ES2334656T3 - USE OF EPA AND DHA IN SECONDARY PREVENTION OF BRAIN SPILLS. - Google Patents

Abstract

<WC 1><WC 1><WC 1><WC 1><WC 1>Use of the n-3 polyunsaturated fatty acids EPA and /or DHA in the preparation of an oral medicament for preventing cerebral damage in patients having symptoms of atherosclerosis of arteries supplying the brain.

Description

Use of EPA and DHA in secondary prevention of strokes

The present invention relates to the use of a n-3 specific acid mixture PUFA-eicosapentaenoic acid (EPA) and / or acid docosahexaenoic acid (DHA) in the prevention of strokes, in patients with symptoms of transient ischemic attack and / or Amaurosis fugax.

There is substantial epidemiological evidence that the consumption of fish or polyunsaturated fatty acids (PUFA) n-3 long chain, especially EPA and DHA, found in fatty fish and fish oils, protects against cardiovascular disease in the populations of the West. The PUFA n-3 long chain reduce concentrations of plasma triacylglycerol (GAD) and reduce postprandial lipemic response. It has been shown that Dietary fish reduces atherosclerosis in animal models, which which could be due to lipid decrease, production reduced growth factors, decreased inflammation, or a combination of these effects. Secondary prevention studies, that provide long chain PUFA n-3 to patients who had already suffered a myocardial infarction (MI), demonstrate significant benefit, as described and claimed in EP-B-1152755. The PUFAs n-3 are especially potent in reducing sudden death (EP-B-1,152,755), an effect that occurs in the absence of significant reduction of lipids It has been assumed that this effect could be due to anti-thrombotic actions and PUFA n-3 anti-arrhythmic. In contrast, it has been considered possible that PUFAs n-3 could contribute to the stabilization of atherosclerotic plaques for their actions anti-inflammatory Conversely, there are indications that PUFA n-6 linoleic acid, found in vegetable oils such as oil Sunflower, can promote inflammation, in which case ingestion Increased linoleic acid could contribute to instability  of the plate.

WO 00/44361 describes pharmaceutical compositions containing at least 95% EPA and less than 5% DHA for the stroke treatment.

According to the knowledge and understanding of the authors of the present invention, there is no study that records the effects of PUFA n-6 or n-3 on plaque stability. Rapp et al (Arterioscler Thromb 1991, II, 903-911) carried out a study in which patients destined to undergo endarterectomy consumed very high doses of fish oil (48-64 g / day) during a period prior to surgery and found that levels of PUFA n-3, eicosapentaenoic acid (EPA; 20: 5 n-3) and docosahexaenoic acid (DHA; 22: 6 n-3) in the plates removed in surgery were significantly higher than in the plates Withdrawals from control patients. However, Rapp et al did not provide any structural detail of the plates.

It has been found now, according to the present invention, that dose administration relatively Moderate fish oil to patients with symptoms of atherosclerosis of the arteries that water the brain not only gives as a result the incorporation of EPA and DHA into the lipoprotein of low density (LDL) and atherosclerotic plaque lipids but which, significantly, also leads to stability increased atherosclerotic plaque.

More particularly, it has been discovered that those patients to whom fish oil is supplied by route oral tend to exhibit more plaques with a fibrous capsule well formed, instead of a thin inflamed capsule, and additionally the plates are less strongly infiltrated with macrophages As is well known, the characteristics of a plate atherosclerotic that make it vulnerable to rupture include a thin fibrous capsule and increased cell numbers inflammatory such as macrophages. The presence of macrophages in the carotid plaques are also known to be associated with a increased incidence of neurological events, i.e. effusions cerebral and transient ischemic attacks. Therefore, the oral administration of fish oil provides a method effective and safe to help prevent events neurological, particularly strokes, in patients with atherosclerosis symptoms of the arteries that water the brain.

Thus, the present invention is directed to the use of a mixture of EPA and DHA, or a salt or derivative pharmaceutically acceptable thereof, in the preparation of a oral medication to prevent a stroke in a patient with symptoms of transient ischemic attack and / or amaurosis fugax, where the dosage will range between 0.5 and 5.0 g of EPA and DHA daily, and where the ratio of EPA and DHA in said mixture It is from 1: 2 to 2: 1.

