Everolimus

Everolimus is a macrocyclic lactone used in transplantation medicine to prevent rejection after heart and kidney transplants. It has a high structural similarity to the actinomycete-derived tacrolimus, but is produced synthetically.

Everolimus belongs to the group of drugs called immunosuppressants. The active substance suppresses the immune response in a very specific way. Everolimus (like tacrolimus) binds with great affinity to a cytosolic receptor protein of T lymphocytes (FKBP). The resulting FKBP-everolimus complex inhibits the protein mTOR (mammalian target of rapamycin). As a key enzyme in the signal transduction of the IL-2 receptor, this kinase ensures a regulated cell cycle. The blockade of this signal transduction leads to an inhibition of the IL-2-controlled maturation and proliferation of T cells. The biological function of T cells and downstream of B cells are suppressed.

Also, proliferation processes in tumor cells, endothelial cells, fibroblasts and blood vessel-associated smooth muscle cells are suppressed.More generally, everolimus can be described as a "potent inhibitor of proliferation factors".

The mean half-life of everolimus is approximately 30.0 h.

Prophylaxis of graft rejection after kidney, heart or liver transplantation.

Advanced stages (under precisely described conditions in each case) of the following diseases:

• hormone receptor positive breast carcinoma
• neuroendocrine tumours of pancreatic origin and of lung or gastrointestinal origin
• gastrointestinal tract
• advanced renal cell carcinoma
• renal angiomyolipoma and a specific giant cell astrocytoma.

Mode of administration oral. Dosage usually 1 x 10 mg/day

Infections, anemia, angioedema, pneumonitis, stomatitis, proteinuria, renal failure (monitoring of renal function is recommended).

Other common side effects: loss of appetite, vomiting, weight loss, hyperglycemia, hypercholesterolemia, dehydration, hypokalemia, hypocalcemia, insomnia, headache, hypertension, dysphagia, dyspepsia, arthralgia, peripheral edema, fatigue.

Dermatological side effects: exanthema (including hand-foot syndrome); pruritus, nail changes, diffuse alopecia.

In many human tumors, the activity of "mTOR" is significantly increased.

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4. Sedrani, R. et al. (1998) Chemical modification of rapamycin: the discovery of SDZ RAD. Transplant Proc 30: 2192-2194 .