Topoisomerase IV

体外活性：环丙沙星是一种氟喹诺酮类抗生素，对肠杆菌科、铜绿假单胞菌、流感嗜血杆菌、淋病奈瑟菌、链球菌、金黄色葡萄球菌和脆弱拟杆菌菌株的 MIC90（90% 最低抑制浓度）为 0.008 至 2 μg/ml。环丙沙星抑制拓扑异构酶 IV 作为主要拓扑异构酶靶标，抑制促旋酶作为次要靶标。环丙沙星的 AUC（曲线下面积）为 24 μg×h/ml。激酶测定：环丙沙星 (Bay-09867) 是一种氟喹诺酮类抗生素，具有有效的抗菌活性。环丙沙星 (CIP) 对鼠疫耶尔森氏菌具有有效的活性，MIC90 为 0.03 μg/mL。细胞测定：通过将菌落悬浮在羊血琼脂 (SBA) 平板上的 Mueller-Hinton 肉汤 (CAMHB)（含有环丙沙星）中 18 至 24 小时（炭疽杆菌）或 42 至 48 小时（鼠疫杆菌）来制备细菌接种物在 35°C 下孵育。悬浮培养物用 CAMHB 稀释至细菌细胞密度为 105 CFU/mL，并根据 600 nm 处的光密度进行调整。向 96 孔板的每个孔中添加 50 μL 稀释液，最终接种量约为 5×104 CFU/孔。板在 35°C 下孵育。 MIC 在 18 至 24 小时（炭疽芽孢杆菌）或 42 至 48 小时（鼠疫耶尔森氏菌）时目视测定，也可通过 600 nm 处的吸光度测定

Ciprofloxacin (Bay-09867) (1 mg/L) 会诱导谷胱甘肽-S-转移酶 (GST) 活性，而暴露于恩诺沙星的幼虫则会抑制 GST 和过氧化氢酶 (CAT)。环丙沙星 (Bay-09867) (≥10 μg/L) 和恩诺沙星对无尾两栖动物幼虫的发育、生长、解毒和氧化应激酶具有生态毒性。在肺鼠疫鼠模型中，环丙沙星 (Bay-09867)（30 毫克/公斤，腹膜内注射）导致的药物暴露与人体口服 500 毫克剂量的环丙沙星 (Bay-09867) 后观察到的药物暴露相似。 。与腹膜内 PBS 治疗的对照相比，腹膜内环丙沙星 (Bay-09867) 可减少肺部细菌负荷。

细胞系：肌腱细胞
浓度：5、10、20 和 50 μg/mL
孵育时间：24 小时
结果：肌腱细胞的细胞结构减少。

Absorption, Distribution and Excretion
A 250mg oral dose of ciprofloxacin reaches an average maximum concentration of 0.94mg/L in 0.81 hours with an average area under the curve of 1.013L/h\*kg. The FDA reports an oral bioavailability of 70-80% while other studies report it to be approximately 60%. An early review of ciprofloxacin reported an oral bioavailability of 64-85% but recommends 70% for all practical uses.
27% of an oral dose was recovered unmetabolized in urine compared to 46% of an intravenous dose. Collection of radiolabelled ciprofloxacin resulted in 45% recovery in urine and 62% recovery in feces.
Cirpofloxacin follws a 3 compartment distribution model with a central compartment volume of 0.161L/kg and a total volume of distribution of 2.00-3.04L/kg.
The average renal clearance after a 250mg oral dose is 5.08mL/min\*kg. Following a 100mg intravenous dose, the average total clearance is 9.62mL/min\*kg, average renal clearance is 4.42mL/min\*kg, and average non renal clearance is 5.21mL/min\*kg.
Based on population pharmacokinetics, bioavailability of ciprofloxacin oral suspension in children is approximately 60%. Following a single oral dose of 10 mg/kg of ciprofloxacin given as the oral suspension to children 4 months to 7 years of age, the mean peak plasma concentration was 2.4 ug/mL. There was no apparent age dependence and no increase in peak plasma concentrations following multiple doses.
When extended-release tablets containing ciprofloxacin hydrochloride (ProQuin XR) are administered with food, approximately 87% of the drug is gradually released from the tablet over a 6- hour period. When administered following a meal, peak plasma concentrations are attained approximately 4.5-7 hours after the dose. Bioavailability is substantially lower if ProQuin XR tablets are given while fasting. In healthy adults receiving ProQuin XR extended-release tablets in a dosage of 500 mg once daily given following a standardized meal, peak plasma concentrations at steady state (day 3) average 0.82 mcg/mL and are attained 6.1 hours after the dose. /Ciprofloxacin hydrochloride/
Following oral administration of extended-release tablets containing ciprofloxacin hydrochloride and base (Cipro XR), peak plasma concentrations of ciprofloxacin are attained within 1-4 hours. Cipro XR tablets contain approximately 35% of the dose within an immediate-release component; the remaining 65% of the dose is contained in a slow-release matrix. Oral administration of ciprofloxacin 500 mg daily as Cipro XR extended-release tablets or 250 mg twice daily as conventional tablets results in steady-state mean peak plasma concentrations of 1.59 or 1.14 ug/mL, respectively; however, the area under the concentration-time curve (AUC) is similar with both regimens. /Ciprofloxacin hydrochloride/
Peak serum concentrations of ciprofloxacin and AUCs of the drug are slightly higher in geriatric patients than in younger adults; this may occur because of increased bioavailability, reduced volume of distribution, and/or reduced renal clearance in these patients. Single-dose oral studies using ciprofloxacin conventional tablets and single- and multiple-dose IV studies indicate that, compared with younger adults, peak plasma concentrations are 16-40% higher, mean AUC is approximately 30% higher, and elimination half-life is prolonged approximately 20% in individuals older than 65 years of age. These differences can be at least partially attributed to decreased renal clearance in this age group and are not clinically important.
For more Absorption, Distribution and Excretion (Complete) data for CIPROFLOXACIN (18 total), please visit the HSDB record page.

