Displaying publications 1 - 20 of 68 in total

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  1. Fulltext Insights into Heterologous Biosynthesis of Arteannuin B and Artemisinin in Physcomitrella patens
    Ikram NKK, Kashkooli AB, Peramuna A, Krol ARV, Bouwmeester H, Simonsen HT
    Molecules, 2019 Oct 23;24(21).
    PMID: 31652784 DOI: 10.3390/molecules24213822
    : Metabolic engineering is an integrated bioengineering approach, which has made considerable progress in producing terpenoids in plants and fermentable hosts. Here, the full biosynthetic pathway of artemisinin, originating from Artemisia annua, was integrated into the moss Physcomitrella patens. Different combinations of the five artemisinin biosynthesis genes were ectopically expressed in P. patens to study biosynthesis pathway activity, but also to ensure survival of successful transformants. Transformation of the first pathway gene, ADS, into P. patens resulted in the accumulation of the expected metabolite, amorpha-4,11-diene, and also accumulation of a second product, arteannuin B. This demonstrates the presence of endogenous promiscuous enzyme activity, possibly cytochrome P450s, in P. patens. Introduction of three pathway genes, ADS-CYP71AV1-ADH1 or ADS-DBR2-ALDH1 both led to the accumulation of artemisinin, hinting at the presence of one or more endogenous enzymes in P. patens that can complement the partial pathways to full pathway activity. Transgenic P. patens lines containing the different gene combinations produce artemisinin in varying amounts. The pathway gene expression in the transgenic moss lines correlates well with the chemical profile of pathway products. Moreover, expression of the pathway genes resulted in lipid body formation in all transgenic moss lines, suggesting that these may have a function in sequestration of heterologous metabolites. This work thus provides novel insights into the metabolic response of P. patens and its complementation potential for A. annua artemisinin pathway genes. Identification of the related endogenous P. patens genes could contribute to a further successful metabolic engineering of artemisinin biosynthesis, as well as bioengineering of other high-value terpenoids in P. patens.
    Matched MeSH terms: Artemisinins/metabolism*
  2. Fulltext Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in healthy adults
    Salman S, Bendel D, Lee TC, Templeton D, Davis TM
    Antimicrob Agents Chemother, 2015;59(6):3197-207.
    PMID: 25801553 DOI: 10.1128/AAC.05013-14
    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in two open-label studies. In study 1, 16 healthy males were randomized to each of four single-dose treatments administered in random order: (i) 15.0 mg of sublingual artemether (5 × 3.0 actuations), (ii) 30.0 mg of sublingual artemether (10 × 3.0 mg), (iii) 30.0 mg of sublingual artemether (5 × 6.0 mg), and (iv) 30.0 mg of artemether in tablet form. In study 2, 16 healthy males were randomized to eight 30.0-mg doses of sublingual artemether given over 5 days as either 10 3.0-mg or 5 6.0-mg actuations. Frequent blood samples were drawn postdose. Plasma artemether and dihydroartemisinin levels were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In study 1, sublingual artemether absorption was biphasic, with both rate constants being greater than that of the artemether tablets (1.46 and 1.66 versus 0.43/h, respectively). Relative to the tablets, sublingual artemether had greater bioavailability (≥1.24), with the greatest relative bioavailability occurring in the 30.0-mg dose groups (≥1.58). In study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of the total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism occurring in later versus earlier doses but with no difference in bioavailability between the dose actuations. Sublingual artemether is more rapidly and completely absorbed than are equivalent doses of artemether tablets in healthy adults. Its disposition appears to be complex, with two absorption phases, the first representing pregastrointestinal absorption, as well as dose-dependent bioavailability and autoinduction of metabolism with multiple dosing.
    Matched MeSH terms: Artemisinins/administration & dosage*; Artemisinins/pharmacokinetics*
  3. Fulltext Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in African children with malaria
    Salman S, Bendel D, Lee TC, Templeton D, Davis TM
    Antimicrob Agents Chemother, 2015;59(6):3208-15.
    PMID: 25801552 DOI: 10.1128/AAC.05014-14
    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197-3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg · h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg · h/liter, respectively; P ≥ 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick children before transfer for definitive management of severe or moderately severe malaria.
