Sirolimus

sirolimus

Sirolimus (or rapamycin) is a macrolide compound used primarily to prevent organ rejection during transplants, treat lymphangioleiomyomatosis (a rare lung disease), and coat coronary stents

Sirolimus’ primary immunosuppressive mechanism of action is its inhibition of the mechanistic Target Of Rapamycin (mTOR). It accomplishes this by inhibiting B cells and T cells’ activation by reducing their sensitivity to interleukin-2, a protein that regulates immune cell activity. 

Sirolimus was approved by the US Food and Drug Administration (FDA) in September 1999. It is marketed by Pfizer under the trade name Rapamune.

History

Sirolimus was isolated for the first time by Surendra Nath Sehgal and colleagues in 1972 from samples of Streptomyces hygroscopicus, a bacterial species found on Easter Island. It was initially named rapamycin after Rapa Nui, the native name of the island. Originally used as an antifungal, researchers soon observed that sirolimus had immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR. 

Medical Uses

Prevention of organ transplant rejection

Sirolimus is used as an immunosuppressive agent to prevent transplant rejection. It is preferred over the use of calcineurin inhibitors due to its reduced toxic effects on the kidneys. 

Sirolimus can be used as a steroid-free immunosuppression regimen, either alone or in combination with mycophenolate mofetil and/or a calcineurin inhibitor

Since impaired wound healing and thrombocytopenia (low blood platelet levels) are possible side effects of Sirolimus, some practitioners administer it after several weeks or months following transplant surgery.

Lymphangioleiomyomatosis

Sirolimus was approved by the FDA to treat lymphangioleiomyomatosis, a rare progressive lung disease that predominantly affects women 20-50 years of age.  

Coronary stent coating

Coronary stents are expandable tube-shaped metallic devices that can be used to open clogged arteries. Sirolimus has been used in conjunction with these devices to prevent re-narrowing of the arteries following surgery. 

Venous malformations

Sirolimus is used to treat venous malformations – a condition where veins stretch or enlarge abnormally over time. The compound is additionally used to relieve pain and reduce vein fullness while slowing the growth of abnormal lymphatic vessels and improving clotting levels. 

Sirolimus is also emerging as a way to address vascular tumors through its action on mTOR.

sirolimus

Sirolimus Research Studies

Tuberous sclerosis complex

Research suggests that sirolimus can help treat tuberous sclerosis complex, a disease that causes benign tumor growth in the heart, brain, skin and other organs. Several studies linking mTOR inhibitors to tumor remission led to increased prescribing of sirolimus along with everolimus, a rapamycin analog. As a result, clinical trials with both adults and children using both these rapamycin analogs are underway in the United States.

Lymphatic malformation

Lymphatic malformation occurs when lymphatic vessels grow abnormally. Conventional treatment is typically the removal or destruction of lymph vessel tissue, however regrowth is usually high following treatment. One study involving the use of topical rapamycin found that symptoms improved in 9 out of 11 patients. 

Longevity

Research studies have demonstrated that the use of sirolimus was found to inhibit and slow aging in flies, worms, yeast and mice through its action on mTOR.

A 2009 study published by NIH investigators found that sirolimus extended the life of mice and has since been replicated in mice of various genetic backgrounds. Other findings, such as those published in a 2020 study, found rapamycin dosing later in life resulted in sex-specific results where male lifespan increased, but not female. 

SARS-CoV-2

Rapamycin was proposed as a treatment for SARS-CoV-2 due to its immunosuppressive effects in preventing or reducing cytokine storms – a physiological reaction where the immune system releases a large amount of pro-inflammatory signaling molecules. Researchers also proposed that rapamycin’s cell inhibition effects may reduce viral replication.

Atherosclerosis

Oxidized LDL cholesterol was shown to contribute to atherosclerosis. Subsequent research has then led to suggestions that rapamycin can lower the risk of atherosclerosis through accelerated oxidized LDL degradation in endothelial cells. 

Cancer

Research suggests that Sirolimus’ antiproliferative effects may have a role in addressing cancer by mediating the immune response to tumor targeting. Sirolimus has also been shown to promote tumor regression in clinical trials and lower cancer risk in some patients undergoing transplants.

Lupus

Studies in cells, animals, and humans suggest that systemic lupus erythematosus may result from mTOR activation, and that treatment with rapamycin may help individuals with the disease. 

Graft-versus-host disease

Rapamycin’s immunosuppressant activity has led to suggestions it can be used as prophylaxis or treatment for Graft-versus-host disease, a resulting complication of hematopoietic stem cell transplantation

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Contraindications

The use of sirolimus is contraindicated for people that have been previously screened and found to have a hypersensitivity to the drug.

Adverse Effects

Some common adverse reactions observed with sirolimus in organ rejection prophylaxis clinical studies of kidney transplant patients include:

  • Headache
  • Nausea
  • Diarrhea
  • Pain
  • Fever
  • Urinary tract infection
  • Anemia
  • Arthralgia
  • Peripheral edema
  • Abdominal pain
  • Hypercholesterolemia
  • Thrombocytopenia
  • Constipation
  • Hypertriglyceridemia
  • Hypertension
  • Increased creatinine

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Adverse Conditions

Some adverse conditions associated with sirolimus use include:

Symptoms of Diabetes

The inhibition of mTORC1 was also shown to inhibit mTORC2, resulting in symptoms similar to diabetes.

Lung toxicity

Sirolimus use was shown to produce severe toxic effects on the lungs through the interstitial pneumonitis mechanism. Researchers postulate that interstitial pneumonitis may not be dose-dependent, and more common in patients suffering from lung disease.

Reduced immune system function

Some researchers warn that there is an increased risk of infections and decreased immunity associated with sirolimus use.

Cancer risk

FDA prescription information advises that sirolimus may increase skin cancer risk from exposure to UV radiation. 

Impaired wound healing

Individuals taking sirolimus may experience delayed or impaired wound healing, particularly if they are obese or have a body mass index greater than 30 kg/m2.

Sirolimus FAQ's

Sirolimus and tacrolimus are both immunosuppressive drugs used to prevent organ transplant rejections. Each has a different mechanism of action.

Sirolimus is used primarily as an agent to prevent organ transplant rejections. Its action on mTOR – a mechanism that causes growth in the body – has also led to research into its potential to treat cancer.