EP2925311A1 - Use of a dha ester for prophylactic and/or curative treatment of drepanocytosis - Google Patents

Use of a dha ester for prophylactic and/or curative treatment of drepanocytosis

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Publication number
EP2925311A1
EP2925311A1 EP13795784.1A EP13795784A EP2925311A1 EP 2925311 A1 EP2925311 A1 EP 2925311A1 EP 13795784 A EP13795784 A EP 13795784A EP 2925311 A1 EP2925311 A1 EP 2925311A1
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EP
European Patent Office
Prior art keywords
dha
sickle cell
acid
cell disease
red blood
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP13795784.1A
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German (de)
French (fr)
Inventor
Jean- Paul CAUBERE
Frédérique LANTOINE-ADAM
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Pierre Fabre Medicament SA
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Pierre Fabre Medicament SA
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Publication date
Application filed by Pierre Fabre Medicament SA filed Critical Pierre Fabre Medicament SA
Publication of EP2925311A1 publication Critical patent/EP2925311A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to the use of a DHA ester as a prophylactic and / or curative treatment in sickle cell disease.
  • Sickle cell disease also known as hemoglobin S or sickle cell anemia is a genetic disorder of hemoglobin, the protein that carries oxygen through the blood.
  • Sickle cell disease is not a very rare disease. It is particularly common in populations of sub-Saharan African origin, the West Indies, India, the Middle East and the Mediterranean basin, particularly in Greece and Italy. It is estimated that more than 100 million people are affected worldwide. It is the first genetic disease in France, and probably in the world.
  • Sickle cell disease is due to an abnormality of hemoglobin, the main constituent of the red blood cell also called erythrocyte. These are flattened disks, with a finer center than the edges. Their so-called biconcave shape is characteristic, it gives them a very great flexibility, essential to pass into the finest blood capillaries.
  • the erythrocyte membrane consists of a lipid bilayer whose central part between the outer and inner surfaces is hydrophobic and contains fatty acids. The adhesion, aggregation and deformability of blood cells is greatly impacted by the fatty acid content of their membrane.
  • Hemoglobin consists of four chains assembled together. Hemoglobin A, predominant in adults, consists of two so-called alpha chains and two so-called beta chains. In case of sickle cell disease, beta chains are abnormal. Hemoglobin formed from abnormal beta chains and normal alpha chains is a hemoglobin that "agglomerates" in red blood cells; it is called hemoglobin S, an abbreviation for sickle, which means sickle.
  • a red blood cell normally has the shape of a disk which each face is a little hollow. In case of sickle cell disease, the agglomeration of hemoglobin S causes the red blood cells to take the form of a sickle or a crescent, especially when the amount of oxygen is lower.
  • beta chain of hemoglobin depends on two genes, the "beta-globin" genes located on chromosome 11. At the molecular level, beta chains are abnormal because of a 6-position glutamic acid replaced by a valine.
  • Hemoglobin S is distinguished from normal hemoglobin A by its slower electrophoretic mobility, but especially by the insolubility of its deoxygenated form, which crystallizes easily. Hemoglobin S is now the most common genetic abnormality in France. Heterozygous (A / S) forms, usually silent, should be distinguished from homozygous (S / S) or heterozygous composite forms (essentially S / C, S / beta thalassemia, S / D-Punjab, S / O-Arab) that are responsible for major sickle cell syndromes, which are always clinically and hematologically serious.
  • the severity of sickle cell disease varies greatly between people and over time for the same person. The condition is noted in the infant, but is usually not manifest at birth because red blood cells of the newborn still contain 50-90% fetal hemoglobin. The symptoms of this disease can appear from the age of two to three months, date of appearance of the beta chain. The three main manifestations are anemia, vaso-occlusive attacks and less resistance to certain infections.
  • Anemia refers to a lack of hemoglobin and results in excessive fatigue and a feeling of weakness.
  • the red blood cells which are constantly renewed, are produced in the center of the bones, in the red bone marrow. From there, they pass into the general circulation where normally they remain 120 days in the bloodstream and are then destroyed in the spleen.
  • sickle cell disease as the sickle-shaped red blood cells are abnormally fragile, they are easily destroyed which causes anemia.
  • the severity of the anemia varies over time, it can worsen brutally in case of excessive operation of the spleen, it is called splenic sequestration.
  • abnormal red blood cells are quickly eliminated by the body, and more specifically by the spleen.
  • Sickle red blood cells are considered abnormal by the spleen that captures them (or sequesters) and then eliminates them, which increases anemia.
  • the vaso-occlusive crises or painful crises are manifested by sharp and brutal pains.
  • the sickle-shaped red blood cells block circulation in the blood vessels, which prevents the optimal distribution of oxygen in the body. This process can occur in different parts of the body (bone, abdomen, kidney, brain, retina ). These crises can be very painful. These pains are the most common manifestations of the disease, they can be sudden and transient or chronic. They are favored by dehydration, cold, stress, altitude ... All parts of the body may be involved, but osteo-articular involvement is very common. In the long term, bone infarctions can occur causing problems in the joints. Ocular involvement is also common, intraocular hemorrhages can occur. They limit the field of vision more or less completely.
  • Infections are one of the most common complications of sickle cell disease. They can occur throughout the life of sickle cell disease and can put life at risk, especially in infants and young children. Bacterial infection is susceptible to rapid spread and severe localization such as meningitis or osteomyelitis. Pneumococcus and salmonella are the most common bacteria. This increased susceptibility to infections is due to the fact that the spleen, which plays an important role in the defense process against bacteria, is almost always damaged in patients.
  • anemia evolves by relapses, or "haemolytic seizures," which are promoted or triggered by infections. Painful vaso-occlusive attacks occur at varying intervals, more or less markedly. The evolution is even better than the access and the quality of the care are good.
  • nonsteroidal anti-inflammatory drugs paracetamol, codeine, tramadol, buprenorphine, nalbuphine, orphan, fentanyl, hydromorphone, oxycodone.
  • Oxygen therapy is often established during hospitalization, it consists of daily inhalation of oxygen enriched air to increase oxygenation of the organs and thus relieve pain.
  • a drug treatment can be proposed to patients with severe sickle cell disease, it is hydroxyurea (or hydroxycarbamide), a product used in leukemias.
  • This molecule acts on ribonucleotide reductase. It is the key enzyme in the transformation of the four ribonucleotides into deoxyribonucleotides essential for DNA synthesis.
  • This molecule is able to increase in the adult the production of a hemoglobin normally present in the fetus and in a small quantity at birth (hemoglobin F). The forced production of this fetal hemoglobin F makes it possible to reduce the agglomeration of hemoglobin S.
  • this molecule does not act on pulmonary or bone infections nor does it protect secondary bone lesions.
  • hydroxyurea is not devoid of undesirable effects, such as an influence on male fertility.
  • bone marrow transplant healthy bone marrow will make healthy erythrocytes. This procedure is, however, reserved for only a very small part of the patients. It is an operation that requires extremely heavy treatment and can lead to serious life-threatening complications.
  • the polyunsaturated fatty acids of the Omega 3 series in particular docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), advantageously purified and concentrated in the form of ethyl ester are known for their potential use in the treatment of certain cardiovascular diseases and the modulation of the corresponding risk factors. In particular, they are known in the treatment of hyperlipidemia, hypercholesterolemia and arterial hypertension. Clinical trials conducted with formulations containing a high concentration of DHA ethyl ester in patients who had suffered from myocardial infarction have been shown to be effective in reducing mortality and in particular sudden death.
  • DHA docosahexaenoic acid
  • EPA eicosapentaenoic acid
  • DHA which plays a preponderant role in this pathology.
  • An intake of DHA could increase the erythrocyte rate in DHA in people with sickle cell disease and therefore reduce the damage of these red blood cells, these cells being the real hub of sickle cell disease but also the alteration of other cells involved in the physiopathology of the sickle cell disease such as endothelial cells, platelets, mononuclear cells.
  • Vitamins or provitamins of group B have the advantages related to their function.
  • nicotinol is the alcohol derived from nicotinic acid (vitamin B3). It is rapidly converted to nicotinic acid in the human body.
  • Nicotinic acid also known as niacin, is a group B water soluble vitamin that can be synthesized from tryptophan. Vitamin B3 plays an important role in the release of energy from food but also in the reduction of cholesterol.
  • the effective therapeutic doses for hypocholesterolemic and hypolipidemic purposes are greater than the quantities synthesized by the body and oral supplementation is necessary in a hypocholesterolemic and / or hypotriglyceridemic aiming.
  • vitamin B3 intake Deficiencies of vitamin B3 intake still exist in some countries in Asia and Africa, ie in areas where sickle cell disease is highly prevalent. Vitamin B3 deficiency leading to general fatigue, vitamin B3 intake could be a real benefit for people anemic and therefore getting tired already faster.
  • Panthenol is the alcohol derived from pantothenic acid, better known as vitamin B5. In the body, panthenol is converted into pantothenic acid which then becomes an important part of the compound "coenzyme A", which is particularly interesting in cell metabolism. Indeed, it takes part in the metabolism of lipids, carbohydrates and proteins. Panthenol also participates in the formation of acetylcholine and adrenal steroids. It is also involved in the detoxification of foreign bodies and in the resistance to infections which is particularly interesting in people with sickle cell disease.
  • Inositol or vitamin B7 mobilizes fats avoiding their accumulation. It also has an anxiolytic effect. It tones the nervous system and the liver. It also reduces the level of cholesterol in the blood. She is involved in the enhancement of serotonin activity, control of intracellular calcium concentration, maintenance of cell membrane potential and cytoskeletal assembly. Inositol deficiency can lead to muscle pain and eye diseases. Consequently, an intake of inositol can only be favorable for sickle cell disease.
  • Isosorbide in particular isosorbide mononitrate, is a potent peripheral vasodilator. It also has diuretic properties relieving the work of the kidneys, this organ being a preferred target during vaso-occlusive crises, an intake of isosorbide can also be beneficial in sickle cell patients.
  • vitamins B3 and B5 are involved in the production of red blood cells.
  • the provision of one or other of these vitamins in people with sickle cell disease therefore makes them the preferred alcohols of this invention.
  • the subject of the present invention is therefore an ester of docosahexaenoic acid with an alcohol chosen from the group consisting of:
  • the DHA ester with an alcohol selected from the group consisting of nicotinol, panthenol, inositol, isosorbide or isosorbide mononitrate is used as a medicament for preventing and / or relieve vaso-occlusive seizures in a patient with sickle cell disease.
  • the DHA ester with an alcohol selected from the group consisting of nicotinol, panthenol, inositol, isosorbide or isosorbide mononitrate is used as a medicament for prevent and / or treat anemia in a patient with sickle cell disease.
  • sickle cell disease is understood to mean all the genetic forms of sickle cell disease, homozygous or heterozygous sickle cell disease.
  • prophylactic treatment is understood to mean treatment intended to prevent the onset or spread of the disease.
  • Curative treatment is a treatment that is intended to cure, minimize or relieve symptoms.
  • enantiomers is intended to denote optical isomeric compounds which have identical molecular formulas but which differ in their spatial configuration and which are non-superimposable mirror images.
  • diastereoisomers means optical isomers which are not images in a mirror of each other.
  • a “racemic mixture” is a mixture in equal proportions of the levorotatory and dextrorotatory enantiomers of a chiral molecule.
  • the term "pharmaceutically acceptable” or “pharmaceutically acceptable” is intended to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary as well as human pharmaceutical use.
  • salts of a compound is intended to mean salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydoxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, acid methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzo
  • the salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; either coordinates with an organic or inorganic base.
  • a metal ion for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; either coordinates with an organic or inorganic base.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • Preferred pharmaceutically acceptable salts are salts formed from hydrochloric acid, trifluoroacetic acid, dibenzoyl-L-tartaric acid and phosphoric acid.
  • references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same acid addition salt.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the DHA ester with an alcohol selected from the group consisting of nicotinol, panthenol, inositol, isosorbide or isosorbide mononitrate, and at least one pharmaceutically acceptable excipient for use as a medicament for the prophylactic and / or curative treatment of sickle cell disease.
  • the pharmaceutical composition according to the present invention can be used as a medicament for preventing and / or alleviating vaso-occlusive attacks in a patient with sickle cell disease.
  • the pharmaceutical composition according to the present invention can be used as a medicament for preventing and / or treating anemia in a patient with sickle cell disease.
  • composition according to the present invention can be administered orally or any other pharmaceutical route of administration.
  • compositions according to the present invention can be formulated for administration to mammals, including humans. These compositions are made so that they can be administered orally, sublingually, subcutaneously, intramuscularly, intravenously, transdermally, locally or rectally.
  • the active ingredient can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals or humans.
  • Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, subcutaneous forms of administration , topical, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.
  • the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, silica or the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, silica or the like.
  • the tablets can be coated sucrose or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and that they continuously release a predetermined quantity of active ingredient.
  • a capsule preparation is obtained by mixing the active ingredient with a diluent (optional step) and pouring the resulting mixture into soft or hard gelatin capsules.
  • a syrup or elixir preparation may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable colorant.
  • Water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, as well as with taste correctors or sweeteners.
  • suppositories are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.
  • aqueous suspensions for parenteral (intravenous, intramuscular, etc.), intranasal, or intraocular administration, aqueous suspensions, isotonic saline solutions, or sterile and injectable solutions containing dispersing agents and / or pharmacologically compatible wetting agents are used.
  • the active ingredient may also be formulated as microcapsules, optionally with one or more additive carriers.
  • the pharmaceutical composition according to the present invention is intended for oral or intravenous administration, more advantageously orally.
  • Dosages of pharmaceutical compositions containing a DHA ester with an alcohol selected from the group consisting of nicotinol, panthenol, inositol, isosorbide or isosorbide mononitrate in the compositions of the invention are adjusted to obtain an amount of active substance that is effective in achieving the desired therapeutic response for a particular composition in the method of administration.
  • the chosen level of dosage therefore depends on the desired therapeutic effect, the route of administration chosen, the desired duration of treatment, the weight, age and sex of the patient, the sensitivity of the individual to be treated . Consequently, the optimal dosage should be determined according to the parameters deemed relevant by the specialist in the field.
  • the DHA ester is administered in acceptable pharmaceutical compositions in which the daily dose is between 250 mg and 10 g per day, more preferably the daily dose is between 1 and 6 g per day, for example 1 g, 2 g or 4 g / day. It may be necessary to use larger doses (called loading dose) at the beginning of prophylactic and / or curative treatment and then reduce the doses (maintenance dose) during treatment.
  • loading dose larger doses
  • maintenance dose maintenance dose
  • the pharmaceutical composition according to the present invention may further comprise at least one other active ingredient, such as an analgesic and / or hydroxyurea leading to a complementary or possibly synergistic effect.
  • at least one other active ingredient such as an analgesic and / or hydroxyurea leading to a complementary or possibly synergistic effect.
  • Example 1 Effect of nicotinol DHA on the fatty acid composition of plasma and red blood cells of dogs treated orally.
  • the purpose of this first study is to measure the total DHA in the blood (plasma and red blood cells) of dogs receiving oral nicotinol DHA.
  • Group 2 nicotinol of DHA at 2g per day.
  • All animals receive orally for 28 days, either a placebo or nicotinol DHA at 2g per day.
  • the Blood samples are taken at (control), D7, D14, D21 and D28.
  • the total lipids of plasma (500 L) and red blood cells ("500 mg, weighing red blood cells is more accurate than measuring a volume) are extracted with 4 mL of a mixture of hexane and isopropanol (2/1, v / v), in acid medium (3M HCl, 500 L) in the presence of margaric acid as internal standard (100 ⁇ g). After stirring and centrifugation (2000g, 15 minutes, 10 ° C) the organic phase is separated. A second extraction with 2 ml of the same solvent is carried out under the same conditions. The organic phases are washed with 2 mL of salt water (NaCl 9 ° a). The solvents are evaporated under a stream of nitrogen at 40 ° C.
  • the total lipids from the plasma and the red blood cells are then saponified (1 mL of 0.5M NaOH in methanol, 70 ° C., 30 minutes) and then converted into methyl esters (1 mL, 14% BF 3 in methanol, 70% strength). ° C, 15 minutes). After hydrolysis (4 mL NaCl 9 °) they are extracted with 4 then 2 mL of pentane. The organic phases are washed with 2 mL of salt water (9Cl NaCl). The solvents are evaporated under a stream of nitrogen at 40 ° C. The methyl esters are taken up in 200 L of hexane for plasma and red blood cells. The extracted fatty acid methyl esters are analyzed by gas chromatography.
  • the chromatograph (Agilent Technologies 6890N) is equipped with a split injector heated to 260 ° C (1:10 division), a capillary column (60 m length, 0.25 mm diameter) with a stationary phase BPX70 (70% cyanopropylpolyphenylene siloxane, thickness 0.25 ⁇ ) and a flame ionization detector heated to 260 ° C (hydrogen: 40 mL / min, air: 450 mL / min).
  • the carrier gas is helium (constant flow rate 1.5 mL / min).
  • the temperature of the column is initially 150 ° C. and then rises according to a temperature gradient of 1.3 ° C./min up to 220 ° C.
  • Table 1 Evolution of the plasma DHA level during treatment with nicotinol DHA at 2 g / day.
  • DHA levels are expressed in g / mL, Avg: mean value; SD: standard deviation; G 1: group 1; G2: group 2. The differences between the 2 groups are statistically significant regardless of the treatment time.
  • Plasma DHA levels are equivalent between the 2 groups at the beginning of the experiment. In contrast, throughout the course of treatment, the plasma DHA content is higher in the "nicotinol DHA" group compared to the control group.
  • Table 2 shows DHA levels of red blood cells.
  • Table 2 Evolution of red blood cell DHA during treatment with nicotinol DHA at 2 g / day.
  • DHA levels of red blood cells are equivalent between the 2 groups at the beginning of the experiment. In contrast, throughout the course of treatment, the DHA content of red blood cells is higher in the "nicotinol DHA" group compared to the control group.
  • nicotinol DHA induces an increase in plasma DHA but above all induces a rise in the red blood cell DHA level.
  • Example 2 incorporation of plasma DHA and into the red blood cells of rats receiving orally panthenol DHA.
  • the purpose of this study is to measure the total DHA in the blood (plasma and red blood cells) of rats receiving panthenol DHA by oral gavage for 7 days.
  • Group 1 vehicle group (olive oil)
  • Group 2 panthenol DHA at 300 mg / kg daily.
  • Group 3 Panthenol DHA at 1000 mg / kg per day.
  • the total lipids of the plasma (500 L) and red blood cells are extracted with a mixture of hexane and isopropanol (3/2, v / v), in acidic medium (3M HCl, 1 mL) in the presence of acid. margaric as internal standard.
  • the total lipids from the plasma and the red blood cells are then saponified (1 mL of 0.5M NaOH in methanol, 70 ° C., 30 minutes) and then converted into methyl esters (1 mL, 14% BF 3 in methanol, 70% strength). ° C, 15 minutes).
  • the fatty acid methyl esters are extracted with pentane and analyzed by gas chromatography.
  • the chromatograph (Agilent Technologies 6890N) is equipped with an injector with split heated to 250 ° C (split at 1:10), a capillary column (length 60 m, diameter 0.25 mm) with a stationary phase BPX70 (70% cyanopropylpolyphenylene siloxane, thickness 0.25 ⁇ ).
  • the carrier gas is helium.
  • the temperature of the column is initially 150 ° C. and then rises according to a temperature gradient of 1.3 ° C./min up to 220 ° C. and then remains at 220 ° C. for 10 minutes.
  • the retention times of standard methyl esters make it possible to identify the methyl esters of extracted fatty acids.
  • DHA is quantified relative to the internal standard (C17: 0) added in known quantity to the sample before extraction of total lipids. It is expressed in g / mL for plasma, in g / g for red blood cells. Values are presented as mean ⁇ standard deviation.
  • Figure 1 represents the plasma levels of DHA (top panels) in male rats (left panels) and in female animals (right panels) as well as DHA levels in red blood cells (bottom panels), in the control group (G1), in rats receiving DHA panthenol at 300 mg / kg / day (G2) and in rats receiving 1000 mg / kg / day of DHA panthenol (G3).
  • the amount of DHA found in red blood cells and in the plasma depends on the dose of panthenol of DHA that the animals received.
  • the amount of DHA found in red blood cells and plasma is increased only with the highest dose of panthenol DHA.
  • panthenol of DHA makes it possible to release DHA at the plasma level but, above all, to incorporate DHA into the red blood cells in the rat.
  • Example 3 Concentration of DHA in human red blood cells after absorption of panthenol DHA.
  • the objective of this clinical study was to determine the total DHA levels in red blood cells in volunteers receiving orally once daily panthenol DHA for 28 days.
  • Three doses of panthenol of DHA were tested in this study, 1, 2 and 4 g / day. Twelve subjects were included in this study, 3 subjects received placebo (without panthenol DHA) and 9 received panthenol DHA.
  • Blood samples were taken prior to administration of panthenol DHA (baseline level) and on days 4, 7, 10, 14, 15, 19, 22, 25 and 29 to determine DHA levels in the blood.
  • red blood cells Two blood samples of 4 ⁇ L each were made in tubes containing EDTA. The tubes are centrifuged at 3000 g for 15 minutes at room temperature within 30 minutes after the sampling. The red blood cells were stored at 4 ° C and sent under refrigerated conditions (2 ° C to 8 ° C) in the laboratory that performed the analyzes.
  • the lipids were extracted from the red blood cell samples ( ⁇ 500 mg) with a mixture of hexane / isopropanol (3/2 v / v) in an acid medium in the presence of margaric acid as internal standard (100 ⁇ g). .
  • Total lipid extracts are saponified and converted to methyl esters.
  • the methyl esters of extracted fatty acids are analyzed by gas chromatography.
  • the chromatograph (Agilent Technologies 6890N) is equipped with a split injector heated to 250 ° C, a capillary column (length 60 m, diameter 0.25 mm).
  • the carrier gas is helium (constant flow rate 1.5 mL / min).
  • the temperature of the column is initially 150 ° C.
  • the flame ionization detector is heated to 250 ° C (hydrogen: 40 mL / min, air: 450 mL / min).
  • the retention times of standard methyl esters make it possible to identify the methyl esters of extracted fatty acids.
  • DHA is quantified relative to the internal standard (C17: 0) added in known quantity to the sample before extraction of the total lipids. Values are presented as mean ⁇ standard deviation.
  • FIG. 2 shows the DHA level at the end of the study, calculated as a percentage of fatty acid in human red blood cells according to the doses of panthenol of DHA administered. Regardless of the dose of panthenol DHA administered, the level of DHA in red blood cells is increased compared to the placebo group. At 28 days of treatment, a dose-dependent effect is demonstrated, the maximum effect seems to be reached from 2 g / day even if the variability is lower with a dose of 4 g / day.

Abstract

The present invention relates to a docosahexaenoic acid ester including an alcohol selected from among the group made up of nicotinol, panthenol, inositol, isosorbide, and isosorbide mononitrate, or one of the pharmaceutically acceptable salts, enantiomers, diastereoisomers, or mixtures thereof, including racemic mixtures, for the use thereof as a drug for the prophylactic and/or curative treatment of drepanocytosis.

Description

UTILISATION D'UN ESTER DE DHA POUR LE TRAITEMENT PROPHYLACTIQUE ET/OU CURATIF DE LA DREPANOCYTOSE  USE OF A DHA ESTER FOR THE PROPHYLACTIC AND / OR CURATIVE TREATMENT OF DREPANOCYTOSIS
La présente invention concerne l'utilisation d'un ester de DHA en tant que traitement prophylactique et/ou curatif dans la drépanocytose . The present invention relates to the use of a DHA ester as a prophylactic and / or curative treatment in sickle cell disease.
