sirolimus and gusperimus

Due to the improvement in the understanding of the anti-allogenic immune response, the success of transplantation medicine has increased rapidly over the last two decades. The knowledge that the T-lymphocyte played an integral role in transplant rejection, brought cyclosporine A and FK-506 to the fore as therapeutic immunosuppressants. However, the current mainstays in transplant rejection are not without their problems and many drug companies are exploring the possibilities of improving the available therapies by developing drugs with reduced toxicity, improved long-term survival and efficacy against chronic rejection and improved immunosuppressive selectivity. The advances in the understanding of T-cell activation and lymphocyte trafficking has highlighted ways to improve the existing therapies and more selective immunosuppressant targets.

Topics: Antibodies, Monoclonal; Antimetabolites; Calcineurin Inhibitors; Cyclosporine; Cytokines; Drug Design; Fingolimod Hydrochloride; Graft Rejection; Guanidines; Humans; Immunosuppressive Agents; Lymphocyte Activation; Molecular Structure; Organ Transplantation; Propylene Glycols; Signal Transduction; Sirolimus; Sphingosine; T-Lymphocytes; Tacrolimus; Triterpenes

Graft versus host disease (GVHD) remains the major obstacle to successful allogeneic bone marrow transplantation. Cyclosporin with methotrexate is the most common prophylactic regimen. Tacrolimus is associated with less GVHD and is gaining ground especially in unrelated donor transplants where current regimens are unsatisfactory. Mycophenolate mofetil (MMF) and rapamycin have not yet shown benefit in acute GVHD prophylaxis. In vivo T-cell depletion with Campath 1H or thymoglobulin used during transplant conditioning are increasingly used in place of ex vivo T-cell depletion, where results remain disappointing. Steroids remain first choice for therapy of GVHD but anti-CD25 antibodies, daclizumab or basiliximab are gaining popularity as second-line therapy ahead of ATG. Chronic GVHD is increasing with greater use of peripheral blood stem cell grafts and older patients. The combination of tacrolimus and MMF is promising for patients with extensive disease. Tolerance induction using CTLA-4-Ig, anti-CD40L, tresperimus and/or rapamycin may revolutionise GVHD therapy. However, due to the desirability of tumour intolerance, tolerance is likely to be developed in organ transplantation before bone marrow transplantation for traditional indications. Bone marrow transplants performed to induce organ tolerance may see increasing use of these agents. TNF blockade using infliximab or etanercept (Enbrel) is promising but the role of these agents is not yet defined.

Topics: Abatacept; Alemtuzumab; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antigens, CD; Antigens, Differentiation; Antimetabolites; Bone Marrow Transplantation; CD40 Ligand; Clinical Trials as Topic; CTLA-4 Antigen; Cyclosporine; Drug Design; Graft vs Host Disease; Guanidines; Guidelines as Topic; Humans; Immunoconjugates; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Methotrexate; Mycophenolic Acid; Sirolimus; T-Lymphocytes; Tacrolimus

The last decade has witnessed an expansion of the arsenal of new immunosuppressive agents to include several novel drugs and antibodies. The main indication of all these immunosuppressive agents is organ transplantation. In terms of its action, tacrolimus resembles cyclosporin A and is employed as the mainstay immunosuppressant or for what is referred to as rescue therapy in refractory rejection. Mycophenolate mofetil is an anti-metabolite replacing azathioprine in immunosuppressive protocols. Sirolimus is an agent for prophylactic use, either as part of a cyclosporin-based regimen to enhance the effect of cyclosporin or as an alternative of non-nephrotoxic immunosuppression to cyclosporin-based regimens; its indications are still being specified. Gusperimus could be used for anti-rejection therapy; however, it is not being used in this country as yet. Recently, two monoclonal antibodies against the IL-2 receptor, chimeric basiliximab and humanized daclizumab, have been employed. Both agents are of non-depletion type and are indicated for induction therapy in the early post-transplant period.

Topics: Antibodies, Monoclonal; Guanidines; Humans; Immunosuppressive Agents; Mycophenolic Acid; Receptors, Interleukin-2; Sirolimus; Tacrolimus

Topics: Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Models, Biological; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; T-Lymphocytes; Tacrolimus; Transplantation Immunology

Tacrolimus (FK506), mycophenolate mofetil, sirolimus (rapamycin), gusperimus, and monoclonal antibody preparations are new immunosuppressive agents, some of which are already approved for clinical use, while others are currently undergoing clinical trials. The present article provides an overview of adverse drug interactions between these immunosuppressants and other drugs which may be used concomitantly. Preliminary data suggest that a pharmacodynamic interaction can occur between tacrolimus and nonsteroidal anti-inflammatory drugs, associated with an increased risk of nephrotoxicity. Erythromycin, clarithromycin, clotrimazole, fluconazole, ketoconazole, and danazol have been shown to increase tacrolimus blood concentrations, while rifampicin (rifampicin) was found to decrease tacrolimus blood concentrations. Evidence from experimental studies suggest that several other drugs also known to affect cytochrome P450 activity may have significant effects on the pharmacokinetics of tacrolimus. On the other hand, tacrolimus itself may inhibit the metabolism of coadministered drugs. This interaction may be attributed to the enhanced renal impairment which has been observed in patients treated with tacrolimus and cyclosporin. The bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, has been reported to be reduced by aluminium/magnesium hydroxide-containing antacids and cholestyramine. Mycophenolic acid, sirolimus and gusperimus may impair bone marrow function and this adverse effect may be enhanced by concomitant administration of other myelosuppressive drugs. There is some evidence that coadministered sirolimus and cyclosporin cause an increase in each other's blood concentrations. An increased risk of central nervous system adverse effects has been described following the combined use of indomethacin and the monoclonal antibody muromonab CD3 (OKT3).

