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Some groups refer to these adverse events as "fluoroquinolone toxicity". These groups of people claim to have suffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuit by people harmed by the use of fluoroquinolones as well as action by the consumer advocate group [[Public Citizen]].<ref>http://www.consumeraffairs.com/news04/2006/08/pubcit_cipro.html</ref><ref>http://www.mnd.uscourts.gov/MDL-Levaquin/index.shtml</ref> Partly as a result of the efforts of [[Public Citizen]] the FDA ordered a [[black box warning]]s on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.<ref>{{cite web |url=http://www.cnn.com/2008/HEALTH/07/08/antibiotics.risk/index.html|title=FDA orders 'black box' label on some antibiotics |accessdate=2008-07-08 |format= |work=}}</ref>
Some groups refer to these adverse events as "fluoroquinolone toxicity". These groups of people claim to have suffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuit by people harmed by the use of fluoroquinolones as well as action by the consumer advocate group [[Public Citizen]].<ref>http://www.consumeraffairs.com/news04/2006/08/pubcit_cipro.html</ref><ref>http://www.mnd.uscourts.gov/MDL-Levaquin/index.shtml</ref> Partly as a result of the efforts of [[Public Citizen]] the FDA ordered a [[black box warning]]s on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.<ref>{{cite web |url=http://www.cnn.com/2008/HEALTH/07/08/antibiotics.risk/index.html|title=FDA orders 'black box' label on some antibiotics |accessdate=2008-07-08 |format= |work=}}</ref>

==Interactions==

The toxicity of drugs that are metabolised by the [[cytochrome P450]] system is enhanced by concomitant use of some quinolones. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. Coadministration may dangerously increase coumadin [[warfarin]] activity; INR should be monitored closely.
<ref> http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/019384s046LTR.pdf</ref>

They may also interact with the [[GABA A receptor]] and cause neurological symptoms; this effect is augmented by certain [[non-steroidal anti-inflammatory drug]]s.<ref>{{cite journal |author=Brouwers JR |title=Drug interactions with quinolone antibacterials |journal=Drug Saf |volume=7 |issue=4 |pages=268–81 |year=1992 |pmid=1524699 |doi=10.2165/00002018-199207040-00003 |month=Jul |first1=JR |issn=0114-5916 }}</ref>
The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, norfloxacin should be used with caution in individuals receiving NSAIDS concomitantly. <ref> http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/019384s045LTR.pdf</ref>

Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly.

The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered.

===Significant drug interactions===

Some quinolones exert an inhibitory effect on the cytochrome P-450 system, thereby reducing theophylline clearance and increasing theophylline blood levels. Coadministration of certain fluoroquinolones and other drugs primarily metabolized by CYP1A2 (e.g. theophylline, methylxanthines, tizanidine) results in increased plasma concentrations and could lead to clinically significant side effects of the coadministered drug. Additionally other fluoroquinolones, especially enoxacin, and to a lesser extent ciprofloxacin and pefloxacin, also inhibit the metabolic clearance of theophylline.<ref>{{cite journal |author=Janknegt R |title=Drug interactions with quinolones |journal=J. Antimicrob. Chemother. |volume=26 Suppl D |issue= |pages=7–29 |year=1990 |month=November |pmid=2286594 |doi= |url= |first1=R |issn=0305-7453}}</ref>

Such drug interactions are associated with the molecular structural modifications of the quinolone ring, specifically interactions involving [[NSAIDS]] and [[theophylline]]. As such, these drug interactions involving the fluoroquinolones appear to be drug specific rather than a class effect. The fluoroquinolones have also been shown to interfere with the metabolism of caffeine<ref>{{cite journal |author=Harder S, Fuhr U, Staib AH, Wolff T |title=Ciprofloxacin-caffeine: a drug interaction established using in vivo and in vitro investigations |journal=Am. J. Med. |volume=87 |issue=5A |pages=89S–91S |year=1989 |month=November |pmid=2589393 |doi= 10.1016/0002-9343(89)90031-4|url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+58-08-2 |first1=S |first2=U |first3=AH |first4=T |issn=0002-9343 |format=Free full text}}</ref> and the absorption of levothyroxine. The interference with the metabolism of caffeine may lead to the reduced clearance of caffeine and a prolongation of its serum half-life, resulting in a caffeine overdose. This may lead to reduced clearance of caffeine and a prolongation of it’s the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin.
<ref> http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/019384s046LTR.pdf</ref>

