Skip to main content

Double blinded, vehicle controlled, crossover study on the efficacy of a topical endocannabinoid membrane transporter inhibitor in atopic Beagles

Abstract

The endocannabinoid system is important for skin homeostasis and alterations are linked to inflammatory diseases like atopic dermatitis (AD). Importantly, activation of cannabinoid receptor CB2 decreases pruritus and inflammation in mouse models. Reduction of inactivation of endogenous cannabinoids could, therefore, be a therapeutic option for AD. Dogs spontaneously develop AD, which closely mimics the human disease making them suitable to test new therapies. Our study aimed to test the effects of a topical endocannabinoid membrane transporter inhibitor (WOL067-531, 1% gel) on pruritus and dermatitis in a canine model of AD. Nineteen Beagles allergic to dust mites (DM) were randomized to receive either active ingredient or vehicle on inguinal area while challenged epicutaneously with DM twice weekly for 28 days. Treatment was administered twice daily and started after three challenges (day 8). Dermatitis and pruritus were scored weekly by personnel blinded to treatment allocation. Dermatitis was scored using a validated scoring system and pruritus was scored using camera recordings. After a 4-week washout, dogs were crossed over and the study was repeated. On days 15 and 22, dermatitis scores were significantly increased after DM challenge in the vehicle group (16.34, p = 0.0089 and 7.42, p = 0.04845, respectively) but not in the active ingredient group (p = 0.3177 and p = 0.3190, respectively). Significant decrease on pruritus both on inguinal area and overall (p = 0.048 and p = 0.032, respectively) occurred in the active ingredient group. No adverse effects were noted. In conclusion, the newly developed topical endocannabinoid membrane transporter inhibitor (WOL067-531) minimized allergic flares and pruritus in a canine model of AD.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Campora L, Miragliotta V, Ricci E, Cristino L, Di Marzo V, Albanese F, Federica Della Valle M, Abramo F (2012) Cannabinoid receptor type 1 and 2 expression in the skin of healthy dogs and dogs with atopic dermatitis. Am J Vet Res 73(7):988–995. https://doi.org/10.2460/ajvr.73.7.988

    Article  PubMed  Google Scholar 

  2. Chicca A, Nicolussi S, Bartholomäus R, Blunder M, Aparisi Rey A, Petrucci V, Reynoso-Moreno IDC, Viveros-Paredes JM, Dalghi Gens M, Lutz B, Schiöth HB, Soeberdt M, Abels C, Charles RP Altmann KH, Gertsch J (2017) Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake. Proc Natl Acad Sci USA 114(25):E5006–E5015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488949/

    CAS  Article  Google Scholar 

  3. Eckert L, Gupta S, Amand C, Gadkari A, Mahajan P, Gelfand JM (2017) Impact of atopic dermatitis on health-related quality of life and productivity in adults in the United States: an analysis using the National Health and Wellness Survey. J Am Acad Dermatol. https://doi.org/10.1016/j.jaad.2017.04.019 (epub ahead of print). https://www.sciencedirect.com/science/article/pii/S0190962217305066?via%3Dihub

    Article  Google Scholar 

  4. Edwards T, Patel NU, Blake A, Prabakaran S, Reimer D, Feldman SR, Strowd LC (2018) Insights into future therapeutics for atopic dermatitis. Expert Opin Pharmacother 19(3):265–278. https://doi.org/10.1080/14656566.2018.1430140

    CAS  Article  PubMed  Google Scholar 

  5. Haruna T, Soga M, Morioka Y, Hikita I, Imura K, Furue Y, Yamamoto M, Imura C, Ikeda M, Yamauchi A et al (2015) S-777469, a novel cannabinoid type 2 receptor agonist, suppresses itch-associated scratching behavior in rodents through inhibition of itch signal transmission. Pharmacology 95:95–103. https://www.karger.com/Article/FullText/371890

    CAS  Article  Google Scholar 

  6. Hill P, Lau P. Rybnicek J (2007) Development of an owner-assessed scale to measure the severity of pruritus in dogs. Vet Dermatol 18(5):301–308. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-3164.2007.00616.x

    CAS  Article  Google Scholar 

  7. Karsak M, Gaffal E, Date R, Wang-Eckhardt L, Rehnelt J, Petrosino S, Starowicz K, Steuder R, Schlicker E, Cravatt B et al (2007) Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316:1494–1497. https://science.sciencemag.org/content/316/5830/1494.long

    CAS  Article  Google Scholar 

  8. Kendall AC, Nicolaou A (2013) Bioactive lipid mediators in skin inflammation and immunity. Prog Lipid Res 52(1):141–164. https://www.sciencedirect.com/science/article/pii/S0163782712000562?via%3Dihub

    CAS  Article  Google Scholar 

  9. Kusakabe K, Iso Y, Tada Y, Sakagami M, Morioka Y, Chomei N, Shinonome S, Kawamoto K, Takenaka H, Yasui K, Hamana H, Hanasaki K (2013) Selective CB2 agonists with anti-pruritic activity: discovery of potent and orally available bicyclic 2-pyridones. Bioorg Med Chem 21(11):3154–3163. https://www.sciencedirect.com/science/article/pii/S0968089613002447?via%3Dihub

