Coartem®: the journey to the clinic

Artemisinin, from which the artemether component of Coartem®(artemether/lumefantrine, AL) is derived, is obtained from the plant sweet wormwood (Artemisia annua) which has been used for over 2,000 years as a Chinese herbal remedy. Artemisinin was first identified by Chinese researchers as the active anti-malarial constituent of A. annua and its derivatives were found to be the most potent of all anti-malarial drugs. Artemether acts rapidly, reducing the infecting parasite biomass by approximately 10,000-fold per asexual life cycle. Lumefantrine, the other active constituent of AL, acts over a longer period to eliminate the residual 100-100,000 parasites that remain after artemether is cleared from the body and thus minimizes the risk of recrudescence. The two agents have different modes of action and act at different points in the parasite life cycle and show a synergistic action against Plasmodium falciparum in vitro. The combination of artemether and lumefantrine reduces the risk of resistance developing to either agent, and to date there are no reports of resistance to AL combined therapy in the malaria parasite that infects humans. Following a unique partnership agreement between Chinese authorities and Novartis, the manufacturer of AL, over 20 sponsored clinical studies have been undertaken in various malaria endemic regions and in travellers. These trials have involved more than 3,500 patients (including over 2,000 children), and led to identification of a six-dose, three-day regimen as the optimal dosing strategy for AL in uncomplicated falciparum malaria. AL has consistently shown 28-day polymerase chain (PCR)-corrected cure rates greater than 95% in the evaluable population, meeting WHO recommendations. More recently, Novartis and the Medicines for Malaria Venture have worked in partnership to develop Coartem® Dispersible, a new formulation designed specifically to meet the specific needs of children with malaria. The dispersible tablets have shown similar high response rates to those observed with crushed standard tablets of AL. A partnership agreement between Novartis and WHO has seen over 250 million AL (Coartem®) treatments (75% for children) being distributed to malaria patients in developing countries without profit, supported by training programmes and educational resources

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case–control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10–13) and African ancestries (rs2066702; P = 2.2 × 10–9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit–hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.</p

Methods, fluxes and sources of gas phase alkyl nitrates in the coastal air

The daily and seasonal atmospheric concentrations, deposition fluxes and emission sources of a few C3-C9 gaseous alkyl nitrates (ANs) at the Belgian coast (De Haan) on the Southern North Sea were determined. An adapted sampler design for low- and high-volume air-sampling, optimized sample extraction and clean-up, as well as identification and quantification of ANs in air samples by means of gas chromatography mass spectrometry, are reported. The total concentrations of ANs ranged from 0.03 to 85 pptv and consisted primarily of the nitro-butane and nitro-pentane isomers. Air mass backward trajectories were calculated by the Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model to determine the influence of main air masses on AN levels in the air. The shorter chain ANs have been the most abundant in the Atlantic/Channel/UK air masses, while longer chain ANs prevailed in continental air. The overall mean N fluxes of the ANs were slightly higher for summer than those for winter-spring, although their contributions to the total nitrogen flux were low. High correlations between AN and HNO2 levels were observed during winter/spring. During summer, the shorter chain ANs correlated well with precipitation. Source apportionment by means of principal component analysis indicated that most of the gas phase ANs could be attributed to traffic/combustion, secondary photochemical formation and biomass burning, although marine sources may also have been present and a contributing factor. © 2014 Springer International Publishing Switzerland

Molecular analyses of ostracod flocks from Lake Baikal and Lake Tanganyika

Ancient lakes are excellent laboratories for evolutionary research, where species can be studied in the cradle where they originated. In this article, we investigate two endemic ostracod species flocks from the two oldest lakes in the world, Lake Baikal (LB) (ca. 28 myr) and Lake Tanganyika (LT) (ca. 12 myr), with DNA sequence data. Nuclear ITS1 failed to resolve the phylogeny of both flocks. Whilst most phylogenetic relationships of the Tanganyika flock are resolved with mitochondrial COI, the Baikalian tree contains multifurications of up to seven different clades. The Tanganyikan Cyprideis flock shows higher genetic variability, which matches its higher morphological variability. A significant deviation from a constant divergence rate through time indicates that the Cytherissa flock most likely experienced explosive speciation events during its earlier history. Comparative analyses of substitution rates furthermore revealed that they are not clock-wise for COI. Ancestral Cytherissa probably radiated in LB 5-8 myr ago, around the time when the cold, oxygenated abyss was formed in LB. The Tanganyikan Cyprideis flock is almost twice as old as the Baikalian Cytherissa flock, and possibly older than LT itself, ca. 15 myr. The Cyprideis flock has survived drastic lake level changes and resulting salinity crises during its entire history.Marine & Freshwater Biology; Ancient lakes; Ostracods; Genetic variability; Phylogeny; Divergence rate