Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro

Aim: To study the pharmacokinetics of sifuvirtide, a novel anti-human immunodeficiency virus (HIV) peptide, in monkeys and to compare the inhibitory concentrations of sifuvirtide and enfuvirtide on HIV-1-infected-cell fusion. Methods: Monkeys received 1.2 mg/kg iv or sc of sifuvirtide. An on-line solid-phase extraction procedure combined with liquid chromatography tandem mass spectrometry (SPELC/MS/MS) was established and applied to determine the concentration of sifuvirtide in monkey plasma. A four-I-127 iodinated peptide was used as an internal standard. Fifty percent inhibitory concentration (IC50) of sifuvirtide on cell fusion was determined by co-cultivation assay. Results: The assay was validated with good precision and accuracy. The calibration curve for sifuvirtide in plasma was linear over a range of 4.88-5000 mu g/L, with correlation coefficients above 0.9923. After iv or sc administration, the observed peak concentrations of sifuvirtide were 10626 +/- 2886 mu g/L and 528 +/- 191 mu g/L, and the terminal elimination half-lives (T,12) were 6.3 +/- 0.9 h and 5.5 +/- 1.0 h, respectively. After sc, T-max was 0.25-2 h, and the absolute bioavailability was 49% +/- 13%. Sifuvirtide inhibited the syncytium formation between HIV-1 chronically infected cells and uninfected cells with an IC50 of 0.33 mu g/L. Conclusion: An on-line SPE-LC/MS/MS approach was established for peptide pharmacokinetic studies. Sifuvirtide was rapidly absorbed subcutaneously into the blood circulation. The T-1/2 of sifuvirtide was remarkably longer than that of its analog, enfuvirtide, reported in healthy monkeys and it conferred a long-term plasma concentration level which was higher than its IC50 in vitro.

Effects of irradiation on formaldehyde concentration and nutritional changes of formalin treated fish, Pampus chinensis

Formaldehyde is a very reactive compound capable of interacting with many functional groups of proteins including intermolecular and intramolecular cross-links of the molecules. The formation of cross-linking bonds may induce conformational change in proteins that favor further interaction of functional and hydrophobic groups. Formaldehyde which has been using illegally as a chemical preservative by some fish traders in our country. A study was carried out to determine the effects of irradiation (1.5 KGy) on formaldehyde concentration and nutritional (protein and lipid) changes of formalin (37% formaldehyde) treated fish (fresh) samples and found that the concentration of formaldehyde both in treated samples (0.37% formalin and 0.37% formalin with 1.5 KGy irradiation) were 37.0 µg/gm and 36.75 µg/gm. On the other hand, the amount of protein and lipid in treated samples before radiation (14.56% and 3.49%) and after radiation (14.15% and 3.25%). That means, radiation has no effect on the change of protein, lipid and formaldehyde.

Natural selection on EPAS1 (HIF2 alpha) associated with low hemoglobin concentration in Tibetan highlanders

By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200 3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2 alpha, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.

The successful double cryopreservation of rabbit (Oryctolagus cuniculus) semen in large volume using the directional freezing technique with reduced concentration of cryoprotectant

Using directional freezing, Our objective was to cryopreserve rabbit semen and achieve fertility that was equal or higher than that achieved with conventional freezing. The working hypothesis was that controlling the ice-front propagation would allow redu

Effect of bend orientation on life and puncture point location due to solid particle erosion of a high concentration flow in pneumatic conveyors

An investigation into predicting failure of pneumatic conveyor pipe bends due to hard solid particle impact erosion has been carried out on an industrial scale test rig. The bend puncture point locations may vary with many factors. However, bend orientation was suspected of being a main factor due to the biased particle distribution pattern of a high concentration flow. In this paper, puncture point locations have been studied with different pipe bend orientations and geometry (a solids loading ratio of 10 being used for the high concentration flow). Test results confirmed that the puncture point location is indeed most significantly influenced by the bend orientation (especially for a high concentration flow) due to the biased particle distribution and biased particle flux distribution. © 2004 Elsevier B.V. All rights reserved.

Effect of particle concentration on erosion rate of mild steel bends in a pneumatic conveyor

Particle concentration is known as a main factor that affects erosion rate of pipe bends in pneumatic conveyors. With consideration of different bend radii, the effect of particle concentration on weight loss of mild steel bends has been investigated in an industrial scale test rig. Experimental results show that there was a significant reduction of the specific erosion rate for high particle concentrations. This reduction was considered to be as a result of the shielding effect during the particle impacts. An empirical model is given. Also a theoretical study of scaling on the shielding effect, and comparisons with some existing models, are presented. It is found that the reduction in specific erosion rate (relative to particle concentration) has a stronger relationship in conveying pipelines than has been found in the erosion tester. © 2004 Elsevier B.V. All rights reserved.

The distribution and concentration levels of trace metals in water and sediments of Lake Victoria, Kenya

The water and bottom sediments of Lake Victoria (Kenya) were analysed for A1, Fe, Mn, Zn, Pb, Cu, Cr and Cd. The total metal concentrations were determined and their mean variations and distributions discussed. The bottom lake waters showed higher concentration levels than the surface waters. The range of values (in mg/l) in the bottom and surface lake waters were as follows: Surface Waters: A1(0.08 - 3.98), Fe(0.09 - 4.01), Mn(0.02 - 0.10). Zn(0.01 -0.07), Pb(0.001- 0.007), Cu(not detected - 0.006), Cr(not detected - 0.004). Bottom Waters: A1(0.1 0 - 6.59), Fe(0.23 - 9.64), Mn(0.04 - 0.39), Zn(0.01- 0.08), Pb(0.002 - 0.009), Cu(not detected - 0.03). Cr(not detected -0.002). River mouths and shallow areas in the lake showed higher total metal concentrations than offshore deeper areas. Apart from natural metal levels, varied urban activities and wastes greatly contribute to the lake metal pollution as shown by high Pb and Zn levels in sediments, around Kisumu and Homa Bay areas. Other comparatively high values and variations could be attributed to the varied geological characteristics of the lake and its sediments. Compared to the established W.H.O (1984) drinking water standards manganese, aluminium and iron levels were above these limits whereas zinc, lead, chromium, copper and cadmium were below.

Influence of leaf tissue structure on host feeding selection by pea leaf miner Liriomyza huidobrensis (Diptera : Agromyzidae)

Host feeding selection by the female pea leafminer, Liriomyza huidobrensis, on 47 species of plants was studied. The leaves were sectioned by microtome, and 15 characteristics of the leaf tissue structure were measured under a microscope. Correlation analysis between host feeding selection and leaf tissue structure indicated that the preference of host feeding selection was positively correlated with the percentage of moisture content of leaves and negatively with thickness of the epidermis wall, and densities of the palisade and spongy tissues of leaves. Leaf tissue structure was influential in feeding and probing behavior of female L. huidobrensis. So, thickness of epidermis wall, densities of the palisade and spongy tissues can act as a physical barrier to female oviposition. Furthermore, higher densities of palisade and spongy tissues can be considered a resistant trait which affects mining of leaf miner larvae as well. As a result, plants with lower leaf moisture content may not be suitable for the development of L. huidobrensis.