MXPA97008577A - Endothelin antagonists and inhibitors of endothelin synthesis for the prevention and treatment of uterine contractility disorders, preeclampsia, vascular aterosclerotic diseases, hypertension and for replacement therapy - Google Patents

Abstract

A pharmaceutical composition for and methods of treating menstrual disorders, for example dysmenorrhea, in non-pregnant human females, preterm labor, preeclampsia and / or growth retardation of the fetus in pregnant human mammalian females, treatment of atherosclerotic vascular diseases, are disclosed. and hypertension in males as well as in females, and for hormone replacement therapy in peri and postmenopausal women, which comprises administering effective amounts of an endothelin antagonist and / or an inhibitor of endothelin synthesis, or both, in combination with (a) a progestin, and / or in estrogen, and / or (b) a cyclooxygenase inhibitor, and / or a nitric oxide donor and / or nitric substrate, to prevent and / or mitigate said conditions. In aspects of the method, the endothelin antagonist and / or the endothelin synthesis inhibitor can be administered alone for the treatment of menstrual disorders, for example dysmenorrhea in non-pregnant women, preterm labor, preeclampsia and / or retardation of the growth of the fetus in pregnant human mammalian females. Additionally, methods to classify compounds for such treatment are disclosed

Description

ENDOTHELIN ANTAGONISTS AND SYNTHESIS INHIBITORS OF ENDOTHELIN FOR THE PREVENTION AND TREATMENT OF UTERINE CONTRACTILITY DISORDERS, PREECLAMPSIA, VASCULAR DISEASES ATTEROSCLEROTICAS, HYPERTENSION AND FOR HORMONE REPLACEMENT THERAPY This application is a partial sequel to the U.S. Series No. 08 / 254,584 filed June 6, 1994. Background of the Invention The invention relates to a method for the treatment of uterine contractility disorders, such as preterm labor, abortion, dysmenorrhea and menstrual disorders, and to the treatment of preeclampsia with an endothelin antagonist, an inhibitor of endothelin synthesis, or both, alone (s) or also in combination with a progesterone or a cyclooxygenase inhibitor. Additionally, the invention relates to the treatment of atherosclerotic vascular diseases and hypertension in men as well as in women, with an endothelin antagonist and / or an inhibitor of endothelin synthesis, in combination with estrogens and / or progestins, and as a component in hormone replacement therapies in perimenopausal and postmenopausal women.

Preterm labor and subsequent preterm labor is a major problem of perinatalism. By definition, a completed pregnancy in humans is one that is completed between 38 and 42 weeks. However, in approximately 5 to 15% of women, birth occurs prematurely, that is, before 37 weeks are completed. Among humans, premature birth is responsible for 75% of infant mortality and 50% of long-term neurological impairments (Creasy, 1989). To date there are no effective methods for the treatment and prevention of preterm labor or premature birth. The current use of ß-mimetics for the treatment of preterm labor has only limited value. Meta-analyzes of the results of controlled trials show that β-mimetics have little or no effect on the frequency of the lack of breathing syndrome (dyspnea) or on perinatal mortality (King et al., 1988). There is increasing evidence that preterm labor is a syndrome that can be induced by a variety of factors. Moreover, preterm labor should be considered as a chronic pathological condition of the uterus in response to a variety of etiological factors. In some clinical states, the reduction of progesterone levels or the activity of progesterone at the receptor level may cause premature labor. In many species, preterm labor can be induced with progesterone antagonists (eg, RU 486, onapriston) or inhibitors of progesterone synthesis (epostan, trilostan). However, there is increasing evidence that intrauterine or systemic infections play an important role in the etiology and pathogenesis of preterm labor in humans (for review see Romero et al.). In 20-40% of premature labor there is clinical and / or biochemical evidence of intrauterine infection, such as hyperthermia, cultures of positive bacteria, increased cytokines, such as IL-lb, TNFa, IL-8, in the amniotic fluid (Romero et al., 1991, 1992). It is well documented that cytokines are released or emitted by uterine macrophages, activated lymphocytes and other white blood cells in response to a lipopolysaccharide (LPS) that is a major component of the external bacterial membrane. In turn, cytokines stimulate the emission of protaglandins from decidual cells and amnion, which directly induce uterine contagion that leads to preterm labor and subsequently to premature birth. Premature birth that is associated with intrauterine infections is very resistant to conventional treatments (ß-mimetics, antibiotics). To date there is no effective therapy for the treatment of preterm birth associated with intrauterine infection. Preeclampsia (toxemia) of pregnancy is characterized by a triad of hypertension, pathological edema and proteinuria. This disease that affects 6 to 10% of all pregnancies represents a major health problem and is the main cause of fetal growth retardation, fetal mortality and morbidity, premature birth and maternal mortality. The etiology of the disease is largely unknown and there is no effective therapy. Epidemiological data indicate that approximately half of deaths in economically developed countries can be attributed 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 lethal cardiovascular disease is coronary heart disease. In men there is a continuous increase in the prevalence of cardiovascular diseases after the age of 30-40 years. On the other hand, the rate of cardiovascular diseases, especially coronary heart disease, is relatively low among premenopausal women, but it increases markedly with increasing age, which suggests that sex steroids (estrogen and progesterone) have an effect protector in women. The increased risk of coronary heart disease among women with bilateral oophorectomy further supports the view that steroid hormones have a protective role in cardiovascular diseases. Cardiovascular diseases can be prevented in postmenopausal women by hormone replacement therapy (HRT) with estrogen. The recently conducted meta-analysis of 29 studies demonstrated a reduced risk of cardiovascular disease among those who used estrogen in 23 of the studies (Stampfer et al., 1991). There is also experimental evidence from studies with monkeys that the development of coronary atherosclerosis induced by oophorectomy and diet can be reversed by an estrogen supplement (Adams et al., 1992). On the other hand there are no effective methods to prevent cardiovascular diseases in men, since estrogen can not be used due to side effects.

