[Affective mentalizing in Addictive Borderline Personality: A literature review]. / La mentalisation affective de la personnalité limite addictive : une revue de la littérature.

This literature review concerns affective mentalizing in borderline addictive personality. This concept postulates the group between addictions and borderline personalities may correspond to Personality Disorders (PDs). First, we will present conceptualizations and evaluations of affective mentalizing. The latter refers to one dimension of mentalization, a process by which an individual interprets his/her mental states and those of others. Lecours and Bouchard proposed a hierarchic model: the Élaboration verbale de l'affect (EVA). They also developed an empiric methodology: the Grille de l'élaboration verbale de l'affect (GEVA). The methodological approach of Lecours fulfils the requirements made by Cho-Kain, Gunderson and Luyten, involving a narrower operationalization of the mentalization concept through the evaluation of its dimensions. Conceptualizations and evaluations enabled focus on mentalization psychopathology. Fonagy and Bateman studied this latter in the subjects with PDs, particularly in Borderline Personality Disorders (BPD). We describe mentalization failure, its etiology and consequences in the BPD. Several forms of mentalization psychopathology are identified. Its etiology is largely environmental. Fonagy and Bateman developed the optimum developmental model of mentalization and referred to it to explain etiology of mentalization failure in BPD. Consequences of mentalization failure explicate its functioning. Mentalization may be considered as essential in their comprehension and their care. Research about mentalization of PDs does not integrate addiction as one comorbidity factor. However, Allen, Fonagy and Bateman describe a bidirectional interaction between mentalization failure and addiction. We propose to examine the mentalization of Borderline Addictive Personality. This concept groups addictions and borderline personalities in just one clinical entity other than their links of co-morbidities.

Mutagenicity and cytotoxicity of five antitumor ellipticines in mammalian cells and their structure-activity relationships in Salmonella.

The mutagenicity and cytotoxicity of five antitumor compounds (ellipticines) were investigated in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay and in six strains of Salmonella. All five compounds (ellipticine, 9-methoxyellipticine, 9-hydroxyellipticine, 9-aminoellipticine, and 2-methyl-9-hydroxyellipticinium) were cytotoxic and mutagenic in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay in the presence or absence of Aroclor 1254-induced rat liver S9, and all except the last compound were mutagenic in Salmonella. Based on the reversion pattern obtained in various frame-shift and DNA repair-proficient (uvrB+) or -deficient (uvrB) strains of Salmonella in the presence or absence of S9, the first three compounds appear to cause frame-shift mutations by both intercalation and covalent bonding with DNA; thus, these are classified as reactive intercalators. However, 9-aminoellipticine intercalates only weakly and may instead exert its mutagenic activity primarily (or exclusively) by forming a covalent adduct with DNA. Compared to the published antitumor data obtained in mice, the results in Salmonella and Chinese hamster ovary cells suggest that the ability of ellipticine, 9-methoxyellipticine, and 9-hydroxyellipticine to intercalate with DNA, induce frame-shift mutations, and cause cell killing is associated with and may be the basis for their antitumor activity. The observation that the ellipticines are mutagenic in mammalian cells suggests that these antitumor agents may be carcinogenic.

A class of strong inhibitors of microsomal monooxygenases: the ellipticines.

Ellipticine (E) and its 9-hydroxy derivative inhibit strongly various liver monooxygenase activities mediated by microsomes from control and phenobarbital (PB), benzo[alpha]pyrene (BP) or Aroclor 1254 (Aroclor)-pretreated rats. The inhibition constants, Ki, are remarkably low, and often smaller than 1 micron, particularly in the case of microsomes containing cytochrome P-448. The inhibitory potency (I50) of 9-hydroxyellipticine (9-OHE) is larger (about ten-fold) than the one of classical inhibitors (metyrapone or 7,8-benzoflavone (7,8-BF)), whatever the activities studied and the induction of microsomes. Differences exist between the mechanisms of inhibition according to the form of cytochrome P-450 present in microsomes of differently pretreated rats; whichever the activities studied, one observes: (a) a competitive inhibition towards the activity of non-induced or PB-induced microsomes and (b) a non-competitive inhibition towards the activity of Aroclor or BP-induced microsomes, at variance with 7,8-BF. These results are in good agreement with the interaction properties of the ellipticines with microsomal cytochromes P-450.

