Of
interest:
January 2000 Pharmacology
and Toxicology Guidance for Industry Photosafety Testing.
U.S. Department of Health and Human Services; Food and Drug Administration;
Center for Drug Evaluation and Research (CDER)
See
also:
A
partial list of Phototoxic Pesticides -
Light-dependent peroxidizing herbicides
(LDPHs)
KEYWORDS:
photocarcinogenic
photoclastogenic
photocytotoxic
photogenotoxic
photomutagenic
phototoxic
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10047594
Archives
of Environmental Contamination and Toxicology 1999:36:270-280.
Toxicity
and phototoxicity of mixtures of highly lipophilic PAH
compounds in marine sediment: can the [sigma]PAH model
be extrapolated?
Boese,
Bruce L, Robert J. Ozretich, Janet O. Lamberson, Richard
C. Swartz, Judith Pelletier, F.A. Cole, J. Pelletier,
and J. Jones.
Coastal
Ecology Branch, Western Ecology Division, U.S.
Environmental Protection Agency, National Health
and Environmental Effects Research Laboratory, Hatfield
Marine Science Center, 2111 SE Marine Science Dr., Newport,
Oregon 97365-5260, USA.
The
additivity of toxic units was tested using sediments contaminated
with mixtures of highly lipophilic (log Kow>4.5) parent
and alkylated PAHs. The direct toxicity and photoinduced
toxicity of these mixtures were examined in standard 10-day
sediment toxicity tests using the infaunal amphipod Rhepoxinius
abronius, with mortality and survivors’ ability
to rebury as endpoints. Survivors of the initial 10 day
tests were then exposed for 1 h to ultraviolet (UV) radiation
and the results compared to initial (10 day) endpoints.
Tissue residues and lipids were measured and biota-sediment
accumulation factor (BSAF) values determined. The results
indicated that the bioaccumulated contaminants were not
initially toxic, however, they were highly phototoxic.
Although the summed toxic units of these contaminants
appeared to be nonadditive, additivity was not disproved
as inaccuracies in extrapolating the Kow-LC50 QSAR or
insufficient exposure duration might also have accounted
for the observed results. Critical body residue (CBR)
estimates for R. abronius were similar while BSAF values
were much larger (10X) in comparison to other studies,
which used amphipods and PAHs. The phototoxicity of mixtures
of contaminants were similar to the phototoxicity of single
contaminants when expressed on a molar basis, which
suggests that phototoxicities may be roughly additive.
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10667924
Archives
of Environmental Contamination and Toxicology 2000
Apr;38(3):274-82.
Phototoxic
evaluation of marine sediments collected from a PAH contaminated
site.
Boese
BL, Ozretich RJ, Lamberson JO, Cole FA, Swartz RC, Ferraro
SP.
Coastal
Ecology Branch, Western Ecology Division, U.S.
Environmental Protection Agency, National Health
and Environmental Effects Research Laboratory, Hatfield
Marine Science Center, 2111 SE Marine Science Dr., Newport,
Oregon 97365-5260, USA.
The
phototoxicity potential of PAH-contaminated field sediment
was evaluated and compared to standard sediment toxicity
test results. Marine sediments were collected from 30
sites along a presumed PAH sediment pollution gradient
in Elliot Bay, WA. Standard 10-day acute and 28-day chronic
sediment toxicity tests were conducted with the infaunal
amphipods Rhepoxynius abronius and Leptocheirus plumulosus
using mortality and the ability to rebury as endpoints.
The survivors of these tests were then subjected to 1-h
exposures to UV radiation with mortality and reburial
again determined. The most highly toxic sediments identified
in these experiments were evaluated further for toxicity
and phototoxicity by serially diluting them with uncontaminated
sediment and repeating the toxicity tests. Standard 10-day
toxicity test results indicated that over 70% of the sites
sampled in Elliot bay exhibited measurable toxicity with
nine sites being highly toxic to both species of amphipods.
Result of standard 28-day chronic sediment toxicity tests
were similar. In contrast, almost all of the sites were
found to be highly phototoxic. Results
indicated that exposure to UV increased toxicity five
to eightfold. This suggests that standard toxicity
tests underestimate the potential ecological risk of PAH-contaminated
sediments in animals exposed to sunlight. However, only
when PAH contamination was between 0.05 and 1.0 toxic
units would conducting a phototoxicity evaluation add
information to that gained from conducting a standard
sediment toxicity test alone.
|
Toxicology
in Vitro - Volume 15, Issues 4-5 , August-October 2001,
Pages 585-590
Session 9: Education, Validation and Regulatory
Issues
Lessons learned from validation of in vitro toxicity test:
from failure to acceptance into regulatory practice
H.
Spielmann, and M. Liebsch
National
Centre for Documentation and Evaluation of Alternative
Methods to Animal Experiments (ZEBET) at the Federal Institute
for Health Protection of Consumers and Veterinary Medicine
(BgVV), Berlin, Germany
Excerpts:
... Phototoxicity
is an acute reaction, which can be induced by a single
treatment with a chemical and UV or visible radiation.
As no standard guideline for the testing of photoirritation
potential, either in vivo or in vitro, had been accepted
for regulatory purposes at the international level by
the OECD, in 1991 the European Commission (EC) and the
European Cosmetics, Toiletry and Perfumery Association
(COLIPA) established a joint programme on developing and
validating in vitro photoirritation tests. In the first
phase of the study, which was funded by DG XI of the EC
and co-ordinated by ZEBET, in vitro phototoxicity tests
established in laboratories of the cosmetics industry
were evaluated, and a new assay, the
3T3 NRU PT test, which is a photocytotoxicity test using
the mouse fibroblast cell line 3T3 and neutral red uptake
(NRU) as the endpoint for cytotoxicity.
In
the prevalidation study, which was conducted with 20 test
chemicals (11 phototoxic and nine non-phototoxic ones)
quite unexpectedly, the 3T3 NRU PT in vitro phototoxicity
test was the only in vitro test in which all of the test
chemicals were correctly identified as phototoxic or non-phototoxic
(Spielmann et al., 1994a). Independently of this prevalidation
exercise, a laboratory in Japan subsequently obtained
the same correct results in the 3T3 NRU PT, when testing
the same set of 20 test chemicals.
