Search PubMed⌕ Search

Biomedical subjects

C Advenier

Publications and source records attributed to C Advenier.

At least 145 records · Page 8Linked to original sources
PubMed1992

Effects on the isolated human bronchus of SR 48968, a potent and selective nonpeptide antagonist of the neurokinin A (NK2) receptors.

Tachykinins produce concentration-dependent contraction of the human isolated bronchus by stimulation of receptors that belong to the NK2 type. The aim of this study was to investigate the inhibitory effects of a new, potent, and selective nonpeptide antagonist of the neurokinin A (NKA) (NK2) receptors, SR 48968 [(S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl) butyl]benzamide] on human isolated airways. Our experiments were performed on human isolated bronchi obtained from patients with lung cancer. Phosphoramidon, 10(-5) M, was added to the bath to inhibit neurokinin metabolism. SR 48968 induced a parallel shift to the right of the concentration-response (C/R) curves to [Nle10]-NKA(4-10), a specific NK2 receptor agonist. The antagonism was of the competitive type, with a pA2 of 9.40 +/- 0.19 (slope = 0.95 +/- 0.08, n = 13). The (R)-enantiomer of SR 48968 was 100-fold less potent and a noncompetitive antagonist (slope = 0.56 +/- 0.11, n = 8); pA2 and slope of the racemate were 8.86 +/- 0.21 and 1.09 +/- 0.21 (n = 7), respectively. Under similar conditions, racemic CP-96,345, a nonpeptide NK1 antagonist, did not modify the C/R curves to [Nle10]-NKA(4-10) until 10(-7) M. SR 48968 did not modify C/R curves to acetylcholine, histamine, KCI, or PGF2 alpha on the human isolated bronchus. Finally, SR 48968 shifted to the right C/R curves to substance P on isolated human bronchi, whereas racemic CP-96,345 was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

Activation of an epithelial neurokinin NK-1 receptor induces relaxation of rat trachea through release of prostaglandin E2.

We studied the type of neurokinin (NK) receptor involved in the epithelium-dependent substance P (SP)-induced relaxation of rat trachea precontracted with serotonin (5-HT). We first compared the relaxant effects of different agonists to the three NK receptors on rat trachea in the presence (E+) and absence (E-) of the epithelium. The three agonists to the NK-1 receptor, SP, SP-O-methylester and [beta Ala4, Sar9, Met(O2)] SP(4-11), at a concentration of 1 microM induced a relaxation of 40 +/- 5, 33 +/- 4 and 31 +/- 6%, respectively in E+ segments. They had weak and nonsignificant effects in E- segments. In addition, (+/-)CP-96,345 (1 microM), the NK-1-selective non-peptide antagonist, inhibited the SP-induced relaxation by 45%. Conversely, the three NK-2 receptor agonists, NKA, NKA(4-10) and [Nle10]NKA(4-10), and the two NK-3 receptor agonists, neurokinin B (NKB) and [MePhe7]NKB(4-10), had no effect on E+ or E- tracheal segments. The N-terminal SP fragment SP(1-9) was also inactive. These results suggest that SP-induced relaxation is mediated through activation of epithelial NK-1 receptors. Preincubation with the cyclooxygenase inhibitor, indomethacin (2.8 microM), abrogated the relaxant effect of the three NK-1 receptor agonists on E+ tracheas. We measured in additional experiments prostaglandin E2 (PGE2), PGF2 alpha, 6-keto PGF1 alpha and thromboxane B2. SP (1 microM) induced a 6.1-fold increase in PGE2 production (from 13 pg after 5-HT to 78 pg) in E+ segments, whereas only a 1.5-fold increase occurred in E- preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1992

[Acute hemodynamic effects of SIN-1 and isosorbide dinitrate in stable left ventricular failure: a comparative double-blind, cross-over study].