Ellipticines as potent inhibitors of microsomes-dependent chemical mutagenesis.

9-Hydroxyellipticine (9-OHE), an inhibitor of microsomal monooxygenase activities has been shown to exert a large or even complete decrease of the mutagenicity, on the Salmonella strains of a great number of compounds (aromatic amines, polycyclic aromatic hydrocarbons, fungal toxins, azo compounds, tobacco smoke condensate). 9-OHE and 9-fluoroellipticine are more potent inhibitors than ellipticine itself. The inhibitions exerted by 9-OHE are not even equalled by 10-fold higher doses of 7,8-benzoflavone (7,8-BF). There is a good correlation between these data and the interaction properties of ellipticines with microsomal cytochromes P-450.

Some antitumor derivatives of ellipticine deprived of mutagenic properties.

Seven derivatives of the antitumor alkaloid ellipticine were assayed for activity against murine leukaemia L1210 and for mutagenicity in Ames' Salmonella-microsomes test. Not only did the results show a complete lack of correlation between these two properties, but it was possible to choose a highly efficient analog which was completely devoid of mutagenic and hence, probably, carcinogenic effect. The lack of interaction of this product (2-methyl-9-hydroxyellipticinium acetate) with Cytochrome P-450 of hepatic monooxygenases prevents the formation of reactive intermediates and their subsequent binding to DNA. These data are discussed in view of the currently admitted mode of action of ellipticines i.e., intercalation in DNA and their therapeutic use.

Comparative cytotoxic and antitumoral effects of ellipticine derivatives on mouse L 1210 leukemia.

Twelve derivatives of the antitumoral alkaloid ellipticine (E) and ellipticinium were assayed in vitro on cultured L 1210 cells. These drugs possess varying abilities to decrease the cell growth rate in a 1--1000-fold range. Some of them have a highly cytotoxic effect in the 10(-8)--10(-6) M range. Non-specific intracellular damages are produced: multilobation of nuclei, occurrence of numerous lipid granules, diminution of the size and increase in the number of mitochondrial profiles and several modifications of the internal architecture of mitochondria. 2-Methyl-9-hydroxyellipticinium (2-CH3-9-OHE) was submitted to a bioassay; it inactivates the tumorigenic potency of the cells exposed to it, when they are grafted back into mice in the same dose range which reduces in vitro the growth rate of the cells. A fairly good correlation holds between the in vitro and in vivo (antitumor effect) assays, offering a possible prescreening test for a cheaper and rapid evaluation of chemotherapeutic activity of these compounds. The results stress again the importance of the 9-hydroxy substitution in these series for improving the anticancer efficiency. The nature of the biochemical target of E and derivatives is discussed according to our data.

A dual assay for the specific screening of 3-methylcholanthrene- and phenobarbital-like chemical inducers of cytochrome P-450 monooxygenases.

We present and evaluate a dual assay, the CYPIA (Cytochrome P-450 induction assay) for the detection and the simultaneous identification of chemicals belonging either to the 3-methylcholanthrene or phenobarbital classes of cytochrome P-450 monooxygenase inducers. These inducers play an important role in the mutagenic activation of chemical compounds as well as in many pharmacological and toxicological events and therefore should be screened by drug and chemical designers. After treatment of male rats or mice by chemicals, the liver preparations (S9) have been used in the Salmonella typhimurium test, to activate either ethidium bromide or cyclophosphamide into mutagenic metabolites. These transformations are specifically catalyzed by cytochrome P-450-dependent monooxygenases induced by 3-methylcholanthrene-like and phenobarbital-like chemical inducers, respectively. The mutagenicity data were strikingly correlated with other methods (production of [3H]benzo[a]pyrene bay-region metabolites, benzphetamine demethylase activity, immunological double-diffusion analysis). Compared to the latter methods, the CYPIA, based on a single and widespread technology, introduces an interesting simplification, and improves the specificity and the sensitivity of the responses.