In
the second phase of the study, which was funded by ECVAM
and co-ordinated by ZEBET, the 3T3 NRU PT test was validated
with 30 carefully selected test chemicals in 11 laboratories
in a blind trial on the 3T3 NRU PT test. A special ECVAM
workshop was held to independently select a representative
set of test chemicals covering all major classes of phototoxins,
selected according to results from standardised photopatch
testing in humans (Spielmann et al., 1994b). The results
obtained in this in vitro test under blind conditions
were reproducible, and the correlation between in vitro
and in vivo data was almost perfect ( Spielmann et al.,
1998a). Therefore, the ECVAM Scientific Advisory Committee
(ESAC) concluded that the 3T3 NRU PT is a scientifically
validated test which is ready to be considered for regulatory
acceptance ( Balls and Corcelle, 1998).
However,
the EU expert committee on the safety of cosmetics, the
Scientific Committee on Cosmetology and Non-Food-Products
(SCCNFP), criticised the fact that there was an insufficient
number of UV-filter chemicals (widely used as sunblockers)
tested in the formal validation study. In the blind trial
on UV filter chemicals, which was again funded by ECVAM
and co-ordinated by ZEBET, the phototoxic potential of
all of the 20 test chemicals (10 UV-filter chemicals,
which were non-phototoxic, and 10 phototoxic test chemicals)
was predicted correctly in the 3T3 NRU PT in vitro phototoxicity
test (Spielmann et al., 1998b).
Therefore
in 1998 the EU, having accepted the 3T3 NRU PT test as
the first experimentally validated in vitro toxicity test
for regulatory purposes, officially applied to the OECD
for worldwide acceptance of this in vitro toxicity test.
Early in 2000 the European Commission has officially accepted
and published the 3T3 NRU PT phototoxicity test in Annex
V of Directive 67/548 EEC on the Classification, Packaging
and Labelling of Dangerous Substances (European Commission,
2000a). Thus, this in vitro test is the first formally
validated in vitro toxicity test that has been accepted
into Annex V, and it is the only phototoxicity that is
accepted for regulatory purposes in Europe. However, the
OECD has so far not taken the acceptance of this in vitro
toxicity test on their agenda during the past 2 years...
|
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15792876
J Photochem Photobiol
B. 2005 Apr 4;79(1):25-34. Epub 2005
Jan 12.
Evaluation of phototoxic and photoallergic
potentials of 13 compounds by different in vitro and in vivo methods.
Neumann
NJ, Blotz A, Wasinska-Kempka G, Rosenbruch M, Lehmann P, Ahr HJ,
Vohr HW.
Hautklinik, Heinrich-Heine-Universitat,
Moorenstrasse 5, 40225 Dusseldorf, Germany.
Phototoxic side effects
of pharmaceutical and cosmetic products are of increasing concern
for patients, dermatologists and the chemical industry. Moreover,
the need of new chemicals and drugs puts pressure on pre-clinical
test methods for side effects, especially interactive adverse-effects
with UV-light. So, the predictive potential of different established
test methods, which are used regularly in our departments in order
to detect the phototoxic potential of chemicals, were analyzed.
Namely the fibroblast 3T3 test, the photo hen's egg test, a guinea
pig test for measuring acute photoreactions, and a modified Local
Lymph Node Assay, the Integrated Model for the Differentiation
of Skin Reactions. Various agents with different photoreactive
potential were tested: quinolones like Bay y 3118, ciprofloxacin,
enoxacin, lomefloxacin, moxifloxacin, ofloxacin, sparfloxacin,
as well as promethazine, chlorpromazine, 8-methoxypsoralen and
olaquindox serving as control. Special emphasis was taken to evaluate
the capability of the employed test procedures to predict phototoxic
side effects in patients. Following our results, both in vitro
assays were useful tools to detect photoirritancy while the photoallergic
potentials of tested compounds were exclusively detected by an
in vivo assay. As long as no in vitro model for photoallergy is
available, the UV-IMDS should be considered to evaluate photoallergic
properties of a supposed photoreactive agent.
PMID: 15792876
[PubMed - in process]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14769204
Acta Pharmacol Sin. 2004 Feb;25(2):171-5.
Compare two methods of measuring DNA damage
induced by photogenotoxicity of fluoroquinolones.
Zhang T, Li JL, Xin J, Ma XC, Tu ZH.
State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Shanghai Institute for Biological Sciences, Chinese
Academy of Sciences, Shanghai 201203, China.
AIM: To compare two methods of measuring DNA damage induced by
photogenotoxicity of fluoroquinolones (FQ).
METHODS: Lomefloxacin (LFLX), sparfloxacin (SPFX), ciprofloxacin
(CPFX), and levofloxacin (LELX) were tested by comet assay and
photodynamic DNA strand breaking activity under the different
conditions of UVA irradiation.
RESULTS: In comet assay, photogenotoxicity
was evident at SPFX 1 mg/L, LFLX 5 mg/L, and CPFX 5 mg/L, and
LELX 10 mg/L. In photodynamic DNA strand-breaking activity,
SPFX and LFLX induced the conversion of the supercoiled form into
the nicked relaxed form at 10-50 micromol/L, while CPFX at 25
micromol/L and LELX at 50 micromol/L.
CONCLUSION: There were good correlations between the two methods
to detect DNA damage induced by phototoxicity of fluoroquinolones.
Photodynamic DNA strand breaking activity was a good method to
detect DNA damage induced by photogenotoxicity of fluoroquinolones
as well as comet assay.
PMID: 14769204 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14706512
Mutat Res. 2004 Jan;566(1):65-91.
Photochemical genotoxicity: principles and test methods. Report
of a GUM task force.
Brendler-Schwaab S, Czich A, Epe B, Gocke
E, Kaina B, Muller L, Pollet D, Utesch D.
Toxicology, Bayer AG, D-42096 Wuppertal,
Germany. susanne.brendler-schwab.sb@bayer-ag.de
In recent years, assessing the photogenotoxic potential of a
compound became an issue for certain drugs and cosmetical products.
