{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T18:33:58Z","timestamp":1787855638241,"version":"build-2784847793"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T00:00:00Z","timestamp":1638316800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T00:00:00Z","timestamp":1638316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01-EY025752"],"award-info":[{"award-number":["R01-EY025752"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Vet Res"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Despite the common use of topical ophthalmic corticosteroids in dogs, detailed reports on systemic and dermatologic adverse effects are limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Nine purpose-bred research Beagles were treated with difluprednate 0.05% ophthalmic emulsion in one or both eyes 2\u20133 times daily. Some difluprednate treated dogs developed mild to severe alopecia of the periocular region, face, and distal pinna (5\/9). The median duration of treatment prior to onset of dermatologic signs for difluprednate treated dogs was 550\u2009days (453\u20131160\u2009days). Diagnostic testing included complete blood count (CBC) and serum biochemistry, adrenocorticotropic hormone (ACTH) stimulation testing combined with endogenous ACTH measurement, and skin biopsy. The CBC and chemistry were within normal limits for all dogs. There were varying degrees of suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis with difluprednate treatment. Dogs with the most profound alopecic changes had less pronounced HPA axis suppression compared to dogs with no integumentary changes. Skin biopsies demonstrated follicular atrophy and follicular keratosis. When topical difluprednate was reduced to unilateral therapy, the hair regrew on the untreated side of the face. In addition to the affected research dogs, a 7-year old female spayed Chihuahua that was being treated as a clinical patient with long-term difluprednate 0.05% ophthalmic emulsion developed generalized hypotrichosis on the head and body and a potbellied appearance. ACTH stimulation testing revealed suppression of the HPA axis with a mild increase in serum alkaline phosphatase (ALP) activity and a urine specific gravity of 1.016. The combination of clinical signs and laboratory abnormalities was supportive of iatrogenic hyperadrenocorticism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In dogs long-term use of difluprednate ophthalmic emulsion results in HPA axis suppression and in some cases iatrogenic hyperadrenocorticism. A novel pattern of localized alopecia is suspected to be related to dermal absorption and local action due to superior potency and penetration compared to other commonly utilized ophthalmic corticosteroids.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12917-021-03072-9","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T01:31:18Z","timestamp":1638322278000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Localized alopecia and suppression of hypothalamic-pituitary-adrenal (HPA) axis in dogs following treatment with difluprednate 0.05% ophthalmic emulsion (Durezol\u00ae)"],"prefix":"10.1186","volume":"17","author":[{"given":"Katelin","family":"Quantz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine D.","family":"Harman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica L.","family":"Noland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn M.","family":"Del Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence M.","family":"Occelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica B.","family":"Burn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon M.","family":"Petersen-Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel K.","family":"Langlois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris G.","family":"Pirie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette D.","family":"Petersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8845-0588","authenticated-orcid":false,"given":"Andr\u00e1s M.","family":"Kom\u00e1romy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,1]]},"reference":[{"key":"3072_CR1","unstructured":"Meli\u00e1n C, P\u00e9rez-Alenza MD, Peterson ME. Hyperadrenocorticism in dogs. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine. Elsevier; 2010. p. 1816\u201339."