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Cytochrome P-450 Enzyme System; Drug Design; Drug Interactions; Guanidines; Humans; Immunosuppressive Agents; Kidney; Liver; Mycophenolic Acid; Polyenes; Sirolimus; Tacrolimus

Topics: Graft Rejection; Guanidines; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Mycophenolic Acid; Nitriles; Organ Transplantation; Polyenes; Sirolimus; Tacrolimus

Topics: Animals; Clinical Trials as Topic; Guanidines; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Mycophenolic Acid; Polyenes; Sirolimus; Tacrolimus; Transplantation Immunology

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

Topics: Anti-Bacterial Agents; Cyclosporins; Guanidines; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Molecular Structure; Mycophenolic Acid; Polyenes; Sirolimus; Tacrolimus; Transplantation Immunology

Topics: Animals; Anti-Bacterial Agents; Cyclosporins; Graft Survival; Guanidines; Humans; Immunosuppressive Agents; Mycophenolic Acid; Polyenes; Sirolimus; Tacrolimus; Transplantation

As experience of the most effective way to use cyclosporine for immunosuppression in organ transplantation grows, new drugs are emerging, which may improve the potency of future immunosuppressive protocols or at least provide alternative drugs in selected situations. These newer agents include FK506, which is undergoing extensive clinical trials, rapamycin, RS-61443 and deoxyspergualin. The increasing understanding of the mechanism of action of some of these drugs on signal transduction pathways in the T cell should allow the development of drugs with perhaps more specific actions.

Topics: Cyclosporine; Guanidines; Humans; Mycophenolic Acid; Polyenes; Signal Transduction; Sirolimus; T-Lymphocytes; Tacrolimus; Transplantation Immunology

Allogeneic bone marrow (BM) engraftment for chimerism and transplantation tolerance may be promoted by combinations of costimulation blocking biologics and small molecular weight inhibitors. We showed previously in a mouse model that anti-CD40Ligand (anti-CD40L, CD154) combined with anti-LFA-1 or everolimus (40-O-(2-hydroxyethyl)-rapamycin) resulted in stable chimerism in almost all BM recipients, whereas anti-LFA-1 plus everolimus conferred approximately 50% chimerism stability. Here, we investigated whether this lower incidence could be increased with deoxyspergualin (DSG) in place of or in addition to everolimus. However, DSG and everolimus were similarly synergistic with costimulation blockade for stable hematopoietic chimerism. This correlated with allospecific T cell depletion and inhibition of acute but not chronic skin allograft rejection. Different treatments were also compared for their inhibition of alloreactive T cell proliferation in vivo. While anti-CD40L did not impair T cell proliferation, anti-LFA-1 reduced both CD4 and CD8 T cell proliferation, and combining anti-LFA-1 with everolimus or DSG had an additive inhibitory effect on CD4 T cell proliferation. Thus, despite their strong inhibition of alloreactive T cell proliferation, combinations of anti-LFA-1 with everolimus or DSG did not reach the unique potency of anti-CD40L-based combinations to support stable hematopoietic chimerism in this system.

Topics: Animals; Antibodies, Monoclonal; CD40 Ligand; Cell Proliferation; Chimerism; Everolimus; Graft Rejection; Guanidines; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Immunosuppressive Agents; Lymphocyte Depletion; Lymphocyte Function-Associated Antigen-1; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Sirolimus; Skin Transplantation; T-Lymphocytes

The aim of this study was to develop a new quantitative method for measuring in vitro the effects of T-cell immunosuppressive drugs by flow cytometry. Rat whole blood samples were stimulated with the T-cell mitogen succinylated concanavalin A in the presence or absence of different drugs. After 3 days, the expression of CD25 and CD8alpha in mitogen-stimulated CD4(+) cells increased 10- to 20-fold as measured by flow cytometry. Drug efficacy and potency was calculated based on dose-response curves of the drug-mediated decrease in CD4(+)/CD8alpha(+)/CD25(+) cells. The expression of CD8alpha in mitogen-stimulated CD4(+) cells was blocked completely by calcineurin inhibitors (cyclosporine A and FK-506), and partially by rapamycin and SDZ-RAD. The IC(50) (50% inhibitory concentration) values obtained were (mean+/-S.E.): 99.5+/-16.6 nM for cyclosporine A, 10.4+/-1.3 nM for FK-506, 1.8+/-0.7 nM for rapamycin, and 6.4+/-1.1 nM for SDZ-RAD. Our results show, for the first time, that CD8alpha, used as an activation antigen, is a sensitive marker for monitoring T-cell immunosuppression.

