Glycogen synthase kinase-3 (GSK-3) a magic enzyme: it’s role in diabetes mellitus and glucose homeostasis, interactions with fluroquionlones. A mini-review / Glicogênio sintase quinase-3 (GSK-3), uma enzima mágica: seu papel no diabetes mellitus e na homeostase da glicose: interações com fluoroquinolonas. Uma mini-revisão

Diabetes mellitus (DM) is a non-communicable disease throughout the world in which there is persistently high blood glucose level from the normal range. The diabetes and insulin resistance are mainly responsible for the morbidities and mortalities of humans in the world. This disease is mainly regulated by various enzymes and hormones among which Glycogen synthase kinase-3 (GSK-3) is a principle enzyme and insulin is the key hormone regulating it. The GSK-3, that is the key enzyme is normally showing its actions by various mechanisms that include its phosphorylation, formation of protein complexes, and other cellular distribution and thus it control and directly affects cellular morphology, its growth, mobility and apoptosis of the cell. Disturbances in the action of GSK-3 enzyme may leads to various disease conditions that include insulin resistance leading to diabetes, neurological disease like Alzheimer’s disease and cancer. Fluoroquinolones are the most common class of drugs that shows dysglycemic effects via interacting with GSK-3 enzyme. Therefore, it is the need of the day to properly understand functions and mechanisms of GSK-3, especially its role in glucose homeostasis via effects on glycogen synthase.

O diabetes mellitus (DM) é uma doença não transmissível em todo o mundo, na qual existe nível glicêmico persistentemente alto em relação à normalidade. O diabetes e a resistência à insulina são os principais responsáveis pelas morbidades e mortalidades de humanos no mundo. Essa doença é regulada principalmente por várias enzimas e hormônios, entre os quais a glicogênio sintase quinase-3 (GSK-3) é uma enzima principal e a insulina é o principal hormônio que a regula. A GSK-3, que é a enzima-chave, normalmente mostra suas ações por vários mecanismos que incluem sua fosforilação, formação de complexos de proteínas e outras distribuições celulares e, portanto, controla e afeta diretamente a morfologia celular, seu crescimento, mobilidade e apoptose do célula. Perturbações na ação da enzima GSK-3 podem levar a várias condições de doença que incluem resistência à insulina que leva ao diabetes, doenças neurológicas como a doença de Alzheimer e câncer. As fluoroquinolonas são a classe mais comum de drogas que apresentam efeitos disglicêmicos por meio da interação com a enzima GSK-3. Portanto, é necessário hoje em dia compreender adequadamente as funções e mecanismos da GSK-3, principalmente seu papel na homeostase da glicose via efeitos na glicogênio sintase.

Evaluation of the influence of fluoroquinolone chemical structure on stability: forced degradation and in silico studies

ABSTRACT Fluoroquinolones are a known antibacterial class commonly used around the world. These compounds present relative stability and they may show some adverse effects according their distinct chemical structures. The chemical hydrolysis of five fluoroquinolones was studied using alkaline and photolytic degradation aiming to observe the differences in molecular reactivity. DFT/B3LYP-6.31G* was used to assist with understanding the chemical structure degradation. Gemifloxacin underwent degradation in alkaline medium. Gemifloxacin and danofloxacin showed more degradation perceptual indices in comparison with ciprofloxacin, enrofloxacin and norfloxacin in photolytic conditions. Some structural features were observed which may influence degradation, such as the presence of five member rings attached to the quinolone ring and the electrostatic positive charges, showed in maps of potential electrostatic charges. These measurements may be used in the design of effective and more stable fluoroquinolones as well as the investigation of degradation products from stress stability assays.

