Synthesis of 4-(dimethylamino)pyridine propylthioacetate coated gold nanoparticles and their antibacterial and photophysical activity.

BACKGROUND: Gold nanoparticles are useful candidate for drug delivery applications and are associated with enhancement in the bioavailability of coated drugs and/or therapeutic agent. Since, heterocyclic compounds are known to exhibit antimicrobial potential against variety of pathogens, we designed this study to evaluate the antibacterial effects of gold nanoparticles conjugation with new synthesized cationic ligand; 4-Dimethyl aminopyridinium propylthioacetate (DMAP-PTA) in comparison with pure compound and antibiotic drug Pefloxacin. Antibacterial activity of DMAP-PTA coated gold nanoparticles was investigated against a fecal strain of E. coli (ATCC 8739). RESULTS: A new dimethyl aminopyridine based stabilizing agent named as DMAP-PTA was synthesized and used for stabilization of gold nanoparticles. Gold nanoparticles coated with DMAP-PTA abbreviated as DMAP-PTA-AuNPs were thoroughly characterized by UV-visible, FT-IR spectroscopic methods and transmission electron microscope before biological assay. DMAP-PTA, DMAP-PTA-AuNPs and Pefloxacin were examined for their antibacterial potential against E. coli, and the minimum inhibitory concentration (MIC) was determined to be 300, 200 and 50 µg/mL respectively. Gold nanoparticles conjugation was found to significantly enhance the antibacterial activity of DMAP-PTA as compared to pure compound. Moreover, effects of DMAP-PTA-AuNPs on the antibacterial potential of Pefloxacin was also evaluated by combination therapy of 1:1 mixture of DMAP-PTA-AuNPs and Pefloxacin against E. coli in a wide range of concentrations from 5 to 300 µg/mL. The MIC of Pefloxacin + DMAP-PTA-AuNPs mixture was found to be 25 µg/mL as compared to Pefloxacin alone (50 µg/mL), which clearly indicates that DMAP-PTA-AuNPs increased the potency of Pefloxacin. AFM analysis was also carried out to show morphological changes occur in bacteria before and after treatment of test samples. Furthermore, DMAP-PTA-AuNPs showed high selectivity towards Pefloxacin in spectrophotometric drug recognition studies which offers tremendous potential for analytical applications. CONCLUSIONS: Gold nanoparticles conjugation was shown to enhance the antibacterial efficacy of DMAP-PTA ligand, while DMAP-PTA-AuNPs also induced synergistic effects on the potency of Pefloxacin against E. coli. DMAP-PTA-AuNPs were also developed as Pefloxacin probes in recognizing the drug in blood and water samples in the presence of other drugs.

Report: pharmacokinetic and drug interaction studies of pefloxacin with paracetamol (NNAID) in healthy volunteers in Pakistan.

In the present study, the pharmacokinetic and drug interaction evaluation of two drugs pefloxacin and paracetamol was carried out by a single-dose, two-treatment and two-sequence crossover design. Total fifteen healthy volunteers participated out of which ten completed the study. All were male volunteers, aged 22.36 years (means), with a mean weight of 76.45±12.05 Kg. The washout period between treatments was 5 week. Initially the method utilized for quantitative analysis of the drug was developed which was further validated. The study involved plasma protein precipitation with ethyl acetate and detection was done at 275nm. The retention time for pefloxacin 18±1 min and paracetamol were approximately 6±1 min, respectively. The calibration curve for pefloxacin was linear in the concentration range of 0.125-12.0mg/ml with r(2)=0.9987 in plasma. Standard concentration solution was maintained on the same temperature as that of volunteer's samples to optimize the periods for the determination of drug concentration in the plasma samples. Blood samples were collected from volunteers at different time intervals. The pharmacokinetics and drug interaction studies were anticipated by plotting concentration versus time-profiles. The value of AUC0-∞ in control was 67.355±3.174µg.h/ml, in treatment 61.242±3.868µg.h/ml along with relative bioavailability =91.395±4.864. Under the control and treatment condition the mean maximum plasma concentrations were found to be 4.679±0.248 µg/ml and 4.6595±0.266 µg/ml respectively. The average T(max) for plasma concentrations was 1.819±0.1743hr and 1.605 ±0.1134hr respectively. The biological half-lives in the two phases of studies were found to be 7.953±0.33hr in control and 7.7257±0.355hr in treatment. No significant effect were observed on the bioavailability and pharmacokinetics of pefloxacin by the concomitant administration with paracetamol, however very minor effect were observed that might be related with inter-individual variation in human volunteers. This pharmacokinetic studies also indicated that the level of drug (Cmax) do not differ from previous studies in different races.

