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Biomedical subjects

P Lefebvre

Publications and source records attributed to P Lefebvre.

At least 325 records · Page 18Linked to original sources
PubMedDate not supplied

[International study of the effect of dexfenfluramine in obesity (ISIS): 6 months' results].

International study of the effect of dexfenfluramine in obesity (ISIS): 6 months results. ISIS is a multicentre therapeutic trial of the "intention to treat" type organized to test the effectiveness and side-effects of dexfenfluramine combined with diet in the treatment of obesity. This was a randomized, double-blind drug versus placebo study programmed for a one-year period. Eight hundred and twenty-two obese patients were included. Dexfenfluramine was administered in doses of 15 mg b.d. The intermediate results after 6 months of treatment are presented. Significant differences were observed between the dexfenfluramine group (n = 404) and the placebo group (n = 418). In the treated group: 1) the drug withdrawal rate was lower, mainly due to a greater number of patients in the placebo group dissatisfied with their weight loss; 2) about twice as many patients achieved an important loss of weight in terms of percentage of the initial weight or overweight; 3) the cumulative loss of weight was greater; 4) there was a higher incidence of transient side-effects, such as fatigue, diarrhoea, dry mouth, polyuria and drowsiness. These results suggest that dexfenfluramine will be suitable for a more prolonged treatment of obese patients, in addition to diet.

Adult↗
PubMedDate not supplied

Alteration of the glucocorticoid receptor subcellular localization by non steroidal compounds.

The glucocorticoid receptor (GR) engages transient or stable interactions with chaperones (hsp90, hsp70), co-chaperones (p60/hop, hsp40) and several other polypeptides such as immunophilins (Cyp40, FKBP59) and p23 to achieve a high affinity ligand binding state. This complex dissociates in response to hormonal stimuli and holo-GR translocates into the nucleus, where it regulates the activity of glucocorticoid-sensitive genes. GR activity is controlled through its ligand binding domain by steroids displaying either agonistic or antagonistic activity. An alternative approach to modulate GR activity is to target receptor-associated proteins (RAPs), and several non steroidal compounds binding to RAPs affect GR transcriptional activity. We have studied the effect of such drugs on the intracellular localization of a EGFP-GR fusion protein, which has wild type GR pharmacological properties. Agonist and antagonist binding induced nuclear translocation of GR, whereas rifampicin was found to be inactive in our system. Immunosuppressants FK506 and cyclosporin A were able to induce partial nuclear translocation of GR, suggesting that potentiation of glucocorticoid action by these compounds may also proceed through enhanced GR nuclear transfer. Short treatment of cells with the hsp90 inhibitor geldanamycin (GA) did not prevent nuclear translocation of GR. However, longer treatments, in parrallel to the inhibition of GR transcriptional activity, strongly perturbed GR subcellular localization concomitantly to the disruption of the actin network, and caused GR aggregation and down-regulation. The GA-induced transcriptional shutdown was also observed for other nuclear receptors which do not interact stably with hsp90. Thus RAP-binding compounds may exert their effects at least in part through perturbation of the GR cytosol to nucleus partitioning, and identify these proteins as valuable therapeutic targets to control nuclear receptor activity.

Actins↗
PubMedDate not supplied

[Hormones and antihormones. The steroidal model].

Antiglucocorticoids despite very limited clinical application (in contrast with other antisteroids) are extensively studied, since the glucocorticoid receptor, present in numerous target cells, constitute a very convenient experimental model. Structure activity relationships of a series of 17 beta-carboxamide derivatives of dexamethasone are described. The affinity of these compounds for the glucocorticoid receptor depends on the nature of the 17 beta-side chain substituent. An effect is observed at a rather large distance from the steroid nucleus. Maximal affinity is obtained with aromatic substituents. Antiglucocorticoid activity seems to be correlated with a high dissociation rate constant of the steroid receptor complexes and probably exclude the existence of a very active antiglucocorticoid in these series. Dexamethasone 17 beta-carboxamide derivates share with all other antiglucocorticoids tested the same ability to stabilize a high molecular form of the receptor associated to HSP90, a heat shock protein, in intact cells.

Animals↗