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Single I.p. Injection (single + i.p._injection)
Selected AbstractsInteractions between N,acetylcysteine and sodium selenite in modulating the clastogenicity of urethane and 2,acetylaminofluorene in miceINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Roumen M. Balansky Abstract Combined treatment with different agents represents a promising approach in cancer chemoprevention. Therefore, it is useful to assess in preclinical models the efficacy of combinations that are selected by taking into account mechanistic considerations. We designed 2 studies evaluating the interaction between N,acetylcysteine (NAC) and sodium selenite (Se), both given with the drinking water to Balb/c mice, in modulating clastogenic effects in bone marrow polychromatic erythrocytes. In a first study, a single i.p. injection of urethane considerably enhanced the frequency of micronucleated cells. While NAC produced a significant inhibition, Se further enhanced urethane clastogenicity. When given in combination at the same doses, NAC prevented the adverse effect of Se. In a second study, a single i.p. injection of 2,acetylaminofluorene enhanced the frequency of micronucleated cells. Se did not reduce this effect to a significant extent, while NAC produced a dose,dependent inhibition. When tested at the lower dose in combination with Se, the protective effect of NAC was unchanged. Especially in association with Se, NAC also prevented the toxicity of 2,acetylaminofluorene by normalizing the ratio of polychromatic to normochromatic erythrocytes. In conclusion, NAC attenuated the clastogenicity of both urethane and 2,acetylaminofluorene and the toxicity of this aromatic amine. In addition, NAC prevented the clastogenic and toxic effects resulting from the interaction of Se with urethane. Together with the findings of previous studies, it appears that, besides its intrinsic protective properties in carcinogenesis, NAC is capable of attenuating the adverse effects of several cytotoxic drugs and chemopreventive agents. © 2003 Wiley-Liss, Inc. [source] Diazoxide, a KATP opener, accelerates restitution of ethanol or indomethacin-induced gastric ulceration in rats independent of polyaminesJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2001M Rahgozar Abstract Background and Aims: Experimental acute gastric ulcerations (EAGU) are healed very rapidly. This healing process has two steps; mucosal restitution and delayed repair. Adenosine 5,-triphosphate (ATP)-dependent potassium channels (KATP) have a regulatory role in the gastrointestinal physiology. In the present study, the effects of KATP channel modulators; diazoxide (channel opener) and glibenclamide (channel antagonist) on the healing of EAGU were investigated. The effect of polyamine (mediators presumably responsible for restitution) biosynthesis by difluoromethylornithine (DFMO) on diazoxide-induced alterations, and the effects of acid secretion inhibitors (cimetidine, omeprazole and atropine) on the mucosal restitution of EAGU were also studied. Methods: Groups of 10 male rats were starved for 24 h and EAGU was induced by oral administration of 1 mL 60% ethanol or a subcutaneous injection of 30 mg/kg indomethacin. Different groups were subjected to various doses of diazoxide (5, 15, 45 mg/kg) and/or glibenclamide (2, 6, 18 mg/kg) administered intraperitoneally (i.p.) after EAGU induction. Polyamine biosynthesis was inhibited by a single i.p. injection of DFMO (500 mg/kg), administered 10 min before EAGU induction. Cimetidine, omeprazole or atropine were administered intraperitoneally at doses of 200, 5 and 1 mg/kg, respectively, after EAGU induction. Animals were killed and their gastric mucosa was examined for ulcerations. Results: Diazoxide accelerated the healing of EAGU, whereas glibenclamide aggravated EAGU. The concomitant administration of glibenclamide antagonized the diaoxide effect. Diazoxide-induced acceleration of mucosal restitution was not abolished by DFMO. Cimetidine, omeprazole and atropine had no effect on the healing of EAGU. Conclusion: The KATP channels may play an important role in the gastric mucosal restitution independent of polyamines. Acid inhibition cannot reverse EAGU. [source] Anticonvulsant activity, teratogenicity and pharmacokinetics of novel