Navegando por Palavras-chave "cyclosporin A"
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- ItemSomente MetadadadosCyclosporin A tubular effects contribute to nephrotoxicity: role for Ca2+ and Mg2+ ions(Oxford Univ Press, 2003-11-01) Costa, Maristela Carvalho da; Castro, Isac de; Cuvello Neto, Américo L; Ferreira, Alice T. [UNIFESP]; Burdmann, Emmanuel A.; Yu, Luis; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP); Sao Jose do Rio Preto Med SchBackground. Cyclosporin A (CsA) nephrotoxicity has been attributed primarily to renal haemodynamic alterations caused by afferent arteriolar vasoconstriction. However, CsA nephropathy is also characterized by CsA-induced pre-glomerular disturbances and interstitial injury that may occur independently of haemodynamic changes. Given the high lipophilic activity of CsA, we hypothesized that direct tubular injury is likely to contribute to nephrotoxicity.Methods. To investigate tubular toxicity of CsA, increasing concentrations of CsA (1, 2.5, 10, 25, 50 and 100 mug/ml) and its vehicle (cremophor) were added to isolated rat proximal tubules (PT). Cell injury was assessed by lactate dehydrogenase (LDH) release. the role of Ca2+ ions in tubular toxicity and the effect of calcium channel blockers on CsA toxicity were evaluated by measuring intracellular calcium using the fluorescent dye Fura-2 AM. the role of Mg2+ ions was assessed using high extracellular Mg2+ medium (2 in M).Results. Whereas cremophor alone was not toxic to PT, CsA caused PT injury but only at the highest concentration (100 mug/ml). After 90 min incubation, LDH was 22.5% in control PT and 41.9% in PT treated with 100 mug/ml CsA (P < 0.001, n = 11). There was a transient increase in intracellular calcium ([Ca2+]i) after CsA administration. A low calcium medium (100 nM) prevented CsA injury to renal tubules. However, verapamil, but not nifedipine, enhanced cell damage. Only nifedipine completely prevented [Ca 21]i increases following CsA. Finally, a high Mg2+ medium attenuated CsA-induced injury.Conclusion. We found that high CsA concentrations caused Ca2+- and Mg2+-dependent PT injury. Thus, low extracellular Ca2+ and high Mg2+ media attenuated CsA-induced tubular injury. Verapamil, but not nifedipine, enhanced CsA tubular toxicity. Therefore, CsA-induced tubular injury may contribute to CsA nephrotoxicity independently of haemodynamic disturbances.
- ItemSomente MetadadadosEffect of cyclosporin A on nitric oxide production in cultured LLC-PK1 cells(Marcel Dekker Inc, 2001-01-01) Lima, R.; Serone, A. P.; Schor, N.; Higa, EMS; Universidade Federal de São Paulo (UNIFESP)The effect of Cyclosporin A on nitric oxide production was studied in cultured LLC- PK1 cells. for this purpose the cells were incubated with vehicle (olive oil, 10 mug/ml in DMSO), Cyclosporin A (CsA, 10 mug/ml), tumor necrosis factor (TNF-alpha, 150 U/ml) + interferon (IFN-gamma, 500 U/ml) to upregulate NOS synthesis, and therefore, NO production (used as a positive control), or CsA + TNF-alpha + IFN-gamma. After 72 hours the culture medium was collected and nitrite was determined by the Griess method. the results were normalized to the protein harvested from these cells as measured by the Lowry method. Viability was determined by the exclusion of the fluorescent dyes (acridine orange and ethidium bromide). Intracellular calcium was measured spectrophotometrically using the fluorescent calcium indicator fura-2 AM. in CsA treated cells, the nitrite (pmoles/mg of protein) was decreased when compared to control (12.8 +/- 0.5 vs. 18.3 +/- 0.6; p < 0.05; both n = 8). TNF- + IFN-gamma increased the nitrite synthesis (52.0 +/- 0.2; p < 0.05 vs. control; n = 6). This effect was decreased significantly by the simultaneous treatment with CsA (38.8 +/- 0.3; p < 0.05; n = 6). Cell viability in CsA group was decreased when compared to the cdntrol (84.7 +/- 0.2% vs. 93.6 +/- 0,1%; p < 0.05: both n = 10). TNF- +/- IFN-gamma had no effect on viability (93.0 +/- 0.3%; n = 10). However, when combined with CsA, viability was decreased relative to the control (85.0 +/- 0.2%; p < 0.05; n = 10). Acute (1 h) or chronic (72 h) treatment of LLC- PK1 cells with CsA had no effect on basal calcium levels.Our results demonstrate a reduced level of nitric oxide production in LLC- PK1 cells treated with CsA. There was no effect of the drug on intracellular calcium levels, however CsA treatment did reduce cellular viability. We suggest that, in part, the decreased levels of NO production are a secondary consequence of direct cell damage. However, CsA may also be exerting direct effects on NO synthesis through its interactions with both iNOS and cNOS. These results also provide a dual mechanism of action for CsA induced nephrotoxicity, that is, direct cell damage and interference with the NO system within the nephron.
- ItemSomente MetadadadosStudy of acute chagasic mice under immunosuppressive therapy by cyclosporin A: modulation and confocal analysis of inflammatory reaction(Elsevier B.V., 2000-04-01) Calabrese, K. S.; Paradela, ASRC; Valle, T. Z. do; Tedesco, R. C.; Silva, S.; Mortara, R. A.; Costa, SCG da; Ist Oswaldo Cruz; Universidade Federal de São Paulo (UNIFESP)The in vivo effects of cyclosporin A (CsA) on Trypanosoma cruzi infection were examined using different schedules of the drug in mice infected with the Y strain. Parasitaemia at day 8 after infection among CsA-treated animals was usually higher than control infected non-treated mice. On the other hand, mortality analysis showed that animals CsA-treated either with 200 mg/kg 2 days before infection or with therapeutic doses (10 mg/kg every other day) showed almost the same mean time of death (35.8 and 38.2 days, respectively). in these groups mice died 50% less than control infected non-treated ones. the mean time of death in the animals treated with 200 mg/kg 5 days after infection and in infected non-treated control mice were respectively 29.0 and 22.6 days. the kinetics analysis of the leukocyte population of animals treated with a single dose of 200 mg/kg of CsA before or after infection did not show the alternate pattern of leukopenia/leukocytosis observed in control groups of infected mice but differential cell counts indicated a modulatory action upon circulating leukocytes of therapeutic doses of CsA. the animals treated with any of the CsA schedules showed a moderate to intense diffuse inflammatory reaction exhibiting mainly mononuclear cells in the heart. Immunofluorescence analysis by confocal microscopy revealed that macrophages are a major component of the inflammatory infiltrate in all groups of CsA-treated mice and also in the control group. (C) 2000 Elsevier Science B.V. All rights reserved.