Artemisinin-induced delayed hemolysis after administration of artesunate and artesunate-amodiaquine in malaria-free Wistar rats

Abstract

Background: Hemolysis is common in malaria infection and during the course of treatment. Previous studies have reported delayed post-artemisinin hemolysis occurring in naïve and immune individuals treated with parenteral or oral artemisinin-derivatives. This study aims to understand if delayed hemolysis occurs in the absence of malaria parasites and the underlying mechanisms for the hemolytic effects after administration of two antimalarial drugs to malaria-free Wistar rats. Methods: Forty animals were randomized into 5 groups of eight animals each; they received 4 mg/kg artesunate for 7 days (AS), 4 mg/kg artesunate plus 10mg/kg amodiaquine for 3 days (ASQ), 10mg/kg amodiaquine for 3 days (AQ), distilled water [normal control], (Control) and 1mg/kg phenylhydrazine for 1 day to induce hemolysis (PHZ) groups respectively. Packed cell volume (PCV), white blood cell differential count and serum haptoglobin (Hpt) levels were determined in all groups on day 4 and 18 to detect hemolysis. Mean values were compared using t-test and ANOVA with p values <0.05 taken to be significantly different. Results: Post-treatment mean PCV on day 4 was significantly lower than day 18 in all groups except AS group which had similar PCV all through evaluation. Although AQ had lowest mean PCV on day 4, by day 18, mean PCV returned to normal and hpt levels was significantly higher than AS and ASQ groups (p<0.001). Hpt level (mean ± sem) for AS, ASQ, AQ, and control on day 18 were: 18.67 ± 0.004, 50.66 ± 0.014, 73.06 ± 0.003, and 74.13 ± 0.032 mg/dl respectively (p < 0.0001). On day 18, AS and ASQ had significantly lower Hpt level compared to day 4 (p <0.001). No neutropenia was observed during the study. Conclusion: Artesunate induces delayed hemolysis in malaria-free animals possibly through an oxidative toxic effect on the red blood cell membrane. Delayed post-treatment hemolysis was not observed with artesunateamodiaquine or amodiaquine alone.

Artemisinin and l‐carnitine combination therapy alters the erythrocytes redox status

“…Hemolysis is one of the most common and reversible adverse effects of ART and its derivatives (Rehman et al, 2014), which has been observed even in malaria‐free rats treated with ART derivatives (Dokunmu et al, 2017). According to the lack of oxidative stress in treatment with therapeutic doses ART and its derivatives and the delayed occurrence of hemolysis after treatment with these compounds, reduced G6PD activity and changes in expression of genes involved in stress response and apoptosis may be more important in explaining the mechanism of hemolysis than the direct induction of oxidative stress.…”

“…Hemolysis is one of the most common and reversible adverse effects of ART and its derivatives (Rehman et al, 2014), which has been observed even in malaria-free rats treated with ART derivatives (Dokunmu et al, 2017). According to the lack of oxidative stress in…”

Artemisinin and l‐carnitine combination therapy alters the erythrocytes redox status

“…Hemolysis is one of the most common and reversible adverse effects of ART and its derivatives (Rehman et al, 2014), which has been observed even in malaria‐free rats treated with ART derivatives (Dokunmu et al, 2017). According to the lack of oxidative stress in treatment with therapeutic doses ART and its derivatives and the delayed occurrence of hemolysis after treatment with these compounds, reduced G6PD activity and changes in expression of genes involved in stress response and apoptosis may be more important in explaining the mechanism of hemolysis than the direct induction of oxidative stress.…”

“…Hemolysis is one of the most common and reversible adverse effects of ART and its derivatives (Rehman et al, 2014), which has been observed even in malaria-free rats treated with ART derivatives (Dokunmu et al, 2017). According to the lack of oxidative stress in…”

Artemether-Loaded Zein Nanoparticles: An Innovative Intravenous Dosage Form for the Management of Severe Malaria

“…In clinical management of malaria, hemolysis commonly occurred after artemisinin-based therapy [ 11 ]. A recent study suggested that the hemolysis was malaria-independent and mediated through a toxic oxidative effect of artemisinin derivative(s) on the red blood cell membrane as malaria-free rats receiving artesunate also suffered from hemolysis [ 48 ]. In the present study, we confirmed that free artemether was highly hemolytic in our in vitro test.…”

<p>Indole: The After Next Scaffold of Antiplasmodial Agents?</p>

“…Moreover, tryptanthrin and its derivatives did not show any disruption of red blood cell membrane integrity, which is a severe side effect of the conventional antimalarial agents. 35,72 It has been demonstrated that cytotoxicity of indole alkaloids is mainly due to their interference with topoisomerase II-DNA complex stability as well as a tendency to intercalate into DNA (Figure 8). It was also noted that indoles can directly inhibit topoisomerase in the absence of DNA.…”

