ES2352547T3 - METHOD FOR TREATING AN ACUTE VASCULAR DISORDER. - Google Patents

Abstract

The present invention relates to a method of treating an acute vascular disorder in a mammal, said method comprising orally administering to said mammal, upon demand, an effective amount of a steroid to said mammal, said steroid being selected from the group consisting of: substances represented by formula (I), in which R1, R2, R3, R4 independent ly are a hydrogen atom, a hydroxyl group or an alkoxy group with 1-5 carbon atoms; each of R5, R6, R7 is a hydroxyl group; no more than 3 of R1, R2, R3, R4 are hydrogen atoms; precursors capable of liberating a substance according to the aforementioned formula when used in the present method; and mixtures of one or more of the aforementioned substances and/or precursors.

Description

Method to treat a vascular disorder acute.

Technical field

The present invention relates to the use of a steroid in the manufacture of a pharmaceutical composition for use in a method for treating an acute vascular disorder, for example a peripheral cardiovascular, cerebrovascular or vascular disorder, said method comprising oral administration ad libitum al mammal, on demand, of an effective amount of a steroid.

Background of the invention

Vascular disease can affect any part of the arterial system. Smoking, blood pressure High, obesity, high blood cholesterol, and diabetes are risk factors for all types of vascular disease.

Acute cardiovascular disorders include, eg angina pectoris, myocardial ischemia, infarction myocardial and diseases that arise from thrombotic states in the that the coagulation cascade is activated.

Angina pectoris is typically described as a substernal chest discomfort that is perceived as oppression, heaviness, or pressure, or a burning sensation. Angina pectoris results when the demand for myocardial oxygen increases to levels that cannot be satisfied through an increased coronary blood flow, usually due to injuries atherosclerotic stenotic in one or more of the coronary vessels epicardial Therefore, angina is typically caused for excessive physical exertion or emotional stress.

Many patients with stable angina can identify specific activities or situations that will arise predictably discomfort; climbing a slope or rushing They are common examples. Angina that has recently progressed or increased spontaneously in severity, frequency, or duration, particularly if accompanied by pain at rest, it consider unstable angina. Patients with recent beginnings of angina, particularly if it occurs at low levels of activity or in rest, they are also included in this category.

Ischemia is a condition in which an organ or a part of the body does not receive a blood supply enough. When an organ is deprived of a supply of blood, it is said to be hypoxic. An organ will become hypoxic even when the blood supply temporarily ceases, such as during a surgical procedure or during temporary blockage of the artery. Ischemia initially results in a decrease in or loss of contractile activity. When the affected organ It is the heart, this condition is known as myocardial ischemia. When myocardial ischemia is of sufficient severity and duration, cell injury can progress to cell death, that is myocardial infarction, and subsequently to heart failure, hypertrophy,  or congestive heart failure.

Acute cerebrovascular disorders include, for example, migraine, cerebral ischemia, infarction cerebral, cerebral vasospasm and thrombotic stroke.

Migraine is a painful syndrome characterized for pulsating unilateral headaches, nausea, vomiting, and sensitivity to light and sound. The pathophysiology of the pains of Migraine head implies vasoconstriction (closing or tightening of the arteries, which reduces blood flow) and vasodilation (the opening of the vessels to increase blood flow). It seems that a variety of stimuli, such as intense light, the noise, anxiety, excessive effort, cold, heat, hormones, food additives and certain foods, result in constriction of extracranial vessels. The vasoconstriction is followed by potent sequential vasodilation or reflex, which subsequently extends to the vessels intracranial It is during this phase that a patient feels pain with an intense throbbing head.

Cerebral infarction is a cerebral dysfunction Severe induced by cerebral ischemia or hypoxemia. The conditions that can cause cerebral ischemia include the stroke and stroke.

The term "cerebral vasospasm" is commonly used to refer to both the clinical picture of the delayed onset of ischemic neurological deficits associated with aneurysmal subarachnoid hemorrhage ("symptomatic vasospasm") and narrowing of the cerebral vessels documented by angiography or other studies. ("arterial or angiographic vasospasm"). Arterial vasospasm typically appears 3 to 4 days after rupture and reaches a maximum value in incidence and severity at 7 to 10 days. The incidence and time course of symptomatic vasospasm is parallel to that of arterial vasospasm. However, while 40% to 70% of patients have evidence of arterial narrowing (angiography or Doppler ultrasound), only 20% to 30% develop the clinical syndrome. The most important factors in determining the clinical effect of vasospasm are the severity and extent of the narrowing of the vessels. Symptomatic vasospasm typically begins 4-5 days after hemorrhage and is characterized by the insidious appearance of confusion and a decreasing level of consciousness. When arterial narrowing is severe, these symptoms may progress to focal neurological deficits, heart attack, coma and
death.

Acute peripheral vascular disorders include, for example, occlusive peripheral arterial disease, Buerger's disease, erectile dysfunction (impotence) and peripheral arterial functional diseases, such as, the Raynaud's disease, Raynaud's phenomenon and acrocyanosis.

Most people with occlusive peripheral arterial disease have atherosclerosis, a disease process in which fatty material accumulates under the lining of the arterial wall, gradually narrowing the artery. However, a partial or complete occlusion of an artery can result from other causes, such as a blood clot. When an artery narrows, the parts of the body it serves may not receive enough blood, resulting in a decrease in oxygen supply (ischemia). Depending on the site in the affected body, the obstruction of a peripheral artery can produce various symptoms, which can sometimes be deadly such as obstruction of the abdominal aorta or renal arteries. With the narrowing of the leg artery, the first symptom is a painful, painful, cramping, or tired feeling in the muscles of the leg during physical activity; This sensation is called intermittent claudication. Muscles hurt when the person walks, and the pain progresses faster and is more severe when the person walks quickly or uphill. More commonly, the pain is in the calf, but it can also be in the foot, thigh, hip, or buttocks, depending on the location of the narrowing. The same type of pain from excessive strain is also caused by narrowing of the arteries in the arms. Some symptom relief can be obtained by pentoxifylline, calcium antagonists or aspirin. However, beta-blockers that are prescribed to patients with coronary artery obstructions worsen symptoms in patients with arterial obstructions of the leg or
arm.

