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I Setnikar

Publications and source records attributed to I Setnikar.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1977

Antimicrobial activity of tibezonium (TBZ).

The activity in vitro of tibezonium (Rec 15-0691), a new 1,5-benzodiazepine derivative, has been investigated. The drug was found active especially against Streptococcus, Diplococcus and Corynebacterium strains which are agents of oropharyngeal diseases. The activity of tibezonium was pH dependent against Staphylococcus aureus SG 511 and Streptococcus pyogenes 821 (at pH 8.0-8.5 It was more active) and the presence of horse serum provoked a small decrease of the antimicrobial properties. No interference on the activity of the tibezonium has been found in presence of smokers and non-smokers saliva.

Anti-Bacterial Agents↗
PubMed1975

Flavoxate and 3-methylflavone-8-carboxylic acid. Assay methods in blood and urine, plasma-red cells repartition and stability.

The following assay methods for pharmacokinetic studies on flavoxate (F) and on its main metabolite, i.e. 3-methylflavone-8-carboxylic acid (A), are described. 1. Spectrophotometry for the assay of F and of A in plasma, 2. TLC-Spectrodensitometry and GLC for the assay of A in urine after acid hydrolysis, 3. TLC-Spectrodensitometry for determining the F : A ratio in plasma or in urine. It was found that F hydrolyzes into A. This process depends on the pH and on the medium. In water, at pH 5.0, F is stable, while in phosphate buffer at pH 7.4 the semi-hydrolysis time is 60 min. In a solution with bovine serum albumin, in rat, rabbit, dog or human plasma the semi-hydrolysis times are between 5 and 60 min. Finally the plasma-red cells repartitions of F and of A were studied in vitro in rat, rabbit, dog and human blood and found between 0.8 and 2.0 for F and between 2.1 and 4.6 for A.

Animals↗