Combined Immunosuppression With Cyclosporine (Neoral) and SDZ Rad in Non-Human Primate Lung Transplantation: Systematic Pharmacokinetic-Based Trials to Improve Efficacy and Tolerability 1

Hausen, Bernard; Ikonen, Tuija; Briffa, Norman; Gj, Berry; Christians, Uwe; Robbins, RC; Hook, Laura; Serkova, Natalie J.; Lz, Benet; Schüler, W.; Moon, Re

doi:10.1097/00007890-200001150-00015

Cited by 47 publications

(11 citation statements)

References 26 publications

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“…35,36,62 Like sirolimus, RAD showed high efficacy in preventing and treating allograft rejections in rat models of heart, 46 kidney, 63 and lung transplantation [64][65][66] and in transplant models of nonhuman primates. [67][68][69] Most interesting were the results of studies investigating the effects of TOR inhibitors on chronic allograft diseases. Similar to the in vitro effects on mesenchymal cells, sirolimus was able to prevent and suppress intimal thickening in vascular grafts in small-animal models, 30,31 as well as in nonhuman primates: Although animals did not receive immunosuppressive therapy during the first 6 weeks after aorta transplantation between MLR-mismatched cynomolgus monkeys, sirolimus monotherapy started posttransplantation day 45 was able to halt and reverse graft vascular disease (Fig.…”

Section: Preclinical Animal Studiesmentioning

confidence: 99%

mTOR inhibitors: An overview

Neuhaus

Klupp

Langrehr

2001

Liver Transplantation

184

142

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Section: Preclinical Animal Studiesmentioning

confidence: 99%

mTOR inhibitors: An overview

Neuhaus

Klupp

Langrehr

2001

Liver Transplantation

184

142

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“…These observations suggest that everolimus may be able to suppress the fibroproliferative processes and attenuate OB in human lung transplant recipients, in a manner analogous to the inhibition of myointimal proliferation and reduction of allograft vasculopathy in cardiac transplant recipients treated with an everolimus-containing regimen (13). A synergistic interaction between everolimus and CsA has been documented in experimental studies (14,15), and the combination has shown excellent immunosuppressive activity in lung transplant models (15)(16)(17) as well as in clinical trials in cardiac (13) and renal (18)(19)(20) transplant recipients. Everolimus possesses novel properties that may be able to target both acute and chronic rejection processes in lung transplant recipients.…”

Section: Introductionmentioning

confidence: 99%

Everolimus Versus Azathioprine in Maintenance Lung Transplant Recipients: An International, Randomized, Double-Blind Clinical Trial

Snell

Valentine

Vitulo

et al. 2006

American Journal of Transplantation

146

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Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce the rate of progression of chronic rejection, bronchiolitis obliterans syndrome (BOS), after lung transplantation. In a randomized, double-blind clinical trial, 213 BOS-free maintenance patients received everolimus (3 mg/day) or azathioprine (AZA, 1-3 mg/kg/day) in combination with cyclosporine and corticosteroids. The prospectively defined primary endpoint was the incidence of efficacy failure (decline in FEV 1 >15% [∆FEV 1 >15%], graft loss, death or loss to follow-up) at 12 months. Incidence of efficacy failure at 12 months was significantly lower in the everolimus group than AZA (21.8% vs. 33.9%; p = 0.046); at 24 months, rates of efficacy failure became similar between the groups. At 12 months, the everolimus group had significantly reduced incidences of ∆FEV 1 >15%, ∆FEV 1 >15% with BOS, and acute rejection. At 24 months, only incidence of acute rejection remained significantly less in the everolimus group. Treatment discontinuations (particularly due to adverse events), serious adverse events and high serum creatinine values were more common with everolimus. For the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing AZA with everolimus 3 months after lung transplantation.

