莫西沙星类似物的合成及其体内外抗菌活性

目的合成具有良好抗菌活性的莫西沙星类似物。方法以盐酸莫西沙星为原料,先与甲基乙烯酮发生加成反应生成N-(3-氧代-1-正丁基)莫西沙星(1),接着经氧化并重排及中和反应得到N-羟基莫西沙星(2)。测定化合物1和2的体内外抗菌活性。结果1的体外活性与对照药莫西沙星基本相当,且优于2(P<0.05);1和2对试验菌株所致小鼠系统感染均具有疗效,其中1的体内疗效与对照药莫西沙星基本相当(P>0.05),且优于2(P<0.05)。结论在莫西沙星7-位侧链的亚氨基上引入3-氧代-1-正丁基后其活性基本保持,但引入羟基后其活性明显降低。     

盐酸莫西沙星片剂的血药浓度及药动学分析

目的 分析盐酸莫西沙星在人体内的血药浓度及药动学.方法 10名志愿受试者单剂量口服莫西沙星400mg后,采用固相萃取-高效液相色谱方法测定盐酸莫西沙星的血药浓度及药动学参数,用DAS2.0软件自动拟合处理,计算药动学参数.结果 莫西沙星的药动参数:t1/2α=(5.26±0.20)h;t1/2 β=(7.80±0.50)h;AUC(0～t)=(111.8±10.3)μg/ (mL·h);tmax=(3.13±0.32)h;Cmax=(13.5±0.42) μg/ mL;莫两沙星在体内的药-时曲线符合二室开放模型,在体内消除半衰期为12h,生物利用度约为95.4％.结论 该方法操作简单、准确可靠,可用于莫西沙星的临床药动学研究及临床特殊人群的血药浓度测定.     

测定莫西沙星和利福布汀联合给药后大鼠的血药浓度及其药动学变化

目的:建立测定大鼠血浆中莫西沙星和利福布汀浓度的HPLC法,并分别研究莫西沙星和利福布汀单独及联合灌胃给药后,大鼠血浆中两药的药动学.方法:血浆样品采用甲醇沉淀蛋白,莫西沙星采用HPLC-UV法测定,利福布汀采用HPLC-MS法测定.18只大鼠随机分为3组:莫西沙星(40 mg/kg)和利福布汀(30 mg/kg)单独给药组,以及莫西沙星(40mg/kg)和利福布汀(30 mg/kg)联合给药组,比较联合给药后两种药品的药动学与单独给药时的差异.结果:莫西沙星和利福布汀浓度在0.05～5、0.15～ 30 μg/ml线性关系良好(r=0.999 9);最低定量限分别为0.05和0.15 μg/ml;两药提取回收率及日内、日间RSD均符合方法学测定要求.与各自单独给药相比,联合给药时莫西沙星AUC0～1AUC0～∞显著升高(P＜0.05),清除率显著降低(P＜0.05);利福布汀AUC0-t、AUC0-∞显著升高(P＜0.05),表观分布容积(Vd)、清除率显著降低(P＜0.05).结论:本研究建立的两药血药浓度测定方法简单、准确、可靠,适用于莫西沙星与利福布汀药动学研究.与单独给药时相比,莫西沙星和利福布汀联合给药后两药的清除率降低,生物利用度增加,在体内具有协同作用.     

莫西沙星对由脆弱拟杆菌引起的腹内脓肿的疗效

脆弱拟杆菌是最常引起人体腹内脓肿的厌氧菌，环丙沙星与克林霉素对脆弱拟杆菌具有协同作用，已报道莫西沙星、曲伐沙星、克林霉素和左氧氟沙星体外对脆弱拟杆菌的活性增加，莫西沙星体外对脆弱拟杆菌的活性为环丙沙星的8倍。莫西沙星体外对各种厌氧菌有效，但体内对厌氧菌感染的活性是未知的。Thadepalli等研究的目的是确定用莫西沙星治疗由脆弱拟杆菌引起的腹内脓肿的体内疗效。     