Topics: Animals; Biomarkers; CD4 Antigens; CD4-Positive T-Lymphocytes; CD8 Antigens; Concanavalin A; Cyclosporine; Everolimus; Fingolimod Hydrochloride; Flow Cytometry; Guanidines; Immunosuppressive Agents; Mitogens; Propylene Glycols; Rats; Rats, Inbred Lew; Sirolimus; Sphingosine; Tacrolimus

Topics: Animals; Blood Glucose; Cyclosporine; Diabetes Mellitus, Experimental; Dogs; Drug Administration Schedule; Drug Therapy, Combination; Graft Survival; Guanidines; Immunosuppression Therapy; Immunosuppressive Agents; Islets of Langerhans Transplantation; Polyenes; Rats; Rats, Inbred Lew; Sirolimus; Tacrolimus; Transplantation, Heterologous

Transplantation of the small intestine would be an attractive therapeutic option for treatment of short bowel syndrome if effective, nontoxic immunosuppressive agents could be developed. This study examines the effect of three newly developed immuno-suppressive agents: rapamycin, deoxyspergualin, and mycophenolate mofetil, on the nutritional status and intestinal function of normal juvenile rats.. Rapamycin (2 mg/kg every second day), deoxyspergualin (2 mg/kg every second day) and mycophenolate mofetil (MM) (25 mg/kg every second day) were injected subcutaneously for six weeks.. Rapamycin and deoxyspergualin caused significant reductions in weight gain without impairing feed intake. Both drugs caused small decreases in fat absorption; treatment with DSG induced an increase in permeability to 99Tc-DTPA. However, the permeability to other markers, such as mannitol and lactulose, was decreased in the rapamycin and mycophenolate mofetil-treated animals. Intestinal function in vitro was quantified using glucose flux (absorption). In the rapamycin group, there was a significant decrease in ileal uptake of glucose, with the net flux (absorption) being zero; there was an associated loss of villous size histologically. In the deoxyspergualin-treated groups, there was a decrease in the jejunal glucose flux. In the mycophenolate mofetil-treated animals, there was a decrease in jejunal with a compensatory increase in ileal glucose absorption. There were minor variations in intestinal morphology, but these were not consistent.. Rapamycin and deoxyspergualin in these doses cause a significant reduction in weight gain in healthy juvenile animals, and all the drugs caused changes in the active transport characteristics of the intestine. Accordingly, the use of these drugs for intestinal transplantation should be evaluated carefully for their nutritional impact.

Topics: Animals; Eating; Gastrointestinal Motility; Guanidines; Immunosuppressive Agents; Intestine, Small; Lactulose; Male; Mannitol; Mycophenolic Acid; Permeability; Polyenes; Rats; Rats, Inbred Lew; Sirolimus; Weight Gain

Topics: Animals; Cyclophosphamide; Cyclosporine; Fetal Tissue Transplantation; Graft Rejection; Graft Survival; Guanidines; Immunosuppressive Agents; Islets of Langerhans Transplantation; Killer Cells, Natural; Macrophages; Male; Mycophenolic Acid; Polyenes; Prednisolone; Rats; Rats, Inbred Lew; Sirolimus; Swine; T-Lymphocytes; Tacrolimus; Transplantation, Heterologous

Topics: Animals; Antibodies, Monoclonal; Antilymphocyte Serum; Bone Marrow Transplantation; CD4 Antigens; CD8 Antigens; Cell Transplantation; Drug Administration Schedule; Guanidines; Immunosuppression Therapy; Immunosuppressive Agents; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Polyenes; Sirolimus; Skin Transplantation; Transplantation, Homologous

Topics: Animals; Cyclophosphamide; Guanidines; Humans; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Plasmapheresis; Polyenes; Rats; Rats, Sprague-Dawley; Sirolimus; Splenectomy

Topics: Antigen-Presenting Cells; Azathioprine; Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; In Vitro Techniques; Monocytes; NADH, NADPH Oxidoreductases; NADPH Oxidases; Neutrophils; Polyenes; Sirolimus; Tacrolimus

Topics: Animals; Aorta; Carotid Arteries; Carotid Artery Injuries; Cell Division; Cells, Cultured; Cyclosporine; Guanidines; Immunosuppressive Agents; Male; Muscle, Smooth, Vascular; Mycophenolic Acid; Polyenes; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus

Topics: Animals; Guanidines; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; Spiro Compounds; Tacrolimus

Topics: Animals; Combined Modality Therapy; Cricetinae; Drug Therapy, Combination; Graft Rejection; Graft Survival; Guanidines; Heart Transplantation; Immunosuppressive Agents; Male; Mesocricetus; Mycophenolic Acid; Polyenes; Rats; Rats, Inbred Lew; Sirolimus; Splenectomy; Transplantation, Heterologous