The use of NSAIDs (Non Steroid Anti Inflammatory Drugs) while undergoing fluoroquinolone therapy is contra-indicated due to the risk of severe CNS adverse reactions, including but not limited to seizure disorders. Fluoroquinolones with an unsubstituted piperazinyl moiety at position 7 have the potential to interact with NSAIDs and/or their metabolites, resulting in antagonism of GABA neurotransmission.<ref>{{cite journal |author=Domagala JM |title=Structure-activity and structure-side-effect relationships for the quinolone antibacterials |journal=J. Antimicrob. Chemother. |volume=33 |issue=4 |pages=685–706 |year=1994 |month=April |pmid=8056688 |doi= 10.1093/jac/33.4.685|url=http://jac.oxfordjournals.org/cgi/reprint/33/4/685 |first1=JM |issn=0305-7453}}</ref>

The use of norfloxacin concomitantly has also been associated with transient elevations in serum creatinine in patients receiving cyclosporine, on rare occasions, resulted in severe hypoglycemia with sulfonylurea. Renal tubular transport of methotrexate may be inhibited by concomitant administration of norfloxacin, potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate toxic reactions.

Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendon rupture, especially in elderly patients who are also taking the fluoroquinolones.<ref>{{cite journal |author=van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH |title=Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids |journal=Arch. Intern. Med. |volume=163 |issue=15 |pages=1801–7 |year=2003 |pmid=12912715 |doi=10.1001/archinte.163.15.1801 |url=http://archinte.ama-assn.org/cgi/content/full/163/15/1801 |month=Aug |first1=PD |first2=MC |first3=RM |first4=HM |first5=S |first6=BH |issn=0003-9926}}</ref>


== Susceptible bacteria==
== Susceptible bacteria==

Revision as of 03:19, 20 September 2009

Norfloxacin
Clinical data
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability30 to 40%
Protein binding10 to 15%
MetabolismHepatic
Elimination half-life3 to 4 hours
ExcretionRenal and fecal
Identifiers
  • 1-ethyl-6-fluoro-4-oxo-7-piperazin-1-yl-1H-quinoline-
    3-carboxylic acid
CAS Number
PubChem CID
DrugBank
CompTox Dashboard (EPA)
ECHA InfoCard100.067.810 Edit this at Wikidata
Chemical and physical data
FormulaC16H18FN3O3
Molar mass319.331 g/mol g·mol−1
  (verify)

Norfloxacin is a synthetic chemotherapeutic agent occasionally used to treat common as well as complicated urinary tract infections. It is sold under various brand names with the most common being Noroxin. In form of ophthalmic solutions it is known as Chibroxin. Norfloxacin is a second generation synthetic fluoroquinolone (quinolone) developed by Kyorin Seiyaku K.K. (Kyorin).[1]

The licensed uses for Norfloxacin are quite limited as Norfloxacin is to be considered a drug of last resort when all other antibiotics have failed. There are currently only three approved uses in the adult population[2] (one of which is restricted[3]) and the other ineffective due to bacterial resistance. Chibroxin[4] (ophthalmic) is approved use in children older than one year of age.

Norfloxacin interacts with a number of other drugs, as well as a number of herbal and natural supplements. Such interactions increase the risk of anticoagulation and the formation of non-absorbable complexes, as well as increasing the risk of toxicity.[5]

Norfloxacin is associated with a number of serious and life threatening adverse reactions as well as spontaneous tendon ruptures and irreversible peripheral neuropathy. Such reactions may manifest long after therapy had been completed and in severe cases may result in life long disabilities. Hepatoxicity resulting in fatalities has also been reported with the use of Norfloxacin.

History

Since its establishment in 1946, the Japanese Society of Chemotherapy (JSC) has been and currently is involved is the development of synthetic antibacterial agents from nalidixic acid and pipemidic acid, leading to new quinolones.[6] Subsequent work led to the birth of a new era with the introduction of norfloxacin as the first new quinolone in Japan in 1984 and then in many other countries throughout the world. Since the discovery of norfloxacin (1980), around 10,000 new analogues have been described. [7]

Norfloxacin was first patented in 1979.[8] Kyorin granted Merck & Company, Inc., an exclusive license (in certain countries, including the United States), to import and distribute Norfloxacin under the brand name Noroxin. The U.S. Food and Drug Administration (FDA) approved Noroxin for distribution in the United States on October 31, 1986.

