JPS6257605B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to formulations for the treatment or prevention of thrombotic conditions. It has long been known that many substances affect platelet aggregation, but simply knowing the effect of a particular substance on platelet aggregation in vitro does not mean that the substance will affect clot formation in vivo. It is not known whether it acts to prevent it, promote it, or even have no effect at all. This is because it is not clear what initiates the formation of thrombus or embolism, for example in stroke or myocardial infarction. MJSilver, JBSmith, etc. (Prostaglandins, 4
(6), 863-75, 1973), platelet aggregation caused by arachidonic acid (5,8,11,14-eicosatetraenoic acid), a component in food, was inhibited in vitro by many substances. It has been shown that this can be achieved. These substances include adenosine, β
- naphthol, non-steroidal anti-inflammatory drugs (e.g. indomethacin, sodium salicylate and aspirin), unsaturated fatty acids [e.g.
14, 17-eicosatrienoic acid, 8, 11, 14-eicosatrienoic acid (dihomo-γ-linolenic acid,
DHLA), 5,8,11,14,17-eicosapentaenoic acid, 5,8,11,14-eicosatetraenoic acid and 4,7,10,13,16,19-docosahexaenoic acid] and human albumin. be. In addition, platelet aggregation caused by collagen and secondary aggregation of platelets caused by adenosine diphosphate (ADP) are inhibited by β-naphthol, aspirin, 8,11,14-eicosatrienoic acid,
It was also shown to be inhibited by 5,8,11,14,17-eicosapentaenoic acid and human albumin. On the other hand, among fatty acids, 8, 11, 14-eicosatrienoic acid, 11, 14, 17-eicosatrienoic acid,
5, 8, 11, 14, 17-eicosapentaenoic acid,
5.8.11.14-eicosatetraenoic acid, 4.
It has also been found that 7,10,13,16,19-docosahexaenoic acid, linolenic acid, linoleic acid, oleic acid, arachidic acid, stearic acid, and decanoic acid do not themselves cause platelet aggregation. These series of in vitro tests showed that
Silver et al. seem to conclude that arachidonic acid plays an important role in hemostasis and thrombosis. However, in humans, the effects of various fatty acids on diseases including thrombosis are unclear.
Research to date has not yielded any clear conclusions. For example, before the experiment of Silver et al. mentioned above, the
Norwegian Vegetable Oil Experiment, ll.
Conducted by Natvig, Chr.I.Borchgrevink, etc.
Reported (Scand.J.Clin.Lab.Invest.,
22 , Suppl. 105, 1-20, 1968). In this study,
Compares the effects of two foods on human mortality from various coronary heart diseases, including myocardial infarction. That is, one is sunflower seed oil (approximately 63%
compared the effects of foods containing cottonseed oil (approximately 55% linolenic acid) and cottonseed oil (approximately 55% linolenic acid). The daily intake of both oils is 10ml.
The group that received linolenic acid, which was more unsaturated,
It has been reported that they are more dangerous than the group that took linoleic acid. Linoleic acid, eicosapentaenoic acid and docosahexaenoic acid are also known to reduce plasma cholesterol levels, which is believed to be related to arteriosclerosis. Arteriosclerosis is often found in humans who have suffered myocardial infarction. However, Robertson (Lancet, 1 , 44, 1959)
conducted autopsies on cadavers of indigenous people in Jamaica, where arteriosclerosis is widely observed, and confirmed that secondary thrombosis or myocardial infarction was rare.