La drépanocytose également appelée hémoglobinose S ou anémie à cellules falciformes est une maladie génétique de l'hémoglobine, la protéine assurant le transport de l'oxygène dans le sang. La drépanocytose n'est pas une maladie très rare. Elle est particulièrement fréquente dans les populations d'origine africaine subsaharienne, des Antilles, d'Inde, du Moyen-Orient et du bassin méditerranéen particulièrement en Grèce et en Italie. Il est estimé que plus de 100 millions d'individus en sont atteints dans le monde. C'est la première maladie génétique en France, et probablement dans le monde.  Sickle cell disease also known as hemoglobin S or sickle cell anemia is a genetic disorder of hemoglobin, the protein that carries oxygen through the blood. Sickle cell disease is not a very rare disease. It is particularly common in populations of sub-Saharan African origin, the West Indies, India, the Middle East and the Mediterranean basin, particularly in Greece and Italy. It is estimated that more than 100 million people are affected worldwide. It is the first genetic disease in France, and probably in the world.
La drépanocytose est due à une anomalie de l'hémoglobine, constituant principal du globule rouge appelé aussi érythrocyte. Ces derniers sont des disques aplatis, avec un centre plus fin que les bords. Leur forme dite biconcave est caractéristique, elle leur confère une très grande souplesse, indispensable pour passer dans les capillaires sanguins les plus fins. La membrane érythrocytaire est constituée d'une bicouche lipidique dont la partie centrale entre les surfaces externe et interne est hydrophobe et contient des acides gras. L'adhésion, l'agrégation et la déformabilité des cellules sanguines est très impactée par la teneur en acides gras de leur membrane.  Sickle cell disease is due to an abnormality of hemoglobin, the main constituent of the red blood cell also called erythrocyte. These are flattened disks, with a finer center than the edges. Their so-called biconcave shape is characteristic, it gives them a very great flexibility, essential to pass into the finest blood capillaries. The erythrocyte membrane consists of a lipid bilayer whose central part between the outer and inner surfaces is hydrophobic and contains fatty acids. The adhesion, aggregation and deformability of blood cells is greatly impacted by the fatty acid content of their membrane.
L'hémoglobine est constituée de quatre chaînes assemblées entre elles. L'hémoglobine A, majoritaire chez l'adulte, est ainsi constituée de deux chaînes dites alpha et deux chaînes dites bêta. En cas de drépanocytose, les chaînes bêta sont anormales. L'hémoglobine formée à partir des chaînes bêta anormales et des chaînes alpha normales est une hémoglobine qui « s'agglomère » dans les globules rouges, on parle d'hémoglobine S, abréviation pour le mot anglais « sickle » qui signifie faucille. Un globule rouge a normalement la forme d'un disque dont chaque face est un peu creuse. En cas de drépanocytose, l'agglomération de l'hémoglobine S conduit les globules rouges à prendre la forme d'une faucille ou d'un croissant, surtout lorsque la quantité d'oxygène est plus faible. Leur déformation « en faucille » est appelée falciformation et les globules rouges déformés sont qualifiés de « falciformes ». Dans le sang, on trouve une majorité de globules rouges d'aspect normal et des globules rouges falciformes. En plus d'être déformés, les globules rouges falciformes sont plus fragiles et plus rigides que les globules rouges normaux. Ils circulent mal dans les vaisseaux, ce qui les empêche de jouer pleinement leur rôle de transporteur d'oxygène, ils s'hémolysent facilement dans les fins capillaires. La fabrication de la chaîne bêta de l'hémoglobine dépend de deux gènes, les gènes « bêta-globines » localisés sur le chromosome 11. Au niveau moléculaire, les chaînes bêta sont anormales en raison d'un acide glutamique en position 6 remplacé par une valine. Hemoglobin consists of four chains assembled together. Hemoglobin A, predominant in adults, consists of two so-called alpha chains and two so-called beta chains. In case of sickle cell disease, beta chains are abnormal. Hemoglobin formed from abnormal beta chains and normal alpha chains is a hemoglobin that "agglomerates" in red blood cells; it is called hemoglobin S, an abbreviation for sickle, which means sickle. A red blood cell normally has the shape of a disk which each face is a little hollow. In case of sickle cell disease, the agglomeration of hemoglobin S causes the red blood cells to take the form of a sickle or a crescent, especially when the amount of oxygen is lower. Their "sickle" deformation is called sickling and the red deformed red blood cells are called "falciform". In the blood, there is a majority of normal-looking red blood cells and sickle-cell red blood cells. In addition to being deformed, falciform red blood cells are more fragile and more rigid than normal red blood cells. They circulate badly in the vessels, which prevents them from fully playing their role of oxygen carrier, they easily become haemolysed in the fine capillaries. The manufacture of the beta chain of hemoglobin depends on two genes, the "beta-globin" genes located on chromosome 11. At the molecular level, beta chains are abnormal because of a 6-position glutamic acid replaced by a valine.
L'hémoglobine S se distingue de l'hémoglobine A, normale, par sa mobilité électrophorétique plus lente, mais surtout par l'insolubilité de sa forme désoxygénée qui cristallise facilement. L' hémoglobinose S est aujourd'hui la plus fréquente des anomalies génétiques en France. Il faut distinguer les formes hétérozygotes (A/S), habituellement silencieuses, des formes homozygotes (S/S) ou hétérozygotes composites (essentiellement S/C, S/bêta thalassémie, S/D-Punjab, S/O-Arab) qui sont responsables de syndromes drépanocytaires majeurs, toujours graves sur le plan clinique et hématologique.  Hemoglobin S is distinguished from normal hemoglobin A by its slower electrophoretic mobility, but especially by the insolubility of its deoxygenated form, which crystallizes easily. Hemoglobin S is now the most common genetic abnormality in France. Heterozygous (A / S) forms, usually silent, should be distinguished from homozygous (S / S) or heterozygous composite forms (essentially S / C, S / beta thalassemia, S / D-Punjab, S / O-Arab) that are responsible for major sickle cell syndromes, which are always clinically and hematologically serious.
La sévérité de la drépanocytose est très variable selon les personnes et au cours du temps pour une même personne. L'affection se signale chez le nourrisson, mais n'est d'ordinaire pas manifeste à la naissance parce que les globules rouges du nouveau-né contiennent encore 50-90% d'hémoglobine fœtale. Les symptômes de cette maladie peuvent apparaître dès l'âge de deux à trois mois, date d'apparition de la chaîne bêta. Les trois principales manifestations sont l'anémie, les crises vaso-occlusives et une moindre résistance à certaines infections . The severity of sickle cell disease varies greatly between people and over time for the same person. The condition is noted in the infant, but is usually not manifest at birth because red blood cells of the newborn still contain 50-90% fetal hemoglobin. The symptoms of this disease can appear from the age of two to three months, date of appearance of the beta chain. The three main manifestations are anemia, vaso-occlusive attacks and less resistance to certain infections.
L'anémie désigne un manque d'hémoglobine et se traduit par une fatigue excessive et une sensation de faiblesse. Les globules rouges, qui se renouvellent sans cesse, sont produits au centre des os, dans la moelle osseuse rouge. De là, ils passent dans la circulation générale où, normalement ils restent 120 jours dans la circulation sanguine puis sont détruits dans la rate. En cas de drépanocytose, comme les globules rouges en forme de faucille sont anormalement fragiles, ils sont facilement détruits ce qui provoque l'anémie. La sévérité de l'anémie varie au cours du temps, elle peut s'aggraver brutalement en cas de fonctionnement excessif de la rate, on parle de séquestration splénique. En effet les globules rouges anormaux sont rapidement éliminés par l'organisme, et plus spécifiquement par la rate. Les globules rouges falciformes sont considérés comme anormaux par la rate qui les capture (ou séquestre) puis les élimine, ce qui accentue l'anémie.  Anemia refers to a lack of hemoglobin and results in excessive fatigue and a feeling of weakness. The red blood cells, which are constantly renewed, are produced in the center of the bones, in the red bone marrow. From there, they pass into the general circulation where normally they remain 120 days in the bloodstream and are then destroyed in the spleen. In case of sickle cell disease, as the sickle-shaped red blood cells are abnormally fragile, they are easily destroyed which causes anemia. The severity of the anemia varies over time, it can worsen brutally in case of excessive operation of the spleen, it is called splenic sequestration. In fact abnormal red blood cells are quickly eliminated by the body, and more specifically by the spleen. Sickle red blood cells are considered abnormal by the spleen that captures them (or sequesters) and then eliminates them, which increases anemia.
D'autres cellules sont impliquées dans la physiopathologie des crises vaso-oclusives : les cellules endothéliales , les réticulocytes , les polynucléaires neutrophiles , les plaquettes sanguines. Or, les cellules mononuclées et les plaquettes ont une composition anormale en acides gras polyinsaturées chez les patients drépanocytaires .  Other cells are involved in the pathophysiology of vaso-occlusive attacks: endothelial cells, reticulocytes, neutrophils, blood platelets. However, mononuclear cells and platelets have an abnormal composition of polyunsaturated fatty acids in sickle cell patients.
Les crises vaso-occlusives ou les crises douloureuses, se manifestent par des douleurs vives et brutales. Les globules rouges en forme de faucille bloquent la circulation au niveau des vaisseaux sanguins ce qui empêche la distribution optimale de l'oxygène dans l'organisme. Ce processus peut se produire dans différentes parties du corps (os, abdomen, rein, cerveau, rétine ...) . Ces crises peuvent être très douloureuses. Ces douleurs sont les manifestations les plus fréquentes de la maladie, elles peuvent être soudaines et transitoires ou chroniques. Elles sont favorisées par la déshydratation, le froid, le stress, l'altitude... Toutes les parties du corps peuvent être concernées, mais l'atteinte ostéo-articulaire est très fréquente. A terme, des infarctus osseux peuvent survenir entraînant des problèmes au niveau des articulations . Une atteinte oculaire est également fréquente, des hémorragies intraoculaires peuvent survenir. Elles limitent plus ou moins complètement le champ visuel. The vaso-occlusive crises or painful crises, are manifested by sharp and brutal pains. The sickle-shaped red blood cells block circulation in the blood vessels, which prevents the optimal distribution of oxygen in the body. This process can occur in different parts of the body (bone, abdomen, kidney, brain, retina ...). These crises can be very painful. These pains are the most common manifestations of the disease, they can be sudden and transient or chronic. They are favored by dehydration, cold, stress, altitude ... All parts of the body may be involved, but osteo-articular involvement is very common. In the long term, bone infarctions can occur causing problems in the joints. Ocular involvement is also common, intraocular hemorrhages can occur. They limit the field of vision more or less completely.
Les infections représentent une des complications les plus fréquentes de la drépanocytose . Elles peuvent survenir tout au long de la vie du drépanocytaire et peuvent mettre en péril la vie, en particulier chez les nourrissons et les jeunes enfants. L'infection bactérienne est susceptible de diffusion rapide et de localisations graves telles que méningites ou ostéomyélites. Le pneumocoque et les salmonelles sont les bactéries les plus fréquentes. Cette susceptibilité accrue aux infections est due au fait que la rate, qui joue un rôle important dans le processus de défense contre les bactéries, est quasiment toujours endommagée chez les malades.  Infections are one of the most common complications of sickle cell disease. They can occur throughout the life of sickle cell disease and can put life at risk, especially in infants and young children. Bacterial infection is susceptible to rapid spread and severe localization such as meningitis or osteomyelitis. Pneumococcus and salmonella are the most common bacteria. This increased susceptibility to infections is due to the fact that the spleen, which plays an important role in the defense process against bacteria, is almost always damaged in patients.