耐多药肺结核病治疗方案中使用莫西沙星的临床效果

目的：对比分析耐多药肺结核病治疗方案中使用莫西沙星和左氧氟沙星的临床效果。方法48例耐多药肺结核病患者分为两组,即莫西沙星组24例和左氧氟沙星组24例,两组患者均以对氨基水杨酸异烟肼片、乙胺丁醇、吡嗪酰胺和丙硫异烟胺为基础抗结核方案,左氧氟沙星组联合应用左氧氟沙星片,莫西沙星组联合应用莫西沙星片,治疗12个月观察疗效和不良反应。结果治疗后莫西沙星组总有效率为91.7%,高于左氧氟沙星组的75.0%,差异有统计学意义(P<0.05);用药期间两组胃肠道反应、皮疹、肝功能异常、白细胞减少等不良反应发生率(29.2%VS 25.0%)比较,差异无统计学意义(P>0.05)。结论在耐多药肺结核病治疗方案中莫西沙星的疗效明显优于左氧氟沙星。     

1H定量核磁共振波谱法测定盐酸莫西沙星及其杂质7-氨基莫西沙星喹啉羧酸的含量

目的:建立采用1H定量核磁共振波谱(1H quantitative nuclear magnetic resonance,1H qNMR)法测定盐酸莫西沙星及其杂质7-氨基莫西沙星喹啉羧酸对照品含量的方法。方法:采用核磁共振波谱法,使用Bruker Ascend 600超导核磁共振谱仪,以氘代二甲基亚砜(DMSO-d6)为溶剂,脉冲序列为noesyigld1d,弛豫延迟时间为30 s,扫描次数16次。结果:选取氢谱图中δ6.09为内标物的定量信号,δ8.67和δ7.68为盐酸莫西沙星的定量信号,δ8.60和δ7.69为7-氨基莫西沙星喹啉羧酸的定量信号,测得盐酸莫西沙星及其杂质7-氨基莫西沙星喹啉羧酸的含量与质量平衡法结果基本一致。结论:本研究建立的核磁定量方法可用于盐酸莫西沙星及其杂质7-氨基莫西沙星喹啉羧酸的含量测定,该方法准确、快速,并为质量平衡法对标准物质定值提供有力的佐证。     

金葡球菌和肺炎链球菌在体内对莫西沙星耐药性研究

目的考察金葡球菌和肺炎链球菌在体内对莫西沙星的耐药性.方法利用大鼠肉芽肿袋模型测定金葡球菌和肺炎链球菌体内对莫西沙星的耐药性.体内试验所用的菌株是野生株(对莫西沙星敏感)、第一代耐药株(敏感性轻度下降)和多代耐药株(体外敏感性明显下降).不同菌株感染大鼠产生肉芽肿袋,用莫西沙星进行治疗.感染后1h(100mg@kg-1@d-1)或24h(100或50 mg@kg-1@d-1)开始治疗.每天采集肉芽肿袋渗出物并测定是否有莫西沙星耐药株产生.结果100mg@kg-1@d-1莫西沙星对金葡球菌和肺炎链球菌有明显的杀菌作用,感染后1h给药效果更明显.感染后24h开始治疗,且剂量降到50 mg@kg-1@d-1时,对野生株菌株仍然有效,但疗效不如100mg@kg-1@d-1.第一代耐药株可以像野生株一样被很快消灭,多代耐药株不能被低剂量莫西沙星所抑制.给予100mg@kg-1@d-1莫西沙星的动物模型中,肉芽肿袋中药物浓度与给予400mg@d-1的人血清药物浓度不相同.从各治疗组中分离出的菌株均未发现对莫西沙星耐药,试验期间突变株的MIC保持不变.结论莫西沙星在体内对肺炎链球菌和金葡球菌的野生株和第一代耐药株有显著的杀菌作用,既使浓度低于人体中预期的治疗浓度,仍可见到良好的杀菌效果;且G+菌对莫西沙星耐药的产生速度比其他氟喹诺酮药物慢.     

