Synthesis and anticonvulsant activity of N-(benzoylalkyl)imidazoles and N-(omega-phenyl-omega-hydroxyalkyl)imidazoles.

A novel series of N-(benzoylalkyl)imidazoles and N-(omega-phenyl-omega-hydroxyalkyl)imidazoles was synthesized and evaluated for anticonvulsant activity in mice against maximal electroshock induced seizures. Some of the compounds showed an activity comparable to or better than phenytoin and phenobarbital. The N-[beta-[4-(beta-phenylethyl)phenyl]-beta-hydroxyethyl]imidazole (38) was selected for further studies; preclinical toxicology and additional efficacy evaluations are in progress. Structure-activity relationships are discussed.

Comparative bioavailability of Silipide, a new flavanolignan complex, in rats.

The comparative pharmacokinetics of Silipide (IdB 1016, a silybin-phosphatidylcholine complex) and silybin were investigated by measuring unconjugated and total plasma silybin levels as well as total biliary and urinary silybin excretion in rats following administration of a single oral dose (200 mg/kg as silybin). Mean peak levels of unconjugated and total silybin after IdB 1016 were 8.17 and 74.23 micrograms/ml respectively. Mean AUC (0-6 h) values were 9.78 and 232.15 h.micrograms.ml-1 indicating that about 94% of the plasma silybin is present in a conjugated form. After administration of silybin, plasma levels of both unconjugated and total compound were under the analytical detection limit. Cumulative biliary (0-24 h) and urinary (0-72 h) excretion values after administration of IdB 1016 accounted for 3.73% and 3.26% of the administered dose, respectively. After silybin administration, the biliary and urinary excretion accounted for only 0.001% and 0.032% of the dose respectively. Our results indicate a superior bioavailability of silybin administered orally as IdB 1016. This was due mainly to an impressive increase in gastrointestinal absorption.

Protective activity of silipide on liver damage in rodents.

The activity of silipide, a silybin-phosphatidylcholine complex (IdB 1016), was tested in different models of liver damage in rodents. After oral administration, silipide exhibited a significant and dose-related protective effect against the hepatotoxicity induced by CCl4, praseodymium, ethanol and galactosamine. The ED50 values for inhibition of the rise in ASAT and ALAT levels caused by CCl4 and praseodymium and for antagonism of the increase in liver triglycerides caused by ethanol ranged from 93 to 156 mg/kg (as silybin). At a dose of 400 mg/kg (as silybin), silipide was also active in protecting against paracetamol-induced hepatotoxicity. Silybin and phosphatidylcholine at doses equivalent to those contained in the active doses of silipide failed to show any significant protective activity in these models. The liver protective effect of silipide is probably related to its antioxidant activities and to a stimulating effect on the hepatic synthesis of RNA and proteins.

Pharmacokinetics of flavoxate in rats.

The plasma levels, the urinary excretion and the biliary excretion of piperidinoethyl-3-methylflavone-8-carboxylate (flavoxate, F) were studied in rats after i.v. and after oral administration. Parallel experiments were made with 3-methyl-flavone-8-carboxylic acid (M), the main metabolite of F. The substances are found in blood and are excreted in the urine and in the bile. The quantities excreted in the urine after oral administration are similar to those excreted after i.v. administration, showing that the enteric availability of the drugs is almost complete. The end product in urine and in bile is represented by a substance which yields M after a strong acid hydrolysis. There are marked pharmacokinetic differences between F and M, probably related to their physical properties.

[New esters of N-arylanthranilic acids]. / Nuovi esteri di acidi N-arilantranilici

A series of acyloxy- and alkyloxymethyl esters of meclofenamic, flufenamic and mefenamic acids has been synthesized and its antiinflammatory, analgesic and antipyretic activities have been compared with those of the corresponding acids and the methyl, beta,gamma-isopropylidene-dioxypropyl, N,N-diethylaminoethyl esters. The acyloxy- and alkyloxymethyl esters are the most interesting compounds, because they possess pharmacological activity of the same order as that of the corresponding acids and a lower toxicity. The ethoxymethyl ester of the N-(2,6-dichloro-m-tolyl)anthranilic acid is presently under clinical investigation.

[4-aminobutyrophenones with hypotensive activity]. / 4-Aminobutirrofenoni ad attività ipotensiva

A series of new butyrophenones was synthesized, the aim being to reduce neuroleptic activity and enhance the hypotensive effects of this class of drugs. The compounds were screened for toxicity according to the Irwin scheme and tested in anaesthetized cats for their effects on systemic arterial pressure. The most interesting compound, i.e. 1-(4'-fluorobenzoyl)-3-pyrrolidinyl-propane, was tested also in anaesthetized rabbits, cats, and dogs and in concious dogs. Moreover its central nervous system effects were tested in rats and mice. The compound proved practically devoid of neurological effects and showed interesting hypotensive activity.

Effects of Vaccinium Myrtillus anthocyanosides on arterial vasomotion.

The effects of Vaccinium Myrtillus anthocyanosides (Myrtocyan, VMA; CAS 84082-34-8) on arteriolar vasomotion were assessed in cheek pouch microcirculation of anesthetized hamsters and in skeletal muscle microvasculature of unanesthetized hamster skin fold window preparation. Intravenously injected VMA induced vasomotion in cheek pouch arterioles and terminal arterioles with higher frequency in smaller vessels. In the skeletal muscle arteriolar networks VMA increased vasomotion frequency and amplitude in all vessel orders. The results indicate that VMA are effective in promoting and enhancing arteriolar rhythmic diameter changes, that play a role in the redistribution of microvascular blood flow and interstitial fluid formation.

Effect of a natural flavonoid on gastric mucosal barrier.

The effects of 3,5,7-trihydroxy-2-(3,4-dihydroxyphenyl)-1-benzopyrylium chloride (IdB 1027) on the rat gastric mucosa were evaluated. IdB 1027 administered intragastrically at doses ranging from 100 to 400 mg/kg inhibited the fall in transmucosal potential difference and the increase in H+ back-diffusion induced by acetylsalicylic acid. Moreover, IdB 1027 at doses of 50 and 200 mg/kg by intragastric route increased the gastric bicarbonate secretion. These results suggest that the gastroprotective activity of IdB 1027 is mediated by an increase in the efficiency of gastric mucosal barrier.

Antiulcer activity of an anthocyanidin from Vaccinium myrtillus.

The antiulcer effects of 3,5,7-trihydroxy-2-(3,4-dihydroxyphenyl)-1-benzopyrylium chloride (IdB 1027) were assessed in various experimental models. Given orally, IdB 1027 antagonized gastric ulcerations induced by pylorus ligation, stress, nonsteroidal antiinflammatory drugs, ethanol, reserpine, histamine and duodenal ulceration induced by mercaptamine (cysteamine). Moreover it antagonized chronic gastric ulcers induced by acetic acid. Given intraperitoneally, it was more potent than after oral administration. IdB 1027 did not affect gastric secretion in pylorus-ligated rats and increased gastric mucus in normal animals both in the absence and in the presence of indometacin treatment. Tolerability was very good. These results indicate that IdB 1027 possesses a promising antiulcer activity, probably by potentiating the defensive barriers of the gastrointestinal mucosa.