Fantofarone (SR 33557): cardiovascular actions in anesthetized dogs.

We have compared the ability of a new calcium channel-blocking agent, fantofarone (SR 33557), to modify the cardiovascular function in anesthetized dogs, with that of nifedipine. Administration of fantofarone (50 micrograms/kg, i.v.) resulted in substantial changes in cardiac function, such that stroke volume was increased by 40% (p < 0.05) and left ventricular relaxation diminished by approximately 10% (p < 0.05), while heart rate was not significantly altered. Total peripheral resistance was simultaneously reduced by 40% (p < 0.05). Higher doses of fantofarone (100 and 500 micrograms/kg, i.v.) produced further modifications of cardiovascular function without significant effect on heart rate. Administration of nifedipine also resulted in significant reductions in total peripheral resistance and diastolic arterial pressure and, at the same time, in increased cardiac output. However, an important distinction between the effects of nifedipine and fantofarone was that nifedipine increased heart rate. To differentiate between the direct and indirect effects of fantofarone, studies were performed in stellectomized anesthetized dogs. In these conditions, in contrast to nonstellectomized dogs, fantofarone (100 micrograms/kg, i.v.) lowered heart rate considerably (from 122 +/- 9 to 67 +/- 10 beats/min; p < 0.01) and the increase in stroke volume was greatly limited in comparison to nonstellectomized dogs. The cardiovascular actions of fantofarone are, therefore, significantly influenced by reflex mechanisms. Thus, these studies indicate that fantofarone is a new calcium antagonist capable of significantly modifying the cardiovascular function without increasing heart rate.

SR 48692, a non-peptide neurotensin receptor antagonist, blocks the cardiovascular effects elicited by neurotensin in guinea pigs.

In guinea pigs anaesthetized with sodium pentobarbital, SR 48692, a non peptide neurotensin receptor antagonist blunted the blood pressure increase induced by exogenous neurotensin in a dose dependent manner. Furthermore, in isolated spontaneously beating guinea pig atria, both the tachycardia and inotropic responses induced by neurotensin were potently antagonized. SR 48692 did not show any intrinsic effect in vivo or in vitro.

Pharmacological characterization of SR 47436, a new nonpeptide AT1 subtype angiotensin II receptor antagonist.

SR 47436, 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, is a new potent and selective AT1 angiotensin II (AII) receptor antagonist. It competitively inhibited [125I]AII binding to AT1 subtype receptors in rat liver membranes (IC50 = 1.7 nM) and did not interact with AT2 subtypes in rat adrenal cortical membranes. In rabbit aorta, SR 47436 inhibited contractions induced by 10 nM AII (IC50 = 4.0 nM) and shifted AII contractile response curves to the right in a parallel fashion, without total recovery of the maximal response. The potency of SR 47436 was higher than that of the lead compound, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole (DuP 753) (rat liver binding: IC50 = 16 nM; rabbit aorta: IC50 = 26 nM), and equivalent to saralasin (IC50 = 1.8 and 2.7 nM, respectively). The high specificity of SR 47436 was demonstrated by its lack of activity (IC50 > 10 microM) on various other receptors, ionic channels and antiports and rabbit aorta contracted by norepinephrine and KCl, and its lack of inhibition of renin and converting enzyme. In conscious rats, SR 47436 as well as DuP 753 (0.1 to 3 mg/kg, i.v., and 0.3 to 30 mg/kg, p.o.) antagonized the AII-pressor response in a dose-related manner. In conscious dogs, SR 47436 (1-10 mg/kg, p.o.) was a more potent antagonist of the AII pressor response than DuP 753. In conscious chronically implanted cynomolgus monkeys, SR 47436 antagonized the AII-pressor response at 1 mg/kg (89% i.v. and 66% p.o.) much more strongly than DuP 753 at 10 mg/kg (83% i.v. and 20% p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombotic activity of SR 46349, a novel, potent and selective 5-HT2 receptor antagonist.