L'évolution de la maladie est très variable. Généralement, l'anémie évolue par poussées, ou « crises hémolytiques », qui sont favorisées ou déclenchées par des infections. Les crises vaso-occlusives douloureuses surviennent à intervalles variables, de façon plus ou moins marquée. L'évolution est d'autant meilleure que l'accès et la qualité des soins sont bons .  The evolution of the disease is very variable. Generally, anemia evolves by relapses, or "haemolytic seizures," which are promoted or triggered by infections. Painful vaso-occlusive attacks occur at varying intervals, more or less markedly. The evolution is even better than the access and the quality of the care are good.
A ce jour, on ne sait pas guérir la drépanocytose, il est simplement possible de soulager les douleurs en période de crise, de prévenir au mieux les infections graves. Les crises douloureuses constituent la première cause de consultation ou d'hospitalisation. Les analgésiques (peuvent ne pas suffire, généralement les douleurs sont telles que l'on a recours à la morphine ou des dérivés de la morphine (opioïdes) .  To date, we do not know how to cure sickle cell disease, it is simply possible to relieve pain in times of crisis, to best prevent serious infections. Painful crises are the first cause of consultation or hospitalization. Analgesics (may not be enough, usually the pain is such that it is used morphine or derivatives of morphine (opioids).
On peut citer comme analgésiques utilisés dans la drépanocytose, les anti-inflammatoires non stéroïdiens, le paracétamol, la codéine, le tramadol, la buprénorphine, la nalbuphine, l'orphine, le fentanyl, l' hydromorphone, l'oxycodone. Dans certain cas, ces traitements ne suffisent pas toujours à calmer les douleurs. Souvent une oxygénothérapie est mise en place pendant l'hospitalisation, elle consiste en l'inhalation quotidienne d'un air enrichi en oxygène pour augmenter l'oxygénation des organes et donc soulager les douleurs. Il n'existe pas de traitement particulier pour traiter l'anémie. Lorsque cette dernière s'aggrave en raison d'un épisode de séquestration splénique, une transfusion sanguine peut se révéler nécessaire. Un traitement médicamenteux peut être proposé aux malades atteints de drépanocytose sévère, il s'agit de 1 ' hydroxyurée (ou hydroxycarbamide) , un produit utilisé dans les leucémies. Cette molécule agit sur la ribonucléotide réductase. Il s'agit de l'enzyme clé de la transformation des quatre ribonucléotides en désoxyribonucléotides essentiels à la synthèse de l'ADN. Cette molécule est capable d'augmenter chez l'adulte la production d'une hémoglobine présente normalement chez le fœtus et en infime quantité à la naissance (hémoglobine F) . La production forcée de cette hémoglobine F fœtale permet de diminuer l'agglomération de l'hémoglobine S. Cependant cette molécule n'agit pas sur les infections pulmonaires ou osseuses et ne met pas non plus à l'abri des atteintes osseuses secondaires. Par ailleurs, 1 ' hydroxyurée n'est pas dénuée d'effets indésirables, comme par exemple une influence sur la fertilité masculine. Actuellement, il n'y a qu'une seule option pour traiter durablement la maladie, la greffe de moelle osseuse, la moelle saine fabriquera des érythrocytes sains. Cette procédure n'est cependant réservée qu'à une infime partie des malades. C'est une opération qui nécessite un traitement extrêmement lourd et peut entraîner des complications graves potentiellement mortelles. As analgesics used in sickle cell disease, nonsteroidal anti-inflammatory drugs, paracetamol, codeine, tramadol, buprenorphine, nalbuphine, orphan, fentanyl, hydromorphone, oxycodone. In some cases, these treatments are not always enough to calm the pain. Oxygen therapy is often established during hospitalization, it consists of daily inhalation of oxygen enriched air to increase oxygenation of the organs and thus relieve pain. There is no particular treatment for treating anemia. When the latter worsens due to an episode of splenic sequestration, a blood transfusion may be necessary. A drug treatment can be proposed to patients with severe sickle cell disease, it is hydroxyurea (or hydroxycarbamide), a product used in leukemias. This molecule acts on ribonucleotide reductase. It is the key enzyme in the transformation of the four ribonucleotides into deoxyribonucleotides essential for DNA synthesis. This molecule is able to increase in the adult the production of a hemoglobin normally present in the fetus and in a small quantity at birth (hemoglobin F). The forced production of this fetal hemoglobin F makes it possible to reduce the agglomeration of hemoglobin S. However, this molecule does not act on pulmonary or bone infections nor does it protect secondary bone lesions. In addition, hydroxyurea is not devoid of undesirable effects, such as an influence on male fertility. Currently, there is only one option to sustainably treat the disease, bone marrow transplant, healthy bone marrow will make healthy erythrocytes. This procedure is, however, reserved for only a very small part of the patients. It is an operation that requires extremely heavy treatment and can lead to serious life-threatening complications.
Il apparaît donc clairement que les traitements proposés aux personnes atteintes de drépanocytose sont loin d'être suffisants. Il existe un besoin médical important pour de nouveaux médicaments ayant le moins d'effets indésirables possibles puisqu'ils s'adressent à des personnes physiologiquement fragilisées.  It is therefore clear that the treatments offered to people with sickle cell disease are far from sufficient. There is a significant medical need for new drugs with the fewest possible side effects since they are aimed at physiologically weakened individuals.
Les acides gras polyinsaturés de la série des Oméga 3, en particulier l'acide docosahexaénoïque (DHA) et l'acide eicosapentaénoïque (EPA) avantageusement purifiés et concentrés sous forme d'ester éthylique sont connus pour leur potentiel d'utilisation dans le traitement de certaines maladies cardiovasculaires et la modulation des facteurs de risques correspondants. En particulier, ils sont connus dans le traitement de 1 ' hyperlipidémie, de 1 ' hypercholestérolémie et de l'hypertension artérielle. Les essais cliniques conduits avec des formulations contenant une forte concentration en ester éthylique de DHA sur des patients qui avaient souffert d'un infarctus du myocarde ont démontré leur efficacité en réduisant la mortalité et en particulier la mort subite. Ces résultats ont été en partie attribués à un effet de stabilisation des membranes cellulaires des cardiomyocytes ventriculaires , ce qui empêchent l'apparition d'arythmie maligne en présence de myocytes ischémiques chez les patients ayant subi un infarctus ou dans des modèles expérimentaux qui reproduisent de telles conditions. Par ailleurs, de faibles niveaux de DHA ont été associés entre autres à des troubles de l'attention (ADHD) et la dépression et il semblerait que la prise de compléments de DHA soit efficace dans la lutte contre ce type de maladies. De même, un taux élevé de DHA serait corrélé avec un moindre risque de survenue d'une démence. Le DHA jouerait donc un rôle important dans une multitude de pathologies . The polyunsaturated fatty acids of the Omega 3 series, in particular docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), advantageously purified and concentrated in the form of ethyl ester are known for their potential use in the treatment of certain cardiovascular diseases and the modulation of the corresponding risk factors. In particular, they are known in the treatment of hyperlipidemia, hypercholesterolemia and arterial hypertension. Clinical trials conducted with formulations containing a high concentration of DHA ethyl ester in patients who had suffered from myocardial infarction have been shown to be effective in reducing mortality and in particular sudden death. These results were partly attributed to a stabilizing effect of ventricular cardiomyocyte cell membranes, which prevents the occurrence of malignant arrhythmias in the presence of ischemic myocytes in infarcted patients or in experimental models that reproduce such conditions. In addition, low levels of DHA have been associated with attention deficit disorders (ADHD) and depression, among others, and it appears that supplementation with DHA is effective in the fight against this type of disease. Similarly, a high rate of DHA would be correlated with a lower risk of dementia. DHA thus plays an important role in a multitude of pathologies.
Dans le cas de la drépanocytose, 1 ' homéostasie lipidique est modifiée et le DHA érythrocytaire est diminué (Ren et al., Prostaglandins , leukotrienes and essential fatty acid 72 :415- 421, 2005), d'autant plus que la pathologie induit une forte anémie. Plus récemment, Ren et al., 2008 (Int J Vitam Nutr Res, 78(3) :139-147) montre que la teneur en oméga-3 est différente dans sa répartition au sein de la bicouche lipidique des érythrocytes chez les patients drépanocytaires . La cause serait une peroxydation accrue chez ces patients due à une faible capacité anti-oxydante. Une étude clinique réalisée sur 10 patients montrent un intérêt d'un traitement à l'huile de poisson chez des drépanocytaires en réduisant le nombre de crises douloureuses mais sans en expliquer le mécanisme (Tomer et al., Thromb. Haemost. 85(6) :966-974, 2001) . Très récemment dans une étude clinique pilote (16 patients) les auteurs montrent qu'une supplémentation de 6 mois en DHA + EPA (lOmg + 15mg/kg/J) chez les malades drépanocytaires diminue le nombre de crises vaso-occlusives et l'hémolyse (Okpala et al., APMIS, 119 (7) : 442-448, 2011) . In the case of sickle cell disease, lipid homeostasis is modified and erythrocyte DHA is decreased (Ren et al., Prostaglandins, leukotrienes and essential fatty acid 72: 415-421, 2005), especially since the pathology induces a strong anemia. More recently, Ren et al., 2008 (Int J Vitam Nutr Res, 78 (3): 139-147) shows that the omega-3 content is different in its distribution within the lipid bilayer of erythrocytes in sickle cell patients. . The cause would be increased peroxidation in these patients due to low antioxidant capacity. A clinical study carried out on 10 patients shows an interest of a treatment with fish oil in sickle cell patients by reducing the number of painful crises but without explaining the mechanism (Tomer et al., Thromb Haemost 85 (6) 966-974, 2001). Very recently in a pilot clinical study (16 patients) the authors show that a 6-month supplementation with DHA + EPA (10 mg + 15 mg / kg / day) in sickle cell patients decreases the number of vaso-occlusive attacks and hemolysis (Okpala et al., APMIS, 119 (7): 442-448, 2011).
En revanche, les auteurs ne cherchent pas à démontrer si l'activité est principalement portée par l'EPA seul ou le DHA seul, ou si c'est l'association des deux qui est active pharmacologiquement .  In contrast, the authors do not seek to demonstrate whether the activity is predominantly carried by EPA alone or DHA alone, or whether it is the combination of the two that is pharmacologically active.
Une étude menée chez l'homme (Terano et al., Atherosclerosis, 46(3) : 321-331, 1983) a permis de montrer que la prise d'EPA pendant 4 semaines chez 8 volontaires sains entraînait une réduction de la viscosité du sang et une augmentation de la déformabilité des globules rouges. Les auteurs rapportent même une corrélation positive entre le contenu d'EPA dans les membranes des globules rouges et la déformabilité de ces derniers.  A study conducted in humans (Terano et al., Atherosclerosis, 46 (3): 321-331, 1983) has shown that taking EPA for 4 weeks in 8 healthy volunteers resulted in a reduction in the viscosity of the patient. blood and an increase in the deformability of red blood cells. The authors even report a positive correlation between the EPA content in red blood cell membranes and the deformability of red blood cell membranes.
De même, dans une autre étude (Ide et al., Int. J. Mol. Med. 11(6) : 729-732, 2003) menée chez des patients anémiés suite à une hépatite C chronique, les auteurs ont voulu vérifier si un apport en EPA (1800 mg) pendant 2 mois pouvait être bénéfique. Il a ainsi été montré que le niveau moyen d'hémoglobine chez ces patients était significativement augmenté après un mois de traitement chez tous les patients et cette augmentation était due à une réduction de la perte en hématies .  Similarly, in another study (Ide et al., Int.Med., Mol., 11 (6): 729-732, 2003) carried out in anemic patients following chronic hepatitis C, the authors wanted to check whether an intake of EPA (1800 mg) for 2 months could be beneficial. It was thus shown that the average level of hemoglobin in these patients was significantly increased after one month of treatment in all patients and this increase was due to a reduction in the loss of red blood cells.
