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The assessment of the protective actions of H2-receptor antagonists against gastric mucosal lesions by necrotizing agents relies on the gross observation of the gastric mucosa only. We examined the activity of famotidine against 0.6 N HCl-induced damage and the role of parietal cells by light and transmission electron microscopy. Rats received famotidine 0.3-10 mg/kg intragastrically. Sixty minutes later 0.6 N HCl (1 ml/rat) was given and after an additional 30 min the stomachs were removed. Macroscopically visible lesions were measured. Histologic lesions were scored on the basis of the depth. The ultrastructure of parietal cells in the isthmus-neck region was examined. Pretreatment with famotidine resulted in a slight increase of macroscopically visible gastric lesions in response to HCl. While the extent of total histologic damage was not modified, the antisecretory dose significantly reduced only lesions deep within the mucosa. Famotidine alone determined the dose-dependent occurrence of a distinct parietal cell morphological state, suggestive of inhibition of the secretory system. A causal link between the protective effect on the region where parietal cells are located, the percentage of cells shifting to the inhibited morphological state, and the inhibitory effect on acid secretion is proposed.

The histamine H(3) receptor shows high degree of stereoselectivity for histamine analogues branched in the side chain. The hypothesis that gastroprotection by (R)-alpha-methylhistamine could be H(3) receptor-mediated was tested by comparing the effect of (R)-alpha-methylhistamine and of (S)-alpha-methylhistamine on ethanol-induced histologic lesions in the rat gastric mucosa. Extensive damage was caused by 60 min exposure to absolute ethanol, 91% of the mucosa examined being damaged. Conversely only 23% of the mucosa was damaged after pretreatment with (R)-alpha-methylhistamine (100 mg/kg i.g.). In the groups pretreated with (S)-alpha-methylhistamine (55.44 and 166.3 mg/kg i.g.) total damage ranged from 77 to 79%, though it was confined to the upper portion of the mucosa. Morphometric analysis of stained intraepithelial mucosubstances revealed that (R)-alpha-methylhistamine pretreatment resulted in an increase in number and volume of surface mucous cells, not evident after (S)-alpha-methylhistamine pretreatment. Scanning electron microscopy confirmed light microscopy evaluations. The two isomers of alpha-methylhistamine differently affect the response of rat gastric mucosa to absolute ethanol and they appear to differ in their influence on surface mucous cells. A basis for interpreting the effects of the two isomers of alpha-methylhistamine rests on the high degree of stereoselectivity of H(3) receptors and on the different affinities of the two isomers for these receptors.

The effect of the nonsteroidal antiinflammatory drug (NSAID) amtolmetin guacyl (AMG) on the gastric mucosa was studied in the rat by means of histological and functional techniques. AMG administered at 50-300 mg/kg intragastrically was virtually devoid of gastrolesive properties after either acute or repeated treatment. By contrast, its metabolite, tolmetin (TOL, 15-60 mg/kg, intragastrically) caused dose-dependent gastric damage after both treatments. Light and electron microscopy revealed that AMG induced minimal changes in the surface epithelium layer, without signs of vasocongestion or leukocytes adherence. AMG (50 mg/kg intragastrically) did not change basal gastric potential difference (PD), whereas acetylsalicylic acid and ibuprofen induced falls in PD of 22 and 27 mV, respectively. AMG (50 mg/kg intragastrically) reduced by 60% the fall in PD induced by 50% ethanol; this inhibition was dependent on the incubation time, and was maximal when AMG was given 4 hr before ethanol. AMG (100 mg/kg intragastrically) induced an increase in NO synthase type 2 (NOS2) activity, which was significantly different from control values, when AMG was administered 4 hr before the test. The metabolites of AMG, tolmetin, MED 5, and guaiacol were ineffective. Pharmacokinetic analysis of the residence time of AMG in the different areas of the gastrointestinal tract, revealed that AMG remains in the gastrointestinal tract at least for 4 hr, the time necessary for a maximal induction of NOS2 and for maximal protection against ethanol-induced damage. In conclusion, these data indicate that the nonsteroidal antiinflammatory drug amtolmetin guacyl is devoid of gastrolesive properties; this gastro-sparing effect seems to involve the production of nitric oxide, which can counteract the damaging effects due to prostaglandin inhibition. The presence in the stomach of the native molecule of amtolmetin guacyl seems to be necessary for the protective effect observed.

