Subject fluoroquinolones

The data on the adverse reactions of the fluoroquinolones which have received the most extensive clinical evaluation (ciprofloxacin, ofloxacin, pefloxacin, norfloxacin and enoxacin), involving about 30,000 patients, have been the subject of a review [54a], An important point noted in this review involves the difficulty in detecting an important severe adverse reaction if it is of relatively low frequency, until there has been a very large patient exposure (some examples are provided in which at least 150,000-300,000 exposures would be required to observe the importance of side-effects, resulting in an alert, which have been discovered with specific drugs). However, the majority of side-effects observed thus far with the fluoroquinolones have been minor,... 

We then used this Caco-2 cell assay to categorize representative fluoroquinolone drug substance permeability [50], The drugs demonstrated some concentration-dependent permeability indicative of active drug transport. Based upon comparison to labetalol, ciprofloxacin was classified as a LP drug, whereas levofloxacin, lomefloxacin, and ofloxacin were classified as HP drugs, which matched their human in vivo bioavailabilities. All four fluoroquinolone drugs were subject to efflux transport (ciprofloxacin > lomefloxacin > rhodamine 123 > levofloxacin > ofloxacin). 

The pharmacokinetic properties of fluoroquinolone antibacterial agents have been well described [23]. Gemifloxacin is rapidly absorbed with a time to maximum plasma concentration (T ax) of 0.5-2 h in healthy subjects and displays linear pharmacokinetics over the dose range studied (20-800 mg), with an apparent plasma terminal half-life (fi/2) after single or repeated administration of about 8 h. A minimum of 20-30% of the oral dose is excreted imchanged in the urine. Following repeat oral... 

The syntheses of the fluoroquinolones were completed by subjecting the corresponding esters to basic hydrolysis. Treatment of 15a and 15b with 2N sodium hydroxide solution for two hours at reflux resulted in near quantitative yields of Norfloxacin (1) and the N-methylpiperazine derivative 16. ... 

Kozawa, O. Uematsu, T. Matsuno, H. Niwa, M. Nagashima, S. Kanamaru, M. Comparative study of pharmacokinetics of two new fluoroquinolones, balofloxacin and grepafloxacin, in elderly subjects, Antimicrob.Agents Chemother., 1996, 40, 2824-2828. 

The incidence of serious cardiac arrhythmia with the use of fluoroquinolones was investigated in a retrospective, nested case-controlled study. Fluoroquinolones were associated witir an increased risk of serious cardiac arrhythmia (RR 1.76) with gatifloxacin giving the highest risk (RR7.38), followed by moxifloxacin (RR 3.30) and ciprofloxacin (RR 2.15) [20 ]. Hypersensitivity reactions to fluoroquinolones are more likely in subjects who have had a previous reaction to beta-lactam antibiotics (OR 4.57) [21 ]. 

In order to obtain structure-biological activity relationships mathematic methods have been used [191-193]. Quantitative correlations between molecular structure and pharmacokinetic and pharmacodynamic characteristics of fluoroquinolones in combination with informative hanometric approach have been used to forecast anti-pneumococcus activity [194]. Elucidation of the structure - activity relationships in the series of fluoroquinolones is the subject of numerous publications [195-197]. Dependence of antibacterial activity on the nature of substituents has been established for several series of bicyclic fluoroquinolones [11,198-200]. 

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