Chemistry:Mycophenolic acid

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Short description: Immunosuppressant medication
Mycophenolic acid
Mycophenolicacid.svg
Mycophenolic acid ball-and-stick.png
Clinical data
Pronunciation/ˌmaɪkoʊfɪˈnɒlɪk/
Trade namesCellcept, Myfortic, others
Other namesMPA, Mycophenolate sodium, Mycophenolate mofetil (AAN AU), Mycophenolate mofetil (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa601081
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous[2]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability72% (sodium),
94% (mofetil)[10]
Protein binding82–97%[10]
MetabolismLiver[10]
Elimination half-life17.9±6.5 hours[10]
ExcretionUrine (93%),
faeces (6%)[10]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H20O6
Molar mass320.341 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Mycophenolic acid is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus.[11][12] Specifically it is used following kidney, heart, and liver transplantation.[12] It can be given by mouth or by injection into a vein.[12] It comes as mycophenolate sodium and mycophenolate mofetil.[12]

Common side effects include nausea, infections, and diarrhea.[12] Other serious side effects include an increased risk of cancer, progressive multifocal leukoencephalopathy, anemia, and gastrointestinal bleeding.[12] Use during pregnancy may harm the baby.[12] It works by blocking inosine monophosphate dehydrogenase (IMPDH), which is needed by lymphocytes to make guanosine.[12]

Mycophenolic acid was initially discovered by Italian Bartolomeo Gosio in 1893.[13][14] It was rediscovered in 1945 and 1968.[14] It was approved for medical use in the United States in 1995 following the discovery of its immunosuppressive properties in the 1990s.[12][13] It is available as a generic medication.[15] In 2020, it was the 313th most commonly prescribed medication in the United States, with more than 900 thousand prescriptions.[16]

Medical uses

Organ transplant

Mycophenolate is used for the prevention of organ transplant rejection. Mycophenolate mofetil is indicated for the prevention of organ transplant rejection in adults and kidney transplantation rejection in children over 2 years; whereas mycophenolate sodium is indicated for the prevention of kidney transplant rejection in adults. Mycophenolate sodium has also been used for the prevention of rejection in liver, heart, or lung transplants in children older than two years.[17]

Autoimmune disease

Mycophenolate is increasingly utilized as a steroid sparing treatment in autoimmune diseases and similar immune-mediated disorders including Behçet's disease, pemphigus vulgaris, immunoglobulin A nephropathy, small vessel vasculitides, and psoriasis.[18] It is also used for retroperitoneal fibrosis along with a number of other medications.[19] Specifically it has also be used for psoriasis not treatable by other methods.[20]

Its increasing application in treating lupus nephritis has demonstrated more frequent complete response and less frequent complications[18] compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy.[11] Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side-effects.[11][21] Walsh proposed that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in people without kidney dysfunction.[22]

Comparison to other agents

Compared with azathioprine it has higher incidence of diarrhea, and no difference in risk of any of the other side effects in transplant patients.[23] Mycophenolic acid is 15 times more expensive than azathioprine.[24]

Adverse effects

Common adverse drug reactions (≥ 1% of people) include diarrhea, nausea, vomiting, joint pain; infections, leukopenia, or anemia reflect the immunosuppressive and myelosuppressive nature of the drug. Mycophenolate sodium is also commonly associated with fatigue, headache, cough and/or breathing issues. Intravenous (IV) administration of mycophenolate mofetil is also commonly associated with thrombophlebitis and thrombosis. Infrequent adverse effects (0.1–1% of people) include esophagitis, gastritis, gastrointestinal tract hemorrhage, and/or invasive cytomegalovirus (CMV) infection.[17] More rarely, pulmonary fibrosis or various neoplasia occur: melanoma, lymphoma, other malignancies having an occurrences of 1 in 20 to 1 in 200, depending on the type, with neoplasia in the skin being the most common site.[25][26][not specific enough to verify] Several cases of pure red cell aplasia (PRCA) have also been reported.[27]

The U.S. Food and Drug Administration (FDA) issued an alert that people are at increased risk of opportunistic infections, such as activation of latent viral infections, including shingles, other herpes infections, cytomegalovirus, and BK virus associated nephropathy. In addition the FDA is investigating[when?] 16 people that developed a rare neurological disease while taking the drug. This is a viral infection known as progressive multifocal leukoencephalopathy; it attacks the brain and is usually fatal.[28]

Pregnancy

Mycophenolic acid is associated with miscarriage and congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to get pregnant.[29][30]

