Experience gained from the application of GLP principles to multi-site studies in plant protection

The multi-site study (MSS) concept is not new and was already being used by the Swiss plant protection and pharmaceutical industries, across all areas of expertise, 11 years before the publication of the Organisation for Economic Co-operation and Development (OECD) Consensus Document No. 13. The need for this type of study set-up was and remains unavoidable, not only because of the way in which field studies for the determination of product residues in food are conducted in the plant protection industry, but also because of the fractionation of other study types ( e.g. toxicology studies) and the related subcontracting to contract labs as a consequence of insufficient capacity and/or lack of expertise as well as for cost reduction reasons. This paper deals with the historical background of the introduction of the MSS concept, its development, known facts, reasons for its extension to other areas, frequent difficulties in its daily implementation, regulatory and monitoring weaknesses, as well as, consequences and measures. Statements are corroborated by practical examples. Experience shows that there are weaknesses ( differences) among the various national Compliance Monitoring Authorities in charge of inspecting MMSs and there are still substantial differences from country to country regarding the interpretation and enforcement of GLP principles. Doubts are arising about the sense of OECD Mutual Joint Visits, and the mutual acceptance of data appears to be at jeopardy. A lot of time and patience is still needed to improve harmonisation at the international level so that GLP principles are followed uniformly across companies and countries. There is also the need for increased involvement of quality assurance units and Compliance Monitoring Authorities. Received: 18 October 2002 Accepted: 24 October 2002 Correspondence to P. Capon     

Towards measuring the ground state hyperfine splitting of antihydrogen – a progress report

We report the successful commissioning and testing of a dedicated field-ioniser chamber for measuring principal quantum number distributions in antihydrogen as part of the ASACUSA hyperfine spectroscopy apparatus. The new chamber is combined with a beam normalisation detector that consists of plastic scintillators and a retractable passivated implanted planar silicon (PIPS) detector.     

Aspergillazines A-E: novel heterocyclic dipeptides from an Australian strain of Aspergillus unilateralis

Biological and chemical profiling of an Australian strain of the fungus Aspergillus unilateralis(MST-F8675), isolated from a soil sample collected near Mount Isa, Queensland, revealed a complex array of metabolites displaying broad chemotherapeutic properties. Noteworthy among these metabolites were a unique series of highly modified dipeptides aspergillazines A-E, incorporating a selection of unprecedented and yet biosynthetically related heterocyclic systems. Co-occurring with the aspergillazines was the recently described marine-derived fungal metabolite trichodermamide A (cf. penicillazine), whereas re-fermentation of A. unilateralis in NaCl (1%) enriched media resulted in co-production of the only other known example of this structure class, the marine-derived fungal metabolite trichodermamide B. Further investigation of A. unilateralis returned the known terrestrial fungal metabolite viridicatumtoxin as the cytotoxic and antibacterial principle, together with E-2-decenedioic acid, ferulic acid, (7E,7'E)-5,5'-diferulic acid and (7E,7'E)-8,5'-diferulic acid. The aromatic diacids have previously been reported from the chemical and enzymatic (esterase) treatment of plant cell wall material, with their isolation from A. unilateralis being their first apparent reported occurrence as natural products. Structures for all metabolites were determined by detailed spectroscopic analysis and, where appropriate, comparison to literature data and/or authentic samples.     

Electrochemical and Theoretical Investigations of the Role of the Appended Base on the Reduction of Protons by [Fe(2) (CO)(4) (κ(2) -PNP(R) )(μ-S(CH(2) )(3) S] (PNP(R) ={Ph(2) PCH(2) }(2) NR, R=Me, Ph)

The behavior of [Fe(2) (CO)(4) (κ(2) -PNP(R) )(μ-pdt)] (PNP(R) =(Ph(2) PCH(2) )(2) NR, R=Me (1), Ph (2); pdt=S(CH(2) )(3) S) in the presence of acids is investigated experimentally and theoretically (using density functional theory) in order to determine the mechanisms of the proton reduction steps supported by these complexes, and to assess the role of the PNP(R) appended base in these processes for different redox states of the metal centers. The nature of the R substituent of the nitrogen base does not substantially affect the course of the protonation of the neutral complex by CF(3) SO(3) H or CH(3) SO(3) H; the cation with a bridging hydride ligand, 1?μH(+) (R=Me) or 2?μH(+) (R=Ph) is obtained rapidly. Only 1?μH(+) can be protonated at the nitrogen atom of the PNP chelate by HBF(4) ?Et(2) O or CF(3) SO(3) H, which results in a positive shift of the proton reduction by approximately 0.15?V. The theoretical study demonstrates that in this process, dihydrogen can be released from a η(2) -H(2) species in the Fe(I) Fe(II) state. When R=Ph, the bridging hydride cation 2?μH(+) cannot be protonated at the amine function by HBF(4) ?Et(2) O or CF(3) SO(3) H, and protonation at the N atom of the one-electron reduced analogue is also less favored than that of a S atom of the partially de-coordinated dithiolate bridge. In this situation, proton reduction occurs at the potential of the bridging hydride cation, 2?μH(+) . The rate constants of the overall proton reduction processes are small for both complexes 1 and 2 (k(obs) ≈4-7?s(-1) ) because of the slow intramolecular proton migration and H(2) release steps identified by the theoretical study.     

Citrinin revisited: from monomers to dimers and beyond

Detailed chemical analysis of the solid phase fermentation of an Australian Penicillium citrinum isolate has returned the known compounds citrinin (1), phenol A acid (6), dihydrocitrinone (7) and dihydrocitrinin (8), together with a novel cytotoxic dimer, dicitrinin A (5). Dicitrinin A (5) was determined to be a dimerised artefact of the major co-metabolite citrinin, and its structure solved by spectroscopic analysis and chemical modification. Analysis of the products encountered during the controlled decomposition of citrinin led to the discovery of additional citrinin dimers and delineated a plausible mechanistic pathway linking all monomeric and dimeric citrinin degradation products.