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{{Short description|Chemical compound}}
{{Drugbox {{Drugbox
| Verifiedfields = changed
| Watchedfields = changed | Watchedfields = changed
| verifiedrevid = 437181023 | verifiedrevid = 449919827
| IUPAC_name = (''RS'')-6-Fluoro-1-methyl-7--4-oxo-4''H''-thiazetoquinoline-3-carboxylic acid | IUPAC_name = (''RS'')-6-Fluoro-1-methyl-7--4-oxo-4''H''-thiazetoquinoline-3-carboxylic acid
| image = Prulifloxacin.png | image = Prulifloxacin.svg


<!--Clinical data--> <!--Clinical data-->
| tradename = | tradename = Quisnon, Unidrox, Prixina, Glimbax
| Drugs.com = {{drugs.com|international|prulifloxacin}} | Drugs.com = {{drugs.com|international|prulifloxacin}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> | legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = Rx-only (Japan, Italy) | legal_status = Rx-only (Japan, Italy, Austria)
| routes_of_administration = Oral | routes_of_administration = Oral


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<!--Identifiers--> <!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 123447-62-1 | CAS_number = 123447-62-1
| ATC_prefix = J01 | ATC_prefix = J01
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| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = J42298IESW | UNII = J42298IESW
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 422648

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 59351
| smiles = CC1N2C3=CC(=C(C=C3C(=O)C(=C2S1)C(=O)O)F)N4CCN(CC4)CC5=C(OC(=O)O5)C
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C21H20FN3O6S/c1-10-16(31-21(29)30-10)9-23-3-5-24(6-4-23)15-8-14-12(7-13(15)22)18(26)17(20(27)28)19-25(14)11(2)32-19/h7-8,11H,3-6,9H2,1-2H3,(H,27,28)
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = PWNMXPDKBYZCOO-UHFFFAOYSA-N


<!--Chemical data--> <!--Chemical data-->
| C=21 | H=20 | F=1 | N=3 | O=6 | S=1 | C=21 | H=20 | F=1 | N=3 | O=6 | S=1
| molecular_weight = 461.463403 g/mol
}} }}
'''Prulifloxacin''' is an older synthetic ] ] of the fluoro] drug class<ref>{{cite journal |last1=Nelson |first1=Jennifer M. |last2=Chiller |first2=Tom M. |last3=Powers |first3=John H. |last4=Angulo |first4=Frederick J. |title=Food Safety: Fluoroquinolone‐Resistant Campylobacter Species and the Withdrawal of Fluoroquinolones from Use in Poultry: A Public Health Success Story |journal=Clinical Infectious Diseases |volume=44 |issue=7 |pages=977–80 |year=2007 |pmid=17342653 |doi=10.1086/512369}}</ref><ref>{{cite journal |author=Kawahara S |title= |language=Japanese |journal=Nippon Rinsho |volume=56 |issue=12 |pages=3096–9 |year=1998 |pmid=9883617}}</ref> currently undergoing clinical trials prior to a possible NDA (New Drug Application) submission to the U.S. Food and Drug Administration (FDA). It is a ] which is metabolized in the body to the active compound ulifloxacin.<ref name="autogenerated1221">{{cite journal |last1=Fritsche |first1=T. R. |last2=Biedenbach |first2=D. J. |last3=Jones |first3=R. N. |title=Antimicrobial Activity of Prulifloxacin Tested against a Worldwide Collection of Gastroenteritis-Producing Pathogens, Including Those Causing Traveler's Diarrhea |journal=Antimicrobial Agents and Chemotherapy |volume=53 |issue=3 |pages=1221–4 |year=2008 |pmid=19114678 |pmc=2650572 |doi=10.1128/AAC.01260-08}}</ref><ref name=pmid19207096>{{cite journal |last1=Giannarini |first1=Gianluca |last2=Tascini |first2=Carlo |last3=Selli |first3=Cesare |title=Prulifloxacin: clinical studies of a broad-spectrum quinolone agent |journal=Future Microbiology |volume=4 |pages=13–24 |year=2009 |pmid=19207096 |doi=10.2217/17460913.4.1.13}}</ref> It was developed over two decades ago by Nippon Shinyaku Co. and was patented in Japan in 1987 and in the United States in 1989.<ref>{{Ref patent |country=JP |number=1294680 |status=patent |title=Quinolinecarboxylic Acid Derivative |gdate={{Date|1989-11-28|mdy}} |inventor=Kise Masahiro; Kitano Masahiko; Ozaki Masakuni; Kazuno Kenji; Matsuda Masato; Shirahase Ichiro; Segawa Jun}}</ref><ref name="drugfuture.com">. Drugfuture.com. Retrieved on 2010-11-03.</ref> '''Prulifloxacin''' is an older synthetic ] of the ] class<ref>{{cite journal | vauthors = Nelson JM, Chiller TM, Powers JH, Angulo FJ | title = Food Safety: Fluoroquinolone-Resistant Campylobacter Species and the Withdrawal of Fluoroquinolones from Use in Poultry: A Public Health Success Story | journal = Clinical Infectious Diseases | volume = 44 | issue = 7 | pages = 977–80 | year = 2007 | pmid = 17342653 | doi = 10.1086/512369 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kawahara S | title = | language = ja | journal = Nippon Rinsho | volume = 56 | issue = 12 | pages = 3096–9 | year = 1998 | pmid = 9883617 }}</ref> undergoing clinical trials prior to a possible NDA (New Drug Application) submission to the U.S. Food and Drug Administration (FDA). It is a ] which is metabolized in the body to the active compound ulifloxacin.<ref name="autogenerated1221">{{cite journal | vauthors = Fritsche TR, Biedenbach DJ, Jones RN | title = Antimicrobial Activity of Prulifloxacin Tested against a Worldwide Collection of Gastroenteritis-Producing Pathogens, Including Those Causing Traveler's Diarrhea | journal = Antimicrobial Agents and Chemotherapy | volume = 53 | issue = 3 | pages = 1221–4 | year = 2008 | pmid = 19114678 | pmc = 2650572 | doi = 10.1128/AAC.01260-08 }}</ref><ref name=pmid19207096>{{cite journal | vauthors = Giannarini G, Tascini C, Selli C | title = Prulifloxacin: clinical studies of a broad-spectrum quinolone agent | journal = Future Microbiology | volume = 4 | issue = 1 | pages = 13–24 | year = 2009 | pmid = 19207096 | doi = 10.2217/17460913.4.1.13 }}</ref> It was developed over two decades ago by Nippon Shinyaku Co. and was patented in Japan in 1987 and in the United States in 1989.<ref>{{Ref patent |country=JP |number=1294680 |status=patent |title=Quinolinecarboxylic Acid Derivative |gdate=November 28, 1989 |inventor=Kise Masahiro; Kitano Masahiko; Ozaki Masakuni; Kazuno Kenji; Matsuda Masato; Shirahase Ichiro; Segawa Jun}}</ref>