The following will describe in detail the experimental study that has led to the present invention.

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Patients and Methods Study design

Patients destined to suffer endarterectomy carotid is that they exhibited symptoms of atherosclerosis advanced of the arteries that water the brain, and that were of agreement to participate were distributed randomly, in double blind mode, to receive one of three types of oil provided in capsules. The control oil was a mixture 80:20 of palm and soybean oils; the fatty acid composition of this mixture closely matches that of the average diet of the adults in the UK The other oils were sunflower oil and a Fish oil containing EPA / DHA. Acid composition Fatty oils are shown in Table 1. Each capsule It contained 1 g of oil and 1 mg of α-tocopherol. Patients consumed 6 capsules / day until surgery; be recommended that patients consume two capsules with one Food three times a day. So, the amount of PUFA Long chain n-3 provided was 1.4 g / day. The amount of linoleic acid provided was 3.6 g / day, which It represented a 40% increase in the intake of this fatty acid.

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TABLE 1 Fatty acid composition of the capsules used in the study

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The sample size was calculated based on the fatty acid composition of the plate phospholipids (PL) described by Rapp et al . (Arteriscler. Thromb. 1991, 11, 903-11) taking into account the 10 to 15 times lower dose of EPA + DHA used in the present study. On this basis, it was calculated that a sample size of 50 would be required to detect a double increase in EPA in the PL of the plate at P <0.05. To make a 20% decrease in the rate possible, 188 patients were recruited into the study.

At the beginning of the study, a sample of fasting venous blood in EDTA. The patients then started on capsule consumption as described above, and completed a Weighted daily feed over 7 days. The patients continued with medications throughout the study period and they were advised not to change their diet. He compliance was favored by regular contact with patients and It was evaluated by counting the capsules returned and by measuring the Fatty acid composition of the LDL lipid fractions. The patients who reported impossibility of compliance (n = 5) were excluded from the study. The capsule counts returned suggested compliance> 85% in each treatment group. Additionally, the proportion of EPA in each fraction of LDL lipids of plasma increased by more than 0.5 g / 100 g of total fatty acids in > 90% of patients in the fish oil group. These observations indicate that compliance was at least 85 to 90% in Each treatment group.

Surgical removal of plaques Carotid was usually performed between 7 and 190 days after the Patient entry into the study. The patients who went to Surgery within 7 days were excluded from the study. In the the morning before surgery, a second fasting sample was taken from venous blood. At the time of surgery, plaque was collected carotid and washed. It was then cut into cross sections of 2 mm wide starting with the common carotid artery. The sections for biochemical analysis were frozen in nitrogen liquid. The sections for histology were fixed in formaldehyde and They were then embedded in paraffin wax. Sections for immunohistochemistry froze in the middle of encrustation to the optimum cutting temperature (Agar Scientific, Stansted, RU), and it stored at -70 ° C.

Analysis of usual nutrient intakes

Feed diaries were analyzed for usual nutrient intakes using a modification of FOODBASE (Institute of Brain Chemistry, London, UK), which has been validated for acid intake determination fatty

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Lipids and lipoproteins in plasma

Total concentrations were determined in cholesterol and triacylglycerol (TAG) plasma using assays commercially available colorimetrics (Sigma Chemical Co., Poole, RU). Low density lipoproteins (LDL) were prepared at starting from plasma in a two step density gradient formed by stratification of 1.7 ml of plasma (adjusted to a density of 1.24 g / ml by adding solid potassium bromide) under 3.3 ml of phosphate buffered saline and tube centrifugation tightly closed at a speed of 100,000 rpm for 2 h at 15 ° C in a Beckman TLA-100.4 rotor in a Beckman Optima ultracentrifuge. The purified LDLs were frozen to -70 ° C for analysis of fatty acid composition.

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Analysis of fatty acid composition

The fatty acid compositions of the PDL, cholesteryl ester (CE) and TAG fractions of LDL and the frozen section closest to the bifurcation of the carotid plaques were determined. Total lipid was extracted, lipid fractions were separated by thin layer chromatography and the fatty acid composition of each fraction was determined by gas chromatography as described by Thies et al . (Am. J. Clin. Nutr. 2001, 73, 539-48).

