tacrolimus and brequinar

Maintenance immunosuppressive drugs act by partially blocking rate-limiting steps in the immune response. The new maintenance immunosuppressive drugs are either inhibitors of de novo synthesis of nucleotides (purines or pyrimidines), or are immunophilin-binding drugs that inhibit signal transduction in lymphocytes. The new inhibitors of de novo nucleotide synthesis include mycophenolate mofetil (MMF), mizoribine (MZ), brequinar (BQR), and leflunomide (LEF). MMF and MZ act to inhibit de novo purine synthesis, by inhibition of inosine monophosphate dehydrogenase (IMPDH). They create a selective immunodeficiency in T and B lymphocytes. MMF is hydrolyzed to mycophenolic acid (MPA), an uncompetitive inhibitor of IMPDH. MPA reduces the pools of guanine nucleotides, and increases some adenine nucleotides, inhibiting the cell cycle. Thus the number of specific effector T and B lymphocytes is reduced by limiting clonal expansion. MZ is a competitive inhibitor of IMPDH, which creates a similar defect. The relative clinical effectiveness of MMF versus MZ is not known. MMF has been approved in a number of countries; MZ has been approved in Japan. The inhibitors of de novo pyrimidine synthesis (BQR, LEF) act on the enzyme dehydroorotate dehydrogenase. Neither is currently in clinical trials in transplantation. The new immunophilin-binding drugs inhibit either the calcium-dependent phosphatase calcineurin (CN) [tacrolimus (or FK-506) and the microemulsion form of cyclosporine (CsA)] or signaling from growth factor receptors [rapamycin (sirolimus)]. Tacrolimus binds to FK binding protein-12 (FKBP-12) to create a complex that inhibits CN. CsA binds to cyclophilin to create a complex that inhibits CN. Inhibition of CN prevents activation of cytokine genes in T cells. The relative clinic effectiveness of tacrolimus versus microemulsion CsA is unknown. Rapamycin inhibits signaling from growth factor receptors, such as IL-2R. Rapamycin binds to FKBP to create a complex that engages proteins called TOR (target of rapamycin), or RAFT (rapamycin and FKBP target), which may be kinases. The result is a block in the ability of cytokine receptors to activate cell cycling, interfering with clonal expression. Deoxyspergualin, a parenteral drug in development for induction or antirejection therapy, may inhibit intracellular chaperoning by Hsc70, a member of the heat shock protein family. It may have its principal effect by inhibiting the activation of transcription factor NF-kappa B i

Topics: Amino Acid Isomerases; B-Lymphocytes; Biphenyl Compounds; Calcineurin; Calmodulin-Binding Proteins; Carrier Proteins; Cyclosporine; Enzyme Inhibitors; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Isoxazoles; Leflunomide; Mycophenolic Acid; Oxidoreductases; Peptidylprolyl Isomerase; Phosphoprotein Phosphatases; Polyenes; Purines; Pyrimidines; Receptors, Cytokine; Ribonucleosides; Signal Transduction; Sirolimus; T-Lymphocytes; Tacrolimus

Topics: Biphenyl Compounds; Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; Spiro Compounds; Tacrolimus; Transplantation Immunology

Topics: Animals; Antimetabolites; Azathioprine; Biphenyl Compounds; Cell Differentiation; Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Lymphocytes; Lymphokines; Oligonucleotides, Antisense; Polyenes; Receptors, Cytokine; Ribonucleosides; Signal Transduction; Sirolimus; Tacrolimus

In summary, many new modalities of immunosuppression after transplantation are being investigated (Fig. 1). These approaches include various new drugs or monoclonal antibodies that target different cell subsets, cellular activation pathways, cellular effector function or mediators (such as cytokines) of effector function, ligands that stabilize cellular interactions, or antimetabolites that preferentially affect lymphocytes (Tables 4 and 5). Because of the excellent early graft and patient survival results after liver transplantation under various current immunosuppressive protocols, future clinical trials using these various new modalities will require large numbers of patients to show statistically significant differences in graft or patient survival. Therefore, other criteria in addition to graft and patient survival must be analyzed to evaluate the importance of new immunosuppressive therapies. These criteria may include incidence of acute or chronic rejection, long-term graft function, incidence of infectious complications, length of hospitalization, drug toxicity, and patient tolerance and compliance with new therapies.

