Пазуфлоксацин

Описание

Pazufloxacin is a novel quinolone marketed for the treatment of bacterial infections in Japan. This tricyclic fluoro-quinolone can be synthesized in 11 steps from commercially available 2,3,4,5tetrafluorobenzoic acid. The cyclopropyl substituent is first introduced in 6 steps including 4-F-substitution with tert-butylcyanoacetate, decarboxylation, aa alkylation with 1 ,Zdibromoethane, partial nitrile hydrolysis and Hoffmann-rearrangement. The pyridoxazine ring is then introduced in 5 steps including 6-ketoester formation and pryridoxazine annulation. Pazufloxacin displays a broad spectrum activity against Grampositive and Gram-negative bacteria, although it is less active that ciprofloxacin against pneumococci and is not active against ciprofloxacin-resistant isolates. In patients with gonococcal urethritis a high prevalence of fluoroquinolone-resistant N. gonorrhoeae isolates with the Ser-91-to-Phe mutation in GyrA was observed. However, good clinical responses have been seen in clinical trials of patients with urinary tract infections and to a lesser extent with respiratory tract infections. Pazufloxacin is mainly excreted in urine with a short half-life (2-2.5 h). It has a phototoxicity equal to that of ciprofloxacin and its adverse effect profile resembles that of other quinolones.

Использование

Pazufloxacin is a potential antimicrobial and/or antiviral agent.

Фармацевтические приложения

A tricyclic fluoroquinolone, formulated as mesylate and hydrochloride salts for oral or parenteral use or as a methane sulfonate (eye ointment).
It displays good activity in vitro against methicillin susceptible Staph. aureus (MIC 0.2 mg/L), but is inactive against Str. pyogenes, Str. pneumoniae (MIC ≥4 mg/L) and enterococci. L. pneumophila is inhibited by 0.03 mg/L. Activity against Enterobacteriaceae, fastidious Gram-negative bacilli, Ps. aeruginosa and Acinetobacter spp. is similar to that of ofloxacin. It is weakly active against Sten. maltophilia and Burkholderia cepacia (MIC c. 2 mg/L). Against M. tuberculosis, MICs range from 0.8 to 4 mg/L. It is inactive against anaerobes.
After oral doses of 100 or 400 mg, peak plasma concentrations range from 0.94 mg/L (100 mg) to 4.5 mg/L (400 mg) after <1 h. The apparent elimination half-life is around 2 h. Most of the administered dose is eliminated in urine, about 70% within 24 h. Four metabolites have been reported. In elderly patients, according to the renal function, the peak plasma concentration may be elevated (up to 5.6 mg/L) and significantly delayed (2–6 h). The plasma protein binding ranges from 17% to 28%.