The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform

William E. Fitzsimmons - One of the best experts on this subject based on the ideXlab platform.

  • Assessment of efficacy and safety of FK778 in comparison with standard care in renal transplant recipients with untreated BK nephropathy.
    Transplantation, 2010
    Co-Authors: Antonio Guasch, William E. Fitzsimmons, Prabir Roy-chaudhury, E. Steve Woodle, John M. Holman, M. Roy First
    Abstract:

    Background. BK polyomavirus infection has been reported in 10% to 60% of renal transplant recipients with progression to BK nephropathy (BKN) occurring in 1% to 5% of patients. Graft loss occurs in up to 60% of renal transplant recipients with BKN. Because BK polyomavirus infection is believed, in part, to be a manifestation of overimmunosuppression, the current standard of care involves the reduction of immunosuppressants. This strategy has been associated with clearance of viral load, preservation of renal function, and improvement in graft survival; however, this may come at a risk of rejection. A safe and effective immunosuppressive agent that does not predispose to viral infection is needed in transplantation. Methods. In a phase 2, proof-of-concept, randomized, open-label, parallel-group, 6-month study in renal transplant patients, FK778 (an investigational immunosuppressant from the Malononitrilamides class) was compared with the current standard of care (reduction of immunosuppression) for treatment of newly diagnosed or untreated BKN, which was confirmed by renal biopsy. Results. Demographic characteristics were similar between the two groups, except there were numerically more females in the FK778 group than in the standard care group. Although the treatment with FK778 decreased BK viral load in this study, it was associated with a less favorable rejection profile and renal function and a higher incidence of serious adverse events compared with reduction of immunosuppression. Conclusions. Data from this study are consistent with the findings of previous studies that found no benefit of drug therapy in the treatment of BKN in kidney transplant recipients.

  • FK778, a synthetic Malononitrilamide.
    Yonsei medical journal, 2004
    Co-Authors: William E. Fitzsimmons, M. Roy First
    Abstract:

    FK778 is a synthetic Malononitrilamide (MNA) that has been demonstrated to have both both immunosuppressive and anti-proliferative activities. The MNAs inhibit both T-cell and B-cell function by blocking de novo pyrimidine synthesis, through blockade of the pivotal mitochondrial enzyme dihyroorotic acid dehydrogenase (DHODH), and the inhibition of tyrosine kinase activity. FK778 has been demonstrated to prevent acute allograft rejection in multiple experimental transplant models in rodents, dogs and primates and to be effective in the rat model of chronic renal allograft rejection. In addition, FK778 has been shown to prevent vascular remodeling after mechanical intimal injury via a mechanism which may be related to tyrosine kinase inhibitory activity in vascular smooth muscle cells. Another intriguing activity of the MNA family is the ability to block replication of members of the Herpes virus family with in vitro evidence that of efficacy against cytomegalovirus (CMV) and polyoma virus, important pathogens in the transplant recipient. FK778 is currently being explored in a number of trials in solid organ transplant recipients.

  • Synergistic effects of Malononitrilamides (FK778, FK779) with tacrolimus (FK506) in prevention of acute heart and kidney allograft rejection and reversal of ongoing heart allograft rejection in the rat.
    Transplantation, 2003
    Co-Authors: Kupa K. Bilolo, Jun Ouyang, Xiang Wang, Shengyun Zhu, Wenlei Jiang, Marie J. Hebert, Ihor Bekersky, William E. Fitzsimmons
    Abstract:

    Background The effects of tacrolimus (FK506) and Malononitrilamides (MNA) (FK778 and FK779) monotherapy and combination therapy were examined in prevention of acute heart and kidney allograft rejection and reversal of ongoing acute heart allograft rejection in the rat. Methods. Brown Norway (RT1 n )-to-Lewis (RT1 1 ) and ACI (RT1 a )-to-Lewis (RT1 1 ) combinations were used, respectively, for heart and kidney transplantation models. Immunosuppressants were administered orally from day 1 to day 14 for preventing acute rejection and from day 4 to day 34 after transplantation for the reversal of ongoing acute rejection. Results. In the prevention of acute heart rejection model, recipient rats treated with monotherapy of tacrolimus or MNA (FK778, FK779) showed a dose-related prolongation of mean survival time (MST) compared with naive control rats (P