比较6种氟喹诺酮类药物对金黄色葡萄球菌的防耐药变异浓度

目的比较6种氟喹诺酮类药物对临床分离金黄色葡萄球菌耐药突变体的选择能力。方法用呼吸道标本,选择对苯唑西林、环丙沙星敏感的金黄色葡萄球菌36株,采用标准琼脂二倍稀释法、标准琼脂平板稀释法,测定6种氟喹诺酮类药物对金黄色葡萄球菌的MIC、MPC。结果 MPC值比较,莫西沙星最低;而环丙沙星最高。选择指数(MPC90/MIC90)较低有如下4种:莫西沙星、卡屈沙星、加替沙星和帕珠沙星,均为2。6种药物MPC90值与其体内药动学参数比较,莫西沙星和卡屈沙星小于其Cmax。结论莫西沙星、卡屈沙星和加替沙星对金葡菌的MPC值较低,突变选择窗范围相对较窄。     

盐酸莫西沙星氯化钠注射液与4种止血药的配伍稳定性考察

目的:考察盐酸莫西沙星氯化钠注射液与酚磺乙胺注射液、氨甲苯酸注射液、维生素K1注射液、氨基己酸注射液配伍后的稳定性。方法:分别采用紫外分光光度法及等吸收双波长消去法测定盐酸莫西沙星氯化钠注射液与4种止血药配伍后在25℃、37℃条件下,8h内莫西沙星的含量;并考察混合液的pH值及外观的变化。结果:盐酸莫西沙星氯化钠注射液与4种止血药配伍后,其含量及混合液pH值、外观均无显著变化。结论:盐酸莫西沙星氯化钠注射液与4种止血药配伍后8h内,莫西沙星的含量和混合液的性质保持稳定,但对4种止血药的含量是否有影响还需进一步探讨。     

莫西沙星灌胃给药在肺炎大鼠血液及肺组织中的药代动力学特点分析

目的研究莫西沙星灌胃给药在肺炎大鼠血液及肺组织中的药代动力学特点。方法首先采用灌胃给药的方式给肺炎链球菌肺炎大鼠模型灌莫西沙星,其次利用微透析技术对肺炎大鼠进行血液和肺部附近组织同时采样的操作,然后使用液相色谱法对莫西沙星的分散药量进行测量,最后计算并分析药代动力学指标。实验后,观察肺炎大鼠血液和肺组织的T_(max)、C_(max)、t_(1/2)A、UC0-∞AUC肺/AUC血液药代动力学参数。结果血液和肺组织内的游离药物的T_(max)、C_(max)数值都比较高,在二者同时减小之后,药物在肺部的穿透率比再血浆中大的多。与此同时,在血液内消除半衰期(t_(1/2))比肺组织内的小,差异显著,P <0.05。结论莫西沙星灌胃给药一定的剂量下,肺炎大鼠体内的药物有助于更好的消除肺炎链球菌,从而得到好的治疗。     

莫西沙星8-二氟甲氧基类似物的合成与体内外抗菌作用

1-环丙基-6，7-二氟-8-甲氧基-1，4-二氢．4-氧代喹啉．3-羧酸乙酯依次经醚键断裂、酯化、二氟甲基醚化得1．环丙基-6，7-二氟-8-二氟甲氧基-1，4-二氢-4-氧代喹啉．3-羧酸乙酯，然后经过螫合、与[1S，6S]-2．叔丁氧羰基．2，8．二氮杂双环[4，3，0]壬烷缩合、最后脱除叔丁氧羰基保护得到1-环丙基．8．二氟甲氧基-7-[（1S，6S）．2，8．二氮杂双环[4，3，0]壬烷．8．基]-6-氟．1，4-二氢-4-氧代喹啉-3-羧酸。目标化合物的结构经核磁共振氢谱和质谱（ESI）所确证，并测定了其体内外抗菌作用，结果表明该化合物优于对照药环丙沙星，与莫西沙星相当或略优，尤其对肺炎链球菌29074的体内活性突出，值得深入评价。     

莫西沙星对224株肠球菌的体外抗菌活性研究

目的观察莫西沙星对224株肠球菌的体外抗菌活性。方法采用二倍琼脂稀释法对224株肠球菌进行体外抗菌实验．并与意大利Aventis公司生产的替考拉宁和Lilly公司生产的万古霉素进行抗菌效果对比。结果莫西沙星的抗菌效果较好，对169株粪肠球菌和51株屎肠球菌的MIC90均为4mg／L，替考拉宁和万古霉素对169株粪肠球菌的MIC90分别为1、2mg／L；对51株屎肠球菌的MIC90分别为0．5和2mg／L。结论莫西沙星对224株肠球菌的抗菌效果较好，肠球菌对莫西沙星的敏感率均为76．34％。莫西沙星的抗菌效果低于替考拉宁和万古霉素。     

