Involvement of endothelial CK2 in the radiation induced perivascular resistant niche (PVRN) and the induction of radioresistance for non-small cell lung cancer (NSCLC) cells

BACKGROUND: Tumor microenvironment (TME) plays a vital role in determining the outcomes of radiotherapy. As an important component of TME, vascular endothelial cells are involved in the perivascular resistance niche (PVRN), which is formed by inflammation or cytokine production induced by ionizing radiation (IR). Protein kinase CK2 is a constitutively active serine/threonine kinase which plays a vital role in cell proliferation and inflammation. In this study, we investigated the potential role of CK2 in PVRN after IR exposure. RESULT: Specific CK2 inhibitors, Quinalizarin and CX-4945, were employed to effectively suppressed the kinase activity of CK2 in human umbilical vein endothelial cells (HUVECs) without affecting their viability. Results showing that conditioned medium from IR-exposed HUVECs increased cell viability of A549 and H460 cells, and the pretreatment of CK2 inhibitors slowed down such increment. The secretion of IL-8 and IL-6 in HUVECs was induced after exposure with IR, but significantly inhibited by the addition of CK2 inhibitors. Furthermore, IR exposure elevated the nuclear phosphorylated factor-κB (NF-κB) p65 expression in HUVECs, which was a master factor regulating cytokine production. But when pretreated with CK2 inhibitors, such elevation was significantly suppressed. CONCLUSION: This study indicated that protein kinase CK2 is involved in the key process of the IR induced perivascular resistant niche, namely cytokine production, by endothelial cells, which finally led to radioresistance of non-small cell lung cancer cells. Thus, the inhibition of CK2 may be a promising way to improve the outcomes of radiation in nonsmall cell lung cancer cells.

The effect of CA1 administration of orexin-A on hippocampal expression of COX-2 and BDNF in a rat model of orofacial pain / O efeito da administração de CA1 de orexina-A na expressão hipocampal de COX-2 e BDNF em um modelo de dor orofacial em ratos

ABSTRACT The neuropeptide orexin-A and its receptors are widely distributed in both hippocampal circuitry and pain transmission pathways. Objective: Involvement of the CA1 orexin 1 receptor (OX1R) on the modulation of orofacial pain and pain-induced changes in hippocampal expression of cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) was investigated. Methods: Orofacial pain was induced by an intra-lip injection of capsaicin (100 μg). Reverse transcription polymerase chain reaction and immunoblot analysis were used to indicate changes in hippocampal BDNF and COX-2 expression, respectively. Results: Capsaicin induces a significant pain response, which is not affected by either orexin-A or SB-334867-A, an OX1R antagonist. However, an increased expression of COX-2 and decreased expression of BDNF was observed in the hippocampus of animals that received capsaicin or SB-334867-A (80 nM) plus capsaicin. Meanwhile, orexin-A (40 pM) attenuated the effects of capsaicin on the expression of COX-2 and BDNF. Conclusions: CA1 OX1R activation moderates capsaicin-induced neuronal inflammation and neurotrophic deficiency.

RESUMO O neuropeptídeo orexina-A e seus receptores estão amplamente distribuídos nos circuitos do hipocampo e nas vias de transmissão da dor. Objetivo: O envolvimento do receptor de orexina 1 CA1 (OX1R) na modulação da dor orofacial e alterações induzidas pela dor na expressão do hipocampo de ciclooxigenase-2 (COX-2) e fator neurotrófico derivado do cérebro (BDNF) foi investigado. Métodos: A dor orofacial foi induzida por injeção intra-labial de capsaicina (100 μg). A reação em cadeia da polimerase de transcrição reversa e a análise de imunotransferência foram utilizadas para indicar alterações na expressão de BDNF e COX-2 no hipocampo, respectivamente. Resultados: A capsaicina induz uma resposta significativa à dor, que não é afetada pela orexina-A ou pelo SB-334867-A, um antagonista do OX1R. No entanto, uma expressão aumentada de COX-2 e uma expressão diminuída de BDNF foi observada no hipocampo de animais que receberam capsaicina ou SB-334867-A (80 nM) mais capsaicina. Enquanto isso, a orexina A (40 pM) atenuou os efeitos da capsaicina na expressão de COX-2 e BDNF. Conclusões: A ativação de CA1 OX1R modera a inflamação neuronal induzida por capsaicina e a deficiência neurotrófica.

