Phototoxic Fluoroquinolones  
 

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Abstracts

KEYWORDS:
photocarcinogenic, photocarcinogenicity
photoclastogenic
photocytotoxic
photogenotoxic
photohemolytic
photomutagenic
, photomutagenicity
phototoxic, phototoxicity

       
       
Bay Y3118
Ciprofloxacin
Clinafloxacin
Enoxacin
Fleroxacin
Gemifloxacin
Grepafloxacin
Levofloxacin
Lomefloxacin
Moxifloxacin
Norfloxacin
Ofloxacin
Pefloxacin
Sitafloxacin
Sparfloxacin
Temafloxacin
Tosufloxacin
Trovafloxacin

 

Name: Moxifloxacin
CAS No. 151096-09-2  
Formula: C21-H24-F-N3-O4  
Structure:  
Other Names: Vigamox
Class Fluoroquinolone
Effects
(some, not all)
Phototoxic
• May induce QT prolongation and ventricular arrhythmias
Use: Antibacterial (ophthalmic)


Moxifloxacin Abstracts:

Excerpts: Since noncardiovascular drug-induced prolongation of the QT interval is often associated with the onset of torsades de pointes resulting in life-threatening ventricular arrhythmias (De Ponti et al., 2001; Haverkamp et al., 2000 and Tamargo, 2000), worldwide regulatory authorities have raised a heightened awareness on the submission of data surrounding the ventricular repolarization process. Moreover, general nonclinical testing strategy for delayed ventricular repolarization by human pharmaceuticals is being discussed in draft stage guideline ICH S7B for safety pharmacology studies (The ICH Steering Committee, 2002).
In the case of fluoroquinolone antibacterial agents, it has been reported that sparfloxacin and grepafloxacin can prolong the QT interval to cause lethal ventricular arrhythmias (Bertino and Fish, 2000; Demolis et al., 1996; Dupont et al., 1996 and Owens, 2001), which were withdrawn in most countries. Recently, gatifloxacin and moxifloxacin were developed as third generation of fluoroquinolones (Ball, 2000). However, in vitro studies have indicated that gatifloxacin and moxifloxacin markedly prolonged the action potential duration of the isolated guinea pig ventricular myocardium and canine Purkinje fibers (Gintant et al., 2001; Hagiwara et al., 2001 and Patmore et al., 2000). Also, gatifloxacin and moxifloxacin inhibited the human cardiac repolarizing K+ current (Anderson et al., 2001; Bischoff et al., 2000 and Kang et al., 2001). Clinical studies on the safety pharmacology of gatifloxacin and moxifloxacin indicated that these fluoroquinolones may induce QT prolongation and ventricular arrhythmias (Bertino et al., 2002; Démolis et al., 2000; Iannini and Circiumaru, 2001; Noel et al., 2003; Siepmann and Kirch, 2001 and Von Keutz and Schlüter, 1999).
Ref: In vivo experimental approach for the risk assessment of fluoroquinolone antibacterial agents-induced long QT syndrome; by Katsuyoshi Chiba et al. European Journal of Pharmacology Volume 486, Issue 2 , 20 February 2004, Pages 189-200.

Clinical trials in patients with community- and hospital-acquired infections have established that the clinical effectiveness and safety of fluoroquinolones are similar to -lactam and macrolide agents. The most common drug-related adverse effects (AEs) with fluoroquinolone therapy involve the gastrointestinal troct and central nervous system and are usually transient and mild to moderate in severity. However, serious toxic reactions have led to the limited and restrictive use of trovafloxacin in the United States and the withdrawal of temafloxacin and grepafloxacin from worldwide markets. In addition, postmarketing spontaneous AE reports have imposed updates in the precautions and warning sections of product package inserts of selected fluoroquinolones. This article reviews the AEs associated with the fluoroquinolones and compares the safety profiles of ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin.
Ref: Safety and tolerability of fluoroquinolones; by Kelly A. Sprandel PharmD and Keith A. Rocivold PharmD, FCP, FCCP. Clinical Cornerstone Volume 5, Supplement 3 , 2003, Pages S29-S36.

Name: Norfloxacin
CAS No.  70458-96-7  
Formula: C16-H18-F-N3-O3
Structure:  
Other Names: AM-715
BRN 0567897
Baccidal
Barazan
CCRIS 6302
Chibroxin
Fulgram
MK 0366
MK-366
Noroxin
Sebercim
Class Fluoroquinolone
Effects
(some, not all)
Photogenotoxic
• Photohemolytic
 
• Phototoxic
• Retarded fracture healing in rats
 
Use:

Anti-infective agents, fluoroquinolone
Antibacterial
Drug / Therapeutic Agent

1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Quinoline-derived synthetic antibacterial agent with a very broad spectrum of action. Oral administration yields highly bactericidal plasma, tissue, and urine levels. Norfloxacin inhibits bacterial DNA-gyrase and is used in gastrointestinal, eye, and urinary infections.

