Dimeric Artesunate-Phosphatidylcholine-Based Liposomes for Irinotecan Delivery as a Combination Therapy Approach.

In this work, dimeric artesunate-phosphatidylcholine conjugate (dARTPC)-based liposomes encapsulated with irinotecan (Ir) were developed for anticancer combination therapy. First, dARTPC featured with unique amphipathic properties formed liposomes by classical thin-film methods. After that, Ir was encapsulated into dARTPC-based liposomes (Ir/dARTPC-LP) by the triethylammonium sucrose octasulfate gradient method. Physicochemical characterization indicated that Ir/dARTPC-LP had a mean size of around 140 nm and a negative ζ potential of approximately -30 mV. Most noticeably, liposomes displayed an encapsulation efficiency of greater than 98% with a controllable drug loading of 4-22%. The in vitro release of dihydroartemisinin (DHA) and Ir from Ir/dARTPC-LP was investigated by dialysis in different media. It was found that effective release of both DHA (65.42%) and Ir (77.28%) in a weakly acidic medium (pH 5.0) after 48 h was achieved in comparison to very slow release under a neutral environment (DHA 9.90% and Ir 8.72%), indicating the controllable release of both drugs. Confocal laser scanning microscopy confirmed the improved cellular internalization of Ir/dARTPC-LP. The cytotoxicity of Ir/dARTPC-LP was evaluated in the MCF-7, A549, and HepG2 cell lines. The results showed that Ir/dARTPC-LP had significant synergistic efficacy in the loss of cell growth. In vivo anticancer evaluation was performed using a 4T1 xenograft tumor model. Ir/dARTPC-LP had a high tumor inhibition rate of 62.7% without significant toxicity in comparison with the injection of Ir solution. Taken together, dARTPC encapsulated with Ir has great potential for anticancer combination therapy.

Bioinspired Microenvironment Responsive Nanoprodrug as an Efficient Hydrophobic Drug Self-Delivery System for Cancer Therapy.

Artemisinin compounds have shown satisfactory safety records in anti-malarial clinical practice over decades and have revealed value as inexpensive anti-tumor adjuvant chemotherapeutic drugs. However, the rational design and precise preparation of nanomedicines based on the artemisinin drugs are still limited due to their non-aromatic and fragile chemical structure. Herein, a bioinspired coordination-driven self-assembly strategy was developed to manufacture the artemisinin-based nanoprodrug with a significantly increased drug loading efficacy (∼70 wt %) and decreased preparation complexity compared to conventional nanodrugs. The nanoprodrug has suitable size distribution and robust colloidal stability for cancer targeting in vivo. The nanoprodrug was able to quickly disassemble in the tumor microenvironment with weak acidity and a high glutathione concentration, which guarantees a better tumor inhibitory effect than direct administration and fewer side effects on normal tissues in vivo. This work highlights a new strategy to harness a robust, simplified, organic solvent-free, and highly repeatable route for nanoprodrug manufacturing, which may offer opportunities to develop cost-effective, safe, and clinically available nanomedicines.

In Vitro Assessment of Cytoprotective Effects of CANOVA against Cell Death Induced by the Anti-malarial Artesunate - A Preliminary Experiment.

BACKGROUND: Artesunate (ATS) is a semi-synthetic compound derived from artemisinin, which is widely accepted in the treatment of malaria. However, there is evidence that ATS, under certain in vitro conditions, induces several impairments to normal cell functions. Canova (CA) is a Brazilian homeopathic formulation indicated for patients with depressed immune system. CA shows both in vitro and in vivo protective effects against mutagenic/carcinogenic compounds. Therefore, we aimed to assess in vitro the cytoprotective effects of CA against the cytotoxicity of ATS in Vero cells. METHODS: Viability of Vero cells exposed to ATS was assessed by MTT assay, whereas the anti-cytotoxic effect of CA was evaluated by apoptosis and necrosis quantification with fluorescent dyes. RESULTS: After 24 hours of ATS treatment, a reduction in cell viability was observed at 32 and 64 µg/mL, the latter being statistically significant (p < 0.05) in relation to the negative control. The concentration of 64 µg/mL was chosen for the subsequent experiments. ATS significantly induced both apoptosis and necrosis in Vero cells in relation to controls (p < 0.01). We also observed a statistically significant decrease in the number of apoptotic cells observed in the CA 16% + ATS co-treatment compared with ATS treatment (p < 0.01). Treatment with CA alone also had no influence on either type of cell death. CONCLUSION: Our results demonstrated that ATS is cytotoxic in the assessed conditions. However, such cytotoxicity was attenuated when the cells were treated simultaneously with ATS and CA.