Buerger's disease ( Thromboangiitis obliterans ) is the obstruction due to inflammation of the small and medium-sized arteries and veins caused by smoking. The symptoms of a reduced blood supply to the arms or legs develop gradually, beginning at the fingertips of the hands or feet and progressing towards the arms or legs. Patients may feel cold, numbness, tingling, or burning. They often have the Raynaud phenomenon (see below) and experience muscle cramps.

The biggest cause of erectile dysfunction is vascular; other large pathogenic categories include the hormonal disorders, drug use, and disorders neurological The biggest types of vascular problems that can result in erectile dysfunction are atherosclerotic disease of penile arteries, inadequate impedance of outflow venal (venous leaks), or a combination of both. With age and underlying diseases (for example, atherosclerosis, hypertension), dilation of arterial blood vessels and Smooth muscle relaxation decrease, decreasing the amount of blood that enters the penis. Venal leaks make it difficult for The blood remains in the penis during erection. The diseases that accelerate atherosclerosis (for example, diabetes, smoking, hypertension) increase the prevalence of erectile dysfunction. Sildenafil is an oral drug released recently belonging to the class of inhibitors of phosphodiesterase Promotes erection enhancing the effect of nitric oxide in the smooth vascular muscle, thus increasing the blood flow to the penis Create a more normal erectile response because it works with concomitant sexual arousal. The drug it has to take 30 to 60 minutes before the sexual act and it is contraindicated in people taking nitrates; cause pains of Head in approximately 16% of users.

Raynaud's disease and Raynaud's phenomenon are conditions in which small arteries (arterioles), usually in the fingers and toes, go into spasm, causing the skin to turn pale or an uneven red to blue. The spasm of the small arteries in the fingers and toes develops rapidly, most often triggered by exposure to cold and can last for minutes or hours. Between 60 and 90 percent of Raynaud's disease cases occur in young women. Possible underlying causes of Raynaud's disease and Raynaud's phenomenon include scleroderma, rheumatoid arthritis, atherosclerosis, nerve disorders, decreased thyroid activity, injury, and reactions to certain drugs, such as ergotamine and methysergide. Some people with Raynaud's phenomenon also have migraine headaches, variant angina, and high blood pressure in their lungs (pulmonary hypertension). These associations suggest that the cause of arterial spasms may be the same in all these disorders. Anything that stimulates the sympathetic nervous system, such as emotion or exposure to cold, can cause arterial spasms. Occasionally, in some patients drugs such as phenoxybenzamine, methyldopa, or pentoxifylline help relieve the
symptom.

Acrocyanosis is a blue color persistent, painless of both hands and, less commonly, of the feet, caused by the unexplained spasm of the small vessels blood from the skin The disorder usually occurs in women, not necessarily those with occlusive arterial disease. The fingers or toes and hands or feet are constantly cold and bluish and sweat profusely; They can swell.

It is known in the art that patients who suffer from the aforementioned acute cardiovascular disorders, Cerebrovascular and peripheral vascular can be treated successfully with vasodilation agents such as nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, minoxidil, papaverine HCl, isoxsuprine HCl, hydralazine, pentoxifylline and sildenafil. However, the use of these agents of vasodilation is associated with problems such as slow onset of action and / or undesirable side effects (e.g. ex. headache, nausea, dizziness, hypotension).

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WO 03/103683 describes the use of estetrol and estetrol derivatives to treat or prevent pathologies cardiovascular such as hypercholesterolemia, dyslipidemia, atherosclerosis, arteriosclerosis, xanthomatosis, myocardial infarction, stroke, silent stroke, unstable angina, loss of cognitive function, vascular dementia and disease of Alzheimer's

Summary of the Invention

The present inventors have unexpectedly found that particular steroids can be advantageously employed in methods to treat the aforementioned acute cardiovascular, cerebrovascular and peripheral vascular disorders that employ oral administration ad libitum within 30 minutes after the mammal has begun experience the first symptoms The steroids used in accordance with the present invention are represented by the following formula

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one

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in whose formula R 1, R 2, R 3, R 4 are independently a hydrogen atom; a hydroxyl group or an alkoxy group with 1-5 atoms of carbon; each of R 5, R 6, R 7 is a group hydroxyl; and no more than 3 of R 1, R 2, R 3, R 4 are atoms of hydrogen.

It is known in the art that estrogens, in particular 17β-estradiol, can have a relaxing effect on the cerebral and coronary arteries as demonstrated in vitro by Ospina et al . (Am J Physiol Heart Circ Physiol, 2003 Jul; 285 (1): H241-50), Salom et al . (J Cereb Blood Flow Metab. 2001 Apr; 21 (4): 422-9) and Kalenic et al . (WV med J. 2000 Nov-Dec; 96 (6): 617-21). It has also been observed by Martin et al . (Headache, 2003 Apr; 43 (3): 309-21) that estrogen restitution therapy in medically oophorectomized women, provides a modest benefit in the prevention of migraine headaches. However, pharmacokinetic deficits, such as delayed onset of action and rapid clearance by the liver, combined with a high risk of inducing venous thromboembolism / pulmonary embolism and hepatotoxicity at the required high dose levels, have so far prevented treatment. successful of acute peripheral cardiovascular, cerebrovascular or vascular disorders with estrogens administered orally, for example 17β-estradiol.

Surprisingly, it was discovered that, after oral administration, the steroids according to the present invention exhibit an extremely rapid onset of action. Thus, the present steroids can be properly
(self-) administered orally for the instantaneous treatment of an acute vascular disorder.

The high efficacy of the present steroids in the treatment of acute vascular disorders is believed to be associated with the relatively high affinity of these substances for the estrogen receptor a (REa) as compared to the β estrogen receptor (RE?).

