Glialia

Food for special medical purposes. Without: gluten, lactose, sugars.
Glìalia is to be used under medical supervision in subjects with disorders supported by neuroinflammatory processes associated with: transient ischemic events (TIA); post-ictal states on an ischemic basis; post-traumatic states of the CNS; states of cognitive decline (Mild Neurocognitive Disorder - Mild-NCD); early-stage dementia; early-stage parkinsonism; inflammatory demyelinating diseases; motor neuron diseases; states of altered mood.
Palmitoylethanolamide
It is a natural endogenous substance of lipid nature with an N-acylethanolamide structure which has the function of intervening physiologically in the organism to maintain intersystemic tissue homeostasis.
Luteolin
It is also a natural substance belonging to the flavone family, endowed with considerable and peculiar antioxidant effects.
The association of Palmitoylethanolamide and Luteolin in co-ultramicronized form (ultramicrocomposite PEALUT) allows the two active ingredients to exert a synergic effect in the control of neuroinflammation induced by different endogenous and exogenous noxae affecting the Central Nervous System; this control is exerted through the inhibitory modulation of non-neuronal cells - astrocytes, microglia, mast cells - normally responsible for ensuring the homeodynamic balance of the central nervous tissue.

Ingredients

	for 1 envelope
Palmitoylethanolamide	700 mg
Luteolin in co-ultramicronized form (PEALUT® Ultramicrocomposite)	70 mg
Mixture of excipients (Sorbitol, Polysorbate 80, Sucrose Palmitate)	500.00 mg

How to use
Glìalia microgranules for sublingual use must be used under medical supervision following acute events associated with neuroinflammation in the CNS (post-ictal, post-traumatic situations) or, as an attack therapy, in the initial stages of promptly diagnosed neurodegenerative diseases; it is recommended to take 2 sachets per day for cycles of 20-30 days possibly repeated using, when possible, the sublingual route.

Warnings and precautions for use
Use under medical supervision.
The product cannot represent the sole source of nutrition.
Keep out of reach of children under 3 years.
Interactions: not highlighted.
Pregnancy: the administration of the product is not recommended during confirmed or suspected pregnancy, due to insufficient adequate data regarding the use of the combination of Palmitoylethanolamide and Luteolin in these situations.
Effects on ability to drive and use machines: Palmitoylethanolamide and Luteolin, at the recommended doses, do not interfere with the ability to drive and use machines.
Side effects: No side effects have been reported even after long-term administration and at high doses of Palmitoylethanolamide, nor have cases of habituation or dependence been reported. In humans, administration of 100 mg/day of Luteolin for 4 months has proven to be very well tolerated and safe.
Overdose: There are no known clinical cases of overdose.

Pharmacological properties
Health Authorization Category (Ministry of Health): Food for Special Medical Purposes.
Pharmacodynamic properties
Palmitoylethanolamide is an endogenous N-acylethanolamide, devoid of psychotropic effects. Preclinical studies have shown that Palmitoylethanolamide acts, in a pleiotropic manner, on the mechanisms of neuroinflammation, exerting an effective neuroprotective effect. The use of translational experimental models has clearly demonstrated that Palmitoylethanolamide is able to act on central neuroinflammation through the synchronous modulation of non-neuronal cells (astrocytes, microglia, mast cells), thus determining effective neuroprotection.
Luteolin exerts a high normalization of the local oxidative state associated with neuroinflammation in the CNS. The available data demonstrate how the association between Palmitoylethanolamide and Luteolin, administered in the form of an ultramicrocomposite. Pealut obtained by co-ultramicronization, is highly synergic on the mechanisms of neuroinflammation in the CNS.
Mechanisms of action
Recent studies have shown that the administration of Palmitoylethanolamide + Luteolin, in the form of ultramicro-composite Pealut obtained by co-ultramicronization in the mass ratio 10:1, increases the cell viability of both macrophage and astrocyte lines subjected to oxidative stress. The ultramicrocomposite Pealut synergistically inhibits lipid peroxidation, mitochondrial dysfunctions associated with cell apoptosis, nitric oxide (NO) production and the expression of inducible enzymes (NO-synthase and cyclooxygenase-2). Similar results were observed in organotypic cultures of hippocampus damaged by amyloid protein fragment Ab1-42. In ischemia models, the ultramicrocomposite Pealut has been shown to completely protect neurons from cell death, confirming the synergistic effect of the two molecules in the co-ultramicronized form. Pealut has demonstrated its efficacy in vivo in models of CNS trauma and mood alteration.