    Matched MeSH terms: Artemisinins/administration & dosage*; Artemisinins/pharmacokinetics*; Artemisinins/therapeutic use
  4. Fulltext Antimicrobial activity of artemisinin and precursor derived from in vitro plantlets of Artemisia annua L
    Appalasamy S, Lo KY, Ch'ng SJ, Nornadia K, Othman AS, Chan LK
    Biomed Res Int, 2014;2014:215872.
    PMID: 24575401 DOI: 10.1155/2014/215872
    Artemisia annua L., a medicinal herb, produces secondary metabolites with antimicrobial property. In Malaysia due to the tropical hot climate, A. annua could not be planted for production of artemisinin, the main bioactive compound. In this study, the leaves of three in vitro A. annua L. clones were, extracted and two bioactive compounds, artemisinin and a precursor, were isolated by thin layer chromatography. These compounds were found to be effective in inhibiting the growth of Gram-positive and Gram-negative bacteria but not Candida albicans. Their antimicrobial activity was similar to that of antibactericidal antibiotic streptomycin. They were found to inhibit the growth of the tested microbes at the minimum inhibition concentration of 0.09 mg/mL, and toxicity test using brine shrimp showed that even the low concentration of 0.09 mg/mL was very lethal towards the brine shrimps with 100% mortality rate. This study hence indicated that in vitro cultured plantlets of A. annua can be used as the alternative method for production of artemisinin and its precursor with antimicrobial activities.
    Matched MeSH terms: Artemisinins/isolation & purification; Artemisinins/pharmacology*; Artemisinins/toxicity
  5. Validation of high performance liquid chromatography-electrochemical detection methods with simultaneous extraction procedure for the determination of artesunate, dihydroartemisinin, amodiaquine and desethylamodiaquine in human plasma for application in clinical pharmacological studies of artesunate-amodiaquine drug combination
    Lai CS, Nair NK, Muniandy A, Mansor SM, Olliaro PL, Navaratnam V
    J Chromatogr B Analyt Technol Biomed Life Sci, 2009 Feb 15;877(5-6):558-62.
    PMID: 19147417 DOI: 10.1016/j.jchromb.2008.12.037
    With the expanded use of the combination of artesunate (AS) and amodiaquine (AQ) for the treatment of falciparum malaria and the abundance of products on the market, comes the need for rapid and reliable bioanalytical methods for the determination of the parent compounds and their metabolites. While the existing methods were developed for the determination of either AS or AQ in biological fluids, the current validated method allows simultaneous extraction and determination of AS and AQ in human plasma. Extraction is carried out on Supelclean LC-18 extraction cartridges where AS, its metabolite dihydroartemisinin (DHA) and the internal standard artemisinin (QHS) are separated from AQ, its metabolite desethylamodiaquine (DeAQ) and the internal standard, an isobutyl analogue of desethylamodiaquine (IB-DeAQ). AS, DHA and QHS are then analysed using Hypersil C4 column with acetonitrile-acetic acid (0.05M adjusted to pH 5.2 with 1.00M NaOH) (42:58, v/v) as mobile phase at flow rate 1.50ml/min. The analytes are detected with an electrochemical detector operating in the reductive mode. Chromatography of AQ, DeAQ and IB-DeAQ is carried out on an Inertsil C4 column with acetonitrile-KH(2)PO(4) (pH 4.0, 0.05M) (11:89, v/v) as mobile phase at flow rate 1.00ml/min. The analytes are detected by an electrochemical detector operating in the oxidative mode. The recoveries of AS, DHA, AQ and DeAQ vary between 79.1% and 104.0% over the concentration range of 50-1400ng/ml plasma. The accuracies of the determination of all the analytes are 96.8-103.9%, while the variation for within-day and day-to-day analysis are <15%. The lower limit of quantification for all the analytes is 20ng/ml and limit of detection is 8ng/ml. The method is sensitive, selective, accurate, reproducible and suited particularly for pharmacokinetic study of AS-AQ drug combination and can also be used to compare the bioavailability of different formulations, including a fixed-dose AS-AQ co-formulation.
    Matched MeSH terms: Artemisinins/administration & dosage; Artemisinins/blood*; Artemisinins/pharmacokinetics; Artemisinins/pharmacology*
  6. Fulltext Plasmodium knowlesi exhibits distinct in vitro drug susceptibility profiles from those of Plasmodium falciparum
    van Schalkwyk DA, Blasco B, Davina Nuñez R, Liew JWK, Amir A, Lau YL, et al.