Therefore, existing methods performed according to international
guidelines (e.g. OECD guidelines) were adapted to the use of concurrent
UV-visible (UV-Vis) light irradiation for the assessment of photomutagenicity/photogenotoxicity.
In this review, photobiological bases of the processes occurring
in the cell after irradiation with UV- and/or visible (vis)-light
as well as a compilation of testing methods is presented. Methods
comprise cell free investigations on naked DNA and in vitro methods,
such as the photo-Ames test, the photo-HPRT/photo-mouse lymphoma
assay (MLA), the photo-micronucleus test (MNT), the photo-chromosomal
aberration test (CA) and the photo-Comet assay. A compilation
of the currently available international literature of compounds
tested on photogenotoxicity is given for each method. The state
of the art of photogenotoxicity testing as well as the rational
for testing are outlined in relation to the recommendations reached
in expert working groups at different international meetings and
to regulatory guidance papers. Finally, photogenotoxicity
testing as predictor of photocarcinogenicity and in the light
of risk assessment is discussed.
Publication Types:
• Review
• Review, Tutorial
PMID: 14706512 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12547282
Mutat Res. 2003 Feb 5;535(1):43-54.
Phototoxicity and photogenotoxicity of
nine pyridone derivatives.
Gocke E, Chetelat AA, Csato M, McGarvey
DJ, Jakob-Roetne R, Kirchner S, Muster W, Potthast M, Widmer U.
Mutagenicity Group, PRNS, F Hoffmann-La
Roche Ltd, CH 4070 Basel, Switzerland. elmar.gocke@roche.com
Nine structurally related pyridone derivatives were assayed for
photogenotoxicity and phototoxicity in the Ames test, the chromosomal
aberration test in V79 cells and the neutral red uptake (NRU)
test in 3T3 cells. All nine compounds absorb light to a comparable
degree at wavelengths between 380 and 430 nm. Seven of the nine
compounds were found to produce high quantities of singlet oxygen
(1O(2)) upon irradiation in the presence of oxygen. These seven
compounds were highly phototoxic in the NRU test, three were clearly
and two were marginally photomutagenic in the Ames test, five
were assessed as clearly and two as equivocally photoclastogenic
in the chromosomal aberration test. Two compounds showed substantially
lower 1O(2) yields. The pyridone ring of these two compounds is
attached to a non-aromatic ring, while for the seven other compounds
the chromophore system including the pyridone ring consists of
two or three aromatic rings. One of the two compounds with low
1O(2) yields was distinctly less phototoxic and did not induce
photogenotoxic effects. The other, structurally an indolo derivative
and not the common thieno derivative, was, however, similarly
phototoxic as the seven compounds with high 1O(2) quantum yield
and was also clearly photogenotoxic indicating that different
action pathways, not involving singlet oxygen, have to be considered
at least for this compound. Copyright 2002 Elsevier Science B.V.
PMID: 12547282 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11837431&dopt=Abstract
J Environ Qual 2002 Jan-Feb;31(1):268-74
Photochemistry
and photoinduced toxicity of acifluorfen,
a diphenyl-ether herbicide.
Scrano L, Bufo SA, D'Auria M, Meallier
P, Behechti A, Shramm KW.
Dipartimento di Produzione Vegetale, Universita della Basilicata,
Potenza, Italy.
Photochemistry
studies can be helpful in assessing the environmental fate of
chemicals. Photochemical reactions lead to the formation of by-products
that can exhibit different toxicological properties from the original
compound. For this reason the photochemical behavior of the herbicide
acifluorfen (5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic
acid) in the presence of different solvents was studied. Photochemical
reactions were carried out using a high-pressure mercury arc and
a solar simulator. Kinetic parameters and quantum yields were
determined. The identification of photoproducts
was performed by mass spectrometry and [1H] nuclear magnetic resonance
(NMR). Nitrofluorfen,hydroxy-nitrofluorfen,
2-chloro-4-(trifluoromethyl)phenol, 5-trifluoromethyl-5'-nitrodibenzofuran,
and other derivatives were identified. The photochemical reactions
were also carried out in the presence of either a singlet or a
triplet quencher, and in the presence of either a radical initiator
or a radical inhibitor. Substances used as inhibitors of the excited
levels T1 and S1 showed that photodegradation of acifluorfen begins
from a singlet state S1 through a pi,pi* transition. The role
of free radicals in the photodegradation of acifluorfen was determined
and a radical mechanism was proposed. Toxicity tests against Daphnia
magna Strauss showed that acifluorfen was not toxic at a concentration
of 0.1 mM; however, photoproducts formed
after 36 h of UV exposure of the herbicide induced a remarkable
toxicity to the test organism.
PMID: 11837431 [PubMed
- indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12160891
Mutat Res. 2002 Aug 26;519(1-2):49-66.
Use of the photo-micronucleus assay in
Chinese hamster V79 cells to study photochemical genotoxicity.
Kersten B, Kasper P, Brendler-Schwaab SY,
Muller L.
Federal Institute for Drugs and Medical Devices, Friedrich-Ebert-Allee
38, D-53113 Bonn, Germany. kersten@molgen.mpg.de
Photochemical genotoxicity can be detected
using appropriately adapted versions of most of the standard in
vitro genotoxicity assays. The most sensitive approach to detect
potentially photogenotoxic agents seems to be the investigation
of DNA damage (DNA strand breakage, chromosomal aberrations, micronuclei)
in mammalian cells in vitro. In a previous paper, we proposed
the use of the micronucleus assay in Chinese hamster V79 cells
for this purpose. This assay was found suitable to detect various
photogenotoxic compounds with different photoactivation mechanisms.
In order to extend the experimental experiences with this assay,
we present here further data from a screening mode testing of
16 different potential photosensitizers. The photoclastogenic
and photocytotoxic potential of the compounds was investigated
concomitantly. So far, all substances detected in the photo-micronucleus
assay as photogenotoxins also exhibited photocytotoxic properties
but not vice versa. Among the compounds tested in the present
study, tiaprofenic acid, 5-MOP, angelicin, nitrazepam, bendroflumethiazide,
and dacarbazine were photogenotoxic and photocytotoxic. Further,
6-mercaptopurine, a metabolite of azathioprine was positive for
both endpoints, whereas azathioprine was found negative. Azathioprine
seems to be an example of a compound which lacks photo(geno)toxic
properties in vitro but may be converted to a photosensitizer
by enzymatical metabolization. With the results obtained in this
study, the data base for the photo-micronucleus assay was extended
to 35 compounds, which were tested using the same protocol and
the same irradiation conditions. The photogenotoxicity results
of all these compounds are summarized and discussed in correlation
to their different photoactivation mechanisms, photocytotoxicity
and photocarcinogenicity.