Norfloxacin Abstracts:

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.
Ref: In vitro method for prediction of the phototoxic potentials of fluoroquinolones; by T. Yamamoto et al. Toxicology in Vitro - Volume 15, Issue 6 , December 2001, Pages 721-727.

BACKGROUND: The objective of the present study was to test and compare the effect of floroquinolones on fracture healing as assessed histopathologically. METHODS: A total of twenty five Wistar rats were arbitrarily assigned to five groups with five animals each. Bilateral closed femoral fracture was constructed manually in all groups. The first group did not receive any drug as control (C). The 2nd, 3rd, 4th, and the last group were treated with norfloxacin (N), ofloxacin (O), pefloxacin (P) and ciprofloxacin (Ci) respectively. Antibiotic administration was started on the 7th day after the fracture incident. All the treatments were discontinued twenty days after the incident all the rats were sacrificed , and the fracture calluses together with affected femurs were resected en bloc at the fourth week after fracture. RESULTS: Average healing grades of control group was higher than all the other antibiotic groups. Mean healing grades of control ( 5 ; n:8), ofloxacin (4.1; n:7), ciprofloxacin (3.9; n:8), norfloxacin (3.4 ; n:9) and pefloxacin groups (2.6 ; n:10) were recorded.. Statistically significant differences between antibiotherapy groups ( excluding. norfloxacin) and the control group were detected. CONCLUSIONS: The current histopathological study has shown that all the studied floroquinolones retarded fracture healing in rats.
Ref: A Comparison of effects of floroquinolones on fracture healing (An experimental study in rats). By Tuncay I, Ozbek H, Kosem M, Unal O. Ulus Travma Derg. 2005 Jan;11(1):17-22.

Name: Ofloxacin
CAS No. 82419-36-1  
Formula: C18-H20-F-N3-O4  
Structure:  
Other Names: BRN 3657947
CCRIS 5233
DL 8280
DL-8280
Floxin
HOE 280
ORF 18489
Ocuflox
Oflocet
Oxaldin
PT 01
Tarivid
Visiren
Class Fluoroquinolone
Effects
(some, not all)
Photogenotoxic
• Photocytotoxic
• Phototoxic
• Teratogenic
• Chondrotoxicity
• Significantly impaired testicular function and structure in rats.
• Retarded fracture healing in rats  
 
Use:

Anti-infective agents, fluoroquinolone
Anti-infective agents, urinary
Antibacterial

An Orally administered broad-spectrum quinolone antibacterial drug active against most gram-negative and gram-positive bacteria. Clinical efficacy has been confirmed in a variety of systemic infections as well as in acute and chronic urinary tract infections.

Ofloxacin Abstracts:

The anti-bacterial drug ofloxacin is teratogenic in experimental animals. The aim of this study was to evaluate the teratogenic effects on the developing chick tail bud. ... The defects consist of a blunt ending neural tube, dysplasia of the caudal structures and absence of caudal vertebrae and ganglia. The notochord is severely affected at its caudal end. It exits the vertebral column ventro-laterally, and follows an S-shaped course to fuse with the tail gut. The incidence of defects is more pronounced at higher dosages. Care should be taken in prescribing the drug to pregnant women, as ofloxacin may cause embryonic abnormalities.
Ref: Effect of ofloxacin on chick tail bud development. By Vorster W and Lizamore DJ. J Morphol 1997;232(3):337.

Ofloxacin and ciprofloxacin are two closely-related fluoroquinolones which both induce chondrotoxicity in juvenile dogs. In immature rats, however, cartilage lesions have been described with ofloxacin only...
Ref: Ciprofloxacin and N-methyl-ciprofloxacin induce joint cartilage lesions in immature rats. By E Lozo et al. Teratology 1996 May;53(5):32A.

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.
Ref: In vitro method for prediction of the phototoxic potentials of fluoroquinolones; by T. Yamamoto et al. Toxicology in Vitro - Volume 15, Issue 6 , December 2001, Pages 721-727.

