It is sudden in patients with post-myocardial infarction, improved endothelial function and hyperlipidemias. U.S. Pat. US 5,502,077. US 5,656,667 and US 5,698,594 can be cited as examples. The prevention of cardiovascular events, especially mortality in patients who have survived the hospitalization stage of acute myocardial infarction (AMI) is described in the international patent application O 00/48592. The. Prior art above, in particular, provides a knowledge about the utility of fatty acids belonging to the family? -3. more specifically acid- (20: 5? 3) eicosapentanoic (EPA) and acid (22: 6? 3) docosahexanoic acid (DHA) in the treatment of the above mentioned disorders. The fatty acid EPA, being a precursor of PGI3 and TxA3. exerts an effect of prevention of platelet aggregation and an antithrombotic effect that can be attributed to the inhibition of cyclooxygenase (effect similar to that of aspirin) and / or competition with arachidonic acid for this enzyme, with the subsequent reduction in the synthesis of PGE2 and TxA2. which are well-known platelet aggregation agents. On the other hand, the fatty acid DHA is the most important component of brain lipids in man and, in addition, being a structural component of the platelet cell, it intervenes indirectly in the increase of the fluidity of the platelets, thus playing a important role in the antithrombotic activity. The international patent application WO
89/11521. The description of which is incorporated herein by reference, describes, in particular, an industrial process for extracting mixtures with a high content of polyunsaturated acids, including EPA and DHA and their ethyl esters, from animal and / or vegetable oils. . It is reported that mixtures of fatty acids, especially EPA / DHA, obtained according to WO 89/11521. they are particularly useful in the treatment of cardiovascular diseases. However, current treatment methods used in human therapy have been shown to be insufficient in patients with coronary artery disease. THE INVENTION In one aspect, this invention concerns the use of a pharmaceutical composition containing essential fatty acid ethyl esters derived from fish oils, in particular as a mixture of high concentration of ethyl esters of acid (20: 5? 3) eicosapentanoic (EPA) and acid (22: 6? 3) docosahexanoic acid (DHA) in the prevention and / or treatment of depression in patients with a cardiovascular disease such as coronary, coronary artery or vascular heart disease. In one embodiment, the present invention provides a new method for preventing and / or treating depression in patients with cardiovascular disease. In another embodiment, patients have coronary or vascular artery disease. In yet another embodiment, cardiovascular disease is coronary or vascular artery disease. The method of the present invention comprises administering to said patient one. Therapeutically effective amount of a medicine containing essential fatty acids containing a high content of ethyl ester of eicosapentaenoic acid (EPA), docosahexaenoic acid ethyl ester (DHA) or a high concentration mixture of ethyl ester of eicosapentanoic acid (EPA) and ethyl ester of docosahexaenoic acid. (DHA). In one embodiment, the high concentration mixture comprises a mixture of high concentration of ethyl ester of eicosapentanoic acid (EPA) and ethyl ester of docosahexaenoic acid (DHA). A high content of ethyl ester of. EPA or DHA ethyl ester or a mixture of high concentration thereof is to be understood as containing at least 20% by weight of EPA or DH, or at least 20% by weight of a mixture of EPA and DHA. In one aspect, this invention pertains to the use of essential fatty acids containing a mixture of ethyl ester of eicosapentaenoic acid (EPA) and ethyl ester of docosahexaenoic acid (DHA) in the prophylaxis and / or treatment of depression in patients with cardiovascular disease, in one example in patients with coronary heart disease and / or coronary or vascular artery disease, in which the EPA and DHA content in such a mixture is greater than 25% by weight. In another embodiment, the invention provides a use of a therapeutically effective amount of essential fatty acids containing a high content of EPA, DHA or a mixture of high concentration thereof in the formation of a medicament for the treatment of cardiovascular disease. , such as, coronary heart disease and / or coronary or vascular artery disease. Other features and advantages of the present invention will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will be apparent to the inventors. skilled in the art from this detailed description. DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT The expression "containing" or "comprising", as it is. used in this memory, is an inclusive and non-exclusive expression. Recently, new risk factors have been identified for coronary artery disease, including depression. Major depressive disorders, as well as symptoms of depression, are associated with high rates of cardiovascular morbidity and mortality. In addition, once ischemic heart disease has been established, the risk of suffering a fatal cardiac event is increased. "Serious ventricular arrhythmias that result in sudden cardiac death appear to be the leading cause of mortality in patients with depression." In