The mechanism of protective effect of female sex hormones is not yet fully understood. An impact on the lipid profile is possible. Among postmenopausal women, estrogen reverses the atherogenic changes of the lipid profile associated with early menopause, such as the increase in LDL cholesterol and serum triglyceride levels, and the reduction of HDL cholesterol. However, there is new evidence to suggest that both estrogen and progesterone can have a direct effect on blood vessels. The presence of estrogen and progesterone receptors in arterial endothelial cells and smooth muscle cells supports the view that sex steroids can have a direct effect on blood vessels (Lin et al., 1986). It has also been shown that treatment with estrogen results in the redistribution of the arterial estrogen receptors and in the increase of arterial progesterone receptors in baboon monkeys (Lin et al., 1986). Studies in monkeys suggest that estrogens can prevent oophorectomy-induced atherosclerosis by inhibiting the absorption and degradation of LDL in the arterial wall (Adams et al., 1992). The effects of estrogen and / or progesterone on arterial tone may also explain some of the beneficial effects of HRT on the risk of diseases of the arteries. Through animal models it is known that estrogens increase uterine blood flow by regulating vascular tone (Greiss &Anderson, 1970, Ganger et al., 1993). The effects of a sexual spheroid on vascular tone suggest that sex steroids may play a role in the pathogenesis of hypertension. The effects of steroids on the vessels may be due to the intermediation of several locally produced hormones that include nitric oxide (NO), prostacyclin and endothelin. Both nitric oxide and prostacyclin induce vascular relaxation and inhibit platelet aggregation. On the other hand, endothelin has a strongly vasoconstrictor effect. Nitric oxide is produced by endothelial cells and is involved in the regulation of vascular tone, platelet aggregation, neurotransmission and activation of immunity (Furchgott and Zawadzki, 1980, Moneada, Palmer and Higgs, 1991). Nitric oxide, formerly known as EDRF (endothelin-derived relaxant factor) (Furchgott and Zawadzki, 1980; Moneada, Palmer and Higgs, 1991) is synthesized by the oxidation deamination of a guanidino nitrogen of L-arginine by at least three different isoforms of an enzyme containing flavin, nitric oxide synthesis (Moneada, Palmer and Higgs, 1991). Nitric oxide increases the levels of cGMP (guanosine monophosphate 1, 3, 5-cyclic) within the vascular smooth muscle to produce relaxation and reduce the tone of the blood vessels (Moneada, Palmer and Higgs, 1991). Preeclampsia is often considered an acute form of atherosclerosis. The spiral arteries that pass through the intervillous space of the normal placenta undergo vast morphological changes during a normal pregnancy, namely a fourfold increase in diameter and a loss of its muscular and elastic components (Robertson, 1986). These changes make it possible for the uterine blood flow that occurs during normal pregnancy to increase approximately tenfold. These changes are absent in preeclampsia (Robertson, 1986), so that the intramyometrial segments of the spiral arteries are not able to dilate. Additionally, the basal arteries and the myometrial segments of the spiral arteries of the preeclampsic plastic show characteristic lesions that have been called "acute atherosis" (Roberts, 1989). During acute atherosis of the uterus with preeclampsia there is an injury of the endothelial cell, a focal interruption of the basal membrane, lipoid necrosis of the muscle cells by platelet deposition (foam cells), (a result of chronic hypoxia and / or cytotoxins), mural thrombi and fibrinoid necrosis (Robertson, 1967, DeWolf, 1980, Roberts, 1989), (all of them) effects very similar to those that present a vascular atherosclerotic disease. Endothelins are a family of small proteins that were originally isolated from cultured endothelial cells. Endothelin is a vasoactive peptide composed of 21 amino acid residues. Endothelin was isolated from the culture supernatant of the endothelial cells of porcine aortas. M. Yanagisawa determined its structure in 1988. More recently, research on the genetic code for endothelin revealed the presence of peptides similar in structure to endothelin. The peptides are named endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3). These peptides of 21 residues are formed from a preproendothelin (200 residues) via an intermediate of 38/39 residues (proendotelins). Preproendothelin-1 is divided by endopartases specific to dibasic pair to form proendothelin-1, a precursor peptide of 38 amino acids. Proendothelin-1 is divided by the activity of an "endothelin converting enzyme" (ECE). In the conversion of proendothelin-1 to endothelin 1, several endopeptidases are also involved, including phosphonide-sensitive metalendopeptidase and SQ-sensitive endopeptidase-2.4.11 28 608 (Haynes and Webb, (1993)). Peptides from the endothelin family show vasopressor activity in vi tro and in vivo. In addition to its effects on vascular contractility, ET-1 is one of the most potent stimulators of uterine contractility, experiments in vi tro with uterine tissue of rats and rabbits have demonstrated a pronounced uterotonic activity of ET-1 in function of The dose The uterine contractions induced by ET-1 were similar to those induced with oxytocin and were inhibited with calcium channel antagonists (Kozuka et al., 1989; Calixto & Rae, 1991; Suzuki, 1991). In the rabbit, specific immunostaining of ET-1 has been observed in the endometrium, but not in the myometrium, although the specific ET-1 receptors were only found in the myometrium (Maggi et al., 1991). These findings suggest a paracrine activity of ET-1. These studies also indicate that the density of the endothelin receptor in the myometrial cells is controlled by the steroid hormones (ie, estrogen stimulates the number or amount of receptors and progesterone acts against this activity). It has been suggested that ET-1 levels in maternal plasma are increased during labor; however, Mitchell et al. (1991) and Romero et al. (1992) have shown that levels of ET-1 and ET-2 do not increase with labor at the end of management or premature in the absence of infection. It has recently been discovered that ET-1 is produced in relatively high amounts in the human endometrium, predominantly in stromal cells (Economos et al., 1992). The highest concentrations of ET-1 in the human endometrium have been found during periods of menstruation (Ohbuchi et al., 1992). Receptors have been identified for ET-1, ET-2 and ET-3 in the human glandular epithelium and in the spiral arteries (Davenport et al., 1991). The exact mechanism of menses is not yet fully understood). In the uterus endothelin are degraded by enkephalinase. Enkephalinases (membrane metalendopeptidase, MMEP) catalyze the degradation of small btive peptides such as endothelin, enkephalin, atrial natriuretic factor, substance P, and others. It has been discovered that endometrial enkephalinase is a progesterone-dependent protein. It correlates with progesterone levels in the plasma in an exceptionally significant way (MacDonal et al., 1991, Casey et al., 1992). It has been suggested that the reduction of endometrial enkephalinase during luteolysis coupled with increased synthesis of ET-1 by stromal cells may result in an increase in the local concentration of ET-1 and in turn in menstruation (Casey et al. , 1992). It was therefore suggested that the ET-1 / enkephalinase system in the endometrium has a role in the onset of menstruation in humans (MacDonal et al., 1991). Since it appears that enkephalinases in the uterus are regulated by steroid hormones, particularly progesterone, it is possible that enkephalinases in vascular tissues are controlled in a similar way, and that during pregnancy, when hormone levels are increased steroids, there is some function of vascular enkephalinases to maintain blood flow. Therefore, the mechanisms that control both the onset of labor and that of menstruation by intermediation of endothelin may be similar. Five different sequences of endothelin receptors have been reported. The receptors form two different receptor subtypes, A and B, which can be distinguished by their affinities to the various endothelins. The endothelin A receptor (ETA-R) has a higher affinity to ET-1 and ET-2 than did ET-3, while subtype B is not specific. The cycle (D-Trp.D-Asp.Pro.D-Val.Leu) called BQ-123 was reported for the first time as a selective antagonist of the ETA receptor by K. Ishikawa et al. in 1991 (Proc.12th Am. Peptide Symp. Abst. P506). The manufacture and structure of this antagonist is described in R.A. Atkinson and J.P. Pelton, (1992). The biological effects of BQ-123 were reported by K. Nakamichi et al., (1992). PD 142 893 is an example of a nonselective ET antagonist that binds both ETA-R and ETB-R (Warner et al., 1993). Ro 46-2005 is a non-specific, non-peptidic orally active ET antagonist whose efficacy was demonstrated in several animal models (prevention of postischemic renal vasoconstriction in rats, prevention of cerebral blood flow reduction after a subarachnoid hemorrhage in rats, and reduction of blood pressure in squirrel monkeys with sodium depletion). Clozel et al., (1993). Other ET antagonists include BMS 182847 [5- (dimethylamino) -N- (3,4-dimethyl-5-isoxazolyl) -1-naphatalene-sulfonamide], an extremely selective orally active ETA antagonist.; SB 209670 carboxylic acid 2- [(+) -IS, 2R, S-3- (2-carboxymethoxy-4-methoxy-phenyl) -1- (3,4-m ethylenedioxyphenyl) -5- (prop-1) -iloxy) indane] and bosentan, revealed, for example, in SA Douglas et al., (1994). DESCRIPTION OF THE INVENTION The present invention provides a method for the prevention and treatment of preterm labor, impending abortion, dysmenorrhea and menstrual disorders (such as dysfunctional uterine bleeding, menorrhagia, bleeding) with an endothelin antagonist and / or an inhibitor of endothelin synthesis (ECE). Additionally, the invention provides a method in which a progestational agent (progestin), a cyclooxygenase inhibitor and / or a nitric oxide (NO) donor and / or a NO substrate is used in combination with an endothelin antagonist and / or an inhibitor of endothelin synthesis for the prevention and treatment of preterm labor, impending abortion, dysmenorrhea and menstrual disorders (such as dysfunctional uterine bleeding, menorrhagia, exsanguination). This invention further provides a method for the prevention and treatment of preeclampsia of pregnancy with an endothelin antagonist and / or an inhibitor of endothelin synthesis in combination with one or more of a progestin, a cyclooxygenase inhibitor and / or a donor. of NO and / or a NO substrate. Still other aspects of the invention provide methods for the prevention and