n the last few years, a marked decrease in male fertility has been reported. Environmental factors were recently suspected for this effect. Among those factors is the misuse of drugs and in particular antibiotics. Quinolones are a group of antibacterial agents with broad-spectrum activity. Testicular impairment of some quinolone members is controversial; a matter which stimulated our attention to investigate the adverse testicular effects of the most familiar quinolone members, namely: ofloxacin, ciprofloxacin and pefloxacin. They were given to rats in doses of 72, 135 and 72 mg kg-1day-1p.o., respectively, for 15 consecutive days. Ofloxacin was also used to establish a dose–response relationship in doses of 36, 72 and 360 mg kg-1day-1p.o. for 15 consecutive days. Results revealed that ofloxacin, ciprofloxacin and pefloxacin reduced testicular LDH-X activity by 39.8%, 62.7% and 60.7%, respectively. Moreover, sperm count, motility and daily sperm production were markedly decreased. Ofloxacin induced a dose-dependent decrease in testicular LDH-X activity, sperm count and motility. Furthermore, daily sperm production showed a marked reduction which amounted to 26.1% and 40.0% following administration of ofloxacin (72, 360 mg kg-1day-1*15 days), respectively. Moreover, administration of ofloxacin resulted in marked testicular histopathological changes. It is concluded that, ofloxacin, ciprofloxacin and pefloxacin significantly impaired both testicular function and structure in rats.
Ref: ADVERSE TESTICULAR EFFECTS OF SOME QUINOLONE MEMBERS IN RATS; by ADEL R. A. ABD-ALLAH et al. Pharmacological Research Volume 41, Issue 2 , February 2000, Pages 211-219.

BACKGROUND: The objective of the present study was to test and compare the effect of floroquinolones on fracture healing as assessed histopathologically. METHODS: A total of twenty five Wistar rats were arbitrarily assigned to five groups with five animals each. Bilateral closed femoral fracture was constructed manually in all groups. The first group did not receive any drug as control (C). The 2nd, 3rd, 4th, and the last group were treated with norfloxacin (N), ofloxacin (O), pefloxacin (P) and ciprofloxacin (Ci) respectively. Antibiotic administration was started on the 7th day after the fracture incident. All the treatments were discontinued twenty days after the incident all the rats were sacrificed , and the fracture calluses together with affected femurs were resected en bloc at the fourth week after fracture. RESULTS: Average healing grades of control group was higher than all the other antibiotic groups. Mean healing grades of control ( 5 ; n:8), ofloxacin (4.1; n:7), ciprofloxacin (3.9; n:8), norfloxacin (3.4 ; n:9) and pefloxacin groups (2.6 ; n:10) were recorded.. Statistically significant differences between antibiotherapy groups ( excluding. norfloxacin) and the control group were detected. CONCLUSIONS: The current histopathological study has shown that all the studied floroquinolones retarded fracture healing in rats.
Ref: A Comparison of effects of floroquinolones on fracture healing (An experimental study in rats). By Tuncay I, Ozbek H, Kosem M, Unal O. Ulus Travma Derg. 2005 Jan;11(1):17-22.

Name: Pefloxacin
CAS No. 70458-92-3
Formula: C17-H20-F-N3-O3  
Structure:  
Other Names: 1584RB
BRN 0567618
EINECS 274-611-8
EU 5306
Pefloxacine
Class Fluoroquinolone
Effects
(some, not all)
• Phototoxic
Significantly impaired testicular function and structure in rats. 
Retarded fracture healing in rats 
Use:

Anti-infective agents, urinary
Antibacterial

An Orally administered broad spectrum quinolone antibacterial agent active against most gram-negative and gram-positive bacteria. It is effective against urinary tract infections as well as against many other systemic infections. The drug is well tolerated in adults, but should not be given to children and pregnant women.


Pefloxacin Abstracts:

In the last few years, a marked decrease in male fertility has been reported. Environmental factors were recently suspected for this effect. Among those factors is the misuse of drugs and in particular antibiotics. Quinolones are a group of antibacterial agents with broad-spectrum activity. Testicular impairment of some quinolone members is controversial; a matter which stimulated our attention to investigate the adverse testicular effects of the most familiar quinolone members, namely: ofloxacin, ciprofloxacin and pefloxacin. They were given to rats in doses of 72, 135 and 72 mg kg-1day-1p.o., respectively, for 15 consecutive days. Ofloxacin was also used to establish a dose–response relationship in doses of 36, 72 and 360 mg kg-1day-1p.o. for 15 consecutive days. Results revealed that ofloxacin, ciprofloxacin and pefloxacin reduced testicular LDH-X activity by 39.8%, 62.7% and 60.7%, respectively. Moreover, sperm count, motility and daily sperm production were markedly decreased. Ofloxacin induced a dose-dependent decrease in testicular LDH-X activity, sperm count and motility. Furthermore, daily sperm production showed a marked reduction which amounted to 26.1% and 40.0% following administration of ofloxacin (72, 360 mg kg-1day-1*15 days), respectively. Moreover, administration of ofloxacin resulted in marked testicular histopathological changes. It is concluded that, ofloxacin, ciprofloxacin and pefloxacin significantly impaired both testicular function and structure in rats.
Ref: ADVERSE TESTICULAR EFFECTS OF SOME QUINOLONE MEMBERS IN RATS; by ADEL R. A. ABD-ALLAH et al. Pharmacological Research Volume 41, Issue 2 , February 2000, Pages 211-219.