It has been approved for the treatment of uncomplicated and complicated urinary tract infections, community-acquired respiratory tract infections in Italy and gastroenteritis, including infectious diarrheas, in Japan.<ref name="autogenerated1221"/><ref>{{cite journal |author=Anonymous |title=Prulifloxacin &#91;'Quisnon'; Nippon Shinyaku&#93; has been approved in Japan |journal=Inpharma |year=2002 |volume=1 |issue=1362 |page=22 |url=http://www.ingentaconnect.com/content/adis/inp/2002/00000001/00001362/art00025}}</ref> Prulifloxacin has not been approved for use in the United States. It has been approved for the treatment of uncomplicated and complicated urinary tract infections, community-acquired respiratory tract infections in Italy and gastroenteritis, including infectious diarrheas, in Japan.<ref name="autogenerated1221"/><ref>{{cite journal |author=Anonymous |title=Prulifloxacin &#91;'Quisnon'; Nippon Shinyaku&#93; has been approved in Japan |journal=Inpharma |year=2002 |volume=1 |issue=1362 |page=22 |url=http://www.ingentaconnect.com/content/adis/inp/2002/00000001/00001362/art00025}}</ref> Prulifloxacin has not been approved for use in the United States.


==History== ==History==
In 1987 a European Patent (EP 315828) for prulifloxacin (Quisnon ) was issued to the Japanese based pharmaceutical company, Nippon Shinyaku Co., Ltd (Nippon). Ten years after the issuance of the European patent, marketing approval was applied for and granted in Japan (March 1997). Subsequent to being approved by the Japanese authorities in 1997 prulifloxacin (Quisnon) was co-marketed and jointly developed in Japan with Meiji Seika as licensee (Sword).<ref name="drugfuture.com"/> In 1987 a European patent for prulifloxacin was issued to the Japanese-based pharmaceutical company, Nippon Shinyaku Co., Ltd (Nippon).<ref>{{Cite patent | country = EU | number = 315828}}</ref> Ten years after the issuance of the European patent, marketing approval was applied for and granted in Japan (March 1997). Subsequent to being approved by the Japanese authorities in 1997 prulifloxacin was co-marketed and jointly developed in Japan with Meiji Seika as licensee (Sword).


In more recent times, Angelini ACRAF SpA, under license from Nippon Shinyaku, has fully developed prulifloxacin, for the European market.<ref>. Angelinipharma.com. Retrieved on 2010-11-03.</ref> In more recent times, Angelini ACRAF SpA, under license from Nippon Shinyaku, has fully developed prulifloxacin, for the European market.<ref> {{Webarchive|url=https://web.archive.org/web/20120308055624/http://www.angelinipharma.com/en/corporate-file/R-D.htm |date=2012-03-08 }}. Angelinipharma.com. Retrieved on 2010-11-03.</ref>
Angelini is the licensee for the product in Italy. Following its launch in Italy, Angelini launched prulifloxacin in Portugal (January 2007) and it has been stated that further approvals will be sought in other European countries.<ref>, Annual Report 2007</ref><ref>{{cite journal|title=Prulifloxacin. NAD-441A, NM 441, Quisnon.|journal=Drugs in R&D|volume=3|issue=6|pages=426–30|year=2002|pmid=12516950}}</ref> Angelini is the licensee for the product in Italy. Following its launch in Italy, Angelini launched prulifloxacin in Portugal (January 2007) and it has been stated that further approvals will be sought in other European countries.<ref>, Annual Report 2007</ref><ref>{{cite journal | title = Prulifloxacin. NAD-441A, NM 441, Quisnon | journal = Drugs in R&D | volume = 3 | issue = 6 | pages = 426–30 | year = 2002 | pmid = 12516950 | doi = 10.2165/00126839-200203060-00013 }}</ref>


