Photodegradation of sparfloxacin and isolation of its degradation products by preparative HPLC

Sparfloxacin, a third generation fluoroquinolone derivative, is a potent antibacterial agent active against a wide range of Gram-positive and Gram-negative organisms including Streptococcus pneuinoniae, Staphylococcus aureus, methicillin resistant S. aureus, Legionella spp., Mycoplasina spp., Chlamydia spp. and Mycobacterium spp. A drawback of fluoroquinolones is their photoreactivity. Sparfloxacin has been studied in terms of therapeutic activities. However, there are few published of analytical methods being applied to sparfloxacin. The aim in this study was to determine the photodegradation products of sparfloxacin, when submitted to UV light, and to characterize two of these products, designated SPAX-PDP1 and SPAX-PDP2. An accelerated study of stability in methanol solution was carried out by exposing a solution of sparfloxacin to UV light (peak wavelength 290 nm) for 36 hours at room temperature. The products were analyzed by NMR spectrophotometry, IR spectrometry and mass spectrophotometry. The results suggest that the products isolated here could be used to estimate the degradation of sparfloxacin in a stability study. However, the low activity exhibited by UV-irradiated sparfloxacin is a source of concern that demands further investigation of the mechanism of its photodegradation mechanism.

Observations on photochemical fluorescence enhancement of the terbium(III) sparfloxacin system

Fluorescence of terbium(III) was sensitized when excited in the presence of sparfloxacin (SPFX) in the aqueous solution because a Tb(III)-SPFX complex was formed. The sensitized fluorescence was further enhanced when this system was exposed to 365 nm ultraviolet light. By the spectral properties and contrast experiments, it is proved that irradiation makes this system undergo photochemical reactions and a new terbium complex which is more favorable to the intramolecular energy transfer is formed. The mechanism of photochemical fluorescence enhancement of the Tb(III)-SPFX system is discussed and a new sensitive and selective photochemical fluorimetry for the determination of SPFX is established. Under the optimum conditions, the linear range is 1.0-50 x 10(-7) M for SPFX, the detection limit is 3.0 x 10(-9) M and the R.S.D. for 5.0 x 10(-7) M SPFX is 1.3% (n = 9). Without any pretreatment the recovery of SPFX in human urine was determined with satisfaction. (C) 1999 Elsevier Science B.V. All rights reserved.

Development and validation of a nonaqueous titration with perchloric acid to determine sparfloxacin in tablets

A simple, rapid and inexpensive method for the determination of sparfloxacin in tablets is described. The procedure is based on the use of volumetric dosage in a nonaqueous medium in glacial acetic acid with 0.1 M perchloric acid. The method validation yielded good results and included precision and accuracy. It was also found that the excipients in the commercial tablet preparation did not interfere with the assay. (C) 2001 Elsevier B.V. B.V. All rights reserved.

Spectrophotometric determination of sparfloxacin in pharmaceutical formulations using bromothymol blue

A visible light spectrophotometric method is described for them determination of sparfloxacin in tablets. The procedure is based on the complexation of bromothymol blue 0.5% and sparfloxacin to form a compound of yellow colour with maximum absorption at 385 nm. The Lambert-Beer law was obeyed in the concentration range of 2-12 mg/l. The present study describes a sensitive and accurate method for the determination of the concentration of sparfloxacin in tablets. It was also found that the excipients in the commercial tablet preparation did not interfere with the assay.

A high-performance liquid chromatographic assay for sparfloxacin

A specific and sensitive high-performance liquid chromatographic procedure was developed for the assay of sparfloxacin in raw material and tablets. It was also found that the excipients in the commercial tablet preparation did not interfere with the assay. The method validation yielded good results and included the range, linearity, precision, accuracy, specificity and recovery. This method can also be applied to stability studies. (C) 1999 Elsevier B.V. B.V. All rights reserved.

Performance characteristics of bioassay, UV-spectrophotometry and high performance liquid chromatographic determination of sparfloxacin in tablets

The microbiological bioassay, the UV-spectrophotometry and the high performance liquid chromatography (HPLC) methods for assaying sparfloxacin in tablets were compared. The accuracy, repeatability, and precision of each method was assessed and precise. All methods were reliable within acceptable limits for antibiotic pharmaceutical preparations being accurate and precise. The microbiological bioassay and HPLC are more specific than UV-spectrophotometric analysis. However, the microbiological bioassay requires 20 h to get results, and HPLC is the most expensive analysis. The application of each method as a routine analysis should be investigated considering cost, simplicity, equipment, solvents, speed, and application to large or small workloads.