A la vue de ces études, il semblerait donc qu'un apport en EPA soit responsable de l'activité démontrée chez les patients drépanocytaires .  At the sight of these studies, it would therefore seem that EPA intake is responsible for the activity demonstrated in sickle cell patients.
Or les inventeurs font l'hypothèse inverse et pensent que c'est le DHA qui joue un rôle prépondérant dans cette pathologie. Un apport de DHA pourrait augmenter le taux érythrocytaire en DHA chez les personnes atteintes de drépanocytose et par conséquent diminuer l'altération de ces globules rouges, ces cellules étant la véritable plaque tournante de la drépanocytose mais également l'altération des autres cellules impliquées dans la physiopathologie de la drépanocytose telle que les cellules endothéliales , les plaquettes, les cellules mononuclées. But the inventors make the opposite hypothesis and think that it is the DHA which plays a preponderant role in this pathology. An intake of DHA could increase the erythrocyte rate in DHA in people with sickle cell disease and therefore reduce the damage of these red blood cells, these cells being the real hub of sickle cell disease but also the alteration of other cells involved in the physiopathology of the sickle cell disease such as endothelial cells, platelets, mononuclear cells.
Les vitamines ou provitamines du groupe B ont les avantages liés à leur fonction. En particulier, le nicotinol est l'alcool dérivé de l'acide nicotinique (vitamine B3) . Il est converti rapidement en acide nicotinique dans le corps humain. L'acide nicotinique appelé aussi niacine est une vitamine hydrosoluble du groupe B qui peut être synthétisée à partir du tryptophane . La vitamine B3 joue un rôle important dans la libération d'énergie à partir des aliments mais aussi dans la réduction du cholestérol. Cependant les doses thérapeutiques efficaces à des fins hypocholestérolémiantes et hypolipidémiantes sont supérieures aux quantités synthétisées par l'organisme et une supplémentation orale s'avère nécessaire dans une visée hypocholestérolémiante et/ou hypotriglycéridémiante . Les carences d'apport en vitamine B3 existent encore dans certains pays d'Asie et d'Afrique, c'est à dire dans des régions où la drépanocytose sévit fortement. La carence en vitamine B3 entraînant une fatigue générale, l'apport en vitamine B3 pourrait être un vrai bénéfice chez des personnes anémiées et donc se fatiguant déjà plus vite.  Vitamins or provitamins of group B have the advantages related to their function. In particular, nicotinol is the alcohol derived from nicotinic acid (vitamin B3). It is rapidly converted to nicotinic acid in the human body. Nicotinic acid, also known as niacin, is a group B water soluble vitamin that can be synthesized from tryptophan. Vitamin B3 plays an important role in the release of energy from food but also in the reduction of cholesterol. However, the effective therapeutic doses for hypocholesterolemic and hypolipidemic purposes are greater than the quantities synthesized by the body and oral supplementation is necessary in a hypocholesterolemic and / or hypotriglyceridemic aiming. Deficiencies of vitamin B3 intake still exist in some countries in Asia and Africa, ie in areas where sickle cell disease is highly prevalent. Vitamin B3 deficiency leading to general fatigue, vitamin B3 intake could be a real benefit for people anemic and therefore getting tired already faster.
Le panthénol est l'alcool dérivé de l'acide pantothénique, plus connu sous le nom de vitamine B5. Dans l'organisme, le panthénol se transforme en acide pantothénique qui devient alors une partie importante du composé « coenzyme A », qui est particulièrement intéressant dans le métabolisme cellulaire. En effet, il prend part au métabolisme des lipides, des glucides et des protides. Le panthénol participe également à la formation de 1 ' acétylcholine et des stéroïdes de la surrénale. Il intervient également dans la détoxication des corps étrangers et dans la résistance aux infections ce qui est particulièrement intéressant chez des personnes atteintes de drépanocytose.  Panthenol is the alcohol derived from pantothenic acid, better known as vitamin B5. In the body, panthenol is converted into pantothenic acid which then becomes an important part of the compound "coenzyme A", which is particularly interesting in cell metabolism. Indeed, it takes part in the metabolism of lipids, carbohydrates and proteins. Panthenol also participates in the formation of acetylcholine and adrenal steroids. It is also involved in the detoxification of foreign bodies and in the resistance to infections which is particularly interesting in people with sickle cell disease.
L'inositol ou vitamine B7 mobilise les graisses en évitant leur accumulation. Elle possède également un effet anxiolytique. Elle tonifie le système nerveux et le foie. Elle permet également de diminuer le taux de cholestérol dans le sang. Elle est impliquée dans l'augmentation de l'activité de la sérotonine, le contrôle de la concentration en calcium intracellulaire, le maintien du potentiel membranaire des cellules et l'assemblage du cytosquelette . La carence en inositol peut entraîner des douleurs musculaires et des maladies oculaires. En conséquence un apport en inositol ne peut qu'être favorable aux drépanocytaires . Inositol or vitamin B7 mobilizes fats avoiding their accumulation. It also has an anxiolytic effect. It tones the nervous system and the liver. It also reduces the level of cholesterol in the blood. She is involved in the enhancement of serotonin activity, control of intracellular calcium concentration, maintenance of cell membrane potential and cytoskeletal assembly. Inositol deficiency can lead to muscle pain and eye diseases. Consequently, an intake of inositol can only be favorable for sickle cell disease.
L' isosorbide, en particulier l'isosorbide mononitrate est un puissant vasodilatateur périphérique. Il possède en outre des propriétés diurétiques soulageant le travail des reins, cet organe étant une cible privilégiée lors des crises vaso- occlusives, un apport en isosorbide peut également être bénéfique chez les drépanocytaires.  Isosorbide, in particular isosorbide mononitrate, is a potent peripheral vasodilator. It also has diuretic properties relieving the work of the kidneys, this organ being a preferred target during vaso-occlusive crises, an intake of isosorbide can also be beneficial in sickle cell patients.
Il est important de noter que les vitamines B3 et B5 interviennent dans la production des globules rouges. L'apport de l'une ou l'autre de ces vitamines, chez les personnes atteintes de drépanocytose en fait donc les alcools préférés de cette invention.  It is important to note that vitamins B3 and B5 are involved in the production of red blood cells. The provision of one or other of these vitamins in people with sickle cell disease therefore makes them the preferred alcohols of this invention.
De façon surprenante, les inventeurs ont découvert que l'administration d'un ester de DHA avec un alcool permettait une augmentation importante du taux de DHA au sein même des globules rouges .  Surprisingly, the inventors have discovered that the administration of a DHA ester with an alcohol allows a significant increase in the level of DHA within red blood cells.
La présente invention a donc pour objet un ester de l'acide docosahexaénoïque avec un alcool choisi parmi le groupe constitué par:  The subject of the present invention is therefore an ester of docosahexaenoic acid with an alcohol chosen from the group consisting of:
- le nicotinol de formule suivante : the nicotinol of the following formula:
le panthénol de formule suivante  Panthenol of the following formula
l' inositol de formule suivante the next formula inositol
'isosorbide de formule suivante :  isosorbide of the following formula:
'isosorbide mononitrate de formule suivante :  isosorbide mononitrate of the following formula:
ou l'un de ses sels pharmaceutiquement acceptables, énantiomères , diastéréoisomères, ou leur mélange, y compris les mélanges racémiques, pour son utilisation à titre de médicament pour le traitement prophylactique et/ou curatif de la drépanocytose . or a pharmaceutically acceptable salt thereof, enantiomers, diastereoisomers, or mixtures thereof, including racemic mixtures, for use as a medicament for the prophylactic and / or curative treatment of sickle cell disease.
Avantageusement, l'ester l'invention e docosahexaenoate de panthényle, « ester de DHA panthénol » de formule suivante : Advantageously, the ester of the invention and panthenyl docosahexaenoate, "ester of DHA Panthenol" of the following formula:
pour son utilisation à titre de médicament pour le traitement prophylactique et/ou curatif de la drépanocytose. for use as a medicament for the prophylactic and / or curative treatment of sickle cell disease.
Dans un mode particulier de l'invention, l'ester de DHA avec un alcool choisi parmi le groupe constitué par le nicotinol, le panthénol, l'inositol, l'isosorbide ou l'isosorbide mononitrate est utilisé en tant que médicament destiné à prévenir et/ou à soulager les crises vaso-occlusives chez un patient atteint de drépanocytose . In a particular embodiment of the invention, the DHA ester with an alcohol selected from the group consisting of nicotinol, panthenol, inositol, isosorbide or isosorbide mononitrate is used as a medicament for preventing and / or relieve vaso-occlusive seizures in a patient with sickle cell disease.
Dans un autre mode particulier de l'invention, l'ester de DHA avec un alcool choisi parmi le groupe constitué par le nicotinol, le panthénol, l'inositol, l'isosorbide ou l'isosorbide mononitrate est utilisé en tant que médicament destiné à prévenir et/ou à traiter l'anémie chez un patient atteint de drépanocytose.  In another particular embodiment of the invention, the DHA ester with an alcohol selected from the group consisting of nicotinol, panthenol, inositol, isosorbide or isosorbide mononitrate is used as a medicament for prevent and / or treat anemia in a patient with sickle cell disease.
Dans la présente invention, on entend par drépanocytose, toutes les formes génétiques des maladies drépanocytaires , aussi bien la drépanocytose homozygote qu'hétérozygote composite.  In the present invention, sickle cell disease is understood to mean all the genetic forms of sickle cell disease, homozygous or heterozygous sickle cell disease.
Dans la présente invention, on entend par traitement prophylactique, un traitement ayant pour but de prévenir l'apparition ou la propagation de la maladie. On entend par traitement curatif, un traitement qui a pour but de guérir, de minimiser ou de soulager les symptômes.  In the present invention, prophylactic treatment is understood to mean treatment intended to prevent the onset or spread of the disease. Curative treatment is a treatment that is intended to cure, minimize or relieve symptoms.
Dans la présente invention, on entend désigner par « énantiomères » des composés isomères optiques qui ont des formules moléculaires identiques mais qui diffèrent par leur configuration spatiale et qui sont des images dans un miroir non superposables . On entend par « diastéréoisomères » les isomères optiques qui ne sont pas des images dans un miroir l'un de l'autre. Au sens de la présente invention, un « mélange racémique » est un mélange en proportions égales des énantiomères lévogyre et dextrogyre d'une molécule chirale.  In the present invention, the term "enantiomers" is intended to denote optical isomeric compounds which have identical molecular formulas but which differ in their spatial configuration and which are non-superimposable mirror images. The term "diastereoisomers" means optical isomers which are not images in a mirror of each other. Within the meaning of the present invention, a "racemic mixture" is a mixture in equal proportions of the levorotatory and dextrorotatory enantiomers of a chiral molecule.
Dans la présente invention, on entend désigner par « pharmaceutiquement acceptable » ou « acceptable sur le plan pharmaceutique » ce qui est utile dans la préparation d'une composition pharmaceutique qui est généralement sûre, non toxique et ni biologiquement ni autrement non souhaitable et qui est acceptable pour une utilisation vétérinaire de même que pharmaceutique humaine.  In the present invention, the term "pharmaceutically acceptable" or "pharmaceutically acceptable" is intended to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary as well as human pharmaceutical use.
