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Biomedical subjects

I Setnikar

Publications and source records attributed to I Setnikar.

At least 37 records · Page 2Linked to original sources
PubMed1987

Evaluation of a new and potent cholecystokinin antagonist on motor responses of the guinea-pig intestine.

The potency and selectivity of D,L-4-(3,4-dichloro-benzoyl-amino)-5-(dipentyl-amino)-5-oxo-pen tan oic acid (CR 1409) as a cholecystokinin (CCK) antagonist was investigated on motor responses of the longitudinal and circular muscles of the guinea-pig isolated ileum. CR 1409 was further used to examine whether nerve-mediated motor responses to electrical field stimulation or distension of the gut wall may involve the release of CCK-like peptides. CR 1409 (0.06-2.1 microM) antagonized longitudinal muscle responses to ceruletide (caerulein, a CCK-related decapeptide) in a concentration dependent and competitive manner (pA2 7.77); responses to CCK-octapeptide (CCK-8) were antagonized with a similar potency. Contractions of the circular muscle evoked by ceruletide were also blocked by CR 1409 (0.2-0.4 microM). Longitudinal muscle contractions in response to dimethylphenylpiperazinium, bethanechol, histamine, substance P, or 5-hydroxytryptamine (5-HT), and circular muscle contractions evoked by acetylcholine, 5-HT, substance P, or substance K were not altered by CR 1409 (0.4 microM). Longitudinal muscle contractions induced by electrical field stimulation (with pulses delivered at 0.05 and 1 Hz in the absence, and at 5 Hz in the presence of atropine) were not or only slightly reduced by CR 1409 (0.4 microM). Longitudinal contractions due to activation of extrinsic nerves by capsaicin remained unaltered in the presence of CR 1409 (0.4 microM). Reflex contractions of the circular muscle, induced by balloon distension and recorded orally to the site of distension, and peristaltic activity elicited by intraluminal infusion of Tyrode solution remained unaffected by CR 1409 (0.4 microM). 5 These findings indicate that CR 1409 is a potent and selective antagonist of CCK-like peptides in the guinea-pig ileum. The results do not provide any evidence that CCK-like peptides, released from extrinsic or intrinsic neurones, are involved in nerve-mediated contractions of intestinal muscle and in the peristaltic reflex.

Animals↗
PubMed1987

Anticholecystokinin activities of loxiglumide.

The anticholecystokinin activities of loxiglumide, (D,L-4-(3,4-dichloro-benzoylamino)-5-(N-3-methoxypropyl-pentylamino++ +)-5-oxo- pentanoic acid, CR 1505) are described. Loxiglumide antagonizes in vivo the contractions of the gall bladder of guinea pig induced or mediated by cholecystokinin-8 (CCK-8) (i.v. ED50 = 0.24 mumol/kg), the emptying of the gall bladder of the mouse induced by CCK-8 (i.v. ED50 = 29 mumol/kg, oral ED50 = 42 mumol/kg), the retardation of gastric emptying of the rat induced by CCK-8 (i.p. ED50 = 13 mumol/kg), the retardation of the pyloric transit in the mouse induced by CCK-8 (i.v. ED50 = 3.7 mumol/kg, oral ED50 = 11 mumol/kg), the hypermotility of the ileum of the rabbit induced by CCK-8 (i.v. ED50 = 1.2 mumol/kg) and the contractions of the gall bladder of the non-anesthetized dog induced by caerulein (i.v. ED50 ca. 11 mumol/kg). Loxiglumide also antagonizes the satiety behaviour of the rat elicited by CCK-8 (i.p. ED50 = 0.65 mumol/kg) and the exocrine pancreatic hypersecretion in the anaesthetized dog induced by CCK-8 (i.v. ED50 ca. 0.35 mumol/kg). Loxiglumide has a simple, non-polypeptidic chemical structure and is active after parenteral and after oral administration.

Anesthesia↗
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↗
PubMed1987

Pharmacokinetics and metabolism of [14C]-proglumetacin after oral administration in the rat.