“…Moreover, tryptanthrin and its derivatives did not show any disruption of red blood cell membrane integrity, which is a severe side effect of the conventional antimalarial agents. 35 , 72 …”

Artemisinin and l‐carnitine combination therapy alters the erythrocytes redox status

“…Hemolysis is one of the most common and reversible adverse effects of ART and its derivatives (Rehman et al, 2014), which has been observed even in malaria‐free rats treated with ART derivatives (Dokunmu et al, 2017). According to the lack of oxidative stress in treatment with therapeutic doses ART and its derivatives and the delayed occurrence of hemolysis after treatment with these compounds, reduced G6PD activity and changes in expression of genes involved in stress response and apoptosis may be more important in explaining the mechanism of hemolysis than the direct induction of oxidative stress.…”

“…Hemolysis is one of the most common and reversible adverse effects of ART and its derivatives (Rehman et al, 2014), which has been observed even in malaria-free rats treated with ART derivatives (Dokunmu et al, 2017). According to the lack of oxidative stress in…”

Artemether-Loaded Zein Nanoparticles: An Innovative Intravenous Dosage Form for the Management of Severe Malaria

“…In clinical management of malaria, hemolysis commonly occurred after artemisinin-based therapy [ 11 ]. A recent study suggested that the hemolysis was malaria-independent and mediated through a toxic oxidative effect of artemisinin derivative(s) on the red blood cell membrane as malaria-free rats receiving artesunate also suffered from hemolysis [ 48 ]. In the present study, we confirmed that free artemether was highly hemolytic in our in vitro test.…”

<p>Indole: The After Next Scaffold of Antiplasmodial Agents?</p>

“…Moreover, tryptanthrin and its derivatives did not show any disruption of red blood cell membrane integrity, which is a severe side effect of the conventional antimalarial agents. 35,72 It has been demonstrated that cytotoxicity of indole alkaloids is mainly due to their interference with topoisomerase II-DNA complex stability as well as a tendency to intercalate into DNA (Figure 8). It was also noted that indoles can directly inhibit topoisomerase in the absence of DNA.…”

“…Moreover, tryptanthrin and its derivatives did not show any disruption of red blood cell membrane integrity, which is a severe side effect of the conventional antimalarial agents. 35 , 72 …”

Artemisinin and l‐carnitine combination therapy alters the erythrocytes redox status

“…Hemolysis is one of the most common and reversible adverse effects of ART and its derivatives (Rehman et al, 2014), which has been observed even in malaria‐free rats treated with ART derivatives (Dokunmu et al, 2017). According to the lack of oxidative stress in treatment with therapeutic doses ART and its derivatives and the delayed occurrence of hemolysis after treatment with these compounds, reduced G6PD activity and changes in expression of genes involved in stress response and apoptosis may be more important in explaining the mechanism of hemolysis than the direct induction of oxidative stress.…”

“…Hemolysis is one of the most common and reversible adverse effects of ART and its derivatives (Rehman et al, 2014), which has been observed even in malaria-free rats treated with ART derivatives (Dokunmu et al, 2017). According to the lack of oxidative stress in…”

Artemether-Loaded Zein Nanoparticles: An Innovative Intravenous Dosage Form for the Management of Severe Malaria

“…In clinical management of malaria, hemolysis commonly occurred after artemisinin-based therapy [ 11 ]. A recent study suggested that the hemolysis was malaria-independent and mediated through a toxic oxidative effect of artemisinin derivative(s) on the red blood cell membrane as malaria-free rats receiving artesunate also suffered from hemolysis [ 48 ]. In the present study, we confirmed that free artemether was highly hemolytic in our in vitro test.…”

<p>Indole: The After Next Scaffold of Antiplasmodial Agents?</p>

“…Moreover, tryptanthrin and its derivatives did not show any disruption of red blood cell membrane integrity, which is a severe side effect of the conventional antimalarial agents. 35,72 It has been demonstrated that cytotoxicity of indole alkaloids is mainly due to their interference with topoisomerase II-DNA complex stability as well as a tendency to intercalate into DNA (Figure 8). It was also noted that indoles can directly inhibit topoisomerase in the absence of DNA.…”

“…Moreover, tryptanthrin and its derivatives did not show any disruption of red blood cell membrane integrity, which is a severe side effect of the conventional antimalarial agents. 35 , 72 …”