In-vitro activity of dicationic aromatic compounds and fluconazole against Cryptococcus neoformans and Candida spp. (17/1563)

We investigated the in-vitro activity of three selected dicationic aromatic compounds for nine clinical isolates of Cryptococcus neoformans and 93 clinical isolates of Candida spp., representing 12 different species, using a broth macrodilution method following NCCLS recommendations. All the clinical isolates were also tested for fluconazole susceptibility. The in-vitro data demonstrate that compounds 39 and 57 have excellent in-vitro activity for all tested strains (MIC 0.19-1.56 mg/L) except Candida pelliculosa. Moreover, compound 39 showed excellent in-vitro fungicidal activity against Candida krusei, Candida glabrata, Candida lusitaniae and Cryptococcus neoformans with MFCs in the range 0.39-6.25 mg/L. Both compounds 39 and 57 showed excellent in-vitro activity against fluconazole-resistant Candida albicans isolates, including a C. albicans strain that contains all known fluconazole-resistant mechanisms. Comparing MIC data from compounds 21, 39 and 57 with fluconazole, we found a statistically significant difference only with compound 39 (P = 0.043). However, comparing MFC data from compounds 21, 39 and 57 with fluconazole, we found statistically significant differences with all three compounds (P < 0.00001). These data indicate the potential antifungal breadth of two bis-benzimidazoles (compounds 39 and 57) as antifungal agents against yeasts. If it can be determined that compounds 39 and 57 are effective and non-toxic in vivo, the prospect of these compounds as clinically useful antifungal agents will be enhanced.  (+info)

Genotoxic activity of chlorohydroxyfuranones in the microscale micronucleus test on mouse lymphoma cells and the unscheduled DNA synthesis assay in rat hepatocytes. (18/1563)

Chlorohydroxyfuranones (CHFs) are mutagenic disinfection by-products found in chlorine-treated drinking water. In the current study, the genotoxicity of four CHFs, 3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA), 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF), 3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone (CMCF) and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), was determined. Two in vitro assays, the microscale micronucleus assay on L5178Y mouse lymphoma cells and the unscheduled DNA synthesis assay on a hepatocyte primary culture from Fisher F344 rats, were carried out. All four CHFs demonstrated genotoxic effects in both assays. In the two systems used, CMCF was the most genotoxic compound, followed by MCA, MX and MCF, respectively. This work was the first study of the DNA damaging properties of all four CHFs in two in vitro genotoxicity tests. These new data expand the range of genetic damages induced by this group of compounds.  (+info)

Dietary defatted sesame flour decreases susceptibility to oxidative stress in hypercholesterolemic rabbits. (19/1563)

Plant glucosides possess antioxidative properties due to their ability to scavenge free radicals. Sesame seeds contain a class of these compounds, the sesaminol glucosides. To evaluate their antioxidative activity in vivo, we fed rabbits diets containing 1% cholesterol (Chol) with or without 10% defatted sesame flour (DSF) (containing 1% sesaminol glucosides) for 90 d. We determined the susceptibility of their tissues to oxidation ex vivo as well as serum total cholesterol (TC), phospholipid (PL), triglyceride (TG) and HDL cholesterol (HDL-C) concentrations. Serum TC, HDL-C, PL and TG levels were unaffected by the addition of DSF. The HDL-C in the Chol + DSF group was greater than in the Chol group at 45 d. Both were greater than in the groups that did not consume cholesterol. Liver TC and TG were significantly lower in rabbits fed the diet containing DSF plus 1% cholesterol than in those fed 1% cholesterol alone. Lipid peroxidation activity, measured as 2-thiobarbituric acid reactive substances (TBARS), was lower in the liver (P < 0.05) and serum (P = 0.06) of rabbits fed DSF plus cholesterol than in rabbits fed the cholesterol diet. Although we did not detect sesaminol glucosides in peripheral tissues, we observed abundant quantities of sesaminol in rabbits fed DSF, the principal metabolite. Our findings suggest that feeding DSF to rabbits does not protect cholesterol-induced hypercholesterolemia, but may decrease susceptibility to oxidative stress in rabbits fed cholesterol, perhaps due to the antioxidative activity of sesaminol.  (+info)

The anticonvulsant effects of the enantiomers of losigamone. (20/1563)