A typical representative of those present steroids, the natural fetal compound estetrol, interacts with estrogen receptors selectively similar to that of the called Selective Estrogen Receptive Modulators (SERM). In view of its MRSE-type properties and its high REa affinity, the steroids of the present invention will refer to as' α-SERM.

Detailed description of the invention

Accordingly, the present invention relates to the use of a steroid in the manufacture of a pharmaceutical composition for use in a method for treating an acute vascular disorder in a mammal, said method comprising oral administration ad libitum to said mammal, on demand. , of an effective amount of a steroid to said mammal, said steroid being selected from the group consisting of:

Substances represented by the following formula

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2

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in whose formula R 1, R 2, R 3, R 4 are independently a hydrogen atom, a hydroxyl group or an alkoxy group with 1-5 atoms of carbon; each of R 5, R 6, R 7 is a group hydroxyl; no more than 3 of R 1, R 2, R 3, R 4 are hydrogen atoms; precursors capable of releasing a substance according to the aforementioned formula when used in the present method, whose precursors are derived from the mentioned steroids in where the hydrogen atom of at least one of the groups of hydroxyl has been replaced by an acyl radical of a carboxylic, sulfonic or sulfamic acid hydrocarbon of 1-25 carbon atoms; tetrahydrofuranyl; tetrahydropyranal; or a straight chain glycosidic residue or branched containing 1-20 units glycosides for each residue; and mixtures of one or more of the mentioned substances and / or precursors, where the steroid is administered within 30 minutes after the mammal has started experiencing the first symptoms associated with the vascular disorder acute.

The term "acute vascular disorder" is refers to vascular disorders of a non-chronic nature with sudden manifestations of symptoms.

The term "on demand" as used here means that the steroid is administered as soon as it is states that the mammal is experiencing, or is about to experience symptoms associated with a vascular disorder acute.

The present method does not cover treatment prophylactic of the aforementioned vascular disorders since the benefits of the invention are manifested particularly in the therapeutic treatment of these disorders. The present estrogen substances are different from both estrogen synthetic as biogenic that are commonly applied in pharmaceutical formulations, in which they contain at least 4 groups hydroxyl The present substances are particularly special in which the 5-member ring on the steroid skeleton it comprises 3 hydroxyl substituents instead of 0-2.

Preferably, the steroid applied as the active component in the present composition is a so-called biogenic estrogen, that is an estrogen that originates naturally in the human body, a precursor of an estrogen biogenic or a mixture thereof. Because estrogens biogenic are naturally present in the body of the fetus and of the woman, side effects are not expected to occur, particularly not if the serum levels that result from the exogenous administration of such estrogens do not exceed substantially the naturally occurring concentrations. Naturally occurring steroids typically exhibit a 8?, 9?, 13?, 14? configuration of the steroid skeleton.

In a preferred embodiment of the Present invention the steroid contains 4 hydroxyl groups. Also, in the aforementioned formula, R1 represents preferably a hydrogen atom. In said formula preferably at least 2, more preferably at least 3 of the groups R 1, R 2, R 3 and R 4 represent an atom of hydrogen.

Steroids according to the formula include several enantiomers since the carbon atoms that carry the hydroxyl substituents R 5, R 6 and R 7 are chirally active In a preferred embodiment, the Present steroid is 15α-hydroxy substituted. In another preferred embodiment the substance is 16α-hydroxy substituted. In a form of more preferred embodiment, the substance is 17α-hydroxy substituted. The most preferably steroids are 15α, 16α, 17β-trihydroxy replaced.

In a preferred embodiment of the present invention R 3 represents a hydroxyl group or a alkoxy group. In another preferred embodiment the groups R 1, R 2 and R 4 represent hydrogen atoms, in which case, if R 3, R 5, R 6 and R 7 are hydroxyl groups, the substance is 1,3,5 (10) -estrict-3, 15,16,17-tetrol. A preferred isomer of the latter substance is 1,3,5 (10) -estrict-3, 15α, 16α, 17β-tetrol (estetrol).

Typical examples of precursors that can be used properly according to the invention are the esters that they can be obtained by reacting the hydroxyl groups of the estrogen substances with substances that contain one or more carboxy groups (M + - OOC-), where M + represents a hydrogen cation or (alkali) metal. For the therefore, in a particularly preferred embodiment, the precursors are derived from estrogen substances, where the hydrogen atom of at least one of the hydroxyl groups in said formula has been replaced by -CO-R, where R is a hydrocarbon radical comprising 1-25 carbon atoms Preferably R is hydrogen, or a radical alkyl, alkenyl or aryl from 1-20 carbon atoms

In an embodiment particularly preferred of the invention, the present method is used to treat an acute vascular disorder selected from the group that It consists of acute cardiovascular disorders, disorders acute cerebrovascular and peripheral vascular disorders acute

The good results obtained here method is considered to be associated with the properties vasodilators of the present steroid. So, in a way of preferred embodiment, said steroid is administered in a effective amount to induce vascular dilation in the mammal.

The present method is particularly suitable. to treat an acute cardiovascular disorder selected from group consisting of angina pectoris, myocardial ischemia, infarction myocardial The present method offers the advantage that it will induce almost instantaneous relaxation of the coronary arteries, giving as result a decrease in blood pressure, blood increased (and oxygen supply) to myocardial tissue and decreased demand for oxygen by the heart muscles. Thus, the method is particularly suitable for treating angina pectoris as it will help restore the balance between the demand for Myocardial oxygen and coronary oxygen supply. He increased coronary oxygen supply achieved by the present method is also beneficial in the treatment of ischemia acute myocardial and myocardial infarction resulting from such ischemia.

