CN1163569A - Combination of prostacyclin withe strogen or progestin for prevention and treatment of atherosclerotic vascular disease including preeclampsia and for treatment of hypertension and for hormone... - Google Patents

Abstract

Cardiovascular disease, including preeclampsia in pregnant women and hypertension in both women and men, are prevented or treated by administering thereto prostacyclin or a prostacyclin analog in combination with one or both of an estrogen and a progestin, which combination is also useful for HRT in peri- and post-menopausal women.

Description

Be used to prevent and treat atherosclerotic angiopathy, treatment hypertension and the prostacyclin of hormone replacement therapy and the compositions of estrogen or progestogen that comprises preeclampsia

Background of invention

The present invention relates to a kind of atherosclerotic angiopathy (cardiovascular diseases) of preventing and treat; The hormone replacement therapy of prevention and treatment anemia of pregnant woman's preeclampsia and premenopausal and postmenopausal women and the hypertensive method of treatment masculinity and femininity.

EPDML data show death in developed country about 1/2nd owing to a main cause, and promptly cardiovascular disease comprises coronary heart disease, apoplexy and other forms of angiopathy (Green, A, Bain, C., 1993).Cardiovascular disease the most common and the most fatal form is a coronary heart disease.The popular sustainable growth of 30-40 cardiovascular disease after year in the male.On the other hand, particularly the ratio of coronary heart disease is relatively low at premenopausal women's center angiopathy, but this with advancing age ratio obviously raises, and this shows that gonadal hormone (estrogen and progestogen) has protective effect to the women.The such viewpoint of the dangerous further support of the growth of coronary heart disease among the women of bilateral oophorectomy, promptly steroid hormone shields to cardiovascular disease.

Can prevent postmenopausal women trouble cardiovascular diseases with estrogenic Hormone Replacement Therapy (HRT).Reduced cardiovascular diseases's danger (Stamper etc., 1991) at the verified 23 routine estrogen user in these researchs of 29 example research post analysis that carry out recently.In with the research of monkey, also there is experimental evidence to show the development (Adams etc., 1992) that can reverse the coronary atherosclerosis disease of bringing out with the estrogen replenishment by ovariectomy and diet.On the other hand, can not use, so the prevention cardiovascular diseases does not have effective method among the male owing to estrogenic side effect.

Now also do not illustrate the mechanism of estrogen protective effect fully.May exist influential to lipid profile.In postmenopausal women, estrogen can reverse the growth of content of variation that the atheroma of the lipid profile relevant with premature menopause forms such as LDL-cholesterol and blood plasma triglyceride and the reduction of HDL-cholesterol.But nearest data show no matter be that estrogen or progestogen all have direct effect to blood vessel.This viewpoint has been supported in the existence of estrogen and progesterone receptor in arterial endothelial cell and smooth muscle cell, and promptly gonadal hormone can directly act on blood vessel (Lin etc., 1986).Confirm also that at present in baboon estrin treatment can cause distributing again of tremulous pulse estrogen receptor and cause the increase (Lin etc., 1986) of tremulous pulse progesterone receptor.The test of monkey shows that estrogen prevents to form (Adams etc., 1992) by the atheroma that ovariectomy is brought out by the absorption and the degraded of inhibition arterial wall to LDL.Estrogen and/or progestogen also can be interpreted as HRT some useful effects to arterial disease danger to the effect of tremulous pulse environment.Can know that from animal model estrogen is to increase uterine blood flow (Greiss by regulating vascular environment; Anderson, 1970, Ganger etc., 1993).Gonadal hormone shows that to the effect of vascular environment gonadal hormone plays a role in hypertensive pathogeny.

The various hormones that produce by the part comprise that nitrogen oxide, prostacyclin and Endothelin can regulate the effect of steroidal compounds to blood vessel.No matter be that nitrogen oxide or prostacyclin can both bring out the lax and inhibition platelet aggregation of blood vessel.On the other hand, Endothelin has intensive vasoconstriction effect.Nitrogen oxide be produce by endotheliocyte and participate in vascular environment, hematoblastic cohesion, neurotransmission and immunocompetent adjusting (Furchgott and Zawadzki, 1980; Moncadc, Palmer andHiggs, 1991).Be called EDRF (Endothelin-bring out relaxation factor) (Furchgottund Zawadzki, 1980 in the past; Moncadc, Palmer and Higgs, 1991) nitrogen oxide be that with at least three kinds of different isomerization bodies that contain flavo-enzyme nitric oxide synthase (Moncada, Palmer and Higgs, 1991) the arginic guanidine radicals nitrogen of L-to be carried out oxidative deamination synthetic.The content that nitrogen oxide can improve the cGMP (1,3,5-ring-type one phosphoric acid guanosine) in the vessel smooth muscle produces lax and reduction vasotonia (Moncada, Palmer and Higgs, 1991).