Aqueous humor concentrations of topical fluoroquinolones alone or in combination with a steroid / Concentração de fluorquinolonas no humor aquoso após instilação tópica das associações com corticosteroides

ABSTRACT Purpose: To compare the aqueous humor (AH) concentrations of moxifloxacin 0.5% and gatifloxacin 0.3% solutions alone or when treatment was combined with steroids, and to correlate these concentrations with the minimum inhibitory concentrations (MIC) for the most common endophthalmitis-causing organisms. Methods: Patients undergoing phacoemulsification were enrolled to receive one drop of one of the following solutions: moxifloxacin (G1), moxifloxacin + dexamethasone (G2), gatifloxacin (G3), or gatifloxacin + c (G4), every 15 min, 1h before surgery. AH samples were collected before surgery and analyzed using HPLC-tandem mass spectrometry. Results: The mean antibiotic concentrations in the AH were: G1= 1280.8 ng/mL; G2= 1644.3 ng/mL; G3= 433.7 ng/mL; and G4= 308.1 ng/mL. The mean concentrations statistically differed between G1 and G2 (p=0.01), and G3 and G4 (p=0.008). All samples achieved the MIC for Staphylococcus epidermidis; 100% of the samples from G1 and G2, and 97% from G3 and G4 reached the MIC for fluoroquinolone-sensitive Staphylococcus aureus; 100% of the samples from G1 and G2, 88% from G3, and 72% from G4 reached the MIC for enterococci (p<0.001); and 100% of samples from G1 and G2, 59% from G3, and 36% from G4 reached the MIC for Streptococcus pneumoniae (p<0.001). For fluoroquinolone-resistant S. aureus, 23% from G1, 44% from G2, and no samples from G3 or G4 achieved the MIC (p<0.001). Conclusions: Moxifloxacin + dexamethasone demonstrated a higher concen­tration in the AH than the moxifloxacin alone. Gatifloxacin + steroids demonstrated less penetration into the anterior chamber than gatifloxacin alone. Moxifloxacin was superior to gatifloxacin considering the MIC for enterococci, S. pneumoniae, and fluoroquinolone-resistant S. aureus.

RESUMO Objetivos: Comparar a concentração no humor aquoso entre as soluções de moxifloxacina 0,5% e gatifloxacina 0,3% sozinhas ou combinadas com corticosteroides, e correlacionar a concentração com a concentração inibitória mínima (MIC) para os agentes microbianos mais comumente relacionados a endoftalmites. Métodos: Pacientes que seriam submetidos a cirurgia de catarata foram selecionados para receber 1 gota a cada 15 min, 1 hora antes do procedimento de uma das seguintes soluções: moxifloxacina (G1), moxifloxacina + dexametasona (G2), gatifloxacina (G3) ou gatifloxacina + prednisolona (G4). Amostras do humor aquoso foram coletadas antes do início da cirurgia. Espectrofotometria de massa por HPLC determinou a concentração do antibiótico nas amostras. Resultados: A concentração media de antibiótico nas amostras foram: G1= 1280,8 ng/mL; G2= 1644,3 ng/mL; G3= 433,7 ng/mL; G4= 308,1 ng/mL. Concentração média entre G1 e 2 (p=0,01), e G3 e 4 (p=0,008). Todas as amostras alcançaram MIC para S. epidermidis; 100% das amostras do G1 e 2, e 97% do G3 e 4 atingiram o MIC para S. aureus fluoroquinolona-sensível; 100% das amostras do G1 e 2, 88% do G3 e 72% do G4 atingiram o MIC para Enterococci (p<0,001); e 100% das amostras do G1 e 2, 59% do G3 e 36% do G4 atingiram o MIC para S. pneumoniae (p<0,001). Para o S. aureus resistente a fluoroquinolona, 23% do G1, 44% do G2, e nenhuma das amostras G3 e 4 atingiram o MIC (p<0,001). Conclusão: Moxifloxacina + dexamethasona demonstrou maior concentração no humor aquoso comparado com a moxifloxacina sozinha. Gatifloxacina + esteróide demonstrou menor penetração na câmara anterior comparado a solução de ga­ti­floxacin sem corticóide. A moxifloxacina foi superior a gatifloxacina considerando o MIC para Enterococci, S. pneumoniae e S. aureus fluorquinolona resistente.

Detection of quinolone-resistance mutations in Salmonella spp. strains of epidemic and poultry origin

Mutations into codons Aspartate-87 (62 percent) and Serine-83 (38 percent) in QRDR of gyrA were identified in 105 Salmonella strains resistant to nalidixic acid (94 epidemic and 11 of poultry origin). The results show a high incidence of mutations associated to quinolone resistance but suggest association with others mechanisms of resistance.

