Сиролимус: Қолданылуы мен қасиеттері

Pharmaceutical drug

Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumor (PEComa). The compound was originally named rapamycin after the native name of the island, Rapa Nui. Hyftor was approved for treatment of facial angiofibroma in the European Union in May 2023.

Sirolimus is indicated for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis (LAM). In the EU, sirolimus, as Rapamune, is indicated for the prophylaxis of organ rejection in adults at low to moderate immunological risk receiving a renal transplant In 2009, the FDA notified healthcare professionals that a clinical trial conducted by Wyeth showed an increased mortality in stable liver transplant patients after switching from a calcineurin inhibitor based immunosuppressive regimen to sirolimus. A 2019 cohort study of nearly 10,000 lung transplant recipients in the US demonstrated significantly improved long term survival using sirolimus + tacrolimus instead of mycophenolate mofetil + tacrolimus for immunosuppressive therapy starting at one year after transplant. Sirolimus can also be used alone, or in conjunction with a calcineurin inhibitor (such as tacrolimus), and/or mycophenolate mofetil, to provide steroid free immunosuppression regimens. Impaired wound healing and thrombocytopenia are possible side effects of sirolimus; therefore, some transplant centers prefer not to use it immediately after the transplant operation, but instead administer it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and it remains the subject of a number of ongoing clinical trials.

In May 2015, the FDA approved sirolimus to treat lymphangioleiomyomatosis (LAM), a rare, progressive lung disease that primarily affects women of childbearing age. This made sirolimus the first drug approved to treat this disease. While sirolimus was considered for treatment of LAM, it received orphan drug designation status because LAM is a rare condition. However, this kind of stent may also increase the risk of vascular thrombosis.

Sirolimus is used to treat vascular malformations. Treatment with sirolimus can decrease pain and the fullness of vascular malformations, improve coagulation levels, and slow the growth of abnormal lymphatic vessels. Sirolimus is a relatively new medical therapy for the treatment of vascular malformations in recent years, sirolimus has emerged as a new medical treatment option for both vascular tumors and vascular malformations, as a mammalian target of rapamycin (mTOR), capable of integrating signals from the PI3K/AKT pathway to coordinate proper cell growth and proliferation. Hence, sirolimus is ideal for "proliferative" vascular tumors through the control of tissue overgrowth disorders caused by inappropriate activation of the PI3K/AKT/mTOR pathway as an antiproliferative agent.

Sirolimus has been used as a topical treatment of angiofibromas with tuberous sclerosis complex (TSC). Facial angiofibromas occur in 80% of patients with TSC, and the condition is very disfiguring. A retrospective review of English language medical publications reporting on topical sirolimus treatment of facial angiofibromas found sixteen separate studies with positive patient outcomes after using the drug. The reports involved a total of 84 patients, and improvement was observed in 94% of subjects, especially if treatment began during the early stages of the disease. Sirolimus treatment was applied in several different formulations (ointment, gel, solution, and cream), ranging from 0.003 to 1% concentrations. Reported adverse effects included one case of perioral dermatitis, one case of cephalea, and four cases of irritation. In April 2022, sirolimus was approved by the FDA for treating angiofibromas.

The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis in individuals with kidney transplants include: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia. This includes decreased glucose tolerance and insensitivity to insulin. In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus.

Lung toxicity is a serious complication associated with sirolimus therapy, especially in the case of lung transplants. The mechanism of the interstitial pneumonitis caused by sirolimus and other macrolide MTOR inhibitors is unclear, and may have nothing to do with the mTOR pathway. The interstitial pneumonitis is not dose dependent, but is more common in patients with underlying lung disease.

There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections.

Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a body mass index in excess of 30 kg/m2 (classified as obese).