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Morphology of the carotid plaques

Sections embedded in paraffin were stained with hematoxylin and eosin. The section closest to the fork was classified using both the guidelines published by the American Heart Association (Stary et al ., Circulation, 1995, 92, 1355-74) and also using a modification of this system proposed by Virmani et al (Arterioscler. Thromb. Vasc. Biol. 2000, 20, 1262-75). Sections were examined by a cardiovascular pathologist (PJG) in random order and without access to any patient information. The classification of the American Heart Association (AHA) comprises 6 grades, or types, as follows: Type I (initial injury); Type II (early injury or fatty streak); Type III (intermediate or pre-atheroma lesion); Type IV (atheroma or atheromatous plaque); Type V (fibroateroma or fibrotic lesion); Type VI (lesion with superficial defect and / or hemorrhage and / or thrombotic deposit). The modification of this classification proposed by Virmani et al . It implies a series of descriptive degrees of increasing severity as follows: pathological thickening of the intima (smooth muscle cells in the matrix with areas of extracellular accumulation of lipids but with absence of necrosis or thrombus); atheroma with fibrous capsule (a well-formed necrotic nucleus with an overlying fibrous capsule (without thrombus); atheroma with thin fibrous capsule (a thin fibrous capsule infiltrated by macrophages and lymphocytes with rare smooth muscle cells and an underlying necrotic nucleus; absence of thrombus) ; erosion (luminal thrombosis); plaque rupture (fibroateroma with rupture); luminal thrombus that communicates with the necrotic nucleus); calcified nodule and fibrocalcic plaque (eruptive calcification).

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Immunohistochemistry of carotid plaques

The second section of the plate from the fork was used for immunohistochemistry. The sections were stained for the presence of macrophages (distinguished by the presence of CD68 on their surface) and T lymphocytes (distinguished by the presence of CD3 on their surface) and for two adhesion molecules, the adhesion molecule-1 of the vascular cells (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1), involved in the movement of immune cells in the plaque. Cryostatic sections of frozen plaque were mounted on microscope slides coated with organosilane. The endogenous peroxidase activity was blocked and then sections were successively incubated with optimal dilutions of the different anti-human antibodies, biotinylated goat anti-mouse immunoglobulin G (anti-pig goat for VCAM-1 staining) (DAKO, Ely , RU) and horseradish streptavidin peroxidase (DAKO, Ely, RU). Finally, peroxidase activity was visualized using hydrogen peroxide as a substrate and 3-amino-9-ethyl-carbazole (Sigma Chemical Co., Poole, RU) as chromogen. The stained sections were fixed using formalin, subjected to contraction with Harris hematoxylin, and observed using a microscope under 10 x magnification power. The primary antibodies used were anti-human mouse CD3 (Leu 4; Vector Dickinson, Oxford, RU), anti-human mouse CD68 (KP1; DAKO, Ely, RU); ICAM-1 anti-human mouse (R&D Systems, Oxford, RU), and VCAM-1 anti-human goat (R&D Systems, Oxford, RU). Staining was cataloged from 0 (no staining), 1 (moderate staining) or 2 (staining
high).

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Statistic analysis

Data are presented only for patients who completed the study (n = 57 in the control group; n = 52 in the sunflower oil group; n = 53 in the fish oil group). Age, body mass index (BMI), blood lipid concentrations at the start of the study, medical history, medication use and usual nutrient intakes between different treatment groups were compared using single-use ANOVA. factor. The effects of the treatment on blood lipid concentrations and on the fatty acid compositions of the LDL lipid fractions were determined as a change from the baseline value. The changes with respect to the baseline between the different treatment groups were compared by single-factor ANCOVA using the baseline value and the duration of treatment as covariates; where there was an important effect of the treatment, the Student's t-test was used to identify the differences between groups. In some cases, post-treatment values were compared with baseline values within the same treatment group by the paired Student's t-test and post-treatment values were compared between treatment groups by single-use ANOVA. factor with the post-hoc Student t test. The fatty acid compositions of the lipid fractions of the carotid plaque between the different treatment groups were compared using single-factor ANCOVA, using the duration of the oil treatment as a covariant; where there was an important effect of the treatment, the Student's t-test was used to identify differences between the groups. Distributions of staining intensity (immunohistochemistry) and plaque morphology were compared between the treatment groups using the Chi-square test. The average range of each distribution in each treatment group was determined and these were compared using the Jonckheere-Terpstra test. Correlations were determined as Spearman's correlation coefficients (p). All analyzes were performed using SPSS11 version 11 (SPSS, Chicago, IL, USA) and in all cases a value for P <0.05 was taken to indicate a statistically significant difference.