Blood tests

Among the most common effects of this drug is increased blood cholesterol levels. Other changes in blood chemistry such as hypomagnesemia, hypocalcemia, hyperkalemia, and an increase in blood urea nitrogen (BUN) can occur.[2][31]

Mechanism of action

Purines (including the nucleosides guanosine and adenosine) can either be synthesized de novo using ribose 5-phosphate or they can be salvaged from free nucleotides. Mycophenolic acid is a potent, reversible, non-competitive inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH), an enzyme essential to the de novo synthesis of guanosine-5'-monophosphate (GMP) from inosine-5'-monophosphate (IMP).[32] IMPDH inhibition particularly affects lymphocytes since they rely almost exclusively on de novo purine synthesis.[33] In contrast, many other cell types use both pathways, and some cells, such as terminally differentiated neurons, depend completely on purine nucleotide salvage.[34] Thus, use of mycophenolic acid leads to a relatively selective inhibition of DNA replication in T cells and B cells.

Pharmacology

Mycophenolate can be derived from the fungi Penicillium stoloniferum, P. brevicompactum and P. echinulatum.[35] Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It reversibly inhibits inosine monophosphate dehydrogenase,[36] the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes.[37] Other cells recover purines via a separate salvage pathway and are thus able to escape the effect.[2]

Mycophenolate is potent and can, in many contexts, be used in place of the older anti-proliferative azathioprine.[38] It is usually used as part of a three-compound regimen of immunosuppressants, also including a calcineurin inhibitor (ciclosporin or tacrolimus) and a glucocorticoid (e.g. dexamethasone or prednisone).[39]

Chemistry

Mycophenolate mofetil, a prodrug form of mycophenolic acid used in medicine

Mycophenolate mofetil is the morpholino‌ ethyl ester of mycophenolic acid; the ester masks the carboxyl group.[40] Mycophenolate mofetil is reported to have a pKa values of 5.6 for the morpholino moiety and 8.5 for the phenolic group.

History

Mycophenolic acid was discovered by Italian medical scientist Bartolomeo Gosio. Gosio collected a fungus from spoiled corn and named it Penicillium glaucum. (The species is now called P. brevicompactum.[citation needed]) In 1893 he found that the fungus had antibacterial activity. In 1896 he isolated crystals of the compound, which he successfully demonstrated as the active antibacterial compound against the anthrax bacterium.[20] This was the first antibiotic that was isolated in pure and crystalline form. But the discovery was forgotten.[41] It was rediscovered by two American scientists C.L. Alsberg and O.M. Black in 1912, and given the name mycophenolic acid. The compound was eventually demonstrated to have antiviral, antifungal, antibacterial, anticancer, and antipsoriasis activities.[42] Although it is not commercialised as antibiotic due to its adverse effects, its modified compound (ester derivative) is an approved immunosuppressant drug in kidney, heart, and liver transplantations, and is marketed under the brands CellCept (mycophenolate mofetil by Roche) and Myfortic (mycophenolate sodium by Novartis).[43]

Cellcept was developed by a South African geneticist Anthony Allison and his wife Elsie M. Eugui. In the 1970s while working at the Medical Research Council, Allison investigated the biochemical causes of immune deficiency in children. He discovered the metabolic pathway involving an enzyme, inosine monophosphate dehydrogenase, which is responsible for undesirable immune response in autoimmune diseases, as well as for immune rejection in organ transplantation. He conceived an idea that if a molecule that could block the enzyme is discovered, then, it would become an immunosuppressive drug that could be used for autoimmune diseases and in organ transplantation. In 1981 he decided to go for drug discovery and approached several pharmaceutical companies, which turned him down one by one as he had no primary knowledge of drug research. However, Syntex liked his plans and asked him to join the company with his wife.[44] He became vice president for the research. In one of their experiments the Allisons used an antibacterial compound, mycophenolate mofetil, which was abandoned in clinical use due to its adverse effects. They discovered that the compound had immunosuppressive activity.[45][46] They synthesised a chemical variant for increased activity and reduced adverse effects.[47][48][49][50][51] They subsequently demonstrated that it was useful in organ transplantation in experimental rats.[52][53] After successful clinical trials,[54] the compound was approved for use in kidney transplant by the U.S. Food and Drug Administration on 3 May 1995,[55] and was sold under the brand name CellCept.[56][57] It was approved for use in the European Union in February 1996.[9]

Names

It was initially introduced as the prodrug mycophenolate mofetil (MMF, trade name CellCept) to improve oral bioavailability. The salt mycophenolate sodium has also been introduced. Enteric-coated mycophenolate sodium (EC-MPS) is an alternative MPA formulation.