The present method is also very suitable for treat an acute cerebrovascular disorder selected from the group consisting of migraine, cerebral ischemia, cerebral infarction, cerebral vasospasm and thrombotic stroke. The cerebral vasodilation achieved by the present method will increase the oxygen supply to the brain and therefore will help minimize the adverse effects of cerebral ischemia, such as those result from cerebral infarction or cerebral vasospasm that occurs after subarachnoid hemorrhage. The present method is particularly suitable for the treatment of migraine, especially if the treatment is started before the acute phase Headache

The phases of a migraine headache have been separated in the prodrome, aura and headache phases acute painful The prodrome is the primary phase of an attack by migraine characterized by an alteration of mood, energy or passive functions This phase can occur for hours before the Headache onset Mood alterations include euphoria, loquacity, unprovoked apathy, depression, inertia, drowsiness, irritability, repetitive yawning, aggression and a high sensitivity to various sound levels (sonophobia). The nausea and vomiting, as well as paresthesia in the extremities, They can also accompany these symptoms. The aura or second phase It has been defined by the appearance of fear of light (photophobia) and visual discomfort induced by a reduction in blood flow brain due to vasospasm. The headache phase is vascular with distension and increased pulsation of the arteries cranial The increased vascular permeability is associated with the release of peptides, especially bradykinin and substance  P, like molecules such as histamine and serotonin, which cause local pain when it reaches nerve endings perivascular

The present method can also be used. advantageously in the treatment of a peripheral disorder acute vascular, particularly a peripheral vascular disorder acute selected from the group consisting of arterial disease peripheral occlusive, Buerger's disease, erectile dysfunction, Raynaud's disease, Raynaud's phenomenon and acrocyanosis.

The advantages of the present method are more pronounced if the steroid is administered orally within 15 minutes after the mammal has begun to experience the first symptoms associated with acute vascular disorder. The rapid appearance of the action of the present steroid facilitates a rapid suppression / inhibition of the undesirable symptoms and consequences of the aforementioned vascular disorders. By counteracting these negative effects soon, the intensity of the consequent symptoms (eg migraine headache or chest pain) can be effectively suppressed and tissue damage (heart attack and / or ischemic reperfusion damage) can be mini -
mized

The method according to the invention is particularly suitable for treating a mammal that suffers from acute symptoms associated with vasoconstriction or vascular occlusion. Both the vasoconstriction such as vascular occlusion will result in a high blood pressure, limited and high oxygen supply oxygen demand by the heart muscles. As explained previously, vasodilation induced by the present method, will counteract these negative effects of vasoconstriction or vascular occlusion The present method is particularly suitable. to treat acute vasoconstriction in the brain or sensation of unhealthiness caused by vasoconstriction in the brain. To derive the full benefits of this method, it is It is advisable that the steroid be administered within 30 minutes after the mammal has begun to experience the First symptoms associated with vasoconstriction.

As explained above, this invention does not cover the prophylactic treatment of disorders acute vascular Instead, the present method employs the administration on demand of the steroid. Thus, typically the method does not include steroid administration according to a default protocol, for example administration to regular intervals

The present method can be used advantageously in the treatment of humans, livestock, sheep, pigs, goats, horses as well as pets such as dogs and cats. Most preferably the present method is used in humans. In one embodiment particularly preferred, the present method is used in subjects human men.

The present method offers the important advantage that allows subjects to treat themselves, self-administering the steroid orally so Soon as the need arises.

Thus, the method comprises the self-administration ad lib ( ad libitum ) of the steroid.

You can get good results with the present method if the steroid is administered orally in an amount of less than 10 mg per kg of body weight, preferably less than 5 mg per kg body weight, more preferably less than 2.5 mg per kg body weight. TO in order to achieve a significant impact of the administration of present steroid, it is advisable to administer orally a amount of at least 2.5 µg per kg of body weight. Preferably, the amount administered orally is at minus 5 µg per kg of body weight. More preferably, the orally administered amount is at least 10 µg per each kg body weight

In the present method, particularly when used in humans, the steroid is normally administered at an average dose of at least 0.125 mg, preferably at least 0.25 mg and more preferably at least 0.5 mg. The maximum dose it is normally kept below 500 mg, preferably by below 250 mg and more preferably below 125 mg.

In the present method, the steroid is preferably administered in an effective amount to achieve a blood serum concentration of at least 150 nanograms per each liter, more preferably at least 300 nanograms for each liter, most preferably at least 600 nanograms per every liter Generally, the resulting serum concentration in Steroid blood will not exceed 1200 \ mug per liter, preferably it will not exceed 600 µg per liter, more preferably it will not exceed 300 µg per liter.

In a specific embodiment, the steroid of the present invention is administered in combination with one or more vasoactive agents in the treatment of patients who suffer from acute, cerebrovascular or cardiovascular disorders peripheral vascular Steroid administration of the present invention in combination with one or more vasoactive agents It can improve the effectiveness of the treatment. In addition, such a combination It can generate minor or less pronounced side effects. The vasoactive agents for use in the oral treatment of acute cardiovascular, cerebrovascular or vascular disorders Peripherals can be suitably: (1) a direct vasodilator (eg nitroglycerin, isosorbide dinitrate, mononitrate isosorbide, nitroprusside, minoxidil, papaverine HCl, isoxsuprine HCl, hydralazine), (2) an antiplatelet agent (eg aspirin, clopidrogel, dipyridamole, ticlodipine), (3) a thrombolytic (e.g. tPA alteplase, anistreplase, streptokinase, urokinase), (4) a anticoagulant (eg heparin, low molecular weight heparins, warfarin), (5) an antiarrhythmic agent (eg adenosine, amiodarone, disopyramide, flecainide, ibutilide, lidocaine, procainamide, sotalol), (6) an agent α-adrenergic (eg prazosin, indoramine, methyldopa), (7) a β-adrenergic agent (e.g. ex. atenolol, carvedilol, labetalol, metoprolol, propranolol), (8) an antilipemic agent (eg clofibrate, lovastatin, pravastatin, simvastatin), (9) a channel blocking agent calcium (eg amlodipine, felodipine, nimodipine, verapamil), (10) an anticholinergic agent (eg atropine), (11) an agent hypotensive (eg phenoxybenzamine), (12) a system inhibitor of renin-angiotensin (eg captopril, enalapril, lisinopril, losartan), (13) an inotopic agent (e.g. dobutamine, dopamine), (14) a diuretic (eg aldactone, chlorothiazide, furosemide), (15) an analgesic (eg morphine, diamorphine), (16) a glycoprotein receptor antagonist IIb / IIIa (eg abciximab), (17) an inhibitor of phosphodiesterase (eg pentoxifylline, sildenafil), (18) a vasopressor (eg 1 adrenaline) and / or a combination of same.