Therefore, it is thought that myocardial infarction can occur even in the absence of highly developed arteriosclerosis. Furthermore, other dietary components have also been suggested to assist in thrombosis prevention. This is DHLA (PBKernoff, ALWillis, KJStone, JA
Davis and GPMc Nicol, BritishMed.J., 2 ,
1441−1444, 1977). DHLA is a potent inhibitor of platelet function, prostaglandin _E1
(PGE ₁ ), and PGE ₁ is said to be a promising antithrombotic agent. According to Kernoff et al., administration of DHLA reduced PGE ₁ production by an average of 55
% increase, but in 6 out of 8 subjects,
They also reported that undesirable prostaglandin E ₂ (PGE ₂ ) increased by an average of 33%, and there was no clear correlation with DHLA dose. On the other hand, it has been reported that plasma heparin neutralizing activity, which is said to be high in thrombotic conditions, is reduced by DHLA administration, but Kernoff et al. It is not known whether this reflects a biological mechanism, and a relationship with blood clots has not been clearly demonstrated. The study's author, Kernoff, says, ``DHLA administered in small doses is as effective, if not more effective, in preventing and treating these conditions, namely arteriosclerosis and coronary heart disease, than dietary supplementation. It is estimated that it is equally effective." However, in the same issue of the journal mentioned above, in the editorial (pages 1437 and 1438), "Before discussing what clinical implications the results obtained by Kernoff et al. I need to find out more about my diet.'' The reason for this description is that when conducting an investigation using only collected blood,
The point is that it ignores the in vivo mechanisms of thrombotic conditions. This study with DHLA also questions the often-cited view that unsaturated fatty acids in the diet are more effective than their more saturated counterparts. This question is addressed by the undesirable effects of arachidonic acid (Silver et al. and Kernoff, cited above).
) contains four double bonds,
Enhanced by the fact that it is even more unsaturated than DHLA (3 double bonds). Based on the above background, we surprisingly discovered the following. That is, among many fatty acids, (all-z)-5.
8, 11, 14, 17-eicosapentaenoic acid (hereinafter referred to as
It has been discovered that thrombotic conditions (hereinafter simply referred to as thrombi) can be effectively treated or prevented using eicosapentaenoic acid (simply referred to as eicosapentaenoic acid) or its salts, esters or amides. An example where our findings may be useful is that eicosapentaenoic acid or its salts, esters or amides can be used to treat cardiovascular diseases where the formation of blood clots is involved, such as myocardial infarction, stroke or deep vein thrombosis during surgery. It can be used for the treatment or prevention of. We found that injecting eicosapentaenoic acid into rabbits tended to prolong bleeding time and reduce blood clot formation or adhesion to injured tissue. Furthermore, it has been found that eicosapentaenoic acid produces a substance that has a strong anti-aggregation effect on platelets. Eicosapentaenoic acid has also been found to have the ability to disperse blood clots that have already formed. On the other hand, aspirin is effective both in vivo and in vitro.
Although an excellent inhibitor of platelet aggregation in vitro,
It is not an antithrombotic drug and cannot disperse blood clots that have already formed. This ability of eicosapentaenoic acid to cause blood clot disintegration is important in the treatment and prevention of blood clots. We further demonstrated that after pre-incubating human platelets with eicosapentaenoic acid,
It has also been found that when stimulated with ADP, it becomes difficult to aggregate. This suggests the following to us. That is, if human platelets could be filled with eicosapentaenoic acid, they would be less susceptible to ADP stimulation and less likely to form blood clots. The dosage of eicosapentaenoic acid required for the therapeutic or prophylactic effect of the formulation disclosed in this invention may vary depending on the route of administration and the nature of the condition to be treated. However, generally it will be at least 1 g/day, preferably 1.5 to 3 g/day. Eicosapentaenoic acid is known to be present in cod liver oil or other oils such as sardine oil, herring oil, etc., and can be extracted from these oils by techniques known in the art or by methods described in the literature. sell. Eicosapentaenoic acid can also be synthesized by conventional methods of synthetic organic chemistry. The method used depends on the availability of suitable starting materials. The amount of eicosapentaenoic acid that occurs naturally or in cod liver oil or herring oil is
If you try to give them the required amount of eicosapentaenoic acid, you will end up giving too many calories because of the coexistence of other fatty acids. Additionally, cod liver oil (and other fish oils) is rich in vitamin A (at least 850 I.U./g) and vitamin D (at least 85 I.U./g), so provide the required amount of eicosapentaenoic acid. In this case, the recommended daily doses of these vitamins for humans would be far exceeded, resulting in hypervitaminosis. The recommended human dose of vitamin A is 5000 I.U. and vitamin D is 400 I.U.
It is. The FDA in the United States recommends that vitamin A
The daily dose of should not exceed 10000I.U.