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. ...
Ref: Fluoroquinolone antimicrobials: singlet oxygen, superoxide and phototoxicity.
Martinez LJ, Sik RH, Chignell CF.1998 Photochem Photobiol; Apr;67(4):399-403.

BACKGROUND: The objective of the present study was to test and compare the effect of floroquinolones on fracture healing as assessed histopathologically. METHODS: A total of twenty five Wistar rats were arbitrarily assigned to five groups with five animals each. Bilateral closed femoral fracture was constructed manually in all groups. The first group did not receive any drug as control (C). The 2nd, 3rd, 4th, and the last group were treated with norfloxacin (N), ofloxacin (O), pefloxacin (P) and ciprofloxacin (Ci) respectively. Antibiotic administration was started on the 7th day after the fracture incident. All the treatments were discontinued twenty days after the incident all the rats were sacrificed , and the fracture calluses together with affected femurs were resected en bloc at the fourth week after fracture. RESULTS: Average healing grades of control group was higher than all the other antibiotic groups. Mean healing grades of control ( 5 ; n:8), ofloxacin (4.1; n:7), ciprofloxacin (3.9; n:8), norfloxacin (3.4 ; n:9) and pefloxacin groups (2.6 ; n:10) were recorded.. Statistically significant differences between antibiotherapy groups ( excluding. norfloxacin) and the control group were detected. CONCLUSIONS: The current histopathological study has shown that all the studied floroquinolones retarded fracture healing in rats.
Ref: A Comparison of effects of floroquinolones on fracture healing (An experimental study in rats). By Tuncay I, Ozbek H, Kosem M, Unal O. Ulus Travma Derg. 2005 Jan;11(1):17-22.

In electrophysiological and behavioral experiments on rats we studied the effects of pefloxacin, a member of fluoroquinolone family, on the nociceptive system. Intraperitoneal injection of pefloxacin (80 mg/kg) decreased the thresholds of nociceptive response to noxious stimulation in the hot-plate test. In addition, it decreased the threshold of the late component of nociceptive flexor reflex. Intrathecal application of pefloxacin in a dose of 20 microg provoked allodynia, while the higher dose of 400 microg induced behavioral pattern characteristic of central pain syndrome. It was hypothesized that pain induced by pefloxacin results from disturbances in GABAergic inhibition in the central subdivisions of the nociceptive system.
Ref: Mechanisms of pefloxacin-induced pain. By Kukushkin ML, Igonkina SI, Guskova TA. Bull Exp Biol Med. 2004 Apr;137(4):336-8.

Name: Sitafloxacin
CAS No. 127254-12-0 (and 163253-35-8)
Formula: C19-H18-Cl-F2-N3-O3 
Structure:  
Other Names: DU 6859
DU 6859a  
Class Fluoroquinolone
Effects
(some, not all)
• Photoclastogenic
• Phototoxic
Use:

Sitafloxacin Abstracts:

The photochemical clastogenic potential of 12 quinolone antibacterial agents with or without light irradiation was assessed by an in vitro chromosomal aberration test using cultured CHL cells. Exposure to all test compounds, except for DK-507k, increased the incidence of cells with structural aberrations excluding gap (TA) following light irradiation. Test compounds used in the present study under light irradiation were divided into three groups based on their ED50 values, doses inducing chromosomal aberrations in 50% of cells. The first group with ED50 values below 30 g/ml includes sparfloxacin (SPFX), clinafloxacin (CLFX), gemifloxacin (GMFX), lomefloxacin (LFLX), sitafloxacin (STFX), grepafloxacin (GPFX) and fleroxacin (FLRX); the second group with ED50 values of 100 g/ml, enoxacin (ENX) and levofloxacin (LVFX); the third group with little or no potency, moxifloxacin (MFLX), trovafloxacin (TVFX) and DK-507k. The photochemical clastogenicity of these compounds correlates well with their reported in vivo phototoxic potentials. In the chemical structure and clastogenicity relationships, substitution of a methoxy group at the C-8 position in the quinolone nucleus was confirmed to reduce not only photochemical clastogenicity, but also the clastogenic potential of quinolone antibacterial agents.
Ref: In vitro photochemical clastogenicity of quinolone antibacterial agents studied by a chromosomal aberration test with light irradiation. By Satoru Itoh et al. Mutation Research/Genetic Toxicology and Environmental Mutagenesis Volume 517, Issues 1-2 , 27 May 2002, Pages 113-121.

 
 
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