WUXI CIMA SCIENCE CO.,LTD

Palmitoylethanolamide P E A

Wuxi Cima Science Co., Ltd

General Introduction

Palmitoylethanolamide (PEA), a peroxisome proliferator-activated receptor alpha (PPAR-α) ligand that exerts anti-inflammatory, analgesic, and neuroprotective actions, for the treatment of neuroinflammation, especially related to chronic pain, glaucoma, and diabetic retinopathy.

The mechanism(s) of action of PEA involve its effects on the nuclear receptor PPARα (Gabrielsson et al., 2016). It also involves mast cells, cannabinoid receptor type 2 (CB2)-like cannabinoid receptors, ATP-sensitive potassium-channels, transient receptor potential (TRP) channels, and nuclear factor kappa B (NFkB).

It can affect endocannabinoid signaling by acting as a competing substrate for the endocannabinoid homolog anandamide (N-arachidonoyl ethanolamine).

The initial observation was in 1943 by Coburn et al. as part of an epidemiological study focused on childhood rheumatic fever, the incidence of which was higher in those children consuming diets low in eggs.

These investigators noted that occurrence was reduced in children fed egg yolk powder, and subsequently, they demonstrated anti-anaphylactic properties in guinea pigs with a lipid extract from egg yolk.

1957 Kuehl Jr. and coworkers reported having succeeded in isolating a crystalline anti-inflammatory factor from soybean. They isolated the compound also from a phospholipid fraction of egg yolk and from hexane-extracted peanut meal.

Hydrolysis of PEA resulted in palmitic acid and ethanolamine and thus the compound was identified as N-(2-hydroxyethyl)-palmitamide (Kepple Hesselink et al., 2013).

Flow Chart of Semi-synthesize Palmitoylethanolamide

Many specifications of Palmitoylethanolamide

Food Science & Nutrition DOI 10.1002/fsn3.392

Safety of micronized palmitoylethanolamide (micro-PEA): lack of toxicity and genotoxic potential

Palmitoylethanolamide (PEA) is a natural fatty acid amide found in a variety of foods, which was initially identified in egg yolk.
MicroPEA of defined particle size (0.5–10 μm) was evaluated for mutagenicity in Salmonella typhimurium, for aneuploidy in cultured human lymphocytes, and for acute and subchronic rodent toxicity in the rat, following standard OECD test protocols, in accordance with Good Laboratory Practice (GLP).
PEA did not induce mutations in the bacterial assay using strains TA1535, TA97a, TA98, TA100, and TA102, with or without metabolic activation, in either the plate incorporation or liquid preincubation methods. Similarly, PEA did not induce genotoxic effects in human cells treated for 3 or 24 h without metabolic activation, or for 3 h with metabolic activation.
PEA was found to have an LD50 greater than the limit dose of 2000 mg/kg body weight (bw), using the OECD Acute Oral Up and Down Procedure. Doses for the 90-day rat oral toxicity study were based on results from the preliminary 14-day study, that is, 250, 500, and 1000 mg/kg bw /day.
The No Effect Level (NOEL) in both subchronic studies was the highest dose tested.

Br J Clin Pharmacol. 2016 Oct;82(4):932-42.

Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety, and efficacy

Clinical evidence

Special Food for Medical Purposes, in the Treatment of Chronic Pain
Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients
Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome
Palmitoylethanolamide in Fibromyalgia: Results from Prospective and Retrospective Observational Studies
Ultra-micronized palmitoylethanolamide: an efficacious adjuvant therapy for Parkinson's disease.
Chronic pelvic pain, quality of life and sexual health of women treated with palmitoylethanolamide and α-lipoic acid
Randomized clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome.
Co-ultra micronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: from Rodent to Man
Palmitoylethanolamide, a Natural Retinoprotectant: Its Putative Relevance for the Treatment of Glaucoma and Diabetic Retinopathy
N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: results of a randomized, double-blind, controlled study in 60 patients

Pain Physician. 2016 Feb;19(2):11-24.

Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis.