Vitamin D should not exceed 400 I.U. Larger amounts require a doctor's prescription. Therefore, when taking eicosapentaenoic acid as a medicine, it is necessary to combine eicosapentaenoic acid or a pharmaceutically acceptable salt, ester or amide of eicosapentaenoic acid with It would be desirable to provide a substantially vitamin-free formulation including an acceptable carrier. Furthermore, fatty acids other than eicosapentaenoic acid,
It is more desirable to provide a formulation of eicosapentaenoic acid or a pharmaceutically acceptable salt, ester or amide thereof and a pharmaceutically acceptable carrier that contains as little as possible of eicosapentaenoic acid or a salt, ester or amide thereof. Excess calorie intake, for example when using cod liver oil or herring oil, may be tolerated as eicosapentaenoic acid or its pharmaceuticals, where at least 50% by weight of the fatty acid content of the formulation is provided by eicosapentaenoic acid. Although largely avoided when using formulations containing salts, esters, or amides and pharmaceutically acceptable carriers, dietary adjustment of caloric intake is still necessary. However, if eicosapentaenoic acid is to be administered without substantially altering the recipient's diet, the content of eicosapentaenoic acid should be at least 90% by weight, preferably at least 95% by weight of the fatty acids in the dose. Or should occupy all. Arachidonic acid should preferably not be present or at most should not exceed 5% in the fatty acid content. For example, the desired content specification for eicosapentaenoic acid when used as a drug should be at least 90%, arachidonic acid and DHLA about 2% each, and the others are palmitic acid, oleic acid and other pharmaceutically acceptable levels. Fatty acid. If vitamins are present, do not exceed the recommended daily dosage. When administering eicosapentaenoic acid with a fatty acid content of at least 90%, there is no need to substantially alter the diet of the recipient. It is also possible to administer eicosapentaenoic acid in place of butter and/or ordinary margarine, and special margarines, e.g. in the form of emulsions, with normal use
It may also be possible to enable the recipient to ingest the required amount of eicosapentaenoic acid. Culinary oils and fats can similarly be formulated to contain eicosapentaenoic acid. Eicosapentaenoic acid need not necessarily be used as such, but may be used as its pharmaceutically acceptable salt, ester or amide. Although esters or amides and other pharmaceutically acceptable forms that can be converted to acids in vivo can be used, preferred esters are triglycerides, ethyl esters, and the like. The alcohol used to esterify the acid should preferably be non-polymeric and should preferably not contain more than two hydroxyl groups in the molecule. Furthermore, it is desirable that the ester used is not a cholesteryl ester.
This is because some cholesterol is liberated and can increase serum cholesterol levels. Preferred salts are sodium, potassium or other pharmaceutically acceptable salts, which are suitable for tabletting. The tablet may contain a solid pharmaceutically acceptable derivative of eicosapentaenoic acid. Eicosapentaenoic acid is highly unsaturated and it or its derivatives are susceptible to oxidation and formulations containing them are used as antioxidants, e.g. butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, as pharmaceuticals. It should contain acceptable quinones and alpha-tocopherols. As a convenient route of administration for daily administration, eicosapentaenoic acid (or its salts, esters or amides) is preferably administered orally, but it can also be administered by any route by which it can be absorbed, such as externally, subcutaneously, intramuscularly or intravenously, rectally. It can be administered or, in the case of women, intravaginally. Unit dosage forms of the formulation, eg tablets or capsules, contain from 0.25 to 1.0 g, eg 0.5 g, of active compound. Generally administered three times a day. Since eicosapentaenoic acid itself is liquid and tasteless, it is advantageous to encapsulate it in a capsule, such as a soft capsule, and administer it orally, so that it does not taste like eicosapentaenoic acid. Another way to mask this taste is to administer it orally as an emulsion. The emulsion can be of the multiple type. Briefly, eicosapentaenoic acid is made into an oil-in-water emulsion with a pharmaceutically acceptable surfactant, and then this emulsion is mixed with another oil,
