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US20090018193A1 - Essential fatty acids in the prevention of cardiovascular events - Google Patents

Essential fatty acids in the prevention of cardiovascular events Download PDF

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Publication number
US20090018193A1
US20090018193A1 US12/192,627 US19262708A US2009018193A1 US 20090018193 A1 US20090018193 A1 US 20090018193A1 US 19262708 A US19262708 A US 19262708A US 2009018193 A1 US2009018193 A1 US 2009018193A1
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dha
epa
ethyl ester
mixture
content
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Franco Pamparana
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Pfizer Italia SRL
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Pfizer Italia SRL
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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
    • 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
    • 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
    • A61K31/231—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 one or two double bonds
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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) eicosapentaenoic acid (EPA) and (22:6 ⁇ 3) docosahexaenoic acid (DHA) in the prevention of cardiovascular events, especially of mortality in patients who have survived the hospitalization phase of acute myocardial infarction (AMI).
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • EPA being a precursor of PGI3 and TxA3 exerts a preventing platelet aggregation effect and an antithrombotic 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 PGE2 and TxA2, which are well known platelet aggregating agents.
  • 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 antithrombotic activity.
  • Object of this invention is the use of essential fatty acids with a high content in EPA-ethyl ester or DHA-ethyl ester or a high concentration mixture thereof, in the preparation of a medicament useful for preventing mortality, due, for instance, to cardiovascular events or sudden death, in patients who have suffered from a myocardial infarction.
  • this invention therefore provides the use of essential fatty acids with a high content in EPA-ethyl ester or DHA-ethyl ester or a high concentration mixture thereof, in the preparation of a medicament useful for preventing sudden death in patients who have suffered from a myocardial infarction.
  • An essential fatty acid with high content in EPA-ethyl ester or DHA-ethyl ester, according to the present invention preferably contains more than 25% by weight (b.w.), in particular from about 60 to about 100% of such ester.
  • an essential fatty acid with a high concentration mixture of EPA-ethyl ester and DHA-ethyl ester preferably such mixture has a content in EPA+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 about 60% by weight and DHA, preferably in a percentage from about 25 to about 45-50%.
  • the preferred EPA/DHA ratio in such EPA/DHA mixture is about 0.9/1.5.
  • the efficacy of the treatment is, for instance, proven by the fact that a surprising and highly significant reduction in post-infarction mortality was observed by such treatment in a clinical trial that lasted for 3.5 years, with protocols substantially designed as follows:
  • this invention provides a method for preventing mortality in a patient who has survived a myocardial infarction, 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.
  • a medicament containing essential fatty acids with a high content in EPA-ethyl ester or DHA-ethyl ester or a high concentration mixture thereof.
  • sudden death is an important contributor to the mortality rate in patients with cardiac disease, accounting for over 450,000 death per year in the USA.
  • the present invention provides a new and valuable therapeutic tool for preventing sudden death in patients in particular in those who survived acute myocardial infarction.
  • the present invention also provides a method for preventing sudden death in a patient, who is survivor of myocardial infarction, 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-ethyl ester or DHA-ethyl ester or in a mixture thereof.
  • EPA-ethyl ester and DHA-ethyl ester are preferably present as a mixture thereof with a content in EPA+DHA higher than 25% b.w, in particular from about 30 to about 100% b.w., preferably about 85% b.w.
  • the dosage of an essential fatty acid containing a EPA+DHA mixture with 85% b.w. titer for oral administration to a patient may vary from about 0.7 g to about 1.5 g daily, preferably about 1 g daily.
  • This amount of product as EPA+DHA mixture (or amount of EPA-ethyl ester alone or DHA-ethyl ester alone) 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.
  • the medicament e.g. 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.
  • capsules having the composition below and containing 1 g of active ingredient (EPA+DHA, 85% titer) per capsule are prepared.
  • Formulation 1 EPA-ethyl ester 525 mg/capsule; DHA-ethyl ester 315 mg/capsule; d-alpha tocopherol 4 IU/capsule; gelatin 246 mg/capsule glycerol 118 mg/capsule; red iron oxide 2.27 mg/capsule; yellow iron oxide 1.27 mg/capsule

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Fats And Perfumes (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention concerns the use of essential fatty acids with a high content in eicosapentaenoic acid ethyl ester (EPA) or docosahexaenoic acid ethyl ester (DHA) or a high concentration mixture thereof in the preparation of a medicament useful for preventing mortality, in particular due to sudden death, in patients who have suffered from a myocardial infarction.

