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Cornea: Mélody Dutot, François Pouzaud, Isabelle Larosche, Françoise Brignole-Baudouin, Jean-Michel Warnet, and Patrice Rat Fluoroquinolone Eye Drop–Induced Cytotoxicity: Role of Preservative in P2X7 Cell Death Receptor Activation and Apoptosis Invest. Ophthalmol. Vis. Sci. 2006; 47: 2812-2819 [Abstract] [Full text] [PDF]

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Fluoroquinolone Cytotoxicity

Vincenzo Papa   (8 February 2007)

Author Response: Fluoroquinolone Cytotoxicity

Patrice Rat   (8 February 2007)

Fluoroquinolone Cytotoxicity 8 February 2007
Vincenzo Papa Send letter to journal: Re: Fluoroquinolone Cytotoxicity dchin{at}arvo.org Vincenzo Papa	We read with interest the article published in the July issue of IOVS by Dutot et al.1 entitled "Fluoroquinolone eye drop-induced cytotoxicity: role of preservative in P2X7 cell death receptor activation and apoptosis," which investigated whether the fluoroquinolone ocular toxicity is attributable to the antibiotic or to the preservative included in ophthalmic formulations. The authors conclude that "fluoroquinolone eye-drop cytotoxicity seems to be mainly caused by the preservative." Furthermore, they highlight the "important difference between cellular toxicity of BAC [benzalkonium chloride]-preserved and preservative-free fluoroquinolone medications." We have recently shown that the toxic effect of commercial ophthalmic antibiotics preserved with BAC is almost comparable to that of BAC alone, suggesting a major role of preservative in this regard.2 However, we would like to bring to your attention that several pieces of evidence suggest also a direct cytotoxic effect of all the currently available ophthalmic fluoroquinolones. In our experience, ofloxacin was highly toxic in vitro to several human ocular cells in culture, such as keratocytes2 or conjunctival and corneal epithelial cells.3 Similar conclusions have been drawn for ciprofloxacin and norfloxacin,4 levofloxacin, gatifloxacin, and moxifloxacin (Nakamura M, et al. IOVS 2002;43:ARVO E-Abstract 4216; Skelnik DL, et al. IOVS 2003;44:ARVO E-Abstract 4739; Chang-Lin J-E, et al. IOVS 2005;46:ARVO E-Abstract 4882). Our feeling is that the incubation time used by Dutot (15 minutes)1 was sufficient to demonstrate the toxicity of BAC but not that of the antibiotic. In our experience, the demonstration of fluoroquinolone toxicity becomes evident only after at least 4 hours incubation.2 Vincenzo Papa, Medical Department, SIFI S.p.A., Catania, Italy Andrea Leonardi, Department of Neuroscience, Ophthalmology Unit, University of Padova, Italy References 1. Dutot M, Pouzaud F, Larosche I, Brignole-Baudouin F, Warnet J-M, Rat P. Fluoroquinolone eye drop-induced cytotoxicity: role of preservative in P2X7 cell death receptor activation and apoptosis. Invest Ophthalmol Vis Sci. 2006;47:2812-2819. 2. Leonardi A, Papa V, Fregona I, Russo P, De Franchis G, Milazzo G. In vitro effects of fluoroquinolone and aminoglycoside antibiotics on human keratocytes. Cornea. 2006;25:85-90. 3. Papa V, Leonardi A, Getuli C, Pacelli V, Russo P, Milazzo G. Effect of ofloxacin and netilmicin on human corneal and conjunctival cells in vitro. J Ocul Pharmacol Ther. 2003;19:535-545. 4. Seitz B, Hayashi S, Wee WR, LaBree L, McDonnell PJ. In vitro effects of aminoglycosides and fluoroquinolones on keratocytes. Invest Ophthalmol Vis Sci. 1996;37:656-665.
Author Response: Fluoroquinolone Cytotoxicity 8 February 2007
Patrice Rat Send letter to journal: Re: Author Response: Fluoroquinolone Cytotoxicity melhorizon{at}free.fr Patrice Rat	Benzalkonium chloride cytotoxicity: first step of fluoroquinolone eye drops intolerance Fluoroquinolones are now known to induce toxicity on different tissues; our team showed that high doses of fluoroquinolones (higher than those used in ophthalmology) lead to cytolytic oxidative stress after a 72-hour incubation time on tenocytes.1 Studies cited by Papa showing fluoroquinolone-induced cytotoxicity were performed using several hours (up to 48 hours); over some period of time and at high concentrations, any xenobiotic has a cytotoxic potential, which is far from physiological conditions of eye drop medication. Our study concerning the cytotoxic effect of preserved ofloxacin versus unpreserved ofloxacin on ocular cells was performed using a short incubation time (15 minutes) to be closer to the physiological conditions of eye drops topical administration. Our results then suggested that fluoroquinolone eye drops intolerance is mainly due to the preservative (benzalkonium chloride, BAC) and not the fluoroquinolone. Numerous papers already reported on BAC toxicity.2,3,4 BAC has even been implicated in antiglaucoma eye drops intolerance.5 Our paper then concluded that BAC could be the first step of fluoroquinolone eye drops intolerance since it induced conjunctival and corneal cytotoxicity prior to any effect of the fluoroquinolone. Mélody Dutot1 François Pouzaud1 Isabelle Larosche1 Françoise Brignole-Baudouin1,2,3 Jean-Michel Warnet1,2,3 Patrice Rat1,2,3 1Laboratoire de Toxicologie, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes-Paris, Paris, France 2INSERM U598, Institut Biomédical des Cordeliers, Paris, France 3Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France References 1. Pouzaud F, Bernard-Beaubois K, Thevenin M, Warnet JM, Hayem G, Rat P. In vitro discrimination of fluoroquinolones toxicity on tendon cells: involvement of oxidative stress. J Pharmacol Exp Ther. 2004;308:394-402. 2. De Saint Jean M, Brignole F, Bringuier AF, Bauchet A, Feldmann G, Baudouin C. Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells. Invest Ophthalmol Vis Sci. 1999;40:619-630. 3. Debbasch C, Brignole F, Pisella PJ, Warnet J-M, Rat P, Baudouin C. Quaternary ammoniums and other preservatives' contribution in oxidative stress and apoptosis on Chang conjunctival cells. Invest Ophthalmol Vis Sci. 2001;42:642-652. 4. Xue, Y, Hieda, Y, Kimura, K, Takayama, K, Fujihara, J, Tsujino, Y. Kinetic characteristics and toxic effects of benzalkonium chloride following intravascular and oral administration in rats. J Chromatogr B Analyt Technol Biomed Life Sci. 2004;811:53-58. 5. De Saint Jean M, Debbasch C, Brignole F, Rat P, Warnet JM, Baudouin C. Toxicity of preserved and unpreserved antiglaucoma topical drugs in an in vitro model of conjunctival cells. Curr Eye Res. 2000;20:85-94.