treatment of atherosclerotic vascular diseases and hypertension in men and women, with a combination of an endothelin antagonist and / or inhibitor of the synthesis of endothelin with steroid hormones (with an estrogen or with the combination of an estrogen and a progestin for women, with a progestin for men), and / or with a NO donor and / or a NO substrate, and optionally with a cyclooxygenase inhibitor. Yet another object of the invention is to provide a hormone replacement therapy for peri and postmenopausal women requiring such treatment, with a combination of an endothelin antagonist and / or inhibitor of the synthesis of endothelin with steroid hormones (a estrogen or the combination of an estrogen and a progestin), and / or with a NO donor and / or a NO substrate, and optionally with a cyclooxygenase inhibitor. Still another object of the invention is to provide pharmaceutical compositions useful for practicing the method according to the present invention. Other objects and advantages of the present invention will become apparent to those skilled in the art upon further study of the specification and the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS Several other objects, features and advantages inherent in the present invention will be more clearly appreciated while it is better understood in the light of the accompanying drawings, in which: Figure 1, left side, shows the inhibitory effects of the endothelin antagonist BQ-123 in preterm deliveries induced with LPS lipopolysaccharide in guinea pigs with advanced pregnancy. LPS is a non-specific labor-inducing agent that mimics preterm labor that is associated with intrauterine infection (premature birth model). In the group treated with LPS all animals gave birth within 48 hours. Treatment with BQ-123 resulted in a partial inhibition (60%) of premature births induced by LPS and reduced fetal mortality (to 50%); Figure 1, right side, demonstrates the effects of BQ-123 on the result of fetuses in guinea pigs. The fetal mortality rate in the group treated with LPS was 100%. Treatment with BQ-123 reduced fetal mortality (50%). All the fetuses born at the end of gestation survived. The general state of the maternal animals treated with BQ-123 plus LPS was better than that of those treated only with LPS (subjective assessment of the technician); Figure 2 shows the effect of BQ-123 on hypertension in pregnant rats (preeclampsia model) induced by L-NAME (inhibitor of nitric oxide synthesis). BQ-123 significantly reduced blood pressure (BP) in animals treated with L-NAME, compared to animals that were only treated with L-NAME; Figure 3 shows the weights of the fetuses in rats and in puppies born after treatment with L-NAME, with and without BQ-123. The weight of the puppies was significantly lower after treatment with L-NAME. However, the weight of the puppies was similar to that of the control puppies in the animals treated with L-NAME plus BQ-123. DETAILED DESCRIPTION OF THE INVENTION In one aspect of the method, this invention relates to a method for treating at least one of the menstrual problems of dysmenorrhea, or others (e.g. dysfunctional uterine bleeding), in a non-pregnant woman, a method comprising administering a non-pregnant woman who is in the menstrual cycle and exhibits the symptoms of the problem (a) one or both of an endothelin antagonist and an inhibitor of endothelin synthesis, and, optionally (b) one or more of a progestin and / or cyclooxygenase inhibitor, and, optionally (c) one or more of a nitric oxide (NO) donor and / or NO substrate, in effective amounts to ameliorate the symptoms of the problem, the amount being of the progestational agent that is administered is bioequivalent to 50-300 mg of injected prsgesterone and the amount of the endothelin antagonist, the endothelin synthesis inhibitor, or both, is effective for locker the activity of endothelin at the receptor level or inhibit the synthesis of endothelin, respectively. In another aspect of the method, this invention relates to a method of treating preterm labor in a pregnant woman, which method comprises administering to a pregnant woman exhibiting the symptoms of preterm labor quantities of (a) one or both of an endothelin antagonist and / or an inhibitor of endothelin synthesis to inhibit preterm labor, and (b), optionally one of a progestin and / or cyclooxygenase inhibitor, and optionally, (c) one or Several of a nitric oxide (NO) donor and / or NO substrate, where the amount of the progestational agent that is administered is bioequivalent to 50-300 mg of injected progesterone and the amount of the endothelin antagonist, the inhibitor of the Endothelin synthesis, or both, is respectively effective either to increase the blood level of circulating endothelin in a pregnant woman to whom the composition is administered, or to block the receptor and endothelin, and the amount of the cyclooxygenase inhibitor is bioequivalent at 10-2000 mg / day. In another aspect of the method, this invention relates to a method for treating preeclampsia in a pregnant woman, which method comprises administering to a pregnant woman who exhibits the symptoms of preeclampsia amounts of (a) at least one of an endothelin antagonist. and / or of an inhibitor of endothelin synthesis to inhibit preeclampsia, and optionally, (b) one or more of a progestin and / or cyclooxygenase inhibitor, and optionally, (c) one or more of an oxide donor. nitric oxide (NO) and / or NO substrate, in dosing rates as described above. In another aspect of the method, this invention relates to a method for treating or preventing atherosclerotic vascular diseases, which method comprises administering to a man or woman requiring such treatment (a) one or both of an endothelin antagonist and / or or of an inhibitor of endothelin synthesis in combination with (b) one or more of a progestin (for men) and / or estrogen (for women), and / or one or more of a nitric oxide (NO) donor and / or NO substrate, and optionally(c) an inhibitor of cyclooxygenase, in effective amounts to improve the symptoms of the problem, since the amount of the progestational agent that is administered is bioequivalent to 50-300 mg of progesterone injected, the amount of the estrogen agent that is administered is a daily dose bioequivalent to approximately 1-2 mg / day of estrogen, and the amount of the endothelin antagonist, the endothelin synthesis inhibitor, or both, is effective to block the activity of endothelin at the receptor level or inhibit the synthesis of endothelin by at least 20%, respectively. In still another aspect of the method, this invention relates to a method for treating or preventing hypertension, which method comprises administering to a man or woman who requires such treatment (a) one or both of an endothelin antagonist and / or of an inhibitor of endothelin synthesis in combination with (b) a progestin (for men) and / or estrogen (for women), and / or one or more of a nitric oxide donor (NO) and / or substrate of NO, and optionally, (c) a cyclooxygenase inhibitor, in effective amounts to improve the symptoms of the problem, being that the amount of the progestational agent that is administered is bioequivalent at 50-300 mg of Injected progesterone, the amount of the estrogen agent that is administered is a daily dose bioequivalent to approximately 1-2 mg / day of estrogen, and the amount of the endothelin antagonist, the endothelin synthesis inhibitor, or both, is effective to block the activity of endothelin at the receptor level or to inhibit the synthesis of endothelin by at least 20%, respectively. In yet another aspect of the method, this invention relates to a method for providing a hormone replacement therapy to peri and postmenopausal women who require such treatment, i.e., women who due to disease, surgery or age do not produce enough of female hormones for maintaining health or comfort, which method comprises administering (a) one or both of an endothelin antagonist and / or an inhibitor of endothelin synthesis in combination with (b) a progestin, and / or one or more of a nitric oxide donor (NO) and / or NO substrate, and optionally, (c) a cyclooxygenase inhibitor, in effective amounts to improve the symptoms of the problem, the amount of the progestational agent being administered is bioequivalent to 50-300 mg of injected progesterone, the amount of the estrogen agent that is administered is a daily dose bioequivalent to approximately 1-2 mg / day of estrogen, and the amount d of the endothelin antagonist, of the endothelin synthesis inhibitor, or both, is effective to block the activity of endothelin at the receptor level or inhibit the synthesis of endothelin by at least 20%, respectively. In one aspect of the product this invention relates to a pharmaceutical composition that is constituted by (a) an endothelin antagonist and / or an inhibitor of endothelin synthesis in combination with at least one of (b) a progestin, (c) ) an estrogen, (d) a cyclooxygenase inhibitor, (e) a nitric oxide (NO) donor and / or (f) a NO substrate, the amount of the endothelin antagonist being equivalent to that required to block 80% of the endothelin receptor; the amount of the inhibitor of endothelin synthesis is equivalent to that amount which endothelin levels in the blood are required by at least 20%, preferably 50%; the progestational agent per unit dose is bioequivalent to 50-300 mg of injected progesterone; the estrogen agent per unit dose is bioequivalent at 1-2 mg / day of estrogen; the cyclooxygenase inhibitor is bioequivalent to 10-2000 mg of aspirin; the NO donor is bioequivalent to the amount required to increase the NO at the target site by > 20%, preferably 50%; and / or the amount of NO substrates is bioequivalent to 100-10,000 mg / day of L-arginine. In another aspect of the product this invention relates to a pharmaceutical composition which is constituted by an endothelin antagonist and / or an inhibitor of endothelin synthesis, and by one or both of an estrogen and a progestin, and / or one or several of a nitric oxide (NO) donor and / or NO substrate, and optionally, a cyclooxygenase inhibitor, wherein the amount of the endothelin antagonist is equivalent to that which is required to block 80% of the endothelin receptor and the endothelin synthesis inhibitors required to reduce endothelin levels in the blood by at least 20%, preferably 50%; the progestational agent per unit dose is bioequivalent to 50-300 mg of injected progesterone; the estrogen agent per unit dose is bioequivalent at 1-2 mg / day of estrogen; the amount of the NO donor is bioequivalent to the amount required to increase the NO at the target site by > 20%, preferably 50%; the amount of NO substrate is bioequivalent to 100-10,000 mg / day of L-arginine; and the amount of the cyclooxygenase inhibitor is bioequivalent to 10-2000 mg of aspirin.

