Beneficial Effects of Antioxidant Furfuryl Palmitate in Non-pharmacologic Treatments (Prescription Emollient Devices, PEDs) for Atopic Dermatitis and Related Skin Disorders

Beneficial Effects of Antioxidant Furfuryl Palmitate in Non-pharmacologic Treatments... Dermatol Ther (Heidelb) https://doi.org/10.1007/s13555-018-0239-0 REVIEW Beneficial Effects of Antioxidant Furfuryl Palmitate in Non-pharmacologic Treatments (Prescription Emollient Devices, PEDs) for Atopic Dermatitis and Related Skin Disorders Paolo Daniele Pigatto Marco Diani Received: March 20, 2018 The Author(s) 2018 reported for the following conditions: atopic, ABSTRACT seborrheic, irritative, and allergic contact der- matitis, eczema, xerosis, and cutaneous inflam- Introduction: Atopic dermatitis (AD) is a com- matory pathologies. All the products tested mon chronic inflammatory skin disease; it showed a good tolerability profile. requires long-term treatments focused on Conclusion: Studies performed up to now symptomatic relief. Current first-line treatments showed that furfuryl derivatives can effica- include moisturizers and topical corticosteroids. ciously contrast signs and symptoms of mild-to- Recently, topical antioxidants have been added moderate AD, erythema, and widespread diffuse to moisturizer formulations to alleviate mild-to- cutaneous pathologies in both adult and pedi- moderate AD. The aim of this review was to atric patients, representing a real alternative to evaluate the efficacy and tolerability of furfuryl steroids and a valid aid in the treatment of skin palmitate, a new antioxidant molecule, and disorders, with no side effects and without furfuryl derivatives. requiring precautions in use. Methods: A PubMed/Google Scholar search was Funding: Relife S.r.l. - Menarini Group. conducted using the term ‘‘furfuryl palmitate’’ Plain Language Summary: Plain language (and its derivatives, including AR-GG27 ) summary available for this article. combined with ‘‘skin,’’ ‘‘atopic dermatitis,’’ and ‘‘atopic eczema.’’ Existing trials including adult Keywords: Antioxidants; Atopic dermatitis; and pediatric patients with AD and related skin Cutaneous inflammatory pathologies; disorders were evaluated. The treatment indi- Dermatitis; Eczema; Furfuryl derivatives; cation(s), number of subjects, treatment proto- Furfuryl palmitate; Prescription emollient cols, results, and side effects were recorded. devices; Topical treatments Results: Effective treatments with furfuryl palmitate and furfuryl derivatives have been PLAIN LANGUAGE SUMMARY Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.6166121. Atopic dermatitis (AD), also called eczema, is a common skin disease. Its main symptoms are Paolo Daniele Pigatto (&)  M. Diani redness and itching of the skin, but symptoms Dipartimento di Scienze biomediche, chirurgiche e can vary from person to person; it also presents odontoiatriche, Clinica Dermatologica, Universita` features of asthma and/or hay fever. It tends to degli Studi di Milano, Milan, Italy flare periodically and clear up for the rest of the e-mail: paolo.pigatto@unimi.it Dermatol Ther (Heidelb) time. It is a disease more common in childhood, function, causing cutaneous inflammation and but may persist in adolescence and adulthood. increased transepidermal water loss (TEWL). There is no cure for this disease, but it Also, the lack of intercellular lipids in the stra- requires long-term treatments to relieve itching tum corneum and inadequate ratios among and prevent new outbreaks. First-line treatment compounds (cholesterol, essential fatty acids, includes substances called skin moisturizers ceramides), typical of AD patients, enhance (that help prevent skin dryness) and corticos- TEWL, leading to epidermal microfissuring, teroids (drugs that can lessen redness and itch- facilitating easier allergen penetration [14, 15]. ing). Recently, substances called antioxidants Atopic dermatitis, being a complex and have been added to moisturizer formulations to multifactorial disease, can be treated by differ- alleviate AD symptoms. Antioxidants can pro- ent physicians according to different therapies tect the skin from damage caused by harmful and approaches. However, all clinical modifi- molecules called free radicals. cations have to be considered as one condition Our research aimed to evaluate the efficacy and, requiring AD lifelong or long-term per- and safety of using furfuryl palmitate, a new spective treatments, special attention must be antioxidant, and furfuryl derivatives added to given to safety aspects. moisturizer formulations. A literature search Several guidelines have been published [16] was conducted, and existing research works to suggest a proper clinical approach to manage including adult and pediatric patients with AD AD, but the goal of any treatment is to gain a and related skin disorders were evaluated. state in which no or only minor symptoms What has been seen up to now is that fur- occur and drug treatments are not much nee- furyl palmitate and its derivatives can effica- ded, with the disease rarely showing acute or ciously contrast symptoms of mild and intense exacerbations. No treatments can heal moderate AD, erythema, and widespread diffuse the disease, but treatments basically focus on cutaneous disturbances in both adult and symptom relief. pediatric patients. Thus, this treatment repre- All the management guidelines review topical sents a valid aid in the treatment of skin disor- therapy for AD [17–20]; current first-line treat- ders, with no side effects and without requiring ment includes moisturizers and topical corti- precautions for use. costeroids. According to the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology [11], the regular use of moisturizers INTRODUCTION represents the mainstay of the general manage- ment of AD and of maintenance of remission Atopic dermatitis, also referred as ‘‘atopic from flares [10]. They relieve the severe dryness eczema’’ or ‘‘eczema,’’ is a common, non-con- of the atopic skin and the accompanying symp- tagious, chronically relapsing and inflammatory toms, such as intense pruritus and inflamma- skin disease [1–4], usually associated with tion, improving the barrier function and asthma and inhalant allergies [5]. It usually decreasing the TEWL [21]. Their constant use appears in childhood, but with growth most could be sufficient to control mild eczema and children move to a condition that no longer should also form part of the treatment regimen requires medical care; adults make up only for more severe forms, being also able to decrease about one-third of all cases. A hereditary com- the use of topical steroids [22–25]. ponent of the disease is known,but a crucial role Moisturizers ideally perform all the following in disease expression can be attributed to the functions: improve skin barrier functions by environment [6–9]. delivering lipids and water to the stratum cor- The clinical features leading to a diagnosis of neum [26] (restoring barrier function and thus AD are variable, but the hallmark of atopic also ameliorating antimicrobial defense); dermatitis is extremely itchy and dry skin maintain skin integrity and appearance; reduce [10–13], resulting in impaired skin barrier TEWL; facilitate barrier repair by encouraging Dermatol Ther (Heidelb) the natural restorative process [27, 28]. They possible that antioxidants may be beneficial in can be formulated in a variety of delivery sys- the treatment of AD, i.e., that suppressing the tems and have different compositions and oxidative stress may be a potentially useful properties to enhance efficacy; the most effica- strategy for the treatment of AD [1, 35–39]. cious moisturizers contain both occlusive and Furfuryl palmitate is an ester obtained when humectant ingredients [18, 21, 26, 29]. furfuryl alcohol reacts with palmitic acid, and it Moisturizers are considered very safe, but has remarkable singlet oxygen-quenching adverse skin reactions are not uncommon, also properties, O . This is a radical with no ionic considering that atopics are particularly at risk charge and relatively low reactivity, which for adverse skin reactions because of their facilitates its spread through the dermis and impaired barrier function, whereas systemic into the cells, where it can damage cytoplasmic side effects are extremely rare [30, 31]. structures and nuclear material. Besides being Recently, new antiinflammatory agents have one of the prime causes of skin aging, O plays been added into the moisturizer formulations to a role in the genesis of symptomatic topical alleviate mild to moderate AD. The term PED disorders such as irritant and allergic contact (prescription emollient devices) has been intro- dermatitis, seborrheic dermatitis, inflamma- duced to identify this new class of topical agents tion, psoriasis and sun erythema [30, 40]. designed to target the specific defects in skin O is formed from atmospheric O by pho- 2 2 barrier function observed in AD, and they con- tochemical activation, and the process has tain several components including antiinflam- intensified in recent years following the thin- matory agents, emollients or humectants. PEDs ning of the ozone layer and the reduction in its are also knows as prescription barrier repair protection against UV radiation. Production of creams (BRCs) [18, 28, 32, 33]. They are O from O is effectively inhibited by the pres- 2 2 approved as 510(k) medical devices based on the ence of furfuryl alcohol, as widely demonstrated assertion that they serve a structural role in skin by experimental data [41]. Thanks to the pres- barrier function and do not exert their effects by ence of a conjugated diene, furfuryl alcohol and any chemical actions. The moisturizers qualify its derivatives can interact with PO by either as devices because they can change the water conversion to oxygen in the ground state (triplet content of the skin, demonstrated by measuring state) or sequestering the radical through a Dies the TEWL. According to this approval route, Alder type diene dienophile addition reaction. safety, not efficacy, is of primary concern. Esterification of the furyl ring with palmitate These compounds represent the answer to enhances molecule penetration into the mem- the awareness of the primary role of the stratum branes, thus facilitating skin absorption [42]. corneum in the pathogenesis of AD and of the In 2008, furfuryl derivatives and their use in need not only to treat the inflammation but the treatment of dermatologic disorders, espe- also to restore the barrier, delivering stratum cially when caused by free radicals, were the corneum-specific lipids to help correct the epi- objects of a US patent [43]. dermal barrier dysfunction [34]. The first in vitro experiments for sorbityl PEDs may provide additional barrier repair furfural palmitate (ARGG27 ) demonstrated its and control xerosis without topical corticos- antioxidant and lenitive actions [44, 45], sup- teroid treatment and include preparations hav- porting the hypothesis of a positive effect of the ing distinct ratios of lipids that mimic ARGG27 molecule on the control of AD and endogenous compositions. other inflammatory skin diseases. PEDs may contain an antioxidant agent, such as furfuryl palmitate or furfuryl deriva- METHODS tives. Oxidative stress and altered antioxidant defenses are involved in the pathophysiology of A search using PubMed and Google Scholar was acute exacerbation of AD, and AD patients are conducted up to September 2017 using the term more prone to report damages caused by reac- ‘‘furfuryl palmitate’’ (and its derivatives tive oxygen species (ROS) or oxidants. Thus, it is Dermatol Ther (Heidelb) including AR-GG27 ) combined with ‘‘skin,’’ protocol populations were reported (this could ‘‘atopic dermatitis,’’ ‘‘atopic eczema,’’ ‘‘dermati- also be the reason for the discrepancy between tis’’ and ‘‘eczema.’’ The search results were the table and figure reporting mean SCORAD reviewed for clinical trials, case reports and case index scores). The sample size (relatively small) series examining the usage and efficacy of fur- was not based on differences from baseline, and furyl palmitate to treat dermatologic condi- a possible bias in statistics could also be attrib- tions. The following information was recorded uted to the difference in food allergy in the from these publications: the dermatologic con- groups (respectively 28% and 39% in group A dition being studied, test agents, number of and B). Concerning patient selection, eligibility subjects, treatment protocol, results and safety criteria were not completely clarified, no mini- profile. mal/maximal severity of disease score was This article is based on previously conducted mentioned for inclusion, and the SCORAD studies and does not contain any studies with index was not homogeneous between groups, human participants or animals performed by being 25.6 (mean score, corresponding to any of the authors. ‘‘mild,’’ up to 25) in the basic emollient cream group, group A, and 28.1 (mean score, corre- sponding to ‘‘moderate,’’ between 25 and 50) in RESULTS the furfuryl palmitate cream group, group B. The analysis seemed not to have considered this Six papers on furfuryl palmitate and its deriva- difference, and the standard deviation was high tive therapies (meeting the following criteria: (respectively 10.1 and 10.6 in group A and B), being a clinical study; having furfuryl palmitate increasing the doubts regarding patient and its derivatives as one of the experimental selection. agents; describing a dermatologic application for furfuryl palmitate and its derivatives) were obtained and reviewed, including adult and CONCLUSIONS pediatric patients with AD and related skin disorders. Moisturizers traditionally have a key role in The studies are outlined in Table 1 improving and maintaining the skin barrier [37, 42, 46–49]. function and reducing skin susceptibility to In the clinical study by Tripodi et al. [49], the irritants; they represent the standard care for efficacy and tolerability of furfuryl palmitate AD therapy, useful for both prevention and were evaluated, and the main results are shown maintenance therapy, and it has been shown in Table 1. that their regular use has a short- and long-term The quality and scientific validity of the steroid-sparing effect in mild-to-moderate AD. study have been challenged, based on the fol- Over time, the traditional therapy based on lowing issues. moisturizers has been enriched and improved Concerning the study product, the percent- by topical agents for physiologic lipid base age of furfuryl palmitate was not specified, thus barrier repair. They focus on physiologic lipid potentially invalidating the study and in any replacement therapy, particularly ceramides, case confounding the outcome, and a proper being able to restore the normal balance of the placebo or a pure emollient alone (as control) epidermal barrier. was missing. Concerning the study methodol- Several studies demonstrated that these ogy, it seemed that only a comparison within agents are safe and effective in treating AD, as groups was presented, whereas a comparison either monotherapy or adjuvant treatment, between groups was missing; furthermore, the showing comparable efficacy, in terms of statistical power calculation was at minimum improving symptoms and timing to resolution - 80%, invalidating the reliability of conclu- compared with traditional agents [28, 50]. sions. No superiority or non-inferiority design Today, considering the new research per- was clarified, and only results for the per formed on the role of oxidative stress in AD, Dermatol Ther (Heidelb) Table 1 Clinical studies Disease Test agent Comparison N Study design Treatment Results Safety Year References agent protocol Atopic dermatitis and ARGG27 Placebo 60 pediatric RCT BL DB BID 9 30 days Itching and severity No SAEs reported 2012 [37] pityriasis alba patients significantly reduced in No AEs reported in the AR GG27 group ARGG27 group compared with placebo 6 AEs reported in placebo group after 15 and group (2 possibly 30 days of treatment correlated) Atopic dermatitis (33), Superoxidodismutase None 60 pediatric CT UL BID 9 Significant improvement of The product did not show 2002 [42] irritant and allergic (SOD), 18 beta patients 2 weeks the inflammatory skin any relevant side effect contact dermatitis (17), glycyrrethic acid, conditions, with evident miscellaneous vitamin E, alpha and fast inflammation pathologies with an bisabolol and and eczema reduction in inflammatory cutaneous furfuryl palmitate all the investigated component and pathologies symptomatic manifestations such as eczema or xerosis (10, including 3 seborrheic dermatitis and 2 psoriasis) Atopic dermatitis (40), Superoxidodismutase None 64 adult CT UL BID 9 Efficacy assessed as good or No relevant side effects or 2002 [46] seborrheic dermatitis (SOD), 18 beta and 44 2 weeks excellent in most of the intolerances were (30), allergic contact glycyrrethic acid, pediatric cases treated; a observed dermatitis (13), irritative vitamin E, alpha patients significant reduction