硝基咪唑类抗生素在大鼠口腔组织的分布与药代动力学研究
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摘要
硝基咪唑类抗生素是口腔常用的抗厌氧菌感染药物,目前的用药方案大都依赖药物在血液的药代动力学特征,对药物在口腔局部组织的分布与代谢状况、硝基咪唑类抗生素能否在口腔组织达到有效的治疗浓度以及最大限度发挥药物治疗作用均不清楚,因此有必要对硝基咪唑类抗生素给药后在口腔组织的分布状况进行研究,为指导临床用药提供参考。本研究以大鼠为实验对象,采用高效液相色谱法(HPLC)法,测定了甲硝唑、替硝唑、奥硝唑给药后在牙龈、牙髓、咬肌、下颌骨四种口腔厌氧菌感染常见组织中的分布状况。
第一部分:样品中硝基咪唑类抗生素含量测定的HPLC方法的建立
目的:建立检测大鼠口腔组织中硝基咪唑类药物的HPLC方法。
方法:甲硝唑采用Agilent Zorbax SB-C18(250mm×4.6mm、5μm)分析柱,流动相为水∶甲醇=70∶30,替硝唑,奥硝唑采用Agilcnt Zorbax SBC18(150mm×4.6mm,5μm)分析柱,流动相为水∶甲醇∶75∶25,进样量20μ1,流速1.0ml/min,测定波长为316nm。取大鼠血液与牙髓、牙龈、咬肌、下颌骨的组织匀浆液,以5%的异丙醇氯仿萃取,离心后取有机层,吹干复溶后进样检测。
结果:上述条件下,样品中甲硝唑、替硝唑、奥硝唑峰形良好,分离完全,线形范围均为31.25ng-12.5μg/ml,最低检测限为0.2ng(信噪比≥3),药品浓度与峰面积线性关系良好,R均大于0.9990。各组织中甲硝唑回收率平均84.1%,替硝唑平均86.2%,奥硝唑85.4%,日内、日间变异均小于10%。
结论:本实验建立的HPLC方法灵敏准确,重复性好,可信性高,简便且易于推广,能够用于大鼠生物样本中三类硝基咪唑类抗生素浓度的测定与药代动力学研究。
第二部分:硝基咪唑类抗生素在大鼠口腔组织的分布与药代动力学研究
目的:检测甲硝唑、替硝唑、奥硝唑静脉和腹腔给药后,药物在大鼠牙龈、牙髓、咬肌、下颌骨中的分布并分析其药代动力学特征。
方法:取4-6周的雄性SD大鼠,腹腔或静脉注射甲硝唑(5mg/100g),奥硝唑(5mg/100g),替硝唑(4mg/100g)后,于设定时间点采集血液、牙龈、牙髓、咬肌、下颌骨组织,按照第一部分的HPLC方法检测药物在上述组织的分布。
结果:
1.甲硝唑、替硝唑、奥硝唑在检测组织中均有分布;
2.奥硝唑在各种组织中的浓度峰值均低于甲硝唑、替硝唑;
3.咬肌、下颌骨中各种药物浓度均低于其他组织;
4.牙龈与咬肌中,浓度峰值大小依次均为甲硝唑＞替硝唑＞奥硝唑;牙髓与下颌骨中浓度峰值大小依次均为替硝唑＞甲硝唑＞奥硝唑;
5.腹腔注射后,奥硝唑达峰时间最短,在各种组织中均为10min,替硝唑在各种组织中均为30min,甲硝唑在血液、咬肌分布较快,10min;牙龈30min,牙髓下颌骨1h;
6.腹腔注射后,甲硝唑与奥硝唑均符合静脉给药一室模型,替硝唑符合二室模型;
7.腹腔注射后,Cmax大小依次为甲硝唑＞替硝唑＞奥硝唑,消除半衰期大小依次为甲硝唑＞替硝唑＞奥硝唑,清除率大小依次为奥硝唑＞甲硝唑＞替硝唑;
8.替硝唑在大鼠上述组织中有效浓度维持时间最长,可达8h,奥硝唑最短,仅有4.5h。
结论:甲硝唑、替硝唑、奥硝唑均可以有效进入上述口腔组织,替硝唑在各组织的浓度峰值、有效浓度维持时间、分布速率上均相对优于甲硝唑、奥硝唑,更适于上述组织厌氧菌感染的防治。
Nitroimidazole Antimicrobials are widely used for the treatment of anaerobic infections in dental clinic,the current dosage regimen is based on the pharmacokinetics of Nitroimidazole Antimicrobials in blood,it is still unclear about the distribution and pharmacokinetics of nitroimidazole antimicrobials in oral tissues,and it is also unclear whether the nitroimidazole antimicrobials could reach the effective concentration and achieve the maximum effect under current dosage regimen,so it is necessary to investigate the distribution and pharmacokinetics of nitroimidazole antimicrobials in oral tissues to provide necessary references for clinical drμg therapy.Rat was chosen as animal model in this research to investigate distribution of metronidazole,tinidazloe and ornidazole in gingiva,dental pulp, masseter muscle,and mandible by high performance liquid chromatography (HPLC)method.
1.Pharmacokinetics and oral tissue distribution of metronidazole in rats
Objective:To develop appropriate HPLC method to measure the distribution of nitroimidazole antimicrobials in rat samples.
Methods:for metrodizaole,the Agilent Zorbax SB-C18(250mm×4.6mm, 5μm)analytical columm was employed,the mobile phase consisted of watermethanol (70:30,v/v);and for tinidazole and ornidazole,the analytical columm was Agilent Zorbax SB- C18(150mm×4.6mm,5μm),the mobile phase consisted of water- methanol(75:25,v/v),20μl was pumped throμgh the system at a rat of 1.0ml/min, the effluent was monitored at 316 nm.The plasma and tissues homogenate sapmples of rats were extracted by 5%dimethylcarbinol chloroform,after centrifμgation the supematant were collected and dried for following analysis.
Results:under the condition above,all chromatograms of metronidazole, tinidazole and ornidazole were free from any interference at the retention times, linear relationships were ranging from 31.25 to 12.5μ/ml with correlation coefficient above 0.999,and the limits of detection were 0.2ng with signal-to-noise ratio of 3.The mean recovery of metronidazole,tinidazole and ornidazole in rat tissues was 84.1%,86.2%and 85.4%respectively.The withinand between-day variability were all below 10%.
Conclusion:A sensitive,accurate and rapid HPLC method was developed to quantitate concentration of nitroimidazole antimicrobials in rat oral tissues.
2.The pharmacokineties and distribution of nitroimidazole antimierobiais in rat oral tissues
Objective:to observe and analyze the pharmacokinetics and distribution of metronidazole,tinidazole and ornidazole in rat gingival,dental pulp,masseter muscle and mandible.
Methods:metronidazole and ornidazole 5mg/100g,tinidazole 4mg/ml was administered to male rats through intraperitoneal and tail vein injection.The samplaes of plasma,gingival,dental pulp and mandible were collected at different time interval.The pharmacokinetics of drug was analysed by established HPLC method.