Effect of trikatu pretreatment on the pharmacokinetics of pefloxacin administered orally in mountain Gaddi goats.

The pharmacokinetics of orally administered pefloxacin were studied to evaluate the bio-enhancing effect of the herbal bio-enhancer, trikatu, in mountain Gaddi goats (n = 6). The findings of the study revealed a decreased plasma concentration (p > 0.05) of pefloxacin following trikatu administration during the absorption phase (10, 15, 20 min post pefloxacin administration). In contrast, the plasma concentrations of pefloxacin were significantly higher at 4, 6, 8 and 12 h (during the elimination phase) of the pefloxacin administration. The findings of the investigation revealed higher values for the area under the curve, the area under the first moment of the plasma drug concentration time curve, the mean residential time, the total duration of pharmacological action and bioavailability. Trikatu treatment, however, significantly reduced the elimination half life (t 1/2 beta) and zero time intercept of the elimination phase. The apparent volume of distribution based on the total area under the plasma drug concentration curve [(Vd(area)] and the apparent volume of distribution based on the zero time plasma concentration intercept of the elimination phase [Vd(B)] were significantly higher in trikatu treated animals indicating a better penetration of the drug. Based on the MIC of 0.8 microg/ml of pefloxacin, a priming dose of 6.0 mg/kg and a maintenance dose of 2.21 mg/kg is required to be administered at 8 h intervals. For practical purposes in goats this would mean a priming dose of 6 mg/kg and a maintenance dose of 2 mg/kg given by the oral route, to be repeated at 8 h intervals.

Multicomponent kinetic spectrophotometric determination of pefloxacin and norfloxacin in pharmaceutical preparations and human plasma samples with the aid of chemometrics.

A spectrophotometric method for the simultaneous determination of the important pharmaceuticals, pefloxacin and its structurally similar metabolite, norfloxacin, is described for the first time. The analysis is based on the monitoring of a kinetic spectrophotometric reaction of the two analytes with potassium permanganate as the oxidant. The measurement of the reaction process followed the absorbance decrease of potassium permanganate at 526 nm, and the accompanying increase of the product, potassium manganate, at 608 nm. It was essential to use multivariate calibrations to overcome severe spectral overlaps and similarities in reaction kinetics. Calibration curves for the individual analytes showed linear relationships over the concentration ranges of 1.0-11.5 mg L(-1) at 526 and 608 nm for pefloxacin, and 0.15-1.8 mg L(-1) at 526 and 608 nm for norfloxacin. Various multivariate calibration models were applied, at the two analytical wavelengths, for the simultaneous prediction of the two analytes including classical least squares (CLS), principal component regression (PCR), partial least squares (PLS), radial basis function-artificial neural network (RBF-ANN) and principal component-radial basis function-artificial neural network (PC-RBF-ANN). PLS and PC-RBF-ANN calibrations with the data collected at 526 nm, were the preferred methods--%RPE(T) approximately 5, and LODs for pefloxacin and norfloxacin of 0.36 and 0.06 mg L(-1), respectively. Then, the proposed method was applied successfully for the simultaneous determination of pefloxacin and norfloxacin present in pharmaceutical and human plasma samples. The results compared well with those from the alternative analysis by HPLC.

Pefloxacin treatment of meningitis caused by gram-negative bacteria.

Ten patients with acute meningitis caused by gram-negative bacteria were treated with pefloxacin intravenously for a mean period of 10 days. Eight patients responded clinically to pefloxacin treatment, and the causative organisms were eradicated from the cerebrospinal fluid in 9 of the 10 patients. Pefloxacin may offer a new, efficacious, and safe therapy for gram-negative meningitis.