In another preferred embodiment of the invention the present method comprises co-administration of a progestogen, particularly if the method is used in the Treatment of female mammals. In order to counter any potential negative effect of estrogen administration without opposition in the present method, it is preferred to co-administer a oral progestogenic component to inhibit stimulation of estrogen from the endometrium or to administer a component progestogenic at least for a period of ten days at least every three months. Alternatively; intrauterine administration of a progestogen (eg an intrauterine delivery device of progestogen) can be used properly to counteract any potential negative effects of the administration of estrogen without opposition in the present method.

In another specific embodiment, the steroid of the present invention is administered orally in combination with a 5-HT1 agonist in the Treatment of patients suffering from migraine. The administration of the steroid of the present invention in combination with a 5-HT1 agonist (eg sumatriptan, rizatriptano, almotriptano, naratriptano, zolmitriptano, frovatriptan, eletriptan) can enhance the effectiveness of treatment. In addition, such a combination can generate effects. minor or less pronounced secondary.

The present steroid can be administered properly in any form of pharmaceutical formulation known in the art. The pharmaceutical formula can be a form solid or semi-solid dosage such as pills, capsules, sachets, tablets, pills, powders and granules as well as fluid dosage forms such as solutions, emulsions and suspensions.

Another aspect of the present invention relates to to a pharmaceutical composition containing:

to.

to the minus 0.05 mg of the present steroid;

b.

to the minus 0.01 mg of a direct vasodilator, preferably a direct vasodilator selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, nitroprusside, minoxidil, papaverine, isoxsuprine and hydralazine; Y

C.

pharmaceutically excipient (s) acceptable (s). Combined steroid administration and a direct vasodilator is particularly advantageous in the treatment of acute cardiovascular disorders.

Although it is feasible to combine the steroid and the direct vasodilator in a single pharmaceutical formulation, can be advantageous to incorporate them in separate dosage units designed for different modes of administration. In In particular, it may be advantageous to provide the steroid in a oral dosing unit and provide the direct vasodilator in the form of a sublingual or transdermal dosage unit.  Accordingly, an embodiment of the invention concerns a pharmaceutical team comprising one or more units oral dosages containing at least 0.05 mg of this steroid and a pharmaceutically excipient (s) acceptable (s); and one or more dosage units sublingual or transdermal containing at least 0.01 mg of a direct vasodilator; and an excipient (s) pharmaceutically acceptable (s).

A further aspect of the invention concerns a Pharmaceutical composition containing:

to.

to the minus 0.05 mg of the present steroid;

b.

to the minus 0.01 mg of a 5-HT agonist, preferably a 5-HT_ {1} agonist selected from the group that It consists of sumatriptan, rizatriptan, almotriptan, naratriptan, zolnutriptane, frovatriptan and eletriptan; Y

C.

pharmaceutically excipient (s) acceptable (s). Formulations containing the steroid in combination with a 5-HT1 agonist produce exceptionally favorable results in the treatment of acute cerebrovascular disorders, especially the migraine.

Another aspect of the invention relates to a pharmaceutical composition that contains:

to.

to the minus 0.05 mg of the present steroid;

b.

to the minus 0.01 mg of a phosphodiesterase inhibitor, preferably a phosphodiesterase inhibitor selected from the group consisting of pentoxifylline and sildenafil; Y

C.

pharmaceutically excipient (s) acceptable (s). The formulations that contain this particular combination of active ingredients produce results exceptionally good in the treatment of dysfunction erectile.

The present invention also encompasses a system of drug administration comprising a composition pharmaceutical as defined above, said system of drug administration being selected from the group that It consists of an oral dosage unit and a suppository. The most preferably, the drug delivery system is a unit of oral dosage

Examples of oral dosage units that are may use in accordance with the present invention include ways of solid or semi-solid dosage such as tablets, capsules, sachets, tablets, pills, powders and granules The term "solid dosage form or semi-solid "also covers capsules that they contain a liquid, for example an oil, in which the present Steroid is dissolved or dispersed. The pills and forms of solid and semi-solid dosage may contain suitably materials such as binders (eg cellulose from hydroxypropylmethyl, polyvinyl pyrrolidine, other materials cellulosics and starch), diluents (eg lactose and others sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (eg starch polymers and materials cellulosics) and lubricating agents (e.g., stearates and talcum powder).

The invention is further illustrated by middle of the following examples.

Examples

Example one

A double-blind, randomized study placebo-controlled individual doses, was performed to determine the safety, tolerability and pharmacokinetics of 1, 10 and 100 mgs of estetrol administered orally in volunteers healthy postmenopausal women (menopause defined as \ geq 12 months of amenorrhea or six months of amenorrhea with serum levels FSH? 40 IU / L and serum E2 <73 pmol / L), a mass index 18-30 kg / m2 body, non-smoking, good physical and mental health as judged by the researcher and determined by medical history, physical examination, clinical laboratory, constants vital and ECG registration). In each dose group, six subjects they received estetrol treatment and two subjects received placebo.

