Biomedical subjects

L Revel

Publications and source records attributed to L Revel.

26 records · Page 2Linked to original sources

PubMed1987

Loxiglumide protects against experimental pancreatitis.

Loxiglumide (D,L-4-(3,4-dichloro-benzoylamino)- 5-(N-3-methoxypropyl-pentylamino)-5-oxo-pentanoic acid, CR 1505) is a derivative of pentanoic acid and belongs to a newly discovered class of agents with cholecystokinin antagonistic activities. Loxiglumide has preventive effects on different types of experimental pancreatitis, induced e.g. by ceruletide (i.p. ED50 ca. 9 mumol/kg), by intrapancreatic taurocholate (i.p. ED50 ca. 80 mumol/kg) or by choline-deficient ethionine-supplemented diet (i.p. ED50 ca. 45 mumol/kg). Loxiglumide has a simple, non-polypeptidic chemical structure and may be a candidate for clinical investigations in man, e.g. for pancreatitis.

Animals↗

PubMed1987

Pharmacological properties of lorglumide as a member of a new class of cholecystokinin antagonists.

Derivatives of 5-(dipentylamino)-5-oxo-pentanoic acid are a new class of non-peptide cholecystokinin (CCK) antagonists. The most potent compound, D,L-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxo-pen tanoic acid (lorglumide, CR 1409), has a great affinity for the pancreatic CCK receptors and is a competitive, specific and potent CCK antagonist on the smooth muscles of the gall bladder and ileum of the guinea pig and on the CCK-induced amylase secretion of isolated pancreatic acini. In vivo lorglumide antagonizes the contraction of the gall bladder of the guinea pig and of the dog provoked by i.v. CCK-8 or ceruletide (caerulein). It antagonizes the satiety effect of CCK-8 in the rat and is protective against ceruletide-, taurocholate- and diet-induced pancreatitis. Lorglumide is therefore a useful pharmacological tool to study the functions of CCK. For its pharmacological properties, its relatively low toxicity and because it is active also after oral administration, lorglumide is a candidate for diagnostic or therapeutic use in man when an involvement of CCK is suspected.

Animals↗

PubMed1987

Plasma levels of proglumetacin and its metabolites after intravenous or oral administration in the dog.

The absolute bioavailability of 1H-indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl 2-[4-[4-[[4-(benzoylamino)-1,5-dioxopentyl]oxy]propyl]-1- piperazinyl]-ethyl ester (+/-) (proglumetacin, CR 604) was studied in 12 dogs, in a triple cross-over experiment with single doses of i.v. proglumetacin diphosphate, oral proglumetacin diphosphate or oral proglumetacin dimaleate. Determined were proglumetacin, 2'-[4-(3-hydroxypropyl)-piperazin-1-yl]-ethyl-(1-p- chlorobenzoyl-5-methoxy-2-methylindol-3-yl)-acetic acid (CR 1015), indometacin and proglumide in plasma. Proglumetacin and CR 1015 were found in plasma only after the i.v. administration. Conversely indometacin and proglumide were found after all administration routes. The areas under the curve of indometacin and of proglumide did not differ significantly after the three treatments, as shown by the analysis of variance.

Administration, Oral↗

PubMed1987

Pharmacological characterisation of a new potent and specific nonpolypeptidic cholecystokinin antagonist.

D,L-4-(3,4-Dichloro-benzoylamino)-5-(N-3-methoxypropyl- pentylamino)-5-oxo-pentanoic acid (CR 1505) belongs to a newly discovered class of agents with cholecystokinin (CCK) antagonistic activity. CR 1505 displaces CCK-8 from the central CCK receptors at concentrations of 9.1 mumol/l, and from the peripheral CCK receptors at concentrations of 0.33 mumol/l. CR 1505 antagonizes in vitro the contractant effects of CCK-8 on gall bladder strips of the guinea pig at 0.79 mumol/l and those on the small intestine at 1.6 mumol/l. These antagonistic effects are dose dependent and of competitive type. The antagonistic activities of CR 1505 against contractions of smooth muscles elicited by CCK-8 are at least 1000 times more potent than those against the contractions elicited by acetylcholine, BaCl2, histamine, serotonin, Substance P, bradykinin or dimethylphenylpiperazine. CR 1505 is also practically ineffective against the contractions of the small intestine of the guinea pig elicited by electrical field stimulations either as "cholinergic twich" (0.05 Hz), or as "cholinergic contractions" (trains of 10 min at 1 Hz), or as "non-cholinergic contractions" (200 impulses at 5 Hz in presence of atropine). CR 1505 is therefore a potent, specific, competitive and reversible CCK antagonist.

