Synthesis of hydroperoxide and perketal derivatives of polyunsaturated fatty acids as potential antimalarial agents

Hydroperoxide derivatives of beta-oxa-substituted polyunsaturated fatty acids were prepared by 15-lipoxygenase catalysed oxidation and perketal derivatives of fatty acid hydroperoxides were synthesized. The perketals are more stable than their parent fatty acid hydroperoxides, but less active as antimalarial agents in the in vitro growth inhibition of Plasmodium falciparum. (C) 1998 Elsevier Science Ltd. All rights reserved.

Hepatic structure-pharmacokinetic relationships: The hepatic disposition and metabolite kinetics of a homologous series of O-acyl derivatives of salicylic acid

1 The hepatic disposition and metabolite kinetics of a homologous series of O-acyl (acetyl, propionyl, butanoyl, pentanoyl, hexanoyl and octanoyl) esters of salicylic acid (C2SA, C3SA, C4SA, C5SA, C6SA and C8SA, respectively) was determined using a single-pass, in-sills rat liver preparation. 2 The hepatic venous outflow profiles for the parent esters and the generated metabolite, salicylic acid (SA) were analysed by HPLC. Non-parametric moments analysis was used to determine the area under the curve (AUC'), mean transit time (MTT) and normalized variance (CV2) for the parent esters and generated SA. 3 Pregenerated SA ([C-14]-salicylic acid) was injected into each liver with the parent ester to determine its distribution characteristics. 4 The overall recovery of ester plus metabolite was 89% of the ester dose injected and independent of the ester carbon number, suggesting that ester extraction was due to hepatic metabolism to salicylic acid. 5 The metabolite AUC' value increased directly with the lipophilicity of the parent ester (from 0.12 for C2SA to 0.95 for C8SA). By contrast, the parent AUC' decreased with the lipophilicity (from 0.85 for C2SA to zero for C8SA). The metabolite MTT value also showed a trend to increase with the lipophilicity of the parent ester (from 15.72 s for C3SA to 61.97 s for C8SA). However, the parent MTT value shows no significant change across the series. 6 The two-compartment dispersion model was used to derive the kinetic parameters for parent ester, pregenerated SA and generated SA. Consequently, these parameters were used to estimate the values of AUG', MITT and CV2 for the parent ester and metabolite. The moments values obtained using the two-compartment dispersion model show similar trends to the corresponding moments values obtained from the outflow profiles using a non-parametric approach. 7 The more lipophilic aspirin analogues are more confined to the portal circulation after oral administration than aspirin due to their more extensive hepatic elimination avoiding systemic prostacyclin inhibition. Given that aspirin's selectivity as an anti-thrombotic agent has been postulated to be due to selective anti-platelet effects in the portal circulation, the more lipophilic and highly extracted analogues are potentially more selective anti-thrombotic agents than aspirin.

Adsorption characteristics of phenolic compounds onto coal-reject-derived adsorbents

Carbonaceous adsorbents were prepared by heat treatment of coal reject at 600 degrees C, after chemical treatment in HNO3, H2SO4, and NaOH at 25 and 75 degrees C. Pore structure characterization and the phenol adsorption capacities of the adsorbents showed that nitric acid pretreatment significantly enhanced the surface properties, consequently the adsorption capacities of the adsorbents. A number of samples were subsequently prepared by carbonizing coal reject at 600 degrees C, after pretreatment in HNO3 under various conditions. The acid concentration, residence time, and reaction temperature were varied to obtain adsorbents with various pore structures. The adsorption capacities of the derived adsorbents for phenol, p-nitrophenol, and benzene were measured to gain further insights into the pore structure evolution. Adsorption isotherms of phenol, p-nitrophenol, and p-chlorophenol on the best adsorbent prepared were determined and correlated with theoretical isotherm equations, such as the Langmuir, Freundlich, and Redlich-Peterson equations.

Focused antithrombotic therapy: Novel anti-platelet salicylates with reduced ulcerogenic potential and higher first-pass detoxification than aspirin in rats