Prulifloxacin is currently marketed in Japan and Italy as Quisnon (Nippon Shinyaku); Sword (Meiji); Unidrox (Angelini) and generic as Pruquin. Prulifloxacin is marketed in Japan and Italy as Quisnon (Nippon Shinyaku); Sword (Meiji); Unidrox (Angelini); Prixina (Angelini) and Glimbax (ITF Hellas) in Greece and generic as Pruquin.


In 1989 and 1992 United States patents (US 5086049) were issued to Nippon Shinyaku for prulifloxacin. It was not until June 2004, when Optimer Pharmaceuticals acquired exclusive rights to discover, develop and commercialize prulifloxacin (Pruvel) in the U.S. from Nippon Shinyaku Co., Ltd., that there were any attempts to seek FDA approval to market the drug in the United States. Optimer Pharmaceuticals In 1989 and 1992 United States patents (US 5086049) were issued to Nippon Shinyaku for prulifloxacin. It was not until June 2004, when Optimer Pharmaceuticals acquired exclusive rights to discover, develop and commercialize prulifloxacin (Pruvel) in the U.S. from Nippon Shinyaku Co., Ltd., that there were any attempts to seek FDA approval to market the drug in the United States. Optimer Pharmaceuticals
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==Licensed uses== ==Licensed uses==
Prulifloxacin has been approved in Italy and Japan, (as indicated), for treatment of infections caused by susceptible bacteria, in the following conditions: Prulifloxacin has been approved in Italy, Japan, China, India and Greece (as indicated), for treatment of infections caused by susceptible bacteria, in the following conditions:


;Italy ;Italy
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Like other fluoroquinolones, Prulifloxacin prevents bacterial DNA replication, transcription, repair and recombination through inhibition of bacterial DNA gyrase. Like other fluoroquinolones, Prulifloxacin prevents bacterial DNA replication, transcription, repair and recombination through inhibition of bacterial DNA gyrase.


Quinolones and fluoroquinolones are bactericidal drugs, eradicating bacteria by interfering with ].
Quinolones and fluoroquinolones are chemotherapeutic bactericidal drugs, eradicating bacteria by interfering with ]. The other ]s used today, (e.g., tetracyclines, lincomycin, erythromycin, and chloramphenicol) do not interact with components of ] ] particle and, thus, have proven not to be toxic to eukaryotes,<ref>{{Cite book|last1=Murray |first1=Robert K. |last2=Granner |first2=Darryl K. |last3=Mayes |first3=Peter A. |last4=Rodwell |first4=Victor W. |title=Harper's Illustrated Biochemistry |url=http://books.google.com/?id=QrJCZ1v5T6AC |edition=27 |date=1 July 2006 |publisher=McGraw-Hill Medical |isbn=0071461973 |page=378 |chapter=Protein Synthesis and the Genetic Code |quote=The most useful members of this class of antibiotics (eg tetracyclines, lincomycin, erythromycin and chloramphenicol) do not interact with components of eukaryotic ribosomal particles and thus are not toxic to eukaryotes... }}</ref> as opposed to the fluoroquinolone class of drugs. Safer drugs used to treat bacterial infections, such as ]s and ]s, inhibit cell wall biosynthesis, thereby causing bacterial cell death, as opposed to the interference with DNA replication as seen within the fluoroquinolone class of drugs.


