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Benzalkonium Chloride Toxicity in Fluoroquinolone Eye Drops

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  • Benzalkonium Chloride Toxicity in Fluoroquinolone Eye Drops

    Investigative Ophthalmology and Visual Science. 2006 Jul;47(7):2812-9.
    Fluoroquinolone eye drop-induced cytotoxicity: role of preservative in P2X7 cell death receptor activation and apoptosis.

    * Dutot M,
    * Pouzaud F,
    * Larosche I,
    * Brignole-Baudouin F,
    * Warnet JM,
    * Rat P.

    Laboratoire de Toxicologie, Faculte des Sciences Pharmaceutiques et Biologiques, Universite Rene Descartes-Paris, and Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France.

    PURPOSE: To investigate in vitro whether eye toxicity is attributable to the preservative or the fluoroquinolone used in ophthalmic formulations. METHODS: Corneal and conjunctival cell lines were incubated with preserved (benzalkonium chloride [BAC]) or unpreserved ofloxacin solutions for 15 minutes. Several concentrations of BAC were also tested (0.0025%-0.01%). Membrane integrity, reactive oxygen species, and superoxide anion production were assessed with the neutral red test, the 2',7'-dichlorofluorescein diacetate test, and the dihydroethidium test, respectively. P2X7 cell death receptor activation was evaluated using the YO-PRO-1 assay and apoptosis (chromatin condensation and translocation of phosphatidylserine) using the Hoechst 33342 and annexin V-FITC dyes. Tests were performed with microplate cytofluorometry, inverted fluorescence microscopy, and flow cytometry. RESULTS: The preserved solution and all tested BAC concentrations induced a significant decrease in membrane integrity, unlike the unpreserved ofloxacin. Reactive oxygen species and superoxide anion productions observed for all solutions were significantly higher for the preserved ofloxacin and BAC solutions, which also induced apoptosis (chromatin condensation and translocation of phosphatidylserine) through P2X7 pore opening, whereas unpreserved ofloxacin did not. CONCLUSIONS: The cytotoxicity observed with fluoroquinolone eye drops seems to be caused mainly by the preservative, which induced P2X7 cell death receptor activation associated with oxidative stress and apoptosis. Therefore, it is recommended that fluoroquinolone be used in preservative-free formulations.

    PMID: 16799018 [PubMed - in process]
    Last edited by Scout; 02-Aug-2006, 13:30. Reason: spelling

  • #2
    Great post,
    I have known this for ages but it's great that these type of study confirms the need to have non-preserved options available for fragile eyes, frequent use, etc...
    steroids and antibiotics should exists in PF solutions so imagine DE drops.
    of course BAC is particlarly dangerous, but there are others...
    I'm glad there is an increased awareness of this problem.
    Take care


    • #3
      I'm posting this here too... on BAC specifically

      study on BAC (benzalkonium)
      take care K

      Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication.

      Comparison of the Short-Term Effects on the Human Corneal Surface of Topical Timolol Maleate With and Without Benzalkonium Chloride.

      Original Articles
      Journal of Glaucoma. 12(6):486-490, December 2003.
      Ishibashi, Takeshi MD; Yokoi, Norihiko MD, PhD; Kinoshita, Shigeru MD, PhD

      Purpose: To compare the short-term effects of timolol maleate with and without preservative (0.005% benzalkonium chloride) on pre-corneal tear film stability and corneal epithelial barrier function.

      Subjects and Methods: The study population consisted of 20 healthy volunteers. To obtain baseline values, 7 days before the experiment the non-invasive breakup time of the pre-corneal tear film was measured using a tear specular microscope; corneal fluorescein uptake was measured with a fluorophotometer. Unpreserved or preserved 0.5% timolol was applied to one eye; the contralateral eye was exposed to the other drug. At 30 minutes after instillation, the pre-study tests were repeated.

      Results: Preserved timolol did, while unpreserved timolol did not, significantly reduce the non-invasive breakup time from the baseline values (baseline and post-exposure values 11.4 and 6.8 seconds, respectively, P = 0.008 for preserved timolol, and 11.7 vs. 11.0 seconds, P = 0.55 for unpreserved timolol). Corneal fluorescein uptake, on the other hand, was significantly increased upon exposure to either preserved or unpreserved timolol (baseline and post-exposure values 37.5 and 82.0 ng/ml, P < 0.001 for preserved timolol, and 35.4 vs. 57.6 ng/ml, P < 0.001 for unpreserved timolol). Preserved timolol exerted the greater effect (P = 0.028).

      Conclusions: Exposure to preserved timolol resulted in significant instability in the pre-corneal tear film. Moreover, it disrupted the corneal epithelial barrier function to a greater degree than unpreserved timolol. The elimination of preservatives may be desirable in efforts to protect the integrity of the corneal surface and its interaction with the tear film.


      • #4
        Saline Nasal Spray preservative toxicity

        I'll see you one and raise you one!

        If any of you use saline nasal spray for your sinuses . . .

        American Journal of Rhinology. 2006 May-Jun;20(3):243-\

        Benzalkonium chloride and nasal mucociliary clearance: a randomized, placebo-controlled, crossover, double-blind trial.

        * Rizzo JA,
        * Medeiros D,
        * Silva AR,
        * Sarinho E.

        Research Center in Allergy and Immunology, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil.

