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氨基糖苷类抗生素时辰给药方案的实验研究

Experimental Study of Chronological Dosage Regimens on Aminoglycoside Antibiotics

【作者】 朱立勤

【导师】 娄建石; 焦建杰;

【作者基本信息】 天津医科大学 , 药理学, 2005, 硕士

【摘要】 目的:以庆大霉素为例,研究氨基糖苷类抗生素按时辰给药对大鼠肾毒性、血药浓度和药代参数的影响。 方法:1、建立庆大霉素(GTM)的柱前衍生HPLC-UV测定方法,以2,4-二硝基氟苯为衍生剂,以威替米星为内标,测定大鼠血浆中GTM的浓度。2、将大鼠分为6组,包括Control组、时辰每日单次给药组(N100组、D100组分别于1∶00和13∶00给药100mg/kg)、时辰每日两次不等量给药组和传统每日两次等量给药组(N90+D10组、N70+D30组、N50+D50组,每日1∶00和13∶00分两次给GTM共100mg/kg,各组剂量分别为90mg/kg+10mg/kg、70mg/kg+30mg/kg、50mg/kg+50mg/kg),给药方式为肌内注射。各组分别于给药第1天和第10天、第20天,测定体重、尿蛋白、血清肌苷、血清尿素氮指标。并抽样作病理切片。3、在给药后第1天、第10天、第20天分别于0.25h、0.5h、1h、2h、5h、8h眼眶取血,测定血药浓度,绘制药时曲线,计算药代动力学参数。 结果:1、肾毒性:给药后第20天,N50+D50组Cr和BUN水平最高,分别为115.82±23.85μmol/l和11.34±1.22 mmol/l,与给药第1天和同期Control组有显著性差异(P<0.05);N100组最低,分别为69.04±4.75μmol/l和7.10±1.01mmol/l。给药后第20天,N50+D50组体重增长最慢,为194.69±30.68g(P<0.05),而N100组体重增长接近Control组,为223.75±15.44g。 2、血药浓度:给药后第10天单剂量组N100组和D100组最高浓度分别为527.72±93.19μg/ml和806.44±28.959μg/ml(P<0.05)。时辰两次不等

【Abstract】 Objective: Selecting gentamicin as an example of aminoglycoside antibiotics, it is to study the effects of different administration time on kidney toxicity, serum concentrations, and pharmacokinetic parameters in rats.Method: 1. The HPLC-UV assay of gentamicin was developed after precolumn derivatization. In this method, FDNB was used as derivatizer, and vertilmicin was used as internal standard. The serum concentrations of gentamicin in rats were examined by developed HPLC-UV method. 2. The rats was divided into 6 groups: control group; single daily dose group(N100 and D100 group was intramuscularly administrated 100mg/kg gentamicin at 1:00 and 13:00 respectively); the mutiple dose groups(N90+D10 group, N70+D30 group, N50+D50 group, 100mg/kg/d gentamicin was adminstrated in twice at 1:00 and 13:00). Different dose for these groups was respectively 90mg/kg+10mg/kg, 70mg/kg+30mg/kg and 50mg/kg+50mg/kg. Gentamicin was administrated intramuscularly. The difference of weight, urine protein, BUN and Cr level was observed at the 1st, the 10th and the 20th day after administrations. 3. The serum concentrations of gentamicin at 0.25h, 0.5h, 1h, 2h, 5h, 8h was determined. This process was repeated at the 10th day and 20th day. C-T curves were depicted to caculate the pharmacokinetic parameters.Results: 1. Nephrotoxicity: At the 20th day after administration, Cr(115.82 ±23.85μmol/l) and BUN(11.34± 1.22mmol/l) of N50+D50 group was the highest. There were significant difference between these data and that ofthe 1st day after administration and of control group at the same time(P<0.05). The Cr(69.04 ± 4.75umol/l) and BUN(7.10 ± l.Olmmol/1) were the lowest among all groups. At the 20th day after administration, the N50+D50 group exhibited the lowest increase(P<0.05) in weight(194.69±30.68g), while the increase in weight(223.75±15.44g) of NlOO group was close to that of control group.2. Gentamicin Concentrations: The peak concentration of single dose daily group(N100 group and DlOO group) was respectively 527.72 + 93.19ug/ml and 806.44 + 28.95ng/ml at the 10th day after administration(P<0.05). Among the mutiple administration regimens, the peak concentration of N50+D50 group at 20th day after administration was 606.57+144.11 jig/ml, which was higher than that of groups of different doses(592.17 + 82.77ug/ml and 514.67+ 15.67|^g/ml), but there was no significantly statistical difference.3. The pharmacokinetic parameters: At the 20th day after administration, AUC(o-inn (1195.84±309.42ng/ml/h) of N50+D50 group was the highest, and that(621.71 +122.5lug/ml/h) of NlOO group was the lowest(P<0.05) among these groups. The CLs of N50+D50 group(0.0784 + 0.0183L/kg/h) was the smallest, while that of NlOO group(0.1484 + 0.0280L/kg/h) was largest. At the 1st, the 10th and the 20th day after administration, T\a of the NlOO group was the shortest(respectively 1.03 + 0.05h, 1.32 + 0.08h and 1.24 + 0.18h) while that of N50+D50 group was the longest(respectively 2.04 + 0.28h, 1.90 + 0.01h and 2.11 ±0.5 lh(P<0.05).Conclusion: In chronological dosage regimens, the nephrotoxicity is lowest when dosing at active phase for single daily dose. The range of concentrations was narrow when dosing at active phase than that of dosing at

  • 【分类号】R96
  • 【被引频次】2
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