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Results Patient characteristics

Eighteen patients withdrew from the study, 13 for clinical reasons and 5 because they did not comply with the protocol of the study. Eight more patients were excluded from the study due to who went into surgery within 7 days of entry into the study.

The characteristics of the patients who completed the study are shown in Table 2. There were no significant differences between the treatment groups at the time of entry into the study with respect to sex mix, age, BMI, fasting plasma GAD and cholesterol concentrations, energy consumption and individual macro- and micro-nutrients including individual fatty acids, number of smokers / ex-smokers, degree of stenosis of the affected carotid artery, clinical history and use of medications (all of them P > 0.1438 at least; single factor ANOVA) (Table 2). Each group received the supplemented oils for similar periods of time (Table 2). Patients in the sunflower oil group received an additional amount of 3.6 g of linoleic acid / day, increasing the daily consumption of this fatty acid by approximately 40%. Patients in the fish oil group received an additional 1.4 g of long-chain n-3 PUFA n-3, increasing EPA intake approximately 10 times and DHA intake approximately 4 times.

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TABLE 2 Patient characteristics at the beginning of study

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Data for age, DMI, blood lipids and Nutrient intake are mean values ± SD (age and DMI intervals are shown in parentheses).

The data for stenosis are medians with the 25th and 75th centiles indicated in parentheses.

Data for duration of treatment with oil is medium with the 10th and 90th centiles represented in brackets.

\ dagger Data are calculated from 7th Day of the weighted food diaries.

\ text {*} Most of the former smokers had quit smoking more than 3 years before the entrance of the study.

¶ I mean stroke

\ ddagger Partial temporary vision loss or complete.

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Plasma lipid concentrations

There was no significant effect of treatment on plasma cholesterol concentration (data not shown), however, there was a significant effect of treatment on plasma TAG concentration (P = 0.0184; single-factor ANCOVA). Fish oil resulted in a significant decrease (-0.48 ± 1.06 mmol / l) in plasma TAG concentration, which did not change significantly in the other groups. Thus, the plasma TAG concentration was significantly lower after treatment with fish oil (1.2 ± 0.8 mmol / l) compared to the baseline ( P = 0.0032; paired Student t test) . Additionally, the plasma TAG concentration in the fish oil group at the end of the treatment was significantly lower than that in the other two groups ( P = 0.0294 versus the control and P = 0.0347 against the sunflower oil ; ANOVA single factor). There was a significant linear correlation between the duration of treatment with fish oil and the change in plasma TAG concentration ( P = -0.44; P = 0.0118).

Fatty acid composition of the lipid fractions of LDL

There was a significant effect of the treatment on the proportions of various fatty acids in LDL, PL, CE and TAG. The proportions of EPA and DHA increased in the three lipid fractions of LDL after treatment with fish oil (Table 3). These proportions were significantly different from the baseline ( P <0.0001 for EPA in each fraction, P = 0.0031 for DHA in CE, P = -0,0001 for DHA in PL and TAG; paired Student t test) and those of the other two groups after treatment ( P ≤ 0.0003 at least; single factor ANOVA). Increases in the proportions of long-chain n-3 PUFA in LDL PL in the fish oil group were accompanied by significant decreases in the proportions of linoleic, di-homo-γ-linolenic acids (20: 3 n -6) and arachidonic (20: 4 n-6). Increases in the proportions of long-chain PUFA n-3 in EC of LDL and TAG in the fish oil group were accompanied by significant decreases in the proportions of linoleic and oleic acids (18: 1 n-9), respectively . Treatment with sunflower oil resulted in an increased proportion of linoleic acid in LDL EC, largely at the expense of oleic acid. These observations are summarized in Table 3.

