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At least 811 records · Page 45Linked to original sources
PubMed1990

[Therapeutic perspectives in the irritable bowel syndrome].

Future treatments of functional intestinal disorders (FID) are essentially dependent on the possible pathophysiologic hypotheses. Schematically, symptoms experienced by patients with FID can be attributed to intestinal (small or large intestine) motor disturbances or to visceral sensitivity derangement, which, in turn, may be primary or secondary to an anomalous response to alimentation, liberation of hormones or neuromediators, or to a "stress" situation. New therapeutic agents can be directed against the symptoms experienced by patients (? action on pain or intestinal transit disorders) or against the initial pathophysiologic mechanisms. In the treatment of functional diarrhea, several substances have been proposed recently. Encephalines are peptides with extremely short duration of action which are degraded by two membranous enzymes, encephalinase and carboxypeptidase. Recently, it has been shown that acetorphan, an inhibitor of encephalinase, is efficacious in acute diarrhea. Alpha-2-antagonists are substances which are capable of slowing intestinal transit time and increasing intestinal absorption. Their antidiarrheic action is moderate, and they do not act on abdominal pain. Molecules that do not traverse the neuromeningeal barrier but that act selectively on the digestive tract and are better tolerated are expected. In patients complaining of severe idiopathic constipation substances capable of stimulating colonic motility are useful: substance P or neurotensin analogues might prove interesting. Antagonists of opium receptors such as Naloxone have proved efficacious in the treatment of certain cases of chronic idiopathic intestinal pseudo-obstructions or severe constipation. The development of orally active substances or with hepatic elimination are a prerequisite. Therapy based on well characterized pathophysiologic abnormalities would be welcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdominal Pain↗
PubMed1990

The effect of a novel CCK-antagonist (lorglumide) on human and guinea pig gallbladder strips: a tensiometric study.

The effect of a novel CCK-antagonist (lorglumide, CR 1409) was evaluated by "in vitro" tensiometric studies on 16 human (gallstone patients) and 12 guinea pig gallbladder smooth muscle strips. In the animal experiments, increasing doses of lorglumide (0.2-6.5 uM) caused a rightward shift of the dose-response curves of CCK-OP, with an increase of the ED50 from 8.2 nM +/- 1.62 SEM, n = 12; to 100 nM +/- 12, n = 4) without affecting the maximal effect (Emax). Schild plot gave an affinity constant of 7.19. In human gallbladders, the effect of lorglumide was also present (ED50 increased from 47 nM +/- 8 SEM, n = 16; to 300 nM +/- 10 SEM, n = 4) coexisting with a large inter-sample variation for CCK-OP ED50s and maximal contractions, most likely due to the histological changes of the wall in chronic cholecystitis. The affinity constant was similar to that found in animal experiments. We confirm the studies previously reported in animals on the existence of a competitive antagonism of lorglumide on CCK gallbladder receptors. Moreover, our results on gallbladders from gallstone patients show that lorglumide is a highly effective antagonist of CCK-induced contractions despite the presence of chronic cholecystitis. Our study might help for a better comprehension of the role of these new anti-CCK drugs in the treatment of biliary pain.

Adult↗
PubMed1988

Identification of separate bombesin and substance P receptors on isolated muscle cells from canine gallbladder.

Smooth muscle cells were isolated from the dog gallbladder and used to examine whether bombesin-14 and substance P cause direct contraction and whether this effect is mediated by the same or different receptors. Both peptides caused concentration-dependent contraction that was inhibited by two substance P derivatives, [D-Pro2,D-Trp7,9]SP ([PTT]SP) and [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP ([APTTL]SP). In nonmuscle cells, these substance P derivatives exhibit preferential antagonism of responses to substance P and bombesin, respectively; accordingly, these properties were used to demonstrate the presence of separate bombesin and substance P receptors. Estimates of the apparent Ki showed that [PTT]SP was 40 times more potent than [APTTL]SP as an antagonist of the response to substance P, whereas [APTTL]SP was 85 times more potent than [PTT]SP as an antagonist of the response to bombesin-14. Estimates of median inhibitory concentration obtained from inhibition curves for the effect of various concentrations of each antagonist on the responses to substance P and bombesin-14 confirmed that [PTT]SP was a preferential antagonist of the response to substance P and [APTTL]SP, a preferential antagonist of the response to bombesin-14. The results demonstrate the presence of separate bombesin and substance P receptors mediating contraction of smooth muscle cells of the dog gallbladder.

