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Biomedical subjects

H T Silva

Publications and source records attributed to H T Silva.

15 recordsLinked to original sources
PubMed2007

One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients.

Once-daily tacrolimus extended-release formulation (Prograf XL, formerly referred to as MR or MR4) was compared with the twice-a-day tacrolimus formulation (TAC) and cyclosporine microemulsion (CsA), all administered in combination with mycophenolate mofetil (MMF), corticosteroids and basiliximab induction, in a phase 3, randomized (1:1:1), open-label trial in 638 de novo kidney transplant recipients. In combination with MMF and corticosteroids, XL had an efficacy profile comparable to TAC and CsA. XL/MMF and TAC/MMF were statistically noninferior at 1-year posttransplantation to CsA/MMF for the primary efficacy endpoint, efficacy failure (death, graft loss, biopsy-confirmed acute rejection (BCAR) or lost to follow-up). One-year patient and graft survival were 98.6% and 96.7% in the XL/MMF group, 95.7% and 92.9% in TAC/MMF group and 97.6% and 95.7% in CsA/MMF group. The safety profile of XL in comparison with CsA was similar to that observed with TAC in this study and consistent with previously published reports of TAC in comparison with CsA. The results support the safety and efficacy of tacrolimus in combination with MMF, corticosteroids and basiliximab induction, as well as XL as a safe and effective once-daily dosing alternative.

Adolescent↗
PubMed2004

FTY720 impairs necrosis development after ischemia-reperfusion injury.

Ischemia-reperfusion (IR) injury is a common early feature that contributes to graft damage by impairing resident cell function. Our previous results showed that IR injury impaired renal function, by causing extensive tubular necrosis and increasing MHC class II and ICAM-1 molecule expression by mesangial cells (MC). MCs are likely candidates to come into close contact with immune cells such as monocytes or lymphocytes. It has been suggested that under inflammatory circumstances, there is increased MC expression of MHC class II, of adhesion molecules (such as ICAM-1), of cytokines receptors, and of molecules associated with cellular death (apoptosis). The immunosuppressive properties of FTY720 have been shown in clinical and experimental situations. It has also been shown to be protective against IR injury in rats. We sought to evaluate the role of FTY720 in a murine IR model by measuring renal function, tubular necrosis, and surface molecule expression by cultured mesangial cells. Intravenous administration of FTY720 (1 mg/kg) immediately before IR induction did not improve the short-term (24 hours) outcome of renal function or reduced MHC class II and ICAM-1 surface molecule expression. However, there was a decreased percentage of tubular necrosis in mice treated with FTY720 (51.3% +/- 1.6%) compared with vehicle-treated mice (66% +/- 5.5%). These results suggest a protective role of FTY720 in an IR injury model. More studies are required to identify the mechanisms involved in the protective activity of FTY720 in the IR injury model.

Analysis of Variance↗
PubMed2004

FTY720 treatment prolongs skin graft survival in a completely incompatible strain combination.

FTY720 has shown potent immunomodulatory activity in a variety of animal organ transplant models. However, the in vivo immunosuppressive mechanism of FTY720 is still not fully understood. It has been suggested that the marked decrease in the number of peripheral blood lymphocytes during FTY720 administration could be responsible for its immunosuppressive effects. Our aims were: (1) to study the effects of FTY720 treatment on skin graft survival using a fully mismatched strain combination and (2) to evaluate lymphocyte numbers in different sites at 5 days after skin transplant. C57BL/6 mice and BALB/c mice were the donors and recipients respectively. BALB/c mice received FTY720 (1 mg/kg/d) orally for 4 consecutive days. Drug administration started 1 day before skin transplants. A small segment of tail skin was affixed on the right dorsal side of the mouse via sutures. The administration of FTY720 (4 mg/kg) prolonged skin graft survival from 12.6 +/- 2.2 days (no treatment) to 16.6 +/- 4.2 days. The histologic findings of rejection were similar for all groups. Five days after transplant, lymphocyte numbers were significantly increased in lymph nodes compared with nontransplanted or isogenic graft mice. FTY720 decreased lymphocyte numbers only in the spleen. In conclusion, FTY720 prolonged skin graft survival in a fully mismatched strain combination when administered for 4 days (day -1 to day +2) at a dose of 1 mg/kg/d. The decreased number of lymphocytes in the spleen suggests that the spleen may be a target of FTY720 activity, during the early posttransplant period.

Animals↗
PubMed1999

Flow cytometric analysis of the molecular mechanisms of immunosuppressive action of the active metabolite of leflunomide and its malononitrilamide analogues in a novel whole blood assay.

Malononitrilamides (MNAs) are a new class of immunomodulatory drug highly effective in in vivo models of allo- and xenotransplantation. Knowledge of their effects on immune cells, however, is limited and has been derived solely from investigations using isolated mononuclear cells. This use of purified cells to investigate drug activity is not ideal, so we have combined the analytical power of flow cytometry with our mitogen-driven, whole blood lymphocyte activation and proliferation assays to investigate the in vitro mechanism of action of MNAs. We first show that MNAs (A77 1726, HMR1279, and HMR1715), as well as brequinar (BQR) and cyclosporine (CsA), effectively inhibit cell activation antigen expression and lymphocyte proliferation. We next show that the inhibitory effects of MNAs and BQR, but not CsA, are reversed by the addition of uridine to the culture. These results suggest that inhibition of pyrimidine biosynthesis may be a mechanism by which MNAs suppress both lymphocyte activation and proliferation since these effects were reversed when uridine nucleotide pools were replenished. This novel finding of suppression of activation antigen expression by MNAs in whole blood expands our understanding of the effects of this new class of drug.

Acrylamides↗
PubMed1997

Leflunomide and malononitriloamides.

Leflunomide is a new immunomodulatory drug effective in experimental models of autoimmune diseases and allo- or xenotransplantation. In a Phase II clinical trial leflunomide has shown high tolerability and efficacy in patients with advanced rheumatoid arthritis. The immunomodulatory activity of leflunomide is attributed to its primary metabolite, A77 1726, a malononitriloamide. The in vitro and in vivo mechanisms of action of this class of compounds remain to be completely defined. A77 1726 and several malononitriloamide analogues inhibit T- and B-cell proliferation, suppress immunoglobulin production, and interfere with cell adhesion. While no one central molecular mechanism of action has been proposed to explain all the effects of the malononitriloamides, inhibition of de novo pyrimidine biosynthesis and inhibition of cytokine- and growth factor-receptor associated tyrosine kinase activity are leading hypotheses for the effects of A77 1726 on T- and B-cell proliferation and function. Leflunomide is effective when administered at daily doses of 10 and 25 mg to patients with active rheumatoid arthritis. The improved efficacy at the 25 mg dose is associated with a higher incidence of adverse effects (gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia). Due to the long plasma half-life of A77 1726 (11-16 days), loading doses are required to achieve steady-state concentrations. Phase III randomised, placebo-controlled trials using daily doses of 10 or 20 mg are underway in the US and Europe to confirm and extend the results of the Phase II study. Malononitriloamide analogues of A77 1726 are being evaluated for immunosuppressive efficacy in preclinical models of transplantation, because these compounds have a shorter half-life in animals than A77 1726. If these analogues show efficacies similar to leflunomide in these models and have shorter half-lives than A77 1726 in Phase I trials, the preclinical and Phase I data will be used to select the analogues for Phase II trials in organ transplant recipients.

Journal Article↗