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| Trade names | Rapamune |
| Synonyms | Rapamycin |
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| Bioavailability | 14% (oral solution), lower with high-fat meals; 18% (tablet), higher with high-fat meals[1] |
| Protein binding | 92% |
| Metabolism | Hepatic |
| Biological half-life | 57–63 hours[2] |
| Excretion | Mostly faecal |
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| ECHA InfoCard | 100.107.147 |
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| Formula | C51H79NO13 |
| Molar mass | 914.172 g/mol |
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| Solubility in water | 0.0026 [3] mg/mL (20 °C) |
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Sirolimus, also known as rapamycin, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection and to treat a rare lung disease called lymphangioleiomyomatosis.[4][5][6] It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It inhibits activation of T cells and B cells by reducing the production of interleukin-2 (IL-2).
It is produced by the bacterium Streptomyces hygroscopicus and was isolated for the first time in 1972 by Surendra Nath Sehgal and colleagues from samples of Streptomyces hygroscopicus found on Easter Island.[7][8] The compound was originally named rapamycin after the native name of the island, Rapa Nui.[5] Sirolimus was initially developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR. It was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune by Pfizer (formerly by Wyeth).
Contents
- 1 Medical uses
- 1.1 Prevention of transplant rejection
- 1.2 Lymphangioleiomyomatosis
- 1.3 Coronary stent coating
- 2 Contraindications
- 3 Adverse effects
- 3.1 Diabetes-like symptoms
- 3.2 Lung toxicity
- 3.3 Lowered effectiveness of immune system
- 3.4 Cancer risk
- 3.5 Impaired wound healing
- 4 Interactions
- 5 Pharmacology
- 5.1 Pharmacodynamics
- 5.2 Pharmacokinetics
- 6 Chemistry
- 6.1 Biosynthesis
- 7 Research
- 7.1 Cancer
- 7.2 Tuberous sclerosis complex
- 7.3 Effects on longevity
- 7.4 Lupus
- 7.5 Applications in biology research
- 8 References
- 9 External links
Medical uses
Sirolimus is indicated for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis (LAM).[4]
Prevention of transplant rejection
See also: Organ rejection and Immunosuppression § Deliberately induced
The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity toward kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even chronic renal failure; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on 7 October 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use.[9][10] 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.[11]
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 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.[12]
Lymphangioleiomyomatosis
On May 28, 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.[13] LAM involves lung tissue infiltration with smooth muscle-like cells with mutations of the tuberous sclerosis complex gene (TSC2). Loss of TSC2 gene function activates the mTOR signaling pathway, resulting in the release of lymphangiogenic growth factors. Sirolimus blocks this pathway.[4]
The safety and efficacy of sirolimus treatment of LAM were investigated in clinical trials that compared sirolimus treatment with a placebo group in 89 patients for 12 months. The patients were observed for 12 months after the treatment had ended. The most commonly reported side effect 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 elevated cholesterol. Serious side effects including hypersensitivity and swelling (edema) have been observed in renal transplant patients.[13]
While sirolimus 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.[13]
The safety of LAM treatment by sirolimus in patients younger than 18 years old has not been tested.[4]
Coronary stent coating
Further information: Drug-eluting stent
The antiproliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures. A sirolimus-eluting coronary stent was marketed by Cordis, a division of Johnson & Johnson, under the tradename Cypher.[6] However, this kind of stent may also increase the risk of vascular thrombosis.[14]
Contraindications
Sirolimus is contraindicated in individuals with a known hypersensitivity to the drug.[4]
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, increased creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia.[4]
The most common adverse reactions (≥20% occurrence, leading to a 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, and myalgia.[4]
The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant:[4]
| System | Adverse effects |
|---|---|
| Body as a Whole | Sepsis, lymphocele, herpes zoster infection, herpes simplex infection |
| Cardiovascular | Venous thromboembolism (pulmonary embolism and deep venous thrombosis), rapid heart rate |
| Digestive | Stomatitis |
| Hematologic/Lymphatic | Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia |
| Metabolic | Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes |
| Musculoskeletal | Bone necrosis |
| Respiratory | Pneumonia, epistaxis |
| Skin | Melanoma, squamous cell carcinoma, basal cell carcinoma |
| Urogenital | Pyelonephritis, ovarian cysts, menstrual disorders (amenorrhea and menorrhagia) |
Diabetes-like symptoms
While sirolimus inhibition of mTORC1 appears to mediate the drug's benefits, it also inhibits mTORC2, which results in diabetes-like symptoms.[citation needed] This includes decreased glucose tolerance and insensitivity to insulin.[15] Sirolimus treatment may additionally increase the risk of type 2 diabetes.[16] In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus.[17]
Lung toxicity
Lung toxicity is a serious complication associated with sirolimus therapy,[18][19][20][21][22][23][24] especially in the case of lung transplants.[25] 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.[26][27][28] The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease.[18][29]
Lowered effectiveness of immune system
There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections.[4][30]
Cancer risk
According to the FDA prescribing information, sirolimus may increase an individual's risk for contracting skin cancers from exposure to sunlight or UV radiation, and risk of developing lymphoma.[4] In studies, the skin cancer risk under sirolimus was lower than under other immunosuppressants such as azathioprine and calcineurin inhibitors, and lower than under placebo.[31][32]