BACKGROUND: A growing body of evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory mediators in the peripheral and central nervous systems, has an important role in the induction and maintenance of chronic pain. These findings support the notion that new therapeutic opportunities for chronic pain might be based on anti-inflammatory and pro-resolving mediators that act on immune cells, in particular, mast cells and glia, to mitigate or abolish neuroinflammation. Among anti-inflammatory and pro-resolving lipid mediators, palmitoylethanolamide (PEA) has been reported to down-modulate mast cell activation and to control glial cell behaviors.
OBJECTIVE: The aim of this study was to perform a pooled meta-analysis to evaluate the efficacy and safety of micronized and ultra-micronizedpalmitoylethanolamide (PEA) on pain intensity in patients suffering from chronic and/or neuropathic pain.
STUDY DESIGN: Pooled data analysis consisting of double-blind, controlled, and open-label clinical trials.
METHODS: Double-blind, controlled, and open-label clinical trials were selected consulting the PubMed, Google Scholar, and Cochrane databases, and proceedings of neuroscience meetings. The terms chronic pain, neuropathic pain, and micronized and ultra-micronized PEA were used for the search. Selection criteria included the availability of raw data and comparability between tools used to diagnose and assess pain intensity. Raw data obtained by authors were pooled in one database and analyzed by the Generalized Linear Mixed Model. The changes in pain over time, measured by comparable tools, were also assessed by linear regression post-hoc analysis and the Kaplan-Meier estimate. Twelve studies were included in the pooled meta-analysis, 3 of which were double-blind trials comparing active comparators vs placebo, 2 were open-label trials vs standard therapies, and 7 were open-label trials without comparators.
RESULTS: Results showed that PEA elicits a progressive reduction of pain intensity significantly higher than control. The magnitude of reduction equals 1.04 points every 2 weeks with a 35% response variance explained by the linear model. In contrast, in the control group pain, reduction intensity equals 0.20 points every 2 weeks with only 1% of the total variance explained by the regression. The Kaplan-Meier estimator showed a pain score = 3 in 81% of PEA treated patients compared to only 40.9% in control patients by day 60 of treatment. PEA effects were independent of patient age or gender, and not related to the type of chronic pain.
LIMITATIONS: Noteworthy, serious adverse events related to PEA were not registered and/or reported in any of the studies.
CONCLUSION: These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.

Pain Res Treat. 2014;2014:849623.

Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients.

The present study evaluated the effectiveness of micronized PEA treatment in reducing the painful symptoms experienced by diabetic patients with peripheral neuropathy.

PEA-m was administered (300 mg twice daily) to 30 diabetic patients suffering from painful diabetic neuropathy.

Before treatment starts, after 30 and 60 days the following parameters were assessed: painful symptoms of diabetic peripheral neuropathy using the Michigan Neuropathy Screening instrument; the intensity of symptoms characteristic of diabetic neuropathic pain by the Total Symptom Score; and intensity of different subcategories of neuropathic pain by the Neuropathic Pain Symptoms Inventory. Hematological and blood chemistry tests to evaluate metabolic control and safety were also performed.

Statistical analysis (ANOVA) indicated a highly significant reduction in pain severity (P < 0.0001) and related symptoms (P < 0.0001) evaluated by Michigan Neuropathy Screening instrument, Total Symptom Score, and Neuropathic Pain Symptoms Inventory.

Hematological and urine analyses did not reveal any alterations associated with PEA-m treatment, and no serious adverse events were reported.

These results suggest that PEA-m could be considered as a promising and well-tolerated new treatment for symptomatology experienced by diabetic patients suffering from peripheral neuropathy.

Clin Interv Aging. 2014 Jul 17;9:1163-9.

N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: results of a randomized, double-blind, controlled study in 60 patients.

BACKGROUND: Asteatotic eczema (AE) is characterized by itchy, dry, rough, and scaling skin. The treatments for AE are mainly emollients, usually containing urea, lactic acid, or a lactate salt. N-palmitoylethanolamide (PEA) and N-acylethanolamine (AEA) are both endogenous lipids used as novel therapeutic tools in the treatment of many skin diseases. The purpose of this study was to compare a PEA/AEA emollient with a traditional emollient in the treatment of AE.

