Long-term topical application of preservative-free prostaglandin analogues evokes macrophage infiltration in the ocular adnexa

Trzeciecka, Anna; Paterno, Jussi J.; Toropainen, Elisa; Koskela, Ali; Podracka, Lucia; Korhonen, Eveliina; Kauppinen, Anu; Kaarniranta, Kai; Smędowski, Adrian

doi:10.1016/j.ejphar.2016.06.014

Cited by 25 publications

(17 citation statements)

References 40 publications

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“…The cell membrane's permeability for LDH has been used widely as a method for cytotoxicity assays in different settings [ 52 , 53 ]. In our study, the LDH membrane's permeability was affected by the toxic concentration of gentamicin and the protective mechanisms were activated using CNTF.…”

Section: Discussionmentioning

confidence: 99%

FluoroGold‐Labeled Organotypic Retinal Explant Culture for Neurotoxicity Screening Studies

Smędowski

Pietrucha‐Dutczak

Maniar

et al. 2018

Oxidative Medicine and Cellular Longevity

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Preclinical toxicity screening of the new retinal compounds is an absolute requirement in the pathway of further drug development. Since retinal neuron cultivation and in vivo studies are relatively expensive and time consuming, we aimed to create a fast and reproducible ex vivo system for retinal toxicity screening. For this purpose, we used rat retinal explant culture that was retrogradely labeled with the FluoroGold before the isolation. Explants were exposed to a toxic concentration of gentamicin and ciliary neurotrophic factor (CNTF), a known neuroprotective agent. The measured outcomes showed the cell density in retinal ganglion cell layer (GCL) and the activity of lactate dehydrogenase (LDH) in the culture medium. Gentamicin-induced oxidative stress resulted in retinal cell damage and rapid LDH release to the culture medium (p < 0.05). Additional CNTF supplementation minimized the cell damage, and the increase of LDH release was insignificant when compared to LDH levels before gentamicin insult (p > 0.05). As well as this, the LDH activity was directly correlated with the cell count in GCL (R = −0.84, p < 0.00001), making a sensitive marker of retinal neuron damage. The FLOREC protocol could be considered as a fast, reproducible, and sensitive method to detect neurotoxicity in the screening studies of the retinal drugs.

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Section: Discussionmentioning

confidence: 99%

FluoroGold‐Labeled Organotypic Retinal Explant Culture for Neurotoxicity Screening Studies

Smędowski

Pietrucha‐Dutczak

Maniar

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…PF prostaglandin analogues have been found to induce ocular adnexa macrophage infiltration, which may be partially explained by excipients in the medications. 56 Other common adverse effects of prostaglandin analogues such as orbitopathy 57 are not attributed to their preservatives. A recent Japanese study found better IOP control post-trabeculectomy in those patients who did not exhibit signs of orbitopathy due to preoperative prostaglandin analogues.…”

Section: Introductionmentioning

confidence: 99%

Preservatives in glaucoma medication

2018

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Preservatives continue to be in widespread use in ophthalmic medications due to the convenience they provide, regulatory requirements and the higher cost of alternatives. Benzalkonium chloride (BAK) remains the most commonly used preservative but there is a trend towards the use of preservative-free (PF) drops for glaucoma, although at a higher price. An extensive body of literature explores BAK toxicity on ocular structures in animal and laboratory studies (in vitro and in vivo). Non-randomised controlled studies have provided some supporting evidence of its toxicity in patients, especially in those with pre-existing ocular surface disease (OSD) or on multiple medications. However, there have been very few randomised controlled trials that compare the same medication with and without BAK preservative. Several of these trials have never been published in any peer reviewed journals. Notwithstanding, those that have been published, have not demonstrated any clear benefits of the BAK-free formulations. Short duration and exclusion of those with OSD are limitations of these studies. There is a lack of evidence of clinically significant harm from a small number of BAK preserved drops in patients without OSD. This means that generally more expensive PF glaucoma medications should only be recommended for those on poly pharmacy or those with OSD but are not necessarily required for all patients.

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“…Yet, we could not find any published study on the leukocyte activity associated with prostaglandin analogs, one of the most frequently prescribed drugs for glaucoma treatment and a known proinflammatory molecule. We reiterate that the chemotactic properties of BAK, prostaglandins and other active and nonactive ingredients of hypotensive eye drops should continue to be the subject of future laboratory studies [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

The chemotactic properties of various topical brimonidine tartrate ophthalmic preparations

Alonso

Solari

Damasceno

et al. 2020

BMC Pharmacol Toxicol

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Background: The study aimed to evaluate and compare the leukocyte chemotactic activities of various brimonidine tartrate (BT) eye drop formulations. Methods: A 96-well dot-blot platet using a Boyden-style well was used to study the chemotactic effects of BT ophthalmic preparations. A modification was made to create blind wells where the tested agents were placed. Leukocytes were isolated from the peripheral blood of healthy volunteers. As positive controls, we used diluted drugs, benzalkonium chloride solution (BAK), zymosan-activated serum, and formyl-methionine-leucinephenylalanine peptides. The negative control in our study was a phosphate-buffered saline solution. For each experimental condition, we measured leukocyte migration through a Millipore membrane. The differences in the mean migration distance between groups were compared using the analysis of variance (ANOVA). Results: The measured migration distances (in μm ± SD) were 62.14 ± 3.71 for BT 0.2% with BAK (Alcon Laboratories Inc.); 63.61 ± 3.81 for BT 0.2% with BAK (Allergan Inc); 40.36 ± 3.17 for BT 0.15% without BAK; and 41.02 ± 2.17 for BAK alone. The negative controls showed no chemotactic activity, while the positive controls showed the highest neutrophil migration of all experimental conditions. The differences between BT 0.15% without BAK and the other commercial formulations were statistically significant. Conclusion: Commercial ophthalmic preparations of BT 0.2% with BAK 0.005% had higher chemotactic properties than the alternative of a lower concentration of BT and without the preservative BAK. Therefore, the latter should be considered for patients with glaucoma or ocular hypertension in order to minimize iatrogenic ocular inflammation.

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Long-term topical application of preservative-free prostaglandin analogues evokes macrophage infiltration in the ocular adnexa

Cited by 25 publications

References 40 publications

FluoroGold‐Labeled Organotypic Retinal Explant Culture for Neurotoxicity Screening Studies

FluoroGold‐Labeled Organotypic Retinal Explant Culture for Neurotoxicity Screening Studies

Preservatives in glaucoma medication

The chemotactic properties of various topical brimonidine tartrate ophthalmic preparations

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