    Int J Parasitol Drugs Drug Resist, 2019 04;9:93-99.
    PMID: 30831468 DOI: 10.1016/j.ijpddr.2019.02.004
    New antimalarial agents are identified and developed after extensive testing on Plasmodium falciparum parasites that can be grown in vitro. These susceptibility studies are important to inform lead optimisation and support further drug development. Until recently, little was known about the susceptibility of non-falciparum species as these had not been adapted to in vitro culture. The recent culture adaptation of P. knowlesi has therefore offered an opportunity to routinely define the drug susceptibility of this species, which is phylogenetically closer to all other human malarias than is P. falciparum. We compared the in vitro susceptibility of P. knowlesi and P. falciparum to a range of established and novel antimalarial agents under identical assay conditions. We demonstrated that P. knowlesi is significantly less susceptible than P. falciparum to six of the compounds tested; and notably these include three ATP4 inhibitors currently under development as novel antimalarial agents, and one investigational antimalarial, AN13762, which is 67 fold less effective against P. knowlesi. For the other compounds there was a less than two-fold difference in susceptibility between species. We then compared the susceptibility of a recent P. knowlesi isolate, UM01, to that of the well-established, older A1-H.1 clone. This recent isolate showed similar in vitro drug susceptibility to the A1-H.1 clone, supporting the ongoing use of the better characterised clone to further study drug susceptibility. Lastly, we used isobologram analysis to explore the interaction of a selection of drug combinations and showed similar drug interactions across species. The species differences in drug susceptibility reported by us here and previously, support adding in vitro drug screens against P. knowlesi to those using P. falciparum strains to inform new drug discovery and lead optimisation.
    Matched MeSH terms: Artemisinins/pharmacology
  7. Simultaneous determination of artesunic acid and dihydroartemisinin in blood plasma by high-performance liquid chromatography for application in clinical pharmacological studies
    Navaratnam V, Mordi MN, Mansor SM
    J Chromatogr B Biomed Sci Appl, 1997 Apr 25;692(1):157-62.
    PMID: 9187395
    A selective reproducible high-performance liquid chromatographic assay for the simultaneous quantitative determination of the antimalarial compound artesunic acid (ARS), dihydroartemisinin (DQHS) and artemisinin (QHS), as internal standard, is described. After extraction from plasma, ARS and DQHS were analysed using an Econosil C8 column and a mobile phase of acetonitrile-0.05 M acetic acid (42:58, v/v) adjusted to pH 5.0 and electrochemical detection in the reductive mode. The mean recovery of ARS and DQHS over a concentration range of 50-200 ng/ml was 75.5% and 93.5%, respectively. The within-day coefficients of variation were 4.2-7.4% for ARS and 2.6-4.9% for DQHS. The day-to-day coefficients of variation were 1.6-9.6% and 0.5-8.3%, respectively. The minimum detectable concentration for ARS and DQHS in plasma was 4.0 ng/ml for both compounds. The method was found to be suitable for use in clinical pharmacological studies.
    Matched MeSH terms: Artemisinins*
  8. Fulltext Repurposing Antimalarials to Tackle the COVID-19 Pandemic
    Krishna S, Augustin Y, Wang J, Xu C, Staines HM, Platteeuw H, et al.
    Trends Parasitol, 2021 01;37(1):8-11.
    PMID: 33153922 DOI: 10.1016/j.pt.2020.10.003
    Artemisinin-based combination therapies (ACTs) have demonstrated in vitro inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Artemisinins have also shown anti-inflammatory effects, including inhibition of interleukin-6 (IL-6) that plays a key role in the development of severe coronavirus disease 2019 (COVID-19). There is now sufficient evidence for the effectiveness of ACTs, and in particular artesunate/pyronaridine, to support clinical studies for COVID-19 infections.
    Matched MeSH terms: Artemisinins/pharmacology
  9. Effects of Environmental Factors on Growth and Artemisinin Content of Artemisia annua L
    Thu BT, Van Minh T, Lim BP, Keng CL
    Trop Life Sci Res, 2011 Dec;22(2):37-43.
