Leflunomide

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2.3.5.1 History. Leflunomide(LF), a derivative of isoxazole (HWA 486; Hoechst, Basel, Switzerland), inhibits various T-lymphocyte functions (317,318) and was first described as an inhibitor of the T-cell-dependent antibody production by B-cells (319-321). In recent years several studies have demonstrated that the effect of LF is mediated through inhibition of de novo pyrimidine synthesis and tyrosine phosphorylation (322-324).

2.3.5.2 Chemical Structure. Leflunomide (13; Fig. 12.17) is an isoxazole derivative [A^(4-trifluoro-methylphenyl)-5-methylisox-azol-4-carboxamide], with potent immuno-suppresive, anti-inflammatory, and anticancer activity (SU 101, Sugen Inc., USA).

2.3.5.3 Pharmacokinetics. Although leflunomide has been extensively studied in animal models of transplantation, its clinical use has been initially approved as a disease-modifying antirheumatic drug (Arava) for the treatment of rheumatoid arthritis. This has been attributed to the long half-life (14 days) of lefluno-mide in humans, which can lead to a difficult situation with regard to its dose adjustment. In rodents, A771726 an active metabolite of LF (13a; Fig. 12.18), however, had a half-life of 10-30 h, which is 10 times shorter than its half-life in humans. Because the absorption of

Figure 12.18. Structure of leflunomide analog A771726 (13a).

leflunomide varies significantly between individuals and produces severe adverse effects, less-toxic analogs of leflunomide are needed.

2.3.5.4 Pharmacology. After its administration, leflunomide is metabolized quickly to form an active metabolite, A771726, which has been identified as N-(4-trifluoromethyl-phenyl-2-cyano-3-hydroxy crotoamide. In vitro, A771726 is a potent inhibitor of protein tyrosine kinases (325) and human DHODH, an enzyme involved in pyrimidine biosynthesis (326). This in turn inhibits the proliferation of several immune and nonimmune cell lines and cell cycle progression (327,328).An-other important effect of A771726 is its ability to inhibit humoral-mediated responses by directly blocking T-cell-dependent and T-cell-in-dependent B-cell proliferation and antibody production (298).

In spite of the chemical potential of leflujio-mide, its mechanism of action is not yet clear. It has been hypothesized that leflunomide inhibits T-cell activation by blocking the lck and fyn families of tyrosine kinases. These enzymes are known to be associated with the transduction of such growth factor receptor signals as IL-2, interleukin 3 (IL-3) and tumor necrosis factor alpha (TNF-a) but not interleukin 1 (329). However, the most recent data show that leflunomide inhibits signal transduction after binding of interleukin 4 (IL-4) to the IL-4 receptor (330).

In vivo, leflunomide was found to prevent GVHD and prolonged allograft and xenograft survival in animal models. Moreover, lefluno-mide also suppressed antibody production in several animal models with alio and xenograft transplantation. In a rat model of GVHD, leflunomide not only was a powerful agent to prevent this otherwise terminal disorder, but was also effective when used as a therapy in an established GVHD. Its efficacy in preventing

GVHD has been attributed to the inhibition of uridine biosynthesis by leflunomide, which leads to a dual antiproliferative effect on both lymphocytes and smooth muscle cells (331, 332). It significantly prolonged survival of allografts: heart (333), pulmonary (334), and islet (335) in rat recipients. In the hamster-to-rat pulmonary model, although leflunomide displayed significant inhibition in xenograft rejection, it was accompanied by severe side effects (334,335). However, subsequent studies with combination therapy using a variety of clinically used immunosuppressants such as leflunomide plus MMF plus cyclosporine (336), leflunomide plus DSG (337), leflunomide plus cyclosporine (338, 339), leflunomide plus tacrolimus (340), and leflunomide plus brequinar (276) have been reported to be very effective in preventing several xenograft and allograft rejections in animal models. In one of the experiments, the combination of cyclosporine (20 mg/kg/day by gavage) and leflunomide (5mg/kg/day by gavage for 14-21 days) continuously from the day of transplant was able to completely inhibit the rejection of kidney, spleen, and pancreas xenografts in a hamster-to-rat xenotransplantation model. Only a transient treatment with leflunomide was necessary, and long-term graft survival could be maintained by cyclosporine alone. Histological examination of these grafts at >80 days posttransplantation indicated minimal signs of rejection (341). Leflunomide is currently undergoing clinical evaluation in a phase 1/11 clinical trial, to test its efficacy for preventing the rejection of kidney allografts.