Topics: Alprostadil; Animals; Antibodies, Monoclonal; Biphenyl Compounds; Child; Disease Models, Animal; Dogs; Guanidines; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Polyenes; Rats; Sirolimus; Tacrolimus

Topics: Biphenyl Compounds; Cyclosporins; Guanidines; Humans; Immunosuppressive Agents; Kidney; Mycophenolic Acid; Polyenes; Sirolimus; T-Lymphocytes; Tacrolimus; Transplantation Immunology

Topics: Animals; Biphenyl Compounds; Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; Polyenes; Sirolimus; Tacrolimus

Topics: Animals; Biphenyl Compounds; Cyclosporine; Graft Rejection; Guanidines; Humans; Immunosuppressive Agents; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; Tacrolimus; Xenobiotics

Drug toxicity is one of the major problems in clinical immunosuppression. Combining two immunosuppressants in low or ineffective doses is an attractive strategy if it helps to reduce drug-related toxicity. We examined the immunosuppressive efficacy of brequinar (BQR) in combination with leflunomide (Lef) or tacrolimus (FK) in a heterotopic rat cardiac allotransplantation model. Abdominal heterotopic heart grafts (DA x LEW) were immunosuppressed from the time of transplantation and continued until the ninth posttransplant day (POD) in experiments examining prophylaxis of rejection treatment (PRT). In a separate series of experiments designed to test rescue treatment (RT), immunosuppression was begun on POD 4 and continued for 10 days; transplanted rats were sacrificed the following day intentionally. Cardiac rejection was monitored by palpation and documented by light microscopy. Immunosuppressive drugs (BQR 3 mg/kg and 12 mg/kg; BQR 3 mg/kg + Lef 5 mg/kg; BQR 3 mg/kg + FK 0.5 mg/kg) were given orally by gavage; thrice weekly according to the monotherapy or dual-therapy dosing protocol. Median survival time of the cardiac graft for controls (no treatment) was 5 days. BQR monotherapy 3 mg/kg (low dose) improved graft survival (P = 0.003); graft histology showed moderate acute rejection. BQR monotherapy 12 mg/kg (therapeutic dose) application in the PRT or RT treatment arms of the study design resulted in aortic-graft ruptures and clinical toxicity in each treatment arm due to overimmunosuppression; normal graft morphology was maintained. Successful rescue of rejecting grafts was histologically documented. Combining BQR with Lef or FK in the PRT protocol showed prolonged graft survival in both drug combination groups (median survival time, 14 days; P = 0.009 and 0.014, respectively). Using an identical combination protocol for RT, all grafts achieved a 14-day graft survival; cardiac histology showed reversible moderate acute rejection. BQR given in the presence of Lef or FK not only prevented acute rejection but intercepted it so long as it was administered; grafts were rejected within 4 days of stopping immunosuppression in the PRT study. These combinations using low or subtherapeutic doses may be important for controlling transplant rejection and rescuing ongoing graft rejection. The need for continuing treatment in this strongly allogeneic model is highlighted.

Topics: Animals; Biphenyl Compounds; Drug Evaluation, Preclinical; Drug Therapy, Combination; Graft Rejection; Heart Transplantation; Immunosuppression Therapy; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Postoperative Period; Rats; Rats, Inbred Lew; Tacrolimus; Transplantation, Homologous; Transplantation, Isogeneic

Topics: Animals; Biphenyl Compounds; Drug Therapy, Combination; Graft Rejection; Graft Survival; Heart Transplantation; Histocompatibility Testing; Immunosuppressive Agents; Isoxazoles; Leflunomide; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Spleen; Tacrolimus; Transplantation, Homologous

