Classifications

• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• this invention concerns the use of a pharmaceutical composition containing essential fatty acid ethyl esters originating from fish oils, in particular as a high concentration mixture of ethyl esters of (20:5 ⁇ 3) eipcosapentaenoic acid (EPA) and (22:6 ⁇ 3) docosahexaenoic acid (DHA) in the prevention and/or treatment of depression in patients with coronary artery disease.
• EPA eipcosapentaenoic acid
• DHA docosahexaenoic acid
• the above prior art in particular provide knowledge about the utility of fatty acids belonging to the ⁇ -3 family, more specifically (20:5 ⁇ 3) eicosapentaenoic acid (EPA) and (22:6 ⁇ 3) docosahexaenoic acid (DHA), in treating the above-mentioned disorders.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• the fatty acid EPA being a precursor of PGI3 and TxA3, exerts a preventing platelet aggregation effect and an antithombotic effect that can be ascribed to inhibition of cyclooxygenase (similar effect to that of aspirin) and/or to competition with arachidonic acid for this enzyme, with consequent reduction in the synthesis of
• fatty acid DHA is the most important component of cerebral lipids in man and furthermore, being a structural component of the platelet cell it intervenes indirectly in increasing platelet fluidity, thus playing an important role in antithombotic activity.
• the international patent application WO 89/1 1521 whose description is herein incorporated by reference, describes in particular an industrial process for extracting mixtures with a high content in poly-unsaturated acids, including EPA and DHA and their ethyl esters, from animal and/or vegetable oils. Mixtures of fatty acids, especially EPA/DHA, obtained according to WO
• 89/1 1521 are reported to be particularly useful in the treatment of cardiovascular diseases.
• this invention concerns the use of a pharmaceutical composition containing essential fatty acid ethyl esters originating from fish oils, in particular as a high concentration mixture of ethyl esters of (20:5 ⁇ 3) eicosapentaenoic acid (EPA) and (22:6 ⁇ 3) docosahexaenoic acid (DHA) in the prevention and/or treatment of depression in patients with cardiovascular disease, such as coronary heart, coronary artery or vascular disease.
• cardiovascular disease such as coronary heart, coronary artery or vascular disease.
• the present invention provides a novel method for preventing and/or treating depression in patients with cardiovascular disease.
• the patients have coronary heart and/or coronary artery or vascular disease.
• the cardiovascular disease is coronary artery or vascular disease.
• the method of the present invention comprises administering to said patient a therapeutically effective amount of a medicament containing essential fatty acids containing a high content in eicosapentanoic acid ethyl ester (EPA), in docosahexaenoic acid ethyl ester (DHA) or in a high concentration mixture of eicosapentanoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester (DHA).
• EPA eicosapentanoic acid ethyl ester
• DHA docosahexaenoic acid ethyl ester
• the high concentration mixture comprises a high concentration mixture of eicosapentanoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester (DHA).
• EPA eicosapentanoic acid ethyl ester
• DHA docosahexaenoic acid ethyl ester
• a high content in EPA-ethyl ester or DHA-ethyl ester or a high concentration mixture thereof, is to be understood to contain at least 20 % b.w. EPA or DHA, or at least 20 % b.w. of a mixture of EPA and DHA.
• this invention pertains to the use of essential fatty acids containing a mixture of eicosapentanoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester (DHA) in the prophylaxis and/or treatment of depression in patients with cardiovascular disease, in one example in patients with coronary heart and/or coronary artery or vascular disease, where the content in EPA and DHA in such mixture is greater than 25% b.w.
• EPA eicosapentanoic acid ethyl ester
• DHA docosahexaenoic acid ethyl ester
• the invention provides a use of a therapeutically effective amount of essential fatty acids containing a high content in EPA, in DHA or a high concentration mixture thereof in the formation of a medicament for the treatment of cardiovascular disease, such as coronary heart and/or coronary artery or vascular disease.
• the term "containing” or “comprising” as used herein is an inclusive and not exclusive term.
• Recently new risk factors for coronary artery disease have been identified, among them depression.
• Major depressive disorders, as well as depression symptoms are associated with higher rates of cardiovascular morbidity and mortality.
• the risk for suffering a fatal cardiac event is increased.
• Severe ventricular arrhythmias resulting in sudden cardiac death appear to be the leading cause of mortality in patients with depression.