    PMID: 24575216
    Seeds of two selected clones of Artemisia annua L., TC1 and TC2, were germinated in a greenhouse. Four-week-old seedlings from both clones were grown in the Thù Đúc province of Ho Chi Minh City on 2(nd) January 2009 and Đà Lat on 20(th) January 2009. During this study period in Thù Đúc province, which is situated 4-5 m above sea level, was experiencing a tropical, dry season with temperatures ranging from 26.2°C-32.8°C. Đà Lat, situated at 1500-2000 m above sea level, was having temperate, dry season with lower temperatures, ranging from 10.5°C-18.0°C. The high temperatures and low elevation in Thù Đúc Province led to slow vegetative growth for all of the plants from the two different clones and the artemisinin contents were significantly reduced. The temperate environment of Đà Lat supported robustly growing plants, with plant heights and branch lengths 4-5 times taller and longer that those planted at Thù Đúc Province. The artemisinin contents of A. annua planted at Đà Lat were 3-4 times greater than those cultivated at Thù Đúc Province. Hence, this study indicated that the variations observed in plant growth and artemisinin contents were due to temperature effects because the two selected clones were genetically homogenous. The cold weather of Đà Lat was suitable for planting of A. annua as opposed to the tropical weather of Thù Đúc Province.
    Matched MeSH terms: Artemisinins
  10. An oxidatively stressful situation: a case of Artemisia annua L
    Kam MYY, Yap WSP
    Biotechnol Genet Eng Rev, 2020 Apr;36(1):1-31.
    PMID: 32308142 DOI: 10.1080/02648725.2020.1749818
    Artemisinin (ART) is an antimalarial compound that possesses a variety of novel biological activities. Due to the low abundance of ART in natural sources, agricultural supply has been erratic, and prices are highly volatile. While heterologous biosynthesis and semi-synthesis are advantageous in certain aspects, these approaches remained disadvantageous in terms of productivity and cost-effectiveness. Therefore, further improvement in ART production calls for approaches that should supplement the agricultural production gap, while reducing production costs and stabilising supply. The present review offers a discussion on the elicitation of plants and/or in vitro cultures as an economically feasible yield enhancement strategy to address the global problem of access to affordable ART. Deemed critical for the manipulation of biosynthetic potential, the mechanism of ART biosynthesis is reviewed. It includes a discussion on the current biotechnological solutions to ART production, focusing on semi-synthesis and elicitation. A brief commentary on the possible aspects that influence elicitation efficiency and how oxidative stress modulates ART synthesis is also presented. Based on the critical analysis of current literature, a hypothesis is put forward to explain the possible involvement of enzymes in assisting the final non-enzymatic transformation step leading to ART formation. This review highlights the critical factors limiting the success of elicitor-induced modulation of ART metabolism, that will help inform strategies for future improvement of ART production. Additionally, new avenues for future research based on the proposed hypothesis will lead to exciting perspectives in this research area and continue to enhance our understanding of this intricate metabolic process.
    Matched MeSH terms: Artemisinins/chemical synthesis; Artemisinins/metabolism*; Artemisinins/therapeutic use
  11. Therapeutic equivalence of a low dose artemisinin formulation in falciparum malaria patients
    Wong JW, Yuen KH, Nagappan S, Shahul WS, Ho SS, Gan EK, et al.
    J Pharm Pharmacol, 2003 Feb;55(2):193-8.
    PMID: 12631411
    We have evaluated the therapeutic equivalence of a beta-cyclodextrin-artemisinin complex at an artemisinin dose of 150 mg, with a commercial reference preparation, Artemisinin 250 at a recommended dose of 250 mg. One hundred uncomplicated falciparum malarial patients were randomly assigned to orally receive either beta-cyclodextrin-artemisinin complex (containing 150 mg artemisinin) twice daily for five days or the active comparator (containing 250 mg artemisinin) twice daily for five days. The patients were hospitalized for seven days and were required to attend follow up assessments on days 14, 21, 28 and 35. All patients in both treatment groups were cured of the infection and achieved therapeutic success. At day seven of treatment, all patient blood was clear of the parasites and the sublingual temperature of all patients was less than 37.5 degrees C. Moreover, the parasite clearance time in both treatment groups was similar, being approximately three days after initiation of treatment. Comparable plasma artemisinin concentrations were observed between patients in both treatment groups at 1.5 and 3.0 h, although slightly higher levels were obtained with patients in the beta-cyclodextrin-artemisinin complex-treated group. The beta-cyclodextrin-artemisinin complex at a dose of 150 mg artemisinin was therapeutically equivalent to 250 mg Artemisinin 250. Additionally, patients receiving beta-cyclodextrin-artemisinin complex showed less variability in their plasma artemisinin concentrations at 1.5 h post-dosing, which suggested a more consistent rate of drug absorption.