On entend désigner par « sels pharmaceutiquement acceptables » d'un composé des sels qui sont pharmaceutiquement acceptables, comme défini ici, et qui possèdent l'activité pharmacologique souhaitée du composé parent. De tels sels comprennent : - les sels d'addition d'acide formés avec des acides minéraux tels que l'acide chlorhydrique, l'acide bromhydrique, l'acide sulfurique, l'acide nitrique, l'acide phosphorique et similaires ; ou formés avec des acides organiques tels que l'acide acétique, l'acide benzènesulfonique, l'acide benzoïque, l'acide camphresulfonique, l'acide citrique, l'acide éthane- sulfonique, l'acide fumarique, l'acide glucoheptonique, l'acide gluconique, l'acide glutamique, l'acide glycolique, l'acide hydoxynaphtoïque, l'acide 2-hydroxyéthanesulfonique, l'acide lactique, l'acide maléique, l'acide malique, l'acide mandélique, l'acide méthanesulfonique, l'acide muconique, l'acide 2- naphtalènesulfonique, l'acide propionique, l'acide salicylique, l'acide succinique, l'acide dibenzoyl-L-tartrique, l'acide tartrique, l'acide p-toluènesulfonique, l'acide triméthylacétique , l'acide trifluoroacétique et similaires ; ouThe term "pharmaceutically acceptable salts" of a compound is intended to mean salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydoxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, acid methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulphonic acid, trimethylacetic acid, trifluoroacetic acid and the like; or
- les sels formés lorsqu'un proton acide présent dans le composé parent soit est remplacé par un ion métallique, par exemple un ion de métal alcalin, un ion de métal alcalino-terreux ou un ion d'aluminium ; soit se coordonne avec une base organique ou inorganique. Les bases organiques acceptables comprennent la diéthanolamine, l' éthanolamine, N-méthylglucamine, la triéthanolamine, la trométhamine et similaires. Les bases inorganiques acceptables comprennent l'hydroxyde d'aluminium, l'hydroxyde de calcium, l'hydroxyde de potassium, le carbonate de sodium et l'hydroxyde de sodium. the salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; either coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
Les sels pharmaceutiquement acceptables préférés sont les sels formés à partir d'acide chlorhydrique, d'acide trifluoroacétique, d'acide dibenzoyl-L-tartrique et d'acide phosphorique  Preferred pharmaceutically acceptable salts are salts formed from hydrochloric acid, trifluoroacetic acid, dibenzoyl-L-tartaric acid and phosphoric acid.
Il devrait être compris que toutes les références aux sels pharmaceutiquement acceptables comprennent les formes d' addition de solvants (solvates) ou les formes cristallines (polymorphes) tels que définis ici, du même sel d'addition d'acide.  It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same acid addition salt.
La présente invention concerne en outre une composition pharmaceutique comprenant l'ester de DHA avec un alcool choisi parmi le groupe constitué par le nicotinol, le panthénol, l'inositol, l'isosorbide ou l'isosorbide mononitrate, et au moins un excipient pharmaceutiquement acceptable pour son utilisation à titre de médicament pour le traitement prophylactique et/ou curatif de la drépanocytose. The present invention further relates to a pharmaceutical composition comprising the DHA ester with an alcohol selected from the group consisting of nicotinol, panthenol, inositol, isosorbide or isosorbide mononitrate, and at least one pharmaceutically acceptable excipient for use as a medicament for the prophylactic and / or curative treatment of sickle cell disease.
La composition pharmaceutique selon la présente invention peut être utilisée en tant que médicament destiné à prévenir et/ou à soulager les crises vaso-occlusives chez un patient atteint de drépanocytose.  The pharmaceutical composition according to the present invention can be used as a medicament for preventing and / or alleviating vaso-occlusive attacks in a patient with sickle cell disease.
La composition pharmaceutique selon la présente invention peut être utilisée en tant que médicament destiné à prévenir et/ou à traiter l'anémie chez un patient atteint de drépanocytose .  The pharmaceutical composition according to the present invention can be used as a medicament for preventing and / or treating anemia in a patient with sickle cell disease.
La composition pharmaceutique selon la présente invention peut être administrée par voie orale ou toute autre voie d'administration pharmaceutique.  The pharmaceutical composition according to the present invention can be administered orally or any other pharmaceutical route of administration.
Les compositions pharmaceutiques selon la présente invention peuvent être formulées pour l'administration aux mammifères, y compris l'homme. Ces compositions sont réalisées de façon à pouvoir être administrées par voie orale, sublinguale, sous-cutanée, intramusculaire, intraveineuse, transdermique, locale ou rectale. Dans ce cas, l'ingrédient actif peut être administré sous formes unitaires d'administration, en mélange avec des supports pharmaceutiques classiques, aux animaux ou aux êtres humains. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale et buccale, les formes d'administration sous-cutanée, topique, intramusculaire, intraveineuse, intra nasale ou intraoculaire et les formes d'administration rectale.  The pharmaceutical compositions according to the present invention can be formulated for administration to mammals, including humans. These compositions are made so that they can be administered orally, sublingually, subcutaneously, intramuscularly, intravenously, transdermally, locally or rectally. In this case, the active ingredient can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals or humans. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, subcutaneous forms of administration , topical, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.
Lorsque l'on prépare une composition solide sous forme de comprimé, on mélange l'ingrédient actif principal avec un véhicule pharmaceutique tel que la gélatine, l'amidon, le lactose, le stéarate de magnésium, le talc, la gomme arabique, la silice ou analogues. On peut enrober les comprimés de saccharose ou d'autres matières appropriées ou encore on peut les traiter de telle sorte qu'ils aient une activité prolongée ou retardée et qu'ils libèrent d'une façon continue une quantité prédéterminée de principe actif. When a solid composition in tablet form is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, silica or the like. The tablets can be coated sucrose or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and that they continuously release a predetermined quantity of active ingredient.
On obtient une préparation en gélules en mélangeant l'ingrédient actif avec un diluant (étape facultative) et en versant le mélange obtenu dans des gélules molles ou dures.  A capsule preparation is obtained by mixing the active ingredient with a diluent (optional step) and pouring the resulting mixture into soft or hard gelatin capsules.
Une préparation sous forme de sirop ou d'élixir peut contenir l'ingrédient actif conjointement avec un édulcorant, un antiseptique, ainsi qu'un agent donnant du goût et un colorant approprié .  A syrup or elixir preparation may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable colorant.
Les poudres ou les granules dispersibles dans l'eau peuvent contenir l'ingrédient actif en mélange avec des agents de dispersion ou des agents mouillants, ou des agents de mise en suspension, de même qu'avec des correcteurs du goût ou des édulcorants .  Water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, as well as with taste correctors or sweeteners.
Pour une administration rectale, on recourt à des suppositoires qui sont préparés avec des liants fondant à la température rectale, par exemple du beurre de cacao ou des polyéthylènes glycols.  For rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.
Pour une administration parentérale (intraveineuse, intramusculaire etc.), intra nasale ou intraoculaire , on utilise des suspensions aqueuses, des solutions salines isotoniques ou des solutions stériles et injectables qui contiennent des agents de dispersion et/ou des agents mouillants pharmacologiquement compatibles .  For parenteral (intravenous, intramuscular, etc.), intranasal, or intraocular administration, aqueous suspensions, isotonic saline solutions, or sterile and injectable solutions containing dispersing agents and / or pharmacologically compatible wetting agents are used.
Le principe actif peut être formulé également sous forme de microcapsules, éventuellement avec un ou plusieurs supports additifs .  The active ingredient may also be formulated as microcapsules, optionally with one or more additive carriers.
Avantageusement, la composition pharmaceutique selon la présente invention est destinée à une administration par voie orale ou intraveineuse, de façon plus avantageuse par voie orale .  Advantageously, the pharmaceutical composition according to the present invention is intended for oral or intravenous administration, more advantageously orally.
Les dosages des compositions pharmaceutiques contenant un ester de DHA avec un alcool choisi parmi le groupe constitué par le nicotinol, le panthénol, l'inositol, l'isosorbide ou l'isosorbide mononitrate dans les compositions de l'invention sont ajustés afin d'obtenir une quantité de substance active qui est efficace pour obtenir la réponse thérapeutique désirée pour une composition particulière à la méthode d'administration. Le niveau choisi de dosage dépend donc de l'effet thérapeutique désiré, de la voie de l'administration choisie, de la durée désirée du traitement, le poids, l'âge et le sexe du patient, la sensibilité de l'individu à traiter. En conséquence la posologie optimale devra être déterminée en fonction des paramètres jugés pertinents, par le spécialiste en la matière. Préférentiellement, l'ester de DHA est administré dans des compositions pharmaceutiques acceptables où la dose quotidienne est comprise entre 250 mg et 10 g par jour, plus préférentiellement la dose quotidienne est comprise entre 1 et 6 g par jour, comme par exemple 1 g, 2 g ou 4 g/ jour. Il peut être nécessaire d'utiliser des doses plus importantes (appelées dose de charge) en début de traitement prophylactique et/ou curatif et de réduire ensuite les doses (dose de maintien) au cours du traitement . Dosages of pharmaceutical compositions containing a DHA ester with an alcohol selected from the group consisting of nicotinol, panthenol, inositol, isosorbide or isosorbide mononitrate in the compositions of the invention are adjusted to obtain an amount of active substance that is effective in achieving the desired therapeutic response for a particular composition in the method of administration. The chosen level of dosage therefore depends on the desired therapeutic effect, the route of administration chosen, the desired duration of treatment, the weight, age and sex of the patient, the sensitivity of the individual to be treated . Consequently, the optimal dosage should be determined according to the parameters deemed relevant by the specialist in the field. Preferably, the DHA ester is administered in acceptable pharmaceutical compositions in which the daily dose is between 250 mg and 10 g per day, more preferably the daily dose is between 1 and 6 g per day, for example 1 g, 2 g or 4 g / day. It may be necessary to use larger doses (called loading dose) at the beginning of prophylactic and / or curative treatment and then reduce the doses (maintenance dose) during treatment.
La composition pharmaceutique selon la présente invention peut comprendre en outre au moins un autre principe actif, tel qu'un analgésique et/ou 1 ' hydroxyurée conduisant à un effet complémentaire ou éventuellement synergique.  The pharmaceutical composition according to the present invention may further comprise at least one other active ingredient, such as an analgesic and / or hydroxyurea leading to a complementary or possibly synergistic effect.
L'invention sera mieux comprise en référence aux exemples qui suivent .  The invention will be better understood with reference to the following examples.
Exemple 1 : effet du nicotmol de DHA sur la composition en acides gras du plasma et des globules rouges de chiens traités par voie orale. L'objet de cette première étude est de doser le DHA total dans le sang (plasma et globules rouges) de chiens recevant du nicotinol de DHA par voie orale. Example 1: Effect of nicotinol DHA on the fatty acid composition of plasma and red blood cells of dogs treated orally. The purpose of this first study is to measure the total DHA in the blood (plasma and red blood cells) of dogs receiving oral nicotinol DHA.
Deux groupes de 10 chiens sont utilisés :  Two groups of 10 dogs are used:
Groupe 1 : groupe témoin  Group 1: control group
Groupe 2 : nicotinol de DHA à 2g par jour.  Group 2: nicotinol of DHA at 2g per day.
Tous les animaux reçoivent par voie orale pendant 28 jours soit un placebo, soit du nicotinol de DHA à 2g par jour. Les prélèvements de sang sont effectués à J-l (contrôle), J7 , J14, J21 et J28. All animals receive orally for 28 days, either a placebo or nicotinol DHA at 2g per day. The Blood samples are taken at (control), D7, D14, D21 and D28.
Les lipides totaux du plasma (500 L) et des globules rouges (« 500 mg, la pesée des globules rouges est plus précise que la mesure d'un volume) sont extraits par 4 mL d'un mélange d'hexane et d' isopropanol (2/1, v/v) , en milieu acide (HC1 3M, 500 L) en présence d'acide margarique comme étalon interne (100 ig) . Après agitation et centrifugation (2000g, 15 minutes, 10 °C) la phase organique est séparée. Une deuxième extraction par 2 mL du même solvant est effectuée dans les mêmes conditions. Les phases organiques sont lavées par 2 mL d'eau salée (NaCl 9°a) . Les solvants sont évaporés sous flux d'azote à 40°C.  The total lipids of plasma (500 L) and red blood cells ("500 mg, weighing red blood cells is more accurate than measuring a volume) are extracted with 4 mL of a mixture of hexane and isopropanol (2/1, v / v), in acid medium (3M HCl, 500 L) in the presence of margaric acid as internal standard (100 μg). After stirring and centrifugation (2000g, 15 minutes, 10 ° C) the organic phase is separated. A second extraction with 2 ml of the same solvent is carried out under the same conditions. The organic phases are washed with 2 mL of salt water (NaCl 9 ° a). The solvents are evaporated under a stream of nitrogen at 40 ° C.
