AEB-071 versus tacrolimus monotherapy to prevent acute cardiac allograft rejection in the rat: a preliminary report.

Inhibition of T-cell activation is the most efficient way to prevent transplant rejection. Protein kinase C (PKC) is an important signaling enzyme in the activation and regulation of T lymphocytes. AEB-071 (AEB) is a low-molecular-weight compound that blocks early T-cell activation via selective inhibition of PKC, a mechanism that differs from that of the calcineurin inhibitors. The present study sought to compare the effects of AEB versus tacrolimus (Tac) to prevent acute rejection in rats that had undergone heterotopic heart transplantation. We investigated the Brown Norway-Lewis rat strain combination for cardiac graft survival over 30 days after transplantation using varying doses of oral AEB and Tac monotherapy. Grafts were monitored by daily palpation; cessation of palpable ventricular contraction was considered to be rejection. Apart from necropsy, we performed histologic examinations of cardiac graft at 7 days after transplantation. In untreated recipients, allograft mean survival times (MST) was 6.83+/-0.41 days. AEB at 15, 30, or 60 mg/kg versus Tac at 1.2 mg/kg significantly prolonged graft survival to a MST of 12.33+/-1.21, 16.67+/-1.21, and 19.33+/-3.83, versus 17.00+/-6.90 days, respectively. Histologic assessment at 7 days after transplantation showed that high-dose AEB significantly decreased the histologic rejection score, indicative of decreased inflammatory cell infiltration into the graft. These results suggested that the administration of AEB (medium or high-dose), a PKC inhibitor, mitigated acute rejection and displayed significantly longer MST, similar to high-dose Tac after heterotopic heart transplantation in the rat.

Fang YH ，Joo DJ ，Lim BJ ，Kim JY ，Kim MS ，Jeong HJ ，Kim YS ... -  《-》

The effects of AEB071 (sotrastaurin) with tacrolimus on rat heterotopic cardiac allograft rejection and survival.

AEB071 (sotrastaurin) is a specific inhibitor of protein kinase C that prevents T-cell activation. Our previous study demonstrated that AEB071 monotherapy could prevent acute cardiac allograft rejection in rats. Herein, we investigated the effects of AEB071 combined with various doses of tacrolimus (Tac) on the allograft rejection and survival in a rat heart transplantation model. Heterotopic cardiac transplantation from Brown-Norway to Lewis rats was performed. Cardiac allograft survival was assessed by monitoring heartbeats in six recipients of each experimental group. Another four recipient rats were selectively sacrificed in each group at d 7 post-transplantation for histologic examination. Serum transaminases, blood urea nitrogen, and creatinine concentrations were measured. AEB071 monotherapy prolonged allograft mean survival time (MST) compared with the untreated control group. Also a combination of AEB071 and Tac prolonged MST compared with monotherapy groups with higher dose of Tac. In the cardiac graft histology, AEB071 combined with Tac 0.6 mg/kg/d significantly decreased the rejection grade as indicative of decreased inflammatory cell infiltration into the graft. No experimental group was found with any abnormal histologic or serologic evidence of liver and kidney toxicity. AEB071 combined with a smaller dosage of Tac may be clinically possible to establish calcineurin inhibitor (CNI) minimization protocol in solid organ transplantation.

Fang YH ，Joo DJ ，Lim BJ ，Huh KH ，Kim MS ，Suh H ，Kim YS ... -  《-》

Effects of the novel protein kinase C inhibitor AEB071 (Sotrastaurin) on rat cardiac allograft survival using single agent treatment or combination therapy with cyclosporine, everolimus or FTY720.

Weckbecker G ，Pally C ，Beerli C ，Burkhart C ，Wieczorek G ，Metzler B ，Morris RE ，Wagner J ，Bruns C ... -  《-》

Significant reduction of acute cardiac allograft rejection by selective janus kinase-1/3 inhibition using R507 and R545.

Deuse T ，Hua X ，Taylor V ，Stubbendorff M ，Baluom M ，Chen Y ，Park G ，Velden J ，Streichert T ，Reichenspurner H ，Robbins RC ，Schrepfer S ... -  《-》

Is the malononitrilamide FK778 better for the prevention of acute or chronic rejection?

Deuse T ，Schrepfer S ，Pelletier MP ，Fischbein MP ，Robbins RC ，Reichenspurner H ... -  《TRANSPLANTATION PROCEEDINGS》