环丙沙星对人肝微粒体药物酶活性的影响

目的：观察环丙沙星对人肝微粒体药物代谢酶活性的影响。方法：用正常人新鲜肝组织低温匀浆,低温超速离心分离肝微粒体,测定肝微粒体细胞色素P450（CP450）的含量。以环丙沙星为处理因素,作肝微粒体药物代谢活性测定的体外试验。反应体系中微粒体蛋白的终浓度为1．0g/L,环丙沙星的终浓度为400mg/L。结果：环丙沙星对人肝微粒体药物代谢酶的活性抑制有选择性,对不同酶其抑制强度不同。对多种酶的抑制强弱顺序为：戊巴比妥侧链羟化酶＞苯并芘羟化酶＞乙基吗啡N－脱甲基酶, 其抑制率分别为0．34、0．30、和0．18。结论：环丙沙星对人肝微粒体多种药物代谢酶活性有明显的抑制作用。提示对肝功异常者、使用戊巴比妥钠麻醉的病人、经常服用吗啡类药物及高苯比芘含量环境工作人员该类药物应慎用。     

环丙沙星,氧氟沙星和诺氟沙星对大鼠肝微粒体混合功能氧化酶…

本文在肝微粒体水平上观察了环丙沙星、氧氟沙星和诺氟沙星对大鼠肝微粒体混合物能氧化酶活性的影响。以４００ｍｇ／ｋｇ环丙沙星、氧沙星和诺氟沙星灌胃，ｑｄ×７天，环丙沙星组细胞色素ｂ５，氨基比林Ｎ－脱甲基酶、乙基吗啡Ｎ－脱甲基酶、ＮＡＤＰＨ－细胞色素Ｃ还原，７－氧基香豆素Ｏ－脱乙基酶和苯并芘羟化酶被抑制，而氧氟沙星、诺氟沙星权制制ＮＡＤＰＨ－细胞色素Ｃ还原酶和苯并芘羟化酶活性。三种药物对肝重及肝微粒体蛋     

环丙沙星、氧氟沙星和诺氟沙星对大鼠肝微粒体混合功能氧化酶的作用

本文在肝微粒体水平上观察了环丙沙星、氧氟沙星和诺氟沙星对大鼠肝微粒体混合功能氧化酶活性的影响。以４００ｍｇ／ｋｇ环丙沙星、氧氟沙星和诺氟沙星灌胃，ｑｄ×７天后，环丙沙星组细胞色素ｂ５、氨基比林Ｎ－脱甲基酶、乙基吗啡Ｎ－脱甲基酶、ＮＡＤＰＨ－细胞色素Ｃ还原酶，７－乙氧基香豆素Ｏ－脱乙基酶和苯并（ａ）芘羟化酶被抑制，而氧氟沙星、诺氟沙星仅抑制ＮＡＤＰＨ－细胞色素Ｃ还原酶和苯并（ａ）芘羟化酶活性。三种药物对肝重及肝微粒体蛋白含量、细胞色素Ｐ－４５０和戊巴比妥钠侧链羟化酶活性均无影响。该结果对指导临床合理联合用药，减少副反应，避免药物蓄积中毒有重要意义。     

培氟沙星对大鼠肝微粒体酶系的抑制作用

大鼠经培氟沙星４００ｍｇ／ｋｇ，ｉｇ，ｑｄ×７ｄ后，肝微粒体酶系中的细胞色素ｂ５、氢基比林－Ｎ－脱甲基醉，７－乙氧基香豆素－Ｏ－脱乙基酶及苯并芘羟化酶含量显著减少，细胞色素Ｃ还原酶活性降低，但细胞色素Ｐ－４５０、乙基吗啡－Ｎ－脱甲基酶、戊巴比妥侧链羟化酶活性无改变。表明培氟沙星有抑制大鼠肝微粒体酶系中一些酶的活性。     