Animals↗

PubMed1986

Different peripheral and central antagonistic activity of new glutaramic acid derivatives on satiety induced by cholecystokinin in rats.

New glutaramic acid derivatives with cholecystokinin antagonistic activity were evaluated for their capacity to inhibit the satiety effect induced in the rat by intraperitoneal (i.p.) injection of cholecystokinin octapeptide (CCK-8). The most active compound, CR 1409, is about 4000 times more potent than proglumide when injected peripherally (i.p.). This compound competitively inhibits the action of CCK-8 at the receptor responsible for the satiety effect. In contrast, CR 1409, i.p. or intracerebroventricularly (i.c.v.) injected does not exhibit antagonistic effects when CCK-8 is administered i.c.v., confirming the existence of at least two different populations of CCK receptors.

Animals↗

PubMed1986

Differentiation of central and peripheral cholecystokinin receptors by new glutaramic acid derivatives with cholecystokinin-antagonistic activity.

Three glutaramic acid derivatives provided with a potent antagonistic activity on the contractions elicited by the carboxyl terminal octapeptide CCK-8 in the guinea pig gallbladder have been evaluated for their capacity to inhibit the binding of [125I]-(Bolton-Hunter)-CCK-8 to both central and peripheric cholecystokinin (CCK) receptors. The most active compound inhibits the CCK binding to rat pancreas acini at a concentration 10(-7) mol/l, but only at 10(-4) mol/l on cerebral cortex membranes, confirming the existence of at least two different populations of CCK receptors.

Animals↗

PubMed1983

Loperamide: evidence of interaction with mu and delta opioid receptors.

Loperamide was tested on electrically-evoked contractions using a series of "in vitro" isolated preparations, in comparison with morphine, met-enkephalin, beta-endorphin, ethylketocyclazocine used as representative agonists of mu, delta, epsilon, kappa receptors respectively. The IC50 of loperamide on myenteric plexus longitudinal muscle of guinea pig ileum was found to be 1.90 X 10(-7)M and equal to that of morphine. The IC50 on mouse vas deferens was found to be 13.02 X 10(-7)M. In this tissue, loperamide resulted as active as morphine, but 54 times less active than met-enkephalin (IC50 0.24 X 10(-7)M). On the rat vas deferens where, as expected, beta-endorphin was strongly active (IC50 1.38 X 10(-7)M), morphine exerted a stimulatory action within the range 10(-5)M-10(-4)M and loperamide was only poorly depressive. The Ke value of naloxone, a specific mu receptor antagonist, against loperamide in the guinea pig ileum was 3.83 nM, and in the mouse vas deferens was 82.87 nM indicating that loperamide in the guinea pig ileum acts on mu receptors while in the mouse vas deferens on another opiate receptor.

Animals↗

PubMedDate not supplied

Protective effect of CR 1409 (cholecystokinin antagonist) on experimental pancreatitis in rats and mice.

CR 1409, a glutaramic acid derivative with competitive cholecystokinin-antagonistic activity, was administered IP and evaluated in comparison with proglumide (the model CCK-receptor antagonist), gabexate (protease inhibitor) and PGE2 (cytoprotective) on two different models of experimental pancreatitis. Acute pancreatitis was induced in mice by six IP injections of 50 micrograms/kg caerulein at hourly intervals. The drugs were administered 30 minutes before each caerulein administration. Blood samples and pancreata were collected 3 hours after the last caerulein injection. In the second experiment, pancreatitis was induced in rats by injecting 0.3 ml 6% sodium taurocholate interstitially into the pancreas. The drugs were administered twice, 30 minutes before and 3 hours after taurocholate. The animals were killed 6 hours after laparotomy and blood samples and pancreata were collected. CR 1409 exhibited on both pancreatitis models a protective effect in a dose range of 0.3-10 mg/kg. Proglumide exhibited a protective activity at higher doses (200-400 mg/kg). Gabexate and PGE2 were effective only in pancreatitis induced by taurocholate in a dose range of 30-60 mg/kg and 60-130 micrograms/kg respectively. These results, showing a high protective effect of CR 1409 on different models of acute pancreatitis, suggest an important role of CCK in the pathogenesis of pancreatitis.

Acute Disease↗