The effect of a new histamine H2-receptor antagonist derived from the lamtidine molecule and containing a nitric oxide (NO)-donor furoxan moiety (derivative 1) was studied for its gastric antisecretory activity and for a possible gastroprotective effect, in comparison with the analog without the furoxan moiety (derivative 2). The H2-receptor antagonistic activity was also investigated in the isolated guinea pig papillary muscle. Derivative 1 was approximately 10 times less potent than derivative 2 at the H2-receptor level; conversely, it was about 10 times more effective as a gastroprotective agent against ethanol- and 0.6 N HCl-induced gastric lesions. The mechanism of the gastroprotection exerted by derivative 1 is probably connected with the release of NO, whose vasodilating action on gastric mucosa vessels is crucial. The combined antisecretory and gastroprotective activity of derivative 1 allows this compound to be considered as a prototype of a new class of antiulcer agents.

(R)-alpha-Methylhistamine, a selective agonist of histamine H3 receptors, prevents macroscopically visible gastric lesions by absolute ethanol in the rat. A further insight into its activity was the aim of our study. Rats were given saline or (R)-alpha-methylhistamine (100 mg/kg) intragastrically. After 30 min, absolute ethanol was given and gastric mucosa was sampled 60 min later. Histologic damage and intracellular and adherent mucus were quantified. Luminal surface and mucous cells were examined by scanning and transmission electron microscopy. (R)-alpha-Methylhistamine reduced the extent of lesions by ethanol from 96 to 18%. Surface mucous cells and mucous neck cells were increased in volume and number, packaging of intracellular mucus was modified, and the secretory processes were promoted by (R)-alpha-methylhistamine itself, although these modifications were mostly evident in stomachs subsequently exposed to ethanol. Adherent mucus layer thickness was increased by (R)-alpha-methylhistamine only after ethanol exposure. It is concluded that (R)-alpha-methylhistamine predisposes mucous cells to react to ethanol.

The ability of (R)-alpha-methylhistamine, the selective agonist of histamine H3 receptors, to reduce ethanol-induced gastric damage was examined in the rat. (R)-alpha-methylhistamine (1-100 mg/kg intragastrically) caused a dose-related reduction in the amount of damage produced by ethanol. This protective effect was not shared by the S enantiomer of alpha-methylhistamine. Thioperamide, selective H3 receptor antagonist, inhibited the protective effect of 10 but not 100 mg/kg of (R)-alpha-methylhistamine. Pretreatment with (R)-alpha-methylhistamine, 100 mg/kg i.g., resulted in a significant increase in the thickness of adherent mucus gel layer, which may contribute to the protective action of the compound.

This study examined the gastroprotective effect of (R)-alpha-methylhistamine (MHA), a selective agonist of histamine H3 receptors. Gastric lesions were induced in the rat by administering absolute ethanol in a volume of 1 ml. Stomachs were removed 1 h later and lesions evaluated both macroscopically and histologically. MHA dose-dependently inhibited ethanol-induced lesions in the range 1-100 mg/kg both by the intragastric and intraperitoneal route. Histological findings indicated that the number of mucous granules in surface and neck cells was increased and the process of reepithelialization was rapidly promoted by MHA. Thioperamide, at 10 mg/kg, inhibited the protective effect of 10 but not of 100 mg/kg of MHA. Larger doses of thioperamide could not be tested because of an interaction with ethanol causing central nervous system effects. Famotidine and indomethacin pretreatment only partially counteracted the MHA effect. The results indicate that MHA is highly effective in preventing ethanol-induced lesions but the exact mechanism is still uncertain.

Starting from the structure of thioperamide, a known H3-antagonist, a new series of compounds with a benzothiazole nucleus instead of the cyclohexylcarbothioamide moiety was synthesized. Various substituents, selected by experimental design, were introduced in position 6 of the benzothiazole nucleus, in order to change its physico-chemical characteristics. The lipophilicity of the synthesized compounds was measured by means of RP-HPLC, and their H3-receptor affinity was evaluated by competitive binding assays on rat cortex synaptosomes, with the labelled ligand N alpha-[3H]methylhistamine. A QSAR analysis was performed on the experimental data, using also substituent constants taken from the literature. The newly synthesized compounds showed lower H3-affinities than thioperamide; quantitative structure-activity relationships, described by models obtained with PLS and MRA techniques, were observed among benzothiazole derivatives. According to these relationships, any attempt to improve the potency of these compounds should involve the substitution of the benzothiazole moiety with less bulky and/or more flexible structures, which should also be less lipophilic and allow better electronic interactions with the binding site. 1-(Benzothiazol-2-yl)-4-[(1H)-imidazol-4-yl]piperidine represents a limit structure for H3-activity, since it seems impossible to improve its affinity by means of substitution in the studied position of the benzothiazole nucleus, as shown by predictions performed by a PLS model.

