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Prulifloxacin

Clinical data
Trade names	Quisnon, Unidrox, Prixina, Glimbax
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	J01MA17 (WHO)
Legal status
Legal status	Rx-only (Japan, Italy, Austria)
Pharmacokinetic data
Metabolism	By esterases, to ulifloxacin
Elimination half-life	7.7 to 8.9 hours
Excretion	Renal and fecal
Identifiers
IUPAC name (RS)-6-Fluoro-1-methyl-7--4-oxo-4H-thiazetoquinoline-3-carboxylic acid
CAS Number	123447-62-1
PubChem CID	65947
ChemSpider	59351
UNII	J42298IESW
ChEMBL	ChEMBL422648
CompTox Dashboard (EPA)	DTXSID0046480
ECHA InfoCard	100.254.386
Chemical and physical data
Formula	C21H20FN3O6S
Molar mass	461.46 g·mol
3D model (JSmol)	Interactive image
SMILES CC1N2C3=CC(=C(C=C3C(=O)C(=C2S1)C(=O)O)F)N4CCN(CC4)CC5=C(OC(=O)O5)C
InChI InChI=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) Key:PWNMXPDKBYZCOO-UHFFFAOYSA-N
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Prulifloxacin is an older synthetic antibiotic of the fluoroquinolone class undergoing clinical trials prior to a possible NDA (New Drug Application) submission to the U.S. Food and Drug Administration (FDA). It is a prodrug which is metabolized in the body to the active compound ulifloxacin. 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.

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. Prulifloxacin has not been approved for use in the United States.

History

In 1987 a European patent for prulifloxacin 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 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. 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.

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 expects to file an NDA (new drug application) for prulifloxacin some time in 2010. As the patent for prulifloxacin has already expired, Optimer Pharmaceuticals has stated that this may have an effect on the commercial prospects of prulifloxacin within the United States market.

Licensed uses

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

• Acute uncomplicated lower urinary tract infections (simple cystitis)
• Complicated lower urinary tract infections
• Acute exacerbation of chronic bronchitis

Japan

• Gastroenteritis, including infectious diarrheas

Other countries

• Prulifloxacin has not been approved for use in the United States, but may have been approved in other Countries, other than that which is indicated above.

Availability

Prulifloxacin is available as:

• Tablets (250 mg, 450 mg or 600 mg)

In most countries, all formulations require a prescription.

Mechanism of action

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 DNA replication.

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 DNA gyrase and topoisomerase IV. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. For many gram-negative bacteria, DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria. It is believed that eukaryotic cells do not contain DNA gyrase or topoisomerase IV.

Contraindications

There are only four contraindications found within the package insert:

• "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 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, pregnancy, nursing mothers, and in patients with epilepsy or other seizure disorders."

Special populations

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.

Pediatric population

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.

Special precautions

"As with other quinolones, exposure to the sun or ultra-violet rays may cause phototoxicity reactions in patients treated with prulifloxacin."

"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."

Adverse Events

Within one review prulifloxacin was stated to have a similar tolerability profile to that of ciprofloxacin. 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. 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.

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.

Interactions

• Probenecid: Prulifloxacin urinary excretion decreases when concomitantly administered with probenecid.
• Fenbufen: The concomitant administration of fenbufen can cause increased risk of convulsions.
• Hypoglycemic agents: May cause hypoglycemia in diabetic patients under treatment with hypoglycemic agents.
• Theophylline: May cause a decreased theophylline clearance.
• Warfarin: May enhance the effects of oral anticoagulants such as warfarin and its derivatives.
• Nicardipine: May potentiate the phototoxicity of prulifloxacin.

Overdose

In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage; the patient should be carefully observed and given supportive treatment.

Pharmacokinetics

Prulifloxacin 600 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 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.