addition, patients with anxiety and depressive disorders have been shown to have reduced heart rate variability.This finding may have important implications of diagnosis, since a low variability of the cardiac rate is a potent predictor of sudden cardiac death.There is substantial evidence that major depression is associated with alterations in the omega-3 acid state. significant depletion of omega-3 fatty acids in the red cell membrane Another study reported a negative correlation between the two, the content of omega-3 fatty acids in the red blood cell membrane and the dietary intake of these polyunsaturated fatty acids with the severity of the depression- a supplement with EPA and DHA is known to increase the content or of these unsaturated fatty acids in erythrocyte membranes. Studies in patients with post-myocardial infarction have shown that the supplement with EPA and DHA improves the variability of the cardiac rate. | However, currently there are no known effective and safe treatments to prevent depression in patients with cardiovascular disease and just other treatments for depression in patients with cardiovascular disease. A study with sertraline showed beneficial effects in post-myocardial patients with concomitant depression. It is well known that patients with cardiovascular disease and depression are at a substantially increased risk of cardiovascular events and death. Therefore, there continues to be a substantial need for improved and effective prophylaxis and / or treatments with drugs, in particular to prevent these recurrences in patients with both cardiovascular diseases and depression, and the effective treatment of depression in these patients. In one embodiment, the object of this invention, therefore, is to provide improved and effective prophylaxis (prevention) and / or treatment of this type of said patients with an effective drug and, in particular, the prevention of recurrences before mentioned in patients with both, cardiovascular diseases and depression and / or treatment of depression in these patients. In one aspect, this invention provides a new method to prevent and / or treat depression in patients with cardiovascular disease. In one embodiment, the cardiovascular disease is coronary heart disease and / or coronary or vascular artery disease. In another embodiment, the cardiovascular disease is coronary or vascular artery disease. In one embodiment, the method comprises administering to said patient a therapeutically effective amount of a medicament containing essential fatty acids containing a high ester content. Eicosapentanoic acid ethyl ester (EPA), in. ethyl ester of docosahexaenoic acid (DHA) or in a mixture of high concentration of ethyl ester of eicosapentaenoic acid (EPA) and ethyl ester of docosahexaenoic acid (DHA). In one embodiment, a high concentration mixture of ethyl ester of eicosapentanoic acid (EPA) and docosahexaenoic acid ethyl ester (DHA) is administered.The invention also provides a use of essential fatty acids such as a high concentration of EPA, DHA. or a mixture thereof, for the prevention and treatment of depression in patients with cardiovascular disease For the ease of description, "ethyl ester of EPA" and "ethyl ester of DHA" will also be noted here as ???? " and "DHA". A high content of ethyl ester of EPA or DHA ethyl ester or a mixture of high concentration thereof is to be understood as containing at least 20% by weight of EPA or DHA, or at least 20% by weight of a mixture of EPA and DHA. In particular, this invention relates to the use of essential fatty acids containing a mixture of ethyl ester of eicosapentaenoic acid (EPA) and ethyl ester of docosahexaenoic acid (DHA) in the prophylaxis and / or treatment of depression in patients with disease cardiovascular disease, in particular in patients with coronary heart disease and / or coronary or vascular artery disease, in which the content of EPA and. DHA in a mixture of this type is greater than 25% by weight. In one embodiment, an essential fatty acid with high content of EPA or DHA, according to the present invention, preferably contains more than 25% by weight, in particular from about 60 to about 100% of said ester. These compounds can be obtained by known methods. In an essential fatty acid with a high concentration mixture of EPA and DHA, preferably such a mixture has an EPA and DHA content greater than 25% by weight, in particular from about 30 to about 100% by weight, of preference approximately 85% by weight. In the EPA / DHA mixture, EPA is present, preferably, in a percentage of about 40 to 60% by weight and DHA, preferably in a percentage of about 25 to about 45-50%. In any case, the preferred weight ratio of EPA / DHA in an EPA / DHA mixture of this type is from about 0.9 to 1.5. PHARMACOLOGY The. cardiovascular disease is the main cause of morbidity and disability in the United States, estimating 6 million people with symptomatic coronary heart disease. The main depression appears at a yor age and with higher incidence in those that used to manifest. Alterations in phospholipids and cholesterol, which are structural components of all cellular membranes in the brain, can induce changes in the microviscosity of the membrane in the brain and, consequently, in various