  • Combination therapy of Malononitrilamide FK778 with tacrolimus on cell proliferation assays and in rats receiving renal allografts.
    Transplantation, 2003
    Co-Authors: Minh Diem Vu, William E. Fitzsimmons, Xiang Wang, Wenlei Jiang, Ihor Bekersky, Shijie Qi, Anlun Ma, Dasheng Xu, Jiangping Wu, Huifang Chen
    Abstract:

    Background. Malononitrilamide FK778, an analogue of leflunomide's active metabolite, is a promising novel small molecule with immunosuppressive and immunomodulatory properties. In this study, we evaluated the ability of combination therapy of FK778 with tacrolimus to inhibit lymphocyte proliferation and to prevent acute allograft rejection. Methods. Proliferation assay was used to evaluate the effect of FK778 plus tacrolimus on murine splenocytes, monkey lymphocytes, and human peripheral blood mononuclear cells, after activation with T or B cell-specific mitogens. A rat kidney transplantation model was used to evaluate the ability of FK778 combined with tacrolimus to prolong allograft survival. Median-effect principle and combination index (CI) were used to determine synergism, summation, or antagonism. Results. A total of 58 combinations of FK778 plus tacrolimus were evaluated. Of the combinations tested, 82.8% (24/29) produced additive to synergistic effects in B cells, whereas 79.3% (23/29) produced moderate antagonistic effects in T cells. A concomitant 14-day therapy of FK778 (10 mg/kg/day) and tacrolimus (1 mg/kg/day) synergistically prolonged renal allograft survival to 25.5±5.9 days (CI=0.458). However, when addition of FK778 to tacrolimus therapy was delayed to day 7 after transplantation, a strong synergism was obtained (mean survival time=74.9±14.8 days, CI

  • combination therapy of Malononitrilamide fk778 with tacrolimus on cell proliferation assays and in rats receiving renal allografts
    Transplantation, 2003
    Co-Authors: Xiang Wang, William E. Fitzsimmons, Wenlei Jiang, Ihor Bekersky, Huifang Chen
    Abstract:

    Background. Malononitrilamide FK778, an analogue of leflunomide's active metabolite, is a promising novel small molecule with immunosuppressive and immunomodulatory properties. In this study, we evaluated the ability of combination therapy of FK778 with tacrolimus to inhibit lymphocyte proliferation and to prevent acute allograft rejection. Methods. Proliferation assay was used to evaluate the effect of FK778 plus tacrolimus on murine splenocytes, monkey lymphocytes, and human peripheral blood mononuclear cells, after activation with T or B cell-specific mitogens. A rat kidney transplantation model was used to evaluate the ability of FK778 combined with tacrolimus to prolong allograft survival. Median-effect principle and combination index (CI) were used to determine synergism, summation, or antagonism. Results. A total of 58 combinations of FK778 plus tacrolimus were evaluated. Of the combinations tested, 82.8% (24/29) produced additive to synergistic effects in B cells, whereas 79.3% (23/29) produced moderate antagonistic effects in T cells. A concomitant 14-day therapy of FK778 (10 mg/kg/day) and tacrolimus (1 mg/kg/day) synergistically prolonged renal allograft survival to 25.5±5.9 days (CI=0.458). However, when addition of FK778 to tacrolimus therapy was delayed to day 7 after transplantation, a strong synergism was obtained (mean survival time=74.9±14.8 days, CI<0.001). Conclusions. This study demonstrates that the combination of FK778 with tacrolimus in vitro produces synergistic inhibition on B-cell proliferation but not on T cell proliferation in mice, nonhuman primates, and humans. When the addition of FK778 treatment was delayed to day 7 after transplantation, a strong synergism was produced in prolongation of renal allograft survival in the rat.

R. Kurrle - One of the best experts on this subject based on the ideXlab platform.

  • Regulation of alloreactivity in the popliteal lymph node assay by the new immunosuppressants: Malononitrilamides.
    Transplant International, 1998
    Co-Authors: Hans-ulrich Schorlemmer, E. Ruuth, R. Kurrle
    Abstract:

    Malononitrilamides (MNAs) represent a new class of low molecular weight immunosuppressants and have been shown to prevent and reverse ongoing acute allograft rejection and effectively prolong xenograft survival in rodents. MNAs were also found to be potent inhibitors of B and T cell-mediated autoimmune processes and mediate their effects by binding specifically to dihydro-orotate dehydrogenase (DHODH), inhibiting de novo pyrimidine biosynthesis, thereby blocking T and B cell proliferation and strongly suppressing the IgM and IgG antibody production. Here we evaluated the effects of the MNAs (HMR 1279 and HMR 1715) on the in vivo lymphoproliferation that occurs after challenge with allogeneic cells in a local graft-versus-host reaction in Lewis x Brown Norway F1 hybrid rats by measuring the enlargement of the popliteal lymph nodes (PLN) draining the site of allogeneic cell injection. Oral administration of the MNAs dose-dependently prevented the localized lymphoproliferative response in the PLN assay and suppressed the lymph node hyperplasia. The MNAs even acted therapeutically when they were given during an ongoing alloreactivity as late as days 4 or 5 after challenge. Consistent with the mode of action, a complete reversal of the immunosuppression on the lymphoproliferation in vivo was attempted in this protocol by the addition of exogenous uridine during days 0-5. These data suggest the HMR 1279 and HMR 1715 mediate their antiproliferative and immunosuppressive effects in the PLN assay in vivo by decreasing the activity of DHODH in the lymph node cells and thereby inhibiting pyrimidine biosynthesis.

  • Malononitrilamides synergistically prevent acute and treat ongoing skin allograft rejection with cyclosporine
    Transplant International, 1998
    Co-Authors: H. U. Schorlemmer, E. Ruuth, R. Kurrle
    Abstract:

    The low molecular weight Malononitrilamides (MNAs), a new class of immunosuppressive agents, belong to the derivatives of leflunomide's active metabolite, A771726. They have been shown to bind specifically to dehydroorotate dehydrogenase and inhibit de novo pyrimidine biosynthesis, thereby blocking T- and B-cell proliferation and strongly suppressing IgM and IgG antibody production. Here we evaluated their efficacy together with cyclosporine (CyA) in rat skin allotransplantation models, using different strain combinations. Monotherapy of transplanted animals in these models with the MNAs HMR 1279 and HMR 1715 resulted in a significant and dose-dependent prolongation of the graft survival time. Even a short-term application showed efficacy in the prevention of acute rejection. The MNAs were also effective when treatment was started at the time of expected rejection crisis, demonstrating strong therapeutic activity to reverse ongoing acute rejection, whereas CyA was ineffective for the treatment of ongoing allograft rejection episodes. Combination therapy of MNAs with CyA proved to be very effective for the prevention of acute skin graft rejection. Interestingly, whereas CyA alone was unable to treat ongoing acute rejection episodes, comedication of MNAs and CyA, even after a short-term application, was synergistically effective and significantly suppressed ongoing allogeneic skin graft rejection. These results demonstrate that MNAs are potent and well tolerated immunosuppressants with a potential comparable to that of CyA, but they are superior to CyA in their ability to reverse acute rejection episodes. They represent powerful rescue drugs and demonstrate synergistic activity with CyA to prevent acute and treat ongoing skin allograft rejection.

  • Long-Term Allograft Survival and Tolerance Induction by the Synergistic Activity of Malononitrilamides and Tacrolimus
    Transplantation proceedings, 1998
    Co-Authors: H. U. Schorlemmer, J. K. Lindner, R. R. Bartlett, R. Kurrle
    Abstract:

    IN TRANSPLANTATION medicine the combination of agents that separately act on early T-cell and later B-cell functions and on acute and chronic rejection might provide the benefit of a complementary immunosuppressive response. Despite the clinical successes achieved over the past two decades in transplantation, there continues to be a need for new immunosuppressive agents that are less toxic and more effective in down-regulating humoral alloreactivity in presensitized recipients. The novel immunosuppressive Malononitrilamides (MNAs) belong to the derivatives of leflunomide’s well-tolerated active metabolite (A77 1726), are chemically unrelated, and distinct in their mode of action to any other immunosuppressant known. The low molecular weight HMR 1279 (C14H11N3O2) and HMR 1715 (C15H11F3N2O2) have been developed in preclinical models of transplantation because they have a shorter half-life in animals and would make dose-adjustment easier in transplant patients. Both MNAs have been shown to bind specifically to dihydro-orotate-dehydrogenase (DHODH) and inhibit de novo pyrimidine biosynthesis, thereby blocking Tand B-cell proliferation and strongly suppressing the IGM and IgG antibody production in vitro. They are able to dose-dependently suppress the proliferation of several immune and nonimmune cell lines. At concentrations that block cell proliferation, the MNAs inhibit DHODH. This antiproliferative effect is consistently antagonized by adding uridine to cell cultures to replenish nucleotide pools. The MNAs inhibit both the cellular and humoral immune response, and they have potent immunosuppressive activity against a variety of experimental autoimmune diseases, primarily reducing autoantibody formation. HMR 1279 and HMR 1715 effectively control graft-versus-host (GvH) diseases in various rodent models, and they can control xenograft survival in hamsterto-rat or mouse-to-rat models. They also were shown to prevent and reverse acute heart and skin allograft rejection, while they were well tolerated in these rodent transplantation studies. Due to the unique pharmacologic profile of the MNAs to inhibit the cellular and humoral immune response and their already described synergistic effects in combination with cyclosporine (CyA) to prolong alloand xenograft survival, we tested the combination therapy of HMR 1279 or HMR 1715 and FK 506 in view of their individual and distinct immunosuppressive actions in rat skin allotransplantation models using different donor-recipient strain combinations.

