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Abstracts

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

Name:	Sparfloxacin
CAS No.	110871-86-8  and (111542-93-9)
Formula:	C19-H22-F2-N4-O3
Structure:
Other Names:	AT 4140 AT-4140 BRN 3658018 CI 978 CI-978 CP 103826 DRG-0143 Esparfloxacino [INN-Spanish] PD-131501 Sparfloxacin Sparfloxacine [INN-French] Sparfloxacinum [INN-Latin] Zagam
Class	Fluoroquinolone
Effects (some, not all)	• Photogenotoxic   • Photoclastogenic • Phototoxic • Teratogenic effects  • Can prolong the QT interval to cause lethal ventricular arrhythmias - withdrawn in most countries.
Use:	Antibacterial Drug / Therapeutic Agent Withdrawn in most countries.

Sparfloxacin Abstracts:

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.
Ref: Compare two methods of measuring DNA damage induced by photogenotoxicity of fluoroquinolones. By Zhang T, Li JL, Xin J, Ma XC, Tu ZH. Acta Pharmacol Sin. 2004 Feb;25(2):171-5.

... In fetuses, decreased body weight, increased incidence of ventricular septal defect, decreased incidence of 14th ribs, and delayed ossification were found in the 300 mg/kg dose group...
Ref: [Reproductive and developmental toxicity studies of sparfloxacin (2) -- teratogenicity study in rats]; by H Funabashi et al. Yakuri To Chiryo 1991 Apr;19(4):69-86.

Sparfloxacin interfered slightly with limb bud growth at 30 mg/L; none of the other fluoroquinolones impaired development at this concentration.
Ref: Effects of fluoroquinolones in a mouse limb bud culture system using regular and magnesium-deficient medium; by R Stahlmann et al. Teratology 1997 Jan;55(1):61-2.

... Teratogenic effects have been observed in animals treated with the oldest quinolones (flumequine, nalidixic acid and pipemidic acid) and also with sparfloxacin, a fluoroquinolone...
Ref: Quinolones and pregnancy: worrying animal findings, few clinical data. Prescrire Int 1999 Feb;8(39):29-31.

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.

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.

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.

The new fluoroquinolones (clinafloxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, moxifloxacin, sitafloxacin, sparfloxacin and trovafloxacin) offer excellent activity against Gram-negative bacilli and improved Gram-positive activity (e.g. against Streptococcus pneumoniae and Staphylococcus aureus) over ciprofloxacin... Several of these agents have either been withdrawn from the market, had their use severely restricted because of adverse effects (clinafloxacin because of phototoxicity and hypoglycaemia; grepafloxacin because of prolongation of the QTc and resultant torsades de pointes; sparfloxacin because of phototoxicity; and trovafloxacin because of hepatotoxicity), or were discontinued during developmental phases. The remaining fluoroquinolones such as gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin have adverse effect profiles similar to ciprofloxacin. Extensive post-marketing safety surveillance data (as are available with ciprofloxacin and levofloxacin) are required for all new fluoroquinolones before safety can be definitively established. Drug interactions are limited; however, all fluoroquinolones interact with metal ion containing drugs (eg. antacids)..
Ref: A critical review of the fluoroquinolones: focus on respiratory infections; by GG Zhanel et al. Drugs. 2002;62(1):13-59.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11790155

Significant safety issues that have arisen with fluoroquinolones include phototoxicity, cardiotoxicity, tendinitis, CNS effects and drug interactions. Ciprofloxacin is well tolerated; the incidence of adverse events is low and serious adverse events are rare. Levofloxacin has a reduced CNS adverse event rate compared with ofloxacin. Sparfloxacin has significant phototoxicity and potential cardiac toxicity. Grepafloxacin has significantly increased adverse event rates, particularly gastrointestinal intolerance. Taste perversion and nausea are common. Trovafloxacin has an increased potential for CNS adverse reactions, notably dizziness. Post-marketing surveillance data indicate the possibility of serious hepatic reactions and pancreatitis. Interactions between fluoroquinolones and drugs metabolised by the hepatic cytochrome P450 system affect the clearance of theophylline and caffeine. Quinolone absorption is significantly reduced by co-administration of antacids. Hospitalised patients are likely to be receiving multiple-drug therapy, but drug interactions are avoidable. The interactions of specific fluoroquinolones should be checked prior to prescription.
Ref: Safety of the new fluoroquinolones compared with ciprofloxacin. By P Ball. J Chemother. 2000 Jan;12 Suppl 1:8-11.

