| Mycophenolate mofetil,MMF,was used as an antibacterial and antifungal drug in early time,then it was used as antitumor drug at the end of 1960's.It wasn't recognized that MMF has immunosuppressive function until late in 1980's. Mycophenolate mofetil(MMF) suppresses antibody formation by B cells through impairment of de novo purine synthesis suggested that MMF may reduce proteinuria in a variety of glomerular diseases,Lei-Shi Li adopted MMF to adult patients with glomerulus diseases first,and we did it in children for several years.1.PharmacokineticsMMF can be absorbed thoroughly and be hydrolyzed into MPA rapidly and reaches its peak concentration in 1 hour and 8～12 hours.About 97.5 percent of MPA is combined with protein and inactivated.Only 2.5 percent of MPA is dissociated, which has immunosuppressive function.It is metabolised into 7-O-MPA-glucuronide (MPAG) in liver,gastrointestinal tract and kidney by uridine diphosphate gluconosyltransferases(UGTs) and loses its active,and is excreted into urine by tubular secretion.The half-life of MPA is 17.9 hours.The pharmacokinetics of MMF 1200mg/m2.d-1 in children is similar to that of MMF 2g/d in adults.2.the mechanism of MMF as an immunosuppressor2.1 MMF inhibits actived T-lymphocyte and B-lymphocyte:Mycophenolate mofetil inhibits lymphocyte proliferation via a blockade of the enzyme inosine 5'-monophosphate dehydrogenase,an rate-limiting enzyme on de novo synthesis which lymphocytes solely depend to generate the purines necessary for DNA/RNA synthesis,whereas other cells can synthesize GMP sufficiently through the salvage pathway.So MMF is a distinctive immunosuppressive2.2 MMF can inhibit glycosylation of adhesion molecules and the binding of activated lymphocytes to activate endothelial cells to reduce tissue damage which was caused by adhesion molecules.MMF can also reduce the soakage of lymphocyte,monocyte and neutrophilic granulocyte in inflammation tissue.2.3 MMF can inhibit multiplication of glomerulus mesangial cells,and its degree depends on the concentration of MPA.When the concentration of MPA≥5μM, 98 percent of IMPDH's activity will be repressed.It is discovered that MMF can inhibit multiplication of glomerulus mesangial cells in vivo and in vitro.2.4 MMF can reduce the morbidity of Heymarm nephritis in experiment animal model through inhibiting the generation of serum anti-Fx1A antibody and the deposition of immunoglobulin in glomerulus basilar membrane.According to this, MMF may became a hopeful therapy to primary membranous nephropathy.2.5 MMF inhibits the express of auto-antibodies and their deposits,reduces the adhesion molecules and inhibits adhesion molecules' binding function:MMF can inhibit the express of auto-antibodies(especially anti-DNA antibody) and the secretion of IgG,reduce the titer serum immunocomplex through inhibiting the proliferation of lymphocyte proliferation,and suppress the development of lupus glomerulonephritis through reducing the immunoglobulin and immune complexes deposits to glomerular capillary wall in lupus nephritis.So MMF will delay the occur of protein urine in lupus nephritis,reduce 24-hour urinal protein,relieve the kidney damage,prolong the living period and reduce the mortality.MMF can also reduce vascular lesions in lupus nephritis through inhibiting the gathering and soakage of lymphocyte,monocytes and neutrophils in inflammation tissue.Inspire of this,MMF doesn't affect the rate of CD4/CD8.2.6 MMF inhibits the damage of vessel's endothelium and will benefit to kidney vasculitis:MMF inhibits the proliferation of lymphocyte,the expression of adhesion molecules,the soakage of lymphocyte,monocyte and neutrophilic granulocyte in inflammation tissue,and the multiplication of endothelium and mesangial cells.MMF also inhibits the multiplication of endothelim cells in vessels,smooth muscle cells of artery and fibrocyte.And Henoch-Schonlein purpura(HSP) is a systemic immunoglobulin A-mediated leukocytoclastic vasculitis.So MMF can alleviate the damage of vessel's endothelium and treat the pathological changes of kidney vasculitis.2.7 Mycophenolate mofetil blocks de novo biosynthesis of guanine nucleotides by inhibiting inosine monophosphate dehydrogenase(IMPDH) which is a rate-limiting enzyme in the de novo synthesis of guanine nucleotide and depletes the intracellular guanosine triphosphate(GTP) & pool of 2-deoxyguanosine 5-triphosphate(dGTP) which is a prerequisite for DNA and RNA synthesis.It is reported in vitro and in vivo that IMPDH inhibitor has a broad-spectrum antiviral activity against a variety of viruses,including DNA viruses(hepatitis B virus,human cytomegalovirus,and herpes simplex virus type 1) and RNA viruses(respiratory syncytial virus,parainfluenza-3 virus,bovine viral diarrhea virus,Venezuelan equine encephalomyelitis virus,dengue virus,yellow fever virus,coxsackie B3 virus, encephalomyocarditis virus and influenza A virus),even human immunodeficiency virus(HIV).Mycophenolate mofetil may have the inhibitory effect on HBV replication,especially before integration of HBV-DNA into the host genome which probably prevents the HBV-associated nephropathy induced by immunopathologenetic mechanisms between viral and host factors.These finding may imply that HBV-associated nephrotic syndrome would receive MMF as an immunosuppressive therapy together with anti-Hepatitis B viral drugs.3.Laboratory study—MMF delays rabbit artery cirrhosis lead by high fat.The progress of artery cirrhosis includes inflammation,soakage and activated of immunologically competent cells.Foam cells derived from macrophages act an important function in formation of artery cirrhosis.MMF can inhibit the soakage of macrophages and the multiplication of smooth muscle cells,reduce the overexpression of P-selectin,vascular cell adhesion molecule(1ICAM-1),inducible nitric oxide synthase(iNOS),etc.So it can delay process of artery cirrhosis,relieve the proliferation of tunica intima.Our study showes that MMF can delay process of artery cirrhosis though it doesn't reduce the concentration of total cholesterol,triglyceride,HDL,LDL,VLDL.4.MMF therapy in glomerulus diseases4.1 MMF and primary nephrotic syndrome:Several reports about MMF therapy primary nephrotic syndrome were reported since Briggs used MMF to treat the primary glumerulus disease in 1998,but they came to a series of results.Some of them drew a conclution that MMF is an effective immunosuppressant for primary nephrotic syndrome,and others think it is not better than other immunosuppressants especially for frequently relapse nephrotic syndrome.It is appropriate for the patients with increased serum enzymes,renal function failure,accompanied HBV or HCV infection,or the patients who can't be tolerant of other immunosuppressants such as CsA,CTX,etc.We reported that MMF achieved nice short-term curative effect similar to that reported by Briggs,But the long-term curative effect of MMF for primary nephrotic syndrome especially those relapse frequently should be estimated again 4.2 MMF and nephritis lupus:Although we human being have got a big progress in nephritis lupus because of intravenous cyclosphosphamide therapy,there is still a thorn in our back that the long prognosis of nephritis lupus especially with vasculitis is awfully.MMF has unique curative effect to theⅣtype of nephritis lupus with evidence vasculitis.The remission rate of different studies is quite different.It maybe relate to the following factors:①the period of MMF therapy,②the pathology of different studies(Ⅳ,Ⅲ+Ⅳ,Ⅴ,Ⅳ+Ⅴ),③race(the rate of black,white,yellow),④vasculitis degree in mesenchyme.We used MMF(800-1200mg/m2.d) to treat patients withⅣtype of nephritis lupus,and got an exciting resultOu drew a statistic conclution that the availability and safety of MMF therapy for nephritis lupus was similar to CTX.But it still need large-bind studies to confirm them.4.3 MMF and HBV-associated nephrotic syndrome:It is well known that immunosuppressive agents such as corticosteroids and cytotoxic drugs can accelerate the replication of HBV and antiviral drugs alone have been considered to be kind of treatment for patients with HBV-associated nephrotic syndrome.But when such therapy fails,there is little guidance about how to treat these patients.Recently, mycophenolate mofetil,a new immunosuppressive agent,has been reported to have the inhibitory effects on viral replication and to enhance the antiviral activity of antiviral drugs both in vitro and in vivo.mycophenolate mofetil may have the inhibitory effect on HBV replication,especially before integration of HBV-DNA into the host genome which probably prevents the HBV-associated nephropathy induced by immunopathologenetic mechanisms between viral and host factors.Sequential research showed that mycophenolate mofetil also can potentiate the activity of guanine- and diaminopurine-based nucleoside analogues[such as penciclovir(PCV), lobucavir(LBV),3'-fluorodideoxyguanosine(FLG) and diaminopurine dioxolane (DAPD)]against hepatitis B virus.The mechanisms about the potentiation effect is not finally defined,probably assumed that the 5'-triphosphorylated derivatives of the guanine-based nucleoside analogues,in the presence of reduced levels of dGTP, inhibit more efficiently the priming reaction as well as the reverse transcription and