Transcript Cytotoxicity of topical medications after cataract surgery

Cytotoxicity of topical medications
after cataract surgery for human
corneal endothelial/epithelial cells,
and conjunctival epithelial cells
1)Masahiko
Ayaki, MD, 1)Shigeo Yaguchi, MD, PhD, 2)Atsuo
Iwasawa, PhD, 3)Ryohei Koide, MD PhD.
1)Department
of Ophthalmology and 2) Department of Clinical
Pathology, Fujigaoka Hospital, Showa University School of
Medicine, 3) Department of Ophthalmology, Showa University
School of Medicine
Authors have no financial interest.
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Purpose and Methods
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Purpose
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Cataract surgeons sometimes encounter unexplained persistent corneal edema after surgery
and drug toxicity may be one of the potential etiologies. The purpose of this study is to
evaluate cytotoxicity of topical medications to corneal and conjunctival cells.
Cells
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Human corneal endothelial cells (primary culture from eye bank eyes)
SIRC (human corneal epithelial cells, ATCC CCL-60,ATCC; American tissue and Cells
Corporation)
Chang conjunctiva (human conjunctival epithelial cells, ATCC CCL-20.2, ATCC)
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Cell survival was measured using the WST-1 assay for endothelial cells and the MTT
assay for epithelial cells after 48 hours exposure at 10, 100, and 1000-fold dilution.
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Culture method (reference)
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Masahiko Ayaki, Shigeo Yaguchi, Ryohei Koide, Atsuo Iwasawa Cytotoxicity of ophthalmic
solutions with and without preservatives for human corneal endothelial cells, epithelial cells,
and conjunctival epithelial cells. Exp Clin Ophthalmol, 2008：36（6）；553-559
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Tested ophthalmic solutions
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Antibiotics
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Anti-inflammatory; Non steroid
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diclofenac (DiclodR, DiclostarR, Nitten, Japan, DiclostarRPF)
bromfenac (BronuckR , Senjyu)
pranoprofen (NiflanR, Senjyu)
Anti-inflammatory; Steroid
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gatifloxacin (GatifloR , Senjyu, Japan)
moxifloxacin (VegamoxR , Alcon)
levofloxacin (CravitR , Santen)
norfloxacin (NofloR, Banyu, Japan)
tosufloxacin (TosufloR, Nidek)
dibekacin (PanimycinR, Meiji, Japan)
cefmenoxime( BestronR, Kaken, Japan)
betamethasone (RinderonR, Shinogi, Japan, RinbetaR, Nitten, Japan, RinbetaRPF)
betamethason&fradiomycin (RinderonR A, Shionogi)
fluolomethorone (FlumethoronR, Santen)
Topical anesthetics
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oxybuprocain (BenoxilR, Santen)
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Preservatives in Tested Ophthalmic Solutions
Trade Name
ActiveComponent
Preservative
Rinderon
Betamethason
Methyl Para, Propyl Para
Rinderon A
Betamethason,
Fradiomycin
Methyl Para, Propyl Para
Rinbeta
Betamethason
(Generic)
Boric acid, EDTA
RinbetaPF
Betamethason (Generic
with filter in the tip)
Removed by filtration
Flumethoron 0.1%
Fluolomethoron 0.1%
BAK, Polysorbate 80,
EDTA
Flumethoron 0.02%
Fluolomethoron 0.02%
BAK, Polysorbate 80,
EDTA
Diclod (Voltaren)
Diclofenac
Chlorobutanol,
Polysorbate 80 Boric Acid
Diclostar
Diclofenac (Generic)
Boric Acid, EDTA
Diclostar PF
Diclofenac (Generic with
filter in the tip)
Removed by filtration
Bronuck (Zybrom)
Bromfenac
BAK, Polysorbate 80
Niflan
Pranoprofen
BAK, Polysorbate 80,
Boric Acid, EDTA
Benoxil
Oxybuprocain
BAK, EDTA
Trade Name
ActiveComponent