The preclinical discovery and development of rectal artesunate for the treatment of malaria in young children: a review of the evidence.

INTRODUCTION: Plasmodium falciparum, the deadliest malaria parasite, kills hundreds of thousands of people per year, mainly young children in Sub-Saharan Africa. Artesunate suppositories are recommended as pre-referral malaria treatment in remote endemic areas for severely ill children to prevent progression of the disease and to provide extra time for patients until the definitive severe malaria treatment can be administered. AREAS COVERED: The authors provide an overview of the discovery of artesunate and its different formulations focusing on rectal administration, summarizing key studies concerning the pharmacokinetic, pharmacodynamic, safety, tolerability and efficacy of rectal artesunate leading to WHO recommendation and market authorization in Africa. In addition, studies on acceptance and adherence to rectal artesunate administration and the post-launch status are also covered. EXPERT OPINION: Efforts by ministries of health in malaria endemic countries together with international health organizations should establish and enforce guidelines to ensure the correct use of artesunate suppositories only as pre-referral medication in presumed severe malaria cases to minimize the risk of abuse as a monotherapy for treatment of uncomplicated malaria. The priority is to not jeopardize the efficacy of artesunate and to prevent resistance development against this valuable drug class in Africa.

pH-Responsive Artesunate Polymer Prodrugs with Enhanced Ablation Effect on Rodent Xenograft Colon Cancer.

PURPOSE: In this study, pH-sensitive poly(2-ethyl-2-oxazoline)-poly(lactic acid)-poly(ß-amino ester) (PEOz-PLA-PBAE) triblock copolymers were synthesized and were conjugated with an antimalaria drug artesunate (ART), for inhibition of a colon cancer xenograft model. METHODS: The as-prepared polymer prodrugs are tended to self-assemble into polymeric micelles in aqueous milieu, with PEOz segment as hydrophilic shell and PLA-PBAE segment as hydrophobic core. RESULTS: The pH sensitivity of the as-prepared copolymers was confirmed by acid-base titration with pKb values around 6.5. The drug-conjugated polymer micelles showed high stability for at least 96 h in PBS and 37°C, respectively. The as-prepared copolymer prodrugs showed high drug loading content, with 9.57%±1.24% of drug loading for PEOz-PLA-PBAE-ART4. The conjugated ART could be released in a sustained and pH-dependent manner, with 92% of released drug at pH 6.0 and 57% of drug released at pH 7.4, respectively. In addition, in vitro experiments showed higher inhibitory effect of the prodrugs on rodent CT-26 cells than that of free ART. Animal studies also demonstrated the enhanced inhibitory efficacy of PEOz-PLA-PBAE-ART2 micelles on the growth of rodent xenograft tumor. CONCLUSION: The pH-responsive artesunate polymer prodrugs are promising candidates for colon cancer adjuvant therapy.

An evaluation of rectal artesunate for the pre-hospital management of severe malaria.