in and irritative contact bisabolol and erythema, itching and dermatitis (25) furfuryl palmitate the presence of blisters is obtained just 48 h after starting to apply the product Dermatol Ther (Heidelb) Table 1 continued Disease Test agent Comparison N Study design Treatment Results Safety Year References agent protocol Mild-to-moderate atopic Furpalmate Vehicle 40 adult RCT BL DB BID 9 21 days The study product was One patient requested 2011 [47] dermatitis patients shown to efficaciously rescue therapy with contrast signs and corticosteroids for a symptoms of mild-to- flare up of inflammation moderate atopic in the furpalmate group dermatitis in adult compared with six in patients, resulting in a the control group more effective vehicle (p \ 0.01). No SAE Atopic dermatitis of hands Furpalmate Topical 40 adult RCT BL BID 9 14 days Both groups significantly – 2011 [48] corticosteroid patients investigator improved in signs and blinded symptoms on either the physician’s or patient’s evaluation scores with respect to baseline (p \ 0.001) with no significant difference between the two groups Atopic dermatitis Emollient cream Emollient 117 RCT BID 9 14 days While the emollient cream No statistical differences 2009 [49] enriched with cream pediatric containing furfuryl were found for the furfuryl palmitate patients palmitate was efficacious tolerability of the two to a certain extent, the products, even if the results were less enriched cream was clinically relevant than reported to be less well those observed for the tolerated, with same cream not complaints of itching containing the active and burning sensation ingredient after application CT clinical trial, RCT randomized clinical trial, DB double blind, BID bis in die/twice daily, UL unilateral comparison, BL bilateral comparison (test versus control) Dermatol Ther (Heidelb) products enriched in antioxidants, such as fur- ACKNOWLEDGEMENTS furyl derivatives, can represent a valid aid in the treatment of a range of skin disorders, such as atopic and seborrheic dermatitis, with no side Funding. This research was sponsored and effects or requirement of precautions in use. funded by Relife S.r.l. Menarini Group. Article Even if the preliminary data shown should processing charges were funded by Relife S.r.l. be confirmed in larger trials considering both Menarini Group. pediatric and adult patients, studies performed up to now have shown that furfuryl derivatives Medical Writing and/or Editorial Assis- are able to efficaciously contrast the signs and tance. Medical writing and editorial assistance symptoms of mild-to-moderate AD and ery- in the preparation of this manuscript were thema and also widespread diffuse cutaneous provided by Dr. Federica Sbrocca, MSc (SPRIM pathologies, such as irritative, seborrheic and ALS GCP, Milan, Italy). Support for this assis- allergic contact dermatitis, in both adult and tance was funded by Relife S.r.l. Menarini pediatric patients [37, 42, 46–48]. The only Group. The authors are fully responsible for all paper published up to now not agreeing with content and editorial decisions related to the what is outlined here is biased by several issues, development of this manuscript. as discussed above, whereas all other clinical Authorship. All named authors meet the investigations carried out not only did not International Committee of Medical Journal highlight any negative aspects, but instead Editors (ICMJE) criteria for authorship for this confirmed several positive outcomes, showing a article, take responsibility for the integrity of clear superiority of verum with respect to the work as a whole and have given their placebo. approval for this version to be published. The products containing these compounds can constitute a valuable alternative to topical Disclosures. Paolo Pigatto and Marco Diani corticosteroids in mild-medium severity skin have nothing to disclose. disorders, especially when preferring to avoid a pharmacologic agent, such as in pediatric Compliance with Ethics Guidelines. This patients, intolerant subjects or atopic patients. article is based on previously conducted studies In addition, they can also act in synergy with and does not contain any studies with human other topical or systemic treatments, as well as participants or animals performed by any of the pharmacologic, to promote faster recovery of authors. the normal skin condition, reducing inflam- mation and restoring the skin barrier. Data Availability. The manuscript has no Thus, in patients with mild or moderate AD, associated data. these products represent a real alternative to steroids, which instead constitute an important Open Access. This article is distributed health risk. under the terms of the Creative Commons All the products tested showed, in addition, a Attribution-NonCommercial 4.0 International good tolerability profile, thus promoting com- License (http://creativecommons.org/licenses/ pliance by both the patient and caregiver. This by-nc/4.0/), which permits any noncommer- is of main importance, because the choice of cial use, distribution, and reproduction in any therapy can be primarily considered as depen- medium, provided you give appropriate credit dent on the patient’s preferences and also the to the original author(s) and the source, provide ideal moisturizing agent should be safe, effec- a link to the Creative Commons license, and tive, inexpensive. indicate if changes were made. Despite the positive results outlined above in the confirmatory studies, research with bigger sample sizes is advisable to confirm and emphasize the results already achieved. 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Beneficial Effects of Antioxidant Furfuryl Palmitate in Non-pharmacologic Treatments (Prescription Emollient Devices, PEDs) for Atopic Dermatitis and Related Skin Disorders