Pharmacokinetic properties
The temporal profile of Palmitoylethanolamide in human plasma after a single oral dose of 300 to 1200 mg shows a dose-dependent increase in the molecule. The plasma peak of Palmitoylethanolamide is observed one hour after administration; subsequently, plasma levels begin to decrease and reach baseline within six hours. At one hour, plasma levels of Palmitoylethanolamide double compared to baseline after administration of 300 mg, while they increase sevenfold after administration of 1200 mg. Experimental studies have shown that after oral administration, Palmitoylethanolamide is uniformly distributed in the tissues; a percentage of the administered dose crosses the blood-brain barrier and reaches brain tissues. Free Luteolin has been found in plasma in both experimental animals and humans, after oral administration, demonstrating that a portion of luteolin escapes degradation due to the first hepatic passage, in any case avoided by sublingual administration. In rats, after oral administration, the maximum peak of Luteolin in plasma is reached after 1 hour, while the peak of maximum excretion in feces and urine occurs around 8 hours.

Toxicology and Tolerability
Toxicology studies have shown that the LD/50 of Palmitoylethanolamide administered by injection (intraperitoneally) in dogs is greater than 400 mg/kg, and in rats, after a single administration by gastric probe, it exceeds 5000 mg/kg, while after repeated administration by gastric probe, it exceeds 500 mg/kg/day.
Clinical studies conducted on a large number of patients demonstrate the excellent tolerability of Palmitoylethanolamide even for very high doses and the absence of clinically relevant changes in the haematological and blood chemistry tests performed. Toxicological studies in rats have demonstrated that the administration of up to 1 g/kg of Luteolin does not induce toxic effects. Chronic administration of Luteolin at doses of 23, 48 and 87 mg/kg respectively for 26 weeks, did not show any toxic effect related to body weight, haematological, blood chemistry and histopathological tests performed.
Palmitoylethanolamide and embryotoxicity: No teratogenic or embryotoxic effect of Palmitoylethanolamide was observed after administration of 50 mg/kg body weight for 12 days during pregnancy. Furthermore, neonates from mothers who received PEA before delivery and up to 10 days after delivery were more resistant to Shigella Shigae toxin. Similarly, neonates from mothers who received PEA after delivery showed an increasing resistance evident as early as 5 days after birth: these data suggest that mothers may have transferred PEA to neonates through milk.
Mutagenicity: although a potential mutagenic effect of Palmitoylethanolamide can be excluded since it is already physiologically present in mammalian organisms, the mutagenicity of PEA was verified using the Ames test, using 5 mutant species of S. typhimurium (TA 1535-TA1537-TA1538-TA98 and TA 100). With the Ames test, Palmitoylethanolamide, used at doses between 10,000 and 1,000 µg/ml did not significantly modify the number of revertants. Luteolin also did not show mutagenic effects in the Ames test, using concentrations between 12.1 and 225.0 nmol/ml.
Palmitoylethanolamide and gastric tolerability: Oral administration of Palmitoylethanolamide at a dose of 50 mg/kg (approximately 5 times higher than the active dose), and at a dose of 10 mg/kg in repeated administrations for 5 days does not induce ulcer formation. Furthermore, when administered at a dose of 50 mg/kg simultaneously with diclofenac 15 mg/kg, a dosage known to induce gastric lesions, PEA decreases the ulcerogenic potential of NSAIDs, reducing the number of animals that develop ulcerations and mitigating any damage.

Conservation
Store at room temperature.

Format
Pack of 20 heat-sealed sachets.

Code 8060