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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: Diagnosis of Dry Eye Disease Using Principal Component Analysis: A Study in Animal Models of the Disease.

Honkanen, Robert / Nemesure, Barbara / Huang, Liqun / Rigas, Basil

Current eye research

2021 Volume 46, Issue 5, Page(s) 622–629

Abstract: Purpose: To evaluate whether principal component analysis (PCA) can assess various diagnostic tests of dry eye disease (DED), providing a simplified, more informative measure of disease status than individual clinical test parameters (ICTP).: ... ...

Abstract	Purpose: To evaluate whether principal component analysis (PCA) can assess various diagnostic tests of dry eye disease (DED), providing a simplified, more informative measure of disease status than individual clinical test parameters (ICTP). Materials and methods: ICTP were analyzed using PCA in two groups of normal rabbits (Groups 1 and 2). Group 3, not truly normal, was also assessed. DED was induced in Group 1 by complete dacryoadenectomy; in Groups 2 and 3 by injection of concanavalin A. Tear break up time, tear osmolarity, Schirmer's tear test and rose bengal staining were the ICTP measured in all groups. Statistical analysis including descriptive statistics, t test, correlation coefficients and PCA was done. PCA using ICTP data from Group 1 generated axes; Group 2 and 3 were plotted over these axes. Results: All groups had induction of DED. Correlations for all ICTP were in the correct direction and were strongest for Group 1 and weakest in Group 3. PCA clearly separated DED and normal eyes. Principal component (PC) 1, made up of nearly equal contributions from the four clinical tests, explained 73% of the variation and provided a means to separate normal from DED. PC 1 values under 0.52 can be mathematically defined as DED. Of all pairwise comparisons, PC 1 vs PC 2 and PC 1 vs PC 3 were the most informative providing excellent spatial separation and additional information regarding DED status. Conclusions: PCA proved useful for evaluating DED providing a simpler, more comprehensive assessment than ICTP. PC 1 is a valuable, clinically relevant, and informative metric for DED status and severity having superior diagnostic value and statistical strength compared to ICTP. Spatial information on biplots of PC 1 vs PC 3 is also informative. PCA, and specifically PC 1, has the potential to serve as a biomarker for DED.
MeSH term(s)	Animals ; Diagnostic Techniques, Ophthalmological ; Disease Models, Animal ; Dry Eye Syndromes/diagnosis ; Dry Eye Syndromes/physiopathology ; Male ; Osmolar Concentration ; Principal Component Analysis/methods ; Rabbits ; Tears/chemistry ; Tears/physiology
Language	English
Publishing date	2021-01-14
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	82079-9
ISSN	1460-2202 ; 0271-3683
ISSN (online)	1460-2202
ISSN	0271-3683
DOI	10.1080/02713683.2020.1830115
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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 ; Online: An Improved Ocular Impression Cytology Method: Quantitative Cell Transfer to Microscope Slides Using a Novel Polymer.

Master, Adam / Huang, Wei / Huang, Liqun / Honkanen, Robert / Rigas, Basil

Current eye research

2021 Volume 47, Issue 1, Page(s) 41–50

Abstract: Purpose: To develop a more efficient impression cytology (IC) method for the transfer of ocular surface cells onto glass microscope slides for cytochemical, immunocytochemical, and immunofluorescence studies.: Methods: Cells are lifted off the ocular ...

