Strategies for multi-site GLP studies

 A GLP study can be performed at more than one site. This is called a multi-site study. Although, the study is performed at different sites, it is still one study and must completely comply with the GLP principles. The fact that different activities are conducted at different sites implies that the planning, the organization and the communication are crucial for the success of the study. This means that all the staff involved should know their responsibilities and should have the knowledge and skills to realize all the phases of the study according to the GLP principles. To achieve a well managed multi-site study, several strategies for setting up such a study can be followed. This paper focuses on the responsibilities, communication, and collaboration of the personnel, which are involved in a multi-site study. Several case studies are highlighted, and we concluded that the basic communication triangle in a single-site GLP study between test facility management, study director, and the quality assurance unit should be extended to the communication among test facility and test site management, study director, principle investigator(s), and the quality assurance units at the test sites. Introduction Received: 14 August 2002 Accepted: 26 November 2002     

A microwave-assisted click chemistry synthesis of 1,4-disubstituted 1,2,3-triazoles via a copper(I)-catalyzed three-component reaction

A microwave-assisted three-component reaction was used to prepare a series of 1,4-disubstituted-1,2,3-triazoles from corresponding alkyl halides, sodium azide, and alkynes. This procedure eliminates the need to handle organic azides, as they are generated in situ, making this already powerful click process even more user-friendly and safe.     

Conformational analysis of dimethylmethylphosphonate

The results of a CNDO/2 conformation analysis on dimethylmethylphosphonate are reported. Six stable conformers were found; their relative stabilities can be understood in terms of steric hindrance and gauche effect. Calculated barriers to internal rotation around P—O and O—C bonds are tabulated.     

Occurrence of chain folding in micelles : A C NMR relaxation and photophysical study

¹³CT₁ relaxation times for the different carbons of the sodium dodecyl sulphate chain in micellar systems have been measured, using Gd³⁺ as a paramagnetic relaxation reagent. The fluorescence decay of ω-(-naphthyl) dodecanoic acid, solubflized in the sodium dodecyl sulphate micelles was obtained in the presence of various amounts of counterion quencher Both series of experiments point to the occurrence of chain folding and to the fact that the terminal group can approach the Stern region of the micelle.     

The molecular structure of gaseous methyl vinyl ether at room temperature, studied by molecular orbital constrained electron diffraction and microwave spectroscopy

The gas phase molecular structure of methyl vinyl ether at room temperature has been studied by joint analysis of electron diffraction and microwave data. Constraints on geometrical and thermal parameters were derived from the geometry and force field of the s-cis form, obtained by ab-initio calculations (4–21 G basis set) after complete geometry relaxation. A range of models was investigated that fits all available data (infrared, microwave and electron diffraction). The following r_g/r-parameters were obtained: C=C: 1.337 Å, C(sp²)---O: 1.359 Å, C(sp³)---O: 1.427 Å, : 1.102 Å C=C---O : 127.3° and COC: 116.8°. Experimental r_g---r_e (ab initio) corrections are given for C=C, C(sp²)---O and Csp³)---O.

This investigation demonstrates that molecular orbital constrained electron diffraction is sufficiently reliable and in such a manner that it can be applied to more complicated problems.     

Mass spectrometric analysis of ceramide perturbations in brain and fibroblasts of mice and human patients with peroxisomal disorders

In this study, the levels and composition of ceramides in brains of newborn mice lacking peroxisomes (Pex5-/-, Zellweger mice) were analyzed using normal-phase high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry (HPLC/APCI-MS). Total ceramide compositions were found to be comparable to that of control animals. However, a minor ceramide species, containing hexacosanoic/hexacosenoic acid as the amide fatty acid, was 9-fold increased. Also, in the sphingomyelin-derived ceramides this species was elevated. Subsequent analysis of extracts from fibroblasts of Pex5-/- mice and mice with a defective peroxisomal beta-oxidation (lacking D-specific multifunctional protein 2 (MFP2)), revealed, again, a similar rise in this particular ceramide. Further, this ceramide was elevated in human X-ALD fibroblasts as well. Whether C26:1/0-ceramide is linked to some of the pathology seen in Zellweger syndrome remains to be investigated. However, an increase in this sphingolipid can be considered as a diagnostic criterion for diseases caused by defects in peroxisome biogenesis or peroxisomal beta-oxidation.     