Clarithromycin vs. gemifloxacin in quadruple therapy regimens for empiric primary treatment of Helicobacter pylori infection: a randomized clinical trial

Eradication of Helicobacter pylori infection plays a crucial role in the treatment of peptic ulcer. Clarithromycin resistance is a major cause of treatment failure. This randomized clinical trial aimed at evaluating the efficacy of a clarithromycin versus gemifloxacin containing quadruple therapy regimen in eradication of H.pylori infection. In this randomized double blind clinical trial [RCT 2012102011054N2], a total of 120 patients were randomized to two groups of 60 patients each. Patients with proven H.pylori infection were consecutively assigned into two groups to receive OBAG or OBAC in gastroenterology clinic in Rasoul-e-Akram General Hospital in Tehran, Iran. The patients in the OBAG group received omeprazole [20 mg] twice daily, bismuth subcitrate [240 mg] twice daily, amoxicillin [1 gr] twice daily, and gemifloxacin [320 mg] once daily, and those in the OBAC group received omeprazole [20 mg] twice daily, 240 mg of bismuth subcitrate twice daily, amoxicillin [1 gr] twice daily, and clarithromycin [500 mg] twice daily for 10 days. Five patients from each group were excluded from the study because of poor compliance, so 110 patients completed the study. The intention-to-treat eradication rate was 61.6% and 66.6% for the OBAC and OBAG groups, respectively. According to the per protocol analysis, the success rates of eradication of H.pylori infection were 67.2% and 72.7% for OBAC and OBAG groups, respectively [p=0.568]. The results of this study suggest that gemifloxacin containing regimen is at least as effective as clarithromycin regimen; hence, this new treatment could be considered as an alternative for the patients who cannot tolerate clarithromycin

Design, synthesis, antibacterial and anti-cell proliferation activities of 1,2,4triazino3,4-h 1,8naphthyridine-8-one-7-carboxylic acid derivatives / 药学学报

To discover novel fluoroquinolone lead compounds as possible anti-infective or/and antitumor chemotherapies, combination principle of pharmacophore-based drug design, a series of novel tricyclic fluoroquinolone title compounds, [1,2,4]triazino[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives ( 5a-5p), were designed and synthesized with a fused [1,2,4]-triazine ring unit. Their structures were characterized by spectral data and elemental analysis and the in vitro antibacterial and anti-cell proliferation activities were also evaluated. The results showed that the titled compounds exhibited more significant inhibitory activities against drug-resistant bacteria (Methicillin-resistant Staphylococcus aureus and multi drug-resistant Escherichia coli strains) and three tested cancer cell lines (human hepatoma SMMC-7721, murine leukemia L1210 and human murine leukemia HL60 cells). Interestingly, SAR showed that compounds with electron-donating groups attached to benzene ring had stronger antibacterial activity than antitumor activity, but electron-withdrawing compounds displayed more potential antitumor activity than antibacterial activity, especially antitumor activity of nitro compounds was comparable to comparison doxorubicin. Thus, novel triazine-fused tricyclic fluoroquinolones as potent anti-infective or/and antitumor lead compounds are valuable to pay attention and for further development.