Pharmacokinetics of pefloxacin and its interaction with cyclosporin A, a P-glycoprotein modulator, in rat blood, brain and bile, using simultaneous microdialysis.

1. In vivo microdialysis with HPLC was used to investigate the pharmacokinetics of pefloxacin and its interaction with cyclosporin A. Microdialysis probes were inserted into the jugular vein/right atrium, the striatum and the bile duct of male Sprague-Dawley rats. Biological fluid sampling thereby allowed the simultaneous determination of pefloxacin levels in blood, brain and bile. 2. Following pefloxacin administration, the brain-to-blood coefficient of distribution was 0.036. This was calculated by dividing the area under the concentration curve (AUC) of pefloxacin in brain by its AUC in blood (k=AUC(brain)/AUC(blood)). 3. When the P-glycoprotein cyclosporin A (10 mg kg(-1)) was co-administered with pefloxacin (10 mg kg(-1)), the AUC and the mean residence time in rat blood did not differ significantly (P>0.05). Similarly, the pharmacokinetics of pefloxacin in rat brain was not affected by the presence of cyclosporin A. 4. The AUC of unbound pefloxacin in bile was significantly greater than that in blood. The disposition of pefloxacin in rat bile shows a slow elimination phase following a peak concentration 30 min after pefloxacin administration (10 mg kg(-1), i.v.). The bile-to-blood coefficient of distribution (k=AUC(bile)/AUC(blood)) was 1.53. 5. The results indicated that pefloxacin was able to penetrate the blood-brain barrier and that the concentration in bile was greater than that in the blood, suggesting active biliary excretion of pefloxacin. Current data obtained from rats show no significant impact of cyclosporin A on the pharmacokinetics of pefloxacin in rat blood and brain when administered by concomitant i.v. bolus.

Application of terbium sensitized fluorescence for the determination of fluoroquinolone antibiotics pefloxacin, ciprofloxacin and norfloxacin in serum.

A simple, rapid and sensitive spectrofluorimetric method for the determination of fluoroquinolone antibiotics, norfloxacin (NOR), ciprofloxacin (CIP) and pefloxacin (PEF) is described. The method is based on the radiative energy transfer from fluoroquinolones to terbium ions (Tb3+) in the presence of tri-n-octylphosphine oxide (TOPO) in weakly acidic (pH 5.5) micellar solution of cetylpyridinium chloride (CPCI). Optimum conditions for the formation of the fluoroquinolone-Tb(3+)-TOPO ternary complexes have been investigated. Under optimized conditions the detection limits are 1.7, 1.2 and 4.4 nM for NOR, CIP and PEF, respectively, while the range of application for all three drugs is 0.05-10 microM. The method has been successfully applied to the determination of NOR, CIP and PEF in serum samples after deproteinization with acetonitrile (serum-acetonitrile; 1:2, v/v). The mean recoveries from serum samples spiked with NOR, CIP and PEF (5.0-50.0 microM) were (90.3 +/- 4.9), (105.0 +/- 3.6), and (95.3 +/- 1.5)% respectively. Within-run and day-to-day s, values for 5.0, 25.0 and 50.0 microM of each fluoroquinolone varied from 1.7 to 5.4% and from 3.3 to 12.8%, respectively. The influence of several usually coadministered drugs on the determination of fluoroquinolones in serum has been investigated.

Comparative activities of pefloxacin and ciprofloxacin in the treatment of chronic respiratory tract infections.