The present invention provides pharmaceutical compositions and methods for the treatment of menstrual disorders, for example dysmenorrhea in a non-pregnant mammal, or preterm labor, impending abortion, and / or preeclampsia in a pregnant mammal, preferably a human who manifests the symptoms of the exposed disorders or that is a candidate who is at high risk of suffering them, that is, as determined by the progress of the current pregnancy or a previous pregnancy. Additionally, the invention provides pharmaceutical compositions and methods for the treatment of atherosclerotic vascular diseases, hypertension, and for hormone replacement therapy (HRT) in mammals, preferably human females, and in the latter case women who exhibit the symptoms of these disorders (atherosclerotic vascular disease or hypertension) or that require treatment (HRT). Because abnormal conditions are produced or aggravated by levels in excess of normal synthesis or endothelin activity, endothelin antagonists and / or endothelin synthesis inhibitors are useful to ameliorate the symptoms of those abnormal conditions and, in One aspect of the method of the present invention may be a combination of both. In addition, since progestins and cyclooxygenase inhibitors respectively control the synthesis, metabolism or activity of endothelin, a combination of one or more of these compounds with one or more of an endothelin antagonist and / or synthesis inhibitor. of endothelin will be particularly useful for the abnormal conditions mentioned above. Moreover, for the treatment of atherosclerotic vascular diseases and hypertension a combination of one or more of an endothelin antagonist and / or an inhibitor of the synthesis of endothelin with a progestin (in the case of men) or a estrogen or a combination of an estrogen and a progestin (in the case of women); The latest combinations are also useful for hormone replacement therapy in women. In cases exposed to the latter, the combination of an endothelin antagonist in combination with a progestin has surprisingly provided synergistic activity. Other additional combinations may include NO donors and / or NO substrates, which increase the amount of nitric oxide, thereby inducing vascular relaxation and which can substitute steroid hormones. Accordingly, aspects of the method and pharmaceutical compositions of the present invention employ (a) an endothelin antagonist (e.g., BQ-123, PD 142 893, Ro 46-2005, BMS 182874, SB 209670, bosentan) and / or an inhibitor of the synthesis of endothelin (for example phosphoramidon or SQ 28 608) and optionally (in the case of menstrual disorders, preterm labor, preeclampsia or growth retardation of the fetus) (b) one or more of a progestin (for example progesterone, levonorgestrel, desogestrel, gestodene), a cyclooxygenase inhibitor (for example aspirin, indomethacin), a NO donor (for example nitroglycerin, sodium nitroprusside, SIN-1, mono or isosorbite binitrate) and / or a substrate of NO (for example L-arginine). In the case of the treatment of atherosclerotic vascular diseases, hypertension and for hormone replacement therapy, components (a) and (c) are used, where (c) it is a progestin (or, when treating a woman, it is a estrogen or a combination of a progestin and an estrogen), and / or a nitric oxide donor and / or a nitric oxide substrate, and, optionally, an oxygenase inhibitor. In particular, combinations of an endothelin antagonist with a NO donor or a NO substrate are preferred. Examples of combinations of active agents that can be administered concurrently with an endothelin antagonist and / or an inhibitor of endothelin synthesis are progestin (progesterone) and / or an inhibitor of cyclooxygenase (aspirin), and / or a NO (nitroglycerin) donor or NO (L-arginine) substrate. Endothelin antagonists and inhibitors of endothelin synthesis: Examples of endothelin antagonist dosing ranges and typical endothelin synthesis inhibitors are: Dosage Antagonist Endothelin position mg / day / 50 ks mg / kg BQ-123 1-2000 s.c. 1-40, s.c., i .m. , i.v.