The acute hemodynamic effects of intravenous SIN-1 (1 mg) and sublingual isosorbide dinitrate (5 mg) were investigated in 12 patients (8 men and 4 women) between 38 and 80 years of age and suffering from stable chronic left ventricular failure (NYHA Classes III-IV) secondary to ischemic myocardiopathy (n = 5), hypertensive disease (n = 2) or idiopathic disorder (n = 5) corresponding to the following hemodynamic inclusion criteria: stable condition, cardiac index > or = 2 l/min/m2, mean capillary pressure > or = 18 mmHg and < or = 28 mmHg. Previous treatments were continued with the exception of vasodilators and diuretics which were stopped 24 hours earlier. The hemodynamic data from this cross-over, double-blind double-dummy trial were collected for two 60-hour periods separated by a washout period of 120 minutes. Simultaneously, venous samples were taken for the assay of plasma levels of SIN-1. The heart rate, cardiac output, pulmonary artery resistance and blood pressure were not affected by either SIN-1 or isosorbide dinitrate. An obvious reduction (> 15% of the basal value) in the mean capillary pressure, pulmonary artery pressure and mean right atrial pressure was observed in 10 subjects after SIN-1 and in 7 patients isosorbide dinitrate. A statistically non-significant trend towards a more marked effect (number of patients responding and maximum amplitude of pressure reduction) which occurred more rapidly and lasted longer was observed after SIN-1. Analysis of the relationship between the pharmacodynamics and pharmacokinetics of SIN-1 suggests that an active metabolites is involved. No adverse effects were reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

High-performance liquid chromatographic method for the determination of the three main oxidative and 3-carboxylic antipyrine metabolites in human urine.

The oxidative metabolism of xenobiotics is usually explored using the antipyrine test, which consists of determining the production clearances and urinary percentages of three major antipyrine metabolites 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethylantipyrine. The total forms of these compounds are generally determined by high-performance liquid chromatography (HPLC). However, the 3-carboxylic acid metabolite (3-carboxyantipyrine), which is the ultimate oxidation form in the 3-hydroxylation pathway, should also be taken into account, but so far its determination by HPLC has not been reported. A simple and accurate HPLC method has now been developed to determine the three major metabolites plus 3-carboxyantipyrine. In this method, all compounds are extracted in an aprotic non-polar solvent, at pH 3.5 for the major metabolites and unchanged antipyrine, then at pH 0.9 for 3-carboxyantipyrine. Total forms are evaluated after enzymatic hydrolysis. Throughout the procedure, attention is paid to the relative instability of norantipyrine and 4-hydroxyantipyrine. Recovery, accuracy and precision are discussed. The method has been applied to the determination of relative amounts (percentage of the dose administered) excreted in the urine of ten adult subjects 48 h after ingestion of antipyrine (600 mg). The proportion of 3-carboxyantipyrine excreted was 4.5 +/- 0.2%, which is in agreement with published values obtained by gas chromatography. The excretion rates of the major metabolites also were similar to those reported in the literature, thereby confirming that the reported method is valid. 3-Carboxyantipyrine is totally excreted as the free form and norantipyrine almost completely as glucuroconjugate.

Antipyrine↗
PubMed1991

Tachykinin receptors and the airways.

The tachykinins, substance P, neurokinin A and neurokinin B, belong to a structural family of peptides. In mammalian airways, substance P and neurokinin A are colocalized to afferent C-fibres. Substance P-containing fibres are close to bronchial epithelium, smooth muscle, mucus glands and blood vessels. Sensory neuropeptides may be released locally, possibly as a result of a local reflex, and produce bronchial obstruction through activation of specific receptors on these various tissues. Three types of tachykinin receptors, namely NK-1, NK-2 and NK-3 receptors, have been characterized by preferential activation by substance P, neurokinin A and neurokinin B respectively. NK-1 and NK-2 receptors were recently cloned. The determination of receptor types involved in the effects of tachykinins in the airways has been done with synthetic agonists and antagonists binding specifically to NK-1, NK-2 and NK-3 receptors. Although the existence of species differences, the conclusion that bronchial smooth muscle contraction is mainly related to activation of NK-2 receptors on bronchial smooth muscle cell has been drawn. The hypothesis of a NK-2 receptor subclassification has been proposed with NK-2A receptor subtype in the guinea-pig airways. Other effects in the airways are related to stimulation of NK-1 receptors on mucus cells, vessels, epithelium and inflammatory cells. A non-receptor-mediated mechanism is also involved in the effect of substance P on inflammatory cells and mast cells.

Airway Resistance↗
PubMed1991

The effect of cetirizine on the human isolated bronchus: interaction with salbutamol.