Moxifloxacin sensitivity of respiratory pathogens in the United Kingdom

The in vitro activity of moxifloxacin and comparator agents against respiratory isolates from a range of geographically distinct centres around the United Kingdom was investigated in the following study. Clinical isolates of Streptococcus pneumoniae (n = 257), Haemophilus influenzae (n = 399) and Moraxella catarrhalis (n = 253) were obtained between March 1998 and April 1999 from nine centres in the United Kingdom. Sensitivity was determined by testing each isolate for its minimum inhibitory concentration (MIC) by agar dilution. Against Streptococcus pneumoniae moxifloxacin and grepafloxacin were the most active (MIC90 = 0.25 mg/l). Trovafloxacin and sparfloxacin were the next most active (MIC90 = 0.5 mg/l) followed by levofloxacin and ciprofloxacin. MIC90 values of the six fluoroquinolones versus H. influenzae ranged from ciprofloxacin > levofloxacin. Against M. catarrhalis the lowest MIC90 was that of grepafloxacin at 0.0625 mg/l followed by moxifloxacin, sparfloxacin, levofloxacin and ciprofloxacin. Trovafloxacin demonstrated the highest MIC90 at 0.5 mg/l. These results demonstrate that moxifloxacin has superior in vitro activity against respiratory tract pathogens than any other comparator quinolones available for clinical use.

Phosphorylation of Skeletal Muscle Pyruvate Dehydrogenase Phosphatase in Response to Insulin Stimulation

Pyruvate dehydrogenase phosphatase (PDP) regulates carbohydrate oxidation through the pyruvate dehydrogenase (PDH) complex. PDP activates PDH, enabling increased carbohydrate flux towards oxidative energy production. In culture myoblasts, both PDP1 and PDP2 undergo covalent activation in response to insulin–stimulation by protein kinase C delta (PKCδ). Our objective was to examine the effect of insulin on PDP phosphorylation and PDH activation in skeletal muscle. Intact rat extensor digitorum longus muscles were incubated (oxygenated at 25°C, 1g of tension) for 30min in basal or insulin–stimulated (10 mU/mL) media. PDH activity increased 58% following stimulation, (p=0.057, n=11). Serine phosphorylation of PDP1 (p=0.047) and PDP2 (p=0.006) increased by 29% and 48%, respectively (n=8), and mitochondrial PKCδ protein content was enriched by 45% in response to stimulation (p=0.0009, n=8). These data suggest that the insulin–stimulated increase in PDH activity in whole tissue is mediated through mitochondrial migration of PKCδ and subsequent PDP phosphorylation.

Esparfloxacino e as fluorquinolonas: Uma revisao de sua classificacao, atividade antibacteriana, mecanismo de acao, caracteristicas farmacocineticas, tolerabilidade e perspectivas farmaceuticas

A revision was accomplished in the literature on the quinolones, antibacterial class that presents wide action spectrum, focusing, mainly, the sparfloxacin, third generation fluorquinolone which has potente activity against Gram positive organisms, including Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA), Gram negative organisms, Legionelia spp, Mycoplasma spp, Chlamydia spp and Mycobacterium spp, including multidrug resistant organisms.

Analise citotoxica de esparfloxacino e seus produtos de degradaçao em células mononucleares humanas