Clinical Effects of Gemifloxacin on the Delay of Tuberculosis Treatment

Although gemifloxacin has low in vitro activity against Mycobacterium tuberculosis, the effect of gemifloxacin on the delay of tuberculosis (TB) treatment has not been validated in a clinical setting. The study group included patients with culture-confirmed pulmonary TB who initially received gemifloxacin for suspected community-acquired pneumonia (CAP). Two control groups contained patients treated with other fluoroquinolones or nonfluoroquinolone antibiotics. Sixteen cases were treated with gemifloxacin for suspected CAP before TB diagnosis. Sixteen and 32 patients were treated with other fluoroquinolones and nonfluoroquinolones, respectively. The median period from the initiation of antibiotics to the administration of anti-TB medication was nine days in the gemifloxacin group, which was significantly different from the other fluoroquinolones group (35 days). The median times for the nonfluoroquinolone group and the gemifloxacin group were not significantly different. There were no significant differences between the gemifloxacin and other fluoroquinolone group in terms of symptomatic and radiographic improvements. However, the frequency of radiographic improvement in the other fluoroquinolones group tended to be higher than in the gemifloxacin group. Gemifloxacin might be the preferred fluoroquinolone for treating CAP, to alleviate any concerns about delaying TB treatment.

Cytotoxicity and Structure-activity Relationships of Naphthyridine Derivatives in Human Cervical Cancer, Leukemia, and Prostate Cancer

Naphthyridine compounds are important, because they exhibit various biological activities including anticancer, antimicrobial, and anti-inflammatory activity. Some naphthyridines have antimitotic effects or demonstrate anticancer activity by inhibiting topoisomerase II. These compounds have been investigated as potential anticancer agents, and several compounds are now part of clinical trials. A series of naphthyridine derivatives were evaluated for their in vitro cytotoxic activities against human cervical cancer (HeLa), leukemia (HL-60), and prostate cancer (PC-3) cell lines using an MTT assay. Some compounds (14, 15, and 16) were more potent than colchicine against all three human cancer cell lines and compound (16) demonstrated potency with IC50 values of 0.7, 0.1, and 5.1 microM, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used for quantitative structure-activity relationship (QSAR) molecular modeling of these compounds. We obtained accurate and predictive three-dimensional QSAR (3D-QSAR) models as indicated by the high PLS parameters of the HeLa (q2, 0.857; r2, 0.984; r2pred, 0.966), HL-60 (q2, 0.777; r2, 0.937; r2pred, 0.913), and PC-3 (q2, 0.702; r2, 0.983; r2pred, 0.974) cell lines. The 3D-QSAR contour maps suggested that the C-1 NH and C-4 carbonyl group of the naphthyridine ring and the C-2 naphthyl ring were important for cytotoxicity in all three human cancer cell lines.

Gemifloxacin for the treatment of community-acquired pneumonia and acute exacerbation of chronic bronchitis: a meta-analysis of randomized controlled trials / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Gemifloxacin is a fluoroquinolone antibiotic with broad spectrum of antibacterial activity. The aim of the study was to evaluate the comparative effectiveness and safety of gemifloxacin for the treatment of patients with community-acquired pneumonia (CAP) or acute exacerbation of chronic bronchitis (AECB).</p><p><b>METHODS</b>We performed a meta-analysis of randomized controlled trials (RCTs) comparing gemifloxacin with other approved antibiotics. The PubMed, EMBASE, Chinese Biomedical Literature Database and the Cochrane Central Register of Controlled Trials were searched, with no language restrictions.</p><p><b>RESULTS</b>Ten RCTs, comparing gemifloxacin with other quinolones (in 5 RCTs) and β-lactams and/or macrolides (in 5 RCTs), involving 3940 patients, were included in this meta-analysis. Overall, the treatment success was higher for gemifloxacin when compared with other antibiotics (odds ratio 1.39, 95% confidence interval 1.15 - 1.68 in intention-to-treat patients, and 1.33, 1.02 - 1.73 in clinically evaluable patients). There was no significant difference between the compared antibiotics regarding microbiological success (1.19, 0.84 - 1.68) or all-cause mortality (0.82, 0.41 - 1.63). The total drug related adverse events were similar for gemifloxacin when compared with other quinolones (0.89, 0.56 - 1.41), while lower when compared with β-lactams and/or macrolides (0.71, 0.57 - 0.89). In subgroup analyses, administration of gemifloxacin was associated with fewer cases of diarrhoea and more rashes compared with other antibiotics (0.66, 0.48 - 0.91, and 2.36, 1.18 - 4.74, respectively).</p><p><b>CONCLUSIONS</b>The available evidence suggests that gemifloxacin 320 mg oral daily is equivalent or superior to other approved antibiotics in effectiveness and safety for CAP and AECB. The development of rash represents potential limitation of gemifloxacin.</p>

Current development of the second generation of mTOR inhibitors as anticancer agents / 癌症

The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, acts as a "master switch" for cellular anabolic and catabolic processes, regulating the rate of cell growth and proliferation. Dysregulation of the mTOR signaling pathway occurs frequently in a variety of human tumors, and thus, mTOR has emerged as an important target for the design of anticancer agents. mTOR is found in two distinct multiprotein complexes within cells, mTORC1 and mTORC2. These two complexes consist of unique mTOR-interacting proteins and are regulated by different mechanisms. Enormous advances have been made in the development of drugs known as mTOR inhibitors. Rapamycin, the first defined inhibitor of mTOR, showed effectiveness as an anticancer agent in various preclinical models. Rapamycin analogues (rapalogs) with better pharmacologic properties have been developed. However, the clinical success of rapalogs has been limited to a few types of cancer. The discovery that mTORC2 directly phosphorylates Akt, an important survival kinase, adds new insight into the role of mTORC2 in cancer. This novel finding prompted efforts to develop the second generation of mTOR inhibitors that are able to target both mTORC1 and mTORC2. Here, we review the recent advances in the mTOR field and focus specifically on the current development of the second generation of mTOR inhibitors as anticancer agents.

Toxic Epidermal Necrolysis Associated with Sorafenib and Tosufloxacin in a Patient with Hepatocellular Carcinoma

This is the first case report to describe a 44-year-old woman with a history of advanced hepatocellular carcinoma who developed toxic epidermal necrolysis (TEN) clinically after taking 400 mg sorafenib (Nexavar(R), BAY 43-9006) and tosufloxacin orally once per day. Both sorafenib and tosufloxacin were eventually discontinued, and the TEN resolved with corticosteroids and supportive treatment. Clinical physicians should be aware of this possible complication so that early interventions can be made.

Rhinoscleroma causing severe bilateral nasal obstruction

Rhinoscleroma is a chronic, infectious and granulomatous disease of the respiratory tract. There is often a delay in diagnosis due to unfamiliarity with the disease and also because culture is not always positive. We report a case in a 26-year-old woman with granular mass obstructing bilateral nasal cavities and causing breathing difficulty. Histopathological examination showed characteristic Mikulicz histiocytes containing numerous Gram-negative intracellular rod-shaped bacilli consistent with the diagnosis of rhinoscleroma. The patient was treated with gemifloxacin and tetracycline and remains asymptomatic over a year follow-up period. It is important to consider rhinoscleroma in cases of chronic nasal obstruction. As culture is not always positive, histopathological examination may be crucial to the diagnosis.

Antimicrobial Susceptibility Patterns of Legionella isolates in the Environment and in Patients / 대한진단검사의학회지

BACKGROUND: Antimicrobial susceptibility of Legionella spp. has rarely been studied in Korea. Therefore, we aimed to determine the susceptibility of Legionella spp. to various antibiotics. METHODS: We assessed the antimicrobial susceptibility of 66 environmental and clinical Legionella isolates collected between January 2001 and December 2008 from Korea and Japan. The minimum inhibitory concentrations (MICs) of 6 antibiotics, namely, azithromycin, ciprofloxacin, clarithromycin, clindamycin, gatifloxacin, and gemifloxacin were determined by the broth microdilution method using buffered starch yeast extract broth. RESULTS: The MIC ranges of the 6 antibiotics used against the Legionella isolates were as follows: 0.004-0.062 microgram/mL (azithromycin), 0.002-0.5 microgram/mL (ciprofloxacin), 0.004-0.5 microgram/mL (clarithromycin), 0.12-4 microgram/mL (clindamycin), 0.002-0.12 microgram/mL (gatifloxacin), and 0.008-1 microgram/mL (gemifloxacin). CONCLUSIONS: Legionella spp. isolates from Korea and Japan were most susceptible to gatifloxacin. Azithromycin, clarithromycin, ciprofloxacin, and gemifloxacin were also effective for treating legionellosis.