MMF and EC-MPS appear to be equal in benefits and safety.[58]

Research

Mycophenolate mofetil is beginning to be used in the management of auto-immune disorders such as idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), scleroderma (systemic sclerosis or SSc), and pemphigus vulgaris (PV) with success for some patients.[59]

It is also currently being used as a long-term therapy for maintaining remission of granulomatosis with polyangiitis, though thus far, studies have found it inferior to azathioprine.[citation needed] A combination of mycophenolate and ribavirin has been found to stop infection by and replication of dengue virus in vitro.[60][61] It has also shown promising antiviral activity against MERS, especially in combination with interferon.[62]

Preliminary data suggests that mycophenolate mofetil might have benefits in people with multiple sclerosis. However the evidence is insufficient to determine the effects as an add‐on therapy for interferon beta-1a in people with RRMS.[63]

References

  1. ↑ "Mycophenolate mofetil (CellCept) Use During Pregnancy". 24 January 2020. https://www.drugs.com/pregnancy/mycophenolate-mofetil.html. 
  2. ↑ 2.0 2.1 2.2 (in de) Austria-Codex (62nd ed.). Vienna: Österreichischer Apothekerverlag. 2007. pp. 1484–95. ISBN 978-3-85200-181-4. 
  3. ↑ "CellCept® (mycophenolate mofetil)". Australian Product Information. 30 November 2021. https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropccept10215. 
  4. ↑ "Pharmacor mycophenolate, mycocell, alcept (Pharmacor Pty Ltd)". 11 November 2022. https://www.tga.gov.au/resources/prescription-medicines-registrations/pharmacor-mycophenolate-mycocell-alcept-pharmacor-pty-ltd. 
  5. ↑ "CellCept 1g/5ml powder for oral suspension - Summary of Product Characteristics (SmPC)". 27 February 2020. https://www.medicines.org.uk/emc/product/1569/smpc. 
  6. ↑ "Cellcept 250mg Capsules - Summary of Product Characteristics (SmPC)". 17 June 2020. https://www.medicines.org.uk/emc/product/1102/smpc. 
  7. ↑ "Cellcept 500mg Film-Coated Tablets - Summary of Product Characteristics (SmPC)". https://www.medicines.org.uk/emc/product/1103/smpc. 
  8. ↑ "CellCept- mycophenolate mofetil tablet, film coated CellCept- mycophenolate mofetil capsule CellCept- mycophenolate mofetil hydrochloride injection, powder, lyophilized, for solution CellCept- mycophenolate mofetil powder, for suspension". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=37241e87-4af4-4dc3-a1aa-ea6f20d8dc40. 
  9. ↑ 9.0 9.1 "CellCept EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/cellcept. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 "CellCept" (PDF). TGA eBusiness Services. Roche Products Pty Limited. 13 December 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03448-3. 
  11. ↑ 11.0 11.1 11.2 "Systemic lupus erythematosus". Lancet 369 (9561): 587–96. February 2007. doi:10.1016/S0140-6736(07)60279-7. PMID 17307106. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 "Mycophenolate Monograph for Professionals" (in en). https://www.drugs.com/monograph/mycophenolate.html. 
  13. ↑ 13.0 13.1 (in en) Schiff's Diseases of the Liver. John Wiley & Sons. 2011. p. PT3219. ISBN 978-1-119-95048-6. https://books.google.com/books?id=HsxFSx_B4sUC&pg=PT3219. Retrieved 2020-09-23. 
  14. ↑ 14.0 14.1 (in en) Advances in Applied Microbiology. Gulf Professional Publishing. 2001. p. 236. ISBN 978-0-12-002648-7. https://books.google.com/books?id=0WqTtYOVPTMC&pg=PA236. Retrieved 2020-09-23. 
  15. ↑ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 826–827. ISBN 978-0-85711-338-2. 
  16. ↑ "Mycophenolate Mofetil - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/MycophenolateMofetil. 
  17. ↑ 17.0 17.1 Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. 2006. ISBN 978-0-9757919-2-9. [page needed]
  18. ↑ 18.0 18.1 "Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis". Arthritis Research & Therapy 8 (6): R182. 2006. doi:10.1186/ar2093. PMID 17163990. 