The use of aspirin as an anti-platelet drug is limited by its propensity to induce gastric injury and by its adverse effect on vascular prostacyclin formation. Two phenolic non-steroidal anti-inflammatory drugs (salicyclic acid and diflunisal) were modified by esterification with a series of O-acyl moieties. The short-term ulcerogenic in vitro and in vivo anti-platelet properties, pharmacodynamic profiles, and extent of hepatic extraction of these phenolic esters were compared with aspirin (acetylsalicylic acid). The more lipophilic esters (longer carbon chain length in O-acyl group) show significantly less gastrotoxicity in stressed rats than does aspirin after a single oral dose. The in vitro and in vivo anti-platelet studies show that these phenolic esters inhibited (1) arachidonate-triggered human platelet aggregation and (2) thrombin-stimulated rat serum thromboxane Ag production by platelets in the clotting process almost as effectively as aspirin. The hepatic extractions of these O-acyl derivatives are significantly higher than those of aspirin. The pharmacodynamic studies show that these O-acyl derivatives of salicylic acid and diflunisal probably bind to, or combine with, the same site on the platelet cyclooxygenase as aspirin. Replacing the O-acetyl group with longer chain O-acyl moiety in this series of phenolic esters markedly reduced the potential of these agents to induce short-term gastric injury but did not lessen their activity as inhibitors of platelet aggregation. These non-acetyl salicylates may therefore represent a novel class of anti-platelet drugs with less ulcerogenic potential.

Absorption of sunscreens across human skin: an evaluation of commercial products for children and adults

Aims Topical sunscreens are routinely applied to the skin by a large percentage of the population. This study assessed the extent of absorption of a number of common chemical sunscreen agents into and through human skin following application of commercially available products. Methods Sunscreen products were applied to excised human epidermis in Franz diffusion cells with the amount penetrating into and across the epidermis assessed by h.p.l.c. for 8 h following application. Results All sunscreen agents investigated penetrated into the skin (0.25 g m(-2) or 14% of applied dose), but only benzophenone-3 passed through the skin in significant amounts (0.08 g m(-2) or 10% of the applied dose). With one exception, suncreen agents in corresponding products marketed for adults and children had similar skin penetration profiles. Conclusions Whilst limited absorption across the skin was observed for the majority of the sunscreens tested, benzophenone-3 demonstrated sufficiently high penetration to warrant further investigation of its continued application.

Reverse transcription of a naturally occurring nonretroviral RNA produces a precise deletion in the majority of its cDNA products

A precise, reproducible deletion made during in vitro reverse transcription of RNA2 from the icosahedral positive-stranded Helicoverpa armigera stunt virus (Tetraviridae) is described. The deletion, located between two hexamer repeats, is a 50-base sequence that includes one copy of the hexamer repeat. Only the Moloney murine leukemia virus reverse transcriptase and its derivative Superscript I, carrying a deletion of the carboxy-terminal RNase H region, showed this response, indicating a template-switching mechanism different from one proposed that involves a RNase H-dependent strand transfer, Superscript II, however, which carries point mutations to reduce RNase H activity, does not cause a deletion. A possible mechanism involves the enzyme pausing at the 3' side of a stem-loop structure and the 3' end of the nascent DNA strand separating from the template and reannealing to the upstream hexamer repeat.

Identification of physiologically functional peptides in dairy products

A wide range of peptides produced from milk proteins have been demonstrated to produce a physiological response in model systems. These peptides may be released from intact proteins in the gastrointestinal tract by proteolytic digestion, but are also present in fermented products such as cheese and yogurt, as a result of the action of inherent proteases, such as plasmin, and/or bacterial proteases released by the starter culture. This study investigated the presence of peptides, previously reported to have bioactive properties, in commercially available yogurts and cheeses.

Phorbasin B and C: Novel diterpenes from a southern Australian marine sponge, Phorbas species

A southern Australian Phorbas sp. has yielded the novel diterpenes phorbasin B (2) and phorbasin C (3). Phorbasins B and C possess a hitherto unknown carbon skeleton, and their structures were assigned on the basis of detailed spectroscopic analyses.

Phoriospongin A and B: Two new nematocidal depsipeptides from the Australian marine sponges Phoriospongia sp and Callyspongia bilamellata

Bioassay-directed fractionation of two southern Australian sponges, Phoriospongia sp. and Callyspongia bilamellata, yielded two new nematocidal depsipeptides, identified as phoriospongins A (1) and B (2). The structures of the phoriospongins were determined by detailed spectroscopic analysis and comparison with the previously reported sponge depsipeptide cyclolithistide A (3), as well as ESIMS and HPLC analysis of acid hydrolysates. It is noteworthy that the unique and yet structurally related metabolites 1-3 are found in sponges spanning three taxonomic orders, Poescilosclerida, Haplosclerida, and Lithistida.

Development Resource Planning: Complexity of Product Development and the Capacity to Launch New Products

Overcommitment of development capacity or development resource deficiencies are important problems in new product development (NPD). Existing approaches to development resource planning have largely neglected the issue of resource magnitude required for NPD. This research aims to fill the void by developing a simple higher-level aggregate model based on an intuitive idea: The number of new product families that a firm can effectively undertake is bound by the complexity of its products or systems and the total amount of resources allocated to NPD. This study examines three manufacturing companies to verify the proposed model. The empirical results confirm the study`s initial hypothesis: The more complex the product family, the smaller the number of product families that are launched per unit of revenue. Several suggestions and implications for managing NPD resources are discussed, such as how this study`s model can establish an upper limit for the capacity to develop and launch new product families.

