Prulifloxacin

Last updated
Prulifloxacin
Prulifloxacin.svg
Clinical data
Trade names Quisnon, Unidrox, Prixina, Glimbax
AHFS/Drugs.com International Drug Names
Routes of
administration 		Oral
ATC code
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
  • (RS)-6-Fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.254.386 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H20FN3O6S
Molar mass 461.46 g·mol−1
3D model (JSmol)
  • CC1N2C3=CC(=C(C=C3C(=O)C(=C2S1)C(=O)O)F)N4CCN(CC4)CC5=C(OC(=O)O5)C
  • 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) X mark.svgN
  • Key:PWNMXPDKBYZCOO-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Prulifloxacin is an older synthetic antibiotic of the fluoroquinolone class [1] [2] 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. [3] [4] 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. [5]

Contents

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. [3] [6] 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). [7] 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. [8] 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. [9] [10]

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. [11]

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
Japan
Other countries

Availability

Prulifloxacin is available as:

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: [12]

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. [13] [14]

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." [12]

"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." [12]

Adverse Events

Within one review prulifloxacin was stated to have a similar tolerability profile to that of ciprofloxacin. [15] 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. [16] 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. [17]

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. [18] [19]

Interactions

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. [12]

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. [12]

See also

Related Research Articles

<span class="mw-page-title-main">Ciprofloxacin</span> Fluoroquinolone antibiotic

Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra-abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin infections, typhoid fever, and urinary tract infections, among others. For some infections it is used in addition to other antibiotics. It can be taken by mouth, as eye drops, as ear drops, or intravenously.

<span class="mw-page-title-main">Levofloxacin</span> Antibiotic

Levofloxacin, sold under the brand name Levaquin among others, is an antibiotic medication. It is used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, H. pylori, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis, meningitis, or pelvic inflammatory disease. Use is generally recommended only when other options are not available. It is available by mouth, intravenously, and in eye drop form.

<span class="mw-page-title-main">Ofloxacin</span> Antibiotic to treat bacterial infections

Ofloxacin is a quinolone antibiotic useful for the treatment of a number of bacterial infections. When taken by mouth or injection into a vein, these include pneumonia, cellulitis, urinary tract infections, prostatitis, plague, and certain types of infectious diarrhea. Other uses, along with other medications, include treating multidrug resistant tuberculosis. An eye drop may be used for a superficial bacterial infection of the eye and an ear drop may be used for otitis media when a hole in the ear drum is present.

<span class="mw-page-title-main">Nalidixic acid</span> First of the synthetic quinolone antibiotics

Nalidixic acid is the first of the synthetic quinolone antibiotics.

<span class="mw-page-title-main">Norfloxacin</span> Chemical compound, antibiotic

Norfloxacin, sold under the brand name Noroxin among others, is an antibiotic that belongs to the class of fluoroquinolone antibiotics. It is used to treat urinary tract infections, gynecological infections, inflammation of the prostate gland, gonorrhea and bladder infection. Eye drops were approved for use in children older than one year of age.

<span class="mw-page-title-main">Moxifloxacin</span> Antibiotic

Moxifloxacin is an antibiotic, used to treat bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It can be given by mouth, by injection into a vein, and as an eye drop.

<span class="mw-page-title-main">Enoxacin</span> Chemical compound

Enoxacin is an oral broad-spectrum fluoroquinolone antibacterial agent used in the treatment of urinary tract infections and gonorrhea. Insomnia is a common adverse effect. It is no longer available in the United States.

<span class="mw-page-title-main">Gemifloxacin</span> Chemical to treat chronic bronchitis

Gemifloxacin mesylate is an oral broad-spectrum quinolone antibacterial agent used in the treatment of acute bacterial exacerbation of chronic bronchitis and mild-to-moderate pneumonia. Vansen Pharma Inc. has licensed the active ingredient from LG Life Sciences of Korea.

<span class="mw-page-title-main">Sparfloxacin</span> Chemical to treat bacterial infections

Sparfloxacin is a fluoroquinolone antibiotic used in the treatment of bacterial infections. It has a controversial safety profile.

<span class="mw-page-title-main">Cinoxacin</span> Chemical compound

Cinoxacin is a quinolone antibiotic that has been discontinued in the U.K. as well the United States, both as a branded drug or a generic. The marketing authorization of cinoxacin has been suspended throughout the EU.

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

<span class="mw-page-title-main">Temafloxacin</span> Chemical compound, antibiotic drug

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<span class="mw-page-title-main">Fleroxacin</span> Chemical compound

Fleroxacin is a quinolone antibiotic. It is sold under the brand names Quinodis and Megalocin.

<span class="mw-page-title-main">Flumequine</span> Chemical compound

Flumequine is a synthetic fluoroquinolone antibiotic used to treat bacterial infections. It is a first-generation fluoroquinolone antibacterial that has been removed from clinical use and is no longer being marketed. The marketing authorization of flumequine has been suspended throughout the EU. It kills bacteria by interfering with the enzymes that cause DNA to unwind and duplicate. Flumequine was used in veterinarian medicine for the treatment of enteric infections, as well as to treat cattle, swine, chickens, and fish, but only in a limited number of countries. It was occasionally used in France to treat urinary tract infections under the trade name Apurone. However this was a limited indication because only minimal serum levels were achieved.

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Difloxacin (INN), marketed under the trade name Dicural, is a second-generation, synthetic fluoroquinolone antibiotic used in veterinary medicine. It has broad-spectrum, concentration dependent, bactericidal activity; however, its efficacy is not as good as enrofloxacin or pradofloxacin.

<span class="mw-page-title-main">Clinafloxacin</span> Chemical compound

Clinafloxacin is an investigational fluoroquinolone antibiotic. Despite its promising antibiotic activity, the clinical development of clinafloxacin has been hampered by its risk for inducing serious side effects.

<span class="mw-page-title-main">Quinolone antibiotic</span> Class of antibacterial drugs, subgroup of quinolones

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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). "[Chemotherapeutic agents under study]". Nippon Rinsho (in Japanese). 56 (12): 3096–9. PMID   9883617.
  3. 1 2 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. ↑ JPpatent 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. 1 2 3 4 5 6 7 8 9 10 11 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

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