Aromatic antiepileptic drugs and mitochondrial toxicity: Effects on mitochondria isolated from rat liver

Idiosyncratic hepatotoxicity is a well-known complication associated with aromatic antiepileptic drugs (AAED), and it has been suggested to occur due to the accumulation of toxic arene oxide metabolites. Although there is clear evidence of the participation of an immune process, a direct toxic effect involving mitochondria dysfunction is also possible. The effects of AAED on mitochondrial function have not been studied yet. Therefore, we investigated, in vitro, the cytotoxic mechanism of carbamazepine (CB), phenytoin (PT) and phenobarbital (PB), unaltered and bioactivated, in the hepatic mitochondrial function. The murine hepatic microsomal system was used to produce the anticonvulsant metabolites. All the bioactivated drugs (CB-B, PB-B, PT-B) affected mitochondrial function causing decrease in state three respiration, RCR, ATP synthesis and membrane potential, increase in state four respiration as well as impairment of Ca(2+) uptake/release and inhibition of calcium-induced swelling. As an unaltered drug, only PB, was able to affect mitochondrial respiration (except state four respiration) ATP synthesis and membrane potential; however, Ca(2+) uptake/release as well as swelling induction were not affected. The potential to induce mitochondrial dysfunction was PT-B > PB-B > CB-B > PB. Results suggest the involvement of mitochondrial toxicity in the pathogenesis of AAED-induced hepatotoxicity. (C) 2008 Elsevier Ltd. All rights reserved.

Cytotoxicity of monocrotaline in isolated rat hepatocytes: Effects of dithiothreitol and fructose

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Mendelian inheritance, linkage and genotypic disequilibrium in microsatellite loci isolated from Hymenaea courbaril (Leguminosae)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Effect of non-steroidal anti-inflammatory drugs (NSAID) on the histamine release induced by compound 48/80 and cardiac anaphylaxis in guinea-pig isolated heart

Histamine release from guinea pig heart treated with compound 48/80 was potentiated by the cyclooxygenase inhibitors indomethacin and piroxicam but not by aspirin or phenylbutazone. This differential effect suggests that the potentiation is not merely due to an inhibition of prostaglandin synthesis. Piroxicam potentiated the histamine release induced by cardiac anaphylaxis whereas indomethacin reduced this effect. The SRS-A antagonist FPL 55712 inhibited histamine release induced by cardiac anaphylaxis, but not that evoked by compound 48/80, and also prevented the potentiation due to indomethacin and piroxicam. In total, these data suggest that the potentiation of histamine release by piroxicam and indomethacin is probably due to a diversion of arachidonic acid metabolism from the cyclooxygenase to the lipoxygenase pathways. The resulting lipoxygenase products may then regulate histamine release, with the secretion due to antigen being more sensitive to such modulation than that evoked by compound 48/80.

Study of the contraction induced by norepinephrine and clonidine in the isolated guinea-pig ileum

Norepinephrine (NE) and clonidine produce a phasic, dose-dependent contraction of the isolated guinea-pig terminal ileum. The effect of NE was blocked by prazosin which produced a parallel rightward shift of the concentration-effect curve to NE, with a significant depression of maximum effects. Yohimbine and indomethacin noncompetitively blocked, whereas practolol potentiated, the contractile effect of NE. The contractile effect of clonidine was not antagonized by indomethacin or atropine. These results suggest that the isolated guinea-pig terminal ileum has excitatory receptors sensitive to clonidine stimulation and excitatory alpha receptors sensitive to blockade by prazosin, and that the activation of the latter may be related to the activation of endogenous prostaglandin synthesis.

Comparative mechanical study of isolated papillary muscle from Wistar-Kyoto and Wistar rats