The preparation of a representative group of derivatives of the known H3-antagonist thioperamide is described. Binding affinity for histamine H3-receptors of thioperamide and its derivatives, which were obtained by substitution on the imidazole ring, was measured on rat brain cortex synaptosomes. Competitive binding assays were performed with two different labelled ligands, the physiological agonist [3H]histamine ([3H]HA) and the potent H3-agonist N alpha-[3H]methyl-histamine ([3]NAMHA). We observed a remarkable difference in Ki values obtained versus the two labelled ligands, both for thioperamide and its derivatives. In particular, 5-methylthioperamide showed a considerable selectivity for the system recognized by [3H]NAMHA, being about 100 times more potent versus this system than versus the system recognized by [3H]HA. On the basis of these observations, we suggest that it is necessary to consider this difference in evaluating the affinity of new compounds for the H3-receptors.

This paper reports the pharmacological assessment of beta-blocking properties of new benzisothiazole and benzisoxazole derivatives, substituted in position 3-, 5- or 7- with the oxypropanolaminic side chain (I-VI), to of which contain the -OCH3 group in position 3- (III, V) in comparison with propranolol. The results, obtained on isoprenaline-induced chronotropic response of rat isolated atria and on isoprenaline-induced relaxation of guinea-pig tracheal strips precontracted by carbachol, suggest that the compounds (I, II, IV, VI), at variance with the methoxy-substituted (III, V), possess a beta 1-blocking activity 4-300 times lower than propranolol. pA2 values drop from 8.36 to 7.56 and 7.04 from the relative compounds substituted in position 7- (IV), 3- (I) and 5- (II), thus indicating that the position of the oxypropanolaminic chain in the benzisothiazole ring affects the ability of the molecules to interact with the beta 1-adrenoceptor. Furthermore, benzisothiazole rather than benzisoxazole ring seems to facilitate the drug-beta 1 adrenoceptor interaction, the compound (I) displaying a 10-fold higher affinity than compound (VI).

Thioperamide is a potent and selective antagonist on histamine H3 receptors. A method for its isolation and quantitation by HPLC from rat plasma and brain samples has been developed. Using this technique, thioperamide concentrations in rat plasma and brain were measured after systemic administration, in order to evaluate its persistence in blood and its ability to cross the blood-brain barrier. We observed that, at a dose of 60 mg/Kg, thioperamide undergoes a slow elimination from plasma, with a half-life of 10 hours, and can readily cross the blood-brain barrier.

Continuing their studies on benzisothiazolyl derivatives, Authors refer to the preparation and pharmacological properties of 4-(1,2-benzisothiazol-3-yl) alkanoic and phenylalkanoic acids. All substances were tested for anti-inflammatory, analgesic and antipyretic properties. As reference compounds, 1,2-benzisothiazolin-3-one and 4-(3-oxo-1,2-benzisothiazolin-3-yl) phenylacetic acid, as prototypes of benzisothiazolinonic derivation. Ibuprofen, as a prototype of substituted arylalkanoic acids, and Phenylbutazone were used. Analysis of the data leaded to the following conclusions. Introduction of the aryl moiety, passing from benzisothiazolylalkanoic to benzisothiazolyl-phenylalkanoic structures, produced a remarkable increase of activity. 2-[4-(1,2-benzisothiazol-3-yl)phenyl] propionic and 2-[4-(1,2-benzisothiazol-3-yl)phenyl]butyiric acids showed anti-inflammatory, analgesic and antipyretic properties comparable to those of Ibuprofen. Substantial differences in variations in activities were observed comparing the properties of benzisothiazolylphenylalcanoic acids with those of the benzisothiazolinonic series, object of preceding studies.

It has been recently pointed out that the most reliable method of assessment of gastric mucosal injury is the microscopic examination of the tissue. The purpose of the present paper was, therefore, to study the histological features of gastric lesions induced by a six week isolation in rats. It has also been investigated whether a two week treatment, beginning four weeks after isolation, with cimetidine 80 and 160 mg kg-1 p.o. daily could protect the gastric mucosa. In saline treated rats, histological examination of haemorrhagic areas showed that both surface epithelium and gastric pits were damaged or even completely absent with a consequent surfacing of subepithelial vessels. Damage extended deeply into the gastric glands with evidence of necrotic cells in the corpus and fundus. Simultaneous occurrence of the process of restitution was evident. Cimetidine partially lessened the severity of damage and appeared to favour the restitution processes.

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.

The synthesis of a new series of 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenylalkanoic compounds and some of their functional derivatives is described. The compounds, on the basis of data obtained from 1,2-benzisothiazolin-3-one derivatives, were biologically examined mainly for their antiphlogistic and analgesic actions. Results obtained, in analyzing the relationship between structure and pharmacological actions, suggest that both 4-(3-oxo-1,2-benzisothiazolin-2-yl)-phenyalkanoic acids and o-sulphobenzimido alkanoic esters are endowed with pain-killing effects comparable in potency and efficacy with phenylbutazone.

