approximately 1 to 2 mg / day, for example "Pre arin R" (Wyeth-Ayerst), 0.625 mg / day; estradiol valerate, 50 U / 9 / day transdermal, vaginal estradiol creams, 1.25 mg / day and vaginal estradiol rings, 0.2 mg / day.

Progestins: a daily dose bioequivalent to 50-300 mg of progesterone / day, for example an injectable suspension of medroxyprogesterone acetate, to provide a weekly dose of 100-1000 mg in tablets or lozenges that provide an oral dose of 5-10 mg / day, an injectable solution of hydroxyprogesterone caproate that provides a weekly dose of 250-500 mg.; tablets, capsules or tablets of nortrindrone acetate that provides a daily dose of 5-20 mg.

Examples of estrogens and progestins are listed below. ("Natural" oral estrogens used in hormone replacement therapy are usually available in the UK).

Product Composition Dosage (mg per day) Climaval (Sandoz) estradiol valerate 1 or 2 Progynova (Schering) estradiol valerate 1 or 2 Harmogen (Abbott) piperazine sulfate 1.5 or 2.5 estrone Hormonin (Shire) estradiol 0.6 + estrone + estriol "Premarin" (equine Wyeth-estrogens conjugated 0.625 or 1.25 Ayerst) or 2.5 A commercially available combination of scheduled packages or hormone replacement therapy includes "Estrapak", "Prempak-C", "Trisequens", "Trisequens forte" and "Cycloprogynova". The following are illustrative compositions of these products: Estradiol 50 mg / day (28 days, 8 patches); conjugated equine estrogens 0.625 mg / day (28 days); estradiol valerate 2 mg / day (11 days); estradiol valerate 2 mg / day; norgestrel 0.5 mg / day (12 days); norgestrel 0.15 mg / day (12 days); conjugated equine estrogens 1.25 mg / day (28 days); Norethisterone acetate 1 mg / day (10 days); estradiol 1 mg / day + estriol 0.5 mg / day (6 days); Norethisterone acetate 1 mg / day (10 days); estradiol 1 mg / day + estriol 0.5 mg / day (6 days); estradiol valerate 1 mg / day (21 days); levonorgestrel 0.25 mg / day (10 days); estradiol valerate 2 mg / day (21 days); levonorgestrel 0.5 mg / day (10 days).

Daily doses of progestogen will be taken for 12 days per month by patients receiving oral or transdermal estrogens: Norestisterone 0.7-2.5 mg / day; Medroxyprogesterone acetate 10 mg / day; norgestrel 150 mg / day; and dydrogesterone 10-20 mg / day.

The pharmacologically active agents employed in this invention can be administered in admixture with conventional excipients, for example pharmaceutically acceptable liquid, semi-liquid or solid carriers., organic or inorganic, suitable, for example for parenteral or enteral application and which do not react badly with the active compound in mixture. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, crude paraffin, perfume oil, monoglycerides and acid diglycerides. fatty acids, fatty acid esters pentaerythritol, hydroxymethylcellulose, polyvinylpyrrolidone, etc.

The pharmaceutical preparations can be sterilized and, if desired, mixtures with auxiliary agents, for example, lubricants, preservatives, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavors and / or aromatic substances and the like. similar that they do not react in a harmful manner with the active compounds.

For parenteral application, particularly suitable solutions are, preferably oily solutions or aqueous solutions, as well as suspensions, emulsions or implants, including suppositories and transdermal patches. The ampoules are conveniently unit dosages.

In the preferred aspect, the compositions of this invention are adapted for ingestion, For enteral application, unit dosage forms are particularly suitable, for example tablets, dragees or capsules having talc and / or carbohydrates as binding carriers or the like, the carrier being preferably lactose and / or corn starch and / or starch of dad; particulate solids, for example, granules; and liquids and semi-liquids, for example syrups and elixirs or the like, wherein an adulterant vehicle is used. Sustained release compositions can be formulated including those in which the active compound is protected with differently degradable coatings, for example by microencapsulation, multiple coatings, etc .:.

Suitable for oral administration are, among other forms, tablets, dragees, capsules, pills, granules, suspensions and solutions. Each unit dose, for example, each tablespoon of liquid or each tablet or dragee contains, for example 5-5000 mg of each active agent.

Solutions for parenteral administration contain, for example, 0.01 to 1% of each active agent in an aqueous solution or in an alcohol solution.

The prostacyclin analog can be administered as a mixture with an estrogen and / or progestin and any other optional active agent or as a separate unit dosage form, either simultaneously or at different times during the day from each other.

The combination of active agents preferably is administered at least once a day (at least administered in a dosage form that delivers the active agents continuously) and more preferably several times a day, for example, in 2 to 6 divided doses .

In humans, both the prostacyclin analogue and progesterone (or bioequivalent of another progestin) will occur in a ratio that produces blood plasma levels of approximately 30 to 100 micromolar progesterone and 500 to 1000 nmolar estradiol.

