Pharmacokinetic study of praziquantel enantiomers and its main metabolite R-trans-4-OH-PZQ in plasma, blood and dried blood spots in Opisthorchis viverrini-infected patients

Praziquantel (PZQ) is the treatment of choice for infections with the liver fluke Opisthorchis viverrini, a major health problem in Southeast Asia. However, pharmacokinetic (PK) studies investigating the disposition of PZQ enantiomers (R- and S-PZQ) and its main metabolite, R-trans-4-OH-PZQ, in diseased patients are lacking. The implementation of a dried blood spot (DBS) sampling technique would ease the performance of PK studies in remote areas without clinical facilities. The aim of the present study is to provide data on the disposition of PZQ enantiomers and R-trans-4-OH-PZQ in opisthorchiasis patients and to validate the use of DBS compared to plasma and blood sampling.; PZQ was administered to nine O. viverrini-infected patients at 3 oral doses of 25 mg/kg in 4 h intervals. Plasma, blood and DBS were simultaneously collected at selected time points from 0 to 24 h post-treatment. PK parameters were determined using non-compartmental analysis. Drug concentrations and areas under the curve (AUC0-24h) measured in the 3 matrices were compared using Bland-Altman analysis. We observed plasma AUC0-24hs of 1.1, 9.0 and 188.7 μg/ml*h and half-lives of 1.1, 3.3 and 6.4 h for R-PZQ, S-PZQ and R-trans-4-OH, respectively. Maximal plasma concentrations (Cmax) of 0.2, 0.9 and 13.9 μg/ml for R-PZQ, S-PQZ and R-trans-4-OH peaked at 7 h for PZQ enantiomers and at 8.7 h for the metabolite. Individual drug concentration measurements and patient AUC0-24hs displayed ratios of blood or DBS versus plasma between 79-94% for R- and S-PZQ, and between 108-122% for R-trans-4-OH.; Pharmacodynamic (PD) in vitro studies on PZQ enantiomers and R-trans-4-OH-PZQ are necessary to be able to correlate PK parameters with efficacy. DBS appears to be a valid alternative to conventional venous sampling for PK studies in PZQ-treated patients

Stereoselective synthesis of the naturally occurring 2-pyranone dodoneine

The first total synthesis of the naturally occurring dihydropyranone dodoneine is reported. Asymmetric allylations were used for the stereoselective generation of the two stereogenic centers. The pyranone ring was created by means of a ringclosing metathesi

Financial Transmission Rights in Europe’s Electricity Market

After their theoretical development in the early 1990s, Financial Transmission Rights (FTRs) have been applied in restructured US electricity markets for about a decade now. Lately, FTRs have also been proposed as a potential feature of the emerging European electricity market. This paper reviews the crucial differences between FTRs and the currently implemented physical transmission rights (PTRs), and investigates the institutional and regulatory prerequisites for introducing FTRs in Europe. Also, the paper analyzes whether FTRs could be used as a means to replace existing transmission contracts (ETCs) in Europe. The paper concludes that the introduction of FTRs would imply a conceptual shift from the current self-scheduling and bilateral approach to cross-border trading in Europe, to a more central scheduling approach. The smoothest transition from PTRs to FTRs would be achieved by auctioning PTRs with a use-it-or-sell-it property and gradually phasing out their physical usage. As a prerequisite, the introduction of cross-border FTRs requires the integration of national markets through power exchanges. The resulting quasi-monopoly position of the power exchanges with respect to cross-border trading would require a tighter relationship between power exchanges and transmission system operators (TSOs) and a new regulatory approach to power exchanges, e.g., regulated fees. An introduction of regionally applied FTRs would also require a closer cooperation between national TSOs, especially with regard to the determination of a simultaneously feasible set of FTRs and a more detailed grid model reflecting the actual congestion situation. The paper argues that FTRs have not been subject to financial regulation in the past, as both their volume and their value are determined purely by the physical dispatch and network situation. Hence, any manipulation of FTRs would occur by manipulating the physical market, which is covered by energy regulation. Regarding ETCs, it is shown that FTRs can only cover their congestion cost aspect, while other ETC provisions related to transmission and energy supply can’t be accounted for by FTRs. As there are no historical entitlements to offsetting crossborder congestion cost in Europe (in the absence of ETCs), FTRs would not be allocated to load scheduling entities for free, but would be auctioned off with the auction proceeds being allocated to transmission owners or transmission investors, e.g. via Auction Revenue Rights (ARRs). Finally, further research is needed to determine the extent to which financial instruments such as futures are able to replace or complement FTRs for hedging cross-border congestion risk

Hydrophobically directed aldol reactions: polystyrene-supported L-proline as a recyclable catalyst for direct asymmetric aldol reactions in the presence of water