六氯对二甲苯对豚鼠肝微粒体药物代谢酶的抑制特性

<正> 前文报道抗华支睾吸虫病药六氯对二甲苯(hexachloro—p—xylene,HCX)对豚鼠肝药酶的抑制作用,HCX能明显延长戊巴比妥催眠时间和血浆戊巴比妥t_(1/2β),并抑制肝匀浆中戊巴比妥侧链羟化酶(pentobarbital side—chain hydroxylase,PSCH)和氨基比林N—脱甲基酶(aminopyrine N—demethylase,ADM)活性。本文在肝微粒体和S9水平,进一步研究了HCX对肝微粒体药物代谢酶的作用,同时对其抑制特性进行了探讨。     

白花前胡中总香豆素组分对小鼠肝药酶活性的影响

目的：观察白花前胡中总香豆素组分(TCP)对小鼠肝药酶活性的影响。方法：将小鼠随机分组，以氯霉素(25mg·kg 1，ig)为阳性对照，观察TCP(50，100，200 mg·kg 1，ig)分别对戊巴比妥钠(36 mg·kg 1，ip)和巴比妥钠(180 mg·kg 1，ip)催眠作用的影响；并用分光光度法测定肝微粒体苯胺羟化酶(ANH)和氨基比林N 脱甲基酶(ADM)活性。结果：TCP呈剂量依赖性地延长戊巴比妥钠的催眠时间，但对巴比妥钠的催眠时间无明显影响；且TCP能显著降低ANH和ADM活性。结论：TCP能抑制小鼠肝药酶活性。     

18α-甘草酸下调“胶原蛋白凝胶三明治”培养的大鼠肝细胞P450酶活性及mRNA表达

研究 18α 甘草酸 (18α GA)对肝细胞主要细胞色素P4 50 (CYP)药物代谢酶的影响 ,并初步探讨其分子机理 .采用“胶原蛋白凝胶三明治”培养的原代大鼠肝细胞 ,加 18α GA孵育 ,酶学测定CYP1A1(7 乙氧基异口恶唑O 脱乙基酶 ,EROD) ,CYP2E1(苯胺羟化酶 ,ANH)和CYP3A(红霉素N 脱甲基酶 ,ERD)活性 ,逆转录聚合酶链反应测定CYP1A1,CYP2E1和CYP3A1mRNA表达水平 .结果可见 ,18α GA浓度依赖性 (50～ 4 0 0mg·L- 1)抑制大鼠肝细胞EROD ,ANH和ERD活性 ,2 0 0mg·L- 1作用最强 ,抑制率分别可达 59.6 % ,6 9.7%和 4 4 .7% ,且呈时间依赖性 ,于d 4达高峰 ;浓度依赖性 (50～ 2 0 0mg·L- 1)抑制CYP1A1,CYP2E1和CYP3A1mRNA表达水平 ,分别可达 4 4 .5% ,58.1%和 37.0 % .上述结果表明 18α GA在转录水平下调大鼠肝细胞CYP1A1,CYP2E1和CYP3A1表达     

大鼠肝微粒体细胞色素P450酶系检测方法学研究

目的 :建立大鼠肝微粒体蛋白含量以及肝微粒体细胞色素P4 5 0酶系含量与活性测定的紫外和荧光分光光度方法。方法 :应用差速离心法提取大鼠肝微粒体 ,Lowery法测定肝微粒体蛋白浓度 ,应用紫外和荧光分光光度法测定肝微粒体细胞色素P4 5 0酶系含量及活性。结果 :牛血清白蛋白标准曲线的线性范围为 2 5～ 2 5 0mg·L-1,最低检测限为2 5mg·L-1,相关系数r为 0 .9975 ;紫外分光光度法测定细胞色素P4 5 0和细胞色素b5含量及NADPH CytC还原酶活性的结果显示方法灵敏 ;测定氨基比林N 脱甲基酶、红霉素N 脱甲基酶活性的甲醛标准曲线 ,线性范围为 0 .0 5～ 0 .5mmol·L-1,最低检测限为 0 .0 5mmol·L-1,相关系数r为 0 .9988;测定 7 乙氧基香豆素脱烃酶活性的resorufin标准曲线线性范围为 1～ 8μmol·L-1,最低检测限为 1μmol·L-1,相关系数r为 0 .9998。结论 :紫外和荧光分光光度方法测定大鼠肝微粒体细胞色素P4 5 0酶系中 6种酶的含量及活性的灵敏可靠 ,重复性较好。     

