Nonsteroidal antiinflammatory agents. XXIII. Synthesis and activity of stereomeric (+/-)-erythro- and (+/-)-threo-2-(4-biphenylyl)-3-hydroxy-2-methyl-3-phenyl-propionic acids.

In pursuing our research on the NSAIDs, the diastereomeric (+/-)-erythro- and (+/-)-threo-2-(4-biphenylyl)-3-hydroxy-2-methyl-3-phenyl-propionic acids (4 and 5) were synthesized; the last was also resolved in its optical isomers (6 and 7). The attribution of the relative configuration to 4 and 5 was performed by means of X-ray analysis. The compounds were tested for their antiinflammatory activity. The acid 4, which resulted very interesting, was tested also for analgesic and antipyretic activity, as well as for behavioural effects, gastric tolerability and acute toxicity. On the basis of the obtained data, this compound resulted a very promising one.

Nonsteroidal antiinflammatory agents. Part 21: optically active stereoisomers of p-trifluoromethylphenyl- and p-thioanisyl-biphenylyl- hydroxypropionic acids.

The synthesis, diastereomeric separation, assignment to erythro- and threo-configuration by 1HNMR, and optical resolution of 3-(p-trifluoromethyl-phenyl)- and (p-thioanisyl)-2-biphenylyl-3-hydroxypropionic acids are described. The enantiomers were submitted to a preliminary assay to determine antiinflammatory activity.

[Non-steroidal anti-inflammatory agents. XXII. Chiral aryl-hydroxy-fluorenylpropionic acids]. / Antiinfiammatori non steroidei. XXII--Acidi aril-idrossi-fluorenilpropionici chirali.

As fluorenyl rigid analogues of previous biphenylyl alcanoic acids with very interesting antiinflammatory activity, the 3-(m-tolyl and m-anisyl)-3-hydroxy-3-(2-fluorenyl)-propionic acids have been prepared by means of the Reformatsky reaction and following hydrolysis of the obtained ethyl esters. The preliminary antiinflammatory assay showed that the structural modification inactivates the compounds.

Correlation of biliary epomediol-beta-glucuronide levels with bile flow enhancement in the rat.

In female Wistar rats, epomediol (Clesidren) (30-300 mg/kg p.o.) induced a dose-dependent increase of bile flow and a concomitant enhancement in both unchanged drug and its mono-beta-glucuronide (M 3) biliary levels. Pretreatment with galactosamine (300 mg/kg i.p.) abolished the bile flow increase and resulted in a marked decrease of M 3 but not of the unchanged drug. Moreover, a highly significant correlation (r = 0.809) between M 3 biliary concentration and bile flow was found.

Hexaprazol antagonism to gastric electrical potential fall by acetylsalicylic acid in rat.

Hexaprazol was tested against the gastric barrier breaking effect of aspirin (ASA), using the electric potential difference (PD) test in rats without pyloric ligation. The activity of hexaprazol was evident at a dose lower than the antisecretory one and also at the same range of antiulcer doses. The drug's activity in reducing the PD fall induced by ASA was compared with that of carbenoxolone, pirenzepine, cimetidine and ranitidine administered by the same route. Their relative activity, measured by AUB (area under baseline) index, followed this order: carbenoxolone greater than hexaprazol greater than pirenzepine greater than cimetidine greater than ranitidine. Measured by RI (irritancy index) inhibition, the order of activity was similar: carbenoxolone greater than hexaprazol greater than or equal to pirenzepine greater than cimetidine greater than ranitidine. It was demonstrated that hexaprazol had an anti-barrier breaker activity of marked intensity and duration; this efficacy was always dose-dependent.

[Pharmacologic profile of a new compound with antiinflammatory activity: 2-(4-dimethylvinylphenyl)propionic acid (Gx 258)]. / Profilo farmacologico di un nuovo composto ad attività antiinfiammatoria: l'acido 2-(4-dimetilvinilfenil)propionico (Gx 258).

Gx 258, a new phenylalkanoic acid derivative, was shown in animal tests to possess potent antiinflammatory, analgesic and antipyretic activity. Its antiinflammatory activity was not mediated via the pituitary-adrenal axis, since it was also effective in adrenalectomized rats. Since large doses of Gx 258, 9-83 times greater than those showing antiinflammatory activity, were required to produce gastrointestinal lesions in rats, Gx 258 appears to have a very good therapeutic index. Its therapeutic index as an antiinflammatory and analgesic agent was 2.3-20.5 times greater than that of the parent compound ibuprofen. Gx 258, like ibuprofen, inhibited the biosynthesis of prostaglandins in vitro.

Pharmacological studies with almagate, a potent new antacid compound.

Pharmacological screening tests have been done in order to provide an initial assessment of the new antacid compound almagate (aluminium-magnesium hydroxycarbonate hydrate, Al2Mg6(OH)14(CO3)2 X 4 H2O, Almax). In rats with pyloric ligatures, almagate (125-500 mg/kg) was significantly more potent than aluminium hydroxide in raising the pH and reducing the total acidity of the gastric juice produced, without affecting the volume secreted. Pepsin activity in the gastric juice was also significantly inhibited by almagate even after adjustment to the optimal enzyme pH 2, a phenomenon not demonstrable with aluminium hydroxide. Almagate in oral doses up to 3 g/kg was without effects on the central, autonomic and somatic nervous systems in mice, nor at 500 mg/kg did it influence the cardiovascular system or blood pressure responses to agonist drugs in anaesthetised cats. The results confirm almagate to be a potent antacid drug devoid of systemic pharmacological or toxicological effects.

Efficacy in vivo of almagate in neutralising histamine-induced acid secretion in a rat re-perfused stomach preparation.

The efficacies of almagate (hydrated aluminium-magnesium hydroxycarbonate, Al2Mg6(OH)14(CO3)2 X 4H2O, Almax) and aluminium hydroxide to neutralise histamine-induced gastric acid hypersecretion were compared in a closed-circuit perfused stomach preparation modified for pH-stat titration in the intact, anaesthetised rat. After intravenous injection of histamine (0.75 mg/kg), the amount of antacid automatically added to the closed system to maintain the stomach perfusion fluid at pH 4 was measured during 60 min. The results obtained show that the acid neutralising capacity of almagate in this hypersecretion model was some 8 times greater than that of aluminium hydroxide. Analysis of the titration curves obtained also demonstrates that the velocity of neutralisation to pH 4 at the start of the experiment was considerably more rapid with almagate. It is concluded that almagate will be a rapid acting, potent drug to reduce acidity of the gastric contents in conditions of acid hypersecretion.

Protective action of almagate against bile-facilitated gastric ulceration in the pylorus-ligated (Shay) rat.

In man, the reflux of duodenal contents into the stomach leads to gastritis and produces a mucosa susceptible to ulceration. This effect, predominantly due to bile acids, was studied in an animal model in which the oral administration of bile (ox bile powder containing a minimum of 45% cholic acid) markedly increased the gastrolesive action of subcutaneous indomethacin in the pylorus-ligated rat. Oral administration of the new antacid almagate (hydrated aluminium-magnesium hydroxycarbonate, Al2Mg6(OH)14 (CO3)2 X 4 H2O, Almax) gave a significant dose-related reduction in the severity of bile-facilitated gastric lesions whereas aluminium hydroxide gel did not. The antiulcer activity of almagate in this model is presumed to be attributable to its ability to sequester and inactivate bile acids at the pH of the stomach contents, an effect which should beneficially contribute to its acid-neutralising property in the treatment of gastritis, peptic ulcer and associated conditions.