Prostacyclin is a kind of effective endothelium platelet suppressant drug and as the anticoagulative substance (Willis and Smith 1989) of the local modulation agent of cell-blood vessel wall effect.Its pharmacological action is similar to nitrogen oxide.It is a kind of effective vasodilation, and it can dependent dose reduces the resistance and the blood pressure of peripheral arterial.Because its chemical instability has limited the clinical use of prostacyclin.So preferred prostacyclin analogs promptly has the derivatives of prostaglandins with the prostaglandin dependency structure, it has the effect to cardiovascular system, as suppressing platelet aggregation.Ilomedin and cicaprost (cicaprost) are the stable analogs of prostacyclin.Ilomedin is synthetic first kind of chemically stable cpd, and this chemical compound combines (Skuballa etc., 1985) with the biological characteristic and the chemical stability of prostacyclin.Cicaprost is metabolism and chemically stable prostacyclin analogs, and it has the action time (Skuballa etc., 1986) of high bioavailability and prolongation.It is efficient special prostacyclin analogs, if other prostaglandins are to any effect sensitivity of tract, the minimum that it has.

Evidence suggests that the internal leatherware of prostacyclin analogs has protective effect.The beneficial effect that Ilomedin and cicaprost form atherosclerosis has been described in animal model.Having reduced the formation of atherosclerosis of aorta and partial prophylaxis with the rabbit of cicaprost oral medication cholesterol feed, hypercholesterolemia brought out depends on the lax infringement (Braun of endothelium, M., Deng, 1992), in addition, cicaprost has reduced the too high platelet of bringing out of cholesterolemia of rabbit and the superfunction (Hohfeld etc., 1992) of neutrophilic leukocyte.People have thought that platelet and leukocyte have formed certain effect to atherosclerosis.And the too high coronary artery diastole infringement of bringing out has useful effect (Woditschl, etc., 1992) to cholesterolemia to the oral cicaprost of studies show that of rabbit.It has been found that Ilomedin can protect microvascular arterial endothelium not to be subjected to the infringement (Burton GA etc., 1992) of cyclosporin.

These zooscopies show that single prostacyclin can protectiveness prevent that atherosclerosis from forming.But now also not prostacyclin analogs and progestogen or estrogen Combined Trials or clinical research.

Preeclampsia is a kind of special disease of pregnancy, and to be hypertension, pathology edema lack relevant albuminuretic three with general and fetal viability to traditional definition levies.People do not know the etiology and the pathology of this universality disease (be approximately all anemia of pregnant woman 10%).People it is generally acknowledged that preeclampsia is the generation that links to each other with the shortage of prostacyclin and increased TXA2..Current therapies is confined to bed and goes up have a rest (tender type), regulate symptom and follow operative delivery and the precocious early stage childbirth danger of doctor's originality with antihypertensive, in preeclampsia, the afterload that has the preload that reduces, low heart output and raise, these are consistent with the peripheral vascular resistance of vascular inner volume that reduces and increase.Increase blood vessel to the blood vessel sensitivity of hypertensor and the existence of (2) vaso-active substance by (1), explained the Peripheral resistance that increases.

A large amount of evidences shows preeclampsia, and (Abdul-Karim 1961 with pressurization to angiotensin 11 and other vasoactive agents, Gant 1973, Gant 1974), hematoblastic activation (Bonnar1971, Perkins 1979, Giles 1981) and endothelial cell damage (Roberts 1989, and Shanklin1989) sensitivity increases relevant.Preeclampsia, edema and albuminuretic main clinical characteristics are consistent with the forfeiture of the transportation function of endothelium.