  • The alloreactivity in the popliteal lymph node (PLN) assay is regulated by Malononitrilamides (MNAs).
    International journal of tissue reactions, 1997
    Co-Authors: H. U. Schorlemmer, E. Ruuth, R. Kurrle
    Abstract:

    Malononitrilamides (MNA 279 and MNA 715) represent a new class of low molecular weight immunosuppressants and belong to the derivatives of the primary metabolite of leflunomide A7771726. They have been shown to prevent and reverse established acute allograft rejection and effectively prolong xenograft survival, and have also been found to be potent inhibitors of B- and T-cell mediated autoimmune processes. The MNAs mediate their effects by binding specifically to dehydro orotate-dehydrogenase (DHODH) and inhibiting de novo pyrimidine biosynthesis, thereby blocking T- and B-cell proliferation and strongly suppressing the IgM and IgG antibody production. In this study we evaluated the effects of MNA 279 and MNA 715 on the in vivo lymphoproliferation that occurs after challenge with allogeneic cells in a local graft-versus-host (GvH) reaction in Lewis x Brown-Norway (LBN) F1-hybrid rats by measuring the enlargement of the PLN draining the site of allogeneic cell injection. Oral administration of one of the two MNAs (7.5 to 50 mg/kg) on day 0, dose-dependently prevented the localized lymphoproliferative response and suppressed the lymph node hyperplasia. The MNAs even acted therapeutically when they were given during an ongoing alloreactivity as late as day 4 or 5 after challenge. Consistent with the mode of action that MNAs inhibit de novo pyrimidine biosynthesis, a complete reversal of the immunosuppression on the lymphoproliferation in vivo was attempted in this protocol by addition of exogenous uridine during days 0 to 5. These data suggest that MNA 279 and MNA 715 mediate their antiproliferative and immunosuppressive effects in the PLN-assay in vivo by decreasing the activity of DHODH in the lymph node cells and thereby inhibiting pyrimidine biosynthesis.

Huifang Chen - One of the best experts on this subject based on the ideXlab platform.

  • combination therapy of Malononitrilamide fk778 with tacrolimus on cell proliferation assays and in rats receiving renal allografts
    Transplantation, 2003
    Co-Authors: Xiang Wang, William E. Fitzsimmons, Wenlei Jiang, Ihor Bekersky, Huifang Chen
    Abstract:

    Background. Malononitrilamide FK778, an analogue of leflunomide's active metabolite, is a promising novel small molecule with immunosuppressive and immunomodulatory properties. In this study, we evaluated the ability of combination therapy of FK778 with tacrolimus to inhibit lymphocyte proliferation and to prevent acute allograft rejection. Methods. Proliferation assay was used to evaluate the effect of FK778 plus tacrolimus on murine splenocytes, monkey lymphocytes, and human peripheral blood mononuclear cells, after activation with T or B cell-specific mitogens. A rat kidney transplantation model was used to evaluate the ability of FK778 combined with tacrolimus to prolong allograft survival. Median-effect principle and combination index (CI) were used to determine synergism, summation, or antagonism. Results. A total of 58 combinations of FK778 plus tacrolimus were evaluated. Of the combinations tested, 82.8% (24/29) produced additive to synergistic effects in B cells, whereas 79.3% (23/29) produced moderate antagonistic effects in T cells. A concomitant 14-day therapy of FK778 (10 mg/kg/day) and tacrolimus (1 mg/kg/day) synergistically prolonged renal allograft survival to 25.5±5.9 days (CI=0.458). However, when addition of FK778 to tacrolimus therapy was delayed to day 7 after transplantation, a strong synergism was obtained (mean survival time=74.9±14.8 days, CI<0.001). Conclusions. This study demonstrates that the combination of FK778 with tacrolimus in vitro produces synergistic inhibition on B-cell proliferation but not on T cell proliferation in mice, nonhuman primates, and humans. When the addition of FK778 treatment was delayed to day 7 after transplantation, a strong synergism was produced in prolongation of renal allograft survival in the rat.