METHODS: A monocentric, randomized, double-blind, comparative trial was conducted in 60 AE patients to evaluate and compare the efficacy of the two emollients. The level of skin dryness among the subjects ranged from mild to moderate. The subjects' skin barrier function and the current perception threshold were tested for 28 days by clinical scoring and bioengineering technology.

RESULTS: The results showed that, although some aspects were improved in both groups, the group using the emollient containing PEA/AEA presented a better skin surface change in capacitance. However, the most impressive finding was the ability of the PEA/AEA emollient to increase the 5 Hz current perception threshold to a normal level after 7 days, with a significant difference between values at baseline and after 14 days. A current perception threshold of 5 Hz was positively and significantly correlated with skin surface hydration and negatively correlated with transepidermal water loss in the PEA/AEA emollient group.

CONCLUSION: Compared with traditional emollients, regular application of a topical PEA/AEA emollient could improve both passive and active skin functions simultaneously.

J Pain Res. 2015 Oct 23;8:729-34.

Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome.

Here we describe the results of all clinical trials evaluating PEA's efficacy and safety in nerve compression syndromes: sciatic pain and pain due to carpal tunnel syndrome, and review preclinical evidence in nerve impingement models.

In total, eight clinical trials have been published in such entrapment syndromes, and 1,366 patients have been included in these trials.
In one pivotal, double-blind, placebo-controlled trial in 636 sciatic pain patients, the number needed to treat to reach 50% pain reduction compared to baseline was 1.5 after 3 weeks of treatment.
PEA proved to be effective and safe in nerve compression syndromes, no drug interactions or troublesome side effects have been described.

PEA should be considered as a new and safe treatment option for nerve compression syndromes.

Since the often prescribed co-analgesic pregabalin has been proven to be ineffective in sciatic pain in a double-blind enrichment trial.
Physicians are not always aware of PEA as a relevant and safe alternative to opioids and co-analgesics in the treatment of neuropathic pain.

CNS Neurol Disord Drug Targets. 2017 Mar 21.

Ultra-micronized palmitoylethanolamide: an efficacious adjuvant therapy for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the subject of intense efforts to develop strategies that slow down or stop disease progression and disability. Substantial evidence points to a prominent role for neuroinflammation in the underlying dopaminergic cell death. Ultra-micronized palmitoylethanolamide (um-PEA) is well-known for its ability to promote the resolution of neuroinflammation and exert neuroprotection. This study was designed to assess the efficacy of um-PEA as adjuvant therapy in patients with advanced PD.

METHODS: Thirty PD patients receiving levodopa were included in the study. The revise- Movement Disorder Society/Unified Parkinson's Disease Rating Scale (MDS-UPDRS) questionnaire was used to assess motor and non-motor symptoms. Clinical assessments were carried out before and after the addition of um-PEA (600 mg). MDS-UPDRS questionnaire total score for parts I, II, III, and IV was analyzed using the Generalized Linear Mixed Model, followed by the Wilcoxon signed-rank test to evaluate the difference of each item's mean score between baseline and end of um-PEA treatment.

RESULTS: Addition of um-PEA to PD patients receiving levodopa therapy elicited a significant and progressive reduction in the total MDS-UPDRS score (parts I, II, III and IV). For each item, the mean score difference between baseline and end of um-PEA treatment showed a significant reduction in most non-motor and motor symptoms. The number of patients with symptoms at basal was reduced after one year of um-PEA treatment. None of the participants reported side effects attributable to the addition of um-PEA.

CONCLUSION: um-PEA slowed down disease progression and disability in PD patients, suggesting that um-PEA may be an efficacious adjuvant therapy for PD.

J Ophthalmol. 2015;2015:430596.

Palmitoylethanolamide, a Natural Retinoprotectant: Its Putative Relevance for the Treatment of Glaucoma and Diabetic Retinopathy.

