Rapamycin Derivative

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Walter Schuler - One of the best experts on this subject based on the ideXlab platform.

  • Cleavage of the cyclohexyl-subunit of Rapamycin results in loss of immunosuppressive activity.
    Bioorganic & Medicinal Chemistry Letters, 1999
    Co-Authors: Richard Sedrani, Walter Schuler, Lyn H. Jones, Anne-marie Jutzi-eme, Sylvain Cottens
    Abstract:

    The cyclohexyl-subunit of Rapamycin was cleaved by a sequence involving a Baeyer-Villiger reaction and acid hydrolysis of the resulting lactone-acetal as key steps. Binding of this new Rapamycin Derivative to FKBP12 was only slightly reduced by this modification, whereas the loss of antiproliferative and immunosuppressive activity was dramatic. These findings indicate that part of the cyclohexyl-subunit of Rapamycin could belong to its effector domain.

  • sdz rad a new Rapamycin Derivative pharmacological properties in vitro and in vivo
    Transplantation, 1997
    Co-Authors: Walter Schuler, Richard Sedrani, Sylvain Cottens, Barbara Haberlin, M Schulz, Henkjan Schuurman, Gerhard Zenke, Hansguenter Zerwes, Max H Schreier
    Abstract:

    Background. This report describes the preclinical pharmacological profile of the new Rapamycin analog, SDZ RAD, i.e., 40-O-(2-hydroxyethyl)-Rapamycin. Methods. The pharmacological effects of SDZ RAD were assessed in a variety of in vitro and in vivo models, which included an autoimmune disease model as well as kidney and heart allotransplantation models using different rat strain combinations. Results. SDZ RAD has a mode of action that is different from that of cyclosporine or FK606. In contrast to the latter, SDZ RAD inhibits growth factor-driven cell proliferation in general, as demonstrated for the in vitro cell proliferation of a lymphoid cell line and of vascular smooth muscle cells. SDZ RAD is immunosuppressive in vitro as demonstrated by the inhibition of mouse and human mixed lymphocyte reactions and the inhibition of antigen-driven proliferation of human T-cell clones. The concentrations needed to achieve 50% inhibition in all of these assays fall into the subnanomolar range. SDZ RAD is effective in the in vivo models when given by the oral route in doses ranging between 1 mg/kg/day and 5 mg/kg/day. When compared with Rapamycin, the in vitro activity of SDZ RAD is generally about two to three times lower; however, when administered orally, SDZ RAD is at least as active in vivo as Rapamycin. Conclusions. In conclusion, SDZ RAD is a new, orally active Rapamycin-Derivative that is immunosuppressive and that efficiently prevents graft rejection in rat models of allotransplantation. SDZ RAD has therefore been selected for development for use in combination with cyclosporine A to prevent acute and chronic rejection after solid organ allotransplantation.

  • sdz rad a new Rapamycin Derivative synergism with cyclosporine
    Transplantation, 1997
    Co-Authors: Henkjan Schuurman, Richard Sedrani, Sylvain Cottens, Gerhard Zenke, Serge Fuchs, Joanne Joergensen, Timo Meerloo, Madeleine Tanner, Walter Schuler
    Abstract:

    Background. SDZ RAD is a new Rapamycin analog with potent immunosuppressive activity. Compounds of the Rapamycin class differ in their mode of action from cyclosporine, thus providing a rationale for potential synergism of these two potent immunosuppressants. Methods. The two-way mouse mixed lymphocyte reaction (BALB/c-CBA strain combination) was applied. Orthotopic kidney and heterotopic heart allografting was performed in the stringent DA-to-Lewis rat strain combination, with administration of compounds orally as microemulsion preconcentrate (i.e., Neoral in the case of cyclosporine). Results. Isobologram analysis of checkerboard titrations of SDZ RAD and cyclosporine in two-way mouse mixed lymphocyte reactions indicates a synergistic interaction in vitro. In vivo, the minimal effective dose of microemulsion cyclosporine giving long-term graft survival was 5.0 mg/kg/day; for SDZ RAD, the minimal effective dose was 5.0 mg/kg/day in kidney transplantation and >5.0 mg/kg/day in heart transplantation. Long-term allograft survival was noted for combinations of microemulsion cyclosporine administered at 1.0 or 2.0 mg/kg/day and SDZ RAD given at between 0.5 and 2.0 mg/kg/day. The index of synergy in different combinations ranged between 0.3 and 0.7. 1 Conclusions. SDZ RAD and cyclosporine show synergism in immunosuppression, both in vitro and in vitro. They form a promising synergistic drug combination in allotransplantation.

