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Palmitoylethanolamide (PEA)
CAS No.: 544-31-0
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Other names:
Palmidrol;
Palmitamide MEA;
N-(2-Hydroxyethyl)hexadecanamid;
N-(2-Hydroxyethyl)hexadecanamide;
Hexadecanamide, N-(2-hydroxyethyl)-;
Hydroxyethylpalmitamide;
N-Palmitoylethanolamine

Health benefits of palmitoylethanolamide

Palmitoylethanolamide is a natural pleiotropic compound. It’s a “magic shotgun” capable of modulating numerous complex systems by hitting different important cellular targets simultaneously. Oral supplementation with palmitoylethanolamide is an interesting alternative or worthwhile complementary strategy in the treatment of a large number of disease states, especially chronic pain, inflammation and degenerative diseases of the central nervous system.

Merits of palmitoylethanolamide supplementation

Scientific studies and experimental data have shown that palmitoylethanolamide is an effective natural dietary supplement in the treatment of a large number of disorders. These range from chronic pain and inflammation to influenza and the common cold. The fact that the protective effects of palmitoylethanolamide on cell and tissue health were retained throughout the evolution of eventually all plant and animal life may explain its very broad applicability and lack of side effects.

Though not all mechanisms of action have been fully clarified, current clinical opinion cites palmitoylethanolamide as a way of capitalizing on nature’s defense mechanisms. Tackling inflammation effectively requires one to commandeer nature’s own anti-inflammatory mechanisms to induce a ‘dominant’ program of resolution. One such program involves local production of lipid mediators, including palmitoylethanolamide, capable of switching off inflammation when it exceeds its natural function of damage control and itself becomes part of the problem.

A large body of literature documents the beneficial effects of exogenously administered palmitoylethanolamide in experimental models of a variety of acute and chronic inflammatory pain syndromes. Whether these effects can ultimately be attributed to correction of local depletion, to boosting of normal tissue values, or to still other mechanisms, continues to be studied and may vary from one indication to the other—which also means: from one stage or course (acute/chronic) to the next.

The pleiotropic nature of palmitoylethanolamide can also be described as a “shotgun” because it hits different important cellular targets simultaneously. Moreover, research has confirmed the ‘entourage hypothesis’ suggesting that palmitoylethanolamide may act as an enhancer of the anti-inflammatory and antinociceptive activity exerted by other endogenous substances via the inhibition of their metabolic degradation. The effects of palmitoylethanolamide can thus be contrasted to the “magic bullet” approaches seen in the development of many pharmaceuticals. This makes oral supplementation with palmitoylethanolamide an interesting alternative or worthwhile complementary, strategy in the treatment of a large number of disease states.

Palmitoylethanolamide in the human body

Palmitoylethanolamide can be produced in almost every cell by on-demand synthesis when needed, and in the amounts that are needed. Its production is naturally increased in situations where cells or tissues are damaged, or are threatened to become damaged. The metabolism of palmitoylethanolamide in cells is not complex. Cells can synthesize palmitoylethanolamide from fat-like substances already present in the cell membrane via the precursor n-acylphosphatidylethanolamine (NAPE). Degradation is simple as well: any cell that can synthesize palmitoylethanolamide has access to the fatty acid amide hydrolase (FAAH) enzyme. This enzyme can break palmitoylethanolamide down to its building blocks which can then be reintegrated in the cell membrane.

Palmitoylethanolamide restores unbalanced regulatory biological processes that may be disturbed, acutely or chronically, by a host of endogenous and exogenous mechanisms. This is achieved via impact on a particular nuclear receptor, the PPAR receptor. This nuclear receptor restores biochemical balance in cells and thereby preventing an excess of inflammatory factors and pain-promoting substances. Activation of this nuclear receptor plays an important role in analgesia.

Additional specific cellular targets of palmitoylethanolamide are mast cells and glial cells. Excessive activation of these cells are important factors in chronic pain. In fact, it has been known for several years that these satellite, non-neuronal cells may maintain chronic pain. Palmitoylethanolamide inhibits any excessive activity of these inflammatory cells. It restores their normal activity, thereby considerably decreasing the reactivity of chronic pain systems throughout the body. In addition to PPAR receptor activation and the calming effect on particularly mast cells and glial cells, many other mechanisms of action have been identified.

Recommended use of palmitoylethanolamide

General palmitoylethanolamide dosing guidelines are as follows:
    ●Initial dose: 1200 mg per day, with or without food, for the first 6 weeks.
    ●Maintenance dose: 600 mg per day, with or without food.
A minimum dose of 20 mg per kg of body weight and maximum dose of 100 mg per kg of body weight can be used for a more individualized approach.

Safety of palmitoylethanolamide

Since 1972 dozens of clinical trials reported in the medical literature, involving thousands of patients have documented the benefits of palmitoylethanolamide. These have shown that palmitoylethanolamide is an effective and safe natural compound to use. In these studies, many of which included elderly and child subjects, no negative side effects have been identified.

In clinical studies, doses up to 100 mg per kg of body weight per day have been used without any adverse effects that could be distinguished from placebo effects. The LD50 is not determinable because the substance is a natural fat.

Whether it is safe to use palmitoylethanolamide during pregnancy or lactation is still insufficiently investigated. For individuals who suffer from renal or hepatic conditions it is generally advised to start cautiously with a single daily dose of 400 mg and increase slowly. To date, no adverse interactions between palmitoylethanolamide and regular medicines have come to light.

History of palmitoylethanolamide

The analgesic and anti-inflammatory properties of palmitoylethanolamide have been known for decades but they were initially poorly understood. During the 1990s Italian Nobel Prize laureate Dr. Rita Levi-Montalcini caused renewed worldwide attention among researchers when she showed for the first time that palmitoylethanolamide may control overactive inflammatory cells in many diseases. This insight was the engine behind the clinical revival of palmitoylethanolamide over the past decades.

Renewed research led to a number of clinical trials which clarified the value and the safety of palmitoylethanolamide as a treatment modality in chronic pain care. Many of the early publications and clinical research reports on palmitoylethanolamide were published in Italian. This, as well as the complex biology, explains why it stayed under the medical radar for years. Today there is a solid and growing Anglophone and international research base.

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