To determine the efficacy in vivo of pefloxacin and ciprofloxacin in the treatment of acute infectious bronchopneumopathies, 90 patients, suffering from acute exacerbation of chronic bronchitis and with no known allergies to quinolones, were admitted to the study. Patients were randomly divided into three groups of 30; the first group was dosed with pefloxacin 800 mg i.v. every 24 hours; the second group with pefloxacin 800 mg per os every 24 hours and the third with 500 mg per os of ciprofloxacin every 12 hours. Blood and bronchial secretion samples were simultaneously collected 2, 4, 8, 12, 14 and 24 hours after the first daily dose of antibiotic. Serum and bronchial secretion concentrations of pefloxacin and ciprofloxacin were determined by using a microbiological agar disk diffusion assay, employing Escherichia coli Kp 712 as test organism. Eradication of responsible microorganisms (Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis) were achieved in 98% of patients around 72 hours post treatment. Generally, both antibiotics expressed similar bactericidal properties when orally administered, while intravenous administration of pefloxacin displays a more rapid antibacterial action in comparison with the oral administration schedules. Maximal concentrations of both drugs in bronchial secretion were recorded at the same time after treatment (4 hours), with concentrations of about 2.5 micrograms/ml. Pefloxacin, having a longer half-life, was found 24 hours post-treatment with plasma concentrations of 1.5 micrograms/ml following a single oral dose of 800 mg. Ciprofloxacin, having a shorter half-life, showed a peak of about 1 microgram/ml, 12 hours after administration (500 mg/12 hours/os).

Effects of ketoprofen (NSAID) on the pharmacokinetics of pefloxacin and ofloxacin in healthy volunteers.

The influence of ketoprofen (K), a non steroidal antiinflammatory drug (NSAID) on the pharmacokinetics of two fluoroquinolone derivatives: ofloxacin (O) and pefloxacin (P) was studied in ten healthy adult male volunteers. All subjects orally received every 12 h the fluoroquinolone derivative (either O or P) for three days and the combination of the quinolone and ketoprofen (once a day) during the three following days. Two pharmacokinetic studies were performed for each quinolone, on days four and eight of the treatment. Blood samples were taken at times 0, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h after dosing. Urine was collected during 4 time-periods: 0-4 h, 4-8 h, 8-12 h and 12-24 h. Plasma and urine concentrations of the active drug of O and P were measured by microbiological assay. Ketoprofen did not significantly modify the pharmacokinetic parameters of the two fluoroquinolones studied in terms of peak plasma levels, time to peak, area under the curve, elimination half-life, volume of distribution and total and renal clearances.

Selective separation and simultaneous determination of trace levels of five types of fluorinated quinolone drugs by thin-layer chromatography/fluorescence densitometry.

This paper reports the determination of trace levels of 5 types of fluorinated quinolone drugs, i.e., ciprofloxacin, norfloxacin, enoxacin, pefloxacin, and ofloxacin, by thin-layer chromatography (TLC)/fluorescence densitometry. The new analytical method uses 2-step TLC development, selective separation, and simultaneous determination of the 5 drugs. The method was also applied to the determination of recoveries of standards of the 5 drugs in plasma and urine samples. The results show that the method has a wide linear range, high repeatability, and good stability.

Changes in serum levels of quinolones in rats under the influence of experimental trauma.

Administration of antibiotics is considered an important factor during, or after, operational procedures in the maxillofacial area, in order to avoid post-surgical complications. In the present study, the levels of quinolones in serum and tissues such as the parotid gland, the tongue and the bone of the jaws were estimated during traumatic injury in the oral cavity. For this purpose, two groups (A and B) of Wistar rats, consisting of 35 animals each were used. Group A (control) and group B (experimental) were divided in five subgroups (A1, A2, A3, A4, A5, and B1, B2, B3, B4, B5). In the experimental group, model traumatic injury was performed through the whole lenght of the cheek. Subjects received orally ciprofloxacin, pefloxacin, norfloxacin, ofloxacin and cinoxacin. The concentration of quinolones in serum and in most of the tissues was significantly higher in the experimental groups than in controls. In addition, the FFA levels and the weight of adrenals (as indicators of stress) were higher in the trauma groups. Stress seemed to affect many pathophysiological mechanisms which are responsible for the alterations observed.

Pharmacokinetics of pefloxacin in goats after intravenous or oral administration.