},{"key":"3072_CR2","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1053\/j.tcam.2012.06.001","volume":"27","author":"HS Kooistra","year":"2012","unstructured":"Kooistra HS, Galac S. Recent advances in the diagnosis of Cushing\u2019s syndrome in dogs. Top Companion Anim Med. 2012;27(1):21\u20134.","journal-title":"Top Companion Anim Med"},{"issue":"9","key":"3072_CR3","first-page":"1711","volume":"45","author":"SM Roberts","year":"1984","unstructured":"Roberts SM, Lavach JD, Macy DW, Severin GA. Effect of ophthalmic prednisolone acetate on the canine adrenal gland and hepatic function. Am J Vet Res. 1984;45(9):1711\u20134.","journal-title":"Am J Vet Res"},{"issue":"6","key":"3072_CR4","first-page":"685","volume":"191","author":"RD Zenoble","year":"1987","unstructured":"Zenoble RD, Kemppainen RJ. Adrenocortical suppression by topically applied corticosteroids in healthy dogs. J Am Vet Med Assoc. 1987;191(6):685\u20138.","journal-title":"J Am Vet Med Assoc"},{"key":"3072_CR5","first-page":"705","volume":"24","author":"JD Eichenbaum","year":"1988","unstructured":"Eichenbaum JD, Macy DW, Severin GA, Paulsen ME. Effect in large dogs of ophthalmic prednisolone acetate on adrenal gland and hepatic function. J Am Anim Hosp Assoc. 1988;24(6):705\u20139.","journal-title":"J Am Anim Hosp Assoc"},{"issue":"1","key":"3072_CR6","first-page":"73","volume":"192","author":"MB Glaze","year":"1988","unstructured":"Glaze MB, Crawford MA, Nachreiner RF, Casey HW, Nafe LA, Kearney MT. Ophthalmic corticosteroid therapy: systemic effects in the dog. J Am Vet Med Assoc. 1988;192(1):73\u20135.","journal-title":"J Am Vet Med Assoc"},{"issue":"6","key":"3072_CR7","first-page":"640","volume":"26","author":"CJ Murphy","year":"1990","unstructured":"Murphy CJ, Feldman E, Bellhorn R. Iatrogenic Cushing\u2019s syndrome in a dog caused by topical ophthalmic medications. J Am Anim Hosp Assoc. 1990;26(6):640\u20132.","journal-title":"J Am Anim Hosp Assoc"},{"key":"3072_CR8","doi-asserted-by":"publisher","first-page":"200","DOI":"10.5326\/15473317-35-3-200","volume":"35","author":"HP Huang","year":"1999","unstructured":"Huang HP, Yang HL, Liang SL, Lien YH, Chen KY. Iatrogenic hyperadrenocorticism in 28 dogs. J Am Anim Hosp Assoc. 1999;35(3):200\u20137.","journal-title":"J Am Anim Hosp Assoc"},{"key":"3072_CR9","first-page":"554","volume-title":"Muller and Kirk\u2019s small animal dermatology","author":"WH Muller","year":"2003","unstructured":"Muller WH, Muller GH, Scott DW, Griffin CE, Campbell KL. Miscellaneous alopecias. In: Muller WH, Muller GH, Scott DW, Griffin CE, Campbell KL, editors. Muller and Kirk\u2019s small animal dermatology: Elsevier; 2003. p. 554\u201372."},{"key":"3072_CR10","first-page":"381","volume":"3","author":"KN Jamal","year":"2009","unstructured":"Jamal KN, Callanan DG. The role of difluprednate ophthalmic emulsion in clinical practice. Clin Ophthalmol. 2009;3:381\u201390.","journal-title":"Clin Ophthalmol"},{"key":"3072_CR11","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1111\/vop.12629","volume":"22","author":"K Sato","year":"2019","unstructured":"Sato K, Iwasaki K, Nagai N, Yamashita Y, Chikazawa S, Hoshi F, et al. Comparison of early posttreatment effects of steroidal anti-inflammatory ophthalmic drugs on the ocular inflammatory response induced by paracentesis in healthy canine eyes. Vet Ophthalmol. 2019;22(5):607\u201313.","journal-title":"Vet Ophthalmol"},{"issue":"5","key":"3072_CR12","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1089\/jop.2010.0059","volume":"26","author":"CS Foster","year":"2010","unstructured":"Foster CS, DaVanzo R, Flynn TE, McLeod K, Vogel R, Crockett RS. Durezol \u00ae (difluprednate ophthalmic emulsion 0.05%) compared with Pred forte \u00ae 1% ophthalmic suspension in the treatment of endogenous anterior uveitis. J Ocul Pharmacol Ther. 2010;26(5):475\u201383.","journal-title":"J Ocul Pharmacol Ther"},{"issue":"6","key":"3072_CR13","doi-asserted-by":"publisher","first-page":"826","DOI":"10.2460\/ajvr.72.6.826","volume":"72","author":"AJ Rankin","year":"2011","unstructured":"Rankin AJ, Khrone SG, Stiles J. Evaluation of four drugs for inhibition of paracentesis-induced blood-aqueous humor barrier breakdown in cats. Am J Vet Res. 2011;72(6):826\u201332.","journal-title":"Am J Vet Res"},{"issue":"2","key":"3072_CR14","doi-asserted-by":"publisher","first-page":"262","DOI":"10.2460\/ajvr.74.2.262","volume":"74","author":"AJ Rankin","year":"2013","unstructured":"Rankin AJ, Sebbag L, Bello NM, Crumley WR, Allbaugh RA. Effects of oral administration of anti-inflammatory medications on inhibition of paracentesis-induced