PMID: 12160891 [PubMed - indexed for MEDLINE]
Toxicology Letters - Volume 127, Issues 1-3 , 28 February 2002,
Pages 269-277
Clinical toxicological aspects of fluoroquinolones
Ralf Stahlmann
Institute of Clinical Pharmacology and Toxicology, Freie Universität
Berlin, Garystrasse 5, 14195 Berlin, Germany
Reactions of the gastrointestinal tract and the central nervous
system are the most often observed adverse effects during therapy
with fluoroquinolones. Pathogenesis of the neurotoxic effects
of fluoroquinolones could be related to the activation of the
NMDA receptor. Animal experiments as well as clinical experience
show that the cardiotoxic potentials of sparfloxacin and grepafloxacin
are higher than those of the other fluoroquinolones: they cause
QT prolongation at rather low doses thus increasing the risk for
severe arrhythmia (torsades de pointes). Phototoxicity has been
described for all quinolones, but derivatives
with a halogen atom at position 8 show the highest potential for
such reactions (e.g. clinafloxacin). Chondrotoxicity of
quinolones can affect the articular cartilage and the epiphyseal
growth plate in immature animals; the use of these drugs in pediatrics
should be restricted to carefully selected indications (such as
the use of ciprofloxacin in cystic fibrosis). Tendinitis and tendon
ruptures can also be induced by quinolones. Overall, quinolones
are as well tolerated as most other anti-microbial agents. However,
their specific toxic potentials have to be considered when they
are chosen for treatment of bacterial infections.
Toxicology in Vitro - Volume 16, Issue 6 , December 2002,
Pages 683-693
In vitro phototoxic properties of new
6-desfluoro and 6-fluoro-8-methylquinolones
G. Miolo (a), G. Viola (a), D. Vedaldi
(a), F. Dall'Acqua (a), A. Fravolini (b), O. Tabarrini (b)and
V. Cecchetti (b)
(a) Department of Pharmaceutical Sciences, University of Padova
and Center for Chemical Investigation of Drugs (associated to
the National Institute for the Chemistry of Biological Systems-CNR),
via Marzolo 5, Padova, Italy
(b) Department of Chemistry and Technology of Drug, University
of Perugia via del Liceo, Perugia, Italy
Abstract
A representative set of potent antibacterial 6-desfluoro-8-methylquinolones,
in which the C-6 fluorine atom is replaced by –NH2 or –H,
and their 6-fluoro counterparts, were investigated to evaluate
their phototoxic potential and to explore the mechanism behind
their phototoxicity. The capacity to photosensitize biological
substrates (lipids, proteins, DNA) has been analyzed, as well
as their photocytotoxicity on red blood cells and 3T3 murine fibroblasts.
The results obtained show that the quinolones studied are able
to photosensitize red blood cell lysis in an oxygen-dependent
way and induce a high decrease in cell viability after UVA irradiation.
A major correlation with phototoxicity lies in the structure of
the individual antibacterials and their hydrophobicity; in particular,
6-amino derivatives are less phototoxic than corresponding unsubstituted
and fluorinated compounds. Cellular phototoxicity was inhibited
by the addition of free radical and hydroxyl radical scavengers
(BHA, GSH and DMTU), suggesting the involvement of a radical mechanism
in their cytotoxicity. A good correlation was observed between
lipid peroxidation and phototoxicity, indicating that the test
compounds exert their toxic effects mainly in the cellular membrane.
Preliminary experiments on pBR322 DNA show that these derivatives
do not photocleave DNA, differently from the two photogenotoxic
fluoroquinolones, ciprofloxacin and lomefloxacin, used as reference
compounds...
Excerpts:
Photoreactivity is mostly influenced by the substituent at the
C-8 position; in fact, quinolones bearing in that position halogen
atoms, such as fluorine and chlorine, show a relatively high incidence
of phototoxic reactions (Marutani et al., 1993). In keeping
with this structure–activity relationship, the
presence of a fluorine atom at the C-8 position may explain the
high incidence of phototoxic events reported in patients taking
lomefloxacin, fleroxacin and sparfloxacin ( Domagala, 1994).
The current challenge in this field is therefore to develop new
quinolones which cause less phototoxicity.
Previously, some of us have described a new series of quinolones
in which the fluorine atom at C-6 is replaced with a hydrogen
atom or an amino group which showed potent antibacterial activity
(Cecchetti; Cecchetti; Cecchetti and Wise).
Consequently, we felt it would be interesting to determine whether
the lack of C-6 fluorine would reduce phototoxic side-effects.
Therefore, the present paper is aimed at analyzing the phototoxic
properties of some selected 6-unsubstituted-quinolones (1 and
2) and 6-amino- (3 and 4), collectively called 6-desfluoroquinolones,
when compared to their 6-fluorine analogues (5 and 6). This is
done by determining whether phototoxicity is influenced by the
nature of the C-6 substituent, in comparison with two well-known
quinolones, lomefloxacin and ciprofloxacin. In particular, observations
of the in vitro effects on murine erythrocytes, using photohemolysis
as an endpoint, and the evaluation of the cellular phototoxicity
on murine fibroblasts are reported. For this latter experiment,
the MTT test, which yields comparable data to the NR assay (Borenfreund
et al., 1988), was applied to screening the acute toxicity of
test compounds. ...
Discussion
The purpose of this study was to verify whether newly synthesized
8-methylquinolones, exhibiting good antimicrobial activity, possess
the photosensitizing side-effects of classical fluoroquinolones.
Since the test quinolones mainly absorb in the UVA range, fluorescent
UVA tubes were used as irradiation source for studying their relative
phototoxic potency. All test compounds,
both the four 6-desfluoro-8-methylquinolones and the two 6-fluoro
analogues, showed marked photosensitizing properties, with
a rank order of phototoxicity emerging by structure–photoactivity
relationships: F>H>>NH2. This suggests
that the C-6 substituent plays a major role in conferring their
phototoxic properties. Indeed, in this head-to-head comparative
study between desfluoro and fluoro derivatives, which is the first
to our knowledge, it has
been shown that the presence of a fluorine atom in the C-6 position
can enhance phototoxicity. On 3T3 cells, 6-fluoro
derivatives (5 and 6), followed by 6-unsubstituted derivatives
(1 and 2), were highly phototoxic, even at the lowest concentration
(12.5 ) and UVA dose applied (1 J/cm2). The 6-amino derivatives
showed a different behaviour: compound 3 appeared to be endowed
with the lowest phototoxicity among the six derivatives studied,
in good agreement with the photohemolysis experiments. On the
contrary, compound 4 showed considerable phototoxicity in this
model. The particular kinetics exhibited by this compound should
be noted. At low UVA doses it appeared ineffective as the parent
compound 3. However, under increasing irradiation doses, its inherent
toxicity was clearly manifested. This particular behavior parallels
that one exhibited in photodegradation experiments, suggesting
that the phototoxic effects of this compound are probably mediated
by one or more photoproducts formed during irradiation...
Toxicology in Vitro - Volume 15, Issue 6 , December 2001,
Pages 721-727
In vitro method for prediction of the phototoxic
potentials of fluoroquinolones
T. Yamamoto, Y. Tsurumaki, M. Takei, M.
Hosaka and Y. Oomori
Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd,
2399-1, Nogi-Mitarai, Shimotsuga-gun, Tochigi, 329-0114, Japan
The phototoxic potential of eight fluoroquinolones (norfloxacin,
ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin,
sparfloxacin and gatifloxacin) was evaluated by using three in
vitro methods of cytotoxicity against mammalian cells, erythrocyte
lysis and DNA strand breakage. All fluoroquinolones
tested with the exception of gatifloxacin, an 8-methoxy quinolone,
showed DNA strand breaking activities under UV-A irradiation.
Their cytotoxicity against HeLa cells was also enhanced by UV-A
irradiation. In particular, the phototoxic potential of
sparfloxacin, enoxacin and lomefloxacin was high in both methods.
Ofloxacin is very photocytotoxic against HeLa cells, while it
has low potential to cause DNA strand breakage. Norfloxacin, ciprofloxacin
and enoxacin were very photohemolytic, but sparfloxacin was not,
indicating that the in vivo phototoxic potencies of fluoroquinolones
might not be predictable by the photohemolysis study. Gatifloxacin,
a non-phototoxic quinolone, showed no phototoxic potential in
any of these three in vitro tests. These results suggest that
determination of DNA strand breaking activity, combined with cytotoxicity
against mammalian cells, is available to predict the phototoxic
potential of fluoroquinolones without laboratory animals.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11460529&dopt=Abstract
2001
Photochem Photobiol; Jul;74(1):1-7
Effect
of fluoride anions on gramicidin
photoinactivation sensitized by sulfonated aluminum phthalocyanines.
Shapovalov
VL, Rokitskaya TI, Kotova EA, Krokhin OV, Antonenko YN.
Semenov Institute of Chemical Physics, Russian Academy of Sciences,
Kosygina, Moscow, Russian Federation.
Interaction of potent photodynamic agents, sulfonated aluminum
phthalocyanines (AlPcSn where n is a number of sulfonic groups),
with biological membranes was studied here using model systems:
sensitized photoinactivation of gramicidin channels in planar
lipid bilayers and adsorption on lipid monolayers.
Fluoride anions known to form complexes with aluminum were
found to inhibit both the adsorption of aluminum phthalocyanines
on lipid monolayers, as measured with a Langmuir trough by surface
pressure and surface potential changes, and photodynamic efficacy
of the dyes, as studied by gramicidin channel photoinactivation.
The similar effects were caused by the alkalinization of the medium.
Fluoride anions appeared to be much more effective in the
case of AlPcS4 as compared to AlPcS3. The suppression of the photodynamic
potency of aluminum phthalocyanines was attributed to desorption
of the dyes from lipid bilayers induced by fluoride or hydroxyl
ions. With AlPcS4 an enhancement of the dye aggregation leading
to a decrease in the sensitizing activity was probably involved
in the fluoride effect as revealed by absorption and fluorescence
spectral measurements. Capillary electrophoresis was employed
to understand the mechanism of the dye desorption. The
results of these experiments indicated that the reduction in the
membrane affinity was associated with an increase in the negative
charge of the dye molecules due to the binding of fluoride or
hydroxyl ions.
PMID: 11460529 [PubMed - indexed for MEDLINE]
Full report
available free at
http://www.biophysj.org/cgi/content/full/78/5/2572
2000
Biophys J; May;78(5):2572-80
Photosensitizer
binding to lipid bilayers as a precondition for the photoinactivation
of membrane channels.
Rokitskaya
TI, Block M, Antonenko YN, Kotova EA, Pohl P.
A. N. Belozersky Institute of Physico-Chemical Biology, Moscow
State University, Moscow 119899, Russia.
The photodynamic activity of sulfonated aluminum phthalocyanines
(AlPcS(n), 1 </= n </= 4) was found to correlate with their
affinity for membrane lipids. Adsorbing to the surface of large
unilamellar vesicles (LUVs), aluminum phthalocyanine disulfonate
induced the highest changes in their electrophoretic mobility.
AlPcS(2) was also most efficient in mediating photoinactivation
of gramicidin channels, as revealed by measurements of the electric
current across planar lipid bilayers. The increase in the degree
of sulfonation of phthalocyanine progressively reduced its affinity
for the lipid bilayer as well as its potency of sensitizing gramicidin
channel photoinactivation. The portion of photoinactivated gramicidin
channels, alpha, increased with rising photosensitizer concentration
up to some optimum. The concentration at which alpha was at half-maximum
amounted to 80 nM, 30 nM, 200 nM, and 2 microM for AlPcS(1), AlPcS(2),
AlPcS(3), and AlPcS(4), respectively. At high concentrations alpha
was found to decrease, which was attributed to quenching of reactive
oxygen species and self-quenching of the photosensitizer triplet
state by its ground state. Fluoride anions
were observed to inhibit both AlPcS(n) (2 </= n </= 4) binding
to LUVs and sensitized photoinactivation of gramicidin channels.