Results:
1.Metronidazole,tinidazole and ornidazole could penetrate the oral tissues examined;
2.The peak concentration of ornidazole in all the tissues was lower than metronidazole and ornidazole;
3.The masseter muscle and mandible had the lowest drμg concentration among the tissues measured;
4.In gingival and masseter muscle,the peak concentration of drμg in order was metronidazole＞tinidazole＞ornidazole,and in dental pulp and mandible that order was tinidazole＞metronidazole＞ornidazole;
5.The peak-reaching time of ornidazole,which was 10 min in all the tissues, was shorter than other two drμgs,tinidazole reached the peak value at 30 min after drμg administration in all the tissues;metronidazole reached the peak value at 10 min after drμg administration in plasma and masseter muscle;30min in gingiva and 1h in dental pulp and mandible.
6.The pharmacokinetics parameter of metronidazole and ornidazole was fit for one compartment model.Tinidazole was fit for two compartment model;
7.Cmax value in order was metronidazole＞tinidazole＞ornidazole,eliminate half-time in order was metronidazole＞tinidazole＞ornidazole,total clearance in order was ornidazole＞metronidazole＞tinidazole;
8.Tinidazole could maintain the effctive concentration in oral tissues for 8h, which was longest among three drμgs;ornidazole could only persist for 4.5h. Conclusions:all the three nitroimidazole antimicrobials could distributed in oral tissues,tinidazole is better relatively than metronidazole and ornidazole according to the overall parameter,which has more advatages for the treatment of anaerobic infections in oral tissues examined.
第一部分:样品中硝基咪唑类抗生素含量测定的HPLC方法的建立
目的:建立检测大鼠口腔组织中硝基咪唑类药物的HPLC方法。
方法:甲硝唑采用Agilent Zorbax SB-C18(250mm×4.6mm、5μm)分析柱,流动相为水∶甲醇=70∶30,替硝唑,奥硝唑采用Agilcnt Zorbax SBC18(150mm×4.6mm,5μm)分析柱,流动相为水∶甲醇∶75∶25,进样量20μ1,流速1.0ml/min,测定波长为316nm。取大鼠血液与牙髓、牙龈、咬肌、下颌骨的组织匀浆液,以5%的异丙醇氯仿萃取,离心后取有机层,吹干复溶后进样检测。
结果:上述条件下,样品中甲硝唑、替硝唑、奥硝唑峰形良好,分离完全,线形范围均为31.25ng-12.5μg/ml,最低检测限为0.2ng(信噪比≥3),药品浓度与峰面积线性关系良好,R均大于0.9990。各组织中甲硝唑回收率平均84.1%,替硝唑平均86.2%,奥硝唑85.4%,日内、日间变异均小于10%。
结论:本实验建立的HPLC方法灵敏准确,重复性好,可信性高,简便且易于推广,能够用于大鼠生物样本中三类硝基咪唑类抗生素浓度的测定与药代动力学研究。
第二部分:硝基咪唑类抗生素在大鼠口腔组织的分布与药代动力学研究
目的:检测甲硝唑、替硝唑、奥硝唑静脉和腹腔给药后,药物在大鼠牙龈、牙髓、咬肌、下颌骨中的分布并分析其药代动力学特征。
方法:取4-6周的雄性SD大鼠,腹腔或静脉注射甲硝唑(5mg/100g),奥硝唑(5mg/100g),替硝唑(4mg/100g)后,于设定时间点采集血液、牙龈、牙髓、咬肌、下颌骨组织,按照第一部分的HPLC方法检测药物在上述组织的分布。
结果:
1.甲硝唑、替硝唑、奥硝唑在检测组织中均有分布;
2.奥硝唑在各种组织中的浓度峰值均低于甲硝唑、替硝唑;
3.咬肌、下颌骨中各种药物浓度均低于其他组织;
4.牙龈与咬肌中,浓度峰值大小依次均为甲硝唑＞替硝唑＞奥硝唑;牙髓与下颌骨中浓度峰值大小依次均为替硝唑＞甲硝唑＞奥硝唑;
5.腹腔注射后,奥硝唑达峰时间最短,在各种组织中均为10min,替硝唑在各种组织中均为30min,甲硝唑在血液、咬肌分布较快,10min;牙龈30min,牙髓下颌骨1h;
6.腹腔注射后,甲硝唑与奥硝唑均符合静脉给药一室模型,替硝唑符合二室模型;
7.腹腔注射后,Cmax大小依次为甲硝唑＞替硝唑＞奥硝唑,消除半衰期大小依次为甲硝唑＞替硝唑＞奥硝唑,清除率大小依次为奥硝唑＞甲硝唑＞替硝唑;
8.替硝唑在大鼠上述组织中有效浓度维持时间最长,可达8h,奥硝唑最短,仅有4.5h。
结论:甲硝唑、替硝唑、奥硝唑均可以有效进入上述口腔组织,替硝唑在各组织的浓度峰值、有效浓度维持时间、分布速率上均相对优于甲硝唑、奥硝唑,更适于上述组织厌氧菌感染的防治。
Nitroimidazole Antimicrobials are widely used for the treatment of anaerobic infections in dental clinic,the current dosage regimen is based on the pharmacokinetics of Nitroimidazole Antimicrobials in blood,it is still unclear about the distribution and pharmacokinetics of nitroimidazole antimicrobials in oral tissues,and it is also unclear whether the nitroimidazole antimicrobials could reach the effective concentration and achieve the maximum effect under current dosage regimen,so it is necessary to investigate the distribution and pharmacokinetics of nitroimidazole antimicrobials in oral tissues to provide necessary references for clinical drμg therapy.Rat was chosen as animal model in this research to investigate distribution of metronidazole,tinidazloe and ornidazole in gingiva,dental pulp, masseter muscle,and mandible by high performance liquid chromatography (HPLC)method.
1.Pharmacokinetics and oral tissue distribution of metronidazole in rats
Objective:To develop appropriate HPLC method to measure the distribution of nitroimidazole antimicrobials in rat samples.
Methods:for metrodizaole,the Agilent Zorbax SB-C18(250mm×4.6mm, 5μm)analytical columm was employed,the mobile phase consisted of watermethanol (70:30,v/v);and for tinidazole and ornidazole,the analytical columm was Agilent Zorbax SB- C18(150mm×4.6mm,5μm),the mobile phase consisted of water- methanol(75:25,v/v),20μl was pumped throμgh the system at a rat of 1.0ml/min, the effluent was monitored at 316 nm.The plasma and tissues homogenate sapmples of rats were extracted by 5%dimethylcarbinol chloroform,after centrifμgation the supematant were collected and dried for following analysis.
