T Hirano1, T Akashi, T Keira, K Oka, N Ihoya, M Yoshida. 1. Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan. hiranot@ps.toyaku.ac.jp
Abstract
BACKGROUND: Cellular pharmacodynamics of cyclosporine (INN, cyclosporin) is considered to be closely implicated in clinical efficacy of the drug in kidney transplantation and other immunologic disorders. We applied this strategy to patients with minimal change nephrotic syndrome to predict individual clinical efficacy of cyclosporine. METHODS: Drug sensitivity tests were carried out with peripheral blood mononuclear cells from 31 patients with minimal change nephrotic syndrome. The 50% lymphocyte-mitosis inhibition of cyclosporine on in vitro blastogenesis of peripheral blood mononuclear cells stimulated with concanavalin A were estimated, and interpatient variations of 50% lymphocyte-mitosis inhibition were evaluated. The relationship between cyclosporine-50% lymphocyte-mitosis inhibition and clinical outcomes indicated a decrease of urinary protein and the period required for complete remission under cyclosporine therapy was examined in 14 patients. We also evaluated the correlation between cyclosporine-50% lymphocyte-mitosis inhibition and interleukin-2 production and percentages of interleukin 2 receptor-positive peripheral blood mononuclear cells in vitro. RESULTS: Cyclosporine 50% lymphocyte-mitosis inhibition on peripheral blood mononuclear cell blastogenesis deviated largely between patients from 0.2 to 86.0 ng/mL. We found a statistically significant negative correlation between cyclosporine-50% lymphocyte-mitosis inhibition in vitro and decreasing rates of urinary protein at 1 week after onset of cyclosporine administration (r = -0.655, P < .02). When we arbitrarily divide the 14 patients who received cyclosporine therapy according to their median 50% lymphocyte-mitosis inhibition of cyclosporine into two groups, that is, a high-sensitivity group (50% lymphocyte-mitosis inhibition < 18.1 ng/mL, n = 6) and a low-sensitivity group (50% lymphocytemitosis inhibition > 18.1 ng/mL, n = 8), the period required for complete remission was significantly shorter in the high-sensitivity group (P < .03). The 50% lymphocyte-mitosis inhibition of cyclosporine on interleukin-2 production in culture medium was correlated with 50% lymphocyte-mitosis inhibition of the drug on peripheral blood mononuclear cell blastogenesis (r = 0.806, P < .02). Decreasing rates of interleukin-2R-positive cells by cyclosporine treatment in vitro were negatively correlated with peripheral blood mononuclear cells blastogenesis in the presence of the drug (r = -0.694, P < .02). CONCLUSIONS: Peripheral blood mononuclear cell response to cyclosporine in vitro is closely related to clinical efficacy of the drug in minimal change nephrotic syndrome. Peripheral blood mononuclear cell resistance to cyclosporine was correlated with ability of the cells to express interleukin 2 and interleukin 2R.
BACKGROUND: Cellular pharmacodynamics of cyclosporine (INN, cyclosporin) is considered to be closely implicated in clinical efficacy of the drug in kidney transplantation and other immunologic disorders. We applied this strategy to patients with minimal change nephrotic syndrome to predict individual clinical efficacy of cyclosporine. METHODS: Drug sensitivity tests were carried out with peripheral blood mononuclear cells from 31 patients with minimal change nephrotic syndrome. The 50% lymphocyte-mitosis inhibition of cyclosporine on in vitro blastogenesis of peripheral blood mononuclear cells stimulated with concanavalin A were estimated, and interpatient variations of 50% lymphocyte-mitosis inhibition were evaluated. The relationship between cyclosporine-50% lymphocyte-mitosis inhibition and clinical outcomes indicated a decrease of urinary protein and the period required for complete remission under cyclosporine therapy was examined in 14 patients. We also evaluated the correlation between cyclosporine-50% lymphocyte-mitosis inhibition and interleukin-2 production and percentages of interleukin 2 receptor-positive peripheral blood mononuclear cells in vitro. RESULTS:Cyclosporine 50% lymphocyte-mitosis inhibition on peripheral blood mononuclear cell blastogenesis deviated largely between patients from 0.2 to 86.0 ng/mL. We found a statistically significant negative correlation between cyclosporine-50% lymphocyte-mitosis inhibition in vitro and decreasing rates of urinary protein at 1 week after onset of cyclosporine administration (r = -0.655, P < .02). When we arbitrarily divide the 14 patients who received cyclosporine therapy according to their median 50% lymphocyte-mitosis inhibition of cyclosporine into two groups, that is, a high-sensitivity group (50% lymphocyte-mitosis inhibition < 18.1 ng/mL, n = 6) and a low-sensitivity group (50% lymphocytemitosis inhibition > 18.1 ng/mL, n = 8), the period required for complete remission was significantly shorter in the high-sensitivity group (P < .03). The 50% lymphocyte-mitosis inhibition of cyclosporine on interleukin-2 production in culture medium was correlated with 50% lymphocyte-mitosis inhibition of the drug on peripheral blood mononuclear cell blastogenesis (r = 0.806, P < .02). Decreasing rates of interleukin-2R-positive cells by cyclosporine treatment in vitro were negatively correlated with peripheral blood mononuclear cells blastogenesis in the presence of the drug (r = -0.694, P < .02). CONCLUSIONS: Peripheral blood mononuclear cell response to cyclosporine in vitro is closely related to clinical efficacy of the drug in minimal change nephrotic syndrome. Peripheral blood mononuclear cell resistance to cyclosporine was correlated with ability of the cells to express interleukin 2 and interleukin 2R.