mycophenolic-acid and Vascular-Diseases

Mycophenolate mofetil (MMF, CellCept) is a prodrug of mycophenolic acid (MPA), an inhibitor of inosine-5'-monophosphate dehydrogenase. MPA depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation. MPA also inhibits the glycosylation and expression of adhesion molecules, and the recruitment of lymphocytes and monocytes into sites of inflammation. MPA depletes tetrahydrobiopterin and decreases the production of nitric oxide by inducible NO synthase without affecting the activity of constitutive NO synthases. Activated macrophages produce NO and superoxide, which combine to generate tissue-damaging peroxynitrite. By these two mechanisms MMF exerts anti-inflammatory activity. Unlike calcineurin inhibitors, MMF is not nephrotoxic and does not induce the production of TGFbeta, which is fibrogenic. MMF does not increase blood pressure, cholesterol levels or triglyceride levels in recipients. MMF reduces acute and chronic rejection in allograft recipients and is efficacious in some nephropathies. Evidence is accumulating that MMF may have clinical utility in some autoimmune disorders.

Topics: Azathioprine; B-Lymphocytes; Cytokines; Humans; Immunosuppressive Agents; Mycophenolic Acid; Nitric Oxide; T-Lymphocytes; Vascular Diseases

Topics: Adult; Arterioles; Blood Pressure; Cyclosporine; Diarrhea; Drug Resistance; Drug Therapy, Combination; Eye Diseases, Hereditary; Female; Fibrosis; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Hyalin; Immunosuppressive Agents; Intestinal Diseases; Male; Mycophenolic Acid; Prednisolone; Prospective Studies; Proteinuria; Skin Abnormalities; Treatment Outcome; Vascular Diseases

Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown.. In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8 ± 4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression.. No significant difference in CAV progression was evident between the treatment groups (P = 0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n = 39), CAV progression was attenuated with everolimus versus standard CNI (Δmaximal intimal thickness 0.00 ± 0.04 and 0.04 ± 0.04 mm, Δpercent atheroma volume 0.2% ± 3.0% and 2.6% ± 2.5%, and Δtotal atheroma volume 0.25 ± 14.1 and 19.8 ± 20.4 mm(3), respectively [P < 0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Δmaximal intimal thickness 0.06 ± 0.12 vs. 0.02 ± 0.06 mm and Δpercent atheroma volume 4.0% ± 6.3% vs. 1.4% ± 3.1%, respectively; P < 0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor.. Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.

Topics: Aged; Azathioprine; C-Reactive Protein; Calcineurin Inhibitors; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Scandinavian and Nordic Countries; Sirolimus; Ultrasonography, Interventional; Vascular Cell Adhesion Molecule-1; Vascular Diseases; von Willebrand Factor

The presence of renal noninflammatory necrotizing vasculopathy (NNV) is often associated with a severe form of lupus nephritis (LN), which is unresponsive to standard therapy. We conducted a 6-month randomized, prospective, open-label trial comparing mycophenolate mofetil (MMF) (1.5-2.0 g/day) with monthly i.v. cyclophosphamide (CTX) (0.75-1.0 g/m2) as induction therapy for class IV LN with NNV. The primary and second end points were complete remission (CR) and partial remission (PR), respectively. Of 20 patients recruited, nine were randomly assigned to MMF and 11 to CTX. The baseline characteristics between groups were not significant. CR was achieved in four patients (44.4%) receiving MMF and in none of the patients receiving CTX (P = 0.026). PR was achieved in two patients (22.2%) in the MMF group and three patients (27.2%) in the CTX group. The total remission rate (CR + PR) in the MMF and CTX group was 66.6 and 27.2%, respectively (P = 0.17). MMF was more effective than i.v. CTX in reducing proteinuria and haematuria. Adverse events were significantly less frequent with MMF than with CTX (P = 0.028). MMF was superior to i.v. CTX in inducing CR of LN with NNV and had a more favourable safety profile.

Topics: Adolescent; Adult; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; Glucocorticoids; Hematuria; Humans; Immunosuppressive Agents; Infusions, Intravenous; Lupus Nephritis; Middle Aged; Mycophenolic Acid; Prospective Studies; Proteinuria; Remission Induction; Vascular Diseases

A 17-year-old girl received lung transplantation after chronic respiratory failure. She developed a fever (> 38 °C) once or twice weekly starting 2 months after surgery, and multiple papulopustules on the skin waxed and waned for 4 months. She then developed blood-tinged sputum. She had been treated with triple immunosuppressants, including prednisolone, tacrolimus, and mycophenolate mofetil after lung transplantation, and her symptoms appeared during prednisolone dose reduction.

Topics: Adolescent; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Mycophenolic Acid; Prednisolone; Tacrolimus; Vascular Diseases

A 52-year-old man presented to our cardiology service for an elective diagnostic coronary angiogram for risk stratification in the context of stable angina. He was diagnosed with antiphospholipid syndrome 2 years prior and had three known thrombotic episodes in the form of a stroke, retinal artery occlusion and deep vein thrombosis. Our initial differential was atherosclerotic coronary artery disease, however, coronary angiography demonstrated a dominant right coronary artery with a long segment of chronic spontaneous dissection distally but with thrombolysis in myocardial infarction III flow. He was treated medically with antianginals which rendered him asymptomatic and is currently on regular follow-up in the cardiology outpatient department.

Topics: Angina, Stable; Angiography; Antibiotics, Antineoplastic; Anticoagulants; Antiphospholipid Syndrome; Calcium Channel Blockers; Coronary Vessel Anomalies; Diagnosis, Differential; Humans; Male; Middle Aged; Mycophenolic Acid; Myocardial Infarction; Treatment Outcome; Vascular Diseases

Whether the immunosuppressive regimen is associated with micro- and macro-vascular status in pediatric kidney transplant recipients (KTx) is unknown.. We performed a cross-sectional, case-control study in 44 pediatric KTx patients on either everolimus (EVR) plus calcineurin inhibitor or standard treatment, i.e. mycophenolate mofetil plus calcineurin inhibitor. Measurement of carotid intima-media thickness (cIMT) via ultrasound, central pulse wave velocity (PWV) by a cuff-based oscillometric technique, and skin microvascular blood flow during local heating via laser-Doppler-fluximetry (LDF) served as marker of subclinical vascular disease. Serum concentrations of angiopoietin-1 and -2, fibroblast-growth factor 23 (FGF23) and soluble klotho were measured.. EVR-treated patients exhibited a similar degree of hypertension, increased cIMT, elevated pro-inflammatory angiopoietin-2, and diminished endothelial survival factor angiopoietin-1 compared to healthy children but presented with a twofold more reduced skin micro-vascular function compared to standard treatment (each p< 0.001). By contrast, PWV and soluble klotho levels were normal in both groups.. Endothelial dysfunction seems more frequent in KTx patients on EVR-based immunosuppressive regimen compared to standard immunosuppression.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Endothelium; Everolimus; Fibroblast Growth Factor-23; Humans; Immunosuppressive Agents; Kidney Transplantation; Microcirculation; Mycophenolic Acid; Vascular Diseases

Topics: Azathioprine; Calcineurin Inhibitors; Cell Proliferation; Disease Progression; Drug Therapy, Combination; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Muscle, Smooth, Vascular; Mycophenolic Acid; Risk Factors; Sirolimus; Vascular Diseases

Immunosuppressive drugs common in clinical transplantation are known to have untoward effects on the vascular system. The effects of some drugs, notably cyclosporin A (CyA), have been studied on the vascular system, while those of others have not. In the vascular system, endothelial cells are the predominant cell type exposed to intravascular concentrations of immunosuppressive drugs. We therefore studied the effects of drugs common in clinical transplantation on endothelial cells in a capillary tube assay. The endothelial cells in the capillary tubes are morphologically more similar to those in the microvasculature than endothelial cells in monolayers. We studied the kinetics and extent of capillary tube formation and prostacyclin (PGI2) and endothelin-1 (ET-1) release from the in vitro capillaries to determine the morphological and biochemical effects of five immunosuppressive agents on endothelial function. We found a significant difference in the morphological and biochemical effects of the two common calcineurin inhibitors, CyA and tacrolimus (FK506) on capillary morphology in vitro. The former had a pronounced injurious effect on the morphology of the in vitro capillaries, while the latter did not. CyA also significantly increased ET-1 release by the capillaries, but FK506 did not. Mycophenolate mofetil (MMF) was the only other agent that had a moderately injurious effect on the morphology of the in vitro capillaries. Sirolimus (rapamycin) and dexamethasone, similar to FK506, had no effect on the capillary morphology. All these agents, except dexamethasone, increased PGI2 release. Our data suggest that CyA adversely affects the morphology of the microvasculature and that this is mediated, at least partly, by an increased ET-1 release by endothelial cells exposed to CyA. These findings describe a novel effect of CyA and MMF on endothelial cells that could be relevant to understanding the mechanisms of immunosuppressive drug-mediated endothelial injury in clinical transplantation.

Topics: Cell Survival; Cyclosporine; Dexamethasone; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Immunosuppressive Agents; In Vitro Techniques; Mycophenolic Acid; Sirolimus; Tacrolimus; Vascular Diseases