Biosynthesis of [ C]-11-De-O-Methyltomaymycin, a Precursor of Radiolabelled Antibody Drug Conjugates.

Antibody drug conjugates (ADCs) are one of the most promising technologies to treat cancer as they combine the specificity of an antibody with the high potency of a cytotoxic molecule such as tomaymycin derivatives, which are DNA-interactive antitumor antibiotics previously isolated from bacterial broth. The multistep chemical synthesis of some tomaymycin derivatives is complicated because their structures contain a reactive imine bond. Therefore, we turned to biosynthesis to obtain C radiolabelled tomaymycin derivative to support ADME studies.

Synthesis of stable isotope labelled internal standards for drug-drug interaction (DDI) studies.

The syntheses of stable isotope labelled internal standards of important CYP-isoform selective probes, like testosterone 1, diclofenac 3, midazolam 5, and dextromethorphan 7, as well as their corresponding hydroxylated metabolites 6β-hydroxytestosterone 2, 4'-hydroxydiclofenac 4, 1'-hydroxymidazolam 6 and dextrorphan 8 are reported. Microwave-enhanced H/D-exchange reactions applying either acid, base, or homogeneous and heterogeneous transition metal catalysis, or combinations thereof proved to be highly efficient for direct deuterium labelling of the above mentioned probes. Compared to conventional stepwise synthetic approaches, the combination of H/D exchange and biotransformation provides the potential for considerable time- and cost savings, in particular for the synthesis of the stable isotope labelled internal standards of 4'-hydroxydiclofenac 4 and 1'-hydroxymidazolam 6.

An improved method for specific and quantitative determination of the clopidogrel active metabolite isomers in human plasma.

Pharmacokinetic analyses of clopidogrel are hampered by the existence of multiple active metabolite isomers (H1 to H4) and their instability in blood. We sought to retest the pharmacodynamic activities of the four individual active metabolite isomers in vitro, with the ultimate aim of determining the isomers responsible for clopidogrel activity in vivo. In vitro activity was evaluated by measuring binding of [³³P]-2-methylthio-ADP on P2Y₁₂-expressing Chinese hamster ovary (CHO) cells and human platelets in platelet-rich plasma (PRP).

[Utero-ovarian actinomycosis and intrauterine contraceptive devices].

Up to now a rare affection difficult to diagnose in its abdominal localizations, actinomycosis is becoming of topical interest because of the appearance of a new form of the disease: utero-ovarian infection associated with an intra-uterine contraceptive device (IUD). A recent case, of surgical expression, is reported and used as a basis for an update of epidemiologic and pathogenic data concerning the affection. Diagnosis should be facilitated by regular cytobacteriologic examinations in women with the IUD, and simple preventive measures should limit the number of severe forms sometimes requiring more or less extensive excision.