The biosynthesis of the rapamycin core is accomplished by a type I polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three multienzymes, RapA, RapB, and RapC, which contain a total of 14 modules (figure 1). The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the biosynthesis of the linear polyketide are in RapC. Then, the linear polyketide is modified by the NRPS, RapP, which attaches L pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, prerapamycin. The core macrocycle, prerapamycin (figure 2), is then modified (figure 3) by an additional five enzymes, which lead to the final product, rapamycin. First, the core macrocycle is modified by RapI, SAM dependent O methyltransferase (MTase), which O methylates at C39. Next, a carbonyl is installed at C9 by RapJ, a cytochrome P 450 monooxygenases (P 450). Then, RapM, another MTase, O methylates at C16. Finally, RapN, another P 450, installs a hydroxyl at C27 immediately followed by O methylation by Rap Q, a distinct MTase, at C27 to yield rapamycin. The biosynthetic genes responsible for rapamycin synthesis have been identified. As expected, three extremely large open reading frames (ORF's) designated as rapA, rapB, and rapC encode for three extremely large and complex multienzymes, RapA, RapB, and RapC, respectively. The gene rapP, which is embedded between the PKS genes and translationally coupled to rapC, encodes for an additional enzyme, an NPRS responsible for incorporating L pipecolic acid, chain termination and cyclization of prerapamycin. In addition, genes rapI, rapJ, rapM, rapN, rapO, and rapQ have been identified as coding for tailoring enzymes that modify the macrocyclic core to give rapamycin (figure 3). Finally, rapG and rapH have been identified to code for enzymes that have a positive regulatory role in the preparation of rapamycin through the control of rapamycin PKS gene expression. Biosynthesis of this 31 membered macrocycle begins as the loading domain is primed with the starter unit, 4,5 dihydroxocyclohex 1 ene carboxylic acid, which is derived from the shikimate pathway. or otherwise promote tumor regression in clinical trials. Sirolimus seems to lower the cancer risk in some transplant patients. Sirolimus was shown to inhibit the progression of dermal Kaposi's sarcoma in patients with renal transplants. Other mTOR inhibitors, such as temsirolimus (CCI 779) or everolimus (RAD001), are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma. However, these drugs have a higher rate of fatal adverse events in cancer patients than control drugs. A combination therapy of doxorubicin and sirolimus has been shown to drive Akt positive lymphomas into remission in mice. Akt signalling promotes cell survival in Akt positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs, such as doxorubicin or cyclophosphamide. Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy. Bcl 2 positive lymphomas were completely resistant to the therapy; eIF4E expressing lymphomas are not sensitive to sirolimus.

Sirolimus also shows promise in treating tuberous sclerosis complex (TSC), a congenital disorder that predisposes those afflicted to benign tumor growth in the brain, heart, kidneys, skin, and other organs. After several studies conclusively linked mTOR inhibitors to remission in TSC tumors, specifically subependymal giant cell astrocytomas in children and angiomyolipomas in adults, many US doctors began prescribing sirolimus (Wyeth's Rapamune) and everolimus (Novartis's RAD001) to TSC patients off label. Numerous clinical trials using both rapamycin analogs, involving both children and adults with TSC, are underway in the United States.

mTOR, specifically mTORC1, was first shown to be important in aging in 2003, in a study on worms; sirolimus was shown to inhibit and slow aging in worms, yeast, and flies, and then to improve the condition of mouse models of various diseases of aging. Sirolimus was first shown to extend lifespan in wild type mice in a study published by NIH investigators in 2009; the studies have been replicated in mice of many different genetic backgrounds. The results are further supported by the finding that genetically modified mice with impaired mTORC1 signalling live longer. This led to many in the anti aging community self experimenting with the compound. However, because of the different biochemical properties of Sirolimus the dosing is potentially very different than everolimus. Ultimately, due to known side effects of sirolimus, as well as inadequate evidence for optimal dosing, more research is required before sirolimus could be widely prescribed for this purpose. Sirolimus has complex effects on the immune system—while IL 12 goes up and IL 10 decreases, which suggests an immunostimulatory response, TNF and IL 6 are decreased, which suggests an immunosuppressive response. The duration of the inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but are not yet well understood.

When applied as a topical preparation, researchers showed that rapamycin can regenerate collagen and reverse clinical signs of aging in elderly patients. The concentrations are far lower than those used to treat angiofibromas.

Rapamycin has been proposed as a treatment for severe acute respiratory syndrome coronavirus 2 insofar as its immunosuppressive effects could prevent or reduce the cytokine storm seen in very serious cases of COVID 19. Moreover, inhibition of cell proliferation by rapamycin could reduce viral replication. Oxidized LDL cholesterol is a major contributor to atherosclerosis.

As of 2016, studies in cells, animals, and humans have suggested that mTOR activation as process underlying systemic lupus erythematosus and that inhibiting mTOR with rapamycin may be a disease modifying treatment. As of 2016 rapamycin had been tested in small clinical trials in people with lupus.

Due to its immunosuppressant activity, Rapamycin has been assessed as prophylaxis or treatment agent of Graft versus host disease (GVHD), a complication of hematopoietic stem cell transplantation. While contrasted results were obtained in clinical trials, pre clinical studies have shown that Rapamycin can mitigate GVHD by increasing the proliferation of regulatory T cells, inhibiting cytotoxic T cells and lowering the differentiation of effector T cells.

Rapamycin is used in biology research as an agent for chemically induced dimerization. In this application, rapamycin is added to cells expressing two fusion constructs, one of which contains the rapamycin binding FRB domain from mTOR and the other of which contains an FKBP domain. Each fusion protein also contains additional domains that are brought into proximity when rapamycin induces binding of FRB and FKBP. In this way, rapamycin can be used to control and study protein localization and interactions.

A number of veterinary medicine teaching hospitals are participating in a long term clinical study examining the effect of rapamycin on the longevity of dogs.