Canadian national retrospective chart review comparing the long term effect of cyclosporine vs. tacrolimus on clinical outcomes in patients with post-liver transplantation hepatitis C virus infection.

The transition from regular use of cyclosporine to the newer calcineurin-inhibitors, such as tacrolimus, has been suggested as a contributing factor to the "era effect" of worsening outcomes of post-transplant HCV recurrence. This retrospective medical chart review of 458 patients was undertaken to evaluate the role of immunosuppressant choice (cyclosporine vs. tacrolimus) in determining virologic response and clinical outcomes of post-liver transplant HCV infection recurrence. Our results showed that patients undergoing interferon-based treatment taking cyclosporine have significantly better odds (OR: 2.59, P = 0.043) of presenting a sustained viral response (66.7%) compared to tacrolimus (52.8%). This did not result in a significant effect on post-liver transplantation clinical events including HCV-related deaths, graft loss, fibrosing cholestatic hepatitis, hepatocellular carcinoma or graft rejection. Other variables, which showed a significant relationship with the achievement of sustained viral response included donor age (OR 0.96, P = 0.001) and HCV genotype 1 infection (OR 0.05, P < 0.001). The observed significant increase in the odds of acute/hyperacute (OR 6.49, P = 0.001) and chronic rejection (OR 10.45, P < 0.001) in the cyclosporine to tacrolimus switch group, accompanied by an increase in the odds of HCV-related death (OR 2.30, P < 0.047) compared to tacrolimus merits further study. A significant increase (P < 0.044) in new-onset diabetes mellitus with tacrolimus (28.3%) compared to cyclosporine (18.7%) was also observed. Pre-transplant diabetes mellitus was associated with a significantly increased likelihood of graft fibrosis (HR 1.95, P = 0.003).

Reduction of cyclosporine following the introduction of everolimus in maintenance heart transplant recipients: a pilot study.

Data are scarce concerning the calcineurin inhibitor dose reduction required following introduction of everolimus in maintenance heart transplant recipients to maintain stable renal function. In a 48-week, multicenter, single-arm pilot study in heart transplant patients >12 months post-transplant, everolimus was started at 1.5 mg/day (subsequently adjusted to target C(0) 5-10 ng/ml). Mycophenolate mofetil or azathioprine was discontinued on the same day and cyclosporine (CsA) dose was reduced by 25%, with a further 25% reduction each time calculated glomerular filtration rate (cGFR) decreased to <75% of baseline. Of 36 patients enrolled, 25 were receiving everolimus at week 48. From baseline to week 48, there was a mean decrease of 44.5%, 50.9% and 44.6% in CsA dose, C(0) and C(2), respectively. Mean cGFR was 68.9 +/- 14.5 ml/min at baseline and 61.6 +/- 11.5 ml/min at week 48 (P = 0.018). The prespecified criterion for stable renal function was met, i.e. a mean decrease

Acyclic tethers mimicking subunits of polysaccharide ligands: selectin antagonists.

We report on the design and synthesis of molecules having E- and P-selectins blocking activity both in vitro and in vivo. The GlcNAc component of the selectin ligand sialyl Lewis(X) was replaced by an acyclic tether that links two saccharide units. The minimization of intramolecular dipole-dipole interactions and the gauche effect would be at the origin of the conformational bias imposed by this acyclic tether. The stereoselective synthesis of these molecules, their biochemical and biological evaluations using surface plasmon resonance spectroscopy (SPR), and in vivo assays are described. Because the structure of our analogues differs from the most potent E-selectin antagonists reported, our acyclic analogues offer new opportunities for chemical diversity.

A new approach to explore the binding space of polysaccharide-based ligands: selectin antagonists.

The discovery of molecules that interfere with the binding of a ligand to a receptor remains a topic of great interest in medicinal chemistry. Herein, we report that a monosaccharide unit of a polysaccharide ligand can be replaced advantageously by a conformationally locked acyclic molecular entity. A cyclic component of the selectin ligand Sialyl Lewis(x), GlcNAc, is replaced by an acyclic tether, tartaric esters, which link two saccharide units. The conformational bias of this acyclic tether originates from the minimization of intramolecular dipole-dipole interaction and the gauche effect. The evaluation of the binding of these derivatives to P-selectin was measured by surface plasmon resonance spectroscopy. The results obtained in our pilot study suggest that the discovery of tunable tethers could facilitate the exploration of the carbohydrate recognition domain of various receptors.

Cyclosporine reduction in the presence of everolimus: 3-month data from a Canadian pilot study of maintenance cardiac allograft recipients.

BACKGROUND: Concentration-controlled everolimus with concomitant cyclosporine (CsA) dose reduction in renal transplantation permits preservation of kidney function without loss of efficacy. Data are lacking regarding everolimus with reduced-dose CsA in maintenance cardiac transplant patients. METHODS: In a multicenter, open-label, single-arm pilot study, concentration-controlled everolimus was initiated in patients receiving CsA microemulsion (Neoral) with/without mycophenolate mofetil (MMF) or azathioprine, and with/without corticosteroids. On the day of everolimus initiation, MMF/azathioprine was discontinued and CsA dose was reduced by 25% with further reductions as required in response to decreasing calculated glomerular filtration rate (cGFR). RESULTS: Of the 36 patients enrolled (intent-to-treat [ITT]), 27 underwent CsA dose reduction as planned (per protocol [PP]). During Week 1, the CsA dose was reduced by 23.3 +/- 7.3% in the ITT population (p < 0.0001) and 26.9 +/- 2.9% in the PP population (p < 0.0001). Mean cGFR (Nankivell) was 68.9 +/- 14.5 ml/min at baseline and 64.4 +/- 14.3 ml/min at Week 12 in the ITT population (p = 0.021), and 69.5 +/- 14.4 ml/min and 66.6 +/- 8.6 ml/min in the PP cohort (p = 0.132). cGFR at Week 12 met the criterion for non-inferiority vs baseline. One case of acute rejection of Grade >or=3A occurred (2.7%). There was no graft loss or death. Hemoglobin and hematocrit levels decreased significantly, whereas cholesterol and triglyceride levels increased (all p < 0.0001). CONCLUSIONS: This pilot study suggests that initiation of concentration-controlled everolimus with a concomitant 25% reduction in CsA dose in maintenance heart transplant patients is associated with no significant decline in renal function, and no indication of increased rejection to Month 3 post-conversion. Evaluation of more substantial CsA dose reductions is required.