• 'PD 142 893 Effective dose to block 50% of recipients Ro 46-2005 50-5000, p.o. 0.1-100, p.o.

SB 209670 1-100, p.o. 0.01-20, p.o. BMS 182874 1-100, p.o. 0.01-20, p.o. bosentan 1-100, p.o. 0.01-20, p.o.

Inhibitor of 20 Synthesis of Endothelin Dosage of phosphoramidon Effective dose to reduce SQ 28 608 levels of endothelin in > twenty% The following are oral dosage ranges Typical, progestin active agents and the other optional active agents administered concurrently with the endothelin antagonist and / or the endothelin synthesis inhibitor: Progestins: A daily dose bioequivalent to * 50-300 mg of progesterone / day, is to say, an injectable suspension of medroxyprogesterone acetate to provide a weekly dose of 100-1000 mg of progesterone; tablets or lozenges that provide a dose of 5-10 mg / day of progesterone; an injectable solution of hydroxyprogesterone caproate that provides a weekly dose of 250-500 mg; tabs, capsules or tablets of norethindrone acetate that provide a daily dose of 5-20 mg. Daily doses of progestogens taken for 12 days / month in patients receiving oral or transdermal estrogens: Pro? Restina Dosage Ñorestisterone 0.7-2.5 mg / day Medroxyprogesterone acetate 10 mg / day Norgestrel 150 μg / day Dydrogesterone 10-20 mg / day Estrogens and estrogens plus progestins: Estrogens and estrogens plus progestins can be administered in typical dosages such as those used for contraception and hormone replacement therapy. Examples of suitable estrogens and their dosages include a bioequivalent of daily dose of about 1-2 mg / day of estrogen, for example Premarin®, Wyeth-Ayerst, or 625 mg / day; estradiol valerate, 50 μg / day, transdermal application; vaginal creams of stadiol, 1.25 mg / day; and stadiol vaginal rings, 0.2 mg / day, as well as the currently available naturally occurring estrogens that are used in hormone replacement therapy, for example, in the United Kingdom. Examples of estrogens and combinations of estrogen plus progestin include: Product Composition Dose, ms / day Climoval® (Sandoz) Estradiol valerate 1 or 2 Progynova® Estradiol valerate 1 or 2 Harmogen® (Abbott) 1.5 or 2.5 piperazine estrone sulfate Hormonin® (Shire) Estradiol + estrone 0.6 + estriol Premarin® conjugated estrogens 0.625, de equine 1.25 or 2.5 Among the calendar packages of commercially available combinations for hormone replacement therapy include "Estrapak", "Prempak-C", "Trisequens", "Trisequens forte" and "Cicloproginova". The following are illustrative compositions of such products: Estradiol 50 mg / day (28 days, 8 plates) Conjugated equine estrogens 0.0625 mg / day (28 days) Estradiol valerate 2 mg / day (11 days) Estradiol valerate 2 mg / day Norgestrel 0.5 mg / day (10 days) Norgestrel 0.15 mg / day (12 days) Conjugated equine estrogens 1.25 mg / day (28 days) Norgestrel 0.15 mg / day (12 days) Estradiol 2 mg / day + estriol 1 mg / day (22 days) Norethisterone acetate 1 mg / day (10 days) Estradiol 1 mg / day + estriol 0.5 mg / day (6 days) Estradiol 4 mg / day + estriol 1 mg / day (21 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) Levonogestrel 0.25 mg / day (10 days) Estradiol valerate 2 mg / day (21 days) Levonogestrel 0.5 mg / day (10 days) Cyclooxygenase inhibitors: Aspirin can be used in a dosage of 10-2000 mg / kg / day p.o. Other suitable inhibitors of cyclooxygenase include both COX-1 and COX-2 inhibitors, including, for example, indomethacin; and dexamethasone, 6- (2,3-difluorophenoxy) -5-methylsulfonylamino-l-indanone (ZK 38,997, PGP 28 238 or Flosulide), 5-methylsulfonylamino-6-phenoxy-1-indanone (CGP 28 237), and several 1,2-diarylcyclopentenes (e.g., as disclosed in Reitz et al., 1994) (COX inhibitors) -2) . Each of these can be administered in conventional or smaller dosages. In particular, the preferred cyclooxygenase inhibitors are those that are specific COX-2 inhibitors, such as those disclosed in Bottcher et al., Wiesenberg-Bdttecher, Reitz et al., Zimmerli et al., And Mitchell et al. Nitric oxide donors and / or substrates: Suitable donors and nitric oxide substrates can be selected from the well-known antianginal agents; see, for example, "Nitrates and Other Anti-Angina Agents" in Martidale: The Extra Pharmacopoeia, (1993); the exemplary agents and the appropriate dosages for each are listed below: Nitric acid donor Dosage Nitroglycerin 2.5 mg twice daily p.o. 0.8 mg 1-4 times a day, sublingual 0.2-0.4 mg / hr transdermal plate Nitroprusside sodium 500-2000 μg / kg / day SIN-1 Effective dosage for mono or dinitrate isosorbid increase NO at the target site to > twenty% N -ric Acid Substrate L-Arginine 100-10,000 mg / day i.m., i.v., p.o.