valproyltaurinamide derivatives in miceBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Nina Isoherranen The purpose of this study was to synthesize novel valproyltaurine (VTA) derivatives including valproyltaurinamide (VTD), N -methyl-valproyltaurinamide (M-VTD), N,N -dimethyl-valproyltaurinamide (DM-VTD) and N -isopropyl-valproyltaurinamide (I-VTD) and evaluate their structure,pharmacokinetic,pharmacodynamic relationships with respect to anticonvulsant activity and teratogenic potential. However, their hepatotoxic potential could not be evaluated. The metabolism and pharmacokinetics of these derivatives in mice were also studied. VTA lacked anticonvulsant activity, but VTD, DM-VTD and I-VTD possessed anticonvulsant activity in the Frings audiogenic seizure susceptible mice (ED50 values of 52, 134 and 126 mg kg,1, respectively). VTA did not have any adverse effect on the reproductive outcome in the Swiss Vancouver/Fnn mice following a single i.p. injection of 600 mg kg,1 on gestational day (GD) 8.5. VTD (600 mg kg,1 at GD 8.5) produced an increase in embryolethality, but unlike valproic acid, it did not induce congenital malformations. DM-VTD and I-VTD (600 mg kg,1 at GD 8.5) produced a significant increase in the incidence of gross malformations. The incidence of birth defects increased when the length of the alkyl substituent or the degree of N -alkylation increased. In mice, N-alkylated VTDs underwent metabolic N-dealkylation to VTD. DM-VTD was first biotransformed to M-VTD and subsequently to VTD. I-VTD's fraction metabolized to VTD was 29%. The observed metabolic pathways suggest that active metabolites may contribute to the anticonvulsant activity of the N-alkylated VTDs and reactive intermediates may be formed during their metabolism. In mice, VTD had five to 10 times lower clearance (CL), and three times longer half-life than I-VTD and DM-VTD, making it a more attractive compound than DM-VTD and I-VTD for further development. VTD's extent of brain penetration was only half that observed for the N-alkylated taurinamides suggesting that it has a higher intrinsic activity that DM-VTD and I-VTD. In conclusion, from this series of compounds, although VTD caused embryolethality, this compound emerged as the most promising new antiepileptic drug, having a preclinical spectrum characterized by the highest anticonvulsant potential, lowest potential for teratogenicity and favorable pharmacokinetics. British Journal of Pharmacology (2003) 139, 755,764. doi:10.1038/sj.bjp.0705301 [source] 1,,25-Dihydroxyvitamin D3 inhibits rat liver ultrastructural changes and the development of ,-glutamyltranspeptidase-positive foci in diethylnitrosamine-initiated and streptozotocin-induced diabetes-promoted hepatocarcinogenesisCELL BIOCHEMISTRY AND FUNCTION, Issue 3 2002Barun Kanti Saha Abstract In the present study, the chemopreventive effect of the active metabolite of vitamin D, 1,,25-dihydroxyvitamin D3 (VD3), against chemically-induced and diabetes-promoted rat liver carcinogenesis was investigated. Hepatocarcinogenesis was initiated with a single intraperitoneal (i.p.) injection of diethylnitrosamine (DEN) (125 mg kg,1 body weight) at week 4 followed by promotion with streptozotocin (STZ) (65 mg kg,1 body weight with a single i.p. injection) at week 7. With this basic experimental regimen, the effect of VD3 (0.3 ,g (0.1 ml),1 propylene glycol per os twice a week) was investigated with effect from 4 weeks prior to the exposure of DEN. The results showed that VD3 supplementation throughout the experimental period reduced the incidence, total number and multiplicity and altered the size of visible persistent nodules (PNs) in DEN- or DEN,+,STZ-treated rats as compared with their respective controls. In these two groups, it also caused a significant decrease in the number (p,<,0.002 and 0.001 respectively) and focal area (p,<,0.05) of ,-glutamyltranspeptidase (GGT)-positive hepatic foci. Moreover, continuous supplementation of VD3 exhibits a protective effect in maintaining the normal cellular architecture of the hepatocytes in DEN- or DEN,+,STZ-treated rats. Our results thus strongly suggest that VD3 is very effective in the inhibition of DEN-initiated and STZ-induced diabetes-promoted rat liver carcinogenesis. Copyright © 2002 John Wiley & Sons, Ltd. [source] | ||||||||||