blood-aqueous barrier breakdown in clinically normal cats. Am J Vet Res. 2013;74(2):262\u20137.","journal-title":"Am J Vet Res"},{"issue":"3","key":"3072_CR15","doi-asserted-by":"publisher","first-page":"260","DOI":"10.2460\/ajvr.81.3.260","volume":"81","author":"RA Allbaugh","year":"2020","unstructured":"Allbaugh RA, Wehrman RF, Sebbag L. Comparison of topically administered 0.05% difluprednate and 1% prednisolone acetate for inhibition of aqueocentesis-induced breakdown of blood-aqueous barrier in healthy dogs. Am J Vet Res. 2020;81(3):260\u20136.","journal-title":"Am J Vet Res"},{"issue":"8","key":"3072_CR16","doi-asserted-by":"publisher","first-page":"569","DOI":"10.3109\/00498254.2010.490308","volume":"40","author":"T Taijka","year":"2010","unstructured":"Taijka T, Takahashi H, Sakai Y, Fujii H, Isowaki A, Sakaki H. Metabolic profiles of difluprednate in rabbit ocular tissues after instillation of difluprednate ophthalmic emulsion. Xenobiotica. 2010;40(8):569\u201377.","journal-title":"Xenobiotica."},{"issue":"13","key":"3072_CR17","first-page":"2653","volume":"48","author":"H Sakaki","year":"2007","unstructured":"Sakaki H, Nemoto S, Kida T, Tajika T, Ohtori A. Preclinical toxicity of difluprednate emulsion (abstract). Investig Ophthamol Vis Sci. 2007;48(13):2653.","journal-title":"Investig Ophthamol Vis Sci"},{"key":"3072_CR18","unstructured":"Alcon Laboratories, Inc. DUREZOL\u00ae (difluprednate ophthalmic emulsion) [package insert]. U.S. Food and Drug Administration website. https:\/\/www.accessdata.fda.gov\/spl\/data\/4c254cb3-4989-4640-80b4-5c461fb32c28\/4c254cb3-4989-4640-80b4-5c461fb32c28.xml. Revised May 2020.\u00a0 Accessed 7 Apr\u00a02021."},{"issue":"2","key":"3072_CR19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1001306","volume":"7","author":"JLM Kuchtey","year":"2011","unstructured":"Kuchtey J, Olson LM, Rinkoski T, MacKay EO, Iverson TM, Gelatt KN, Haines JL, Kuchtey RW. Mapping the disease locus and identification of ADAMTS10 as a candidate gene in a canine model of primary open angle glaucoma. PLoS Genet. 2011;7(2):e1001306.","journal-title":"PLoS Genet"},{"key":"3072_CR20","first-page":"108","volume-title":"Muller and Kirk\u2019s small animal dermatology","author":"WH Muller","year":"2003","unstructured":"Muller WH, Muller GH, Scott DW, Griffin CE, Campbell KL. Dermatologic therapy. In: Muller WH, Muller GH, Scott DW, Griffin CE, Campbell KL, editors. Muller and Kirk\u2019s small animal dermatology: Elsevier; 2003. p. 108\u201383."},{"key":"3072_CR21","doi-asserted-by":"publisher","first-page":"1798","DOI":"10.1111\/jvim.14589","volume":"30","author":"AJ Gold","year":"2016","unstructured":"Gold AJ, Langlois DK, Refsal KR. Evaluation of basal serum or plasma cortisol concentrations for the diagnosis of hypoadrenocorticism in dogs. J Vet Intern Med. 2016;30(6):1798\u2013805.","journal-title":"J Vet Intern Med"},{"key":"3072_CR22","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.domaniend.2017.03.002","volume":"60","author":"KM Fowler","year":"2017","unstructured":"Fowler KM, Frank LA, Morandi F, Whittemore JC. Extended low-dose dexamethasone suppression test for diagnosis of atypical Cushing's syndrome in dogs. Domest Anim Endocrinol. 2017;60:25\u201330.","journal-title":"Domest Anim Endocrinol"}],"container-title":["BMC Veterinary Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12917-021-03072-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12917-021-03072-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12917-021-03072-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T01:31:52Z","timestamp":1638322312000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcvetres.biomedcentral.com\/articles\/10.1186\/s12917-021-03072-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12]]},"references-count":22,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["3072"],"URL":"https:\/\/doi.org\/10.1186\/s12917-021-03072-9","relation":{},"ISSN":["1746-6148"],"issn-type":[{"value":"1746-6148","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12]]},"assertion":[{"value":"10 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 December 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All the procedures were approved by the Michigan State University Institutional Animal Care and Use Committee (IACUC). The owner of the Chihuahua provided an informed written consent for inclusion in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"366"}}