The effects of cetirizine (C), a new generation, nonsedative, H1-antihistamine drug, were studied on human isolated bronchi. C is a potent antagonist of the bronchial muscle contraction induced by histamine, irrespective of whether C is administered by cumulative addition or prophylactically. In the former case, this effect of C was significant at a concentration of 3 X 10(-8) mol/L and was maximal at a concentration of 10(-5) mol/L. The -log of concentration of C causing 50% of the maximal effect induced was 7.30 +/- 0.05 (n = 6), and the effect produced was not significantly modified by bronchial epithelium removal. When C was administered prophylactically, the concentration-response curves to histamine were displaced to the right, but the reduction of maximum histamine response suggests a noncompetitive type of antagonism. C is devoid of notable anticholinergic effects. At concentrations of 10(-8) to 10(-7) mol/L, C proved capable of enhancing the relaxant effect produced by salbutamol (10(-7) to 3 X 10(-7) mol/L) on human isolated bronchi that had been contracted by either histamine or acetylcholine (ACh). The synergy appeared to be additive or potentiating, depending on salbutamol (SAL) concentrations. Under similar conditions, mepyramine does not potentiate the effects of SAL against histamine. Finally, at concentrations of 10(-8) to 10(-6) mol/L, C reduced the functional antagonism observed between SAL and ACh, as can be observed by the increase, in the presence of C, of the maximal relaxant effect of SAL on contractions produced by 10(-3) mol/L of ACh. We may, therefore, conclude that C appears to be a specific antihistamine on human isolated bronchi and that it appears to potentiate the bronchodilator effect of SAL on this preparation.

Acetylcholine↗
PubMed1991

Effect of atrial natriuretic peptide and on atriopeptins on the human isolated bronchus. Comparison with the reactivity of the guinea-pig isolated trachea.

ANF, ANF7-28 and atriopeptins (AP1, AP2 and AP3) (10(-11) to 3 x 10(-7) M) induce a relaxant response on the guinea-pig isolated trachea, which is partially potentiated by the enkephalinase inhibitor thiorphan 10(-5) M but is unmodified by epithelium removal. Conversely, these drugs were found to be without any significant relaxant effect on the isolated human bronchus. Several hypotheses, such as the activation of ANF receptors not located on airway smooth muscle or an indirect effect of ANF in vivo are suggested to explain the discrepancy between these in vitro results and those of clinical trials in asthmatic subjects.

Amino Acid Sequence↗
PubMed1991

Pharmacokinetics of molsidomine and its active metabolite, linsidomine, in patients with liver cirrhosis.

The pharmacokinetics of molsidomine were investigated in six healthy volunteers and in seven patients with alcoholic cirrhosis. After a 2 mg oral dose, molsidomine elimination half-life was prolonged in cirrhotic patients (13.1 +/- 10.0 h vs 1.2 +/- 0.2 h, P less than 0.01) because of a decrease in its apparent plasma clearance (CL/F) (39.8 +/- 31.9 ml h-1 kg-1 in patients with cirrhosis vs 590 +/- 73 ml h-1 kg-1 in volunteers). The elimination half-life of the active metabolite, linsidomine (SIN-1) was also prolonged in cirrhotic patients (7.5 +/- 5.4 h vs 1.0 +/- 0.19 h, P less than 0.05). The AUC values of both molsidomine and linsidomine were increased in the cirrhotic group, but the increase in the former was considerably greater than in the latter as shown by the significant decrease of the ratio AUClinsidomine/AUCmolsidomine x 100 (4.5 +/- 6.1 in cirrhotic patients vs 23.5 +/- 3.4 in healthy volunteers, P less than 0.001). These results suggest that liver cirrhosis profoundly alters the pharmacokinetics and metabolism of molsidomine.

Adult↗
PubMed1991

Penetration of minocycline into lung tissues.

The penetration of minocycline into different lung tissues and bronchial mucus was studied in 17 patients undergoing pulmonary surgery for cancer. The patients received oral minocycline 100 mg at night for 3 days preceding surgery. Minocycline concentrations were measured in plasma samples collected before the operation and in tissues and mucus taken from in and around the part of the lung that was surgically removed. Mean tissue or mucus concentration to plasma concentration ratios were 3.78 +/- 1.10 for lung parenchyma, 4.04 +/- 1.31 for bronchial walls, 3.37 +/- 1.00 for pulmonary arterial walls, 1.99 +/- 1.80 for intraluminal mucus collected from bronchi located in healthy tissue proximal to the tumour, 5.16 +/- 3.26 for intraluminal mucus collected in a bronchus distal to the tumour, and 3.06 +/- 1.99 for catheter-collected mucus from the trachea and principal bronchi. These results indicate that minocycline is found in high concentration in all types of lung tissue and mucus in man.

Adult↗
PubMed1991

Influence of diazepam, alpidem, zolpidem and zopiclone, on the response to adenosine of the guinea pig isolated trachea.

It has been reported that dipyridamole and some benzodiazepines potentiate the responses to adenosine in peripheral organs and in particular in the guinea pig isolated atria or trachea by inhibition of adenosine uptake and/or metabolism. In this study, we have examined the sensitization of guinea pig isolated trachea to relaxant responses to adenosine produced by dipyridamole, diazepam and 3 compounds chemically unrelated to benzodiazepines but which display selective agonistic activity towards the central (zolpidem and zopiclone) or peripheral (alpidem) type benzodiazpine receptors. In preparations under spontaneous tone and in the absence of adenosine, dipyridamole (10(-5) M) and diazepam (10(-5)-10(-4) M), alpidem (3 x 10(-6) M-10(-5) M) and zopiclone (10(-6)-10(-4) M) induced a relaxation of the airway smooth muscle. In addition, dazepam (10(-4) M) attenuated the phasic response to histamine (10(-5) M). Dipyridamole (10(-5) M) and diazepam (10(-4) M) respectively produced a 56.2 and 32.4-fold potentiation of adenosine relaxant effects. Alpidem (10(-6)-10(-5) M), zolpidem (10(-6)-10(-4) M) and zopiclone (10(-6)-10(-4) M) were without any significant effect on the adenosine concentration-response curves. Moreover, alpidem, zolpidem, and zopiclone did not modify the 2-chloroadenosine dose-response curves nor the diazepam induced sensitization of adenosine-induced relaxation. In conclusion, adenosine sensitization of the guinea pig isolated trachea caused by diazepam might involve a peripheral benzodiazpine receptor subtype coupled to a nucleoside transporter system which is different from those recognized by compounds derived from the imidazopyridine series.

2-Chloroadenosine↗
PubMed1991

Pharmacokinetics of molsidomine and of its active metabolite, SIN-1 (or linsidomine), in the elderly.

The pharmacokinetics of molsidomine were investigated in six young (25.5 +/- 0.6 years) and in six elderly healthy volunteers (81.1 +/- 3.1 years). After a 2 mg oral administration, molsidomine elimination half-life was prolonged in elderly subjects (1.9 +/- 0.2 h versus 1.2 +/- 0.1 h, P less than 0.05) because of a decrease in its plasma clearance (15.1 +/- 3.2 l.h-1 versus 41.8 +/- 2.5 l.h-1 (P less than 0.01) in young volunteers). The elimination half-life of the active metabolite, SIN-1 or linsidomine was also prolonged in elderly subjects (1.8 +/- 0.2 h versus 1.0 +/- 0.08 h, P less than 0.05). AUCs of both molsidomine and SIN-1 were increased in the elderly subjects, but the increase in the former was greater (x 3.4) than the increase in the latter (x 1.6). These results suggest that pharmacokinetics and metabolism of molsidomine are impaired in elderly subjects.

Administration, Oral↗
PubMed1990

Calcium dependence of the contraction produced by endothelin (ET-1) in isolated guinea-pig trachea.

Endothelin (ET-1, 1 pM to 0.1 microM) produced a concentration-dependent contraction of isolated guinea-pig trachea. BAY K 8644 (1 microM) did not significantly alter the concentration-response curve for ET-1. Incubation with nicardipine (10 microM) partly inhibited responses to low concentrations (10 pM to 1 nM) of ET-1 while verapamil (10 microM) and diltiazem (10 microM) were ineffective. La3+ (10 microM) and Cd2+ (10 microM) preferentially depressed the responses evoked by high concentrations (30 nM-0.1 microM) of ET-1 without affecting the responses evoked by low concentrations of the peptide. Incubation in Ca2(+)-free (with EDTA, 1 mM) medium resulted in suppression of the responses elicited by low concentrations of ET-1 and partial inhibition of the responses elicited by high concentrations of the peptide. It is concluded that responses to ET-1 are dependent on extracellular Ca2+. The promotion of Ca2+ entry by ET-1 is not confined to a particular class of Ca2+ channel. An intracellular source of Ca2+ is also mobilized by high concentrations (greater than 10(-9) M) of ET-1.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Determination of the active metabolite of molsidomine in human plasma by reversed-phase high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic method, with ultraviolet detection, is proposed for the plasma determination of SIN-1, the active metabolite of molsidomine, which involves propoxycarbonyl derivatization. The internal standard is the ethoxycarbonyl derivative of SIN-1 (i.e. molsidomine). Derivatization and extraction are each performed in one step (2 min) with 70% yield. The nature of a by-product is discussed. The method provides rapid elution (less than 15 min), linearity over the range 0.4-200 ng/ml, day-to-day precision between 2.5 and 11.3% and a limit of determination of 0.5 ng/ml. This method is also suitable for the simultaneous determination of molsidomine and SIN-1. In this case the internal standard is an ethoxycarbonyl derivative of a piperazino-3-sydnonimine, a SIN-1 analogue.

