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Biomedical subjects

J L Junien

Publications and source records attributed to J L Junien.

At least 91 records · Page 5Linked to original sources

JO 1784, a potent and selective ligand for rat and mouse brain sigma-sites.

JO 1784 ((+)-cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene) is a potent ligand for (+)-[3H]SKF 10,047 (2'-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan) binding sites in rat brain membrane preparations with an IC50 of 39 +/- 8 nM, which is comparable to that of haloperidol. The stereoisomer of JO 1784 is ten fold less potent. When administered to mice i.p. or p.o. JO 1784 displaced (+)-[3H]SKF 10,047 (5 muCi i.v.) from its sites in the brain with ID50 values of 1.2 and 3.5 mg kg-1, respectively. The high selectivity of JO 1784 for the sigma-binding site was assessed by its lack of significant affinity for more than 20 other sites including those for phencyclidine.

Animals↗

Effects of fedotozine on gastrointestinal motility in dogs: mechanism of action and related pharmacokinetics.

The effects of fedotozine, (+)-(1R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N,N-dim eth yl- n-propylamine, on motility of the antrum and small intestine were investigated in dog. In fasted dogs, following i.v. administration, fedotozine at 1 and 2 mg kg-1 stimulated and at 5 mg kg-1 inhibited antral motility. Between 1 to 5 mg kg-1, fedotozine exhibited a sustained and potent stimulatory effect on the small intestine inducing 1 to 4 phases III of the migrating motor complex (MMC) lasting up to 32 min in the duodenum and migrating to the jejunum. Following oral administration, fedotozine at 2.5 and 5 mg kg-1 constantly stimulated both antrum and small intestinal motility. In fed dogs, fedotozine i.v. (2 mg kg-1) increased antral motility and induced phase III of MMC in the place of postprandial pattern. Naloxone (0.3 mg kg-1 i.v.) and naloxone methylbromide (2 mg kg-1 i.v.) inhibited the stimulatory effects of fedotozine on gastrointestinal motility indicating a peripheral opiate site of action of the drug whereas phentolamine, hexamethonium, propranolol and methysergide were inactive. In-vitro fedotozine showed submicromolar affinity for opiate receptors with a weak specificity for the mu-receptors in guinea-pig brain and myenteric plexus preparations. Plasma concentrations in dogs receiving fedotozine administered orally at 2.5 mg kg-1 (and in all dogs except one at 5 mg kg-1) were below the detection limit (less than 20 ng g-1). In contrast, tissue concentrations in the muscle and mucosal layers of the gut were above 1 microgram g-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Biochemical and pharmacological evaluation of the novel antidepressant and serotonin uptake inhibitor 2-(3,4-Dichlorobenzyl)-2-dimethylamino-1-propanol hydrochloride.

2-(3,4-Dichlorobenzyl)-2-dimethylamino-1-propanol, hydrochloride (JO 1017) is a novel antidepressant drug. Its biochemical and pharmacological properties were investigated in mice, rats, dogs, rabbits and guinea pigs. In vitro, it selectively inhibited serotonin uptake and had a high affinity for the 3H-paroxetine and 3H-imipramine binding sites. Biochemical studies demonstrated the lack of MAO-A and MAO-B inhibition and the absence of marked affinity for muscarinic, histaminic or other conventional brain receptors. Chronic treatment with JO 1017 induced a decrease in the Bmax values for imipramine sites but did not modify the Bmax for beta-adrenergic and 5-HT2 receptors. The neuropsychopharmacological profile of JO 1017 is characterized by a decrease of the immobility times in behavioural despair tests with mice, a decrease of the escape failures in the rat learned helplessness test, a strong potentiation of L-5-HT P-induced head-twitches in mice and an antagonism of reserpine-induced ptosis in rabbits. It weakly antagonized oxotremorine-induced hypothermia and did not influence the hypothermia induced by apomorphine. In contrast to most other antidepressants, a high dose of JO 1017 induced hypermotility in mice placed in an activity meter without producing stereotyped behaviour and group toxicity. Unlike tricyclic antidepressants, JO 1017 was devoid of severe cardiotoxicity in guinea pigs and had no central anticholinergic nor antihistaminic properties. These results suggest that JO 1017 is a selective serotonin uptake inhibitor with a high safety margin. JO 1017 may have a potential clinical utility both in the treatment of depression and for indications where serotonin transmission is involved, e.g., anxiety, panic attack, obsessive compulsive disorder, obesity and alcohol consumption.

Animals↗

Effect of selective sigma ligands on duodenal alkaline secretion in the rat.