The plasma concentrations and pharmacokinetics of the fluoroquinolone antimicrobial agent pefloxacin, following the administration of a single intravenous (10 mg/kg) or oral (20 mg/kg) dose, were investigated in healthy female goats. The antimicrobial activity in plasma was measured at predetermined times after drug administration by an agar well diffusion microbiological assay, using Escherichia coli (ATCC 25922) as the test organism. Concentrations of the drug > or = 0.25 microg/ml were maintained in plasma for up to 6 and 10 h after intravenous (i.v.) or oral administration of pefloxacin, respectively. The concentration time data for pefloxacin in plasma after i.v. or oral administration conformed to two- and one-compartment open models, respectively. Plasma pefloxacin concentrations decreased rapidly during the initial phase after i.v. injection, with a distribution half-life (t(1/2alpha)) of 0.10 +/- 0.01 h. The terminal phase had a half-life (t(1/2beta)) of 1.12 +/- 0.21 h. The volume of distribution at steady state (Vdss), mean residence time (MRT) and total systemic clearance (ClB) of pefloxacin were 1.08 +/- 0.09 L/kg, 1.39 +/- 0.23 h and 821 +/- 88 (ml/h)/kg, respectively. Following oral administration of pefloxacin, the maximum concentration in the plasma (Cmax) was 2.22 +/- 0.48 microg/ml and the interval from administration until maximum concentration (tmax) was 2.3 +/- 0.7 h. The absorption half-life (t(1/2ka)) mean absorption time (MAT) and elimination half-life of pefloxacin were 0.82 +/- 0.40, 4.2 +/- 1.0 and 2.91 +/- 0.50 h, respectively. The oral bioavailability of pefloxacin was 42% +/- 5.8%. On the basis of the pharmacokinetic data, a dosage regimen of 20 mg/kg, i.v. at 8 h intervals or orally twice daily, is suggested for treating infections caused by drug-sensitive pathogens in goats.

Some pharmacokinetic parameters of pefloxacin in lactating goats.

The aim of this study was to elucidate some of the pharmacokinetic parameters of pefloxacin in lactating goats (n = 5) following intravenous (i.v.) or intramuscular (i.m.) injections of 10 mg/kg bw. Serially obtained serum, milk and urine samples were collected at precise time intervals, and the drug concentrations were assayed using a microbiological assay. A two-compartment open model best described the decrease of pefloxacin concentration in the serum after intravenous administration. The maximum serum concentration (C0(p)) was 8.4 +/- 0.48 microg/ml; elimination half-life (t 1/2 beta) was 1.6 +/- 0.3 h; total body clearance (Cl(tot) was 3.6 +/- 0.3 L/kg/h; steady-state volume of distribution (V(dss)) was 5.14 +/- 0.21 L/kg; and the area under the curve (AUC) was 2.78 +/- 0.22 microg.ml/h. Pefloxacin was absorbed rapidly after i.m. injection with an absorption half-life (t 1/2 ab) of 0.32 +/- 0.02 h. The peak serum concentration (Cmax) of 0.86 +/- 0.08 microg/ml was attained at 0.75 h (Tmax). The absolute bioavailability after i.m. administration was 70.63 +/- 1.13% and the serum protein-bound fraction ranged from 7.2% to 14.3%, with an average value of 9.8 +/- 1.6%. Penetration of pefloxacin from the blood into the milk was rapid and extensive, and the pefloxacin concentration in milk exceeded that in serum from 1 h after administration. The drug was detected in milk and urine for 10 and 72 h, respectively; no samples were taken after 72 h.

[Critical serum concentration of antibiotics. A therapeutic tool and means of comparative evaluation]. / La concentration sérique critique des antibiotiques. Outil thérapeutique et moyen d'évaluation comparative.

It is difficult to predict the clinical activity of antibiotics solely on the basis of in vitro data. Experimental models measuring the relationship between serum concentration and in vivo activity are essential for comparing the activity of different compounds currently available. The critical serum concentration can be used to compare the intrinsic activity of antibiotics on a given bacterial strain. When compared with the minimal inhibiting concentration measured in vitro, "activity loss" can be determined for each antibiotic placed in contact with bacteria in an infected tissue. The relevance of this therapeutic tool in comparison with other methods is discussed.

[Study of pefloxacin concentration in blood and sputum in the aged pneumonia patients with impairment of renal function].

