Immunosuppressive Agent

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 306 Experts worldwide ranked by ideXlab platform

Barry D Kahan - One of the best experts on this subject based on the ideXlab platform.

  • preclinical evaluation of a new Immunosuppressive Agent fty720
    Clinical Biochemistry, 1998
    Co-Authors: Pablo Troncoso, Barry D Kahan
    Abstract:

    FTY720 is a synthetic analog of a fungal metabolite that shows potent Immunosuppressive activity in vitro and in vivo with little apparent toxicity. The drug displays marked synergistic effects in vivo with CsA and/or rapamycin. Therefore, this drug may improve the therapeutic window of Agents that target cytokine synthesis or signal transduction. Because of these promising findings, the Agent is likely to be tested in humans as an adjunct to clinical Immunosuppressive regimens.

  • sirolimus a new potent Immunosuppressive Agent
    Pharmacotherapy, 1997
    Co-Authors: Patrick Kelly, Scott A Gruber, Fariba Behbod, Barry D Kahan
    Abstract:

    Sirolimus (SRL), a potent immunosuppressant, is currently being investigated in phase III trials for prophylaxis of renal transplant rejection. The mechanism of action of SRL is a blockade of the response of T and B cells to cytokines, thereby preventing cell cycle progression in G1 and consequently cell proliferation. There seems to be a good correlation between SRL concentrations, estimated as exposure by the area under the concentration versus time curve, and trough whole blood concentration, so that therapeutic monitoring may be done by trough levels only. Because of the low frequency of allograft rejection, there has been no documented correlation between trough concentrations and efficacy. Trough SRL concentrations of 15 ng/ml or higher seem to be associated with an increased frequency of adverse effects. Drug-associated toxicities include thrombocytopenia, leukopenia, and increases in cholesterol and triglyceride levels. The drug has synergy with cyclosporine (CsA) in vitro as well as in animal and clinical studies. In phase II trials the combination of SRL-CsA therapy reduced the frequency of acute rejection episodes, permit withdrawal of concomitant corticosteroid therapy, and allowed reduction of CsA dosages in nonblack patients.

  • Preclinical evaluation of a new potent Immunosuppressive Agent, rapamycin.
    Transplantation, 1991
    Co-Authors: Barry D Kahan, Joseph Y. Chang, Suren N. Sehgal
    Abstract:

    Since individual Immunosuppressive Agents display pleiotropic arrays of nonimmunologic toxic complications when used at therapeutic concentrations, synergistic drug combinations proffer an attractive strategy. RAPA is a good candidate for this enterprise, because of its unique action to inhibit lymphokine signal transduction. Initial in vivo and in vitro studies using the rigorous pharmacologic tool, the median effect analysis, document a synergistic relation between RAPA and CsA in rodent and canine models. These preclinical findings compel careful Phase I trials, in order to assess the safety and synergistic efficacy of RAPA in combination drug regimens with other Immunosuppressive Agents.

Anita S Chong - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of herpes simplex virus type 1 by the experimental Immunosuppressive Agent leflunomide
    Transplantation, 2001
    Co-Authors: Deborah A Knight, James W Williams, Anita S Chong, Ashley Quintin Hejmanowski, Julie E Dierksheide, James W Waldman
    Abstract:

    Background. Despite advances in antiviral chemotherapy, herpes simplex virus type 1 (HSV-1), continues to complicate the clinical course of many allograft recipients. We have previously demonstrated that the experimental Immunosuppressive Agent leflunomide inhibits production of cytomegalovirus by interference with virion assembly. We test the hypothesis that this Agent exerts similar antiviral activity against HSV-1 Methods and Results. Plaque assay of virus yield from endothelial or Vero cells after inoculation with each of four clinical HSV-1 isolates demonstrated a dose-dependent reduction of virus production in the presence of pharmacologic concentrations of A77 1726, the active metabolite of leflunomide. DNA dot blot and biochemical assay of viral DNA polymerase activity indicated that A77 does not inhibit viral DNA synthesis. Rather, as visualized by transmission electron microscopic method, this Agent seems to disrupt virion assembly by preventing nucleocapsid tegumentation. Conclusions. These findings, in demonstrating that leflunomide exerts antiviral activity against HSV-1 by mechanisms similar to those we have previously shown with cytomegalovirus, imply that this Agent may possess broad spectrum activity against other herpesviruses.