    CAS  Article  Google Scholar 

  10. 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 (2015) Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 36(5):277–296. https://www.ncbi.nlm.nih.gov/pubmed/25796370

    CAS  Article  Google Scholar 

  11. Marsella R, Girolomoni G (2009) Canine models of atopic dermatitis: a useful tool with untapped potential. J Invest Dermatol 129(10):2351–2357. https://www.sciencedirect.com/science/article/pii/S0022202X15341130?via%3Dihub

    CAS  Article  Google Scholar 

  12. Murray C, Ahrens K, Devalaraja M, Dymond M, Fagura M, Hargreaves A, Holt A, Peers I, Price S, Reens J, Riley R, Marsella R (2016) Use of a canine model of atopic dermatitis to investigate the efficacy of a CCR4 antagonist in allergen-induced skin inflammation in a randomized study. J Invest Dermatol 136(3):665–671. https://www.sciencedirect.com/science/article/pii/S0022202X15000676?via%3Dihub

    CAS  Article  Google Scholar 

  13. Nattkemper LA, Tey HL, Valdes-Rodriguez R, Lee H, Mollanazar NK, Albornoz C, Sanders KM, Yosipovitch G (2018) The genetics of chronic itch: gene expression in the skin of patients with atopic dermatitis and psoriasis with severe itch. J Investig Dermatol 138:1311–1317. https://www.sciencedirect.com/science/article/pii/S0022202X18300046?via%3Dihub

    CAS  Article  Google Scholar 

  14. Noli C, Della Valle MF, Miolo A, Medori C, Schievano C, Skinalia Clinical Research Group (2015) Efficacy of ultra-micronized palmitoylethanolamide in canine atopic dermatitis: an open-label multi-centre study. Vet Dermatol 26(6):432–440, e101. https://doi.org/10.1111/vde.12250 (epub 2015 Aug 18)

    Article  Google Scholar 

  15. Oláh A, Ambrus L, Nicolussi S, Gertsch J, Tubak V, Kemény L, Soeberdt M, Abels C, Bíró T (2016) Inhibition of fatty acid amide hydrolase exerts cutaneous anti‐inflammatory effects both in vitro and in vivo. Exp Dermatol 26(4):328–330. https://onlinelibrary.wiley.com/doi/abs/10.1111/exd.12930

    Article  Google Scholar 

  16. Olivry T, Marsella R, Iwasaki T, Mueller R, International Task Force On Canine Atopic Dermatitis (2007) Validation of CADESI-03, a severity scale for clinical trials enrolling dogs with atopic dermatitis. Vet Dermatol 18(2):78–86. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-3164.2007.00569.x

    Article  Google Scholar 

  17. Reynoso-Moreno I, Chicca A, Flores-Soto ME, Viveros-Paredes JM, Gertsch J (2018) The endocannabinoid reuptake inhibitor WOBE437 is orally bioavailable and exerts indirect polypharmacological effects via different endocannabinoid receptors. Front Mol Neurosci 11:180. https://doi.org/10.3389/fnmol.2018.00180

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Schlosburg JE, Boger DL, Cravatt BF, Lichtman AH (2009) Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus. J Pharmacol Exp Ther 329(1):314–323. https://jpet.aspetjournals.org/content/329/1/314.long

    CAS  Article  Google Scholar 

  19. Tóth KF, Ádám D, Bíró T, Oláh A (2019) Cannabinoid signaling in the skin: therapeutic potential of the “C(ut)annabinoid” system. Molecules 24(5):918. https://doi.org/10.3390/molecules24050918

    CAS  Article  PubMed Central  Google Scholar 

  20. Trusler AR, Clark AK, Sivamani RK, Shi VY (2017) The endocannabinoid system and its role in eczematous dermatoses. Dermatitis 28(1):22–32. https://insights.ovid.com/pubmed?pmid=28098721

    CAS  Article  Google Scholar 

  21. Wilkinson JD, Williamson EM (2007) Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis. J Dermatol Sci 45(2):87–92. https://www.sciencedirect.com/science/article/pii/S092318110600315X?via%3Dihub

    CAS  Article  Google Scholar 

Download references

Funding

Funding for this study was provided by Dr. August Wolff GmbH & Co. KG Arzneimittel.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rosanna Marsella.

Ethics declarations

Conflict of interest

Dr. Marsella has received Grants from Novartis, Pfizer, Zoetis, Boehringer, Merial, Bioresponse and Artic. Dr. Marsella does not own stock in any of these companies. Dr. Abels and Dr. Soeberdt are employees of Dr. August Wolff GmbH & Co. KG Arzneimittel. Dr. Abels and Dr. Soeberdt are named as inventor on a patent application claiming novel 1,3-benzoxazol-2(3H)-ones and their use as medicaments and cosmetics.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 77 kb)

Supplementary material 2 (TIFF 77 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Marsella, R., Ahrens, K., Sanford, R. et al. Double blinded, vehicle controlled, crossover study on the efficacy of a topical endocannabinoid membrane transporter inhibitor in atopic Beagles. Arch Dermatol Res 311, 795–800 (2019). https://doi.org/10.1007/s00403-019-01963-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-019-01963-4

Keywords

  • Atopic dermatitis
  • Dog model
  • Topical
  • Endocannabinoids