  19. ↑ Practical nephrology. Springer. 2014. p. 449. ISBN 978-1-4471-5547-8. https://books.google.com/books?id=6GQgBAAAQBAJ&pg=PA449. Retrieved 2020-09-23. 
  20. ↑ 20.0 20.1 "Rediscovering mycophenolic acid: a review of its mechanism, side effects, and potential uses". Journal of the American Academy of Dermatology 37 (3 Pt 1): 445–9. September 1997. doi:10.1016/S0190-9622(97)70147-6. PMID 9308561. 
  21. ↑ "Comparative effectiveness of immunosuppressive drugs and corticosteroids for lupus nephritis: a systematic review and network meta-analysis". Systematic Reviews 5 (1): 155. September 2016. doi:10.1186/s13643-016-0328-z. PMID 27619512. 
  22. ↑ "Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis". Clinical Journal of the American Society of Nephrology 2 (5): 968–75. September 2007. doi:10.2215/CJN.01200307. PMID 17702723. 
  23. ↑ "Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: a systematic review". Transplantation 87 (6): 785–94. March 2009. doi:10.1097/TP.0b013e3181952623. PMID 19300178. 
  24. ↑ "Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial". Lancet 364 (9433): 503–12. 2004. doi:10.1016/S0140-6736(04)16808-6. PMID 15302193. 
  25. ↑ "CellCept, Myfortic (mycophenolate) dosing, indications, interactions, adverse effects, and more". http://reference.medscape.com/drug/cellcept-myfortic-mycophenolate-343209#4. 
  26. ↑ "Homepage - BNF Publications". http://www.bnf.org/. 
  27. ↑ "CellCept (mycophenolate mofetil) August 2009". U.S. Food and Drug Administration. August 14, 2009. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm177397.htm. 
  28. ↑ "CellCept (mycophenolate mofetil) August 2009". U.S. Food and Drug Administration. August 14, 2009. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm177397.htm. 
  29. ↑ "FDA Issues Second CellCept Warning". newsinferno.com. 2008-05-18. http://www.newsinferno.com/archive/fda-issues-second-cellcept-warning/. 
  30. ↑ "MedWatch Safety Alerts for Human Medical Products". fda.gov. May 2008. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm092157.htm. 
  31. ↑ Drugs.com: Mycophenolic acid Side Effects
  32. ↑ Pharmacology North American Edition.. Lippincott Williams & Wilkins. 2014. p. 625. ISBN 978-1-4511-9177-6. 
  33. ↑ Principles of immunopharmacology (2nd rev. and extended ed.). Basel: Birkhèauser Verlag. 2005. p. 453. ISBN 978-3764358044. https://archive.org/details/principlesimmuno00nijk_004. 
  34. ↑ "Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder". Brain 137 (Pt 5): 1282–303. May 2014. doi:10.1093/brain/awt202. PMID 23975452. 
  35. ↑ "5-Hydroxymaltol and mycophenolic acid, secondary metabolites from Penicillium echinulatum". Transactions of the British Mycological Society 91 (4): 649–651. December 1988. doi:10.1016/S0007-1536(88)80040-8. 
  36. ↑ "Mycophenolate mofetil. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation". Drugs 51 (2): 278–98. February 1996. doi:10.2165/00003495-199651020-00007. PMID 8808168. 
  37. ↑ "Mechanism of action of mycophenolate mofetil". Therapeutic Drug Monitoring 17 (6): 681–4. December 1995. doi:10.1097/00007691-199512000-00023. PMID 8588241. 
  38. ↑ "Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis". The New England Journal of Medicine 365 (20): 1886–95. November 2011. doi:10.1056/NEJMoa1014460. PMID 22087680. https://cdr.lib.unc.edu/downloads/8623j6697. Retrieved 2021-11-25. 
  39. ↑ "Enteric-coated mycophenolate sodium: an update". International Journal of Clinical Practice. Supplement 68 (181): 1–3. April 2014. doi:10.1111/ijcp.12399. PMID 24673712. 
  40. ↑ "Mycophenolate mofetil". Lancet 348 (9038): 1357–9. November 1996. doi:10.1016/S0140-6736(96)10310-X. PMID 8918281. 
  41. ↑ Natural Products: Drug Discovery and Therapeutic Medicine. Totowa, N.J.: Humana Press. 2005. p. 14. ISBN 978-1-59259-976-9. https://books.google.com/books?id=iP0i7x_38ZwC. Retrieved 2019-08-16. 