Impaired wound healing
Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a high body mass index (i.e., a BMI of ≥30 kg/m2).[4]
Interactions
Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump;[4] hence, inhibitors of either protein may increase sirolimus concentrations in blood plasma, whereas inducers of CYP3A4 and P-gp may decrease sirolimus concentrations in blood plasma.[4]
Pharmacology
Pharmacodynamics
See also: mTOR inhibitors
Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits IL-2 and other cytokines receptor-dependent signal transduction mechanisms, via action on mTOR, and thereby blocks activation of T and B cells. Ciclosporin and tacrolimus inhibit the secretion of IL-2, by inhibiting calcineurin.[12]
The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mTOR (mammalian Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1).[12]
mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2.[33][12]
Pharmacokinetics
Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump.[4] It has an elimination half-life of 57–63 hours.[2]
The absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose. Drug levels are, therefore, taken to make sure patients get the right dose for their condition.[12] This is determined by taking a blood sample before the next dose, which gives the trough level. However, good correlation is noted between trough concentration levels and drug exposure, known as area under the concentration-time curve, for both sirolimus (SRL) and tacrolimus (TAC) (SRL: r2 = 0.83; TAC: r2 = 0.82), so only one level need be taken to know its pharmacokinetic (PK) profile. PK profiles of SRL and of TAC are unaltered by simultaneous administration. Dose-corrected drug exposure of TAC correlates with SRL (r2 = 0.8), so patients have similar bioavailability of both.[34][non-primary source needed]
Chemistry
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Sirolimus is a natural product and macrocyclic lactone.[2]
Biosynthesis
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.[35] 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.[36]
Figure 1: Domain organization of PKS of rapamycin and biosynthetic intermediates
Figure 2: Prerapamycin, unbound product of PKS and NRPS
Figure 3: Sequence of "tailoring" steps, which convert unbound prerapamycin into rapamycin
Figure 4: Proposed mechanism of lysine cyclodeaminase conversion of L-lysine to L-pipecolic acid
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.[37]
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.[35] The gene rapL has been established to code for a NAD+-dependent lysine cycloamidase, which converts L-lysine to L-pipecolic acid (figure 4) for incorporation at the end of the polyketide.[38][39] 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.[40] 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.[35] Note that the cyclohexane ring of the starting unit is reduced during the transfer to module 1. The starting unit is then modified by a series of Claisen condensations with malonyl or methylmalonyl substrates, which are attached to an acyl carrier protein (ACP) and extend the polyketide by two carbons each. After each successive condensation, the growing polyketide is further modified according to enzymatic domains that are present to reduce and dehydrate it, thereby introducing the diversity of functionalities observed in rapamycin (figure 1). Once the linear polyketide is complete, L-pipecolic acid, which is synthesized by a lysine cycloamidase from an L-lysine, is added to the terminal end of the polyketide by an NRPS. Then, the NSPS cyclizes the polyketide, giving prerapamycin, the first enzyme-free product. The macrocyclic core is then customized by a series of post-PKS enzymes through methylations by MTases and oxidations by P-450s to yield rapamycin.
Research
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This section needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. (August 2016)
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A plaque, written in Portuguese, commemorating the discovery of sirolimus on Easter Island, near Rano Kau
Cancer
The antiproliferative effects of sirolimus may have a role in treating cancer. When dosed appropriately, sirolimus can enhance the immune response to tumor targeting[41] or otherwise promote tumor regression in clinical trials.[42] Sirolimus seems to lower the cancer risk in some transplant patients.[43]
Sirolimus was shown to inhibit the progression of dermal Kaposi's sarcoma in patients with renal transplants.[citation needed] 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.[44]
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.[45][46][47][48]
Tuberous sclerosis complex
Sirolimus also shows promise in treating tuberous sclerosis complex (TSC), a congenital disorder that leaves sufferers prone 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.[49]
Most studies thus far have noted that tumors often regrew when treatment stopped.[medical citation needed]
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.[50]
Effects on longevity
mTOR, specifically mTOR1, was first shown to important in ageing 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.[51] 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.[51][52] The results are further supported by the finding that genetically modified mice with impaired mTOR1 signalling live longer.[51] The known adverse effects caused by sirolimus and marketed analogs, especially the increased risk of infection due to immunosuppression, as well as dose-dependent metabolic impairment, make it unlikely that this could become a widely used anti-aging agent.[51] Among the strategies that have been explored to minimize such side effects are intermittent treatment regimens and combinations with insulin sentitizers (rosiglitazone) or antidiabetics (metformin) to prevent metabolic dysfunction.[53]
Lupus
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-modifiying treatment.[54] As of 2016 rapamycin had been tested in small clinical trials in people with lupus.[54]
Applications in biology research
Rapamycin is used in biology research as an agent for chemically induced dimerization.[55] 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.