INTRODUCTION: Severe falciparum malaria stills accounts for around half a million childhood deaths per year in sub-Saharan Africa. Prompt treatment of sick children close to home starting with artesunate given rectally by appropriately trained people can be lifesaving. AREAS COVERED: Rectal artesunate (RAS) has been developed for use in the WHO approved strategy of pre-referral intervention. This review covers the formulation, pharmacokinetics, safety, efficacy, and implementation of this drug. There is little RCT evidence and the only RCT has been controversial. It is unlikely that there will be further randomized studies in the field. There is a concern that the administration of a single dose of artesunate without adequate follow up therapy may encourage the emergence of artemisinin resistance. EXPERT OPINION: Artesunate is an essential drug and RAS is a very useful, potentially lifesaving formulation designed to be quickly administered in remote areas to severely unwell children by non-medical personnel. However, its use needs to be monitored and onward referral for definitive antimalarial treatment ensured.

Pharmacokinetics and Ex Vivo Antimalarial Activity of Artesunate-Amodiaquine plus Methylene Blue in Healthy Volunteers.

High rates of artemisinin-based combination therapy (ACT) failures in the treatment of Plasmodium falciparum malaria in Southeast Asia have led to triple-drug strategies to extend the useful life of ACTs. In this study, we determined whether methylene blue [MB; 3,7-bis(dimethylamino)phenothiazin-5-ium chloride hydrate] alters the pharmacokinetics of artesunate-amodiaquine (ASAQ) and enhances the ex vivo antimalarial activity of ASAQ. In an open-label, randomized crossover design, a single oral dose of ASAQ (200 mg AS/540 mg AQ) alone or with MB (325 mg) was administered to 15 healthy Vietnamese volunteers. Serial blood samples were collected up to 28 days after dosing. Pharmacokinetic properties of the drugs were determined by noncompartmental analysis. After drug administration, plasma samples from seven participants were assessed for ex vivo antimalarial activity against the artemisinin-sensitive MRA1239 and the artemisinin-resistant MRA1240 P. falciparum lines, in vitro MB significantly increased the mean area under the curve of the active metabolite of AS, dihydroartemisinin (1,246 ± 473 versus 917 ± 405 ng·h/ml, P = 0.009) but did not alter the pharmacokinetics of AQ, AS, or desethylamodiaquine. Comparing the antimalarial activities of the plasma samples from the participants collected up to 48 h after ASAQ plus MB (ASAQ+MB) and ASAQ dosing against the MRA1239 and MRA1240 lines, MB significantly enhanced the blood schizontocidal activity of ASAQ by 2.0-fold and 1.9-fold, respectively. The ring-stage survival assay also confirmed that MB enhanced the ex vivo antimalarial activity of ASAQ against MRA1240 by 2.9-fold to 3.8-fold, suggesting that the triple-drug combination has the potential to treat artemisinin-resistant malaria and for malaria elimination. (This study has been registered in the Australian New Zealand Clinical Trials Registry [https://anzctr.org.au/] under registration number ACTRN12612001298808.).

Association of Lipid Levels with Mefloquine and Carboxy-Mefloquine Concentrations in Patients with Uncomplicated Falciparum Malaria.

Mefloquine shows a high capacity to bind plasma proteins, which influences the amount of drug in erythrocytes. The study investigated the association of lipids levels with plasma concentrations of mefloquine and carboxy-mefloquine in 85 Brazilian patients with uncomplicated falciparum malaria. There were no significant associations between the total cholesterol or triglycerides with plasma concentrations of mefloquine and of carboxy-mefloquine. Lipoprotein levels explained 25.68% and 18.31% of mefloquine and carboxy-mefloquine plasma concentrations, respectively.

Systematic review of artesunate pharmacokinetics: Implication for treatment of resistant malaria.