neurotransmitter systems that are thought to be related in pathophysiology of depression, p. ex. . serotonin and (ñor) adrenaline. Major depression and depressive symptoms, although usually found in medical populations, are often under-diagnosed and not treated in patients with cardiovascular disease. In patients with coronary heart disease, the prevalence of major depression is almost 20% and the preponderance of secondary depression is approximately the 27th%. Depression (major depressive disorders as well as depressive symptoms) is associated with high rates of cardiovascular morbidity. The diagnosis after a. The event of coronary heart disease is more deficient in patients with depression than in patients without depression. Patients with depression are less likely to follow the recommendation to reduce cardiac risk during recovery from a myocardial infarction. In the main depression there are fractions of? -3 decreased in cholesterol esters and a C20: 4 or 6 / C20: 5 ratio increased in cholesterol esters and phospholipids. Depression is an important independent predictor of death after coronary artery bypass surgery. Survival analysis, which control age, sex, number of grafts, diabetes, smoking, left ventricular ejection fraction and previous myocardial infarction, showed that patients with moderate to severe depression in the baseline (hazard ratio (HR). in English), adjusted 2.4 p = 0.001) or with mild or moderate to severe depression that persisted from baseline to 6 months (adjusted HR 2.2) had higher rates of death than those without depression. Moderate to moderate levels of depressive symptoms also occur in patients after acute myocardial infarction associated with decreased survival. The highest mortality rates were observed in patients with the most severe symptoms of depression. However, compared to those without depression, a high mortality was also observed at very low levels of depressive symptoms that are not considered, in general, clinically significant. Increased mortality after myocardial infarction is observed in both men and women. Cardiac mortality of 1 year is approximately 3 times higher in women with depression and 2.5 times higher in men with depression than in women without depression, respectively men without depression. A preliminary investigation indicated that, in addition to the survival risks associated with post-myocardial depression, there are increased health care costs for both readmissions and external contacts among patients with depression who survived the first year of post-myocardial infarction. myocardium The reasons why patients with coronary heart disease and depression have increased mortality and morbidity are not yet known. However, there are indications that in depression there is an abnormal intake or metabolism of essential fatty acids in conjunction with the decreased formation of cholesteryl esters. The ratio of arachidonic acid to eicosapentaenoic acid in the blood correlates positively with the clinical symptoms of depression. There is also an important negative correlation between EPi¾ content in erythrocytes and the severity of depression. Alterations in phospholipids and cholesterol, which are structural components of all cell membranes in the brain, can induce changes in the microviscosity of the membrane and, consequently, in various neurotransmitter systems such as serotonin and (ñor) adrenaline. It is well known that these neurotransmitters play an important role in the pathophysiology of depression. Finally, reduced food intake and weight loss, which accompany severe depression, could lead to changes in the fatty acid composition of serum phospholipids and cholesteryl esters that could, by themselves, affect fluidity of the membrane and inflammatory responses. The efficacy of the treatment, according to the invention, is demonstrated by preclinical and indirect clinical evidence: 1. The ingestion of large fatty acid effects? -3 is associated with a general buffering of the. Signal transduction pathways associated with phosphatidylinisitol, arachidonic acid and other systems. 2. DHA is involved in the metabolism of dopamine and serotonin in the developing rat brain. 3; Serotonergic actions and other neurochemical actions of fatty acids -3 in animals suggest an anti-depressive activity. 4. Epidemiological data show that national rates of major depression and bipolar disorder in different countries vary directly with fish consumption. 5. Epidemiological studies have shown a correlation between plasma fatty acid composition and depression in the elderly. 6. In bipolar disorders, a superactivity of transduction of cell signals may be involved in pathophysiology. 7. Patients with episodes of major depression showed a significant decrease in the DHA and EPA levels of the red blood cell membrane. 8. Omega-3 fatty acids. They have mood stabilizing effects in major depression and other neuropsychiatric disorders. 9. The addition of EPA to treatment-resistant depression was associated with remission of symptoms, structural changes in the brain, and a reduced reversal of neuronal phospholipids. 