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At least 523 records · Page 29Linked to original sources
PubMed1996

Effect of vinconate, an indolonaphthyridine derivative, on dopamine and serotonin concentrations in dialysate from the striatum of freely moving rats: brain microdialysis studies.

The effect of (+/-)-methyl 3-ethyl-2,3,3a, 4-tetrahydro-1H-indolo[3,2,1-de][1,5]naphthyridine -6-carboxylate monohydrochloride (vinconate), an indolonaphthyridine derivative, on dopamine and serotonin concentrations in dialysate from the striatum of freely moving rats was examined by brain microdialysis. Twenty-minute samples collected were used to determine dopamine and serotonin by high-performance liquid chromatography in a single run. The basal extracellular levels of dopamine and serotonin were 41.12 +/- 5.04 and 10.41 +/- 1.71 (fmol/20 min), respectively. Dopamine concentrations in dialysate were significantly increased after a single treatment with vinconate (50-200 mg/kg p.o.). Tetrodotoxin (10 microM) added into the dialysis perfusate decreased dopamine concentrations in dialysate and vinconate had no effect on dopamine concentrations in dialysate when administered after tetrodotoxin. The vinconate-induced increase in dialysate dopamine concentrations was significantly reduced by scopolamine (1 microM) and N0434 (1 microM), respectively. Moreover, daily treatment with vinconate (25 mg/kg p.o.) for 7 days resulted in enhanced dopamine and serotonin concentrations in dialysate induced by subsequent vinconate treatment. These findings suggest that vinconate administered systemically can enhance dialysate dopamine concentrations and this effect may be related to the muscarinic receptor and the dopamine D2 receptor. The present findings also suggest that repeated treatment with vinconate may augment these effects of vinconate on dopamine and serotonin concentrations in dialysate from the brain.

Animals↗
PubMedDate not supplied

Inhibition of tumor growth and polyamine uptake by tetracyclic amidines bearing a putrescine moiety.

Tetracyclic amidines (tetrahydroquino[4.3-b][l]benzazepine: compound 11 and tetrahydrobenzo[k]naphthyridine: compound 12) bearing a putrescine moiety possess significant DNA-binding affinity. We report here that these compounds and their a and b isomers inhibit tumor cell growth and putrescine uptake in 3LL carcinoma cells in vitro. Moreover, compound 11 reduced by 50% the accumulation of putrescine in intestinal brush border membrane vesicles. In CHO-MG, a cell line deficient for the specific polyamine uptake system, the cytotoxicity of these compounds was significantly reduced compared to the CHO wild cell line. The IC50 for CHO-MG was significantly higher than for CHO, demonstrating that the polyamine transport system increased the efficacy of these compounds. The efficacy of compounds 11 and 12 might therefore be related to their ability to interact with DNA as well as their structural analogy with polyamines. Moreover, we clearly show that DFMO enhances the efficacy of these tetracyclic amidines in vivo. Potential mechanisms include: a) lower intracellular polyamine levels reduces polyamine DNA-stabilizing functions, increasing accessibility for DNA-binding drugs; b) DFMO enhances the polyamine uptake system in tumor cells, increasing the entry of tetracyclic amidines bearing a putrescine moiety as well as their accessibility to final DNA-binding sites. The fact that natural polyamine uptake is reduced by the same compounds constitutes an additive mechanism for antitumoral efficiency.

Amidines↗
PubMed1998

Fluoroquinolone antimicrobials: singlet oxygen, superoxide and phototoxicity.

The fluoroquinolone antibacterial agents possess photosensitizing properties that lead to phototoxic responses in both human and animal subjects. The phototoxicity order reported in humans is: fleroxacin > lomefloxacin, pefloxacin >> ciprofloxacin > enoxacin, norfloxacin and ofloxacin. Studies both in vivo and in vitro have related this phototoxicity to the generation of reactive oxygen species including hydrogen peroxide and the hydroxyl radical. We determined the quantum yields of singlet oxygen generation (phi delta) by detection of the singlet oxygen (1O2) luminescence at 1270 nm for several fluoroquinolones, naphthyridines and other structurally related compounds. All the fluoroquinolones examined have low phi delta values ranging from 0.06 to 0.09 in phosphate buffer at pD 7.5. We also determined the 1O2 quenching constants for these compounds and their values were on the order of 10(6) M-1 s-1, except for lomefloxacin whose rate constant was 1.8 x 10(7) M-1 s-1. The phi delta values were significantly decreased in a solvent of lower polarity such as methanol (0.007 < or = phi delta < or = 0.02). The production of 1O2 by these antibiotics did not correlate with the order reported for their phototoxicity. We also measured the photogeneration (lambda > 300 nm) of superoxide by these antibacterials in dimethylsulfoxide using electron paramagnetic resonance and the spin trap 5,5-dimethyl-1-pyrroline N-oxide. Although there is not a one-to-one correspondence between the relative rates of superoxide generation and the phototoxicity ranking of the fluoroquinolones, the more phototoxic compounds tended to produce superoxide at a faster rate. Nevertheless, the magnitudes of the observed differences do not appear sufficient to explain the range of fluoroquinolone phototoxicity potencies in human and animal subjects in general and the high activity of fleroxacin and lomefloxacin in particular. For these latter drugs the photoinduced loss of the F8 atom as fluoride and the concomitant generation of a highly reactive carbene at C-8 provide a more plausible mechanism for their potent phototoxic and photocarcinogenic properties.

Animals↗
PubMed1998

Molecular mechanism of photosensitization. XI. Membrane damage and DNA cleavage photoinduced by enoxacin.

The photosensitizing activity of enoxacin, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)- 1,8-naphthyridine-3-carboxilic acid (ENX), toward membranes and DNA has been studied, taking into account human erythrocyte photohemolysis, unilamellar liposome alterations and plasmid pBR322 DNA photocleavage. Hydroxyl radicals and an aromatic carbene generated from ENX photodefluorination seem to be the active intermediates involved in the photosensitization process. The steady-state photolysis products do not participate in the process. The mechanism of photosensitization responsible for the membrane damage depends on the oxygen concentration and follows a different path with respect to that operative for DNA cleavage. Between oxygenated radicals, the hydroxyl seems the species mainly responsible for membrane damage, whereas DNA cleavage is mainly produced by the carbene intermediate. A molecular mechanism of the photosensitization induced by ENX is proposed.

DNA↗