    Matched MeSH terms: Artemisinins/blood; Artemisinins/pharmacokinetics; Artemisinins/therapeutic use*
  12. Fulltext Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine
    Permala J, Tarning J, Nosten F, White NJ, Karlsson MO, Bergstrand M
    Antimicrob Agents Chemother, 2017 May;61(5).
    PMID: 28242661 DOI: 10.1128/AAC.02491-16
    Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ∼4% malaria incidence per year compared to ∼8% for dosing regimen of two tablets weekly and ∼10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.
    Matched MeSH terms: Artemisinins/administration & dosage; Artemisinins/pharmacokinetics*; Artemisinins/therapeutic use*
  13. Fulltext A systematic review of the efficacy of a single dose artemisinin-naphthoquine in treating uncomplicated malaria
    Naing C, Whittaker MA, Mak JW, Aung K
    Malar J, 2015;14:392.
    PMID: 26445424 DOI: 10.1186/s12936-015-0919-5
    This study aimed to synthesize the existing evidence on the efficacy and safety of a single dose artemisinin-naphthoquine (ASNQ) for treatment of uncomplicated malaria in endemic countries.
    Matched MeSH terms: Artemisinins/administration & dosage*; Artemisinins/adverse effects
  14. Efficacy and safety of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum malaria in endemic countries: meta-analysis of randomised controlled studies
    Naing C, Mak JW, Aung K, Wong JY
    Trans R Soc Trop Med Hyg, 2013 Feb;107(2):65-73.
    PMID: 23222952 DOI: 10.1093/trstmh/trs019
    The present review aimed to synthesise available evidence on the efficacy of dihydroartemisinin-piperaquine (DP) in treating uncomplicated Plasmodium falciparum malaria in people living in malaria-endemic countries by performing a meta-analysis of relevant studies. We searched relevant studies in electronic data bases up to December 2011. Published results from randomised controlled trials (RCTs) comparing efficacy of DP with other artemisinin-based combination therapies (ACTs), or non-ACTs, or placebo were selected. The primary endpoint was 28-day and 42-day treatment failure. We identified 26 RCTs. Many of the studies included in the present review were of high quality. Overall, DP, artesunate-mefloquine (MAS3) and artemether-lumefentrine (AL) were equally effective for reducing the risk of recurrent parasitaemia. The PCR confirmed efficacy of DP (99.5%) and MAS3 (97.7%) at day 28 exceeded 90%; both are efficacious. Comparable efficacy was also found for DP (95.6%) and AL (94.3%). The present review has documented that DP is comparable to other currently used ACTs such as MAS3 and AL in treating uncomplicated falciparum malaria. The better safety profile of DP and once-daily dosage improves adherence and its fixed co-formulation ensures that both drugs are taken together. Our conclusion is that DP has the potential to become a first-line antimalarial drug.
    Matched MeSH terms: Artemisinins/adverse effects; Artemisinins/therapeutic use*
  15. Current progress in antimalarial pharmacotherapy and multi-target drug discovery
    Tibon NS, Ng CH, Cheong SL
    Eur J Med Chem, 2020 Feb 15;188:111983.
    PMID: 31911292 DOI: 10.1016/j.ejmech.2019.111983
    Discovery and development of antimalarial drugs have long been dominated by single-target therapy. Continuous effort has been made to explore and identify different targets in malaria parasite crucial for the malaria treatment. The single-target drug therapy was initially successful, but it was later supplanted by combination therapy with multiple drugs to overcome drug resistance. Emergence of resistant strains even against the combination therapy has warranted a review of current antimalarial pharmacotherapy. This has led to the development of the new concept of covalent biotherapy, in which two or more pharmacophores are chemically bound to produce hybrid antimalarial drugs with multi-target functionalities. Herein, the review initially details the current pharmacotherapy for malaria as well as the conventional and novel targets of importance identified in the malaria parasite. Then, the rationale of multi-targeted therapy for malaria, approaches taken to develop the multi-target antimalarial hybrids, and the examples of hybrid molecules are comprehensively enumerated and discussed.
    Matched MeSH terms: Artemisinins/pharmacology*; Artemisinins/chemistry
  16. Inclusion complexation of artemisinin with alpha-, beta-, and gamma-cyclodextrins
    Wong JW, Yuen KH
    Drug Dev Ind Pharm, 2003 Oct;29(9):1035-44.
