Prolonged survival of renal transplants in nonimmunized and hyperimmunized rats receiving a platelet-activating factor antagonist.
A potent platelet-activating factor (PAF) antagonist, RP 48740, was tested for its ability to delay acute and accelerated rejection in experimental kidney transplantation. Lewis rats (RT1(1] either nonimmunized or preimmunized against Brown Norway (BN) antigens, received allogeneic kidney transplants from BN rats (RT1n) and were bilaterally nephrectomized. Survival of transplanted animals was observed following oral treatment with RP 48740 (100 mg/kg/day). Control animals received orally methylcellulose 5% (placebo), cyclosporine (10 mg/kg/day), or CsA (10 mg/kg/day) plus RP 48740 (100 mg/kg/day). CsA prolonged rat survival in both rejection models. RP 48740 induced prolongation of survival in preimmunized rats and, to a lesser but significant degree, in nonimmunized animals. Although treatment with CsA plus RP 48740 was efficient in acute rejection, it induced no significant increase of survival in preimmunized rats as compared with placebo, indicating a lack of potentiating activities between the two compounds. The pharmacokinetic study of CsA showed that this lack of efficacy of combined treatment may be interpreted as the decreased CsA bioavailability observed when the animals also received RP 48740. The demonstration that a PAF antagonist delays accelerated rejection sheds some light on the biological effects of hyperimmunization in transplantation and on the possible therapeutic approaches.
Freiche
J C
JC
Transplantation and Immunobiology Unit, INSERM U80, CNRS URA 1177, Hôpital E. Herriot, Lyon, France.
Lang
J
J
Sedivy
P
P
Touraine
J L
JL
D000818:Animals; D003524:Cyclosporins / Q000493:pharmacokinetics; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection / Q000187:drug effects; D007114:Immunization; D016030:Kidney Transplantation / Q000401:mortality*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D015996:Survival Rate; D013844:Thiazoles / Q000494:pharmacology*
D003524:Cyclosporins; D010972:Platelet Activating Factor; D011725:Pyridines; D013844:Thiazoles; C052520:3-(3-pyridinyl)-1H,3H-pyrrolo(1,2-c)thiazole-7-carboxamide