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External links
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- Rapamune official website
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UpToDate Contents
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
- 1. 腎移植における哺乳動物ラパマイシン標的タンパク質（mTOR）阻害剤 mammalian target of rapamycin mtor inhibitors in renal transplantation
- 2. 成人肝移植における免疫抑制の概要 overview of immunosuppression in adult liver transplantation
- 3. PTEN hamartoma tumor syndrome, including Cowden syndrome
- 4. 転移性の胃腸膵管系神経内分泌腫瘍：腫瘍増殖およびホルモン過剰分泌による症状を管理
するための全身治療の選択肢 metastatic gastroenteropancreatic neuroendocrine tumors systemic therapy options to control tumor growth and symptoms of hormone hypersecretion - 5. 抗腫瘍療法関連肺毒性：分子標的剤 pulmonary toxicity associated with antineoplastic therapy molecularly targeted agents
English Journal
- Drug release kinetics from a drug-eluting stent with asymmetrical coat.
- Zhang H1, Li X2, Deng W3, Wang X4, Wang S5, Ge J4, Toft E6.
- Frontiers in bioscience (Landmark edition).Front Biosci (Landmark Ed).2017 Jan 1;22:407-415.
- The aim of this study was to investigate the drug release profiles of biodegradable polymer sirolimus- or paclitaxel-eluting stents with asymmetrical coating (BPSES-A or BPPES-A) both in vitro and in vivo. In vitro, the drug release profile was characterized by measuring the drug concentration by HP
- PMID 27814621
- mTOR Inhibitors in Children: Current Indications and Future Directions in Neurology.
- Jeong A1, Wong M2.
- Current neurology and neuroscience reports.Curr Neurol Neurosci Rep.2016 Dec;16(12):102.
- The mammalian/mechanistic target of rapamycin (mTOR) pathway is a key signaling pathway that has been implicated in genetic epilepsy syndromes, neurodegenerative diseases, and conditions associated with autism spectrum disorder and cognitive impairment. The mTOR pathway has become an exciting treatm
- PMID 27815691
- Development of solidified self-microemulsifying delivery systems with enhanced stability of sirolimus and extended release.
- Tao C1, Chen J2, Huang A1, Zhang J1, Lin B1, Liu Z1, Zhang M1, Chen X1, Zeng L1, Zhang L1, Song H3.
- International journal of pharmaceutics.Int J Pharm.2016 Nov 20;513(1-2):255-261. doi: 10.1016/j.ijpharm.2016.09.035. Epub 2016 Sep 11.
- The application of sirolimus (SRL) as immunosuppressive agent is hampered by its poor water solubility and narrow therapeutic range. The self-microemulsifying drug delivery system (SMEDDS) succeeded in improving the solubility of SRL in our previous work. In this study, the formulation of the SMEDDS
- PMID 27628781
Japanese Journal
- Repetitive angioscopic observations of a sirolimus-eluting stent deployed in a patient with silent chronic thrombotic occlusion
- Ichikawa Minoru,Kijima Yoshiyuki,Mishima Masayoshi
- Cardiovascular intervention and therapeutics 27(3), 201-204, 2012-09
- NAID 40019426610
- Five-year clinical outcomes after implantation of sirolimus-eluting stents in patients with and without diabetes mellitus
- Sato Tetsuya,Ono Tamaki,Morimoto Yoshimasa [他]
- Cardiovascular intervention and therapeutics 27(3), 189-195, 2012-09
- NAID 40019426594
Related Links
- Before taking sirolimus, tell your doctor and pharmacist if you are allergic to sirolimus, any other medications, or any of the ingredients in sirolimus tablets or solution. Ask your pharmacist for a list of the ingredients. tell ...
- Easy to read patient leaflet for sirolimus. Includes indications, proper use, special instructions, precautions, and possible side effects. ... How to use sirolimus: Use sirolimus as directed by your doctor. Check the label on the ...
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| リンク元 | 「シロリムス」 |
| 拡張検索 | 「sirolimus-eluting stent」「sirolimus-eluting stents」 |
「シロリムス」
-sirolimus
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