Les lipides totaux provenant du plasma et des globules rouges sont alors saponifiés (1 mL de NaOH 0,5M dans le méthanol, 70°C, 30 minutes) puis convertis en esters méthyliques (1 mL, BF3 14% dans le méthanol, 70 °C, 15 minutes) . Après hydrolyse (4 mL naCl 9°a) ils sont extraits par 4 puis 2 mL de pentane . Les phases organiques sont lavées par 2 mL d'eau salée (NaCl 9¾Ό) . Les solvants sont évaporés sous flux d'azote à 40°C. Les esters méthyliques sont repris par 200 L d'hexane pour le plasma et les globules rouges. Les esters méthyliques d'acides gras extraits sont analysés par chromatographie en phase gazeuse. Le chromatographe (Agilent Technologies 6890N) est équipé d'un injecteur avec split chauffé à 260°C (division au 1:10), d'une colonne capillaire (longueur de 60 m, diamètre de 0,25 mm) avec une phase stationnaire BPX70 (70% cyanopropylpolyphénylène-siloxane ; épaisseur 0,25 μιτι) et d'un détecteur à ionisation de flamme chauffé à 260°C (hydrogène : 40 mL/min, air : 450 mL/min) . Le gaz vecteur est l'hélium (débit constant 1,5 mL/min) . La température de la colonne est initialement de 150°C puis elle s'élève selon un gradient de température de l,3°C/min jusqu'à 220°C puis 40°C/min pour atteindre 260°C pendant 5 minutes. Les temps de rétention d'esters méthyliques standard permettent d'identifier les esters méthyliques d'acides gras extraits. Le DHA est quantifié par rapport à l'étalon interne (C17:0) ajouté en quantité connue à l'échantillon avant l'extraction des lipides totaux. Il est exprimé en g/mL pour le plasma, en g/g pour les globules rouges. Les valeurs sont présentées sous forme de moyenne ± écart type (n=10 en général) . Les différences significatives sont montrées par un test de Student au seuil de 5%. The total lipids from the plasma and the red blood cells are then saponified (1 mL of 0.5M NaOH in methanol, 70 ° C., 30 minutes) and then converted into methyl esters (1 mL, 14% BF 3 in methanol, 70% strength). ° C, 15 minutes). After hydrolysis (4 mL NaCl 9 °) they are extracted with 4 then 2 mL of pentane. The organic phases are washed with 2 mL of salt water (9Cl NaCl). The solvents are evaporated under a stream of nitrogen at 40 ° C. The methyl esters are taken up in 200 L of hexane for plasma and red blood cells. The extracted fatty acid methyl esters are analyzed by gas chromatography. The chromatograph (Agilent Technologies 6890N) is equipped with a split injector heated to 260 ° C (1:10 division), a capillary column (60 m length, 0.25 mm diameter) with a stationary phase BPX70 (70% cyanopropylpolyphenylene siloxane, thickness 0.25 μιτι) and a flame ionization detector heated to 260 ° C (hydrogen: 40 mL / min, air: 450 mL / min). The carrier gas is helium (constant flow rate 1.5 mL / min). The temperature of the column is initially 150 ° C. and then rises according to a temperature gradient of 1.3 ° C./min up to 220 ° C. and then 40 ° C./min, to reach 260 ° C. for 5 minutes. The retention times of standard methyl esters make it possible to identify the methyl esters of extracted fatty acids. DHA is quantified relative to the internal standard (C17: 0) added in known quantity to the sample before extraction of total lipids. It is expressed in g / mL for plasma, in g / g for red blood cells. Values are presented as mean ± standard deviation (n = 10 in general). Significant differences are shown by a Student's test at the 5% threshold.
Les résultats des taux de DHA plasmatiques chez le chien, sont résumés dans le tableau 1  The results of plasma DHA levels in dogs are summarized in Table 1
Tableau 1 : évolution du taux de DHA plasmatique au cours du traitement par le nicotinol de DHA à 2 g/J.  Table 1: Evolution of the plasma DHA level during treatment with nicotinol DHA at 2 g / day.
Les taux de DHA sont exprimés en g/mL, Moy : valeur moyenne ; SD : écart type ; G 1 : groupe 1 ; G2 : groupe 2. Les différences entre les 2 groupes sont statistiquement significatives quel que soit le temps de traitement. DHA levels are expressed in g / mL, Avg: mean value; SD: standard deviation; G 1: group 1; G2: group 2. The differences between the 2 groups are statistically significant regardless of the treatment time.
Les taux de DHA plasmatiques sont équivalents entre les 2 groupes en début d'expérimentation. En revanche, pendant toute la durée du traitement, la teneur en DHA plasmatique est supérieure dans le groupe « nicotinol de DHA » par rapport au groupe témoin.  Plasma DHA levels are equivalent between the 2 groups at the beginning of the experiment. In contrast, throughout the course of treatment, the plasma DHA content is higher in the "nicotinol DHA" group compared to the control group.
Le tableau 2 montre les taux de DHA des globules rouges Tableau 2 : évolution du taux de DHA des globules rouges au cours du traitement par le nicotinol de DHA à 2 g/J.  Table 2 shows DHA levels of red blood cells. Table 2: Evolution of red blood cell DHA during treatment with nicotinol DHA at 2 g / day.
DHA J-l J7 J14 J21 J28 DHA J-1 J7 J14 J21 J28
Moy SD Moy SD Moy SD Moy SD Moy SD Avg SD Avg SD Avg Avg SD Avg Avg SD Avg SD
G 1 1,9 1,1 2,1 1,2 1,9 1,0 1,9 0,7 1,8 0,7G 1 1.9 1.1 2.1 1.2 1.9 1.0 1.9 0.7 1.8 0.7
G 2 1,7 1,0 4,7 2,3 7,1 1,7 8,3 3,2 8,7 2,1 Les taux de DHA sont exprimés en g/mL, Moy : valeur moyenne ; SD : écart type ; G 1 : groupe 1 ; G2 : groupe 2. Les différences entre les 2 groupes sont statistiquement significatives quel que soit le temps de traitement. G 2 1.7 1.0 4.7 2.3 7.1 1.7 8.3 3.2 8.7 2.1 DHA levels are expressed in g / mL, Avg: mean value; SD: standard deviation; G 1: group 1; G2: group 2. The differences between the 2 groups are statistically significant regardless of the treatment time.
Les taux de DHA des globules rouges sont équivalents entre les 2 groupes en début d'expérimentation. En revanche, pendant toute la durée du traitement, la teneur en DHA des globules rouges est supérieure dans le groupe « nicotinol de DHA » par rapport au groupe témoin.  DHA levels of red blood cells are equivalent between the 2 groups at the beginning of the experiment. In contrast, throughout the course of treatment, the DHA content of red blood cells is higher in the "nicotinol DHA" group compared to the control group.
Ainsi, chez le chien l'effet du traitement par le nicotinol de DHA est significatif à tous les temps du traitement, le nicotinol de DHA induit une augmentation du taux de DHA plasmatique mais surtout induit une élévation du taux de DHA des globules rouges.  Thus, in the dog the effect of nicotinol treatment of DHA is significant at all times of treatment, nicotinol DHA induces an increase in plasma DHA but above all induces a rise in the red blood cell DHA level.
Exemple 2 : incorporation de DHA plasmatique et dans les globules rouges de rats recevant par voie orale du panthénol de DHA. L'objet de cette étude est de doser le DHA total dans le sang (plasma et globules rouges) de rats recevant du panthénol de DHA par gavage oral pendant 7 jours. Example 2: incorporation of plasma DHA and into the red blood cells of rats receiving orally panthenol DHA. The purpose of this study is to measure the total DHA in the blood (plasma and red blood cells) of rats receiving panthenol DHA by oral gavage for 7 days.
Trois groupes de 4 rats (2 mâles et 2 femelles) sont utilisés :  Three groups of 4 rats (2 males and 2 females) are used:
Groupe 1 : groupe véhicule (huile d'olive)  Group 1: vehicle group (olive oil)
Groupe 2 : panthénol de DHA à 300 mg/kg par jour.  Group 2: panthenol DHA at 300 mg / kg daily.
Groupe 3 : panthénol de DHA à 1000 mg/kg par jour.  Group 3: Panthenol DHA at 1000 mg / kg per day.
Les lipides totaux du plasma (500 L) et des globules rouges sont extraits par un mélange d'hexane et d' isopropanol (3/2, v/v), en milieu acide (HC1 3M, 1 mL) en présence d'acide margarique comme étalon interne. Les lipides totaux provenant du plasma et des globules rouges sont alors saponifiés (1 mL de NaOH 0,5M dans le méthanol, 70°C, 30 minutes) puis convertis en esters méthyliques (1 mL, BF3 14% dans le méthanol, 70 °C, 15 minutes) . Les esters méthyliques d'acides gras sont extraits avec du pentane puis analysés par chromatographie en phase gazeuse. Le chromatographe (Agilent Technologies 6890N) est équipé d'un injecteur avec split chauffé à 250°C (division au 1:10), d'une colonne capillaire (longueur de 60 m, diamètre de 0,25 mm) avec une phase stationnaire BPX70 (70% cyanopropylpolyphénylène-siloxane ; épaisseur 0,25 μιτι) . Le gaz vecteur est l'hélium. La température de la colonne est initialement de 150°C puis elle s'élève selon un gradient de température de l,3°C/min jusqu'à 220°C puis reste à 220°C pendant 10 minutes. Les temps de rétention d'esters méthyliques standard permettent d'identifier les esters méthyliques d'acides gras extraits. The total lipids of the plasma (500 L) and red blood cells are extracted with a mixture of hexane and isopropanol (3/2, v / v), in acidic medium (3M HCl, 1 mL) in the presence of acid. margaric as internal standard. The total lipids from the plasma and the red blood cells are then saponified (1 mL of 0.5M NaOH in methanol, 70 ° C., 30 minutes) and then converted into methyl esters (1 mL, 14% BF 3 in methanol, 70% strength). ° C, 15 minutes). The fatty acid methyl esters are extracted with pentane and analyzed by gas chromatography. The chromatograph (Agilent Technologies 6890N) is equipped with an injector with split heated to 250 ° C (split at 1:10), a capillary column (length 60 m, diameter 0.25 mm) with a stationary phase BPX70 (70% cyanopropylpolyphenylene siloxane, thickness 0.25 μιτι). The carrier gas is helium. The temperature of the column is initially 150 ° C. and then rises according to a temperature gradient of 1.3 ° C./min up to 220 ° C. and then remains at 220 ° C. for 10 minutes. The retention times of standard methyl esters make it possible to identify the methyl esters of extracted fatty acids.
Le DHA est quantifié par rapport à l'étalon interne (C17:0) ajouté en quantité connue à l'échantillon avant l'extraction des lipides totaux. Il est exprimé en g/mL pour le plasma, en g/g pour les globules rouges. Les valeurs sont présentées sous forme de moyenne ± écart type.  DHA is quantified relative to the internal standard (C17: 0) added in known quantity to the sample before extraction of total lipids. It is expressed in g / mL for plasma, in g / g for red blood cells. Values are presented as mean ± standard deviation.
Les résultats des taux de DHA plasmatiques et dans les globules rouges chez le rat, sont présentés dans la Figure 1.  The results of plasma and red blood cell DHA levels in rats are shown in Figure 1.
