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Review Article Palmitoylethanolamide: a Natural Body-Own Anti-Inflammatory Agent, Effective and Safe Against Influenza and Common Cold

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Review Article Palmitoylethanolamide: a Natural Body-Own Anti-Inflammatory Agent, Effective and Safe Against Influenza and Common Cold Hindawi Publishing Corporation International Journal of Inflammation Volume 2013, Article ID 151028, 8 pages http://dx.doi.org/10.1155/2013/151028 Review Article Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold J. M. Keppel Hesselink,1 Tineke de Boer,2 and Renger F. Witkamp3 1 Faculty of Medicine, University Witten/Herdecke, Alfred-Herrhausen-Straße 50, 58448 Witten, Germany 2 DepartmentofResearchandDevelopment,InstituteforNeuropathicPain,Spoorlaan2a,3735MVBoschenDuin,TheNetherlands 3 Division of Human Nutrition (Bode 62), Wageningen University, P.O. Box 8129, 6700 EV Wageningen, The Netherlands Correspondence should be addressed to J. M. Keppel Hesselink; [email protected] Received 3 April 2013; Revised 9 June 2013; Accepted 10 June 2013 Academic Editor: Juan Carlos Kaski Copyright © 2013 J. M. Keppel Hesselink et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Palmitoylethanolamide (PEA) is a food component known since 1957. PEA is synthesized and metabolized in animal cells via a number of enzymes and exerts a multitude of physiological functions related to metabolic homeostasis. Research on PEA has been conducted for more than 50 years, and over 350 papers are referenced in PubMed describing the physiological properties of this endogenous modulator and its pharmacological and therapeutical profile. The major focus of PEA research, since the work of the Nobel laureate Levi-Montalcini in 1993, has been neuropathic pain states and mast cell related disorders. However, it is less known that 6 clinical trials in a total of nearly 4000 people were performed and published last century, specifically studying PEA as a therapy for influenza and the common cold. This was done before Levi-Montalcini’s clarification of PEA’s mechanism of action, analyzing the role of PEA as an anti-inflammatory agent. We will review in depth these studies, as the results support the effectiveness and safety of PEA in flu and respiratory infections. 1. Introduction PEAisunderevaluationasanutraceuticalforinflammatory bowel syndrome (proposed brand name Recoclix, CM&D Palmitoylethanolamide (PEA) is a food component known Pharma Ltd.; Nestle).´ for more than 50 years. PEA is synthesized and metabolized Research on PEA has been conducted since its discovery by different animal cell types and also present in plants. and over 350 papers are referenced in PubMed describing its It exerts a multitude of physiological functions related to physiological properties and role as endogenous modulator metabolic and cellular homeostasis. PEA was already iden- as well as its pharmacological and therapeutic effects. PEA is tified in the 50s of the last century as a therapeutic substance an interesting anti-inflammatory therapeutic substance and with potent anti-inflammatory properties. Since 1970, the might also hold great promise for the treatment of a number anti-inflammatory and other immune-modulating properties of (auto)immune disorders, including inflammatory bowel of PEA have been shown in a number of placebo-controlled disease and inflammatory diseases of the CNS. In this paper, double-blind clinical trials on influenza and common cold. we will review the role of PEA as an anti-inflammatory agent Positive results coincided with the clinical use of PEA in and as potential treatment for influenza and the common former Czechoslovakia under the brand name Impulsin. cold. The main purpose is to highlight and discuss these Since 2008, PEA has been marketed as a food for special earliest findings, including the 6 double blind studies in these medical purposes in Italy and Spain, under the brand name indications published in the last century using Impulsin. Normast (Epitech Srl). Recently, a food-supplement named Although nearly forgotten, these findings could offer new PeaPure was introduced (JP Russell Science Ltd.). In the USA, insights or perhaps even alternative options in the light of 2 International Journal of Inflammation the intense debate around the efficacy and safety of the nature of the acid group appeared to them to be of no oseltamivir and zanamivir In the present paper, we will importance because in addition to ethanolamine itself, N-(2- discuss the evolution of knowledge on the anti-inflammatory hydroxyethyl)-lauramide, S-(2-hydroxyethyl)-salicylamide, activity of PEA and its effects in the treatment of respiratory and N-(2-hydroxyethyl)-acetamide all had potent anti- infections. inflammatory properties. These pharmacological properties of the ethanolamine-derivatives