        BACKGROUND: Benzalkonium chloride (BKC) has been considered an innocuous preservative for prescription drugs. METHODS: We performed a double-blind, placebo-controlled, randomized, crossover, single-center trial with a 3-week washout period in 43 healthy volunteers comparing the effect of 3-week use of saline nasal spray containing BKC 0.01% to preservative-free saline t.i.d. on nasal mucociliary clearance rate. Evaluations were done at the beginning and the end of each period by gamma-scintigraphy with technetium99m-labeled strontium. RESULTS: Nasal mucociliary clearance rate was significantly impaired by BKC with a difference of 1.23 mm x min(-1) (p < 0.01) between periods. CONCLUSION: BKC in the concentration used in nasal preparations impaired mucociliary clearance in healthy individuals after 3 weeks of use. Presently, when preservative-free alternatives are available, BKC could be a risk without benefit.

        PMID: 16871922 [PubMed - in process]


        • #5
          I think I read this one posted somewhere on DEZ, but here it is again:

          Molecular Vision. 2006 Apr 26;12:415-21.

          Impact of short-term exposure of commercial eyedrops preserved with benzalkonium chloride on precorneal mucin.

          * Chung SH,
          * Lee SK,
          * Cristol SM,
          * Lee ES,
          * Lee DW,
          * Seo KY,
          * Kim EK.

          Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.

          PURPOSE: The aim of this study is to investigate the short-term effects of benzalkonium chloride (BAC), a preservative used in many ophthalmic topical solutions, on precorneal mucin in humans. METHODS: Immortalized human corneal-limbal epithelial (HCLE) cells were exposed to eyedrops containing BAC solutions at 0.0025% and 0.01% concentrations for a period of 15 min. Human corneal epithelium was acquired with consent, as a byproduct of elective excimer photorefractive keratectomy procedures after application of Ocuflox eyedrops (0.3% ofloxacin with 0.0025% BAC) for 1 week before surgery. The relative expression of the MUC1 and MUC16 mucin gene was determined by conventional and real-time reverse transcription-polymerase chain reaction (RT-PCR). Monoclonal antibodies for MUC1 (HMFG-1) and MUC16 (OC125) were used in western blot analysis to detect MUC1 and MUC16. Human corneas exposed to 0.01% BAC solutions were examined by transmission electron microscopy. RESULTS: The expression of MUC1 and MUC16 gene transcripts was not changed after exposure to BAC in HCLE cells and human corneal epithelium. However, MUC1 and MUC16 were reduced after exposure to BAC in HCLE cells and human corneal epithelium. Transmission electron microscopy of the anterior corneal surface revealed fixation of the mucous layer after exposure to 0.01% BAC for 5 or 15 min; prolonged exposure (60 min) to 0.01% BAC destroys the mucous layer. CONCLUSIONS: This study demonstrates that short-term exposure to BAC can alter the precorneal mucin.

          PMID: 16688112 [PubMed - indexed for MEDLINE]


          • #6
            an oldie to show this is not exactly news but still labs are unwilling to face it.

            British Journal of Ophthalmology, 1975, Vol 59, 667-669


            Effect of benzalkonium chloride on the stability of the precorneal tear film in rabbit and man
            WS Wilson, AJ Duncan and JL Jay

            Benzalkonium chloride, a surface-active preservative commonly used in eyedrop preparations, has been shown to hasten the drying of the precorneal tear film. In the rabbit, 0.01 per cent benzalkonium (the concentration usually employed as a preservative) shortened the time required for the appearance of dry spots on the corneal surface by a factor of about four. In man, an approximately twofold hastening was demonstrated. This effect is thought to preclude the use of this substance as a preservative in eyedrop preparations for use as local anaesthetics.


            1975 by the British Journal of Ophthalmology


            • #7
              I'll raise one as well... too bad for Neil who is travelling around in Europe and who will join in this game later on... I hope (By the way, he's happy travelling despite the "DE extra effort" according to his last message).
              Take care

              Preservative-free artificial tear preparations. Assessment of corneal epithelial toxic effects
              G. J. Berdy, M. B. Abelson, L. M. Smith and M. A. George
              Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston.

              Scanning electron microscopy was used to evaluate the corneal epithelium of rabbit eyes after administration of two preservative-free ocular lubricants, preservative-free artificial tear-1 (Hypotears PF) and preservative-free artificial tear-2 (Refresh), and 0.02% benzalkonium chloride. Animals were randomly assigned to either mild or exaggerated use regimens. A quantitative rating system was used to assess epithelial damage. With mild use, scanning electron microscopy revealed normal epithelial morphologic characteristics for both preservative-free artificial tear solutions (mean relative damage score, solution 1, 0.75 +/- 0.16; solution 2, 1.02 +/- 0.23), which were not significantly different from eyes treated with phosphate-buffered saline (1.38 +/- 0.38) or a mild dosage regimen of 0.02% benzalkonium chloride (1.20 +/- 0.12). Exaggerated use with preservative-free artificial tear solutions (solution 1, 1.31 +/- 0.21; solution 2, 1.35 +/- 0.08) induced minimal damage that was not different from control eyes treated with phosphate-buffered saline (1.26 +/- 0.13). Compared with an exaggerated use of 0.02% benzalkonium chloride (4.0 +/- 0.16), both preservative-free artificial tear solutions induced significantly less epithelial damage (P = .0001). These results suggest that with frequent-dosage regimens, preservation-free artificial tear solutions-1 and -2 are free of the toxic effects associated with preserved solutions.


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