Results:under the condition above,all chromatograms of metronidazole, tinidazole and ornidazole were free from any interference at the retention times, linear relationships were ranging from 31.25 to 12.5μ/ml with correlation coefficient above 0.999,and the limits of detection were 0.2ng with signal-to-noise ratio of 3.The mean recovery of metronidazole,tinidazole and ornidazole in rat tissues was 84.1%,86.2%and 85.4%respectively.The withinand between-day variability were all below 10%.
Conclusion:A sensitive,accurate and rapid HPLC method was developed to quantitate concentration of nitroimidazole antimicrobials in rat oral tissues.
2.The pharmacokineties and distribution of nitroimidazole antimierobiais in rat oral tissues
Objective:to observe and analyze the pharmacokinetics and distribution of metronidazole,tinidazole and ornidazole in rat gingival,dental pulp,masseter muscle and mandible.
Methods:metronidazole and ornidazole 5mg/100g,tinidazole 4mg/ml was administered to male rats through intraperitoneal and tail vein injection.The samplaes of plasma,gingival,dental pulp and mandible were collected at different time interval.The pharmacokinetics of drug was analysed by established HPLC method.
Results:
1.Metronidazole,tinidazole and ornidazole could penetrate the oral tissues examined;
2.The peak concentration of ornidazole in all the tissues was lower than metronidazole and ornidazole;
3.The masseter muscle and mandible had the lowest drμg concentration among the tissues measured;
4.In gingival and masseter muscle,the peak concentration of drμg in order was metronidazole＞tinidazole＞ornidazole,and in dental pulp and mandible that order was tinidazole＞metronidazole＞ornidazole;
5.The peak-reaching time of ornidazole,which was 10 min in all the tissues, was shorter than other two drμgs,tinidazole reached the peak value at 30 min after drμg administration in all the tissues;metronidazole reached the peak value at 10 min after drμg administration in plasma and masseter muscle;30min in gingiva and 1h in dental pulp and mandible.
6.The pharmacokinetics parameter of metronidazole and ornidazole was fit for one compartment model.Tinidazole was fit for two compartment model;
7.Cmax value in order was metronidazole＞tinidazole＞ornidazole,eliminate half-time in order was metronidazole＞tinidazole＞ornidazole,total clearance in order was ornidazole＞metronidazole＞tinidazole;
8.Tinidazole could maintain the effctive concentration in oral tissues for 8h, which was longest among three drμgs;ornidazole could only persist for 4.5h. Conclusions:all the three nitroimidazole antimicrobials could distributed in oral tissues,tinidazole is better relatively than metronidazole and ornidazole according to the overall parameter,which has more advatages for the treatment of anaerobic infections in oral tissues examined.
引文
1.Sarkiala,Jarvinen,S.valttila,et al.Phamacokinetics of Tinidazole in dog and cats.Journal of veterinary Pharm and Therap.1991,14(3):257-262.
2.顾宜,张云安.兔静脉注射替硝唑的药物动力学.第四军医大学学报.1998,19(5):596-597.
3.李芹,赵焰,梁永广,等.奥硝唑血药浓度的高效液相色谱法测定及其药动学研究.中国药学杂志.2003,38(9):690-692.
4.温清,李俊生,董瑞谦,等.奥硝唑片、奥硝唑胶囊人体生物等效性研究.中国药师.2003,6(5):259-301.
5.高允生,朱玉云.反相高效液相色谱法测定血清中的甲硝唑及其代谢产物.中国医院药学杂志.1996,16(2):52-54.
6.阳崇德,傅若秋,等.HPLC法测定血浆及组织中替硝唑、环丙沙星和消炎痛的含量.中国药业.2000,1(9):22-23.
7.韩丽萍,孙桂华,等.替硝唑和甲硝唑在胆病患者血浆和胆汁中浓度测定.解放军药学学报.2005,2(21):148-150.
8.王虹,刘克明,辛显桐,等.大鼠经口腔粘膜吸收含甲硝唑牙膏后血清中浓度测定.中国卫生检验杂志.2000,12(6):701-703.
1.Darryl C.Tong,Bruce R.Rothwell.Antibiotic use in dental practice.A review.J Am Dent Assoc.2000,131(3):366-374
2.Ciancio SG,Mather ML,McMullen JA.An Evaluation of Minocycline in Patients with Periodontal Disease.J Periodontol.1980,51(9):530-4.
3.Gordon JM,Walker CB,Murphy JC,et al.Concentrations of Tetracycline in Human Gingival Fluid after Single Doses.J Clin Periodontol.1981,8(2):117-21.
4.V.Liew,G Mack,P.Tseng,M.et al.Single-dose Concentrations of Tinidazole in Gingival Crevicular Fluid,Serum,and Gingival Tissue in Adults with Periodontitis.J Dent Res.1991,70(5):910-912
5.Van Oosten MA,Notten FJ,Mikx FH.Metronidazole concentrations in human plasma,saliva,and gingival crevice fluid after a single dose.J Dent Res.1986,65(12):1420-3
6.Sarkiala-Kessel EM,Jarvinen A,Nokelainen M,et al.Concentrations of tinidazole in gingival crevicular fluid and plasma in dogs after multiple dose administration.J Vet Pharmacol Ther.1996,19(3):171-175
7.Karjagin J,Pahkla R,Starkopf J.Perioperative penetration of metronidazole into muscle tissue:a microdialysis study.Eur J Clin Pharmacol.2004,59(11):809-13
8.Karjagin J,Pahkla R,Karki T,et al.Distribution of metronidazole in muscle tissue of patients with septic shock and its efficacy against Bacteroides fragilis in vitro.J Antimicrob Chemother.2005,55(3):341-346.
9.Viitanen J,Auvinen O,Tunturi T.Serum and tissue tinidazole concentrations after intravenous infusion.Chemotherapy.1983;29(1):13-7.
10.徐淑云.临床药理学.北京:人民卫生出版社,1994:53
11.刘洪臣.人工种植牙全身给药系统的设计.口腔领面修复学杂志,2006,7(4):291-292.
12.刘洪臣.牙根管全身给药假说.中华老年口腔医学杂志.2007,5(1):2-3
13.唐明,章锦才,肖晓蓉等.三种硝基咪唑类药物对牙周病病原菌的抗菌活性比较.临床口腔医学.2002,18(5):327-329.
14.张秀珍,陈东科,胡继红,等.甲硝唑等药物对115株厌氧菌最低抑菌浓度测定.中华医学检验杂志.1996,19(6):366-368.
15.Olsson-Liljequist B,Nord CE.In vitro susceptibility of anaerobic bacteria to nitroimidazoles.Scand J Infect Dis Suppl.1981,26:42-5.
