Twenty four new l-aminoacyl-2,3-dihydro-4( III)-quinazolinone derivatives were prepared and evaluated for their pharmacological properties. The compounds with a cyclic amino group showed a choleretic activity. Some substances displayed also antifibrillatory and antiphlogistic activity.

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.

Silybin has been complexed in 1:1 ratio with phosphatidyl choline to give IdB 1016 in order to increase its bioavailability. The antioxidant and free radical scavenger action of this new form of silybin has been evaluated. One hour after the intragastric administration to rats of IdB 1016 (1.5 g/kg b.wt.) the concentration of silybin in the liver microsomes was estimated to be around 2.5 micrograms/mg protein corresponding to a final concentration in the microsomal suspension used of about 10 microM. At these levels IdB decreased by about 40% the lipid peroxidation induced in microsomes by NADPH, CCl4 and cumene hydroperoxide, probably by acting on lipid derived radicals. Spin trapping experiments showed, in fact, that the complexed form of silybin was able to scavenge lipid dienyl radicals generated in the microsomal membranes. In addition, IdB 1016 was also found to interact with free radical intermediates produced during the metabolic activation of carbon tetrachloride and methylhydrazine. These effects indicate IdB 1016 as a potentially protective agent against free radical-mediated toxic damage.

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.

ABSTRACT-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 CC14, praseodymium, ethanol and galactosamine. The ED50 values for inhibition of the rise in ASAT and ALAT levels caused by CC14 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 activ ities and to a stimulating effect on the hepatic synthesis of RNA and proteins.