Since the approval of Noroxin in 1986, there have been numerous upgrades to the warning sections of the package inserts, as well as recent restrictions placed upon the use of Noroxin to treat urinary tract infections (UTIs). In 2008 the European Medicines Agency had recommended restricting the use of oral Norfloxacin-containing medicines in urinary tract infections because the benefits did not outweigh the risks for this indication. At its July 2008 meeting, the agency's Committee for Medicinal Products for Human Use (CHMP) recommended restricting the use of Norfloxacin due to safety concerns and lack of proven efficacy for treating acute or chronic complicated pyelonephritis. [9]

Licensed uses

In the adult population Oral and I.V. Norfloxacin is limited to the treatment of proven bacterial infections. The initial approval by the U.S. Food and Drug Administration (FDA) in 1986 encompassed the following indications:

  • Uncomplicated urinary tract infections (including cystitis)
  • Complicated urinary tract infections (restricted use) [10]
  • Uncomplicated urethral and cervical gonorrhea (however this indication is no longer considered to be effective by some experts due to bacterial resistance) [11][12]
  • Prostatitis due to Escherichia coli.
  • Syphilis treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis.[13]

In ophthalmology, Norfloxacin licensed use is limited to the treatment of conjunctival infections caused by susceptible bacteria.[14]


Note: Norfloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.

Availability

Norfloxacin is available as:

  • tablets 400-mg
  • eye drops

In most countries, all formulations require a prescription.

See the latest package insert for norfloxacin (Noroxin) for additional details. [15]

Mode of action

Norfloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV,[16] enzymes necessary to separate bacterial DNA, thereby inhibiting cell division.

This mechanism can also affect mammalian cell replication. In particular, some congeners of this drug family (for example those that contain the C-8 fluorine),[17] display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models.[18] Although quinolones are highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986 (Hussy et al.).[19]

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.[20][21][22][23] As such some fluoroquinolones, including Norfloxacin, may cause injury to the chromosome of eukaryotic cells.[24][25][26][27][28][29]

There continues to be considerable debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe adverse reactions experienced by some patients following fluoroquinolone therapy.[18][30][31]

Contraindications

As noted above, under licensed use, norfloxacin is also now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance. [12]

There are three contraindications found within the 2008 package[32] insert:

  • ”Noroxin (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents.”
  • ”Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored.”
  • “Concomitant administration with tizanidine is contraindicated”

Norfloxacin is also considered to be contraindicated within the pediatric population.

  • Pregnancy

Norfloxacin has been reported to rapidly cross the blood-placenta and blood-milk barrier, and is extensively distributed into the fetal tissues.[33] For this reason norfloxacin and other fluoroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The fluoroquinolones have also been reported as being present in the mother’s milk and are passed on to the nursing child, which may increases the risk of the child suffering an adverse reaction even though the child had never been prescribed or taken any of the drugs found within this class.[34][35] Because safer alternatives are generally available norfloxacin is contraindicated during pregnancy, especially during the first trimester. The manufacturer only recommends use of norfloxacin during pregnancy when benefit outweighs risk.[36]


  • Pediatric population

A 1998 retrospective survey found that that numerous side effects have been recorded in reference to the unapproved use of norfloxacin in the pediatric population.[37] Fluoroquinolones are not licensed by the FDA for use in children due to the risk of fatalities[38] as well as permanent injury to the musculoskeletal system, with two exceptions. Ciprofloxacin is being licensed for the treatment of Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli and Inhalational Anthrax (post-exposure) and levofloxacin was recently licensed for the treatment of Inhalational Anthrax (post-exposure). However, the Fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

Adverse effects

See also: Adverse effects of fluoroquinolones

Fluoroquinolones are generally well tolerated with most side effects being mild and serious adverse effects being rare.[39][40] Some of the serious adverse effects which occur more commonly with fluoroquinolones than with other antibiotic drug classes include CNS and tendon toxicity.[41][42] The currently marketed quinolones have safety profiles similar to that of other antimicrobial classes.[43]

The serious events may occur with therapeutic or with acute overdose. At therapeutic doses they include: central nervous system toxicity, cardiovascular toxicity, tendon / articular toxicity, and rarely hepatic toxicity.[44] Events that may occur in acute overdose are rare and include: renal failure and seizure.[44] Children and the elderly are at greater risk.[42][39] Adverse reactions may manifest during, as well as after fluoroquinolone therapy.[45] Acute pancreatitis has been reported as a rare but serious adverse reaction of norfloxacin.[46]

