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Biomedical subjects

C Advenier

Publications and source records attributed to C Advenier.

At least 19 recordsLinked to original sources
PubMed1992

Influence of (+/-)-CP-96,345 and SR 48968 on electrical field stimulation of the isolated guinea-pig main bronchus.

The aim of this study was to investigate the effects of (+/-)-CP-96,345 and SR 48968, two new nonpeptide antagonists of neurokinin NK1 and NK2 receptors, respectively, on the response of isolated guinea pig main bronchi to electrical field stimulation (EFS). Bronchi were stimulated transmurally with biphasic pulses (16 Hz, 1 ms, 320 mA for 10 s) in the presence of indomethacin (10(-6) M) and propranolol (10(-6) M). Two successive contractile responses were observed. Both responses were abolished by tetrodotoxin (10(-6) M) whereas only the first rapid phase was abolished by atropine (10(-6) M). The late and prolonged second phase was strongly reduced by the neurokinin A (NK2) receptor antagonist SR 48968 (10(-11) to 10(-8) M) with an EC50 of 0.056 nM and a maximal inhibition of 83.3 +/- 10.8% (10(-8) M, n = 4). This second response was partially inhibited by the substance P (NK1) receptors antagonist (+/-)-CP-96,345 (10(-8) to 10(-6) M). An incubation of 2 h was necessary for SR 48968 to inhibit the EFS-evoked noncholinergic contraction. These results confirm that EFS of guinea-pig bronchi involves stimulation of cholinergic and noncholinergic excitatory nerves and demonstrate that the new developed tachykinin receptors nonpeptide antagonists (+/-)-CP-96,345 and especially SR 48968 are potent inhibitors of the noncholinergic contraction induced by EFS of the isolated guinea-pig main bronchus.

Animals↗
PubMed1992

Inhibitory and contractile effects of okadaic acid on rat uterine muscle.

The effects of okadaic acid and its interactions with various agents known to increase, by different mechanisms, the intracellular levels of cyclic AMP and/or cyclic GMP were investigated in isolated strips of rat myometrium. Okadaic acid showed inhibitory effects at concentrations between 10(-7) M and 3 x 10(-6) M. At higher concentrations, a biphasic, contractile and then relaxant response was observed. The results obtained suggest that, in rat uterine smooth muscle, the inhibitory effects of okadaic acid are not entirely mediated by the activation of cyclic AMP- and/or cyclic GMP-dependent pathways. The data also point to the existence of a clear interaction between okadaic acid and methylxanthines, although further studies are needed to clarify the mechanisms involved in this interaction.

Animals↗
PubMed1992

Neurokinin A (NK2) receptor revisited with SR 48968, a potent non-peptide antagonist.

SR 48968, a new non-peptide antagonist of NK2 receptors, has been tested in a variety of isolated smooth muscle preparations from rats, guinea pigs, rabbits, hamsters and men, in order to assess its selectivity for NK2 receptors as well as its competitivity and specificity. The compound has been found to be inactive as a stimulant or relaxant in all preparations but to exert a potent, competitive antagonism, particularly in tissues obtained from rabbits (pA2 9.8-10.3), guinea pigs (10.5), rats (9.4-9.6), men (9.36-9.6) and hamsters (7.45-8.6). SR 48968 is therefore more active on the NK2A than on the NK2B receptor subtype and the human receptor is close to the NK2A subtype. SR 48968 exerts an antagonism of the competitive type and is therefore suitable for receptor classification despite its slow reversibility in vitro. The sensitivity of NK2A receptors to SR 48968 is at least 1000 times higher than those of NK1 and NK3 receptors. The compound does not affect the effects of bradykinin, angiotensin or bombesin. Because of its activity in human tissues, its potency and long duration of action, SR 48968 is a new promising pharmacologic and possibly therapeutic agent.

Animals↗
PubMed1992

Separation and identification of the 4-hydroxyantipyrine sulphoconjugate.

In a previous study we observed, during separation of total antipyrine metabolites by high-performance liquid chromatography and after enzymatic hydrolysis, an unidentified peak corresponding to an ionic compound with pyrazolinone features. In the present study, this compound was identified as the 4-hydroxyantipyrine sulphoconjugate, and its structure was definitively confirmed by gas chromatographic-mass spectrometric analysis and by the use of pure synthetic substance. We also demonstrated the inhibitory effect of sodium metabisulphite, a necessary preservative of urinary samples, on hydrolysis of this conjugate in the presence of sulphatases from Helix pomatia or Aerobacter aerogenes. This inhibitory effect makes it impossible to perform a global assay of antipyrine metabolites after enzymatic or chemical hydrolysis and confirms the value of direct assay of the 4-hydroxyantipyrine sulphoconjugate.

Adult↗
PubMed1992

Influence of benzodiazepines on the response of the guinea-pig isolated trachea to the contractile action of adenosine.

The effects of diazepam and other agonists of central or peripheral benzodiazepine receptors were studied on the contractile action of adenosine, 2-chloroadenosine and R-PIA (N6-(L-2-phenylisopropyl)-adenosine) on the guinea-pig isolated trachea. These effects were compared to those of dipyridamole. Diazepam 10(-7) to 10(-5) M potentiated the efficacy of adenosine; the maximal contractile effect of adenosine (% vs. acetylcholine 10(-3) M) was 20.4 +/- 4.2 (n = 21) in control conditions and 45.5 +/- 3.7 (n = 6; P less than 0.001) in the presence of diazepam 10(-5) M. Ro5-4864 (10(-7) to 10(-5) M) or alpidem (10(-7) to 10(-5) M), both agonists of peripheral benzodiazepine receptors, potentiated the contractile effects of adenosine to the same extent as diazepam. Clonazepam and zopiclone, both agonists of central benzodiazepine receptors, did not modify these effects. Antagonists of central (flumazenil) or peripheral (RP 52028) benzodiazepine receptors had no influence on the interaction between diazepam or Ro5-4864 and adenosine. Conversely, dipyridamole significantly reduced (10(-7) M) or suppressed (10(-6) M) the contractile effects of adenosine. The contractile effects of 2-chloroadenosine and R-PIA were weakly affected in presence of high concentrations of diazepam and dipyridamole. Epithelium removal potentiated the contractile effect of adenosine on the guinea-pig isolated trachea and increased the potentiating effect of diazepam. It is concluded that benzodiazepines and related compounds can potentiate the contractile effect of adenosine on the guinea-pig isolated trachea through the activation of a peripheral receptor for the benzodiazepines and the resulting inhibition of adenosine uptake.

2-Chloroadenosine↗
PubMed1992

Effect of epithelium removal and of enkephalin inhibition on the bronchoconstrictor response to three endothelins of the human isolated bronchus.

The three endothelins ET-1, ET-2 and ET-3 induced a potent contractile response in the human isolated bronchus with an intact epithelium, which proceeded on two different stages. The first stage was observed at low concentrations (high potency) (10(-12) to 10(-9) M) but corresponded to a low intrinsic activity (Emax maximal effect induced by ACh 10(-3) M), the second stage appeared at higher concentrations and corresponded to higher intrinsic activity. The rank order of potency for the two stages of contractile activity was ET-1 greater than ET-2 = ET-3. Removal of the epithelium significantly enhanced the two stages of the contractile responses to the three endothelins and abolished the differences in potency efficacy that were observed between ET-1, ET-2 and ET-3 when the epithelium was present. Phosphoramidon (10(-5) M), an enkephalinase inhibitor, was as potent as epithelium removal in enhancing the contractile responses to these agonists at low concentrations (first stage of contraction, 10(-16) to 10(-9) M). However, with high concentrations of endothelins (greater than 10(-9) M, second stage of contraction), phosphoramidon was less potent than epithelium removal in enhancing the contractile responses. In epithelium-denuded strips, preincubation with phosphoramidon did not further increase the maximal contractions induced by/or the potencies of ET-1, ET-2 or ET-3. After epithelium removal, responses to low doses of endothelins were attenuated by nicardipine (10(-6) M) whereas responses to high doses of the endothelins were not affected, as was also observed when the epithelium was present. (ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

A potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor.

SR 48968 is a potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor. SR 48968 selectively inhibited neurokinin A binding to its receptor and was a competitive antagonist of neurokinin A-mediated contraction of different isolated smooth muscle preparations from various species including human. In vivo, the compound inhibited the bronchoconstriction induced by neurokinin A in guinea pigs. SR 48968 can be used to study the physiological or pathological role of neurokinin A and may be useful in the treatment of neurokinin A-dependent pathology.

Animals↗
PubMed1992

Effect of a macrolide (spiramycin) on the pharmacokinetics of L-dopa and carbidopa in healthy volunteers.

In one well-equilibrated parkinsonian patient treated with combined L-dopa and carbidopa (Sinemet), we have observed changes in treatment efficacy while receiving spiramycin (Rovamycine) for an intercurrent respiratory infection. A preliminary study of the pharmacokinetics of L-dopa and its main metabolites 3-O-methyldopa (3-OMD) and dihydroxyphenylacetic acid (dopac) in two parkinsonian patients treated with Sinemet has revealed a marked decrease in the AUC0-360 of these two metabolites after a 3-day course of Rovamycine. In order to confirm this interaction, we have studied the modifications of the pharmacokinetics of L-dopa, 3-OMD, dopac, and carbidopa in eight male healthy volunteers after a single dose of Sinemet 250 (L-dopa, 250 mg and carbidopa, 25 mg) before and after a 3-day course of Rovamycine. Our study confirms this interaction. After spiramycin, we observed a marked reduction in AUC0-360 for L-dopa (p less than 0.001), 3-OMD (p less than 0.001), and carbidopa (p less than 0.001), and an increase in AUC0-360 for dopac (p less than 0.01). The L-dopa elimination half-life was increased (p less than 0.012); differences in peak plasma concentrations did not attain statistical significance. We think that these modifications in L-dopa pharmacokinetics after spiramycin are due to nonabsorption of carbidopa secondary to modified gastrointestinal motility.

Adult↗
PubMed1992

Compared plasma and brain pharmacokinetics of clomipramine and its metabolite demethylclomipramine in two strains of mice (NMRI and CD1).

The fate of clomipramine (CMI) and its main demethylated metabolite demethylclomipramine (DCMI) was studied in two strains of Swiss mice (NMRI and CD1) after intraperitoneal injection. A study of its distribution among various tissues showed that fixation was most marked in lungs, perirenal fat and kidneys, and only moderate in the brain. The pharmacokinetic parameters of both molecules were determined in brain tissue and plasma. Absorption was rapid (tmax CMI = 14 min), metabolism prompt (tmax DCMI = 17 or 18 min according to the breed) and elimination rapid from both plasma and brain tissue. The first two stages were similar in the two strains, but elimination of CMI from both plasma and brain was faster in the NMRI mice (plasma t1/2 = 53 min against 165 min in the CD1 mice). Both values were well below that reported for man (mean plasma t1/2 = 24 h). The data presented can serve as a basis for designing true chronic administration protocol in animals.

Animals↗
PubMed1992

Contractile effect of alpha,beta-methylene ATP on the guinea-pig isolated trachea.

The effects of alpha,beta-methylene adenosine 5'-triphosphate (alpha,beta-methylene ATP), 2-chloroadenosine and R-PIA (N6-(L-2-phenylisopropyl)-adenosine) and their interaction with dipyridamole, indomethacin, 8-phenyl-theophylline, diazepam and other agonists of central or peripheral benzodiazepine receptors were studied on the guinea-pig isolated trachea. alpha,beta-methylene ATP exerted contractile effects on the guinea-pig isolated trachea; - log EC50 and E(max) values were 8.86 +/- 0.19 and 31.3 +/- 2.3 (n = 31) (% vs acetylcholine 10(-3) M) respectively. In comparison with other purinergic receptor agonists, the rank order of potency was: alpha,beta-methylene ATP greater than 2-chloroadenosine greater than R-PIA. alpha,beta-methylene ATP and 2-chloroadenosine had significantly (P less than 0.05) greater efficacy (E(max)) than R-PIA. Indomethacin (3 x 10(-6) M) and 8-phenyltheophylline (10(-7) to 10(-5) M) significantly reduced the contractile effect of 2-chloroadenosine and R-PIA but did not affect alpha,beta-methylene ATP-induced contraction. Conversely, dipyridamole significantly reduced (10(-7) M) or suppressed (10(-6) M) the contractile effects of alpha,beta-methylene ATP whereas it only partially reduced (10(-6) M) the contractile effects of high concentrations of 2-chloroadenosine or R-PIA. Diazepam potentiated the efficacy of alpha,beta-methylene ATP. The E(max) (% vs acetylcholine 10(-3) M) values were 26.1 +/- 2.0 (n = 10) in control conditions and 45.9 +/- 4.6 (n = 5; P less than 0.05) in the presence of diazepam 10(-5) M. Diazepam did not modify the contractile effects of 2-chloroadenosine or R-PIA. Ro5-4864 (10(-7) to 10(-5) M), an agonist of peripheral benzodiazepine receptors, potentiated the contractile effects of alpha,beta-methylene ATP to the same extent as diazepam. Clonazepam, an agonist of central benzodiazepine receptors, did not modify these effects. Antagonists of central (flumazenil) or peripheral (RP 52028) benzodiazepine receptors had no influence on the interaction between diazepam or Ro-4864 and alpha,beta-methylene ATP. In conclusion, alpha,beta-methylene ATP exerts on guinea-pig isolated trachea a contractile effect which is not modified by indomethacin and 8-phenyltheophylline, but is reduced by dipyridamole. It is suggested that this effect might involve P2 chi receptor stimulation.

2-Chloroadenosine↗
PubMed1992

Formoterol and salbutamol inhibit bradykinin- and histamine-induced airway microvascular leakage in guinea-pig.

1. The effects of the beta 2-adrenoceptor agonists, salbutamol and formoterol, on the increase of microvascular permeability induced by histamine or bradykinin in guinea-pig airways have been studied in vivo. Extravasation of intravenously injected Evans blue dye was used as an index of permeability. The effects of salbutamol and formoterol on the increase in pulmonary airway resistance induced by histamine or bradykinin have also been studied. 2. The increase in pulmonary airway resistance induced by histamine or bradykinin was totally inhibited by salbutamol and formoterol. The ED50 of the two mediators were 0.59 +/- 0.21 (n = 5) and 0.20 +/- 0.14 (n = 5) micrograms kg-1 respectively for salbutamol, and 0.13 +/- 0.12 (n = 6) and 0.02 +/- 0.01 (n = 6) micrograms kg-1 respectively for formoterol. 3. Salbutamol (10 and 30 micrograms kg-1) and formoterol (1 and 10 micrograms kg-1) inhibited the increase of microvascular permeability induced by histamine (30 micrograms kg-1) in the guinea-pig airways. The inhibitory effect was predominant in the trachea and the main bronchi, with a maximum inhibition of 20 to 50%. The two drugs had little or no inhibitory effect on the other structures studied, viz. nasal mucosa, larynx, proximal and distal intrapulmonary airways. 4. Salbutamol and formoterol (1 and 10 micrograms kg-1) abolished the increase in microvascular permeability induced by bradykinin (0.3 micrograms kg-1). This inhibitory effect of two beta-adrenoceptor stimulants was predominant in the trachea and the nasal mucosa where it was observed with 1 microgram kg-1 of the beta-adrenoceptor agonists.In the main bronchi, and in the proximal and distal intrapulmonary airways, the effects of bradykinin were abolished by 10 pg kg- of formoterol and salbutamol.5. The effects of bradykinin, but not those of histamine, were significantly reduced (nasal mucosa, main bronchi and distal intrapulmonary airways) or abolished (trachea, proximal intrapulmonary airways) by morphine 10mgkg-1, i.v. These results suggest that an indirect effect, through non-adrenergic noncholinergic (NANC) nerves is involved in the action of bradykinin on the microvascular permeability.6. In conclusion, intravenously injected beta-adrenoceptor stimulants can inhibit, partially or totally, the increase of airways microvascular permeability induced by intravenous histamine or bradykinin. However, these effects require doses that are higher than those that inhibit the increase in pulmonary airway resistance induced by these mediators. As suggested by the results obtained with morphine, the higher efficacy of beta2-adrenoceptor agonists versus bradykinin may occur through activation of presynaptic receptors of the non-adrenergic non-cholinergic (NANC) nerves preventing release of inflammatory neuropeptides such as substance P and neurokinin A.

Adrenergic beta-Agonists↗
PubMed1992

Contractile activity of big endothelin-1 on the human isolated bronchus.

1. We have studied the contractile activity of the 39 amino acid precursor of endothelin-1 (ET-1), big endothelin-1 (big ET-1), on human isolated bronchi. The contribution of the metalloproteases, neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE), in the presence or absence of the epithelium lining, by use of specific inhibitors, was also evaluated on the effects of big ET-1. 2. Big ET-1 elicited a potent contraction of human isolated bronchus. The -log EC50 value for big ET-1 was 7.53 +/- 0.08 (n = 11) and Emax 78.5 +/- 3.8% (% of ACh 3mM). 3. Incubation of human isolated bronchi with the NEP inhibitor phosphoramidon (10(-5) M) induced a rightward shift of the concentration-response curve induced by big ET-1 (10(-9) M to 3 x 10(-7) M). Similar results were observed when human bronchi were incubated with thiorphan (10(-5) M), but the shift to the right was significantly less (P less than 0.01) than that observed in the case of phosphoramidon (-0.35 +/- 0.05 vs -0.67 +/- 0.07 log unit). 4. The two inhibitors of angiotensin I converting enzyme (ACE), captopril or enalapril diacid, did not affect the concentration-response curve for contraction induced by big ET-1. 5. When the epithelium was removed, a leftward shift of the concentration-response curve of big ET-1 (10(-9) M to 3 x 10(-7) M) was observed. Incubation of human isolated bronchi with phosphoramidon or thiorphan (10-5M) or with enalapril diacid or captopril did not modify the leftward shift of the concentration-response curve for big ET-1 after epithelium removal.6. These results suggest that big ET-1 elicits potent contractile activity in the human isolated bronchus and that its effect is the consequence of the conversion to ET-1 by a phosphoramidon-sensitive metalloprotease which, although different from NEP and ACE, appears to be similar to the endothelinconverting enzyme (ECE) described in other studies in animals.

Angiotensin-Converting Enzyme Inhibitors↗
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↗