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Metabolism / Metabolites
Ciprofloxacin is primarily metabolized by CYP1A2. The primary metabolites oxociprofloxacin and sulociprofloxacin make up 3-8% of the total dose each. Ciprofloxacin is also converted to the minor metabolites desethylene ciprofloxacin and formylciprofloxacin. These 4 metabolites account for 15% of a total oral dose. There is a lack of available data on the enzymes and types of reactions involved in forming these metabolites.
The drug is partially metabolized in the liver by modification of the piperazinyl group to at least 4 metabolites. These metabolites, which have been identified as desethyleneciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and N-formylciprofloxacin (M4), have microbiologic activity that is less than that of the parent drug but may be similar to or greater than that of some other quinolones (e.g., M3 and M4 are comparable to norfloxacin for certain organisms).
Hepatic. Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin.
Route of Elimination: Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug.
Half Life: 4 hours

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Biological Half-Life
The average half life following a 250mg oral dose was 4.71 hours and 3.65 hours following a 100mg intravenous dose. Generally the half life is reported as 4 hours.
The serum elimination half-life of ciprofloxacin in adults with normal renal function is 3-7 hours. Following IV administration in healthy adults, the distribution half-life of ciprofloxacin averages 0.18-0.37 hours and the elimination half-life averages 3-4.8 hours. The elimination half-life of the drug is slightly longer in geriatric adults than in younger adults, and ranges from 3.3-6.8 hours in adults 60-91 years of age with renal function normal for their age. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life of ciprofloxacin in children is approximately 4-5 hours. In patients with impaired renal function, serum concentrations of ciprofloxacin are higher and the half-life prolonged. In adults with creatinine clearances of 30 mL/minute or less, half-life of the drug ranges from 4.4-12.6 hours.
t1/2 for ciprofloxacin- normal: 4 (hr), anephric: 8.5 (hr) /from table/

Toxicity Summary
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, strand supercoiling repair, and recombination.

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Interactions
Serious and fatal reactions have been reported in patients receiving concurrent administration of ciprofloxacin and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
... The effects of aluminum hydroxide ... and calcium carbonate ... on the bioavailability of ciprofloxacin /was determined in/ ... a 3 way randomized, crossover study was concluded in 12 healthy male volunteers (ages 21-45 yr) that consisted of 3 treatments: 750 mg ciprofloxacin alone, 750 mg ciprofloxacin with 3.4 g calcium carbonate or 1.8 g aluminum hydroxide admin 5 min before ciprofloxacin. The relative bioavailability of ciprofloxacin was reduced to 60% and 15% of control values when given with calcium carbonate and aluminum hydroxide, respectively. ... It was concluded that antacids containing either aluminum or calcium should not be given concurrently with ciprofloxacin.
Ciprofloxacin, given to a patient successfully treated with methadone for more than 6 yrs, caused profound sedation, confusion, & respiratory depression. We suggest that this was caused by ciprofloxacin inhibition of CYP1A2 & CYP3A4 activity, 2 of the cytochrome p450 isozymes involved in the metab of methadone.
Synergism does not occur in vitro when ciprofloxacin is used in conjunction with vancomycin against Staphylococcus epidermidis, S. aureus (including oxacillin-resistant S. aureus), Corynebacterium, or Listeria monocytogenes.
For more Interactions (Complete) data for CIPROFLOXACIN (35 total), please visit the HSDB record page.

