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WHAT E-EPA IS AND WHAT IT IS USED FOR
E-EPA 500 or 650mg is a vacuum distilled Omega -3. A dietary supplement rich in Omega-3 fatty acids, 70 % pure EPA.
Unmatched in strength and purity when compared to other omega-3 products. Pharmaceutical grade fish oil, especial support for emotional health.
What is In the Pack?
60 capsules in hygienic blisters, which is equivalent to 2 months supply.
Composition
Each capsule contains the amazing amount of 70 % (500 or 650mg) pure vacuum destilled E-EPA plus vitamin E as antioxidant and 5 ĩg vitamin D.
Application/Dosage Advice
One capsule daily, unless an increased dosage is recommended by a health professional.
(One gram of E-EPA corresponds to approximately 5.5 grams of fish-oil concentrate or 10 grams (approximately 2 teaspoons) of cod liver oil.)
Before Taking
For external products: As with all skin products, a patch test for allergies should be made before use.
For Dietary supplements: If you are taking any other medication, you should consult your doctor before taking any dietary supplements.
Adverse side-effects: None. Neither the product nor the method contradict any medical condition nor medication.
How to Store
Store away from children.
Keep out of the direct light.
Ethyl-EPA, the novel pharmaceutical fish oil to support mental health
A pharmaceutical preparation comprising EPA in an appropriately assimilable form where of all the fatty acids present in the preparation at least 70%, and preferably at least 90%, is in the form of EPA and where no DHA is provided for the treatment of a psychiatric or central nervous disorder. In Japan Ethyl-EPA is widely used in for the treatment of cardiovascular disorders and autoimmune diseases like systemic lupus erythematoides (SLE) and ulcerative colitis (UC). Ethyl-EPA may be administered with any conventional drugs to improve their efficacy or reduce their side effects.
A vacuum distilled fish oil preparation comprising EPA (E-EPA) in an appropriately assimilable form, wherein of all the fatty acids present in the preparation at least 70% is in the form of EPA, and where nil docosahexaenoic acid (DHA) and nervonic acid (NA) and less than 5% arachidonic acid (AA) are present. E-EPAacts primarily on neurotransmitter metabolism or receptors, wherein an enhanced effect is obtained.
What is EPA?
EPA is a fatty acid containing 20 carbon atoms and 5 double bonds, all in the cis-configuration. The double bonds are located at the 5, 8, 11, 14 and 17 positions and the full chemical name is therefore all cis (or all z) 5, 8, 11, 14, 17-eicosapentaenoic acid (or sometimes icosapentaenoic acid). The abbreviation which is always used is EPA. EPA is one of the highly unsaturated fatty acids. The reactions which convert alpha-linolenic acid to EPA are slow in humans and only a very small proportion of dietary a-linolenic acid is converted to EPA. EPA is also found in marine micro-organisms and, via the food chain, makes up between 3% and 30% of natural marine oils derived from oily fish and marine mammals. EPA is found linked to many different chemical structures. It can be found in the form of phospholipids, tri, di- and monoglycerides, amides, esters of many different types, salts and other compounds. In each case the EPA moiety can normally be split from the complex molecule to give the free acid form which can then be linked again to other complex molecules.
Purification of EPA
Traditional fish oils, often marketed as Omega-3`s, contain 15 to 35% EPA whereas Ethyl-EPA preparations have at least 70%, preferably 90% EPA. The purification of EPA is difficult and complex. Because its five double bonds must all be in the right positions in the carbon chain and must all be in the cis configuration, EPA is difficult to synthesize. In nature EPA is almost always found mixed with other fatty acids in the forms of triglycerides and phospholipids. The principles of purification of EPA are well known to those skilled in the art and include low temperature crystallisation, urea fractionation, lithium crystallisation, fractional distillation, high pressure liquid chromatography, supercritical carbon dioxide chromatography and various other forms of chromatography using silica gels and other column packings. The application of these known techniques has been difficult to apply in practice on a large scale and only recently has pure EPA become available for testing in psychiatric and CNS disorders. In one version of the purification process, natural fish oil triglycerides rich in EPA are saponified and the fatty acids converted to the ethyl ester form. A preparation enriched in ethyl EPA is then prepared by molecular distillation with collection of the appropriate fraction. This fraction is then converted to a preparation containing over 80% of ethyl EPA by urea precipitation. The final preparation of more than 96% pure ethyl EPA may then be achieved by either silica gel chromatography or high pressure liquid chromatography.