Generally preeclampsia is regarded as the acute form that atherosclerosis forms.Spatial corkscrew arteries has experienced metamorphosis widely between the fine hair that is full of normal Placenta Hominis during the normal pregnancy, that is, diameter has increased by four times and lost their muscle and elastic component (Robertson 1986).These variations make the uterine blood flow that occurs at normal pregnancy duration increase about 10 times.These variations (Robertson 1986) do not occur in preeclampsia thereby the uterus muscle fragment of corkscrew arteries can not expand.In addition, the uterus muscle fragment of basilar artery in the Placenta Hominis of preeclampsia and corkscrew arteries has confirmed the characteristic damage, now is referred to as " acute atherosclerosis " (Roberts 1989).In the acute atherosclerosis in preeclampsia uterus, the damage of endotheliocyte has appearred, the focus blocking-up of basement membrane, myocyte's platelet precipitation lipid necrosis (foam cell), (chronic hypoxia and/or cytotoxic result), (Robertson 1967, and DeWolf 1980 for the thrombosis of chamber wall and fibrinoid necrosis, Roberts 1989), this is very similar to the result who arrives seen in the atherosclerotic blood vessel disease.

Now confirmed that also the production of the prostacyclin in the preeclampsia has been lowered.In normal pregnancy, the generation of comparing at prostacyclin with non pregnant state has increased about 5-10-doubly (Goodman 1982, and Walsh 1985, and Fitzgerald 1,987).On the contrary, the parent in preeclampsia, the production of prostacyclin has reduced (Remuzzi1980, Makila 1984, Walsh 1985) in Placenta Hominis and umbilical duct and the foetal cotyledon.Now advised thromboxane A in the preeclampsia ₂Unbalance with the prostacyclin ratio as pathomechanism main in the preeclampsia (Walsh 1988, Fitzgerld, Friedman 1988).Other experimental studies in pregnant rat and Cavia porcellus (not reporting) show that the shortage of nitrogen oxide is the main performance of preeclampsia.In gestation with synthetic hypertension, albuminuria and the intrauterine growth retardation that can cause classical symptom of L-NAME inhibited oxidation nitrogen.

Prostacyclin can obtain by a kind of stable lyophilized formulations, promptly to people's intravenous administration according to prostate alcohol.According to the main limitation of prostate alcohol is must parenteral, platelet is suppressed and the steep dose-response relationship of the appearance of side effect, and shortterm effect (Moran andFitzgerald 1994; Vane 1993).Special with use according to the relevant systemic blood pressure of prostate alcohol or intravenous Ilomedin obviously be declined to become use prostacyclin and analog thereof can not be in cardiovascular disease widely used cause (Vane 1993).

People had attempted treating preeclampsia with prostacyclin.When in vitro tests, prostacyclin can relax always, and (Glance 1986, and Howard 1986, Maigaard1986) for uterine vascular.But when testing in vivo, the infusion prostacyclin but can not cause sheep (Phernetton1979, Rankin 1979, Landauer 1985) and people's (Husslein 1985) the dabbling increase in uterus.And the research in the sheep model confirms that also the dabbling decline in uterus that the infusion of prostacyclin causes is accompanied by the illeffects to fetus.

When unbalance phenomenon that the prostacyclin of thromboxane that occur to increase in preeclampsia and decline produces, some researcheres are attempted to treat these diseases with a kind of regular venoclysis prostacyclin.Having 3 parts of reports to report is treating with prostacyclin (4-8ng/kg/ minute, 5 hours to 11 days) with conventional medicine failure back 7 women that suffer from serious preeclampsia.All women's blood pressure all descends rapidly in the prostacyclin infusion process.The clinical effectiveness of these researchs is very poor.With precocious all babies of cesarotomy childbirth but have only baby's survival of 4/7.During treating, observed the fetus bradycardia and two foetal deaths have been arranged in the prostacyclin infusion process.The therapy of prostacyclin has caused the phenomenon that a kind of artery blood flow changes its course and has reduced the blood flow on top, uterus unexpectedly in these researchs.At prostacyclin this explanation has been supported in the research of the serious early onset intrauterine growth retardation effect of 2 examples.The prostacyclin intravenously administrable is attempted to promote fetal growth and prolonged gestation thus.This trial not success has also all caused intrauterine death in all cases.The side effect of parent is restricted to 4ng/kg/ minute with infusion rate (Steel and Pearce1988) in this report.

These observations show that treating the therapy of having suffered from preeclampsia with the prostacyclin of high dose is a kind of invalid and dangerous method.On the other hand, do not prevent the effective ways of preeclampsia again.Can suppress the synthetic of prostacyclin to the relative aspirin administration of low dosage, it is believed that aspirin mainly is to suppress the generation of platelet thrombus alkane A2 and the production of blood vessel prostacyclin is not almost suppressed (Masssoti 1979).So people advise the aspirin prevention preeclampsia with low dosage.In the integrating center result of study of announcing recently is disappointed, and nobody recommends to prevent preeclampsia (CLASP Collaborative Group, 1994) with the aspirin of low dosage now.Effective and the safe method that needs a kind of prevention and treatment preeclampsia like this.