It is concluded that photosensitizer binding to membrane lipids
is a prerequisite for the photodynamic inactivation of gramicidin
channels.
PMID: 10777753 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9559584&dopt=Abstract
1998
Photochem Photobiol; Apr;67(4):399-403
Fluoroquinolone
antimicrobials: singlet oxygen, superoxide and phototoxicity.
Martinez
LJ, Sik RH, Chignell CF.
Laboratory of Pharmacology and Chemistry, National Institute of
Environmental Health Sciences, National Institutes of Health,
Research Triangle Park, NC, USA.
The fluoroquinolone antibacterial agents possess photosensitizing
properties that lead to phototoxic responses in both human and
animal subjects. The phototoxicity order reported in humans is:
fleroxacin > lomefloxacin, pefloxacin >> ciprofloxacin
> enoxacin, norfloxacin and ofloxacin. Studies both in vivo
and in vitro have related this phototoxicity to the generation
of reactive oxygen species including hydrogen peroxide and the
hydroxyl radical. We determined the quantum yields of singlet
oxygen generation (phi delta) by detection of the singlet oxygen
(1O2) luminescence at 1270 nm for several fluoroquinolones, naphthyridines
and other structurally related compounds. All the fluoroquinolones
examined have low phi delta values ranging from 0.06 to 0.09 in
phosphate buffer at pD 7.5. We also determined the 1O2 quenching
constants for these compounds and their values were on the order
of 10(6) M-1 s-1, except for lomefloxacin whose rate constant
was 1.8 x 10(7) M-1 s-1. The phi delta values were significantly
decreased in a solvent of lower polarity such as methanol (0.007
< or = phi delta < or = 0.02). The production of 1O2 by
these antibiotics did not correlate with the order reported for
their phototoxicity. We also measured the photogeneration (lambda
> 300 nm) of superoxide by these antibacterials in dimethylsulfoxide
using electron paramagnetic resonance and the spin trap 5,5-dimethyl-1-pyrroline
N-oxide. Although there is not a one-to-one correspondence between
the relative rates of superoxide generation and the phototoxicity
ranking of the fluoroquinolones, the more
phototoxic compounds tended to produce superoxide at a faster
rate. Nevertheless, the magnitudes of the observed differences
do not appear sufficient to explain the range of fluoroquinolone
phototoxicity potencies in human and animal subjects in general
and the high activity of fleroxacin
and lomefloxacin in particular. For
these latter drugs the photoinduced loss of the F8 atom as fluoride
and the concomitant generation of a highly reactive carbene at
C-8 provide a more plausible mechanism for their potent phototoxic
and photocarcinogenic properties.
PMID: 9559584 [PubMed - indexed for MEDLINE]
Toxicol Lett 1998 Dec 28;102-103:375-81
The photomutagenicity of fluoroquinolones
and other drugs.
Gocke , Albertini, Chäetelat A, Kirchner
, Muster W
Department of Toxicology, F. Hoffmann-La Roche Ltd., Basel,
Switzerland. elmar.gocke@roche.com
Induction of DNA damage as a consequence of exposure to UV light
has been established as the major and still increasing cause of
skin cancer. Absorption of the photon energy may be either directly
by the DNA molecules (for wavelengths < 320 nm) or may be by
endogenous or exogenous chemicals (sensitizers) with the potential
of energy or electron transfer to DNA. Oxygen-mediated reactions
(often called type II reactions) appear to be the most important
mechanism since molecular oxygen is a good and abundant substrate
for triplet excited sensitizers. Energy transfer to molecular
oxygen is possible for wavelengths in the near UV and in the visible
part of the solar spectrum since the energy of the excited oxygen
molecule ((1)O2*) is comparatively low. A few light-absorbing
pharmaceuticals have long been known to cause photo(geno)toxic
effects. Notably psoralene and chlorpromazine derivatives have
been established as photomutagens and the reaction mechanisms
have been identified. The fluoroquinolone
antibiotics have more recently been recognized as being photomutagenic.
The type of DNA damage and the modulation by antioxidants
indicate the involvement of reactive oxygen species (ROS) but
other mechanisms are also reported at least for some derivatives.
In routine genotoxicity studies we observed a photomutagenic activity
of a compound under development as an anxiolytic agent in the
Ames tester strain TA102 at 'normal laboratory illumination' conditions.
Further investigations showed strong photogenotoxic activity in
tests for gene mutations and chromosomal aberrations in mammalian
cells. The compound proved to be a potent (1)O2-producer. The
finding led to termination of development but in the course of
studies several structural analogues have been tested for which
structure activity relationships will be described. The relevance
of photogenotoxic properties of drugs for predicting adverse effects
in man will be discussed.
INTERNATIONAL JOURNAL OF TOXICOLOGY; 17 (5). 1998.
551-558.
The relevance of photomutagenicity testing
as a predictor of photocarcinogenicity.
MUELLER L, KASPER P
Federal Inst. Drugs Med. Devices, Sect. Mutagenicity Carcinogenicity,
Seestr. 10, 13353 Berlin, Germany.
Today's lifestyle is associated with frequent and intense exposure
to ultraviolet radiation (UVR). The tumorigenic effects of UVR
are well known. Specifically, the premutagenic lesions of UVB
(290-320 nm) are known to be the most important molecular events
in UVR tumorigenicity. The less carcinogenic UVA (320-400 nm)
mainly generates oxidative damage in the DNA via photodynamic
generation of active oxygen species involving endogenous or exogenous
photosensitizers. Several pharmaceuticals are known to act as
photosensitizers. Photoinstable phenothiazines, furocoumarins,
and fluoroquinolones were shown to be very
efficient inducers of chromosomal damage in mammalian cells in
culture. Photocarcinogenicity testing in hairless mice
of furocoumarins and several fluoroquinolones demonstrated a higher
incidence and a shorter latent period for skin tumors compared
to UVR alone. These data show a good correlation
between the photomutagenic and photocarcinogenic potential of
these [abstract truncated]
1997 - Crisp Data Base National Institutes
Of Health
Document Number: CRISP/98/ES50046-19
MECHANISMS OF CHEMICALLY INDUCED PHOTOSENSITIVITY
CHIGNELL CF
Author Address: NIEHS, NIH
Summary of Work: Photosensitization can result when light interacts
with endogenous or exogenous chemical agents in the skin and eyes.
