Sirolimus

• SRL
• Rapamycin

L04AA10

Immunosuppressants

> 2500 mg · kg -1 ( LD50, mouse, oral)

Template: Infobox chemical / molecular formula search available

Sirolimus ( SRL, rapamycin) is an immunosuppressive macrolide having ( macrocyclic lactone ) and was isolated from the streptomycetes Streptomyces hygroscopicus. This bacterial strain was first found in the soil of the island of Rapa Nui (Easter Island), therefore, the substance also has the name rapamycin. Sirolimus and tacrolimus are mutually related substances, but these were isolated from different streptomycetes and also have different mechanisms of action.

Applications

Sirolimus is usually used in kidney transplant patients in combination with ciclosporin and corticosteroids for the prevention of organ rejection. As one of the major side effects wound healing disorder is mentioned. In contrast to cyclosporine or tacrolimus, sirolimus also is not nephrotoxic, so it does not contribute to chronic allograft.

In cardiology, the anti- proliferative effects of sirolimus be used to prevent re- narrowing ( restenosis ) of the vessel intima hyperplasia after stent implantation in the coronary arteries. With sirolimus -eluting stents in several studies show the formation of less restenosis compared to conventional metal stent. However, there is the risk of stent thrombosis, as sirolimus prevents the formation of neointima and thus start over a longer period platelets to the stent and may occlude the stent.

Due to its anti-proliferative effects on cells rapamycin also moved into the focus of anti-tumor therapy, since it can presumably inhibit growth and neovascularization of certain tumors.

Extension of the life span

In a study from 2009, the life span of mice could be extended by 28-38 % from the start of treatment, representing an overall extension of the maximum life expectancy by 9-14 %. It is worth noting also that the treated mice were already 20 months old, which corresponds to a human age of about 60 years. Because of the strong immunosuppressive effect - and the associated side effects - of rapamycin transfer of the results to humans is generally not possible without further notice.

Potential for the treatment of Alzheimer's disease

In an animal model mouse rapamycin shows a potentially positive effect against the symptoms of Alzheimer 's disease. It is believed that the effect occurs by the inhibition of mTOR. Increased deposits of β -amyloid obviously lead to increased expression of mTOR, while, conversely, the concentration of β -amyloid appears to be reduced by inhibition of mTOR by rapamycin. The mTOR signaling pathway plays a central role in the regulation of protein homeostasis.

Mechanism of Action

SRL has a different mechanism of action than ciclosporin and tacrolimus. SRL inhibits a number of cytokine -mediated signal transduction pathways by complexation with the protein mTOR (mammalian target of rapamycin, such as "The aim of rapamycin in mammals "), a 282 -kDa serine / threonine kinase. Thus, the subsequent activation and subsequent protein synthesis of S6 kinase ( p70SK6 ) remains, and remains under the activation of ribosomal protein S6., Inhibition of mTOR prevents the activation of p34cdc2 kinase, and thus the complex with cyclin E. This has the consequence that both the activation as well as the progression of T- cells from the G1 - phase is prevented from entering the S phase of the cell cycle.

Trade names

Rapamune ®, manufactured by Pfizer