Liberação intraocular de ofloxacina associada a lente de contato biossintética em ceratite bacteriana experimental em cães / Introcular release of ofloxacin associated with biosynthetic contact lens in experimental bacterial keratitis in dogs

Avaliou-se a concentração de ofloxacina liberada por uma lente de contato de membrana de celulose biossintética, para tratamento de ceratite bacteriana experimental em cães, pela inoculação de Staphylococcus aureus intraestromal. Comparou-se o tratamento com a lente de contato biossintética impregnada com ofloxacina à terapia tópica convencional. Realizou-se avaliação microbiológica e dosagem de ofloxacina no humor aquoso por meio do método de cromatografia líquida de alto rendimento (HPLC). Houve diferença estatística na contagem de colônias bacterianas entre os olhos com ceratite e os demais grupos, no primeiro dia de coleta. O biomaterial, impregnado com ofloxacina, promoveu liberação gradual durante o período de avaliação, aos três e sete dias; no terceiro dia, o grupo tratado com a lente de contato obteve mediana de 3,72μg/mL, enquanto o grupo tratado com colírio resultou em 49,56μg/mL. Apesar do valor inferior, o grupo com lente de contato atingiu a concentração inibitória mínima, sendo eficaz no controle da infecção bacteriana.

The concentration of ofloxacin released by contact lens made of biosynthetic cellulose membrane was evaluated for the treatment of experimental bacterial keratitis in dogs by intrastromal inoculation of Staphylococcus aureus. The biosynthetic contact lens impregnated with ofloxacin was compared with the conventional topical therapy. The microbiological evaluation and the determination of ofloxacin in aqueous humor were evaluated by high performance liquid chromatography (HPLC). There was not statistical difference in the counting of bacterial colonies among the eyes with keratitis and other groups, on the first day of collection. The biomaterial, impregnated with ofloxacin, promoted gradual release during the evaluation period, at three and seven days; on the third day, the group treated with the contact lens obtained a median of 3.72μg/mL, while the group treated with eye drops resulted in 49.56μg/mL. Despite the lower value, the group with contact lens reached the minimum inhibitory concentration, which was effective in controlling the bacterial infection.

Fluoroquinolonas x resistência bacteriana na medicina veterinária / Fluoroquinolones x bacterial resistance on veterinary medicine

As fluoroquinolonas são um grupo de substâncias químicas sintéticas com atividade antimicrobiana, com extensiva aplicação tanto na medicina humana como também na medicina veterinária, consideradas importantes armas no combate a organismos Gram-negativos, Grampositivos e as últimas gerações destes agentes antimicrobianos chegam a ser ativas contra as bactérias anaeróbias. Atualmente é uma das maiores classes de agentes antimicrobianos sendo utilizadas, mundialmente, no tratamento de infecções de origem bacteriana. As suas indicações terapêuticas evoluíram da aplicação em infecções urinárias a aplicações nas mais variadas infecções. Este grupo de fármacos foi se desenvolvendo de forma a ultrapassar grande parte das suas adversidades, possuindo hoje um espectro de ação bastante abrangente, boa disponibilidade oral, melhor difusão para os tecidos, uma meia vida maior e uma toxicidade consideravelmente reduzida. Esta revisão reúne informações atuais sobre as propriedades físico-químicas, farmacocinética, metabolismos de ação e de resistência das fluoroquinolonas de uso veterinário.

The fluoroquinolones are a group of synthetic chemicals with antimicrobial activity. They have extensive application in human medicine and also in veterinary medicine, are considered important weapons in fighting Gram-negative and Gram-positive microorganism, and the latest generation of these antimicrobial agents is also active against the anaerobic bacteria. Nowadays it is one of the largest classes of antimicrobial agents globally in use to treat bacterial infections. Its therapeutic indications developed from application in urinary infections to nearly all infections in the body. This group of drugs has been developed in order to overcome most of its adversities, having nowadays, a larger spectrum of action, good oral availability and better dissemination to the tissues, increased half-life and toxicity considerably reduced This review brings together current information about the physical-chemical properties, pharmacokinetics and metabolism of action and resistance of fluoroquinolones for veterinary use.