Name:	Temafloxacin
CAS No.	108319-06-8
Formula:	C21-H18-F3-N3-O3
Structure:
Other Names:	Omniflox A 62254 BRN 4301726 CCRIS 6303 T 1258
Class	Fluoroquinolone
Effects (some, not all)	• Embryolethal (animal study) This drug was on the market for 3 months in 1992 when Abbot Laboratories "voluntarily" recalled it. FDA cited the following "severe adverse effects" in its announcement of the recall: • Hemolytic anemia (destruction of red blood cells) and other blood cell abnormalities (severe hemolytic-uremic syndrome) • Kidney dysfunction • Liver dysfunction • Allergic reactions, some of which have caused life-threatening respiratory distress
Use:	Anti-infective drug • Withdrawn from worldwide markets due to adverse effects.

Temafloxacin Abstracts:

....... The Food and Drug Administration today announced that Abbott Laboratories of Abbott Park, Ill., is voluntarily recalling the broad-spectrum anti-infective drug Omniflox (temafloxacin) tablets, and will halt all further distribution of the drug.
....... This action is being taken because of severe adverse events associated with the use of the drug that have been reported to the company and to FDA in the first three months of marketing.
....... Temafloxacin was approved in late January 1992 and marketed in mid-February. Since that time there have been approximately 50 reports of serious adverse reactions, including three deaths. There were several cases of severe low blood sugar, especially in very elderly patients with decreased kidney function. Among the severe reactions there were a number
of cases of an unusual complex of adverse reactions consisting of hemolytic anemia (destruction of red blood cells) and other blood cell abnormalities. Also observed were patients with kidney dysfunction, about half of which required renal dialysis. Other patients suffered liver dysfunction.
....... There has also been a substantial number of reports of allergic reactions, some of which have caused life-threatening respiratory distress.
....... Temafloxacin is one of a newer class of synthetic oral fluoroquinolones -- broad-spectrum antibiotics -- that are used to treat a variety of infections including lower respiratory tract infections, skin and skin structure infections, infection of the prostate and urinary tract infections. Similar antibiotics of its class have not been reported to be associated with comparable numbers of serious adverse reactions.
....... Consumers who have the medication are advised to consult their physician and return any unused portions of the product to the place of purchase.
....... FDA is one of the eight Public Health Service agencies within HHS.
Ref: June 5, 1992: Press Release from the US Food and Drug Administration.
http://www.fda.gov/bbs/topics/NEWS/NEW00279.html

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.

The potential developmental toxicity of fleroxacin was studied (Phase I) and its pharmacokinetics was compared to ciprofloxacin, temafloxacin, and norfloxacin (Phase II) in the cynomolgus macaque (Macaca fascicularis). Phase I studies involved oral administration of fleroxacin (35 and 70 mg/kg-day) during Gestational Days (GD) 20-34 or 35-49 (N = 10/group); controls received vehicle only. Increased maternal toxicity (weight loss, anorexia, emesis) and embryolethality (4/10, 40%; GD 20-34) were observed at 70 mg/kg-day. Urinary excretion of estrogen conjugates was reduced for females with nonviable pregnancies during both treatment periods (GD 20-34 and 35-49), although steroid hormone levels in serum remained unchanged during treatment; no malformations or growth retardation were observed at gross examination. For Phase II studies, the pharmacokinetics of fleroxacin (70 mg/kg), ciprofloxacin (100 mg/kg), temafloxacin (100 mg/kg), and norfloxacin (150 mg/kg) were studied during a 3-day oral treatment regimen in the nonpregnant (N = 12; 3/quinolone) and pregnant (N = 3; fleroxacin only) macaque. Serial blood samples were collected on the first and third days of treatment in all animals; for pregnant females, the conceptus was removed on GD 31 for analysis of fleroxacin levels. Marked differences between the quinolones were noted in the AUC0-24 hr for nonpregnant females. Based on AUC0-24 hr on the first day of treatment, the rank order was fleroxacin > temafloxacin > ciprofloxacin > norfloxacin. On the third day of treatment, the rank order for exposure was temafloxacin> fleroxacin > ciprofloxacin > norfloxacin. Overall, results indicated (1) no marked differences in pharmacokinetic parameters in pregnant versus nonpregnant females, (2) fleroxacin levels in embryonic tissues were similar to maternal plasma levels, and (3) there was a correlation between exposure and embryolethal doses for all fluoroquinolones which resulted in embryolethality except norfloxacin.
Ref: Developmental Toxicity of Fleroxacin and Comparative Pharmacokinetics of Four Fluoroquinolones in the Cynomolgus Macaque (Macaca fascicularis)
Hummler H., Richter W. F. and Hendrickx A. G. Toxicology and Applied Pharmacology Volume 122, Issue 1 , September 1993, Pages 34-45.

