Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults

ABSTRACT: BACKGROUND: Severe malaria is a medical emergency with high mortality. Prompt achievement of therapeutic concentrations of highly effective anti-malarial drugs reduces the risk of death. The aim of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous artesunate in Ugandan adults with severe malaria. METHODS: Fourteen adults with severe falciparum malaria requiring parenteral therapy were treated with 2.4 mg/kg intravenous artesunate. Blood samples were collected after the initial dose and plasma concentrations of artesunate and dihydroartemisinin measured by solid-phase extraction and liquid chromatography-tandem mass spectrometry. The study was approved by the Makerere University Faculty of Medicine Research and Ethics Committee (Ref2010-015) and Uganda National Council of Science and Technology (HS605) and registered with ClinicalTrials.gov (NCT01122134). RESULTS: All study participants achieved prompt resolution of symptoms and complete parasite clearance with median (range) parasite clearance time of 17 (8-24) hours. Median (range) maximal artesunate concentration (Cmax) was 3260 (1020-164000) ng/mL, terminal elimination half-life (T1/2) was 0.25 (0.1-1.8) hours and total artesunate exposure (AUC) was 727 (290-111256) ngh/mL. Median (range) dihydroartemisinin Cmax was 3140 (1670-9530) ng/mL, with Tmax of 0.14 (0.6 - 6.07) hours and T1/2 of 1.31 (0.8-2.8) hours. Dihydroartemisinin AUC was 3492 (2183-6338) ngh/mL. None of the participants reported adverse events. CONCLUSIONS: Plasma concentrations of artesunate and dihydroartemisinin were achieved rapidly with rapid and complete symptom resolution and parasite clearance with no adverse events.     

AB-QTL analysis reveals new alleles associated to proline accumulation and leaf wilting under drought stress conditions in barley (Hordeum vulgare L.)

ABSTRACT: BACKGROUND: Land plants have evolved several measures to maintain their life against abiotic stresses. The accumulation of proline is the most generalized response of plants under drought, heat or salt stress conditions. It is known as an osmoprotectant which also acts as an instant source of energy during drought recovery process. But, both its role and genetic inheritance are poorly understood in agriculture crops. In the present work, advanced backcross quantitative trait locus (AB-QTL) analysis was performed to elucidate genetic mechanisms controlling proline accumulation and leaf wilting in barley under drought stress conditions. RESULTS: The analysis revealed eight QTL associated to proline content (PC) and leaf wilting (WS). QTL for PC were localized on chromosome 3 H, 4 H, 5 H and 6 H. The strongest QTL effect QPC.S42.5 H was detected on chromosome 5 H where drought inducible exotic allele was associated to increase PC by 54%. QTL effects QPC.S42.3 H, QPC.S42.4 H and QPC.S42.6 H were responsible to heighten PC due to the preeminence of elite alleles over the exotic alleles which ranged from 26% to 43%. For WS, QTL have been localized on chromosome 1 H, 2 H, 3 H and 4 H. Among these, QWS.S42.1 H and QWS.S42.4 H were associated to decrease in WS due to the introgression of exotic alleles. In addition, two digenic epistatic interaction effects were detected for WS where the additive effect of exotic alleles imparted a favorable increase in the trait value. CONCLUSIONS: The present data represents a first report on whole-genome mapping of proline accumulation and leaf wilting in barley. The detected QTL are linked to new alleles from both cultivated and wild accessions which bring out an initial insight on the genetic inheritance of PC and WS. These QTL alleles are fixed in the isogenic background of Scarlett, which will allow for positional cloning of underlying genes and to develop drought resilient barley cultivars.     