Sparfloxacin, a difluorquinolone derivative, is a potent antibacterial agent active against a wide range of gram-positive and gram-negative organisms including Streptococcus pneumoniae, Staphylococcus aureus, methicillin resistant S. aureus, Legionella spp, Mycoplasma spp; Chlamydia spp. and Mycobacteria. A drawback of fluorquinolones is their photoreactivity. Sparfloxacin has been studied in terms of therapeutic activities. However, few reports about analytical methods of sparfloxacin are available in the literature. The aim of this study was to determine cytotoxic effects, using sparfloxacin reference substance (SPAX-SR), sparfloxacin tablets (SPAX-COMP) and sparfloxacin tablets submitted UV light during 36 hours (SPAX-COMP.36) solution, and two isolated products (7 and 9) of SPAX-SR submitted UV-C light, in concentrations of 31.25, 62.5, 125 and 250 μg/mL by in vitro mononuclear humane culture cells. The results, statistically analyzed by Teste de Tukey, showed SPAX, SPAX-COMP and SPAX-COMP.36 solutions could reduce the cells number in these conditions. These results could not be observed for products 7 or 9. These results can suggest that isolated product can be less cytotoxic than SPAX-SR, is method can also be used to identified products degradation of sparfloxacin in stability study. However, the low activity achieved with sparfloxacin submitted to UV-light is a source of concern and requires further investigation about its photodegradation mechanism.

Análise térmica de esparfloxacino

Sparfloxacin, a third-generation fluoroquinolone, is a potent antibacterial agent against a wide range of Gram-positive and Gram-negative organisms, for example Streptococcus pneumonias, Staphylococcus aureus (including methicillin-resistant strains), Legionella spp., Mycoplasma spp., Chlamydia spp. and Mycobacterium spp. This compound has been submitted to thermal analysis and the results are presented here. The DSC curve of sparfloxacin has an endothermic peak that indicates a melting point at 276.5 °C. The DTA curve of the sample in synthetic air shows two exothermic peaks, at 341.6 and 579.2 °C, attributed to compound decomposition. In the TG curve, the loss of mass can be seen to occur in two steps between 285.5 and 645.3 °C. The DTA curve obtained in a nitrogen atmosphere shows an exothermic peak, with decomposition of sparfloxacin at 340.0 °C; from the corresponding TG plot, the loss of mass starts at 254.4 °C.

Molecular hybridization: A useful tool in the design of new drug prototypes

Molecular hybridization is a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hyrid compound with improved affinity and efficacy, when compared to the parent drugs. Additionally, this strategy can results in compounds presenting modified selectivity profile, different and/or dual modes of action and reduced undesired side effects. So, in this described several example of different strategies for drug design, discovery and pharmacomodulation focused on new innovative hybrid compounds presenting analgesic, anti-inflammatory, platelet anti-aggregating, anti-infections, anticancer, cardio- and neuroactive properties.

Efeito do substituinte “-F” nas propriedades electrónicas e estruturais de fluoroquinolonas

Este estudo incide sobre as características que a presença do ião flúor em moléculas concede. Mais concretamente em fluoroquinolonas, antibióticos que cada vez são mais utilizados. Fez-se uma analise de vários parâmetros para obtermos informação sobre a interação fármaco-receptor nas fluoroquinolonas. Sendo para isso utilizadas técnicas de caracterização química computacional para conseguirmos caracterizar eletronicamente e estruturalmente (3D) as fluoroquinolonas em complemento aos métodos semi-empíricos utilizados inicialmente. Como é sabido, a especificidade e a afinidade para o sitio alvo, é essencial para eficácia de um fármaco. As fluoroquinolonas sofreram um grande desenvolvimento desde a primeira quinolona sintetizada em 1958, sendo que desde ai foram sintetizadas inúmeros derivados da mesma. Este facto deve-se a serem facilmente manipuladas, derivando fármacos altamente potentes, espectro alargado, factores farmacocinéticos optimizados e efeitos adversos reduzidos. A grande alteração farmacológica para o aumento do interesse neste grupo, foi a substituição em C6 de um átomo de flúor em vez de um de hidrogénio. Para obtermos as informações sobre a influência do ião flúor sobre as propriedades estruturais e electrónicas das fluoroquinolonas, foi feita uma comparação entre a fluoroquinolona com flúor em C6 e com hidrogénio em C6. As quatro fluoroquinolonas presentes neste estudo foram: ciprofloxacina, moxiflocacina, sparfloxacina e pefloxacina. As informações foram obtidas por programas informáticos de mecânica quântica e molecular. Concluiu-se que a presença de substituinte flúor não modificava de forma significativa a geometria das moléculas mas sim a distribuição da carga no carbono vicinal e nos átomos em posição alfa, beta e gama relativamente a este. Esta modificação da distribuição electrónica pode condicionar a ligação do fármaco ao receptor, modificando a sua actividade farmacológica.