Maisto papildų enciklopedija
ieškoti »
   
 
.

 

Adelmidrolis – natūralių odos aliamidų analogas, uždegimą ir niežulį mažinanti medžiaga.

Pagal cheminę struktūrą ir veikimo mechanizmą, adelmidrolis priskiriamas aliamidams (Angl. Autacoid Local Injury Antagonist Amides - ALIA) – fiziologiškai aktyvioms mežiagoms, kurias žmogaus organizmas sintetina kaip atsaką į stiprius dirgiklius, kad apsaugoti audinius nuo žalingo uždegimo ir skausmo poveikio.

Žodžių trumpinį ALIA sukūrė Nobelio medicinos premijos laureatė (1986 m.) profesorė Rita Levi Montalcini, ištyrusi nervų augimo faktorių (Ang. NGF) ir epdermio augimo faktorių (Angl. EGF). Tyrinėdama neuromimuninį uždegimą, profesorė ištyrė ir aprašė reguliuojantį aliamidų poveikį mastocitams ir kitoms ląstelėms.

Mastocitai – imuninės ląstelės, reaguojančios į alergenus, hormonus, citokinus, traumą, streso hormonus ir kitokius dirgiklius. Vykstant alerginėms reakcijoms mastocitai atpalaiduoja daug histamino, nervų augimo faktoriaus ir kitų uždegimo mediatorių, kurie ir sukelia odos paraudimą, paburkimą, išbėrimą, niežulį.

Uždegimo ar alergijos metu mastocitų aktyvumą reguliuoja aliamidai. Jie, veikdami per vaniloidinius (VR1) ir kanabinoidinius (CB1, CB2) receptorius, kurių yra ant juntamųjų nervų, mastocitų, keratinocitų ir kitų ląstelių, slopina histamino ir kitų uždegiminių medžiagų išsiskyrimą iš mastocitų, mažina nervų augimo faktoriaus kaupimąsi uždegimo pažeistoje odoje.

Atopiniam dermatitui, alerginei egzemai būdinga padidėjęs mastocitų kiekis ir jų sintezuojamo nervų augimo faktoriaus lygis. Šie faktoriai įtakoja uždegimo tęstinumą, epitelio vientisumo praradimą ir odos įsijautrinimą. O nuolat kartojantis dirginimui, besitęsiant uždegimui natūralių odoje sintetinamų aliamidų efekto nebepakanka.

Italijos kompanija EPITECH group, kurios įkūrėjas Dr. Francesco della Valle yra profesorės
Ritos Levi Montalcini mokinys, tęsia profesorės mokslinių tyrinėjimų darbus neuroimuninio uždegimo srityje. Adelmidrolis – šios kompanijos sukurtas ir ištirtas aliamidų (PEA) analogas, sėkmingai taikomas gydant odos ir gleivinių uždegimus. Kompanijos gaminami preparatai su adelmidroliu: Aliatop® kremas vaikams, Aliatop® skystas kremas, Rogonil® tepalas, Sebinil® kremo gelis ir kt.



Adelmidrolis gerai prasiskverbia pro raginį odos sluoksnį ir pasiekia ląstelių membranas. Didindamas natūralių aliamidų kiekį uždegimo židinyje, vietiškai naudojamas adelmidrolis slopina neuroimuninio uždegimo plitimą, mažina periferinių nervų jautrumą ir niežulį, todėl veiksmingai mažina atopinio dermatito ir egzemos simptomus. O sumažėjus odos įsijautrinimui, suretėja ir uždegimo pasikartojimo rizika.


Klinikiniai duomenys

Klinikiniai tyrimai rodo aliamidų efektyvumą gydant odos ligas, kurioms būdingas uždegimas, įsijautrinimas ir niežulys.

Vaikų atopinis dermatitas.

                 

Tirti lengvu atopiniu dermatitu sergantys vaikai (nuo 2 iki 16 metų, viso 20), kurie mažiausiai 4 savaites iki tyrimo nebuvo gydyti vietinio ar sisteminio veikimo vaistais. Klinikinis pagerėjimas stebėtas 80% pacientų po 4 gydymo savaičių. Be to, toliau stebint pacientus dar 8 savaites, ligos atkryčio nebuvo. Kontroliniai odos bėrimai, kurie nebuvo gydyti, liko be pagerėjimo. Su gydymu susijusio šalutinio poveikio nestebėta.
Micali et al, J Am Acad Dermatol. 2006; Pulvirenti et al, Acta Dermatol. Croat, 2007.