BRIEF DESCRIPTION OF THE DRAWINGS Various other objects, features and advantages that are achieved with the present invention will be more fully appreciated when they are better understood, taken in conjunction with the accompanying drawings, in which like reference characters denote the same or similar parts throughout. of the various views and where: Figure 1 (values of the effect of Cicaprost on blood pressure) shows that the progesterone agonist R5020 lowers blood pressure in the postpartum period in precalsic rats treated with Cicaprost (CCP). Preeclampsia was induced with a nitric oxide inhibitor L-NAME (25 mg / animal / day, s.c. infusion). Blood pressure changes with Cicaprost plus L-NAME during pregnancy parallel with endogenous levels if progesterone falls in blood pressure when progesterone levels are high before birth and an increase when progesterone levels are low postpartum.

Figure 2 (values of the drug effect on blood pressure) shows that the progesterone agonist R5020 (0.5 mg / animal / day, s.c.) reduces the induced hypertension of L-NAME in male rats.

Figure 3 (values of the effect of drug on blood pressure) shows that RU486 raises the postpartum blood pressure in animals treated with L-NAME and slightly increases the blood pressure in the controls.

Figure 4 (values of the effect of Iloprost on blood pressure) shows that Hoprost completely reverses the induced hypertension L-NAME during pregnancy when progesterone levels are high, but there is an increase in postpartum blood pressure. R5020 (5 mg / animal / day) dramatically decreases postpartum increase in blood pressure; Y Figure 5 is a bar chart showing that Iloprost partially inverts the fetal development delay induced by L-NAME (upper panel - breeding weight comparison) and reduces fetal mortality induced by L-NAME (bottom panel - comparison of baby mortality).

DISCUSSION OF THE DRAWINGS The results shown in the drawings confirm that progesterone controls the action of a prostacyclin by increasing the vascular response to this agent.

In the experiments whose results are shown by the graph in Figure 1, a specific progesterone agonist (R5020) restores the postpartum decrease in the effectiveness of Cicaprost to lower blood pressure. This study also shows that pregnancy (high levels of progesterone and estrogen) itself has a beneficial effect on hypertension induced by L-NAME. Figure 2 provides additional evidence that progesterone can induce mechanisms that compensate for hypertension produced by L-NAME. This study was conducted in male rats, showing that pregnancy is not essential for this effect. Figure 3 demonstrates that the effect of R5020 is mediated by the progesterone receptor, since the antiprogestin RU486 has an opposite effect (additional increase in blood pressure induced with L-NAME). Figure 4 shows that during pregnancy (high levels of progesterone and estrogen) Iloprost has a blood pressure lowering effect similar to that of Cicaprost and that this effect is highly attenuated postpartum when progesterone levels fall. Figures 5a and 5b show that Iloprost increases the perfusion of the placenta, since the weight of the fetus increases and the mortality of the fetus decreases in animals treated with Iloprost plus L-NAME compared to the group treated with L-NAME.

It can be concluded from these studies that the effects of prostacyclin in reducing blood pressure and increasing fetal perfusion depend on progesterone. In addition, as estrogen is required for the actions of progesterone to induce progesterone receptors, it can be inferred that estrogen is important for these effects. Therefore, the treatment method employed for this invention can be used for the treatment of pre-eclampsia, atherosclerotic vascular disease, hypertension (both in females and in males, and as an adjuvant in hormone replacement therapy).

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Am J Obstet Gynecol 1 67: 828-33 Walsh SW (1 985) Preeclampsia: an imbalance in placental prostacyclin and thromboxane production. Am J Obstet Gynecol 1 52: 335 Walsh SW, Papsi VM 1 986 The role of arachidinic acid metaboiism in preeclampsia. Sem Pennatol 1 0.4: 334 Willis AL, Smith DL (1,989) Therapeutic impact of eicanoids in atherosclerotic disease. Eicosanoids 2: 69-99 Woditsch I, et al. , (1 992), In Sinzinger HF, Schror K (eds) Prostaglandins in the Cardiovascular System. Birkkauser Verlag, Basel, Boston, Berlin, pp. 297-304 Vane IR The Croonian Lecture, 1 993 The master endothelium of the blood stream Phil Trans R Soc London (1 994) 225-246 Without further elaboration it is believed that one skilled in the art can use, using the preceding description, the present invention to all its extension. Therefore, the preferred specific embodiments are constructed as illustrative only and not limitative of the disclosure in any way. The full description of all the above-mentioned applications, patents and publications and the following are incorporated herein by reference.

EXAMPLES EXAMPLE 1: Prevention of atherosclerotic vascular disease with Iloprost and a combination of estrogen / progestin.

A non-pregnant human female (approximately 45 years, 50-80 kg) exhibiting the signs of menopause or postmenopausal symptoms was given an estrogen (eg estradiol valerate 1-2 mg / day) a progestin (eg norgestrel) 150 mg / day) and 50 mg of Iloprost 2 times a day, orally.