A probable association of acute dystonia with gemifloxacin administration.

Gemifloxacin is a recently introduced fluoroquinolone antibiotic frequently used for its broad spectrum and once-daily dosing. Fluoroquinolones are associated with various neuropsychiatric side effects, such as seizures, insomnia, confusion, lightheadedness, psychosis, paranoia and hallucinations. We report a case of a 36-year-old woman given gemifloxacin for an upper respiratory tract infection who developed acute dystonia on the third day following therapy initiation. The clinical implications are discussed.

Antimalarial activity of concanamycin A alone and in combination with pyronaridine.

Concanamycin A, a macrolide antibiotic inhibitor of vacuolar H+-ATPase derived from Streptomyces sp, inhibited Plasmodium falciparum K1 growth in culture with an IC500 value of 0.2 nM. It exhibited an additive effect when tested together with the antimalarial pyronaridine.

Determination of the physicochemical properties of pyronaridine - a new antimalarial drug

The physicochemical properties of pyronaridine, a new antimalarial drug, have been determined for the first time in this study, since these parameters are comprehensively not available in literature. UV-Vis spectral analysis of both pyronaridine and its tetraphosphate salt were carried out in various solvents, in addition to solubility of the two drugs in these solvents. Partition coefficient was done in n-octanol-water mixture using the Leo-Hansch method as well hydrophobicity index determination. pKa determination was carried out on the tetraphosphate. UV-Vis spectral characteristics showed that both the base and the tetraphosphate salt have significant light absorption in the range 190-380nm. Solubility in different solvents revealed that pyronaridine base is sparingly soluble in chloroform [1.34%] while it is slightly soluble in methanol [0.29%] and ethanol [0.42%] and very slightly soluble in octanol and distilled water. The tetraphosphate salt was sparingly soluble in water [1.46%] while it is only very slightly soluble in other solvents. The higher aqueous solubility of the salt was further revealed by a greater Rm value on extrapolation to 100% water concentration in hydrophobicity index determination. Log P value determination showed that the base [log P of 0.26 +/- 0.02] is more liposoluble than the salt [logP of - [1.24 +/- 0.21]]. Four prominent pKa values were obtained for the tetraphosphate titrated which when extrapolated to the base gave values of 7.08 +/- 0.05, 7.39 +/- 0.05, 9.88 +/- 0.05 and 10.30 +/- 0.10. The results should guide in formulation of appropriate dosage forms to improve bioavailability of the drug especially from oral routes

Actividad de las fluoroquinolonas en aislamientos clínicos de Streptococcus pneumoniae con diferente susceptibilidad a la penicilina: Estudio epidemiológico en cinco ciudades de la República Mexicana / Flouroquinolone activity in clinical isolates of Streptococcus pneumoniae with different susceptibility to penicilline: An epidemiological study in five cities of Mexico

Objetivo: Determinar el grado de sensibilidad a cinco fluoroquinolonas, y la resistencia cruzada, en aislados clínicos de neumococo con diferente susceptibilidad a la penicilina Diseño: Estudio transversal Lugar: Los aislamientos de Streptococcus pneumoniae (Sp) se obtuvieron en cinco centros de atención médica y en un laboratorio de referencia de cinco ciudades de la República Mexicana, durante febrero de 1999 a mayo del 2000. Material: 231 aislamientos de Sp obtenidos de muestras de secreción de la vía aérea o sangre, de 231 pacientes con infección respiratoria aguda o bacteriemia adquiridas en la comunidad. Mediciones: Se midió la susceptibilidad in vitro a penicilina (PEN), ciprofloxacina (CIP), levofloxacina (LEV), gatifloxacina (GAT), moxifloxacina (MOX) y gemifloxacina (GEM) mediante la determinación de la concentración mínima inhibitoria (CMI) con la prueba E. Resultados: 42% de los aislamientos mostraron susceptibilidad disminuida a la PEN. La mínima concentración del antibiótico que logró inhibir al 90% de los aislamientos fue de 3 µg/ml (para la CIP), 1 Hg/ml (para la LEV), 0.25ng/ml (para la GAT), 0.125 µg/ml (para la MOX) y 0.032 µg/ml (para la GEM). La mediana de la CMI para la LEV (GAT, MOX y GEM) se incrementó proporcionalmente a la disminución de la sensibilidad del neumococo a la CIP. La susceptibilidad a la CIP fue semejante entre los aislamientos sensibles y resistentes a la PEN. Conclusión: las fluoroquinolonas de tercera y cuarta generación mostraron tener buena actividad inhibitoria del neumococo, incluyendo a las cepas resistentes a la PEN, siendo mayor que la de CIP. Se documentó resistencia cruzada entre las fluoroquinolonas.

