- 1. Quantitative Structure-Activity Relationships of the Antimalarial Agent Artemisinin and some of its Derivatives - A DFT Approach.
Artemisinin form the most important class of antimalarial agents currently available, and is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua. Artemisinin is effectively used in the treatment of drug-resistant Plasmodium falciparum and because of its rapid clearance of cerebral malaria, many clinically useful semisynthetic drugs for severe and complicated malaria have been developed. However, one of the major disadvantages of using artemisinins is their poor solubility either in oil or water and therefore, in order to overcome this difficulty many derivatives of artemisinin were prepared. A comparative study on the chemical reactivity of artemisinin and some of its derivatives are performed using density functional theory (DFT) calculations. DFT based global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries are used to investigate the usefulness of these descriptors for understanding the reactive nature and reactive sites of the molecules. Multiple regression analysis is applied to build up a quantitative structure-activity relationship (QSAR) model based on the DFT based descriptors against the chloroquine-resistant, mefloquine-sensitive Plasmodium falciparum W-2 clone....(more)
Rajkhowa S, et al. Comb Chem High Throughput Screen 2013 Apr 10.
Related Products: Artemisia Annua Extract
- 2. High-level semi-synthetic production of the potent antimalarial artemisinin.
In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price....(more)
Paddon CJ, et al. Nature 2013 Apr 25;496(7446):528-32.
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- 3. Differentially Expressed Genes during Contrasting Growth Stages of Artemisia annua for Artemisinin Content.
Artemisia annua is the source of antimalarial phytomolecule, artemisinin. It is mainly produced and stored in the glandular secretory trichomes present in the leaves of the plant. Since, the artemisinin biosynthesis steps are yet to be worked out, in this investigation a microarray chip was strategized for the first time to shortlist the differentially expressing genes at a stage of plant producing highest artemisinin compared to the stage with no artemisinin. As the target of this study was to analyze differential gene expression associated with contrasting artemisinin content in planta and a genotype having zero/negligible artemisinin content was unavailable, it was decided to compare different stages of the same genotype with contrasting artemisinin content (seedling - negligible artemisinin, mature leaf - high artemisinin). The SCAR-marked artemisinin-rich (∼1.2%) Indian variety 'CIM-Arogya' was used in the present study to determine optimal plant stage and leaf ontogenic level for artemisinin content. A representative EST dataset from leaf trichome at the stage of maximal artemisinin biosynthesis was established. The high utility small scale custom microarray chip of A. annua containing all the significant artemisinin biosynthesis-related genes, the established EST dataset, gene sequences isolated in-house and strategically selected candidates from the A. annua Unigene database (NCBI) was employed to compare the gene expression profiles of two stages. The expression data was validated through semiquantitative and quantitative RT-PCR followed by putative annotations through bioinformatics-based approaches. Many candidates having probable role in artemisinin metabolism were identified and described with scope for further functional characterization....(more)
Nair P, et al. PLoS One 2013;8(4):e60375.
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- 4. Proteomics Analysis of Hepatoprotective Effects for Scoparone Using MALDI-TOF/TOF Mass Spectrometry with Bioinformatics.
Abstract Scoparone is an active ingredient of Yinchenhao (Artemisia annua L.), a well-known Chinese medicinal plant, and has been utilized in prevention and therapy of liver damage. However, the molecular drug targets associated with the pharmacological effects of scoparone are largely unknown. In the present article, we extend the previous research on Yinchenhao through a study of its active ingredient and thus the putative targets of scoparone. We employed two-dimensional gel electrophoresis, and all proteins expressed were identified by MALDI-TOF/TOF MS and database research. Protein-interacting networks and pathways were also mapped and evaluated. The possible protein network associated with scoparone was constructed, and contribution of these proteins to the protective effect of scoparone against the carbon tetrachloride-induced acute liver injury in rats are discussed herein. Hepatoprotective effects of scoparone on liver injury in rats were associated with regulated expression of six proteins which were closely related in our protein-protein interaction network, and appear to be involved in antioxidation and signal transduction, energy production, immunity, metabolism, and chaperoning. These observations collectively provide new insights on the molecular mechanisms of scoparone action against hepatic damage in rats....(more)
Zhang A, et al. OMICS 2013 Apr;17(4):224-9.
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- 5. Is Artemisinin the Only Antiplasmodial Compound in the Artemisia annua Tea Infusion? An in Vitro Study.
In our ongoing investigation into Artemisia annua for the treatment of malaria, we decided to study the possibility that synergism might enhance the efficacy of artemisinin. Our main objective was to test tea infusions and nonpolar extracts prepared from different A. annua varieties against Plasmodium falciparum in vitro in order to determine if synergism will increase the effectiveness of artemisinin in the samples as compared to pure artemisinin. We found that the IC50 of artemisinin in the tea and nonpolar extracts was not significantly different to the IC50 of pure artemisinin. We could show that the year and country of harvest or storage conditions did not have any influence on the activity and that it narrowly followed the concentration of artemisinin in all the extracts. In conclusion, based on these in vitro results, artemisinin seems to be the only active antiplasmodial compound in A. annua.
Georg Thieme Verlag KG Stuttgart · New York....(more)
Mouton J, et al. Planta Med 2013 Apr;79(6):468-70.
Related Products: Artemisia Annua Extract
- 6. Indole-3-Acetic Acid Production by Endophytic Streptomyces sp. En-1 Isolated from Medicinal Plants.
Plant-associated actinobacteria are rich sources of bioactive compounds including indole-derived molecules such as phytohormone indole-3-acetic acid (IAA). In view of few investigations concerning the biosynthesis of IAA by endophytic actinobacteria, this study evaluated the potential of IAA production in endophytic streptomycete isolates sourced from medicinal plant species Taxus chinensis and Artemisia annua. By HPLC analysis of IAA combined with molecular screening approach of iaaM, a genetic determinant of streptomycete IAA synthesis via indole-3-acetamide (IAM), our data showed the putative operation of IAM-mediated IAA biosynthesis in Streptomyces sp. En-1 endophytic to Taxus chinensis. Furthermore, using the co-cultivation system of model plant Arabidopsis thaliana and streptomycete, En-1 was found to be colonized intercellularly in the tissues of Arabidopsis, an alternative host, and the effects of endophytic En-1 inoculation on the model plant were also assayed. The phytostimulatory effects of En-1 inoculation suggest that IAA-producing Streptomyces sp. En-1 of endophytic origin could be a promising candidate for utilization in growth improvement of plants of economic and agricultural value....(more)
Lin L, et al. Curr Microbiol 2013 Mar 20.