The previous demonstration of sigma receptors localized in the mucosa and the submucosal plexus of the duodenum led us to investigate the activity of two specific sigma (sigma H) receptor ligands, di (ortho-tolyl) guanidine (DTG) and (+) N-allyl normetazocine (d-NANM) on the alkaline secretion of the duodenum in anesthetized rats. DTG (0.25-2 mg/kg, i.v.) and d-NANM (0.5-5 mg/kg, i.v.) induced a dose-related increase of bicarbonate output, from a basal level of 7.6 +/- 0.1 microEq/cm/hr to a stimulated plateau of 14.1 +/- 0.2 and 14.2 +/- 0.2 microEq/cm/hr, respectively, for the next 2 hr. In contrast, the venous injection of I-NANM (5 mg/kg) did not significantly stimulate duodenal bicarbonate output. Intravenous administration of naloxone (0.2 mg/kg) failed to modify the response to both DTG and d-NANM, whereas haloperidol (0.5 mg/kg, i.v.) abolished the response to both drugs. The response to DTG was unchanged after indomethacin (0.25 mg/kg), yohimbine (2 mg/kg), atropine (1 mg/kg), sulpiride (1 mg/kg) or SCH 23,390 (0.45 mg/kg), and partly decreased after prazosin (1 mg/kg). Hexamethonium (1 mg/kg), and tetrodotoxin (5 micrograms/kg) reduced the response to DTG, respectively, by 79% (P less than 0.01) and 91% (P less than 0.01), whereas bilateral vagotomy suppressed it. The cholecystokininA receptor antagonist (-)L364,718 decreased the response to DTG by 91% (P less than 0.01). None of the antagonists changed the basal bicarbonate output but vagotomy, which induced a 52% (P less than 0.01) decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Stimulation of kappa opiate receptors in intestinal wall affects stress-induced increase of plasma cortisol in dogs.

In dogs, an acoustic stress (A.S.) produced by hearing of intense music (less than or equal to 90 dB) through earpieces for 1 h induced a 520% maximal rise in plasma cortisol 15-30 min after the beginning of stress. Oral administration of the specific kappa agonists, U-50488 (0.1 mg/kg) and PD 117302 (0.05 mg/kg), 30 min before the A.S. session reduced significantly (P less than 0.01) by 71.2% and 80.9% the maximal increase of plasma cortisol but did not affect the increase observed after intracerebroventricular administration of ovineCRF (100 ng/kg). These effects which are not reproduced by intravenous administration of the drugs at similar doses, were blocked by previous treatment with MR 2266 (0.1 mg/kg) or local anesthesia and vagotomy, suggesting that kappa opioid agonists inhibit the stress-induced activation of the hypothalamo-pituitary-adrenocortical (HPA) system by acting selectively on specific receptors located in the wall of the proximal gut.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

[Effects of trimebutine on intestinal motility in dogs].

The effects of intravenous, oral, intracerebroventricular and local intra-arterial administration of trimebutine were investigated in dogs whose digestive tract had been fitted with electrodes and strain gauge transducers. In fasted conscious dogs, trimebutine (5 mg/kg) stimulated small bowel motility with induction of a propagated phase of regular spiking activity. This stimulation was associated with weak inhibition of gastric motility and a biphasic response of the colon characterized by stimulation followed by inhibition. By the oral route, trimebutine (20 mg/kg) stimulated gastrointestinal motility. The duration of the intestinal migrating phase 2 was increased whereas an additional migrating phase 3 developed. These effects were associated with an increase in colonic contractions lasting two hours. The stimulating effect of trimebutine (phase 3) on intestinal motility was not reproduced after intracerebroventricular administration and was abolished by previous intravenous, but not intraventricular, administration of naloxone. The local effects of trimebutine on the circular muscle of canine gastrointestinal tract were studied after close intra-arterial injection in anesthetized dogs. Under these conditions, the drug stimulated the resting gut through its neural and direct smooth muscle components while it inhibited the contractions induced by field stimulation. In conclusion, the excitatory effect of trimebutine seems to be mediated by mu or delta receptors while its inhibitory activity might involve kappa opiate receptors.

Administration, Oral↗

[Mode of action of trimebutine: involvement if opioid receptors].

