Experimental and clinical methods in the development of anti-Alzheimer drugs.

Methodology used for the development of anti-Alzheimer's disease (AD) drugs raises specific problems which are rarely examined in the literature. While the general development scheme is similar to that required for most drugs, some specific aspects must be analyzed, highly dominated by the dual goal of pharmacology, i.e., to obtain both symptomatic and etiopathogenic drugs. During preclinical studies, aged or lesioned animals are mainly useful for symptomatic drugs, whereas transgenic models or neurodegeneration-induced techniques would probably lead to etiopathogenic drugs potentially slowing down the process of AD. The first administrations of a new compound to human beings raise the question of the activity measurement techniques. Psychometry remains the most informative procedure to detect and analyze the activity of the drugs on the different components of cognition. Electrophysiology and neuroimaging need some complementary studies before they can be proposed as surrogate criteria in phase III trials. At this stage of development, American and the recently published European guidelines are of great help while insisting on long-term (6 months) placebo controlled trials with the use of the triple efficacy criterion: an objective cognition scale, a global assessment, and the opinion of the caregiver. In the long term, pharmacoepidemiology and pharmacoeconomy will have to confirm the rationale of this recent progress in the methodology of anti-AD drug development.

Water/n-octanol partition coefficients of 1,2-dithiole-3-thiones.

Water/n-octanol partition coefficients (log P) for 33 1,2-dithiole-3-thiones and for 18 1,2-dithiol-3-ones were determined by RP-HPLC measurement of the concentration of the solute in aqueous solution after equilibrium. Depending on the nature of the substituents (alkyl or aryl) and their position(s) (4,5, or both) on the dithiole nucleus, some peculiar behaviors were revealed. Therefore, different fragmental constants containing the 1,2-dithiole-3-thione nucleus were inferred in order to calculate in a complementary work, a priori, the log P values of new dithiolethiones and dithiolones.

[Drugs on the Internet. Hazards of public health]. / Médicaments sur Internet. Un enjeu de santé publique.

The development of internet and more generally of telematics has given rise to many practical consequences in medicine. Whatever the context (communication, medias, teaching, imaging or data transmissions), Internet appears as a familiar tool in many medical fields. However some drift with harmful consequences for public health is emerging. This is particularly true for drugs sales via Internet. The absence of any control by health authorities over Internet drug sales raises acute legal problems for jurists, pharmacists, pharmacologists and public health physicians. A debate on the main difficulties is urgently needed.

Integrated physical and genetic mapping of Bacillus cereus and other gram-positive bacteria based on IS231A transposition vectors.

The genome structure of Bacillus cereus is relatively complex, its DNA being modulated between a size-varying chromosome and large plasmids. To study the genetic organization of the B. cereus type strain ATCC 14579, thermosensitive transposition vectors were designed on the basis of IS231A-derived cassettes containing uncommon restriction sites. A highly preferred insertion site for IS231A was detected in the chromosome by Southern blotting and pulsed-field gel electrophoresis (PFGE) analyses of independent insertion mutants. However, once this insertional hot spot was occupied, secondary IS231A insertions occurred randomly, as demonstrated by isolation of independent B. cereus auxotrophs at a frequency of approximately 0.6%. The hot-spot site, as well as several auxotrophic mutations, were mapped by using NotI, SfiI, and AscI PFGE restriction profiles. It was confirmed by sequencing that one of the insertions, generating an Ade- phenotype, had disrupted a gene of the purine synthesis pathway. These results showed that combined PFGE and sequencing analyses of mini-IS231A insertions enable the construction of integrated physical and genetic maps of B. cereus type strain. Moreover, the presence of the ultrarare I-SceI restriction site in the mini-IS231A allowed the isolation, in double-insertion mutants, of contiguous and nonoverlapping large chromosomal fragments, convenient for direct sequencing. The system detailed in this report is therefore a powerful tool for comparative genetic studies among members of the B. cereus group (i.e., B. cereus, B. thuringiensis, B. mycoides, and B. anthracis) and could also be applied to more distantly related gram-positive bacteria.

Ionization constants of ginkgolide B in aqueous solution.

The thermodynamic ionization constants (pK(a)(1), pK(a)(2), and pK(a)(3)) of ginkgolide B (9H-1,7a-(epoxymethano)-1H,6aH-cyclopenta[c]furo[2,3-b]furo-[3',2':3,4]cyclopenta[1,2-d]furan-5,9,12-(4H)-trione, 3-tert-butylhexahydro-4,7b,11-trihydroxy-8-methyl-) in aqueous solution have been settled by pH-metric and NMR studies. The three macroscopic pK(a) values as well as the water solubility and the water/n-octanol partition coefficient have been extracted from pH-metric data by means of a nonlinear regression methodology. NMR spectroscopy provided confirmation of the values of the macroscopic constants, information about the effective ionization pathways, and an estimation of the proportions of the various forms under physiologically relevant conditions.