sirolimus and sotrastaurin

By their suppressive functions, regulatory B (Breg) cells are considered as key elements in the control and development of various disease states. Many signals can induce Bregs in vivo and in vitro and often from heterogeneous populations. Several specific signals delivered in a timely immunological context contribute to the establishment of Bregs. These are endogenous and physiological signals or stimuli, widely discussed in the literature participating in the establishment of an effective immune response. However, exogenous signals, much less clearly identified can also be considered as Bregs inducers. These extrinsic signals are capable of directly or indirectly influencing the suppressive capacity of Bregs, but also their expansion and functional restoration in its absence. Faced with the excitement generated by the development of processes favoring the expansion of Bregs in mice for therapeutic purposes, the challenge today is to extrapolate such approaches in humans. This perspective may already be in effect.

Topics: Adrenal Cortex Hormones; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; B-Cell Activating Factor; B-Lymphocytes, Regulatory; CD40 Antigens; Cytokines; Humans; Immunosuppressive Agents; Methotrexate; Mycophenolic Acid; Pyrroles; Quinazolines; Receptors, Antigen, B-Cell; Semaphorins; Sirolimus; Toll-Like Receptors; Tretinoin; Vitamin D; Vitamins

Current strategies for immunosuppression in liver transplant (LT) recipients include the design of protocols targeting a more individualized approach to reduce risk factors such as renal failure, cardiovascular complications and malignancies. Renal injury in LT recipients may be often multifactorial and is associated with increased risk of post-transplant morbidity and mortality. The quest for low toxicity immunosuppressive regimens has been challenging and resulted in CNI minimization protocols or CNI withdrawal and conversion to mycophenolate mofetil (MMF) and/or mammalian target of rapamycin inhibitor-based immunosuppressive regimens. Use of antibody induction to delay CNI administration may be an option in particular in immunocompromized, critically ill patients with high MELD scores. Protocols including MMF introduction and concomitant CNI minimization have the potential to recover renal function even in the medium and long term after LT. We review on hot topics in the prevention and management of acute and chronic renal injury in LT patients. For this purpose, we present and critically discuss results from immunosuppressive studies published in the current literature or presented at recent LT meetings.

Topics: Abatacept; Calcineurin Inhibitors; Everolimus; Humans; Immunoconjugates; Immunosuppression Therapy; Liver Transplantation; Mycophenolic Acid; Precision Medicine; Pyrroles; Quinazolines; Renal Insufficiency; Risk Factors; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

A persistent challenge facing the transplant community is avoiding renal compromise, whether protecting a newly placed kidney allograft or preserving native renal function after another organ has been implanted. One of the principal ways to achieve this is by altering the immunosuppressive regimen. We review some of the more important recent studies in this area.. Over the past year, two new immunosuppressive agents have received attention. An immunoselective biologic agent, belatacept, continued to demonstrate a sustained benefit in renal function when compared with a cyclosporine-based regimen. In a phase 2 multicenter study, sotrastaurin, a protein kinase C inhibitor, has shown promise in preserving renal graft function but lacks potency as an immunosuppressive agent. A known agent, everolimus, in combination with reduced doses of calcineurin inhibitors or with other agents, continues to be in the forefront as a promising renal-sparing option. Finally, further investigation into mycophenolate mofetil has shown that it has some advantages as a long-term agent when used in monotherapy.. The new therapies investigated show some promise as potential alternative agents. As no drug regimen yet demonstrates an overwhelming benefit over calcineurin inhibitors, particularly regarding overall efficacy, efforts should continue to move forward toward the goal of minimizing chronic kidney disease.

Topics: Abatacept; Calcineurin Inhibitors; Cyclosporine; Everolimus; Graft Rejection; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney; Kidney Transplantation; Mycophenolic Acid; Pyrroles; Quinazolines; Sirolimus; TOR Serine-Threonine Kinases

The prevalence of acute renal allograft rejection has decreased substantially in past decades due to new and more specific immunosuppressive compounds but improvements in long-term graft function have not been achieved. There is a large need for new immunosuppressive agents that lack toxicity of current agents such as calcineurin inhibitors but show high synergistic efficiency in preventing rejection processes.. This review summarizes data concerning the pharmacokinetics, pharmacodynamics and clinical efficacy of the new PKC inhibitor sotrastaurin with a focus on renal transplantation. The article contains information that has been presented at international transplant meetings and congresses and that has been published between 2006 and 2010. Additionally, current ongoing trials are described in detail.. Immunosuppressive regimens after kidney transplantation consist of a combination of several agents in order to minimize drug toxicity. Therefore, the reader is presented with the most up-to-date/current developments in sotrastaurin applications in Phase I and II trials with emphasis on data maintained from studies that combined sotrastaurin with established agents such as mycophenolic acid and tacrolimus.. Several trials are ongoing and planned to determine the optimal immunosuppressive regimen to benefit from sotrastaurin's distinct mechanism of action.