  • Combination therapy of Malononitrilamide FK778 with tacrolimus on cell proliferation assays and in rats receiving renal allografts.
    Transplantation, 2003
    Co-Authors: Minh Diem Vu, William E. Fitzsimmons, Xiang Wang, Wenlei Jiang, Ihor Bekersky, Shijie Qi, Anlun Ma, Dasheng Xu, Jiangping Wu, Huifang Chen
    Abstract:

    Background. Malononitrilamide FK778, an analogue of leflunomide's active metabolite, is a promising novel small molecule with immunosuppressive and immunomodulatory properties. In this study, we evaluated the ability of combination therapy of FK778 with tacrolimus to inhibit lymphocyte proliferation and to prevent acute allograft rejection. Methods. Proliferation assay was used to evaluate the effect of FK778 plus tacrolimus on murine splenocytes, monkey lymphocytes, and human peripheral blood mononuclear cells, after activation with T or B cell-specific mitogens. A rat kidney transplantation model was used to evaluate the ability of FK778 combined with tacrolimus to prolong allograft survival. Median-effect principle and combination index (CI) were used to determine synergism, summation, or antagonism. Results. A total of 58 combinations of FK778 plus tacrolimus were evaluated. Of the combinations tested, 82.8% (24/29) produced additive to synergistic effects in B cells, whereas 79.3% (23/29) produced moderate antagonistic effects in T cells. A concomitant 14-day therapy of FK778 (10 mg/kg/day) and tacrolimus (1 mg/kg/day) synergistically prolonged renal allograft survival to 25.5±5.9 days (CI=0.458). However, when addition of FK778 to tacrolimus therapy was delayed to day 7 after transplantation, a strong synergism was obtained (mean survival time=74.9±14.8 days, CI

  • Small molecule immunosuppressive agents in experimental and clinical transplantation.
    Current drug targets. Cardiovascular & haematological disorders, 2002
    Co-Authors: Huifang Chen
    Abstract:

    Immunosuppression is currently the major approach used for the prevention and management of transplant rejection. In this overview, preclinical and clinical studies of the small molecule immunosuppressive agents are reviewed from the discovery of cyclosporine. More recently it was demonstrated that certain agents, namely tacrolimus (FK506), sirolimus (rapamycin), and mycophenolate mofetil (CellCept, MMF), act selectively on adaptive host responses at different stages of T- and B-cell cycles and spare nonspecific host resistance. Because each agent has its specific and significant toxic effects, it has been difficult to optimize the use of individual agents in monotherapy. Therefore, drug combination therapy has been of great interest in addition to the introduction of new small molecule agents, such as Malononitrilamides [MNAs (leflunomide, FK778, FK779)], 15-deoxyspergualin (DSG) and its analogues, FTY720 and inhibitors of signal transduction, which offer promising modes of immunosuppression.

Herbert Waldmann - One of the best experts on this subject based on the ideXlab platform.

  • atp competitive inhibitors of d alanine d alanine ligase based on protein kinase inhibitor scaffolds
    Bioorganic & Medicinal Chemistry, 2009
    Co-Authors: Gemma Triola, Stefan Wetzel, Katja Hübel, Daniel Rauh, Bernhard Ellinger, Marcus A Koch, Herbert Waldmann
    Abstract:

    Abstract d -Alanine– d -alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. Here, we describe a new approach to identify new inhibitor scaffolds for DDl based on similarity in the ATP binding region of different kinases and DDl. After an initial screening of several protein kinase inhibitors, we found that the Brutons’s tyrosine kinase inhibitor LFM-A13, an analog of the Leflunomide metabolite A771726, inhibits DDl with a Ki of 185 μM. A series of Malononitrilamide and salicylamide derivatives of LFM-A13 has been synthesized to confirm the validity of this scaffold as an inhibitor of DDl.