The result of study of the beyong contemplation that describes below shows with progestogen can control blood vessel to the reaction of prostacyclin and blood pressure reduction effect subsequently.Can produce the phenomenon of preeclampsia and symptom (for example, hypertension, fetus is slow and the tradition of albuminuria-preeclampsia three is levied) with nitric oxide inhibitor (L-NAME) treatment pregnant rat.These symptoms are all relevant with uterus perfusion with the reduction vascular resistance.In the mouse model of preeclampsia (with L-NAME inhibited oxidation nitrogen synthetic), when the content of rising progestogen in pregnant rat, the blood pressure reduction effect of cicaprost and Ilomedin is bigger in the gestation late.Divide the puerperium, when the haemoconcentration of progestogen descended, the blood pressure of the animal for the treatment of with L-NAME and cicaprost or Ilomedin increased sharply.The progesterone receptor of injecting anti-R5020 (promegestone) can recover the effect that Ilomedin/cicaprost brings high blood pressure down.In addition, progesterone has partly reduced blood pressure and gestation RU 486 blood pressure that raise in this model in the male mouse of L-NAME-treatment.Like this, Ren Shen condition and progestogen therapy have increased the reaction of blood vessel to exogenous prostacyclin than the highland.The vascular reaction that increases has caused the reduction of prostacyclin analogs effective dose and the decline of side effect subsequently.Bringing high blood pressure down and fetal mortality and reverse aspect the intrauterine growth retardation extremely effective with the combination treatment preeclampsia Mus of prostacyclin and progestogen like this.

Can reverse the progestogen agent by the caused blood pressure growth of inhibited oxidation nitrogen in conjunction with prostacyclin analogs.Like this, progesterone in conjunction with prostacyclin can the full remuneration nitrogen oxide shortage.These observations show that with regard to controlling of blood pressure aspect prostacyclin and nitrogen oxide system all be complementary.

Preeclampsia is the model that the atherosclerosis of called optical imaging forms, and realizes the decline of the atherosis formation of mid-uterine artery by the formation that increases fibrinous precipitation of uterine vascular and increase thrombosis.So this method also is effective preventing and treating female atherosclerosis formation disease with boar.

Everybody knows estrogen can actively regulate progesterone receptor in the various target organs.So, preferred progestogen and estrogen administration together.

Goal of the invention

An object of the present invention is to provide a kind of with prostacyclin or its stable analog such as Ilomedin and cicaprost, with the prevention of a kind of progestogen and/or estrogenic compositions with treat the method for the atherosclerotic blood vessel disease (cardiovascular diseases) of female and boar.

Another purpose provides a kind of with estrogenic agents and prostacyclin or the next method that substitutes the hormonotherapy (HRT) of jenny before and after the menopause of its stable analogs combination.

Another purpose is a kind of with estrogenic agents and a kind of progestogen and prostacyclin or the next method that substitutes the hormonotherapy (HRT) of jenny before and after the menopause of its stable analogs combination.

Another purpose provides a kind of like this method, promptly a kind of progestogen and/or estrogen and prostacyclin or its stable analogs is made up and prevents and treat pregnant mammiferous preeclampsia.

Another purpose provides a kind of like this method, and promptly for example Ilomedin and cicaprost make up and treat female and hypertension boar a kind of progestogen and/or estrogen and prostacyclin or its stable analogs.

Another purpose provides a kind of pharmaceutical composition that is used to realize the inventive method.

Other purposes that the present invention includes are conspicuous to those of ordinary skills.

Summary of the invention

Aspect method, the present invention relates to a kind of method of preventing and treating the atherosclerotic blood vessel disease (cardiovascular diseases) of female and boar, it comprises the preeclampsia for the treatment of pregnant female mammal and treatment is female and the hypertensive method of boar, this method comprises to the target that this symptom occurs takes (a) prostacyclin or one kind analog, for example vein gives the prostacyclin of 0.1-10ng/kg/ minute bioequivalence, (b) one or both in progestogen and the estrogen for example effectively improve these symptoms with the estrogen of about 2mg/ days estradiol bioequivalence with the progestogen of the progesterone bioequivalence of injection 50-300mg.