Relative efficiencies of a series of square-planar plantinum(II) compounds on Salmonella mutagenesis.

Twelve Pt(II) compounds have been tested for mutagenicity on Salmonella typhimurium (strain TA 100). Very high mutagenic activities were found for the cis derivatives. A correlation is suggested between these results and a formerly described model of chemical reactivity towards DNA, according to which cis derivatives from intra-strand chelates with guanine. A smaller activity was found with monodentate complexes with DNA.

Synthesis of a 125I-labelled derivative of the antibiotic griseofulvin.

A derivative of griseofulvin has been synthesised, in which the 2'-O-methyl group is replaced by a 2'-(2-iodoethoxy), 125I-labelled group. This derivative is at least as potent as griseofulvin itself, when assayed for inhibition of growth on the Myxomycete Physarum polycephalum.

[Metabolism and pharmacokinetics of methoxy-9-ellipticine and its principal metabolite, hydroxy-9-ellipticine]. / Métabolisme et pharmacocinétique de la méthoxy-9-ellipticine et son métabolite principal, l'hydroxy-9-ellipticine.

The biliary and urinary excretion of 9-methoxyellipticine in Rats yield the 0-demethylated metabolite 9-hydroxyellipticine, partly present as the glucuronide. Whole blood kinetics of 9-methoxyellipticine in Rabbits following a single i.v. administration is extremely fast, but is deeply modified after repeated dosage.

Metabolism of ethidium bromide in rats.

The biliary excretion products recovered after iv administration of ethidium bromide to rats were found to consist of: unchanged drug, 8-acetylethidium, and an 8-acetylated hydroxylated metabolite. Proofs of structure were obtained by field desorption mass spectroscopy and 1H NMR, which indicated that the latter metabolite is probably substituted at position 2-. The yield of these various metabolites was critically influenced by pretreatment of the animals with inducers of the hepatic mixed function oxidases. Similar results were obtained in vitro, using various subfractions of differently pretreated rat liver. The role of each cellular fraction and order of completion of the acetylation and hydroxylation steps are determined and the putative occurrence of transient intermediates is discussed.

[Induction of rat hepatic mono-oxygenases by ellipticine: formation of cytochrome p448. Hydroxylating activity]. / Induction des mono-oxygénases hépatiques par l'ellipticine chez le Rat: Formation de cytochrome P448. Activité hydroxylante

Ellipticine is able to induce cytochrome P448 synthesis in Rat liver microsomes which converts the drug into 9-hydroxy derivative, with a higher rate than microsomal cytochrome P450 of non-treated or phenobarbital induced Rats. In vivo, ellipticine is also transformed into a second hydroxylated product on the indole aromatic ring.

Cytochrome P-450-mediated O-demethylation of two ellipticine derivatives. Differential effect of the murine Ah locus phenotype.

The O-demethylation of two antitumor drugs (9-methoxyellipticine and a 1-polyalkylamino-substituted analog) was studied by incubation with liver microsomes from rats and mice. The former drug underwent a cytochrome P1-450-independent biotransformation in mice, as shown by an indiscriminate response from individuals genetically responsive or nonresponsive to induction by 3-methylcholanthrene. On the other hand, the second drug was O-demethylated only by genetically responsive mice after pretreatment by 3-methylcholanthrene. It was also O-demethylated predominantly in rats pretreated with either 3-methylcholanthrene or Aroclor 1254.