BIND – An algorithm for loss-less compression of nucleotide sequence data

Recent advances in DNA sequencing technologies have enabled the current generation of life science researchers to probe deeper into the genomic blueprint. The amount of data generated by these technologies has been increasing exponentially since the last decade. Storage, archival and dissemination of such huge data sets require efficient solutions, both from the hardware as well as software perspective. The present paper describes BIND-an algorithm specialized for compressing nucleotide sequence data. By adopting a unique 'block-length' encoding for representing binary data (as a key step), BIND achieves significant compression gains as compared to the widely used general purpose compression algorithms (gzip, bzip2 and lzma). Moreover, in contrast to implementations of existing specialized genomic compression approaches, the implementation of BIND is enabled to handle non-ATGC and lowercase characters. This makes BIND a loss-less compression approach that is suitable for practical use. More importantly, validation results of BIND (with real-world data sets) indicate reasonable speeds of compression and decompression that can be achieved with minimal processor/ memory usage. BIND is available for download at http://metagenomics.atc.tcs.com/compression/BIND. No license is required for academic or non-profit use.     

Fused heterocyclic amido compounds as anti-hepatitis C virus agents

We identified a fused heteroaromatic amido structure based on the phenanthridine skeleton as a superior scaffold for candidate drugs with potent anti-HCV activity. Among the compounds synthesized, a phenanthridine analogue with a 1,3-dioxolyl group (24) possessed the most potent anti-HCV activity (EC(50) value: 50 nM), with acceptable cytotoxicity. The structural development and structure-activity relationships of these compounds are described.     

Cardiac mitochondrial preconditioning by Big Ca2+-sensitive K+ channel opening requires superoxide radical generation

ATP-sensitive K+ channel opening in inner mitochondrial membranes protects hearts from ischemia-reperfusion (I/R) injury. Opening of the Big conductance Ca2+-sensitive K+ channel (BK(Ca)) is now also known to elicit cardiac preconditioning. We investigated the role of the pharmacological opening of the BK(Ca) channel on inducing mitochondrial preconditioning during I/R and the role of O2-derived free radicals in modulating protection by putative mitochondrial (m)BK(Ca) channel opening. Left ventricular (LV) pressure (LVP) was measured with a balloon and transducer in guinea pig hearts isolated and perfused at constant pressure. NADH, reactive oxygen species (ROS), principally superoxide (O2(-*)), and m[Ca2+] were measured spectrophotofluorometrically at the LV free wall using autofluorescence and fluorescent dyes dihydroethidium and indo 1, respectively. BK(Ca) channel opener 1-(2'-hydroxy-5'-trifluoromethylphenyl)-5-trifluoromethyl-2(3H)benzimid-axolone (NS; NS-1619) was given for 15 min, ending 25 min before 30 min of global I/R. Either Mn(III)tetrakis(4-benzoic acid)porphyrin (TB; MnTBAP), a synthetic dismutator of O2(-*), or an antagonist of the BK(Ca) channel paxilline (PX) was given alone or for 5 min before, during, and 5 min after NS. NS pretreatment resulted in a 2.5-fold increase in developed LVP and a 2.5-fold decrease in infarct size. This was accompanied by less O2(-*) generation, decreased m[Ca2+], and more normalized NADH during early ischemia and throughout reperfusion. Both TB and PX antagonized each preconditioning effect. This indicates that 1) NS induces a mitochondrial-preconditioned state, evident during early ischemia, presumably on mBK(Ca) channels; 2) NS effects are blocked by BK(Ca) antagonist PX; and 3) NS-induced preconditioning is dependent on the production of ROS. Thus NS may induce mitochondrial ROS release to initiate preconditioning.     

Bioavailability of hydroxycinnamates: a brief review of in vivo and in vitro studies

Hydroxycinnamates including p-coumaric acid, caffeic acid, ferulic acid, sinapic acid, and their esterified/etherified conjugates such as chlorogenic acids are abundant in cereals, coffee, fruit and vegetables. Studies have shown their potential in the prevention of chronic diseases such as cardiovascular disease and cancer. The impact of these dietary hydroxycinnamates on health depends on their bioavailability. In this article, in vivo and in vitro studies pertaining to bioavailability of hydroxycinnamates are reviewed and discussed. The chemical structures, existing forms, and/or doses of hydroxycinnamates may affect their metabolic fate. Limited studies suggest that the relative bioavailability of hydroxycinnamates may be in the following order: chlorogenic acid < rosmarinic acid < caffeic acid < ferulic acid < p-coumaric acid. Bound hydroxycinnamates generally have lower bioavailability than their monomer counterparts. Further pharmacokinetic and phamacodynamic studies are required to characterize the metabolism of hydroxycinnamates and their potential health impact in humans.     