Related Products: Artemisia Annua Extract
- 7. Genetic Surveillance Detects Both Clonal and Epidemic Transmission of Malaria following Enhanced Intervention in Senegal.
Using parasite genotyping tools, we screened patients with mild uncomplicated malaria seeking treatment at a clinic in Thiès, Senegal, from 2006 to 2011. We identified a growing frequency of infections caused by genetically identical parasite strains, coincident with increased deployment of malaria control interventions and decreased malaria deaths. Parasite genotypes in some cases persisted clonally across dry seasons. The increase in frequency of genetically identical parasite strains corresponded with decrease in the probability of multiple infections. Further, these observations support evidence of both clonal and epidemic population structures. These data provide the first evidence of a temporal correlation between the appearance of identical parasite types and increased malaria control efforts in Africa, which here included distribution of insecticide treated nets (ITNs), use of rapid diagnostic tests (RDTs) for malaria detection, and deployment of artemisinin combination therapy (ACT). Our results imply that genetic surveillance can be used to evaluate the effectiveness of disease control strategies and assist a rational global malaria eradication campaign....(more)
Daniels R, et al. PLoS One 2013 Apr 4;8(4):e60780.
Related Products: Artemisinin
- 8. Quantitative Structure-Activity Relationships of the Antimalarial Agent Artemisinin and some of its Derivatives - A DFT Approach.
Artemisinin form the most important class of antimalarial agents currently available, and is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua. Artemisinin is effectively used in the treatment of drug-resistant Plasmodium falciparum and because of its rapid clearance of cerebral malaria, many clinically useful semisynthetic drugs for severe and complicated malaria have been developed. However, one of the major disadvantages of using artemisinins is their poor solubility either in oil or water and therefore, in order to overcome this difficulty many derivatives of artemisinin were prepared. A comparative study on the chemical reactivity of artemisinin and some of its derivatives are performed using density functional theory (DFT) calculations. DFT based global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries are used to investigate the usefulness of these descriptors for understanding the reactive nature and reactive sites of the molecules. Multiple regression analysis is applied to build up a quantitative structure-activity relationship (QSAR) model based on the DFT based descriptors against the chloroquine-resistant, mefloquine-sensitive Plasmodium falciparum W-2 clone....(more)
Rajkhowa S, et al. Comb Chem High Throughput Screen 2013 Apr 10.
Related Products: Artemisinin
- 9. Expression in yeast links field polymorphisms in PfATP6 to in vitro artemisinin resistance and identifies new inhibitor classes.
Background. The mechanism of action of artemisinins against malaria is unclear, despite their widespread use in combination therapies and the emergence of resistance.Results. Here, we report expression of PfATP6 (a SERCA pump) in yeast and demonstrate its inhibition by artemisinins. Mutations in PfATP6 identified in field isolates (such as S769N) and in laboratory clones (such as L263E) decrease susceptibility to artemisinins, whereas they increase susceptibility to unrelated inhibitors such as cyclopiazonic acid. As predicted from the yeast model, Plasmodium falciparum with the L263E mutation is also more susceptible to cyclopiazonic acid. An inability to knockout parasite SERCA pumps provides genetic evidence that they are essential in asexual stages of development. Thaperoxides are a new class of potent antimalarial designed to act by inhibiting PfATP6. Results in yeast confirm this inhibition.Conclusions. The identification of inhibitors effective against mutated PfATP6 suggests ways in which artemisinin resistance may be overcome....(more)
Pulcini S, et al. J Infect Dis 2013 Apr 18.
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- 10. Early parasitological response following artemisinin-containing regimens: a critical review of the literature.
BACKGROUND:
Parasitaemia on Day 3 has been proposed as useful alert of potential artemisinin resistance, however, the normal variation of parasite clearance observed in artemisinin-based combination therapy clinical trials is poorly documented.
METHODS:
The trends in early parasitological response following treatment with an artemisinin anti-malarial regimen were reviewed. A PubMed literature search identified all studies using an artemisinin regimen for uncomplicated falciparum malaria published between January 2000 and December 2011. Data from clinical studies were extracted for analysis using a standardized questionnaire.
RESULTS:
In total 65,078 patients were enrolled into 213 clinical trials with 413 treatment arms containing either an artemisinin derivative alone (n=26) or in combination with a partner drug (n=387). The proportion of patients remaining parasitaemic at 24, 48 and 72 hours was documented in 115 (28%), 167 (40%) and 153 (37%) treatment arms, respectively. Excluding resistance studies in Cambodia, the median proportion of patients still parasitaemic was 53.8% [range 3--95, IQR=30.5-69.2] on Day 1, 6% [range 0--65.9, IQR=2-11.5] on Day 2 and 0 [range 0--12.6, IQR=0-2] on Day 3. Comparing studies from 2000 to 2005 and 2006 to 2011, the median proportion of patients reported to remain parasitaemic at 72 hours decreased in Africa (1.2% vs 0%, p=0.007), but increased in Asia (0.4% vs 3.9%, p=0.076). In 95% of studies the proportion of patients with peripheral parasitaemia was less than 6% at 72 hours.
CONCLUSIONS:
These results highlight the normal distribution of early parasitological responses following ACT, and the influence that heterogeneity in study design, host and parasite factors have in confounding a surveillance system based on Day 3 parasite positivity. Greater understanding of factors influencing parasite clearance is crucial, but will require analysis of pooled data from individual patient records....(more)
Das D, et al. Malar J 2013 Apr 19;12(1):125.
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- 11. A new derivative detected in accelerated ageing of artesunate-amodiaquine fixed dose combination tablets.
An unknown impurity detected in small amounts during the heat treatment of artesunate-amodiaquine bilayer tablets was purified by semipreparative HPLC and identified by MS and NMR as the tetrahydrofuranyl acetate-rearranged derivative of anhydrodihydroartemisinin. When anhydrodihydroartemisinin was treated with a Fe<sup>II</sup> salt in acetonitrile-water solution, the same product was generated, together with an isomeric 2-deoxy-4α-hydroxy-anhydrodihydroartemisinin derivative, as expected from the usual homolytic radical opening of the endoperoxide bond previously described for other artemisinin derivatives....(more)
Charrier C, et al. J Pharm Biomed Anal 2013 Mar 26;81-82C:20-26.
