Chronic dose urinary and serum pharmacokinetics of norfloxacin in the elderly.

1. Norfloxacin was administered as two daily 400 mg oral doses to eight elderly patients requiring treatment for urinary tract infections. Blood specimens were obtained for pharmacokinetic profiles following the first and fifteenth doses. Further specimens were obtained before each morning's dose of norfloxacin. Specimens of urine were obtained to ascertain if adequate antimicrobial concentrations were reached in these patients with diminished renal function. 2. Norfloxacin half-life was consistent with that expected in mild renal impairment and was not different between the first and fifteenth doses. Based on ratios of AUC values, accumulation is probably related to renal function, being greatest for creatinine clearance values below 30 ml min-1. 3. On the great majority of occasions, the urinary concentrations of norfloxacin exceeded 20 micrograms ml-1. On days 2-7, the mean percentage 12 h renal elimination of norfloxacin was 18.6 +/- 1.47 (mean of 82 separate observations). Norfloxacin 400 mg twice daily was well tolerated in this group of elderly patients and produced adequate antimicrobial concentrations in urine.     

Norfloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use

Norfloxacin is one of the new 4-quinolone antibacterial agents. A fluorinated piperazinyl-substituted congener of nalidixic acid, it demonstrates a much wider in vitro antibacterial spectrum and greater potency than the parent compound. Its antibacterial activity against most Gram-negative pathogens is enhanced in comparison to nalidixic acid, but is similar to that of some of the other new 4-quinolones like enoxacin, and slightly less than that of ciprofloxacin. Unlike nalidixic acid, norfloxacin is also active against Pseudomonas aeruginosa and some Gram-positive organisms. In acute or uncomplicated urinary tract infections, norfloxacin has repeatedly been shown to be as effective as co-trimoxazole. Single studies have demonstrated a significantly better bacteriological cure rate with norfloxacin than with pipemidic acid, and similar cure rates with norfloxacin and both a nalidixic acid/sodium citrate mixture and amoxycillin. Similar results were found in a few studies comparing norfloxacin to pipemidic acid or amoxycillin in patients with chronic and/or complicated urinary tract infections. Norfloxacin is as effective as spectinomycin in gonorrhoea due to penicillin-resistant N. gonorrhoeae, and cures bacterial gastroenteritis caused by several gastrointestinal pathogens. Norfloxacin appears to be well tolerated and may have a low propensity to select for bacterial resistance during clinical use, although the latter needs further confirmation.     

Clinical trial of norfloxacin in the treatment of uncomplicated gonococcal urethritis: preliminary report

Fifteen male outpatients with uncomplicated gonococcal urethritis were treated by a single oral dose of norfloxacin (800 mg). Fourteen patients completely recovered from infection and a recurrence was noted in only one. Five of the Neisseria gonorrhoeae isolated (33.3%) were penicillin-resistant. However, the extremely low MICs confirm that norfloxacin possesses high antibacterial activity against N. gonorrhoeae. Norfloxacin was well tolerated with only a transient nausea occurring in four patients.     

Quantitation of norfloxacin, a new antibacterial agent in human plasma and urine by ion-pair reverse-phase chromatography

A specific and sensitive high-performance liquid chromatographic method for the analysis of norfloxacin in human plasma and urine is described. Norfloxacin was extracted from the sample matrix using dichloromethane under neutral conditions, followed by back extraction into dilute phosphoric acid for chromatographic analysis on a reverse-phase column with a mobile phase consisting of methanol, phosphate buffer, and ion-pairing reagent (pH 3.0) at a flow rate of 2.0 mL/min. The ability of this method to distinguish intact norfloxacin from its metabolites was demonstrated. The method is linear, quantitative, and reproducible for both plasma analysis (0.05-2.5 microgram/mL) and urinalysis (1.0-500 micrograms/mL) using peak area ratios (norfloxacin-internal standard) for quantitation. The stability of norfloxacin and its metabolites in dilute phosphoric acid was studied. To assess the presence of norfloxacin conjugates in the urine of dosed individuals, the effects of urine hydrolysis on drug quantitation were examined. Urine and plasma levels of norfloxacin at selected time points following the administration of single drug doses are presented.     