Antibacterial activity of tosufloxacin against major organisms detected from patients with respiratory infections

We determined the susceptibility of bacteria which were isolated from the patients with respiratory infections between January and October 2005, to tosufloxacin and other fluoroquinolones. A total of 900 isolate including 300 Streptococcus pneumoniae, 100 Streptococcus pyogenes, 100 Moraxella catarrhalis, 200 Haemophilus influenzae, 100 Klebsiella pneumoniae and 100 Pseudomonas aeruginosa were tested. Tosufloxacin, gatifloxacin, levofloxacin, moxifloxacin, ciprofloxacin and prulifloxacin were used as the test antimicrobials. Tosufloxacin, gatifloxacin and moxifloxacin were potent antibiotics tested for the antibacterial activity against Streptococcus including penicillin-resistant S. pneumoniae; the MIC90 were 0.12-0.5/ micromL. Fluoroquinolones exerted the potent antibacterial activity against M. catarrhalis and H. influenzae; the MIC90 of fluoroquinolones tested were < or =0.06 microg/mL. Tosufloxacin, ciprofloxacin and prulifloxacin showed to be more active against K. pneumoniae and P. aeruginosa, but parts of some strains were resistant. These results indicate that tosufloxacin has the potent antibacterial activity against major organisms detected from patients with respiratory infections. Since it was approved in 1990, tosufloxacin was considered to be useful as a therapeutic antimicrobial for the treatment of respiratory infections.     

Wide spread of Tn2006 in an AbaR4-type resistance island among carbapenem-resistant Acinetobacter baumannii clinical isolates in Taiwan

The bactericidal activity and resistance selectivity of garenoxacin against Streptococcus pneumoniae with mutations in ParC (S79F) or both GyrA (S81F) and ParC (D83Y and K137N) were investigated using in vitro pharmacokinetic models simulating plasma concentrations for a standard clinical regimen [400mg once daily (q.d.)]. The efficacy of garenoxacin was compared with that of levofloxacin (500 mg q.d.) and moxifloxacin (400mg q.d.). Garenoxacin showed excellent bactericidal activity against S. pneumoniae, including quinolone-resistant S. pneumoniae (QRSP), achieving ratios of area under the plasma concentration-time curve over 24h to minimum inhibitory concentration (AUC(0-24)/MIC) ≥ 26.3, without emerging resistant subpopulations. The area above the killing curves was greater and the time to achieve 99.9% killing was shorter for garenoxacin than the corresponding values for levofloxacin and moxifloxacin. No resistant subpopulations and no additional substitution of amino acids in GyrA or ParC emerged following treatment with garenoxacin. On the other hand, in the parC mutant strain, levofloxacin and moxifloxacin treatment caused an increase in the frequency of the resistant population and an additional substitution of amino acids in GyrA (levofloxacin, S81Y/F/C; moxifloxacin, S81Y or E85K). In QRSP with mutations in GyrA and ParC, levofloxacin had no bactericidal activity, whilst the bactericidal activity of moxifloxacin was less than that of garenoxacin; moreover, an additional substitution of amino acids in ParC (S79Y) was noted. In conclusion, garenoxacin corresponding to an oral dose of 400mg showed excellent bactericidal activity against S. pneumoniae, including QRSP, without the emergence of resistant mutants.     

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.     

Multicentre study of the in vitro evaluation of moxifloxacin and other quinolones against community acquired respiratory pathogens.