Several studies in dogs, cats, rabbits and humans have suggested that the motility-stimulating properties of trimebutine (TMB) are mediated by peripheral opiate receptors. The present work deals with the capacity of the drug and its N-desmethyl metabolite (NDTMB) to displace mu, delta and kappa specific ligands from their receptors using guinea-pig whole brain membranes and ileum myenteric plexus synaptosomes membranes. The activity of both compounds on the twitch response induced by transmural stimulation of the guinea-pig ileum and of the mouse and rabbit vas deferens was also investigated. These preparations have been claimed to be specific for the mu, delta and kappa receptor subtypes respectively. TMB (0.2 to 1.8 microM) and NDTMB (0.3 to 6 microM) displayed a good affinity for all receptor subtypes in brain and myenteric plexus preparations. The decreasing order of IC50 (50 per cent inhibitory concentration)'S of TMB ranged from 0.75 microM in the guinea-pig ileum to 7.1 and 39 microM in the vas deferens of the rabbit and the mouse respectively. These results indicate that TMB and NDTMB possess mu, delta as well as kappa agonistic properties without true specificity for one or the other of these subtypes. They also confirm that activation of peripheral mu, delta and kappa opiate receptors mediate the gastrointestinal motility effect of TMB.

Animals↗

Autoradiographic localization of sigma opioid receptors in the gastrointestinal tract of the guinea pig.

The distribution of sigma and phencyclindine binding sites in the gastrointestinal tract of the guinea pig was studied by autoradiography after in vitro incubation of tissue slices with (+)3H-SKF 10,047 and 3H-1-1-[(2-thienyl)cyclohexyl] piperidine to locate sigma and phencyclidine receptors, respectively. A dense distribution of sigma binding sites was observed in the mucosa and in the submucosal plexus, particularly at the level of the fundus and duodenum. Muscular layers were only marginally labeled. No phencyclidine binding site could be demonstrated in any area. This selective distribution suggests a functional role of sigma receptors mainly in the control of endocrine or exocrine secretions, or both.

Animals↗

Vagally mediated inhibition of acoustic stress-induced cortisol release by orally administered kappa-opioid substances in dogs.

The effects of oral vs. iv administration of kappa- and mu-opioid agonists on plasma cortisol release induced by acoustic stress (AS) were evaluated in fasted dogs with an implanted jugular catheter. AS was induced by 1 h of music (less than or equal to 86 decibels) played through earphones and was accompanied by a 382% maximal rise in plasma cortisol after 15-30 min. Administered orally 30 min before the AS session, both U-50488 (0.1 mg/kg) and PD 117-302 (0.05 mg/kg) significantly (P less than or equal to 0.01) decreased (by 71.2% and 80.9%, respectively) the maximal increase in plasma cortisol induced by AS, while bremazocine, morphine, as well as iv administration of U-50488 at similar doses were ineffective. The effects of U-50488 and PD 117-302 orally administered (0.1 mg/kg) on the hypercortisolemia induced by AS were abolished by pretreatment with iv naloxone (0.1 mg/kg) or MR 2266 (0.1 mg/kg). Naloxone given alone significantly (P less than 0.01) increased basal plasma cortisol, without affecting cortisol increase induced by AS. Vagotomy abolished the effects of orally administered U-50488 on the AS-induced increase in plasma cortisol. Neither U-50488 nor PD 117302 (0.1 mg/kg, orally) reduced the increase in plasma cortisol induced by intracerebroventricular administration of ovine CRF (100 ng/kg). It is concluded that kappa- but not mu-opioid agonists are able to inhibit the stimulation of the hypothalamo-pituitary-adrenocortical axis induced by AS by acting selectively on peripheral kappa-receptors located in the wall of the proximal gut. This action is neurally mediated through afferent vagal fibers affecting central nervous system release of CRF induced by a centrally acting stressor.

Administration, Oral↗

Total pancreatic insufficiency in pigs: a model to study intestinal enzymes and plasma levels of digestive hormones after pancreatic supplementation by a whole pancreas preparation.

