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Article ; Online: The Antiangiogenic Effect and Ocular Pharmacology of Novel Modified Nonsteroidal Anti-Inflammatory Drugs in the Treatment of Oxygen-Induced Retinopathy.

Huang, Wei / Huang, Liqun / Wen, Ziyi / Honkanen, Robert A / Rigas, Basil

Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics

2023 Volume 39, Issue 4, Page(s) 279–289

Abstract: Purpose: ...

Abstract	Purpose:
MeSH term(s)	Humans ; Animals ; Mice ; Infant, Newborn ; Oxygen ; Retinal Vessels ; Animals, Newborn ; Tissue Distribution ; Retinal Diseases/drug therapy ; Angiogenesis Inhibitors/pharmacology ; Angiogenesis Inhibitors/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Disease Models, Animal ; Mice, Inbred C57BL ; Retinal Neovascularization/chemically induced ; Retinal Neovascularization/drug therapy ; Retinopathy of Prematurity/drug therapy
Chemical Substances	Oxygen (S88TT14065) ; OXT-328 ; Angiogenesis Inhibitors ; Anti-Inflammatory Agents
Language	English
Publishing date	2023-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1237021-6
ISSN	1557-7732 ; 1080-7683
ISSN (online)	1557-7732
ISSN	1080-7683
DOI	10.1089/jop.2022.0113
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Article ; Online: A Rabbit Model of Aqueous-Deficient Dry Eye Disease Induced by Concanavalin A Injection into the Lacrimal Glands: Application to Drug Efficacy Studies.

Honkanen, Robert A / Huang, Liqun / Rigas, Basil

Journal of visualized experiments : JoVE

2020 , Issue 155

Abstract: Dry eye disease (DED), a multifactorial inflammatory disease of the ocular surface, affects 1 in 6 humans worldwide with staggering implications for quality of life and health care costs. The lack of informative animal models that recapitulate its key ... ...

Abstract	Dry eye disease (DED), a multifactorial inflammatory disease of the ocular surface, affects 1 in 6 humans worldwide with staggering implications for quality of life and health care costs. The lack of informative animal models that recapitulate its key features impedes the search for new therapeutic agents for DED. Available DED animal models have limited reproducibility and efficacy. A model is presented here in which DED is induced by injecting the mitogen concanavalin A (Con A) into the orbital lacrimal glands of rabbits. Innovative aspects of this model are the use of ultrasound (US) guidance to ensure optimal and reproducible injection of Con A into the inferior lacrimal gland; injection of Con A into all orbital lacrimal glands that limits compensatory production of tears; and use of periodic repeat injections of Con A that prolong the state of DED at will. DED and its response to test agents are monitored with a panel of parameters that assess tear production, the stability of the tear film, and the status of the corneal and conjunctival mucosa. They include tear osmolarity, tear break-up time, Schirmer's tear test, rose bengal staining, and tear lactoferrin levels. The induction of DED and the monitoring of its parameters are described in detail. This model is simple, robust, reproducible, and informative. This animal model is suitable for the study of tear physiology and of the pathophysiology of DED as well as for the assessment of the efficacy and safety of candidate agents for the treatment of DED.
MeSH term(s)	Animals ; Concanavalin A/adverse effects ; Disease Models, Animal ; Dry Eye Syndromes/chemically induced ; Female ; Humans ; Injections ; Lacrimal Apparatus/drug effects ; Male ; Quality of Life/psychology ; Rabbits ; Reproducibility of Results
Chemical Substances	Concanavalin A (11028-71-0)
Language	English
Publishing date	2020-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/59631
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Article: A rabbit model of aqueous-deficient dry eye disease induced by concanavalin a injection into the lacrimal glands: application to drug efficacy studies