16.Ralph ED,Clarke JT,Libke RD,et al.Pharmacokinetics of metronidazole as determined by bioassay.Antimicrob Agents Chemother.1974,6:691-696
17.Jensen JC,Gugler R.Single and multiple-dose metronidazole kinetics.Clin Pharmacol Ther.1983,34:481-7
18.Fredricsson B,Hagstrom B,Nord CE,et al.Systemic concentrations of metronidazole and its main metabolites after intravenous oral and vaginal administration.Gynecol Obstet Invest.1987,24(3):200-207
19.G W.Hoμghton,P.S.Thorne,Joy Smith,R.Templeton,and J.Collier.Comparison of the pharmacokinetics of metronidazole in healthy female volunteers following either a single oral or intravenous dose.Br J Clin Pharmacol.1979,8(4):337-341
20.高允生 朱玉云.反相高效液相色谱法测定血清中的甲硝唑及其代谢产物.中国医院药学杂志,1996,16(2):52-54
21.周宏兵,张恒,李伟,等.反相高效液相色谱法测定兔血清和脑脊液甲硝唑浓度和药代动力学参数的研究.药物分析杂志.1996,16(3):175-178
22.Koch A,Federspil P,Hartmetz G Metronidazole pharmacokinetics in perilymph,aqueous humor and cerebrospinal fluid.Laryngol Rhinol Otol (Stuttg).1985,64(12):649-51
23.顾宜,蒋永培,赵德化.替硝唑和甲硝唑的人体药动学对比研究.中国药 学杂志,2000,35(5):323-326
24.J Mattila,P T Mannisto,R Mantyla,et al.Comparative Pharmacokinetics of Metronidazole and Tinidazole as Influenced by Administration Route.Antimicrob Agents Chemother.1983,23(5):721-725.
25.Pyorala,-S;Kotilainen,-T;Silvennoinen,-P,et al.Pharmacokinetics of tinidazole in the horse.J-Vet-Pharmacol-Ther.1990,13(1):76-80
26.Sarkiala E,Jarvinen A,Valttila S,et al.Pharmacokinetics of tinidazole in dogs and cats.J-Vet-Pharmacol-Ther.1991,14(3):257-262
27.蔡鸿生,张先洲,李荣凌.替硝唑药物动力学研究.中国医院药学杂志.1995,15(12):531-532
28.顾宜,张云安,高苏莉,等.兔静脉注射替硝唑的药物动力学.第四军医大学学报.1998 19(5):596-597
29.Pyorala S,Soback S,Rainio V,et al.Pharmacokinetics of single-dose administration of tinidazole in unweaned calves.Am J Vet Res.1994,55(6):831-834
30.Martin C,Brμguerolle B,Mallet MN,et al.Pharmacokinetics and Tissue Penetration of a Single Dose of Ornidazole(1,000 Milligrams Intravenously)for Antibiotic Prophylaxis in Colorectal Surgery.Antimicrob Agents Chemother.1990,4(10):1921-1924
31.祁金文,马珂,吴远航.奥硝唑对大鼠血胰屏障通透性的研究.中国现代应用药学杂志.2006,23(5):425-428
32.陈燕,石涛,柳晓泉,等.左旋和右旋奥硝唑在大鼠体内的药代动力学.中国药科大学学报.2006,37(1):41-44
1.邱蔚六.口腔颌面外科学第四版.北京,人民卫生出版社,117
2.Sandor GK,Low DE,Judd PL,et al.Antimicrobial treatment options in the management of odontogenic infections.J Can Dent Assoc.1998,64(7):508-14.
3.Bresco-Salinas M,Costa-Riu N,Berini-Aytes L,et al.Antibiotic susceptibility of the bacteria causing odontogenic infections.Med Oral Patol Oral Cir Bucal.2006,11(1):E70-5.
4.Haapasalo M.Black-pigmented gram-negative anaerobes in endodontic infections.FEMS Immunol Med Microbiol.1993,6(2-3):213-217.
5.Khemaleelakul S,Baumgartner JC,Pruksakorn S.Identification of bacteria in acute endodontic infections and their antimicrobial susceptibility.Oral Surg Oral Med Oral Pathol Oral Radiol Endod.2002,94(6):746-55
6.Slot J,Bragd L,Wikstrom M,et al.The occurrence of Actinobactillus actinomycetemocmitans,Bacterides gingivalis and Bacterides i ntermedius in destructive periodontal disease in adults.J Clin Periodontol.1996,13(6):570-577
7.肖刚,吴坚,陈月燕.慢性牙周炎相关菌群分析.实用医技杂志.2006,13(8):3239-3240
8.黄洪章.现代口腔颌面外科学.北京:科学技术文献出版社,2001.145.
9.Sixou JL,Magaud C,Jolivet-Goμgeon A,et al.Microbiology of mandibular third molar pericoronitis:incidence of beta-lactamase-producing bacteria.Oral surg oral med oral pathol oral radiol endod.2003,95(6):655-9
10.Blum IR.Contemporary views on dry socket(alveolar osteitis):a clinical appraisal of standardization,aetiopathogenesis and anagement:a critical review.Int J Oral Maxillofac Surg.2002,31(3):309-17.
11.杜达耿.替硝唑简介.中国医院药学杂志.1994,14(5):232
12.Muller M.Mode of action of metronidazole on anaerobic bacteria and protozoa.Surgery.1983,93(1 Pt 2):165-71
13. Ralph ED, Clarke JT, Libke RD, et al. Pharmacokinetics of metronidazole as determined by bioassay. Antimicrob Agents Chemother 1974, 6: 691-6
14. Jensen JC, Gμgler R. Single and multiple-dose metronidazole kinetics. Clin Pharmacol Ther. 1983, 34(3): 481-487.
15. Fredricsson B, Hagstrom B, Nord CE, et al. Systemic concentrations of metronidazole and its main metabolites after intravenous oral and vaginal administration. Gynecol Obstet Invest. 1987, 24(3): 200-207
16. Amon I, Amon K, Huller H. Pharmacokinetics and therapeutic efficacy of metronidazole at different dosages. Int J Clin Pharmacol. 1978, 16(8): 384-386
17. Lau AH, Emmons K, Seligsohn R. Pharmacokinetics of intravenous metronidazole at different dosages in healthy subjects. Int J Clin Pharmacol Ther Toxicol. 1991, 29(10): 386-90
18. Mattila J, Mannisto PT, Mantyla R, et al. Comparative pharmacokinetics of metronidazole and tinidazole as influenced by administration route. Antimicrob Agents Chemother. 1983, 23(5): 721-5
19. G. W. Houghton, P. S. Thorne, Joy Smith, et al. Comparison of the pharmacokinetics of metronidazole in healthy female volunteers following either a single oral or intravenous dose. Br J Clin Pharmacol. 1979, 8(4): 337-341.