Oral pancreatic enzyme replacement therapy generally benefits patients with severe pancreatic deficiency. However, the fate of oral pancreatic supplements in the digestive lumen and their possible effects on circulating gut hormones are only partially known. The purpose of this article is to validate an experimental model that produces total pancreatic insufficiency in pigs, and to study the fate of orally administered Eurobiol, a whole pancreas lyophilized preparation, and its effects on circulating plasma levels of five digestive hormones. Pancreatic insufficiency was created by pancreatic duct ligation, and the duodenal, jejunal and ileal contents were sampled through cannulas before a normal meal and 0.5-24 h later. Blood samples were taken at the same times, and plasma neurotensin, pancreatic polypeptide, secretin, cholecystokinin (CCK), and gastrin were measured. In pigs with pancreatic insufficiency, Eurobiol, given during the meal, induced a significant increase in all enzyme activities in the duodenum and the jejunum, and in the levels of amylase, trypsin, and chymotrypsin in the ileum, relative to placebo. In the duodenum, the peak concentrations of enzyme activities were 19, 11, 17, and 29% (p less than 0.001) of the postprandial peak activities measured in control pigs with an intact pancreas for lipase, amylase, trypsin, and chymotrypsin, respectively. In the jejunum, the same activities were, respectively, 30, 11, 25, and 36% (p less than 0.01-0.001) of normal peaks. In pigs with pancreatic insufficiency, basal and integrated meal-stimulated neurotensin levels were increased; basal, peak, and integrated meal-stimulated pancreatic polypeptide and secretin levels were increased, whereas gastrin and CCK were not different from controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Central and peripheral opioid modulation of gastric relaxation induced by feeding in dogs.

The influence of i.v. vs. i.c.v. administration of [( D-Ala2, MetPhe4, Gly-ol5]enkephalin (DAMGO) and morphine), kappa U 50488 and ethylketocyclazocine and delta ([D-Pen2, D-Pen5]enkephalin (DPDPE)] opioid agonists on gastric relaxation induced by a standard meal was evaluated in conscious dogs with strain-gauge transducers implanted on the gastric fundus and antrum. Under control conditions, the amplitude of the gastric relaxation in response to feeding was 2.46 +/- 0.23 g. Given i.v. 10 min before feeding, both U 50488 (10 micrograms/kg) and ethylketocyclazocine (10 micrograms/kg) significantly (P less than .01) reduced the amplitude of the gastric relaxation by 57 and 68%, respectively, whereas DAMGO and morphine (10 micrograms/kg i.v.) increased markedly the response to feeding by 67 and 51%, respectively. In contrast, DPDPE had no effect on the gastric relaxation induced by feeding. Previous administration of naloxone (0.3 mg/kg i.v.) or MR 2266 (0.3 mg/kg i.v.) blocked the effect of U 50488 on gastric relaxation with no effect per se on the amplitude of response; naloxone also blocked the increase in gastric relaxation induced by DAMGO. When administered i.c.v. (0.1 microgram/kg) DAMGO induced a significant (P less than .05) increase in the amplitude of gastric relaxation whereas U 50488 and DPDPE (0.1 and 1 microgram/kg i.c.v.) had no effect. The effect of i.c.v. DAMGO on gastric relaxation was unaffected by a previous i.v. administration of SR 58002C (1 mg/kg). Truncal vagotomy blocked the increase in gastric relaxation induced by DAMGO (10 micrograms/kg i.v.), but did not change the effect of U 50488 (10 micrograms/kg i.v.) on gastric relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

Purification, characterization and kinetic properties of the rabbit gastric lipase.

Rabbit gastric lipase was purified from an acetonic powder of rabbit stomach fundus. 25 mg of pure rabbit gastric lipase (glycerol ester hydrolase, EC 3.1.1.3) was obtained from 30 rabbit stomachs after ammonium sulfate fractionation, Sephadex G-100 gel filtration and cation exchange (mono S column) using a fast protein liquid chromatography (FPLC) system. The pure enzyme obtained was resistant to acidic pH conditions, and had specific activities of 1200, 850 and 280 U/mg, using, respectively, short- (tributyroylglycerol (TC4)), medium- (trioctanoyl- to tridecanoylglycerol (TC8-TC10)) and long-chain (soybean oil) triacylglycerols. The amino-acid composition was determined, and the first 30 N-terminal amino-acid residues were sequenced. Interfacial denaturation and catalytic properties on triacylglycerol emulsions were studied. Rabbit gastric lipase turned out to be structurally and kinetically very similar to human gastric lipase.

Amino Acid Sequence↗

Screening of preduodenal lipases in several mammals.

The tissular localization of preduodenal lipases was studied from the tongue to the pyloric portion of the stomach in 11 mammals. Lipolytic activities were clearly differentiated from those of pancreas. All lipase activities show an acidic pH optimum, except the gastric enzyme from hog. For every mammal tested, preduodenal lipase activity was associated mainly with only a single tissue located either in tongue, or in the pharyngeal area, or in the stomach. Resistance to acidic pH medium allows the classification of lipase activities into three groups. These results are related to the dietary habits and zoologic classification of the different animal species.

Animals↗

Interference of eicosapentaenoic and docosahexaenoic acids with arachidonate-and U46619-induced platelet activation and desensitization.

