Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy.

A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by a fusion protein which has been obtained from human beta-glucuronidase and humanized CEA-specific binding region. The six prodrugs are highly stable and are more than 100-fold less cytotoxic than doxorubicin against murine L1210 cell lines. The ortho-substituted phenyl carbamates 25a,b,c are better substrates for beta-glucuronidase than the corresponding para-substituted analogues. After taking into account additional factors such as stability in plasma and kinetics of enzymatic cleavage, we selected the o-nitro prodrug 25c for clinical trials.

Synthesis and antitumor activity of isodoxorubicin analogues.

The synthesis and biological activity of the new 4-demethoxyanthracyclines 15, 22, and 23 are reported. They were obtained from synthetic 9-deacetyl-9-(hydroxymethyl)-4-demethoxydaunomycinone (isopropylidene derivative 9) and from 4-azido- or 4-amino-2,4,6-trideoxy-L- lyxo-hexoses. Anthracycline 22 (hydrochloride salt), the most active compound in the series, was slightly more potent than doxorubicin in vitro against three cell lines (L1210, HT29, A549). It was found to exhibit similar antitumor activity in vivo (iv route) against L1210 leukemia, but was less active than doxorubicin against three human tumors in a subrenal capsule assay LXF, A549, and HT29).

Attenuation of response to antidepressants in animals induced by reduction in food intake.

A salient feature of depression is eating disorders (reduced appetite and caloric intake) and/or weight loss. In the present study, reduction in food intake in rats, resulting in moderate weight loss, markedly attenuated the ability of various antidepressant drugs to reverse depressive-like behaviors: escape deficits provoked by previous exposure to uncontrollable stress. Further data support the notion that hypofunctioning of central noradrenergic processes, perhaps linked to reduced thyroid hormone levels, might contribute to such an altered response to antidepressants. These findings suggest that current nutritional status, even with marginal weight loss, could be an intervening factor in the delayed therapeutic response to antidepressants and/or in drug-resistant depression.

Thyroid function and reversal by antidepressant drugs of depressive-like behavior (escape deficits) in rats.

Several investigations have suggested that a special relationship exists between thyroid function and affective disorders and/or therapeutic response to antidepressants. The present study shows that the reversal by clomipramine, desipramine, imipramine and nialamide of depressive-like behavior in rats (escape deficits produced by previous exposure to uncontrollable stress) was markedly attenuated in hypothyroid rats (propylthiouracil, 0.05% in the drinking water). Conversely, the effect of these same antidepressants was significantly hastened in euthyroid rats given daily triiodothyronine. This supports the notion of intricate thyroid/CNS interactions in the mechanisms of action of antidepressant drugs.

Acute versus repeated administration of desipramine in rats and mice: relationships between brain concentrations and reduction of immobility in the swimming test.

Immobility scores in the swimming test and brain concentrations of desipramine were determined in rats and mice following repeated injection of the antidepressant versus acute administration of either a behaviorally effective or ineffective dose of the drug. Five injections (IP) of desipramine (each injection being performed at the measured T1/2 of the drug in the brain) reduced immobility scores by 30%, whereas this regimen resulted in brain drug concentrations not different from those obtained after a single, behaviorally ineffective dose of desipramine. It is suggested that the enhanced "antidepressant" response such as that frequently observed in animals after repeated injection of imipramine-like drugs does not involve accumulation of the drug in the brain.

[Plasma assay of clomipramine and demethylclomipramine by high performance liquid chromatography]. / Dosage plasmatique de la clomipramine et de la dèméthylclomipramine par chromatographie liquide à haute performance.

A technique for assay of clomipramine (Anafranil) and its demethylated metabolite by high performance liquid chromatography is described in this study. This technique utilizes an XoA 800 normal phase column and a quaternary solvent composed of dietylamine, water, acetonitrile, and ethanol. Plasma of patients was extracted with hexane in an alkaline medium (pH 10). The use of an internal standard seemed to improve the assay's repeatability. The simplicity and rapidity of this technique should make it a useful aid for determining optimal doses of Anafranil for patients with depression.

[Complications of anticoagulant treatment. Report of 98 accidents and incidents (author's transl)]. / Complications du traitement anticoagulant. A propos de 98 accidents et incidents.

According to an estimation on 1 587 patients under anticoagulant treatment, 84 of them have caught a therapeutic accident so a frequency of 5,3 per cent. It concerns 98 therapeutic accidents : 89 haemorrhagic spontaneous accidents (11 digestive haemorrhages, 5 cerebro-vascular accidents, 54 hematomas with 18 retro-peritoneals and 11 in musculis rectis abdominis, 9 hematuries, 2 serous haemorrhages, 8 various haemorrhages) ; 8 "induced" haemorrhages, in which 5 after arterial catheterism, and an accident allergic to the phenyl-indane-dione. Nine deceases were revealed : in which 5 are directly attributed to the hemorrhagic accident (3 cerebro-vascular accidents and 2 serous haemorrhages).