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

  • Effects of immunomodulators on airways hyperresponsiveness to adenosine induced in actively sensitised Brown Norway rats by exposure to allergen
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2003
    Co-Authors: Bruno Tigani, Jason P. Hannon, Elisabeth Schaeublin, Lazzaro Mazzoni, John R. Fozard
    Abstract:

    We have recently demonstrated a marked and selective augmentation of the bronchoconstrictor response to adenosine in actively sensitised Brown Norway (BN) rats challenged with ovalbumin (OA). The augmented response is mediated by 5-hydroxytryptamine (5-HT) released as a consequence of mast cell activation. We describe here the effects of budesonide, a clinically used glucocorticosteroid, IMM125, a hydroxyethyl Derivative of D -serine-cyclosporine, MLD987, a close analogue of ascomycin and SAR943, a Rapamycin Derivative, on the hyperresponsiveness to adenosine induced in actively sensitised BN rats by exposure to allergen. Bronchoconstrictor responses to adenosine elicited 3 h following intratracheal (i.t.) instillation of OA, 0.3 mg kg^−1 were reduced dose-dependently by budesonide, IMM125, and MLD987, given i.t. 25 and 1 h prior to allergen challenge. In contrast, SAR943 had no effect on responses to adenosine. Responses to methacholine and 5-HT were minimally affected by these agents. Bronchoconstrictor responses to bradykinin were dose-dependently reduced by budesonide, but unaffected following IMM125, MLD987 or SAR943 pre-treatment. Challenge with OA at a dose of 0.3 mg kg^−1, induced increases in bronchoalveolar lavage (BAL) fluid, leukocyte numbers, eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activities and protein concentration measured 24 h post challenge. Budesonide (1 mg kg^−1 given i.t. 25 and 1 h prior to OA challenge) induced reductions in the BAL fluid parameters of inflammation; IMM125 and MLD987, at a dose of 1 mg kg^−1 had no significant effect whereas SAR943 reduced lymphocyte numbers. Thus, budesonide, IMM125 and MLD987 block the hyperresponsiveness to adenosine induced by allergen challenge in sensitised rats. In the case of budesonide the effect is associated with a powerful, generalised anti-inflammatory effect although an effect directly on the mast cells is also likely. With IMM125 and MLD987, the effect is seen at doses that are not anti-inflammatory and may reflect direct suppression of mast cell activation by these agents.

  • Effects of immunomodulators on airways hyperresponsiveness to adenosine induced in actively sensitised Brown Norway rats by exposure to allergen
    Naunyn-schmiedebergs Archives of Pharmacology, 2003
    Co-Authors: Bruno Tigani, Jason P. Hannon, Elisabeth Schaeublin, Lazzaro Mazzoni, John R. Fozard
    Abstract:

    We have recently demonstrated a marked and selective augmentation of the bronchoconstrictor response to adenosine in actively sensitised Brown Norway (BN) rats challenged with ovalbumin (OA). The augmented response is mediated by 5-hydroxytryptamine (5-HT) released as a consequence of mast cell activation. We describe here the effects of budesonide, a clinically used glucocorticosteroid, IMM125, a hydroxyethyl Derivative of D-serine-cyclosporine, MLD987, a close analogue of ascomycin and SAR943, a Rapamycin Derivative, on the hyperresponsiveness to adenosine induced in actively sensitised BN rats by exposure to allergen.

Henkjan Schuurman - One of the best experts on this subject based on the ideXlab platform.