The pharmacokinetics and metabolism of 1H-indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl 2-[4-[3-[[4-(benzoylamino)-5-(dipropylamino)-1, 5-dioxopentyl]oxy]propyl]-1-piperazinyl]ethyl ester (+/-) (proglumetacin, CR 604), 14C-labelled in position C-2 of the indolic moiety, was studied in male and female rats after oral administration. The radioactivity is slowly absorbed from the gastrointestinal tract and reaches the peak in plasma 6 h after administration. Afterwards the radioactivity is eliminated from plasma according to a bi-exponential equation, with an initial elimination rate having a t1/2 of 4.5 h and a terminal elimination rate having a t1/2 of 16 h. The elimination rate is probably dependent on the slow absorption rate (flip-flop system) and on an entero-hepatic recirculation of the radioactivity. The radioactivity is excreted with the feces (60.8%) and with the urines (33.5%). No radioactivity is eliminated with the expired air. About 13% of the fecal radioactivity is represented by proglumetacin. This fraction or radioactivity (ca. 8% of the administered) represents probably the non-absorbed amount of substance. The parent proglumetacin is not found in blood, urine and organs. Conversely several indolic metabolites are found, with a predomination of indometacin. Proglumetacin is therefore a pro-drug of indometacin and of other indolic metabolites, which are responsible for the antiinflammatory activity of proglumetacin. The radioactivity is distributed in all tissues. The maximum radioactivity is found in liver and kidneys, however, always in a smaller concentration than in plasma. No "deep compartment" was found.

Administration, Oral↗
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

Structural features of various proglumide-related cholecystokinin receptor antagonists.

Thirteen proglumide derivatives that varied in the length of the di-n-alkyl group and in the substitutions on the benzoyl moiety were tested for their ability to interact with guinea pig pancreatic cholecystokinin (CCK) receptors. Each derivative was more potent than proglumide. There was a close correlation between their abilities to inhibit CCK-stimulated amylase release and to inhibit binding of 125I-CCK. For the di-n-alkyl derivatives the relative potency was n-pentyl greater than n-hexyl greater than n-butyl greater than n-propyl. For the benzoyl moiety, adding two electron-withdrawing groups increased potency more than adding a single electron-withdrawing group or adding electron-donating groups. The 3,4-dichloro-di-n-pentyl derivative of proglumide was 1,300 times more potent than proglumide, and its action was specific, competitive, and it functioned as a CCK receptor antagonist in rat, mouse, and guinea pig pancreas. For all proglumide derivatives there was a good correlation (r = 0.84, P less than 0.001) between their abilities to inhibit CCK-stimulated amylase release and that previously reported for their abilities to inhibit CCK-induced gallbladder contraction. However, certain proglumide derivatives had a much higher affinity for the pancreatic CCK receptor than for the CCK receptor mediating gallbladder contraction. For other proglumide derivatives the pattern was reversed. These results demonstrate that both the di-n-alkyl group and the substitution on the benzoyl moiety of proglumide are equally important determinants of affinity and that derivatives such as the di-n-pentyl 3,4-dichloro analogue can be produced that are 1,300 times more potent than proglumide.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1986

Pharmacokinetics of glucosamine in the dog and in man.

The pharmacokinetics, organ distribution, metabolism and excretion of glucosamine were studied in the dog giving uniformly labelled [14C]-glucosamine (sulfate), i.v. or orally, in single doses. Immediately after i.v. administration, the radioactivity in plasma is due to glucosamine, and freely diffuses into organs and tissues. This radioactivity disappears quickly from plasma (initial t1/2 = 13 min, terminal t1/2 = 118 min). After 30-60 min the radioactivity in plasma is no longer due to glucosamine, but is incorporated into alpha- and beta-globulins. The protein-incorporated radioactivity is found already 20-30 min after i.v. administration, reaches a peak after 8 h and then slowly disappears, with a t1/2 = 2.9 days. Of the administered radioactivity, more than 34% is excreted in the urine, mainly as glucosamine, and 1.7% is excreted in the feces. Radioactivity is excreted also as [14C]-CO2 in the expired air. The radioactivity, after i.v. administration, diffuses rapidly from blood into the body. Some organs show an active uptake of radioactivity, e.g. the liver and the kidney. Other tissues, such as the articular cartilage, also have an active uptake. In most other organs the radioactivity found can be explained by passive diffusion processes from plasma. After oral administration of a single dose of [14C]-glucosamine the radioactivity is quickly and almost completely absorbed from the gastrointestinal tract. The pattern of disappearance, metabolic transformation, tissue distribution and excretion of the radioactivity are consistent with those found after i.v. administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Pharmacokinetics of tiropramide after single doses in man.

