{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T17:26:17Z","timestamp":1767633977299,"version":"3.48.0"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Veterinary Sciences"],"abstract":"<jats:p>Pigmentary keratitis (PK) is a prevalent ocular surface disease in Pug dogs, yet comparative evidence on topical immunosuppressants remains limited. This prospective comparative clinical study evaluated the efficacy and safety of two agents with distinct mechanisms\u2014tacrolimus, a calcineurin inhibitor, and sirolimus, an mTOR inhibitor\u2014for the treatment of PK. Thirty-two Pugs (63 eyes) were randomly assigned to receive either 0.03% tacrolimus or 0.03% sirolimus three times daily for six months. Tear film quantity and quality were assessed using the Schirmer tear test, tear break-up time, and Ferning patterns, alongside serial clinical scoring of corneal pigmentation and ocular surface signs. Both treatments improved tear-film parameters, although only tacrolimus produced statistically significant increases in tear production and more frequent formation of a pigment-free \u201cclear line,\u201d indicating enhanced pigment regression. Pigment lightening and transparency recovery improved similarly in both groups. Adverse events\u2014including blepharospasm, diffuse corneal oedema, and complicated ulcers\u2014occurred more frequently in the sirolimus group, suggesting a comparatively less favorable short-term safety profile. Overall, both tacrolimus and sirolimus demonstrated therapeutic benefit in PK, although tacrolimus showed superior quantitative efficacy and better tolerability. Further long-term studies are warranted to clarify safety considerations and to optimize immunomodulatory strategies for this breed-specific condition. These findings suggest tacrolimus may be considered a first-line immunomodulatory therapy for PK in Pug dogs.<\/jats:p>","DOI":"10.3390\/vetsci13010047","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T12:38:56Z","timestamp":1767616736000},"page":"47","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prospective Comparative Study of Topical Tacrolimus and Sirolimus for the Treatment of Pigmentary Keratitis in Pug Dogs"],"prefix":"10.3390","volume":"13","author":[{"given":"Diana","family":"Sarmiento Quintana","sequence":"first","affiliation":[{"name":"Hospital Cl\u00ednico Veterinario, Facultad de Veterinaria, Universidad de Las Palmas de Gran Canaria, 35413 Las Palmas, Spain"},{"name":"Dioftalmo, Oftalmolog\u00eda Veterinaria, 35003 Las Palmas, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6430-9096","authenticated-orcid":false,"given":"Inmaculada","family":"Morales Fari\u00f1a","sequence":"additional","affiliation":[{"name":"Hospital Cl\u00ednico Veterinario, Facultad de Veterinaria, Universidad de Las Palmas de Gran Canaria, 35413 Las Palmas, Spain"},{"name":"Instituto Universitario de Investigaciones Biom\u00e9dicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, 35016 Las Palmas, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00e9ssica","family":"Gonz\u00e1lez P\u00e9rez","sequence":"additional","affiliation":[{"name":"Cl\u00ednica Veterinaria Escaleritas, Las Palmas de Gran Canaria, 35011 Las Palmas, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Morales Doreste","sequence":"additional","affiliation":[{"name":"Hospital Cl\u00ednico Veterinario, Facultad de Veterinaria, Universidad de Las Palmas de Gran Canaria, 35413 Las Palmas, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6413-3230","authenticated-orcid":false,"given":"Jos\u00e9 Raduan","family":"Jaber","sequence":"additional","affiliation":[{"name":"Departamento de Morfolog\u00eda, Universidad de Las Palmas de Gran Canaria, 35016 Las Palmas, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7812-2065","authenticated-orcid":false,"given":"Juan Alberto","family":"Corbera","sequence":"additional","affiliation":[{"name":"Hospital Cl\u00ednico Veterinario, Facultad de Veterinaria, Universidad de Las Palmas de Gran Canaria, 35413 Las Palmas, Spain"},{"name":"Instituto Universitario de Investigaciones Biom\u00e9dicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, 35016 Las Palmas, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/vop.13054","article-title":"The Pandemic of Ocular Surface Disease in Brachycephalic Dogs: The Brachycephalic Ocular Syndrome","volume":"26","author":"Sebbag","year":"2023","journal-title":"Vet. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.cvsm.2022.11.001","article-title":"Diagnosing Corneal Pigmentation in Small Animals","volume":"53","author":"Labelle","year":"2023","journal-title":"Vet. Clin. N. Am. Small Anim. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"667","DOI":"10.2460\/javma.243.5.667","article-title":"Characteristics of, Prevalence of, and Risk Factors for Corneal Pigmentation (Pigmentary Keratopathy) in Pugs","volume":"243","author":"Labelle","year":"2013","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/S0195-5616(90)50052-2","article-title":"A New Perspective on Canine Keratoconjunctivitis Sicca","volume":"20","author":"Kaswan","year":"1990","journal-title":"Vet. Clin. N. Am. Small Anim. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/eye.1997.126","article-title":"A Comparative Approach to Topical Cyclosporine Therapy","volume":"11","author":"Williams","year":"1997","journal-title":"Eye"},{"key":"ref_6","first-page":"251","article-title":"Clinical Evaluation of Tacrolimus Eye Drops for Chronic Superficial Keratitis Treatment in Dogs","volume":"54","author":"Balicki","year":"2010","journal-title":"Bull. Vet. Inst. Pulawy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"667","DOI":"10.2478\/v10181-012-0104-5","article-title":"Clinical Study on the Application of Tacrolimus and DMSO in the Treatment of Chronic Superficial Keratitis in Dogs","volume":"15","author":"Balicki","year":"2012","journal-title":"Pol. J. Vet. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1111\/vop.12173","article-title":"Use of Episcleral Cyclosporine Implants in Dogs with Keratoconjunctivitis Sicca: Pilot Study","volume":"18","author":"Barachetti","year":"2015","journal-title":"Vet. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"415","DOI":"10.24425\/pjvs.2021.138733","article-title":"Clinical Study on the Application of Dexamethasone and Cyclosporine\/Dimethyl Sulfoxide Combination Eye Drops in the Initial Therapy of Chronic Superficial Keratitis in Dogs","volume":"24","author":"Balicki","year":"2021","journal-title":"Pol. J. Vet. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Padjasek, M., Qasem, B., Cis\u0142o-Pakuluk, A., and Marycz, K. (2022). Cyclosporine A Delivery Platform for Veterinary Ophthalmology\u2014A New Concept for Advanced Ophthalmology. Biomolecules, 12.","DOI":"10.3390\/biom12101525"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1034\/j.1600-0749.2003.00081.x","article-title":"Effect of Cyclosporin A on Melanogenesis in Cultured Human Melanocytes","volume":"16","author":"Lee","year":"2003","journal-title":"Pigment. Cell Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/CMR.0b013e328322fc20","article-title":"Immunosuppression and Melanocyte Proliferation","volume":"19","author":"Zattra","year":"2009","journal-title":"Melanoma Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Barreiro, C., Iba\u00f1ez, A., Garrido-Chamorro, S., and Barredo, J.L. (2024). The Immunosuppressant Tacrolimus (FK506) Facing the 21st Century: Past Findings, Present Applications and Future Trends. Fermentation, 10.","DOI":"10.3390\/fermentation10120645"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1034\/j.1399-0012.1999.130301.x","article-title":"Cyclosporine and Tacrolimus (FK506): A Comparison of Efficacy and Safety Profiles","volume":"13","author":"Henry","year":"1999","journal-title":"Clin. Transplant."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"487592","DOI":"10.4061\/2011\/487592","article-title":"An Investigation Comparing the Efficacy of Topical Ocular Application of Tacrolimus and Cyclosporine in Dogs","volume":"2011","author":"Hendrix","year":"2011","journal-title":"Vet. Med. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1111\/j.1463-5224.2005.00390.x","article-title":"Effect of Topical 0.02% Tacrolimus Aqueous Suspension on Tear Production in Dogs with Keratoconjunctivitis Sicca","volume":"8","author":"Berdoulay","year":"2005","journal-title":"Vet. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.survophthal.2009.02.002","article-title":"Topical Ophthalmic Cyclosporine: Pharmacology and Clinical Uses","volume":"54","author":"Donnenfeld","year":"2009","journal-title":"Surv. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2165\/11587010-000000000-00000","article-title":"Tacrolimus in the Treatment of Ocular Diseases","volume":"25","author":"Zhai","year":"2011","journal-title":"BioDrugs"},{"key":"ref_19","first-page":"92","article-title":"Topical Tacrolimus in Anterior Segment Disorders in Ophthalmology: A Review","volume":"68","author":"Alrashidi","year":"2024","journal-title":"Rom. J. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.1007\/s11033-023-08283-x","article-title":"Molecular and Therapeutic Insights of Rapamycin: A Multi-Faceted Drug from Streptomyces hygroscopicus","volume":"50","author":"Ganesh","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1002\/stem.3036","article-title":"Inhibition of MTOR by Rapamycin Aggravates Corneal Epithelial Stem Cell Deficiency by Upregulating Inflammatory Response","volume":"37","author":"Woo","year":"2019","journal-title":"Stem Cells"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115620","DOI":"10.1016\/j.bcp.2023.115620","article-title":"The MTOR Signalling in Corneal Diseases: A Recent Update","volume":"213","author":"Li","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/vop.12503","article-title":"The Effects of Topical Aqueous Sirolimus on Tear Production in Normal Dogs and Dogs with Refractory Dry Eye","volume":"21","author":"Spatola","year":"2018","journal-title":"Vet. Ophthalmol."},{"key":"ref_24","first-page":"25158414221097418","article-title":"A Comprehensive Review of Intravitreal Immunosuppressants and Biologicals Used in Ophthalmology","volume":"14","author":"Hasan","year":"2022","journal-title":"Ther. Adv. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2175925","DOI":"10.1080\/10717544.2023.2175925","article-title":"Research Progress of Ophthalmic Preparations of Immunosuppressants","volume":"30","author":"Liu","year":"2023","journal-title":"Drug Deliv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/vop.13190","article-title":"Subconjunctival Liposomal Sirolimus vs. Cyclosporine or Tacrolimus as Treatment of Keratoconjunctivitis Sicca in Dogs: A Double-blind, Randomized Study","volume":"27","author":"Margay","year":"2024","journal-title":"Vet. Ophthalmol."},{"key":"ref_27","first-page":"32","article-title":"Tear Mucus Ferning Test in Normal and Keratoconjunctivitis Sicca Eyes","volume":"2","author":"Rolando","year":"1984","journal-title":"Chibret Int. J. Ophthalmol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1097\/ICO.0000000000002081","article-title":"Comprehensive Clinical, Diagnostic, and Advanced Imaging Characterization of the Ocular Surface in Spontaneous Aqueous Deficient Dry Eye Disease in Dogs","volume":"38","author":"Leonard","year":"2019","journal-title":"Cornea"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/vop.13044","article-title":"A Review of Diagnostic Tests for Qualitative and Quantitative Tear Film Deficiency in Dogs","volume":"26","author":"Iwashita","year":"2023","journal-title":"Vet. Ophthalmol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/j.1463-5224.2012.01056.x","article-title":"A Topical Aqueous Calcineurin Inhibitor for the Treatment of Naturally Occurring Keratoconjunctivitis Sicca in Dogs","volume":"16","author":"Gilger","year":"2013","journal-title":"Vet. Ophthalmol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1556\/004.2016.030","article-title":"Comparative Clinical Evaluation of Tacrolimus and Cyclosporine Eye Drops for the Treatment of Canine Keratoconjunctivitis Sicca","volume":"64","author":"Radziejewski","year":"2016","journal-title":"Acta Vet. Hung."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.tvjl.2007.08.034","article-title":"Clinical Evaluation of Pimecrolimus Eye Drops for Treatment of Canine Keratoconjunctivitis Sicca: A Comparison with Cyclosporine A","volume":"179","author":"Ofri","year":"2009","journal-title":"Vet. J."},{"key":"ref_33","first-page":"E34","article-title":"Abstracts: 44th Annual Meeting of the American College of Veterinary Ophthalmologists, Puerto Rico, November 4\u20139, 2013","volume":"16","author":"Fonzar","year":"2013","journal-title":"Vet. Ophthalmol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7331","DOI":"10.1167\/iovs.15-17757","article-title":"In Vitro and In Vivo Sustained Zero-Order Delivery of Rapamycin (Sirolimus) From a Biodegradable Intraocular Device","volume":"56","author":"Lance","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.clae.2015.04.004","article-title":"Treatment of Sj\u00f6gren\u2019s Syndrome Dry Eye Using 0.03% Tacrolimus Eye Drop: Prospective Double-Blind Randomized Study","volume":"38","author":"Moscovici","year":"2015","journal-title":"Contact Lens Anterior Eye"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1089\/jop.2015.0032","article-title":"Preformulation Studies of a Liposomal Formulation Containing Sirolimus for the Treatment of Dry Eye Disease","volume":"32","author":"Fonzar","year":"2016","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1111\/vop.12074","article-title":"Central Corneal Thickness Measurements in Normal Dogs: A Comparison between Ultrasound Pachymetry and Optical Coherence Tomography","volume":"17","author":"Alario","year":"2014","journal-title":"Vet. Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Gelatt, K., Gelatt, J., and Plummer, C. (2021). Veterinary Ophthalmic Surgery, Saunders Ltd.. [2nd ed.].","DOI":"10.1016\/B978-0-7020-8163-7.00014-7"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/j.1463-5224.2010.00863.x","article-title":"The Effect of UV-blocking Contact Lenses as a Therapy for Canine Chronic Superficial Keratitis","volume":"14","author":"Denk","year":"2011","journal-title":"Vet. Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1463-5224.2010.00858.x","article-title":"Superficial Corneal Squamous Cell Carcinoma Occurring in Dogs with Chronic Keratitis","volume":"14","author":"Dreyfus","year":"2011","journal-title":"Vet. Ophthalmol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/vop.12285","article-title":"Protozoal Infections of the Cornea and Conjunctiva in Dogs Associated with Chronic Ocular Surface Disease and Topical Immunosuppression","volume":"19","author":"Gasper","year":"2016","journal-title":"Vet. Ophthalmol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1089\/jop.2017.0108","article-title":"The SPOTS System: An Ocular Scoring System Optimized for Use in Modern Preclinical Drug Development and Toxicology","volume":"33","author":"Eaton","year":"2017","journal-title":"J. Ocul. Pharmacol. Ther."}],"container-title":["Veterinary Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-7381\/13\/1\/47\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T13:08:03Z","timestamp":1767618483000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-7381\/13\/1\/47"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,5]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["vetsci13010047"],"URL":"https:\/\/doi.org\/10.3390\/vetsci13010047","relation":{},"ISSN":["2306-7381"],"issn-type":[{"value":"2306-7381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,5]]}}}