*2.3.1. Mechanism of action*

MPA produces potent selective, noncompetitive, and reversible inhibition of inosine mono‐ phosphate dehydrogenase (IMPDH), an important enzyme in the *de novo* pathway of guanine nucleotide synthesis (Table 1). B and T lymphocytes are highly dependent on this pathway for cell proliferation, while other cell types can use salvage pathways; MPA therefore selectively inhibits lymphocyte proliferation and functions, including antibody formation, cellular adhesion, and migration [1,30]. *In vitro* and *in vivo* studies have demonstrated the ability of MPA to block proliferative responses of T and B lymphocytes, and inhibit antibody formation and the generation of cytotoxic T-cells [31]. In a preclinical study in mice, MPA increased survival of heart and pancreatic islet cell allografts. Studies in rats have also demonstrated prolonged heart allograft survival, as well as reversal of acute rejection and prevention of rejection in the sensitized animal. Antirejection effects have been attributed to decreased recruitment of activated lymphocytes to the graft site [32].

#### *2.3.2. Side effects*

The principal adverse effects of MPA are gastrointestinal, these include diarrhea, nausea and vomiting; hypertension; hematologic effects (anemia and leukopenia) and neurologic effects (anxiety asthenia dizziness headache insomnia tremor). There also is an increased incidence of some infections, especially sepsis associated with cytomegalovirus [1,33-35]. Diarrhea was reported in 36.1% of renal transplant patients, 45.3% of cardiac transplant patients, and 51.3% of hepatic transplant patients in a clinical study. Vomiting was reported in 33.9% of cardiac transplant patients, and 32.9% of hepatic transplant patients. Nausea was reported in 23.6% of renal transplant patients, 54% of cardiac transplant patients, and 54.5% of hepatic transplant. The incidence of adverse gastrointestinal complications requiring dose reduction. Usually occurs early in therapy and respond to dose reduction or switching from two to three divided daily doses [34].

while immunotherapy with SRL *per se* is not nephrotoxic, patients treated with CsA plus SRL have impaired renal function compared to patients treated with CsA and either azathioprine or placebo. Renal function therefore must be monitored closely in such patients. Other adverse effects include anemia, leukopenia, thrombocytopenia, hypokalemia or hyperkalemia, fever, and gastrointestinal effects. Delayed wound healing may occur with SRL use. As with other immunosuppressive agents, there is an increased risk of neoplasms, especially lymphomas,

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Like SRL, EVL binds to the cytosolic immunophyllin FKBP12; both agents inhibit growth factor-driven cell proliferation, including that of T-cells and vascular smooth muscle cells. After binding to and forming a complex with the cytoplasmic protein FKBP-12, this complex binds to and inhibits the mammalian Target Of Rapamycin (mTOR) and phosphorylates P70 S6 ribosomal protein kinase (a substrate of mTOR) (Table 1). The phosphorylation of P70 S6 ribosomal protein kinase by the EVL complex prevents protein synthesis and cell proliferation. The EVL:FKBP-12 complex does not affect calcineurin activity [40,41]. Binding of EVL to FKBP12 is weaker than that of SRL (about 3-fold), related to 40-O-alkylation, and this correlates with a 2- to 3-fold lower in vitro immunosuppressive activity for EVL. However, the oral *in vivo* activity of EVL has been at least equipotent to oral SRL in several animal allotransplan‐ tation/autoimmune disease models. This appears related to the chemical modification in EVL (2-hydroxyethyl chain), providing more favorable pharmacokinetic properties (eg, absorption, disposition) which compensate for relatively poor *in vitro* activity [40]. EVL and SRL antago‐

Side effects seem to be the same as with SRL [1]. Endocrine abnormalities, including hyperli‐ pidemia and hypertriglyceridemia, have been reported with EVL treatment. Monitoring for hyperlipidemia is recommended in all patients; diet, exercise, and lipid lowering therapy should be initiated if hyperlipidemia occurs. In a clinical study with EVL, the most important causes of discontinuation in 69 patients were severe infections (2.3%), pneumonitis (6.8 %), acute rejection episode (4.1%), proteinuria (4.1%). Although the overall incidence discontinu‐ ation due to side effects was higher in the EVL than SRL group, there was no greater frequency

Azathioprine is a purine antimetabolite. It is an imidazolyl derivative of 6-mercaptopurine. Azathioprine was first introduced as an immunosuppressive agent in 1961, helping to make allogeneic kidney transplantation possible. It is indicated as an adjunct for prevention of organ transplant rejection and in severe rheumatoid arthritis. It has long been used as a steroid sparing agent in a variety of clinical scenarios [1,45]. In the United States azathioprine was usually combined with prednisone and CsA. Azathioprine was regarded as an adjunctive agent to CsA and the combination was often called "triple therapy". The term "adjunctive

nize TRL based calcineurin inhibition via saturation of FKBP12 [1,42].

and infections [1,36,37].

*2.4.4. Side effects of EVL*

of severe side effects [43,44].

**2.5. Azathioprine**

*2.4.3. Mechanism of action of EVL*

Hypertension was reported in 28.2% of renal transplant patients, 77.5% of cardiac transplant patients, and 62.1% of hepatic transplant patients [34]. Leukopenia was 23.2% and 34.5% in renal transplant, 30.4% in cardiac transplant, and 45.8% in hepatic transplant in a clinical study. Complete blood counts should be performed weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year [34].