The plasma levels and urinary excretions of (+/-) alpha-(benzoylamino)-4-[2-(diethylamino)ethoxy]-N, N-dipropyl-benzenepropanamide (tiropramide) and of some of its metabolites were studied in healthy volunteers after the following single-dose administrations of tiropramide hydrochloride: a) i.v. 50 mg, oral 100 mg or rectal 200 mg; b) i.v. 50 mg or i.m. 50 mg; c) oral 100, 200 or 400 mg. After i.v. bolus the plasma levels of tiropramide are consistent with a three-compartment open pharmacokinetic model. The steady-state volume of distribution is 221 l. The terminal elimination constant is 0.279 h-1 (t1/2 = 2.5 h). After i.m. injection the plasma levels increase rapidly (invasion t1/2 = 2 min) and then are similar to those found after i.v. bolus. After oral administration appreciable plasma levels are found after lag times of 18-27 min. They increase with an invasion t1/2 of 14-22 min. The peak is reached 1-1.7 h after administration and the elimination occurs with a constant of 0.20-0.23 h-1. After rectal administration appreciable plasma levels are found after a lag time of 11 min and increase with an invasion t1/2 of 6 min. The peak is reached at 2.2 h. The elimination constant is 0.21 h-1. Tiropramide and some of its metabolites can be determined in the urine by gas-liquid chromatography. The following percentages of the administered dose of tiropramide and tiropramide-related substances can be found in the 24-h urines. After i.v. bolus: 16.2; after i.m. injection: 17.0; after oral administration: 19.6; after rectal administration 13.1.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

New glutaramic acid derivatives with potent competitive and specific cholecystokinin-antagonistic activity.

New glutaramic acid derivatives were evaluated for anti-cholecystokinin (CCK) activity in vitro on guinea pig gallbladder. The compounds are competitive and specific CCK-antagonists, causing a parallel right shift of the cumulative dose-response curve of the agonist. The affinity for the binding site of the CCK-receptor for some of these compounds was hundreds of times higher than that of pro-glumide, the model compound.

Acetylcholine↗
PubMed1984

Absorption, distribution and excretion of radioactivity after a single intravenous or oral administration of [14C] glucosamine to the rat.

Blood levels, tissue distribution and excretion patterns of radioactivity were studied in the rat after administration of [14C] glucosamine sulphate by the intravenous or oral route. After intravenous administration, plasma radioactivity declined in the first 30 min, then increased, reaching a peak at the 2nd hour, and disappeared, with a half-disappearance time of 28 hours. The radioactivity diffused rapidly in the tissues. Higher levels than in plasma were reached in the liver and kidneys. There was early incorporation of radioactivity in the skeletal tissues (cartilage and bone). About 50% of the administered radioactivity was excreted with the expired CO2 and about 35% with the urine. Faecal excretion was small (2% of the administered dose). After oral administration, radioactivity was quickly found in plasma, where it reached a peak at 4 hours. It then declined slowly, with biphasic kinetics. The tissue distribution, including uptake in the skeleton, repeated the pattern found after intravenous administration. There was only small faecal excretion, showing an almost complete bioavailability of glucosamine given orally, and the large excretion with the CO2 (82%) showed that glucosamine is to a large extent broken down to smaller fragments. Autoradiographic studies confirmed the tissue distribution pattern and showed in more detail the tissue localization of radioactivity.

Administration, Oral↗
PubMed1981

Mechanism of smooth muscle relaxation by tiropramide.