Influence of pH and human urine on the antibacterial activity of ciprofloxacin, norfloxacin and ofloxacin

The influence of pH on the antibacterial activity of ciprofloxacin, norfloxacin and ofloxacin was studied in broth and pooled human urine by microdilution susceptibility tests. Selected strains of E. coli, Staphylococcus aureus and Pseudomonas aeruginosa were used as test organisms. The results show that cultivation at pH 5.7 in urine increased the MIC values for all three quinolones 8, 16 and 32-fold compared with broth at pH 7.1. Killing curves show that in urine with 10 mcg/ml ciprofloxacin, rapid killing of E. coli and Pseudomonas aeruginosa occurred, whereas ofloxacin and especially norfloxacin were less effective.     

Fluorimetric determination of norfloxacin in plasma and urine samples after thin-layer chromatographic separation

A thin-layer chromatographic (TLC) assay for the determination of norfloxacin (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (piperazinyl)-3-quinolinecarboxylic acid), a new antibacterial agent, in human plasma and urine is described. Norfloxacin was extracted from plasma samples using commercial cartridges, urine samples were simply diluted with methanol. Plasma extracts or urine samples were applied to TLC plates (silica gel). Chromatography was performed with a mobile phase consisting of methanol, ethanol and water, the atmosphere in the tank being saturated with ammonia. The fluorescence intensity of norfloxacin was enhanced by dipping the plate into a paraffin/citric acid mixture. Peaks were quantified by fluorimetric measurement (excitation 313 nm/emission 390 nm, cut-off filter). The method showed acceptable precision and linearity in the range of 0.01 to 4 micrograms/ml for plasma and 1 to 100 micrograms/ml for urine. The assay was shown to be applicable to human plasma and urine samples.     

Norfloxacin in prostatitis: correlation between HPLC tissue concentrations and clinical results

Prostatic infections are difficult both to diagnose and to treat and have negative influences on the fertility of the patient. Norfloxacin, a new quinolone antibacterial agent particularly active in urinary tract infections, gave excellent results (400 mg every 12 h for 10 days) in the treatment of chronic-relapsing prostatitis in a group of 20 patients. An 85% success rate was recorded at the end of a follow-up period of 30 days without any undesired effects. This clinical study was paralleled by a pharmacokinetic evaluation of the serum, urine and prostatic tissue concentrations attained by the drug, measured by an HPLC assay on biological fluids and tissue extracts from surgical specimens of 15 patients suffering from benign prostatic hypertrophy and given two 400 mg doses of norfloxacin in the 12 h preceding prostatectomy. The average tissue concentrations (1 microgram/gm), as compared with the MIC90 of the drug for the pathogens sustaining prostatic infections, appear quite sufficient to control the bacterial foci responsible for the chronic-relapsing course of prostatitis and easily account for the clinical success rate.     

N-formimidoyl-thienamycin and norfloxacin against multiple-resistant Pseudomonas aeruginosa strains. Combined in vitro activity and comparison with 14 other antibiotics

The in vitro susceptibility of 54 multiple-resistant strains of Pseudomonas aeruginosa to 16 antipseudomonal agents were determined. The majority of these organisms were also beta-lactamase-producing strains. Norfloxacin, N-formimidoyl-thienamycin and aztreonam showed the best antipseudomonal activity, with minimum inhibitory concentrations for 90% of isolates (MIC90) of 2, 8, and 8 mg/l respectively. Of the aminoglycosides, only amikacin (MIC90 = 32 mg/l) showed satisfactory activity, whereas among beta-lactam antibiotics, cefotaxime, ceftriaxone and moxalactam (MIC90 = 32 mg/l) were more active than cefoperazone (MIC90 = 128 mg/l), cefsulodin (MIC90 = 128 mg/l), piperacillin (MIC90 = 512 mg/l) and azlocillin (MIC90 = 1024 mg/l). A synergistic or partially synergistic interaction (fractional inhibitory concentration index less than 1) was demonstrated in vitro against 37% of the strains when N-formimidoyl-thienamycin was combined with norfloxacin.     