The pharmacologically active agents that are employed in this invention can be administered intermixed with conventional excipients, i.e., liquid, semi-liquid or solid pharmaceutically acceptable organic and inorganic carriers, suitable, for example, for parenteral or enteric application and which do not react in harmful form with the active compound interspersed with them. Acceptable vehicles include, but are not limited to, water, saline solutions, alcohols, vegetable oils, polyethylene glycols, gelatins, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, monoglycerides and diglycerides. Fatty acids, fatty acid esters of pentaerythritol, hydroxymethylcellulose, pslivinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to influence the osmotic pressure, buffers, coloring, flavoring and / or aromatic substances and similar that they do not react in a harmful way with the active compounds. Particularly suitable for parenteral application are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants, including suppositories. The ampoules are convenient unit dosages. In a preferred aspect the composition of this invention is adpta for oral ingestion. Particularly suitable for enteric administration are unit dosage forms, such as tablets, dragees or capsules having talc and / or a carbohydrate carrier or binder or the like, wherein the carrier is preferably lactose and / or starch. corn and / or potato starch; particulate solids, for example granules; and liquids and semi-liquids, for example syrups and elixirs or the like, in which a sweetened vehicle is used. Slow release compositions can be formulated including those in which the active compound is protected with differentially degradable coating layers, such as microencapsulation, multiple layers, etc. Tablets, dragees, capsules, pills, granules, suspensions and solutions are suitable for oral administration, among others. 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, 0.1-1% of each active agent in an aqueous or alcoholic solution. The endothelin antagonist and / or the endothelin synthesis inhibitor can be administered intermixed with the progestational agent and any other optional active agent, or as a separate or single unit dosage, either simultaneously with those or at different times of the day each one of them. RESULTS Figure 1 demonstrates for the first time the efficiency of an endothelin antagonist in the treatment (prevention) of premature birth. The LPS dose used in this study (600 μ / animal) was very high, since it consistently induced 100% of abortions both in guinea pigs in the middle of pregnancy (day 42-43 pc) and in guinea pigs at the end of pregnancy (day 60 pc) in previous studies. This explains why the effects of BQ-123 were only partial. Premature birth associated with intrauterine infection is very resistant to conventional treatments (ß-mimetics, antibiotics), and to date there is no effective therapy for the treatment of preterm birth associated with intrauterine infection. This study indicates that endothelin antagonists or inhibitors of endothelin synthesis can be used for the prevention and / or treatment of premature birth, in particular premature birth associated with intrauterine infection. In nonpregnant women, dysmenorrhea is also associated with increased uterine activity. This study indicates that endothelin antagonists and / or inhibitors of endothelin synthesis may be effective in the treatment of uterine contractility in non-pregnant women.

The results shown in Figures 2 and 3 show that BQ-123 effectively reduces blood pressure and fetal weights in pregnant rats with preeclampsia (treated with L-NAME). This is the first demonstration of a reversal of the symptoms of preeclampsia (blood pressure and fetal growth retardation) with an endothelin antagonist. It can be concluded from these studies that endothelin antagonists and / or inhibitors of endothelin synthesis will be useful for the treatment of preeclampsia or other forms of fetal growth retardation (eg, kidney diseases, hypoperfusion of the placenta). The blood pressure lowering effect of BQ-123 is greatly attenuated in the postpartum period when progesterone levels decline, so that pregnancy (progesterone) is essential for its effectiveness. This observation indicates that an endothelin antagonist acts synergistically with progesterone. The method of treatment used in this invention can also be used for the treatment of hypertension in both women (in combination with estrogen and / or progestin) and also in men (in combination with progestin), for the replacement therapy of hormones in climacteric disorders (hot flashes, mood swings) in peri and postmenopausal women (in combination with estrogen or estrogen and progestin), for atherosclerotic vascular diseases in women (in combination with estrogen and / or progestin) and men (in combination with progestin), for thrombotic disorders, and for bleeding, etc., following the dosing regimen described herein. Selective assays for compounds or compositions that are effective for the treatment of preeclampsia, gestational hypertension and fetal growth retardation can be carried out essentially as described in C. Yallampalli et al., (1993). This method involves administering varying amounts of L-nitro arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, to pregnant rats. For example, lower amounts (10-25 mg / day / rat) of L-NAME induce only gestational hypertension, while larger amounts (50 mg / day / rat) also induced preeclampsia and / or fetal growth retardation. Selective tests for compounds or compositions which are effective for the treatment of preeclampsia and premature birth can be carried out essentially as described in Bukowski et al., (1993); and Garfield et al., (1994). This method involves administering varying amounts of the methyl ester of L-nitro arginine (L-NAME), an inhibitor of nitric oxide synthesis, to pregnant guinea pigs. For example, minor amounts (less than 10 mg / day / animal) of L-NAME induce only preeclampsia, while larger amounts (10-25 mg / day / animal) also induced preterm labor. Other selective assays for compounds and compositions that are effective for such treatments, in particular premature birth caused by bacetrial infections, especially gram-negative bacteria, are disclosed, for example, in Romero et al., (1992). This model uses the induction of preterm labor in mice by lipopolysaccharides (LPS). Without further elaboration we think that one skilled in the art can use the present invention to its maximum capacity using the preceding description. The following preferred embodiments should therefore be considered as merely illustrative, but in no way limiting the remainder of the disclosure. In the preceding examples and the following examples all temperatures are given in uncorrected degrees Celsius and, unless otherwise indicated, all parts and percentages are by weight.

Full disclosures of all applications, patents and publications cited before and after are incorporated herein by reference.