Topics: Animals; Antibody-Dependent Cell Cytotoxicity; Biphenyl Compounds; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Graft Rejection; Graft Survival; Heart Transplantation; Immunization; Immunosuppressive Agents; Lymphocyte Culture Test, Mixed; Male; Rats; Rats, Inbred BUF; Rats, Inbred Lew; Skin Transplantation; T-Lymphocytes; Tacrolimus; Transplantation, Homologous

Topics: Adult; Biphenyl Compounds; Cyclosporine; Dose-Response Relationship, Drug; Dose-Response Relationship, Immunologic; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Leukocytes, Mononuclear; Lymphocyte Activation; Pokeweed Mitogens; Tacrolimus

Topics: Animals; Antibodies; Antineoplastic Agents; Azathioprine; Biphenyl Compounds; Cricetinae; Cyclophosphamide; Graft Survival; Guanidines; Heart Transplantation; Immunosuppressive Agents; Liver Transplantation; Male; Mesocricetus; Methotrexate; Mycophenolic Acid; Rats; Rats, Inbred Lew; Ribonucleosides; Tacrolimus; Transplantation, Heterologous

Topics: Aspartic Acid; Biphenyl Compounds; Calcimycin; Cells, Cultured; Cyclosporine; Humans; Immunosuppressive Agents; Interleukin-2; Lymphocyte Activation; Lymphocytes; Mycophenolic Acid; Phosphonoacetic Acid; Ribonucleosides; T-Lymphocytes; Tacrolimus; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Heterotopic hamster hearts transplanted to unmodified LEW rats underwent humoral rejection in 3 days. Survival was prolonged to a median of 4 days with 2 mg/kg/day FK506. As monotherapy, 15 mg/kg/day cyclophosphamide greatly prolonged graft survival--far more than could be accomplished with RS-61443, brequinar (BQR), mizoribine, methotrexate, or deoxyspergualin. However, when FK506 treatment, which was ineffective alone, was combined with a short induction course (14 or 30 days) of subtherapeutic BQR, RS-61443, or cyclophosphamide, routine survival of heart xenografts was possible for as long as the daily FK506 was continued. In addition, a single large dose of 80 mg/kg cyclophosphamide 10 days preoperatively allowed routine cardiac xenograft survival under FK506. The ability of these antimetabolites to unmask the therapeutic potential of FK506 correlated, although imperfectly, with the prevention of rises of preformed heterospecific cytotoxic antibodies immediately postoperatively. As an adjunct to FK506, azathioprine was of marginal value, whereas mizoribine, methotrexate, and deoxyspergualin (DSPG) were of intermediate efficacy. After orthotopic hepatic xenotransplantation, the perioperative survival of the liver with its well-known resistance to antibodies was less dependent than the heart on the antimetabolite component of the combined drug therapy, but the unsatisfactory results with monotherapy of FK506, BQR, RS-61443, or cyclophosphamide were changed to routine success by combining continuous FK506 with a short course of any of the other drugs. Thus, by breaking down the antibody barrier to xenotransplantation with these so-called antiproliferative drugs, it has been possible with FK506 to transplant heart and liver xenografts with consistent long-term survival of healthy recipients.

Topics: Animals; Antibody Formation; Antilymphocyte Serum; Biphenyl Compounds; Cricetinae; Cyclophosphamide; Drug Synergism; Drug Therapy, Combination; Fluorescent Antibody Technique; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Transplantation; Immunoglobulin A; Immunoglobulin M; Immunosuppressive Agents; Liver Transplantation; Male; Mesocricetus; Mycophenolic Acid; Rats; Splenectomy; Tacrolimus; Transplantation, Heterologous

Topics: Animals; Biphenyl Compounds; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Graft Rejection; Heart Transplantation; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Models, Biological; Polyenes; Sirolimus; Tacrolimus; Transplantation, Homologous

Topics: Animals; B-Lymphocytes; Biphenyl Compounds; Cells, Cultured; Dose-Response Relationship, Drug; Gene Expression Regulation; Immunosuppressive Agents; Interleukin-10; Interleukin-2; Lymphocyte Activation; Mice; Mycophenolic Acid; Polymerase Chain Reaction; Ribonucleosides; Tacrolimus