  • No in vivo infection of triple immunosuppressed non-human primates after inoculation with high titers of porcine endogenous retroviruses
    Xenotransplantation, 2009
    Co-Authors: Volker Specke, Henkjan Schuurman, Roland Plesker, Cheick Coulibaly, Reinhard Kurth, James C. Wood, Kristen M. Suling, Clive Patience, Joachim Denner
    Abstract:

    UNLABELLED: Porcine endogenous retroviruses (PERVs) released from pig tissue can infect selected human cells in vitro and therefore represent a safety risk for xenotransplantation using pig cells, tissues, or organs. Although PERVs infect cells of numerous species in vitro, attempts to establish reliable animal models failed until now. Absence of PERV transmission has been shown in first experimental and clinical xenotransplantations; however, these trials suffered from the absence of long-term exposure (transplant survival) and profound immunosuppression. METHODS: We conducted infectivity studies in rhesus monkeys, pig-tailed monkeys, and baboons under chronic immunosuppression with cyclosporine A, methylprednisolone, and the Rapamycin Derivative. These species were selected because they are close to the human species and PERVs can be transmitted in vitro to cells of these species. In addition, the animals received twice, a C1 esterase inhibitor to block complement activation before inoculation of PERV. In order to overcome the complications of microchimerism, animals were inoculated with high titers of cell-free PERV. In addition, to enable transmission via cell-cell contact, some animals also received virus-producing cells. For inoculation the primate cell-adapted strain PERV/5 degrees was used which is characterized by a high infectious titer. Produced on human cells, this virus does not express alpha 1,3 Gal epitopes, does not contain porcine antigens on the viral surface and is therefore less immunogenic in non-human primates compared with pig cell-derived virus. Finally, we present evidence that PERV/5 degrees productively infects cells from baboons and rhesus monkeys. RESULTS: In a follow-up period of 11 months, no antibody production against PERV and no integration of proviral DNA in blood cells was observed. Furthermore, no PERV sequences were detected in the DNA of different organs taken after necropsy. CONCLUSION: These results indicate that in a primate model, in the presence of chronic immunosuppression, neither the inoculation of cell-free nor cell-associated PERV using a virus already adapted to primate cells results in an infection; this is despite the fact that peripheral blood mononuclear cells of the same animals are infectible in vitro.

  • Oral efficacy of the new immunomodulator FTY720 in cynomolgus monkey kidney allotransplantation, given alone or in combination with cyclosporine or RAD.
    Transplantation, 2002
    Co-Authors: Henkjan Schuurman, Klaus Menninger, Maxime Audet, Adrien Kunkler, Claudine Maurer, Corinne Vedrine, Mario Bernhard, Lorrie Gaschen, Volker Brinkmann, Valérie F. J. Quesniaux
    Abstract:

    BACKGROUND: FTY720 is a novel immunomodulator with a unique mechanism of action, i.e. chemokine-dependent lymphocyte homing into secondary lymphoid organs associated with profound lymphocyte depletion in blood. We investigated its efficacy, either FTY720 alone or together with cyclosporine or the Rapamycin Derivative Rapamycin Derivative (RAD), in cynomolgus monkey kidney allotransplantation. METHODS: Life-supporting allotransplantation was performed in bilaterally nephrectomized hosts. Compounds were given once daily by oral gavage. Monitoring was done by serum creatinine and urea, and rejection was concluded when values exceeded 500 micromol/L and 50 mmol/L, respectively (5-6 times the upper limit of reference values). Rejection was confirmed by graft histology. The termination point was set to 100 days after transplantation. In addition, animals were monitored for 24 hr drug concentrations and thorough inspection of potential adverse side effects. RESULTS: FTY720 given alone at 3.0 mg/kg per day prolonged rejection-free survival (33-85 days, mean 24 hr concentration between 54 and 66 ng/mL [n=3]), but it was not efficacious at a 0.3 mg/kg per day dose. For cyclosporine alone, 30 mg/kg per day during maintenance was efficacious (average concentration above 100 ng/mL, historical data from our group), and for RAD alone 0.75 mg/kg per day (concentration above 10 ng/mL). Efficacious FTY720-cyclosporine-A (CsA) or FTY720-RAD combinations were established using 0.1-0.3 mg/kg per day FTY720, 10-30 mg/kg per day cyclosporine, and/or 0.25-0.50 mg/kg per day RAD. Compared with single-compound treatment, FTY720 effective doses and 24 hr trough concentrations were at least tenfold lower in combination treatment and those of cyclosporine and RAD about twofold lower, indicative of effective synergy between the compounds. Already at the lowest FTY720 dose tested (0.03 mg/kg per day), there was a profound lymphocyte depletion down to about 30% of pretransplant values, which further increased at the highest dose (3.0 mg/kg per day, to about 14% of pretransplant values). Lymphocyte depletion was reflected by a decrease in T and B subpopulations. CONCLUSION: FTY720 is an effective immunosuppressant in prevention of acute kidney allograft rejection in cynomolgus monkeys and synergizes with cyclosporine and/or RAD in yielding rejection-free allograft survival.