Ethyl-EPA as adjunct treatment in mental health
Even though many new drugs have been discovered over the past twenty years, psychiatric disorders are still relatively poorly treated. With most psychiatric illnesses, drug treatments do not treat all patients successfully. This is true of schizophrenia, schizoaffective and schizotypal disorders, bipolar disorder (manic-depression), unipolar depression, dementias, panic attacks, anxiety, sleep disorders, attention, hyperactivity and conduct disorders, autism, personality disorders, and all other psychiatric conditions. For example, in depression, standard drugs achieve a 50% reduction in standard depression scores in about two thirds of patients: the others do not respond. In schizophrenia, the average improvements are only of the order of 20-30% although individual patients may do much better than this. The same is true of neurological disorders like Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, stroke, epilepsy and Huntington's disease. Again, many patients fail to respond to existing treatments, or respond only to a limited degree. In none of these conditions do existing drugs reliably produce a complete remission of symptoms. There is therefore a great need for new treatments, particularly ones which have novel mechanisms of action.
Why Ethyl-EPA, why not traditional fish oil or enriched DHA?
In recent years attention has been drawn to the value of a particular fatty acid, eicosapentaenoic acid (EPA), and its derivatives, in the treatment of schizophrenia, depression and dementias. EPA seems to be the only omega-3 fatty acid exerting antidepressive and antispychotic action. In the 1990īs Professor Malcolm Peetīs team at Sheffield University, UK, unexpectedly found that an oil enriched in EPA was of value in treating schizophrenia, while an oil enriched in the closely related fatty acid, docosahexaenoic acid (DHA), was not. This was surprising because on one hands DHA is found in large amounts in human brain whereas EPA is found only in trace quantities and on the other the DHA levels in the red blood cells of mental patients are significantly lower than those of healthy controls. It was therefore anticipated that supplementation with DHA would be effective but EPA would not. In fact the opposite was found, not only at Sheffield but also elsewhere. It is therefore important in treatment of psychiatric disorders to use pure or nearly pure EPA and EPA derivatives. DHA and related fatty acids may not only be ineffective but may actually reduce the efficacy of EPA and its derivatives. A number of eminent psychiatrists recommend EPA and its derivatives for the treatment of psychiatric disorders. The EPA may be in the form of ethyl-EPA. Such pharmaceutical preparations may be used for the treatment of a psychiatric or central nervous system disorder, including: schizophrenia, schizoaffective disorder or a schizotypal disorder; depression or manic-depression (bipolar disorder); anxiety or panic disorder or social phobia, or a sleep disorder or an attention deficit, conduct, hyperactivity or personality disorder; autism; Alzheimer's disease, vascular dementia or another dementia, including multi-infarct dementia, Lewy body disease and diseases attributable to prion disorders; Parkinson's disease, or other motor system disorder; multiple sclerosis; stroke; epilepsy; and Huntington's disease or any other neuro-degenerative disorder.
Combination with psychopharmaca
Ethyl-EPA may be administered with any drug known to have an effect on the treatment of psychiatric or central nervous system disorders to improve the efficacy of the drug or reduce its side effects.
Ethyl-EPA may advantageously coadministered with other drugs used in psychiatry and neurology. Such drugs may include drugs of the typical or atypical neuroleptic class such as chlorpromazine, haloperidol, risperidone, olanzapine, sertindole, ziprasidone, zotepine or amisulpiride. thioxanthene, sulpiride, droperidol, perphenazine, loxapine, thioridazine, fluphenazine, pericyazine, methotrimeprazine or pimozide among others: clozapine; drugs which have antidepressant actions including tricyclic and related antidepressants, noradrenaline reuptake inhibitors, serotonin reuptake inhibitors, monoamine oxidase inhibitors and drugs with atypical antidepressant actions: drugs for sleep disorders, anxiety disorders, panic disorders, social phobias, conduct disorders, personality disorders and attentional deficit hyperactivity disorder; drugs for any form of dementia, including Alzheimer's disease, vascular and multi-infarct dementias, Lewy body disease and other dementias; drugs for any form of neurological disease including Parkinson's disease, multiple sclerosis, Huntington's disease and other neurodegenerative disorders.
