Anti-Trypanosoma cruzi effects of cyclosporin A derivatives: possible role of a P-glycoprotein and parasite cyclophilins.

Cyclophilins are target molecules for cyclosporin A (CsA), an immunosuppressive antimicrobial drug. We have previously reported the in vitro anti-Trypanosoma cruzi activity of H-7-94 and F-7-62 non-immunosuppressive CsA analogues. In this work, we continue the study of the parasiticidal effect of H-7-94 and F-7-62 CsA analogues in vitro and in vivo and we analyse 3 new CsA derivatives: MeIle-4-CsA (NIM 811), MeVal-4-CsA (MeVal-4) and D-MeAla-3-EtVal-4-CsA, (EtVal-4). The most efficient anti-T. cruzi effect was observed with H-7-94, F-7-62 and MeVal-4 CsA analogues evidenced as inhibition of epimastigote proliferation, trypomastigote penetration, intracellular amastigote development and in vivo T. cruzi infection. This trypanocidal activity could be due to inhibition of the peptidyl prolyl cis-trans isomerase activity on the T. cruzi recombinant cyclophilins tested. Furthermore, CsA and F-7-62 derivative inhibited the efflux of rhodamine 123 from T. cruzi epimastigotes, suggesting an interference with a P-glycoprotein activity. Moreover, H-7-94 and F-7-62 CsA analogues were not toxic as shown by cell viability and by aminopyrine-N-demethylase activity on mammalian cells. Our results show that H-7-94, F-7-62 and MeVal-4 CsA analogues expressed the highest inhibiting effects on T. cruzi, being promissory parasiticidal drugs worthy of further studies.

Monitorização terapêutica de ciclosporina em um grupo de pacientes transplantados reanis / Blood monitoring of cyclosporine in renal transplant patiens

A ciclosporina é um dos imunossupressores mais utilizados em transplantes. neste trabalho foram avaliados resultados das dosagens sangíneas de ciclosporina de pacientes transplantados renais atendidos pelo Laboratório de Toxicologia da Universidade Estadual de Maringá (UEM) em 2001. A monitorização compreendru dosagens em C0 (concentração anterior à ingestão da próxima dose) e C3 (concentração três horas após a ingestão do medicamento), por imunofluorescência polarizada. Infromações sobre sexo, idade, data de transplante e medicamentos utilizados, foram obtidas. 82% dos pacientes tinham entre 25-59 anos, com predominância do sexo masculino (68%). Cicliosporina-Neoral®, azatioprina e prednisona constituiu o esquema terapêutico mais utilizado (72%). em C0, 83,6% dos resultados apresentaram-se dentro, enquanto que em C3,62,4% mostraram-se acima da faixa terapêutica recomendada (100 a 400 ng/ml). Não houve relação entre C0 ou C3 e tempo de transplante ou tratamento imunossupressor. A monitorização terapêutica é fundamental para minimizar efeitos tóxicos ou mesmo a rejeição do rrgão transplantado...

Propuesta para investigacion de ciclosporina a alta diluciones como posibilidad homeoterapeutica en el S.I.D.A / Proposition to research of ciclosporine in high dilutions as possible homeopathic terapy in AIDS

Se ha hecho una investigacion toxicologica, revisando la farmacologia de la Ciclosporina, y comparandola con los sintomas de los enfermos de SIDA y de los portadores del HIV. El acomodo de los efectos secundarios de la droga aparecen por separado en sistemas y aparatos, asi como en su accion general. De acuedo com la ley de semejantes, el autor sugiere estudios con Ciclosporina preparada homeopaticamente, doble-ciego y aleatorios, para ser comparados contra un placebo, para posible tratamiento de enfermos con SIDA y portadores de HIV

Cyclosporin A in the oophorectomized rat: unexpected severe bone resorption.

Local factors, such as interleukin-1, may mediate the accelerated bone remodeling in the acute estrogen-deficient rat. Cyclosporin A (CsA), which in vitro inhibits some of these local factors, was administered to oophorectomized (OX) rats in an attempt to modify this high turnover state. Three groups of 15 rats were studied. Group A was sham operated, group B was OX, and group C was OX and received CsA (15 mg/kg per day) by gavage commencing 4 days postoophorectomy for 28 days. Estradiol levels were determined to confirm oophorectomy. Blood was sampled on days -7, 0, 7, 14, 21, and 28 for ionized calcium (Ca2+), 1,25-(OH)2-vitamin D, PTH, and bone gla protein (BGP). Rats received tetracycline hydrochloride for bone histomorphometric labeling. All results were compared to group A. Body weight was increased in group B (p less than 0.003) but not in group C. There was no difference in Ca2+ or PTH between the groups. BGP levels were higher in group B by day 28 (p less than 0.005); BGP levels were increased in group C from days 7-28 (p less than 0.002). 1,25-(OH)2-vitamin D was significantly increased in group C (p less than 0.0001) but not in group B. Tibial bone histomorphometry revealed increased measurements of bone formation and osteoclast number without a loss of bone volume (BV/TV) in group B. Group C showed a dramatic increase in bone turnover with significant loss of BV/TV (p less than 0.001). In conclusion, CsA in the OX rat resulted in unexpected enhanced bone remodeling with high BGP levels and severe bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of platelet-activating factor antagonist on cyclosporine nephrotoxicity. Glomerular hemodynamics evaluation.

In order to evaluate the effect of platelet-activating factor (PAF) antagonist BN 52021 (5 mg/kg i.v.) on cyclosporine (50 mg/kg i.v.) nephrotoxicity, euvolemic Munich-Wistar rats were submitted to micropuncture studies. BN 52021 alone did not change the total (1.08 +/- 0.07 vs. 1.04 +/- 0.06 ml/min) or single nephron (SN) (29.1 +/- 50 vs. 31.3 +/- 4.0 nl/min) and glomerular filtration rate. The CsA administration caused a decline on GFR (0.47 +/- 0.07 vs. 0.96 +/- 0.04 ml/min, P less than 0.05) and on SNGFR (14.0 +/- 3.5 vs. 27.9 +/- 3.4 ml/min, P less than 0.05). An increase in afferent (RA) and efferent (RE) arteriolar resistances, 180% and 360%, respectively, that caused a decrease on glomerular plasma flow rate (QA) from 100.99 +/- 17.09 to 44.37 +/- 13.37 nl/min (P less than 0.05) was observed. Moreover, the glomerular ultrafiltration coefficient (Kf) declined by 70% (0.096 +/- 0.003 to 0.031 +/- 0.10 ml/sec mmHg, P less than 0.05). The previous BN 52021 administration on rats treated with CsA blunted its effects on superficial nephrons. The SNGFR (22.3 +/- 3.0 vs. 28.0 +/- 25 nl/min), QA (72.2 +/- 5.9 vs. 91.7 +/- 12.1 nl/min) and KF (0.038 +/- 0.009 vs. 0.048 +/- 0.005 nl/s mmHg) remained unaltered. By contrast, the total renal function was not prevented by BN 52021 treatment: GFR 0.45 +/- 0.12 vs. 0.94 +/- 0.05 ml/min (P less than 0.05). Thus, this study suggests that PAF may participate in CsA nephrotoxicity. Furthermore, the protective effect of BN 52021 on superficial nephrons may indicate that BN 52021 is a drug that can minimize the impairment of renal function induced by CsA.