The pharmaceutical death-ride of dihydroartemisinin

Jansen, F. H.

doi:10.1186/1475-2875-9-212

Cited by 35 publications

(27 citation statements)

References 8 publications

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“…DHA is considered to be the least stable artemisinin derivative formulated in ACTs. 16 , 31 Before degradation ( Figure 2E and Table 2 ), chromatographic peaks were observed, which corresponded to the two epimers of DHA (α- and β-DHA, retention times 7.2 and 9.3 minutes, respectively). In addition, a further peak, accepted as an impurity or degradation product of DHA, was observed (retention time 6.3 minutes; Figure 2E ).…”

Section: Resultsmentioning

confidence: 99%

Degradation of Artemisinin-Based Combination Therapies Under Tropical Conditions

Hall¹,

Allan²,

Schalkwyk³

et al. 2016

The American Society of Tropical Medicine and Hygiene

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Poor quality antimalarials, including falsified, substandard, and degraded drugs, are a serious health concern in malaria-endemic countries. Guidelines are lacking on how to distinguish between substandard and degraded drugs. “Forced degradation” in an oven was carried out on three common artemisinin-based combination therapy (ACT) brands to detect products of degradation using liquid chromatography mass spectrometry and help facilitate classification of degraded drugs. “Natural aging” of 2,880 tablets each of ACTs artemether/lumefantrine and artesunate/amodiaquine was undertaken to evaluate their long-term stability in tropical climates. Samples were aged in the presence and absence of light on-site in Ghana and in a stability chamber (London), removed at regular intervals, and analyzed to determine loss of the active pharmaceutical ingredients (APIs) over time and detect products of degradation. Loss of APIs in naturally aged tablets (both in Ghana and the pharmaceutical stability chamber) was 0–7% over 3 years (∼12 months beyond expiry) with low levels of degradation products detected. Using this developed methodology, it was found that a quarter of ACTs purchased in Enugu, Nigeria (concurrent study), that would have been classified as substandard, were in fact degraded. Presence of degradation products together with evidence of insufficient APIs can be used to classify drugs as degraded.

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Section: Resultsmentioning

confidence: 99%

Degradation of Artemisinin-Based Combination Therapies Under Tropical Conditions

Hall¹,

Allan²,

Schalkwyk³

et al. 2016

The American Society of Tropical Medicine and Hygiene

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“…However, the "DHAbinding" thesis is open to question (Coertzen et al, 2018). The notable lability of DHA under physiological conditions wherein DHA rearranges irreversibly via ring-opening and closure to the peroxyhemiacetal 5 (Figure 1) (Haynes et al, 2007;Jansen, 2010;Parapini et al, 2015) precludes binding of the intact molecule to Pf KI3. No experimental evidence for binding, as opposed to a best fit generated by in silico modeling of the intact DHA, was adduced in this respect.…”

Section: Introductionmentioning

confidence: 99%

“…However, there are apparent exceptions (Toovey and Jamieson, 2004), and the perception of a neurotoxic burden is enhanced by the report of a fatality due to an artesunate overdose (Campos et al, 2008). Overall, the persistence with the widespread clinical use and development of yet newer formulations of DHA in combination therapies must be questioned, given the literature data indicative of neurotoxicity of DHA (Toovey, 2006), its reduced efficacy against artemisinin-resistant parasites (Siriwardana et al, 2016;Hamilton et al, 2019), its intrinsic instability (Haynes et al, 2007;Jansen, 2010;Parapini et al, 2015), and reports of major treatment failures, especially of the DHA-piperaquine ACT in Thailand, Cambodia, and Vietnam (WHO, 2019). Thus, artemisinins that do not undergo metabolism to DHA and are not neurotoxic have to be employed.…”

