Disease relevance of CCRIS 7284

• Grepafloxacin (OPC-17116) is a new once-daily fluoroquinolone antimicrobial agent which appears to have high tissue penetration and the wide spectrum of antimicrobial activity typical of this class of agents, but with improved activity against Gram-positive organisms, notably Streptococcus pneumoniae [1].
• OPC-17116 inhibited 50% of the members of the family Enterobacteriaceae tested and 90% of Haemophilus influenzae, Neisseria species, and Moraxella catarrhalis isolates at less than or equal to 0.25 microgram/ml [2].
• Evaluation of OPC-17116 against important pathogens that cause respiratory tract infections [3].
• This study demonstrates that 10-day courses of grepafloxacin given at 400 or 600 mg once daily were as effective, clinically and bacteriologically, as ciprofloxacin given at 500 mg twice daily for the treatment of acute bacterial exacerbations of chronic bronchitis [4].
• OPC-17116 showed a postantibiotic effect against Pseudomonas aeruginosa and Staphylococcus aureus similar to the postantibiotic effects reported for other fluoroquinolones [2].

High impact information on CCRIS 7284

• As DRSP continues to spread and resistant strains with penicillin MIC >2 mg/L become more prevalent, new agents such as the azabicyclo-methoxyquinolone, moxifloxacin, and perhaps grepafloxacin, but not the more toxic sparfloxacin and trovafloxacin, will undoubtedly flourish as treatments for CAP [5].
• p38 MAPK associated with stereoselective priming by grepafloxacin on O2- production in neutrophils [6].
• These results strongly suggest that grepafloxacin stereospecifically primes neutrophil respiratory burst, and p38 MAPK activation is closely related to the grepafloxacin priming [6].
• Twenty-nine rabbits with pneumococcal meningitis receiving grepafloxacin at 15 mg/kg of body weight (intravenous administration at 0 h), 30 mg/kg (at 0 h), or 50 mg/kg twice (at 0 and 4 h) were studied [7].
• Modeling of transfer kinetics at the serum-cerebrospinal fluid barrier in rabbits with experimental meningitis: application to grepafloxacin [7].

Chemical compound and disease context of CCRIS 7284

• Antibacterial activities of OPC-17116, ofloxacin, and ciprofloxacin against 200 isolates of Neisseria gonorrhoeae [8].
• The in vitro susceptibilities of 12 strains of Chlamydia pneumonia to a new quinolone, OPC-17116; ofloxacin; and sparfloxacin were determined [9].
• The MICs at which 90% of isolates are inhibited for gemifloxacin, trovafloxacin, and grepafloxacin were low (</=0.01 microg/ml) for 271 Legionella isolates when they were determined by the broth microdilution method but increased (>/=6 dilutions) when they were determined by the agar dilution method [10].
• The in vitro activities of ciprofloxacin, trovafloxacin, moxifloxacin, and grepafloxacin against 174 strains of Neisseria gonorrhoeae isolated in Sydney, Australia, were determined [11].
• Ureaplasma urealyticum was less susceptible; the MICs of OPC 17116 and temafloxacin for 90% of isolates tested were 2 and 4.0 micrograms/ml, respectively [12].

Biological context of CCRIS 7284

• We recently found that grepafloxacin induced a priming effect on neutrophil respiratory burst induced by N-formylmethionylleucylphenylalanine [6].
• Effect of age and gender on the pharmacokinetics of grepafloxacin [13].
• Effect of food and gastric pH on the bioavailability of grepafloxacin [14].
• Saturation in the metabolism of grepafloxacin and possibly in the distribution into a peripheral compartment, as suggested by a decrease in the total plasma clearance and in the apparent volume of distribution, could be the origin of the nonlinear kinetics [15].
• Animal models and human studies with ciprofloxacin, grepafloxacin and levofloxacin show that a 24-hour AUC/MIC ratio of about 100, or a Cmax/MIC ratio of about 10 gives maximum clinical and bacteriological efficacy [16].

Anatomical context of CCRIS 7284

• Interestingly, grepafloxacin stereospecifically bound to the membrane fractions of neutrophils [6].
• Involvement of multidrug resistance-associated protein 2 in intestinal secretion of grepafloxacin in rats [17].
• Superfusion of canine tracheal mucosa with 100 microg each of grepafloxacin and ciprofloxacin per ml reduced the electrical transepithelial potential difference in vivo by more than 50% [18].
• Gallbladder tissue concentrations, biliary excretion and pharmacokinetics of OPC-17116 [19].
• The intestinal secretory clearance in SDRs after intravenous administration of grepafloxacin was shown to be greater for the ileum than for the duodenum, which is in good agreement with the previously reported regional expression profile of MRP2 mRNA [17].

Associations of CCRIS 7284 with other chemical compounds

• Famotidine treatment had no significant effect on grepafloxacin pharmacokinetics [14].
• Similarly, warfarin had no significant effect on the pharmacokinetics of grepafloxacin [20].
• No changes were observed in the placebo group and theophylline appeared to have no effect on the pharmacokinetics of grepafloxacin [20].
• For mutants selected from F77, moxifloxacin, grepafloxacin and sparfloxacin selected preferentially for mutations in gyrA (Glu-88-->Lys) [21].
• Randomized, double-blind, comparative study of grepafloxacin and amoxycillin in the treatment of patients with community-acquired pneumonia [22].

Gene context of CCRIS 7284

• Differential involvement of multidrug resistance-associated protein 1 and P-glycoprotein in tissue distribution and excretion of grepafloxacin in mice [23].
• 7. In conclusion, the transepithelial secretion of grepafloxacin is mediated by both MRP2 and MDR1, whereas ciprofloxacin is a substrate for neither [24].
• Taken together, these findings suggest that grepafloxacin evokes a priming effect on neutrophil superoxide generation intracellularly through the translocation of p47-phox and even p67-phox protein to the membrane fractions [25].
• Grepafloxacin 1-30 mg/L inhibited the production of interleukin 1alpha (IL-1alpha) and IL-1beta, and the expression of IL-1alpha, IL-1beta, tumour necrosis factor alpha (TNFalpha), IL-6 and IL-8 mRNA [26].
• Grepafloxacin MICs >4 mg/L were associated with this GyrA mutation alone; no relationship was detected between grepafloxacin MICs and mutation of the QRDR of parC [27].

Analytical, diagnostic and therapeutic context of CCRIS 7284

• Pharmacokinetics of grepafloxacin after oral administration of single and repeat doses in healthy young males [15].
• In comparative clinical trials, grepafloxacin demonstrated similar efficacy to amoxicillin in community-acquired pneumonia, ofloxacin in pneumonia and chronic respiratory tract infection, and cefixime in uncomplicated gonococcal urethritis and gonococcal cervicitis [1].
• In an open, randomized, six-period crossover study, the pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin were compared after a single oral dose in 12 healthy volunteers (6 men and 6 women) [28].
• A randomized, prospective, double-blind, double-dummy, multicenter study investigated the efficacy and safety of 10 days of oral therapy with grepafloxacin at 400 mg once daily, grepafloxacin at 600 mg once daily, or ciprofloxacin at 500 mg twice daily in 624 patients with acute bacterial exacerbations of chronic bronchitis [4].
• After continuous intravenous infusion, significantly greater penetration of grepafloxacin was found in the iris, cornea and chorioretina of pigmented rabbits compared with albino rabbits [29].

References