Objective: Determine the susceptibility to five fluoroquinolones and cross resistance of pneumococcus clinical isolates with different penicillin susceptibilities gathered in a community based study . Design: Cross sectional survey. Materials: Two hundred and thirty one (231) isolates were obtained from respiratory secretions or blood specimensfrom 231 patients with acquired acute respiratory infection or bacteremia. Outcome measures: In vitro susceptibility to penicillin (PEN), ciprofloxacin (CIP), levofloxacin (LEV), gatifloxacin (GAT), moxifloxacin (MOX) and gemifloxacin (GEM) was determined with minimal inhibitory concentration (MIC) using the E test. Results: 42% of the isolates showed decreased susceptibility to PEN. The lowest antibiotic concentration that inhibited 90% of the isolates was 3 Hg/ml (for CIP), 1 µg/ml (forLEV), 0.25 µg/ml (for GAT), 0.125 µg/ml (for MOX) and 0.032 µg/ml (for GEM). Median MIC for LEV, GAT, MOX and GEM increased with decreasing susceptibility to CIP. Susceptibility to CIP was similar between penicillin susceptible and penicillin resistant pneumococci. Conclusion: Third and fourth generation fluoroquinolones showed very high inhibitory activity, higher than that for CIP, for both penicillin susceptible and penicillin resistant pneumococci. We noted cross resistance among fluoroquinolones.

In vitro Activity of Gemifloxacin Against Recent Clinical Isolates of Bacteria in Korea

Gemifloxacin is an enhanced-affinity fluoroquinolone with broad-spectrum antibacterial activity. In Korea, resistant bacteria are relatively more prevalent than in other industrialized countries. In this study, we studied the in vitro activities of gemifloxacin, gatifloxacin, moxifloxacin, levofloxacin, ciprofloxacin, and other commonly used antimicrobial agents against 1,689 bacterial strains isolated at four Korean university hospitals during 1999-2000. Minimum inhibitory concentrations (MICs) were determined using the agar dilution method of National Committee for Clinical Laboratory Standards. Gemifloxacin had the lowest MICs for the respiratory pathogens: 90% of Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae were inhibited by 0.06, 0.03, and 0.03 mg/L, respectively. Gemifloxacin was more active than the other fluoroquinolones against methicillin-susceptible Staphylococcus aureus, coagulase-negative staphylococci, streptococci, and Enterococcus faecalis. The MIC90s of gemifloxacin for Klebsiella oxytoca, Proteus vulgaris, and nontyphoidal Salmonella spp. were 0.25, 1.0, and 0.12 mg/L, respectively, while those for other Gram-negative bacilli were 4-64 mg/L. In conclusion, gemifloxacin was the most active among the comparative agents against Gram-positive species, including respiratory pathogens isolated in Korea.