Aspect product, the present invention relates to a kind of pharmaceutical composition, it contains at least a prostacyclin analogs and about 2mg estradiol (for example " Progynova; R. ", Schering, A.G.) estrogen of bioequivalence and/or with the progestogen of progesterone bioequivalence of injection 50-300mg in one or more.

Other aspects that the present invention includes are conspicuous to those of ordinary skills.

Describe in detail

The present composition can be used for preventing and treat female and atherosclerotic blood vessel disease (cardiovascular diseases) and the hypertension preferred people of boar, and can be used for the Hormone Replacement Therapy of premenopausal and postmenopausal women.Pregnant mammiferous preeclampsia can be prevented and treat to method of the present invention, the people of preeclampsia symptom for example occurs or the preceding or pregnant excessive risk candidate of being measured by gestation.

Because female sex steroid (progesterone and estrogen) and prostacyclin and analog thereof can play synergism, so prostacyclin analogs can the two be used in combination with progestogen, estrogen or estrogen and progestogen.When progestogenic and/or when estrogenic agents and prostacyclin or its analog co-administered, can reach synergy.

So, method of the present invention aspect and pharmaceutical composition of the present invention aspect have all used prostacyclin or its analog and one or more estrogen (as premarin, 17 beta estradiols, estriol or the ethinylestradiol of estradiol valerate, coupling as " Pyrgynova R ", Schering is A.G.) with a kind of progestogen (as progesterone, hydrogenation progesterone, diformazan dehydrogenation progesterone, norethindrone, levonorgestrel oxime, 18-methylnorethindron or gestodene).

Have with the example of the compositions of the prostacyclin analogs of a kind of progestogen and/or a kind of estrogen co-administered: prostacyclin (table prostate alcohol), Ilomedin, cicaprost.Following is the typical oral dose scope of estrogen and progestogen and prostacyclin active component:

Prostacyclin: Ilomedin, 10-1000 μ g/ patient; One day oral twice; Cicaprost, 1-100pg/ patient; One day oral twice.

Estrogen: every day the dosage bioequivalence every day about 1 to 2mg, for example " Premarin R " (Wyeth-Ayerst), 0.625mg/ days; Estradiol valerate, 50 U9/ days percutaneous dosing, estradiol vagina frost, 1.25mg/ days and estradiol pessary, 0.2mg/ days.

Progestogen: every day, the dosage bioequivalence was in 50-300mg progesterone/sky, for example, a kind of injectable diformazan dehydrogenation progesterone acetate suspension, providing weekly dosage with the form of the tablet that provided in oral dose 5-10mg/ days or dragee is 100-1000mg, a kind of injectable hydroxyprogesterone caproate solution, it is 250-500mg that dosage is provided weekly; It is norethindrone acetate tablet, capsule or the dragee of 5-20mg that every day dosage is provided.

The example of estrogen and progestogen is following listed.(oral " natural " estrogen that is used for alternative hormonotherapy can obtain in Britain now.)

Product component dosage (mg/ days) Climaval (Sandoz) estradiol valerate 1 or 2Progynova (Schering) estradiol valerate 1 or 2Harmogen (Abbott) piperazine estrone sulfate 1.5 or 2.5Hormonin (Shire) estradiol 0.6

+ estrone

The commercial available compositions catalog of the premarin 0.625 of+estriol " Premarin " coupling or 1.25 or 2.5 (Wyeth-Ayerst) is packed or is substituted hormonotherapy and comprises " Estrapak ", " Prempak-C ", " Trisequens ", " Trisequens Forte " and " Cycloprogynova ".Following is the component of this series products of detailed description: estradiol, 50mg every day (28 days, 8 pairs of plaster); The premarin of coupling, 0.625mg every day (28 days); Estradiol valerate, 2mg every day (11 days); Estradiol valerate, every day 2mg; Norgestrel, 0.5mg/ days (12 days) norgestrels, 0.15mg/ days (12 days); The premarin of coupling, 1.25mg every day (28 days); The norethindrone acetate, 1mg every day (10 days); Estradiol, every day the 1mg+ estriol, 0.5mg every day (6 days); The norethindrone acetate, 1mg every day (10 days); Estradiol, every day the 1mg+ estriol, 0.5mg every day (6 days); Estradiol valerate, 1mg every day (21 days); Levonorgestrel oxime, 0.25mg every day (10 days); Estradiol valerate, 2mg every day (21 days); Levonorgestrel oxime, 0.5mg every day (10 days).