Novel analogues of 3-substituted-2,3-dihydro-1,4-dioxino[2,3-b]pyridines: modifications in the dioxane ring

The synthesis of a series of novel analogues of the 3-substituted-2,3-dihydro-1,4-dioxino[2,3-b]pyridine core, modified in the non-aromatic ring, is described. Due to the presence of a versatile hydroxymethyl group in their structure, these novel scaffolds are attractive intermediates for the preparation of potential new therapeutic agents.     

Perfluormethyl-Element-Liganden. XXIX. Darstellung und spektroskopische Untersuchungen von M(CO)4L2-Komplexen (M = Cr,Mo, W; L = Me2PSMe,Me2PSeMe, (CF3)2PSMe, (CF3)2PSeMe)

Perfluoromethyl Element Ligands. XXIX. Preparation and Spectroscopic Investigation of M(CO)₄L₂ Complexes (M ? Cr, Mo, W; L ? Me₂PSMe, Me₂PSeMe, (CF₃)₂PSMe, (CF₃)₂PSMe) The complexes M(CO)₄L₂ (see Inhaltsübersicht) have been prepared by the reaction of tetracarbonyl norbornadiene metal compounds M(CO)₄NBD with L at room temperature or 35°C, respectively. The cis-complexes formed in the first step undergo rearrangement to trans-isomers at higher temperatures. New compounds have been characterized by analytical and spectroscopic (IR, NMR, MS) methods.     

In viva PHOTODYNAMIC EFFECTS OF PHTHALOCYANINES IN A SKIN-FOLD OBSERVATION CHAMBER MODEL: ROLE OF CENTRAL METAL ION AND DEGREE OF SULFONATION

Six sulfonated metallophthalocyanines, chelated with either aluminum or zinc and sulfonated to different degrees, were studied in vivo for their photodynamic activity in a rat skin-fold chamber model. The chamber, located on the back of female WAG/Rij rats, contained a syngeneic mammary carcinoma implanted into a layer of subcutaneous tissue. Twenty-four hours after intravenous administration of 2.5 μmol/kg of one of the dyes, the chambers received a treatment light dose of 600 J/cm² with monochromatic light of 675 nm at a power density of 100 mW/ cm². During light delivery and up to a period of 7 days after treatment, vascular effects of tumor and normal tissue were scored. Tumor cell viability was determined by histology and by reimplantation of the chamber contents into the skin of the same animal, either 2 h after treatment or after the 7 day observation period. Vascular effects of both tumor and subcutaneous tissue were strongest with dyes with the lowest degree of sulfonation and decreased with increasing degree of sulfonation. Tumor regrowth did not occur with aluminum phthalocyanine mono- and disulfonate and with zinc phthalocyanine monosulfonate. With the protocol that was used, complete necrosis without recovery was only observed when reimplantation took place at the end of the 7 day follow-up period. Reimplantation 2 h after treatment always resulted in tumor regrowth. At this interval, the presence of viable tumor cells was confirmed histologically. In general tumor tissue vasculature was more susceptible to photodynamic damage than vasculature of the normal tissue. The effect on the circulation of both tumor and normal tissue increased with decreasing degree of sulfonation. Based on this study, the photodynamic effects using the six sulfonated metallophthalocyanines on the vasculature can be ranked from high to low as: AlPcS₂= ZnPcS₁ > AIPcS₁ > AIPcS₄ > ZnPcS₂ > ZnPcS₄.     

Ionization of aqueous toluic acids: Conductance and thermodynamics

Conductivities of aqueous solutions ofortho-, meta-, andpara-toluic acids have been measured for the concentration range 0.1–2 millimolar and at 5° intervals from 5 to 100°C. At each temperature pK _a(m) andA ₀ have been calculated using the paired ion model recently described by Fuoss. Thermodynamic parameters have been calculated for the ionization of each acid, and Walden products for the anions. Results are discussed in terms of contributions to acidity by enthalpy and entropy changes as well as by hydration of the various solute species.