Biomedical subjects

G Regnier

Publications and source records attributed to G Regnier.

13 recordsLinked to original sources

PubMed1996

New purines and purine analogs as modulators of multidrug resistance.

A series of 36 purine and purine analog derivatives have been synthesized and tested for their ability to modulate multidrug resistance in vitro (P388/VCR-20 and KB-A1 cells) and in vivo (P388/VCR leukemia). Compounds were compared to S9788, a triazine derivative which has already shown some activity during phase 1 clinical trials and also a limiting cardiovascular side effect possibly linked to its calcium channel affinity. The fact that active compounds increase adriamycin accumulation in the resistant KB-A1 cells, and not in the sensitive KB-3-1 cells, suggests they act predominantly by inhibiting the P-glycoprotein-catalyzed efflux of cytotoxic agents. No direct relation was found between the affinity for the phenylalkylamine binding site of the calcium channel and in vitro sensitization of resistant cells. In vivo, when administered po in association with vincristine (0.25 mg/kg), five compounds (3, 4, 9, 25, and 26), of very differing calcium channel affinities (Ki from 5 to 560 nM), fully restored (T/V > or = 1.4) the sensitivity of P388/VCR leukemia to vincristine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

S 12340: a potent inhibitor of the oxidative modification of low-density lipoprotein in vitro and ex vivo in WHHL rabbits.

Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in the formation of foam cells and in the initiation and progression of the atherosclerotic plaque. After evaluation of a large number of original drugs, S 12340 was found to be the most potent compound in inhibiting in a dose-dependent manner the human LDL oxidative modification induced either by copper ions or by cultured endothelial cells. Both the electrophoretic mobility and the thiobarbituric acid reactive substances returned to almost normal values in the presence of 0.5 microM of S 12340. Watanabe heritable hyperlipidemic rabbits were treated orally for 3 days or for 1 month with S 12340 to evaluate the potential protective effect of the compound on LDL oxidative modification induced ex vivo. Purified LDL from placebo and treated rabbits were submitted to oxidation, and S 12340 was effectively able to protect LDL in a dose-dependent manner and at doses as low as 10 mg/kg/day. Purified LDL from animals sacrificed at various times after oral administration of S 12340 were protected against oxidation for at least 6 h after the last administration of the compound. These findings are in good agreement with the plasma and LDL levels of S 12340 in these WHHL rabbits. S 12340, probucol and vitamin E were all able to decrease the optical density of the 1,1-diphenyl-2-picrylhydrazyl solution, demonstrating their free radical scavenging properties. The pharmacological properties of the compound suggest that S 12340 may be of potential interest for a new therapeutic approach to atherosclerosis.

Animals↗

PubMed1992

In vivo evidence of complete circumvention of vincristine resistance by a new triazinoaminopiperidine derivative S 9788 in P388/VCR leukemia model.

S 9788, a new triazinoaminopiperidine derivative, was found to be a potent reversant of vincristine resistance in the in vivo murine leukemic P388/VCR model. In two treatment regimens (Q4D days 1, 5 and 9 and QD days 1-9), S 9788 enhanced the antitumor activity of vincristine in a dose-dependent manner, resulting in a complete circumvention of drug resistance for well-tolerated doses of S 9788. S 9788 was also effective in enhancing therapeutic effects of vincristine in the treatment of sensitive P388-bearing mice. These results strongly suggest that S 9788 may be a potential candidate for circumvention of multidrug resistance (MDR) in clinical practice.

Animals↗

PubMed1987

Pharmacological properties of a new antiasthmatic xanthine derivative devoid of central stimulatory activity.

The bronchodilating effect and other related pharmacological properties of an 8-amino alkyl substituted xanthine (S 9795) were compared with those of reference drugs, in particular theophylline. The in vitro studies using the tracheal ring, taenia coli, rat peritoneal mastocytes and enzymic preparations demonstrated the potency of S 9795 as an antiasthmatic drug, possessing protective activity superior to that of theophylline and enprofylline. S 9797 was 100 times more active as a cAMP phosphodiesterase inhibitor than theophylline. The compound also protected against mast cell degranulation and consequent release of spasmogen due to antigen-antibody reaction or induced by Ca2+ movements. Given orally or intravenously. S 9795 had a highly selective protective effect against bronchoconstriction induced by pharmacological reagents or allergic reactions with no demonstrable effect on the central nervous or cardiovascular systems. The pharmacological effects of S 9795 were of longer duration than those of theophylline and enprofylline. These studies demonstrate the potential therapeutic value of S 9795 in the therapy of bronchospastic disorders.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1984

[The almitrine dimesylate molecule. Various structure-activity relationship aspects].