Section: Introductionmentioning

confidence: 99%

Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites

et al. 2020

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We have demonstrated previously that amino-artemisinins including artemiside and artemisone in which an amino group replaces the oxygen-bearing substituents attached to C-10 of the current clinical artemisinin derivatives dihydroartemisinin (DHA), artemether and artesunate, display potent activities in vitro against the asexual blood stages of Plasmodium falciparum (Pf). In particular, the compounds are active against late blood stage Pf gametocytes, and are strongly synergistic in combination with the redox active drug methylene blue. In order to fortify the eventual selection of optimum amino-artemisinins for development into new triple combination therapies also active against artemisinin-resistant Pf mutants, we have prepared new amino-artemisinins based on the easily accessible and inexpensive DHA-piperazine. The latter was converted into alkyl-and aryl sulfonamides, ureas and amides. These derivatives were screened together with the comparator drugs DHA and the hitherto most active amino-artemisinins artemiside and artemisone against asexual and sexual blood stages of Pf and liver stage P. berghei (Pb) sporozoites. Several of the new amino-artemisinins bearing aryl-urea and-amide groups are potently active against both asexual, and late blood stage gametocytes (IC 50 0.4-1.0 nM). Although the activities are superior to those of artemiside (IC 50 1.5 nM) and artemisone (IC 50 42.4 nM), the latter are more active against the liver stage Pb sporozoites (IC 50 artemisone 28 nM). In addition, early results indicate these compounds tend not to display reduced susceptibility against parasites bearing the Pf Kelch 13 propeller domain C580Y mutation characteristic of Wong et al. Transmission-Blocking Amino-Artemisinins for New ACTs artemisinin-resistant Pf. Thus, the advent of the amino-artemisinins including artemiside and artemisone will enable the development of new combination therapies that by virtue of the amino-artemisinin component itself will possess intrinsic transmission-blocking capabilities and may be effective against artemisinin resistant falciparum malaria.

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“…Although the specific mode of action of artemisinin‐type drugs is still controversial,72 there is general consensus on the fact that their antimalarial activity is due to the activation of the endoperoxide bridge, that in turn could be exploited through reductive radicalic32 or Lewis acid promoted charge transfer18 processes. Moreover, in DHA the lactol system undergoes base‐catalysed fast epimerisation in solution,44, 45 a process that results in tetrahydropyran ring‐opening and that has been claimed to be an important factor in promoting its observed lability 12b…”

Section: Resultsmentioning

confidence: 99%

Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study

Saleh

Soave

Presti

et al. 2013

Chemistry A European J

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The accurate, experimental charge density distribution, ρ(r), of the potent antimalarial drug dihydroartemisinin (DHA) has been derived for the first time from single-crystal X-ray diffraction data at T=100(2) K. Gas-phase and solid-state DFT simulations have also been performed to provide a firm basis of comparison with experimental results. The quantum theory of atoms in molecules (QTAIM) has been employed to analyse the ρ(r) scalar field, with the aim of classifying and quantifying the key real-space elements responsible for the known pharmacophoric features of DHA. From the conformational perspective, the bicyclo[3.2.2]nonane system fixes the three-dimensional arrangement of the 1,2,4-trioxane bearing the active O-O redox centre. This is the most nucleophilic function in DHA and acts as an important CH⋅⋅⋅O acceptor. On the contrary, the rest of the molecular backbone is almost neutral, in accordance with the lipophilic character of the compound. Another remarkable feature is the C-O bond length alternation along the O-C-O-C polyether chain, due to correlations between pairs of adjacent C-O bonds. These bonding features have been related with possible reactivity routes of the α- and β-DHA epimers, namely 1) the base-catalysed hemiacetal breakdown and 2) the peroxide reduction. As a general conclusion, the base-driven proton transfer has significant non-local effects on the whole polyether chain, whereas DHA reduction is thermodynamically favourable and invariably leads to a significant weakening (or even breaking) of the O-O bond. The influence of the hemiacetal stereochemistry on the electronic properties of the system has also been considered. Such findings are discussed in the context of the known chemical reactivity of this class of important antimalarial drugs.

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The pharmaceutical death-ride of dihydroartemisinin

Cited by 35 publications

References 8 publications

Degradation of Artemisinin-Based Combination Therapies Under Tropical Conditions

Degradation of Artemisinin-Based Combination Therapies Under Tropical Conditions

Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites

Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study

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