See also

• Quinolone

References

1. Nelson JM, Chiller TM, Powers JH, Angulo FJ (2007). "Food Safety: Fluoroquinolone-Resistant Campylobacter Species and the Withdrawal of Fluoroquinolones from Use in Poultry: A Public Health Success Story". Clinical Infectious Diseases. 44 (7): 977–80. doi:10.1086/512369. PMID 17342653.
2. Kawahara S (1998). "". Nippon Rinsho (in Japanese). 56 (12): 3096–9. PMID 9883617.
3. ^ Fritsche TR, Biedenbach DJ, Jones RN (2008). "Antimicrobial Activity of Prulifloxacin Tested against a Worldwide Collection of Gastroenteritis-Producing Pathogens, Including Those Causing Traveler's Diarrhea". Antimicrobial Agents and Chemotherapy. 53 (3): 1221–4. doi:10.1128/AAC.01260-08. PMC 2650572. PMID 19114678.
4. Giannarini G, Tascini C, Selli C (2009). "Prulifloxacin: clinical studies of a broad-spectrum quinolone agent". Future Microbiology. 4 (1): 13–24. doi:10.2217/17460913.4.1.13. PMID 19207096.
5. JP patent 1294680, Kise Masahiro; Kitano Masahiko; Ozaki Masakuni; Kazuno Kenji; Matsuda Masato; Shirahase Ichiro; Segawa Jun, "Quinolinecarboxylic Acid Derivative", issued November 28, 1989 
6. Anonymous (2002). "Prulifloxacin ['Quisnon'; Nippon Shinyaku] has been approved in Japan". Inpharma. 1 (1362): 22.
7. EU 315828 
8. Research and Development Department of Angelini Archived 2012-03-08 at the Wayback Machine. Angelinipharma.com. Retrieved on 2010-11-03.
9. Nippon Shinyaku, Annual Report 2007
10. "Prulifloxacin. NAD-441A, NM 441, Quisnon". Drugs in R&D. 3 (6): 426–30. 2002. doi:10.2165/00126839-200203060-00013. PMID 12516950.
11. Annual Report 2008, p. 34
12. ^ Prulifloxacin Tablets Archived 2010-11-02 at the Wayback Machine
13. Shin HC, Kim JC, Chung MK, Jung YH, Kim JS, Lee MK, Amidon GL (2003). "Fetal and maternal tissue distribution of the new fluoroquinolone DW-116 in pregnant rats". Comparative Biochemistry and Physiology C. 136 (1): 95–102. doi:10.1016/j.cca.2003.08.004. PMID 14522602.
14. Dan M, Weidekamm E, Sagiv R, Portmann R, Zakut H (1993). "Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women". Antimicrob. Agents Chemother. 37 (2): 293–6. doi:10.1128/AAC.37.2.293. PMC 187655. PMID 8452360.
15. Keam SJ, Perry CM (2004). "Prulifloxacin". Drugs. 64 (19): 2221–34, discussion 2235–6. doi:10.2165/00003495-200464190-00005. PMID 15456336.
16. Grassi C, Salvatori E, Rosignoli MT, Dionisio P (2002). "Randomized, Double-Blind Study of Prulifloxacin versus Ciprofloxacin in Patients with Acute Exacerbations of Chronic Bronchitis". Respiration. 69 (3): 217–22. doi:10.1159/000063623. PMID 12097764. S2CID 25523559.
17. "FDA orders 'black box' label on some antibiotics". CNN.com. 2008-07-08. Retrieved 2010-03-19.
18. Rosignoli MT, Di Loreto G, Dionisio P (2010). "Effects of Prulifloxacin on Cardiac Repolarization in Healthy Subjects". Clinical Drug Investigation. 30 (1): 5–14. doi:10.2165/11319400-000000000-00000. PMID 19995094. S2CID 10169230.
19. Malik M (2010). "Does the Prulifloxacin ECG Study Prove Cardiac Safety of the Drug?". Clinical Drug Investigation. 30 (1): 1–3. doi:10.2165/11319780-000000000-00000. PMID 19995093. S2CID 19677457.

Bibliography

• "Annual Report 2008". Optimer Pharmaceuticals, Inc. Archived from the original on 2011-07-04. Retrieved 2010-04-08.

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• Fluoroquinolone antibiotics
• 1,4-di-hydro-7-(1-piperazinyl)-4-oxo-3-quinolinecarboxylic acids
• Carbonate esters
• Sulfur heterocycles
• Heterocyclic compounds with 3 rings