OBJECTIVE: To study the drug concentration in blood and sputum, clinical effect and drug toxicity of pefloxacin in the aged pneumonia patients with different degree of impairment of renal function. METHODS: The patients were divided into four groups according to the impairment of renal functions pefloxacin 400 mg/12 h venous inflow, period of treatment is 10 days. Clinical manifestation and experimental index were registered; the drug concentration in blood and sputum was measured with biochemical technique, then compared and analyzed. RESULTS: The drug concentration in blood and sputum in four groups differed from the degree of the impairment of renal function. The concentration of drug in blood and sputum of the normal renal function was close to that in the low-grade impairment of renal function. Their clinical effective ratios were 83%, 80%, bacterium cleanup ratio was 86%. The difference of drug concentration in blood and sputum in the severe impairment of renal function was greater than that in the moderate renal function group, their clinical effective ratios were 66%, 53%, bacterial cleanup ratios were 57%, 36%, adverse reaction was growing along with degree of impairment of renal function. This drug has renal toxicity for moderate and severe impairment of renal function. CONCLUSION: In case of moderate impairment of renal function, prolongation of dose interval should be considered; pefloxacin should be avoided in severe impairment of renal function.

[Study on fluorescence method of pefloxacin].

Pefloxacin is a new kind of antibiotic. In this paper, a sensitive fluorescence method has been developed for the analysis of Pefloxacin. It has stronger fluorescence excitation. The fluorescence of Pefloxacin was measured at excitation wavelength 282nm and emission wavelength 440nm. The method is highly sensitive with lower limit of detection, calibration curves were linear between 1 x 10(-9) - 1 x 10(-6)mol/L, with a regression coefficient of 0.9999. At the same time, recoveries of pefloxacin in Human serum Albumin and Urine are 95% and 105% respectively.

[Clinico-pharmacologic studies on pefloxacin]. / Klinikofarmakológiai vizsgálatok Péflacine-nal.

The impact of liver impairment, renal insufficiency and age-related changes on the pharmacokinetics of pefloxacin was studied in 55 patients. The elderly patients were stratified into three age groups (61-70, 71-80 and above 81 years). The patients suffering from various infections were treated with oral or intravenous pefloxacin in a dose of 400 mg bid. Blood samples were withdrawn on the first and seventh day of therapy. The pharmacokinetics of pefloxacin was characterized by marked interindividual differences that became even more pronounced during multiple dosing. The elimination rate of pefloxacin during therapy slowed down, presumably due to its decreased metabolism. In elderly patients, the rate of cumulation is greater than in the young ones, but no significant differences could be detected among the elderly age-groups. Pefloxacin elimination also decreased in renal and hepatic impairment. There was no correlation between serum concentrations of pefloxacin and the development of adverse effects. In elderly subjects and in patients with renal or hepatic impairment, dose reduction might be considered. In mild or moderate infections or in urinary tract infections smaller doses of pefloxacin also could assure good therapeutic results. However, in severe infections especially caused by less susceptible pathogens, routine dose reduction is not recommended because of the significant interindividual differences in serum concentrations of pefloxacin.

[Preclinical pharmacokinetics of pefloxacin]. / Doklinicheskaia farmakokinetika pefloksatsina.

The substance and tablets of pefloxacin mesilate manufactured by the Urals Polytechnical University and the National Research Centre of Antibiotics were studied on rats and dogs with the drug oral administration in single and multiple doses equivalent to the human ones. The bioavailability of the drug was good and its blood levels were efficient for a prolonged period (at least 24 hours) after a single oral administration. No cumulation of the antibiotic after its repeated use was observed. The pefloxacin mesilate tablets proved to be fully equivalent to the drug manufactured by Rhone-Poulenc-Rorer (France).

[The pharmacodynamics and pharmacokinetics of fluoroquinolones in the evaluation of antibacterial therapy regimens]. / Farmakodinamika i farmakokinetika ftorkhinolonov pri otsenke rezhimov antibakterial'noi terapii.

Sensitivity of 505 strains of gram-negative and gram-positive microorganisms to II generation fluoroquinolones (ciprofloxacin, pefloxacin) was determined. Strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus with different level of sensitivity were selected. Pharmacokinetics of the drugs was investigated after their administration per os in one dose. The resulting indices were used for calculation of the following parameters--Cmax/MIC and AUC/MIC. These parameters may be used in evaluation of the drugs efficacy and for dosing corrections.