CNS access of selected H3-antagonists: ex vivo binding study in rats

Inflammation Research -     

Gastrointestinal activities of a new pirenzepine-analog, nuvenzepine, in the cat

Nuvenzepine, a new pirenzepine-analog, administered intraduodenally, displayed a long-lasting and dose-dependent inhibition of neostigmine-induced intestinal motility in anaesthetized cats. On ileal motor activity, the compound showed a potency 10 times greater than that of pirenzepine, and, although to a lesser extent, it was also active, unlike pirenzepine, on colonic stimulated motility. Furthermore, in conscious cats, nuvenzepine inhibited pentagastrin-stimulated gastric acid secretion resulting 25-30 times more potent than pirenzepine. The observed differences between antisecretory and antispastic activities displayed by nuvenzepine and pirenzepine suggest that the new pirenzepine-analog may act on gastrointestinal functions through an additional non-anticholinergic mechanism.     

Characterization of antisecretory and antiulcer activity of CR 2945, a new potent and selective gastrin/CCK(B) receptor antagonist

The antigastrinic, antisecretory and antiulcer activities of CR 2945, (R)-1-naphthalenepropanoic acid,beta-[2-[[2-(8-azaspiro[4.5]dec-8-yl-carbonyl)-4,6-dimethylph enyl] amino]-2-oxoethyl], were investigated in vitro and in vivo in rats and cats. Its activities were compared with those of two gastrin/CCK(B) receptor antagonists, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin -3-yl)-N'-(3-methylphenyl)urea and CAM-1028 (4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[1,7,7-trimethylbicyclo [2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino -4-oxo-[1S-1alpha,2beta[S'(S')4alpha]]-butanoate -N-methyl-D-glucamine), of the histamine H2 receptor antagonist, ranitidine, and the proton pump inhibitor, omeprazole. Cytosolic Ca2+ elevation in rabbit parietal cells induced by gastrin (50 nM) was blocked by CR 2945 with an IC50 value of 5.9 nM. CAM-1028 and L-365,260 showed similar activity. CR 2945 antagonized pentagastrin-stimulated gastric acid secretion in rats (ED50 = 1.3 mg kg(-1) i.v. and 2.7 mg kg(-1) i.d.) and cats (1.6 mg kg(-1) i.v.). CR 2945 was slightly less potent than the reference compounds after i.v. administration, whereas after intraduodenal (i.d.) administration, it was more potent than both ranitidine and omeprazole. In the rat, the gastrin antagonism exhibited by CR 2945 was reversible and competitive, with a pA2 value of 7.33. CR 2945 had specific antigastrin activity, as it was unable to antagonize the gastric acid secretion stimulated by histamine or carbachol in rats up to the dose of 30 mg kg(-1). CR 2945 was about as efficacious as ranitidine against the indomethacin- and ethanol-induced gastric ulcers and the cysteamine-induced duodenal ulcer in rats. On the contrary, L-365,260 was only slightly effective. These results suggest that CR 2945 might be a promising compound for the therapy of acid-related disorders, and that its clinical use could help clarify the therapeutic potential of gastrin/CCK(B) receptor antagonists in the gut.     

Anomalous responses to histamine stimulation of guinea-pig oesophageal muscularis mucosae.

The incomplete tachyphylaxis of the contractile response to the H1-stimulants observed on guinea-pig oesophageal muscularis mucosae seems to be H2- and H3-antagonist as well as atropine- and tetrodotoxin-resistant. Lidocaine and eserine partially prevented this process probably by a mechanism independent of their main activity. The dualistic antagonism exerted by mepyramine and methysergide on reproducible histamine responses could be explained by a kinetic condition of "hemi-equilibrium state" together with changes of drug-receptor interaction and by non-specific properties of methysergide. On the whole, the present data indicate that the role of histamine in this tissue has still to be defined.     

Evidence for the involvement of 5-HT2A receptors in mild mesenteric ischemia/reperfusion dysfunctions in mice

