Sotrastaurin, a Novel Protein Kinase C- Inhibitor: Evaluation of a CNI-Free Combination with Everolimus in Renal Transplant Recipients

Tedesco‐Silva, Hélio; Weimar, Willem; Hartmann, Anders; Vı́tko, Štefan; Russ, Graeme R.; Toselli, L.; Colussi, Giacomo; Rostaing, Lionel; Krishnan, Ipsita; Gopalakrishnan, Unnikrishnan; Klupp, J

doi:10.1097/00007890-201211271-00460

Cited by 2 publications

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“…Twenty‐one patients were randomized to receive either sotrastaurin 300 mg twice daily ( n = 14) or neoral [starting dose 4 mg/kg/day, aimed trough levels 100–200 ng/ml (month 1), 75–150 ng/ml (months 2–3), 50–100 ng/ml (months 4–5) and 25–50 ng/ml (months 6–12), n = 7] 1 day after living (un)related de novo kidney transplantation. This cohort involved all (adult) patients in our center participating in an open‐label, multi‐centre, randomized Phase II trial (trial number CAEB071A2206, stage 1) (Table ). Both regimens included steroids, basiliximab [anti‐CD25 monoclonal antibody (mAb)] and the mTOR‐inhibitor everolimus [starting dose 1·5 mg twice daily, aimed trough levels 4–8 ng/ml)].…”

Section: Methodsmentioning

confidence: 99%

“…Twenty-one patients were randomized to receive either sotrastaurin 300 mg twice daily (n = 14) or neoral [starting dose 4 mg/kg/day, aimed trough levels 100-200 ng/ml (month 1), 75-150 ng/ml (months 2-3), 50-100 ng/ml (months 4-5) and 25-50 ng/ml (months 6-12), n = 7] 1 day after living (un)related de novo kidney transplantation. This cohort involved all (adult) patients in our center participating in an open-label, multi-centre, randomized Phase II trial [15] (trial number CAEB071A2206, stage 1) ( Peripheral blood mononuclear cells (PBMC) from patient heparinized blood samples were isolated by density gradient using Ficoll-Paque (density gradient 1077 g/ml). After isolation the PBMC samples were frozen in 10% dimethylsulphoxide (DMSO) (Merck, Schuchardt, Germany) and stored at −140°C until analysis.…”

Section: Patientsmentioning

confidence: 99%

“…Sotrastaurin has recently been tested in psoriasis and kidney transplantation . Oncology trials in melanoma and lymphoma patients (ClinicalTrials.gov NCT01430416 and NCT01402440) are on their way.…”

Section: Introductionmentioning

confidence: 99%

“…Oncology trials in melanoma and lymphoma patients (ClinicalTrials.gov NCT01430416 and NCT01402440) are on their way. Our center participated in a randomized, multi‐center trial comparing sotrastaurin and the calcineurin inhibitor neoral in de novo renal transplant recipients . We conducted an ex vivo study on patient samples (stage 1 phase) to investigate the frequency and function of FoxP3 + CD4 + CD25 high T cells.…”

Section: Introductionmentioning

confidence: 99%

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The protein kinase C inhibitor sotrastaurin allows regulatory T cell function

Weerd

Kho

Kraaijeveld

et al. 2014

Clinical and Experimental Immunology

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SummaryThe novel immunosuppressant sotrastaurin is a selective inhibitor of protein kinase C isoforms that are critical in signalling pathways downstream of the T cell receptor. Sotrastaurin inhibits nuclear factor (NF)-κB, which directly promotes the transcription of forkhead box protein 3 (FoxP3), the key regulator for the development and function of regulatory T cells (Tregs). Our center participated in a randomized trial comparing sotrastaurin (n = 14) and the calcineurin inhibitor Neoral (n = 7) in renal transplant recipients. We conducted ex vivo mixed lymphocyte reaction (MLR) and flow cytometry studies on these patient samples, as well as in vitro studies on samples of blood bank volunteers (n = 38). Treg numbers remained stable after transplantation and correlated with higher trough levels of sotrastaurin (r = 0·68, P = 0·03). A dose-dependent effect of sotrastaurin on alloresponsiveness was observed: the half maximal inhibitory concentration (IC50) to inhibit alloactivated T cell proliferation was 45 ng/ml (90 nM). In contrast, Treg function was not affected by sotrastaurin: in the presence of in vitro-added sotrastaurin (50 ng/ml) Tregs suppressed the proliferation of alloactivated T effector cells at a 1:5 ratio by 35 versus 47% in the absence of the drug (P = 0·33). Signal transducer and activator of transcription 5 (STAT)-5 phosphorylation in Tregs remained intact after incubation with sotrastaurin. This potent Treg function was also found in cells of patients treated with sotrastaurin: Tregs inhibited the anti-donor response in MLR by 67% at month 6, which was comparable to pretransplantation (82%). Sotrastaurin is a potent inhibitor of alloreactivity in vitro, while it did not affect Treg function in patients after kidney transplantation.

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Section: Methodsmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The protein kinase C inhibitor sotrastaurin allows regulatory T cell function

Weerd

Kho

Kraaijeveld

et al. 2014

Clinical and Experimental Immunology

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Glomerular filtration rate: utility for assessing long-term renal allograft outcomes in kidney allograft recipients

Marcén¹,

Canton²

2013

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Glomerular filtration rate (GFR) is the parameter currently used in renal transplantation to monitor renal function and to predict long-term survival of the graft. Due to practical difficulties in measuring GFR through inulin or creatinine clearance, formulas have been  designed to estimate GFR from serum creatinine and indirect indices of creatinine production from muscles, i.e., gender, age and body weight. These formulas have been used to monitor renal graft function and to predict graft outcome. Present evidence indicates that estimated GFR (eGFR) can be a relatively imprecise instrument to measure renal function, but remains useful for monitoring graft function and predicting graft outcome. Despite certain limitations, eGFR has provided invaluable information on the determinants of renal graft outcome, especially on the effects of different immunosuppressive regimens. A number of trials examining new immunosuppressive regimens (including calcineurin inhibitor minimization and novel therapeutics) have employed eGFR as an endpoint for assessing clinical benefit. In this capacity, eGFR  assessment has provided important data for comparing regimens. This paper reviews the usefulness of eGFR for predicting renal transplant outcomes.

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Sotrastaurin, a Novel Protein Kinase C- Inhibitor: Evaluation of a CNI-Free Combination with Everolimus in Renal Transplant Recipients

Cited by 2 publications

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The protein kinase C inhibitor sotrastaurin allows regulatory T cell function

The protein kinase C inhibitor sotrastaurin allows regulatory T cell function

Glomerular filtration rate: utility for assessing long-term renal allograft outcomes in kidney allograft recipients

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