EXAMPLE 2: Prevention of atherosclerotic disease with Cicaprost and estrogen plus progestin hormone replacement therapy.

To a human female comparable to and exhibiting the same symptoms as in Example 1, one or both of the following was administered daily, an estrogen (estradiol valerate) 1-2 mg / day and a progestin (for example norgestrel at 150 mg / day). mg / day). Estrogen was administered with a prostacyclin, for example Iloprost or Cicaprost either continuous or in sequence with a progestin taken for only 6 to 12 days per month.

EXAMPLE 3: Prevention of atherosclerotic vascular disease with Iloprost and estrogen.

A human female similar to and exhibiting the same symptoms as in Example 1 is administered daily in combination with an estrogen (for example estradiol valerate, 1-2 mg / day) 50 g of Iloprost 2 times a day, orally.

EXAMPLE 4: Prevention of atherosclerotic vascular disease with Iloprost and progesterone.

A human male (approximately 45 years, 50-80 kg) who exhibits the signs of cardiovascular disease is administered a progestin (for example norgeststrel 150 mg / day) and 50 mg of Iloprost 2 times a day, orally.

EXAMPLE 5: Treatment of hypertension with Iloprost and progesterone.

To a male or female human who exhibits hypertension, 50 mg of Iloprost is administered twice daily orally with a progestin (for example norgestrel) 150 mg / day.

EXAMPLE 6: Prevention of pre-eclampsia with Iloprost and progesterone.

To a human female who exhibits the symptoms of pre-eclampsia, 50 mg of Iloprost is administered twice daily orally with progesterone (for example 200 mg of micronized progesterone per os).

The preceding examples can be repeated with similar success by substituting the generic or specifically described reagents and / or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily determine the essential characteristics of this invention and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions.

Claims (23)

R E I V I N D I C A C I O N S

1. - Method for selective treatment of the group consisting of: a) preventing or treating atherosclerotic vascular disease in a mammal; b) hormone replacement therapy in peri or postmenopausal female mammals; and c) treating hypertension in a mammal; which comprises administering to the diseased mammal an amount of prostacyclin or prostacyclin analogue in combination with one or more of an estrogen and a progestin, in effective amounts to improve or prevent the onset of symptoms.

2. - Method according to clause 1, wherein the mammal is a human female suffering from menopausal or postmenopausal climacteric symptoms.

3. - Method according to clause 1, wherein the mammal is a human female that is a candidate for hormone replacement therapy.

4. - Method according to clause 1, wherein the mammal is a human male suffering from cardiovascular disease.

5. - Method according to clause 1, wherein the mammal is a human suffering from hypertension.

6. - Method according to clause 1, wherein the mammal is a pregnant human female suffering from pre-eclampsia.

7. - Method according to clause 1, wherein the mammal is a human and the prostacyclin or prostacyclin analogue administered is Iloprost or Cicaprost.

8. - Method according to clause 7, wherein a prostaglandin analog is administered orally.

9. - Method according to clause 1, wherein the mammal is a human and the prostacyclin or prostacyclin analogue is administered in combination with a progestin.

10. - Method according to clause 9, wherein the progestin is progesterone, d idroge s t er ona, medroxyprogesterone, norethisterone, levonorgestrel or norgestrel.

11. - Method according to clause 1, wherein the mammal is a human female and the prostacyclin or prostacyclin analogue is administered in combination with an estrogen.

12. Method according to clause 11, wherein the estrogen is estradiol valerate, conjugated equine estrogens, 17beta-estradiol, estrone, estriol or ethinyl estradiol.

13. - Method according to clause 1, wherein the mammal is a human female and the prostacyclin or prostacyclin analogue is administered in combination with an estrogen and a progestin.

14. - Method according to clause 1, wherein the mammal is a human female and the estrogen or progestin are administered continuously.

15. - Method according to clause 1, wherein the mammal is a human female and the estrogen or progestin are administered in sequence.

16. - Pharmaceutical composition comprising a mixture of: a) prostacyclin or prostacyclin analog and at least one (b) estrogen and (c) a progestin.

17. - Composition according to clause 16, comprising an amount of an estrogen equivalent to 1-2 mg of estradiol and / or an amount of a pro-restin bioequivalent to 50-300 mg of injected progesterone.

18. - Composition according to clause 16, where (a) is Iloprost or Cicaprost.

19. - Composition according to clause 16, comprising an estrogen.

20. - Composition according to clause 19, wherein the estrogen (b) is estradiol valerate.

21. - Composition according to clause 16, which comprises a progestin.

22. - Composition according to clause 21, wherein the progestin (c) is norgestrel.

23. - Composition according to clause 16, which comprises a progestin and an estrogen. SUMMARY Cardiovascular diseases, which include pre-eclampsia in embarked women and hypertension in women and men, are prevented or treated by administering prostacyclin or a prostacyclin analogue in combination with an estrogen and a progestin, which combination is also useful for HRT (replacement therapy hormone in peri and postmenopausal women).