[1]. Ciprofloxacin-mediated cell proliferation inhibition and G2/M cell cycle arrest in rat tendon cells. Arthritis Rheum. 2008 Jun;58(6):1657-63.

[2]. In Vitro and In Vivo Activity of Omadacycline against Two Biothreat Pathogens, Bacillus anthracis and Yersinia pestis. Antimicrob Agents Chemother. 2017 Apr 24;61(5):e02434-16.

[3]. Inhaled Liposomal Ciprofloxacin Protects against a Lethal Infection in a Murine Model of Pneumonic Plague. Front Microbiol. 2017 Feb 6;8:91.

[4]. Effect of Ciprofloxacin on Susceptibility to Aortic Dissection and Rupture in Mice. JAMA Surg. 2018 Sep 1;153(9):e181804.

Therapeutic Uses
Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors
Ciprofloxacin (IV, conventional tablets, oral suspension) is used in adults for the treatment of bone and joint infections, including osteomyelitis, caused by susceptible E. cloacae, ... Ps. aeruginosa, or S. marcescens. ... /Included in US product label/
Ciprofloxacin (IV, conventional tablets, oral suspension) is used in adults for the treatment of bone and joint infections, including osteomyelitis, caused by susceptible E. aerogenes, ... E. coli, K. pneumoniae, M. morganii, P. mirabilis, ... . The drug also has been used in adults for the treatment of bone and joint infections caused by susceptible S. aureus, S. epidermidis, other coagulase-negative staphylococci, or Enterococcus faecalis (formerly S. faecalis), but other anti-infectives generally are preferred for these infections. Although resistance to ciprofloxacin has been reported in some strains of oxacillin-resistant S. aureus, oral ciprofloxacin may be a useful alternative to parenteral anti-infectives for the treatment of infections caused by susceptible oxacillin-resistant staphylococci. /NOT included in US product label/
Although only limited experience is available to date, ciprofloxacin is recommended by the American Heart Association (AHA) and Infectious Diseases Society of America (IDSA) as an alternative agent for the treatment of native or prosthetic valve endocarditis caused by fastidious gram-negative bacilli known as the HACEK group (Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Haemophilus aphrophilus, H. influenzae, H. parainfluenzae, H. paraphrophilus, Kingella denitrificans, K. kingae). /NOT included in US product label/
For more Therapeutic Uses (Complete) data for CIPROFLOXACIN (53 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ WARNING: Fluoroquinolones, including Cipro, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
/BOXED WARNING/ WARNING: Fluoroquinolones, including Cipro, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid Cipro in patients with known history of myasthenia gravis.
In 4 corneal transplantation patients treated preoperatively with ciprofloxacin ophthalmic drops, microprecipitates associated with damaged corneal epithelium were noted in 2 patients. Another patient developed a large macroprecipitate in a corneal ulcer. All specimens were examined by electron microscopy & high-pressure liquid chromatography. The crystalline precipitates were pure ciprofloxacin. The macroprecipitate demonstrated a large zone of inhibition on agar plates seeded with a susceptible organism at 24 & 48 hr. It was bioactive & bioavailable in vitro.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.
For more Drug Warnings (Complete) data for CIPROFLOXACIN (41 total), please visit the HSDB record page.

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Pharmacodynamics
Ciprofloxacin is a second generation fluoroquinolone that is active against many Gram negative and Gram positive bacteria. It produces its action through inhibition of bacterial DNA gyrase and topoisomerase IV. Ciprofloxacin binds to bacterial DNA gyrase with 100 times the affinity of mammalian DNA gyrase. There is no cross resistance between fluoroquinolones and other classes of antibiotics, so it may be of clinical value when other antibiotics are no longer effective. Ciprofloxain and its derivatives are also being investigated for its action against malaria, cancers, and AIDS.

C17H18FN3O3

331.34

331.133

C, 61.62; H, 5.48; F, 5.73; N, 12.68; O, 14.49

85721-33-1

86393-32-0;93107-08-5;97867-33-9

2764

White to off-white solid powder

1.5±0.1 g/cm3

581.8±50.0 °C at 760 mmHg

255-257°C

305.6±30.1 °C

0.0±1.7 mmHg at 25°C

1.655

0.65

74.57

2

7

3

24

571

0

O=C(C1C(=O)C2C(=CC(N3CCNCC3)=C(C=2)F)N(C2CC2)C=1)O

MYSWGUAQZAJSOK-UHFFFAOYSA-N

InChI=1S/C17H18FN3O3/c18-13-7-11-14(8-15(13)20-5-3-19-4-6-20)21(10-1-2-10)9-12(16(11)22)17(23)24/h7-10,19H,1-6H2,(H,23,24)

1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。