Bismuth-norfloxacin complex: synthesis, physicochemical and antimicrobial evaluation

Norfloxacin is a fluoroquinolone antibacterial agent which is active against various Gram-positive as well as Gram-negative microorganisms. Presence of metal ions considerably alters the activity of fluoroquinolones against potentially susceptible bacteria. As bismuth is known to possess a good antibacterial activity, bismuth complex of norfloxacin was prepared by reacting bismuth citrate with aqueous solution of norfloxacin. The structure of the bismuth-norfloxacin complex (BNC) was confirmed by spectral, chemical and elemental analysis. Antimicrobial studies were carried out using agar diffusion method against Escherichia coli (ATCC 25922), Klebsiella pneumoniae (NTCC 10320), Staphylococcus aureus (ATCC 29213), Bacillus pumilis (NTCC 8241) and Staphylococcus epidermidis (ATCC 12228). The results showed significant increase (p<0.05, Tukeys test) in antibacterial activity of BNC as compared with norfloxacin and physical mixture of norfloxacin and bismuth citrate. This increase in activity is being considered due to increased bioavailability of the metal drug complex. Thus, the use of the BNC may be preferable over norfloxacin alone.     

In vitro antibacterial activity of E-3604, a new 6-fluoroquinolone, on clinical isolates

From a series of pyrrol-containing antibacterial agents, E-3604 was selected for development and compared with nalidixic acid, norfloxacin and ciprofloxacin against strains of clinical isolates. The in vitro activity of E-3604 was greater than that of nalidixic acid, similar to that of norfloxacin and lower than that of ciprofloxacin, except in the case of Staphylococcus where E-3604 showed the best in vitro activity of all the studied compounds, with a MIC range of 0.25-0.03 mg/ml. E-3604, like the other quinolones, presented a pH-dependent variation of activity, greater activity being observed in slightly acidic pH values.     

诺氟沙星衍生物的合成及其抗菌活性研究

目的 设计合成具有抗菌活性的诺氟沙星衍生物。方法 采用2-甲基-5-硝基咪唑、诺氟沙星等为原料，通过亲核取代反应合成目的物；测定目的物的体内抗菌活性。结果 合成的9个化合物的结构经MS、^1H-NMR和元素分析所确证。结论 合成了9个未见报道的新化合物，体内活性测试结果表明：其中的3个化合物具有较高的抗菌活性。     

氧氟沙星注射液的体内抗菌活性研究

应用实验方法,对国产氧氟沙星注射液和诺氟沙星注射液进行体内抗菌活性研究。经实验,国产氧氟沙星注射液对大肠杆菌感染小鼠的ED_(50)为0.26mg/kg,诺氟沙星注射液的ED(50)。为0.75mg/kg。两种注射液的体内抗菌作用量效线性关系之间具有平行的关系。结果表明,氧氟沙星注射液具有良好的体内抗菌作用,两药作用原理相似。     

国产盐酸洛美沙星体内外抗菌作用实验研究

盐酸洛美沙星对革兰阴性菌具有强的抗菌活性，其ＭＩＣ５０多数为０．２５ｍｇ·Ｌ－１；对金葡球菌ＭＩＣ５０为０．５ｍｇ·Ｌ－１；对绿脓假单胞菌ＭＩＣ５０为１ｍｇ·Ｌ－１。盐酸洛美沙星体外抗菌活性与诺氟沙星、氧氟沙星相近而略逊于环丙沙星。盐酸洛美沙星对金葡球菌、大肠杆菌和绿脓假单胞菌感染小鼠ｉｖ的ＥＤ５０分别是４．４７、１．６２和１７．１３ｍｇ·ｋｇ－１，体内抗菌作用较环丙沙星弱但强于诺氟沙星和／或氧氟沙星。     

用尿药法研究诺氟沙星的药物动力学

用紫外分光光度法测定了诺氟沙星胶囊在5名健康受试者体内的尿药浓度。该法简便、可靠、重现性好(回收率100.984±2.30％,CV=2.27％,日内差,日问差均<3％)。通过尿药速度法求其药动学参数,结果表明:诺氟沙星的消除速度常数K为0.1870h~(-1),半衰期T_(1/2)为3.70h,24h内尿药排泄率为43.09％。     

Studies on prodrugs. 5. Synthesis and antimicrobial activity of N-(oxoalkyl)norfloxacin derivatives

Several N-(oxoalkyl)norfloxacin derivatives (3a-g) were synthesized and evaluated for antibacterial activity in vitro and in vivo. Most of the compounds exhibited in vitro activity comparable to that of norfloxacin for Gram-positive bacteria, whereas their activity was lower than for Gram-negative bacteria. N-(2-Oxopropyl)norfloxacin (3b) liberated norfloxacin in the blood after oral administration in mice, and the serum level of norfloxacin was about 3-fold higher than that of norfloxacin itself. Thus, 3b showed high antibacterial activity in vivo.     

