title: The peripheral lymphocyte count predicts graft survival in DA to Lewis heterotopic heart transplantation treated with FTY720 and SDZ RAD.
abstract: OBJECTIVE
  The new immunomodulator 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720) lowers the peripheral lymphocyte count (PLC) by inducing migration of circulating lymphocytes to secondary lymphoid organs. This effect is dose-dependent at low (up to 0.1 mg/kg per day) doses in rats. We investigated the correlation between PLC and the later rejection, when FTY720 was combined with RAD.
  
  
  METHODS
  Heterotopic cardiac grafting was performed using the DA-Lewis strain combination. FTY720 and RAD were administered as single daily doses by gavage alone and in combination starting 3 days before to 28 days after transplantation. Graft survival was monitored daily by palpation. PLC was determined at 1 and 4 weeks, body weight (BW) weekly. Histologic evaluation of grafted hearts was performed after rejection.
  
  
  RESULTS
  FTY720 at doses of 0.03, 0.1 and 0.3 mg/kg per day prolonged graft survival dose-dependently from 6 (placebo) to 7, 9.5 and 15 days median survival time (MST). RAD at doses of 0.3, 1 and 3 mg/kg per day delayed rejection to 8.5, 18 and 37.5 days MST. Very small FTY720 doses added to the lower RAD doses were effective in maintaining grafts throughout the treatment period and with normal weight gain, as opposed to regimens with 1 mg/kg or more per day RAD, which resulted in delayed weight gain. FTY720 lowered the PLC significantly and dose-dependently. The PLC correlated well with graft survival [Spearman rank correlation (n = 30, rs = -0.75)].
  
  
  CONCLUSIONS
  Fully effective FTY720 + RAD combination regimens caused no side effects with respect to the rats' general well-being or weight gain and were better tolerated than equiactive RAD monotherapy, suggesting a broader therapeutic window for the combinations. Under the experimental conditions, the PLC decrease showed an interesting correlation with the anti-rejection effects in these two-drug regimens. Thus, in rats the PLC is helpful for monitoring the biological activity of FTY720 at low doses (< 0.1 mg/kg per day), i.e. in the range of the steep part of its dose-response relationship.
authors.affiliation: Novartis Pharma Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Z
authors.initials: Z
authors.lastname: Nikolova
authors.forename: A
authors.initials: A
authors.lastname: Hof
authors.forename: Y
authors.initials: Y
authors.lastname: Baumlin
authors.forename: R P
authors.initials: RP
authors.lastname: Hof
mesh_terms: D000818:Animals; D001835:Body Weight; D004359:Drug Therapy, Combination; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018655:Lymphocyte Count; D008297:Male; D009206:Myocardium / Q000473:pathology; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013110:Sphingosine / Q000031:analogs & derivatives; D016042:Transplantation, Heterotopic
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D020123:Sirolimus