EPA and other drug may be taken together, so that a daily dose of EPA of 0.1 g to 10 g per day, and preferably of 0.5 g to 5 g per day, is provided with the normal daily dose of the other drug. When supplied alone, the useful daily dose of EPA may be 0.5 g to 4 g/day. Even larger doses, up to 10 g/day are safe.
Ethyl-EPA and neuronal transmission
Phospholipids are the main components of nerve cell membranes. In nerve cells the middle carbon atom of phospholipids, known as Sn2, is usually attached to a highly unsaturated fatty acid (HUFA) such as DHA, arachidonic acid (AA), and sometimes EPA. HUFAs are fatty acids containing 18-26 carbon atoms and three or more double bonds. When nerve cells are activated, for example by dopamine or serotonin, the activity of a group of enzymes collectively known as phospholipase A2 (PLA2) is frequently increased. PLA2 releases the HUFA from the Sn2 position, giving a free molecule of HUFA and a molecule of what is known as a lysophospholipid (LyPL) (a phospholipid without a fatty acid attached to the Sn2 position). Both of these molecules can be highly active cell signalling agents themselves, and can change cell function in a number of different ways. In addition, the HUFA can be converted to prostaglandins, leukotrienes, hydroxy acids and a whole range of short-lived molecules which regulate neuronal function. For example, one of these molecules derived from arachidonic acid, leukotriene C4, seems to be absolutely required for normal nerve cell growth and development. If cell function is to be normal, it is important that this activation should be temporary and should be terminated by removing the free HUFA and the LyPL. Otherwise membrane damage may result because the LyPL can be destructive. Furthermore the free HUFAs are easily oxidised to highly active free radicals which can do great damage. There is an emerging consensus that such membrane damage is a fundamental pathological basis for many neurodegenerative disorders, including Alzheimer's disease and other dementias, Parkinson's disease, stroke, Huntington's disease, all types of ischaemic damage, and multiple sclerosis. A range of initiating causative factors may all cause damage by the same common route. Phospholipid breakdown to LyPLs and free HUFAs may also be important in epilepsy. The signal transduction processes involving HUFAs and LyPLs are terminated in most cases by a two sequence reaction. First, the HUFA is linked to coenzyme A by a group of enzymes known as fatty acid coenzyme A ligases (FACLs). These enzymes are also known as acyl-CoA synthetases. The HUFA-coenzyme A derivative is then linked to the LyPL by a group of enzymes known as acyl CoA: lysophospholipid acyltransferases (ACLATs) which liberate coenzyme A in the process. This sequence thus removes from the nerve cell the HUFAs and the LyPLs and brings to an end the events associated with signal transduction, so preparing the neuron for the next stimulus.
The phospholipid theory of mental illnesses
There is now a substantial amount of evidence which demonstrates that in the three major psychotic mental illnesses there is increased activity of one or more of the phospholipase group of enzymes and particularly in one or more of the PLA2 group. These three illnesses are schizophrenia, bipolar disorder and major depression: the three disorders are often found together in the same families, and often have overlapping ranges of symptoms. It has long been thought that at least part of their biochemical basis is common to all three disorders and it is possible that the PLA2 abnormality constitutes that common factor. In schizophrenia, there are increasing circulating levels of PLA2 in the blood. In bipolar disorder, lithium, which is the main established treatment, has been shown to inhibit the activity of PLA2. In major depression, there is depletion of HUFAs of the n-3 series from membranes, coupled with activation of inflammatory responses which occurs with enhanced activity of PLA2. Each of those illnesses, however, involves more than one biochemical abnormality: while a PLA2 or related phospholipase abnormality may be common to all three, the other abnormalities are probably specific to each disease. In schizophrenia, it has recently been discovered that there is a second abnormality in the fatty acid cycle. This is a deficit in function of FACL-4, the enzyme which links HUFAs to coenzyme A in human brain. It is known that there is a defect in the incorporation of HUFAs into phospholipids in schizophrenia but the precise enzyme has not been known. However, FACL-4 is found in brain, is specific for HUFAs, and when absent produces both brain abnormalities and also minor physical abnormalities such as a high arched palate which are typical of patients with schizophrenia. It is the combined presence of both the enzyme abnormalities which produces the disease. The second or other abnormalities in bipolar disorder and in major depression are not yet known. Another phospholipase, PLC, which acts at the Sn3 position to liberate inositol phosphates and diacylglycerol may be involved in bipolar disorder. Both of these molecules, like LyPL and HUFAs, are involved in cell signalling: overactivation of both PLC and PLA2 is likely to be related to bipolar disorder. In the neurodegenerative conditions there appears to be an uncontrolled activation of membrane degrading enzymes like phospholipases, coupled with increased formation of free radicals associated with the oxidation of HUFAs and the membrane damage produced by LyPL. This type of phenomenon, with membrane damage associated with excess phospholipase activity, has been well described by many investigators in Alzheimer's disease and other dementias, in multiple sclerosis, in stroke and other brain disorders caused by ischaemia or injury, in Parkinson's disease, in epilepsy and in Huntington's disease. In attention deficit disorder, also known as hyperactivity, there are deficits in the blood of the highly unsaturated fatty acids which can be acted upon by phospholipases. In all of these situations, therefore, there is some evidence of increased phospholipase activity and signal transduction activity which may not be terminated in a normal way. Thus the phospholipases, FACLs and acyl-transferases present new targets for drug action. Our observation that EPA-enriched materials are beneficial in psychiatric disorders may therefore be explained in several ways:
EPA is known to inhibit phospholipase A2 and so will help to down regulate the initial activation process. Interestingly, in this assay system, the related fatty acid docosahexaenoic acid (DHA) had no effect. The role of docosahexaeonic acid (DHA) is enigmatic, as it is autooxidized and may promote production of a newly discovered class of neurotoxic substances known as isoprostanes. On the other hand DHA may turn into a "good" substance called neuroprotectin D1.
EPA has an unusually high affinity for the human brain enzyme FACL-4. Usually with enzymes which act on HUFAs, the activities with HUFAs like EPA, DHA and AA are similar, or very frequently, DHA and AA are more active than EPA. With FACL-4, however, activity for AA was more than twice as great as for DHA, whereas that for EPA was 50% greater than for AA. This means that EPA will more readily than other HUFAs enter the cycle, form an EPA-CoA derivative, link to LyPL and so terminate the activity of free LyPL. Thus EPA will, more effectively than other HUFAs, stop the activation once it has started.
Because EPA will compete with AA for incorporation into the Sn2 position of phospholipids, EPA will also reduce the amount of AA incorporated into that position. This is likely to be particularly important in depression, where AA levels are relatively or absolutely abnormally high.
EPA itself is a HUFA which can be converted to desirable compounds like prostaglandin I3 (PGI3) and prostaglandin E3 (PGE3) which have a range of anti-inflammatory and antithrombotic actions which may be particularly useful in neurodegenerative disorders and in depression. The compounds derived from EPA appear to be less potentially harmful than the equivalent compounds derived from AA. Replacement of AA by EPA is therefore likely to be of particular value in all the neurodegenerative disorders described above, where at least part of the damage is attributable to overactive phospholipases which release AA which can then be converted to pro-inflammatory compounds.
EPA is also known to form a potent anti-inflammatory nanomolecule known as resolving E1. This may explain many of its beneficial functions in the body as chronic inflammation seems to be present in almost all chronic disorders..
Why has research yielded mixed results?