  • ATP competitive inhibitors of d-alanine–d-alanine ligase based on protein kinase inhibitor scaffolds
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Gemma Triola, Stefan Wetzel, Katja Hübel, Daniel Rauh, Bernhard Ellinger, Marcus A Koch, Herbert Waldmann
    Abstract:

    Abstract d -Alanine– d -alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. Here, we describe a new approach to identify new inhibitor scaffolds for DDl based on similarity in the ATP binding region of different kinases and DDl. After an initial screening of several protein kinase inhibitors, we found that the Brutons’s tyrosine kinase inhibitor LFM-A13, an analog of the Leflunomide metabolite A771726, inhibits DDl with a Ki of 185 μM. A series of Malononitrilamide and salicylamide derivatives of LFM-A13 has been synthesized to confirm the validity of this scaffold as an inhibitor of DDl.

H. Reichenspurner - One of the best experts on this subject based on the ideXlab platform.

  • is the Malononitrilamide fk778 better for the prevention of acute or chronic rejection
    Congress of the German Transplantation Society, 2007
    Co-Authors: Tobias Deuse, Sonja Schrepfer, Marc P. Pelletier, Michael P. Fischbein, R.c. Robbins, H. Reichenspurner
    Abstract:

    Objective. The aim of this study was to assess the efficacy of FK778 to prevent acute and chronic allograft rejection compared with other immunosuppressive agents. Materials and Methods. Heterotopic Brown-Norway (BN)-to-Lewis rat cardiac transplantations and heterotopic BN-to-Lewis tracheal transplantations were performed to study acute heart rejection and the development of chronic obliterative airway disease (OAD), respectively. Recipients were treated with FK778, tacrolimus, MMF, or sirolimus for 10 days (acute rejection study) or 28 days (chronic OAD study) at varying doses. Results. In untreated recipients, cardiac allograft survival was 6.2 ± 0.4 days. FK778 (20 mg/kg), tacrolimus (2 or 8 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly prolonged graft survival to 17.0 ± 2.8, 18.5 ± 2.7, 25.0 ± 2.5, 20.7 ± 3.8, 14.5 ± 2.2, and 23.2 ± 1.5 days, respectively (P <.05). Tracheal grafts in untreated recipients showed intense infiltration and complete luminal obliteration by day 28. FK778 (20 mg/kg), tacrolimus (1 or 4 mg/kg), MMF (10 or 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly inhibited tracheal luminal obliteration (19.5% ± 16.4%, 44.2% ± 33.6%, 12.3% ± 3.3%, 61.7% ± 18.6%, 18.3% ± 11.3%, 55.0% ± 30.9%, and 8.5% ± 3.5% (P <.05). All 4 high-dose groups showed similar efficacy. Conclusions. When used in therapeutic doses, tacrolimus and sirolimus were more effective than FK778 to prolong cardiac allograft survival. However, with its antiproliferative effects on smooth muscle cells, its good tolerability, and its blockade of cytomegalovirus replication, FK778 proved effective to prevent chronic OAD development. Thus, FK778 may acquire an important role in maintenance therapy for the prevention of long-term fibroproliferative complications.

  • Is the Malononitrilamide FK778 better for the prevention of acute or chronic rejection
    Transplantation proceedings, 2007
    Co-Authors: Tobias Deuse, Sonja Schrepfer, Marc P. Pelletier, Michael P. Fischbein, R.c. Robbins, H. Reichenspurner
    Abstract:

    Objective. The aim of this study was to assess the efficacy of FK778 to prevent acute and chronic allograft rejection compared with other immunosuppressive agents. Materials and Methods. Heterotopic Brown-Norway (BN)-to-Lewis rat cardiac transplantations and heterotopic BN-to-Lewis tracheal transplantations were performed to study acute heart rejection and the development of chronic obliterative airway disease (OAD), respectively. Recipients were treated with FK778, tacrolimus, MMF, or sirolimus for 10 days (acute rejection study) or 28 days (chronic OAD study) at varying doses. Results. In untreated recipients, cardiac allograft survival was 6.2 ± 0.4 days. FK778 (20 mg/kg), tacrolimus (2 or 8 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly prolonged graft survival to 17.0 ± 2.8, 18.5 ± 2.7, 25.0 ± 2.5, 20.7 ± 3.8, 14.5 ± 2.2, and 23.2 ± 1.5 days, respectively (P