1 Losigamone is a novel anticonvulsant undergoing phase III clinical trials in patients with partial and secondary generalized seizures. This study investigated the effects of the S(+)- and R(-)- enantiomers of losigamone on endogenous amino acid release from BALB/c mouse cortical slices, spontaneous depolarizations in the cortical wedge preparation of the DBA/2 mouse and audiogenic seizures in DBA/2 mice. 2 S(+)-losigamone (100 and 200 microM) significantly reduced both potassium- and veratridine-elicited release of glutamate and aspartate from cortical slices. R(-)-losigamone had no effect on release at concentrations up to 400 microM. 3 Cortical wedges exhibit spontaneous depolarizations when perfused with magnesium-free artificial cerebrospinal fluid. S(+)-losigamone significantly reduced these depolarizations at 50-200 microM whilst R(-)-losigamone had a significant effect at 200-800 microM. 4 DBA/2 mice are susceptible to audiogenic seizures and S(+)-losigamone dose-dependently (5, 10 and 20 mg kg-1, i.p.) significantly inhibited clonic/tonic convulsions with 91% of the mice protected at 20 mg kg-1. There was no protection at 20 mg kg-1 with R(-)-losigamone. 5 These results, from both in vitro and in vivo experiments, confirm that the pharmacological activity profiles of the two losigamone enantiomers are not identical and suggest further that excitatory amino acid-mediated processes are involved in the mode of action of S(+)-losigamone whereas R(-)-losigamone does not possess such properties. For the treatment of neurological conditions involving exaggerated excitatory amino acid function the use of S(+)-losigamone might therefore be more effective clinically than losigamone or its R(-)-enantiomer.  (+info)

Selective cyclo-oxygenase-2 inhibitors aggravate ischaemia-reperfusion injury in the rat stomach. (21/1563)

1. Effects of indomethacin, the selective cyclo-oxygenase (COX)-2 inhibitors NS-398 and DFU, and dexamethasone on gastric damage induced by 30 min ischaemia followed by 60 min reperfusion (I-R) were investigated in rats. Modulation of gastric levels of COX-1 and COX-2 mRNA by I-R was evaluated using Northern blot and reverse transcription-polymerase chain reaction. 2. I-R-induced gastric damage was dose-dependently aggravated by administration of indomethacin (1 - 10 mg kg(-1)), NS-398 (0.4 - 4 mg kg(-1)) or DFU (0.02 - 2 mg kg(-1)) as assessed macroscopically and histologically. 3. Likewise, administration of dexamethasone (1 mg kg(-1)) significantly increased I-R damage. 4. Low doses of 16, 16-dimethyl-prostaglandin(PG)E(2), that did not protect against ethanol-induced mucosal damage, reversed the effects of the selective COX-2 inhibitors, indomethacin and dexamethasone. 5. I-R had no effect on gastric COX-1 mRNA levels but increased COX-2 mRNA levels in a time-dependent manner. Dexamethasone inhibited the I-R-induced expression of COX-2 mRNA. 6. I-R was not associated with a measurable increase in gastric mucosal formation of 6-keto-PGF(1alpha) and PGE(2). PG formation was substantially inhibited by indomethacin (10 mg kg(-1)) but was not significantly reduced by NS-398 (4 mg kg(-1)), DFU (2 mg kg(-1)) or dexamethasone (1 mg kg(-1)). 7. The findings indicate that selective COX-2 inhibitors and dexamethasone markedly enhance gastric damage induced by I-R. Thus, whereas COX-2 has no essential role in the maintenance of gastric mucosal integrity under basal conditions, COX-2 is rapidly induced in a pro-ulcerogenic setting and contributes to mucosal defence by minimizing injury. This suggests that in certain situations selective COX-2 inhibitors may have gastrotoxic effects.  (+info)

Intradialytic removal of protein-bound uraemic toxins: role of solute characteristics and of dialyser membrane. (22/1563)