氟喹诺酮类药物对大鼠肝外组织药物代谢酶的影响

目的:探讨氟喹诺酮类药物(FQs)对大鼠肺、脑、肾、小肠中细胞色素P450(CYP)含量、氨基比林N- 脱甲基酶(AMND)、红霉素N-脱甲基酶(ERND)活性的影响。方法:体外实验中环丙沙星、妥苏沙星和司帕沙星的药物终浓度均为1 mmol·L-1;体内实验按1 mmol·kg-1剂量灌胃,qd×7。制备大鼠肺、脑、肾、小肠S9,分光光度法测定CYP含量、AMND及ERND活性变化。结果:大鼠肺、肾组织CYP含量低;3种药物可不同程度地抑制各组织AMND活性(P<0．05)。肾和小肠中可测到ERND活性,而肺、脑中未测到;给药后肾、小肠 ERND活性有降低趋势,但大多无显著差异。结论:FQs对肝外组织CYP含量无显著影响,对AMND活性有抑制作用,对ERND有抑制趋势。     

加替沙星和环丙沙星对大鼠肝微粒体酶系的影响

目的研究加替沙星和环丙沙星对大鼠肝微粒体细胞色素P450酶系的影响.方法Wistar大鼠经加替沙星和环丙沙星400mg/kg灌胃给药,qd×7d后,应用差速离心法制备大鼠肝微粒体,采用Lowry法测定蛋白浓度,应用分光光度计法检测6种肝微粒体细胞色素P450酶含量及活性,并用单因素方差分析进行统计.结果加替沙星组中6种细胞色素P450酶测定结果与空白对照组相比差异无统计学意义,而环丙沙星能抑制6种细胞色素P450酶中的b5、NADPH-CytC还原酶、氨基比林N-脱甲基酶、红霉素N-脱甲基酶和7-乙氧基香豆素脱烃酶的活性,对CYP450酶系有选择性抑制作用.结论加替沙星对大鼠肝微粒体CYP450酶系无显著影响,而环丙沙星对CYP450酶系有选择性抑制作用.     

盐酸小檗碱与环孢素A合用对大鼠肝P450同工酶和mdr1的影响

目的　阐明盐酸小檗碱 (berberinechloride ,Ber)及其与环孢素A (cyclosporin ,CsA)合用对大鼠肝脏P4 5 0同工酶和多药耐药基因的影响。方法　采用分光光度法测定大鼠肝微粒体红霉素N 脱甲基酶 (ERD)、氨基比林N 脱甲基酶(ADM )的活性 ,采用RT PCR法测定大鼠肝脏CYP3A1、CYP1A1、CYP2E1、mdr1a和mdr1b基因的水平。结果　灌胃给药 6d后 ,除外 10 0mg·kg-1Ber组 ,其余各组对ERD活性有明显的抑制作用 ;给药 12d时 ,所有用药组对ERD活性均有抑制作用。给药 6d后 ,CsA单用组、Ber与CsA合用组对ADM均有抑制作用 ;给药 12d后 ,除了 15 0mg·kg-1酮康唑组和 10 0mg·kg-1Ber组外 ,其余各用药组对ADM均有抑制作用。给药 12d时 ,除了 10 0mg·kg-1Ber组外 ,其余各用药组对大鼠肝脏CYP3A1、CYP2E1、mdr1a、mdr1b基因均有抑制作用。各组的CYP1A1基因均未能检出。结论　抑制CYP3A基因的表达及酶的活性 ,抑制mdr1a、mdr1b基因的表达 ,从而减少CsA在肝脏的代谢及消除 ,可能是Ber增加CsA血浓度的重要机制     