Isolated papillary muscles have often been used in myocardial mechanical function studies. The objective of the present study was to compare the mechanical function of papillary muscle isolated from left ventricle between Wistar (W) and Wistar-Kyoto (WKY) rats of different ages (1, 3, 6 and 12 months), in order to examine whether there is a difference in intrinsic mechanical properties of muscle between the two rat strains. Muscles were perfused with Krebs-Henseleit solution at 28°C and studied isometrically and isotonically at a stimulation rate of 0.2 Hz. The W and WKY showed statistically significant differences during both isometric and isotonic contractions. During isometric contraction? (l) the peak developed tension (DT) and + dT/dt were lower in WKY rats in the 1 mo groups, (2) the resting tension (RT) was greater in WKY at 3, 6 and 12 mo. (3) time to peak tension (TPT) was greater in WKY at 3 and 12 mo, (4) time for tension to fall from peak to 50% of peak tension (RT 1/2) was greater in WKY at 3 mo and (5) - dT/dt was lower in WKY at 1 and 3 mo. During isotonic contraction, (1) the peak shortening (PS) and -dL/dt were lower in WKY at 12 mo, (2) the time to peak shortening (TPS) was greater in WKY at 3 and 12 mo; (3) + dL/dt was lower in WKY at 3, 6, and 12 mo and (4) the relative variation of length (Lmax-PS)/Lmax was greater in WKY at 6 and 12 mo. These data showed a difference in mechanical behaviour of the papillary muscle between Wistar and Wistar-Kyoto rats of different age.

Crystallization and preliminary X-ray analysis of SIII-SPIII, a ahospholipase A2 isolated from the venom of Bothrops jararacussu

Large single crystals have been obtained of SIII-SPIII, a phospholipase A2 from the venom of Bothrops jararacussu. The crystals belong to the orthorhombic system space group C222, and diffract X-rays to a resolution of 1.9 Å. Preliminary analysis reveals the presence of one molecule in the crystallographic asymmetric unit. The crystal structure is currently being determined using molecular replacement techniques.

Prevalence and in vitro antifungal susceptibility of Candida spp isolated from clinical specimens in São Paulo, Brazil

We examined the prevalence and the in vitro susceptibility to antifungal drugs of Candida spp isolated from clinical specimens at our university hospital in São Paulo, Brazil. Among 6,417 samples studied, positive cultures, were obtained from 222 (3.5%) most of them (68%) from the pediatric unit and nursery. Candida albicans and Candida parapsilosis were the most frequent species and the susceptibility patterns of a panel of 130 isolates to amphotericin B, ketoconazole and fluconazole. showed that the order of antifungal efficacy was amphotericin B > ketoconazole > fluconazole.

Re-evaluation of antibiotic and mercury resistance in Escherichia coli populations isolated in 1978 from Amazonian rubber tree tappers and Indians

A study was carried out to assess the stability of antimicrobial susceptibility of wild isolates upon long-term storage using fifty-three Escherichia coli strains isolated in 1978 from feces of healthy children from the Amazon region in Brazil, exposed to low levels of antimicrobial agents, and examined for resistance to mercury and four antibiotics. All of the strains were kept in Lignieres medium at room temperature and were transferred to fresh media four times during this period. Thirty-five out of the 53 strains analyzed in 1978 were viable. Upon recovery, antibiotic and mercury resistance was estimated. All of the 35 strains maintained their original phenotype in a stable fashion, except for one multiresistant strain which became susceptible to kanamycin. Fifty-four percent of the strains exhibited a resistance phenotype, among which 47% had conjugative plasmids.

Long-term nitric oxide inhibition and chronotropic responses in rat isolated right atria

The long-term administration of nitric oxide synthesis inhibitors induces arterial hypertension accompanied by left ventricular hypertrophy and myocardial ischemic lesions. Because the enhancement of sympathetic drive has been implicated in these phenomena, the current study was performed to determine the potency of β-adrenoceptor agonists and muscarinic agonists on the spontaneous rate of isolated right atria from rats given long-term treatment with the nitric oxide inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME). Atrial lesions induced by long-term treatment with L-NAME were also evaluated. Long-term L-NAME treatment caused a time-dependent, significant (P<0.05) increase in tail-cuff pressure compared with control animals. Our results showed that the potency of isoproterenol, norepinephrine, carbachol, and pilocarpine in isolated right atria from rats given long-term treatment with L-NAME for 7, 15, 30, and 60 days was not affected as compared with control animals. Addition of L-NAME in vitro (100 μmol/L) affected neither basal rate nor chronotropic response for isoproterenol and norepinephrine in rat heart. Stereological analysis of the right atria at 15 and 30 days revealed a significant increase on amount of fibrous tissues in L-NAME- treated groups (27±2.3% and 28±1.3% for 15 and 30 days, respectively; P<0.05) as compared with the control group (22±1.1%). Our results indicate that nitric oxide does not to interfere with β-adrenoceptor-mediated and muscarinic receptor-mediated chronotropic responses.