In this study, the involvement of 5-HT2A receptors on mesenteric ischemia-reperfusion injury was examined in mice. Intestinal ischemia produced by 45 min occlusion of superior mesenteric artery was followed by 24h reperfusion (I/R). The 5-HT2A selective antagonist, ketanserin (0.5 mgkg(-1)) or the 5-HT2A agonist DOI (0.25 mgkg(-1)) was intravenously administered before ischemia and 8h after the beginning of reperfusion. The effects were compared with those obtained in sham operated animals (S). Ketanserin prevented the upper gastrointestinal transit delay induced by I/R (P<0.01), protected intestine from leukocyte recruitment as indicated by jejunal myeloperoxidase activity (P<0.05) and reverted Evans Blue extravasation elicited by I/R in lung, colon and jejunum (P<0.05). On the other hand, 5-HT2A activation by DOI mimicked the effects of I/R in S mice prolonging small intestine transit (P<0.05) and enhancing neutrophil accumulation in jejunal tissues (P<0.05). Furthermore, the reduction of ADP-induced platelet aggregation in plasma of I/R mice was prevented by ketanserin treatment. All together, these findings support the critical involvement of 5-HT2A receptor subtype in mediating the damage induced by mesenteric I/R in mice.     

Synthesis and antiphlogistic, antipyretic and analgesic properties of 5-benzisothiazolylalkanoic acids and their functional derivatives

A new series of 3-methoxy-1,2-benzisothiazol-5-ylacetic acid analogs and some of their functional derivatives were synthesized and tested for their analgesic, antipyretic and anti-inflammatory activities. From an analysis of the relationship between structure and pharmacological activity, it was observed that modifications in the acid group induced useful variations in the parameters studied.     

Presence of caerulein in extracts of the skin of Leptodactylus pentadactylus labyrinthicus and of Xenopus laevis

1. The South American amphibian Leptodactylus pentadactylus labyrinthicus and the South African amphibian Xenopus laevis contain in their skin a polypeptide indistinguishable from caerulein prepared from the Australian amphibian Hyla caerulea.2. The caerulein content of different batches of Leptodactylus pentadactylus labyrinthicus skins varies from 10 to 500-600 mug/g tissue. Drying of the skin causes either a moderate decrease or a slight increase in the caerulein content. Methanol extraction gives considerably higher yields of caerulein than acetone extraction.3. Caerulein or caerulein-like polypeptides also occur in the skin of several other species of Leptodactylus together with 5-hydroxyindole alkylamines and imidazole alkylamines. Yet other species of Leptodactylus lack caerulein-like polypeptides and 5-hydroxyindole alkylamines.4. It is suggested that caerulein and caerulein-like polypeptides may have some function either in the regulation of secretory processes of the skin or in the exchange of water and electrolytes through the skin, or in both.     

Stimulation of acid and pepsin secretions in fistulated cats by dimaprit-like compounds

In the present paper the Authors describe the effects of dimaprit analogs on cat gastric acid and pepsin secretions. Such compounds are only weakly active as stimulants of H2-receptors, and studied as antagonists fail to inhibit acid and pepsin secretions evoked by dimaprit. The different mechanisms of action of dimaprit and histamine on H2-receptors are discussed.     

The actions of caerulein on the smooth muscle of the gastrointestinal tract and the gall bladder

1. In the intact conscious dog, caerulein causes emesis and evacuation of the bowel. The mean effective dose by the intravenous route is 0.4-0.5 mug/kg, and by the subcutaneous route 3-4 mug/kg.2. The gall bladder in situ or as an isolated preparation is highly sensitive to caerulein. A few ng/kg injected intravenously are sufficient to stimulate the gall bladder in situ and less than 1 ng/kg per min is effective when infused intravenously. The isolated gall bladder is contracted by caerulein in concentrations as low as 0.03-2 ng/ml. Krebs solution. There is no tachyphylaxis but, generally, a good dose-response relationship. Hence the gall bladder, especially that of the guinea-pig, appears to be very suitable for the bioassay of caerulein and related peptides.3. In situ, the musculature of the gastrointestinal tract is also highly sensitive to caerulein. Doses as low as 1-5 ng/kg, administered intravenously, have a spasmogenic action on jejunal loops of the dog, and slightly larger doses contract the small intestine of the cat. The stomach and the large intestine seem to be somewhat less sensitive to the polypeptide. Caerulein has a considerable spasmogenic action on the rat pylorus but relaxes the sphincter of Oddi of the guinea-pig.4. Isolated preparations of the gastrointestinal tract are relatively insensitive to caerulein and tachyphylaxis occurs readily.5. Blockade with atropine produces different effects in different intestinal segments and in different animal species. The spasmogenic action of caerulein on the gall bladder is atropine-resistant.6. The effects of caerulein are similar to those of cholecystokinin-pancreozymin in the organs tested in situ or as isolated preparations. Caerulein, however, is always more potent than cholecystokinin-pancreozymin, even on a molar basis. Compared with caerulein, human gastrin I has negligible activity.7. The possible use of caerulein in cholecystography is discussed.