BACKGROUND: Artesunate (ART) is an artemisinin derivative used as monotherapy for the treatment of severe malaria and in combination with a partner drug for non-severe malaria. Resistance of malaria parasites to artemisinins have emerged in Southeast Asia. Adjustment of drug regimen may be an option to prevent therapeutic failures considering the relative favourable safety profile of ART high doses. METHODS: For that purpose, a systematic review was done using PubMed, Scopus and Web of Science databases. All studies on ART and DHA pharmacokinetic post-administration of artesunate in human patients or volunteers were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist 2009 was used. FINDINGS: Fifty studies exploring oral, intravenous, rectal, and intramuscular route (1470 persons, volunteers and patients) were included. Correlations between artesunate doses and Cmax or AUC0-∞ of dihydroartemisinin (DHA) and DHA+ART were evaluated. This correlation was good (R2>0.9) using intravenous (IV) route. DHA and ART+DHA average concentrations (Cav) were well above estimated in vivo half-maximal effective concentration (EC50) for intravenous route, but this was not the case for oral route. INTERPRETATION: The favorable Cav/EC50 ratio for IV route provides evidence that IV ART will remain efficient even in the case of increased resistance level, whereas for the oral route, a two-fold increase in EC50 may lead to therapeutic failures, thus providing a rationale for oral dose escalation. Considering the inter-individual variability of ART pharmacokinetic, Therapeutic Drug Monitoring through antimalarial stewardship activities is needed to optimize drug exposure and avoid resistance development.

Population pharmacokinetics and pharmacodynamics of the artesunate-mefloquine fixed dose combination for the treatment of uncomplicated falciparum malaria in African children.

BACKGROUND: The World Health Organization (WHO) recommends combinations of an artemisinin derivative plus an anti-malarial drug of longer half-life as treatment options for uncomplicated Plasmodium falciparum infections. In Africa, artesunate-mefloquine (ASMQ) is an infrequently used artemisinin-based combination therapy (ACT) because of perceived poor tolerance to mefloquine. However, the WHO has recommended reconsideration of the use of ASMQ in Africa. In this large clinical study, the pharmacokinetics (PK) of a fixed dose combination of ASMQ was investigated in an African paediatric population to support dosing recommendations used in Southeast Asia and South America. METHODS: Among the 472 paediatric patients aged 6-59 months from six African centres included in the large clinical trial, a subset of 50 Kenyan children underwent intensive sampling to develop AS, its metabolite dihydroartemisinin (DHA) and MQ PK models. The final MQ PK model was validated using sparse data collected in the remaining participants (NONMEM®). The doses were one or two tablets containing 25/55 mg AS/MQ administered once a day for 3 days according to patients' age. A sensitive LC-MS/MS method was used to quantify AS, DHA and MQ concentrations in plasma. An attempt was made to investigate the relationship between the absence/presence of malaria recrudescence and MQ area under the curve (AUC) using logistic regression. RESULTS: AS/DHA concentration-time profiles were best described using a one-compartment model for both compounds with irreversible AS conversion into DHA. AS/DHA PK were characterized by a significant degree of variability. Body weight affected DHA PK parameters. MQ PK was characterized by a two-compartment model and a large degree of variability. Allometric scaling of MQ clearances and volumes of distribution was used to depict the relationship between MQ PK and body weight. No association was found between the model predicted AUC and appearance of recrudescence. CONCLUSIONS: The population pharmacokinetic models developed for both AS/DHA and MQ showed a large variability in drug exposure in the investigated African paediatric population. The largest contributor to this variability was body weight, which is accommodated for by the ASMQ fixed dose combination (FDC) dosing recommendation. Besides body weight considerations, there is no indication that the dosage should be modified in children with malaria compared to adults. Trial registration Pan African Clinical Trials Registry PACTR201202000278282 registration date 2011/02/16.

Enhancement of solubility and dissolution profile of artesunate by employing solid dispersion approach: An in-vitro evaluation.

Current study was designed with an aim to improve the solubility and dissolution profile of artesunate by preparing solid dispersions through solvent evaporation and freeze-drying techniques using polyethylene glycol 4000 (PEG4000) as solubility enhancer. Developed formulations were characterized for FTIR, XRD, TGA and SEM. Maximum increase in solubility was attained by freeze-dried solid dispersions (FD F444) i.e. 2.99 folds and 2.66 folds by solvent evaporation solid dispersion (SE F44) as compare to pure drug. Amorphous nature of artesunate in solid dispersions was confirmed from XRD diffractographs. Surface morphology indicated the existence of rough surface in freeze- dried solid dispersions (FDDs) and smooth surface in solvent evaporation solid dispersions (SEDs). Rapid dissolution rates were exhibited by fast dissolving tablets of optimized formulations. Moreover, the release of the drug was dominated by the first order kinetics (R2 = 0.9932) with the Fickian type of diffusion mechanism (n<0.450).