For example, it can be emulsified in peanut oil. Alternatively, the eicosapentaenoic acid can be made into a water-in-oil emulsion and then the emulsion itself is emulsified in water. Various types of emulsions may exist as oral gels or hard emulsions. For example, there is emulsion margarine. Other taste masking methods include absorbing eicosapentaenoic acid into carriers such as kaolin, thioyoke, calcium phosphate, calcium sulfate, starch, microcrystalline cellulose, and the like. The resulting powder may remain solid, may be flavored, and optionally may be made into tablets or capsules. Sodium or potassium salts of eicosapentaenoic acid also tend to have an unpleasant taste and it is desirable for tablets containing them to be coated with a film or sugar. Esters or amides of eicosapentaenoic acid can be formulated similarly to acids or salts, depending on whether they are liquids or solids. If desired, oral formulations can be sustained release. For example, they can be beads in capsules or microcapsules. Formulations for intramuscular administration may be in the form of emulsions. Intravenous formulations may be in the form of mixtures that emulsify naturally upon injection. For rectal administration, eicosapentaenoic acid or derivatives may be used in suppositories with a triglyceride base, such as cocoa butter, Witepsol or Suppocire, or in soft gelatin suppository capsules. The formulations are conveniently presented in unit dosage form and may be manufactured by any of the methods well known in the pharmaceutical arts. As used herein and in the claims, "carrier" refers to a carrier suitable for administration to a recipient and containing substantially the active compound, such as the body of a capsule or a coating on a coated tablet. include. Next, the present invention will be explained with examples. (Effect on platelet aggregation) Example 1 Blood is collected from the anterior genus vein of a volunteer who has not taken aspirin in the previous two weeks at a ratio of 1:9 of sodium citrate (0.11M) and blood. Centrifuge at 160g (5 minutes) to separate plasma from blood and use it as platelet-rich plasma (PRP). Arachidonic acid (AA), potassium salt of eicosapentaenoic acid (EPA) (K. Schro¨r, S. Moncada,
FBUbatuba and JRVane, Eur.J.Pharmac.
, 47 103, 1978) and the coagulation device 'Fibromate'(Bie&
Bernsted, Copenhagen, Denmark). Aggregation is recorded in cylindrical cuvettes containing 300 μ of PRP at 37° C. with magnetic stirring at 800 rpm, both nephelometric and turbidimetric. Alternatively, use a Payton 2 channel aggregometer with 500μ PRP. In contrast to AA, EPA does not cause aggregation of human PRP at about 4 times higher concentrations (1.33, 2.66 and 5.3 mM) than AA (0.33, 0.66 and 1.3 mM). Lower concentration ranges of EPA from 0.01 to 0.5mM reduce ADP (2μ
Some inhibition of platelet aggregation by M) was observed. However, the anti-aggregation effect of EPA (0.065mM)
It is not based on conversion by platelet cyclooxygenase. The reason is that this anti-aggregation effect is
It is expressed in aspirin-treated platelets that do not respond to AA (0.065mM) but aggregates with thrombin (0.04-0.4U/ml), and this anti-aggregation effect is also due to the ADP (2-5μ) of aspirin-treated platelets.
This is because it is also expressed in primary aggregation caused by M). Example 2 The inhibitory effect of ADP 1.0 μM on platelet aggregation was investigated in humans. EPA-E
(Ethyl ester) Administration of 1800-2700 mg/day for 16 weeks significantly suppressed the maximum aggregation rate. The results are shown in Table-1. [Table] Example 3 Next, the effect on collagen aggregation was investigated. EPA-E 60mg/Kg/ to healthy Wistar rats
After oral administration for 8 weeks, platelet aggregation was measured. Initial platelet aggregation induced by 8 μg/ml of collagen was 70 ± 12%/min in the control group, while it was 47 ± 21%/min in the EPA-E administration group, indicating significant inhibition of platelet aggregation by EPA-E administration ( t-test, P
<0.05). Example 4 The inhibitory effect of collagen 1.0 μg/ml on platelet aggregation was investigated in humans. Suppression was observed when EPA-E was administered at 1800 mg/day or more. In particular, when administered at 2700 mg/day, a stronger inhibitory effect on platelet aggregation was observed 4 weeks after administration. The results are shown in Table 2 below. [Table] (Effect on blood vessel walls) Example 5 Vascular tissues (thoracic and abdominal aortas) were obtained from freshly killed rats. Approximately 100 mg of tissue was minced and washed once in ice-cold Tris buffer (0.05M, PH7.5). After testing the ability to inhibit platelet aggregation by thrombin when added to the cube, the tissue was washed several times in 10 ml of ice-cold Tris buffer to remove blood and adherent platelets. The tissue was then snap-frozen to -60°C, ground to a coarse powder, and resuspended in 5 volumes of Tris buffer.
This vascular tissue suspension was kept on ice during the experiment and used for the experiment. Aspirin (1.5g/3 days before blood sampling)
Blood was collected from the anterior vein of the human being administered with the drug. Washed human platelets were prepared by BBV Argaftig, Y.