EXAMPLES Example 1: Treatment of preterm labor To a pregnant human female (approximately 20 to 40 years, 60 to 80 kg) usually in the second half of her pregnancy and with symptoms of preterm labor, including uethrin contraction, administering a endothelin antagonist (e.g. BQ-123) in a dosage of 1-2000 mg / day, sc, or BMS 182874 in a dosage of 1-100 mg / kg, po, and optionally a progestin (e.g. 200 mg progesterone micronized po daily), and / or a cyclooxygenase inhibitor (for example aspirin in a dosage of 10-2000 mg / day) until the symptoms improve. Example 2: Treatment of Preterm Labor To a pregnant human female comparable to that described in Example 1 administer an inhibitor of endothelin synthesis (eg in an effective dosage to reduce endothelin levels by> 20% in comparison at normal levels), and optionally a progestin (for example 200 mg of micronized progesterone po daily) or an inhibitor of cyclooxygenase (for example aspirin at a dosage of 10-2000 mg / day po) to mitigate the symptoms of the work of premature birth Example 3: Treatment of dysmenorrhea To a non-pregnant human female (approximately 20 to 50 years old, 60 to 80 kg) who manifests the symptoms of dysmenorrhea or menstrual disorders including painful uterine contractions, administer an endothelin antagonist (eg BQ-123). or BMS 182874) and optionally a progestin (e.g. 200 mg of micronized progesterone po daily), and / or a cyclooxygenase inhibitor (e.g., aspirin in a dosage of 10-2000 mg / day) until the symptoms improve. Example 4: Treatment of dysmenorrhea To a non-pregnant human female comparable to that of example 3, administer an inhibitor of endothelin synthesis (for example phosphoramidon or SQ 28 608 in an effective dosage to reduce endothelin levels by> 20% in comparison to normal levels), and optionally a progestin (for example 200 mg of micronized progesterone per os daily) and / or a cyclooxygenase inhibitor (for example aspirin in a dosage of 10-2000 mg / day po), for mitigate the symptoms. Example 5: Treatment of preeclampsia To a pregnant human female (approximately 20 to 40 years, 60 to 80 kg) usually in the second half of her pregnancy and exhibiting symptoms of preeclampsia, including high blood pressure, fetal retardation and proteinuria, administer an endothelin antagonist (for example BQ-123, 1-2000 mg / day, sc) and optionally a progestin (for example 200 mg of micronized progesterone po daily), and / or a cyclooxygenase inhibitor (for example aspirin in a dosage of 10-2000 mg / day) to mitigate symptoms. Example 6: Treatment of preeclampsia A pregnant human female comparable to that of example 5 administers an inhibitor of endothelin synthesis and optionally a progestin and / or a cyclooxygenase inhibitor and / or a nitric oxide donor and / or a nitric oxide substrate to mitigate the symptoms, all as described above. Example 7; Selection of compounds that are effective for preeclampsia, sestational hypertension and fetal growth retardation The induction of preeclampsia in pregnant rats or guinea pigs approximately on day 16 of gestation in rats and approximately on day 45 of gestation in piglets of guinea is carried out with a daily treatment with L-NAME. Animals treated with L-NAME are used to classify agents that reduce blood pressure and increase the survival of the fetus and prevent the growth retardation of the fetus. PlQ 9 axis; Selection of compounds that are effective in treating preterm labor Pregnant animals (rats or guinea pigs) are treated with a NO inhibitor (for example L-NAME) or an endothelin antagonist (for example endothelin) with and without an antiprogestin for induce preterm labor, followed by treatment with agents to be classified according to their ability to prevent preterm labor. Example 9; Treatment of atherosclerotic vascular diseases To a human male or female (approximately 45 years, 50 to 80 kg) that manifests symptoms of cardiovascular disease to administer 1-100 mg / day / 50 kg of BMS 182874 in a dosage of 0.01-20 mg / kg po, in combination with a progestin (for example 5-20 mg of norethindrone acetate). Example 10: Treatment of hypertension To a male or female human (approximately 45 years; 50 to 80 kg) that manifests the symptoms of hypertension administering 1-10 mg of BMS 182874 per os in combination with a progestin (for example 5-20 mg of norethindrone acetate). Example 11; Hormone replacement therapy A non-pregnant human female (approximately 45 years, 50 to 80 kg) who exhibits signs of perimenopausal or postmenopausal symptoms administer 1-10 mg of BMS 182874 per os in combination with either hormone replacement therapy with estrogen only or with a hormone replacement therapy with estrogen plus progestin.

The preceding examples can be repeated with similar success by replacing the specific or generic reagents described and / or the operating conditions of this invention with those used in the preceding examples. From the foregoing description a person skilled in the art can easily discover the essential characteristics of the present invention and, without departing from the spirit and scope thereof, make various changes and modifications to the invention to adapt it to various uses and conditions.

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Claims (66)

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

1. A pharmaceutical composition characterized in that it comprises: (a) an endothelin antagonist and / or an inhibitor of endothelin synthesis, in combination with (b) at least one of a progestin, an estrogen, an inhibitor of cyclooxygenase, a nitric oxide (NO) donor and / or a NO substrate, together with a pharmaceutically acceptable excipient.

2. A method for treating a menstrual disorder in a non-pregnant mammal female which is characterized in that it comprises administering to the female in need of such treatment an effective amount of a composition according to claim 1, or a pharmaceutical composition comprising only (a).

3. A method for treating preterm labor, preeclampsia or fetal growth retardation in a pregnant mammal female, which is characterized in that it comprises administering to the female requiring such treatment an effective amount of a composition according to the claim 1, or a pharmaceutical composition comprising only (a).

4. A method according to claim 2, characterized in that the female is a human being suffering from dysmenorrhea.

5. A method in accordance with the claim 3, which is characterized by the fact that the mammalian female is a human suffering from preterm labor.

6. A method according to claim 3, characterized in that the mammalian female is a human female suffering from preeclampsia or fetal growth retardation.

7. A method according to claim 2, characterized in that the mammalian female is a human being and (a) is an endothelin antagonist.

8. A method in accordance with the claim 2, which is characterized by the fact that the mammalian female is a human being and (a) is an inhibitor of endothelin synthesis.

9. A method in accordance with the claim 3, which is characterized by the fact that the mammalian female is a human being and (a) is an endothelin antagonist.

10. A method according to claim 3, characterized in that the mammalian female is a human being and (a) is an inhibitor of endothelin synthesis.

11. A method according to claim 2, characterized in that the mammalian female is a human being and (b) is a progestin.

12. A method in accordance with the claim 2, which is characterized by the fact that the mammalian female is a human being and (b) is a NO donor or a NO substrate.

13. A method in accordance with the claim 3, which is characterized by the fact that the mammalian female is a human being and (b) is a progestin.