  • Inhibition of restenosis development after mechanical injury: a new field of application for Malononitrilamides?
    Cardiology, 2006
    Co-Authors: Sonja Schrepfer, Tobias Deuse, Karim R. Sultan, Munif Haddad, Rainer H. Böger, Thomas Münzel, Hansjörg Schäfer, Marc P. Pelletier, Robert C. Robbins, H. Reichenspurner
    Abstract:

    Objective: To investigate the efficacy of the Malononitrilamide FK778 to prevent vascular smooth muscle cell (SMC) migration/proliferation, and vascular fibrosis, the key events in

  • FK778: New Cellular and Molecular Mechanisms of Action
    Transplantation proceedings, 2006
    Co-Authors: Sonja Schrepfer, Tobias Deuse, F. Koch-nolte, Christian Detter, H. Reichenspurner
    Abstract:

    Abstract Purpose The new Malononitrilamide FK778 is currently being evaluated as an immunosuppressant for organ transplantation. Its main mechanism is inhibition of a pivotal enzyme of pyrimidine biosynthesis. This report revealed new mechanisms of action on different cell types involved in acute and chronic allograft rejection. Methods Purified Brown-Norway rat aortic endothelial cell (EC) cultures were pretreated with several concentrations of FK778. Endothelial adhesion molecule expression (ICAM-1/VCAM-1) stimulated with TNF-α was quantified by immunofluorescence. Purified Lewis rat lymphocytes (LC) incubated with FK778 were stimulated via TCR/CD28 signals, and CD25 expression was quantified using FACS analysis. Uridine addition was used in all assays to reverse the pyrimidine synthesis blockade. Lymphocyte–EC interaction was assessed by micromanipulator-assisted single-cell adhesion assays. Finally, smooth muscle cell (SMC) proliferation and migration was analyzed. Uridine addition was used in all assays to reverse the pyrimidine synthesis blockade. Results TNF-α stimulation and TCR/CD28 co-stimulation significantly increased EC ICAM-1/VCAM-1-expression and LC CD25 surface expression, respectively. These effects were dose-dependently inhibited by FK778 and were not reversed by the addition of uridine. FK778 dose-dependently attenuated LC adhesion to allogeneic EC. The dose-dependent inhibition of SMC proliferation by FK778 was abolished by uridine addition, whereas the inhibitory effect on SMC migration was not affected by uridine supplementation. Conclusions FK778 directly reduced endothelial adhesion molecule up-regulation, inhibited lymphocyte activation, and attenuated lymphocyte-endothelium interactions, critical early steps in graft rejection. These effects were separate from the blockade of pyrimidine synthesis. The antiproliferative potency of FK778 on SMC may be an important mechanism to inhibit the fibroproliferative lesions of chronic organ rejection.

  • FK778, a novel immunosuppressive agent, reduces early adhesion molecule up-regulation and prolongs cardiac allograft survival.
    Transplant international : official journal of the European Society for Organ Transplantation, 2005
    Co-Authors: Sonja Schrepfer, Tobias Deuse, Hansjörg Schäfer, H. Reichenspurner
    Abstract:

    The adhesion molecules, P-selectin, ICAM-1, and VCAM-1 are important mediators of T-cell adhesion and T-cell co-stimulation. We investigated the effect of the Malononitrilamide FK778 on cardiac allograft survival, acute allograft rejection, and adhesion molecule up-regulation in a heterotopic, cardiac transplantation model. Rats received low- or high-dose FK778 or no treatment. Grafts were harvested on the fifth postoperative day for histologic examinations. To assess allograft survival, recipients were treated for a maximum of 10 days and grafts were harvested after cessation of the contractile activity. FK778 low dose showed a mild but significant decrease in mononuclear infiltration but failed to markedly reduce histologic rejection, adhesion molecule up-regulation, or to prolong allograft survival. However, high-dose FK778 treatment significantly reduced early up-regulation of P-selectin, ICAM-1, and VCAM-1, abolished infiltration, reduced histologic rejection and resulted in prolonged cardiac allograft survival. Therefore, FK778 is a novel, highly desirable immunosuppressive drug for transplantation medicine.