Honkanen, Robert A / Huang, Liqun / Rigas, Basil

Journal of visualized experiments. 2020 Jan. 24, , no. 155

2020

Abstract	Dry eye disease (DED), a multifactorial inflammatory disease of the ocular surface, affects 1 in 6 humans worldwide with staggering implications for quality of life and health care costs. The lack of informative animal models that recapitulate its key features impedes the search for new therapeutic agents for DED. Available DED animal models have limited reproducibility and efficacy. A model is presented here in which DED is induced by injecting the mitogen concanavalin A (Con A) into the orbital lacrimal glands of rabbits. Innovative aspects of this model are the use of ultrasound (US) guidance to ensure optimal and reproducible injection of Con A into the inferior lacrimal gland; injection of Con A into all orbital lacrimal glands that limits compensatory production of tears; and use of periodic repeat injections of Con A that prolong the state of DED at will. DED and its response to test agents are monitored with a panel of parameters that assess tear production, the stability of the tear film, and the status of the corneal and conjunctival mucosa. They include tear osmolarity, tear break-up time, Schirmer's tear test, rose bengal staining, and tear lactoferrin levels. The induction of DED and the monitoring of its parameters are described in detail. This model is simple, robust, reproducible, and informative. This animal model is suitable for the study of tear physiology and of the pathophysiology of DED as well as for the assessment of the efficacy and safety of candidate agents for the treatment of DED.
Keywords	animal models ; animal physiology ; concanavalin A ; cornea ; drugs ; eye diseases ; health care costs ; humans ; lacrimal apparatus ; lactoferrin ; mitogens ; monitoring ; mucosa ; osmolarity ; pathophysiology ; quality of life ; rabbits ; staining ; tears ; therapeutics ; ultrasonics
Language	English
Dates of publication	2020-0124
Size	p. e59631.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/59631
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Establishment of a Severe Dry Eye Model Using Complete Dacryoadenectomy in Rabbits.

Honkanen, Robert A / Huang, Liqun / Huang, Wei / Rigas, Basil

Journal of visualized experiments : JoVE

2020 , Issue 155

Abstract: Dry eye disease (DED) is a complex disease with multiple etiologies and variable symptoms, having ocular surface inflammation as its key pathophysiologic step. Despite advances in our understanding of DED, significant knowledge gaps remain. Advances are ... ...

Abstract	Dry eye disease (DED) is a complex disease with multiple etiologies and variable symptoms, having ocular surface inflammation as its key pathophysiologic step. Despite advances in our understanding of DED, significant knowledge gaps remain. Advances are limited in part due to the lack of informative animal models. The authors recently reported on a method of DED induced by injecting all orbital lacrimal gland (LG) tissues with the lectin concanavalin A. Here, we report a novel model of aqueous-deficient DED based on the surgical resection of all orbital LG (dacryoadenectomy) tissues. Both methods use rabbits because of their similarity to human eyes in terms of the size and structure of the ocular surface. One week after removal of the nictitating membrane, the orbital superior LG was surgically removed under anesthesia, followed by removal of the palpebral superior LG, and finally removal of the inferior LG. Dacryoadenectomy induced severe DED, evidenced by a marked reduction in the tear break up time test and the Schirmer's tear test, and significantly increased tear osmolarity and rose bengal staining. Dacryoadenectomy-induced DED lasted at least eight weeks. There were no complications and animals tolerated the procedure well. The technique can be mastered relatively easily by those with adequate surgical experience and appreciation of the relevant rabbit anatomy. Since this model recapitulates the features of human aqueous-deficient DED, it is suitable for studies of ocular surface homeostasis, DED, and candidate therapeutics.
MeSH term(s)	Animals ; Disease Models, Animal ; Dry Eye Syndromes/diagnosis ; Female ; Humans ; Lacrimal Apparatus/physiopathology ; Lacrimal Apparatus/surgery ; Lacrimal Apparatus Diseases/surgery ; Male ; Rabbits ; Tears/metabolism
Language	English
Publishing date	2020-01-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/60126
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Article ; Online: Animal models of dry eye disease: Useful, varied and evolving (Review).