Animals↗
PubMed1989

Involvement of cholecystokinin receptors in the adverse effect of glucocorticoids on diet-induced necrotizing pancreatitis.

The mechanism that explains the association between corticoids and acute pancreatitis is unknown. Our hypothesis was that chronic glucocorticoid treatment could adversely affect the course of hemorrhagic pancreatitis by acting through cholecystokinin (CCK) receptors. Acute necrotizing pancreatitis was induced by feeding young female mice a choline-deficient, ethionine-supplemented (CDE) diet for 60 hours. Treatment with hydrocortisone (10 mg/kg/day) was begun 1 week before pancreatitis. At the onset of the CDE diet, a group of hydrocortisone-treated mice were also given the CCK receptor antagonist CR-1409 (5 mg/kg three times a day). Control mice received injections of saline solution. A follow-up of 336 hours was conducted for survival analysis. Hydrocortisone given alone did not produce pancreatitis. Hydrocortisone, however, did increase the pancreatic necrosis caused by the CDE diet (from 40% to 70%) and significantly reduce survival (from 40% to 9%). CR-1409 completely abolished the adverse effects of hydrocortisone on pancreatitis. We measured amylase release by dispersed pancreatic acini from mice chronically treated with hydrocortisone in response to CCK-8. Treatment with hydrocortisone increased both the sensitivity and the responsiveness of the pancreas to CCK-8. We conclude that glucocorticoids alone may not induce acute pancreatitis, but they can increase the risk of a more severe form of pancreatitis developing. The glucocorticoid effect appears to be attributable to a CCK receptor-mediated sensitization of the pancreas to endogenous CCK. Thus, CCK-receptor blockade may improve survival in necrotizing pancreatitis associated with chronic glucocorticoid treatments.

Amylases↗
PubMed1989

Effect of the novel cholecystokinin receptor antagonist CR-1392 on cholecystokinin-induced antroduodenal and pyloric motor activity in vivo.

The effects of i.a. injected cholecystokinin (CCK)-octapeptide on pyloric and antroduodenal motility, measured with strain gauges and combined side hole-sleeve manometry, were investigated in 16 dogs in vivo. CCK-octapeptide (OP) induced strong pyloric contractions when injected into the pylorus (threshold of 2 x 10(-13) mol; ED50, 8 x 10(-13) mol). Similar responses were obtained in the distal antrum (threshold, 6 x 10(-13) mol; ED50, 3 x 10(-12) mol) and the proximal duodenum (threshold, 5 x 10(-13) mol; ED50, 3 x 10(-12) mol). The nonsulfated form of CCK-OP was about 2 to 3 log units less potent in eliciting these excitatory responses in the pylorus (threshold, 9 x 10(-10) mol). Atropine shifted the dose-response curve of CCK-OP in pylorus, duodenum and antrum to the right suggesting a neural action of CCK-OP. However, an excitatory effect of CCK-OP was still present after neural blockade with tetrodotoxin i.a. Therefore, there was probably a muscular as well as a neural site of action of CCK-OP in these tissues. Systemic application of the novel CCK-antagonist CR-1392 in a dose of 1.2 mg/kg i.v. plus 100 micrograms i.a. shifted the dose-response curve of CCK-OP 1 log unit to the right without affecting the dose-response curve to acetylcholine. This dose of CR-1392 did not interfere with the pyloric motor responses to duodenal field stimulation or to intraduodenal acid infusion. These results demonstrate the dual peripheral action on nerve and muscle of CCK-OP in the pylorus in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Distinct requirements for activation at CCK-A and CCK-B/gastrin receptors: studies with a C-terminal hydrazide analogue of cholecystokinin tetrapeptide (30-33).

