| Fluoroquinolones (FQs) have been shown to be very effective for the treatment of various bacterial infections. However, with FQs widely used, more and more adverse drug reactions (ADRs) have been reported. Several new FQs have been withdrawn from the market in recent years because of rare or exceptional but life-threatening ADR (e.g. temafloxacin, trovafloxacin, grepafloxacin and clinafloxacin). Thus, it is necessary to evaluate fluoroquinolone safety for the guideline of clinical rational use and the development of new candidates.The present studies firstly evaluated the safety in everyday clinical usage of fluoroquinolones by hospital intensive monitoring and determining incidence rates and risk factors of ADR. Secondly, the neurotoxicity and toxicokinetics of norfloxacin in freely moving rats were studied. Finally, the underlying mechanisms of neurotoxicity were investigated using molecular biological techniques and patch-clamp electrophysiological techniques. The results are summarized as follows:1. The safety in everyday clinical usage of fluoroquinolones in P. R. China was evaluated by multicentre hospital intensive monitoring. The main outcome measures were patient background factors, including age, sex, underlying disease, complications, history, etc.; the indication for prescribing the drug being monitored; the start and stop dates of treatment and the events recorded during and after treatment. 2003 hospitalized patients who took fluoroquinolones were monitored between May 2001 and June 2002. There were 279 ADRs identified in 262 patients. The overall event rate is 13.93% (279/2003). Eighty-two ADRs were characterized as moderate or severe in degree, and 222 ADR were classified as type A reactions. Causality assessment (according to standardized algorithm of ADR Monitoring Centre, Ministry of Public Health, China) revealed that cerain causality was established in 22 (24.01%) of total ADR. The mostcommonly used FQs were levofloxacin, ciprofloxacin and fleroxacin. The ADR rates of levofloxacin, ciprofloxacin and fleroxacin were 9.96% (110/1104), 13.94% (74/531) and 22.45% (66/294), respectively. Gastrointestinal, CNS and skin manifestations accounted for 38.71% (108/2003), 28.67% (80/2003) and 20.43%(57/2003) of the ADR, respectively. We found some significant differences in the safety profiles of individual FQs: ciprofloxacin was more frequently associated with skin reactions (P<0.05), fleroxacin and levofloxacin with gastrointestinal reactions (P<0.01), and fleroxacin with CNS reactions (P<0.01). Age, sex, number of concomitant drugs, allergic history and renal function were closely related to ADR. The aforementioned risk factors may play an important role for clinician to predict the potential risk of FQs. 2. The neurotoxicity and toxicokinetics of norfloxacin were studied in freely moving rats . Rats were assigned randomly to four treatment groups that received a single iv dose of 50, 100, 200 mg/kg of norfloxacin and 0.9 % saline, respectively. Electroencephalogram (EEG) was continuously recorded with a computerized system in freely moving rats. Venous blood samples were collected for determination of the norfloxacin concentration using microbioassay method with Escherichia coli 441102 as the test strain. Toxicokinetic parameters were determined from serum concentration-time data with the 3p97 program. Result: (1) The epileptiform discharges appeared in all norfloxacin groups with different latent periods, accompanied with limb twitching and clonic-tonic seizures. The relative total power of the EEG increased. (2) Drug serum concentration-time curves of different doses conformed to two compartment model. The values of clearance, volume of distribution, and terminal half-life were dose-independent, while maximum serum concentrations (Cmax) and the areas under the concentration-time curve(AUC0→∞) of norfloxacin increased with dosage. (3) The increase in relative total power of the EEG was chosen as quantitative measurement of CNS stimulant effect of norfloxacin. Th...
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