Preser
vative
Levoquin,
Cravit
Levofloxacine
No
Vegamox
Moxifloxacin
No
Zymer, Gatiflo
Gatifloxacin
No
Noflo
Norfloxacin
No
Tosflo
Tosufloxacin
No
Panimycin
Dibekacin
BAK
Bestron
Cefmenoxime
Methyl
Para,
Propyl
Para,
EDTA,
Boric
acid
BAK=Benzalkonium Chloride
Para= Parahydroxybenzoate
EDTA=ethylene-diaminetetraacetic
acid (edetic acid)
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Results :Corneal Endothelia
Antibiotics (10-fold dilution, 48 hours exposure)
Cell survival (%)
140
120
100
80
60
40
20
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Levofloxacin Moxifloxacin Gatifloxacin
Cell survival (%)
140
Norfloxacin
Tosufloxacin
Panimycin
Bestron
Anti-inflammatory (10-fold dilution, 48 hours exposure)
120
100
80
60
40
20
0
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Results : Epithelia-Antibiotics
Antibiotics (Corneal epithelia, 10-fold dilution, 48 hours exposure)
Cell survival (%)
140
120
100
80
60
40
20
0
Levofloxacin Moxifloxacin Gatifloxacin
Norfloxacin
Tosufloxacin
Dibekacin
Cefmenoxime
Sulperin
Antibiotics (Conjunctival Epithelia, 10-fold dilution, 48 hours exposure)
Cell survival (%)
140
120
100
80
60
40
20
0
Levofloxacin
Moxifloxacin Gatifloxacin
Norfloxacin
Tosufloxacin
Panimycin
Bestron
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Results : Epithelia-Antiinflammatory
Antiinflamatory (Corneal epithelia, 10-fold dilution, 48 hours exposure)
Cell survival (%)
140
120
100
80
60
40
20
0
Antiinflammatory (Conjunctival Epithelia , 10-fold dilution, 48 hours exposure)
Cell survival (%)
140
120
100
80
60
40
20
0
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Summary of Results
• Most of tested solutions had corneal and
conjunctival toxicity in 10-fold dilution
(steroids < antibiotics < non steroidal antiinflammatory medications).
• It decreased (cell survival > 80%) after
1000-fold or more dilution and seemed to
depend mostly on the components of
ophthalmic solution such as benzalkonium
chloride.
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Cause of postoperative corneal edema
(Liu, JCRS, 2001)
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1.Preexisting endothelial damage
– (a) Fuchs‘ corneal endothelial dystrophy or advanced cornea guttata
– (b) Posterior polymorphous corneal dystrophy
– (c) Low endothelial cell count
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2.Surgical trauma
– (a) Cavitational energy
– (b) Direct touch by instruments or intraocular lens
– (c) Turbulent flow of irrigation solution
– (d) Lens or lens particle contact with the cornea
– (e) Repeated anterior chamber collapse
– (f) Descemet‘s detachment
– (g) Corneal burn
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3.Use of unphysiologic or toxic intraocular fluids and drugs
– (a) Hypoosmotic (under 200 mOsm) or hyperosmotic(over 400 mOsm) fluids
– (b) Low or high pH value (under 6.8 or over 8.2)
– (c) Lack of calcium in irrigating fluid
– (d) Toxic concentrations of drugs ( antibiotics, local anesthetics, miotics)
– (e) Detergents and sterilizing agents
– (f) Preservatives
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4.Postoperative conditions
– (a) Excessive inflammation
– (b) High intraocular pressure
– (c) Adherence of vitreous, iriis, or lens capsule
– (d) Epithelial downgrowth
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Conclusions
• The postoperative topical medications had cytotoxicity
and those preserved with benzalkonium showed higher
toxicity than those without them. Considering actual
concentration at corneal endothelium, they do not seem
to cause endothelial damage.
• Correspondence
• Masahiko Ayaki MD, Showa University School of
Medicine, Yokohama, Japan
• [email protected]
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