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Biomedical subjects

R A Lefebvre

Publications and source records attributed to R A Lefebvre.

At least 91 records · Page 5Linked to original sources

Investigation of a possible pharmacokinetic interaction between ibopamine and isosorbide-5-mononitrate.

The possibility of a pharmacokinetic interaction between isosorbide-5-mononitrate (5-ISMN) and epinine, the active metabolite of ibopamine, has been investigated in 8 healthy male subjects given single doses of 200 mg ibopamine and 20 mg 5-ISMN, separately and together. The plasma 5-ISMN concentration-time profile was the same whether 5-ISMN was administered concomitantly with ibopamine or alone [AUC(o-t): 2.24 micrograms.ml-1.h after 5-ISMN alone, 2.16 micrograms.ml-1.h after 5-ISMN+ibopamine]. The plasma concentrations of total and free epinine and the urinary recovery of total epinine, homovanillic acid and dihydroxyphenylacetic acid, too, were not different when ibopamine was administered alone or concomitantly with 5-ISMN. The intake of ibopamine did not change the blood pressure and heart rate. The decrease in diastolic blood pressure induced by 5-ISMN was not influenced by concomitant intake of ibopamine. The observations suggest that in healthy volunteers there is no pharmacokinetic interaction between 5-ISMN and ibopamine.

3,4-Dihydroxyphenylacetic Acid↗

Comparison of salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel.

The salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel have been compared. The bioadhesive tablet consisted of a mixture of thermally modified starch and 5% polyacrylic acid. Although the amount of drug administered via the bioadhesive tablet was sixfold lower than when the gel was used, the salivary miconazole levels were higher and remained above the MIC value of Candida albicans for more than 10 hours. The mean adhesion time of the tablet was 586 min. The bioadhesive tablet appears to be a promising drug delivery system for the buccal administration of drugs for local therapy.

Administration, Buccal↗

Influence of lansoprazole treatment on diazepam plasma concentrations.

The possible influence of long-term treatment with lansoprazole on the single-dose pharmacokinetics of diazepam was investigated in 12 healthy male volunteers. In this double-blind randomized crossover study, 60 mg lansoprazole or placebo was administered once daily for 10 days. One hour after administration on day 7, 0.1 mg/kg diazepam was administered intravenously, and blood was collected up to 96 hours after the injection for plasma diazepam and desmethyldiazepam measurement. During the placebo session, the plasma elimination half-life, clearance, and volume of distribution of diazepam were 26.0 +/- 1.6 hours, 22.5 +/- 1.1 ml/hr/kg, and 0.82 +/- 0.04 L/kg, respectively. These parameters were not significantly different during the lansoprazole session. The mean plasma concentrations of desmethyldiazepam were similar in both sessions. These findings illustrate that long-term treatment with a therapeutic dose of lansoprazole does not interfere with the metabolism of diazepam.

2-Pyridinylmethylsulfinylbenzimidazoles↗

Release of vasoactive intestinal polypeptide from the rat gastric fundus.

1. Auxotonic responses and release of vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI) induced by electrical field stimulation (EFS) were studied in longitudinal muscle strips from the gastric fundus of reserpinized rats suspended between parallel platinum electrodes in Krebs solution containing atropine (1 microM), 5-hydroxytryptamine (3 microM) and bovine serum albumin (50 mg l-1). 2. EFS (supramaximal voltage, 1 ms, 0.25-32.0 Hz, trains of 2 min) induced frequency-dependent relaxations. 3. EFS at frequencies greater than or equal to 8 Hz also produced significant increases in VIP-LI release. 4. VIP-LI release induced by EFS at 16 Hz no longer occurred in the presence of tetrodotoxin (1 microM) or a Ca(2+)-free medium. 5. Detection of VIP-LI upon activation of inhibitory non-adrenergic, non-cholinergic neurones indicates that VIP meets the 'detectable release' criterion for an inhibitory neurotransmitter in the rat gastric fundus.

Animals↗

Influence of NG-nitro-L-arginine methyl ester on vagally induced gastric relaxation in the anaesthetized rat.

1. The influence of the nitric oxide (NO) biosynthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the gastric relaxation induced by peripheral vagal stimulation was investigated in the anaesthetized rat. 2. Peripheral vagal stimulation (10 Hz, 10 V, 1 ms for 20 s) induced a reproducible biphasic response: a short-lasting increase followed by a more pronounced decrease in intragastric pressure. This response also occurred in reserpinized animals (5 mg kg-1, i.p., 24 h before the experiment) while atropine (1 mg kg-1, i.v.) abolished the initial increase in intragastric pressure. 3. L-NAME (1-30 mg kg-1, i.v.) induced an increase in arterial blood pressure. L-NAME (1 mg kg-1, i.v.) had no influence on the vagally induced gastric response while L-NAME (10 and 30 mg kg-1 i.v.) significantly changed it: the initial increase in intragastric pressure was enhanced while the decrease in intragastric pressure was reduced or abolished. NG-nitro-L-arginine (L-NNA, 10 mg kg-1, i.v.) had the same effect. 4. An i.v. infusion of phenylephrine (10 micrograms kg-1 min-1) inducing a pressor response similar to that produced by L-NAME (30 mg kg-1, i.v.) did not influence the vagal gastric response. Infusion of L-arginine (300 mg kg-1 bolus, then 100 mg kg-1 h-1) starting 30 min beforehand, reduced the pressor effect and prevented the influence of L-NAME (10 mg kg-1, i.v.) on the vagal gastric response. Infusion of L-arginine (300mgkg-' bolus, then lOOmgkg-lh-') starting 30min beforehand, reduced the pressor effect and prevented the influence of L-NAME (lOmgkg-,i.v.) on the vagal gastric response. After injection of both atropine (lmgkg-', i.v.) and L-NAME (30mgkg-', i.v.), the vagally induced decrease in intragastric pressure was similar to that obtained under control conditions.5. These results are consistent with NO being released and inducing gastric relaxation during peripheral vagal stimulation. In addition to NO, another inhibitory non-adrenergic non-cholinergic neurotransmitter is released.

Anesthesia↗

Influence of NG-nitro-L-arginine on non-adrenergic non-cholinergic relaxation in the guinea-pig gastric fundus.

1. The influence of NG-nitro-L-Arginine (L-NNA) on non-adrenergic non-cholinergic (NANC) relaxations induced by electrical field stimulation was investigated in circular muscle strips of the guinea-pig gastric fundus. 2. In the presence of 10(-6) M atropine and 4 x 10(-6) M guanethidine, electrical field stimulation (40 V, 1 ms, 0.125-16 Hz) with 10 s trains at 5 min intervals induced short-lasting, frequency-dependent relaxations. Continuous stimulation, with cumulative increase of the stimulation frequency, induced sustained frequency-dependent relaxations. Both types of response were abolished by 3 x 10(-6) M tetrodotoxin. 3. L-NNA (10(-5) M and 10(-4) M) concentration-dependently reduced both types of NANC response. Pre-incubation with 2 x 10(-3) M L-arginine prevented the inhibitory action of 10(-5) M L-NNA and partially antagonized that of 10(-4) M L-NNA. D-arginine (2 x 10(-3) M) did not protect against the inhibitory effect of L-NNA. 4. L-NNA did not consistently influence the basal tone of the tissues. L-Arginine and D-arginine likewise did not influence basal tone; they also had no influence on the electrically-induced NANC relaxations. 5. NO (10(-6)-10(-4) M) induced short-lasting concentration-dependent relaxations, while vasoactive intestinal polypeptide (VIP, (10(-9)-10(-7) M) induced more sustained relaxations, that developed at a slower rate. The NO- and VIP-induced relaxations were not influenced by 10(-4) M L-NNA.6. These results suggest that NO is involved in NANC neurotransmission of the guinea-pig gastric fundus; its contribution to sustained NANC relaxation in the guinea-pig gastric fundus is much more important than in the rat.

Animals↗

Modulation of non-adrenergic non-cholinergic inhibitory neurotransmission in rat gastric fundus by the alpha 2-adrenoceptor agonist, UK-14,304.

1. The influence of the alpha 2-adrenoceptor agonist, UK-14,304, on non-adrenergic non-cholinergic (NANC) relaxation induced by electrical field stimulation was investigated in longitudinal muscle strips of the gastric fundus of reserpinized rats. 2. In tissues where tone was raised by 3 x 10(-7) M prostaglandin F2 alpha (PGF2 alpha), the inhibitory effect of 10(-6) M UK-14,304, on the NANC relaxations induced by short train stimulation (40 V, 1 ms, 20 s) was inversely related to the stimulus frequency (1-4-16 Hz). UK-14,304 (10(-6) M) did not influence relaxations induced by administration of exogenous nitric oxide (NO, 2 x 10(-6) M-10(-4) M). The inhibitory effect of UK-14,304 on the electrically induced relaxations was antagonized by 10(-6) M rauwolscine but not by 10(-6) M prazosin. 3. UK-14,304 (10(-6) M) also reduced the amplitude of the sustained NANC relaxation, induced by electrical field stimulation (40 V, 1 ms, 4 Hz) for 5 min. The effect of UK-14,304 was also antagonized by 10(-6) M rauwolscine but not by 10(-6) M prazosin. UK-14,304 (10(-6) M) did not reduce the relaxation induced by 3 x 10(-9) M vasoactive intestinal polypeptide (VIP). 4. These results suggest that the release of the inhibitory NANC neurotransmitter during short train stimulation, thought to be NO, and during sustained stimulation, thought to be VIP, is inhibited by stimulation of presynaptic alpha 2-adrenoceptors in the rat gastric fundus.

Adrenergic alpha-Agonists↗

Nitric oxide is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens in vitro.

1. In the guinea-pig colon ascendens, 5-hydroxytryptamine (5-HT) induces contractions, mediated by 5-HT2, 5-HT3 and 5-HT4 receptors, and relaxations, through a 5-HT1 receptor subtype, that triggers the release of an inhibitory neurotransmitter. Nitric oxide (NO) is one of the main candidates of NANC inhibitory neurotransmission in the gut. The aim of this study was to establish whether NO is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens. 2. Antagonists to block the contractile responses to 5-HT via 5-HT2, 5-HT3 and 5-HT4 receptors were present throughout the experiments and methacholine was administered to precontract the strips. Under these conditions, 5-HT concentration-dependently induced relaxations from 10 nM onwards (EC50 = 258 (172-387) nM). The relaxations were inhibited by metergoline (10 nM) and methiothepine (100 nM) and abolished by tetrodotoxin (TTX, 320 nM). Guanethidine (3.2 microM) did not affect them. 3. NG-nitro-L-arginine (L-NNA) inhibited the responses to 5-HT (IC50 = 18.7 (13.3-26.3) microM); at the highest 5-HT concentration a maximum inhibition of about 75% was observed with 320 microM L-NNA. This inhibition was reversed with L-arginine. Relaxations to glyceryl trinitrate (GTN) were not inhibited by L-NNA. 4. Haemoglobin (32 microM) inhibited the relaxations to 5-HT and GTN, but not those to isoprenaline (Iso). Methylene blue (10 microM) inhibited the relaxations to 5-HT but did not affect those caused by GTN or Iso. 5. It is concluded that 5-HT induces relaxations that involve NO.We also confirmed that 5-HT induces these relaxations via (a) 5-HT, receptor subtype(s), located on neurones.

Animals↗

The inhibitory effect of dopamine on cat gastric smooth muscle.

The inhibitory effect of dopamine has been studied in longitudinal and circular muscle strips of the cat gastric fundus. When tone was raised by transmural electrical stimulation and by administration of methacholine, dopamine concentration-dependently relaxed the strips but the inhibitory effect of dopamine was clearly more pronounced on electrically-induced tone. The effect of dopamine was not influenced by the presence of cocaine or hydrocortisone. The relaxant effect of dopamine, when tone was raised by methacholine, was not influenced by alpha- and dopamine receptor antagonists but it was significantly reduced by propranolol and ICI 118551 (erythro-DL-1-(7-methylindan-4-yloxy)-3- isopropylaminobutan-2-ol). The inhibitory effect of dopamine on the electrically-induced tone was significantly reduced by phentolamine; domperidone tended to reduce the effect of the lower concentrations of dopamine. In the presence of propranolol, phentolamine and rauwolscine concentration-dependently antagonized the inhibitory effect of dopamine on electrically-induced tone, while prazosin was without influence. These results indicate that the inhibitory effect of dopamine in the cat gastric fundus is mainly due to interaction with postjunctional beta 2-adrenoceptors on the smooth muscle cells and with prejunctional alpha 2-adrenoceptors on the intramural cholinergic neurons.

Adrenergic alpha-Antagonists↗

Urinary excretion of ephedrine after nasal application in healthy volunteers.

The urinary excretion of ephedrine after intranasal administration of the drug was studied in 8 healthy volunteers. Ephedrine (6 drops of a commercial 0.75% nasal ephedrine solution in each nasal cavity) was administered 4 times at intervals of 2 h (total amount applied equivalent to approximately 14 mg ephedrine), and urine was collected each hour for 10 h; the volunteers exercised on a bicycle ergometer at 50% of their VO2max for 2 h after the last ephedrine application. Ephedrine was detected in all urine samples. The urinary ephedrine concentration ranged from 0.9 to 16.5 micrograms mL-1; the number of urine samples with an ephedrine concentration exceeding 5 micrograms mL-1 ranged from 1/10 (volunteer 2) to 9/10 (volunteers 1 and 3). The mean percentage of dose recovered within 10 h was 33% (range 23-50%). There was a weak but significant negative correlation between urinary pH and amount of ephedrine in the urine; exercise did not consistently influence the urinary amount. These results illustrate the systemic availability of ephedrine upon intranasal administration and show that the therapeutic use of a nasal ephedrine formulation by an athlete on the day of a competition can lead to a urinary ephedrine concentration above 5 micrograms mL-1, which is considered positive in current doping regulations of the International Union of Cyclists.

Administration, Intranasal↗

Influence of thiorphan and phosphoramidon on the relaxant effect of vasoactive intestinal polypeptide and non-adrenergic non-cholinergic neurone stimulation in the rat gastric fundus.

Relaxations were induced in longitudinal muscle strips of the rat gastric fundus by exogenous administration of vasoactive intestinal polypeptide (VIP) and by transmural stimulation in the presence of atropine. These responses were not influenced by two neutral endopeptidase inhibitors, thiorphan (3 X 10(-5) M) and phosphoramidon (10(-5) M). This suggests that neutral endopeptidase is not involved in the breakdown of exogenous VIP and non-adrenergic non-cholinergic inhibitory transmitters of the rat gastric fundus.

Animals↗

Determination of cetirizine in human urine by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the determination of the histamine H1-receptor antagonist cetirizine in human urine was developed. Cetirizine and the internal standard are extracted from acidified (pH 5) urine (0.5 ml) into chloroform and the organic layer is evaporated to dryness. The residue is chromatographed on a Spherisorb 5ODS-2 column using Pic A (5 mM aqueous tetrabutylammonium phosphate)-methanol-tetrahydrofuran (33:65:2, v/v) as the mobile phase with ultraviolet detection (230 nm). The calibration graph is linear from 0.1 to 10 micrograms/ml and using 0.5 ml of urine the detection limit is 20 ng/ml. The within-run relative standard deviation is less than 6% and the accuracy is within 10% of the theoretical value at concentrations between 0.1 and 10 micrograms/ml in urine. There is a good correlation (r = 0.99606) with a previously described capillary gas chromatographic assay.

Administration, Oral↗

Relaxant effect of capsaicin in the rat gastric fundus.

The effect of capsaicin was studied in precontracted longitudinal muscle strips of the rat gastric fundus. Capsaicin induced a relaxation in the concentration range 10(-7)-10(-6) M. The relaxation induced by 10(-6) M capsaicin was completely prevented by extrinsic denervation of the stomach. The adrenoceptor antagonists phentolamine and propranolol did not influence the effect of capsaicin while hexamethonium potentiated it; this potentiation was not observed with another nicotinic receptor antagonist trimethaphan. Tetrodotoxin did not have a consistent effect as it reduced the capsaicin-induced relaxation in some but not all tissues. The peptidase trypsin consistently reduced the action of capsaicin but vasoactive intestinal polypeptide (VIP) antiserum, desensitization to calcitonin gene-related peptide (CGRP), and CGRP antiserum had no influence. The neuropeptide involved in the relaxant effect of capsaicin in the rat gastric fundus has thus still to be determined.

Animals↗

Motor activity and neurotransmitter release in the gastric fundus of streptozotocin-diabetic rats.

As deficiencies of the cholinergic and non-adrenergic non-cholinergic innervation of the gastrointestinal tract have been described in diabetic rats, we studied the simultaneous release of, and muscular response to, acetylcholine, vasoactive intestinal polypeptide and adenosine-5'-triphosphate in isolated preparations of gastric fundus from control and 8-week streptozotocin-treated diabetic rats. Muscular responses were measured in longitudinal muscle strips prepared from one half of the gastric fundus and release was studied in the other half. The contractile response to acetylcholine and electrical field stimulation was not different in control and diabetic rats. In the presence of atropine, and when tone was increased with prostaglandin F2 alpha, electrical field stimulation, vasoactive intestinal polypeptide and adenosine-5'-triphosphate induced relaxation with a similar response in control and diabetic rats. The basal release of acetylcholine, vasoactive intestinal polypeptide and adenosine-5'-triphosphate was not significantly different in control and diabetic rats. Electrical field stimulation significantly increased the release of the three substances and this increase was tetrodotoxin-sensitive. While the stimulation-induced increase of acetylcholine and vasoactive intestinal polypeptide was not different in control and in diabetic rats, the stimulation-induced release of adenosine-5'-triphosphate increased 3-fold in diabetic compared to control gastric fundus. Desensitization to alpha,beta-methylene adenosine-5'-triphosphate reduced the relaxant response to adenosine-5'-triphosphate and to electrical field stimulation, suggesting a role of adenosine-5'-triphosphate in non-adrenergic non-cholinergic neurotransmission of rat gastric fundus. The reduction of the non-adrenergic non-cholinergic relaxation by alpha,beta-methylene adenosine-5'-triphosphate was greater in diabetic tissues. This, with the increase in stimulation-induced adenosine-5'-triphosphate release, suggests that the purinergic component of the vagal non-adrenergic non-cholinergic response of the stomach may be increased in diabetics.

Adenosine Triphosphate↗

Comparison of the bioavailability of two slow release preparations of disopyramide.

The bioavailability of two slow release preparations of disopyramide has been compared in a randomized cross-over trial of Rythmodan L.A. 250 mg b.d. and Dirytmin Durettes 300 mg b.d., given to 10 healthy volunteers. The plasma concentrations of disopyramide were measured on the 5th day of each treatment period. With both preparations, plasma concentrations were well sustained. The amount absorbed was slightly lower after Rythmodan L.A. than after Dirytmin Durettes, but the fluctuations over a dosing interval were significantly more pronounced for Dirytmin Durettes than for Rythmodan L.A.

Adult↗

Study of the muscarinic receptor subtypes in N1E 115 mouse neuroblastoma cells.

Muscarinic receptors in N1E 115 mouse neuroblastoma cells were characterized by competition binding experiments using three agonists and five antagonists, including 4-DAMP and AF-DX 116, and by studying the effect of agonist stimulation on the cellular cAMP and cGMP content. The results of the binding studies with the antagonists suggest that only one single homogeneous binding site of the M1 muscarinic receptor subtype is present. For the binding with the agonists, two binding sites were detected, one with high affinity for the ligand (between 53 and 77% of the total binding sites depending on the agonist) and one with low affinity. In contrast to the results obtained with the binding experiments using antagonists, the study of the cellular cyclic nucleotide response upon carbachol stimulation suggested the presence of both the M1 and M2 subtypes as there was an increase in cyclic GMP concentration while at the same time, the prostaglandin-stimulated synthesis of cyclic AMP was inhibited. Considering both binding and functional data we suggest that in N1E 115 cells a majority of M1 and a minority of M2 muscarinic receptors are present; there is no evidence for the presence of M3 muscarinic receptors.

Animals↗

Effect of apamin on the responses to VIP, ATP and NANC neurone stimulation in the rat and cat gastric fundus.

1. The influence of apamin on non-adrenergic non-cholinergic (NANC) relaxation and on the effect of the putative transmitters VIP and ATP was examined in the rat and cat gastric fundus. 2. In longitudinal muscle strips of the rat gastric fundus, ATP induced a biphasic effect, relaxation followed by contraction. The relaxant effect of ATP was blocked by apamin, whereas the relaxations induced by VIP and NANC neurone stimulation were not influenced by apamin. 3. In circular and longitudinal muscle strips of the cat gastric fundus, ATP only induced relaxation at high concentrations. The ATP-induced relaxation was increased in the presence of apamin, whereas the VIP-induced and NANC relaxations were not influenced. 4. It is concluded that the relaxant effect of ATP might be related to activation of apamin-sensitive Ca(2+)-dependent K(+)-channels in the rat gastric fundus. In the cat gastric fundus, apamin did not antagonize the relaxant effect of ATP so that it cannot be used to investigate an ATP involvement in inhibitory NANC neurotransmission in this tissue. No evidence for a presynaptic inhibitory action of apamin on VIP-ergic NANC neurones was obtained.

Adenosine Triphosphate↗

Effect of co-dergocrine in the autoperfused superior mesenteric vascular bed of the rat.

1. The influence of local administration of co-dergocrine in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat was investigated. 2. Local infusion of co-dergocrine (0.1 micrograms kg-1 min-1) reduced the pressor response to electrical stimulation of the periarterial sympathetic nerves for the whole frequency range studied during cumulative frequency-response curves (1-8 Hz). 3. Co-dergocrine (0.01, 0.03, 0.1 micrograms kg-1 min-1) dose-dependently inhibited the pressor response to electrical stimulation at 4 Hz; increases in perfusion pressure produced by locally administered noradrenaline were inhibited to the same degree. 4. Pressor responses induced by locally administered phenylephrine were also inhibited by co-dergocrine (0.1 micrograms kg-1 min-1) while those produced by local injection of angiotensin II were not. 5. Local administration of the DA1-/DA2-receptor antagonist haloperidol (1 microgram kg-1), the DA2-receptor antagonist domperidone (10 micrograms kg-1) and the alpha 2-adrenoceptor antagonist rauwolscine (100 micrograms kg-1) partially prevented the influence of co-dergocrine on the electrically induced response. 6. The results show that the effect of co-dergocrine in the rat superior mesenteric vascular bed cannot simply be ascribed to interaction with the presynaptic inhibitory DA2-receptors on the noradrenergic nerve endings; it also has an antagonistic action at the postsynaptic alpha 1-adrenoceptors and an agonist action at the presynaptic alpha 2-adrenoceptors.

Angiotensin II↗