Season effect on genitalia and epididymal sperm from Iberian red deer, roe deer and Cantabrian chamois

Seasonality deeply affects the physiology and behavior of many species, and must be taken into account when biological resource banks (BRBs) are established. We have studied the effect of seasonality on many reproductive parameters of free-ranging Iberian red deer, roe deer and Cantabrian chamois, living in Spain. Testicles from hunted animals were collected and sent to our laboratory at different times during the year. We recorded the weight and volume of testis, the weight of the epididymis and its separate parts (caput, corpus, and cauda), the weight of the sperm sample collected from the cauda epididymis, and several sperm parameters (sperm concentration, spermatozoa recovered, motility, HOS test reactivity, acrosomal status, and viability). We studied the data according to several periods, defined accordingly to each species. For red deer, we defined rut (mid-September to mid-October), post-rut (mid-October to mid-December), and non-breeding season (February). For roe deer, they were pre-rut (June), rut (July), post-rut (first fortnight of August), and non-breeding season (September). For chamois: non-breeding season (June to mid-September) and breeding season (October-November). The rut/breeding season yielded significantly higher numbers for almost all parameters. However, in the case of red deer, sperm quality was higher in the post-rut. For roe deer, testicular weight was similar in the pre-rut and in the rut, and sperm quality did not differ significantly between these two periods, although we noticed higher values in the rut. In the case of chamois, sperm quality did not differ significantly from the breeding season, but data distribution suggested that in the non-breeding season there are less males with sperm of good quality. On the whole, we find these results of interest for BRB planning. The best season to collect sperm in this species would be the breeding season. However, post-rut in red deer, pre-rut in roe deer, and non-breeding season in chamois could be used too, because of the acceptable sperm quality, despite the lower quantity salvaged. More in-depth research needs to be carried out on the quality of sperm salvaged at different times of the year in order to confirm these findings.     

Seaweed processing using industrial single-mode cavity microwave heating: a preliminary investigation

A single-cavity microwave heating system has been designed and fabricated for microwave-assisted extraction of carrageenans from seaweed. The system comprises a single mode (TE101) waveguide fitted with power and temperature controls, together with a continuous-flow-recycle reactor operating at atmospheric pressure. The system has been tested by extraction of E. cottonii and E. spinosum in aqueous organic solvents. Even without purification, the extraction products were found to have virtually identical FTIR and 13C and 1H NMR spectra to the reference samples of kappa- and iota-carrageenan, respectively. The principal advantages of the microwave system are substantial reduction of extraction time and low consumption of organic solvents.     

Heavy Metal Contamination of Soil,Plant and Air of Scrapyard of Discarded Vehicles at Zarqa City,Jordan

Ninety soil samples, forty plant samples (Anabasis articulata), and twenty air samples were collected from the scrap yard of discarded vehicles near Zarqa city, Jordan. These samples were analyzed for heavy metals: Cd, Pb, Zn, Cu, Mn, Al, and Fe. Longitudinal and vertical profiles of soil samples were studied. Generally, the levels of all heavy metals studied in the scrap yard area were found to be higher than those of the control samples. The levels of heavy metals decreased with depth until reaching a constant value at 9 cm depth. The levels of heavy metals also decreased at distances farther away from the scrap yard area. A significant difference in heavy metal concentrations was found between washed and unwashed plant samples. On the other hand, no significant differences have been found between plant samples from inside and outside the scrap yard area. Air samples showed wide variations in heavy metal levels among the sampling sites. The enrichment factors for non-crustal elements such as Pb, Cd, Cu, and Zn, in both soil and particulate matter, were found to be more than 10, indicating anthropogenic sources such as dust, rust, and exhaust emissions from the scrap yard area, whereas the crustal elements such as Fe and Mn showed enrichment factors of less than 10.