Description

  • 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 (20:5ω3) eicosapentaenoic acid (EPA) and (22:6ω3) docosahexaenoic acid (DHA) in the prevention of cardiovascular events, especially of mortality in patients who have survived the hospitalization phase of acute myocardial infarction (AMI).
  • It is well known that certain essential fatty acids contained in fish oil have a therapeutic effect in the prevention and treatment of cardiovascular disorders, such as in the treatment of thrombosis, hypercholesterolemia, arteriosclerosis, cerebral infarction and hyperlipemias.
  • U.S. Pat. No. 5,502,077, U.S. Pat. No. 5,656,667 and U.S. Pat. No. 5,698,594 can be quoted as examples.
  • From the above prior art, it is known in particular the utility of fatty acids belonging to the ω-3 family, more specifically (20:5ω3) eicosapentaenoic acid (EPA) and (22:6ω3) docosahexaenoic acid (DHA) in treating the above-mentioned disorders.
  • Indeed EPA, being a precursor of PGI3 and TxA3, exerts a preventing platelet aggregation effect and an antithrombotic 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 PGE2 and TxA2, which are well known platelet aggregating agents.
  • On the other hand 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 antithrombotic activity.
  • International patent application WO89/11521, 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 WO89/11521, are reported to be particularly useful in the treatment of cardiovascular diseases.
  • However, currently used treatments in human therapy have been shown to be insufficient in preventing cardiovascular events, and more specifically mortality, in particular due to sudden death, which happen in patients who have had a myocardial infarction, on account of recurrences after a first acute myocardial infarction episode.
  • Therefore, there still is the need for an effective drug, in particular for preventing these recurrences.
  • Object of this invention, therefore, is the use of essential fatty acids with a high content in EPA-ethyl ester or DHA-ethyl ester or a high concentration mixture thereof, in the preparation of a medicament useful for preventing mortality, due, for instance, to cardiovascular events or sudden death, in patients who have suffered from a myocardial infarction. According to a preferred aspect this invention therefore provides the use of essential fatty acids with a high content in EPA-ethyl ester or DHA-ethyl ester or a high concentration mixture thereof, in the preparation of a medicament useful for preventing sudden death in patients who have suffered from a myocardial infarction.
  • For ease of description “EPA-ethyl ester” and “DHA-ethyl ester” will be also quoted here as “EPA” and “DHA”.
  • An essential fatty acid with high content in EPA-ethyl ester or DHA-ethyl ester, according to the present invention, preferably contains more than 25% by weight (b.w.), in particular from about 60 to about 100% of such ester.
  • These compounds can be obtained by known methods.
  • In an essential fatty acid with a high concentration mixture of EPA-ethyl ester and DHA-ethyl ester, preferably such mixture has a content in EPA+DHA greater than 25% by weight, in particular from about 30 to about 100% by weight, preferably about 85% by weight.
  • In the EPA/DHA mixture, EPA preferably is present in a percentage from about 40 to about 60% by weight and DHA, preferably in a percentage from about 25 to about 45-50%.
  • In any case the preferred EPA/DHA ratio in such EPA/DHA mixture is about 0.9/1.5.
    • Pharmacology
  • The efficacy of the treatment, according to the invention, is, for instance, proven by the fact that a surprising and highly significant reduction in post-infarction mortality was observed by such treatment in a clinical trial that lasted for 3.5 years, with protocols substantially designed as follows:
    • 1 a “control” group received the standard therapy which is usually given to infracted patients;