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- 12. Artemisinin-based combination therapy availability and use in the private sector of five AMFm phase 1 countries.
BACKGROUND:
In 2009, the Global Fund to Fight AIDS, Tuberculosis and Malaria established the Affordable Medicines Facility-malaria (AMFm) in order to increase access to quality-assured artemisinin combination therapy (QAACT). AMFm Phase 1, which includes nine pilot programmes in eight countries, was launched in 2009. The objective of this study was to assess anti-malarial stock and purchase patterns at private outlets in five AMFm Phase 1 countries in regard to three of the core AMFm goals: increase the affordability of QAACT, increase the availability of QAACT, and crowd out artemisinin monotherapies and other substandard therapies.
METHODS:
The study was conducted between April and May 2012 and included interviews with personnel in 598 private pharmaceutical outlets in Ghana, Kenya, Nigeria, Tanzania, and Uganda. Questionnaires were administered at private retail outlets and the data were analyzed to assess within- and between-country differences in QAACT price, availability, and popularity.
RESULTS:
AMFm medications were less expensive than their non-AMFm counterparts, yet prices for both types were above country-specific suggested retail prices. Market penetration of AMFm QAACT in both urban and rural areas was high, although stock-outs of both AMFm and non-AMFm products were more common in rural compared with urban outlets in Ghana and Kenya (p = 0.0013). Government recommendation was the most significant factor influencing anti-malarial stock choices in urban (41.5%) and rural (31.9%) outlets. The three top-selling anti-malarials reported for both urban and rural areas in each country were, with the exception of rural Uganda and urban Nigeria, combination therapies.
CONCLUSIONS:
Results from this study indicate that the AMFm has not fully achieved its affordability and crowd-out objectives. Still, the final purchase price of AMFm QAACT was substantially lower than non-AMFm equivalents. Moreover, for both urban and rural areas, AMFm QAACT availability was found to be high, and the various forms of QAACT were the best-selling products among all anti-malarials. These findings suggest a continued need for initiatives like the AMFm that improve the affordability and accessibility of QAACT. Similar programmes may be especially effective if employed in combination with rapid diagnostic testing to ensure the appropriate use of these products....(more)
Davis B, et al. Malar J 2013 Apr 22;12:135.
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- 13. Toxic essential oils. Part II: Chemical, toxicological, pharmacological and microbiological profiles of Artemisia annua L. volatiles.
Botanical drugs based on Artemisia annua L. (Asteraceae) are important in the treatment of malaria. Alongside with artemisinin, this aromatic species produces high and variable amounts of other chemicals that have mostly unknown biological/pharmacological activities. Herein, we have studied the toxicological/pharmacological profile of volatile constituents of a Serbian population of A. annua. Fifty-eight components were identified, among them, artemisia ketone (35.7%), α-pinene (16.5%) and 1,8-cineole (5.5%) were the most abundant ones. Significant variability of A. annua volatile profile was confirmed by means of agglomerative hierarchical cluster analysis indicating the existence of several different A. annua chemotypes. In an attempt to connect the chemical profile of A. annua oil with its biological/toxicological effects, we have evaluated in vivo and/or in vitro toxicity (including hepato- and nephrotoxicity/protection), antinociceptive, antioxidant (DPPH, ABTS and superoxide radical scavenging activity assays), enzyme inhibiting (protein kinase A and α-amylase) and antimicrobial potential of A. annua oil and of its constituents. Our results revealed that the beneficial properties of A. annua botanical drugs are not limited only to their antimalarial properties. Taking into account its relatively low toxicity, the usage of A. annua volatiles (at least of the herein studied population) does not represent a health risk....(more)
Radulovi? NS, et al. Food Chem Toxicol 2013 Apr 20.
Related Products: Artemisinin
- 14. The Artemisinin derivative Artesunate inhibits corneal neovascularization by inducing ROS-dependent apoptosis in vascular endothelial cells.
PURPOSE. Without therapeutic intervention, corneal neovascularization rapidly compromises visual acuity, and is a leading cause of blindness. Artesunate was reported to inhibit angiogenesis in tumors, although, the effects of artesunate on non-tumor angiogenesis have not been investigated. This study was designed to investigate the effect of artesunate on corneal neovascularization and delineate its underlying mechanism of action. METHODS. Rats with alkali-burned cornea were treated with artesunate for 11 days. Corneal neovascularization was evaluated by measuring the length and area of corneal vasculature in rat. Apoptotic cells were stained with AnnexinV and PI, and measured with flow cytometry analysis. Apoptosis-related and p38MAPK signaling were evaluated by Western blot analysis. RESULTS. Artesunate significantly inhibited corneal neovascularization and inflammation via specifically inducing apoptosis of vascular endothelial cells. In vascular endothelial cells, artesunate increased the Bax/Bcl-2 ratio, reduced mitochondrial membrane potential, stimulated release of cytochrome C and cleavage of caspase9 and caspase3, suggesting that the mitochondrial apoptotic pathway was involved. Artesunate activated p38MAPK, and specific p38MAPK inhibitors suppressed artesunate-induced apoptosis in endothelial cells. Reactive oxygen species (ROS) levels were increased by artesunate. N-acetyl-L-cysteine blocked p38MAPK activation and protected endothelial cells from artesunate-induced apoptosis. Ferrous salt increased ROS levels and elevated the cytotoxic effect of artesunate on endothelial cells, while the iron chelating agent deferoxamine decreased ROS levels and artesunate-induced apoptosis. Artesunate had no effect on expression of Fas, Fas Ligand or caspase 8 cleavage. CONCLUSIONS. These results suggest that artesunate induces apoptosis of endothelial cells via an iron/ROS dependent p38MAPK-mitochondrial pathway....(more)
Cheng R, et al. Invest Ophthalmol Vis Sci 2013 Apr 23.
Related Products: Artemisinin
- 15. High-throughput analysis of antimalarial susceptibility data by the WWARN In Vitro Analysis and Reporting Tool (IVART).
Assessment of in vitro susceptibility is a fundamental component of antimalarial surveillance studies, but wide variations in measurement of parasite growth and calculation of inhibitory constants make comparisons of data from different laboratories difficult. Here we describe a web-based, high-throughput, in vitro analysis and reporting tool (IVART) generating inhibitory constants for large datasets. Fourteen primary datasets examining laboratory susceptibility to artemisinin derivatives and artemisinin combination therapy partner drugs were collated from eleven laboratories. Drug concentrations associated with half-maximal inhibition of growth (IC50 values) were determined by a modified sigmoid Emax model fitting algorithm, allowing standardised analysis of 7350 concentration-inhibition assays involving 1592 isolates. Examination of concentration-inhibition data revealed evidence of apparent paradoxical growth at high concentrations of non-artemisinin drugs, supporting amendment of the method for calculating maximal drug effect in each assay. Criteria to define more reliable IC50 values based on estimated confidence intervals and growth ratios improved correlation coefficients for the drug pairs mefloquine-quinine and chloroquine-desethylamodiaquine in 9 of 11 and 8 of 8 datasets respectively. Further analysis showed that maximal drug inhibition was higher for artemisinins than other drugs, particularly in ELISA-based assays, consistent with the earlier onset of action of these drugs in the parasite lifecycle. This is the first high-throughput analytical approach to apply consistent constraints and reliability criteria to large diverse antimalarial susceptibility datasets. The data also illustrate the distinct biological properties of artemisinins, and underline the need to apply more sensitive approaches to assessing in vitro susceptibility to these drugs....(more)
Woodrow CJ, et al. Antimicrob Agents Chemother 2013 Apr 22.
Related Products: Artemisinin
- 16. Ex vivo responses of Plasmodium falciparum clinical isolates to conventional and new antimalarial drugs in Niger.
Little is known about the situation of resistances of Plasmodium falciparum to antimalarials in Sahelian countries. Here, we investigated the drug susceptibilities of fresh isolates collected in Niger, post deployment of artemisinin-based combination therapies (ACTs). We found that the parasites remained highly susceptible to new (dihydroartemisinin, lumefantrine, pyronaridine and piperaquine) and conventional (amodiaquine and chloroquine) antimalarial drugs. The introduction of ACTs in 2005, and their further deployment nationwide, has therefore not resulted in a decrease in P. falciparum susceptibility to these antimalarials....(more)
Issaka M, et al. Antimicrob Agents Chemother 2013 Apr 22.
Related Products: Artemisinin
- 17. Reduced susceptibility of Plasmodium falciparum to artesunate in southern Myanmar.
BACKGROUND:
Plasmodium falciparum resistance to artemisinins, the first line treatment for malaria worldwide, has been reported in western Cambodia. Resistance is characterized by significantly delayed clearance of parasites following artemisinin treatment. Artemisinin resistance has not previously been reported in Myanmar, which has the highest falciparum malaria burden among Southeast Asian countries.
METHODS:
A non-randomized, single-arm, open-label clinical trial of artesunate monotherapy (4 mg/kg daily for seven days) was conducted in adults with acute blood-smear positive P. falciparum malaria in Kawthaung, southern Myanmar. Parasite density was measured every 12 hours until two consecutive negative smears were obtained. Participants were followed weekly at the study clinic for three additional weeks. Co-primary endpoints included parasite clearance time (the time required for complete clearance of initial parasitemia), parasite clearance half-life (the time required for parasitemia to decrease by 50% based on the linear portion of the parasite clearance slope), and detectable parasitemia 72 hours after commencement of artesunate treatment. Drug pharmacokinetics were measured to rule out delayed clearance due to suboptimal drug levels.
RESULTS:
The median (range) parasite clearance half-life and time were 4.8 (2.1-9.7) and 60 (24-96) hours, respectively. The frequency distributions of parasite clearance half-life and time were bimodal, with very slow parasite clearance characteristic of the slowest-clearing Cambodian parasites (half-life longer than 6.2 hours) in approximately 1/3 of infections. Fourteen of 52 participants (26.9%) had a measurable parasitemia 72 hours after initiating artesunate treatment. Parasite clearance was not associated with drug pharmacokinetics.
CONCLUSIONS:
A subset of P. falciparum infections in southern Myanmar displayed markedly delayed clearance following artemisinin treatment, suggesting either emergence of artemisinin resistance in southern Myanmar or spread to this location from its site of origin in western Cambodia. Resistance containment efforts are underway in Myanmar.
TRIAL REGISTRATION:
Australian New Zealand Clinical Trials Registry ACTRN12610000896077....(more)
Kyaw MP, et al. PLoS One 2013;8(3):e57689.
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- 18. Artesunate/Amodiaquine Malaria Treatment for Equatorial Guinea (Central Africa).
The objectives of this study were: 1) to evaluate the safety and efficacy of combination artesunate (AS)/amodiaquine (AQ) therapy, and 2) to determine the difference between recrudescence and resistance. An in vivo efficacy study was conducted in Equatorial Guinea. A total of 122 children 6-59 months of age from two regional hospitals were randomized and subjected to a 28-day clinical and parasitological follow-up. A blood sample on Whatman paper was taken on Days 0, 7, 14, 21, and 28 or on any day in cases of treatment failure, with the parasite DNA then being extracted for molecular analysis purposes. A total of 4 children were excluded, and 9 cases were lost to follow-up. There were 17 cases of late parasitological failure, 3 cases of late clinical failure, and 89 cases of adequate clinical and parasitological response. The parasitological failure rate was 18.3% (20 of 109) and the success rate 81.70% (95% confidence interval [72.5-87.9%]). After molecular correction, real treatment efficacy stood at 97.3%. Our study showed the good efficacy of combination AS/AQ therapy. This finding enabled this treatment to be recommended to Equatorial Guinea's National Malaria Control Program to change the official treatment policy as of March 2008....(more)
Charle P, et al. Am J Trop Med Hyg 2013 Mar 25.
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- 19. Genetic diversity and signatures of selection of drug resistance in Plasmodium populations from both human and mosquito hosts in continental Equatorial Guinea.
BACKGROUND:
In Plasmodium, the high level of genetic diversity and the interactions established by co-infecting parasite populations within the same host may be a source of selection on pathogen virulence and drug resistance. As different patterns have already been described in humans and mosquitoes, parasite diversity and population structure should be studied in both hosts to properly assess their effects on infection and transmission dynamics. This study aimed to characterize the circulating populations of Plasmodium spp and Plasmodium falciparum from a combined set of human blood and mosquito samples gathered in mainland Equatorial Guinea. Further, the origin and evolution of anti-malarial resistance in this area, where malaria remains a major public health problem were traced.
METHODS:
Plasmodium species infecting humans and mosquitoes were identified by nested-PCR of chelex-extracted DNA from dried blood spot samples and mosquitoes. Analysis of Pfmsp2 gene, anti-malarial-resistance associated genes, Pfdhps, Pfdhfr, Pfcrt and Pfmdr1, neutral microsatellites (STR) loci and Pfdhfr and Pfdhps flanking STR was undertaken to evaluate P. falciparum diversity.
