| Quinolones (QNs) are rapidly bactericidal and have an extended antimicrobial spectrum, and they have advantageous pharmacokinetic properties such as absorption from gastrointestinal tract, excellent penetration into many tissues and good intracellular diffusion. Thus, they have been showed to be effective in the treatment of a large variety of bacterial infection in adults. A major drawback of QNs is the potential to induce arthropathy in juvenile animals. The extraordinary form of age-related drug toxicity has been determined with various QNs. In the same time, arthropathy has been reported in rare case reports in pediatricts. Thus, the toxicity potential has led to important restrictions of the use of QNs in children. on the other hand, many investigations showed no evidences of increase chondrotoxicity with QNs in pediatric patients. So in some occasions, many children have received treatment with QNs. Thus, it is necessary to evaluate QNs safety in children.The present studies evaluated the clinical drug utinization in children by hospital intensive monitoring and determined the incidence rates of ADR. Secondly, the chondrotoxicity and toxicokinetics of ciprofloxacin in 4-week old rats were studied. Thirdly, we evaluated the chondrotoxicity of four kinds of QNs (ciprofloxacin, levofloxacin, fleroxacin, pazufloxacin) in animal and child, and evaluated the influence of animal or children age, treatment duration. Finally, the underlying mechanisms of chondrotoxicity were investigated using molecular biological techniques. The results are summarized as follows:1. The clinical investigation in children hospitalThe clinical investigation was eaccomplished by hospital intensive monitoring. The main outcome measures were patient background factors, including age, sex, underlying disease, complications, history, etc. 101 hospitalized patients who took QNs were monitored between July 2002 and February 2002. The children were 8.16±4.20 (0.01~13.64) years old, including 9 patients below 1a (8.91%), 11 patients between1～4 a (10.89%), 19 patients between 4～7 a (18.81%), 22 patients between 7～10 a (21.78%) and 41 patients between 10～14 a (39.60%). The drug involed ciprofloxacin and ofloxacin, and the most commonly used QNs was ciprofloxacin (93 patients, 92.08%). The treatment periods were 5.80±3.94 (1~24) d, including 26 patients between 1～3 d (25.74%), 43 patients between 4～7 d (42.57%), 19 patients between 7～10 d (18.81%) and 13 patients over 13 d (12.87%), respectively. The systems or tissues for treatment category included gastrointestinal tract (33, 32.67%), respiratory system (32, 31.68%), urinary tract (12, 17.82%), otolaryngology (6, 5.94%) and central nerves system (3, 2.97%). The overall ADR rate was 8.91% (9/101). Gastrointestinal, CNS, allergic reaction and phlebitis accounted for 3.96% (4/101), 2.97% (3/101), 1.0%(1/101) and 1.0%(1/101) of the ADR, respectively. The ADR rates of ciprofloxacin were 8.60% (8/93). The symptoms of ADR were gentle or moderate and reversible after drawback. 2. In vivo and in vitro chondrotoxicity of ciprofloxacin in juvenile rats (1) The chondrotoxicity and toxicokinetics of ciprofloxacin were studied in 4-week old rats. Rats were randomly assigned to treatment groups (each including 6 animals) and treated with 0, 400, 800, and 1200 mg/kg ciprofloxacin ig once daily on seven consecutive days. Venous blood on d 1 and d 6 were collected. Four hours after final dosing the rats were killed, the left knee joint was removed for the histopathological examination and the thickness of the cartilage of the femoral condyle was measured with Image Analysis System. Cartilage was obtained from the right knee joint was homogenized. Concentration in serum and cartilage was determined by a validated agar diffusion microbioassay. Results: ①Drug serum concentration-time curves of different doses conformed to one compartment model. The maximum serum concentrations (Cmax), the areas under the concentration-time curve(AUC0→∞) and the concentration in cartilage of ciprofloxac... |
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