Inhibition of drug metabolism by quinolone antibiotics

A number of quinolone antibiotics have been found to reduce the hepatic clearance of coadministered drugs such as theophylline. Enoxacin appears to be the most potent inhibitor, consistently decreasing theophylline clearance by more than 50%, while a single study suggests a similar degree of inhibition with pipemidic acid. Ciprofloxacin and pefloxacin reduce theophylline clearance to a smaller extent (approximately 20 to 30%). However, with ciprofloxacin, larger changes and theophylline toxicity have been reported in some subjects. Norfloxacin, ofloxacin and nalidixic acid appear to have minimal effects on theophylline clearance. Enoxacin and ciprofloxacin have also been found to reduce the clearance of caffeine, while ofloxacin has no effect. Few other substrates have been studied. Enoxacin decreases the clearance of R-warfarin with no effect on S-warfarin. In addition, enoxacin has been reported to reduce the clearance of antipyrine, with no effect on chlorpropamide, glibenclamide (glyburide) or phenytoin. The mechanism of these interactions is largely unexplored. It has been suggested that inhibition may be related to the production of 4-oxoquinolone metabolites; however, this hypothesis has not been confirmed. No unique structural feature has been identified to date which explains differences between these compounds in their propensity to affect drug metabolism. Further studies are needed to evaluate the effects of these drugs on other substrates not yet examined and to assess whether or not inhibition is dose related. Clinically, caution is advised when using a quinolone, particularly enoxacin, pipemidic acid, ciprofloxacin or pefloxacin, in combination with theophylline. Close monitoring of theophylline concentrations is recommended in any patient receiving these drugs. The clinical significance of inhibited metabolism of other substrates remains unclear at present. Until further data are available, clinicians should be aware of the possibility of reduced drug clearance resulting in adverse effects whenever the fluoroquinolones are coadministered with drugs that depend on hepatic metabolism for their elimination.     

氟喹诺酮类抗菌药物致药物不良反应205例调查分析

目的分析氟喹诺酮类抗菌药物(FQNS)药物不良反应(ADR)的特点,为临床合理用药提供依据。方法对2001-2010年某院门、急诊及住院部应用FQNS致ADR患者205例进行回顾性统计、分析。结果男性ADR发生率高于女性,31～40岁年龄段ADR发生率最高(31.2%);引起ADR的主要给药途径为静脉注射,共105例(51.2%);共涉及10种FQNS,不良反应主要表现在神经、循环、皮肤、泌尿、消化、呼吸、血液等系统,其中以神经系统、皮肤及消化系统症状较突出。结论 FQNS致ADR因素较多,临床使用时应注意ADR的监测,合理用药,以提高用药的安全性,减少ADR的发生。     

Influence of fluoroquinolones on the central action of ethanol.

The influence of ciprofloxacin, ofloxacin and pefloxacin on acute toxicity of ethanol, ethanol-induced hypothermia, ethanol sleeping time was investigated in mice. Moreover, the combined effect of fluoroquinolones and ethanol on spontaneous locomotor activity, motor coordination in mice and ethanol abstinence syndrome in rats was examined. The fluoroquinolones (20 and 80 mg/kg) were injected intraperitoneally. The drugs were given in single or repeated doses for 7 days. In acute experiments, drugs were given 30 min before ethanol administration. In chronic experiments, the last dose of fluoroquinolones was given 18 h prior to ethanol injection. It has been shown that the fluoroquinolones decrease acute toxicity of ethanol, antagonize its hypothermic effect, decrease ethanol inhibitory effect on motor coordination in mice, and increase ethanol-induced hypermotility in mice and audiogenic seizure response in rats during alcohol abstinence syndrome. Ciprofloxacin and ofloxacin administered repeatedly increase the influence of ethanol on duration of ethanol-induced sleep. The influence of fluoroquinolones on ethanol central action depends on the drug used, its dose and route of administration.     