• patients with anxiety and depressive disorders have been shown to have reduced heart rate variability. This finding may have important prognostic implications because low heart rate variability is a powerful predictor of sudden cardiac death.
• the object of this invention is to provide such improved and effective prophylaxis (preventing) and/or treatment of said patients with an effective drug, and in particular preventing the before mentioned recurrences in patients with both, cardiovascular diseases and depression ,and/or treatment of depression in these patients.
• this invention provides a novel method for preventing and/or treating depression in patients with cardiovascular disease.
• the cardiovascular disease is coronary heart and/or coronary artery or vascular disease.
• the cardiovascular disease is coronary artery or vascular disease.
• the method comprises administering to said patient a therapeutically effective amount of a medicament containing essential fatty acids containing a high con-tent in eicosapentanoic acid ethyl ester (EPA), in docosahexaenoic acid ethyl ester (DHA) or in a high concentration mixture of eicosapentanoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester (DHA).
• EPA eicosapentanoic acid ethyl ester
• DHA docosahexaenoic acid ethyl ester
• the invention also provides a use of essential fatty acids such as a high concentration of EPA, DNA or mixture thereof for the prevention and treatment of depression in patients with cardiovascular disease.
• EPA-ethyl ester and “DHA-ethyl ester” will be also quoted here as “EPA” and "DHA”.
• a high content in EPA-ethyl ester or DHA-ethyl ester or a high concentration mixture thereof, is to be understood to contain at least 20 % b.w. EPA or DHA, or at least 20 % b.w. of a mixture of EPA and DHA.
• this invention pertains to the use of essential fatty acids containing a mixture of eicosapentanoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester (DHA) in the prophylaxis and/or treatment of depression in patients with cardiovascular disease, in particular in patients with coronary heart and/or coronary artery or vascular disease, where the content in EPA and DHA in such mixture is greater than 25% b.w.
• EPA eicosapentanoic acid ethyl ester
• DHA docosahexaenoic acid ethyl ester
• an essential fatty acid with high content in EPA or DHA preferably contains more than 25% by weight (b.w.), in particular from about 60 to about 100% of such ester.
• b.w. 25% by weight
• an essential fatty acid with a high concentration mixture of EPA and DHA preferably such a mixture has a content of EPA and DHA greater than 25% by weight, in particular from about 30 to about 100% by weight, preferably about 85% by weight.
• EPA preferably is present in a percentage from about 40 to 60% by weight and DHA, preferably in a percentage from about 25 to about 45-50%.
• the preferred EPA/DHA ratio by weight in such EPA/DHA mixture is about 0.9 to 1.5 .
• PHARMACOLOGY Cardiovascular disease is the leading cause of morbidity and disability in the United States with an estimated 6 million people having symptomatic coronary heart disease.
• Major depression is occurring at a younger age and a higher incidence than it used to be.
• Alterations in phospholipids and cholesterol, which are structural components of all cell membranes in the brain, may induce changes in membrane microviscosity and, consequently in various neurotransmitter systems, which are thought to be related in the pathophysiology of depression, e.g. serotonin, and (nor-) adrenaline.
• Major depression and depressive symptoms although commonly encountered in medical populations, are frequently under-diagnosed and untreated in patients with cardiovascular disease.
• depression major depressive disorders as well as depressive symptoms
• depression is associated with higher rates of cardiovascular morbidity.
• the prognosis after a coronary heart disease event is poorer in depressed patients than in non-depressed patients.
• Patients with depression are less likely to follow recommendation to reduce cardiac risk during recovery from a myocardial infarction.
• major depression there is a decreased ⁇ -3 fractions in cholesterol esters and an increased C20:4 ⁇ 6/C20:5 ⁇ 3 ratio in cholesterol esters and phospholipids.
• Depression is an important independent predictor of death after coronary artery bypass surgery.
• DHA is involved in dopamine and serotonin metabolism in the developing rat brain.
• Omega-3 fatty acids possess mood stabilizing effects in major depression and other neuropsychiatric disorders.
• Addition of EPA to treatment resistant depression was associated with symptoms remission, structural brain changes and a reduced neuronal phospholipids turn-over.