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Abstract

Dermatol Ther (Heidelb) https://doi.org/10.1007/s13555-018-0239-0 REVIEW Beneficial Effects of Antioxidant Furfuryl Palmitate in Non-pharmacologic Treatments (Prescription Emollient Devices, PEDs) for Atopic Dermatitis and Related Skin Disorders Paolo Daniele Pigatto Marco Diani Received: March 20, 2018 The Author(s) 2018 reported for the following conditions: atopic, ABSTRACT seborrheic, irritative, and allergic contact der- matitis, eczema, xerosis, and cutaneous inflam- Introduction: Atopic dermatitis (AD) is a com- matory pathologies. All the products tested mon chronic inflammatory skin disease; it showed a good tolerability profile. requires long-term treatments focused on Conclusion: Studies performed up to now symptomatic relief. Current first-line treatments showed that furfuryl derivatives can effica- include moisturizers and topical corticosteroids. ciously contrast signs and symptoms of mild-to- Recently, topical antioxidants have been added moderate AD, erythema, and widespread diffuse to moisturizer formulations to alleviate mild-to- cutaneous pathologies in both adult and pedi- moderate AD. The aim of this review was to atric patients, representing a real alternative to evaluate the efficacy and tolerability of furfuryl steroids and a valid aid in the treatment of skin palmitate, a new antioxidant molecule, and disorders, with no side effects and without furfuryl derivatives. requiring precautions in use. Methods: A PubMed/Google Scholar search was Funding: Relife S.r.l. - Menarini Group. conducted using the term ‘‘furfuryl palmitate’’ Plain Language Summary: Plain language (and its derivatives, including AR-GG27 ) summary available for this article. combined with ‘‘skin,’’ ‘‘atopic dermatitis,’’ and ‘‘atopic eczema.’’ Existing trials including adult Keywords: Antioxidants; Atopic dermatitis; and pediatric patients with AD and related skin Cutaneous inflammatory pathologies; disorders were evaluated. The treatment indi- Dermatitis; Eczema; Furfuryl derivatives; cation(s), number of subjects, treatment proto- Furfuryl palmitate; Prescription emollient cols, results, and side effects were recorded. devices; Topical treatments Results: Effective treatments with furfuryl palmitate and furfuryl derivatives have been PLAIN LANGUAGE SUMMARY Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.6166121. Atopic dermatitis (AD), also called eczema, is a common skin disease. Its main symptoms are Paolo Daniele Pigatto (&)  M. Diani redness and itching of the skin, but symptoms Dipartimento di Scienze biomediche, chirurgiche e can vary from person to person; it also presents odontoiatriche, Clinica Dermatologica, Universita` features of asthma and/or hay fever. It tends to degli Studi di Milano, Milan, Italy flare periodically and clear up for the rest of the e-mail: paolo.pigatto@unimi.it Dermatol Ther (Heidelb) time. It is a disease more common in childhood, function, causing cutaneous inflammation and but may persist in adolescence and adulthood. increased transepidermal water loss (TEWL). There is no cure for this disease, but it Also, the lack of intercellular lipids in the stra- requires long-term treatments to relieve itching tum corneum and inadequate ratios among and prevent new outbreaks. First-line treatment compounds (cholesterol, essential fatty acids, includes substances called skin moisturizers ceramides), typical of AD patients, enhance (that help prevent skin dryness) and corticos- TEWL, leading to epidermal microfissuring, teroids (drugs that can lessen redness and itch- facilitating easier allergen penetration [14, 15]. ing). Recently, substances called antioxidants Atopic dermatitis, being a complex and have been added to moisturizer formulations to multifactorial disease, can be treated by differ- alleviate AD symptoms. Antioxidants can pro- ent physicians according to different therapies tect the skin from damage caused by harmful and approaches. However, all clinical modifi- molecules called free radicals. cations have to be considered as one condition Our research aimed to evaluate the efficacy and, requiring AD lifelong or long-term per- and safety of using furfuryl palmitate, a new spective treatments, special attention must be antioxidant, and furfuryl derivatives added to given to safety aspects. moisturizer formulations. A literature search Several guidelines have been published [16] was conducted, and existing research works to suggest a proper clinical approach to manage including adult and pediatric patients with AD AD, but the goal of any treatment is to gain a and related skin disorders were evaluated. state in which no or only minor symptoms What has been seen up to now is that fur- occur and drug treatments are not much nee- furyl palmitate and its derivatives can effica- ded, with the disease rarely showing acute or ciously contrast symptoms of mild and intense exacerbations. No treatments can heal moderate AD, erythema, and widespread diffuse the disease, but treatments basically focus on cutaneous disturbances in both adult and symptom relief. pediatric patients. Thus, this treatment repre- All the management guidelines review topical sents a valid aid in the treatment of skin disor- therapy for AD [17–20]; current first-line treat- ders, with no side effects and without requiring ment includes moisturizers and topical corti- precautions for use. costeroids. According to the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology [11], the regular use of moisturizers INTRODUCTION represents the mainstay of the general manage- ment of AD and of maintenance of remission Atopic dermatitis, also referred as ‘‘atopic from flares [10]. They relieve the severe dryness eczema’’ or ‘‘eczema,’’ is a common, non-con- of the atopic skin and the accompanying symp- tagious, chronically relapsing and inflammatory toms, such as intense pruritus and inflamma- skin disease [1–4], usually associated with tion, improving the barrier function and asthma and inhalant allergies [5]. It usually decreasing the TEWL [21]. Their constant use appears in childhood, but with growth most could be sufficient to control mild eczema and children move to a condition that no longer should also form part of the treatment regimen requires medical care; adults make up only for more severe forms, being also able to decrease about one-third of all cases. A hereditary com- the use of topical steroids [22–25]. ponent of the disease is known,but a crucial role Moisturizers ideally perform all the following in disease expression can be attributed to the functions: improve skin barrier functions by environment [6–9]. delivering lipids and water to the stratum cor- The clinical features leading to a diagnosis of neum [26] (restoring barrier function and thus AD are variable, but the hallmark of atopic also ameliorating antimicrobial defense); dermatitis is extremely itchy and dry skin maintain skin integrity and appearance; reduce [10–13], resulting in impaired skin barrier TEWL; facilitate barrier repair by encouraging Dermatol Ther (Heidelb) the natural restorative process [27, 28]. They possible that antioxidants may be beneficial in can be formulated in a variety of delivery sys- the treatment of AD, i.e., that suppressing the tems and have different compositions and oxidative stress may be a potentially useful properties to enhance efficacy; the most effica- strategy for the treatment of AD [1, 35–39]. cious moisturizers contain both occlusive and Furfuryl palmitate is an ester obtained when humectant ingredients [18, 21, 26, 29]. furfuryl alcohol reacts with palmitic acid, and it Moisturizers are considered very safe, but has remarkable singlet oxygen-quenching adverse skin reactions are not uncommon, also properties, O . This is a radical with no ionic considering that atopics are particularly at risk charge and relatively low reactivity, which for adverse skin reactions because of their facilitates its spread through the dermis and impaired barrier function, whereas systemic into the cells, where it can damage cytoplasmic side effects are extremely rare [30, 31]. structures and nuclear material. Besides being Recently, new antiinflammatory agents have one of the prime causes of skin aging, O plays been added into the moisturizer formulations to a role in the genesis of symptomatic topical alleviate mild to moderate AD. The term PED disorders such as irritant and allergic contact (prescription emollient devices) has been intro- dermatitis, seborrheic dermatitis, inflamma- duced to identify this new class of topical agents tion, psoriasis and sun erythema [30, 40]. designed to target the specific defects in skin O is formed from atmospheric O by pho- 2 2 barrier function observed in AD, and they con- tochemical activation, and the process has tain several components including antiinflam- intensified in recent years following the thin- matory agents, emollients or humectants. PEDs ning of the ozone layer and the reduction in its are also knows as prescription barrier repair protection against UV radiation. Production of creams (BRCs) [18, 28, 32, 33]. They are O from O is effectively inhibited by the pres- 2 2 approved as 510(k) medical devices based on the ence of furfuryl alcohol, as widely demonstrated assertion that they serve a structural role in skin by experimental data [41]. Thanks to the pres- barrier function and do not exert their effects by ence of a conjugated diene, furfuryl alcohol and any chemical actions. The moisturizers qualify its derivatives can interact with PO by either as devices because they can change the water conversion to oxygen in the ground state (triplet content of the skin, demonstrated by measuring state) or sequestering the radical through a Dies the TEWL. According to this approval route, Alder type diene dienophile addition reaction. safety, not efficacy, is of primary concern. Esterification of the furyl ring with palmitate These compounds represent the answer to enhances molecule penetration into the mem- the awareness of the primary role of the stratum branes, thus facilitating skin absorption [42]. corneum in the pathogenesis of AD and of the In 2008, furfuryl derivatives and their use in need not only to treat the inflammation but the treatment of dermatologic disorders, espe- also to restore the barrier, delivering stratum cially when caused by free radicals, were the corneum-specific lipids to help correct the epi- objects of a US patent [43]. dermal barrier dysfunction [34]. The first in vitro experiments for sorbityl PEDs may provide additional barrier repair furfural palmitate (ARGG27 ) demonstrated its and control xerosis without topical corticos- antioxidant and lenitive actions [44, 45], sup- teroid treatment and include preparations hav- porting the hypothesis of a positive effect of the ing distinct ratios of lipids that mimic ARGG27 molecule on the control of AD and endogenous compositions. other inflammatory skin diseases. PEDs may contain an antioxidant agent, such as furfuryl palmitate or furfuryl deriva- METHODS tives. Oxidative stress and altered antioxidant defenses are involved in the pathophysiology of A search using PubMed and Google Scholar was acute exacerbation of AD, and AD patients are conducted up to September 2017 using the term more prone to report damages caused by reac- ‘‘furfuryl palmitate’’ (and its derivatives tive oxygen species (ROS) or oxidants. Thus, it is Dermatol Ther (Heidelb) including AR-GG27 ) combined with ‘‘skin,’’ protocol populations were reported (this could ‘‘atopic dermatitis,’’ ‘‘atopic eczema,’’ ‘‘dermati- also be the reason for the discrepancy between tis’’ and ‘‘eczema.’’ The search results were the table and figure reporting mean SCORAD reviewed for clinical trials, case reports and case index scores). The sample size (relatively small) series examining the usage and efficacy of fur- was not based on differences from baseline, and furyl palmitate to treat dermatologic condi- a possible bias in statistics could also be attrib- tions. The following information was recorded uted to the difference in food allergy in the from these publications: the dermatologic con- groups (respectively 28% and 39% in group A dition being studied, test agents, number of and B). Concerning patient selection, eligibility subjects, treatment protocol, results and safety criteria were not completely clarified, no mini- profile. mal/maximal severity of disease score was This article is based on previously conducted mentioned for inclusion, and the SCORAD studies and does not contain any studies with index was not homogeneous between groups, human participants or animals performed by being 25.6 (mean score, corresponding to any of the authors. ‘‘mild,’’ up to 25) in the basic emollient cream group, group A, and 28.1 (mean score, corre- sponding to ‘‘moderate,’’ between 25 and 50) in RESULTS the furfuryl palmitate cream group, group B. The analysis seemed not to have considered this Six papers on furfuryl palmitate and its deriva- difference, and the standard deviation was high tive therapies (meeting the following criteria: (respectively 10.1 and 10.6 in group A and B), being a clinical study; having furfuryl palmitate increasing the doubts regarding patient and its derivatives as one of the experimental selection. agents; describing a dermatologic application for furfuryl palmitate and its derivatives) were obtained and reviewed, including adult and CONCLUSIONS pediatric patients with AD and related skin disorders. Moisturizers traditionally have a key role in The studies are outlined in Table 1 improving and maintaining the skin barrier [37, 42, 46–49]. function and reducing skin susceptibility to In the clinical study by Tripodi et al. [49], the irritants; they represent the standard care for efficacy and tolerability of furfuryl palmitate AD therapy, useful for both prevention and were evaluated, and the main results are shown maintenance therapy, and it has been shown in Table 1. that their regular use has a short- and long-term The quality and scientific validity of the steroid-sparing effect in mild-to-moderate AD. study have been challenged, based on the fol- Over time, the traditional therapy based on lowing issues. moisturizers has been enriched and improved Concerning the study product, the percent- by topical agents for physiologic lipid base age of furfuryl palmitate was not specified, thus barrier repair. They focus on physiologic lipid potentially invalidating the study and in any replacement therapy, particularly ceramides, case confounding the outcome, and a proper being able to restore the normal balance of the placebo or a pure emollient alone (as control) epidermal barrier. was missing. Concerning the study methodol- Several studies demonstrated that these ogy, it seemed that only a comparison within agents are safe and effective in treating AD, as groups was presented, whereas a comparison either monotherapy or adjuvant treatment, between groups was missing; furthermore, the showing comparable efficacy, in terms of statistical power calculation was at minimum improving symptoms and timing to resolution - 80%, invalidating the reliability of conclu- compared with traditional agents [28, 50]. sions. No superiority or non-inferiority design Today, considering the new research per- was clarified, and only results for the per formed on the role of oxidative stress in AD, Dermatol Ther (Heidelb) Table 1 Clinical studies Disease Test agent Comparison N Study design Treatment Results Safety Year References agent protocol Atopic dermatitis and ARGG27 Placebo 60 pediatric RCT BL DB BID 9 30 days Itching and severity No SAEs reported 2012 [37] pityriasis alba patients significantly reduced in No AEs reported in the AR GG27 group ARGG27 group compared with placebo 6 AEs reported in placebo group after 15 and group (2 possibly 30 days of treatment correlated) Atopic dermatitis (33), Superoxidodismutase None 60 pediatric CT UL BID 9 Significant improvement of The product did not show 2002 [42] irritant and allergic (SOD), 18 beta patients 2 weeks the inflammatory skin any relevant side effect contact dermatitis (17), glycyrrethic acid, conditions, with evident miscellaneous vitamin E, alpha and fast inflammation pathologies with an bisabolol and and eczema reduction in inflammatory cutaneous furfuryl palmitate all the investigated component and pathologies symptomatic manifestations such as eczema or xerosis (10, including 3 seborrheic dermatitis and 2 psoriasis) Atopic dermatitis (40), Superoxidodismutase None 64 adult CT UL BID 9 Efficacy assessed as good or No relevant side effects or 2002 [46] seborrheic dermatitis (SOD), 18 beta and 44 2 weeks excellent in most of the intolerances were (30), allergic contact glycyrrethic acid, pediatric cases treated; a observed dermatitis (13), irritative vitamin E, alpha patients significant reduction in and irritative contact bisabolol and erythema, itching and dermatitis (25) furfuryl palmitate the presence of blisters is obtained just 48 h after starting to apply the product Dermatol Ther (Heidelb) Table 1 continued Disease Test agent Comparison N Study design Treatment Results Safety Year References agent protocol Mild-to-moderate atopic Furpalmate Vehicle 40 adult RCT BL DB BID 9 21 days The study product was One patient requested 2011 [47] dermatitis patients shown to efficaciously rescue therapy with contrast signs and corticosteroids for a symptoms of mild-to- flare up of inflammation moderate atopic in the furpalmate group dermatitis in adult compared with six in patients, resulting in a the control group more effective vehicle (p \ 0.01). No SAE Atopic dermatitis of hands Furpalmate Topical 40 adult RCT BL BID 9 14 days Both groups significantly – 2011 [48] corticosteroid patients investigator improved in signs and blinded symptoms on either the physician’s or patient’s evaluation scores with respect to baseline (p \ 0.001) with no significant difference between the two groups Atopic dermatitis Emollient cream Emollient 117 RCT BID 9 14 days While the emollient cream No statistical differences 2009 [49] enriched with cream pediatric containing furfuryl were found for the furfuryl palmitate patients palmitate was efficacious tolerability of the two to a certain extent, the products, even if the results were less enriched cream was clinically relevant than reported to be less well those observed for the tolerated, with same cream not complaints of itching containing the active and burning sensation ingredient after application CT clinical trial, RCT randomized clinical trial, DB double blind, BID bis in die/twice daily, UL unilateral comparison, BL bilateral comparison (test versus control) Dermatol Ther (Heidelb) products enriched in antioxidants, such as fur- ACKNOWLEDGEMENTS furyl derivatives, can represent a valid aid in the treatment of a range of skin disorders, such as atopic and seborrheic dermatitis, with no side Funding. This research was sponsored and effects or requirement of precautions in use. funded by Relife S.r.l. Menarini Group. Article Even if the preliminary data shown should processing charges were funded by Relife S.r.l. be confirmed in larger trials considering both Menarini Group. pediatric and adult patients, studies performed up to now have shown that furfuryl derivatives Medical Writing and/or Editorial Assis- are able to efficaciously contrast the signs and tance. Medical writing and editorial assistance symptoms of mild-to-moderate AD and ery- in the preparation of this manuscript were thema and also widespread diffuse cutaneous provided by Dr. Federica Sbrocca, MSc (SPRIM pathologies, such as irritative, seborrheic and ALS GCP, Milan, Italy). Support for this assis- allergic contact dermatitis, in both adult and tance was funded by Relife S.r.l. Menarini pediatric patients [37, 42, 46–48]. The only Group. The authors are fully responsible for all paper published up to now not agreeing with content and editorial decisions related to the what is outlined here is biased by several issues, development of this manuscript. as discussed above, whereas all other clinical Authorship. All named authors meet the investigations carried out not only did not International Committee of Medical Journal highlight any negative aspects, but instead Editors (ICMJE) criteria for authorship for this confirmed several positive outcomes, showing a article, take responsibility for the integrity of clear superiority of verum with respect to the work as a whole and have given their placebo. approval for this version to be published. The products containing these compounds can constitute a valuable alternative to topical Disclosures. Paolo Pigatto and Marco Diani corticosteroids in mild-medium severity skin have nothing to disclose. disorders, especially when preferring to avoid a pharmacologic agent, such as in pediatric Compliance with Ethics Guidelines. This patients, intolerant subjects or atopic patients. article is based on previously conducted studies In addition, they can also act in synergy with and does not contain any studies with human other topical or systemic treatments, as well as participants or animals performed by any of the pharmacologic, to promote faster recovery of authors. the normal skin condition, reducing inflam- mation and restoring the skin barrier. Data Availability. The manuscript has no Thus, in patients with mild or moderate AD, associated data. these products represent a real alternative to steroids, which instead constitute an important Open Access. This article is distributed health risk. under the terms of the Creative Commons All the products tested showed, in addition, a Attribution-NonCommercial 4.0 International good tolerability profile, thus promoting com- License (http://creativecommons.org/licenses/ pliance by both the patient and caregiver. This by-nc/4.0/), which permits any noncommer- is of main importance, because the choice of cial use, distribution, and reproduction in any therapy can be primarily considered as depen- medium, provided you give appropriate credit dent on the patient’s preferences and also the to the original author(s) and the source, provide ideal moisturizing agent should be safe, effec- a link to the Creative Commons license, and tive, inexpensive. indicate if changes were made. Despite the positive results outlined above in the confirmatory studies, research with bigger sample sizes is advisable to confirm and emphasize the results already achieved. 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Dermatology and TherapySpringer Journals

Published: May 22, 2018

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