Abstract	Purpose: To develop a more efficient impression cytology (IC) method for the transfer of ocular surface cells onto glass microscope slides for cytochemical, immunocytochemical, and immunofluorescence studies. Methods: Cells are lifted off the ocular surface with a mixed cellulose ester membrane and then firmly attached to a glass slide using a novel triblock copolymer comprised of collagen type I, polyethylenimine and poly-L-lysine (CPP), and crosslinking cells and glass slide by heating and cooling. The membrane is removed intact after softening it with a butanol/ethanol solution. Transfer of cells is complete in about 10-15 minutes and is ready for staining. The efficiency of our cell transfer method was compared to current methods based on poly-L-lysine and albumin paste. Results: Our method ensured almost complete transfer of cells. In contrast, the transfer of rabbit conjunctiva cells onto poly-L-lysine-covered slides was 37.5 ± 6.3% lower, and onto albumin-paste covered slides 62.5 ± 5.6% lower (mean ± SD); the transfer of rabbit goblet cells was even less efficient. The new method was also more efficient for transfer of cells from human oral mucosa obtained by IC. Transferred cells were successfully stained with H&E, chemiluminescence, and immunofluorescence agents. Using our method, we stained ocular surface cells for S100A4 and ATF4, both of which play a role in the pathophysiology of dry eye disease. We obtained similar results with oral mucosal cells, suggesting the generalizability of our approach. We propose an explanation for the strong adhesion of cells to the glass slide, which is based on their interactions with the triblock copolymer. Conclusions: We developed a novel approach for the efficient and rapid transfer of cells obtained by IC onto glass microscope slides using a novel copolymer. Compared to available methods, our improved approach makes IC robust and simple, and should increase its diagnostic yield and clinical applicability.
MeSH term(s)	Aged ; Animals ; Cytological Techniques/trends ; Female ; Goblet Cells/cytology ; Humans ; Male ; Microscopy/methods ; Middle Aged ; Models, Animal ; Polymers/pharmacology ; Rabbits
Chemical Substances	Polymers
Language	English
Publishing date	2021-11-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	82079-9
ISSN	1460-2202 ; 0271-3683
ISSN (online)	1460-2202
ISSN	0271-3683
DOI	10.1080/02713683.2021.1951300
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Article: Correction: The Chemoprevention of Ovarian Cancer: the Need and the Options.

Kathawala, Rishil J / Kudelka, Andrzej / Rigas, Basil

Current pharmacology reports

2018 Volume 4, Issue 5, Page(s) 414

Abstract: This corrects the article DOI: 10.1007/s40495-018-0133-6.]. ...

Abstract	[This corrects the article DOI: 10.1007/s40495-018-0133-6.].
Language	English
Publishing date	2018-09-10
Publishing country	Switzerland
Document type	Published Erratum
ISSN	2198-641X
ISSN	2198-641X
DOI	10.1007/s40495-018-0159-9
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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 ; Online: NSAID-induced corneal melt: Clinical importance, pathogenesis, and risk mitigation.

Rigas, Basil / Huang, Wei / Honkanen, Robert

Survey of ophthalmology

2019 Volume 65, Issue 1, Page(s) 1–11

Abstract: Corneal melt, an ophthalmological condition in which corneal epithelium is lost accompanied by thinning of the corneal stroma, can lead to corneal perforation and cause loss of vision. Corneal melt is the most serious side effect of topical nonsteroidal ... ...

Abstract	Corneal melt, an ophthalmological condition in which corneal epithelium is lost accompanied by thinning of the corneal stroma, can lead to corneal perforation and cause loss of vision. Corneal melt is the most serious side effect of topical nonsteroidal anti-inflammatory drugs (NSAIDs), one of the topical treatments of ocular inflammation. NSAID-induced corneal melt (NICM), initially doubted, is real, having been reported by multiple groups. NICM is induced by all but one of the approved ocular NSAIDs and occurs usually in patients whose cornea is compromised by ocular surgery, diabetes, or autoimmune diseases. Its true incidence, most likely low, remains unknown. NSAID dose and duration of treatment may be important for NICM. NICM appears to evolve in two stages: the epithelial stage-marked by a corneal epithelial defect, reduced eicosanoid levels, leukocyte infiltration, and matrix metalloproteinase-facilitated desquamation-and the stromal stage, characterized by degradation of stromal collagen by activated matrix metalloproteinases. Awareness of this ominous side effect, its risk factors, and the need for prompt action once diagnosed, including NSAID discontinuation, will help mitigate the risk of NICM. Further understanding of NICM and development of efficacious treatments or safer alternatives should help eliminate this rare, but severe, side effect of ocular NSAIDs.
MeSH term(s)	Administration, Topical ; Anti-Inflammatory Agents, Non-Steroidal/administration & dosage ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects ; Cornea/diagnostic imaging ; Cornea/drug effects ; Corneal Diseases/chemically induced ; Corneal Diseases/diagnosis ; Humans ; Ophthalmic Solutions ; Risk Factors ; Slit Lamp Microscopy
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Ophthalmic Solutions
Language	English
Publishing date	2019-07-12
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	391346-6
ISSN	1879-3304 ; 0039-6257
ISSN (online)	1879-3304
ISSN	0039-6257
DOI	10.1016/j.survophthal.2019.07.001
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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: Phosphosulindac (OXT-328) prevents and reverses chemotherapy induced peripheral neuropathy in mice.

