Sirolimus: continuing the evolution of transplant immunosuppression.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and economic issues associated with sirolimus, the most recent immunosuppressive agent approved for kidney transplantation. DATA SOURCES: A MEDLINE search (1966-June 2000) was completed to identify primary and review articles. In addition, abstracts from recent meetings on transplantation were reviewed for information and research on sirolimus. STUDY SELECTION AND DATA EXTRACTION: Blinded, randomized, controlled studies were the goal, but, as with most newly approved immunosuppressive agents, a significant amount of information on sirolimus is not available in this optimal form. All articles were assessed and all pertinent information was incorporated in this review. DATA SYNTHESIS: Sirolimus is structurally related to the immunosuppressive agent tacrolimus, and retains a pharmacokinetic and drug interaction profile similar to that of the calcineurin inhibitors, cyclosporine and tacrolimus. However, the novel mechanism of action of sirolimus differs significantly from these agents, as does its adverse effect profile. The most significant adverse reaction is hyperlipidemia. Clinical experience with sirolimus has allowed transplant centers to expand its use into other areas of transplantation as well as certain autoimmune disorders. CONCLUSIONS: The definitive role of sirolimus will continue to be determined; however, sirolimus offers an excellent addition to the transplant immunosuppression armamentarium.

Mycophenolate mofetil: effects on clinical transplantation.

Mycophenolate mofetil (MMF) is the morpholinoethylester prodrug of mycophenolic acid, an agent which inhibits the proliferation of B and T lymphocytes through the noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, itself a key enzyme in the de novo synthetic pathway of guanosine nucleotides. Currently, MMF is approved for the prevention of acute renal allograft rejection when used in combination with cyclosporin and corticosteroids. Several studies have also demonstrated that this drug is useful in the treatment of refractory rejection in renal, heart and liver transplant recipients.

Mycophenolate mofetil.

Mycophenolate mofetil is the morpholinoethylester prodrug of mycophenolic acid, an agent that inhibits the proliferation of B and T lymphocytes through noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, a key enzyme in the de novo synthetic pathway of guanine nucleotides. Currently, mycophenolate mofetil is approved for the prevention of acute renal allograft rejection when given in combination with cyclosporine and steroids. Several studies also demonstrated that the agent is effective in the treatment of refractory rejection in renal, heart, and liver transplant recipients, and may have efficacy in the treatment of chronic rejection as well.

Safety and efficacy of Intralipid emulsions of amphotericin B.

To evaluate the clinical role of amphotericin/20% Intralipid emulsions (ILA), we conducted a Medline search of the English literature to locate the relevant case reports and clinical studies involving the use of this formulation. Due to differences in study design and definitions, we applied a set of treatment outcome definitions to determine the clinical efficacy of this treatment modality. Only 37 patients received ILA for the treatment of documented fungal infections. Using our definitions, four were considered successfully treated, one improved, two failed, and 30 were unevaluable. While infusion-related adverse events and nephrotoxicity were reportedly reduced with ILA, use of adjunctive therapies and concomitant nephrotoxic agents, and comparisons with high infusion concentrations complicate evaluation. Furthermore, incomplete and conflicting data exist regarding the physiochemical stability of ILA. The currently available data do not support recommendations for the use of this formulation for the treatment of systemic fungal infections.

Interleukin-6 production by human melanoma cell lines.

We examined the expression of interleukin-6 (IL-6) by 12 established human melanoma cell lines. Two constitutively produced low levels of IL-6 protein, as measured by enzyme-linked immunosorbent assay. Cells from these two lines, as well as those from two non-IL-6-producing cell lines, contained IL-6-specific mRNA as demonstrated by Northern hybridization. Treatment of the two IL-6-producing melanoma cell lines with interleukin-1 beta, tumor necrosis factor-alpha, or phorbol myristate acetate caused a marked increase in IL-6 production. These induction signals failed to stimulate IL-6 production in the nonproducing cells, even those that expressed IL-6 mRNA. IL-6 did not appear to act as an autocrine growth factor since the addition of exogenous human recombinant IL-6 or polyclonal anti-IL-6 antibody did not alter cellular proliferation. The production of this multifunctional cytokine by tumors may play a role in tumor-host interactions and this should be recognized in the design of biologic therapy trials.