    • 2 a “treatment” group, besides the therapy that was given to the “control” group, received 85% EPA+DHA (1 g daily);
    • 3 a “treatment” group, besides the therapy that was given to the “control” group received vitamin E; and
    • 4 a “treatment” group, besides the therapy that was given to the control group, received vitamin E and 85% EPA+DHA (1 g daily).
  • In fact the group of patient “treated” according to protocol 2 showed, in comparison to “control” group 1, a decrease of about 20% in total mortality, with a decrease of about 40% of mortality due to sudden death and a notable reduction in mortality due to other cardiovascular events.
  • On the contrary, no significant results were achieved in group 3 as compared to the control group 1, whereas there was a reduction in total mortality of about 19% in group 4 as compared to the control group, with results that were similar to those obtained in treated group 2. From the above clinical results, the person skilled in the art will appreciate that, the use of a pharmaceutical composition in accordance to the present invention is certainly useful in human therapy in preventing mortality in patients who have suffered from a myocardial infarction.
  • Accordingly, this invention provides a method for preventing mortality in a patient who has survived a myocardial infarction, 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. As known, sudden death is an important contributor to the mortality rate in patients with cardiac disease, accounting for over 450,000 death per year in the USA.
  • About 80% of such patients, particularly those survivors of acute myocardial infarction with low ventricular ejection fractions, are at high risk of sudden death or reinfarction.
  • The above clinical results show that the present invention provides a new and valuable therapeutic tool for preventing sudden death in patients in particular in those who survived acute myocardial infarction.
  • Accordingly, as a preferred aspect, the present invention also provides a method for preventing sudden death in a patient, who is survivor of myocardial infarction, 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, according to the invention, can either have a high content, for instance more than 25% b.w., in EPA-ethyl ester or DHA-ethyl ester or in a mixture thereof. However EPA-ethyl ester and DHA-ethyl ester are preferably present as a mixture thereof with a content in EPA+DHA higher than 25% b.w, in particular from about 30 to about 100% b.w., preferably about 85% b.w.
  • Based on the obtained clinical results, according to a preferred aspect of the invention, the dosage of an essential fatty acid containing a EPA+DHA mixture with 85% b.w. titer for oral administration to a patient may vary from about 0.7 g to about 1.5 g daily, preferably about 1 g daily. This amount of product as EPA+DHA mixture (or amount of EPA-ethyl ester alone or DHA-ethyl ester alone) 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.
  • The medicament, e.g. 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 following examples illustrate preferred formulations for oral administration, but do not intend to limit the invention in any way.
    • Gelatin Capsules
  • According to known pharmaceutical techniques, capsules having the composition below and containing 1 g of active ingredient (EPA+DHA, 85% titer) per capsule are prepared.
  • Formulation 1
    EPA-ethyl ester 525 mg/capsule;
    DHA-ethyl ester 315 mg/capsule;
    d-alpha tocopherol 4 IU/capsule;
    gelatin 246 mg/capsule
    glycerol 118 mg/capsule;
    red iron oxide 2.27 mg/capsule;
    yellow iron oxide 1.27 mg/capsule
  • Formulation 2
    Ethyl esters of poly- 1000 mg
    unsaturated fatty acids
    with content in ethyl esters
    of ω-3 poly-unsaturated esters
    (eicosapentaenoic EPA,
    docosahexaenoic (DNA) 850 mg
    d-1-α tocopherol 0.3 mg
    gelatin succinate 233 mg
    glycerol 67 mg
    sodium p-oxybenzoate 1.09 mg
    sodium propyl p-oxobenzoate 0.54 mg