  • novel mechanism of inhibition of cytomegalovirus by the experimental Immunosuppressive Agent leflunomide
    Transplantation, 1999
    Co-Authors: W J Waldman, Deborah A Knight, Nell S Lurain, Daniel M Miller, Daniel D Sedmak, James W Williams, Anita S Chong
    Abstract:

    Background. Despite progress in antiviral chemotherapy, cytomegalovirus (CMV) remains a major cause of morbidity and mortality among pharmacologically immunosuppressed organ transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide, an inhibitor of protein kinase activity and pyrimidine synthesis, is an experimental Immunosuppressive Agent effective against acute and chronic allograft rejection in animal models. Because a number of CMV proteins are known to be phosphorylated, we tested the hypothesis that this Agent might exert inhibitory activity against CMV. Methods and results. Plaque assays demonstrated dramatic dose-dependent attenuation of production of multiple clinical CMV isolates in leflunomide-treated human fibroblasts and endothelial cells, common targets for CMV infection in vivo. As shown by Northern blot analysis and immunohistochemical staining, leflunomide neither interferes with transcription of immediate early or late viral genes, nor with expression of corresponding proteins. CMV-specific DNA dot blots and biochemical enzyme assays indicated that, in contrast to currently approved anti-CMV drugs, leflunomide exerts no inhibitory effect on the accumulation of viral DNA in infected cells, or on viral DNA polymerase activity. Rather, as visualized by transmission electron microscopy, this Agent appears to act at a late stage in virion assembly by preventing tegument acquisition by viral nucleocapsids. Finally we have demonstrated equivalent inhibitory activity of leflunomide against multi-drug-resistant CMV isolates. Conclusions. These findings imply that leflunomide, an effective Immunosuppressive Agent, shows potential to concurrently attenuate a major complication of immunosuppression, CMV disease, by a novel mechanism of antiviral activity.

  • inhibition of cytomegalovirus in vitro and in vivo by the experimental Immunosuppressive Agent leflunomide
    Intervirology, 1999
    Co-Authors: James W Waldman, Deborah A Knight, Leonard Blinder, Jikun Shen, Nell S Lurain, Daniel M Miller, Daniel D Sedmak, James W Williams, Anita S Chong
    Abstract:

    Despite progress in antiviral chemotherapy, cytomegalovirus (CMV) remains a major cause of morbidity and mortality among pharmacologically immunosuppressed transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide, an inhibitor of protein kinase activity and pyrimidine synthesis, is an experimental Immunosuppressive Agent effective against acute and chronic rejection in animal models. Herein we summarize our recent studies demonstrating that leflunomide inhibits the production of multiple clinical CMV isolates (including multi-drug-resistant virus) in both human fibroblasts and endothelial cells. In contrast to all other anti-CMV drugs currently in use, leflunomide does not inhibit viral DNA synthesis, but rather appears to interfere with virion assembly. Finally, preliminary studies in a rat model suggest that this Agent reduces viral load in vivo. These findings imply that leflunomide, an effective Immunosuppressive Agent, shows potential to concurrently attenuate a major complication of immunosuppression, CMV disease, by a novel mechanism of antiviral activity.

  • prolongation of rat islet allograft survival by the Immunosuppressive Agent leflunomide
    Transplantation, 1997
    Co-Authors: Z Guo, Jikun Shen, Anita S Chong, Preston Foster, Howard N Sankary, Lawrence Mcchesney, Deepak Mital, Stephen C Jensik, James W Williams
    Abstract:

    The purpose of this study was to investigate the effect of Leflunomide (Lef), alone or in combination with a suboptimal dose of cyclosporine (CsA), on rat allogeneic islet transplantation. Two thousands islets were transplanted under the left kidney capsule of a streptozocin-induced diabetic Lewis recipient. In the ACI to Lewis combination, the mean survival time (MST) of the untreated group was 5.2±0.8 days. Lef at 2.5, 5, and 10 mg/kg/day for 14 days significantly prolonged MSTs to 19.0±1.6, 29.8±3.7, and 29.0±5.3 days (P<0.01), respectively. CsA at 5 mg/kg/day also prolonged graft survival to 21±3.5 days. When CsA (5 mg/kg/day) was combined with Lef (5 or 10 mg/kg/day) and administered for 14 days, the survival rate of the islet allografts was further increased to 34.8±4.7 and 36.0±6.6 days, respectively. When Lef or CsA monotherapy was extended to 28 days at a dose of 5 mg/kg/day, MSTs were further increased to 45.8±8.8 or 37.4±4.7 days, respectively. Graft MST was 56.4±9.9 days when Lef and CsA combination therapy was administered for 28 days. In the Brown-Norway to Lewis combination, MST of the allogeneic islets in untreated rats was 6.2±0.8 days. When Lef or CsA alone, at 5 mg/kg/day, was administered for 28 days, two of seven Lef-treated rats remained normoglycemia for more than 100 days. Graft survival longer than 100 days occurred in one of five CsA-treated rats, and in five of eight rats treated with the combination of Lef and CsA. The graft-bearing left kidney was removed after 100 days in rats with functional islet allografts, and a second Brown-Norway islet graft was transplanted into the right kidney. In all recipients, the second graft was rejected by 9.8±1.5 days. In summary, our findings demonstrate that Lef prolonged allogeneic islet graft survival, and its Immunosuppressive effect was improved when combined with CsA.