Topics: Calcineurin Inhibitors; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cyclosporine; Drug Evaluation; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Protein Kinase C; Protein Kinase Inhibitors; Pyrroles; Quinazolines; Sirolimus; Tacrolimus; Treatment Outcome

The last several decades have seen a substantial decrease in the prevalence of acute allograft rejection in kidney transplant recipients, while equivalent improvements in long-term graft function have not been realized. As a result, the primary focus of new immunosuppressive drug development has expanded to include ease of use, improved side effect profiles, and reduced nephrotoxicity in addition to the more traditional goal of improved short-term outcomes. A number of novel drugs are currently under investigation in Phase I, II, or III clinical trials primarily to replace the nephrotoxic but highly effective calcineurin inhibitors. ISA247 (voclosporine) is a cyclosporine (CsA) analog with reduced nephrotoxicity in Phase III study. AEB071 (sotrastaurin), a protein kinase C inhibitor, and CP-690550, a JAK3 inhibitor, are small molecules in Phase II studies. Everolimus is derived from the mTOR inhibitor sirolimus and is in Phase III study. Belatacept is a humanized antibody that inhibits T-cell costimulation and has shown encouraging results in multiple Phase II and III trials. Alefacept and Efaluzimab are humanized antibodies that inhibit T-cell adhesion and are in Phase I and II clinical trials. This article reviews the mechanisms of action as well as published and preliminary results of the Phase I-III clinical trials involving these novel immunosuppressive agents.

Topics: Abatacept; Alefacept; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cyclosporine; Everolimus; Graft Rejection; Graft Survival; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Piperidines; Pyrimidines; Pyrroles; Quinazolines; Recombinant Fusion Proteins; Sirolimus

Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.

Topics: Acute Disease; Adult; Antineoplastic Agents; Biopsy; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Protein Kinase Inhibitors; Pyrroles; Quinazolines; Retrospective Studies; Sirolimus; Transplantation, Homologous; Treatment Outcome

Sotrastaurin is an immunosuppressant that blocks T-lymphocyte activation via protein kinase C inhibition. The authors determined whether a pharmacokinetic interaction occurs between sotrastaurin and everolimus, both of which are substrates and inhibitors of CYP3A4.. This was a randomized, three-period, crossover study in 18 healthy subjects. They received single oral doses of (1) 100 mg sotrastaurin, (2) 2 mg everolimus, and (3) the drug combination. Clinical and pharmacokinetic data were collected to Day 5 after each treatment.. Coadministration of everolimus decreased sotrastaurin C(max) from 638 +/- 295 to 539 +/- 211 ng/ml yielding a combination/ monotherapy ratio (90% confidence interval) of 0.87 (0.76 - 1.00). Sotrastaurin total AUC was not altered by everolimus with values of 3660 +/- 1853 versus 3630 +/- 2006 ng*h/ml and a ratio of 1.00 (0.88 - 1.13). Sotrastaurin increased everolimus C(max) from 15 +/- 6 to 16 +/- 6 ng/ml yielding a ratio of 1.15 (0.99 - 1.33) and increased everolimus total AUC from 114 +/- 50 to 137 +/- 56 ng*h/ml yielding a ratio of 1.20 (1.05 - 1.37). The possibility that a higher dose of sotrastaurin than used in this study might further increase everolimus blood levels cannot be excluded.. Coadministration of a single 100 mg dose sotrastaurin with a single 2 mg dose everolimus did not alter sotrastaurin pharmacokinetics to a clinically relevant extent. Everolimus AUC was increased 20% by sotrastaurin.

Topics: Administration, Oral; Adult; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP3A; Drug Interactions; Everolimus; Humans; Immunosuppressive Agents; Male; Protein Kinase C; Protein Kinase Inhibitors; Pyrroles; Quinazolines; Sirolimus; Young Adult

Antibody-mediated response in solid organ transplantation is critical for graft dysfunction and loss. The use of immunosuppressive agents partially inhibits the B-lymphocyte response leading to a risk of acute and chronic antibody-mediated rejection. This study evaluated the impact of JAK3 and PKC inhibitors tofacitinib (Tofa) and sotrastaurin (STN), respectively, on B-cell proliferation, apoptosis, and activation in vitro.. Human B cells isolated from peripheral blood of healthy volunteers were cocultured with CD40 ligand-transfected fibroblasts as feeder cells in the presence of interleukin (IL) 2, IL-10, and IL-21. The cocultures were treated with immunosuppressants Tofa, STN, and rapamycin (as a control), to analyze the proliferation and apoptosis of B cells by means of Cyquant and flow cytometry, respectively. CD27 and IgG staining were applied to evaluate whether treatments modified the activation of B cells.. Tofa and STN were able to inhibit B-cell proliferation to the same extent as rapamycin, without inducing cell apoptosis. After 6 days in coculture with feeder cells, all B cells showed CD27 memory B-cell phenotype. None of the immunosuppressive treatments modified the proportion between class-switched and non-class-switched memory B cells observed in nontreated cultures. The high predominance of CD27. Our results show that Tofa and STN can suppress B-cell antibody responses to an extent similar to rapamycin, in vitro; therefore these compounds may be a useful therapy against antibody-mediated rejection in transplantation.