Claims (18)

1. A method for preventing mortality in a patient who has survived a myocardial infarction, comprising administering to said patient a therapeutically effective amount of a medicament containing essential fatty acids containing a mixture of eicosapentaenoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester (DHA) wherein the content in EPA+DHA in such mixture is greater than 25% b.w.
2. A method according to claim 1, wherein the content in EPA+DHA in such mixture is from about 30 to about 100% b.w.
3. A method according to claim 1, wherein the content in EPA+DHA in such mixture is about 85% b.w.
4. A method according to claim 1, wherein the medicament is administered orally.
5. A method according to claim 3, wherein the medicament is administered orally at a dosage from about 0.7 g to about 1.5 g daily.
6. A method according to claim 5, wherein the EPA/DHA ratio in the EPA+DHA mixture is about 0.9/1.5.
7. A method for preventing sudden death in a patient, who is survivor of myocardial infarction, comprising administering to said patient a therapeutically effective amount of a medicament containing essential fatty acids containing a mixture of eicosapentaenoic acid ethyl ester (DPA) and docosahexaenoic acid ethyl ester (DHA), wherein the content in EPA+DHA in such mixture is greater than 25% b.w.
8. A method according to claim 7, wherein the content in EPA+DHA in such mixture is from about 30 to about 100% b.w.
9. A method according to claim 7, wherein the content in EPA+DHA in such mixture is about 85% b.w.
10. A method according to claim 7, wherein the medicament is administered orally.
11. A method according to claim 9, wherein the medicament is administered orally at a dosage from about 0.7 g to about 1.5 g daily.
12. A method according to claim 11, wherein the EPA/DHA ration in the EPA+DHA mixture is about 0.9/1.5.
13. A method for preventing morality in a patient who has survived a myocardial infarction, comprising administering to said patient a therapeutically effective amount of a medicament containing essential fatty acids with a content in eicosapentaenoic acid ethyl ester (EPA) or in docosahexaenoic acid ethyl ester (DHA) greater than 25% b.w.
14. A method according to claim 13, wherein the contention EPA or DHA is form about 60 to about 100% b.w.
15. A method according to claim 13, wherein the medicament is administered orally.
16. A method for preventing sudden death in a patient who is survivor of myocardial infarction, comprising administering to said patient a therapeutically effective amount of a medicament containing essential fatty acids with a content in eicosapentaenoic acid ethyl ester (EPA) or docosahexaenoic acid ethyl ester (DHA) greater than 25% b.w.
17. A method according to claim 16, wherein the content in EPA or DHA is from about 60 to about 100% b.w.
18. A method according to claim 16, wherein the medicament is administered orally.
US12/192,627 1999-02-17 2008-08-15 Essential fatty acids in the prevention of cardiovascular events Abandoned US20090018193A1 (en)

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IT1999MI000313A IT1308613B1 (en) 1999-02-17 1999-02-17 ESSENTIAL FATTY ACIDS IN THE PREVENTION OF CARDIOVASCULAR EVENTS.
ITMI99A000313 1999-02-17
PCT/EP2000/000957 WO2000048592A1 (en) 1999-02-17 2000-02-07 Essential fatty acids in the prevention of cardiovascular events
US86933301A 2001-07-26 2001-07-26
US12/192,627 US20090018193A1 (en) 1999-02-17 2008-08-15 Essential fatty acids in the prevention of cardiovascular events

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US20090264520A1 (en) * 2008-04-21 2009-10-22 Asha Lipid Sciences, Inc. Lipid-containing compositions and methods of use thereof
US8715648B2 (en) 2011-02-16 2014-05-06 Pivotal Therapeutics Inc. Method for treating obesity with anti-obesity formulations and omega 3 fatty acids for the reduction of body weight in cardiovascular disease patients (CVD) and diabetics
US8951514B2 (en) 2011-02-16 2015-02-10 Pivotal Therapeutics Inc. Statin and omega 3 fatty acids for reduction of apolipoprotein-B levels
US8952000B2 (en) 2011-02-16 2015-02-10 Pivotal Therapeutics Inc. Cholesterol absorption inhibitor and omega 3 fatty acids for the reduction of cholesterol and for the prevention or reduction of cardiovascular, cardiac and vascular events
US9119826B2 (en) 2011-02-16 2015-09-01 Pivotal Therapeutics, Inc. Omega 3 fatty acid for use as a prescription medical food and omega 3 fatty acid diagniostic assay for the dietary management of cardiovascular patients with cardiovascular disease (CVD) who are deficient in blood EPA and DHA levels
US20160074148A1 (en) * 2009-09-08 2016-03-17 Atrium Medical Corporation Hernia patch

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Publication number Priority date Publication date Assignee Title
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