The in vitro activity of moxifloxacin was compared with that of ciprofloxacin, levofloxacin, ofloxacin and trovafloxacin against 710 strains (180 Streptococcus pneumoniae, 180 Haemophilus influenzae, 160 Moraxella catarrhalis and 190 Streptococcus pyogenes) isolated from patients with community-acquired respiratory tract infections. MIC values for moxifloxacin, trovafloxacin were 0.25/0.25, 0.03/0.03, 0.06/0.03 and 0.125/0.0125 mg/l for S. pneumoniae, H. influenzae, M. catharralis and S. pyogenes. Based upon the MIC(90) values and the MIC distributions, moxifloxacin and trovafloxacin were the most active of the quinolones tested. They showed enhanced activity against Gram-positive organisms including penicillin non susceptible S. pneumoniae strains. Moxifloxacin was also highly active against ciprofloxacin-resistant S. pneumoniae strains.     

莫西沙星合成方法

综述莫西沙星的有关合成反应。莫西沙星是新近上市的氟喹诺酮药物之一，其抗菌谱广，特别是喹诺酮环8位上甲氧基的存在，其抗革兰氏阳性菌活性比环丙沙星、诺氟沙星等明显增强，且无明显的光毒性。     

Moxifloxacin: a review of its clinical potential in the management of community-acquired respiratory tract infections

Moxifloxacin is an extended-spectrum fluoroquinolone which has improved coverage against gram-positive cocci and atypical pathogens compared with older fluoroquinolone agents, while retaining good activity against gram-negative bacteria. The antibacterial spectrum of moxifloxacin includes all major upper and lower respiratory tract pathogens; it is one of the most active fluoroquinolones against pneumococci, including penicillin- and macrolide-resistant strains. In in vitro studies, emergence of bacterial resistance was less common with moxifloxacin than with some other fluoroquinolones, but this requires confirmation in large-scale clinical studies. As with other fluoroquinolones, moxifloxacin achieves good penetration into respiratory tissues and fluids. It shows a low potential for drug interactions and dosage adjustment is not required for patients of advanced age or those with renal or mild hepatic impairment. The efficacy of oral moxifloxacin has been demonstrated in large, well-designed clinical trials in patients with community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute sinusitis. Moxifloxacin 400 mg once daily achieved bacteriological and clinical success rates of approximately 90% or higher. It was as effective as, or more effective than, comparators including clarithromycin, cefuroxime axetil and high dose amoxicillin in these trials. The most commonly reported adverse events in patients receiving moxifloxacin are gastrointestinal disturbances. Moxifloxacin is also associated with QTc prolongation in some patients; there are, as yet, no data concerning the possible clinical sequelae of this effect in high-risk patients. Moxifloxacin has a low propensity for causing phototoxic reactions relative to other fluoroquinolones, and animal data suggest that it has a low potential for causing excitatory CNS and hepatotoxic effects. Conclusions: As an extended-spectrum fluoroquinolone, moxifloxacin offers the benefits of excellent activity against pneumococci, once daily administration and a low propensity for drug interactions. Although studies are needed regarding its tolerability in at-risk patients with QT interval prolongation, available data suggest that moxifloxacin is likely to become a first-line therapy option for the treatment of community-acquired lower respiratory tract infections, particularly in areas where drug-resistant S. pneumoniae or H. influenzae are common.     

三黄泻心汤中西医结合根除幽门螺杆菌感染的体内外实验研究

目的评价三黄泻心汤与莫西沙星对55株幽门螺杆菌体外联合抗菌效应和临床根除率。方法采用二倍稀释法、棋盘格法和Vitek-32型全自动细菌鉴定仪测定三黄泻心汤与莫西沙星单用或联用对55株幽门螺杆菌的最低抑菌浓度(MIC),计算其联合药敏指数(FIC),绘制药物质量浓度-累积抑菌率曲线;对比观察中西医结合与埃索美拉唑三联方根除幽门螺杆菌感染的疗效。结果试验组与对照组中西药联用对幽门螺杆菌的MIC值均较单用显著降低;试验组FIC不大于0.50,有协同作用,对照组FIC为0.50～0.75,有相加作用;两组药物质量浓度-累积抑菌率曲线向低浓度方向移动联用均较单用明显;观察组和对照组的溃疡愈合率分别为90.91%和78.18%,幽门螺杆菌根除率分别为89.09%和81.82%,两组比较,P<0.01或P<0.05。结论三黄泻心汤中西医结合根除幽门螺杆菌感染的疗效确切,可作为二线治疗方案。