Huang, Wei / Tourmouzis, Konstantinos / Perry, Henry / Honkanen, Robert A / Rigas, Basil

Experimental and therapeutic medicine

2021 Volume 22, Issue 6, Page(s) 1394

Abstract: Dry eye disease (DED), which is a prevalent disease that still lacks successful treatment options, remains a major challenge in ophthalmology. Multiple animal models of DED have been used to decipher its pathophysiology and to develop novel treatments. ... ...

Abstract	Dry eye disease (DED), which is a prevalent disease that still lacks successful treatment options, remains a major challenge in ophthalmology. Multiple animal models of DED have been used to decipher its pathophysiology and to develop novel treatments. These models use mice, rats, rabbits, cats, dogs and non-human primates. Each model assesses aspects of DED by focusing on elements of the lacrimal functional unit, which controls the homeostasis of the tear film. The present review outlines representative DED animal models and assesses their contribution to the study of DED. Murine models are the most extensively used, followed by rabbit models; the latter offer the advantage of larger eyes, a favorable biochemical profile for drug studies, experimental ease and relatively low cost, contrasting with non-human primates, which, although closer to humans, are not as accessible and are expensive. No comprehensive 'ideal' animal model encompassing all aspects of human DED exists nor is it feasible. Investigators often choose an animal model based on their experimental needs and the following four features of a given model: The size of the eye, its biochemical composition, the available research reagents and cost. As research efforts in DED expand, more refined animal models are needed to supplement the enormous contribution made to date by existing models.
Language	English
Publishing date	2021-10-01
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	2683844-8
ISSN	1792-1015 ; 1792-0981
ISSN (online)	1792-1015
ISSN	1792-0981
DOI	10.3892/etm.2021.10830
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Article ; Online: Phospho-Sulindac (OXT-328) Inhibits Dry Eye Disease in Rabbits: A Dose-, Formulation- and Structure-Dependent Effect.

Huang, Wei / Wen, Ziyi / Saglam, Muhammet S / Huang, Liqun / Honkanen, Robert A / Rigas, Basil

Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics

2021 Volume 37, Issue 6, Page(s) 321–330

Abstract: Purpose: ...

Abstract	Purpose:
MeSH term(s)	Administration, Topical ; Animals ; Drug Compounding ; Dry Eye Syndromes/drug therapy ; Dry Eye Syndromes/metabolism ; Dry Eye Syndromes/pathology ; Male ; Organophosphorus Compounds/administration & dosage ; Organophosphorus Compounds/chemistry ; Organophosphorus Compounds/pharmacokinetics ; Rabbits ; Sulindac/administration & dosage ; Sulindac/analogs & derivatives ; Sulindac/chemistry ; Sulindac/pharmacokinetics ; Tissue Distribution
Chemical Substances	OXT-328 ; Organophosphorus Compounds ; Sulindac (184SNS8VUH)
Language	English
Publishing date	2021-06-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	1237021-6
ISSN	1557-7732 ; 1080-7683
ISSN (online)	1557-7732
ISSN	1080-7683
DOI	10.1089/jop.2019.0025
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Article: Establishment of a severe dry eye model using complete dacryoadenectomy in rabbits

Honkanen, Robert A / Huang, Liqun / Huang, Wei / Rigas, Basil

Journal of visualized experiments. 2020 Jan. 08, , no. 155

2020

Abstract	Dry eye disease (DED) is a complex disease with multiple etiologies and variable symptoms, having ocular surface inflammation as its key pathophysiologic step. Despite advances in our understanding of DED, significant knowledge gaps remain. Advances are limited in part due to the lack of informative animal models. The authors recently reported on a method of DED induced by injecting all orbital lacrimal gland (LG) tissues with the lectin concanavalin A. Here, we report a novel model of aqueous-deficient DED based on the surgical resection of all orbital LG (dacryoadenectomy) tissues. Both methods use rabbits because of their similarity to human eyes in terms of the size and structure of the ocular surface. One week after removal of the nictitating membrane, the orbital superior LG was surgically removed under anesthesia, followed by removal of the palpebral superior LG, and finally removal of the inferior LG. Dacryoadenectomy induced severe DED, evidenced by a marked reduction in the tear break up time test and the Schirmer's tear test, and significantly increased tear osmolarity and rose bengal staining. Dacryoadenectomy-induced DED lasted at least eight weeks. There were no complications and animals tolerated the procedure well. The technique can be mastered relatively easily by those with adequate surgical experience and appreciation of the relevant rabbit anatomy. Since this model recapitulates the features of human aqueous-deficient DED, it is suitable for studies of ocular surface homeostasis, DED, and candidate therapeutics.
Keywords	anesthesia ; animal models ; concanavalin A ; eye diseases ; homeostasis ; humans ; inflammation ; lacrimal apparatus ; osmolarity ; pathophysiology ; rabbits ; resection ; staining
Language	English
Dates of publication	2020-0108
Size	p. e60126.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/60126
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Phosphosulindac is efficacious in an improved concanavalin A-based rabbit model of chronic dry eye disease.