In previous studies we showed that arachidonate (AA) and the cyclic endoperoxide/thromboxane (Tx) A2 mimic U46619-induced auto- and cross-desensitization of human platelets to either agonist. The desensitizing effect of U46619 is direct, whereas that of AA is mediated by a cyclooxygenase-dependent metabolite. Desensitization by AA and U46619 is suppressed by antagonists of the endoperoxide/Tx receptor sites. In the present investigation we demonstrated that eicosapentaenoic (EPA) and docosahexaenoic acid (DCHA) the major polyunsaturated fatty acids of fish oil suppressed TxB2 formation and prevented platelet activation by AA and U46619. This inhibition required the presence of EPA or DCHA, since platelets pre-treated with these fatty acids and washed before testing responded as controls to the stimulating agents. At 0.1 and 0.3 mM respectively, DCHA and EPA behaved as reversible inhibitors of cyclooxygenase or Tx synthetase (inhibition of the effects of AA) and as endoperoxides/TxA2 receptor antagonist (inhibition of the effects of U46619). Co-exposure of DCHA (0.1 mM) with AA or U46619 prevents auto- and cross-desensitization to AA and U46619. Platelets exposed to 0.3 mM DCHA and washed became refractory to stimulation by AA, but responded as controls to U46619. EPA (0.3 mM) was fully removed from platelets, which responded to AA and to U46619. EPA and DCHA antagonize endoperoxide/TxA2 directly, and thus prevent the stimulation-dependent desensitization, and additionally, inhibit the cyclooxygenase activity required for desensitization.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

Peripheral antagonistic action of trimebutine and kappa opioid substances on acoustic stress-induced gastric motor inhibition in dogs.

The effects of intracerebroventricular (i.c.v.), intravenous (i.v.) and oral (p.o.) administration of trimebutine on the gastric motor inhibition induced by acoustic stress were investigated in fasted dogs fitted with strain-gauge transducers on the antrum and proximal jejunum. Started 40-50 min after the last migrating motor complex, a 1 h acoustic stress delayed by 111% the occurrence of the next gastric migrating motor complex without affecting the jejunal motor pattern. This inhibition of gastric migrating motor complex induced by acoustic stress was abolished by previous p.o. administration of trimebutine (1 mg/kg) but not by its i.v. (0.1 mg/kg) or i.c.v. (0.01 mg/kg) injection. The trimebutine blockade of gastric motor alterations induced by acoustic stress was suppressed after previous i.v. treatment with MR 2266 (0.3 mg/kg) but was unaffected by naloxone (0.3 mg/kg). Furthermore oral administration of U-50488H (10 micrograms/kg) and ethylketocyclazocine (10 micrograms/kg) respectively abolished and reduced the acoustic stress-induced delay of the occurrence of the gastric migrating motor complex. We concluded that trimebutine is able to antagonize the gastric motor disturbances induced in dogs by acoustic stress, probably by acting selectively on peripheral kappa receptors located in the wall of the proximal gut and directly stimulated from a mucosal site.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

Local anti-inflammatory activities of tixocortol 21-pivalate, inhibition of prostaglandins and leukotrienes synthesis, in carrageenin-induced pleurisy. Reversion of effects by RU 486.

Since a direct effect of tixocortol pivalate (TP) has been described on cyclooxygenase pathway, local anti-inflammatory activities of some 21 thiol derivatives of steroids were investigated on the carrageenin-induced pleurisy model in comparison with dexamethasone (Dex) or other anti-inflammatory drugs. LTC4/D4 contents in pleural fluid were assayed by RIA as well as PGE2 levels to characterize the effects on arachidonate pathways. After oral administration, TP was inactive up to 1 g/kg on exudate volume and leukocyte migration as expected for this strict local anti-inflammatory steroid contrary to Dex (ID50 = 0.05-0.41 mg/kg). When administered locally, TP and tixocortol (T) exerted a dose dependent inhibitory activity on exudate volume (ID30 = 12.4 micrograms or 13.1 micrograms/pleural cavity) and leukocyte count (ID30 = 83 or 230 micrograms); in the same conditions. Dex was more active (ID30 = 0.7 and 2.6 micrograms). All these steroids decreased PGE2 and LTC4/D4 contents in exudate fluids, respectively TP (50 micrograms/pleural cavity) by 28 and 63%; T (100 micrograms) by 33 and 31%; Dex (5 micrograms) by 43 and 40%. Local co-administration of RU 486 (50 micrograms) with either TP, T or Dex reversed the anti-inflammatory effects of all steroids, indicating in these conditions a local activity through glucosteroid receptor occupancy.

Administration, Topical↗