A review.We did not state in our review that artemisinin is used clin. to treat malaria, but its use in traditional Chinese medicine was the basis for the development of semisynthetic derivativesTherefore, its discussion is relevant, as artemisinin itself has provided many valuable insights into the antimalarial mechanism and metabolism of the derivatives used in clin. practice.In Table 1 of our review, we summarized the degree to which each artemisinin derivative is impacting cytochrome P 450 (CYP) enzyme activity and state that both artesunate and dihydroartemisinin are the least impactful.Although therapeutic concentrations for dihydroartemisinin have not been established, its combined use with piperaquine or as the active metabolite of artesunate has well-documented clin. literature describing the impact of dosing as well as potential treatment failure if no dose adjustment is made in specific populations (e.g., patients who are obese).In regard to the study conducted by Morris et al,the total sample size was 56 healthy adults randomly assigned in a crossover design to receive either metoprolol tartrate, pyronaridine-artesunate, or a combination of both.The article did not mention the power of the study, and in the letter, Fleckenstein and Miller state the possibility for clin. significant drug interactions with other CYP2D6 substrates that require "careful clin. monitoring".The study does not allow for extrapolation beyond its main objective, which was the point we were making in our review.While the combination of pyronaridine-artesunatein the treatment of uncomplicated Plasmodium falciparum infections is approved by the European Medicines Agency and is listed on the World Health Organization's Model List of Essential Medicines, it is currently not approved by the US Food and Drug Administration.The combination therapy with dapsone, chlorproguanil, and artesunate is not officially approved for the treatment of uncomplicated P falciparum but remains in use due to its low cost and availability if following the World Health Organization's recommendations issued in 2008.Clearly, the clin. impact of ACT in uncomplicated P falciparumis significant.Our review is intended to raise awareness of potential drug interactions ACT may have that are not yet fully explored or described in the literature.