H2-receptor but not H1-receptor antagonists, administered by intravenous infusion, produce a dose-dependent constriction of superior mesenteric arterioles of the anaesthetized rat under resting conditions. However the possibility that this effect could be related to a blockade of H2 receptors is unlikely, since their potency on blood flow changes does not parallel known H2-receptor antagonist activity. Furthermore, the estimated potency ratio is not in the expected order if the vasoconstriction is due to H2-antagonism, the potency ratios on guinea-pig atrial muscle and on mouse gastric acid secretion being famotidine greater than oxmetidine greater than ranitidine greater than cimetidine.

The effects of cimetidine and ranitidine, alone or combined with sulglycotide or carbenoxolone, and those of 16,16-dimethyl prostaglandin E2 were investigated on mucosal lesions induced in pylorus-ligated rats. The drugs were administered orally after pylorus ligation; 3 hr later the animals were killed, the stomachs removed and examined for the presence of mucosal lesions. Volume, pH, total acidity, pepsin, free and barrier mucus were determined. H2-antagonists both at nonantisecretory and antisecretory doses failed to prevent gastric mucosal lesions or to affect significantly mucus and pepsin. Sulglycotide and carbenoxolone inhibited pepsin secretion, the latter enhanced barrier mucus and both reduced lesion severity. A nearly complete prevention of mucosal damage was observed after anti-secretory doses of cimetidine plus sulglycotide or carbenoxolone. Data obtained compared with those of 16,16-dimethyl prostaglandin E2 suggest that mucus and pepsin might have a partial role in ulcer prevention.

The effects of sulglicotide, alone or combined with cimetidine, have been investigated on mucosal lesions induced in rats by pylorus ligation. In the same animals, the measurement of acid and pepsin output and of soluble and barrier mucus has been performed. Dose-dependent sulglicotide prevented the development of mucosal lesions and its protective effect was achieved without significant modifications in gastric acid secretion. The secretion of pepsin and of mucus was markedly inhibited at every dosage of the compound. Neither the damage to gastric mucosa nor the secretion of acid, pepsin and mucus were affected by cimetidine. The combination of the highest doses of both compounds resulted in a synergistic gastro-protective effect, not dependent on a synergistic effect on the reduction in acid secretion.

In the present paper pharmacological properties studied on the gastrointestinal tract of two new alkylaminoalkylphenylbenzisothiazole derivatives, 4-dimethylamino-2-phenyl-2-(1,2-benzisothiazole-3-yl)butyramide (PM2) and N,N-dimethyl-3-phenyl-3-(1,2-benzisothiazole-3-yl)propylamine (PM3) have been reported. Both drugs showed antispasmodic effects on gastroduodenal junction of the anaesthetized rat stimulated by Caerulein, according to previous results obtained on guinea-pig isolated ileum. On this substrate they were different in the potency being PM3 more active than PM2. On the contrary, the hypersecretion induced by Histamine or Gastrin-17 in rat perfused stomach was potentiated by PM2 and inhibited by PM3. Similar effects were observed on guinea-pig "in vitro" stomach preparation where PM2 and Papaverine were ineffective in modifying Histamine dose-response curves and PM3 reduced significantly maximal peak effects of Histamine, behaving as a non-competitive antagonist. The significant differences observed on gastric secretion but not on other substrates, from compounds structural analysis, appear scarcely justified and seem to us important to be further investigated.

Based on previous observations, the preparation, some physicochemical (partition coefficient, pKa) and pharmacological properties of 4-(3-oxo-1,2-benzisothiazolin-2-yl)alkanoic, benzoic, phenyl, phenoxyalkanoic acids and of some of their functional derivatives are reported. All new compounds were biologically examined for their antiphlogistic, analgesic and antipiretic actions, in comparison with those of 1,2-benzisothiazolin-2-one and with those of ibuprofen as the antiphlogistic, analgesic, antipyretic arylalkanoic prototype. Structure-activity relationships showed that the 1,2-benzisothiazolin-2-one and its new alkanoic and arylalkanoic derivatives have strong actions which are however specific for some of the tested pharmacological properties. From this point of view, the synthesized substances have a narrow spectrum of activity, if compared with ibuprofen which is at the same time an antiphlogistic, analgesic and antipiretic substance. The antiphlogistic and antipyretic activities of 4-(3-oxo-1,2-benzisothiazolin-2-yl)benzoic, phenylacetic and phenylmethylacetic acids and the antipyretic and analgesic actions of 3-oxo-1,2-benzisothiazolin-2-ylacetic acid, which are comparable or higher in "potency" than those of ibuprofen, are noteworthy.