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.

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.

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.

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.

Actividad in vitro de trovafloxacina, otras fluoroquinolonas y de diferentes antimicrobianos frente a aislamientos clínicos. Grupo colaborativo WHONET-Argentina / [In vitro activity of trovafloxacin, of other fluoroquinolones and of related antimicrobials against clinical isolates. Grupo colaborativo WHONET-Argentina]

The in vitro activity of trovafloxacin (TRV) has been evaluated in comparison with that of other antimicrobial agents against 5671 clinical isolates recovered by representative institutions of different provinces in our country. The resistance percentage to gentamicin and third generation cephalosporins among enterobacteriaceae was high: 17

respectively, with a considerable variation according to the analyzed species. The resistance to ciprofloxacin (CIP) and TRV affected approximately 9

of the isolates, without significant differences between both drugs. Fluoroquinolones (FQ) presented excellent activity on 166 isolates of Salmonella spp., 208 of Shigella flexneri and 76 of Shigella sonnei, where only one S.sonnei isolate was resistant to CIP, but susceptible to TRV. About half the isolates of Salmonella spp. and S.sonnei and almost all S.flexneri isolates were resistant to ampicillin, and more than 60

of Shigella spp. isolates were resistant to trimethoprim-sulfamethoxazole. A 41

of Staphylococcus aureus and 55

of coagulase-negative staphylococci isolates were resistant to oxacillin, presenting a highly associated multi-resistance. The resistance to FQ was also strongly related to oxacillin resistance, but the resistance to TRV was significantly lower than the CIP resistance: 9

for S.aureus and 4

for coagulase-negative staphylococci. A similar behavior was observed with Enterococcus spp., where 54

of the isolates were resistant to norfloxacin and only 13

were resistant to TRV. Neither Streptococcus pneumoniae (n = 193) nor Haemophilus influenzae (n = 139) isolates presented resistant to TRV.

In vitro sensitivity of Plasmodium falciparum to eight antimalarials in China-Myanmar and China-Lao PDR border areas.

In 1991-1995 by using the Rieckmann in vitro micro-method, susceptibilities of Plasmodium falciparum to eight antimalarials in the China-Lao PDR and China-Myanmar border areas were tested. The resistant rates of P. falciparum to chloroquinine were 95.0%-100%; IC50 114-240nmol/l. P. falciparum resistant rates to amodiaquine resistance accounted for 83.5%-100%, IC50 52-72nmol/l. All cases were sensitive to quinine, IC50 470-608nmol/l. P. falciparum isolates from the Lao PDR frontier were highly sensitive to artesunate, dihydroartemisinin, and arteether. Resistant rates from other areas were 0-11%. P. falciparum from China-Myanmar and Lao PDR border areas were also sensitive to mefloquine, IC50 68-88nmol/l. A longitudinal survey of the sensitivity of P. falciparum in vivo on the China-Lao PDR border showed that the average defervescent time of falciparum malaria was treated by pyronaridine increased from 32.7 +/- 16.0 hours during 1984-85 to 56.2 +/- 27.4 hours in 1995; the recrudescence rate rose up from 15.2% to 37.5%. The results monitored in vitro showed that all cases assessed in 1988 for response to pyronaridine were sensitive, but 36.4% of cases had emerging resistance, IC50 increased from 13nmol/l to 40 nmol/l. The above results suggested that P. falciparum in these areas has expressed resistance to chloroquine and amodiaquine. However, the parasites are still sensitive to artemisinin, pyronaridine, mefloquine, quinine, but with a declining sensitivities.

A 5-year surveillance of sensitivity in vivo of Plasmodium falciparum to pyronaridine/sulfadoxine/pyrimethamine in Diaoluo area, Hainan Province.

The surveillance of sensitivity of P. falciparum to pyronaridine/sulfadoxine/pyrimethamine has been carried out in Diaoluo area in Hainan Province where chloroquine-resistant falciparum malaria is endemic, covering an area of 406 square kilometers, with a population of 3745 in 1986. From 1986 all outpatients diagnosed as falciparum malaria were administered with PND/S/P as the only antimalarial. In vivo sensitivity of P. falciparum was measured in some patients who were treated in hospital. It was demonstrated that P. falciparum in the Diaoluo area has retained its sensitivity to a single oral dose of PND/S/P of 500/1,000/50 mg with 100% cure rate for at least 5 years.

In vitro sensitivity of multiresistant Plasmodium falciparum to new candidate antimalarial drugs in western Thailand.

The present study, carried out in 1987 in Thailand, has been designed to validate the in vitro microtest system, standardized by the World Health Organization (WHO), for the new antimalarials pyronaridine and halofantrine. The sensitivity of naturally acquired, multiresistant populations of Plasmodium falciparum has been assessed in order to develop a data base for further longitudinal investigations. For both drugs the in vitro microtest system seems to be suitable. The concentration range of plates can be considered as almost ideal for pyronaridine (0.1-6.40 mumol/l) while for halofantrine (0.002-0.128 mumol/l) an upward extension of the concentration range would be appropriate. Validation studies with artemisinin demonstrated the need for revising the protocol for the production of the dosing solutions. In the light of current knowledge about therapeutic concentration levels it would probably be appropriate to adopt a range of 0.2-12.8 mumol/l. All tested isolates, except possibly three, showed sensitive responses to pyronaridine. The high EC99 value of halofantrine could be indicative of some resistance to this drug. Rank correlation analysis suggested cross-resistance of pyronaridine and chloroquine which could be of consequence for the future introduction of pyronaridine.

Futuro de las quinolonas en la práctica clínica / Future of quinolones in clinical practice

En los últimos años ha aumentado el interés en las nuevas quinolonas como agentes antimicrobianos. Diversos compuestos se han utilizado y se ha desarrolado un intenso estudio microbiológico, farmacológico y clínico con estos nuevos fármacos. Un informe previo en esta revista, fue dedicado a comunicar la actividad in vitro de algunos de estos compuestos, comparados con aminoglucósidos. Desde la aparición de ese artículo, se ha tenido un considerable avance en el conocimiento de la farmacología de las preparaciones tanto bucales como parenterales. En este trabajo se presenta un panorama lo más completo posible, de los productos que en un futuro próximo podrán estar en la disponibilidad del mercado nacional, de tal manera, que pueda orientarse el conocimiento y posición de cada uno de ellos como son: norfloxacina, pefloxacina, ciprofloxacina, enoxacina y ofloxacina