Lab-on-a-Chip-Surface Enhanced Raman Scattering Combined with the Standard Addition Method: Toward the Quantification of Nitroxoline in Spiked Human Urine Samples.

The emergence of antibacterial resistance and the development of new drugs lead to a continuous change of guidelines for medical treatments. Hence, new analytical tools are required for the detection of drugs in biological fluids. In this study, the first surface enhanced Raman scattering (SERS) detection of nitroxoline (NTX) in purified water and in spiked human urine samples is reported. Insights concerning the nature of the molecule-metal interaction and its influence on the overall SERS signal are provided. Furthermore, three randomly collected urine samples originating from a healthy volunteer were spiked to assess the limit of detection (LOD), the limit of quantification (LOQ), and the linear dynamic range of the lab-on-a-chip SERS (LoC-SERS) method for NTX detection in human urine. The LOD is ∼3 µM (0.57 mg/L), LOQ ∼ 6.5 µM (1.23 mg/L) while the linear range is between 4.28 and 42.8 µM (0.81-8.13 mg/L). This covers the minimum inhibitory concentration (MIC) values of the most commonly encountered uropathogens. Finally, seven clinical samples having an "unknown" NTX concentration were simulated. The LoC-SERS technique combined with the standard addition method and statistical data analysis provided a good prediction of the unknown concentrations. Additionally, it is also demonstrated that the predictions carried out by multicurve resolution alternating least-squares (MCR-ALS) algorithm provides reliable results, and it is preferred to a univariate statistical approach.

Urinary concentrations and antibacterial activities of nitroxoline at 250 milligrams versus trimethoprim at 200 milligrams against uropathogens in healthy volunteers.

Because of the increasing bacterial resistance of uropathogens against standard antibiotics, such as trimethoprim (TMP), older antimicrobial drugs, such as nitroxoline (NTX), should be reevaluated. This randomized crossover study investigated the urinary concentrations of parent drugs and their metabolites and their antibacterial activities (urinary inhibitory titers [UITs] and urinary bactericidal titers [UBTs]) against uropathogens at three different urinary pH values within 24 h in six healthy volunteers after a single oral dose of NTX at 250 mg versus TMP at 200 mg. In three additional volunteers, urinary bactericidal kinetics (UBK) were studied after oral administration of NTX at 250 mg three times a day. The mean urinary concentrations of NTX and NTX sulfate in 24 h were 0.012 to 0.507 mg/liter and 0.28 to 27.83 mg/liter, respectively. The mean urinary concentrations of TMP were 18.79 to 41.59 mg/liter. The antibacterial activity of NTX was higher in acidic urine than in alkaline urine, and that of TMP was higher in alkaline urine than in acidic urine. The UITs and UBTs of NTX were generally lower than those of TMP except for a TMP-resistant Escherichia coli strain, for which NTX showed higher UITs/UBTs than did TMP. UBK showed mainly bacteriostatic activity of NTX in urine. NTX exhibits mainly bacteriostatic activity and TMP also shows bactericidal activity in urine against susceptible strains. NTX is a more active antibacterial in acidic urine, and TMP is more active in alkaline urine. The cumulative effects of multiple doses or inhibition of bacterial adherence could not be evaluated. (This study has been registered at EudraCT under registration no. 2009-015631-32.).

[Disorders of kidney function in patients with benign prostatic hyperplasia]. / Narusheniia funktsional'nogo sostoianiia pochek u bol'nykh dobrokachestvennoi giperplaziei predstatel'noi zhelezy.

The examination of 648 males aged 50 to 86 to conduct an early outpatient detection of renal dysfunction in the elderly men employed an original technique of renal function assessment based on the kinetics of urinary 5-NOK elimination. Renal dysfunctions were revealed in 165 patients, in 159 of them the underlying cause was benign prostatic hyperplasia. The results were compared with those obtained at radionuclide tracing and Reberg-Tareev test. The correlation found indicated the authors' technique informative value and its compatibility with the above methods. Identification of renal dysfunction at early stages of benign prostatic hyperplasia allowed their timely hospitalization and operative treatment which enables the physicians to prevent progression of chronic renal failure in these patients.