Some groups refer to these adverse events as "fluoroquinolone toxicity". These groups of people claim to have suffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuit by people harmed by the use of fluoroquinolones as well as action by the consumer advocate group Public Citizen.[47][48] Partly as a result of the efforts of Public Citizen the FDA ordered a black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.[49]

Interactions

The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. Coadministration may dangerously increase coumadin warfarin activity; INR should be monitored closely. [50]

They may also interact with the GABA A receptor and cause neurological symptoms; this effect is augmented by certain non-steroidal anti-inflammatory drugs.[51] The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, norfloxacin should be used with caution in individuals receiving NSAIDS concomitantly. [52]

Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly.

The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered.

Significant drug interactions

Some quinolones exert an inhibitory effect on the cytochrome P-450 system, thereby reducing theophylline clearance and increasing theophylline blood levels. Coadministration of certain fluoroquinolones and other drugs primarily metabolized by CYP1A2 (e.g. theophylline, methylxanthines, tizanidine) results in increased plasma concentrations and could lead to clinically significant side effects of the coadministered drug. Additionally other fluoroquinolones, especially enoxacin, and to a lesser extent ciprofloxacin and pefloxacin, also inhibit the metabolic clearance of theophylline.[53]

Such drug interactions are associated with the molecular structural modifications of the quinolone ring, specifically interactions involving NSAIDS and theophylline. As such, these drug interactions involving the fluoroquinolones appear to be drug specific rather than a class effect. The fluoroquinolones have also been shown to interfere with the metabolism of caffeine[54] and the absorption of levothyroxine. The interference with the metabolism of caffeine may lead to the reduced clearance of caffeine and a prolongation of its serum half-life, resulting in a caffeine overdose. This may lead to reduced clearance of caffeine and a prolongation of it’s the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin. [55]

The use of NSAIDs (Non Steroid Anti Inflammatory Drugs) while undergoing fluoroquinolone therapy is contra-indicated due to the risk of severe CNS adverse reactions, including but not limited to seizure disorders. Fluoroquinolones with an unsubstituted piperazinyl moiety at position 7 have the potential to interact with NSAIDs and/or their metabolites, resulting in antagonism of GABA neurotransmission.[56]

The use of norfloxacin concomitantly has also been associated with transient elevations in serum creatinine in patients receiving cyclosporine, on rare occasions, resulted in severe hypoglycemia with sulfonylurea. Renal tubular transport of methotrexate may be inhibited by concomitant administration of norfloxacin, potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate toxic reactions.

Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendon rupture, especially in elderly patients who are also taking the fluoroquinolones.[57]

Susceptible bacteria

Gram-positive aerobes:

  • Enterococcus faecalis
  • Staphylococcus aureus
  • Staphylococcus epidermidis
  • Staphylococcus saprophyticus
  • Streptococcus agalactiae

Gram-negative aerobes:

  • Citrobacter freundii
  • Enterobacter aerogenes
  • Enterobacter cloacae
  • Escherichia coli
  • Klebsiella pneumoniae
  • Neisseria gonorrhoeae
  • Proteus mirabilis
  • Proteus vulgaris
  • Pseudomonas aeruginosa
  • Serratia marcescens

As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with Norfloxacin.