We describe here the properties of tert-butyloxycarbonyl-Trp-Leu-Asp-Phe-NHNH2 (A-57696), a C-terminal hydrazide analogue of tert-butyloxycarbonyl-CCK4 (Boc-Trp-Met-Asp-Phe-NH2), at four cholecystokinin (CCK) receptor-bearing tissues, the guinea pig pancreas and gall bladder (Type A), guinea pig cortex (Type B), and NCI-H345 cells, a human small cell lung cancer cell line that expresses CCK-B/gastrin receptors. Using 125I-Bolton-Hunter-cholecystokinin octapeptide (26-33) (125I-Bolton-Hunter-CCK8) as the radioligand, A-57696 was found to be selective for cortical CCK-B receptors (IC50 = 25 nM), compared with pancreatic CCK-A receptors (IC50 = 15 microM). A-57696 behaved as a competitive antagonist in reversing CCK8-stimulated pancreatic amylase secretion and phosphoinositide breakdown. By Schild analysis, its Kd was determined to be 4.7 and 6.8 microM in amylase and phosphoinositide assays, respectively. A-57696 (100 microM) did not elicit gall bladder contraction, and it inhibited contractions induced by CCK8. The Kd of A-57696 at gall bladder CCK-A receptors was 19 microM. In contrast, A-57696 behaved as a partial agonist (80% of maximal CCK8 response) in stimulating calcium mobilization at CCK-B/gastrin receptors on NCI-H345 cells. A-57696 and CCK8 inhibited each other in calcium mobilization experiments utilizing the fluorescent dye Indo-1. Stimulatory actions of CCK8 and A-57696 were reversed by the CCK-B-selective (R)-L-365,260 (100 nM), whereas at the same concentration, the CCK-A-selective (S)-L-365,260 was ineffective. Binding studies using 125I-Bolton-Hunter-CCK8 and 125I-gastrin indicated that binding sites labeled by these two ligands displayed similar affinities for CCK8, desulfated CCK8, gastrin, A-57696, and both enantiomers of L-365,260. A-57696 represents a new class of CCK-A peptide antagonist at guinea pig pancreas a new class of CCK-A peptide antagonist at guinea pig pancreas and gall bladder. Its contrasting functional activities at guinea pig CCK-A and CCK-B/gastrin receptors in a human tumor cell demonstrate that, in addition to the previously described differences in binding specificity for selective agonists and antagonists, CCK-A receptors and CCK-B/gastrin receptors have different requirements for activation.

Amino Acid Sequence↗
PubMed1989

Pharmacokinetics and tolerance of repeated oral doses of loxiglumide.

The study was conducted on 6 adult healthy subjects (5 males and 1 female) in order to investigate the pharmacokinetics and tolerance of repeated b.i.d. oral administration for 7 days of tablets containing 400 mg of loxiglumide (CR 1505). The pharmacokinetics of loxiglumide in plasma after the first single dose of 400 mg is characterized by a lag time of 16 +/- 4 min, a rapid invasion (kinv = 10 h-1), a Cmax of 11.9 +/- 5.1 mg/l at tmax of 2.3 +/- 0.8 h, a mean residence time (MRT) of 6.9 +/- 1.1 h and an AUC of 60.6 +/- 16.3 (mg/l) x h. After the last dose of 400 mg the lag time was 17 +/- 6 min, the Cmax 12.7 +/- 3.8 mg/l at tmax of 2.1 +/- 0.8 h, a MRT of 11.0 +/- 1.9 h and an AUC of 109.8 +/- 39.9 (mg/l) x h. The increases of the AUC and of MRT were statistically significant and are probably due to an accumulation of loxiglumide which occurs during the repeated dose course and reaches the steady state within 48 h of repeated administration. Due to this accumulation the Cmax increased by 7%. The increase was not statistically significant or clinically relevant. No dose adjustment seems required during a repeated dose dosing schedule with 400 mg b.i.d. In the urine loxiglumide and 3 metabolites were found, which were called Metabolite (Met.) 11.2, Met. 12.0 and Met. 12.8. Met. 12.0 was the most abundant, accounting for 45% of the loxiglumide related substances excreted in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Modulation by CR-1409 (lorglumide), a cholecystokinin receptor antagonist, of trypsin inhibitor-enhanced growth of azaserine-induced putative preneoplastic lesions in rat pancreas.