Oral or percutaneous obtains dosage every day that estrogenic patient took progestogen in 12 days every month: norethindrone, 0.7-2.5mg/ days; Methoxyl group progesterone acetate, 10mg/ days; 18-ethyl norethindrone, 150mg/ days; With the hydrogenation progesterone, 10-20mg/ days.

The used drug activity agent of the present invention can with the excipient mixing administration of routine, excipient wherein is pharmaceutically acceptable liquid, semisolid or SOLID ORGANIC or inorganic carrier, they be suitable for as parenteral or intestinal use not with mixture in reactive compound deleterious reaction takes place.Suitable pharmaceutically acceptable carrier comprises but is not defined as: water, saline solution, alcohols, vegetable oil, Polyethylene Glycol, gelatin, lactose, amylose, magnesium stearate, Talcum, silicic acid, various vaseline, volatile oil, glycerine monofatty ester and double glyceride, pentaerythritol fatty ester, hydroxy methocel, polyvinylpyrrolidone etc.

With this pharmaceutical preparation sterilization and mix the adjuvant of reactive compound generation adverse reaction if necessary with or not, wherein adjuvant such as lubricant, antiseptic, stabilizing agent, wetting agent, emulsifying agent, the salt that influences osmotic pressure, buffer, coloring agent, correctives and/or aromatic substance etc.

If parenteral uses, particularly suitable is solution, and preferred oil or aqueous solution, and suspension, emulsion or implant comprise suppository and percutaneous plaster.Ampoule is the unit dose of using always.

One preferred aspect, the present composition is suitable for eating.

If intestinal uses, particularly suitable is unit dosage forms, as contains tablet, dragee or the capsule of the carrier of Talcum and/or a kind of carbohydrate or binding agent etc., and this carrier is lactose and/or corn starch and/or potato starch preferably; Granular solids is as granule; With liquid and semiliquid such as syrup and elixir etc., wherein use a kind of sweet carrier that increases.Also can be prepared into slow releasing composition, it comprises with different degradable coatings waits the active component of protecting wherein by micro encapsulation and multiple coatings parcel.

Being suitable for oral is tablet, dragee, capsule, pill, granule, suspension and solution.Every kind of unit dose such as every soupspoon liquid or every or dragee contain the various activating agents of 5-5000mg.

The solution of parenteral contains for example various activating agents of 0.01-1% in moisture or pure solution.

Prostacyclin analogs can be with a kind of estrogen and/or progestogen and other any active groups resulting mixtures or with isolating unit dose, simultaneously or the different time administration in a day.

The compositions of activating agent is (unless to continue the dosage form administration of release bioactive agent) and take medicine as the mode of 2 to 6 separate administration several times repeatedly preferred every day preferably at least once a day.

Concerning the people, should provide prostacyclin analogs and progesterone (or bioequivalent other progestogen) with the ratio of the plasma content that produces about 30-100 μ mol progesterone and 500-1000nmol estradiol.

Brief description of drawings

When considered in conjunction with the accompanying drawings, of the present invention various other purposes, feature and bonus that will be easier to understand, from several aspects, similarly fixed reference feature is defined in same or similar part, wherein:

Fig. 1 (cicaprost is to the effect of pressure value) has confirmed that progesterone agonist R5020 can reduce the blood pressure of preeclampsia Mus between the childbirth later stage with cicaprost (CCP) treatment.Preeclampsia is brought out with a kind of nitric oxide inhibitor L-NAME (25mg/ animal/sky, subcutaneous perfusion).Be parallel to the content (before progesterone content is higher than childbirth the time blood pressure drops and be lower than branch hypertension during the puerperium when progesterone content) of endogenous progesterone in the blood pressure that pregnancy duration uses cicaprost to add L-NAME;

Fig. 2 (medicine is to the effect of pressure value) has shown that R 5020 (0.5mg/ animal/sky, subcutaneous) can reduce the hypertension of bringing out male mouse with L-NAME;

Fig. 3 (medicine is to the effect of pressure value) has shown that RU 486 can raise with the puerperal blood pressure of animal of L-NAME treatment and slightly increased blood pressure in matched group;

Fig. 4 (Ilomedin is to the effect of pressure value) has shown that Ilomedin can reverse the hypertension that the pregnancy duration when progesterone content is higher brings out with L-NAME fully, but the childbirth bleeding from anus is pressed with an increase.R 5020 (5mg/ animal/sky) can greatly reduce puerperal blood pressure and increase; With

Fig. 5 is a bar chart, and it has represented that Ilomedin partly reverses the intrauterine growth retardation of bringing out with L-NAME (weight of higher square-comparison lamb) and reduces the mortality rate (mortality rate of lower square-comparison lamb) that brings out with L-NAME.