20. O'Keefe JP, Troc KA, Thompson KA. Activity of metronidazole and its hydroxy and acid metabolites against clinical isolates of anaerobic bacteria. Antimicrob Agents Chemother. 1982, 22(3): 426-30
21. Bergan T, Leinebo O, Blom-Hagen T, et al. Pharmacokinetics and bioavailability of metronidazole after tablets, suppositories and intravenous administration. Scand J Gastroenterol. 1984, 19 Suppl, 91: 45-60
22. Lamp KC, Freeman CD, Klutman NE, et al. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials. Clin Pharmacokinet, 1999, 36(5): 353-373
23.Van Oosten MAC,Notten FJW,Mikx FHM.Metronidazole concentrations in human plasma,saliva,and gingival crevice fluid after a single dose.J Dent Res.1986,65(12):1420-3
24.Koch A,Federspil P,Hartmetz G Metronidazole pharmacokinetics in perilymph,aqueous humor and cerebrospinal fluid.Laryngol Rhinol Otol (Stuttg).1985,64(12):649-51
25.周宏兵,张烜,李伟,等.反相高效液相色谱法测定兔血清和脑脊液甲硝唑浓度和药代动力学研究.药物分析杂志.1996,16(3):175-178.
26.高允生 朱玉云.反相高效液相色谱法测定血清中的甲硝唑及其代谢产物.中国医院药学杂志.1996,16(2):52-54.
27.辛显桐,刘克明,王虹,等.甲硝唑经口腔吸收在大鼠体内的代谢动力学.环境与健康杂志.2001,18(2):80-82.
28.柏干荣,胡友梅.替硝唑的药理与临床应用进展.中国药房.1998,9(1):42-43.
29.贾公孚,谢惠民.临床药物新用联用大全.北京:人民卫生出版社,2003.63.
30.Vinge E,Anderson KE,Ando G,et al.Biological availability and pharmacokinetics of tinidazole after single and multiple dose.Scand J Infect Dis.1983,15(4):391-397
31.Carmine AA,Brogden RN,Heel RC,et al.Tinidazole in anaerobic infections.A review of its antibacterial activity,pharmacological properties and therapeutic efficacy.Drμgs.1982,24(2):85-117
32.顾宜,蒋永培,赵德化.替硝唑和甲硝唑的人体药动学对比研究.中国药学杂志.2000,35(5):323-326
33.张先洲,蔡鸿生,彭艳,等.替硝唑在唾液中的药代动力学.中国新药杂志.1996,5(3):216-218
34.王宇,曹世珍,石克成,等.替硝唑在唾液和血浆中浓度的相关性探讨.暨南大学学报(医学版).1999,20(4):11-14
35.V.Liew,G Mack,P.Tseng,M.et al.Single-dose Concentrations of Tinidazole in Gingival Crevicular Fluid,Serum,and Gingival Tissue in Adults with Periodontitis.J Dent Res.1991,70(5):910-912
36.Sarkiala-Kessel EM,Jarvinen A,Nokelainen M,et al.Concentrations of tinidazole in gingival crevicular fluid and plasma in dogs after multiple dose administration.J Vet Pharmacol Ther.1996,19(3):171-175
37.顾宜,张云安,高苏莉,等.兔静脉注射替硝唑的药物动力学.第四军医大学学报.1998,19(5):596-597
38.Pyorala S,Soback S,Rainio V,et al.Pharmacokinetics of single-dose administration of tinidazole in unweaned calves.Am J Vet Res.1994,55(6):831-834
39.李功华,祁金文,马珂.替硝唑对大鼠血胰屏障通透性的研究.医药导报.2004,23(8):525-527
40.蔡鸿生,张先洲,李荣凌.替硝唑药物动力学研究.中国医院药学杂志.1995,15(12):531-532
41.Sarkiala E,Jarvinen A,Valttila S,et al.Pharmacokinetics of tinidazole in dogs and cats.J-Vet-Pharmacol-Ther.1991,14(3):257-262
42.Pyorala,-S;Kotilainen,-T;Silvennoinen,-P,et al.Pharmacokinetics of tinidazole in the horse.J-Vet-Pharmacol-Ther.1990,13(1):76-80
43.Packard RS.Tinidazole:a review of clinical experience in anaerobic infections.J Antimicrob Chemother.1982,10 Suppl A:65-72
44.Jokipii L,Jokipii AMM.Comparative evaluation of the 2-methyl-5-nitroimidazole compounds dimetridazole,metronidazole,secnidazole,ornidazole,carnidazole,and panidazole against Bacteroides fragilis and other bacteria of the Bacteroides fragilis group.Antimicrob Agents Chemother.1985,28(4):561-564
45.Ramamurthy L,Kulkarni RD,Chauhan BL,et al.Relative bioavailability of two brands of ornidazole in twelve healthy volunteers.J Assoc Physicians India.2002,50:1149-52.
46.Jurg Wust.Susceptibility of Anaerobic Bacteria to Metronidazole,Ornidazole,and Tinidazole and Routine Susceptibility Testing by Standardized Methods. Antimicrobial.Agents and Chemotherapy.1977,11(4):631-637.
47.陈燕,石涛,柳晓泉,等.左旋右旋奥硝唑在大鼠的药代动力学研究.中国药科大学学报.2006,37(1):41-44.
48.祁金文,马珂,吴远航.奥硝唑对大鼠血胰屏障通透性的研究.中国现代应用药学杂志.2006,23(5):425-428.
49.唐明,章锦才,肖晓蓉等.三种硝基咪唑类药物对牙周病病原菌的抗菌活性比较.临床口腔医学.2002,18(5):327-329.
50.张秀珍,陈东科,胡继红,等.甲硝唑等药物对115株厌氧菌最低抑菌浓度测定.中华医学检验杂志.1996,19(6):366-368
51.Olsson-Liljequist B,Nord CE.In vitro susceptibility of anaerobic bacteria to nitroimidazoles.Scand J Infect Dis Suppl.1981,26:42-5
52.唐明,章锦才,肖晓蓉等.常用抗厌氧菌药物对牙龈卟啉单胞菌的体外抗菌活性研究.重庆医学.2001,30(3):200-202
53.孙海花,周明,马才顺,等.替硝唑和甲硝唑在口腔科应用效果对比研究.现代中西医结合杂志.2003,12(19):2053-2054
54.丁俊清;周海孝;张远芳,等.奥硝唑用于口腔厌氧菌感染的临床研究.临床口腔医学杂志.2001,17(2):127-129.
55.Ghayoumi N.the use of metronidazole in the treatment of periodontal diseases.J West Soc Periodontol Periodontal Abstr.2001,49(2):37-40.
56.Griffiths GS,Smart GJ,Bulman JS,et al.Comparison of clinical outcomes following treatment of chronic adult periodontitis with subgingival scaling or subgingival scaling plus metronidazole gel.J Clin Periodontol.2000,27(12):910-917.
57.Rooney J,Wade WG,Sprague SV,et al.Adjunctive effects to non-surgical periodontal therapy of systemic metronidazole and amoxycillin alone and combined.A placebo controlled study.J Clin Periodontol.2002,29(4):342-50
58.Carvalho LH,D'Avila GB,Leao A,Haffajee AD,Socransky SS,Fetes M.Scaling and root planing,systemic metronidazole and professional plaque removal in the treatment of chronic periodontitis in a Brazilian population.I. Clinical results.J.Clin.Periodontol.2004,31(12):1070-1076.
