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Disturbance in hemoglobin metabolism and in vivo antimalarial activity of azole antimycoticsDOI: 10.1590/S0036-46652011000100005 Keywords: ?-hematin synthesis, azole antimycotics, hemoglobin degradation, plasmodium berghei. Abstract: plasmodium parasites degrade host hemoglobin to obtain free amino acids, essential for protein synthesis. during this event, free toxic heme moieties crystallize spontaneously to produce a non-toxic pigment called hemozoin or ?-hematin. in this context, a group of azole antimycotics, clotrimazole (ctz), ketoconazole (ktz) and fluconazole (fcz), were investigated for their abilities to inhibit ?-hematin synthesis (i?hs) and hemoglobin proteolysis (ihbp) in vitro. the ?-hematin synthesis was recorded by spectrophotometry at 405 nm and the hemoglobin proteolysis was determined by sds-page 12.5%, followed by densitometric analysis. compounds were also assayed in vivo in a malaria murine model. ctz and ktz exhibited the maximal effects inhibiting both biochemical events, showing inhibition of β-hematin synthesis (ic50 values of 12.4 ± 0.9 μm and 14.4 ± 1.4 μm respectively) and inhibition of hemoglobin proteolysis (80.1 ± 2.0% and 55.3 ± 3.6%, respectively). there is a broad correlation to the in vivo results, especially ctz, which reduced the parasitemia (%p) of infected-mice at 4th day post-infection significantly compared to non-treated controls (12.4 ± 3.0% compared to 26.6 ± 3.7%, p = 0.014) and prolonged the survival days post-infection. the results indicated that the inhibition of the hemoglobin metabolism by the azole antimycotics could be responsible for their antimalarial effect.
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