    PMID: 14606667
    The present study was conducted to investigate the inclusion complexation of artemisinin (ART) with natural cyclodextrins (CyD), namely alpha-, beta-, and gamma-CyDs with the aim of improving its solubility and dissolution rate. Complex formation in aqueous solution and solid state was studied by solubility analysis, dissolution, and thermal analysis. Solubility diagrams indicated that the complexation of ART and the three CyDs occurred at a molar ratio of 1:1, and showed a remarkable increase in ART solubility. Moreover, the thermodynamic parameters calculated by using the van't Hoff equation revealed that the complexation process was associated with negative enthalpy of formation and occurred spontaneously. The complexation capability of CyDs with ART increased in the order of alpha- < gamma- < beta-CyDs and could be ascribed to the structural compatibility between the molecular size of ART and the diameter of the CyD cavities. Dissolution profiles of the three complexes demonstrated an increased rate and extent of dissolution compared with those of their respective physical mixtures and a commercial preparation. In solid-state analysis, using differential scanning calorimetry, the gamma-CyD was capable of complexing the highest percentage of ART, followed by beta- and alpha-CyDs. The respective estimated percentage of ART complexed by the CyDs were 85%, 40%, and 12%.
    Matched MeSH terms: Artemisinins/metabolism; Artemisinins/chemistry*
  17. An analytical method with a single extraction procedure and two separate high performance liquid chromatographic systems for the determination of artesunate, dihydroartemisinin and mefloquine in human plasma for application in clinical pharmacological studies of the drug combination
    Lai CS, Nair NK, Mansor SM, Olliaro PL, Navaratnam V
    J Chromatogr B Analyt Technol Biomed Life Sci, 2007 Oct 01;857(2):308-14.
    PMID: 17719858
    The combination of two sensitive, selective and reproducible reversed phase liquid chromatographic (RP-HPLC) methods was developed for the determination of artesunate (AS), its active metabolite dihydroartemisinin (DHA) and mefloquine (MQ) in human plasma. Solid phase extraction (SPE) of the plasma samples was carried out on Supelclean LC-18 extraction cartridges. Chromatographic separation of AS, DHA and the internal standard, artemisinin (QHS) was obtained on a Hypersil C4 column with mobile phase consisting of acetonitrile-0.05 M acetic acid adjusted to pH 5.2 with 1.0M NaOH (42:58, v/v) at the flow rate of 1.50 ml/min. The analytes were detected using an electrochemical detector operating in the reductive mode. Chromatography of MQ and the internal standard, chlorpromazine hydrochloride (CPM) was carried out on an Inertsil C8-3 column using methanol-acetonitrile-0.05 M potassium dihydrogen phosphate adjusted to pH 3.9 with 0.5% orthophosphoric acid (50:8:42, v/v/v) at a flow rate of 1.00 ml/min with ultraviolet detection at 284 nm. The mean recoveries of AS and DHA over a concentration range of 30-750 ng/0.5 ml plasma and MQ over a concentration of 75-1500 ng/0.5 ml plasma were above 80% and the accuracy ranged from 91.1 to 103.5%. The within-day coefficients of variation were 1.0-1.4% for AS, 0.4-3.4% for DHA and 0.7-1.5% for MQ. The day-to-day coefficients of variation were 1.3-7.6%, 1.8-7.8% and 2.0-3.4%, respectively. Both the lower limit of quantifications for AS and DHA were at 10 ng/0.5 ml and the lower limit of quantification for MQ was at 25 ng/0.5 ml. The limit of detections were 4 ng/0.5 ml for AS and DHA and 15 ng/0.5 ml for MQ. The method was found to be suitable for use in clinical pharmacological studies.
    Matched MeSH terms: Artemisinins/administration & dosage; Artemisinins/blood; Artemisinins/isolation & purification; Artemisinins/pharmacokinetics
  18. Fulltext Eurycoma longifolia extract-artemisinin combination: parasitemia suppression of Plasmodium yoelii-infected mice
    Mohd Ridzuan MA, Sow A, Noor Rain A, Mohd Ilham A, Zakiah I
    Trop Biomed, 2007 Jun;24(1):111-8.