RESULTS:
Prevalence of infection remains high in mainland Equatorial Guinea. No differences in parasite formula or significant genetic differentiation were seen in the parasite populations in both human and mosquito samples. Point mutations in all genes associated with anti-malarial resistance were highly prevalent. A high prevalence was observed for the Pfdhfr triple mutant in particular, associated with pyrimethamine resistance.Analysis of Pfdhps and Pfdhfr flanking STR revealed a decrease in the genetic diversity. This finding along with multiple independent introductions of Pfdhps mutant haplotypes suggest a soft selective sweep and an increased differentiation at Pfdhfr flanking microsatellites hints a model of positive directional selection for this gene.
CONCLUSIONS:
Chloroquine is no longer recommended for malaria treatment in Equatorial Guinea but sulphadoxine-pyrimethamine (SP) remains in use in combination with artesunate and is the only drug recommended in preventive chemotherapy in pregnancy. The high prevalence of point mutations in Pfdhfr and Pfdhps points to the danger of an eventual reduction in the efficacy of SP combined therapy in P. falciparum populations in Equatorial Guinea and to the essential continuous monitoring of these two genes....(more)
Mendes C, et al. Malar J 2013 Mar 27;12:114.
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- 20. Manual blood exchange transfusion does not significantly contribute to parasite clearance in artesunate-treated individuals with imported severe Plasmodium falciparum malaria.
BACKGROUND:
Exchange transfusion (ET) has remained a controversial adjunct therapy for the treatment of severe malaria. In order to assess the relative contribution of ET to parasite clearance in severe malaria, all patients receiving ET as an adjunct treatment to parenteral quinine or to artesunate were compared with patients treated with parenteral treatment with quinine or artesunate but who did not receive ET. ET was executed using a standardized manual isovolumetric exchange protocol.
METHODS:
All patients in the Rotterdam Malaria Cohort treated for severe P. falciparum malaria at the Institute for Tropical Diseases of the Harbour Hospital between 1999 and 2011 were included in this retrospective follow-up study. Both a two-stage approach and a log-linear mixed model approach were used to estimate parasite clearance times (PCTs) in patients with imported malaria. Severe malaria was defined according to WHO criteria.
RESULTS:
A total of 87 patients with severe malaria was included; 61 received intravenous quinine, whereas 26 patients received intravenous artesunate. Thirty-nine patients received ET as an adjunct treatment to either quinine (n = 23) or artesunate (n = 16). Data from 84 of 87 patients were suitable for estimation of parasite clearance rates. PCTs were significantly shorter after administration of artesunate as compared with quinine. In both models, ET did not contribute significantly to overall parasite clearance.
CONCLUSION:
Manual exchange transfusion does not significantly contribute to parasite clearance in artesunate-treated individuals. There may be a small effect of ET on parasite clearance under quinine treatment. Institution of ET to promote parasite clearance in settings where artesunate is available is not recommended, at least not with manually executed exchange procedures....(more)
Kreeftmeijer-Vegter AR, et al. Malar J 2013 Mar 27;12:115.
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- 21. Artesunate has its enhancement on antibacterial activity of β-lactams via increasing the antibiotic accumulation within methicillin-resistant Staphylococcus aureus (MRSA).
Methicillin-resistant Staphylococcus aureus (MRSA) has now emerged as a predominant and serious pathogen because of its resistance to a large group of antibiotics, leading to high morbidity and mortality. Therefore, to develop new agents against resistance is urgently required. Previously, artesunate (AS) was found to enhance the antibacterial effect of β-lactams against MRSA. In this study, AS was first found to increase the accumulation of antibiotics (daunorubicin and oxacillin) within MRSA by laser confocal microscopy and liquid chromatography-tandem MS method, suggesting the increased antibiotics accumulation might be related to the enhancement of AS on antibiotics. Furthermore, AS was found not to destroy the cell structure of MRSA by transmission electron microscope. AS was found to inhibit gene expressions of important efflux pumps such as NorA, NorB and NorC, but not MepA, SepA and MdeA. In conclusion, our results showed that AS was capable of enhancing the antibacterial activity of β-lactams via increasing antibiotic accumulations within MRSA through inhibiting gene expressions of efflux pumps such as NorA, NorB and NorC, but did not destroy the cell structure of MRSA. AS could be further investigated as a candidate drug for treatment of MRSA infection.The Journal of Antibiotics advance online publication, 3 April 2013; doi:10.1038/ja.2013.22....(more)
Jiang W, et al. J Antibiot (Tokyo) 2013 Apr 3.
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- 22. Reversible audiometric threshold changes in children with uncomplicated malaria.
Background. Plasmodium falciparum malaria, as well as certain antimalarial drugs, is associated with hearing impairment in adults. There is little information, however, on the extent, if any, of this effect in children, and the evidence linking artemisinin combination therapies (ACTs) with hearing is inconclusive. Methods. Audiometry was conducted in children with uncomplicated malaria treated with artesunate-amodiaquine (n = 37), artemether-lumefantrine (n = 35), or amodiaquine (n = 8) in Accra, Ghana. Audiometry was repeated 3, 7, and 28 days later and after 9 months. Audiometric thresholds were compared with those of a control group of children (n = 57) from the same area. Findings. During the acute stage, hearing threshold levels of treated children were significantly elevated compared with controls (P < 0.001). The threshold elevations persisted up to 28 days, but no differences in hearing thresholds were evident between treated children and controls after 9 months. The hearing thresholds of children treated with the two ACT regimens were comparable but lower than those of amodiaquine-treated children during acute illness. Interpretation. Malaria is the likely cause of the elevated hearing threshold levels during the acute illness, a finding that has implications for learning and development in areas of intense transmission, as well as for evaluating potential ototoxicity of new antimalarial drugs....(more)
Adjei GO, et al. J Trop Med 2013;2013:360540.
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- 23. Investigation of Hydrogen Sulfide Gas as a Treatment against P. falciparum, Murine Cerebral Malaria, and the Importance of Thiolation State in the Development of Cerebral Malaria.
