Sirolimus

Sirolimus is a natural immunosuppressive agent, which was won from the Actinomyces species "Streptomyces hygroscopicus". Streptomyces hygroscopicus was isolated from a soil sample of Easter Island (Rapa Nui) about 25 years ago. Hence the name Rapamycin.

Sirolimus is a complex macrolide antibiotic (macrocyclic lactone) with the molecular formula C51H79N13; it is related to Tacrolimus.

Sirolimus has been approved Europe-wide since March 2001 for the prophylaxis of organ rejection in adult patients with a slightly to medium increased immunological risk who receive a kidney transplant. Thereby a multi-stage therapy scheme under supervision of an appropriately qualified transplantation specialist is prescribed.

For children and elderly persons (over 65 years of age) there is insufficient data available. No dose adjustment is required for renal dysfunction; in the case of liver dysfunction, the control should be even more closely monitored and the dose adjusted accordingly.

Sirolimus inhibits the proliferation of T cells and thus suppresses the T cell-mediated rejection reactions. In contrast to Ciclosporin A and Tacrolimus, Sirolimus unfolds its T-cell suppressing effects by another, calcineurin-independent mechanism. After uptake into the cell a binding to an immunophilin is also effected, namely to the same protein as tacrolimus (the intracellular FK-binding protein FKBP 12).

However, the resulting complex does not inhibit the phosphatase calcineurin but another kinase(mTOR = mammalian target of rapamycin). After activation by interleukin-(IL)-2, mTOR enables the transition from the late G1- to the S-phase of the cell replication cycle and thus the proliferation of T-cells. Since not the interleukin production itself but a later signal transduction is inhibited, other effects such as IL-2-mediated apoptosis are preserved.

Transplant rejection reactions

A possible application is also being considered for autoimmune diseases. In a European study Sirolimus plus subtherapeutic Ciclosporin proved to be as effective as higher dosed Ciclosporin alone in 150 psoriasis patients, whereas a more favourable side effect profile was observed especially regarding the kidney function.

Promising approaches with Sirolimus have been published several times in the case of the caposiform hemangiendothelioma as well as in the therapy-resistant Kasabach-Merritt-Syndrome.

By means of Sirolimus and Everolimus clinical effects could be achieved in different types of hemangioendothelioma and therapy resistant Kasabach-Merritt-Syndrome. Tumors that occur in "Tuberous Sclerosis" could be achieved with Sirolimus and Everolimus.

The most significant side effects in practice are disturbances of lipid and cholesterol metabolism (hyperlipidemia), which occur in about half of all patients. Often an accompanying medication with statins or fibrates is therefore necessary if the values do not drop to a normal level by themselves after a few months. A dose reduction of Sirolimus should rather be avoided. Due to the immunosuppression higher susceptibility to infections (especially urinary tract infections) up to sepsis and an increased risk for malignant syndromes, especially lymphomas and skin cancer, are observed.

1. Technical information Rapamune, Wyeth Europe. Status March 2001.
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6. Takano A et al (2001) Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin. Mol Cell Biol 15: 5050 - 5062.
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8. Reitamo S et al (20019 Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial. Br J Dermatol 145: 438 - 445.
9. Johnson R W et al (2001) Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. J Transplantation 72: 777 - 786.
10. MacKeigan JP et al (2015) Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex. Neuro Oncol 17:1550-1559.
11. Tan X et al (2018) Successful management of steroid-resistant vascular tumors associated with the Kasabach-Merritt phenomenon using sirolimus. J Dermatol doi: 10.1111/1346-8138.14231.