    PMID: 17568384 MyJurnal
    Eurycoma longifolia, locally known as 'Tongkat Ali' is a popular local medicinal plant that possess a lot of medicinal properties as claimed traditionally, especially in the treatment of malaria. The claims have been proven scientifically on isolated compounds from the plant. The present study is to investigate the anti malaria properties of Eurycoma longifolia standardized extract (root) (TA164) alone and in combination with artemisinin in vivo. Combination treatment of the standardized extract (TA164) with artemisinin suppressed P. yoelii infection in the experimental mice. The 4 day suppressive test showed that TA164 suppressed the parasitemia of P. yoelii-infected mice as dose dependent manner (10, 30 and 60 mg/kg BW) by oral and subcutaneous treatment. By oral administration, combination of TA164 at 10, 30 and 60 mg/kg BW each with artemisinin respectively showed a significant increase in the parasitemia suppression to 63, 67 and 80 percent as compared to artemisinin single treatment (31%). Using subcutaneous administration, at 10 mg/kg BW of TA164 in combination with 1.7 mg/kg BW of artemisinin gave a suppression of 80% of infection. This study showed that combination treatment of TA164 with artemisinin gives a promising potential anti malaria candidate using both oral and subcutaneous route, the later being the most potent.
    Matched MeSH terms: Artemisinins/administration & dosage*; Artemisinins/pharmacology*
  19. Fulltext Intravascular haemolysis with haemoglobinuria in a splenectomized patient with severe Plasmodium knowlesi malaria
    Barber BE, Grigg MJ, William T, Yeo TW, Anstey NM
    Malar J, 2016 Sep 09;15:462.
    PMID: 27613607 DOI: 10.1186/s12936-016-1514-0
    BACKGROUND: Haemoglobinuria is an uncommon complication of severe malaria, reflecting acute intravascular haemolysis and potentially leading to acute kidney injury. It can occur early in the course of infection as a consequence of a high parasite burden, or may occur following commencement of anti-malarial treatment. Treatment with quinine has been described as a risk factor; however the syndrome may also occur following treatment with intravenous artesunate. In Malaysia, Plasmodium knowlesi is the most common cause of severe malaria, often associated with high parasitaemia. Asplenic patients may be at additional increased risk of intravascular haemolysis.

    CASE PRESENTATION: A 61 years old asplenic man was admitted to a tertiary referral hospital in Sabah, Malaysia, with severe knowlesi malaria characterized by hyperparasitaemia (7.9 %), jaundice, respiratory distress, metabolic acidosis, and acute kidney injury. He was commenced on intravenous artesunate, but1 day later developed haemoglobinuria, associated with a 22 % reduction in admission haemoglobin. Additional investigations, including a cell-free haemoglobin of 10.2 × 10(5) ng/mL and an undetectable haptoglobin, confirmed intravascular haemolysis. The patient continued on intravenous artesunate for a total of 48 h prior to substitution with artemether-lumefantrine, and made a good recovery with resolution of his haemoglobinuria and improvement of his kidney function by day 3.

    CONCLUSIONS: An asplenic patient with hyperparasitaemic severe knowlesi malaria developed haemoglobinuria after treatment with intravenous artesunate. There are plausible mechanisms for increased haemolysis with hyperparasitaemia, and following both splenectomy and artesunate. Although in this case the patient made a rapid recovery, knowlesi malaria patients with this unusual complication should be closely monitored for potential deterioration.

    Matched MeSH terms: Artemisinins/administration & dosage; Artemisinins/adverse effects*
  20. Fulltext Plasmodium falciparum artemisinin resistance monitoring in Sabah, Malaysia: in vivo therapeutic efficacy and kelch13 molecular marker surveillance
    Grigg MJ, William T, Piera KA, Rajahram GS, Jelip J, Aziz A, et al.
    Malar J, 2018 Dec 10;17(1):463.
    PMID: 30526613 DOI: 10.1186/s12936-018-2593-x
    BACKGROUND: Spreading Plasmodium falciparum artemisinin drug resistance threatens global malaria public health gains. Limited data exist to define the extent of P. falciparum artemisinin resistance southeast of the Greater Mekong region in Malaysia.

    METHODS: A clinical efficacy study of oral artesunate (total target dose 12 mg/kg) daily for 3 days was conducted in patients with uncomplicated falciparum malaria and a parasite count 

    Matched MeSH terms: Artemisinins/pharmacology*; Artemisinins/therapeutic use
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