appeared to be quite specific 2. The Early Years: Anti-Inflammatory Activity since other homologs did not show a biological response in of Egg-Yolk Based on a Lipid-Fraction the assay. The protective and anti-inflammatory effects of PEA can 3. The Protective Effects of ‘‘Proto-PEA’’ in betracedbackintheliteratureto1939[1]. The American bacteriologists Coburn and Moore demonstrated in that year Streptococcal Infections that feeding dried egg yolk to underprivileged children living Coburn was dedicated to find the cause and prevention of in poor parts of New York City prevented the recurrence rheumatic fever [7]. He presented his hypothesis that eggs of rheumatic fever, in spite of repeated attacks of hemolytic contained an important protective factor against infection, streptococcal infection. especially in rheumatic fever, in 1960 in the Lancet [2]. He After 1939, Coburn et al. studied 30 children at a con- argued that valescent rheumatic home and prescribed four egg yolks daily.Nootherchangeindietwasmadeandnoantibacterial (a) inadequate nutrition is part of a poor environment; drugs were given. Twenty-two of these children contracted 24 serologically positive group-A streptococcal infections, (b) rheumatic-fever children usually lack sufficient eggs but none showed clinical evidence of rheumatic recurrences. in their diets; This was in sharp contrast to previous experience in the (c) the escape from poverty is followed by an increase convalescent home where rheumatic recurrences had been in the consumption of eggs and a decrease in the frequently seen each year [2]. incidence of rheumatic fever; Subsequently in 1954, Coburn and colleagues were also the first to report a phospholipid fraction prepared from egg (d) supplementation of children’s diets with egg yolk or yolk that showed antiallergic activity in an assay in the guinea certain fractions thereof is followed by decreased pig [3]. rheumatic susceptibility; and The antiallergic factor of egg yolk was then purified by (e) there is a fraction of egg yolk, which in extremely LongandMartinin1956insuchawaythatitwasclear small amounts has been found to have high antialler- that this factor showed a biological and chemical similarity gic activity in laboratory animals. to a preparation obtained earlier in 1950 from peanut and what appeared to be a closely related substance described as Coburn described his field studies in great detail [2]. “vegetable lecithin” [4, 5]. Some of these findings are summarized below. ThebirthyearofPEAwas1957.KuehlJr.andcowork- In Field study number 1, =89, rheumatic boys and girls ers reported to have succeeded in isolating a crystalline living at home in New York City all received egg-enriched anti-inflammatory factor from soybean lecithin and they food; no prophylactic drugs were given. Sixty children had identified it as N-(2-hydroxyethyl)-palmitamide [6]. They extra eggs during winter and spring months, and 29 served isolated the compound also from a phospholipid fraction as “controls.” Results were as follows: of the 29 children on of egg yolk and from hexane-extracted peanut meal. The their normal diet (with many nutritional deficiencies) 11 had product obtained was tested positively in a local passive a recurrence. Of the 35 children whose normal diet was joint anaphylaxis assay in the guinea pig. When applying enriched with two eggs daily, a quart of milk, meat, butter, their isolation procedure to soybean lecithin, they obtained and halibut-liver oil, 3 had a recurrence. Of the 25 children a partially purified fraction from which the homogeneous whose normal diet was reinforced only with powdered egg factor was obtained by crystallization from cyclohexane. The yolk (equivalent to six eggs daily), only 1 had a recurrence. ∘ crystalline material had a melting point of 98-99 Candwas Field study number 2, =56,wasatwo-yearstudy described as neutral, optically inactive, and possessing the into the effect of giving egg-yolk powder (equivalent of four chemical formula C18H37O2N. egg yolks daily) to rheumatic children for three to four Hydrolysisofthefactorresultedinpalmiticacidand weeks after they developed hemolytic (group A) streptococcal ethanolamine and thus the compound was identified as N- pharyngitis. No other treatment was given during this period. (2-hydroxyethyl)-palmitamide. In order to close the circle of Results were as follows: of 28 receiving the supplement, isolation and identification, Kuehl et al. were able to synthe- only 1 showed fresh rheumatic activity, whereas among 28 size the compound by reflux in ethanolamine with palmitic “controls,” receiving no supplement, 10 children had fresh acid according to a well-known procedure described in the rheumatic activity. chemical literature of that time. Kuehl et al. further analyzed Field study number 3, =40,wasaone-yearstudy
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