Atopinė egzema.
Multicentrinis tyrimas, į kurį buvo įtraukti 2456 atopine egzema sergantys pacientai, parodė, kad vietinis gydymas kremu su aliamidu, sumažino objektyvius ir subjektyvius simptomus bei kortikosteroidų poreikį.
Eberlein B et al JEADV, 2008.

Atopinis dermatitas.
Vietinis gydymas aliamidu sumažina recidyvų riziką ir leidžia sumažinti kortikosteroidų dozę pacientams, sergantiems atopiniu dermatitu.
Laumann et al, 2006.

Atopinis dermatitas.
Klinikinis tyrimas parodė aliamidų efektyvumą panašų į hidrokortizono (1.0%), kontroliuojant niežulį sergantiesiems atopiniu dermatitu. Kemeny, 63rd Annual Meeting of Am Acad Dermatol, 2006.

Lėtinis niežulys.
Vietinis gydymas aliamidais lėtinį, gydymui atsparų niežulį sumažino 86%.
Stander et al, 2006.

Poherpetinė neuralgija.
Stebėtas ženklus skausmo, niežulio ir alodinijos sumažėjimas 30 tirtų pacientų su poherpetine neuralgija, kurie 6 savaites buvo gydyti adelmidroliu ir mažų dozių kapsaicinu.
Scarpelli and Chisari, 2015 ; Terapia Dolore, Cosenza and Catania - study in progress.

Veido srities poherpetinė neuralgija.
5 iš 8 (62.5 %) pacientų, gydytų aliamido kremu vidutiniškai 87.8 % sumažėjo skaumas. Nebuvo recidyvo ar nemalonių jutimų. Phan et al, 2010


Ikiklinikiniai duomenys


In vitro tyrimas. Adelmidrolis slopina medžiagos P sukeltą histamino atpalaidavimą iš mastocitų.
Fantozzi, 1996, Dpt of pharmacology Univ. of Turin.

Neurogeninio uždegimo modelis. Po oda suleisto adelmidrolio tirpalas (20 mg/kg) iki 67.4% sumažino masyvią neurogeninio uždegimo sukeltą mastocitų degranuliaciją.
Aloe, 1994, Neurobiology Unit of the Italian National Research Council.

Odos uždegimo modelis.
Po oda leidžiamas adelmidrolis (0,3 ir 1,0 mg) veiksmingai sumažino uždegimą, o efektas priklausė nuo dozės.
Mazzari, 1995, Epitech Research Labs.

Karageninu sukelto lėtinio uždegimo gydymas adelmidroliu (dozėmis 15 ir 70 mg/ml) ženkliai sumažino granuliomos dydį, neoangiogenezę, TNF ir mastocitų kiekį.
De Filippis et al, J Cell Mol Med, 2009.

Vietinis gydymas adelmidroliu sumažino edemą, paraudimą ir kitas uždegimines reakcijas bei mastocitų skaičių eksperimentuose su šunimis.
Cerrato et al, 2012, BMC Veterinary Research.

Vietinis gydymas adelmidrolio tepalu (2%) statistiškai patikimai sumažino atopinio dermatito, besitęsiančio 4 savaites, sukeltą niežulį šunims.
Fabbrini et al, 2013, Veterinaria.

Šunų žaizdų odos bioptatuose ženkliai skyrėsi mastocitų granulių sudėtis adelmidrolio ir kontrolinėse grupėse. Eksperimentas parodė, kad adelmidrolis moduliuoja mastocitų reaktyvumą ir mažina degranuliaciją.
Abramo et al, 2004, Vet Dermatol, 15(Suppl.1); Abramo et al. Wounds, 2008.

Šunų odos žaizdų modeliuose, vietiškai gydant adelmidroliu aplinkiniai žaizdos audiniai buvo daug labiau padengti elastinėmis skaidulomis, nei kontrolinėje grupėje (P<0.03). Abramo et al, Vet Derm, 16: 352; 2005.

