Basic cell physiological activities (cell adhesion, chemotaxis and proliferation) induced by selegiline and its derivatives in Mono Mac 6 human monocytes.

Selegiline (R-deprenyl), a monoamine oxidase-B (MAO-B) inhibitor, has complex pharmacological effect that contributes to treatment of neurodegenerative diseases such as Parkinson's and presumably Alzheimer's disease and might work as an inhibitor of tumor growth. In respect of tumorigenesis and metastasis formation, the controlled modifications of adhesion and migration have high therapeutic significance. In the present study, our purpose was to investigate cell physiological responses (adhesion, chemotaxis and proliferation) induced by selegiline, its metabolites and synthetic derivatives and to find some correlations between the molecular structure and the reported antitumor behavior of the derivatives. Our results demonstrated that both R- and S-deprenyls have the potency to elicit increased adhesion and a chemorepellent activity in monocyte model (Mono Mac 6 cell line derived from monoblastic leukemia); however, only the R-enantiomer proved to be cytotoxic. Among the metabolites R-amphetamine has retained the adhesion inducer and the chemorepellent effect of the parent drug on the most significant level. In contrast, a reversed chemotactic effect and an improved cytotoxic character were detected in the presence of fluoro group (p-fluoro-S-deprenyl). In summary, the adhesion inducer activity, chemorepellent and advantageous cytotoxic effects of selegiline and some derivatives indicate that these drug molecules might have inhibitory effects in metastasis formation in primary tumors.

Joint effects of cigarette smoking and irradiation in pregnant mice and their offspring.

BACKGROUND: We have previously reported that irradiation of mice in utero significantly increased the tumor incidence in the offspring of irradiated mothers. The joint effects of irradiation and cigarette smoking (CS) on tumor incidence and on the process of carcinogenesis were investigated. MATERIALS AND METHODS: Pregnant C57Bl/6J female mice were irradiated with a single dose of gamma-ray (1 Gy or 3 Gy) and/or exposed to CS of IR3 non-filtered cigarettes before or during pregnancy, tumors were investigated both with histological and immunohistochemical methods. RESULTS: Longer exposure (60 days) of the mice to CS before pregnancy and irradiation during pregnancy significantly increased the tumor incidence in the mothers and their offspring. Parallel activation of Caspase-8 and inactivation of Caspase-9 was found. CONCLUSION: Joint exposure of mice to prolonged CS before pregnancy and irradiation during pregnancy significantly increased the tumor incidence both in the mothers and their offspring.

Detection of N-monomethyl-lysine generated by metabolic transmethylation.

Administration of radiolabelled deprenyl to rats resulted in the urinary elimination of a (14)C-labelled N(epsilon)-monomethyl-lysine. An increased level of N(epsilon)-monomethyl-lysine was found following an oral dose of another drug, also containing an N-methyl group. The urine sample was treated with 9-fluorenylmethoxycarbonyl chloride and then subjected to high-performance liquid chromatography (HPLC); the radioactive fraction was identified as N(epsilon)-monomethyl-lysine by using HPLC-MS in electrospray mode. Identification of N(epsilon)-monomethyl-lysine in the radioactive fraction gives experimental proof of transmethylation from a well-known drug to an endogenous compound.

In vitro and in vivo activities of ciprofloxacin and levofloxacin against an SHV-5 extended-spectrum beta-lactamase-producing Klebsiella pneumoniae strain.

Activities of ciprofloxacin and levofloxacin against an SHV-5 extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae strain were studied in vitro and in vivo in septic mice using a high inoculum. Susceptibility to ciprofloxacin and levofloxacin was independent of the inoculum size. In killing curve studies, after 24 hours the initial 7.69 log10 CFU/ml increased in the control to 9.34, while it was reduced to 4.83 by ciprofloxacin and to 4.25 by levofloxacin. Mice were infected with 10(7) CFU/g of K. pneumoniae intraperitoneally. Treatment started 2 hours later, when the mean blood bacterial counts were 7.33 log10 CFU/ml, and lasted for 26 hours from the time of infection. Blood bacterial count was reduced from 7.33 log10 CFU/ml to 4.08 log10 CFU/ml by ciprofloxacin (20 mg/kg/6 hours), and to 3.60 log10 CFU/ml by levofloxacin (50 mg/kg/6 hours) 8 hours after the infection, which differed significantly from the infected untreated group. Ciprofloxacin and levofloxacin prolonged significantly the survival of mice compared with the infected untreated group (p<0.001 for both groups). There were not significant differences either in the survival (p=1.0) or in the blood bacterial counts (p=0.216 after 8 hours) between ciprofloxacin and levofloxacin group. Based on these results both ciprofloxacin and levofloxacin could be alternative therapeutic agents for the infection caused by ESBL-producing Klebsiella strains.

Studies of the side chain cleavage of deramciclane in rats with radiolabelled compounds.

The pharmacokinetics of deramciclane and especially the fate of its side chain were studied in rats after oral treatment, using (3)H- and (14)C-labelled (ring- or side chain labelled) deramciclane and (14)C-dimethylamino-ethanol ((14)C-DMAE) radioisomers. The labelled compounds were admixed and the total radioactivities of both labels were simultaneously determined. The data obtained from the analysis of the plasma concentration-time curves revealed that an intensive cleavage (30-40%) of the side chain occurred at the ether bond. The core of deramciclane, carrying the ring label, was almost completely eliminated during 24 h, while the elimination of the side chain was very slow (t(1/2)(beta): 99 h). The side chain residue most probably represents dimethylamino-ethanol, but the presence of dimethylglycine (DMG) cannot be excluded. The AUC(0-infinity) and the MRT values of DMAE were found to be much higher than those of the parent compound. In addition to the plasma levels, the time related changes of the tissue concentrations of the radioisomers of deramciclane were analysed both in the brain and the hypophysis. The concentration-time curves have shown similar characteristics to those of the plasma, but higher concentrations were reached in both organs (the highest in the hypophysis). It is postulated that the low rate of formation and elimination of the metabolite(s) (DMAE or DMG) indicates that, due to their endogenous nature, they can be incorporated into choline/acetylcholine or protein synthesis.