Demand elasticities for food products in Brazil: a two-stage budgeting system

The object of this article is to estimate demand elasticities for a basket of staple food important for providing the caloric needs of Brazilian households. These elasticities are useful in the measurement of the impact of structural reforms on poverty. A two-stage demand system was constructed, based on data from Household Expenditure Surveys (POF) produced by IBGE (The Brazilian Bureau of Statistics) in 1987/88 and 1995/96. We have used panel data to estimate the model, and have calculated income, own-price, and cross-price elasticities for eight groups of goods and services and, in the second stage, for 11 sub groups of staple food products. We estimated those elasticities for the whole sample of consumers and for two income groups.

Synthesis of new amphiphilic chlorin derivatives from protoporphyrin-IX dimethyl ester

A simple synthesis of new amphiphilic chlorin derivatives from protoporphyrin-IX dimethyl ester is reported.The preparation Of Such compounds is based in a straightforward methodology, which involves the Diels-Alder reaction of protoporphyrin-IX dimethyl ester with maleic anhydride followed by addition of nucleophilic species to the initially formed cycloadducts, a transformation, which is highly regioselective. Preliminary photophysical studies with the new compounds show that they meet adequate features for PDT applications. (c) 2008 Elsevier Ltd. All rights reserved.

The alpha-galactosyl derivatives of ganglioside GD(1b) are essential for the organization of lipid rafts in RBL-2H3 mast cells

Gangliosides are complex glycosphingolipids that are important in many biological processes. The present study investigated the role of gangliosides in the organization of lipid rafts in RBL-2H3 mast cells and in the modulation of mast cell degranulation via Fc epsilon RI. The role of gangliosides was examined using two ganglioside deficient cell lines (B6A4A2III-E5 and B6A4C1III-D1) as well as the parent cell line (RBL-2H3). All three cell lines examined express Fc epsilon RI, Lyn, Syk and LAT. However, only in RBL-2H3 cells were Fc epsilon RI, LAT and alpha-galactosyl derivatives of ganglioside GD(1b) mobilized to lipid raft domains following Fc epsilon RI stimulation. The inhibition of glycosphingolipid synthesis in RBL-2H3 cells also resulted in a decrease in the release of beta-hexosaminidase activity after Fc epsilon RI activation. The two mutant cell lines have a reduced release of beta-hexosaminidase activity after Fc epsilon RI stimulation, but not after exposure to calcium ionophore. These results indicate that the alpha-galactosyl derivatives of ganglioside GD(1b) are important in the initial events of Fc epsilon RI signaling upstream of Ca(2+) influx. Since the initial signaling events occur in lipid rafts and in the mutant cell lines the rafts are disorganized, these results also suggest that these gangliosides contribute to the correct assembly of lipid rafts and are essential for mast cell activation via Fc epsilon RI. (c) 2008 Published by Elsevier Inc.

Differential Toxicity of Disperse Red 1 and Disperse Red 13 in the Ames Test, HepG2 Cytotoxicity Assay, and Daphnia Acute Toxicity Test

Azo dyes are of environmental concern due to their degradation products, widespread use, and low-removal rate during conventional treatment. Their toxic properties are related to the nature and position of the substituents with respect to the aromatic rings and amino nitrogen atom. The dyes Disperse Red 1 and Disperse Red 13 were tested for Salmonella mutagenicity, cell viability by annexin V, and propidium iodide in HepG2 and by aquatic toxicity assays using daphnids. Both dyes tested positive in the Salmonella assay, and the suggestion was made that these compounds induce mainly frame-shift mutations and that the enzymes nitroreductase and O-acetyltransferase play an important role in the observed effect. In addition, it was shown that the presence of the chlorine substituent in Disperse Red 13 decreased the mutagenicity about 14 times when compared with Disperse Red 1, which shows the same structure as Disperse Red 13, but without the chlorine substituent. The presence of this substituent did not cause cytotoxicity in HepG2 cells, but toxicity to the water flea Daphnia similis increased in the presence of the chlorine substituent. These data suggest that the insertion of a chlorine substituent could be an alternative in the design of dyes with low-mutagenic potency, although the ecotoxicity should be carefully evaluated. (C) 2010 Wiley Periodicals, Inc. Environ Toxicol 26: 489-497, 2011.