Abstract
BackgroundSolid organ transplant recipients are particularly vulnerable for infectious diseases due to prolonged immunosuppressive treatment. Residents of endemic regions and travellers may be exposed to malaria and may, therefore, require prolonged antimalarial chemoprophylaxis. The hypothesis of this study was that certain immunosuppressive drugs may exert clinically relevant anti-malarial activity. It was therefore designed to assess the intrinsic anti-malarial activity of everolimus, mycophenolic acid, and rapamycin against Plasmodium falciparum in an in vitro model.MethodsThree laboratory adapted clones of P. falciparum and two isolates were used to assess the potential of mycophenolic acid, rapamycin and everolimus to inhibit in vitro growth of P. falciparum. The standard histidine rich protein 2 assay was employed and inhibitory drug concentrations (IC) were computed by non-linear regression analysis.ResultsAll drugs were associated with complete inhibition of P. falciparum growth in in vitro assays. Mycophenolic acid demonstrated IC50 and IC90 values of 5.4 μmol/L and 15.3 μmol/L. Rapamycin inhibited P. falciparum growth at 7.2 μmol/L (IC50) and 12.5 μmol/L (IC90), respectively. Finally, everolimus displayed IC50 and IC90 values of 6.2 μmol/L and 11.5 μmol/L. There was no difference in in vitro activity against chloroquine sensitive or chloroquine resistant parasites.ConclusionsAll immunosuppressive drugs evaluated in this in vitro study demonstrated activity against P. falciparum. Inhibitory concentrations of mycophenolic acid are within clinically achievable plasma concentrations when used in solid organ transplant recipients. Further in vivo evaluation of mycophenolic acid either alone or in combination regimens may prove promising for the concomitant prevention of P. falciparum in solid organ transplant recipients living or travelling in malaria endemic regions.
Highlights
Solid organ transplant recipients are vulnerable for infectious diseases due to prolonged immunosuppressive treatment
Whereas rapamycin – commonly referred to as sirolimus – and cyclosporine A have been shown to exhibit anti-malarial activity in vitro, no conclusive data are available for everolimus and mycophenolic acid – two of the most widely used immunosuppressive drugs [4]
Immunosuppressives All drugs were tested in parallel against the three clones and two strains of P. falciparum resulting in 20 evaluable drug-concentration/growth-inhibition curves
Summary
Solid organ transplant recipients are vulnerable for infectious diseases due to prolonged immunosuppressive treatment. An immunosuppressive combination treatment with collateral prophylactic efficacy against malaria would constitute an important benefit for solid organ transplant recipients in malaria endemic regions and travellers to tropical countries. This would be of even higher clinical benefit as immunosuppressive drugs are prone to clinically significant drug interactions and the interaction of anti-malarials and immunosuppressive drugs is currently not well understood. This study was, designed to assess the in vitro activity of mycophenolic acid, everolimus and rapamycin against P. falciparum to obtain further information about the potential of currently used immunosuppressives as anti-malarial prophylactic drugs
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