Tranier, and M. Chignard. (Prostaglandins,
8 , 133, 1974). The agglutination test was performed as in Example 1. In order to see whether a suspension of vascular tissue can synthesize a substance that has an anti-aggregation effect on human platelets, platelets were obtained from subjects who had taken aspirin using the method described above. Taking aspirin would prevent those platelets from producing prostaglandin endoperoxide, which would be used by vascular tissue to produce anti-aggregation substances. Additionally, vascular tissue is present in the plasma
Washed platelets were used to avoid the possibility of using AA. Under these conditions, anti-aggregation activity should be able to be produced by vascular tissues only from internally or externally added precursors. Initial suspension of the above vascular tissue (10−50μ)
inhibited aggregation by thrombin (0.40-0.4 U/ml). This inhibitory activity is due to centrifugation (Eppendorff
Centrifuge for 30 seconds), discard the supernatant, and resuspend the tissue in fresh buffer (0.5 ml) in duplicate (5-20 seconds).
Disappeared by washing (times). ADP(2-5μ
The inhibitory effect on primary aggregation by M) or the inhibitory effect on aggregation by thrombin (0.04-0.4 U/ml) is generally reversed by the addition of washed vascular tissue and EPA to washed platelets from aspirin-treated subjects. did. The generation of anti-aggregation activity is
The washed vascular tissue was treated with indomethacin (5-10 μg/
This could be prevented by pretreatment with ml). Therefore,
It is thought that EPA was injected by cyclooxygenase in the blood vessel wall and the anti-aggregation activity was generated. The anti-aggregation activity generated appears to be due to the replacement of endogenous AA by EPA and is not considered to be a direct effect of EPA. However, the same concentration of DHLA incubated with washed vascular tissue did not produce anti-aggregation. (Effect on bleeding time) Example 6 Aspirin (10 or 100 mg/Kg, intravenous injection) was administered to a male New Zealand rabbit (2-2.5 kg).
The control group received only the liquid solvent used to dissolve aspirin. After 2-4 hours, the animals were anesthetized with phenobarbitone and injected with EPA (potassium salt, 95% purity) at various rates (1, 50, 200 or 400 μg/Kg/
Bleeding time was measured before and during injection through the auricular vein (min). Measurements were performed twice or three times under each condition. The results are shown in Table 3 below.
Small doses of aspirin (10 mg/Kg) slightly but significantly prolonged bleeding time. 3 of 5 rabbits each
The average value of multiple measurements is 489 ± 27 seconds (mean ± standard error)
In the control group, the time was 278±48 seconds. In animals given high doses of aspirin (100 mg/Kg), the time was 288 ± 11 seconds, which was not a significant change compared to the control group. In the group not receiving aspirin, EPA (1
μg/Kg/min) extended bleeding time more than twice. A further prolongation of the bleeding time was observed with faster injection rates, reaching a constant value of approximately 1000 seconds at a rate of 50 μg/Kg/min. In aspirin-treated animals (10 or 100 mg/Kg), EPA did not significantly change bleeding time. [Table] Example 7 The effect of EPA-E on human bleeding time was investigated. For patients with underlying thrombotic or arteriosclerotic diseases, take 2 to 3 soft capsules containing 300 mg of EPA-E three times a day (daily dose of 1800 mg).
(2700 mg) was administered orally for 16 weeks immediately after each meal. Bleeding time is measured using General Diagnostics' Simpleplate.
Measured using Table 4 shows a comparison of the bleeding time between the 1800mg and 2700mg administration groups. Regarding bleeding time, the same degree of prolongation was observed in both the 1800 mg and 2700 mg administration groups at 4, 8 and 16 weeks after administration, and no prolongation of bleeding time was observed due to an increase in the dose. [Table] [Table] (Deaggregation effect of eicosapentaenoic acid in rabbits) Example 8 Rabbits (2-3 kg) were mixed with pentobarbitone sodium
The animals were anesthetized with 30 mg/Kg and treated with heparin (2000 U/Kg). The carotid artery was removed, blood was circulated extracorporeally, and a piece of collagen obtained from the Achilles tendon of another rabbit was perfused using a roller pump. When blood perfused the collagen pieces, the collagen pieces increased in weight for 35 minutes, reaching a maximum weight increase of 180 to 200 mg.