Basu, Aryah / Yang, Jennifer Y / Tsirukis, Vasiliki E / Loiacono, Andrew / Koch, Gina / Khwaja, Ishan A / Krishnamurthy, Mahila / Fazio, Nicholas / White, Emily / Jha, Aayushi / Shah, Shrila / Takmil, Cameron / Bagdas, Deniz / Demirer, Aylin / Master, Adam / Natke, Ernest / Honkanen, Robert / Huang, Liqun / Rigas, Basil

Frontiers in neuroscience

2024 Volume 17, Page(s) 1240372

Abstract: Background: Chemotherapy-induced peripheral neuropathy (CIPN), a side effect of chemotherapy, is particularly difficult to treat. We explored whether phosphosulindac (PS), a modified NSAID, could treat CIPN.: Methods: CIPN was induced in male C57BL/6 ...

Abstract	Background: Chemotherapy-induced peripheral neuropathy (CIPN), a side effect of chemotherapy, is particularly difficult to treat. We explored whether phosphosulindac (PS), a modified NSAID, could treat CIPN. Methods: CIPN was induced in male C57BL/6 J mice by paclitaxel, vincristine or oxaliplatin. Mechanical allodynia was measured with the von Frey test and cold allodynia with the acetone test. To determine the preventive effect of PS, it was administered 2 days before the induction of CIPN. Mouse Lewis lung carcinoma xenografts were used to determine if PS altered the chemotherapeutic efficacy of paclitaxel. Cultured cell lines were used to evaluate the effect of PS on neuroinflammation. Results: Treatment with each of the three chemotherapeutic agents used to induce CIPN lowered the mechanical allodynia scores by 56 to 85% depending on the specific agent. PS gel was applied topically 3x/day for 16-22 days to the hind paws of mice with CIPN. This effect was dose-dependent. Unlike vehicle, PS returned mechanical allodynia scores back to pre-CIPN levels. PS had a similar effect on paclitaxel-induced CIPN cold allodynia. Sulindac, a metabolite of PS, had no effect on CIPN. PS significantly prevented CIPN compared to vehicle. Given concomitantly with paclitaxel to mice with lung cancer xenografts, PS relieved CIPN without affecting the anticancer effect of paclitaxel. The enantiomers of PS were equally efficacious against CIPN, suggesting the therapeutic suitability of the racemate PS. There were no apparent side effects of PS. PS suppressed the levels of IL-6, IL-10, CXCL1, and CXCL2 induced by paclitaxel in a neuroblastoma cell line, and macrophage activation to the M1 proinflammatory phenotype. Conclusion: Topically applied PS demonstrated broad therapeutic and preventive efficacy against CIPN, preserved the anticancer effect of paclitaxel, and was safe. Its anti-CIPN effect appears to be mediated, in part, by suppression of neuroinflammation. These data support further evaluation of topical PS for the control of CIPN.
Language	English
Publishing date	2024-01-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1240372
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