RAPAMYCIN

Product Description

Rapamycin, is amacrolidecompound that is used to coatcoronary stents, preventorgan transplant rejectionand treat a rare lung disease calledlymphangioleiomyomatosis. It hasimmunosuppressantfunctions in humans and is especially useful in preventing the rejection ofkidneytransplants. It inhibits activation ofT cellsandB cellsby reducing their sensitivity tointerleukin-2(IL-2) throughmTOR inhibition.It is produced by thebacteriumStreptomyces hygroscopicusand was isolated for the first time in 1972 bySurendra Nath Sehgaland colleagues from samples ofStreptomyces hygroscopicusfound onEaster Island. The compound was originally named rapamycin after the native name of the island, Rapa Nui. Sirolimus was initially developed as anantifungalagent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to itsability to inhibit mTOR. It was approved by the USFood and Drug Administrationin September 1999 and is marketed under the trade nameRapamunebyPfizer(formerly byWyeth).

Medical uses

Rapamycin is indicatedfor thepreventionoforgan transplant rejectionand for the treatment oflymphangioleiomyomatosis(LAM).

Prevention of transplant rejection

Sirolimus can also be used alone, or in conjunction with acalcineurin inhibitor(such astacrolimus), and/ormycophenolate mofetil, to provide steroid-free immunosuppression regimens. Impaired wound healing andthrombocytopeniaare a 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.

Lymphangioleiomyomatosis

On 28 May 2015, the FDA approved Rapamycin 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.LAM involves lung tissue infiltration withsmooth muscle-like cells with mutations of thetuberous sclerosis complexgene (TSC2). Loss of TSC2 gene function activates themTORsignaling pathway, resulting in the release of lymphangiogenicgrowth factors. Sirolimus blocks this pathway. The safety and efficacy of Rapamycin treatment of LAM were investigated in clinical trialsthat compared sirolimus treatment with aplacebogroup in 89 patients for 12 months. The patients were observed for 12 months after the treatment had ended. The most commonly reported side effects of sirolimus treatment of LAM were mouth and lip ulcers,diarrhea, abdominal pain, nausea, sore throat, acne, chest pain, leg swelling,upper respiratory tract infection, headache, dizziness, muscle pain and elevatedcholesterol. Serious side effects including hypersensitivity and swelling (edema) have been observed inrenal transplantpatients. While Rapamycin was considered for treatment of LAM, it received orphan product designation status because LAM is a rare condition. Development for the product was partially supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.The safety of LAM treatment by sirolimus in patients younger than 18 years old has not been tested.

Coronary stent coating

Venous malformations

Rapamycin is used to treat venous malformations. Treatment with sirolimus can decrease pain and the fullness of venous 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. Rapamycinis used especially to treat lymphatic malformation.

Contraindications

Rapamycin is contraindicatedin individuals with a knownhypersensitivityto the drug.

Adverse effects

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, increasedcreatinine, fever,urinary tract infection,anemia,arthralgia, andthrombocytopenia. The most common adverse reactions (20% occurrence, leading to an 11% treatment discontinuation rate) observed with sirolimus in clinical studies for the treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, stomatitis,nasopharyngitis, acne,upper respiratory tract infection, dizziness, andmyalgia. The following adverse effects occurred in 320% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant.

SARS-CoV-2

Rapamycin has been proposed as a treatment forsevere acute respiratory syndrome coronavirus 2insofar as itsimmunosuppressiveeffects could prevent or reduce thecytokine storm seen in very serious cases of COVID-19.Moreover, inhibition ofcell proliferationby rapamycin could reduceviral replication.  

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