Potency of atorvastatin in parasitemia clearance of plasmodium and the effects of the combination of atorvastatin and artemisinin derivatives on parasitemia clearance and organ toxicity

Background: With few exceptions, existing tuberculosis drugs were developed many years ago and resistance profiles have emerged. This has created a need for new drugs with discrete modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner similar to that which has proven highly successful in malaria therapy. Objective: To develop an alternative approach to the incorporation of bacterial siderophores that results in the creation of antitubercular peroxidic leads for subsequent development as novel agents against tuberculosis. Methods: Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro. Results: The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic structure results in antitubercular activity in vitro. The same effect is not observed in the absence of the pyrimidine or with other heteroaromatic substituents. Conclusion: The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound. This will be a useful approach for creating oxidative drugs to target tuberculosis.

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An approach to the synthesis of novel 11-hydroxyartemisinin derivatives

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19911037 ◽

1991 ◽

Vol 56 (5) ◽

pp. 1037-1041 ◽

Cited By ~ 9

Author(s):

Orlin Petrov ◽

Iliya Ognyanov

Keyword(s):

Antimalarial Drugs ◽

Artemisinin Derivatives

The conversion of artemisinin (I) to the epoxide V and its use for the preparation of novel artemisinin derivatives as potential antimalarial drugs is described.

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Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs

Scientific Reports ◽

10.1038/srep20030 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 173

Author(s):

Carlota Oleaga ◽

Catia Bernabini ◽

Alec S.T. Smith ◽

Balaji Srinivasan ◽

Max Jackson ◽

...

Keyword(s):

In Vitro System ◽

Organ Toxicity

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Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria

BMC Medicine ◽

10.1186/s12916-021-02033-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Andrea L. Conroy ◽

Robert O. Opoka ◽

Paul Bangirana ◽

Ruth Namazzi ◽

Allen E. Okullo ◽

...

Keyword(s):

Executive Function ◽

Hospital Mortality ◽

Cerebral Malaria ◽

Severe Malaria ◽

Behavioral Outcomes ◽

Artemisinin Derivatives ◽

Neurologic Deficits ◽

Adjusted Scores

Abstract Background In 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM. Methods From 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up. Results 346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07–0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine. Conclusions Treatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.

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