Eksperimentiniuose šunų žaizdų modeliuose vietinis adelmidrolio 2% gelio naudojimas ženkliai sumažino žaizdos dydį, matuojant aukštos rezoliucijos echoskopu.
Mantis et al, Wounds; 19(5):111-119;2007.

Literatūra

1. Acta Dermatovenerol Croat. 2007;15(2):80-3. Topical adelmidrol 2% emulsion, a novel aliamide, in the treatment of mild atopic dermatitis in pediatric subjects: a pilot study. Pulvirenti N, Nasca MR, Micali G.
Recent studies have shown a correlation between an increased number of mast cells in patients with atopic dermatitis (AD) resulting in raised plasma levels of nerve growth factor (NGF), pointing to a possible key role of their interaction in the pathogenesis of AD. It is well known that mast cells synthesize, store and release NGF. Mast cells and NGF both appear to be involved in tissue inflammation and neuroimmune interactions, with NGF acting as a general "alert" molecule capable of recruiting and priming both local tissue and systemic defense processes following stressful events. Also, NGF has been demonstrated to increase mast cell histamine content and intracellular tryptase activity in a dose- and time-dependent fashion. Endogenous aliamides are capable of down-regulating mastocyte reactivity by their action through the vanilloid (VR1) receptors, and keratinocytes, and through the CB1 and CB2 cannabinoid receptors linked to G-protein, also expressed by sensitive nerve endings, macrophages, and epithelial cells. Therefore, aliamide action should be regarded as a multifaceted mechanism interfering with the inflammatory process occurring in AD further beyond the known and controversial anti-histamine pharmacologic effect. In this regard, the reduction of mast cell degranulation by adelmidrol, as demonstrated by in vitro and in vivo investigations in animals, would interfere with the release of other inflammatory mediators, including NGF. Based on these considerations, a pilot study aimed to assess the efficacy and safety of twice daily application of a topical emulsion containing adelmidrol 2%, a novel aliamide, in a series of 20 patients (11 male and 9 female, mean age 8 (range 3-16) years) affected by mild AD was performed. Complete resolution with no side effects was observed in 16 (80%) patients after 4 weeks of treatment, with no relapses at 8-week follow up. Six patches in six subjects with multiple lesions that had not been treated and served as controls showed no improvement.

2. J Eur Acad Dermatol Venereol. 2008 Jan;22(1):73-82. Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). Eberlein B, Eicke C, Reinhardt HW, Ring J.
This study showed substantial relief of objective and subjective symptoms of atopic eczema after regular skin care with the study cream. The patient-related effectiveness (decline of pruritus and loss of sleep) indicated a gain in quality of life in these patients. The reduced use of topical corticosteroids is important in view of safety and pharmacoeconomic implications in the treatment of atopic eczema.

3. J Neuroimmunol. 2005 Apr;161(1-2):87-92. Gene expression and regulation of nerve growth factor in atopic dermatitis mast cells and the human mast cell line-1. Groneberg DA, Serowka F, Peckenschneider N, Artuc M, Grützkau A, Fischer A, Henz BM, Welker P.
The gene expression and regulation of nerve growth factor (NGF) in atopic dermatitis (AD) and the human mast cell line (HMC)-1 was investigated at the molecular level. NGF-stimulation of HMC-1 cells resulted in increases in tryptase activity and histamine contents, paralleled by an increase of tryptase and histamine at the transcriptional level. Also, an increased expression of NGF was found in AD lesions, in association with increased systemic NGF plasma levels. Further cutaneous sources for increased NGF levels were keratinocytes and fibroblasts. These findings demonstrate an increased expression of NGF in AD and effects on tryptase and histamine. Mast cells may be major mediators of neurotrophin effects in AD.