This process can produce undesirable clinical consequences, such
as phototoxicity (exaggerated sunburn), photoallergy, or photocarcinogenicity;
or it can have beneficial effects as in tumor photodynamic therapy
(PDT) and coal tar, anthralin or psoralen (PUVA) therapy for psoriasis.
The objective of this research project is to elucidate the photochemical
mechanisms whereby photosensitizers exert their toxic or therapeutic
effects. Fluoroquinolones (FQ) are
a relatively new class of antibacterials that are useful in the
treatment of gram-negative bacterial infections. When
used in humans FQ's often cause phototoxicity. Recent studies
have shown that lomefloxacin and fleroxacin cause squamous cell
carcinomas in hairless mice injected with these drugs and irradiated
with UV-A (315-400) nm. We have studied the photochemical properties
of lomefloxacin and related FQ's to determine why these drugs
as a class are phototoxic and why lomefloxacin
and fleroxacin are photocarcinogenic. Singlet oxygen (1O2)
and superoxide yields for the FQ antimicrobials do not correlate
with their phototoxic potentials. However, photocleavage of pBR322
DNA by the FQ antibiotics is at least 10-fold more efficient for
difluorinated quinolones (lomefloxcin and fleroxacin) than for
monofluorinated analogs. 1O2 does not induce photocleavage. Futhermore,
the inhibitory effect of O2 on the induction of frank strand breaks
makes it unlikely that superoxide could play a major role in the
photocleavage of DNA by these antibiotics.
We have now found that upon UVA-irradiation the F-8 fluorine atoms
of lomefloxacin and fleroxacin are lost as fluoride with the concomitant
generation of a carbene at C-8. In contrast non-photocarcinogenic
FLQ's norfloxacin and ciprofloxacin did not exhibit UVA-induced
fluoride loss. Oxazepam is a commonly prescribed anti-anxiety
drug that has been shown to induce hepatocellular adenomas and
carcinomas in mice. Studies conducted by the National Toxicology
Program have shown that mice chronically treated with this drug
develop cataracts. We have found that while the drug itself is
a poor generator of singlet oxygen, one of its metabolites, 6-chloro-4-phenyl-2(1H)-quinazoline,
is able to sensitize the formation of 1O2 with high efficiency.
Finally, 5,7,9(11),22- ergosta-tetraen-3 -ol and 5,7,9(11)-cholestatrien-3-ol
have been identified as potential chromophores responsible the
bioeffects of UVA in the skin.
Photochem Photobiol 1996 Apr;63(4):369-72
Interrelationship of photocarcinogenicity,
photomutagenicity and phototoxicity.
Loveday KS
TSI Mason Laboratories, Worcester, MA, USA.
No Abstract
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7972371&dopt=Abstract
1994
Photochem Photobiol; Sep;60(3):215-20
The photochemical
properties of fluoroaluminum phthalocyanine.
Rosenthal
I, Shafirovich VY, Geacintov NE, Ben-Hur E, Horowitz B.
Department of Food Science, Volcani Institute, Bet Dagan, Israel.
Fluoride is known to inhibit the photodynamic activity of aluminium
phthalocyanine in a variety of biological systems. In order to
gain insight into this phenomenon, the effect of fluoride on the
photophysical properties of free and albumin-bound chloroaluminum
phthalocyanine sulfonate (AlPcSn) were studied. The association
constant of NaF with AlPcSn in aqueous solution was measured as
500 +/- 20 M-1. This binding affects the photophysical properties
of the dye: the absorption bands in the visible range are blue-shifted
by 6-8 nm, and this effect is mirrored in the fluorescence emission
spectrum. Human serum albumin significantly quenched the dye fluorescence
independent of the presence of fluoride ion. The
transient absorption spectrum of the excited dye triplet is unchanged
by NaF, but the quantum yield for its generation is increased
by 50%, with no decrease in its lifetime. Formation of
fluoroaluminum phthalocyanine complexes was also observed in tetrabutylammonium
fluoride-assisted solutions in wet acetonitrile. The fluoro-AlPcSn
complex is a better photosensitizer for generation of singlet
oxygen than the original dye-hydroxyl ion complex, as confirmed
using the imidazole-N,N-dimethyl-4-nitrosoaniline method. On the
other hand, the fluoro-AlPcSn complex exhibits
an intense inhibitory effect on photohemolysis of red blood cells
(RBC) even after the cells are washed to remove free dye
and fluoride prior to irradiation, indicating that once the dye
is attached to the cellular site, the fluoride ligand is no longer
prone to displacement (by hydroxyl ion, for example). Nonetheless,
it is clear from the spectroscopic data
that the new fluoro complex is an efficient sensitizer for photooxidation.(ABSTRACT
TRUNCATED AT 250 WORDS)
PMID: 7972371 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8234468&dopt=Abstract
1993
Photochem Photobiol; Sep;58(3):351-5
Phthalocyanine-induced
photohemolysis: structure-activity relationship and the effect
of fluoride.
Ben-Hur
E, Malik Z, Dubbelman TM, Margaron P, Ali H, van Lier JE.
Nuclear Research Center-Negev, Beer-Sheva, Israel.
