Микофенолат: Применение, эффективность и побочные эффекты.

Immunosuppressant medication

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.

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. It is also used for retroperitoneal fibrosis along with a number of other medications. Specifically it has also be used for psoriasis not treatable by other methods. Its increasing application in treating lupus nephritis has demonstrated more frequent complete response and less frequent complications Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side effects. Walsh proposed that mycophenolate should be considered as a first line induction therapy for treatment of lupus nephritis in people without kidney dysfunction.

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

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. Several cases of pure red cell aplasia (PRCA) have also been reported. 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 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.

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.

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.

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). IMPDH inhibition particularly affects lymphocytes since they rely almost exclusively on de novo purine synthesis. In contrast, many other cell types use both pathways, and some cells, such as terminally differentiated neurons, depend completely on purine nucleotide salvage. Thus, use of mycophenolic acid leads to a relatively selective inhibition of DNA replication in T cells and B cells.

Mycophenolate can be derived from the fungi Penicillium stoloniferum, P. brevicompactum and P. echinulatum. Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It reversibly inhibits inosine monophosphate dehydrogenase, 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. Other cells recover purines via a separate salvage pathway and are thus able to escape the effect. 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).

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

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.) 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. 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. 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). 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. 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. They synthesised a chemical variant for increased activity and reduced adverse effects. They subsequently demonstrated that it was useful in organ transplantation in experimental rats. After successful clinical trials, the compound was approved for use in kidney transplant by the U. S. Food and Drug Administration on 3 May 1995, and was sold under the brand name CellCept. It was approved for use in the European Union in February 1996.

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.

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