Topics: Apoptosis; B-Lymphocytes; CD40 Ligand; Cell Proliferation; Cells, Cultured; Humans; Immunosuppressive Agents; Interleukin-10; Interleukin-2; Interleukins; Janus Kinase 3; Leukocytes, Mononuclear; Lymphocyte Activation; Piperidines; Protein Kinase C; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinazolines; Sirolimus

A considerable fraction of renal transplanted patients is susceptible to humoral rejection. Today well-established therapy regimens are available to control antibody-mediated rejection in the short term. Nevertheless, donor-specific antibodies persist and graft function deteriorates over time. This might be due to insufficient maintenance immunosuppression - which always consists of two to three drugs with different mechanisms of action. Since T- and B-cell functions always depend on each other in the alloimmune response it is of interest to analyze the effects of combined standard and new immunosuppressive substances with T-cell inhibitory properties on B-cell function. The effectiveness of complementary administrations of sotrastaurin, mycophenolic acid and everolimus on the activation and function of human primary B-lymphocytes was tested. Everolimus and mycophenolic acid alone and in combination proved to be highly effective in suppressing B-cell activation, whereas the proteinkinase C inhibitor sotrastaurin had an unexpected and reverse impact on various B-cell functions when applied in combination with the mammalian target of rapamycin and the inosine monophosphate dehydrogenase inhibitor.

Topics: Apoptosis; B-Lymphocytes; B7-1 Antigen; Cell Proliferation; Cytokines; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Everolimus; Humans; Immunity, Humoral; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Lymphocyte Activation; Mycophenolic Acid; Primary Cell Culture; Pyrroles; Quinazolines; Sirolimus

Humoral rejection processes may lead to allograft injury and subsequent dysfunction. Today, only one B-cell-specific agent is in clinical use and the effects of standard and new immunosuppressant substances on B-cell activation and function are not fully clarified. The impact of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function was assessed by analysing proliferation, apoptosis, CD80/CD86 expression and immunoglobulin and IL-10 production in primary stimulated B cells. In addition, B-cell co-cultures with pre-activated T cells were performed to evaluate the effect of the different immunosuppressive agents on T-cell-dependent immunoglobulin production. Sotrastaurin did not inhibit B-cell proliferation, CD80/CD86 expression, and IgG production and had only minor effects on IgM levels at the highest concentration administered. In contrast, mycophenolic acid and everolimus had strong effects on all B-cell functions in a dose-dependent manner. All immunosuppressive agents caused decreased immunoglobulin levels in T-cell-dependent B-cell cultures. The data provided here suggest that mycophenolic acid and everolimus, but not sotrastaurin, are potent inhibitors of human B-lymphocyte function and activation.

Topics: Apoptosis; B-Lymphocytes; B7-1 Antigen; B7-2 Antigen; Cell Membrane; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Everolimus; Graft Rejection; Humans; Immunity, Humoral; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunosuppressive Agents; Interleukin-10; Leukocytes, Mononuclear; Mycophenolic Acid; Pyrroles; Quinazolines; Sirolimus; Transplantation, Homologous

NVP-AEB071 (AEB, sotrastaurin), an oral inhibitor of protein kinase C (PKC), effectively blocks T-cell activation. The immunosuppressive effects of oral AEB were demonstrated in a rat local graft versus host (GvH) reaction and rat cardiac transplantation models. T-cell activation was suppressed by 95% in blood from AEB-treated rats, with a positive correlation between T-cell inhibition and AEB blood concentration. In GvH studies, AEB inhibited lymph node swelling dose-dependently (3-30 mg/kg). BN and DA cardiac allografts were acutely rejected within 6-10 days post-transplantation in untreated LEW rats. AEB at 10 and 30 mg/kg b.i.d. prolonged BN graft survival to a mean survival time of 15 and >28 days, and DA grafts to 6.5 and 17.5 days, respectively. In the DA to LEW model, combining a nonefficacious dose of AEB (10 mg/kg b.i.d.) with a nonefficacious dose of cyclosporine, everolimus or FTY720 led to prolonged median survival times (26 days, >68 days and >68 days, respectively). Pharmacokinetic monitoring excluded drug-drug interactions, suggesting synergy. In conclusion, these studies are the first to demonstrate that AEB prolongs rat heart allograft survival safely as monotherapy and in combination with nonefficacious doses of cyclosporine, everolimus or FTY720. Thus, AEB may have the potential to offer an alternative to calcineurin inhibitor-based therapies.

Topics: Animals; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Everolimus; Fingolimod Hydrochloride; Heart Transplantation; Immunosuppressive Agents; Male; Propylene Glycols; Protein Kinase C; Pyrroles; Quinazolines; Rats; Rats, Inbred Lew; Rats, Wistar; Sirolimus; Sphingosine