Permeability classification of representative fluoroquinolones by a cell culture method

This study was undertaken to categorize representative fluoroquinolone drug substance permeability based on the methods outlined in the Food and Drug Administration's biopharmaceutic classification system (BCS) Guidance for Industry. The permeability of ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin was measured in an in vitro Caco-2 assay with previously demonstrated method suitability. The permeability class and efflux potential were ascertained by comparing test drug results with standard compounds (metoprolol, atenolol, labetalol, and rhodamine-123). All 4 quinolones drugs demonstrated concentration-dependent permeability, indicating active drug transport. In comparing absorptive versus secretive in vitro transport, the tested fluoroquinolones were found to be subject to efflux in varying degrees (ciprofloxacin > lomefloxacin > rhodamine 123 > levofloxacin > ofloxacin). Based on comparison to labetalol, the high permeability internal standard, ciprofloxacin was classified as a low permeability drug, whereas lomefloxacin, levofloxacin, and ofloxacin were classified as high permeability drugs. The in vitro permeability results matched human in vivo data based on absolute bioavailabilities. This laboratory exercise demonstrated the applicability of an in vitro permeability method for classifying drugs as outlined in the BCS Guidance.     

Comparative in vitro activity of gemifloxacin to other fluoroquinolones and non-quinolone agents against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1999-2000

This study was undertaken to assess the in vitro activity of gemifloxacin, five other fluoroquinolone antimicrobial agents (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin and ofloxacin) and other non-quinolone comparator agents (ampicillin, erythromycin, clindamycin, doxycycline, penicillin and trimethoprim/sulphamethoxazole) against Streptococcus pneumoniae collected in the United States. Susceptibility testing of 550 S. pneumoniae, 290 Haemophilus influenzae and 205 Moraxella catarrhalis showed that 38.2% of pneumococci were penicillin nonsusceptible, while 26.2 and 95.6% of H. influenzae and M. catarrhalis, respectively, produced beta-lactamase. Overall new fluoroquinolones were the most active agents. The in vitro activity (based on MIC90 in mg/l) of the six fluoroquinolones was gemifloxacin>moxifloxacin>gatifloxacin>levofloxacin>ciprofloxacin and ofloxacin.     

六种氟喹诺酮对肠球菌的体外抗菌活性及利血平的影响

目的：研究氟喹诺酮类抗菌药物对临床分离肠球菌的体外抗菌活性,以及多重耐药泵抑制剂利血平对抗菌活性的影响.方法：收集临床分离的101株肠球菌（66株粪肠球菌和35株屎肠球菌）,用琼脂稀释法测定应用利血平前后6种氟喹诺酮对菌株的最低抑菌浓度（MIC）.结果：诺氟沙星、环丙沙星、氧氟沙星、左氧氟沙星、加替沙星、莫西沙星对66株粪肠球菌的MIC90依次为256、64、64、16、16、8 mg/L,对35株屎肠球菌的MIC90依次为＞512、512、128、128、32、32 mg/L.应用利血平之后,上述6种药物对粪肠球菌抗菌活性提高（MIC下降2倍或2倍以上）的株数依次为66（100%）、54（81.8%）、4（6.1%）、4（6.1%）、32（48.5%）和3（4.5%）株,对屎肠球菌抗菌活性提高的株数依次为35（100%）、29（82.9%）、1（2.9%）、0（0%）、6（20.7%）和2（5.7%）株.结论：新氟喹诺酮加替沙星、莫西沙星增强了对肠球菌的抗菌活性,利血平能够提高全部或部分被检测肠球菌对诺氟沙星、环丙沙星和加替沙星的敏感性,但仅使少数被检测肠球菌对氧氟沙星、左氧氟沙星和莫西沙星的敏感性提高.     