4. BMC Vet Res. 2012 Nov 26;8:230. doi: 10.1186/1746-6148-8-230. Inhibitory effect of topical adelmidrol on antigen-induced skin wheal and mast cell behavior in a canine model of allergic dermatitis. Cerrato S, Brazis P, Della Valle MF, Miolo A, Puigdemont A.
Adelmidrol is a semisynthetic derivative of azelaic acid and analogue of the anti-inflammatory compound palmitoylethanolamide (PEA). Based upon its physicochemical properties, adelmidrol is suitable for topical application. The main objective of the present study was to evaluate the efficacy of a topical adelmidrol emulsion on early and late inflammatory responses in hypersensitive dogs. Repeated intradermal injections of Ascaris suum extract were performed in both lateral thoracic areas of six conscious hypersensitive Beagle dogs, topically treated during 8 consecutive days. Adelmidrol (2%) was applied to one side and vehicle to the other. 24 hours after the last antigen challenge, two biopsies (adelmidrol- and vehicle-treated side) were obtained for each dog at the antigen injection site. A significant reduction in the antigen-induced wheal areas was observed on the 4th and 7th day of adelmidrol treatment. Moreover, cutaneous mast cell numbers were significantly decreased in biopsies obtained after 8 consecutive days of topical adelmidrol treatment. The results obtained in the present study show that topical treatment with adelmidrol might represent a new therapeutic tool in controlling the early and late allergic inflammatory skin responses in companion animals.

5. Trends Pharmacol Sci. 2009 Aug;30(8):411-20. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Bíró T, Tóth BI, Haskó G, Paus R, Pacher P.
The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their G-protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease. Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes (e.g. proliferation, growth, differentiation, apoptosis and cytokine, mediator or hormone production of various cell types of the skin and appendages, such as the hair follicle and sebaceous gland). It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).

6. Trends Pharmacol Sci. 2015 May;36(5):277-96. Endocannabinoid signaling at the periphery: 50 years after THC. Maccarrone M, Bab I, Bíró T, Cabral GA, Dey SK, Di Marzo V, Konje JC, Kunos G, Mechoulam R, Pacher P, Sharkey KA, Zimmer A.
In 1964, the psychoactive ingredient of Cannabis sativa, Δ(9)-tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide) (AEA) in 1992 and 2-arachidonoylglycerol (2-AG) in 1995. Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize, and degrade them and that together form the eCB system (ECS). eCBs control basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation. Unsurprisingly, in the past two decades eCBs have been recognized as key mediators of several aspects of human pathophysiology and thus have emerged to be among the most widespread and versatile signaling molecules ever discovered. Here some of the pioneers of this research field review the state of the art of critical eCB functions in peripheral organs. Our community effort is aimed at establishing consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes.

7. Clin Interv Aging. 2014 Jul 17;9:1163-9. 2014. N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: results of a randomized, double-blind, controlled study in 60 patients. Yuan C, Wang XM, Guichard A, Tan YM, Qian CY, Yang LJ, Humbert P.
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-palmitoylethanolamine (PEA) and N-acetylethanolamine (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. 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. 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. Compared with traditional emollients, regular application of a topical PEA/AEA emollient could improve both passive and active skin functions simultaneously.

8. Ann Dermatol. 2016 Feb;28(1):22-9. Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model. Nam G, Jeong SK, Park BM, Lee SH, Kim HJ, Hong SP, Kim B, Kim BW.
Many inflammatory mediators, including various cytokines (e.g. interleukins and tumor necrosis factor [TNF]), inflammatory proteases, and histamine are released following mast cell activation. However, the endogenous modulators for mast cell activation and the underlying mechanism have yet to be elucidated. Endogenous cannabinoids such as palmitoylethanolamide (PEA) and N-arachidonoylethanolamine (anandamide or AEA), were found in peripheral tissues and have been proposed to possess autacoid activity, implying that cannabinoids may downregulate mast cell activation and local inflammation. In order to investigate the effect of cannabinoid receptor-1 (CB1R) agonists on mast cell activation, AEA-derived compounds were newly synthesized and evaluated for their effect on mast cell activation. The effects of selected compounds on FcεRI-induced histamine and β-hexosaminidase release were evaluated in a rat basophilic leukemia cell line (RBL-2H3). To further investigate the inhibitory effects of CB1R agonist in vivo, an oxazolone-induced atopic dermatitis mouse model was exploited. We found that CB1R inhibited the release of inflammatory mediators without causing cytotoxicity in RBL-2H3 cells and that CB1R agonists markedly and dose-dependently suppressed mast cell proliferation indicating that CB1R plays an important role in modulating antigen-dependent immunoglobulin E (IgE)-mediated mast cell activation. We also found that topical application of CB1R agonists suppressed the recruitment of mast cells into the skin and reduced the level of blood histamine. Our results indicate that CB1R agonists down-regulate mast cell activation and may be used for relieving inflammatory symptoms mediated by mast cell activation, such as atopic dermatitis, psoriasis, and contact dermatitis.