Quinolones are synthetic agents that have a broad spectrum of antimicrobial activity as well as a unique mechanism of action, resulting in inhibition of bacterial ] and ]. Quinolones inhibit the bacterial ] or the ] enzyme, thereby inhibiting ] replication and ]. For many ], DNA gyrase is the target, whereas topoisomerase IV is the target for many ]. It is believed that eukaryotic cells do not contain DNA gyrase or topoisomerase IV.
Quinolones are synthetic chemotherapeutic agents that have a broad spectrum of antimicrobial activity as well as a unique mechanism of action, resulting in inhibition of bacterial ] and ]. Quinolones inhibit the bacterial ] or the ] enzyme, thereby inhibiting ] replication and ]. Quinolones can enter cells easily via ] and, therefore, are often used to treat ] ]s such as '']'' and '']''. For many ], DNA gyrase is the target, whereas topoisomerase IV is the target for many ]. It is believed that eukaryotic cells do not contain DNA gyrase or topoisomerase IV. However, there is debate concerning whether the quinolones still have such an adverse effect on the DNA of healthy cells, in the manner described above, hence contributing to their adverse safety profile. This class has been shown to damage ].<ref name=pofq1988>{{cite journal |author=Bergan T. |coauthors=Bayer |year=1988 |title=Pharmacokinetics of fluorinated quinolones |journal=Academic Press |pages=119–154 }}</ref><ref>{{cite journal |author=Bergan T |coauthors=Dalhoff A, Thorsteinsson SB |year=1985 |title=A review of the pharmacokinetics and tissue penetration of ciprofloxacin |pages=23–36 |publisher= }}</ref><ref>{{cite journal |last1=Castora |first1=FJ |last2=Vissering |first2=FF |last3=Simpson |first3=MV |title=The effect of bacterial DNA gyrase inhibitors on DNA synthesis in mammalian mitochondria. |journal=Biochimica et biophysica acta |volume=740 |issue=4 |pages=417–27 |year=1983 |pmid=6309236}}</ref><ref>{{cite journal |last1=Kaplowitz |first1=Neil |title=Hepatology highlights |journal=Hepatology |volume=41 |pages=227–8 |year=2005 |doi=10.1002/hep.20596}}</ref><ref>{{cite journal |last1=Enzmann |first1=H |last2=Wiemann |first2=C |last3=Ahr |first3=HJ |last4=Schlüter |first4=G |title=Damage to mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey liver. |journal=Mutation research |volume=425 |issue=2 |pages=213–24 |year=1999 |pmid=10216214 |doi=10.1016/S0027-5107(99)00044-5}}</ref><ref>{{cite journal |author=MCQUEEN CA. |coauthors=WILLIAMS GM. |year=1987 |title=Effects of quinolone antibiotics in tests for genotoxicity |journal=Am. J. Med |volume=82 |issue=Suppl. 4A |pages=94–96 }}</ref><ref>{{cite journal |last1=Holden |first1=Henry E. |last2=Barett |first2=John F. |last3=Huntington |first3=Channing M. |last4=Muehlbauer |first4=Paula A. |last5=Wahrenburg |first5=Margitta G. |title=Genetic profile of a nalidixic acid analog: A model for the mechanism of sister chromatid exchange induction |journal=Environmental and Molecular Mutagenesis |volume=13 |issue=3 |pages=238–52 |year=1989 |pmid=2539998 |doi=10.1002/em.2850130308}}</ref><ref>{{cite journal |last1=Suto |first1=Mark J. |last2=Domagala |first2=John M. |last3=Roland |first3=Gregory E. |last4=Mailloux |first4=Gail B. |last5=Cohen |first5=Michael A. |title=Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity and antimicrobial activity |journal=Journal of Medicinal Chemistry |volume=35 |issue=25 |pages=4745–50 |year=1992 |pmid=1469702 |doi=10.1021/jm00103a013}}</ref>


==Contraindications== ==Contraindications==
There are only four contraindications found within the package insert: There are only four contraindications found within the package insert:
<ref name="cipladoc.com"></ref> <ref name="cipladoc.com"> {{webarchive|url=https://web.archive.org/web/20101102142625/http://cipladoc.com/therapeutic/pdf_cipla/pruflox.pdf |date=2010-11-02 }}</ref>


*"Avoid using Prulifloxacin in elderly population (Risk of Tendon damage)."
*“Prulifloxacin is contraindicated in patients with anamnesis of tendon diseases related to the administration of quinolones.” *"Prulifloxacin is contraindicated in patients with anamnesis of tendon diseases related to the administration of quinolones."
⚫ *"Prulifloxacin is contraindicated in persons with a history of hypersensitivity to Prulifloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components."
⚫ *"Prulifloxacin is contraindicated in subjects with celiac disease."'
⚫ *"Prulifloxacin is also considered to be contraindicated within the pediatric population, ], nursing mothers, and in patients with ] or other seizure disorders."


==Special populations==
⚫ *“Prulifloxacin is contraindicated in persons with a history of hypersensitivity to Prulifloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components.”
⚫ ===Pregnancy===
⚫ The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. The fluoroquinolones have also been reported as being present in the mother’s milk and are passed on to the nursing child.<ref>{{cite journal | vauthors = Shin HC, Kim JC, Chung MK, Jung YH, Kim JS, Lee MK, Amidon GL | title = Fetal and maternal tissue distribution of the new fluoroquinolone DW-116 in pregnant rats | journal = Comparative Biochemistry and Physiology C | volume = 136 | issue = 1 | pages = 95–102 | year = 2003 | pmid = 14522602 | doi = 10.1016/j.cca.2003.08.004 }}</ref><ref>{{cite journal | vauthors = Dan M, Weidekamm E, Sagiv R, Portmann R, Zakut H | title = Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women | journal = Antimicrob. Agents Chemother. | volume = 37 | issue = 2 | pages = 293–6 | year = 1993 | pmid = 8452360 | pmc = 187655 | doi = 10.1128/AAC.37.2.293 }}</ref>


⚫ ===Pediatric population===
⚫ *“Prulifloxacin is contraindicated in subjects with celiac disease.”'
⚫ Fluoroquinolones are not licensed by the U.S. FDA for use in children due to the risk of permanent injury to the musculoskeletal system, with two exceptions. However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

⚫ *”Prulifloxacin is also considered to be contraindicated within the pediatric population, ], nursing mothers, and in patients with ] or other seizure disorders.”