Binding characteristics of fluoroquinolones to synthetic levodopa melanin

To define the binding characteristics of fluoroquinolones to synthetic levodopa melanin, the binding of various drugs, including levofloxacin and ofloxacin, and positive controls (timolol and chloroquine), was investigated in-vitro. The affinity and capacity of the drug binding were calculated by Langmuir's adsorption isotherm. The affinity constant (K) and the binding capacity (r(max)) of levofloxacin were similar to those of timolol and much lower than those of chloroquine. Racemic ofloxacin and its enantiomers showed similar K and r(max), suggesting that the binding lacked stereoselectivity. The binding experiment with levofloxacin derivatives indicated that the basic nitrogen atom at position 7 of the quinolone ring, but not carboxyl group at position 3, would play a critical role in the interaction of fluoroquinolones with melanin. The melanin-drug complexes of levofloxacin and chloroquine were washed with neutral phosphate buffer, ethanol and 1 M HCl solution to explain the nature of the interaction of melanin with the drugs. Electrostatic forces mainly participate in the formation of the chloroquine-melanin complex, whereas van der Waals' and hydrophobic interactions are involved in the levofloxacin-melanin complex in addition to electrostatic forces. The interactions of various fluoroquinolones such as norfloxacin, enoxacin, sparfloxacin, ciprofloxacin and lomefloxacin with melanin were also studied. The results showed that the relative K value was: chloroquine approximately ciprofloxacin, sparfloxacin >/= lomefloxacin > timolol, levofloxacin approximately enoxacin, norfloxacin, and that the relative r(max) value was: norfloxacin, enoxacin >/= chloroquine, sparfloxacin > levofloxacin, ciprofloxacin, timolol, lomefloxacin. The fluoroquinolones vary in their affinity and capacity to bind with melanin, and ciprofloxacin and sparfloxacin showed a stronger interaction with melanin than the other fluoroquinolones studied.     

Febrile neutropenia in a bone marrow transplantation unit

A total of 119 strains of coagulase-negative staphylococci isolated from clinical specimens were speciated and tested for sensitivity to methicillin and four fluoroquinolones (ciprofloxacin, sparfloxacin, levofloxacin and ofloxacin). Resistance to fluoroquinolones was significantly more common in Staphylococcus haemolyticus (43%) than in Staphylococcus epidermidis (11%). Methicillin-resistant strains of S. haemolyticus were more often resistant to ciprofloxacin than were methicillin-resistant strains of S. epidermidis (P < 0.05). Sparfloxacin was the most active against fluoroquinolone-sensitive strains, and levofloxacin was twice as active as ofloxacin. There was cross-resistance between the four fluoroquinolones. Levofloxacin was the most active against resistant strains, but MICs obtained for all the compounds seemed to be outside the clinically useful range for the treatment of systemic infections.     

Oral toxicity of pefloxacin, norfloxacin, ofloxacin and ciprofloxacin: comparison of biomechanical and histopathological effects on Achilles tendon in rats

Four fluoroquinolones (pefloxacin, norfloxacin, ofloxacin and ciprofloxacin) were compared according to their biomechanical and histopathological effects on rat Achilles tendon. Wistar rats were divided into one untreated control and four treatment groups in parallel. Pefloxacin mesylate dihydrate (40 mg/kg), norfloxacin (40 mg/kg), ofloxacin (20 mg/kg) and ciprofloxacin (50 mg/kg) were administered by gavage twice daily for three consecutive weeks. 6 weeks after treatment, the test animals were euthanised and Achilles tendon specimens were collected. A computer monitored tensile testing machine was utilised for biomechanical testing. The mean elastic modulus of the control group was significantly higher than that of the norfloxacin and pefloxacin groups (p<0.05 and p<0.01, respectively). The mean yield force (YF) of the control group was significantly higher than those of ciprofloxacin, norfloxacin and pefloxacin groups (p<0.001, p<0.05 and p<0.01, respectively). The mean ultimate tensile force (UTF) of the control group was significantly higher than of the ciprofloxacin, norfloxacin, and pefloxacin groups (p<0.001, p<0.05 and p<0.01, respectively). Hyaline degeneration and fibre disarrangement were observed in the tendons of the ciprofloxacin, pefloxacin, and ofloxacin treated-groups, whereas myxomatous degeneration was observed only in the ciprofloxacin and pefloxacin groups. In conclusion, these findings in our rat model reveal significant deterioration of biomechanical parameters following fluoroquinolone exposure, and indicate significantly higher biomechanical toxicity for ciprofloxacin and pefloxacin.