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“…[3][4][5] The macrocyclic lactone everolimus (SDZ, RAD) RAD is a rapamycin derivative with potent immunosuppressive and antiproliferative properties. [6][7][8][9][10] It is further known to inhibit growth factor-driven cell proliferation of hematopoietic and nonhematopoietic cells. 6,10 In addition, RAD is a potent inhibitor of human Epstein-Barr virus (EBV)-transformed B lymphocytes in vitro and in vivo, arresting cell-cycle progression and increasing the apoptotic rate of EBV ϩ B cells.…”

Section: Introductionmentioning

confidence: 99%

A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein β and NF-κB activity in Hodgkin and anaplastic large cell lymphomas

Jundt

Raetzel

Müller

et al. 2005

Blood

133

113

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The immunosuppressive macrolide rapamycin and its derivative everolimus (SDZ RAD, RAD) inhibit the mammalian target of rapamycin (mTOR) signaling pathway. In this study, we provide evidence that RAD has profound antiproliferative activity in vitro and in NOD/SCID mice in vivo against Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) cells. Moreover, we identified 2 molecular mechanisms that showed how RAD exerts antiproliferative effects in HL and ALCL cells. RAD down-regulated the truncated isoform of the transcription factor CCAAT enhancer binding protein ␤ (C/ EBP␤), which is known to disrupt terminal differentiation and induce a transformed phenotype. Furthermore, RAD inhibited constitutive nuclear factor B (NF-B) activity, which is a critical sur- IntroductionHodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) share morphologic and immunophenotypic markers in a subgroup of cases although they are biologically distinct entities. 1 Therefore, pathologic diagnosis is sometimes difficult to achieve and these cases are classified as "gray-zone lymphomas." 2 Moreover, in both entities novel therapeutic options are needed, as curative therapy of HL is compromised by a high risk of long-term complications, and anaplastic lymphoma kinase (ALK)-negative ALCL still has a very unfavorable prognosis with current treatment strategies. [3][4][5] The macrocyclic lactone everolimus (SDZ, RAD) RAD is a rapamycin derivative with potent immunosuppressive and antiproliferative properties. [6][7][8][9][10] It is further known to inhibit growth factor-driven cell proliferation of hematopoietic and nonhematopoietic cells. 6,10 In addition, RAD is a potent inhibitor of human Epstein-Barr virus (EBV)-transformed B lymphocytes in vitro and in vivo, arresting cell-cycle progression and increasing the apoptotic rate of EBV ϩ B cells. 10 Therefore, it has been suggested that RAD might be effective in the prevention and treatment of human posttransplant lymphoproliferative disorders. 10 Here, we investigated whether RAD inhibits tumor cell proliferation of HL and ALCL. We show that RAD significantly inhibits proliferation of HL and ALCL cells in vitro and arrests cell-cycle progression in G 0 /G 1 . Furthermore, we demonstrate that in vivo, RAD markedly suppresses tumor cell proliferation of HL and ALCL cells, xenotransplanted into NOD/SCID mice. Our data suggest that RAD might be used in combination chemotherapy for the treatment of HL and ALCL. Moreover, we studied the mechanisms of proliferation arrest mediated by the mammalian target of rapamycin (mTOR) inhibitor RAD to identify the molecular targets in HL and ALCL. The mTOR pathway controls the translation initiation machinery in response to nutrients and growth factors thereby coordinating cell growth with cell division. 11 A transcription factor that is a critical target of mTOR is the CCAAT enhancer binding protein (C/EBP)␤. 11-13 C/EBP␤ has previously been identified as an essential downstream target in tumors expressing activated cyclin D1. 14 Our dat...

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Combined Immunosuppression With Cyclosporine (Neoral) and SDZ Rad in Non-Human Primate Lung Transplantation: Systematic Pharmacokinetic-Based Trials to Improve Efficacy and Tolerability 1

Abstract: Combination of orally administered SDZ RAD and Neoral showed excellent immunosuppressive efficacy in a stringent lung transplant model. The drug interaction and the narrow therapeutic index of this drug combination required careful dose adjustments to optimize tolerability and efficacy.

Cited by 47 publications

References 26 publications

mTOR inhibitors: An overview

mTOR inhibitors: An overview

Everolimus Versus Azathioprine in Maintenance Lung Transplant Recipients: An International, Randomized, Double-Blind Clinical Trial

A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein β and NF-κB activity in Hodgkin and anaplastic large cell lymphomas

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