Grepafloxacin Abstracts:

Fluoroquinolone development from 1985 to the present was reviewed. Severe drug adverse events were noted for enoxacin, pefloxacin and fleroxacin, which were phototoxic. Temafloxacin was associated with severe hemolytic-uremic syndrome, lomefloxacin caused phototoxicity and central nervous system (CNS) effects, and sparfloxacin was associated with phototoxicity and QTc prolongation. Tosufloxacin caused severe thrombocytopenia and nephritis, and hepatotoxicity was reported for trovafloxacin. Grepafloxacin was withdrawn due to cardiovascular effects, and clinafloxacin was associated with phototoxicity and hypoglycaemia. The structure of the quinolones directly relates to both their activity and side-effect profiles. The relationship among specific substituents attached to the quinolone nucleus are clarified. The incidence of specific adverse events associated with individual fluoroquinolones was reviewed in a five-year post-marketing surveillance (PMS) study in Japan, in which a total adverse drug reaction (ADR) rate of 1.3% was found for levofloxacin, compared to total ADR rates of 3.3% for pazufloxacin, 3.6% for tosufloxacin, 4.5% for gatifloxacin and 5.4% for balofloxacin. Gastrointestinal effects were the most common adverse events for all fluoroquinolones. Levofloxacin had the lowest rate of CNS effects and skin adverse events among the agents listed.
Ref: History of quinolones and their side effects by E Rubinstein. Chemotherapy. 2001;47 Suppl 3:3-8; discussion 44-8.

Name:	Tosufloxacin
CAS No.	100490-36-6
Formula:	C19-H15-F3-N4-O3
Structure:
Other Names:	A 61827 A 67107 BRN 4913117 CCRIS 6304
Class	Fluoroquinolone
Effects (some, not all)	• Photogenotoxic     • Phototoxic  • Thrombocytopenia • Nephritis
Use:

Tosufloxacin Absracts:

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.

Fluoroquinolone development from 1985 to the present was reviewed. Severe drug adverse events were noted for enoxacin, pefloxacin and fleroxacin, which were phototoxic. Temafloxacin was associated with severe hemolytic-uremic syndrome, lomefloxacin caused phototoxicity and central nervous system (CNS) effects, and sparfloxacin was associated with phototoxicity and QTc prolongation. Tosufloxacin caused severe thrombocytopenia and nephritis, and hepatotoxicity was reported for trovafloxacin. Grepafloxacin was withdrawn due to cardiovascular effects, and clinafloxacin was associated with phototoxicity and hypoglycaemia. The structure of the quinolones directly relates to both their activity and side-effect profiles. The relationship among specific substituents attached to the quinolone nucleus are clarified. The incidence of specific adverse events associated with individual fluoroquinolones was reviewed in a five-year post-marketing surveillance (PMS) study in Japan, in which a total adverse drug reaction (ADR) rate of 1.3% was found for levofloxacin, compared to total ADR rates of 3.3% for pazufloxacin, 3.6% for tosufloxacin, 4.5% for gatifloxacin and 5.4% for balofloxacin. Gastrointestinal effects were the most common adverse events for all fluoroquinolones. Levofloxacin had the lowest rate of CNS effects and skin adverse events among the agents listed.
Ref: History of quinolones and their side effects by E Rubinstein. Chemotherapy. 2001;47 Suppl 3:3-8; discussion 44-8.