INTRODUCTION:
Cerebral malaria (CM) is a potentially fatal cerebrovascular disease of complex pathogenesis caused by Plasmodium falciparum. Hydrogen sulfide (HS) is a physiological gas, similar to nitric oxide and carbon monoxide, involved in cellular metabolism, vascular tension, inflammation, and cell death. HS treatment has shown promising results as a therapy for cardio- and neuro- pathology. This study investigates the effects of fast (NaHS) and slow (GYY4137) HS-releasing drugs on the growth and metabolism of P. falciparum and the development of P. berghei ANKA CM. Moreover, we investigate the role of free plasma thiols and cell surface thiols in the pathogenesis of CM.
METHODS:
P. falciparum was cultured in vitro with varying doses of HS releasing drugs compared with artesunate. Growth and metabolism were quantified. C57Bl/6 mice were infected with P. berghei ANKA and were treated with varying doses and regimes of HS-releasing drugs. Free plasma thiols and cell surface thiols were quantified in CM mice and age-matched healthy controls.
RESULTS:
HS-releasing drugs significantly and dose-dependently inhibited P. falciparum growth and metabolism. Treatment of CM did not affect P. berghei growth, or development of CM. Interestingly, CM was associated with lower free plasma thiols, reduced leukocyte+erythrocyte cell surface thiols (infection day 3), and markedly (5-fold) increased platelet cell surface thiols (infection day 7).
CONCLUSIONS:
HS inhibits P. falciparum growth and metabolism in vitro. Reduction in free plasma thiols, cell surface thiols and a marked increase in platelet cell surface thiols are associated with development of CM. HS drugs were not effective in vivo against murine CM....(more)
Dellavalle B, et al. PLoS One 2013;8(3):e59271.
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- 24. High-level semi-synthetic production of the potent antimalarial artemisinin.
In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price....(more)
Paddon CJ, et al. Nature 2013 Apr 25;496(7446):528-32.
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- 25. Potent Antimalarial 1,2,4-Trioxanes through Perhydrolysis of Epoxides.
Perhydrolysis of a sterically congested multifunctional epoxide was achieved in ethereal H2 O2 with the aid of a recently developed Mo catalyst. The resulting hydroperoxide cyclized to give a 1,2,4-trioxane, which could be readily elaborated into qinghaosu and a range of novel analogues. Some of the compounds with two such trioxane moieties showed in vitro antimalarial activity comparable to or even better than that of artesunate or chloroquine....(more)
Hao HD, et al. Chemistry 2013 Apr 9.
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- 26. Evaluation of the immunosuppressive activity of artesunate in vitro and in vivo.
Artemisinin and its derivatives have been reported to have immunosuppressive activity in some laboratory studies. However, the detail of mechanism remains to be demonstrated. The objective of this study is to clarify the immunosuppressive activity of artesunate (AST), one kind of artemisinin derivatives, and to find its unexplored mode of action. In vitro, the proliferation of T lymphocytes and its cytotoxicity were measured by WST-1 and MTT assay. In vivo, the immunomodulatory effect of AST was evaluated in a mouse model of delayed type hypersensitivity reaction (DTH), which was based on a T cell-mediated immune response. The data displayed that AST had a relatively high immunosuppressive activity with low toxicity, and could inhibit T lymphocyte proliferation induced by mitogen and alloantigen. Meanwhile, topical administration of AST could suppress DTH response significantly. Moreover, AST could also increase the secretion of TFG-β, coupling with the striking enhance of NF-κB/p65 and Smad2/3 signaling. The promotion of CD4<sup>+</sup>CD25<sup>+</sup> regulatory T cells (Tregs) was shown to be a possible mechanism involved in AST-mediated regulation. Taken together, these observations exhibit the potential of developing AST as a novel safe remedy for the treatment of T cell-mediated immune disorders....(more)
Li T, et al. Int Immunopharmacol 2013 Apr 10.
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- 27. Beneficial effects of artichoke leaf extract supplementation on increasing HDL-cholesterol in subjects with primary mild hypercholesterolaemia: a double-blind, randomized, placebo-controlled trial.
The aim of this study was to evaluate the effects of artichoke leaf extract (ALE) supplementation (250 mg, 2 b.i.d.) on the lipid pattern. A randomized, double-blind, placebo-controlled clinical trial was performed on 92 overweight subjects with primary mild hypercholesterolaemia for 8 weeks. Forty-six subjects were randomized to supplementation (age: 54.2 ± 6.6 years, body mass index (BMI): 25.8 ± 3.9 kg/m(2), male/female: 20/26) and 46 subjects to placebo (age: 53.8 ± 9.0 years, BMI: 24.8 ± 1.6 kg/m(2), male/female: 21/25). Verum supplementation was associated with a significant increase in mean high-density lipoprotein (HDL)-cholesterol (p < 0.001) and in mean change in HDL-cholesterol (HDL-C) (p = 0.004). A significantly decreased difference was also found for the mean change in total cholesterol (p = 0.033), low-density lipoprotein (LDL)-cholesterol (p < 0.001), total cholesterol/HDL ratio (p < 0.001) and LDL/HDL ratio (p < 0.001), when verum and placebo treatment were compared. These results indicate that ALE could play a relevant role in the management of mild hypercholesterolaemia, favouring in particular the increase in HDL-C, besides decreasing total cholesterol and LDL-cholesterol....(more)
Rondanelli M, et al. Int J Food Sci Nutr 2013 Feb;64(1):7-15.
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- 28. Artichoke leaf extract for treating hypercholesterolaemia.
BACKGROUND:
Hypercholesterolaemia is directly associated with an increased risk for coronary heart disease and other sequelae of atherosclerosis. Artichoke leaf extract (ALE) has been implicated in lowering cholesterol levels. Whether ALE is truly effective for this indication is still a matter of debate. This is an update of a review first published in 2002 and last updated in 2009.
OBJECTIVES:
To assess the efficacy and safety of ALE in the treatment of hypercholesterolaemia.,
SEARCH METHODS:
We updated searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) (2012, Issue 5); MEDLINE Ovid (1966 to May Week 2, 2012); EMBASE Ovid (1980 to 2012 Week 19); and CINAHL Ebsco (1982 to May 2012) on 17 May 2012. CISCOM was last searched until June 2001, and AMED until June 2008. We checked reference lists of articles, and contacted manufacturers of preparations containing artichoke extract, and experts on the subject. No language restrictions were applied.
SELECTION CRITERIA:
We included randomised controlled trials (RCTs) of ALE mono-preparations compared with placebo or reference medication for patients with hypercholesterolaemia. We excluded trials assessing ALE as one of several active components in a combination preparation or as a part of a combination treatment.