Conventionally, most studies on the uses of EPA and related fatty acids have used traditional omega-3 products and materials partially enriched in EPA but also containing substantial amounts of other fatty acids, especially docosahexaenoic acid (DHA) which is found alongside EPA in most natural oils. In traditional fish oils the DHA:EPA ratio is 3:2. The fatty acids have usually been in the triglyceride or ethyl ester forms, and occasionally in the free acid and phospholipid forms. Arachidonic acid (AA), Docosapentaenoic acid (DPA n-3), Nervonic acid (NA) are also a common component of such materials. The new understanding of possible mechanisms of action of EPA, however, has led to the realisation that the purer is the EPA the better is likely to be the activity. This is not just a question of dose, although that is indeed a valuable aspect of the application of pure EPA. From the point of view of a patient, particularly a mentally disturbed patient, it is obviously better to give, say, 1 g of EPA as a 90% pure preparation than, say, 5 g of a 20% pure preparation providing the same total amount of EPA. The patient is much more likely to comply with the lower volumes required with the highly purified compound. More importantly, other fatty acids such as AA, DPAn-3, and DHA, which are relatively similar in structure to EPA, but do not share the same spectrum of biological activity, compete with EPA for binding to the active sites of all the relevant enzymes. Thus these other fatty acids will compete with EPA for occupation of these active sites and reduce its activity. The purer the preparation of EPA the more likely is it to occupy the relevant active binding sites, and the more likely is it to be able to have desirable biological effects.
Conclusions
1. Ethyl-EPA has strong therapeutic effects in its own right on schizophrenia, bipolar disorder, depression, attention deficit disorder and dementia. Like other drugs with antipsychotic actions it is likely to have some beneficial effects in most psychiatric disorders and also in neurological disorders associated with membrane damage. These include the various types of dementia (including Alzheimer's disease, multi-infarct vascular dementia and Lewy body disease), multiple sclerosis, Parkinson's disease and Huntington's chorea.
2. Ethyl-EPA enhances the beneficial effects of a wide range of psychiatric and neurological drugs. This makes a great deal of sense since it is increasingly apparent that many abnormalities in psychiatry and neurology lie beyond the neurotransmitter receptor in the signal transduction systems of neurons and other cells. EPA acts on, these signal transduction systems, providing a rational explanation for the positive interactions between EPA and other drugs.
3. Ethyl-EPA has the ability to reduce the adverse effects of psychiatric and neurological drugs. The mechanism is unknown but it appears to be a relatively general phenomenon as it has been noted with drug-induced obesity, movement disorders, sedation, dysphoria and salivation.
Although the reports of the effects of ethyl-EPA are convincing and in some cases dramatic, unequivocal proof of its efficacy must come from randomised, placebo-controlled trials. The studies published so far are presented in tables 1 and 2. As can be seen, the EPA groups did substantially better than the placebo group. E-EPA (ethyl-EPA) was effective in reducing symptoms of schizophrenia, symptoms of depression and side effects of existing drugs. These results therefore confirm the individual patient reports and demonstrate unequivocally that E-EPA has a strong therapeutic effect. Of particular note is the fact that there were no reported side effects attributable to the E-EPA and no differences at all between placebo and active treatment in the side effects which were reported. This means effectively that, in dramatic contrast to almost all other drugs used in psychiatry or neurology, EPA has no important side effects at all. The present review has identified ethyl-EPA as being highly effective. However, it is likely that any form of highly purified EPA which is able to raise EPA levels in the blood is of value in psychiatric disorders. These EPA compounds will all be of value in the treatment of psychiatric and neurological disorders when prepared in pure form. It will always be important to keep to the absolute minimum the presence of related fatty acids, which might interfere with the EPA. There should be less than 5% and preferably less than 3% of DHA, DPA or AA or other competing fatty acids individually. In aggregate there should be less than 10% and preferably less than 5% of these competing fatty acids. Ethyl-EPA in 70% and preferably 90% or even purer forms, may be administered orally soft gelatin capsules. For children or adults, who cannot swallow capsules, the capsules may be pierced and the pil be pressed out. The capsule may also be chewed and the shell spitted out.
Other applications Omega-3 fatty acids like EPA may be valuable in the treatment of inflammatory disorders of the joints, respiratory system, gastro-intestinal system, kidneys, skins, reproductive system and all other organs.
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