La figure 1 représente les taux plasmatique de DHA (panels du haut) chez les rats mâles (panels de gauche) et chez les animaux femelles (panels de droite) ainsi que les taux de DHA dans les globules rouges (panels du bas), dans le groupe témoin (Gl), chez les rats recevant du panthénol de DHA à 300 mg/kg/J (G2) et chez les rats recevant du 1000 mg/kg/J de panthénol de DHA (G3) .  Figure 1 represents the plasma levels of DHA (top panels) in male rats (left panels) and in female animals (right panels) as well as DHA levels in red blood cells (bottom panels), in the control group (G1), in rats receiving DHA panthenol at 300 mg / kg / day (G2) and in rats receiving 1000 mg / kg / day of DHA panthenol (G3).
Pour les rats mâles, la quantité de DHA trouvé dans les globules rouges et dans le plasma dépend de la dose de panthénol de DHA que les animaux ont reçu. Pour les rats femelles la quantité de DHA trouvé dans les globules rouges et dans le plasma n'est augmentée qu'avec la plus haute dose de panthénol de DHA.  For male rats, the amount of DHA found in red blood cells and in the plasma depends on the dose of panthenol of DHA that the animals received. For female rats the amount of DHA found in red blood cells and plasma is increased only with the highest dose of panthenol DHA.
Ainsi le panthénol de DHA permet bien de libérer du DHA au niveau plasmatique mais surtout d'incorporer du DHA dans les globules rouges chez le rat.  Thus the panthenol of DHA makes it possible to release DHA at the plasma level but, above all, to incorporate DHA into the red blood cells in the rat.
Exemple 3 : concentration de DHA dans les globules rouges humains après absorption de panthénol de DHA. L'objectif de cette étude clinique était de déterminer les concentrations de DHA total dans les globules rouges chez des volontaires recevant oralement une fois par jour du panthénol de DHA pendant 28 jours. Trois doses de panthénol de DHA ont été testées dans cette étude, 1, 2 et 4 g/ jour. Douze sujets ont été inclus dans cette étude, 3 sujets ont reçu du placebo (sans panthénol de DHA) et 9 ont reçu du panthénol de DHA. Example 3: Concentration of DHA in human red blood cells after absorption of panthenol DHA. The objective of this clinical study was to determine the total DHA levels in red blood cells in volunteers receiving orally once daily panthenol DHA for 28 days. Three doses of panthenol of DHA were tested in this study, 1, 2 and 4 g / day. Twelve subjects were included in this study, 3 subjects received placebo (without panthenol DHA) and 9 received panthenol DHA.
Des prélèvements de sang ont été effectués avant l'administration du panthénol de DHA (correspondant au niveau de base), puis aux jours 4, 7, 10 14, 15, 19, 22, 25 et 29 afin de déterminer les concentrations de DHA dans les globules rouges. Deux prélèvements de sang de 4 raL chacun ont été effectués dans des tubes contenant de l'EDTA. Les tubes sont centrifugés à 3000g pendant 15 minutes à température ambiante dans les 30 minutes qui suivent le prélèvement. Les globules rouges ont été stockés à 4°C et envoyés dans des conditions réfrigérées (2°C à 8°C) dans le laboratoire qui a fait les analyses  Blood samples were taken prior to administration of panthenol DHA (baseline level) and on days 4, 7, 10, 14, 15, 19, 22, 25 and 29 to determine DHA levels in the blood. red blood cells. Two blood samples of 4 μL each were made in tubes containing EDTA. The tubes are centrifuged at 3000 g for 15 minutes at room temperature within 30 minutes after the sampling. The red blood cells were stored at 4 ° C and sent under refrigerated conditions (2 ° C to 8 ° C) in the laboratory that performed the analyzes.
Les lipides ont été extraits à partir des échantillons de globules rouges (~ 500 mg) avec un mélange d' hexane/isopropanol (3/2 v/v) en milieu acide en présence d'acide margarique comme étalon interne (100 ]ig) . Les extraits de lipides totaux sont saponifiés et convertis en esters méthyliques. Après extraction au pentane, les esters méthyliques d'acides gras extraits sont analysés par chromatographie en phase gazeuse. Le chromatographe (Agilent Technologies 6890N) est équipé d'un injecteur avec split chauffé à 250°C, d'une colonne capillaire (longueur de 60 m, diamètre de 0,25 mm) . Le gaz vecteur est l'hélium (débit constant 1,5 mL/min) . La température de la colonne est initialement de 150°C puis elle s'élève selon un gradient de température de l,3°C/min jusqu'à 220°C puis reste à 220°C pendant 10 minutes. Le détecteur à ionisation de flamme est chauffé à 250°C (hydrogène : 40 mL/min, air : 450 mL/min) . Les temps de rétention d'esters méthyliques standard permettent d'identifier les esters méthyliques d'acides gras extraits.  The lipids were extracted from the red blood cell samples (~ 500 mg) with a mixture of hexane / isopropanol (3/2 v / v) in an acid medium in the presence of margaric acid as internal standard (100 μg). . Total lipid extracts are saponified and converted to methyl esters. After extraction with pentane, the methyl esters of extracted fatty acids are analyzed by gas chromatography. The chromatograph (Agilent Technologies 6890N) is equipped with a split injector heated to 250 ° C, a capillary column (length 60 m, diameter 0.25 mm). The carrier gas is helium (constant flow rate 1.5 mL / min). The temperature of the column is initially 150 ° C. and then rises according to a temperature gradient of 1.3 ° C./min up to 220 ° C. and then remains at 220 ° C. for 10 minutes. The flame ionization detector is heated to 250 ° C (hydrogen: 40 mL / min, air: 450 mL / min). The retention times of standard methyl esters make it possible to identify the methyl esters of extracted fatty acids.
Le DHA est quantifié par rapport à l'étalon interne (C17:0) ajouté en quantité connue à l'échantillon avant l'extraction des lipides totaux. Les valeurs sont présentées sous forme de moyenne ± écart type. DHA is quantified relative to the internal standard (C17: 0) added in known quantity to the sample before extraction of the total lipids. Values are presented as mean ± standard deviation.
Les résultats des taux de DHA dans les globules rouges humains après administration de différentes doses de panthénol de DHA (ou de placebo) pendant 28 jours sont présentés dans la Figure 2. La Figure 2 représente le taux de DHA en fin d'étude, calculé en pourcentage d'acide gras dans les globules rouges humains en fonction des doses de panthénol de DHA administrées. Quelle que soit la dose de panthénol de DHA administré, le taux de DHA dans les globules rouges est augmenté par rapport au groupe placebo. A 28 jours de traitement, un effet dose- dépendant est démontré, l'effet maximal semble atteint dès 2 g/jour même si la variabilité est plus faible avec une dose de 4 g/jour. Les taux de base de DHA (calculés en pourcentage d'acides gras) dans les globules rouges humains en l'absence de traitement que l'on retrouve dans la littérature sont de l'ordre de 4,8% (Payet et al. British Journal of Nutrition, 91 :789-796, 2004 ; Weill et al. Annals of Nutrition & Metabolism, 46 :182- 191, 2002) donc très proches de nos valeurs trouvées dans le groupe placebo (4,9%) . Dans nos groupes traités, les taux de DHA atteignent 6,6% pour 1 g/ jour de panthénol de DHA et 7,8% pour les groupes de 2 et 4 g/ jour de panthénol de DHA. Ces différences indiquent clairement un enrichissement du contenu en DHA des globules rouges humains par l'apport de panthénol de DHA.  The results of DHA levels in human red blood cells after administration of different doses of panthenol of DHA (or placebo) for 28 days are shown in Figure 2. Figure 2 shows the DHA level at the end of the study, calculated as a percentage of fatty acid in human red blood cells according to the doses of panthenol of DHA administered. Regardless of the dose of panthenol DHA administered, the level of DHA in red blood cells is increased compared to the placebo group. At 28 days of treatment, a dose-dependent effect is demonstrated, the maximum effect seems to be reached from 2 g / day even if the variability is lower with a dose of 4 g / day. The basic levels of DHA (calculated as percentage of fatty acids) in human red blood cells in the absence of treatment found in the literature are of the order of 4.8% (Payet et al., British Journal of Nutrition, 91: 789-796, 2004, Weill et al., Annals of Nutrition & Metabolism, 46: 182-191, 2002) therefore very close to our values found in the placebo group (4.9%). In our treated groups, the levels of DHA reached 6.6% for 1 g / day of panthenol DHA and 7.8% for the groups of 2 and 4 g / day of Panthenol DHA. These differences clearly indicate an enrichment of the DHA content of human red blood cells by the addition of panthenol of DHA.

Claims

Revendications claims
1. Ester de l'acide docosahexaénoïque avec un alcool choisi parmi le groupe constitué par: 1. Ester of docosahexaenoic acid with an alcohol selected from the group consisting of:
- le nicotinol de formule suivante : the nicotinol of the following formula:
le panthénol de formule suivante  Panthenol of the following formula
l'inositol de formule suivante  inositol of following formula
l'isosorbide de formule suivante  isosorbide of following formula
H H
et l'isosorbide mononitrate de formule suivante and the isosorbide mononitrate of the following formula
NO2 NO 2
ou l'un de ses sels pharmaceutiquement acceptables, énantiomères , diastéréoisomères, ou leur mélange, y compris les mélanges racémiques, pour son utilisation à titre de médicament pour le traitement prophylactique et/ou curatif de la drépanocytose . or a pharmaceutically acceptable salt thereof, enantiomers, diastereoisomers, or mixtures thereof, including racemic mixtures, for use as a medicament for the prophylactic and / or curative treatment of sickle cell disease.
2. Ester selon la revendication 1, de formule suivante 2. Ester according to claim 1, of the following formula
3. Ester selon la revendication 1 ou 2, pour son utilisation en tant que médicament destiné à prévenir et/ou à soulager les crises vaso-occlusives chez un patient atteint de drépanocytose. 3. Ester according to claim 1 or 2 for its use as a medicament for preventing and / or alleviating vaso-occlusive attacks in a patient with sickle cell disease.
4. Ester selon la revendication 1 ou 2, pour son utilisation en tant que médicament destiné à prévenir et/ou à traiter l'anémie chez un patient atteint de drépanocytose. An ester according to claim 1 or 2 for use as a medicament for preventing and / or treating anemia in a patient with sickle cell disease.
5. Composition pharmaceutique comprenant un ester selon l'une des revendications 1 à 4 et un excipient acceptable sur le plan pharmaceutique pour son utilisation à titre de médicament pour le traitement prophylactique et/ou curatif de la drépanocytose. 5. A pharmaceutical composition comprising an ester according to one of claims 1 to 4 and a pharmaceutically acceptable excipient for use as a medicament for the prophylactic and / or curative treatment of sickle cell disease.
6. Composition pharmaceutique, selon la revendication 5 pour son utilisation en tant que médicament destiné à prévenir et/ou à soulager les crises vaso-occlusives chez un patient atteint de drépanocytose . The pharmaceutical composition of claim 5 for use as a medicament for preventing and / or alleviating vaso-occlusive seizures in a patient with sickle cell disease.
7. Composition pharmaceutique, selon la revendication 5 pour son utilisation en tant que médicament destiné à prévenir et/ou à traiter l'anémie chez un patient atteint de drépanocytose. The pharmaceutical composition according to claim 5 for use as a medicament for preventing and / or treating anemia in a patient with sickle cell disease.
8. Composition pharmaceutique selon l'une quelconque des revendications 5 à 7 pour son administration par voie orale. 8. Pharmaceutical composition according to any one of claims 5 to 7 for its oral administration.
9. Composition pharmaceutique selon l'une quelconque des revendications 5 à 8, comprenant en outre au moins un autre principe actif tel qu'un analgésique et/ou 1 ' hydroxyurée . The pharmaceutical composition according to any one of claims 5 to 8, further comprising at least one other active ingredient such as an analgesic and / or hydroxyurea.
EP13795784.1A 2012-11-27 2013-11-27 Use of a dha ester for prophylactic and/or curative treatment of drepanocytosis Withdrawn EP2925311A1 (en)

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