Antihypertensive Agents↗
PubMed1990

Receptors for neurokinins in human bronchus and urinary bladder are of the NK-2 type.

Human tissues such as the isolated bronchus and urinary bladder respond to neurokinins with concentration-dependent contractions, which appear to be due to the activation of receptors. We characterized these receptors in the present study using agonists (the naturally occurring neurokinins and some selective agonists) as well as newly identified antagonists. The order of potency of the agonists in the two preparations was as follows: neurokinin A (NKA) greater than substance P (SP) greater than neurokinin B (NKB) (bronchus) and NKA greater than NKB greater than SP (bladder), which suggests the presence of NK-2 receptors. This was confirmed by data obtained with two antagonists, one of which was shown to be competitive and selective for NK-2 type receptors. It thus appears that receptors of the NK-2 type are present in humans along the tracheo-bronchial tree and in the urinary system.

Bronchi↗
PubMed1990

Quinidine oxidative metabolism. Identification and biosynthesis of quinidine 10,11-dihydrodiol stereoisomers.

The isocratic reversed phase high performance liquid chromatographic method proposed for quinidine metabolic studies facilitates particularly the separation of 10(R) and (S) isomers of quinidine 10,11-dihydrodiols. The finding of each of these forms following a new synthetic pathway allows us to identify and quantify them in biological fluids. These two isomers have especially been observed in rat bile and hepatocyte secretions. The metabolic inducing effect of phenobarbital on the oxidative metabolism of quinidine is verified in rat isolated hepatocytes. Simultaneous secretion of the two dihydrodiols is also verified in human urine by a gas chromatography/mass spectrometry procedure.

Animals↗
PubMed1990

Peripheral type benzodiazepine receptors and response to adenosine on the guinea-pig isolated trachea.

It has been reported that dipyridamole, an adenosine uptake inhibitor, and some benzodiazepines potentiate the responses to adenosine in peripheral organs and in particular, on guinea-pig isolated atria. In this paper, we have examined the potentiation of responses to adenosine produced by dipyridamole, diazepam and four compounds with selective agonistic activity towards the central (clonazepam) or peripheral (Ro5-4864) type benzodiazepine receptors or antagonistic activity towards the central (flumazenil) or peripheral (PK 11195) benzodiazepine receptors in guinea-pig trachea in vitro. In preparations under basal tone and in the absence of adenosine, dipyridamole (10(-5) M) and benzodiazepines (10(-4) M) with the exception of flumazenil induced a relaxation of the airway smooth muscle. In addition, diazepam (10(-4) M) attenuated the phasic response to histamine (10(-5) M). Dipyridamole, and the benzodiazepine agonists diazepam, Ro5-4864 and clonazepam (10(-5) to 10(-4) M) produced potentiation of the tracheal response to adenosine, the rank order of potency being dipyridamole (pKi = 7.77 +/- 0.12, n = 8) greater than Ro5-4864 (pKi = 5.43 +/- 0.18, n = 6) greater than or equal to diazepam greater than clonazepam (pKi = 4.84 +/- 0.11, n = 6). The two benzodiazepine receptor antagonists, flumazenil and PK 11195, gave a significant but small potentiation to adenosine only at 10(-4) M. In the presence of dipyridamole (10(-5) M), diazepam (10(-4) M) did not cause any further potentiation to adenosine. Additionally, the potentiation produced by diazepam was not antagonised by flumazenil, whereas it was potently antagonised by PK 11195. Similarly, PK 11195 potently inhibited the adenosine potentiation produced by Ro5-4864.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