The estetrol and placebo medication was formulated as a solution (propylene glycol / water mixture) and was Delivered in bottles separately for each volunteer. The bottles contained 1 mg or 10 mg of estetrol per 50 ml for subjects of the groups that received 1 mg or 10 mg of estetrol and 100 mg per 200 ml for the group that received 100 mg of Estetrol

The screening took place within two weeks before administration of the research drug. During and after drug administration, the subjects were admitted to a clinical pharmacology unit during approximately 60 hours for security monitoring intensive Safety and tolerability were documented by the monitoring of adverse (serious) events, physical exams including vital signs, and laboratory tests of safety (hematology, biochemistry, urinalysis). Sampling of frequent blood (within the range of 15 minutes to 168 hours) were performed to assess the plasma concentration of estetrol and the pharmacokinetic variables. For this, the samples plasma were subjected to extraction liquid-liquid (hexane and diethyl ether) and further subjected to HPLC analysis (Perkin Elmer 200) and tandem mass spectrometry using a mass spectrometer in tandem PE sciex 4000 and APCI interface. With each batch of sample, A calibration curve with 6 calibrators was registered. The curve  calibration was calculated using linear regression (correlation coefficient> 0.98), which allowed the quantification of estetrol plasma concentrations.

The safety and tolerability assessment of estetrol in unit oral doses of 1, 10 and 100 mg demonstrated a Safe and well tolerated drug profile. The incidence of events Adverse was similar in frequency and in nature in medication placebo and sterol of 1, 10 and 100 mg. No adverse events Severe or serious were informed. In addition, they were not observed no clinically significant changes in the constants vital, hematology, biochemistry or urinalysis in reference to use of study medication.

The pharmacokinetic profile of estetrol after of the oral dosage was very consistent within each group of dose and through the dose range evaluated, demonstrating a good gastrointestinal absorption and low variability inter-subject Plasma concentration graphs of estetrol as a function of time showed an increase very pronounced that starts directly after ingestion of the drug. Maximum plasma concentrations were observed at 15 minutes after dosing in the oral dose group 1 mg, between 15 minutes and 30 minutes after dosage in the oral dose group of 10 mg and between 15 minutes and 1 hour after dosing in the 100 mg group. C max values after oral dosing of estetrol of 1 mg ranged between 0.39 and 1.2 ng / ml (average of 0.52 ng / ml), after dosing oral estetrol of 10 mg between 5.4 and 11.6 ng / ml (mean of 9.4 ng / ml) and after dosing of 100 mg oral sterol between 119 and 213 ng / ml (mean 148 ng / ml).

Estetrol absorption was extremely fast and followed by redistribution to extravascular tissues, after which the reabsorption to blood flow was evident during the first 18 hours after oral intake. Subsequently, a slow phase of final elimination of estetrol started approximately 24 hours after dosing and during which, estetrol was eliminated with a half-life terminal of approximately 28 hours.

These data convincingly demonstrate that the administration of estetrol at an individual oral dose produces a extremely favorable profile in which it combines the fast absorption and kinetics of slow elimination. Thus, estetrol It is ideally suited for the therapeutic application on demand in the treatment of acute vascular disorders where it is required a rapid appearance of action and sustained activity.

Example 2

Estetrol as described in this invention It can be processed in the usual way for the preparation of orally administered drugs, for example for pills, dragees, capsules, pills, suspensions, or solutions. The drugs of the invention can be used to treat disorders acute cardiovascular such as angina pectoris induced by coronary artery disease.

A clinical trial is carried out with the administration of an individual dose, at the request of oral estetrol of 100 mg in subjects suffering from documented angina pectoris and Compare with the placebo treatment. Additionally, to the patients in this trial they are offered to use their standard demand medication, for example nitroglycerin. One hundred patients, males and females, with a diagnosis of angina pectoris induced by disease of the coronary artery, substantiated by positive dynamic tests of Myocardial ischemia, participate in the clinical trial. The patients are selected according to the following inclusion criteria (I) and exclusion (e): patients with a clear diagnosis of angina chest, (I) patients who have chest pain attacks more than twice a week (I). Patients with myocardial infarction active or other cardiopulmonary coronary heart disease, such as severe psychoneurosis, menopausal syndrome and chest pain caused by cervical spondylopathy (e), angina patients chest combined with hypertension (blood pressure> 24 / 14.87 Kpa) (e), patients with deficiency of cardiopulmonary function severe, severe arrhythmia, liver and abnormal renal function and / or hematopoietic disease (e), nursing women and patients with a known history of allergenic disease (e), minor patients 18 or over 70 (e).

The diagnostic standard for the severity of angina pectoris is used to describe the characteristics of the patient's starting point and subsequently monitor the effectiveness of the treatment (see below). Low grade : typical angina attack, which usually lasts a few minutes and occurs 1-3 times a day. The attack is not severe, but sometimes the patient needs to take nitroglycerin.

Medium grade : angina attack occurs more than 3 times every day and lasts several to ten minutes each time. The pain is more severe than that of the low grade attack and the patient usually needs sublingual nitroglycerin. High grade : Angina attack frequently occurs daily. Lasts longer and more seriously. Routine life is affected. The patient needs to use nitroglycerin frequently.

The diagnostic standard for angina types Chest is used to describe the characteristics of the point of heading and classify patient types.

Stress-induced angina pectoris : The attack of transient chest pain is typically caused by exertion or other conditions that increase the demand for myocardial oxygen. The pain usually disappears quickly after rest or administration of sublingual nitroglycerin.

Spontaneous angina pectoris : the attack of chest pain is obviously not related to the increase in myocardial oxygen consumption. Compared to angina-induced fatigue, pain lasts longer and is more severe. It cannot be easily relieved by nitroglycerin.

Mixed angina pectoris: Spontaneous angina pectoris can come with fatigue-induced angina pectoris and is classified as mixed angina pectoris.

After establishing the characteristics of the starting point, patients are randomized by age, sex, duration of the condition, type and severity of angina pectoris to receive on-demand treatment of oral estetrol with 100 mg for each dose (n = 50) or oral treatment with placebo medication (n = 50). Subjects are instructed in the use of drug medication of research, which is preferably taken instantly in the moment when the first signs of angina appear chest. Additionally, subjects are offered to choose the Nitroglycerin as an alternative mode of medication on demand. TO Patients are asked to keep a daily log stating the number of attacks, severity of attacks, duration of attacks and medication use (investigational drug or nitroglycerin) during the entire study period of 4 weeks. Those who leave due to non-compliance are substituted if they do not take the medication as prescribed or if the record sheets are incompletely filled.