  • regulation of b cell function by the Immunosuppressive Agent leflunomide
    Transplantation, 1996
    Co-Authors: Karyn F Siemasko, James W Williams, Anita S Chong, Eric G Bremer, Alison Finnegan
    Abstract:

    Leflunomide is an Immunosuppressive drug capable of inhibiting cellular and humoral mediated responses in vivo. The mechanism responsible for suppression of B cell antibody responses in vivo has not been identified. In this study we demonstrate that leflunomide functions to inhibit murine B cell antibody production by directly acting on the B cell. Experiments performed in vivo showed that both T cell-dependent as well as T cell-independent antigen responses were suppressed by leflunomide. Initial in vitro experiments demonstrated that leflunomide inhibited B cell antibody production by decreasing B cell proliferation. The suppression of B cell proliferation induced by a variety of stimuli that use different signal cascade components suggested that leflunomide was acting on a common component required for B cell proliferation. Kinetic studies with LPS activated B cells revealed that leflunomide retained its inhibitory activity when added as late as 24 hr after stimulation in an 88-hr assay. By analyzing the cell cycle of LPS-stimulated B cells we observed that leflunomide targets two different stages in cell cycle transition: (1) from G1 to S phase and (2) from S phase to G2/M phase. Analysis of one of the cyclin-dependent kinases, Cdk2 protein, by Western blot revealed that Cdk2 levels were decreased, in the presence of leflunomide, 48 hr after stimulation. These data further confirmed that leflunomide inhibited B cell progression through the S phase. We also present evidence that the addition of exogenous uridine reversed the antiproliferative activity of leflunomide. This indicated that leflunomide acted as a pyrimidine synthesis inhibitor, thereby inhibiting B cell proliferation and cell cycle progression.

James W Williams - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of herpes simplex virus type 1 by the experimental Immunosuppressive Agent leflunomide
    Transplantation, 2001
    Co-Authors: Deborah A Knight, James W Williams, Anita S Chong, Ashley Quintin Hejmanowski, Julie E Dierksheide, James W Waldman
    Abstract:

    Background. Despite advances in antiviral chemotherapy, herpes simplex virus type 1 (HSV-1), continues to complicate the clinical course of many allograft recipients. We have previously demonstrated that the experimental Immunosuppressive Agent leflunomide inhibits production of cytomegalovirus by interference with virion assembly. We test the hypothesis that this Agent exerts similar antiviral activity against HSV-1 Methods and Results. Plaque assay of virus yield from endothelial or Vero cells after inoculation with each of four clinical HSV-1 isolates demonstrated a dose-dependent reduction of virus production in the presence of pharmacologic concentrations of A77 1726, the active metabolite of leflunomide. DNA dot blot and biochemical assay of viral DNA polymerase activity indicated that A77 does not inhibit viral DNA synthesis. Rather, as visualized by transmission electron microscopic method, this Agent seems to disrupt virion assembly by preventing nucleocapsid tegumentation. Conclusions. These findings, in demonstrating that leflunomide exerts antiviral activity against HSV-1 by mechanisms similar to those we have previously shown with cytomegalovirus, imply that this Agent may possess broad spectrum activity against other herpesviruses.