59.王仁飞,陈莉丽,倪可夫,等.替硝唑治疗成人牙周炎的疗效评价.中华口腔医学杂志.1996,31(5):303-306.
60.段延华.奥硝唑联用培氟沙星对牙周致病菌的抑菌作用及最佳配比研究.第三军医大学硕士论文.2006
61.Radvar M,Pourtaghi N,Kinane DF.Comparison of 3 periodontal local antibiotic therapies in persistent periodontal pockets.J Periodontol.1996,67(9):860-5
62.Stellini E,Migliorato A,Mazzoleni S,et al.Topical treatment of peri-implantitis with metronidazole dental gel 25%.Clinical analysis and microbiological control.Minerva Stomatol.2000,49(1-2):59-67
63.Bergdahl M,Hedstrom L.Metronidazole for the prevention of dry socket after removal of partially impacted mandibular third molar:a randomised controlled trial.Br J Oral Maxillofac Surg.2004,42(6):555-8.
64.邹纯才,鄢海燕,林润台.替硝唑明胶海绵剂的研制及临床应用.中国医院药学杂志.1999,19(9):525-526.
65.汤爱明,铁朝荣.86例急性冠周炎抗厌氧菌药物治疗的临床评价.临床口腔医学杂志.1998,14(2):106-107
66.李可兴.奥硝唑治疗急性冠周炎临床疗效观察.实用诊断与治疗杂志.2004,18(2):127-128
2.顾宜,张云安.兔静脉注射替硝唑的药物动力学.第四军医大学学报.1998,19(5):596-597.
3.李芹,赵焰,梁永广,等.奥硝唑血药浓度的高效液相色谱法测定及其药动学研究.中国药学杂志.2003,38(9):690-692.
4.温清,李俊生,董瑞谦,等.奥硝唑片、奥硝唑胶囊人体生物等效性研究.中国药师.2003,6(5):259-301.
5.高允生,朱玉云.反相高效液相色谱法测定血清中的甲硝唑及其代谢产物.中国医院药学杂志.1996,16(2):52-54.
6.阳崇德,傅若秋,等.HPLC法测定血浆及组织中替硝唑、环丙沙星和消炎痛的含量.中国药业.2000,1(9):22-23.
7.韩丽萍,孙桂华,等.替硝唑和甲硝唑在胆病患者血浆和胆汁中浓度测定.解放军药学学报.2005,2(21):148-150.
8.王虹,刘克明,辛显桐,等.大鼠经口腔粘膜吸收含甲硝唑牙膏后血清中浓度测定.中国卫生检验杂志.2000,12(6):701-703.
1.Darryl C.Tong,Bruce R.Rothwell.Antibiotic use in dental practice.A review.J Am Dent Assoc.2000,131(3):366-374
2.Ciancio SG,Mather ML,McMullen JA.An Evaluation of Minocycline in Patients with Periodontal Disease.J Periodontol.1980,51(9):530-4.
3.Gordon JM,Walker CB,Murphy JC,et al.Concentrations of Tetracycline in Human Gingival Fluid after Single Doses.J Clin Periodontol.1981,8(2):117-21.
4.V.Liew,G Mack,P.Tseng,M.et al.Single-dose Concentrations of Tinidazole in Gingival Crevicular Fluid,Serum,and Gingival Tissue in Adults with Periodontitis.J Dent Res.1991,70(5):910-912
5.Van Oosten MA,Notten FJ,Mikx FH.Metronidazole concentrations in human plasma,saliva,and gingival crevice fluid after a single dose.J Dent Res.1986,65(12):1420-3
6.Sarkiala-Kessel EM,Jarvinen A,Nokelainen M,et al.Concentrations of tinidazole in gingival crevicular fluid and plasma in dogs after multiple dose administration.J Vet Pharmacol Ther.1996,19(3):171-175
7.Karjagin J,Pahkla R,Starkopf J.Perioperative penetration of metronidazole into muscle tissue:a microdialysis study.Eur J Clin Pharmacol.2004,59(11):809-13
8.Karjagin J,Pahkla R,Karki T,et al.Distribution of metronidazole in muscle tissue of patients with septic shock and its efficacy against Bacteroides fragilis in vitro.J Antimicrob Chemother.2005,55(3):341-346.
9.Viitanen J,Auvinen O,Tunturi T.Serum and tissue tinidazole concentrations after intravenous infusion.Chemotherapy.1983;29(1):13-7.
10.徐淑云.临床药理学.北京:人民卫生出版社,1994:53
11.刘洪臣.人工种植牙全身给药系统的设计.口腔领面修复学杂志,2006,7(4):291-292.
12.刘洪臣.牙根管全身给药假说.中华老年口腔医学杂志.2007,5(1):2-3
13.唐明,章锦才,肖晓蓉等.三种硝基咪唑类药物对牙周病病原菌的抗菌活性比较.临床口腔医学.2002,18(5):327-329.
14.张秀珍,陈东科,胡继红,等.甲硝唑等药物对115株厌氧菌最低抑菌浓度测定.中华医学检验杂志.1996,19(6):366-368.
15.Olsson-Liljequist B,Nord CE.In vitro susceptibility of anaerobic bacteria to nitroimidazoles.Scand J Infect Dis Suppl.1981,26:42-5.
16.Ralph ED,Clarke JT,Libke RD,et al.Pharmacokinetics of metronidazole as determined by bioassay.Antimicrob Agents Chemother.1974,6:691-696
17.Jensen JC,Gugler R.Single and multiple-dose metronidazole kinetics.Clin Pharmacol Ther.1983,34:481-7
18.Fredricsson B,Hagstrom B,Nord CE,et al.Systemic concentrations of metronidazole and its main metabolites after intravenous oral and vaginal administration.Gynecol Obstet Invest.1987,24(3):200-207
19.G W.Hoμghton,P.S.Thorne,Joy Smith,R.Templeton,and J.Collier.Comparison of the pharmacokinetics of metronidazole in healthy female volunteers following either a single oral or intravenous dose.Br J Clin Pharmacol.1979,8(4):337-341
20.高允生 朱玉云.反相高效液相色谱法测定血清中的甲硝唑及其代谢产物.中国医院药学杂志,1996,16(2):52-54
21.周宏兵,张恒,李伟,等.反相高效液相色谱法测定兔血清和脑脊液甲硝唑浓度和药代动力学参数的研究.药物分析杂志.1996,16(3):175-178
22.Koch A,Federspil P,Hartmetz G Metronidazole pharmacokinetics in perilymph,aqueous humor and cerebrospinal fluid.Laryngol Rhinol Otol (Stuttg).1985,64(12):649-51
23.顾宜,蒋永培,赵德化.替硝唑和甲硝唑的人体药动学对比研究.中国药 学杂志,2000,35(5):323-326
24.J Mattila,P T Mannisto,R Mantyla,et al.Comparative Pharmacokinetics of Metronidazole and Tinidazole as Influenced by Administration Route.Antimicrob Agents Chemother.1983,23(5):721-725.