Honkanen, Robert A / Huang, Liqun / Xie, Gang / Rigas, Basil

Translational research : the journal of laboratory and clinical medicine

2018 Volume 198, Page(s) 58–72

Abstract: Dry eye disease (DED) currently has no satisfactory treatment partly because of the lack of informative animal models. We evaluated the anti-inflammatory phosphosulindac (PS) for the treatment of DED using a new rabbit model of DED based on the ... ...

Abstract	Dry eye disease (DED) currently has no satisfactory treatment partly because of the lack of informative animal models. We evaluated the anti-inflammatory phosphosulindac (PS) for the treatment of DED using a new rabbit model of DED based on the concanavalin A (Con A) acute DED model: we injected all lacrimal glands with Con A weekly under ultrasound guidance, which prolonged DED to >3 weeks, and thoroughly assessed efficacy with tear break-up time (TBUT), tear osmolarity, Schirmer test, and tear lactoferrin levels. Rabbits with DED (n = 8-10 eyes per group) were treated topically with PS or vehicle 3×/day for 21days. PS restored TBUT, tear osmolarity, and lactoferrin levels (P < 0.0001-0.04) to normal but did not significantly improve the results of the Schirmer test. PS showed no side effects and was much more efficacious than cyclosporine or lifitegrast. In the cornea, PS suppressed the activation of nuclear factor kappa-B, the levels of transforming growth factor beta, interleukin-1 beta, interleukin-6, and interleukin-8, and the levels of matrix metalloproteinase (MMP)-1 and MMP-9, and MMP activity. Levels of prostaglandin E
MeSH term(s)	Administration, Ophthalmic ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/administration & dosage ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Cells, Cultured ; Chronic Disease ; Concanavalin A/toxicity ; Cytokines/metabolism ; Dinoprostone/metabolism ; Disease Models, Animal ; Dry Eye Syndromes/drug therapy ; Humans ; Lactoferrin/metabolism ; Matrix Metalloproteinase 1/metabolism ; Matrix Metalloproteinase 9/metabolism ; Organophosphorus Compounds/administration & dosage ; Organophosphorus Compounds/therapeutic use ; Osmolar Concentration ; Rabbits ; Sulindac/administration & dosage ; Sulindac/analogs & derivatives ; Sulindac/therapeutic use ; Tears/metabolism
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Cytokines ; OXT-328 ; Organophosphorus Compounds ; Concanavalin A (11028-71-0) ; Sulindac (184SNS8VUH) ; Lactoferrin (EC 3.4.21.-) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Matrix Metalloproteinase 1 (EC 3.4.24.7) ; Dinoprostone (K7Q1JQR04M)
Language	English
Publishing date	2018-04-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2246684-8
ISSN	1878-1810 ; 1532-6543 ; 1931-5244
ISSN (online)	1878-1810 ; 1532-6543
ISSN	1931-5244
DOI	10.1016/j.trsl.2018.04.002
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Article: Ischemic central retinal vein occlusion and neovascular glaucoma as a result of optic nerve head drusen.