14. A method according to claim 3, characterized in that the mammalian female is a human being and (b) is a NO donor or a NO substrate.

15. A method in accordance with the claim 11, which is characterized by the fact that the progestin is progesterone.

16. A method according to claim 13, characterized in that the progestin is progesterone.

17. A method in accordance with the claim 12, which is characterized by the fact that the NO substrate is L-arginine.

18. A method according to claim 14, characterized in that the substrate of NO is L-arginine.

19. A method in accordance with the claim 7, which is characterized by the fact that the endothelin antagonist is BQ-123.

20. A method in accordance with the claim 9, which is characterized by the fact that the endothelin antagonist is BQ-123.

21. A method in accordance with the claim 8, which is characterized by the fact that the inhibitor of endothelin synthesis is SQ 28 608.

22. A method in accordance with the claim 10, which is characterized in that the inhibitor of endothelin synthesis is SQ 28 608.

23. A composition according to claim 1, characterized in that (a) is an endothelin antagonist. .

24. A composition according to claim 23, characterized in that the endothelin antagonist is BQ-123.

25. A composition according to claim 1, characterized in that (a) is an inhibitor of endothelin synthesis.

26. A composition according to claim 25, characterized in that the inhibitor of endothelin synthesis is SQ 28 608.

27. A composition according to claim 1, characterized in that the progestin is progesterone.

28. A composition according to claim 27, characterized in that the cyclooxygenase inhibitor is aspirin.

29. A method according to claim 2, characterized in that the endothelin antagonist is administered orally.

30. A method in accordance with the claim 2, which is characterized by the fact that the inhibitor of endothelin synthesis is administered orally.

31. A method in accordance with the claim 3, which is characterized by the fact that the endothelin antagonist is administered orally.

32. A method according to claim 3, characterized in that the inhibitor of endothelin synthesis is administered orally.

33. A method for classifying compounds and compositions for the treatment of premature birth, which is characterized in that it comprises: (a) administering to a pregnant guinea pig an amount of L-NAME effective to induce premature birth, (b) administering to said guinea pig an amount of a compound to be classified on its effectiveness in treating premature birth, and (c) measuring the effectiveness of said compound.

34. A method for classifying compounds and compositions for the treatment of preeclampsia, fetal growth retardation or gestational hypertension, which is characterized in that it comprises: (a) administering to a pregnant rat an effective amount of L-NAME to induce said condition, (b) administering to said rat an amount of a compound to be classified on its effectiveness to treat such condition, and (c) measuring the effectiveness of said compound to treat said condition.

35. A pharmaceutical composition according to claim 1, characterized in that it comprises: (a) an endothelin antagonist and / or an inhibitor of endothelin synthesis, and (b) a progestin, an estrogen, or a combination of an estrogen and a progestin, and / or (c) a nitric oxide donor and / or a nitric oxide substrate, and optionally, a cyclooxygenase inhibitor, together with a pharmaceutically acceptable excipient.

36. A method for treating atherosclerotic vascular diseases or hypertension in male or female mammals, characterized in that it comprises administering to the mammal in need of such treatment an effective amount of a composition according to claim 35, wherein, when the mammal is a male LO, component (b) does not include an estrogen.

37. A method for providing hormone replacement therapy to a mammalian female, which is characterized in that it comprises administering to the female requiring such treatment an amount

38. A method according to claim 36, characterized in that the mammal is a human female suffering from hypertension, and (b) is an estrogen or a combination. of an estrogen and a 20 progestin.

39. A method according to claim 36, characterized in that the mammal is a human male suffering from hypertension, and (b) it is a progestin.

40. A method according to claim 37, characterized in that the mammalian female is a human female and (b) is a progestin or a combination of an estrogen and a progestin.

41. A method according to claim 36, characterized in that the mammal is a human being and (a) is an endothelin antagonist.

42. A method in accordance with the claim 36, which is characterized by the fact that the mammal is a human being and (a) is an inhibitor of endothelin synthesis.

43. A method in accordance with the claim 37, which is characterized by the fact that the mammalian female is a human being and (a) is an endothelin antagonist.

44. A method according to claim 37, characterized in that the mammalian female is a human being and (a) is an inhibitor of endothelin synthesis.

45. A method according to claim 36, characterized in that the mammal is a human female suffering from atherosclerotic vascular disease and (b) is an estrogen or a combination of an estrogen and a progestin.

46. A method according to claim 36, characterized in that the mammal is a human male suffering from atherosclerotic vascular disease and (b) is a progestin.

47. A method in accordance with the claim 36, which is characterized by the fact that the mammal is a human being and the composition includes a nitric oxide donor and / or a nitric oxide substrate.

48. A method in accordance with the claim 37, which is characterized by the fact that the mammalian female is a human being and the composition includes a nitric oxide donor and / or a nitric oxide substrate.

49. A method in accordance with the claim 36, which is characterized by the fact that the progestin is progesterone.

50. A method in accordance with the claim 37, which is characterized by the fact that the progestin is progesterone.

51. A method in accordance with the claim 36, which is characterized by the fact that the nitric oxide donor and / or the nitric oxide substrate are respectively nitroglycerin and L-arginine.

52. A method in accordance with the claim 37, which is characterized by the fact that the nitric oxide donor and / or the nitric oxide substrate are respectively nitroglycerin and L-arginine.

53. A method according to claim 41, characterized in that the endothelin antagonist is BQ-123.

54. A method according to claim 43, characterized in that the endothelin antagonist is BQ-123.

55. A method in accordance with the claim 42, which is characterized by the fact that the inhibitor of endothelin synthesis is SQ 28 608.

56. A method according to claim 42, characterized in that the inhibitor of endothelin synthesis is SQ. 28 608.

57. A composition according to claim 35, characterized in that (a) is an endothelin antagonist.

58. A composition according to claim 57, characterized in that the endothelin antagonist is BQ-123.

59. A composition according to claim 57, characterized in that (a) is an inhibitor of endothelin synthesis.

60. A composition according to claim 59, characterized in that the inhibitor of endothelin synthesis is SQ 28 608.

61. A composition according to claim 35, characterized in that the progestin is progesterone.

62. A composition according to claim 35, characterized in that the nitric oxide donor and / or the nitric oxide substrate are respectively nitroglycerin and L-arginine.

63. A method according to claim 36, characterized in that the endothelin antagonist is administered orally.

64. A method in accordance with the claim 36, which is characterized by the fact that the inhibitor of endothelin synthesis is administered orally.

65. A method in accordance with the claim 37, which is characterized by the fact that the endothelin antagonist is administered orally.

66. A method according to claim 37, characterized in that the inhibitor of endothelin synthesis is administered orally.