The discussion of accompanying drawing

Result shown in the drawings has confirmed that progesterone controls the prostatitis by increasing blood vessel to the reaction of this medicament The effect of gland ring element.

In result's shown in Figure 1 test, a kind of special progesterone activator (R 5020) has recovered The cicaprost antihypertensive effect is in puerperal decline. This research also shows gestation (progesterone and estrogen Content is higher) self the hypertension of bringing out with L-NAME is had useful effect. Fig. 2 is further The hypertensive mechanism that provides the proof progesterone can excite compensation to bring out with L-NAME. This grinds Study carefully with male mouse and carry out, show that gestation is dispensable concerning this effect. Fig. 3 has confirmed R 5020 effect mediates by PgR, at this moment because antiprogestin RU 486 has a kind of Opposite effect (more can increase the blood pressure that brings out with L-NAME). Fig. 4 has shown in gestation (pregnant Ketone and estrogen content are higher) during, Ilomedin has the step-down similar to cicaprost and does With and this acting on also weaken widely when branch puerperium progesterone content descends. Fig. 5 a and 5b confirm Ilomedin can increase uterus perfusion, at this moment because add L-NAME with Ilomedin and control The animal for the treatment of is compared the weight increase of fetus and the death of fetus with the animal groups for the treatment of with L-NAME Rate descends.

The effect of reaching a conclusion the prostacyclin step-down and increasing the fetus perfusion liquid from these tests is with pregnant Ketone is relevant. And, owing to concerning progesterone excites PgR, need estrogen, so can Reasoning estrogen concerning these effects is important. The used methods for the treatment of of the present invention just can like this Be used for the treatment of preeclampsia, atherosclerotic blood vessel disease, hypertension (female and male the two) with And as the adjuvant in the HRT.

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581Robertson WB, Khong TY, Brosens I, Wolf FD (1986) Placenta Hominis bed biopsy: the summary of coming three European centers.Am J Obstet Gynecol 159:401Skuballa W, Raduchel B, Vorbruggen (1985) stablizes the chemistry of prostacyclin analogs: ciloprost synthetic.In Gryglewski RJ, Stock G (eds) prostacyclin and its stable analogs ciloprost.Springer-Verlag Berlin: 17-25Skuballa WE, Schillinger E, Sturzebecher CS, Vorbruggen H (1986) have stable prostacyclin synthetic of the new chemistry of efficient and long-acting Orally active and metabolic activity.J Med Chem 29:313Shanklin DR, the Placenta Hominis bed of Sibai BM (1989) preeclampsia and the ultrastructure of border, uterus blood vessel.Am J Obstet Gynecol:161,3735Stampfer MJ, Willet WC, Colditz GA, Rosner B, Speizer FE, the prospect research of treatment and coronary heart disease after Hennekens CH (1985) menopause.The epidemiology of N Engl J Med 313:1044-9Stamfer MJ (1992) postmenopausal estrogen and the summary of coronary heart disease risk.InRamwell P, Rubanyi G, Schillinger E. 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Be not further explained, believe that those of ordinary skills can just can farthest use the present invention according to the description of front.Therefore, even more ideal particular is understood that it only is to be used for explanation, rather than limits the invention by any way.Above and the full content of the patent application of hereinafter being quoted, patent and publication all be cited as list of references at this.

EXAMPLE Example 1: with Ilomedin and the atherosis angiopathy of a kind of estrogenic/progestogenic compositions prevention of arterial

Give not gravid woman (about 45 years old that symptoms of menopause or postmenopausal symptom occur; 50-80kg) the Ilomedin of twice oral a kind of estrogen every day (as 1-2mg estradiol valerate every day), a kind of progestogen (as the 18-methylnorethindron of μ g every days 150) and 50ug.Embodiment 2: the atherosis angiopathy of Hormone Replacement Therapy prevention of arterial that adds progestogen with cicaprost and a kind of estrogen

Give following one or both medicines every day for women similar to Example 1 and same symptoms: estrogen (as estradiol valerate, every day 1-2mg), and progestogen (as 18-methylnorethindron 150mg every day).Estrogen and a kind of prostacyclin such as Ilomedin or cicaprost or continuous or sequential administration, be accompanied by every month 6-12 days and take a kind of progestogen.Embodiment 3: with Ilomedin and the atherosis angiopathy of estrogen prevention of arterial

