title: Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing-Remitting Multiple Sclerosis.
abstract: Palmitoylethanolamide (PEA) is an endogenous lipid mediator known to reduce pain and inflammation. However, only limited clinical studies have evaluated the effects of PEA in neuroinflammatory and neurodegenerative diseases. Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease of the central nervous system. Although subcutaneous administration of interferon (IFN)-β1a is approved as first-line therapy for the treatment of relapsing-remitting MS (RR-MS), its commonly reported adverse events (AEs) such as pain, myalgia, and erythema at the injection site, deeply affect the quality of life (QoL) of patients with MS. In this randomized, double-blind, placebo-controlled study, we tested the effect of ultramicronized PEA (um-PEA) added to IFN-β1a in the treatment of clinically defined RR-MS. The primary objectives were to estimate whether, with um-PEA treatment, patients with MS perceived an improvement in pain and a decrease of the erythema width at the IFN-β1a injection site in addition to an improvement in their QoL. The secondary objectives were to evaluate the effects of um-PEA on circulating interferon-γ, tumor necrosis factor-α, and interleukin-17 serum levels, N-acylethanolamine plasma levels, Expanded Disability Status Scale (EDSS) progression, and safety and tolerability after 1 year of treatment. Patients with MS receiving um-PEA perceived an improvement in pain sensation without a reduction of the erythema at the injection site. A significant improvement in QoL was observed. No significant difference was reported in EDSS score, and um-PEA was well tolerated. We found a significant increase of palmitoylethanolamide, anandamide and oleoylethanolamide plasma levels, and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group. Our results suggest that um-PEA may be considered as an appropriate add-on therapy for the treatment of IFN-β1a-related adverse effects in RR-MS.
authors: Department of Pharmacy, "Federico II" University, 80131, Naples, Italy.
authors: Nicola S
authors: NS
authors: Orefice
authors: Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
authors: Mireille
authors: M
authors: Alhouayek
authors: Department of Neurosciences, Reproductive and Odontostomatological Sciences, "Federico II" University of Naples, Naples, Italy.
authors: Antonio
authors: A
authors: Carotenuto
authors: Department of Neurosciences, Reproductive and Odontostomatological Sciences, "Federico II" University of Naples, Naples, Italy.
authors: Silvana
authors: S
authors: Montella
authors: Department of Neurosciences, Reproductive and Odontostomatological Sciences, "Federico II" University of Naples, Naples, Italy.
authors: Franscesco
authors: F
authors: Barbato
authors: Department of Biopathology and Medical Biotechnologies, Section of Radiological Sciences, University of Palermo, 90129, Palermo, Italy.
authors: Albert
authors: A
authors: Comelli
authors: Department of Pharmacy, "Federico II" University, 80131, Naples, Italy.
authors: Antonio
authors: A
authors: Calignano
authors: Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
authors: Giulio G
authors: GG
authors: Muccioli
authors: Department of Neurosciences, Reproductive and Odontostomatological Sciences, "Federico II" University of Naples, Naples, Italy. orefice@unina.it.
authors: Giuseppe
authors: G
authors: Orefice
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000577:Amides; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood*; D018450:Disease Progression; D004311:Double-Blind Method; D004983:Ethanolamines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000068556:Interferon beta-1a / Q000009:adverse effects / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D010169:Palmitic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004983:Ethanolamines; D020381:Interleukin-17; D010169:Palmitic Acids; D014409:Tumor Necrosis Factor-alpha; C005958:palmidrol; D007371:Interferon-gamma; D000068556:Interferon beta-1a
keywords: Anandamide; FAAH; N-acylethanolamines; NAAA; Neuroinflammation; Oleoylethanolamide; Pain