BACKGROUND: The efficiency of dialysis membranes is generally evaluated by assessing their capacity to remove small, water-soluble and non-protein-bound reference markers such as urea or creatinine. However, recent data suggest that protein-bound and/or lipophilic substances might be responsible for biochemical alterations characterizing the uraemic syndrome. METHODS: In the present study, the total concentrations of four uraemic retention compounds (indoxyl sulphate, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) and p-cresol) and of tryptophan, the only protein-bound amino acid and a precursor of indoxyl sulphate, were compared with those of urea and creatinine in pre- and post-dialysis serum and in dialysate of 10 patients; two high-flux (HF) membranes (cellulose triacetate (CTA) and polysulphone (PS)) and a low-flux polysulphone (LFPS) membrane were compared in a crossover design, using HPLC. RESULTS: Except for hippuric acid (67.3+/-17.5% decrease), major differences were found in the percentage removal of the classical uraemic markers on one hand (creatinine 66.6+/-7.0% and urea 75.5+/-5.8% decrease) and the studied protein-bound and/or lipophilic substances on the other (indoxyl sulphate, 35.4+/-15.3% and p-cresol 29.0+/-14.2% decrease; tryptophan, 27.5+/-40.3%, and CMPF, 22.4+/-17.5% increase; P<0.01 vs urea and creatinine in all cases). Hippuric acid removal was more pronounced than that of the remaining protein-bound compounds (P<0. 01). After correction for haemoconcentration, per cent increase of tryptophan and CMPF was less substantial, while per cent negative changes for the remaining compounds became more important. There was a correlation between creatinine and urea per cent removal at min 240 (r=0.51, P<0.01), but all the other compounds showed no significant correlation with either of these two. The three membranes were similar regarding the changes of total solute concentrations from the start to the end of dialysis. CONCLUSIONS: Urea and creatinine are far more efficiently removed than the other compounds under study, except for hippuric acid. There are no striking differences between the HF membranes. Moreover, compared with the LF membrane these HF membranes do not appear to be superior in removing the studied compounds.  (+info)

Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. (23/1563)

A biologically aggressive subset of human breast cancers and other malignancies is characterized by elevated fatty-acid synthase (FAS) enzyme expression, elevated fatty acid (FA) synthesis, and selective sensitivity to pharmacological inhibition of FAS activity by cerulenin or the novel compound C75. In this study, inhibition of FA synthesis at the physiologically regulated step of carboxylation of acetyl-CoA to malonyl-CoA by 5-(tetradecyloxy)-2-furoic acid (TOFA) was not cytotoxic to breast cancer cells in clonogenic assays. FAS inhibitors induced a rapid increase in intracellular malonyl-CoA to several fold above control levels, whereas TOFA reduced intracellular malonyl-CoA by 60%. Simultaneous exposure of breast cancer cells to TOFA and an FAS inhibitor resulted in significantly reduced cytotoxicity and apoptosis. Subcutaneous xenografts of MCF7 breast cancer cells in nude mice treated with C75 showed FA synthesis inhibition, apoptosis, and inhibition of tumor growth to less than 1/8 of control volumes, without comparable toxicity in normal tissues. The data suggest that differences in intermediary metabolism render tumor cells susceptible to toxic fluxes in malonyl-CoA, both in vitro and in vivo.  (+info)

Circumvention of tumor multidrug resistance by a new annonaceous acetogenin: atemoyacin-B. (24/1563)

AIM: To explore the effect of atemoyacin-B (Ate) on overcoming multidrug resistance (MDR). METHODS: Bullatacin (Bul) was used as a positive control. Cytotoxic effects of Bul and Ate were studied with cell culture of human MDR breast adenocarcinoma cells, MCF-7/Dox and human KBv200 cells, and their parental sensitive cell lines MCF-7 and KB. Cytotoxicity was determined by tetrazolium (MTT) assay. The function of P-glycoprotein (P-gp) was examined by Fura 2-AM assay. Cellular accumulation of doxorubicin (Dox) was determined by fluorescence spectrophotometry. Apoptosis was measured by flow cytometry. RESULTS: IC50 of Ate for MCF-7/Dox, MCF-7, KBv200, and KB cells were 122, 120, 1.34, and 1.27 nmol.L-1, respectively. IC50 of Bul for MCF-7/Dox, MCF-7, KBv200, and KB cells were 0.60, 0.59, 0.04, and 0.04 nmol.L-1, respectively. The cytotoxicities of Bul and Ate to MDR cells were similar to those to parental sensitive cells. Bul and Ate markedly increased cellular Fura-2 and Dox accumulation in MCF-7/Dox cells, but not in MCF-7 cells. The rates of apoptosis in MDR cells were similar to those in sensitive cells induced by Ate. CONCLUSION: There was no cross-resistance of P-gp positive MCF-7/Dox and KBv200 cell lines to Bul and Ate as compared with their sensitive P-gp negative MCF-7 and KB cell lines. The mechanism of the circumvention of MDR was associated with the decrease of P-gp function and the increase of cellular drug accumulation in MDR cells.  (+info)