Give following medicine every day for women similar to Example 1 and same symptoms: estrogen (as estradiol valerate, every day 1-2mg) and every day twice oral 50ug Ilomedin.Embodiment 4: with Ilomedin and progesterone treatment atherosclerotic blood vessel disease

The male (about 45 years old who give to show the cardiovascular disease symptom; 50-80kg) the Ilomedin of twice oral a kind of progestogen every day (as the 18-methylnorethindron of μ g every days 150) and 50 μ g.Embodiment 5: with Ilomedin and progesterone treatment hypertension

Give the Ilomedin of sex twice oral 50 μ g every day that hypertension symptom occurs, be accompanied by a kind of progestogen (as the 18-methylnorethindron) of taking 150mg every day.Embodiment 6: with Ilomedin and progesterone prevention preeclampsia

Give the Ilomedin of sex twice oral 50 μ g every day that the preeclampsia symptom occurs, be accompanied by oral progesterone every day (as the micronized progesterone of 200mg).

The medicament and/or the operating condition that replace the description of generality used in the foregoing description or particularity can similarly successfully repeat the foregoing description.From the foregoing description, those of ordinary skills can determine basic feature of the present invention easily, and in not exceeding design of the present invention and scope, can do various variations and improvement to the present invention to adapt to various uses and condition.

Claims (23)

1. a Therapeutic Method that is selected from down group a) prevents or treats mammal atherosclerotic blood vessel disease; B) to the Hormone Replacement Therapy of premenopausal and postmenopausal women; And c) treat mammiferous hypertension, this method comprises and will improve or the prevention symptom prostacyclin of effective dose or one or more administering drug combinations in its analog and estrogen and the progestogen occur in ill mammal.

2. be the women who suffers from menopause or postclimacteric menopause syndrome according to the mammal that the process of claim 1 wherein.

3. according to the mammal that the process of claim 1 wherein the women of candidate in the Hormone Replacement Therapy.

4. be the male who suffers from cardiovascular disease according to the mammal that the process of claim 1 wherein.

5. be the mankind that suffer from cardiovascular disease according to the mammal that the process of claim 1 wherein.

6. be the women who suffers from preeclampsia according to the mammal that the process of claim 1 wherein.

7. be people and be Ilomedin or cicaprost according to the mammal that the process of claim 1 wherein to prostacyclin or its analog of its administration.

8. according to the method for claim 7, wherein prostacyclin analogs is an oral administration.

9. be people and prostacyclin or its analog are and a kind of progestogen administering drug combinations according to the mammal that the process of claim 1 wherein.

10. according to the method for claim 9, progestogen wherein are progesterone, hydrogenation progesterone, diformazan dehydrogenation progesterone, norethindrone, levonorgestrel oxime or 18-methylnorethindron.

11. according to the mammal that the process of claim 1 wherein is women and prostacyclin or its analog are and a kind of estrogen administering drug combinations.

12. according to the method for claim 11, estrogen wherein is premarin, 17 beta estradiols, estrone, estriol or the ethinylestradiol of estradiol valerate, coupling.

13. according to the mammal that the process of claim 1 wherein is women and prostacyclin or its analog are and a kind of estrogen and a kind of progestogen administering drug combinations.

14. according to the mammal that the process of claim 1 wherein is women and estrogen or progestogen are successive administrations.

15. according to the mammal that the process of claim 1 wherein is women and estrogen and progestogen are sequential administration.

16. a pharmaceutical composition, it comprises (a) prostacyclin or its analog and at least a (c) estrogen and (d) mixture of progestogen.

17. according to the compositions of claim 16, it comprises that estrogenic amount is equivalent to the amount bioequivalence of the estradiol of 1-2mg and/or progestogen in the injectable progesterone of 50-300mg.

18. according to the compositions of claim 16, wherein (a) is Ilomedin or cicaprost.

19., wherein contain a kind of estrogen according to the compositions of claim 16.

20. according to the compositions of claim 19, estrogen wherein (b) is estradiol valerate.

21., wherein contain a kind of progestogen according to the compositions of claim 16.

22. according to the compositions of claim 21, progestogen wherein (d) are the 18-methylnorethindrons.

23., wherein contain a kind of progestogen and a kind of estrogen according to the compositions of claim 16.

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