Effects of Topical Glaucoma Drugs on Fistuliezed Rabbit Conjunctiva

doi:10.1016/S0161-6420(90)32392-8

Ophthalmology

Volume 97, Issue 11, November 1990, Pages 1423-1427

https://doi.org/10.1016/S0161-6420(90)32392-8 Get rights and content

Abstract

Conjunctival fibroblastic proliferation with contracting scar formation has been implicated as a possible cause of glaucoma filtering surgery failure. The effects of glaucoma medications on bulbar conjunctiva were evaluated in both eyes of 20 pigmented rabbits, with 5 rabbits per group each receiving singular topically applied daily doses of either 0.5% timolol, 1% epinephrine, 4% pilocarpine, or artificial tears in a masked fashion for 4 months. Posterior lip sclerectomies were performed in 16 rabbits-4 from each treatment group. The remaining four rabbits served as nonsurgical controls. Four additional rabbits, which had not received eye drops, were included as a nonmedicated control group, with one rabbit serving as a nonsurgical control. Immunostaining was performed to identify the presence of myofibroblasts in fistulized conjunctiva. Treated surgical eyes, regardless of medication, had higher myofibroblastic cell proliferation than treated nonsurgical eyes. Among fistulized eyes, all medications increased cell proliferation, with pilocarpine eliciting the most dramatic increase compared with all other groups.