Phthalocyanine (Pc) containing A1, Ga or Zn as central metal ligand
and substituted with a varying number of sulfonic acid residues
as well as additional benzene rings were synthesized and their
photodynamic activity was assayed using photohemolysis of human
erythrocytes as an endpoint. The Pc derivatives varied > 300-fold
in their photodynamic activity. Activity correlated with binding
of the dye to the cell, with the exception of some of the amphiphilic
dyes where cell uptake was an order of magnitude higher than expected
from the observed activity. Fluoride was
shown to inhibit A1PcSn-induced photohemolysis. This
effect occurred also with other A1Pc and GaPc derivatives, but
the concentration of F- required to slow photohemolysis by a factor
of two (Ki) varied between 4 microM and 10 mM. Fluorescence
spectral studies indicated complex formation
between F- and the dye, which was stronger for A1Pc than
GaPc derivatives. Ultrastructural studies using scanning electron
microscopy showed that the photosensitized cells were converted
to spherocytes and that F- prevented this to a large extent.
PMID: 8234468 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1798747&dopt=Abstract
1991
Photochem Photobiol; Nov;54(5):703-7
The effect
of fluoride on binding and photodynamic
action of phthalocyanines with proteins.
Ben-Hur
E, Dubbelman TM, Van Steveninck J.
Sylvius Laboratory, Department of Medical Biochemistry, Leiden,
The Netherlands.
Fluoride inhibits chloroaluminum phthalocyanine tetrasulfonate
(AlPcS)-induced photohemolysis when added to dye loaded cells
prior to light exposure. The mechanism by which F- exerts this
effect was studied by measuring the binding of phthalocyanine
(Pc) to various proteins in the absence and presence of F-. Parallel
measurements were made of the photodynamic action under these
conditions. Fluoride reduced the binding to proteins of AlPcS
and CoPcS. The binding of CuPcS, ZnPcS and H2PcS was not affected.
When bound to bovine serum albumin and exposed to light, H2Pc,
ZnPc and AlPcCl were bleached at a biphasic rate. Only the photobleaching
of AlPcCl was affected by F-. The effect of F- was to inhibit
the initial rapid phase without affecting the slower phase. In
the presence of D2O only the second phase of photobleaching was
enhanced, in the absence or presence of F-. No effect of F- was
observed on tryptophan photooxidation or glyceraldehyde-3-phosphate
dehydrogenase photoinactivation by AlPcS. Crosslinking of spectrin
monomers photosensitized by AlPcS was inhibited by F- in parallel
with the reduced binding of dye to the protein. It is concluded
that F- exerts its effect by complexing with metal ligands of
Pc. As a result, the dye may be released from the protein or the
binding mode may be changed in such a way that effective photochemistry
is prevented. Primary photophysical processes of Pc most probably
are not affected by F-.
PMID: 1798747 [PubMed - indexed for MEDLINE]
Note
from FAN:
The molecular formulas for the 4 Fluoroquinolones cited
below are:
sitafloxacin
[C19-H18-Cl-F2-N3-O3]
sparfloxacin [C19-H22-F2-N4-O3]
enoxacin [C15-H17-F-N4-O3]
levofloxacin [C18-H20-F-N3-O4]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14674902&dopt=Abstract
Br J Dermatol. 2003 Dec;149(6):1232-41.
Related Articles, Links
A randomized controlled trial (volunteer study)
of sitafloxacin, enoxacin, levofloxacin and sparfloxacin
phototoxicity.
Dawe RS, Ibbotson SH, Sanderson JB, Thomson EM, Ferguson
J.
Photobiology Unit and DDS Medicines Research Ltd, Ninewells
Hospital and Medical School, Dundee DD1 9SY, Scotland,
U.K.
BACKGROUND: Fluoroquinolone antibiotics (FQs) are associated
with phototoxic skin reactions following exposure to sunlight.
OBJECTIVES: We aimed to compare the phototoxic potential
of sitafloxacin, a novel
FQ with three others: sparfloxacin,
enoxacin, levofloxacin and placebo in Caucasian
volunteers. In a second study, two dosage regimens of
sitafloxacin were compared with placebo in Oriental subjects.
METHODS: Randomized, placebo-controlled, assessor-blinded
clinical trial. In 40 healthy Caucasians, sitafloxacin
100 mg twice a day (n = 8), sparfloxacin 200 mg day-1
(n = 8), enoxacin 200 mg three times a day (n = 8), levofloxacin
100 mg three times a day (n = 8) and placebo (n = 8) were
given in oral doses for 6 days. In the second study, sitafloxacin
50 mg and 100 mg, both twice daily, were compared with
placebo in 17 healthy Oriental subjects. Using an established
monochromator technique, baseline threshold erythema levels
were established pre-drug and on-drug. The phototoxic
index (PI) baseline, minimal erythema dose (MED) divided
by on-drug MED for each medication at each wavelength
was determined and related to sitafloxacin peak plasma
levels. The duration of susceptibility to phototoxicity
was assessed by repeat phototesting daily after stopping
medication.
RESULTS: In the Caucasian study, sitafloxacin 100 mg twice
a day produced mild ultraviolet (UV) A-dependent phototoxicity
(median PI = 1.45) at 365 +/- 30 nm (half-maximum bandwidth),
maximal at 24 h with normalization by 24 h postdrug cessation.
The sparfloxacin group experienced severe phototoxicity
maximal at 24 h and, unusually for an FQ, extended in
the visible region (430 +/- 30 nm), maximal at 400 +/-
30 nm (median PI = 12.35) with abnormal pigmentation at
on-drug phototest sites lasting, although fading, for
up to 1 year. Enoxacin showed UVA-dependent phototoxicity
(335-365 +/- 30 nm) median PI 3.94 (at 365 +/- 30 nm)
returning to normal 48 h after stopping the drug. Fading
pigmentation at phototoxic sites also lasted up to 1 year.
Phototoxicity was not detected in the levofloxacin or
placebo groups. In the Oriental study, no clinically relevant
phototoxicity was seen with either sitafloxacin or placebo
groups.
CONCLUSIONS: We conclude that 100 mg twice a day sitafloxacin
in Caucasians is associated with a mild degree of cutaneous
phototoxicity. Enoxacin 200 mg three times a day and sparfloxacin
200 mg day-1 are much more photoactive. Sparfloxacin phototoxicity
is induced by UVA and visible wavelengths. Levofloxacin
and placebo failed to show a phototoxic effect. In the
Oriental study, sitafloxacin 50 mg twice a day and 100
mg twice a day failed to demonstrate a clinically significant
phototoxic effect.
PMID: 14674902 [PubMed - in process]
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