For patients in the estetrol branch of study no obvious side effects were observed during the clinical trial period, differing significantly of patients taking placebo medication. The use of nitroglycerin in the estetrol branch of the study is significantly lower than in the placebo branch of the study. Patients manifest relief of angina symptoms from chest after taking estetrol medication and are less prone to patients receiving the placebo, to change from the Research drug medication to nitroglycerin. In In general, patients in the estetrol branch manifest statistically more improvement in exercise tolerance, ability to extend the duration of the walk and quality of life. By way of interesting, patients taking estetrol medication state that the concomitant use of estetrol and nitroglycerin provided a faster decrease in angina symptoms of chest, particularly during severe attacks, that the use of only estetrol or nitroglycerin.

It is concluded that the medication on demand for estetrol is safe and effective in the treatment of angina pectoris due to coronary artery disease. In addition, it concludes that the combination of medication on demand estetrol with conventional medication, for example nitroglycerin, acts synergistically in relieving the (severe) symptoms of angina pectoris.

Example 3

A double blind placebo clinical study Multiple attack control is carried out with the administration oral of the individual dose of estetrol on demand in volunteers adults (20 women and 20 men) each of whom seeks the Migraine relief.

Participating subjects show a history of at least 1 year of migraines as defined by the International Headache Society Criteria (IHS; Headache Classification Committee of the International Headache Society, 1988, Cephalalgia 8 (Suppl. 7): 19-28) and manifest migraines of regular occurrence with episodes of pain, photophobia and nausea. Each participant receives medication blinded in two bottles labeled differently, full of pills. One bottle comprises pills that contain 100 mg of estetrol, while the other bottle contains identical pills of placebo. Participants are allowed to choose from which bottle they want to orally ingest a pill at the time the First symptoms of a migraine attack become apparent. To the patients are asked to keep daily records stating the number of migraine attacks, severity of attacks, duration of attacks and medication use (bottle 1 or bottle 2) during the entire study period of 2 months. The patients are withdrawn from the study and are substituted if they do not take the medication as prescribed or if the registration forms are filled out incompletely

No side effects are observed apparent during the clinical trial period that they are directly related to the medication of the investigation. It is observed that during the study the participants use significantly more pills containing estetrol, which placebo pills In addition, the analysis of the data shows that participants who are using pills that contain estetrol manifest less headache and faster relief of migraine symptoms of what they themselves manifested in the starting point for the use of analgesic and / or type medication triptane

It is concluded that estetrol medication a demand as described in this invention is safe and effective for treat migraine

Example 4

An adult woman with an established history of suffer migraine attacks complains of a migraine attack that It consists of the typical migraine headache, nausea and sensitivity to light and sound. It is dosed with a pill oral medication containing 10 mg of sumatriptan and 100 mg of Estetrol Your symptoms begin to decrease within 30 minutes After two hours it is completely symptom free and has no relapse for the next 48 hours. Your pain it is relieved more quickly and with longer uninterrupted relief that when you take sumatriptan only in an oral dose of 10 mg. You experience fewer adverse reactions to the sumatriptan drug than who claims to have previously experimented with doses 25-100 mg sumatriptan recommended, with particular reference to asthenia and suffocation.

Example 5

An adult male exhibits the same history and indication as in example 4. The treatment is by means of a individual oral pill containing 10 mg of sumatriptan and 50 mg of estetrol. The same result is obtained as in example 4.

Example 6

In contrast to subjects suffering from erectile dysfunction due to hormonal insufficiency and who can be adequately treated with androgen replacement therapy, there is no such current standard treatment to overcome impotence in men with vascular deficits. A current treatment option includes oral administration of sildenafil. However, sildenafil is contraindicated in subjects allergic to sildenafil, or who due to vascular problems, are being treated concurrently with a nitrate medicine (e.g. nitroglycerin, a transdermal nitrate, isosorbide nitrate), or an anti-infective such as erythromycin , ketoconazole, itraconazole, or rifampicin. Other non-oral and non-steroid treatments for erectile dysfunction include the use of intracarvernosal injections consisting of direct injection of vasodilator drugs, e.g. eg injections with papaverine, or phentolamine in the corpora cavernosa of the penis (Campell's Urology, ed. WB Saunders Company, 6.sup.th Edition, Volume III, 3055-3057). Although intracarvernous injection is effective and scientifically approved, it has serious disadvantages mainly related to the form (injection) as well as the route of administration (intracarver-
nosa).

As a new method of individual dose, the oral administration of estetrol on demand is evaluated to treat erectile dysfunction and compared to placebo treatment. A clinical trial is performed on 20 subjects, who experience erectile dysfunction mainly due to vascular causes and in who intracarvernous injection of both papaverine and Phentolamine has been shown to be previously successful in restoring erectile function Ten subjects receive estetrol medication (100 mg per dose) and 10 subjects receive placebo medication in this I study outside the clinic.

Subjects with mild, moderate symptoms as well as severe erectile dysfunction are instructed in the use of the investigational drug medication, which is preferably taken 15 minutes to 2 hours before sexual activity. At the beginning of the test, subjects were asked to complete a sexual functioning test of starting point (TFS). The TFS is used as the primary assessment criterion, since this is a self-administered questionnaire designed to measure changes in sexual function (Smith et al ., 2002, British J. Psych., 181: 49-55). Ask detailed questions about libido, arousal (erection), masturbation, orgasm and ejaculation. It is designed in such a way that high scores indicate greater dysfunction. Typically totally normal control scores are less than 14 and patients who are sexually dysfunctional show total scores of more than 18 (Smith et al ., 2002, British J. Psych., 181: 49-55).

During the study estetrol is well tolerated. At the end of the study period at 4 weeks, the responses of the subject to questions from the TFS survey are compared to TFS responses from the starting point. For the variables by separate from the TFS, a comparison is made of those subjects who They initially show a bad starting point score. Then the results are grouped and expressed as the percentage of subjects with an improvement. Dose administration Individuals on demand for estetrol results in a higher percentage of subjects who show an improvement in the ability to develop and maintain erections compared to the subjects receiving the placebo treatment Also more subjects report an improvement in satisfaction with their sex life in general when they take estetrol compared to placebo medication.