⚫ *'''Pregnancy'''
⚫ The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. For this reason the 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 from this syndrome as well, even though the child had never been prescribed or taken any of the drugs found within this class.<ref>{{cite journal |last1=Shin |first1=H |last2=Kim |first2=JC |last3=Chung |first3=MK |last4=Jung |first4=YH |last5=Kim |first5=JS |last6=Lee |first6=MK |last7=Amidon |first7=GL |title=Fetal and maternal tissue distribution of the new fluoroquinolone DW-116 in pregnant rats |journal=Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology |volume=136 |issue=1 |pages=95–102 |year=2003 |doi=10.1016/j.cca.2003.08.004 |pmid=14522602}}</ref><ref>{{cite journal |author=Dan M, Weidekamm E, Sagiv R, Portmann R, Zakut H |title=Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women |journal=Antimicrob. Agents Chemother. |volume=37 |issue=2 |pages=293–6 |year=1993 |pmid=8452360 |pmc=187655 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=8452360 |first1=M |first2=E |first3=R |first4=R |first5=H |issn=0066-4804}}</ref>

⚫ *'''Pediatric population'''
⚫ Fluoroquinolones are not licensed by the U.S. FDA for use in children due to the risk of fatalities<ref name="pmid1592498">{{cite journal |author=Karande SC, Kshirsagar NA |title=Adverse drug reaction monitoring of ciprofloxacin in pediatric practice |journal=Indian Pediatr |volume=29 |issue=2 |pages=181–8 |year=1992 |pmid=1592498 |first1=SC |first2=NA |issn=0019-6061 |format=Free full text}}</ref> as well as permanent injury to the musculoskeletal system, with two exceptions. However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

Within the United States, the FDA has stated that it is their intention to pursue the licensing of the fluoroquinolones for pediatric use in spite of the evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee that the fluoroquinolones cause irreversible joint damage in the pediatric population.<ref>62 Meeting of the Anti-Infective Drugs Advisory Committee http://fqresearch.org/pdf_files/62nd_fda_meeting.pdf</ref>

*'''Depression and anxiety disorders'''
Prulifloxacin has highly pronounced side-effects in people suffering from ] or/and ]. There have been reported cases of psychosis, suicide attempts, panic attacks and acute anxiety, all occurring during or shortly after fluoroquinolone treatment. Patients with previous or current psychiatric conditions, are prone to experiencing this type of side-effect. Caution is highly advised.


==Special precautions== ==Special precautions==
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"When treated with antibacterial agents of the quinolone group, patients with latent or known deficiencies for the glucose-6-phosphate dehydrogenase activity are predisposed to hemolytic reactions."<ref name="cipladoc.com"/> "When treated with antibacterial agents of the quinolone group, patients with latent or known deficiencies for the glucose-6-phosphate dehydrogenase activity are predisposed to hemolytic reactions."<ref name="cipladoc.com"/>


==Adverse Eevents== ==Adverse Events==
⚫ Within one review prulifloxacin was stated to have a similar tolerability profile to that of ciprofloxacin.<ref>{{cite journal | vauthors = Keam SJ, Perry CM | title = Prulifloxacin | journal = Drugs | volume = 64 | issue = 19 | pages = 2221–34; discussion 2235–6 | year = 2004 | pmid = 15456336 | doi = 10.2165/00003495-200464190-00005 }}</ref>
{{See also|Adverse effects of fluoroquinolones}}
⚫ Within another study it was found that prulifloxacin patients experienced a similar number of adverse reactions compared to those in the ciprofloxacin group (15.4% vs 12.7%). There were four serious adverse events in each treatment arm, including 1 death in the prulifloxacin arm. None were considered treatment related by the investigator.<ref>{{cite journal | vauthors = Grassi C, Salvatori E, Rosignoli MT, Dionisio P | title = Randomized, Double-Blind Study of Prulifloxacin versus Ciprofloxacin in Patients with Acute Exacerbations of Chronic Bronchitis | journal = Respiration | volume = 69 | issue = 3 | pages = 217–22 | year = 2002 | pmid = 12097764 | doi = 10.1159/000063623 | s2cid = 25523559 }}</ref> If approved in the U.S., prulifloxacin will likely carry a black box warning for tendon damage, as the FDA has determined that this is a class effect of fluoroquinolones.<ref>{{cite news|url=http://www.cnn.com/2008/HEALTH/07/08/antibiotics.risk/index.html |title=FDA orders 'black box' label on some antibiotics |publisher=CNN.com |date=2008-07-08 |access-date=2010-03-19}}</ref>
There is limited data to be found within the literature, (other than older animal studies) regarding the tolerability of prulifloxacin and what is stated appears to be contradictory.