9. Vet Dermatol. 2015 Dec;26(6):432-40, e101. Efficacy of ultra-micronized palmitoylethanolamide in canine atopic dermatitis: an open-label multi-centre study. Noli C, Della Valle MF, Miolo A, Medori C, Schievano C; Skinalia Clinical Research Group.
Palmitoylethanolamide is a naturally occurring bioactive lipid, produced on-demand by damage-exposed cells. Palmitoylethanolamide is documented to counteract inflammation, itch and pain. The aim of this 8-week study was to evaluate the efficacy of oral ultra-micronized palmitoylethanolamide (PEA-um) in dogs with moderate atopic dermatitis. Clinicians from 39 veterinary clinics enrolled 160 dogs with nonseasonal atopic dermatitis and moderate pruritus. This was a multi-centre open-label study. On days 0 (D0) and 56 (D56), owners evaluated pruritus with a Visual Analog Scale (VAS) and completed a validated Quality of Life (QoL) questionnaire. Veterinarians assessed the severity of skin lesions using the Canine Atopic Dermatitis Lesion Index (CADLI). Mean pruritus VAS score decreased from 5.7 ± 0.08 cm (range 3.8-7.9 cm) to 3.63 ± 0.19 cm (range 0.1-9.2 cm) (P < 0.0001). At D56, 58% of dogs showed a greater than 2 cm reduction from baseline and 30% showed an absent-to-very mild pruritus (VAS ≤ 2 cm). Mean total CADLI at D56 decreased significantly (P < 0.0001); in 62% of dogs this score reached a value in the remission range (≤5). Mean total QoL score was significantly decreased (P < 0.0001) with 45% of dogs reaching QoL values described for healthy animals. Tolerability was good-to-excellent with only four dogs reporting treatment associated reversible adverse events. PEA-um appears to be effective and safe in reducing pruritus and skin lesions, and in improving QoL in dogs with moderate atopic dermatitis and moderate pruritus.

10. Biochem Pharmacol. 2011 Aug 15;82(4):380-8. doi: 10.1016/j.bcp.2011.05.004. Epub 2011 May 12. Endocannabinoids inhibit release of nerve growth factor by inflammation-activated mast cells. Cantarella G, Scollo M, Lempereur L, Saccani-Jotti G, Basile F, Bernardini R.
Nerve growth factor (NGF) is a pleiotropic member of the neurotrophin family. Beside its neuronal effects, NGF plays a role in various processes, including angiogenesis. Mast cells release NGF and are among elements contributing to angiogenesis, a process regulated by arrays of factors, including the inhibitory cannabinoids. The possible inhibitory role of cannabinoids on mast cell-related NGF mitogenic effect on endothelial cells was then investigated. Human mastocytic cells HMC-1, challenged with PMA to yield release of NGF, were preincubated with the endocannabinoid PEA. Then, conditioned media were added to HUVEC cultures. PMA-activated HMC-1 cells released substantial amounts of NGF, whereas PEA inhibited PMA-induced NGF release. HUVEC proliferation increased after treatment with media from activated HMC-1 cells, while was reduced with media from HMC-1 cells treated with PEA. To characterize receptors mediating such effects of PEA, RT-PCR and western blot analysis were performed on HMC-1 cells. None of the two cannabinoid CB1 and CB2 receptors was expressed by HMC-1 cells, which on the other hand expressed the orphan receptor GPR55. PEA was ineffective in inhibiting NGF release from HMC-1 cells treated with PMA and transfected with positive GPR55 RNAi, whereas it induced significant reduction of NGF in cells transfected with the corresponding negative control RNAi. Results indicate that NGF released from inflammatory mast cells induces angiogenesis. Cannabinoids attenuate such pro-angiogenic effects of NGF. Finally, cannabinoids could be considered for antiangiogenic treatment in disorders characterized by prominent inflammation.


 

Aliatop® skystas kremas
 
Rogonil® tepalas
 
Fimosin® gelis
 

 
   

 

Puslapio naudojimosi sąlygosLiteratūraNuorodosKontaktai