  • novel mechanism of inhibition of cytomegalovirus by the experimental Immunosuppressive Agent leflunomide
    Transplantation, 1999
    Co-Authors: W J Waldman, Deborah A Knight, Nell S Lurain, Daniel M Miller, Daniel D Sedmak, James W Williams, Anita S Chong
    Abstract:

    Background. Despite progress in antiviral chemotherapy, cytomegalovirus (CMV) remains a major cause of morbidity and mortality among pharmacologically immunosuppressed organ transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide, an inhibitor of protein kinase activity and pyrimidine synthesis, is an experimental Immunosuppressive Agent effective against acute and chronic allograft rejection in animal models. Because a number of CMV proteins are known to be phosphorylated, we tested the hypothesis that this Agent might exert inhibitory activity against CMV. Methods and results. Plaque assays demonstrated dramatic dose-dependent attenuation of production of multiple clinical CMV isolates in leflunomide-treated human fibroblasts and endothelial cells, common targets for CMV infection in vivo. As shown by Northern blot analysis and immunohistochemical staining, leflunomide neither interferes with transcription of immediate early or late viral genes, nor with expression of corresponding proteins. CMV-specific DNA dot blots and biochemical enzyme assays indicated that, in contrast to currently approved anti-CMV drugs, leflunomide exerts no inhibitory effect on the accumulation of viral DNA in infected cells, or on viral DNA polymerase activity. Rather, as visualized by transmission electron microscopy, this Agent appears to act at a late stage in virion assembly by preventing tegument acquisition by viral nucleocapsids. Finally we have demonstrated equivalent inhibitory activity of leflunomide against multi-drug-resistant CMV isolates. Conclusions. These findings imply that leflunomide, an effective Immunosuppressive Agent, shows potential to concurrently attenuate a major complication of immunosuppression, CMV disease, by a novel mechanism of antiviral activity.

  • inhibition of cytomegalovirus in vitro and in vivo by the experimental Immunosuppressive Agent leflunomide
    Intervirology, 1999
    Co-Authors: James W Waldman, Deborah A Knight, Leonard Blinder, Jikun Shen, Nell S Lurain, Daniel M Miller, Daniel D Sedmak, James W Williams, Anita S Chong
    Abstract:

    Despite progress in antiviral chemotherapy, cytomegalovirus (CMV) remains a major cause of morbidity and mortality among pharmacologically immunosuppressed transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide, an inhibitor of protein kinase activity and pyrimidine synthesis, is an experimental Immunosuppressive Agent effective against acute and chronic rejection in animal models. Herein we summarize our recent studies demonstrating that leflunomide inhibits the production of multiple clinical CMV isolates (including multi-drug-resistant virus) in both human fibroblasts and endothelial cells. In contrast to all other anti-CMV drugs currently in use, leflunomide does not inhibit viral DNA synthesis, but rather appears to interfere with virion assembly. Finally, preliminary studies in a rat model suggest that this Agent reduces viral load in vivo. These findings imply that leflunomide, an effective Immunosuppressive Agent, shows potential to concurrently attenuate a major complication of immunosuppression, CMV disease, by a novel mechanism of antiviral activity.

  • prolongation of rat islet allograft survival by the Immunosuppressive Agent leflunomide
    Transplantation, 1997
    Co-Authors: Z Guo, Jikun Shen, Anita S Chong, Preston Foster, Howard N Sankary, Lawrence Mcchesney, Deepak Mital, Stephen C Jensik, James W Williams
    Abstract:

    The purpose of this study was to investigate the effect of Leflunomide (Lef), alone or in combination with a suboptimal dose of cyclosporine (CsA), on rat allogeneic islet transplantation. Two thousands islets were transplanted under the left kidney capsule of a streptozocin-induced diabetic Lewis recipient. In the ACI to Lewis combination, the mean survival time (MST) of the untreated group was 5.2±0.8 days. Lef at 2.5, 5, and 10 mg/kg/day for 14 days significantly prolonged MSTs to 19.0±1.6, 29.8±3.7, and 29.0±5.3 days (P<0.01), respectively. CsA at 5 mg/kg/day also prolonged graft survival to 21±3.5 days. When CsA (5 mg/kg/day) was combined with Lef (5 or 10 mg/kg/day) and administered for 14 days, the survival rate of the islet allografts was further increased to 34.8±4.7 and 36.0±6.6 days, respectively. When Lef or CsA monotherapy was extended to 28 days at a dose of 5 mg/kg/day, MSTs were further increased to 45.8±8.8 or 37.4±4.7 days, respectively. Graft MST was 56.4±9.9 days when Lef and CsA combination therapy was administered for 28 days. In the Brown-Norway to Lewis combination, MST of the allogeneic islets in untreated rats was 6.2±0.8 days. When Lef or CsA alone, at 5 mg/kg/day, was administered for 28 days, two of seven Lef-treated rats remained normoglycemia for more than 100 days. Graft survival longer than 100 days occurred in one of five CsA-treated rats, and in five of eight rats treated with the combination of Lef and CsA. The graft-bearing left kidney was removed after 100 days in rats with functional islet allografts, and a second Brown-Norway islet graft was transplanted into the right kidney. In all recipients, the second graft was rejected by 9.8±1.5 days. In summary, our findings demonstrate that Lef prolonged allogeneic islet graft survival, and its Immunosuppressive effect was improved when combined with CsA.