Name:	Trovafloxacin
CAS No.	147059-72-1 (and 146836-84-2)
Formula:	C20-H15-F3-N4-O3
Structure:
Other Names:	Trovan
Class	Fluoroquinolone
Effects (some, not all)	• Hepatotoxicity • Diminished healing during the early stages of fracture repair; may compromise fracture healing in humans. • Potential for CNS adverse reactions, notably dizziness.
Use:	• Limited and restrictive use in the United States

Trovafloxacin Abstracts:

... Trovan (trovafloxacin/alatrofloxacin) is an example of a drug with significant limitations of use because of the potential for serious liver injury. The antimicrobial therapy treats a variety of infections, from mild to life threatening. Though no cases of liver failure, liver transplant, or death were reported in the 7,000 patients who took part in premarketing clinical trials for Trovan, the FDA began receiving reports of liver failure after Pfizer began marketing the drug in 1998. As a result, the FDA and Pfizer agreed to restrictions, which include limiting distribution of Trovan to inpatient facilities (hospitals, nursing homes) so doctors can closely monitor patients taking the drug. Trovan use was also limited to the treatment of patients with serious, life- or limb-threatening infections...
Ref: Serious Liver Injury: Leading Reason for Drug Removals, Restrictions. By Michelle Meadows. FDA Consumer magazine May-June 2001.
http://www.fda.gov/fdac/features/2001/301_liver.html

Excerpts: A group of Nigerian families has taken legal action against the pharmaceutical company, Pfizer. The lawsuit, which was filed in a US court on Aug 29, claims that the families' children were entered into a trial of Pfizer's Trovan (trovafloxacin) for bacterial meningitis in 1996 without informed consent. The families accuse the US-based drug company of violating “international law, federal regulations and medical ethics, in its zeal to carry out its test”.
Pfizer gave the children a “new, untested and unproven drug without first obtaining their informed consent, or explaining to the children or their parents that the proposed treatment was experimental and that they were free to refuse it and instead choose the safe, effective treatment for bacterial meningitis offered at the same site, free of charge, by a charitable medical group”, according to the lawsuit... Pfizer said: “the fatality rates in the Kano study, approximately 6% for both Trovan and ceftriaxone, were lower than published results for other forms of treatment in this epidemic.” But, the suit alleges that the deaths and injuries among controls were the result of a lower than recommended dose of ceftriaxone... The Trovan trial supports the veracity of the international concerns that developing countries will merely be used as test areas for medical treatments designed for developed countries, adds Charles Weijer (Dalhousie University, Halifax Nova Scotia, Canada). ... Weijer called on the international community to guard against the exploitation of developing countries, and ensure that all research participants receive equal protection. “The pharmaceutical industry has, as illustrated in this case, demonstrated its willingness to exploit the vulnerable.”
Ref: Drug company sued over research trial in Nigeria by Khabir Ahmad. The Lancet - Volume 358, Issue 9284 , 8 September 2001, Page 815.

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.

Idiosyncratic drug toxicity, defined as toxicity that is dose independent, host dependent, and usually cannot be predicted during preclinical or early phases of clinical trials, is a particularly confounding complication of drug development. An understanding of the mechanisms that lead to idiosyncratic liver toxicity would be extremely beneficial for the development of new compounds. We used microarray analysis on isolated human hepatocytes to understand the mechanisms underlying the idiosyncratic toxicity induced by trovafloxacin. Our results clearly distinguish trovafloxacin from other marketed quinolone agents and identify unique gene changes induced by trovafloxacin that are involved in mitochondrial damage, RNA processing, transcription, and inflammation that may suggest a mechanism for the hepatotoxicity induced by this agent. In conclusion, this work establishes the basis for future microarray analysis of new compounds to determine the presence of these expression changes and their usefulness in predicting idiosyncratic hepatotoxicity. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience. Wiley.com/jpages/0270-9139/suppmat/index.htnd).
Ref:  Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin; by MJ Liguori et al. Hepatology. 2005 Jan;41(1):177-86.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15619227