DATA COLLECTION AND ANALYSIS:
Data were extracted systematically and risk of bias was evaluated using the Cochrane 'Risk of bias' tool. Two authors independently performed the screening of studies, selection, data extraction and assessment of risk of bias. Disagreements in the evaluation of individual trials were resolved through discussion.
MAIN RESULTS:
We included three RCTs involving 262 participants. The trials were of adequate methodological quality but had some shortcomings. One trial was at low quality of risk, one at medium and one of unclear risk of bias. One trial is available as abstract only and includes a small sample. In the first trial the total cholesterol level in participants receiving ALE decreased by 4.2% from 7.16 (0.62) mmol/L to 6.86 (0.68) mmol/L after 12 weeks, and increased from 6.90 (0.49) mmol/L to 7.04 (0.61) mmol/L in patients receiving placebo, the total difference being statistically significant (P = 0.025). In the second trial ALE reduced total cholesterol levels by 18.5% from 7.74 mmol/L to 6.31 mmol/L after 42 ± 3 days of treatment, whereas placebo reduced cholesterol by 8.6% from 7.69 mmol/L to 7.03 mmol/L (P = 0.00001). The third trial, which is available as abstract only and provides limited data, stated that ALE significantly reduced blood cholesterol compared with placebo in a subgroup of patients with baseline total cholesterol levels of more than 230 mg/dL (P < 0.05). Trial reports indicate mild, transient and infrequent adverse events.
AUTHORS' CONCLUSIONS:
Data from three clinical trials assessing ALE for treating hypercholesterolaemia are available. Athough the trials are of adequate methodological quality they have some shortcomings and one is available as abstract only. There is an indication that ALE has potential in lowering cholesterol levels, but the evidence is, as yet, not convincing. The limited data on safety suggest only mild, transient and infrequent adverse events with the short term use of ALE....(more)
Wider B, et al. Cochrane Database Syst Rev 2013 Mar 28;3:CD003335.
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- 29. Artichoke extract lowered plasma cholesterol and increased fecal bile acids in Golden Syrian hamsters.
A study was conducted in hamsters to determine if artichoke leaf extract (ALE) could lower plasma total and non-HDL cholesterol by increasing fecal excretion of neutral bile acids and sterols. Sixty-four Golden Syrian hamsters (8 week old) were fed control diet or a similar diet containing ALE (4.5 g/kg diet) for 6 weeks. No significant changes for total cholesterol, HDL, non-HDL cholesterol triglycerides or fecal neutral sterols and bile acids were found after 21 days for ALE-fed animals compared with controls. But after 42 days, ALE-fed male hamsters had significantly lower total cholesterol (15%), non-HDL cholesterol (30%) and triglycerides (22%) and female hamsters fed ALE showed reductions of 15% for total cholesterol, 29% for non-HDL cholesterol and 29% for triglycerides compared with controls. Total neutral sterol and bile acids concentrations increased significantly by 50% and 53% in fecal samples of ALE fed males, and 82.4% and 25% in ALE fed females compared with controls. The ALE lowered hamster plasma cholesterol levels by a mechanism involving the greater excretion of fecal bile acids and neutral sterols after feeding for 42 days....(more)
Qiang Z, et al. Phytother Res 2012 Jul;26(7):1048-52.
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- 30. Effect of zeolite nano-materials and artichoke (Cynara scolymus L.) leaf extract on increase in urinary clearance of systematically absorbed nicotine.
Nicotine, the main pharmacologically active component in tobacco and cigarette, has some toxic effects and also high potential for addiction. In this study, the effect of artichoke (Cynara scolymus L.) and zeolite nano-materials on urinary excretion of nicotine and consequently elimination of systematically absorbed nicotine was investigated. A simple, valid and highly sensitive high performance liquid chromatography method has been developed for determination of nicotine in rat urine according to guidelines for bioanalysis.It was found that nano-zeolites can cause increase in urinary concentration of nicotine due to its high surface adsorption. Artichoke leaf extract can cause increase in urinary excretion of nicotine in longer post administration times. It was observed that co-administration of nanozeolites and the leaf extract has the synergetic effect on increasing the urinary excretion of nicotine....(more)
Malekshah RE, et al. Arzneimittelforschung 2012 Dec;62(12):650-4.
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- 31. Effect on LDL-cholesterol of a large dose of a dietary supplement with plant extracts in subjects with untreated moderate hypercholesterolaemia: a randomised, double-blind, placebo-controlled study.
PURPOSE:
To determine the effect of 4 weeks of supplementation, then, withdrawal of a dietary supplement (DS) containing red yeast rice extract, policosanol and artichoke leaf extract at twice the recommended daily dose (6 tablets, 6-TAB) compared to the usual dose (3-TAB) or to a placebo (PLA), on blood lipid profiles and safety biomarkers.
METHODS:
Forty-five healthy subjects (15 per group), with untreated hypercholesterolaemia, were included in this randomised, double-blind, placebo-controlled clinical trial.
RESULTS:
After 4 weeks of supplementation, LDL-C was significantly lower in 6-TAB (-0.21 g/l; 95 % CI -0.38 to -0.03 g/l; p = 0.0217) and 3-TAB (-0.25 g/l; 95 % CI -0.42 to -0.07 g/l; p = 0.0071) compared to PLA, although no difference in LDL-cholesterol was observed between the two groups, while no effect was seen on triacylglycerol and HDL-cholesterol. Four weeks after the end of supplementation, no difference in LDL-C was seen between the PLA group and the DS-treated groups. The muscle breakdown biomarkers, as well as biomarkers of liver and renal function, were altered by neither dose of the DS. Acute application of the DS on permeabilised skeletal muscle fibres of rats did not induce deleterious effects on mitochondrial function.
CONCLUSIONS:
Supplementation with twice the recommended dose of the DS was effective in reducing LDL-cholesterol and appeared safe, but according to the present results, no additional benefit could be achieved compared to the recommended dose....(more)
Barrat E, et al. Eur J Nutr 2012 Dec 25.
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- 32. [Development and validation of method for the determination of cynarin, luteolin in plasma].