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Adrenaline is a sympathomimetic drug used to maintain pupil dilation and to decrease the risk of bleeding. The aim of this study was to demonstrate if adrenaline could exert antifibrotic effects in glaucoma surgery. Adrenaline was tested in fibroblast-populated collagen contraction assays and there was a dose-response decrease in fibroblast contractility: matrices decreased to 47.4% (P = 0.0002) and 86.6% (P = 0.0036) with adrenaline 0.0005% and 0.01%, respectively. There was no significant decrease in cell viability even at high concentrations. Human Tenon's fibroblasts were also treated with adrenaline (0%, 0.0005%, 0.01%) for 24 h and RNA-Sequencing was performed on the Illumina NextSeq 2000. We carried out detailed gene ontology, pathway, disease and drug enrichment analyses. Adrenaline 0.01% upregulated 26 G1/S and 11 S-phase genes, and downregulated 23 G2 and 17 M-phase genes (P < 0.05). Adrenaline demonstrated similar pathway enrichment to mitosis and spindle checkpoint regulation. Adrenaline 0.05% was also injected subconjunctivally during trabeculectomy, PreserFlo Microshunt and Baerveldt 350 tube surgeries, and patients did not experience any adverse effects. Adrenaline is a safe and cheap antifibrotic drug that significantly blocks key cell cycle genes when used at high concentrations. Unless contraindicated, we recommend subconjunctival injections of adrenaline (0.05%) in all glaucoma bleb-forming surgeries.
The effects of ripasudil (K-115), a Rho kinase inhibitor, on activation of human conjunctival fibroblasts
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Prostaglandin F2α analogs, which are currently the most widely prescribed first-line treatments, increased proliferation of rabbit subconjunctival fibroblasts (Lark et al., 1999) and induced collagen gel contraction by human Tenon fibroblasts (Liu et al., 2008). Also, prolonged use of antiglaucoma medications, including timolol, epinephrine, and pilocarpine, induced recruitment of inflammatory cells (including macrophages) and increased fibroblast numbers in the conjunctiva (Young et al., 1990; Sherwood et al., 1989). These observations suggest that antiglaucoma drugs may negatively influence subconjunctival wound healing by enhancing the proliferation, contractility, and inflammatory activities of fibroblasts.
The most common cause of glaucoma surgery failure is scar formation induced by activation of wound-healing responses and resultant fibrosis at the surgical site. We investigated the effects of ripasudil, a Rho kinase inhibitor, on activation of human conjunctival fibroblasts (HConF). HConF were pretreated with different concentrations of ripasudil for 1 h before addition of transforming growth factor (TGF)-β2, followed by incubation for 48 h. TGF-β2-treated fibroblasts exhibited a significant increase in expression of α-smooth muscle actin (α-SMA), a marker of fibroblast-to-myofibroblast differentiation, and this increase was significantly suppressed, in a dose-dependent manner, by pretreatment with ripasudil. Ripasudil pretreatment also significantly attenuated TGF-β2-induced fibronectin production and collagen gel contraction. TGF-β2 increased both the number of viable cells and the number of cells in the G2/M phase of the cell cycle; these effects were attenuated by pretreatment with ripasudil. In addition, we explored the effects of ripasudil on stimulation of HConF by activated macrophages. Human monocytic cell line THP-1 cells were differentiated into M1 or M2 macrophage-like cells, and HConF were treated with conditioned media derived from these macrophages in the presence or absence of ripasudil. Conditioned medium from M2 macrophage-like cells induced a significant increase in α-SMA expression, viable cell numbers, and gel contraction, all of which were significantly suppressed by ripasudil. Thus, overall, ripasudil attenuated activation of human conjunctival fibroblasts. Ripasudil may be of therapeutic utility, preventing excessive scarring after glaucoma filtration surgery.
Genomic and post-genomic effects of anti-glaucoma drugs preservatives in trabecular meshwork
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Citation Excerpt :
Moreover BKA oxidative damage is induced in HTM cells in mitochondria, as demonstrated by MTT test. These results are in line with the available scientific literature univocally demonstrating the high level of damage induced in HTM cells by BKA [9,13–17]. However, the rate of cell death we detected was higher than those reported by other author [18] waiting for 24 h after BKA challenge instead of the 3 h we adopted.
Oxidative stress plays an important role in glaucoma. Some preservatives of anti-glaucoma drugs, commonly used in glaucoma therapy, can prevent or induce oxidative stress in the trabecular meshwork. The aim of this study is to evaluate cellular and molecular damage induced in trabecular meshwork by preservatives contained in anti-glaucoma drugs. Cell viability (MTT test), DNA fragmentation (Comet test), oxidative DNA damage (8-oxo-dG), and gene expression (cDNA microarray) have been evaluated in trabecular meshwork specimens and in human trabecular meshwork cells treated with benzalkonium chloride, polyQuad, purite, and sofzia-like mixture. Moreover, antimicrobial effectiveness and safety of preservative contents in drugs was tested. In ex vivo experiments, benzalkonium chloride and polyQuad induced high level of DNA damage in trabecular meshwork specimens, while the effect of purite and sofzia were more attenuated. The level of DNA fragmentation induced by benzalkonium chloride was 2.4-fold higher in subjects older than 50 years than in younger subjects. Benzalkonium chloride, and polyQuad significantly increased oxidative DNA damage as compared to sham-treated specimens. Gene expression was altered by benzalkonium chloride, polyQuad, and purite but not by sofzia. In in vitro experiments, benzalkonium chloride and polyQuad dramatically decreased trabecular meshwork cell viability, increased DNA fragmentation, and altered gene expression. A lesser effect was also exerted by purite and sofzia. Genes targeted by these alterations included Fas and effector caspase-3. The efficacy of the preservatives in inhibiting bacterial growth increased the adverse effects in trabecular meshwork in terms of DNA damage and alteration of gene expression. Presented data indicates the delicate balance between efficacy and safety of drug preservatives as not yet optimized.