References

  1. ^ http://www.faqs.org/rulings/rulings1999HQ545710.html
  2. ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019384s052lbl.pdf
  3. ^ http://www.docguide.com/news/content.nsf/news/852571020057CCF68525749000687709
  4. ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19757S10lbl.pdf
  5. ^ http://www.drugbank.ca/drugs/DB01059
  6. ^ http://sciencelinks.jp/j-east/article/200109/000020010901A0173889.php
  7. ^ http://www.baytril.com/index.php/fuseaction/download/lrn_file/baytril-history_090112.pdf
  8. ^ http://www.uspto.gov/web/offices/pac/dapp/opla/term/certs/4146719.pdf
  9. ^ http://www.docguide.com/news/content.nsf/news/852571020057CCF68525749000687709
  10. ^ http://www.docguide.com/news/content.nsf/news/852571020057CCF68525749000687709
  11. ^ http://prod.hopkins-abxguide.org/literature_review/09-2007/update_to_cdc_s_sexually_transmitted_diseases_treatment.html?contentInstanceId=254789&siteId=153
  12. ^ a b Susan Blank (14th May 2004). "DOHMH ALERT #8:Fluoroquinolone-resistant gonorrhea, NYC". USA: New York County Medical Society. Retrieved 22 July 2009. {{cite web}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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  18. ^ a b Sissi C, Palumbo M (2003). "The quinolone family: from antibacterial to anticancer agents". Curr Med Chem Anticancer Agents. 3 (6): 439–50. doi:10.2174/1568011033482279. PMID 14529452. The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent. Indeed, a distinctive feature of drugs based on the quinolone structure is their remarkable ability to target different type II topoisomerase enzymes. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. {{cite journal}}: Unknown parameter |month= ignored (help)
  19. ^ Hussy P, Maass G, Tümmler B, Grosse F, Schomburg U (1986). "Effect of 4-quinolones and novobiocin on calf thymus DNA polymerase alpha primase complex, topoisomerases I and II, and growth of mammalian lymphoblasts" (PDF). Antimicrob. Agents Chemother. 29 (6): 1073–8. PMC 180502. PMID 3015015. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  21. ^ Forsgren A, Bredberg A, Pardee AB, Schlossman SF, Tedder TF (May 1987). "Effects of ciprofloxacin on eucaryotic pyrimidine nucleotide biosynthesis and cell growth". Antimicrob. Agents Chemother. 31 (5): 774–9. PMID 3606077. PMC: 174831. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=3606077.
  22. ^ Gootz TD, Barrett JF, Sutcliffe JA (1990). "Inhibitory effects of quinolone antibacterial agents on eucaryotic topoisomerases and related test systems". Antimicrob. Agents Chemother. 34 (1): 8–12. PMC 171510. PMID 2158274. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  23. ^ Lawrence JW, Darkin-Rattray S, Xie F, Neims AH, Rowe TC (1993). "4-Quinolones cause a selective loss of mitochondrial DNA from mouse L1210 leukemia cells". J. Cell. Biochem. 51 (2): 165–74. doi:10.1002/jcb.240510208. PMID 8440750. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  24. ^ Elsea SH, Osheroff N, Nitiss JL (1992). "Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast". J. Biol. Chem. 267 (19): 13150–3. PMID 1320012. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  26. ^ Enzmann H, Wiemann C, Ahr HJ, Schlüter G (1999). "Damage to mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey liver". Mutat. Res. 425 (2): 213–24. PMID 10216214. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  27. ^ Kashida Y, Sasaki YF, Ohsawa K; et al. (2002). "Mechanistic study on flumequine hepatocarcinogenicity focusing on DNA damage in mice". Toxicol. Sci. 69 (2): 317–21. doi:10.1093/toxsci/69.2.317. PMID 12377980. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  28. ^ Thomas A, Tocher J, Edwards DI (1990). "Electrochemical characteristics of five quinolone drugs and their effect on DNA damage and repair in Escherichia coli". J. Antimicrob. Chemother. 25 (5): 733–44. doi:10.1093/jac/25.5.733. PMID 2165050. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  29. ^ "Fluoroquinolones and Quinolones". The American Academy of Optometry (British Chapter). Retrieved 29 January 2009.
  30. ^ Yaseen A. Al-Soud; Najim A. Al-Masoudi (2003). "A new class of dihaloquinolones bearing N'-aldehydoglycosylhydrazides, mercapto-1,2,4-triazole, oxadiazoline and a-amino ester precursors: synthesis and antimicrobial activity". J. Braz. Chem. Soc. 14 (5). doi:10.1590/S0103-50532003000500014. Nevertheless, some quinolones cause injury to the chromosome of eukaryotic cells.21,22 These findings prompted us to optimize the substituent at C-3, by... {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
  31. ^ Yaseen A. Al-Soud a and Najim A. Al-Masoudi (2003). "A New Class of Dihaloquinolones Bearing N'-Aldehydoglycosylhydrazides, Mercapto-1,2,4-triazole, Oxadiazoline and α-Amino Ester Precursors: Synthesis and Antimicrobial Activity" (PDF). J. Braz. Chem. Soc. 14 (5): 790–796. Although the current quinolones are not considered to be potent inhibitors of eucaryotic topoisomerases, some effects on these and other enzymes involved with DNA replication have been observed
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