⚫ Prulifloxacin has a reduced effect on the QTc interval compared to other fluoroquinolones and may be a safer choice for patients with pre-existing risk factors for arrhythmia.<ref name="repolarization5">{{cite journal | vauthors = Rosignoli MT, Di Loreto G, Dionisio P | title = Effects of Prulifloxacin on Cardiac Repolarization in Healthy Subjects | journal = Clinical Drug Investigation | volume = 30 | issue = 1 | pages = 5–14 | year = 2010 | pmid = 19995094 | doi = 10.2165/11319400-000000000-00000 | s2cid = 10169230 }}</ref><ref>{{cite journal | vauthors = Malik M | title = Does the Prulifloxacin ECG Study Prove Cardiac Safety of the Drug? | journal = Clinical Drug Investigation | volume = 30 | issue = 1 | pages = 1–3 | year = 2010 | pmid = 19995093 | doi = 10.2165/11319780-000000000-00000 | s2cid = 19677457 }}</ref>
⚫ Within one review prulifloxacin was stated to have a similar tolerability profile to that of ciprofloxacin.<ref>{{cite journal |last1=Keam |first1=Susan J |last2=Perry |first2=Caroline M |title=Prulifloxacin |journal=Drugs |volume=64 |pages=2221–34; discussion 2235–6 |year=2004 |doi=10.2165/00003495-200464190-00005}}</ref>
⚫ Within another study it was found that prulifloxacin patients experienced a larger number of adverse reactions as compared to those in the ciprofloxacin group (16% vs 12.5%). Of the four serious adverse events in the prulifloxacin group one was diagnosed as cardiorespiratory insufficiency which resulted in the death of the patient, although this death was not believed to be related to prulifloxacin.<ref>{{cite journal |last1=Grassi |first1=Carlo |last2=Salvatori |first2=Enrica |last3=Rosignoli |first3=Maria Teresa |last4=Dionisio |first4=Paolo |last5=Prulifloxacin Study |first5=Group |title=Randomized, Double-Blind Study of Prulifloxacin versus Ciprofloxacin in Patients with Acute Exacerbations of Chronic Bronchitis |journal=Respiration |volume=69 |issue=3 |pages=217–22 |year=2002 |pmid=12097764 |doi=10.1159/000063623}}</ref> Ciprofloxacin has an adverse drug reaction rate (one or more reactions) of 16.5%<ref>{{cite web|url=http://fqresearch.org/pdf_files/60day_cipro_study.pdf |title=1013-1159_Bio_Anthrax.fm |format=PDF |accessdate=2010-03-19}}</ref> as well as a Black Box Warning concerning spontaneous tendon ruptures.<ref>{{cite web|url=http://fqresearch.org/pdf_files/updated_labels/cipro_10_2008.pdf |title=label |format=PDF |accessdate=2010-03-19}}</ref> The FDA has requested that all drugs within this class carry such a Black Box Warning, and prulifloxacin would be no exception should it be approved for use in the United States in the future.<ref>{{cite news|url=http://www.cnn.com/2008/HEALTH/07/08/antibiotics.risk/index.html |title=FDA orders 'black box' label on some antibiotics |publisher=CNN.com |date=2008-07-08 |accessdate=2010-03-19}}</ref>


⚫ == Interactions ==
As previously noted the FDA had recommended that sponsor conduct a study to determine the effect of prulifloxacin on the prolongation of the QT interval, a condition that is associated with potentially life-threatening cardiac arrhythmias and death.<ref name=OPTR6061153>{{cite web|url=http://apps.shareholder.com/sec/viewerContent.aspx?companyid=OPTR&docid=6061153 |title=Optimer Pharmaceuticals, Inc. – Prospectus Filed Pursuant to Rule 424 |publisher=Apps.shareholder.com |accessdate=2010-03-19}}</ref>
⚫ The results of one such cardiac study stated that "...prulifloxacin at steady state after therapeutic doses has no significant effects on the QTc interval and thus should prove to have no cardiac liability."<ref name="repolarization5">{{cite journal |last1=Rosignoli |first1=Maria Teresa |last2=Di Loreto |first2=Giorgio |last3=Dionisio |first3=Paolo |title=Effects of Prulifloxacin on Cardiac Repolarization in Healthy Subjects |journal=Clinical Drug Investigation |volume=30 |issue=1 |pages=5–14 |year=2010 |pmid=19995094 |doi=10.2165/11319400-000000000-00000}}</ref> The results of this trial were challenged by Malik ''et al.'' who questioned the validity of using an ECG study to prove the cardiac safety of the drug.<ref>{{cite journal |last1=Malik |first1=Marek |title=Does the Prulifloxacin ECG Study Prove Cardiac Safety of the Drug? |journal=Clinical Drug Investigation |volume=30 |issue=1 |pages=1–3 |year=2010 |pmid=19995093 |doi=10.2165/11319780-000000000-00000}}</ref>
Other drugs within this class (i.e. grepafloxacin, sparfloxacin, moxifloxacin, levofloxacin, gatifloxacin, gemifloxacin) have also been associated with QT interval prolongation, resulting in sudden death of the patient. Grepafloxacin and Sparfloxacin were removed from clinical use due to this adverse event.
<ref>Kimberly Madewell, , Infectious Disease News, August 1, 2005</ref>


⚫ *]: Prulifloxacin urinary excretion decreases when concomitantly administered with probenecid.<ref name="cipladoc.com"/>
The United States sponsor reports that patients treated with prulifloxacin have experienced serious drug-related side effects including renal toxicities, cardiac arrhythmias, photosensitivity, and central nervous system effects, such as seizures.<ref name=OPTR6061153/>
⚫ *]: The concomitant administration of fenbufen can cause increased risk of convulsions.<ref name="cipladoc.com"/>