Artesunate-heparin conjugate based nanocapsules with improved pharmacokinetics to combat malaria.

Artesunate-heparin conjugate (ART-HEP) based nanocapsules as drug delivery vehicle was developed for intracellular release of ART in malaria therapy. Owing both hydrophobic and hydrophilic moieties, the conjugate was successfully self-assembled into artesunate-heparin nanocapsules (ART-HEP-NCPs) with lower critical micelle concentration (CMC) of about 20 µg/mL. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed that ART-HEP-NCPs has an average hydrodynamic diameter of 112.1 nm with a negatively charged surface (-11.2 mV) and typical micellar nanostructure, respectively. Interestingly, such modification achieved high drug loading efficiency (DLE) of ART (29.3 wt%), which is significantly higher than already reported conventional ART-loaded nanoparticles. The nanocapsules demonstrated lower in vitro ART release under neutral physiological environment (33.81%) but higher release rate was observed in simulated acidic microenvironment (92.74%) in 70 h test. This behavior of ART-HEP-NCPs will facilitate the intracellular release of ART under slightly acidic parasitic food vacuole for effective antimalarial effect. Storage stability and hemolytic studies exhibited that ART-HEP based nanocapsules were stable and safe for intravenous (i.v) injection. Notably, ART-HEP-NCPs has promising internalization into Plasmodium infected red blood cells (iRBCs) and also displayed in vitro inhibitory effect against P. falciparum 3D7 with half-maximal inhibitory concentration (IC50) of 10.16 nM, which was slightly higher than free ART (IC50 6.27 nM). This expected slightly lower inhibitory effect of polymeric prodrug could be ascribed to the gradual release of ART from the polymer chain over time. More importantly, the in vivo pharmacokinetics study indicated that the nanoscale characteristic of nanocapsules substantially contributed to the extended circulation of ART in blood. In conclusion, such multifunctional ART-HEP-NCPs with higher ART loading and extended half-life could be a promising platform for targeted antimalarial drug delivery.

Drug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine.

Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artemether-lumefantrine interaction was evaluated in a two-way crossover study and measured artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine over 264 h. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, and desethylamodiaquine over 624 h. Noncompartmental analysis was performed, and geometric mean ratios and 90% confidence intervals were generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, the time to maximum concentration, and the area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine, nor did it significantly alter the AUC for artesunate, dihydroartemisinin, amodiaquine, and desethylamodiaquine. Coadministration of dolutegravir with artemether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Coadministration of dolutegravir with artesunate-amodiaquine resulted in 42 and 24% approximate decreases in the DTG trough concentrations and the AUC, respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance since the DTG trough concentrations were above dolutegravir target concentrations of 300 ng/ml. Study drugs were well tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. (This study has been registered at ClinicalTrials.gov under identifier NCT02242799.).

[Research progress on pharmacokinetics and pharmacological activities of artesunate].

Artesunate (AS), a famous derivative of the artemisinin, is the basic treatment globally for mild to severe malaria infection due to the prominent advantages such as high efficiency, fast effect, low toxicity and not easy to produce resistance. More and more research reports have shown that AS and its active metabolites dihydroartemisinin (DHA) had various bioactivities in addition to antimalarial activity, attracting researchers to further study its new pharmacological effects in order to explore new use of the old drug. A comprehensive understanding of the pharmacokinetic characteristics of AS will be conducive to the further development of new pharmacological actions and clinical application of AS. Therefore, this paper would review the absorption, distribution, metabolism and excretion of AS in vivo, as well as the pharmacokinetics characteristics of AS and DHA after clinical administration of AS by intravenous (IV), intramuscular (IM), oral or rectal routes. The in vivo process and pharmacokinetic parameters of AS and DHA were compared between healthy volunteers, malaria patients, and special populations (children, women). Meanwhile, the research progress on pharmacological effects of AS and active metabolite DHA such as anti-tumor, anti-inflammatory, anti septic, antiangiogenic, anti-fibrosis and immunoregulation activities would be also reviewed, hoping to provide a theoretical basis for the further development and utilization of AS and its metabolites.