25.Pyorala,-S;Kotilainen,-T;Silvennoinen,-P,et al.Pharmacokinetics of tinidazole in the horse.J-Vet-Pharmacol-Ther.1990,13(1):76-80
26.Sarkiala E,Jarvinen A,Valttila S,et al.Pharmacokinetics of tinidazole in dogs and cats.J-Vet-Pharmacol-Ther.1991,14(3):257-262
27.蔡鸿生,张先洲,李荣凌.替硝唑药物动力学研究.中国医院药学杂志.1995,15(12):531-532
28.顾宜,张云安,高苏莉,等.兔静脉注射替硝唑的药物动力学.第四军医大学学报.1998 19(5):596-597
29.Pyorala S,Soback S,Rainio V,et al.Pharmacokinetics of single-dose administration of tinidazole in unweaned calves.Am J Vet Res.1994,55(6):831-834
30.Martin C,Brμguerolle B,Mallet MN,et al.Pharmacokinetics and Tissue Penetration of a Single Dose of Ornidazole(1,000 Milligrams Intravenously)for Antibiotic Prophylaxis in Colorectal Surgery.Antimicrob Agents Chemother.1990,4(10):1921-1924
31.祁金文,马珂,吴远航.奥硝唑对大鼠血胰屏障通透性的研究.中国现代应用药学杂志.2006,23(5):425-428
32.陈燕,石涛,柳晓泉,等.左旋和右旋奥硝唑在大鼠体内的药代动力学.中国药科大学学报.2006,37(1):41-44
1.邱蔚六.口腔颌面外科学第四版.北京,人民卫生出版社,117
2.Sandor GK,Low DE,Judd PL,et al.Antimicrobial treatment options in the management of odontogenic infections.J Can Dent Assoc.1998,64(7):508-14.
3.Bresco-Salinas M,Costa-Riu N,Berini-Aytes L,et al.Antibiotic susceptibility of the bacteria causing odontogenic infections.Med Oral Patol Oral Cir Bucal.2006,11(1):E70-5.
4.Haapasalo M.Black-pigmented gram-negative anaerobes in endodontic infections.FEMS Immunol Med Microbiol.1993,6(2-3):213-217.
5.Khemaleelakul S,Baumgartner JC,Pruksakorn S.Identification of bacteria in acute endodontic infections and their antimicrobial susceptibility.Oral Surg Oral Med Oral Pathol Oral Radiol Endod.2002,94(6):746-55
6.Slot J,Bragd L,Wikstrom M,et al.The occurrence of Actinobactillus actinomycetemocmitans,Bacterides gingivalis and Bacterides i ntermedius in destructive periodontal disease in adults.J Clin Periodontol.1996,13(6):570-577
7.肖刚,吴坚,陈月燕.慢性牙周炎相关菌群分析.实用医技杂志.2006,13(8):3239-3240
8.黄洪章.现代口腔颌面外科学.北京:科学技术文献出版社,2001.145.
9.Sixou JL,Magaud C,Jolivet-Goμgeon A,et al.Microbiology of mandibular third molar pericoronitis:incidence of beta-lactamase-producing bacteria.Oral surg oral med oral pathol oral radiol endod.2003,95(6):655-9
10.Blum IR.Contemporary views on dry socket(alveolar osteitis):a clinical appraisal of standardization,aetiopathogenesis and anagement:a critical review.Int J Oral Maxillofac Surg.2002,31(3):309-17.
11.杜达耿.替硝唑简介.中国医院药学杂志.1994,14(5):232
12.Muller M.Mode of action of metronidazole on anaerobic bacteria and protozoa.Surgery.1983,93(1 Pt 2):165-71
13. Ralph ED, Clarke JT, Libke RD, et al. Pharmacokinetics of metronidazole as determined by bioassay. Antimicrob Agents Chemother 1974, 6: 691-6
14. Jensen JC, Gμgler R. Single and multiple-dose metronidazole kinetics. Clin Pharmacol Ther. 1983, 34(3): 481-487.
15. Fredricsson B, Hagstrom B, Nord CE, et al. Systemic concentrations of metronidazole and its main metabolites after intravenous oral and vaginal administration. Gynecol Obstet Invest. 1987, 24(3): 200-207
16. Amon I, Amon K, Huller H. Pharmacokinetics and therapeutic efficacy of metronidazole at different dosages. Int J Clin Pharmacol. 1978, 16(8): 384-386
17. Lau AH, Emmons K, Seligsohn R. Pharmacokinetics of intravenous metronidazole at different dosages in healthy subjects. Int J Clin Pharmacol Ther Toxicol. 1991, 29(10): 386-90
18. Mattila J, Mannisto PT, Mantyla R, et al. Comparative pharmacokinetics of metronidazole and tinidazole as influenced by administration route. Antimicrob Agents Chemother. 1983, 23(5): 721-5
19. G. W. Houghton, P. S. Thorne, Joy Smith, et al. Comparison of the pharmacokinetics of metronidazole in healthy female volunteers following either a single oral or intravenous dose. Br J Clin Pharmacol. 1979, 8(4): 337-341.
20. O'Keefe JP, Troc KA, Thompson KA. Activity of metronidazole and its hydroxy and acid metabolites against clinical isolates of anaerobic bacteria. Antimicrob Agents Chemother. 1982, 22(3): 426-30
21. Bergan T, Leinebo O, Blom-Hagen T, et al. Pharmacokinetics and bioavailability of metronidazole after tablets, suppositories and intravenous administration. Scand J Gastroenterol. 1984, 19 Suppl, 91: 45-60
22. Lamp KC, Freeman CD, Klutman NE, et al. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials. Clin Pharmacokinet, 1999, 36(5): 353-373
23.Van Oosten MAC,Notten FJW,Mikx FHM.Metronidazole concentrations in human plasma,saliva,and gingival crevice fluid after a single dose.J Dent Res.1986,65(12):1420-3
24.Koch A,Federspil P,Hartmetz G Metronidazole pharmacokinetics in perilymph,aqueous humor and cerebrospinal fluid.Laryngol Rhinol Otol (Stuttg).1985,64(12):649-51
25.周宏兵,张烜,李伟,等.反相高效液相色谱法测定兔血清和脑脊液甲硝唑浓度和药代动力学研究.药物分析杂志.1996,16(3):175-178.
26.高允生 朱玉云.反相高效液相色谱法测定血清中的甲硝唑及其代谢产物.中国医院药学杂志.1996,16(2):52-54.
27.辛显桐,刘克明,王虹,等.甲硝唑经口腔吸收在大鼠体内的代谢动力学.环境与健康杂志.2001,18(2):80-82.
28.柏干荣,胡友梅.替硝唑的药理与临床应用进展.中国药房.1998,9(1):42-43.
29.贾公孚,谢惠民.临床药物新用联用大全.北京:人民卫生出版社,2003.63.