Effect of SX-3228, a selective ligand for the BZ1 receptor, on sleep and waking during the light-dark cycle in the rat

The effects of the benzodiazepine1 (BZ1) receptor agonist SX-3228 were studied in rats (N = 12) implanted for chronic sleep procedures. Administration of 0.5, 1.0 and 2.5 mg/kg SX-3228, sc, to rats 1 h after the beginning of the light phase of the light-dark cycle induced a significant reduction of rapid-eye-movement sleep (REMS) during the third recording hour. Moreover, slow wave sleep (SWS) was increased during the fourth recording hour after the two largest doses of the compound. Administration of 0.5, 1.0 and 2.5 mg/kg SX-3228 one hour after the beginning of the dark period of the light-dark cycle caused a significant and maintained (6-h recording period) reduction of waking (W), whereas SWS and light sleep (LS) were increased. REMS values tended to increase during the entire recording period; however, the increase was statistically significant only for the 1.0 mg/kg dose during the first recording hour. In addition, a significant and dose-related increase of power density in the delta and the theta regions was found during nonREM sleep (LS and SWS) in the dark period. Our results indicate that SX-3228 is a potent hypnotic when given to the rat during the dark period of the light-dark cycle. Moreover, the sleep induced by SX-3228 during the dark phase closely resembles the physiological sleep of the rat

Actividad in vitro de trovafloxacina, otras fluoroquinolonas y de diferentes antimicrobianos frente a aislamiento clinicos / In vitro activity of trovafloxacin, of other fluoroquinolones and of related antimicrobials against clinical isolates

Se evaluó la actividad in vitro de trovafloxacina en comparación con la de otros antimicrobianos frente a 5671 aislamientos clínicos recuperados por instituciones representativas de diferentes provincias del país. Entre las enterobacterias, los porcentajes de resistencia a gentamicina y cefalosporinas de tecera generación fueron elevados: 17 por ciento y 16 por ciento respectivamente, con una variación considerable según la especie analizada. La resistencia a ciprofloxacina (CIP) y trovafloxacina (TRV) afectó a aproximadamente el 9 por ciento de los aislamientos, no observándose diferencias significativas entre ambas drogas. Sobre 166 aislamientos de Salmonella spp., 208 de Shigella flexneri y 76 de Shigella sonnei, las quinolonas fluoradas (QF) presentaron una excelente actividad: sólo 1 aislamiento de S. sonnei fue resistente a CIP, pero sensible a TRV. Alrededor de la mitad de los aislamientos de Salmonella spp. y S.sonnei y la casi totalidad de los de S. flexneri fueron resistentes a ampicilina y más del 60 por ciento de Shigella spp. presentaron resistencia a trimetoprima-sulfametaxazol. El 41 por ciento y 55 por ciento de los aislamientos de Staphylococcus aureus y Staphylococcus coagulasa negativa fueron resistentes a oxacilina presentando una elevada multirresistencia acompañante. La resistencia a QF también estuvo fuertemente asociada a la oxacilino-resistencia, pero la resistencia a TRV fue significativamente menor que a CIP: 9 por ciento vs 57 por ciento para S. aureus y 4 por ciento vs 41 por ciento para a Stafilococcus coagulasa negativa. Un comportamamiento similar se observó frente a Enterococcus spp., donde el 54 por ciento fue resistente a norfloxacina y sólo el 13 por ciento lo fue a TRV. No se detectaron aislamientos de Streptococcus pneumoniae (n=193) y Haemophilus influenzae (n=139) resistentes a TRV.

Farmacocinetica de la trovafloxacina: su significado clinico / Pharmacokinetics of trovafloxacin: its clinical significance

La trovafloxacina se absorbe rápidamente después de su administración oral y llega a su concentración sérica máxima alrededor de una hora. La alatrofloxacina es la prodroga que, al administrarse por vía endovenosa se hidrolisa rápidamente a su estado original. La biodisponibilidad es equivalente cuando se administra por vía oral o endovenosa. La trovafloxacina es una fluoroquinolona de amplio espectro in vitro, con mayor actividad para cocos positivos, anaerobios y para bacterias productoras de neumonías atípicas. Presenta una vida media cercana a las 11 horas y una mayor unión proteica, lo que permite su dosificación única diaria. La excreción renal es inferior al 8 por ciento y no requiere ajuste de dosis en la insuficiencia renal. La trovafloxacina alcanza mayores concentraciones tisulares e intracelulares que las fluoroquinolonas clásicas. Todas estas características farmacocinéticas y farmacodinámicas permiten considerarla como una droga de posible aplicación para el tratamiento de infecciones mixtas o resistentes a drogas de primera línea.