Determination of norfloxacin free interstitial levels in skeletal muscle by microdialysis

Tissue penetration and distribution of antibiotics are important issues when establishing antibiotic therapies. Free concentrations of antibiotics at the infection site are responsible for bacteria killing effect. The knowledge of the correlation between blood levels and tissue concentrations can be helpful for adequate dosing of these drugs. It was the aim of this study to investigate norfloxacin pharmacokinetics in rats to predict free interstitial levels of the drug, determined by microdialysis, using pharmacokinetic parameters derived from total plasma data. Norfloxacin free tissue and total plasma levels were determined in Wistar rats after administering 5 and 10 mg/kg i.v. bolus doses. Plasma and microdialysis samples were analyzed by high-performance liquid chromatography. Norfloxacin plasma pharmacokinetics was consistent with a two compartments model. A simultaneous fitting of plasma and tissue concentrations was performed using a proportionality factor because norfloxacin free tissue levels determined by microdialysis were lower than those predicted using plasma data. A similar proportionality (f(T)) factor was calculated by the computer program Scientist((R)) for both doses (0.25 +/- 0.08). It can be concluded that it is possible to predict concentration time profiles of norfloxacin in the peripheral compartment based on plasma data using the adequate tissue penetration factor.     

In vitro activity of norfloxacin in synthetic media and human urine compared to that of cinnoxacin, nalidixic acid and pipemidic acid

Activity of norfloxacin was compared to that of cinnoxacin, nalidixic acid and pipemidi acid in DST-agar and human urine solidified by adding 1.2% agar. Norfloxacin was the most active compound when tested on DST-agar but the MIC values increased from 64 to 128 fold when tested in urine. Other compounds also showed an increase in MIC in urine-agar, but the increase was less marked. MICs for norfloxacin in DST-agar and Müller-Hinton-Agar were similar. Higher concentrations were required in Müller-Hinton-Broth than in Müller-Hinton-Agar.     

Antibacterial activity of the metabolites of ciprofloxacin and its significance in the bioassay

The antibacterial activity of the metabolites of ciprofloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3- quinolinecarboxylic acid, Bay o 9867; designated tradename: Ciprobay) M1, M2, M3 and M4 was tested with the agar dilution method against various Gram-positive and Gram-negative bacteria in comparison to ciprofloxacin, norfloxacin and nalidixic acid. The results show that M1 had only a weak antibacterial activity comparable to nalidixic acid, whereas M2 was significantly less active. M3, which is one of the main metabolites in urine has a broad antibacterial activity but was less active than ciprofloxacin or norfloxacin. M4 which is a very minor metabolite of ciprofloxacin was the most active compound with minimal inhibitory concentrations for strains of Escherichia coli or Klebsiella pneumoniae in the range of norfloxacin, whereas with staphylococci the antibacterial activity was comparable to ciprofloxacin. Possible interactions between ciprofloxacin and the metabolites in the bioassay system, using Escherichia coli (ICB 4004) were studied, to explain discrepancies between the microbiological assay and the HPLC-method reported in the literature. It could be demonstrated that under conditions where the concentration of ciprofloxacin exceeds or equals the concentration of the metabolites or mixtures of them no increase in the inhibition zones for ciprofloxacin could be observed, which would have led to false high values for ciprofloxacin in the bioassay system. From these data we conclude that the antibacterial activity of the metabolites in biological specimens, e.g. urine, does not influence the bioassay results.     

高效液相色谱法测定诺氟沙星胶囊中诺氟沙星含量

目的建立测定诺氟沙星胶囊中诺氟沙星含量的高效液相色谱法。方法色谱柱为DiamonsilTM钻石C18柱（150 mm×4.6 mm,5μm）,流动相为0.01 mol/L盐酸调pH至2.4的甲醇-水（32∶68）,流速0.8 mL/min,紫外检测波长285 nm。结果诺氟沙星质量浓度在6.5～910μg/mL（n=9）范围内与峰面积线性关系良好（r=0.999 8）,方法精密度的RSD为1.1%（n=6）,样品中诺氟沙星的含量为370.7 mg/g。结论所用方法简便、可靠,可作为诺氟沙星胶囊的质量控制方法。