The new fluoroquinolones (clinafloxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, moxifloxacin, sitafloxacin, sparfloxacin and trovafloxacin) offer excellent activity against Gram-negative bacilli and improved Gram-positive activity (e.g. against Streptococcus pneumoniae and Staphylococcus aureus) over ciprofloxacin... Several of these agents have either been withdrawn from the market, had their use severely restricted because of adverse effects (clinafloxacin because of phototoxicity and hypoglycaemia; grepafloxacin because of prolongation of the QTc and resultant torsades de pointes; sparfloxacin because of phototoxicity; and trovafloxacin because of hepatotoxicity), or were discontinued during developmental phases. The remaining fluoroquinolones such as gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin have adverse effect profiles similar to ciprofloxacin. Extensive post-marketing safety surveillance data (as are available with ciprofloxacin and levofloxacin) are required for all new fluoroquinolones before safety can be definitively established. Drug interactions are limited; however, all fluoroquinolones interact with metal ion containing drugs (eg. antacids)...
Ref: A critical review of the fluoroquinolones: focus on respiratory infections; by GG Zhanel et al. Drugs. 2002;62(1):13-59.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11790155

We previously have shown that experimental fractures exposed to ciprofloxacin have diminished fracture healing. The purpose of this study was to assess the effect of levofloxacin and trovafloxacin on experimental fracture healing to test the hypothesis that diminished fracture healing is a quinolone class effect. Sixty-one male Wistar rats were divided into three groups, which received 25 mg/kg of levofloxacin twice daily for 3 weeks, 35 mg/kg of trovafloxacin twice daily for 3 weeks, or no treatment, beginning 7 days after production of closed, nondisplaced, bilateral femoral fractures. The mean peak serum concentrations of levofloxacin and trovafloxacin drawn 30 minutes after administration were 6.9 and 7.0 microg/mL, respectively. Radiographic, histologic, and biomechanical studies were used to evaluate fracture healing. Torsional strength testing of fracture callus exposed to levofloxacin and trovafloxacin revealed a decrease in strength (299 and 257 N-mm, respectively) as compared with controls (364 N-mm). Radiographs revealed significantly more advanced healing in control animals (Goldberg score of 2.1) compared with the fractures in the rats treated with levofloxacin and trovafloxacin (Goldberg score of 1.5 in both groups). Fracture calluses in the animals treated with levofloxacin and trovafloxacin showed a lower histologic grade (5.3 and 3.5, respectively) as compared with control animals (7.5) representing a less mature callus with the presence of more cartilage and less woven bone. These data suggest that experimental fractures systemically exposed to levofloxacin or trovafloxacin have diminished healing during the early stages of fracture repair. The administration of quinolones during early fracture repair may compromise fracture healing in humans.
Ref: Levofloxacin and trovafloxacin inhibition of experimental fracture-healing; by AC Perry et al. Clin Orthop Relat Res. 2003 Sep;(414):95-100.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12966282

Significant safety issues that have arisen with fluoroquinolones include phototoxicity, cardiotoxicity, tendinitis, CNS effects and drug interactions. Ciprofloxacin is well tolerated; the incidence of adverse events is low and serious adverse events are rare. Levofloxacin has a reduced CNS adverse event rate compared with ofloxacin. Sparfloxacin has significant phototoxicity and potential cardiac toxicity. Grepafloxacin has significantly increased adverse event rates, particularly gastrointestinal intolerance. Taste perversion and nausea are common. Trovafloxacin has an increased potential for CNS adverse reactions, notably dizziness. Post-marketing surveillance data indicate the possibility of serious hepatic reactions and pancreatitis. Interactions between fluoroquinolones and drugs metabolised by the hepatic cytochrome P450 system affect the clearance of theophylline and caffeine. Quinolone absorption is significantly reduced by co-administration of antacids. Hospitalised patients are likely to be receiving multiple-drug therapy, but drug interactions are avoidable. The interactions of specific fluoroquinolones should be checked prior to prescription.
Ref: Safety of the new fluoroquinolones compared with ciprofloxacin. By P Ball. J Chemother. 2000 Jan;12 Suppl 1:8-11.