Side effects rapamycin

Rapamycin has been known for many years to possess immunosuppressive activity by interfering with the activation of B- and T-cells by interleukin-2. Indeed the first clinically approved indication for rapamycin was renal transplantation. Currently, rapamycin and RAD001 also show promise in liver transplantation and cardiac transplantation, respectively. Generally, treatment protocols utilize a combination of an mTORCl inhibitor, a calcineurin inhibitor and steroids to optimize immunosuppression and minimize nephrotoxicity and other side effects. Rapalogs are also... 

Rapamycin, also known as sirolimus, is a new macrolide antibiotic that interacts with cellcycle regulating proteins and inhibits cell division. The main side effects are thrombocytopenia and hyperlipidaemia. There is also evidence that it causes interstitial pneumonitis, which may resolve on withdrawing the drug or dose reduction. The drug is currently being assessed for combination therapy with tacrolimus or cyclosporin. 

The major classes of immunosuppressive drugs employed in clinical practice to avoid tissue rejection include calcineurin inhibitors, target of rapamycin (TOR) inhibitors, sphingosine-1 -phosphate receptor (S1P-R) modulators, cytotoxic agents, glucocorticoids and monoclonal antibodies. These drugs need to be used on a lifelong basis and have major undesirable side effects. 

In Phase II, a daily dose of 180mg of diltiazem was added—the diltiazem used together with oral rapamycin in renal transplant patients has been associated with high therapeutic blood concentration of rapamycin and lower side effects (I 1,12). (In Figure I we can see the study design and patient inclusion of both phases of this pilot study,)... 

As mentioned, due to the homology between mTOR and PI3K, many inhibitors will affect both enzymes. However, since mTOR is located downstream of PI3K it has been postulated that selective inhibition of mTOR may also lead to effective cancer therapeutics while minimizing the side effects associated with pan-PI3K inhibition. Selective mTOR inhibitors may be divided into two classes. The first class consists of the allosteric inhibitors derived from rapamycin, which selectively inhibit mTORCl by binding to FKBP12 and... 

However, some preliminary results show that rapamycin is also not devoid of side effects. The major toxicides associated with rapamycin treatment include thrombocytopenia and hyperlipidemia [23]. Nonetheless, it is of great interest that its action on lymphocytes is quite different from those of FK506 and CsA. FK506 and CsA mediate their inhibition of cytokine transcription early in the G, phase during T-cell activation, whereas rapamycin exhibits its inhibitory effects on the proliferation of T cells at the G/S transition of the cell cycle induced by cytokines. Thus, the events that are blocked by FK506/CsA and rapamycin are independent, but sequentially related in the signaling pathway that follows T-cell activation (Fig. 4) [24]. 

With the aim to overcome the excessive VSMC proliferation observed after BMS implantation, devices able to locally deliver antiproliferative drugs (drug-eluting stents [DESs]) have been developed (Figure 15.21). The most used antiproliferative drugs are sirolimus (Rapamycin ) and paclitaxel (Taxol ). The delivery of these antiproliferative drugs from DES reduces artery restenosis (down to 5%-10% of treated patients [211,212]) more efficiently than BMS. However, DESs did not completely solve the problem [213] as they can trigger unwanted side effects such as stent thrombosis (ST) and delayed restenosis compared to BMS [214,215]. 

Sirohmus and everolimus are new antiproliferative drugs that have successfully been used after liver and kidney transplantation. However, little data are available regarding the treatment of BOS with these therapies in lung transplantation. The available data suggests that addition of rapamycin may arrest the decline of FEVi and may, at least in some patients, improve the FEV] (47,48). In one recent study, everolimus seemed to prevent the decline in FEV], at least one year after the introduction, but this effect was lost in the next year later (49). TLI and ECP may also reduce the speed of FEV] decline, without producing major side effects (50,51). 

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