The improvement in PaO2 induced by almitrine bismesylate is due to better adjustment between alveolar ventilation and lung perfusion (VA/Q ratio). Experimental studies and clinical pharmacology suggest that this improvement involves changes in both alveolar ventilation and pulmonary circulation. By synthesizing and testing compounds with different structures in a series of trisubstituted triazines, it has been possible to determine qualitative structure-activity relationships and to select almitrine bismesylate is due to better adjustment between the greatest, most rapid and longest lasting increase in PaO2. Almitrine bismesylate is a molecule with three components: a di-allylamino-triazine group, a piperazine ring and a bis-parafluoro-benzhydryl fraction. The di-allylamino-triazine group may be regarded as responsible for the effects on blood gases and ventilation. The presence of two allyl-amino substituents is an absolute prerequisite, and the triazine ring can possibly be replaced by a very similar pyrimidine ring. The piperazine ring is mainly responsible for dissociation between the effects on blood gases and on ventilation as well as for the general kinetics of the biological action of the drug. Molecules of this series which have a pyrrolidine ring or an azetidine ring instead of a piperazine ring do increase PaO2 but much more slowly than almitrine bismesilate. Finally, the bis-parafluoro-benzhydryl group modulates the intensity and duration of the effects on blood gases. Other constituents, such as the cinnamylamino, alpha-cyclohexyl-parafluorobenzyl, beta-naphthyl methyl or 5-fluoro-benzofluranyl-methyl groups also exert favourable biological activities comparable to those of the bis-parafluorobenzhydryl group characteristic of almitrine bismesylate.

Almitrine↗

PubMed1983

Almitrine bismesylate: pharmacological review and structure-activity relationships.

In the anaesthetized dog almitrine bismesylate (A) increases ventilation after i.v. injections of more than 100 ug X kg-1. This ventilatory stimulation is due to the specific agonistic action of A on the peripheral chemoreceptors. With lower doses of A no modification of ventilation is recorded even though PaO2 significantly increases. The mechanisms by which A induces pulmonary gas exchange improvement are not clearly demonstrated. A long lasting potentiation of local hypoxic pulmonary vasoconstriction was initially postulated but more recent experimental results recorded on animals with heterogeneously ventilated lungs do not support this hypothesis. However, a redistribution of pulmonary blood flow due to the transient vasoconstrictor effect of A cannot be excluded: it might divert the blood from the well perfused lung bases towards the less well perfused lung apex. Other authors have demonstrated that undetected small ventilatory changes might improve alveolar ventilation and raise PaO2. The almitrine bismesylate molecule is a successful example of pharmacochemical research applied to bronchopulmonary pathology. By using qualitative structure activity relationships it has been possible to choose from a series of triazine derivatives, this remarkable molecule, exerting a clear tropism for the pulmonary tract with a dual effect improving both ventilatory and gasometric parameters through peripheral chemoreceptor stimulation, and characterized by a rapid onset of action and a durable activity. In this respect, the di-allyl-amino-triazine moiety may be considered as an inducer of gasometric and ventilatory effects. The piperazine nucleus is mainly responsible for the ventilatory/gasometric dissociation and for the kinetics of these pulmonary actions. Finally, the bisparafluorobenzydryl component is a 'modulator' of intensity of gasometric effects.

Almitrine↗

PubMed1976

[Arterial time of intravenous pyelography: initial results (author's transl)].

The authors consider that attention should be paid to the arterial time in intravenous pyelography in all patients who undergo the examination. Manual injection or an injector containing 80 to 100 ml of 38% iodine contrast medium set at a speed of 20 ml/sec, on the one hand, and films taken during the arterial phase on the other hand, are the two conditions necessary to obtain a satisfactory arteriogram. Slight abdominal compression and subtraction improve the definition of the films. 600 cases have been collected so far, in the exploration of 105 patients with hypertension, 17 cysts, 7 malignant tumours, extra-renal pathology and various nephropathies in which no indication for arteriography existed. Thus pyelographic arteriography made it possible to avoid renal arteriograms in almost all our patients. Only one selective and one complete arteriogram were necessary. Unusual arterial lesions in nonsurgical renal conditions may be seen (glomerulonephritis, nephroangiosclerosis...) and unexpected images in abdominal conditions with renal manifestations or in association with nephropathies (aneurysms of digestive arteries and the aorta, collagen diseases etc.).

Angiography↗

PubMed1976

[Pharmacological studies of a new antitussive, 1-phenethyl-4-hydroxy-salicylamido-4-methyl-piperidine-hydrochloride (S 1592) (author's transl)].

1-Phenethyl-4-hydroxy-salicylamido-4-methylpiperidine-hydrochloride (S 1592) markedly inhibits coughing induced in laboratory animals by chemical or mechanical irritation of respiratory tract or by electrical stimulation of the superior laryngeal nerve. The drug has low acute toxicity in mice and rats. The new compound possesses bronchodilating and antianaphylactic properties and does not affect gastrointestinal propulsion. Cardiovascular effects are absent.

Analgesia↗

PubMed1975