TABLE 3 Effects of dietary oil treatment on fatty acid composition of the lipid fractions of LDL

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Fatty acid composition of carotid plaques

There was a significant effect of the treatment on the proportions of EPA and DHA in each of the lipid fractions of the plate and on the proportion of linoleic acid in the PL of the plate. The proportion of EPA was higher in the PL, CE and TAG of the carotid plaques of the patients in the fish oil group than in those of the patients in the control group ( P <0.0001, 0.0053 and 0 , 0007 for PL, CE and TAG, respectively; single-factor ANCOVA) and sunflower oil ( P <0.0001, 0.0278 and 0.0024 for PL, C and TAG, respectively, single-factor ANCOVA) . There was a significant positive linear relationship between the proportion of EPA in PL of the plate and the duration of treatment with fish oil (p = 0.41, P = 0.0051). The proportion of DHA was higher in EC and GAD of the carotid plaques of the patients in the fish oil group than in those of the patients in the control group ( P = 0.0042 and 0.0241 for CE and GAD, respectively; ANCOVA single factor). Additionally, the proportion of DHA was higher in the PL and CE of the carotid plaques of the patients in the fish oil group than in those of the patients in the sunflower oil group ( P = 0.0100 and 0.0278 for PL and CE, respectively; single factor ANCOVA). There was a smaller proportion of linoleic acid in the PL of the plaques of the patients in the fish oil group compared with those of the other two groups ( P = 0.0118 versus the control and P = 0.0015 versus sunflower; single factor ANOVA). There was no significant difference in the fatty acid compositions of the lipid fractions of the plate between the control and sunflower oil groups. These observations are summarized in Table 4.

TABLE 4 Fatty acid composition of the solutions lipids of the carotid plaque in different groups of oil treatment

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Morphological classification of the carotid plaque

The distribution of injury types determined using the AHA classification was significantly different between patients taking fish oil and those taking control or sunflower oil ( P = 0.0234 versus control and P = 0.0107 versus sunflower oil; Chi-square test). This appeared to be due to a higher proportion of type IV lesions ("atheromas") and a lower proportion of type V lesions ("fibroateromas and fibrotic lesions") in the fish oil group. The distributions of the types of lesions of the treated patients for shorter or longer periods of time than the median duration in each group were compared. For the plaques of the treated patients for less than the average time, the distribution was not significantly different between the treatment groups. On the other hand, the distribution of lesions in patients who received fish oil for a duration longer than the median was significantly different from those observed in both the control group and the sunflower oil group ( P = 0.0111 and 0.0432, respectively; Chi-square test). All patients considered, the EPA and DHA content were maximum for Type IV plates and minimum for Type VI plates.

The distribution of the types of lesion determined using the modified AHA classification was significantly different between patients taking fish oil and those taking control or sunflower oils ( P = 0.0344 versus control and P = 0.0313 against sunflower oil; Chi-square test). This difference appeared to be due to a higher proportion of lesions with a well-formed fibrous capsule and absence of thrombus (fibrous capsule atheromas) and a lower proportion of lesions with a thin inflamed fibrous capsule (thin fibrous capsule atheroma) in the group of fish oil.

There were no significant differences in the distribution of the types of plaque injury among the groups of control and sunflower oil. These observations are collected in Tables 5 and 6.

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TABLE 5 Morphology of the carotid plaque in different groups oil treatment

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TABLE 6 Content of polyunsaturated fatty acids n = 3 of lipids of the carotid plaque according to the AHA classification and macrophage staining intensity (anti-CD68)

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Lymphocytes and macrophages in the carotid plaques