  • regulation of b cell function by the Immunosuppressive Agent leflunomide
    Transplantation, 1996
    Co-Authors: Karyn F Siemasko, James W Williams, Anita S Chong, Eric G Bremer, Alison Finnegan
    Abstract:

    Leflunomide is an Immunosuppressive drug capable of inhibiting cellular and humoral mediated responses in vivo. The mechanism responsible for suppression of B cell antibody responses in vivo has not been identified. In this study we demonstrate that leflunomide functions to inhibit murine B cell antibody production by directly acting on the B cell. Experiments performed in vivo showed that both T cell-dependent as well as T cell-independent antigen responses were suppressed by leflunomide. Initial in vitro experiments demonstrated that leflunomide inhibited B cell antibody production by decreasing B cell proliferation. The suppression of B cell proliferation induced by a variety of stimuli that use different signal cascade components suggested that leflunomide was acting on a common component required for B cell proliferation. Kinetic studies with LPS activated B cells revealed that leflunomide retained its inhibitory activity when added as late as 24 hr after stimulation in an 88-hr assay. By analyzing the cell cycle of LPS-stimulated B cells we observed that leflunomide targets two different stages in cell cycle transition: (1) from G1 to S phase and (2) from S phase to G2/M phase. Analysis of one of the cyclin-dependent kinases, Cdk2 protein, by Western blot revealed that Cdk2 levels were decreased, in the presence of leflunomide, 48 hr after stimulation. These data further confirmed that leflunomide inhibited B cell progression through the S phase. We also present evidence that the addition of exogenous uridine reversed the antiproliferative activity of leflunomide. This indicated that leflunomide acted as a pyrimidine synthesis inhibitor, thereby inhibiting B cell proliferation and cell cycle progression.

James W Waldman - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of respiratory syncytial virus in vitro and in vivo by the Immunosuppressive Agent leflunomide
    Antiviral Therapy, 2011
    Co-Authors: Melinda Dunn, Deborah A Knight, James W Waldman
    Abstract:

    Background: Respiratory syncytial virus (RSV) is the primary cause of bronchiolitis and pneumonia in infants and young children worldwide and is often the cause of infections in bone marrow, solid organ transplant, cystic fibrosis and congenital heart disease patients, as well as respiratory tract disease in elderly adults. Treatment options are limited to ribavirin, which is only marginally effective, and passive immunoprophylaxis, which is very expensive. The Immunosuppressive Agent leflunomide has been shown to exert potent antiviral activity against several herpesviruses and polyomavirus BK. In the current study we have tested the hypothesis that leflunomide exerts antiviral activity against RSV. Methods: Human Hep-2 or small airway epithelial cells were inoculated with RSV and treated with A77 1726, the active metabolite of leflunomide. Syncytia formation was assessed by immunohistochemical staining, and virus yield was measured by plaque assay. Cotton rats were intranasally inoculated with RSV, treated with leflunomide by gavage, and pulmonary viral loads were measured by plaque assay of lung homogenates. Results: Phase contrast microscopy and immunohistochemical staining demonstrated profound attenuation of RSV-induced syncytia formation in infected cultures treated with A77 1726, the active metabolite of leflunomide. Plaque assays of virus yield in RSV-inoculated cell cultures demonstrated potent, dose-dependent A77-mediated antiviral activity. Likewise, pulmonary viral loads in RSV-inoculated cotton rats were reduced by >3 log by leflunomide compared with vehicle-treated controls, even when leflunomide treatment was delayed until day 3 post-inoculation. Conclusions: These findings suggest promise for lefluno― mide as a convenient, orally administered addition to the growing arsenal of antiviral therapeutics. While specific antiviral mechanisms remain to be elucidated, leflunomide shows unique bifunctional potential to both reduce viral load and, by virtue of its well-documented anti-iniflammatory activity, attenuate the destructive inflammation associated with RSV disease.