Retinopathy is a threat to the eyesight, and glaucoma and diabetes are the main causes for the damage of retinal cells. Recent insights pointed out a common pathogenetic pathway for both disorders, based on chronic inflammation.

PEA has been evaluated for glaucoma, diabetic retinopathy, and uveitis, pathological states based on chronic inflammation, respiratory disorders, and various pain syndromes in a number of clinical trials since the 70s of 20th century.

PEA has been tested in at least 9 double-blind placebo-controlled studies, among which two studies were in glaucoma, and found to be safe and effective up to 1.8 g/day, with excellent tolerability. PEA, therefore, holds a promise in the treatment of a number of retinopathies.

PEA is available as a food supplement (PeaPure) and diet food for medical purposes in Italy (Normast, PeaVera, and Visimast).

These products are notified in Italy for the nutritional support in glaucoma and neuroinflammation. We discuss PEA as a putative anti-inflammatory and retinoprotectant compound in the treatment of retinopathies, especially related to glaucoma and diabetes.

Sci Rep. 2017 Mar 23;7(1):375.

Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor.

The endogenous fatty acid amide palmitoylethanolamide (PEA) has been shown to exert anti-inflammatory actions mainly through the inhibition of the release of pro-inflammatory molecules from mast cells, monocytes and macrophages. Indirect activation of the endocannabinoid (eCB) system is among the several mechanisms of action that have been proposed to underlie the different effects of PEA in vivo.
In this study, we used cultured rat microglia and human macrophages to evaluate whether PEA affects ECB signaling.
PEA was found to increase CB2 mRNA and protein expression through peroxisome proliferator-activated receptor-α (PPAR-α) activation.
This novel gene regulation mechanism was demonstrated through (i) pharmacological PPAR-α manipulation, (ii) PPAR-α mRNA silencing, (iii) chromatin immunoprecipitation.
Moreover, exposure to PEA induced morphological changes associated with a reactive microglial phenotype, including increased phagocytosis and migratory activity.
Our findings suggest indirect regulation of microglial CB2R expression as a new possible mechanism underlying the effects of PEA. PEA can be explored as a useful tool for preventing/treating the symptoms associated with neuroinflammation in CNS disorders.

APPLICATIONS OF PEA

PEA is currently available worldwide in the form of dietary supplements, medical foods, and/or nutraceuticals in different formulations, with and without excipients (Hesselink and Kopsky, 2015).
PEA is currently marketed for veterinary use (skin conditions, Redonyl™, manufactured by Innovet) and as a nutraceutical in humans (Normast™ and Pelvilen™, manufactured by Epitech; PeaPure™, manufactured by JP Russel Science Ltd.) in some European countries (e.g. Italy, Spain and the Netherlands) (Gabrielsson et al., 2016).
It also is a constituent of a cream (Physiogel AI™, manufactured by Stiefel) marketed for dry skin (Gabrielsson et al., 2016).
Ultra-micronized PEA is registered as food for special purposes by the Italian Ministry of Health and is not labeled for use in neuropathic pain (Andersen et al., 2015).
The Food and Drug Administration (FDA) has not previously reviewed the safety of PEA. There are no regulations in the U.S. permitted the use of PEA as a food additive or GRAS substance.

WUXI CIMA SCIENCE PEA

Wuxi Cima's PEA is intended to be used as a medical food ingredient for the dietary management of the metabolic mechanisms underlying inflammation-associated chronic pain, angiogenesis, and renal disease as well as physiological mechanisms underlying neuroprotective and retina protective effects of PEA.

PEA is recommended to be used only under medical supervision.

PEA is proposed for use a daily dose range of 400 mg/day to 800 mg/day. Typical use is expected to be a starting dose of up to 400 mg BID for 3 - 4 days and a maintenance dose of 300 mg BID for up to 1 year. PEA is not recommended for pregnant and lactating women, children and teenagers. In addition, PEA will not be used in ordinary foods for the general population.