SR 46349 (trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-fluorophe nyl) propen-1-yl] phenol, hemifumarate) is the first member of a newly-developed 5-HT2 antagonist series. SR 46349 potently inhibited serotonin-induced aggregation of rabbit and human platelets (IC50 = 1 and 3.9 nM respectively) but had no effect on the action of other platelet aggregating agents. SR 46349 was 118 and 25 times more potent than ketanserin against 5-HT+epinephrine-induced aggregation of rabbit and human platelets respectively. A single per os administration of SR 46349 (1 mg/kg) resulted in a strong inhibition of 5-HT+epinephrine-induced platelet aggregation in the rabbit as measured ex vivo (67% inhibition, 6 h after the administration). Intravenous or oral administration of SR 46346 inhibited in a dose-dependent manner venous thrombosis induced by ligature of the jugular vein of rabbits whose blood was made hypercoagulable by i.v. administration of tissue thromboplastin. The doses of SR 46349 which inhibited 50% of thrombus formation were 1.5 +/- 0.8 mg/kg and 17 +/- 0.5 mg/kg after i.v. or oral administration respectively. When given i.v. to rabbits, SR 46349 exhibited a dose-dependent antithrombotic effect in an arterio-venous shunt model. Significant increase of the bleeding time was observed after the i.v. administration of 5 mg/kg of SR 46349 (3-fold increase). In dogs, SR 46349 inhibited cyclic coronary artery blood flow variations, complete abolition of CFVs being achieved after the i.v. administration of 0.5 mg/kg. In conclusion, SR 46349 is a highly potent, selective antagonist of serotonin in vitro and is to be considered as a potent, orally active antithrombotic agent.

Differential sensitivity to cardiotonic drugs of cyclic AMP phosphodiesterases isolated from canine ventricular and sinoatrial-enriched tissues.

A cardiac phosphodiesterase (PDE) which specifically hydrolyzes cAMP and is inhibited by cyclic GMP has been suggested to be the site of action of new cardiotonic drugs. To investigate the effect of inhibitors, canine cyclic nucleotide PDEs were isolated from left ventricle and from sinoatrial node-enriched tissue, using identical techniques. Four PDE forms could be chromatographically resolved from each tissue, including a peak I PDE (calmodulin-activated phosphodiesterase, CaM-PDE), a peak II PDE (cyclic GMP-stimulated phosphodiesterase, CGS-PDE) and a peak III PDE (specific for cyclic AMP). The latter was further fractionated into two forms: One was inhibited by cyclic GMP and by the platelet antiaggregant AAL 05 (CGI-PDE), and the second was insensitive to cyclic GMP and was inhibited by rolipram (ROI-PDE). Reference PDE inhibitors, isobutyl-1-methylxanthine (IBMX) and papaverine, nonselectively inhibited the four forms isolated from the two tissues. Cardiotonic drugs (CI 930, LY 181512, piroximone, enoximone, and SK&F 94120) selectively inhibited CGI-PDE from ventricular tissue but were poorly active on both CGI-PDE and ROI-PDE from the sinoatrial-enriched fraction. In contrast, milrinone inhibited CGI-PDEs and ROI-PDEs from both ventricular and sinoatrial tissues. These results are in good agreement with pharmacologic data in the literature on the positive chronotropic and inotropic effects of the studied drugs in the dog. They provide a possible basis for the dissociation of these two properties of PDE inhibitors.

[Diagnostic value of 4 biological markers: lactate dehydrogenase, phosphoglucoisomerase, carcinoembryonic antigen and gammaglutamyl transpeptidase, systematically determined in patients in a hematology-oncology department]. / Intérêt diagnostique de quatre marqueurs biologiques: la lacticodéshydrogénase, la phosphogluco-isomérase, l'antigène carcino-embryonnaire et la gammaglutamyl-transpeptidase dosés systématiquement chez les malades d'un service d'hématologie-oncologie.

This article is concerned with a prospective study about the systematical, simultaneous and comparative assay of four biological markers (carcino-embryonic antigen, lactate dehydrogenase, gammaglutamyl transferase and phosphohexose isomerase). This study was conducted in a department of Hematology and oncology on 258 patients. The dosage of each marker separately does not appear to be of diagnostical interest because of a lack of sensibility and specificity. But when there is a positive statistical correlation between several makers, their simultaneous dosage may allow the diagnostic of cancer and sometimes the determination of its origin.