Enantiomerically pure amino-alcohol quinolines: in vitro anti-malarial activity in combination with dihydroartemisinin, cytotoxicity and in vivo efficacy in a Plasmodium berghei mouse model

International audienceBackground: As resistance to marketed anti-malarial drugs continues to spread, the need for new molecules active on Plasmodium falciparum-resistant strains grows. Pure (S) enantiomers of amino-alcohol quinolines previously displayed a good in vitro anti-malarial activity. Therefore, a more thorough assessment of their potential clinical use through a rodent model and an in vitro evaluation of their combination with artemisinin was undertaken. Methods: Screening on a panel of P. falciparum clones with varying resistance profiles and regional origins was performed for the (S)-pentyl and (S)-heptyl substituted quinoline derivatives, followed by an in vitro assessment of their combination with dihydroartemisinin (DHA) on the 3D7 clone and an in vivo assay in a mouse model infected with Plasmodium berghei. Their haemolytic activity was also determined. Results: A steady anti-malarial activity of the compounds tested was found, whatever the resistance profile or the regional origin of the strain. (S)-quinoline derivatives were at least three times more potent than mefloquine (MQ), their structurally close parent. The in vitro combination with DHA yielded an additive or synergic effect for both that was as good as that of the DHA/MQ combination. In vivo, survival rates were similar to those of MQ for the two compounds at a lower dose, despite a lack of clearance of the parasite blood stages. A 50% haemolysis was observed for concentrations at least 1,000-fold higher than the antiplasmodial IC 50 s. Conclusions: The results obtained make those two (S)-amino-alcohol quinoline derivatives good candidates for the development of new artemisinin-based combination therapy (ACT), hopefully with fewer neurologic side effects than those currently marketed ACT, including MQ

Early treatment failure during treatment of Plasmodium falciparum malaria with atovaquone-proguanil in the Republic of Ivory Coast

The increased spread of drug-resistant malaria highlights the need for alternative drugs for treatment and chemoprophylaxis. The combination of atovaquone‐proguanil (Malarone®) has shown high efficacy against Plasmodium falciparum with only mild side-effects. Treatment failures have been attributed to suboptimal dosages or to parasite resistance resulting from a point mutation in the cytochrome b gene. In this paper, a case of early treatment failure was reported in a patient treated with atovaquone-proguanil; this failure was not associated with a mutation in the parasite cytochrome b gene, with impaired drug bioavailability, or with re-infection

Quantitative Analysis of Cepharanthine in Plasma Based on Semiautomatic Microextraction by Packed Sorbent Combined with Liquid Chromatography

The spread of Plasmodium falciparum resistance toward most of the used drugs requires new antimalarial compounds. Taking advantage of the biodiversity, the ethnopharmacological approach opens the way for the discovery and the characterization of potent original molecules. Previous works led to the selection of a bisbenzylisoquinoline, cepharanthine, extracted from Stephania rotunda, which is mainly present in Cambodia. A sensitive and selective liquid chromatography method has been developed for the determination of cepharanthine in mouse plasma. The method involved a semiautomated microextraction by packed sorbent (MEPS) using 4 mg of solid phase silica-C8 sorbent. LC separation was performed on a Kinetex XB-C18 column (2.6 µm) with a mobile phase of acetonitrile containing formic acid and 10 mM ammonium formate buffer pH 3.5. Data were acquired at 282 nm with a diode array detector. The drug/internal standard peak area ratios were linked via linear relationships to plasma concentrations (75–2,000 ng/mL). Precision was below 5% and accuracy was 99.0–102%. Extraction recovery of cepharanthine was 56–58%. The method was successfully used to determine the pharmacokinetic profile of cepharanthine in healthy and Plasmodium berghei infected mice. The infection did not impact pharmacokinetic parameters of cepharanthine

Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

International audienc

Evaluation de l'activité antipaludique de 4-aminoalcools quinoléines énantiomériquement pures

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Nouvelles approches thérapeutiques pour le traitement du paludisme (Inhibiteurs du métabolisme phospholipidique de Plasmodium. Validation de méthodes bioanalytiques en vue d'études précliniques et cliniques)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Molécules inhibitrices du métabolisme phospholipidique de plasmodium (développement préclinique d'une nouvelle approche thérapeutique)