Honkanen, Robert A / Baba, Fadi El / Sibony, Patrick / Prabhu, Sujata P

Retinal cases & brief reports

2011 Volume 5, Issue 1, Page(s) 73–75

Abstract: Purpose: The purpose of this study was to report a case of ischemic central retinal vein occlusion (CRVO) caused by optic nerve head drusen.: Methods: Case report and review of the literature.: Results: A healthy 13-year-old boy was diagnosed with ...

Abstract	Purpose: The purpose of this study was to report a case of ischemic central retinal vein occlusion (CRVO) caused by optic nerve head drusen. Methods: Case report and review of the literature. Results: A healthy 13-year-old boy was diagnosed with bilateral optic nerve head drusen. Two years later, he developed an ischemic CRVO and secondary neovascular glaucoma. A full medical workup was negative. Despite treatment, his vision eventually declined to no light perception from a funnel detachment. Conclusion: Nonischemic CRVO or venous stasis retinopathy is a well-known entity associated with optic nerve head drusen. The authors report a case of ischemic CRVO in a patient with no underlying risks for this other than the observed drusen. This report clearly shows that optic nerve drusen may not be entirely benign and that they can precipitate ischemic CRVO.
Language	English
Publishing date	2011
Publishing country	United States
Document type	Journal Article
ISSN	1935-1089
ISSN	1935-1089
DOI	10.1097/ICB.0b013e3181c33375
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Article ; Online: Heterozygous triplication of upstream regulatory sequences leads to dysregulation of matrix metalloproteinase 19 in patients with cavitary optic disc anomaly.

Hazlewood, Ralph J / Roos, Benjamin R / Solivan-Timpe, Frances / Honkanen, Robert A / Jampol, Lee M / Gieser, Stephen C / Meyer, Kacie J / Mullins, Robert F / Kuehn, Markus H / Scheetz, Todd E / Kwon, Young H / Alward, Wallace L M / Stone, Edwin M / Fingert, John H

Human mutation

2014 Volume 36, Issue 3, Page(s) 369–378

Abstract: Patients with a congenital optic nerve disease, cavitary optic disc anomaly (CODA), are born with profound excavation of the optic nerve resembling glaucoma. We previously mapped the gene that causes autosomal-dominant CODA in a large pedigree to a ... ...

Abstract	Patients with a congenital optic nerve disease, cavitary optic disc anomaly (CODA), are born with profound excavation of the optic nerve resembling glaucoma. We previously mapped the gene that causes autosomal-dominant CODA in a large pedigree to a chromosome 12q locus. Using comparative genomic hybridization and quantitative PCR analysis of this pedigree, we report identifying a 6-Kbp heterozygous triplication upstream of the matrix metalloproteinase 19 (MMP19) gene, present in all 17 affected family members and no normal members. Moreover, the triplication was not detected in 78 control subjects or in the Database of Genomic Variants. We further detected the same 6-Kbp triplication in one of 24 unrelated CODA patients and in none of 172 glaucoma patients. Analysis with a Luciferase assay showed that the 6-Kbp sequence has transcription enhancer activity. A 773-bp fragment of the 6-Kbp DNA segment increased downstream gene expression eightfold, suggesting that triplication of this sequence may lead to dysregulation of the downstream gene, MMP19, in CODA patients. Lastly, immunohistochemical analysis of human donor eyes revealed strong expression of MMP19 in optic nerve head. These data strongly suggest that triplication of an enhancer may lead to overexpression of MMP19 in the optic nerve that causes CODA.
MeSH term(s)	Chromosomes, Human, Pair 12 ; Eye Diseases, Hereditary/genetics ; Eye Diseases, Hereditary/metabolism ; Glaucoma/genetics ; Heterozygote ; Humans ; Matrix Metalloproteinases, Secreted/metabolism ; Optic Disk/abnormalities ; Optic Disk/metabolism ; Pedigree ; Regulatory Sequences, Nucleic Acid
Chemical Substances	Matrix Metalloproteinases, Secreted (EC 3.4.24.-) ; matrix metalloproteinase 19 (EC 3.4.24.-)
Language	English
Publishing date	2014-12-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.22754
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