Galactosyl prodrug of palmitoylethanolamide: Synthesis, stability, cell permeation and cytoprotective activity

Luongo, Elvira; Russo, Roberto; Avagliano, Carmen; Santoro, Anna; Melisi, Daniela; Orefice, Nicola Salvatore; Raso, Giuseppina Mattace; Meli, Rosaria; Magliocca, Salvatore; Nieddu, Maria; Santiago, Gilvandete Maria Pinheiro; Boatto, Gianpiero; Calignano, Antonio; Rimoli, Maria Grazia

doi:10.1016/j.ejps.2014.05.009

Cited by 6 publications

(8 citation statements)

References 24 publications

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“…This implies the observed effect in these two cases, which may be mediated via its peripheral immune properties in the gastrointestinal tract or through vagal nerve transmission. The galactosyl prodrug of palmitoylethanolamide has been proposed as a superior way to deliver PEA to the CNS [ 34 ]. Although this form is not presently available, it may be a target for autism intervention in the future.…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases

Antonucci¹,

Cirillo

Siniscalco

2015

Case Reports in Psychiatry

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Introduction. Autism spectrum disorders are defined by behavioral and language atypias. Growing body of evidence indicates inflammatory mediators may contribute to the condition. Palmitoylethanolamide (PEA) is naturally occurring and has been available as a nonprescription medical food supplement in Europe since 2008. PEA has been tested in thousands of human subjects without any noted significant side effects. Here we report the first cases of the administration of PEA to two children with autism. Case Presentations. The first 13-year-old male child (Subject 1) presented with a total IgE of 572 IU/mL (nl < 200) and with low mature CD57+ natural killer cell counts (32 cells/µL; nl = 60–300 cells/µL) and with significant eczema and allergic stigmata. Expressive language, as measured by mean length of utterance, and overall autism severity as measured by the Childhood Autism Rating Scale, Second Edition, improved significantly. Atopic symptoms diminished. No side effects were reported. The second male child, age 15 (Subject 2), also displayed noticeable and rapid improvements in cognitive, behaviors, and sociability. Conclusion. Currently, there is no definitive treatment for autism condition. Palmitoylethanolamide could be an effective treatment for autism syndrome. We propose appropriate double-blind clinical trials to further explore palmitoylethanolamide efficacy and safety.

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Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases

Antonucci¹,

Cirillo

Siniscalco

2015

Case Reports in Psychiatry

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“…Dyslipidaemia was found to be more prevalent in smokers and alcoholics with diabetes. These persons also face strong coronary heart disease [ 344 ]. Therefore, to cure hypercholesterolemia cholesterol-lowering therapies are shown to reduce both mortality and major adverse cardiovascular events in individuals with FH.…”

Section: Future Biomarkers Of Cvd Risksmentioning

confidence: 99%

Emerging Risk Biomarkers in Cardiovascular Diseases and Disorders

2015

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Present review article highlights various cardiovascular risk prediction biomarkers by incorporating both traditional risk factors to be used as diagnostic markers and recent technologically generated diagnostic and therapeutic markers. This paper explains traditional biomarkers such as lipid profile, glucose, and hormone level and physiological biomarkers based on measurement of levels of important biomolecules such as serum ferritin, triglyceride to HDLp (high density lipoproteins) ratio, lipophorin-cholesterol ratio, lipid-lipophorin ratio, LDL cholesterol level, HDLp and apolipoprotein levels, lipophorins and LTPs ratio, sphingolipids, Omega-3 Index, and ST2 level. In addition, immunohistochemical, oxidative stress, inflammatory, anatomical, imaging, genetic, and therapeutic biomarkers have been explained in detail with their investigational specifications. Many of these biomarkers, alone or in combination, can play important role in prediction of risks, its types, and status of morbidity. As emerging risks are found to be affiliated with minor and microlevel factors and its diagnosis at an earlier stage could find CVD, hence, there is an urgent need of new more authentic, appropriate, and reliable diagnostic and therapeutic markers to confirm disease well in time to start the clinical aid to the patients. Present review aims to discuss new emerging biomarkers that could facilitate more authentic and fast diagnosis of CVDs, HF (heart failures), and various lipid abnormalities and disorders in the future.

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“…Indeed, a prodrug of PEA could facilitate an enhanced absorption and the circumvention of its metabolic inactivation in the liver. A prodrug of PEA having a galactosyl moiety, connected by an ester bond (through a succinyl spacer) to the hydroxyl group of PEA has been recently described [ 22 ]. This compound has been tested in vitro on cell cultures, showing improved cytoprotection in 6-hydroxydopamine-mediated cell death and prolonged intra-cellular levels of PEA.…”

Section: Introductionmentioning

confidence: 99%

Amino Acid Derivatives as Palmitoylethanolamide Prodrugs: Synthesis, In Vitro Metabolism and In Vivo Plasma Profile in Rats

et al. 2015

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Palmitoylethanolamide (PEA) has antinflammatory and antinociceptive properties widely exploited in veterinary and human medicine, despite its poor pharmacokinetics. Looking for prodrugs that could progressively release PEA to maintain effective plasma concentrations, we prepared carbonates, esters and carbamates at the hydroxyl group of PEA. Chemical stability (pH 7.4) and stability in rat plasma and liver homogenate were evaluated by in vitro assays. Carbonates and carbamates resulted too labile and too resistant in plasma, respectively. Ester derivatives, prepared by conjugating PEA with various amino acids, allowed to modulate the kinetics of PEA release in plasma and stability in liver homogenate. L-Val-PEA, with suitable PEA release in plasma, and D-Val-PEA, with high resistance to hepatic degradation, were orally administered to rats and plasma levels of prodrugs and PEA were measured at different time points. Both prodrugs showed significant release of PEA, but provided lower plasma concentrations than those obtained with equimolar doses of PEA. Amino-acid esters of PEA are a promising class to develop prodrugs, even if they need further chemical optimization.

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Galactosyl prodrug of palmitoylethanolamide: Synthesis, stability, cell permeation and cytoprotective activity

Cited by 6 publications

References 24 publications

Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases

Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases

Emerging Risk Biomarkers in Cardiovascular Diseases and Disorders

Amino Acid Derivatives as Palmitoylethanolamide Prodrugs: Synthesis, In Vitro Metabolism and In Vivo Plasma Profile in Rats

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