These results demonstrate an outcome Positive pharmacological estetrol in the treatment of men They suffer from erectile dysfunction. The results also show the rapid appearance of action of estetrol administered via oral and a profile of favorable side effects. The oral administration of estetrol therefore represents a effective treatment modality with advantages over current classes of drugs in the treatment of erectile dysfunction.

Example 7

Preparation of 100 capsules, containing 100 Estetrol mg and 25 mg sildenafil citrate per capsule: 10.0 grams of estetrol and 2.5 grams of sildenafil citrate are mixed. The resulting powder mixture is transferred to a glass of precipitation with volume indication. The volume adjusts to 46.5 ml with Primogel® (sodium starch glycolate). Later, the powder mixture is filled in 100 hard gelatin capsules of two pieces (Capsugel® 1).

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References cited in the description This list of references cited by the applicant has been collected exclusively for the convenience of the reader. Do not It is part of the European patent document. Although it has been taken dedication to collecting references, the EPO does not assume any responsibility for possible errors or omissions Patent documents cited in the description

WO 03103683 A [0018]

Non-patent documents cited in the description

Ospina et al . Am J Physiol Heart Circ Physiol, 2003 , vol. 285, no. 1. 241-50 [0020]

Salom et al . J Cereb Blood Flow Metab., 2001 , vol. 21, no. 4. 422-9 [0020]

Kalenic et al . WV Med J., 2000 , vol. 96, no. 6. 617-21 [0020]

? Martin et al . Headache, 2003 , vol. 43, no. 3. 309-21 [0020]

Campell's Urology vol. III, 3055-3057 [0080]

? Smith et al . British J. Psych., 2002 , vol. 181, 49-55 [0082] [0082]

Claims (14)

1. Use of a steroid in the manufacture of a pharmaceutical composition for use in a method for treating an acute vascular disorder in a mammal, said method comprising oral administration ad libitum to said mammal, on demand, of an effective amount of the steroid to the mammal, said steroid being selected from the group consisting of:

substances represented by the following formula

3

in whose formula R 1, R 2, R 3, R 4 independently are an atom of hydrogen, a hydroxyl group or an alkoxy group with 1-5 carbon atoms; each of R 5, R 6, R 7 is a hydroxyl group; no more than 3 of R_ {1}, R2_, R 3, R 4 are hydrogen atoms; precursors capable of releasing a substance according to the aforementioned formula when used in the present method, whose precursors are derived from mentioned steroids where the hydrogen atom of at least one of the hydroxyl groups has been replaced by a radical acyl of a carboxylic, sulfonic or sulfamic acid hydrocarbon of 1-25 carbon atoms; tetrahydrofuranyl; tetrahydropyranal; or a straight chain glycosidic residue or branched containing 1-20 glycosidic units for each residue; and mixtures of one or more of the aforementioned substances and / or precursors, where the steroid is administered within 30 minutes after the mammal has begun to experience the first symptoms associated with the disorder acute vascular

2. Use according to claim 1, wherein R 3 represents a hydroxyl group or an alkoxy group. 3. Use according to claim 1 or 2, wherein at least 3 of the groups R1, R2, R3 and R4 They represent hydrogen atoms. 4. Use according to any of the claims precedents, where the acute vascular disorder is selected from the group consisting of acute cardiovascular disorders, acute cerebrovascular disorders and vascular disorders sharp peripherals 5. Use according to claim 4, wherein the Acute cardiovascular disorder is angina pectoris. 6. Use according to claim 4, wherein the cerebrovascular disorder is migraine. 7. Use according to any of the claims precedents, where the steroid is administered within 15 minutes after the mammal has begun to experience the first symptoms associated with acute vascular disorder. 8. Use according to any of the claims precedents, where the method does not include the administration of steroid at regular intervals. 9. Use according to any of the claims precedents, where the steroid is administered in a dosage of at least 2.5 µg per kg of body weight, preferably at least 5 µg per kg of weight bodily. 10. Pharmaceutical composition containing:

to.

to the minus 0.05 mg of a steroid as defined in claim one;

b.

to the minus 0.01 mg of a direct vasodilator, preferably a direct vasodilator selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, nitroprusside, minoxidil, papaverine, isoxsuprine and hydralazine; Y

C.

pharmaceutically excipient (s) acceptable (s).

11. Pharmaceutical composition containing:

to.

to the minus 0.05 mg of a steroid as defined in claim one;

b.

to the minus 0.01 mg of a 5-HT1 agonist, preferably a selected 5-HT1 agonist from the group consisting of sumatriptan, rizatriptan, almotriptan, naratriptan, zolmitriptan, frovatriptan and eletriptan; Y

C.

pharmaceutically excipient (s) acceptable (s).

12. Pharmaceutical composition containing:

to.

to the minus 0.05 mg of a steroid as defined in claim one;

b.

to the minus 0.01 mg of a phosphodiesterase inhibitor, preferably a phosphodiesterase inhibitor selected from the group that it consists of pentoxifylline and sildenafil; Y

C.

pharmaceutically excipient (s) acceptable (s).

13. Drug delivery system that comprises a pharmaceutical composition according to any of the claims 10-12, said delivery system of drugs being delivered orally. 14. Pharmaceutical equipment comprising one or more oral dosage units containing at least 0.05 mg of steroid as defined in claim 1 and a (os) pharmaceutically acceptable excipient (s); and one or more sublingual or transdermal dosing units than contain at least 0.01 mg of a direct vasodilator, preferably a direct vasodilator selected from the group that consists of nitroglycerin, isosorbide dinitrate, mononitrate isosorbide, nitroprusside, minoxidil, papaverine, isoxsuprine e hydralazine; and a pharmaceutically acceptable excipient.