Dans le cadre du développement de molécules ciblant le métabolisme phospholipidique de Plasmodium, nous présentons dans cette thèse la validation de méthodes analytiques ainsi que les études réalisés in vivo et in vitro sur quatre composés de cette nouvelle série chimique. Dans la première partie de notre thèse, les mécanismes physiopathologiques du neuropaludisme ainsi que les différentes axes de recherche sont développés. Dans une seconde partie, nous présenterons la série chimique sur laquelle nous avons travaillé. La troisième partie expose les résultats des méthodes analytiques validées selon les citères recommandés par la FDA pour la quantification des composés étudiés dans différentes matrices de différentes espèces animales. Le problème de l'effet matrice en spectrométrie de masse est également développé. Les résultats des études de distribution erythrocytes/plasma et de bioconversion prodrogue/drogue dans des matrices d'éspèces différentes sont présentés dans la quatrième partie. Enfin, dans une dernière partie nous rapporterons les études pharmacocinétiques et pharmacocinétiques / pharmacodynamiques réalisés chez le rat, la souris et le porc.MONTPELLIER-BU Pharmacie (341722105) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

A Validated Volumetric Absorptive Microsampling-Liquid Chromatography Tandem Mass Spectrometry Method to Quantify Doxycycline Levels in Urine: An Application to Monitor the Malaria Chemoprophylaxis Compliance

Because of logistics and cost constraints, monitoring of the compliance to antimalarial chemoprophylaxis by the quantitation of drugs in biological samples is not a simple operation on the field. Indeed, analytical devices are fragile to transport and must be used in a perfectly controlled environment. This is also the case for reagents and supplies, and the waste management is constraining. Thus, samples should be repatriated. They should be frozen after collection and transported with no rupture in the cold chain. This is crucial to generate available and interpretable data but often without any difficulties. Hence, to propose an alternative solution easier to implement, a quantitation method of determining doxycycline in urine has been validated using a volumetric absorptive microsampling (VAMS®) device. As blotting paper, the device is dried after collection and transferred at room temperature, but contrarily to dried spot, the collection volume is perfectly repeatable. Analysis of VAMS® was performed with a high-performance liquid chromatography coupled to a mass spectrometer. The chromatographic separation was achieved on a core-shell C18 column. The mean extraction recovery was 109% (mean RSD, 5.4%, n = 6) for doxycycline and 102% (mean RSD, 7.0%) for the internal standard. No matrix effect has been shown. Within-run as within-day precision and accuracy were, respectively, below 14% and ranged from 96 to 106%. The signal/concentration ratio was studied in the 0.25–50 µg/mL range, and recoveries from back-calculated concentrations were in the 96–105% range (RSD &lt; 11.0%). The RSD on slope was 10%. To achieve the validation, this new quantitation method was applied to real samples. In parallel, samples were analyzed directly after a simple dilution. No statistical difference was observed, confirming that the use of VAMS® is an excellent alternative device to monitor the doxycycline compliance.</jats:p

A Validated Volumetric Absorptive Microsampling-Liquid Chromatography Tandem Mass Spectrometry Method to Quantify Doxycycline Levels in Urine: An Application to Monitor the Malaria Chemoprophylaxis Compliance

Because of logistics and cost constraints, monitoring of the compliance to antimalarial chemoprophylaxis by the quantitation of drugs in biological samples is not a simple operation on the field. Indeed, analytical devices are fragile to transport and must be used in a perfectly controlled environment. This is also the case for reagents and supplies, and the waste management is constraining. Thus, samples should be repatriated. They should be frozen after collection and transported with no rupture in the cold chain. This is crucial to generate available and interpretable data but often without any difficulties. Hence, to propose an alternative solution easier to implement, a quantitation method of determining doxycycline in urine has been validated using a volumetric absorptive microsampling (VAMS®) device. As blotting paper, the device is dried after collection and transferred at room temperature, but contrarily to dried spot, the collection volume is perfectly repeatable. Analysis of VAMS® was performed with a high-performance liquid chromatography coupled to a mass spectrometer. The chromatographic separation was achieved on a core-shell C18 column. The mean extraction recovery was 109% (mean RSD, 5.4%, n = 6) for doxycycline and 102% (mean RSD, 7.0%) for the internal standard. No matrix effect has been shown. Within-run as within-day precision and accuracy were, respectively, below 14% and ranged from 96 to 106%. The signal/concentration ratio was studied in the 0.25–50 µg/mL range, and recoveries from back-calculated concentrations were in the 96–105% range (RSD < 11.0%). The RSD on slope was 10%. To achieve the validation, this new quantitation method was applied to real samples. In parallel, samples were analyzed directly after a simple dilution. No statistical difference was observed, confirming that the use of VAMS® is an excellent alternative device to monitor the doxycycline compliance