Preservatives in eye drops: Toward awareness of their toxicity
2010, Journal Francais d'Ophtalmologie
Les conservateurs sont présents dans de nombreux collyres multidoses. Ils assurent la stérilité de la solution vis-à-vis des bactéries et champignons. Cependant, des études ont montré que les conservateurs sont toxiques pour la surface oculaire notamment chez les patients prenant des collyres au long cours. Le conservateur le plus employé dans les collyres est le chlorure de benzalkonium, ammonium quaternaire utilisé comme détergent, antiseptique, désinfectant, fongicide, bactéricide et spermicide. Son utilisation sur la surface oculaire pourrait avoir des conséquences importantes en particulier sur le long terme. En effet, les conservateurs provoquent la dissolution du film lacrymal et sont pro-apoptotiques et pro-inflammatoires. L’administration prolongée de collyres contenant un ou plusieurs conservateurs conduit à une altération des structures superficielles (conjonctive, cornée) et plus profondes (trabéculum, cristallin). Les signes et symptômes oculaires les moins sévères se manifestent par une gêne ou des irritations : sensation de corps étranger de picotement ou brûlure, d’œil sec. Pour les effets secondaires les plus graves, on observe une inflammation d’intensité variable allant d’une simple réaction infraclinique au développement progressif d’une fibrose avec entre autres un risque accru d’échec en cas de chirurgie du glaucome. Le meilleur moyen de limiter ces complications passe par la réduction du nombre d’instillations de collyres conservés, et idéalement par l’utilisation de collyres sans conservateur, chaque fois que cela est possible. Une meilleure prise en charge de la surface oculaire devrait permettre d’augmenter le confort du patient, l’observance du traitement et d’assurer l’efficacité d’une future chirurgie filtrante chez les patients atteints de glaucome.
Preservatives are present in numerous multidose eyedrops and provide the sterility of the solution against bacteria and fungi. However, numerous studies have shown their toxicity for the ocular surface, particularly in long-term treatments. The most widely used preservative in eyedrops is benzalkonium chloride. This quaternary ammonium acts as a detergent, antiseptic, disinfectant, fungicide, bactericide, and spermicide. Its use on the ocular surface therefore has significant consequences. Indeed, the preservatives are pro-apoptotic, pro-inflammatory and they cause the dissolution of the lachrymal film. The prolonged administration of one or several eye drops containing preservatives induces changes in the superficial structures (conjunctiva, cornea) as well as in deeper structures (trabecula, lens). The least severe symptoms are irritation and discomfort, including sensation of a foreign body, itching, or burning sensations. However, more severe side effects have been described, such as chronic inflammation of variable intensity or the progressive development of fibrosis with higher risk of failure after glaucoma filtering surgery. Ideally, preservative-free eyedrops should be recommended, or at least a reduction of the number of instilled preserved eyedrops should be considered. All these strategies could increase patient comfort, quality of life, and compliance, with better outcome at the time of filtering surgery.
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To describe the intraocular pressure (IOP)-lowering effects in eyes with open-angle glaucoma (OAG) after treatment with an anterior juxtascleral depot of anecortave acetate.
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Seven eyes of six subjects with OAG, with uncontrolled IOP while being administered one or more topical medications, received 24 mg anecortave acetate delivered by anterior juxtascleral depot. IOP was assessed at baseline and regularly after treatment for up to 24 months.
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Both the anterior juxtascleral depot of a drug and anecortave acetate may be promising candidates for IOP reduction in eyes with OAG. Additional studies are required to establish better their efficacy and safety, optimal dosing frequency, mechanism of action, and potential additivity to other IOP-lowering therapies.

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: Presented in part at the Association for Research in Vision and Ophthalmology Annual Meeting, Sarasota, May 1989. Supported in part by training grant 7038 and core grant 1792 from the National Eye Institute, Bethesda, Maryland, and by an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York.

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Effects of Topical Glaucoma Drugs on Fistuliezed Rabbit Conjunctiva

Abstract

Ophthalmology

Ophthalmology

Experiences in surgical treatment of haemorrhagic glaucoma: a follow-up study

Acta Ophthalmol [Suppl]

External filtering operations for glaucoma: the mechanism of function and failure

Trans Am Ophthalmol Soc

Trabecular surgery

Arch Ophthalmol

Trabeculectomy in black patients

Ophthalmic Surg

Myofibroblasts in filtration operations

Ann Ophthalmol

Clinico pathological correlation in eyes with failed fistulizing surgery

Trans Ophthalmol Soc UK