10. Omacor, a mixture of high concentration of EPA and DHA increases the content of EPA and DHA of the red blood cell membranes. The above-mentioned evidence demonstrates that the present invention provides a new and valuable therapeutic method for preventing and / or treating depression in patients with cardiovascular disease, in particular in patients with coronary heart disease and / or coronary or vascular artery disease. Accordingly, this invention provides a method for preventing and / or treating depression in patients with coronary heart disease and / or coronary or vascular artery disease, which comprises administering to a patient of this type a therapeutically effective amount of an acid-containing medicament. fatty acids with a high content of ethyl ester of EPA or DHA ethyl ester or a mixture of high concentration thereof. The essential fatty acids, according to the invention, can have a high content, for example more than 25% by weight, in EPA or DHA or in a mixture thereof. However, the ethyl esters of EPA and DHA are preferably present in the form of a mixture thereof with an EPA and DHA content greater than 25% by weight, in particular from about 30 to about 100.% by weight, in a performing about 80%, 81%, 82%, 83%, 84% or, preferably, about 85% by weight. Based on the available evidence, according to a preferred aspect of the invention, the dosage of an essential fatty acid containing a mixture of EPA and DHA with a titer of 85% by weight for oral administration to a patient can vary from approximately 0.7 g approximately 6 g daily, preferably approximately 1 g daily. In one embodiment, the high content of EPA, DHA or high concentration mixture thereof is formulated into a capsule, such as a gel capsule, using methods known in the art. In one embodiment, the gel capsule is a 1000 mg capsule. In another embodiment, said capsule comprises 90% by weight of ethyl esters of omega-3 fatty acids. In another embodiment, said 90% by weight in a 1000 mg capsule approximately 465 mg is EPA and approximately 375 mg is DHA. In a further embodiment, said 1000 mg capsule comprises about 4 mg of a-tocopherol in a suitable support (such as, preferably, hydrogenated vegetable oils, including soybean oil) and other components of a gel capsule such as gelatin, glycerol and purified water. In a. embodiment of the invention, the dose provided is 4 g per day of the 1000 mg capsule. This amount of product 'in the form of a mixture of EPA and DHA (or amount of EPA alone or DHA alone) can be administered in several divided doses throughout the day or, preferably, in a single dose, to achieve the blood level wanted. Obviously, it is at the discretion of the doctor to adjust the amount of product to be administered according to the age, weight and general condition of the patient. As such, "therapeutically effective amount" is an effective amount, at dosages and. for periods of time necessary to achieve the desired therapeutic result. It is to be understood that such an amount may vary according to factors such as disease state, 'age, sex and weight of the individual' and the ability of a substance to elicit a desired response in an individual. The medication, p. ex. in the form of a pharmaceutical composition, according to this invention can be prepared according to methods known in the art. The preferred route of administration is oral, but alternative administration routes, such as the parenteral route, are left to the discretion of the physician. The medicament or pharmaceutical composition may comprise the desired amount, e.g. ex. a high content of EPA, DHA or a mixture of high concentration thereof according to this invention and a pharmaceutically acceptable carrier, e.g. ex. carriers, excipients, adjuvants and buffers, for example substances used in pharmaceutical products or known in the art, p..ej. Remington's Pharmaceutical Sciences (Alfonso R. Gennaro ed. 18th edition 1990). The variants of the present invention. they are further defined in the subordinate claims. The following examples illustrate formulations suitable for oral administration, but are not intended to limit the invention in any way. Gelatin capsules According to known pharmaceutical techniques capsules are prepared with the composition set out below and - containing 1 g of active ingredient (EPA and DHA, 85% titre) per capsule. Formulation 1 EPA ethyl ester 525 mg / capsule DHA ethyl ester 315 mg / capsule d-alpha-tocopherol 4 IU / gelatin capsule 246 mg / capsule glycerol 118 mg / capsule red iron oxide '2.27 mg / capsule yellow iron oxide 1.27 mg / capsule
Formulation 2 Ethyl esters of 1000 mg polyunsaturated fatty acids containing ethyl esters of? -3 polyunsaturated esters (EPA eicosapentaenoic, DHA docosa-hexanoic) 850 mg / capsule dla-tocopherol 0.3 mg gelatin succinate 233 mg glycerol 67 mg p Sodium oxybenzoate 1.09 mg sodium propyl p-oxobenzoate 0.54 mg While the present invention has been described with reference to what is currently considered a preferred embodiment, it is to be understood that the invention is not limited to the described embodiment. On the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
All publications, patents and patent applications are incorporated herein by reference in their entirety to the same extent as if each publication, patent or patent application was specifically and individually indicated to be incorporated as a reference in its entirety.