The aim of this study was to develop and validate the method of cynarin and luteolin, the main constituents of artichoke (Cynara scolymus L.) leaf extract, determination in plasma. The compounds were separated using the high-performance liquid chromatography technique with diode array detection (HPLC-DAD). The analysis was preceded by liquid-liquid extraction using as the extracting agent ethyl acetate. The HPLC separation was performed on C18 column under gradient conditions using a mobile phase - 0,05% trifluoroacetic acid in water and methanol. The detector was set at lambda=330 nm. The validation was related to linearity, sensitivity (LOD and LOQ), accuracy and repeatability. In the validated method the linearity was achieved within concentration range 1,5625 - 50,0 microg/cm3 for the cynarin (R2=0,9989) and 1,5625 - 200,0 microg/cm3 for the luteolin (R2=0998). The limits of detection for cynarin and luteolin was: 0,75 microg/cm3 and 0,1 microg/cm3 and the limits of quatification: 2,25 microg/cm3 and 0,2 microg/cm3, respectively. Coefficient of variation for the inter-day and the intra-day analysis, which is a precision and accuracy parameter, do not exceed 10%. Recovery was 67% for the cynarin and 96% for the luteolin. The practical application of this method was proved by analysis of plasma samples from rats. The animals were administrated artichoke leaf extract - orally and intraperitoneally at a dose of 3 g/kg body weight or pure substances - intraperitoneally at a dose 1 mg/kg of luteolin and 0,5 mg/kg of cynarin. The presence of investigated compounds was proved only in samples after intraperitoneal administration of pure substances. The developed method is used to determine simultaneously cynarin and luteolin, after intraperitoneal administration of pure compounds....(more)
Kulza M, et al. Przegl Lek 2012;69(10):987-91. Polish.
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- 33. Effect of artichoke leaf extract on hepatic and cardiac oxidative stress in rats fed on high cholesterol diet.
Hypercholesterolemia and lipid peroxidation play complementary roles in atherosclerosis. Artichoke (Cynara scolymus L., Asteraceae) leaf extract (ALE), rich in antioxidants, has cholesterol-reducing effect. We investigated the effect of ALE on serum and hepatic lipid levels and pro-oxidant-antioxidant balance in the liver and heart of hypercholesterolemic rats. Rats were fed on 4% (w/w) cholesterol and 1% cholic acid (w/w) supplemented diet for 1 month. ALE (1.5 g/kg/day) was given by gavage during the last 2 weeks. High cholesterol (HC) diet caused significant increases in serum and liver cholesterol and triglyceride levels. It increased malondialdehyde (MDA) and diene conjugate (DC) levels in both tissues. Hepatic vitamin E levels and hepatic and cardiac glutathione peroxidase (GSH-Px) activities decreased, but superoxide dismutase and glutathione transferase activities, glutathione, and vitamin C levels remained unchanged due to HC diet. Serum cholesterol and triglyceride levels and ratio of cholesterol to high-density lipoprotein (HDL)-cholesterol decreased in ALE plus HC-treated rats, but liver cholesterol and triglyceride levels remained unchanged. Significant decreases in hepatic and cardiac MDA and DC levels and increases in hepatic vitamin E and GSH-Px activities were observed in ALE-treated hypercholesterolemic rats. Our results indicate that ALE decreases serum lipids and hypercholesterolemia-induced pro-oxidant state in both tissues....(more)
Küçükgergin C, et al. Biol Trace Elem Res 2010 Jun;135(1-3):264-74.
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- 34. Artichoke leaf extract reduces oxidative stress and lipoprotein dyshomeostasis in rats fed on high cholesterol diet.
Hypercholesterolemia and lipid peroxidation play complementary role in atherosclerosis. Artichoke leaf extract (ALE) is rich in natural antioxidants and has a cholesterol-reducing effect. However, there is no study investigating the effect of ALE on lipid levels and lipid peroxidation in experimental hypercholesterolemic conditions. Rats were fed on 4% (w/w) cholesterol and 1% (w/w) cholic acid supplemented diet for 1 month. ALE (1.5 g/kg/day) was given by gavage during the last 2 weeks. Serum lipid composition, malondialdehyde (MDA) and diene conjugate (DC) levels and plasma antioxidant activity (AOA) were measured. In addition, endogenous DC and copper-induced MDA levels were determined in apo B-containing lipoproteins (LDL+VLDL fraction). Serum cholesterol and triglyceride levels and the ratio of cholesterol to HDL-cholesterol decreased due to ALE treatment in rats fed on HC diet. Significant decreases in serum MDA and DC levels and increases in plasma AOA were detected in serum in ALE-treated hypercholesterolemic rats. Endogenous DC and copper-induced MDA levels were also lower in LDL+VLDL fraction due to ALE-treatment in hypercholesterolemic rats. Our results indicate that ALE may be useful for the prevention of hypercholesterolemia-induced pro-oxidant state in LDL+VLDL fraction and the reduction of increased serum cholesterol and triglyceride levels....(more)
Küskü-Kiraz Z, et al. Phytother Res 2010 Apr;24(4):565-70.
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- 35. Effects of artichoke leaf extract on acute gastric mucosal injury in rats.
The present study was designed to clarify the effects of an ethanol extract of artichoke leaf on acute gastric mucosal injury in rats. Oral administration of artichoke leaf extract dose-dependently prevented absolute ethanol-induced (125-500 mg/kg) or restraint plus water immersion stress-induced gastric mucosal injury (1000-2000 mg/kg). The artichoke leaf extract contains 1% cynaropicrin and 0.8% chlorogenic acid as main components and 70% dextrin as a vehicle. Cynaropicrin at doses of 1/100 of artichoke leaf extract [ethanol-induced mucosal injury: 5 mg/kg, per os (p.o.); stress-induced mucosal injury: 20 mg/kg, p.o.] also prevented gastric mucosal injury in both animal models. However, dextrin and chlorogenic acid at doses contained in the leaf extract were ineffective in both models. When artichoke leaf extract was given orally to normal rats, it (500-2000 mg/kg, p.o.) dose-dependently increased gastric mucus content. In addition, it (125-500 mg/kg, p.o.) dose-dependently prevented the decrease in gastric mucus content by absolute ethanol. When the effects of artichoke leaf extract on basal gastric acid secretion in rats were evaluated, it (500-2000 mg/kg, p.o.) dose-dependently increased the volume of gastric juice in normal rats. However, it was ineffective in decreasing basal gastric acid secretion in normal rats. These results indicate that artichoke leaf extract is effective against acute gastritis and its beneficial effect is due to that of cynaropicrin. The gastric mucus-increasing action of artichoke leaf extract may be, at least in part, related to the anti-gastritic action of the extract....(more)
Ishida K, et al. Biol Pharm Bull 2010;33(2):223-9.
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