  42. ↑ "Molecular basis for mycophenolic acid biosynthesis in Penicillium brevicompactum". Applied and Environmental Microbiology 77 (9): 3035–43. May 2011. doi:10.1128/AEM.03015-10. PMID 21398490. Bibcode: 2011ApEnM..77.3035R. 
  43. ↑ "Mycophenolic Acid: a one hundred year odyssey from antibiotic to immunosuppressant". Chemical Reviews 100 (10): 3801–26. October 2000. doi:10.1021/cr990097b. PMID 11749328. 
  44. ↑ "Anthony Clifford Allison". The Lancet 383 (9925): 1290. 2014. doi:10.1016/S0140-6736(14)60635-8. 
  45. ↑ "Immunosuppressive drugs: the first 50 years and a glance forward". Immunopharmacology 47 (2–3): 63–83. May 2000. doi:10.1016/S0162-3109(00)00186-7. PMID 10878284. 
  46. ↑ "Mechanisms of action of mycophenolic acid". Annals of the New York Academy of Sciences 696 (1): 63–87. November 1993. doi:10.1111/j.1749-6632.1993.tb17143.x. PMID 7906496. Bibcode: 1993NYASA.696...63A. 
  47. ↑ "Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid". Journal of Medicinal Chemistry 33 (2): 833–8. February 1990. doi:10.1021/jm00164a057. PMID 1967654. 
  48. ↑ "Immunosuppressive activity of mycophenolate mofetil". Annals of the New York Academy of Sciences 685 (1): 309–29. June 1993. doi:10.1111/j.1749-6632.1993.tb35881.x. PMID 8363235. Bibcode: 1993NYASA.685..309E. 
  49. ↑ "Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF)". Clinical Transplantation 10 (1 Pt 2): 77–84. February 1996. PMID 8680053. 
  50. ↑ "The design and development of an immunosuppressive drug, mycophenolate mofetil". Springer Seminars in Immunopathology 14 (4): 353–80. 1993. doi:10.1007/bf00192309. PMID 8322167. 
  51. ↑ "Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil". Immunological Reviews 136 (1): 5–28. December 1993. doi:10.1111/j.1600-065x.1993.tb00652.x. PMID 7907572. 
  52. ↑ "Low-dose combination therapy of DUP-785 and RS-61443 prolongs cardiac allograft survival in rats". Transplant International 5 (Suppl 1): S482-3. 1992. doi:10.1111/tri.1992.5.s1.482. PMID 14621853. 
  53. ↑ "Enhancement of allograft survival by combination RS-61443 and DUP-785 therapy". Transplantation 55 (4): 691–4; discussion 694–5. April 1993. doi:10.1097/00007890-199304000-00001. PMID 8475537. 
  54. ↑ "Mycophenolate mofetil (RS-61443): preclinical, clinical, and three-year experience in heart transplantation". The Journal of Heart and Lung Transplantation 13 (4): 571–82. 1994. PMID 7947873. 
  55. ↑ "Risk Evaluation and Mitigation Strategy (REMS) Under Review for CellCept and Myfortic". U.S. Food and Drug Administration. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm148735.htm. 
  56. ↑ "New Agent to Prevent Kidney Transplant Rejection Now Available". Stanford University. 15 June 1995. https://web.stanford.edu/dept/HPS/transplant/html/cell-cept.htm. 
  57. ↑ "CellCept registry data demonstrated superior long-term organ transplant outcomes". F. Hoffmann-La Roche Ltd.. http://www.roche.com/investors/ir_update/inv-update-2004-05-17a.htm. 
  58. ↑ "Mycophenolate revisited". Transplant International 28 (5): 508–15. May 2015. doi:10.1111/tri.12554. PMID 25758949. 
  59. ↑ "Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil". Archives of Dermatology 139 (6): 739–42. June 2003. doi:10.1001/archderm.139.6.739. PMID 12810504. 
  60. ↑ "Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA". Virology 304 (2): 211–21. December 2002. doi:10.1006/viro.2002.1685. PMID 12504563. 
  61. ↑ "Inhibition of dengue virus replication by mycophenolic acid and ribavirin". The Journal of General Virology 87 (Pt 7): 1947–52. July 2006. doi:10.1099/vir.0.81655-0. PMID 16760396. 
  62. ↑ "Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus". The Journal of Infection 67 (6): 606–16. December 2013. doi:10.1016/j.jinf.2013.09.029. PMID 24096239. 
  63. ↑ "Mycophenolate mofetil for relapsing-remitting multiple sclerosis". The Cochrane Database of Systematic Reviews (2): CD010242. February 2014. doi:10.1002/14651858.CD010242.pub2. PMID 24505016. 

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