⚫ *]s: May cause hypoglycemia in diabetic patients under treatment with hypoglycemic agents.<ref name="cipladoc.com"/>
Future clinical trials, which will involve testing in larger patient populations, may reveal a high prevalence of these or other side effects. In such an event, clinical trials would be interrupted, delayed or halted by the U.S. FDA or comparable foreign regulatory authorities. Such regulatory agencies could then prevent further development of prulifloxacin or ultimately deny its approval. The sponsor of prulifloxacin has stated that such a delay or denial would significantly harm the commercial prospects of prulifloxacin.<ref>Annual Report 2008, p. 23</ref>
⚫ *]: May cause a decreased theophylline clearance.<ref name="cipladoc.com"/>

⚫ *]: May enhance the effects of oral anticoagulants such as warfarin and its derivatives.<ref name="cipladoc.com"/>
==History of the black box warnings==
⚫ *]: May potentiate the phototoxicity of prulifloxacin.<ref name="cipladoc.com"/>
{{See also|Quinolone#Black box warnings}}
Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to ].<ref name="autogenerated604">{{cite journal |author=Bailey RR, Natale R, Linton AL |title=Nalidixic acid arthralgia |journal=Can Med Assoc J |volume=107 |issue=7 |pages=604 passim |year=1972 |pmid=4541768 |pmc=1940945 |first1=RR |first2=R |first3=AL |issn=0008-4409}}</ref> Rheumatic disease after use of a fluoroquinolone (]) was first reported eleven years later.<ref name="autogenerated590">{{cite journal |author=Bailey RR, Kirk JA, Peddie BA |title=Norfloxacin-induced rheumatic disease |journal=N Z Med J |volume=96 |issue=736 |page=590 |year=1983|pmid=6223241 |first1=RR |first2=JA |first3=BA}}</ref> In response to a 1995 letter published in the '']'', representatives of the ] (FDA) stated that the agency would "update the labeling for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture."<ref name="autogenerated193">{{cite journal |last1=Szarfman |first1=A |last2=Chen |first2=M |last3=Blum |first3=MD |title=More on Fluoroquinolone Antibiotics and Tendon Rupture |journal=New England Journal of Medicine |volume=332 |issue=3 |page=193 |year=1995 |doi=10.1056/NEJM199501193320319 |pmid=7800023}}</ref>

By August 1996, the FDA had not taken action, and the consumer advocacy group ] filed a petition with the FDA prompting the agency to act.<ref>{{cite web|title=Petition to Require a Warning on All Fluoroquinolone Antibiotics (HRG Publication #1399) |date=August 1, 1996 |publisher=] |url=http://www.citizen.org/publications/release.cfm?ID=6595}} Retrieved on December 27, 2008.</ref> Two months later, the FDA published an alert in the ''FDA Medical Bulletin'' and requested that fluoroquinolone package inserts be amended to include information on this risk.<ref name=FDA1996>{{cite journal |title=Reports of adverse events with fluoroquinolones |journal=FDA Medical Bulletin |year=1996 |volume=26 |issue=3 |url=http://www.fqresearch.org/text_documents/FDA_Medical_Bulletin_1996.doc |format=Doc}}</ref>

Nine years later, in 2005, the ] filed a second petition with the FDA again seeking ]s and "Dear Doctor" letters emphasizing the risk of tendon rupture; the FDA responded that it had not yet been able to reach a decision on the matter.<ref name=Madigan>{{cite press release |title=Madigan, Public Citizen, petition FDA for "Black Box" warning regarding potential adverse effects of certain popular antibiotics |date=August 29, 2006 |publisher=Office of the Illinois Attorney General |url=http://www.illinoisattorneygeneral.gov/pressroom/2006_08/20060829.html|accessdate = 2008-12-27}} Full text of the and available from the Fluoroquinolone Toxicity Research Foundation, a U.S. consumer advocacy group.</ref> In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for Black Box Warnings by filing a third petition requesting such changes be made.<ref name=Madigan/><ref>{{cite web|title=Public Citizen Petitions the FDA to Include a Black Box Warning on Fluoroquinolone Antibiotics (HRG Publication #1781) |date=August 29, 2006 |publisher=Public Citizen |url=http://www.citizen.org/publications/release.cfm?ID=7453|accessdate = 2008-12-27}}</ref> When the FDA failed to respond to these two petitions as required by law Public Citizen, in January 2008, filed suit to compel the FDA to respond to their 2006 petition.<ref>{{cite web|url=http://www.citizen.org/litigation/forms/cases/CaseDetails.cfm?cID=444 |title=Public Citizen v. Food and Drug Administration (FDA) (Fluoroquinolone) |date=January 3, 2008 |publisher=Public Citizen|accessdate = 2008-12-27}}</ref><ref>{{cite news |last=Ravn |first=Karen |title=Behind the FDA’s ‘black box’ warnings |date=August 18, 2008 |publisher=] |url=http://articles.latimes.com/2008/aug/18/health/he-closer18|accessdate = 2008-12-27}}</ref> On July 7, 2008 the FDA requested that the makers of systemic-use fluoroquinolones add a boxed warning regarding spontaneous tendon ruptures, and to develop a Medication Guide for patients.<ref name=FDA>{{cite press release |url=http://www.fda.gov/bbs/topics/NEWS/2008/NEW01858.html |title=FDA Requests Boxed Warnings on Fluoroquinolone Antimicrobial Drugs |publisher=] |date= 2008-07-08|accessdate = 2008-10-11}}</ref> The package inserts for Ciprofloxacin, Avelox (]), Proquin XR, Factive (]), Floxin (]), Noroxin (]) and Levaquin (]) were amended on September 8, 2008 to include these new warnings.<ref>The complete labeling history of each drug is available from . Medication Guides are available from the FDA's system.</ref> ], which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes.<ref>{{cite web|last=MacCarthy |first=Paul |title=Important Change in the Avelox (moxifloxacin hydrochloride) and Cipro (ciprofloxacin) Complete Prescribing Information&nbsp;– Addition of Boxed Warning and Medication Guide Regarding Tendinitis and Tendon Rupture |date=October 22, 2008 |publisher=Bayer HealthCare Pharmaceuticals |url=http://www.cipro.com/html/pdf/dhpl.pdf |format=PDF| accessdate= 2008-12-27}}</ref> ], the manufacturers of Levaquin, issued a similar letter in November.<ref>{{cite web|last=Rosenthal |first=Norman |title=Important Change in the LEVAQUIN (Ievofloxacin) Complete Prescribing Information&nbsp;-Addition of Boxed Warning and Medication Guide Regarding Tendinitis and Tendon Rupture|year=2008 |publisher=Ortho-McNeil Janssen Scientific Affairs, LLC |url=http://www.fqresearch.org/pdf_files/Levaquin_11_2008_ortho_mcneil_dear_dr_letter.pdf |format=PDF| accessdate= 2008-12-27}}</ref> through the Health Care Notification Network, a registration-only website that distributes drug alerts to licensed healthcare professionals.

