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Rapamycin is a macrulide anfihiutic that inferferes with fhe infracellular s¡gnalling pathways uf fhe IL-2 dependent clonal expansion of activated J ymphucvtes (Figure 1). Rapamycin is currently in phase III clinical trials and promises impruved uufcumes. It shuws pufenf immunosuppressive action aud, mure impurfanfly, it has a differenf mede nf action fu fhaf nf eifher cyclospohn A or FTY 720. Because uf fhis difference, ¡fis likely, and has heen demonstrated in animais, fnaf rapamvcrn cari acf synergistically wifh cycluspurin A. It fhis hulds true in humans, clinicians mav achieve impruveo immunosuppressiun mifh reduced side-effecfs uue fu fhe use uf luwer doses. Moreuver, rapamycin may have snme pofenfial ter fhe prevenfion of chrunic rejection, a hallmark of which is vascular remudelling invulving the pruliferafion and migrafiun nf vascular smooth muscle celís, Rapamycin is directly ahie tu irihihrf fhis proliferafion. Jhe principal side-effecfs nf the agent fhaf need turfher research are fhrumhucyfopenia and hvperfrrglyceridaemia.
"The advent of
rapamycin and RAD
The Novartis approach has been fo develop a chemically derived mure hydruphilic rapamycin analog, RAD, mhich may shom less exfensive fissue dísfribufion. A largo battery uf ¡u vitre assavs comparing rapamycin and RAU has shuwn RAU fu he 2-2 times less active. Bumever, RAU is enuipufent mith rapamycin lo animal modeis of allofransplanfafion and aufoimmuno diseasos using comparable oral formulafions. The synergism botween RAU and Neural has also heen shown. Henk Schuurman (Nuvartis, Smitzerland( showed fhaf rat luug fransplanfs fol lomed up for 21 days demonstrafed a svnergisfic action uf Neural and RAD lo prevonfing rejoction, with four ouf of seven animais nuf shuming any rejectiun, aud three animais shoming ouly minimal sigus of rejectiun. This mas a considerahle improvement over Neural alune lo this animal mudel. There seems fu he a syuergy uf Neural aud RAU le lung franspíanfafion studies lo cynomolgus monkeys. Bernard Hausen (Sfanfurd, USA) presonfed a study shoming, for fhe first time, fhaf combined therapy mifh Neural arid RAU can significantly irupruve graff uufcume lo a cynomolgus monkoy lung transpíanfation modol. Unilateral long franspíanfatiun lo MLR mismafchod, Uuod-gruup identical munkeys mas perfurmed. Urafts mere follumed op for 28 days. Fxperimeofal grojps cuosisfed uf unfreated cuntruis, Neural monothorapy, aud cumhined freafment mifh RAU aud Neoral. Ihe incidence of moderato ur severe rejectiun mas significanfly lomer lo fhe cumhioeu freafmonf groeps rehon compared fu fhe fmo munufhorapy control groups. Umen Cole (Nottingham, UK) said fhat theorefically RAU should be effective againsf the smoofh muscle celímigratiun fhat causes intimal thickening lo fransplanf arteriosclerosis, arid thaf this effecf shuuld he independent uf the aefiulugy uf vascular damage. lo asfudv, fho effect of RAU un fhe infimal fhickoning of rafaortas lo fhe rat aorfic mudel of transplaof arteriosclerosis mas investigafed. It mas shumn fhaf RAU has a significant effect lo reducing toe develupmenf uf chrunic rejectiun-liko foafures lo this mude (Figure 2). TUis may have cíloical implicatiuns furlong-ferm graft survival Farly evidence uf fhe potenfial of RAU lo humaus mas presenfod af fhe rineefing. Haus Helruuf Neumayer (Berlin, Uermany( presented fhe firsf Eurupean clinical sfudv mifh a muglo duse uf RAU given tu sfable renal fransplanf recipienfs. Fiffy-fuur patienfs, aged 29-66 years, un sfahle Neural duses uf 1 UU-4tiUmglday, received RAU ur placeho.
"FTY 720 offers some advantages to the clinician over every agent currently used"
There were only mild to moderate adverse events, with no clinically signiticant changes in vital signs or laboratory parameters, RAD was quickly absorbed at all dose levels. The area-under-the-curve pharmacokinetics results with RAD were dose-proportional in the range 2.5-25 mg. The elimination halt-life tor this dose range averaged 24-20 hours, in contrast to rapamycin, which is about 65 hours. Steady state pharmacokinetics ot cyclosporin A were not attected by RAD. In a phase I multiple dose randomised hlloded trial using 0.75,2.5 or 7.Smg RA0 or placebo, good dose proportionality of pharmacokinetic parameters, similar toxicities to rapamycin and no new or unexpected toxicities have been observed by our group in Houston.
FTY 720 (Figure 2) has a unique mechanism ot action. Unlike any other drug in
development, it acts hy attecting lymphocyte tratticking. Selichi Suzuki (Tokyo, Japan)
was the tirst to show that its major ettect was the marked reduction of the oriwber of
lymphocytes in the peripheral blood. The agent produces lymphodepletion, with emigration
of cells to lymph nodes and Peyer's patches, hut with no eftect on the number of
circulating neutrophils or monocytes, a property which would theretore be expected to keep
host resistance intact. The agent otters some advantages to the clinician over every agent
currently used. A large role tor the agent in transplantation ot the pancreas can be
predicted as, unlike FK 506, cyclosporin A and rapawycin, it is not toxic to islets. A
number ot pre-clinical models have shown it to reduce rejection and it appears to act
synergistically with Neural and with rapamycin (and presumably RAD). Novartis reported
that phase I clinical trials will commence shortly. Stan Stepkowski (Houston, USA)
reported that FTY 720 alone blocks allogratt rejection when delivered immediately
post-transplant or as rescue therapy. A combination ot FTY 720 with cyclosporin A or
sirolimus synergistically blocks the T cell immune response in vifro and prolongs
allogratt survival in vivo.
Suzuki observed that FTY 720 induces lymphocyte apoptosis 10 vivO in rats and reverses ongoing rejection ot rat liver allogratts. The graft survival time ot the 15 recipients treated with FTY 720 was significantly prolonged to 24.1 days in comparison with the control group survival, which was 11.8 days. AccorOing to Hiron Nakajima (Kyoto, Japan) FTY 720 sign iticantly inhiOlts the expression ot intragratt cytotoxic molecules in rat heart transplants. They concluded toat FTY 720 exerts its immunosuppressive effect by inducing apoptosis on intragratt killer lymphocytes or inhibiting their expression ot cytotoxic molecules. Chiba trow Yeshitowi believes that the agent attects the expression of adhesionmolecules on the lymphocyte surtace. The three new iwniunosuppressive agents represent a considerable step towards achieving the goals ot selectivity and synergy.