**6.8 Other drugs**

Many other agents are used to interfere with secondary signaling, and may therefore aid in tolerance induction[18].

#### *Interferons*

108 Liver Transplantation – Basic Issues

Voclosporin is a calcineurin inhibitor that is under development by Isotechnika as of 2010. This company uses calcineurin as a surrogate marker to assess the amount of immunosuppression achieved using drugs in this category. Other companies also have next

Antiproliferative agents inhibit DNA replication and suppress B cells and T cells proliferation. Azathioprine and MMF are commonly used antiproliferative agents. MMF is an organic synthetic derivative of the natural fermentation product mycophenolic acid (MPA) that causes the noncompetitive reversible inhibition of inosine monophosphate dehydrogenase, which interferes with purine synthesis. Adverse effects of MMF include nausea, diarrhea, leukopenia, and thrombocytopenia. Invasive CMV infection has also been rarely associated with MMF. The introduction of MMF has been shown to be associated with improvement or stabilization of renal function, even several years after transplantation. Other antiproliferative agents, such as cyclophosphamide and, more recently, leflunomide,

Sirolimus is a macrocyclic antibiotic produced by *Streptomyces hygroscopicus* fermentation. It is used to prevent rejection reactions. Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side effects. Sirolimus binds to FKBP-12 and modulates the activity of mTOR, which inhibits IL-2-mediated signal transduction and results in T- and B-cell cycle arrest in the G1-S phase. Sirolimus is associated with numerous adverse effects including leukopenia, thrombocytopenia, anemia, hypercholesterolemia, hypertriglyceridemia, proteinuria, ae well as leg oedema. Contrary to Cyclosporine and tacrolimus, drugs that affect the first phase of T lymphocyte activation, sirolimus affects the second phase of T lymphocyte activation, signal transduction and lymphocyte clonal proliferation. So sirolimus is not used early after transplant because of wound dehiscence. Also sirolimus carries a black box warning that cautions against possible development of early postttransplant hepatic artery thrombosis. Although sirolimus binds to FKBP-12 like tacrolimus, the complex inhibits mTOR, not calcineurin. Therefore, sirolimus acts synergistically with Cyclosporine, and when used in combination with other immunosuppressants, it has few side effects. Also, it indirectly inhibits several T lymphocyte-specific kinases and phosphatases, preventing their transition from G1 to the S phase of the cell cycle. In a similar manner, sirolimus prevents plasma cell differentiation, reducing the production of IgM, IgG, and IgA antibodies. It has also been associated with mucositis, delayed wound healing, lymphocele formation, pneumonitis, and prolonged delayed graft function. It is also active against tumors that are PI3K/AKT/mTOR-dependent.

**Everolimus** is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an

*Voclosporin* 

generation drugs in this class in their pipelines.

**6.6 Mammalian target of rapamycin (mTOR) inhibitors** 

**6.5 Antiproliferative agents** 

have also been used.

**6.7 Everolimus** 

IFN-β suppresses the production of Th1 cytokines and monocyte activation; it is used to slow down the progression of multiple sclerosis. IFN-γ can trigger lymphocyte apoptosis.

#### *Opioids*

Prolonged use of opioids can cause immunosuppression of both innate and adaptive immune responses. Decreased proliferation and function have been observed in macrophages and lymphocytes. It is hypothesized that these effects are mediated by opioid receptors expressed on the surface of these immune cell populations.

#### *Small biological agents*

Fingolimod is a new synthetic immunosuppressant that is currently in phase 3 of clinical trials. It increases the expression or changes the function of certain lymphocyte adhesion molecules, such as α4/β7 integrin, causing their accumulation in the lymphatic tissues and their subsequent removal from circulation. In this respect, it differs from all other known immunosuppressants.

The use of any immunosuppressive drug requires a balance between the risk of loss of transplanted organ and the toxicity of the agent. The goal is to balance an appropriate level of immunosuppression with the long-term risks, which include the development of infections, cancer, and metabolic complications.