There was no difference in the presence of ICAM-1 or VCAM-1 in the plaques of the patients in the different treatment groups (data not shown). Similarly, no treatment effect was observed in the presence of T lymphocytes in the plaques. In contrast, the plaque sections of patients who consumed fish oil were less intensely stained with anti-CD68, a macrophage marker, such that the distribution of staining records was different for this group compared to the others. ( P <0.0001 against the control and P = 0.0016 against sunflower oil; Chi-square test) and the average range of staining intensity was significantly lower ( P = 0.0246). The duration of treatment with fish oil was significantly correlated with the intensity of anti-CD68 staining (p = -0.352; P = 0.0301). The plaques of the patients who took fish oil for a shorter time than the median duration of treatment exhibited a greater intensity of anti-CD68 staining (25% staining intensity 1 and 75% staining intensity 2) than those of the patients treated for a duration longer than the median (47% staining intensity 1 and 53% staining intensity 2). However, these distributions of staining intensity were not significantly different ( P = 0.0827; Chi-square test). Anti-CD68 staining intensity distributions of plaques of treated patients were compared for shorter or longer times than the median duration in each group. The distributions observed in the fish oil group were significantly different from those observed in both the control group ( P <0.0001 and 0.0048 for patients treated for a shorter or longer period than the median duration, respectively ) as in sunflower oil ( P = 0.0109 and 0.0363 for patients treated for a shorter or longer period of time than the median duration, respectively) (Chi-square test). Considering all patients, plaques with a high macrophage infiltration (i.e. an anti-CD68 staining intensity of 2) contained significantly less EPA and DHA than moderate infiltration plaques (i.e. an anti-CD68 staining intensity of 1) (Table 6).

There were no significant differences in the distribution of anti-CD68 staining registers or in the average ranges of staining intensity between the groups of control and sunflower oil.

T lymphocyte staining observations and macrophages are summarized in Table 7.

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TABLE 7 Staining of T lymphocytes and macrophages in plaques carotid patients in different treatment groups with oil

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Discussion

Strengthening the diet of patients in this study with sunflower oil, providing 3.6 g of acid linoleic / day, had only a very limited influence on measured results. This is probably because these patients were already consuming a significant amount of acid linoleic in their usual diet; this intake is in accordance with the consigned for adults in the UK. The observations of the inventors showed that the increase in acid intake linoleic up to 40% in individuals with atherosclerosis Advanced carotid and consumption of typical amounts of this acid fatty did not lead to increased acid incorporation linoleic in the carotid plaques nor did they lead to stability altered plate, at least for the period of time studied.

The diet booster with fish oil significantly reduced the concentration of TAG in plasma. He degree of reduction of GAD was consistent with that observed in others reinforcement studies with fish oil, and it was related with the duration of the reinforcement with fish oil.

Long-chain n-3 PUFAs such as EPA and DHA are usually consumed in small amounts, and are therefore found in relatively low proportions in plasma lipids and tissues. However, the increased consumption of these fatty acids is marked by an increase in their proportion in various groups of lipids in blood and tissues, as observed in the present work for LDL lipid fractions. A fundamental observation of the present study is that when long-chain PUFA n-3 is consumed in a moderate dose, they are easily incorporated into the lipids of the atherosclerotic plaque. The incorporation of EPA into plate lipids, especially PL, was linear with respect to time. The only previous study that had examined the effect of fish oil reinforcement on the fatty acid composition of atherosclerotic plaques known to the inventors was that of Rapp et al . supra , which demonstrated the substantial incorporation of EPA and DHA into plaque lipids after the consumption of a very high dose of fish oil. However, Rapp et al . did not investigate the effect of EPA / DHA intake on plaque morphology. The present invention has shown that administration of PUFA n-3 at levels that approximate those that have been used in secondary prevention reference studies (see, eg EP-A-1,152,755) are incorporated into lipid clusters of license plate. Additionally, even at the moderate dosage levels used by the authors of the present invention, the incorporation of PUFA n-3 occurs within a relatively short time frame. This suggests that atherosclerotic plaques are acceptably dynamic, with some degree of lipid renewal, even at an advanced stage of atherosclerosis.

Immunohistochemical staining and measures of Plaque morphology revealed a significant impact of PUFA n-3 There were more plaques with a fibrous capsule well formed, instead of a thin inflamed capsule, in the Fish oil group than in any of the other groups. Additionally, the plaques of patients treated with oil Fish were less strongly infiltrated with macrophages. The changes in plaque morphology observed as a result of reinforcement with fish oil in the present study indicated by both a more stable plate, which is less prone to breakage. These differences (ie less strong infiltration with macrophages and more plates with a well formed fibrous capsule) were related to a higher content of EPA and DHA in the plate lipids, which indicated that these PUFAs are n-3 those that determine the stability of the license plate.

Drug Preparation and Mode of Administration

In the present invention, the active ingredient of the medication is a mixture of EPA and DHA. These fatty acids PUFA n-3 may be present in the form of naturally occurring triglyceride, or they can be found in the form of pharmaceutically acceptable salts or derivatives, especially its ethyl esters or other alkyl esters.