[Inhibition of bacterial adherence by nitroxoline on cellular adhesion and on urinary catheter surfaces]. / Inhibition de l'adhérence bactérienne par la nitroxoline sur support cellulaire et sur sonde urinaire.

Nitroxolin or 5-nitro-8-hydroxyquinoline, used in the treatment of acute or recurrent uncomplicated urinary tract infection (UTI), has been investigated to demonstrate inhibitory effect on bacterial adherence to epithelial cells or solid surfaces. Nitroxolin in vitro and in urine inhibits bacterial adherence of E. coli 38 (MS/MS) on HeLa cells and epithelial cells from human bladder mucosa. In the same conditions, norfloxacin has no effect. Nitroxolin (MIC/8) decreases with a statistically significant difference (p less than 0.001) the bacterial attachment to a urinary catheter surface made in siliconated latex. These results justify the performance of a clinical trial in the prophylaxis of recurrent UTI and the outcome of a bacteriuria associated with indwelling or intermittent bladder catheter.

[Inhibition of bacterial adhesion of uropathogenic Escherichia coli strains by the urine of patients treated with nitroxoline]. / Inhibition de l'adhésion bactérienne de souches d'Escherichia coli uropathogènes par des urines de patients traités par la nitroxoline.

The present study evaluates the effects of sub-inhibitory concentrations of nitroxoline, (oxyquinoline derivative) widely used in the treatment of uncomplicated, urinary tract infections, on the adherence of uropathogenic strains of Escherichia coli. These bacterial strains showed mannose sensitive and/or mannose resistant hemagglutinating activity (HA). In the presence of nitroxoline and at sub-MIC concentrations, inhibition of adherence is 90% (MIC/4), 87% (MIC/8), and 70% (MIC/16), whatever HA's are expressed by the E. coli strains. The inhibitory effect on adherence is also observed in the urine after oral administration of 400 mg of nitroxoline. The concentrations of nitroxoline in the urine are determined by microbiological assay (anti-bacterial activity) and by physico-chemical assay (total nitroxoline and free nitroxoline). The percentages of inhibition are related to the concentrations of free and conjugated nitroxoline. For a 1/16 dilution of urine, the inhibitory effect is 70% and 87% respectively 1 h 30 and 2 h 30 after oral administration of nitroxoline. After 5 h, a similar inhibitory effect is observed for a 1/2 dilution of urine. These results justify the performance of a clinical trial on the prophylaxis of recurrent urinary tract infections by nitroxoline.

High-performance liquid chromatographic analysis of nitroxoline in plasma and urine.

A high-performance liquid chromatographic method has been developed for the determination of nitroxoline in 50-microliter plasma and urine samples. A structural analogue of nitroxoline, 8-hydroxyquinoline, was added to the eluent in order to suppress peak asymmetry. Several parameters of the eluent were studied for the optimisation of the chromatographic system. Plasma concentration-time curves were constructed for three volunteers after they had received an oral dose of 100 mg of nitroxoline. Plasma half-life was about 1 h. Within 12 h, about 1% of the dose was excreted in the urine as free nitroxoline and about 30% as conjugated metabolite of the parent compound.

Clinical pharmacokinetics of nitroxoline.

14C-Nitroxoline was given orally to the rats, and its distribution as well as plasma and bile levels were determined autoradiographically and by the aid of radioactivity measurements, respectively. Nitroxoline was also given to the human volunteers orally and intravenously in three various doses and the corresponding urine concentrations of unconjugated and conjugated nitroxoline were determined spectrophotometrically. A pharmacokinetical model was generated on the basis of the results. The curve fitting procedure between total nitroxoline cumulative quantities in urine and the model response simulated on analog-hybrid computer enabled the evaluation of the validity of the chosen model as well as of the identification of its parameters.