The subsequent weight loss is due to platelet disaggregation. Eicosapentaenoic acid (50 μg/Kg/min) injected intravenously into five rabbits had a deagglomerating effect (approximately 20 mg). On the other hand, no disaggregation effect was observed with aspirin administration. Reference examples Eicosapentaenoic acid (EPA) and eicosapentaenoic acid ethyl ester (EPA-E)
Acute toxicity test on ICR mice (6 weeks old, male weight 27-30 g, female weight 20 g)
The acute toxicity of EPA and EPA-E was investigated using groups of 5 male and 5 female Wistar rats (6 weeks old, weight: 131-145 g for males, 96-113 g for females). The dosage of EPA and EPA-E is 20g/
Kg, and a single dose was administered orally, which is the clinical route of administration. The animals were observed for 14 days after administration, and the LD ₅₀ value (50% lethal dose) was determined from the cumulative mortality rate during this period. Even when 20g/Kg of EPA-E was administered orally, no mortality was observed in male and female mice and rats, and EPA-E
The _LD50 value of E is 20g/ for both mice and rats.
It was estimated to be over Kg (Table 5). Even when 20g/Kg of EPA was administered orally, no deaths were observed in male and female mice, and the effects of EPA on mice were
The _LD50 value was estimated to be 20g/Kg or more (Table 5).
On the other hand, in rats, oral administration of EPA at 20 g/Kg resulted in death in 4 out of 5 males and all 5 females, so oral administration of 10 g/Kg was added. 10g/Kg
No deaths were observed in either sexes during treatment, and EPA
The LD ₅₀ value in rats was estimated to be 10 g/Kg or more (Table 5). [Table] (Formulation Preparation) Example 9 A soft gelatin capsule (approximately 0.5 ml volume) was sterilized, and 90% or more of EPA and approximately 2% of AA were added.
It was filled with a composition of about 2% DHLA and the balance palmitic acid and oleic acid and then sealed. The capsules used may be transparent or colored. A harder gelatin type may also be used, or polymethyl methacrylate, for example, may be used. Example 10 A tablet formulation containing the following ingredients was prepared. Sodium eicosapentaenoate 281 mg Starch powder 62 mg Lactose 250 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate 3.5 mg Butylated hydroxytoluene 2 ppm Total amount 600 mg Tablets were coated with sugar. However, other coatings may also be used. Example 11 600 mg of the formulation described in Example 10 in the form of an untabletted powder
can fill hard gelatin capsules. Examples of embodiments of the present invention will be given below based on the above embodiments. (1) A formulation as claimed, wherein at least 90% by weight of the fatty acid content of the formulation is provided by (all-z)-5,8,11,14,17-eicosapentaenoic acid or a derivative thereof. (2) Approximately 5% arachidonic acid in fatty acids, approximately 2
% dihomo-gamma-linolenic acid, the remainder palmitic acid and oleic acid and other pharmaceutically acceptable fatty acids or derivatives thereof. (3) Provided that the formulation does not substantially contain vitamin A or D, (all-z) -5, 8, 11, 14,
A formulation containing 17-eicosapentaenoic acid or a pharmaceutically acceptable salt, ester or amide thereof and a pharmaceutically acceptable carrier. (4) The claimed formulation, wherein eicosapentaenoic acid is present in the form of a sodium or potassium salt. (5) A claimed formulation present as eicosapentaenoic acid ethyl ester. (6) Claimed formulations using eicosapentaenoic acid itself. (7) Claimed formulations containing antioxidants. (8) Claimed formulations containing flavoring agents. (9) The claimed formulation, wherein the carrier is a solid. (10) The claimed formulations, wherein the carrier is a liquid. (11) The claimed formulation, wherein the formulation is a capsule. (12) A claimed formulation in the form of a tablet.

Claims (1)

[Claims] 1. A formulation for the treatment or prevention of thromboembolic diseases, wherein at least 50% by weight of the fatty acid content of the formulation is (all-z)-5, 8, 11, 14, 17-
(all-z)-5, 8, 11, 14, as provided by eicosapentaenoic acid or its derivatives.
17-eicosapentaenoic acid or a pharmaceutically acceptable salt, ester or amide thereof;
and a pharmaceutically acceptable carrier.