Experiments on rabbit isolated colon show that a carbachol-induced contraction is accompanied by a decrease in cAMP content of the smooth muscle. (+/-)-alpha-(Benzoylamino)-4-[2-(diethylamino)-ethoxy]-NN-di-propylbenzen-propanamid (tiropramide, CR 605), a new tyrosine derivative with antispastic properties, increases cAMP concentrations within the same dose range that produces smooth muscle relaxation with or without carbachol (0.1 microM). These effects are potentiated by 1 mM theophylline, a phosphodiesterase inhibitor. In a purified microsomal preparation from rabbit colon smooth muscle, corresponding to sarcoplasmic reticulum, tiropramide induced a dose-dependent increase Ca2+ binding in the presence of ATP and Mg2+. Tiropramide inhibited phosphodiesterase activity in rabbit colon homogenates in a range of doses about ten times that producing relaxation, cAMP content enhancement and increase Ca2+ binding to sarcoplasmic reticulum. The effects of tiropramide on the carbachol-stimulated rabbit colon in the presence of theophylline, indomethacin of PGE1 are more in agreement with an action of tiropramide as inhibitor of cAMP catabolism than as a result of a prostaglandin-mediated effect. These observations suggest that the smooth muscle relaxant activity of tiropramide arises from drug-induced increase of cAMP concentrations possibly because of inhibition of cAMP catabolism. This effect is accompanied by the binding to the sarcoplasmic reticulum of Ca2+, preventing its interaction with the contractile proteins of the smooth muscle. A direct effect of tiropramide-enhanced cAMP content on contractile proteins in the smooth muscle cannot be excluded.

Animals↗
PubMed1979

Studies on the mechanism of action of protacine (CR 604), a new non-steroidal anti-inflammatory agent.

3'-(4-[2-(1-P-Chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazin-1-yl)propyl-4-benzamido-N,N-dipropyl-glutaramate(+/-)dimaleate (protacine, CR 604), a new non-steroidal compound active on experimental inflammation, in vitro inhibits prostaglandin synthesis from arachidonic acid and platelet aggregation. When administered p.o., it prevents ex vivo platelet aggregation and in vivo arachidonate-induced thrombosis in rabbits. The cAMP levels of rat leucocytes are significantly reduced after treatment in vivo with protacine, even under maximum PGE-mediated stimulation. These effects, the inhibition of the proteolytic activity of trypsin and the fibrinolytic properties evidenced on recalcified plasma clots, contribute to explain the anti-inflammatory activity of protacine.

Animals↗
PubMed1979

Pharmacological study of a new non-steroidal anti-inflammatory drug: protacine (CR 604).

The pharmacological activities of 3'-(4-[2-(1-p-chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazin-1-yl)propyl-4-benzamido-N,N-dipropylglutaramate(+/-)dimaleate (protacine, CR 604), a new indolyl derivative with strong anti-inflammatory, analgesic and antipyretic activities, are described. The dose-dependent activity of protacine on inflammation has been shown both in short-term experiments, like the hind paw edema induced by carrageenin and several other irritants, and long-term tests, like the aminoacetonitrile-induced osteolathyrism, the adjuvant-induced arthritis and the cotton pellet-induced granuloma. The analgesic activity of the drug has been evidenced in the phenylquinone-induced writhing and the Randall-Selitto tests, and the antipyretic effects in the yeast-induced hyperthermia in rats. Other general pharmacological effects have been studied, too. Contrarily to several other anti-inflammatory drugs, including indometacin, showing advers effects at doses which are in the same range of those active on experimental inflammation, protacine shows these effects to a minor degree and at doses which are much larger than those pharmacologically active. The therapeutic index of protacine therefore is superior to that of other anti-inflammatory drugs.

Aminoacetonitrile↗
PubMed1979

Research on durene derivatives. Note I - hypertensive activity of 2-(2,3,5,6-tetramethylbenzyl)imidazoline and related compounds.

A series of substituted 2-(2,3,5,6-tetramethylbenzyl)imidazolines and related compounds have been synthesized to study the steric and hydrophobic effects on the vasoactivity of the introduction of four methyl groups on the phenyl moiety. The 2-(2,3,5,6-tetramethylbenzyl)imidazoline (I) showed a high hypertensive activity, whereas the 2-benzylimidazoline possesses an adrenolytic activity. The 2-(2,3,5,6-tetramethylphenoxy)methylimidazoline (XVII) retained the hypertensive activity, whereas the corresponding thioether (XIX) was inactive. Some structure-activity relationships with regard to the presence of substituents in the 4-position of the phenyl moiety and on the benzylic CH2 are reported.

Animals↗