Feeding of raw soya flour or other trypsin inhibitors such as camostate is a well-established method for promoting growth of (pre)neoplastic foci induced in the exocrine pancreas of rats by azaserine. The effect of trypsin inhibitors is thought to be mediated through an increased release of cholecystokinin. Using the specific cholecystokinin receptor antagonist lorglumide (CR-1409), we performed a 16-wk study to investigate the potential of this drug in inhibiting growth of putative preneoplastic foci and to determine whether and to what extent cholecystokinin is responsible for the effect of trypsin inhibitors on pancreatic growth. After initiation with 30 mg/kg of azaserine at 19 days of age, six groups of 15 rats each received one of the following treatments: camostate, cholecystokinin-8, or gelatin control, either or not in combination with CR-1409, once daily, 3 days wk for 16 wk. Plasma cholecystokinin levels, measured 30 min after the stimulus, were similar after camostate and cholecystokinin octapeptide administration. After 16 wk the pancreata were removed, weighted, and quantitatively analyzed for the number and size of putative preneoplastic foci by light microscopy. Both camostate and cholecystokinin octapeptide stimulated pancreatic growth and development of acidophilic putative preneoplastic foci, whereas growth of basophilic putative preneoplastic foci was inhibited by camostate but stimulated by cholecystokinin. CR-1409 almost completely abolished the effect of cholecystokinin and was found to cause a significant decrease in the effects of camostate. It is concluded that (a) cholecystokinin plays a significant role in camostate-stimulated growth of acidophilic putative preneoplastic foci in rat pancreas and (b) CR-1409 inhibits growth of putative preneoplastic foci induced in rat pancreas by azaserine and hence may be of potential value for the treatment of pancreatic cancer in humans.

Animals↗
PubMed1978

[Several new inhibitors of gastric secretion].

In experiments on dogs, milid (proglymid) entailed a weak inhibition of the 2nd phase of the gastric secretion leaving intact the 1st phase. The action of LS-519 was obvious in the 1st phase, having entailed a significant inhibition. The glycomacropeptid exerted a strong inhibiting effect both on the 1st and the 2nd phases, the effect lasting longer than that of the first two drugs. All the three drugs not only inhibited the gastric secretion but increased pH, reduced the gastric juice acidity while exerting no significan effect on concentration of common proteinases.

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↗
PubMed1987

[Mechanism of the action of amino acids on gastric secretion].

The experiments on dogs using gastrin inhibitors (Milid, secretin) and the data of radioimmunoassay on gastrin blood levels have shown that gastrin is not involved into the activation of gastric glands after parenteral injection of amino acids.

Amino Acids↗
PubMed1978

[Action of some gastric antisecretory drugs on histamine H2-receptors (author's transl)].

A series of compounds endowed with gastric antisecretory activity were examined for their possible effects on histamine H2 receptors in different experimental conditions. The data obtained suggest that, apart from cimetidine, all the other compounds are devoid of antagonistic properties on H2 receptors. The inhibitory effect observed in some of the examined preparations is probably connected with unspecific actions.

Animals↗