DNA-dependent DNA polymerase activity of the HBV polymerase.These finding may imply that the children with HBV-associated nephrotic syndrome would receive MMF as an immunosuppressive therapy together with anti-Hepatitis B viral drugs.We used mycophenolate mofetil and interferon-αto therapy six boys with HBV-associated nephrotic syndrome,and achieved a complete remission of proteinuria,normalization of liver enzymes(alanine aminotransferase) in all patients, and serum HBsAg,HBeAg and anti-HBc became negative as well as HBV-DNA can no longer be detected in four patients after six months therapy.However,serum HBsAg,HBeAg and anti-HBc was still found to be positive and HBV-DNA did not have significant change in other two patients.In our study,the inhibitory effects of mycophenolate mofetil to HBV replication can be observed obviously.However, whether mycophenolate mofetil has ant-viral effect and whether mycophenolate mofetil can potentiate the ant-viral effect of ant-viral drugs or not needs further research.4.4 MMF and HSPN:HSP is a systemic immunoglobulin A-mediated leukocytoclastic vasculitis.IgAl takes an important part in the cause of HSPN,the basic pathological change is broadly vasculitis.The long-term outcome of HSPN mainly depends on the damage degree of nephrotic lession.The symptom and therapy of HSPN vary enormously,and it argues endlessly whether glucocortitoid should be used in HSPN therapy.Recently some experts drew a conclution that MMF may have a peculiar role in HSPN from the immunological mechanism of MMF,and MMF was considered as the first selection for severe HSPN in Research Institute of Nephrology,Jinling Hospital and they reported that the relief rate of urine protein in MMF group was obvious higher than that in CTX group.But the relief rate of urine protein in MMF group was similar to that in CTX groupin our study.It needs more and long period follow-up studies.5.Side effect5.1 Infection:MMF doesn't affect other cells because it inhibits T-lymphocyte and B-lymphocyte alternatively.So patients with MMF will have less infection than those with other immunosuppressors.But Smith found that MMF inhibit the expression of antibody and immunoresponsiveness,and he drew a contrary conclusion,based on this theory,MMF was used in patients with immuno-diseases. Recently,people pay more attention on infection caused by MMF.5.2 Inhibit proliferation of bone marrow:MMF inhibits T-lymphocyte and B-lymphocyte alternatively.In theory,MMF inhibit proliferation of bone marrow slightly.But Hebert reported that proliferation of bone marrow was inhibited in patients with MMF therapy 4 years later,9 out of 19 patients got granulocytopenia,6 anemia,and 5 thrombocytopenia.The auther pointed that the security of MMF is the same as other immunosuppressors.5.3 Gastroenteric reaction:MMF will be hydrolyzed into MPA immediately, which has the activity of immunodepression.MPA hurts the stomach and intestines slightly.The clinical manifestation includes slight nausea,vomiting,diarrhea,even pancreatitis and hemorrhage grastritis.Many of them are dose-dependent and won't last long after drug withdrawal.Even though,it cannot be taken with alkali drugs simultaneous in clinics,otherwise it will reduce the curative effect.5.4 Other side effects:rise of the liver enzymes,skin rash,skelalgia,ostealgia, debilitation,headche,fever,tetany,leukocytosis,photosensitivity,non-infected cough, secondary pulmonary fibrosis,atrophy of intestinal villi,and etc. Overal,MMF inhibits lymphocyte proliferation via a blockade of the enzyme inosine 5'-monophosphate dehydrogenase,an rate-limiting enzyme on de novo synthesis which lymphocytes solely depend to generate the purines necessary for DNA/RNA synthesis.MMF inhibits the express of auto-antibodies and their deposits, reduces adhesion molecules and the titer of serum immunocomplex,inhibits adhesion molecules' binding function,reduces the soakage of lymphocyte,monocyte and neutrophilic granulocyte in inflammation tissue,has the inhibitory effects on viral replication and enhances the antiviral activity of antiviral drugs both in vitro and in vivo,and delays artery cirrhosis lead by high fat.MMF may be used to reduce proteinuria in a variety of glomerular diseases especially for nephritis lupus,HSPN, primary nephrotic syndrome with increased serum enzymes,or renal function failure, or accompanied HBV or HCV infection,or the patients who can't be tolerant of other immunosuppressants such as CsA,CTX,etc.However,whether MMF has ant-viral effect and potentiates the ant-viral effect of ant-viral drugs or not needs further research.
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