A simple synthetic methodology for the preparation of a polystyrene- supported L-proline material is reported, and this material has been used as catalyst in direct asymmetric aldol reactions between several ketones and arylaldehydes to furnish aldol products in high yields and stereoselectivities. Screening of solvents showed that these reactions take place only in the presence of water or methanol, at lower levels of conversion in the latter case. This solvent effect, coupled with the observed high stereoselectivities, has been ex- Introduction In the last decade organocatalysis has became a field of great interest.[1] Organocatalysts are metal-free small organic molecules that are able to function as efficient and selective catalysts for a large variety of enantioselective transformations. In this context, -proline and its derivatives have emerged as powerful organocatalysts.[2] -Proline can be regarded as the simplest “enzyme” and it has been successfully applied in many reactions, such as Robinson annulations,[3] aldol reactions,[4] Mannich reactions,[5] Michael reactions,[6] direct electrophilic α-aminations,[7] Diels– Alder reactions,[8] Baylis–Hillman reactions,[9] aza-Morita- Baylis–Hillman reactions,[10] α-selenenylation,[11] oxidation,[ 12] chlorination,[13] and others.[14] Among all these processes, -proline-mediated aldol reactions affording β-hydroxy ketones have been investigated in great depth. Indeed, the aldol reaction is one of the most important C–C bond-formation methods in organic synthesis.[ 15] Proline and its derivatives operate by bifunctional catalysis and play the role of a simplified version of the type I [a] Dipartimento di Chimica Organica “E.Paternò”, Università di Palermo, Viale delle Scienze, Pad. 17, 90128 Palermo, Italy Fax: +39-091-596825 E-mail: [email protected] © 2007 Wiley-VCH Verlag GmbH 4688 & Co. KGaA, Weinheim Eur. J. Org. Chem. 2007, 4688–4698 plained in terms of the formation of a hydrophobic core in the inner surface of the resin, whereas the hydrophilic proline moiety lies at the resin/water interface. Such a microenvironment both promotes the aldol reaction and increases the stereoselectivity. Recycling investigations have shown that this material can be reused, without loss in levels of conversion and stereoselectivity, for at least five cycles

The Missing Link between Coherence and Performance in Network Industries

The institutional governance of many network industries has been undergoing fundamental developments over the last two decades driven by liberalization efforts and industry restructuring programs aiming at an improvement of the sector performance. Experience has shown that one of the factors explaining the performance of network industries is the degree of coherence between the technology of the network and the institutions that govern the network. This paper examines the relationship between coherence and performance in network industries more closely and further develops the existing concepts. It is proposed that the missing link between coherence and performance is played by the concept of network constraints (capacity constraint, controllability constraint, interoperability and interconnection constraint). It is shown that the degree to which coherence is able to explain the performance of network industries depends on the sector-specific importance of network constraints. To get a better understanding of this dependency, several network sectors (electricity, gas, air traffic, rail, road, water, telecom, postal) are categorized according to the relevance of their network constraints. At the example of the European electricity and air traffic sectors, it is examined in more detail how (in)coherence affects sector performance, and it is illustrated why coherence is getting increasingly important to maintain or even improve sector performance

Towards a Total Synthesis of the Antibiotic Lysolipin I

The original objective of total syntheses was the ultimate proof of structures of natural products. Since this is now much more efficiently done by X-ray analysis, the scientific significance of such work should be shifted to the preparative aspect, which is based on good strategies and progress of synthetic methodology. This report summarizes our efforts directed to a total synthesis of the heptacyclic antibiotic lysolipin I. The crucial point of our synthetic strategy is the use of a cyclohexanone as precursor for the phenolic ring F. In addition to several other advantages, this saturated ring allows a stepwise build-up of steric strain and controls the diastereoselectivity by virtue of additional asymmetric centers relating the configurations of isolated centers of chirality. The scope and limitations of the access to 2-aryl-cyclohexanone derivatives by Michael-addition to p-quinones has been evaluated on a broad basis. A regioselective monoprotection of substituted hydroquinones could be achieved by reductive phosphorylation of p-quinones with phosphites. In relation to a different approach, a new method for the preparation of nitroaromatic compounds by cyclocondensation has been devised

Empirical Analysis of the Congestion Revenue Cycle in the European Electricity Market

In the light of the ongoing electricity market integration in Europe, the debate has turned to a more regional approach of network access. Among other things, this leads to new questions with regard to the handling of congestion revenues. This paper explores the importance of a comprehensive view at the Congestion Revenue Cycle, consisting of the three stages revenue generation, revenue distribution and revenue usage. The relationship between available capacity and congestion revenue is examined and the effect of several revenue distribution keys is empirically investigated. The findings show that a revenue distribution must consider revenue generation and revenue usage to achieve sustainable results

Evolution of Transmission Rights in the European Electricity Market

In the European electricity market, transmission rights currently evolve from a physical to a financial nature. This requires a fundamental change in the underlying market design and the institutional setup. This paper applies the framework of congestion revenue rights (CRRs) to physical and financial transmission rights, which allows a comprehensive view on the issue, including financial regulation. Based on this framework, two options for transmission price hedging in an integrated European electricity market are discussed

Sondeo arqueológico Cueva Pintada sector 13 [Material gráfico]

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 201