title: Stimulated response of peripheral lymphocytes may distinguish cyclosporine effect in renal transplant recipients receiving a cyclosporine+rapamycin regimen.
abstract: BACKGROUND
  Clinically, cyclosporine (CSA, Neoral) is titrated to concentrations, and not to pharmacological effect.
  
  
  METHODS
  Intracellular interleukin- (IL) 2 was measured in phorbol myristic acid-ionomycin-stimulated peripheral lymphocytes by flow cytometry, after isolation from 14 renal transplant recipients receiving CSA+prednisone, and double-blind rapamycin (rapamycin:placebo=4:1).
  
  
  RESULTS
  The proportion (%) of CD4+IL-2+ lymphocytes corresponding to CSA levels (mean+/-SD ng/ml) measured preoperatively (TO=O), and on postoperative day 8, before (356+/-63), and 2 hr after the morning dose (Cmax=1567+/-669), decreased from 39+/-16 to 15+/-8 and 3+/-1.6, respectively. Reciprocally, unresponsive lymphocytes (%CD4+IL-2-) increased with increasing CSA levels and predicted an EC50 of 249 ng/ml (CSA concentration at which CD4+IL-2- cells increased by 50% over baseline) in an Emax pharmacodynamic model.
  
  
  CONCLUSIONS
  Clinically, the pharmacological effect of CSA is quantifiable, and lies in the upper end of the predicted range. In our Neoral-treated sample population, Cmax was associated with the least variable "cyclosporine effect." Such information could potentially individualize immunosuppression, and lead to rational dosing strategies.
authors.affiliation: University of Pittsburgh Medical Center, PA 15213, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sindhi
authors.forename: M F
authors.initials: MF
authors.lastname: LaVia
authors.forename: E
authors.initials: E
authors.lastname: Paulling
authors.forename: J
authors.initials: J
authors.lastname: McMichael
authors.forename: G
authors.initials: G
authors.lastname: Burckart
authors.forename: S
authors.initials: S
authors.lastname: Shaw
authors.forename: L A
authors.initials: LA
authors.lastname: Sindhi
authors.forename: R
authors.initials: R
authors.lastname: Livingston
authors.forename: S
authors.initials: S
authors.lastname: Sehgal
authors.forename: J
authors.initials: J
authors.lastname: Jaffe
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016572:Cyclosporine / Q000008:administration & dosage*; D004311:Double-Blind Method; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation; D008213:Lymphocyte Activation; D020123:Sirolimus / Q000008:administration & dosage*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus