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Biomedical subjects

R A Lefebvre

Publications and source records attributed to R A Lefebvre.

At least 73 records · Page 4Linked to original sources
PubMed1994

Nitric oxide causes contraction in the rat isolated small intestine.

The effect of authentic nitric oxide (NO) was investigated on rat ileal myenteric plexus-longitudinal muscle strips in the presence of atropine. NO (10(-10) to 3 x 10(-6) M) caused a quick, transient contraction of the smooth muscle, with an optimum concentration of 10(-7) M, as well as a slower contraction with a higher optimum concentration. In preparations sub-maximally pre-contracted with 5-hydroxytryptamine, NO (10(-7) to 3 x 10(-6) M) also caused a quick relaxant response. These responses to NO (10(-6) M) were not influenced by tetrodotoxin, indicating a direct effect on the smooth muscle.

Animals↗
PubMed1994

Capillary gas chromatographic determination with nitrogen-phosphorus detection of the calcium antagonist nicardipine and its pyridine metabolite M-5 in plasma.

A capillary gas chromatographic method with nitrogen-phosphorus detection for the simultaneous determination of nicardipine and its pyridine metabolite M-5 was developed. The method involves extraction of the plasma with hexane-methylene chloride (1:1, v/v), followed by evaporation of the organic phase. The extract is injected into a fused-silica capillary column coated with cross-linked 5% phenyl-methylsilicone. A temperature gradient (85-285 degrees C) is applied and the two products and the internal standard can be separated within 22 min. The limit of detection is 0.5 ng/ml for both products. The method is suitable for pharmacokinetic studies in humans.

Calibration↗
PubMed1994

In vitro and in vivo evaluation in dogs and pigs of a hydrophilic matrix containing propylthiouracil.

A hydrophilic matrix tablet containing 300 mg of propylthiouracil was formulated with several types of hydroxypropylmethylcellulose. The influence of polymer and drug granule particle size, polymer concentration, crystallinity and geometry of the polymer particles, the polymer incorporation outside or inside the granule, addition of a filler and tablet hardness were studied. Polymer concentration, polymer particle size and geometry, filler addition and type of the filler used had a major influence on in vitro drug dissolution profiles. The bioavailability of propylthiouracil in dogs from the hydrophilic matrices investigated was low, because of the short gastro-intestinal transit times of the matrix tablets in the dogs. The matrix tablets reached the colon in fasted dogs within 2-3 hours after administration. The results indicated the poor predictability of bioavailability experiments in dogs with hydrophilic matrices. Although the bioavailability data in pigs seemed promising, a transit time study revealed a long stomach residence time of the matrix tablets in pigs. These data suggested that pigs are an inappropriate animal model for bioavailability studies of erodible matrix tablets.

Animals↗
PubMed1994

Tachykinin receptors involved in the contractile effect of the natural tachykinins in the rat gastric fundus.

1. The receptors involved in mammalian tachykinin-induced contractions of longitudinal smooth muscle strips of the rat gastric fundus were characterized pharmacologically. 2. Substance P (SP), neurokinin A, neurokinin B and senktide contracted the strips in a concentration-dependent manner with a potency order of neurokinin A > or = senktide > neurokinin B > substance P. The contractions were not influenced by tetrodotoxin and atropine. 3. L 659877, a NK2B-receptor-preferring antagonist reduced neurokinin A- and neurokinin B-induced contractions (estimated pKB 6.9 and 6.3, respectively) but had less pronounced effects on SP-induced contractions and none on contractions induced by senktide. MEN 10376, an NK2A-receptor-preferring antagonist, reduced the neurokinin A-induced contractions (estimated pKB 5.2), while dactinomycin, reduced the neurokinin A-induced contractions only to a minor extent at 10(-4) M. 4. CP 96345, an NK 1-receptor antagonist, reduced substance P- and neurokinin A-induced responses, but also reduced the contractions induced by KCl and methacholine. RP 67580, another non-peptide NK1-receptor antagonist had no effect on the substance P-, neurokinin A- and neurokinin B-induced contractions up to a concentration of 3 x 10(-6) M. 5. These results suggest that the mammalian tachykinins induce contractions of the longitudinal smooth muscle strip of the rat gastric fundus by direct action at muscular NK2B- and NK3-receptors.

Animals↗
PubMed1994

Influence of S-nitrosothiols and nitrate tolerance in the rat gastric fundus.

1. The relaxant responses of S-nitroso-L-cysteine (CysNO), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), S-nitroso-N-acetyl-L-cysteine (SNAC) and S-nitrosoglutathione (GSNO) in the rat gastric fundus (forestomach) were studied and compared to the relaxant responses obtained in response to nitric oxide (NO) and electrical field stimulation (EFS, 10 s strains) of non-adrenergic non-cholinergic (NANC) nerves. 2. CysNO (10(-7)-3 x 10(-4) M) caused transient relaxation of the precontracted rat gastric fundus, comparable to the response to NO (10(-6)-10(-4) M) and EFS. SNAP, SNAC and GSNO elicited more sustained relaxations. 3. The cyclic GMP-specific phosphodiesterase inhibitor, zaprinast (3 x 10(-5) M) increased the relaxant effect of CysNO, SNAP and GSNO while the NO-synthase inhibitor, NG-nitro-L-arginine (L-NOARG, 3 x 10(-4) M) had no influence. 4. In the presence of LY 83583 (10(-5) M), which releases superoxide anions, the relaxant response to NO and CysNO was decreased, whereas that to all other stimuli was unaltered. The inhibitory effect of LY 83583 on CsNO-induced relaxations was prevented by superoxide dismutase (SOD, 1000 u ml-1). 5. Tissues incubated for 1 h with 5.5 x 10(-4) M nitroglycerin (GTN) became tolerant to GTN. In this condition, the relaxant response to 10(-5) M NO was maintained, while the relaxations by EFS (8 Hz) and 3 x 10(-5) M SNAP were significantly decreased. The reduction of the response to the other S-nitrosothiols was not significant. 6. The combination of nitrate tolerance and 10-5 M LY 83583 caused a significantly larger inhibition of the relaxant response to EFS (8 Hz) than nitrate tolerance alone. The combination of LY 83583 and GTN tolerance reduced the relaxant effect of 10-5 M NO to a similar extent to LY 83583 alone, while the relaxant response to 10-4 M GTN was reduced to the same extent as after 1 h exposure to 5.5 x 10-4 M GTN alone.7. It is concluded that S-nitrosothiols potently relax the rat gastric fundus, possibly by a cyclic GMP-dependent mechanism and S-nitrosothiols such as SNAC and GSNO may be involved in NANC neurotransmission.

Aminoquinolines↗
PubMed1993

Substance P-induced contractions of the guinea-pig proximal colon through stimulation of post-junctional tachykinin NK1 receptors.

The effects of three tachykinin NK1 receptor antagonists and a tachykinin NK2 receptor antagonist against substance P-induced contractions of the guinea-pig proximal colon longitudinal muscle were investigated. Atropine, tetrodotoxin and phosphoramidon did not affect the concentration-response curve for substance P (pEC50 = 7.8). The tachykinin NK1 receptor antagonist, 2S,3S-cis-CP 96345, competitively inhibited the contractions due to substance P (pA2 = 8.5; constrained pA2 = 8.9), but at higher concentrations (> or = 3 x 10(-7) M), 2S,3S-cis-CP 96345 also depressed the concentration-response curve for methacholine. The species-selective tachykinin NK1 receptor antagonists, WIN 51708 and WIN 62577 (both 1 x 10(-6) M), and the tachykinin NK2 receptor antagonist, SR 48968 (3 x 10(-7) M), had no effect. It is concluded that substance P induces contractions through the stimulation of tachykinin NK1 receptors on the smooth muscle cells. In this preparation, tachykinin NK2 receptors do not seem to be involved in the contractile action of substance P.

Androstanes↗
PubMed1993

Involvement of vasoactive intestinal polypeptide in gastric reflex relaxation.

We have previously presented evidence for a non-adrenergic, vagally mediated colono-gastric inhibitory reflex induced by distension of the colon. We also found that pain stimulation by putting pressure on a testicle induced a pronounced gastric relaxation mediated by both adrenergic and vagal non-adrenergic fibres in anesthetized rats. Previous in vitro studies by other workers have strongly indicated that vasoactive intestinal polypeptide (VIP) is a neural mediator of gastric relaxation. The aim of the present in vivo study was to investigate, in anesthetized rats, whether VIP is involved in the gastric reflex relaxation induced by colonic distension and pain stimulation. A volumetric method was used to monitor changes in gastric volume. Gastric reflex relaxation following colonic distension was significantly and markedly inhibited by VIP antiserum as compared to the control relaxation before administration of the antiserum. Non-immunized control serum did not significantly influence gastric relaxation caused by colonic distension. Pain-induced gastric relaxation was moderately but significantly reduced after the administration of VIP antiserum but not after control serum. The selective beta 2-adrenoceptor agonist, salbutamol, induced a pronounced gastric relaxation of the same magnitude before and after the administration of VIP antiserum. VIP antiserum changed the pattern of gastric motility by inducing a specific type of gastric contraction appearing spontaneously or in response to colonic distension. A close intra-arterial injection of VIP induced gastric relaxation and inhibition of phasic gastric contractions. The present results in the rat suggest that VIP or a VIP-like peptide is involved in gastric reflex relaxation induced by colonic distension and pain stimulation.

Animals↗
PubMed1993

Cisapride and a structural analogue, R 76,186, are 5-hydroxytryptamine4 (5-HT4) receptor agonists on the guinea-pig colon ascendens.

UNLABELLED: The purpose of this study was to investigate whether the effects of cisapride and its close structural analogue R 76,186 on the isolated guinea-pig colon ascendens, are mediated through 5-HT4 receptors. Both cisapride and R 76,186 induced contractions in a concentration-dependent fashion, giving monophasic concentration-response curves (cisapride: EC50 = 1.1 x 10(-7) M, maximum effect = 40.3% of methacholine-induced (3 x 10(-7) M) contractions; R 76,186: EC50 = 2.4 x 10(-8) M, maximum effect = 52.1%). Blockade of either 5-HT2 or 5-HT3 receptors did not affect the responses to cisapride. However, tropisetron (in 5-HT4 receptor-blocking concentrations), and DAU 6285 and SDZ 205-557, two novel selective 5-HT4 receptor antagonists, depressed the concentration-response curve to cisapride (to about 50%), and the curve to R 76,186 was shifted to the right. The apparent pA2 values were 6.6 (tropisetron), 6.3 (DAU 6285), and 7.5 (SDZ 205-557). However, none of these antagonisms was purely competitive as higher concentrations of these antagonists depressed the curve to R 76,186. Desensitization of the 5-HT4 receptor with 5-methoxytryptamine (5-MeOT) inhibited the responses to cisapride, and abolished those to R 76,186. The contractions to cisapride and R 76,186 were sensitive to mutual antagonism, depressing their concentration-response curves. CONCLUSIONS: Both cisapride and R 76,186 mediate their contractile effects in the guinea-pig colon ascendens through agonism at the 5-HT4 receptor, though cisapride also uses a non-5-HT mechanism. R 76,186 is a selective and potent 5-HT4 receptor agonist.

4-Aminobenzoic Acid↗
PubMed1993

Influence of the application site on bioadhesion and slow-release characteristics of a bioadhesive buccal slow-release tablet of miconazole.

The influence of the application site on bioadhesion and release characteristics of a bioadhesive buccal slow-release tablet of miconazole has been evaluated. The adhesion time and salivary miconazole levels were measured after application of the tablet to the gingiva, the cheek and the palate in 10 healthy volunteers. The longest adhesion time noted was for the gingiva (565 min), compared to the palate and cheek with adhesion times of 210 and 243 min, respectively. Tablets adherent to the palate showed the highest initial salivary drug levels, followed by those adherent to the cheek and gingiva, respectively. The clearance rate from the oral cavity was similar when the tablet was applied to the palate and the cheek, but it was markedly decreased when applied to the gingiva. It is concluded that the gingiva is the best site for application of a bioadhesive buccal system for local therapy. A study in 8 comatose intubated patients showed that the application site had to be adapted to the state of the patients treated, as salivary miconazole concentrations comparable to those observed with the gingival tablet in healthy volunteers, were obtained after application to the cheek.

Adhesiveness↗
PubMed1993

In vitro/in vivo correlation of the bioadhesive properties of a buccal bioadhesive miconazole slow-release tablet.

An in vitro-in vivo correlation study was performed on the bioadhesive properties of three buccal formulations based on modified starch (drum-dried waxy maize)/polyacrylic acid mixtures. Mixtures containing 10 mg miconazole nitrate, characterized by a different in vitro detachment force and work of adhesion, were evaluated for their bioadhesive properties in human volunteers. The results obtained showed that no significant difference could be seen among the formulations in vivo. The in vitro method showed no significant influence of miconazole nitrate on the bioadhesion properties of the polymers, while the in vivo adhesion time of the pure polymer mixtures was significantly higher than for the polymers containing miconazole. The results from the in vitro method thus did not correlate well with the in vivo data. The in vitro method provided information only on the initial bioadhesion and no correlation could be made with the residence time of the tablet in the oral cavity.

Acrylic Resins↗
PubMed1993

Involvement of the L-arginine: nitric oxide pathway in nonadrenergic noncholinergic relaxation of the cat gastric fundus.

Vasoactive intestinal polypeptide (VIP) is a neurotransmitter of nonadrenergic noncholinergic (NANC) nerves in the cat gastric fundus. A possible additional role for nitric oxide (NO) was investigated in circular and longitudinal muscle strips from this tissue. Incubation with the inhibitor of NO-synthesis, NG-nitro-L-arginine methyl ester (L-NAME, 3 x 10(-4) M), inhibited the relaxant response to both short- and long-lasting electrical field stimulation. The substrate for NO synthesis, L-arginine (2 x 10(-3) M), prevented this inhibition. In experiments with long-lasting electrical field stimulation, trypsin (3 x 10(-6) M) and L-NAME inhibited the beginning of the NANC relaxation to the same extent, but the inhibition by trypsin was more pronounced at the end of the stimulation period. The inhibitory effect of L-NAME and trypsin was additive. L-NAME did not influence the relaxations induced by VIP (10(-7) M), NO (10(-5) M) and isoprenaline (3 x 10(-6) M). NG-nitro-L-arginine (3 x 10(-4) M) also did not change the response to VIP. The relaxation induced by 10(-5) M NO was not transient but was sustained. The plateau phase of this relaxation was reduced by trypsin but not by 3 x 10(-6) M tetrodotoxin. It is concluded that NO is involved in NANC relaxation of the cat gastric fundus. During sustained NANC relaxation in the cat gastric fundus, cotransmission of NO and VIP is possible.

Adrenergic Fibers↗
PubMed1992

Influence of age on responsiveness of rat gastric fundus to agonists and to stimulation of intrinsic nerves.

The contractile effect of methacholine, prostaglandin F2 alpha (PGF2 alpha) and electrical stimulation of cholinergic neurones, and the relaxant effect of nitric oxide (NO), vasoactive intestinal polypeptide (VIP) and electrical stimulation of inhibitory non-adrenergic non-cholinergic (NANC) neurones were studied in longitudinal smooth muscle strips of the gastric fundus of young (3 months), adult (12 months) and old (24 months) male Wistar rats. The contractile responses to methacholine and to electrical stimulation of cholinergic neurones were not significantly different between the three age groups. The responses to PGF2 alpha were significantly more pronounced in young than in adult and old rats. The relaxant response to electrical stimulation of NANC neurones with a cumulative increase in frequency showed a decreased response in old rats at the higher stimulation frequencies. This was mimicked by a decreased response to VIP, suggesting that there is a decrease in muscular sensitivity to VIP rather than an impaired capacity to VIP release with increasing age. The relaxant response to electrical stimulation of NANC neurones with short trains was similar in the three age groups, while the sensitivity to exogenous NO increased with age. The latter might be a compensatory mechanism for a decrease in stimulation-induced NO release with age.

Aging↗
PubMed1992

Influence of vasoactive intestinal polypeptide and NG-nitro-L-arginine methyl ester on cholinergic neurotransmission in the rat gastric fundus.

The possible modulating effect of vasoactive intestinal polypeptide (VIP) and nitric oxide (NO), on cholinergic neurotransmission was assessed in longitudinal muscle strips of rat gastric fundus. VIP and NO are the putative co-transmitters of the inhibitory non-adrenergic non-cholinergic (NANC) neurones in this tissue. VIP concentration dependently inhibited cholinergic contractions induced by 2-min transmural stimulation, relaxed tissues, the tone of which was continuously raised by transmural stimulation, and shifted to the right the frequency-response curves for contraction induced by transmural stimulation with a cumulative increase of frequency. The same effect was found when contractions were induced with methacholine, suggesting that only functional antagonism at the postsynaptic smooth muscle cell level is involved. On 30-min incubations, 3 x 10(-4) M NG-nitro-L-arginine methyl ester (L-NAME) potentiated cholinergic responses to 20-s transmural stimulation, while not influencing contractions of similar amplitude evoked by methacholine; the cholinergic responses to 2-min transmural stimulation were also not influenced. The potentiating effect of L-NAME was prevented by L-arginine but not D-arginine. These results suggest that endogenous NO released from the inhibitory NANC neurones during short trains of transmural stimulation interferes with cholinergic neurotransmission either by functional antagonism of acetylcholine at the postsynaptic level or by presynaptic inhibition of acetylcholine release.

Acetylcholine↗
PubMed1992

Effect of LY 83583 on relaxation induced by non-adrenergic non-cholinergic nerve stimulation and exogenous nitric oxide in the rat gastric fundus.

In the rat gastric fundus, the reported cGMP-lowering agent LY 83583 (10(-5) M) inhibited the relaxation induced by nitric oxide (NO), without altering the response to isoprenaline, vasoactive intestinal polypeptide, sodium nitroprusside or electrical field stimulation of inhibitory non-adrenergic non-cholinergic neurones, which are thought to release NO. Incubation with superoxide dismutase partially prevented the effect of LY 83583. When added during a relaxation maintained by continuous NO infusion, LY 83583 reversed the relaxation. It is concluded that LY 83583 inactivates exogenous NO through the generation of superoxide anions.

Aminoquinolines↗
PubMed1992

Relaxant effects of BRL 38227 and pinacidil on the rat gastric fundus.

Concentration-effect curves for BRL 38227 (lemakalim) and pinacidil were obtained in longitudinal muscle strips of the rat gastric fundus contracted by prostaglandin F2 alpha. Both agents induced a concentration-dependent relaxation, with BRL 38227 (EC50 = 3 x 10(-6) M) being more potent than pinacidil (EC50 = 8 x 10(-6) M). Glibenclamide (10(-7), 10(-6) and 10(-5) M) antagonized the relaxant effect of BRL 38227 and pinacidil but neither antagonism was of the simple competitive type. Phentolamine (10(-7), 10(-6) and 10(-5) M) competitively antagonized the effect of pinacidil and non-competitively that of BRL 38227. Glibenclamide had no influence on the relaxant effect induced by vasoactive intestinal polypeptide or by electrical field stimulation in the presence of atropine and guanethidine. The results suggest that glibenclamide-sensitive K+ channels are present in the rat gastric fundus and that they do not mediate the inhibitory response to non-adrenergic, non-cholinergic neurostimulation.

Animals↗
PubMed1992

Effect of 3-isobutyl-1-methylxanthine and zaprinast on non-adrenergic non-cholinergic relaxation in the rat gastric fundus.

Vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) have been proposed as inhibitory non-adrenergic non-cholinergic (NANC) neurotransmitters in the rat gastric fundus. The smooth muscle relaxant actions of VIP and NO are medaited by cAMP and cGMP, respectively; therefore the effect of inhibitors of phosphodiesterases responsible for cyclic nucleotide breakdown on relaxation induced by VIP, NO and electrical field stimulation was investigated. The non-specific phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), the cGMP-specific phosphodiesterase inhibitor, zaprinast, the adenylate cyclase activator, forskolin, and the cyclic nucleotide analog, 8-bromo cGMP, produced concentration-dependent relaxation of rat gastric fundus strips precontracted by PGF2 alpha. IBMX potentiated isoprenaline-induced relaxation but not relaxation induced by sodium nitroprusside, VIP, NO or electrical field stimulation. Zaprinast potentiated the relaxation induced by sodium nitroprusside, while having no influence on relaxation due to any other stimulus. The combination of both phosphodiesterase inhibitors did not significantly affect the electrically induced relaxation. It is concluded that both cAMP and cGMP mediate relaxation in the rat gastric fundus. Further research is needed to investigate the role of the cyclic nucleotides during NANC relaxation of this tissue.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Performance of a modified starch hydrophilic matrix for the sustained release of theophylline in healthy volunteers.

Two experimental formulations of theophylline with a hydrophilic starch matrix were evaluated for their sustained-release characteristics after single administration in healthy human volunteers. Theo-dur was chosen as a reference sustained-release formulation. In a first study, the extent of absorption was similar for a syrup, for Theo-dur, and for the experimental formulation of theophylline with 70% drum-dried corn starch as the sustained-release agent (DDCS-70). The maximal plasma concentration (Cmax) was significantly lower, and the time to reach Cmax as well as the time span during which the plasma concentration was at least 75% of the Cmax were significantly higher for Theo-dur than for the DDCS-70 formulation. A sustained-release profile, as for Theo-dur, was not reached for DDCS-70. In a second study the influence of the starch:drug ratio on the bioavailability was investigated. The decrease in starch content from 70 to 50% of the formulation did not improve the plasma concentration-time profile towards a sustained-release profile.

Adult↗