Artesunate-induced mitophagy alters cellular redox status.

Artesunate (ART) is a prominent anti-malarial with significant anti-cancer properties. Our previous studies showed that ART enhances lysosomal function and ferritin degradation, which was necessary for its anti-cancer properties. ART targeting to mitochondria also significantly improved its efficacy, but the effect of ART on mitophagy, an important cellular pathway that facilitates the removal of damaged mitochondria, remains unknown. Here, we first observed that ART mainly localizes in the mitochondria and its probe labeling revealed that it binds to a large number of mitochondrial proteins and causes mitochondrial fission. Second, we found that ART treatment leads to autophagy induction and the decrease of mitochondrial proteins. When autophagy is inhibited, the decrease of mitochondrial proteins could be reversed, indicating that the degradation of mitochondrial proteins is through mitophagy. Third, our results showed that ART treatment stabilizes the full-length form of PTEN induced putative kinase 1 (PINK1) on the mitochondria and activates the PINK1-dependent pathway. This in turn leads to the recruitment of Parkin, sequestosome 1 (SQSTM1), ubiquitin and microtubule-associated proteins 1A/1B light chain 3 (LC3) to the mitochondria and culminates in mitophagy. When PINK1 is knocked down, ART-induced mitophagy is markedly suppressed. Finally, we investigated the effect of mitophagy by ART on mitochondrial functions and found that knockdown of PINK1 alters the cellular redox status in ART-treated cells, which is accompanied with a significant decrease in glutathione (GSH) and increase in mitochondrial reactive oxidative species (mROS) and cellular lactate levels. Additionally, knockdown of PINK1 leads to a significant increase of mitochondrial depolarization and more cell apoptosis by ART, suggesting that mitophagy protects from ART-induced cell death. Taken together, our findings reveal the molecular mechanism that ART induces cytoprotective mitophagy through the PINK1-dependent pathway, suggesting that mitophagy inhibition could enhance the anti-cancer activity of ART.

Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs.

Objectives: Characterization of the pharmacokinetic properties of the enantiomers of primaquine and carboxyprimaquine following administration of racemic primaquine given alone and in combination with commonly used antimalarial drugs. Methods: Enantiomeric pharmacokinetics were evaluated in 49 healthy adult volunteers enrolled in three randomized cross-over studies in which a single dose of primaquine was given alone and then, after a suitable washout period, in combination with chloroquine, dihydroartemisinin/piperaquine or pyronaridine/artesunate. Non-linear mixed-effects modelling was used to characterize pharmacokinetics and assess the impact of drug-drug interactions. Results: The volume of distribution of racemic primaquine was decreased by a median (95% CI) of 22.0% (2.24%-39.9%), 24.0% (15.0%-31.5%) and 25.7% (20.3%-31.1%) when co-administered with chloroquine, dihydroartemisinin/piperaquine and pyronaridine/artesunate, respectively. The oral clearance of primaquine was decreased by a median of 19.1% (14.5%-22.8%) when co-administered with pyronaridine/artesunate. These interactions were enantiospecific with a relatively higher effect on (+)-S-primaquine than on (-)-R-primaquine. No drug-drug interaction effects were seen on the pharmacokinetics of either carboxyprimaquine enantiomer. Conclusions: Population pharmacokinetic models characterizing the enantiospecific properties of primaquine were developed successfully. Exposure to primaquine, particularly to the (+)-S-primaquine but not the carboxy metabolites, increased by up to 30% when co-administered with commonly used antimalarial drugs. A better mechanistic understanding of primaquine metabolism is required for assessment of its efficacy and haematological toxicity in humans.