• Omacor, a high concentration mixture of EPA and DHA does increase the red blood cell membrane EPA and DHA content. The above mentioned evidence shows that the present invention provides a new and valuable therapeutic method for preventing and/or treating depression in patients with cardiovascular disease, in particular in patients with coronary heart and/or coronary artery or vascular disease.
• this invention provides a method for preventing and or treating depression in patients with coronary vascular disease, and in particular in patients with coronary heart and/or coronary artery or vascular disease, comprising administering to such patient a therapeutically effective amount of a medicament containing essential fatty acids with a high content in EPA-ethyl ester or DHA-ethyl ester or a high concentration mixture thereof.
• the essential fatty acids can either have a high content, for instance more than 25% b.w., in EPA or DHA or in a mixture thereof.
• EPA and DHA-ethyl ester are preferably present as a mixture thereof with a content of EPA and DHA higher than 25% b.w., in particular from about 30 to about 100% b.w., in one embodiment about 80%, 81%, 82%, 83%, 84%, or preferably about 85% b.w.
• the dosage of an essential fatty acid containing an EPA and DHA mixture with 85% b.w. titer for oral administration to a patient may vary from about 0.7 g to about 6 g daily, preferably about 1 g daily.
• the high content EPA, DHA or high concentration mixture thereof is formulated into a capsule, such as a gel capsule, using methods known in the art.
• the gel capsule is a 1000 mg capsule.
• said capsule comprises 90% bw, ethyl esters of omega-3 fatty acids.
• about 465 mg is EPA and about 375 mg is DHA.
• said 1000 mg capsule comprises about 4 mg ⁇ -tocopherol in a suitable carrier (such as partially hydrogenated vegetable oils, including soybean oil), and other components of a gel capsule, such as gelatin, glycerol and purified water.
• the dose provided is 4g per day of the 1000 mg capsule.
• This amount of product as EPA and DHA mixture may be administered in several divided doses throughout the day or preferably in a single administration, in order to achieve the desired hematic level. Obviously it is at the discretion of the physician to adjust the quantity of product to be administered according to the age, weight and general conditions of the patient.
• “therapeutically effect amount” is an amount effective, at dosages and for periods of time necessary to achieve the desired therapeutic result. It is understood that such amount may vary according to factors such as disease state, age, sex and weight of the individual and the ability of a substance to elicit a desired response in an individual.
• the medicament e.g.
• a pharmaceutical composition in the form of a pharmaceutical composition, according to this invention can be prepared according to known methods in the art.
• the preferred route of administration is the oral one, however leaving alternative routes of administration, such as the parenteral route, to the discretion of the physician.
• the medicament or pharmaceutical composition can comprise the desired amount, e.g. a high content of EPA, DHA or high concentration mixture thereof in accordance with this invention and a pharmaceutical acceptable vehicle, e.g., carriers, excipients, adjuvants and buffers, for instance substances used in pharmaceuticals or known in the art, e.g., Remington's Pharmaceutical Sciences (Alfonso R.Gennaro ed. 18 th edition 1990)
• capsules According to known pharmaceutical techniques, capsules having the composition below and containing 1 g of active ingredient (EPA and DHA, 85% titer) per capsule are prepared.
• active ingredient EPA and DHA, 85% titer

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• Health & Medical Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Pain & Pain Management (AREA)
• Psychiatry (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2005
  • 2005-04-15 ZA ZA200607794A patent/ZA200607794B/en unknown
  • 2005-04-15 JP JP2007507767A patent/JP2007532605A/ja active Pending
  • 2005-04-15 BR BRPI0509878-5A patent/BRPI0509878A/pt not_active IP Right Cessation
  • 2005-04-15 UA UAA200611798A patent/UA94693C2/ru unknown
  • 2005-04-15 CA CA002504280A patent/CA2504280A1/en not_active Abandoned
  • 2005-04-15 WO PCT/EP2005/004031 patent/WO2005110393A1/en not_active Ceased
  • 2005-04-15 MX MXPA06011940 patent/MX291518B/es active IP Right Grant
  • 2005-04-15 RU RU2006140277/14A patent/RU2387448C2/ru not_active IP Right Cessation
  • 2005-04-15 AU AU2005244483A patent/AU2005244483B2/en not_active Ceased
  • 2005-04-15 EP EP05779398A patent/EP1765319A1/en not_active Withdrawn
  • 2005-04-15 CN CNA2005800114285A patent/CN1942180A/zh active Pending
• 2006
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