2.3.5.5 Structure-Activity Relationship. Extensive structure-activity relationship studies with A771726 have been carried out to develop suitable analogs that will be clinically acceptable as immunosuppressants. A large number of compounds have been synthesized by different laboratories (342, 343), which suggests that substitution at position 4 of the aromatic ring results in potent congeners with enhanced activity compared to compounds with substitution at positions 2 and 3. Few malononitrilamide analogs (e.g., 279 and 715) have been identified that inhibit T- and B-cell proliferation, suppress immunoglobulin production, and interfere with cell adhesion.

The effects of these agents have been demonstrated in rat skin and cardiac alio- and xe-notransplant models. The combined effect of MNA and tacrolimus in a high responder rat cardiac allotransplant model has also been investigated. Optimal doses of MNA or tacroli-mus were found to have comparative effects on graft survival and histological changes, whereas a combination of the two drugs,was beneficial with respect to both these parameters. Histological analysis of grafts have confirmed the benefit of the drug combination and no additional toxicity has been observed with combined therapy (344). Interestingly, a novel leflunomide analog, HMR 279, has been found to potentiate the immunosuppressive efficacy of microemulsion cyclosporine (Neoral) in rodent heart transplantation and also in a stringent allogeneic rodent lung transplant model. Combination therapies of Neoral (7.5 mg/kg/ day) plus HMR 279 (10 mg/kg/day) or Neoral plus LFM were found to be most successful in preventing histologic allograft rejection compared to that of LFM monotherapy (345).Malononitrilamide analogs of A771726 are also being evaluated for immunosuppressive efficacy in preclinical models of transplantation.

2.3.5.6 Side Effects. In a phase II clinical trial, leflunomide showed high tolerability and efficacy in patients with advanced rheumatoid arthritis.

3 RECENT DEVELOPMENTS 3.1 Stem Cells

Stem cells are primitive cells that are capable of forming many different types of body cells. At the time of delivery, the blood in the baby's umbilical cord is quite rich in stem cells; however, as the child ages, these stem cells become less abundant and harder to find. Stem cells, induced to transform themselves into pancreatic cells, could overcome the shortage of donor pancreases and could possibly, when necessary, be genetically engineered to resist being rejected by the immune system. Liver tissue, damaged by infection or toxins such as alcohol, can similarly be replaced by stem cells differentiated into liver cells. Because the cells come from the patient's own body, there is no problem of rejection by the immune system, and no risk of introducing an infection that might have been present in a donor. However, the use of adult stem cells for therapy could certainly reduce, or even avoid, the practice of using stem cells obtained from human embryos or human fetal tissue. Adult stem cells, although present in only minute quantities, can be found throughout the body and are used to repair and regenerate certain types of tissue (346, 347).

Recently, exciting work has been performed in which cells exposed to appropriate inducing agents have been made to differentiate into a far larger number of cell types than was previously thought possible. Thus, bone marrow cells have been used to make nerve cells and nerve cells have been used to make liver cells.

Scientists from Stem Cells, Inc., demonstrated the production of mature liver cells from rigorously purified hematopoietic (blood) stem cells in mice. The study provides the first evidence that liver function can be restored from bone marrow cells in mice with a virulent form of liver failure and that highly purified blood stem cells can efficiently give rise to normal liver cells. Bone marrow is known to contain many cell types, including both mesen-chymal (bone- and tissue-forming) and hematopoietic (blood-forming) stem cells. Different subsets of bone marrow cells were purified and each subset was tested by transplantation into mice. Only the subsets containing blood stem cells were able to produce hepato-cytes. Furthermore, normal liver cells could be produced from as few as 50 of these highly purified hematopoietic stem cells. These remarkable results indicate that the hematopoi-etic stem cells are the only cells in the bone marrow responsible for the restoration of liver functions. This exciting development could greatly increase our ability to use adult stem cells therapeutically for the restoration of organs with end-stage disease instead of going for transplantation (348,349).

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