Presence of fluoroquinolones and sulfonamides in urban sewage sludge and their degradation as a result of composting

The concentrations of some widely used pharmaceuticals, namely fluoroquinolones [ciprofloxacin C[17]H[18]FN[3]O[3], norfloxacin C[16]H[18]FN[3]O[3] and ofloxacin C[18]H[20]FN[3]O[4]] and sulfonamides [sulfadimethoxine C[12]H[14]N[4]O[4]S and sulfamethoxazole C[10]H[11]N[3]O[3]S] were determined in urban sewage sludge utilized for making compost. The levels of degradation of these pharmaceuticals resulting from sludge treatment were assessed. The concentrations of the studied pharmaceuticals sufficiently varied both in sewage sludge and in compost and due to this phenomenon the possible danger resulting from the presence of pharmaceuticals in sewage sludge, used for composting, can not be ignored. The concentrations of the studied pharmaceuticals were lower in compost, if compared to the relevant concentrations in sewage sludge. The highest pharmaceutical concentration in sewage sludge - 426 micro g/kg - was detected in the case of ciprofloxacin. The highest concentrations present in compost were 22 micro g/kg of norfloxacin and 20 micro g/kg of ciprofloxacin. Results show that before using the sewage sludge for making compost or before using the compost a fertilizer for food plants, they should be carefully tested against the content of commonly used pharmaceuticals

Effect of probenecid on kinetics of enrofloxacin in lactating goats after subcutaneous administration.

A comparative pharmacokinetic study of enrofloxacin (5 mg/kg, sc) was conducted in probenecid-pretreated (70 mg/kg, orally 1.5 h prior to enrofloxacin administration) lactating goats to assess the effect of probenecid on the kinetics of enrofloxacin. Concentration of enrofloxacin in plasma, milk and urine was estimated by microbiological assay using Escherichia coli (ATCC 25922). Minimum detection level of enrofloxacin was 0.01 microg/ml. The plasma log concentration versus time curve showed monophasic pattern and followed one compartment open model. Plasma drug concentration was significantly higher during 1-2 h in probenecid-pretreated group. Significantly higher drug concentration in milk was noted at most of the time points, while significantly lower urine drug concentration (0.083-1 h and 5-12 h) were obtained in probenecid-pretreated group. The kinetic parameters (A, B and 3) were significantly higher, while t(1/2)beta, MRT and Vd(area) were significantly lower in probenecid-pretreated group. Probenecid pretreatment decreased the urinary excretion of enrofloxacin, whereas enhanced excretion in milk which could be useful in cases of affections of udder in goats.

Residuos de tetraciclina y quinolonas en peces silvestres en una zona costera donde se desarrolla la acuicultura del salmón en Chile / Residues of tetracycline and quinolones in wild fish living around a salmon aquaculture center in Chile

La presencia de antibacterianos y antiparasitarios residuales fue investigada en muestras de carne de peces silvestres de consumo humano pescados alrededor de un recinto de acuicultura en Cochamó (41° 29' S; 72° 19'W), X Región, Chile. Esta investigación demostró que peces silvestres, incluyendo róbalo (Elginops maclovinus), cabrilla (Sebastes capensis) y truchas de vida libre (Oncorhynchus mykiss), ingieren alimento artificial para salmón y que la carne de algunos ejemplares de estos peces contienen tetracicilina y quinolona en cantidades detectables. Estos resultados sugieren que el uso de antibacterianos en la acuicultura del salmón, como ha sido demostrado en otros países, tiene efectos ambientales que se proyectan más allá de los recintos de acuicultura. Se indica que dada la relevancia de estos hallazgos para la salud humana y animal, el ambiente requerirá de estudios más amplios y detallados para implementar futuras regulaciones del uso de antibacterianos en acuicultura.

The presence of residues of tetracycline, quinolones and antiparasitic drugs was investigated in wild fish captured around salmon aquaculture pens in Cochamó, Region X, Chile. Residues of both antibiotics were found in the meta of two species of wild fish that are consumed by humans, robalo (Elginops maclovinus) and cabrilla (Sebastes capensis) . These findings suggest that the antibiotic usage in salmon aquaculture in Chile has environmental implications that may affect human and animal health. More studies are needed in Chile to determine the relevance of these findings for human and animal health and the environment to regulate this use of antibiotics.