  • inhibition of angiogenesis related endothelial activity by the experimental Immunosuppressive Agent leflunomide
    Transplantation, 2001
    Co-Authors: James W Waldman, Deborah A Knight, Alice A Bickerstaff, Gayle M Gordillo, Kathleen Orosz, Charles G Orosz
    Abstract:

    Background. Leflunomide, an inhibitor of protein kinase activity and pyrimidine synthesis, is an experimental Immunosuppressive Agent effective in the prevention/control of acute and chronic rejection in animal models and currently in phase I clinical trials in human transplant recipients. This Agent is also effective in the control of graft-versus-host disease, autoimmune reactions, and the growth of certain tumors. The importance of the endothelium in these disease processes led us to hypothesize that leflunomide might act directly upon the endothelial cell (EC). Methods and Results. Assay of human EC colony formation demonstrated dose-dependent, leflunomide-mediated inhibition of EC proliferation. In addition, the organization of EC into capillary-like networks, which occurs during 18 hr of incubation on Matrigel, was progressively disrupted with increasing concentrations of leflunomide. Finally, fibrin-embedded transverse sections of murine aorta, which sprout numerous microvessels during an 11-day incubation, were inhibited from doing so in the presence of this Agent. All drug concentrations used in these experiments were nontoxic and pharmacologically relevant, and none of these effects were reversible by exogenous uridine, implying that inhibition of these processes was not due to intracellular pyrimidine depletion. Furthermore, neither cyclosporine nor tacrolimus exerted inhibitory activity in any of the experiments described above. Conclusions. Data generated by these studies distinguish leflunomide among immunosuppressants as uniquely capable of inhibiting angiogenesis-related endothelial functions and suggest additional mechanisms by which this Agent might intervene in the diverse array of disease processes against which it has shown therapeutic potential.

  • inhibition of herpes simplex virus type 1 by the experimental Immunosuppressive Agent leflunomide
    Transplantation, 2001
    Co-Authors: Deborah A Knight, James W Williams, Anita S Chong, Ashley Quintin Hejmanowski, Julie E Dierksheide, James W Waldman
    Abstract:

    Background. Despite advances in antiviral chemotherapy, herpes simplex virus type 1 (HSV-1), continues to complicate the clinical course of many allograft recipients. We have previously demonstrated that the experimental Immunosuppressive Agent leflunomide inhibits production of cytomegalovirus by interference with virion assembly. We test the hypothesis that this Agent exerts similar antiviral activity against HSV-1 Methods and Results. Plaque assay of virus yield from endothelial or Vero cells after inoculation with each of four clinical HSV-1 isolates demonstrated a dose-dependent reduction of virus production in the presence of pharmacologic concentrations of A77 1726, the active metabolite of leflunomide. DNA dot blot and biochemical assay of viral DNA polymerase activity indicated that A77 does not inhibit viral DNA synthesis. Rather, as visualized by transmission electron microscopic method, this Agent seems to disrupt virion assembly by preventing nucleocapsid tegumentation. Conclusions. These findings, in demonstrating that leflunomide exerts antiviral activity against HSV-1 by mechanisms similar to those we have previously shown with cytomegalovirus, imply that this Agent may possess broad spectrum activity against other herpesviruses.

  • inhibition of cytomegalovirus in vitro and in vivo by the experimental Immunosuppressive Agent leflunomide
    Intervirology, 1999
    Co-Authors: James W Waldman, Deborah A Knight, Leonard Blinder, Jikun Shen, Nell S Lurain, Daniel M Miller, Daniel D Sedmak, James W Williams, Anita S Chong
    Abstract:

    Despite progress in antiviral chemotherapy, cytomegalovirus (CMV) remains a major cause of morbidity and mortality among pharmacologically immunosuppressed transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide, an inhibitor of protein kinase activity and pyrimidine synthesis, is an experimental Immunosuppressive Agent effective against acute and chronic rejection in animal models. Herein we summarize our recent studies demonstrating that leflunomide inhibits the production of multiple clinical CMV isolates (including multi-drug-resistant virus) in both human fibroblasts and endothelial cells. In contrast to all other anti-CMV drugs currently in use, leflunomide does not inhibit viral DNA synthesis, but rather appears to interfere with virion assembly. Finally, preliminary studies in a rat model suggest that this Agent reduces viral load in vivo. These findings imply that leflunomide, an effective Immunosuppressive Agent, shows potential to concurrently attenuate a major complication of immunosuppression, CMV disease, by a novel mechanism of antiviral activity.

Suren N. Sehgal - One of the best experts on this subject based on the ideXlab platform.