Conveniently, the active ingredient is derived from fish oil, although they may become commercially available other sources of EPA and DHA over the years coming. The methods for manufacturing fish oil from Pharmaceutical quality from raw fish oil, and for vary the concentration of EPA and / or DHA contents in the product, are well known to those skilled in the art. Since the views of obtaining a faster intake of PUFA n-3 and to ensure acceptance by the patient, it is preferred that the concentration of EPA and / or DHA in the fish oil is high so that a adequate dose by, for example, one or two capsules per day. Preferably, a composition is used as active ingredient containing from 20% to 100% by weight of a mixture of EPA and DHA, more preferably a composition containing more than 70% by weight of the mixture of EPA and DHA, and most preferably a composition containing from 70% to 90% by weight of the EPA / DHA mixture. The relative amounts of EPA: DHA should be from 1: 2 to 2: 1, of more preferably about 3: 2.

The medicament of the present invention is for oral administration Conveniently, the oral form is a capsule with hard or soft wrap, although they can be used in case desired other oral forms, e.g. powder obtained by microencapsulation

Medications may include, in addition to EPA and DHA active ingredients defined, one or more vehicles Pharmaceutically acceptable as they are well known in the art. The compositions may also include fillers, stabilizers, extenders, binders, humidifiers, surfactants, lubricants and analogs, as shown in the technique of formulation of pharmaceutical compositions.

Additionally, antioxidants can be used, for example hydroxytoluene, butyrate, quinone, tocopherol, acid ascorbic, etc., preservatives, coloring agents, perfumes, flavorings and other pharmaceutical agents. An antioxidant is a particularly preferred optional component of the medicines.

Example of oral medication preparation

Soft gelatin capsules that contain 1 g / per capsule

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The active ingredients and excipients are Weigh and homogenize with a high speed stirrer. The mixture is then ground in a colloid mill and subjected to deaerated in a stainless steel container ready for encapsulation. The mixture is introduced into oblong soft gelatin capsules of size 20 (average weight 1.4 g) using a machine standard encapsulation.

The medicament of the present invention can administered to patients with symptoms of atherosclerosis of the arteries that irrigate the brain at any suitable dose, for being PUFA n-3 essentially non-toxic even at Very high dose levels. In the test described above, the regimen dosage was such that it provided approximately 1.4 g of Total EPA and DHA per day, and this level was shown to be effective to increase plate stability. Generally the dosage was between 0.5 and 5.0 g of EPA and / or DHA at day, the preferred dose being from 1.0 to 3.0 g / day.

The medicament of the invention is administered. conveniently to patients with symptoms of atherosclerosis of the arteries that water the brain, for example a stroke or a transient ischemic attack, in order to reduce the risk of a subsequent attack possibly fatal. To this end, the medication can also be used in association with other therapeutic agents, for example aspirin and warfarin, which is known to reduce the risk of secondary neurological events in such patients.

Claims (9)

1. The use of a mixture of EPA and DHA, or a pharmaceutically acceptable salt or derivative thereof, for preparation of an oral medication for spill prevention brain in a patient with an ischemic attack symptom transient and / or fugax amaurosis, where the dosage will oscillate from 0.5 to 5.0 g of EPA and DHA per day, and where the ratio of EPA to DHA in said mixture is 1: 2 to 2: 1. 2. The use according to claim 1, in where said ratio is approximately 3: 2. 3. Use in accordance with any of the previous claims, wherein said EPA and / or DHA are present as ethyl esters. 4. Use in accordance with any of the previous claims, wherein said medicament contains as active ingredient from 20% to 100% by weight of said mixture. 5. The use according to claim 4, in where said medicine contains as active ingredient more than 70% by weight of said mixture. 6. The use according to claim 5, in where said medicine contains as active ingredient from 70% to 90% by weight of said mixture. 7. Use in accordance with any of the previous claims, wherein said medicament contains also an antioxidant for said EPA and DHA. 8. Use in accordance with any of the previous claims, wherein said medicament is for administration at a dose of 1.0 to 3.0 g / day of EPA and DHA. 9. Use in accordance with any of the previous claims, wherein the oral medicament is It is in capsule form.