  • Virus safety in xenotransplantation: first exploratory in vivo studies in small laboratory animals and non-human primates
    Transplant Immunology, 2002
    Co-Authors: Volker Specke, Henkjan Schuurman, Roland Plesker, Cheick Coulibaly, M Özel, G Langford, Reinhard Kurth, Joachim Denner
    Abstract:

    a Abstract For xenotransplantation, the transplantation of animal cells, tissues and organs into human recipients, to date, pigs are favored as potential donors. Beside ethical, immunological, physiological and technical problems, the microbiological safety of the xenograft has to be guaranteed. It will be possible to eliminate all of the known porcine microorgansims in the nearby future by vaccinating or specified pathogen-free breeding. Thus, the main risk will come from the porcine endogenous retroviruses (PERVs) which are present in the pig genome as proviruses of different subtypes. PERVs will therefore be transmitted, with the xenograft, to the human recipient. PERVs can infect numerous different types of human primary cells and cell lines in vitro and were shown to adapt to these cells by serial passaging on uninfected cells. Furthermore, PERVs have high homology to other retroviruses, such as feline leukemia virus (FeLV) or murine leukemia virus (MuLV), which are known to induce tumors or immunodeficiencies in the infected host. To evaluate the potential risk of a trans-species transmission of PERV in vivo, naive and immunosuppressed rats, guinea pigs and minks were inoculated with PERV and screened over a period of 3 months for an antibody reaction against PERV proteins or for the integration of proviral DNA into the genomic DNA of the host's cells. Furthermore, we inoculated three different species of non-human primates, rhesus monkey (Macaca mulatta), pig-tailed monkey (Macaca nemestrina) and baboon (Papio hamadryas) with high titers of a human-adapted PERV. To simulate a situation in xenotransplantation, the animals received a daily triple immunosuppression using cyclosporine A, methylprednisolone and RAD, a Rapamycin Derivative, presently under development by Novartis. None of the small laboratory animals or the non-human primates showed production of antibodies against PERV or evidence of integration of proviral DNA in blood cells or cells of several organs, 3 months after virus inoculation, despite the observation that cells of the animals used in the experiment were infectible in vitro. This apparent difference in the outcome of the in vitro and the in vivo data might be explained by an efficient elimination of the virus by the innate or adaptive immunity of the animals. 2002 Elsevier Science B.V. All rights reserved.

  • sdz rad a new Rapamycin Derivative pharmacological properties in vitro and in vivo
    Transplantation, 1997
    Co-Authors: Walter Schuler, Richard Sedrani, Sylvain Cottens, Barbara Haberlin, M Schulz, Henkjan Schuurman, Gerhard Zenke, Hansguenter Zerwes, Max H Schreier
    Abstract:

    Background. This report describes the preclinical pharmacological profile of the new Rapamycin analog, SDZ RAD, i.e., 40-O-(2-hydroxyethyl)-Rapamycin. Methods. The pharmacological effects of SDZ RAD were assessed in a variety of in vitro and in vivo models, which included an autoimmune disease model as well as kidney and heart allotransplantation models using different rat strain combinations. Results. SDZ RAD has a mode of action that is different from that of cyclosporine or FK606. In contrast to the latter, SDZ RAD inhibits growth factor-driven cell proliferation in general, as demonstrated for the in vitro cell proliferation of a lymphoid cell line and of vascular smooth muscle cells. SDZ RAD is immunosuppressive in vitro as demonstrated by the inhibition of mouse and human mixed lymphocyte reactions and the inhibition of antigen-driven proliferation of human T-cell clones. The concentrations needed to achieve 50% inhibition in all of these assays fall into the subnanomolar range. SDZ RAD is effective in the in vivo models when given by the oral route in doses ranging between 1 mg/kg/day and 5 mg/kg/day. When compared with Rapamycin, the in vitro activity of SDZ RAD is generally about two to three times lower; however, when administered orally, SDZ RAD is at least as active in vivo as Rapamycin. Conclusions. In conclusion, SDZ RAD is a new, orally active Rapamycin-Derivative that is immunosuppressive and that efficiently prevents graft rejection in rat models of allotransplantation. SDZ RAD has therefore been selected for development for use in combination with cyclosporine A to prevent acute and chronic rejection after solid organ allotransplantation.

  • sdz rad a new Rapamycin Derivative synergism with cyclosporine
    Transplantation, 1997
    Co-Authors: Henkjan Schuurman, Richard Sedrani, Sylvain Cottens, Gerhard Zenke, Serge Fuchs, Joanne Joergensen, Timo Meerloo, Madeleine Tanner, Walter Schuler
    Abstract:

    Background. SDZ RAD is a new Rapamycin analog with potent immunosuppressive activity. Compounds of the Rapamycin class differ in their mode of action from cyclosporine, thus providing a rationale for potential synergism of these two potent immunosuppressants. Methods. The two-way mouse mixed lymphocyte reaction (BALB/c-CBA strain combination) was applied. Orthotopic kidney and heterotopic heart allografting was performed in the stringent DA-to-Lewis rat strain combination, with administration of compounds orally as microemulsion preconcentrate (i.e., Neoral in the case of cyclosporine). Results. Isobologram analysis of checkerboard titrations of SDZ RAD and cyclosporine in two-way mouse mixed lymphocyte reactions indicates a synergistic interaction in vitro. In vivo, the minimal effective dose of microemulsion cyclosporine giving long-term graft survival was 5.0 mg/kg/day; for SDZ RAD, the minimal effective dose was 5.0 mg/kg/day in kidney transplantation and >5.0 mg/kg/day in heart transplantation. Long-term allograft survival was noted for combinations of microemulsion cyclosporine administered at 1.0 or 2.0 mg/kg/day and SDZ RAD given at between 0.5 and 2.0 mg/kg/day. The index of synergy in different combinations ranged between 0.3 and 0.7. 1 Conclusions. SDZ RAD and cyclosporine show synergism in immunosuppression, both in vitro and in vitro. They form a promising synergistic drug combination in allotransplantation.

Uwe Christians - One of the best experts on this subject based on the ideXlab platform.

  • Polymer-Free Biolimus A9-Coated Stent Demonstrates More Sustained Intimal Inhibition, Improved Healing, and Reduced Inflammation Compared With a Polymer-Coated Sirolimus-Eluting Cypher Stent in a Porcine Model
    Circulation-cardiovascular Interventions, 2010
    Co-Authors: Norio Tada, Uwe Christians, Renu Virmani, Gordon Grant, Lauren Bartlett, Alexander Black, Claudia F. Clavijo, Ron Betts, Doug Savage, Shih-horng Su
    Abstract:

    Background— Drug-eluting stents effectively reduce restenosis but may increase late thrombosis and delayed restenosis. Persistent polymer, the drug, or a combination of both could be responsible. Local delivery of Biolimus A9, a Rapamycin Derivative, from a polymer-free BioFreedom stent (Biosensors International) may prevent these complications. Methods and Results— We compared high-dose (HD) (225 μg/14 mm Biolimus A9) and low-dose (LD) (112 μg/14 mm Biolimus A9) BioFreedom stents with a polymer-coated sirolimus-eluting Cypher stent (SES) and a bare-metal stent (BMS) at 28 days and 180 days in an overstretch coronary mini-swine model with histomorphometric and histological analysis. At 28 days, there was a reduction in neointimal proliferation by HD, LD, and SES compared with BMS (neointimal thickness: HD, 0.080±0.032; LD, 0.085±0.038; SES, 0.064±0.037; BMS, 0.19±0.111 mm; P HD/LD/SES). At 180 days, both BioFreedom stents were associated with reduced neointimal proliferation, whereas SES exhibited increased neointima (neointimal thickness: HD, 0.12±0.034; LD, 0.10±0.040; SES, 0.20±0.111; BMS, 0.17±0.099 mm; P HD/LD; BMS > LD). At 180 days, BioFreedom stents showed decreased fibrin and inflammation, including granuloma and giant cells, compared with SES. Conclusions— The polymer-free Biolimus A9-coated stent demonstrates equivalent early and superior late reduction of intimal proliferation compared with SES in a porcine model. After implantation of BioFreedom stent, delayed arterial healing was minimal, and there was no increased inflammation at 180 days compared with SES implantation. The use of polymer-free stents may have a potential long-term benefit over traditional polymeric-coated drug-eluting stents. Received May 4, 2009; accepted February 22, 2010. # CLINICAL PERSPECTIVE {#article-title-2}

  • suppression of acute rejection in allogeneic rat lung transplantation a study of the efficacy and pharmacokinetics of Rapamycin Derivative sdz rad used alone and in combination with a microemulsion formulation of cyclosporine
    Journal of Heart and Lung Transplantation, 1999
    Co-Authors: Bernard Hausen, Katrin Boeke, Gerald J Berry, Ignacio Segarra, Uwe Christians, Randall E Morris
    Abstract:

    Abstract Background The novel immunosuppressant SDZ RAD, 40-0 (2-hydroxyethyl)- Rapamycin, is an orally active Rapamycin analogue developed for use in combination with cyclosporine (Neoral®). The present study was designed to evaluate the efficacy of SDZ RAD, Neoral®, or a combination of both drugs for suppression of acute rejection in an allogeneic, unilateral rat lung transplant model. Methods Brown–Norway (RT1 n ) donor lungs were implanted into Lewis (RT1 l ) recipients that were observed for 21 days. Postoperative evaluation included daily weights, serial chest radiographs, drug trough levels, and histology scores of the transplanted lung on the day of sacrifice. Treatment groups were comprised of rats treated orally with the RAD vehicle as controls ( n = 6); SDZ RAD 2.5 mg/kg/day ( n = 9); Neoral® 7.5 mg/kg/day ( n = 8); Neoral® 2.5 mg/kg/day ( n = 6); SDZ RAD 2.5 mg/kg/day plus Neoral® 7.5 mg/kg/day ( n = 7); and Neoral® 2.5 mg/kg/day plus SDZ RAD 2.5 mg/kg/day ( n = 6). Results The results of this study showed that neither monotherapy with 2.5 mg/kg/day of Neoral®, nor 2.5 mg/kg/day of SDZ RAD prevented severe acute rejection in unilateral lung transplant recipients. Furthermore, despite high dose (7.5 mg/kg/day) Neoral® treatment, graft histology showed moderate rejection. However, addition of 2.5 mg/kg/day of SDZ RAD to 7.5 mg/kg/day of Neoral® completely prevented histologic rejection in four of seven grafts, although the remaining 3 grafts showed minimal rejection. This combination resulted in significantly higher RAD trough levels when compared to SDZ RAD treatment alone. Combining a lower dose of Neoral® (2.5 mg/kg/day) with 2.5 mg/kg/day of SDZ RAD resulted in less weight loss and improved animal health; however, the histology of lung grafts in these rats showed mild rejection. Conclusions This is the first study on the efficacy of the novel Rapamycin Derivative SDZ RAD for the control of acute lung allograft rejection. Results showed that acute unilateral rat lung allograft rejection is refractory to monotherapy with either high dose Neoral® or SDZ RAD. The two regimens of combined treatment with Neoral® plus SDZ RAD used in these studies produced either minimal rejection and reduced tolerability or mild rejection and better tolerability and showed potentiation of immunosuppression when both drugs were used together. Additional investigation of these two drugs is needed, however, to devise regimens that produce both high immunosuppressive efficacy and good tolerability.

Bruno Tigani - One of the best experts on this subject based on the ideXlab platform.

  • Effects of immunomodulators on airways hyperresponsiveness to adenosine induced in actively sensitised Brown Norway rats by exposure to allergen
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2003
    Co-Authors: Bruno Tigani, Jason P. Hannon, Elisabeth Schaeublin, Lazzaro Mazzoni, John R. Fozard
    Abstract:

    We have recently demonstrated a marked and selective augmentation of the bronchoconstrictor response to adenosine in actively sensitised Brown Norway (BN) rats challenged with ovalbumin (OA). The augmented response is mediated by 5-hydroxytryptamine (5-HT) released as a consequence of mast cell activation. We describe here the effects of budesonide, a clinically used glucocorticosteroid, IMM125, a hydroxyethyl Derivative of D -serine-cyclosporine, MLD987, a close analogue of ascomycin and SAR943, a Rapamycin Derivative, on the hyperresponsiveness to adenosine induced in actively sensitised BN rats by exposure to allergen. Bronchoconstrictor responses to adenosine elicited 3 h following intratracheal (i.t.) instillation of OA, 0.3 mg kg^−1 were reduced dose-dependently by budesonide, IMM125, and MLD987, given i.t. 25 and 1 h prior to allergen challenge. In contrast, SAR943 had no effect on responses to adenosine. Responses to methacholine and 5-HT were minimally affected by these agents. Bronchoconstrictor responses to bradykinin were dose-dependently reduced by budesonide, but unaffected following IMM125, MLD987 or SAR943 pre-treatment. Challenge with OA at a dose of 0.3 mg kg^−1, induced increases in bronchoalveolar lavage (BAL) fluid, leukocyte numbers, eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activities and protein concentration measured 24 h post challenge. Budesonide (1 mg kg^−1 given i.t. 25 and 1 h prior to OA challenge) induced reductions in the BAL fluid parameters of inflammation; IMM125 and MLD987, at a dose of 1 mg kg^−1 had no significant effect whereas SAR943 reduced lymphocyte numbers. Thus, budesonide, IMM125 and MLD987 block the hyperresponsiveness to adenosine induced by allergen challenge in sensitised rats. In the case of budesonide the effect is associated with a powerful, generalised anti-inflammatory effect although an effect directly on the mast cells is also likely. With IMM125 and MLD987, the effect is seen at doses that are not anti-inflammatory and may reflect direct suppression of mast cell activation by these agents.

  • Effects of immunomodulators on airways hyperresponsiveness to adenosine induced in actively sensitised Brown Norway rats by exposure to allergen
    Naunyn-schmiedebergs Archives of Pharmacology, 2003
    Co-Authors: Bruno Tigani, Jason P. Hannon, Elisabeth Schaeublin, Lazzaro Mazzoni, John R. Fozard
    Abstract:

    We have recently demonstrated a marked and selective augmentation of the bronchoconstrictor response to adenosine in actively sensitised Brown Norway (BN) rats challenged with ovalbumin (OA). The augmented response is mediated by 5-hydroxytryptamine (5-HT) released as a consequence of mast cell activation. We describe here the effects of budesonide, a clinically used glucocorticosteroid, IMM125, a hydroxyethyl Derivative of D-serine-cyclosporine, MLD987, a close analogue of ascomycin and SAR943, a Rapamycin Derivative, on the hyperresponsiveness to adenosine induced in actively sensitised BN rats by exposure to allergen.