⚫ ==Interactions==
⚫ *Probenecid: Prulifloxacin urinary excretion decreases when concomitantly administered with probenecid.<ref name="cipladoc.com"/>

⚫ *Fenbufen: The concomitant administration of fenbufen can cause increased risk of convulsions.<ref name="cipladoc.com"/>

⚫ *Hypoglycemic agents: May cause hypoglycemia in diabetic patients under treatment with hypoglycemic agents.<ref name="cipladoc.com"/>

⚫ *Theophylline: May cause a decreased theophylline clearance.<ref name="cipladoc.com"/>

⚫ *Warfarin: May enhance the effects of oral anticoagulants such as warfarin and its derivatives.<ref name="cipladoc.com"/>

⚫ *Nicardipine: May potentiate the phototoxicity of prulifloxacin.<ref name="cipladoc.com"/>


==Overdose== ==Overdose==
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Prulifloxacin 600&nbsp;mg achieves peak plasma concentration (Cmax) of ulifloxacin (1.6μg/mL) in a median time to Cmax (tmax) of 1 hour. Ulifloxacin is ≈45% bound to serum proteins in vivo. It is extensively distributed throughout tissues and shows good penetration into many body tissues. The elimination half-life (t1/2) of ulifloxacin after single-dose prulifloxacin 300–600&nbsp;mg ranged from 10.6 to 12.1 hours. After absorption from the gastrointestinal tract, prulifloxacin undergoes extensive first-pass metabolism (hydrolysis by esterases, mainly paraoxonase to form ulifloxacin, the active metabolite). Unchanged ulifloxacin is predominantly eliminated by renal excretion. ''Quoting from the available package insert.''<ref name="cipladoc.com"/> Prulifloxacin 600&nbsp;mg achieves peak plasma concentration (Cmax) of ulifloxacin (1.6μg/mL) in a median time to Cmax (tmax) of 1 hour. Ulifloxacin is ≈45% bound to serum proteins in vivo. It is extensively distributed throughout tissues and shows good penetration into many body tissues. The elimination half-life (t1/2) of ulifloxacin after single-dose prulifloxacin 300–600&nbsp;mg ranged from 10.6 to 12.1 hours. After absorption from the gastrointestinal tract, prulifloxacin undergoes extensive first-pass metabolism (hydrolysis by esterases, mainly paraoxonase to form ulifloxacin, the active metabolite). Unchanged ulifloxacin is predominantly eliminated by renal excretion. ''Quoting from the available package insert.''<ref name="cipladoc.com"/>


==See also== == See also ==
*]
*]


==References== == References ==
{{Reflist|colwidth=30em}} {{Reflist|35em}}


==Bibliography== ==Bibliography==
*{{cite web|url=http://216.139.227.101/interactive/optr2008/ |title=Annual Report 2008 |publisher=Optimer Pharmaceuticals, Inc. |accessdate=2010-04-08}} *{{cite web |url=http://216.139.227.101/interactive/optr2008/ |title=Annual Report 2008 |publisher=Optimer Pharmaceuticals, Inc. |access-date=2010-04-08 |archive-url=https://web.archive.org/web/20110704185541/http://216.139.227.101/interactive/optr2008/ |archive-date=2011-07-04 |url-status=dead }}


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