FTY720: A new kid on the block for transplant immunosuppression.
FTY720, a synthetic analogue of myriocin (ISP-1), is derived from culture filtrates of the fungus Isaria sinclairii. As a sphingosine analogue, FTY720 appears to undergo phosphorylation and thereby interact with specific G-protein-linked receptors. In vivo, FTY720 causes emigration of lymphocytes from peripheral blood to secondary lymphoid structures. Thus, the drug is the archetype of a new class of agents that alter cellular homing patterns: the adhesion-migration paradigm. Since FTY720 seems to spare nonspecific elements of host resistance, it may address the not infrequent complications of infections associated with existing therapies. In experimental rodent, canine and non-human primate models, FTY720 produces lymphopenia and immunosuppression, prolonging the survival of allografts. Because of synergistic interactions, it promotes the immunosuppressive effects not only of calcineurin antagonists, but also of proliferation signal inhibitors. These interactions proffer the possibility of large reductions in exposure to and mitigated toxicity of existing drugs. In humans, FTY720 causes dose-dependent peripheral blood lymphopenia, a reduced incidence of acute rejection episodes and only one apparent adverse reaction - a negative chronotropic effect - particularly after the loading dose. While the clinical utility of FTY720 is difficult to predict before completion of Phase III studies that elucidate its benefits versus unanticipated side effects, the initial data suggest several potential advantages: it does not produce hyperlipidaemia, diabetes mellitus, nephrotoxicity, neurotoxicity or myelosuppression, which are characteristic of other immunosuppressants. Furthermore, it displays high oral bioavailability and a low interindividual coefficient of variation. Clearly, structural analogues, as well as other agents that alter the balance of chemokines or affect cellular adhesion to activated endothelium, will represent important components of future regimens.
Aki
Fazil Tuncay
FT
The University of Texas Medical School at Houston, Department of Surgery, Suite 6.240, 6431 Fannin, Houston, TX 77030, USA.
Kahan
Barry D
BD
D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004285:Dogs; D004359:Drug Therapy, Combination; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007239:Infections / Q000276:immunology; D051379:Mice; D011323:Primates; D011409:Propylene Glycols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control; D013110:Sphingosine / Q000031:analogs & derivatives; D014181:Transplantation Immunology; D014183:Transplantation, Heterologous / Q000276:immunology
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine