Can we teach old drugs new tricks?—Repurposing of neuropharmacological drugs for inflammatory skin diseases

Abstract

Despite the “hype” for monoclonal antibodies, the so‐called biologics, which added significant value to the therapeutic armamentarium of dermatologists and improved the life of many patients, but may exhibit significant adverse effects, the vast majority of dermatological patients suffering from atopic dermatitis or psoriasis is still treated topically. Thus, there is a huge need for locally applied, locally acting drugs for inflammatory skin diseases with better risk‐benefit profiles compared to topical corticosteroids or calcineurin inhibitors. Drug repositioning is a complex process, but offers advantages, in particular for indications with lower revenues. In this viewpoint, the neuroendocrine system of the skin is described as an attractive drug target because it contributes significantly to neutralizing external noxious agents prior to inducing immune or vascular changes leading to the clinical signs of skin inflammation, for example, itch and erythema. In addition, epidermis and dermis are accessible for topically applied products which may act locally without pharmacodynamically relevant systemic exposure limiting adverse events. Moreover, since numerous drugs have been evaluated for various CNS diseases, some failed and some approved, this resource should be exploited for repurposing as anti‐inflammatory drugs for topical application, for example, cannabidiol, fingolimod or asimadoline. Finally, a screening algorithm is shared which gives direct evidence of links between drug and inflammatory skin diseases.

Hair follicle immune privilege and its collapse in alopecia areata

“…Several neuropharmacological drugs 333 and other treatments are in development or currently available that hold potential for regenerating HF IP (Table 4), though these drugs are largely untested for use in treating AA. For example, the immunosuppressive drug FK506 (tacrolimus) 334,335 downregulates MHC class I expression and has been shown to protect HFs from IFNγ‐induced IP collapse in ex vivo studies 76 .…”

Current and emerging treatments targeting the neuroendocrine system for disorders of the skin and its appendages

“…• Afamelanotide [43][44][45][46][47][48][49] • Dersimelagon (MT-7117) [50] • KdPT a [51,[54][55][56][57] • WOL074-009, WOL074-019 and WOL074-029 a [58] MC1 and additional effector pathways [85,[87][88][89][90]100] • Asimadoline [58,97,99,100] • Difelikefalin (CR845) [95] • WOL071-007 [92,94] • Compounds 5a [104,105] and 8a [104] • Compounds 3a, 4b, 5a and 5b [103] • Naltrexone [72,73,76,77] • Nalmefene [78][79][80] • Nalbuphine [81][82][83] MOR, KOR, DOR • HU-308 [109,113] • Δ 9 -THC [109,111,112] • CBD [118][119][120]…”

“…Asimadoline (EMD-61753), another orally active and peripherally restricted κ agonist with a high affinity and selectivity for human κ-opioid receptors, has been shown to act anti-inflammatory [58,97] and to reduce scratching in animal models [98][99][100] and was evaluated in several clinical studies in over 2,000 individuals where it showed a good safety profile. [101] A phase II trial in patients suffering from pruritus associated with AD (NCT02475447) confirmed the good safety profile.…”

“…This makes asimadoline an interesting candidate for a topical anti-inflammatory treatment option for AD. [58] A series of perhydroquinoxaline-derived κ agonists we shown to reduce the release of Ca 2+ ions into the cytoplasm of ATP-stimulated…”

Topical L‐thyroxine: The Cinderella among hormones waiting to dance on the floor of dermatological therapy?

“…A key regulatory hurdle in repurposing any drug approved for systemic application for topical administration is that its safety and toxicology as well as that of the chosen vehicle have to be rigorously re-evaluated and documented. 216,217 This is associated with major drug development costs. At the same time, patent protection of any topical T4 application in dermatology is made very challenging by the wealth of "prior art" in this field (see above).…”