30.Vinge E,Anderson KE,Ando G,et al.Biological availability and pharmacokinetics of tinidazole after single and multiple dose.Scand J Infect Dis.1983,15(4):391-397
31.Carmine AA,Brogden RN,Heel RC,et al.Tinidazole in anaerobic infections.A review of its antibacterial activity,pharmacological properties and therapeutic efficacy.Drμgs.1982,24(2):85-117
32.顾宜,蒋永培,赵德化.替硝唑和甲硝唑的人体药动学对比研究.中国药学杂志.2000,35(5):323-326
33.张先洲,蔡鸿生,彭艳,等.替硝唑在唾液中的药代动力学.中国新药杂志.1996,5(3):216-218
34.王宇,曹世珍,石克成,等.替硝唑在唾液和血浆中浓度的相关性探讨.暨南大学学报(医学版).1999,20(4):11-14
35.V.Liew,G Mack,P.Tseng,M.et al.Single-dose Concentrations of Tinidazole in Gingival Crevicular Fluid,Serum,and Gingival Tissue in Adults with Periodontitis.J Dent Res.1991,70(5):910-912
36.Sarkiala-Kessel EM,Jarvinen A,Nokelainen M,et al.Concentrations of tinidazole in gingival crevicular fluid and plasma in dogs after multiple dose administration.J Vet Pharmacol Ther.1996,19(3):171-175
37.顾宜,张云安,高苏莉,等.兔静脉注射替硝唑的药物动力学.第四军医大学学报.1998,19(5):596-597
38.Pyorala S,Soback S,Rainio V,et al.Pharmacokinetics of single-dose administration of tinidazole in unweaned calves.Am J Vet Res.1994,55(6):831-834
39.李功华,祁金文,马珂.替硝唑对大鼠血胰屏障通透性的研究.医药导报.2004,23(8):525-527
40.蔡鸿生,张先洲,李荣凌.替硝唑药物动力学研究.中国医院药学杂志.1995,15(12):531-532
41.Sarkiala E,Jarvinen A,Valttila S,et al.Pharmacokinetics of tinidazole in dogs and cats.J-Vet-Pharmacol-Ther.1991,14(3):257-262
42.Pyorala,-S;Kotilainen,-T;Silvennoinen,-P,et al.Pharmacokinetics of tinidazole in the horse.J-Vet-Pharmacol-Ther.1990,13(1):76-80
43.Packard RS.Tinidazole:a review of clinical experience in anaerobic infections.J Antimicrob Chemother.1982,10 Suppl A:65-72
44.Jokipii L,Jokipii AMM.Comparative evaluation of the 2-methyl-5-nitroimidazole compounds dimetridazole,metronidazole,secnidazole,ornidazole,carnidazole,and panidazole against Bacteroides fragilis and other bacteria of the Bacteroides fragilis group.Antimicrob Agents Chemother.1985,28(4):561-564
45.Ramamurthy L,Kulkarni RD,Chauhan BL,et al.Relative bioavailability of two brands of ornidazole in twelve healthy volunteers.J Assoc Physicians India.2002,50:1149-52.
46.Jurg Wust.Susceptibility of Anaerobic Bacteria to Metronidazole,Ornidazole,and Tinidazole and Routine Susceptibility Testing by Standardized Methods. Antimicrobial.Agents and Chemotherapy.1977,11(4):631-637.
47.陈燕,石涛,柳晓泉,等.左旋右旋奥硝唑在大鼠的药代动力学研究.中国药科大学学报.2006,37(1):41-44.
48.祁金文,马珂,吴远航.奥硝唑对大鼠血胰屏障通透性的研究.中国现代应用药学杂志.2006,23(5):425-428.
49.唐明,章锦才,肖晓蓉等.三种硝基咪唑类药物对牙周病病原菌的抗菌活性比较.临床口腔医学.2002,18(5):327-329.
50.张秀珍,陈东科,胡继红,等.甲硝唑等药物对115株厌氧菌最低抑菌浓度测定.中华医学检验杂志.1996,19(6):366-368
51.Olsson-Liljequist B,Nord CE.In vitro susceptibility of anaerobic bacteria to nitroimidazoles.Scand J Infect Dis Suppl.1981,26:42-5
52.唐明,章锦才,肖晓蓉等.常用抗厌氧菌药物对牙龈卟啉单胞菌的体外抗菌活性研究.重庆医学.2001,30(3):200-202
53.孙海花,周明,马才顺,等.替硝唑和甲硝唑在口腔科应用效果对比研究.现代中西医结合杂志.2003,12(19):2053-2054
54.丁俊清;周海孝;张远芳,等.奥硝唑用于口腔厌氧菌感染的临床研究.临床口腔医学杂志.2001,17(2):127-129.
55.Ghayoumi N.the use of metronidazole in the treatment of periodontal diseases.J West Soc Periodontol Periodontal Abstr.2001,49(2):37-40.
56.Griffiths GS,Smart GJ,Bulman JS,et al.Comparison of clinical outcomes following treatment of chronic adult periodontitis with subgingival scaling or subgingival scaling plus metronidazole gel.J Clin Periodontol.2000,27(12):910-917.
57.Rooney J,Wade WG,Sprague SV,et al.Adjunctive effects to non-surgical periodontal therapy of systemic metronidazole and amoxycillin alone and combined.A placebo controlled study.J Clin Periodontol.2002,29(4):342-50
58.Carvalho LH,D'Avila GB,Leao A,Haffajee AD,Socransky SS,Fetes M.Scaling and root planing,systemic metronidazole and professional plaque removal in the treatment of chronic periodontitis in a Brazilian population.I. Clinical results.J.Clin.Periodontol.2004,31(12):1070-1076.
59.王仁飞,陈莉丽,倪可夫,等.替硝唑治疗成人牙周炎的疗效评价.中华口腔医学杂志.1996,31(5):303-306.
60.段延华.奥硝唑联用培氟沙星对牙周致病菌的抑菌作用及最佳配比研究.第三军医大学硕士论文.2006
61.Radvar M,Pourtaghi N,Kinane DF.Comparison of 3 periodontal local antibiotic therapies in persistent periodontal pockets.J Periodontol.1996,67(9):860-5
62.Stellini E,Migliorato A,Mazzoleni S,et al.Topical treatment of peri-implantitis with metronidazole dental gel 25%.Clinical analysis and microbiological control.Minerva Stomatol.2000,49(1-2):59-67
63.Bergdahl M,Hedstrom L.Metronidazole for the prevention of dry socket after removal of partially impacted mandibular third molar:a randomised controlled trial.Br J Oral Maxillofac Surg.2004,42(6):555-8.
64.邹纯才,鄢海燕,林润台.替硝唑明胶海绵剂的研制及临床应用.中国医院药学杂志.1999,19(9):525-526.
65.汤爱明,铁朝荣.86例急性冠周炎抗厌氧菌药物治疗的临床评价.临床口腔医学杂志.1998,14(2):106-107
66.李可兴.奥硝唑治疗急性冠周炎临床疗效观察.实用诊断与治疗杂志.2004,18(2):127-128