The Antimalarial Drug Artesunate Attenuates Cardiac Injury in A Rodent Model of Myocardial Infarction.

Ischemic heart disease remains the leading cause of morbidity and mortality in the Western world. Artesunate is the WHO-recommended drug of choice for complicated malaria (with organ failure). The administration of high doses of artesunate is safe in healthy volunteers (up to 8 mg/kg i.v.) and patients with severe malaria (2.4 mg/kg i.v.). We investigated the effects of artesunate (1 mg/kg) or its active metabolite dihydroartemisinin (DHA; 0.1 mg/kg) in a model of transient myocardial ischemia/reperfusion (I/R) and evaluated the mechanism of action of the observed cardioprotective effects of artesunate and DHA. We report here for the first time that the administration of artesunate at the onset of reperfusion attenuates the myocardial injury associated with I/R. The observed beneficial effects of artesunate are associated with activation of the PI3K/Akt/ERK 1/2 (RISK) pathway, activation of endothelial nitric oxide synthase, inhibition of glycogen synthase kinase-3ß, inhibition of nuclear factor kappa B, and activation of the STAT3 (SAFE) pathway. In conclusion, as artesunate has an excellent safety profile, the above data should stimulate clinical trials in patients with acute coronary syndromes.

[Tissue distribution of TPGS modified artesunate liposome and its metabolites in rats].

Artesunate, which is a widely used anti-malaria medicine, can be made into liposome to overcome its poor bioactivity. Its tissue distribution in rats may change with different dosage forms, which therefore shall be studied after ARS-TPGS-Lipo was injected. Based on this experiment, ARS-TPGS-Lipo and ARS-Lipo were prepared by thin-film hydration method. LC-MS/MS method was used to simultaneously determine ARS and DHA in rat tissues at different time points. The results showed that this method was suitable for the content analysis of ARS and DHA in biological samples. The distribution of ARS and DHA in ARS-TPGS-Lipo, ARS-Lipo and ARS groups were quite different. The content of ARS-TPGS-Lipo in liver was the highest, with significant differences.ARS and DHA contents in ARS group eliminated rapidly. ARS and DHA contents in ARS-Lipo group were higher in liver and spleen, while those in ARS-TPGS-Lipo group significantly increased only in liver (P<0.05).

Population pharmacokinetic and pharmacodynamic properties of artesunate in patients with artemisinin sensitive and resistant infections in Southern Myanmar.

BACKGROUND: Artemisinins are the most effective anti-malarial drugs for uncomplicated and severe Plasmodium falciparum malaria. However, widespread artemisinin resistance in the Greater Mekong Region of Southeast Asia is threatening the possibility to control and eliminate malaria. This work aimed to evaluate the pharmacokinetic and pharmacodynamic properties of artesunate and its active metabolite, dihydroartemisinin, in patients with sensitive and resistant falciparum infections in Southern Myanmar. In addition, a simple nomogram previously developed to identify artemisinin resistant malaria infections was evaluated. METHODS: Fifty-three (n = 53) patients were recruited and received daily oral artesunate monotherapy (4 mg/kg) for 7 days. Frequent artesunate and dihydroartemisinin plasma concentration measurements and parasite microscopy counts were obtained and evaluated using nonlinear mixed-effects modelling. RESULTS: The absorption of artesunate was best characterized by a transit-compartment (n = 3) model, followed by one-compartment disposition models for artesunate and dihydroartemisinin. The drug-dependent parasite killing effect of dihydroartemisinin was described using an Emax function, with a mixture model discriminating between artemisinin sensitive and resistant parasites. Overall, 56% of the studied population was predicted to have resistant malaria infections. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test. CONCLUSION: The pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to differentiate between drug sensitive and resistant infections in these patients. More than half of all patients recruited in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights its potential clinical usefulness.