Synthesis and pharmacological study of ethyl 1-methyl-5-(substituted 3,4-dihydro-4-oxoquinazolin-3-yl)-1H-pyrazole-4-acetates.

Several new ethyl 1-methyl-5-(substituted 3,4-dihydro-4-oxoquinazolin-3-yl)-1H-pyrazole-4-acetates 2, substituted at 2 and, alternatively at, 6, 7 or 8 positions of the quinazolinone nucleus, were synthesised. The compounds were screened for their analgesic and antiinflammatory activities, acute toxicity and ulcerogenic effect. Substitution in the benzene moiety of the quinazolinone ring did not show any advantage for the analgesic activity, whereas it improved in some cases the antiinflammatory activity. Some compounds showed appreciable antiinflammatory activity and, at the same time, very low ulcerogenic index.

Phenylamides of 1-phenyl (or methyl)-5-benzamidopyrazole-4-carboxylic acid as vratizolin analogs with analgesic and antiinflammatory activities.

A number of phenylamides of 5-benzamidopyrazole-4-carboxylic acid were prepared in 50-80% yields from 1-phenyl (or methyl)-6-phenylpyrazolo[3,4-d]1,3-oxazin-4(1H)-ones and aniline derivatives. All the compounds were tested for their analgesic and antiinflammatory activities, as well as for their ulcerogenic potential and acute toxicity. Some derivatives, when compared to phenylbutazone, proved more active in the tests for analgesic and antiexudative activities, but less active in the carrageenin paw oedema test. The compounds proved to posses marginal or no ulcerogenic effect, as well as low systemic toxicity.

Role of soy diet and L-arginine in cyclosporin-A-induced osteopenia in rats.

Our previous studies show that chronic administration of L-arginine decreases cyclosporin-A-induced bone loss. The present study was designed to investigate whether a soy diet could prevent cyclosporin A-induced osteopenia and eventually improve the protective effect of L-arginine. Rats on soy diet were treated with cyclosporin-A, L-arginine, cyclosporin-A + L-arginine or saline. Control groups received a normal diet and the same pharmacological treatment. Our results show that a soy diet prevents osteopenia only in the spinal cord (+30%) and confirm the protective effect of L-arginine in cyclosporin-A-induced osteopenia in whole body, pelvis and spine of rats on a normal diet (+31%, +55%, +55%, respectively). Moreover these data show that the osteoprotective effect of L-arginine in the whole body, pelvis and spine improves in the case of soy diet (+60%, +72%, +89%, respectively). The results suggest that a soy diet exerts a positive effect in cyclosporin-A-induced osteopenia only in sites with high turn-over and improves the osteoprotective effect of L-arginine.

Grapefruit juice effects on the bioavailability of cyclosporin-A in rats.

Previous studies indicate that blood levels of cyclosporin-A are increased by concomittant administration of grapefruit juice in healthy subjects and patients. It was suggested that grapefruit juice could inhibit the metabolism of cyclosporin-A by CYP3A4, the predominant cytochrome P450 enzyme in the gut wall and liver. However, up to date, the mechanism of action of grapefruit juice has not been conclusively identified and no work has been conducted in animals to quantify its effect on cyclosporin-A metabolism. This study compared the disposition of cyclosporin-A (5 mg/kg) coadministered with grapefruit juice, orange juice or water (10 ml/kg) in male Sprague-Dawley rats. Time to peak concentration was about 5 h for each group. Area under the blood concentration-time curve and peak concentration of cyclosporin-A were increased by 31% and 20%, respectively, with grapefruit juice (P < 0.05). The effects of grapefruit juice were not duplicated by orange juice which did not differ significantly from water for any of the parameters tested. These results confirm that grapefruit juice may act as an inhibitor of drug metabolism altering the disposition of concomittantly administered cyclosporin-A in rats. Nonetheless, it was demonstrated that, under appropriate experimental conditions, rats may be suitable models for in vivo investigation of the interaction mechanism between grapefruit juice and cyclosporin-A.

Synthesis and pharmacological screening of 1,3,4-thiadiazino[2,3-b]quinazoline derivatives.

Derivatives of 1,3,4-thiadiazino[2,3-b]quinazoline 7, 9, 9a, 12, 12a, and 13 were prepared from the 3-amino-6-bromo-2,3-dihydro-2-thioxo-4-(1H)-quinazolinone (2) and its analogue without bromine. A series of the title derivatives with or without bromine was tested and the results of pharmacological screening are discussed.

[In vitro effects of L-carnitine on the inhibition of sperm mobility induced by FANS]. / Effetti "in vitro" della L-Carnitina sulla inibizione della motilità degli spermatozoi indotta da F.A.N.S.

OBJECTIVE: We wanted to study the function of some substances present in the seminal fluid (PG and L. Carnitine), which, with different mechanisms, affected Spermatozoa motility, and to study the effect of other substances (F.A.N.S.), known also for their action on P.G. PATIENTS AND METHODS: Ten samples of seminal fluid from healthy subjects were studied according to the indications of the World Health Organization (1992). RESULTS: All the F.A.N.S. used (Cinnoxicam, Salicylic Acetyl Acid) had an inhibitory effect on motility, as did L. Carnitine at high doses. We thought it interesting to observe if L. Carnitine added to the seminal fluid before F.A.N.S. blocked their effects. CONCLUSIONS: The pre-treatment with L. Carnitine had an "in vitro" buffering effect on F.A.N.S.

Effect of acetyl-L-carnitine on ethanol consumption and alcohol abstinence syndrome in rats.

The effect of acetyl-L-carnitine on alcohol consumption and its possible ability to alleviate all symptomatology of ethanol withdrawal syndrome has been investigated in rats. Alcohol-dependence was induced in animals (9-15 g/kg ethanol solution at 20% for a period of 4 days) in order to measure the effects of acetyl-L-carnitine on ethanol abstinence syndrome. The ethanol dependence phase was characterized by the onset of signs and responses of progressive severity: hyperactivity, tremors, spastic rigidity and spontaneous convulsive seizures. After 4 days, 8 h after the last ethanol administration, two groups of animals received acetyl-L-carnitine (125 mg/kg and 250 mg/kg intraperitoneally, respectively) and the intensity of the withdrawal syndrome was assessed on the basis of the appearance of tremors. The effect of acetyl-L-carnitine on voluntary alcohol consumption was investigated in a rat line selected for innate ethanol preference. For 15 days the animals could freely choose both water and/or a hydroalcoholic solution (10% p:v). Acetyl-L-carnitine was given intraperitoneally at a dose of 200 mg/kg twice daily. The water and the hydroalcoholic solution levels were checked at the same time daily. Acetyl-L-carnitine treatment significantly reduced the onset of tremors in ethanol withdrawal syndrome as well as the level of ethanol intake in alcohol-preferring rats. These results suggest a possible pharmacological role of acetyl-L-carnitine in the treatment of alcohol dependence.

Antiinflammatory activity of adrenomedullin in the acetic acid peritonitis in rats.

The antiinflammatory effect of ADM was studied in different models of inflammation and compared to the one of CGRP. Peptides were active against acetic acid-induced peritonitis in the rats. ADM and CGRP exerted the antiinflammatory effect at different doses, 400 and 20 ng/kg respectively, but with different efficacy (ADM >CGRP). This effect was blocked by pretreatment with CGRP (8-37) fragment or with L-NAME. No antiinflammatory activity was evidenced against serotonin- or carrageenin-induced rat paw edema. Our data suggest that ADM exerts antiinflammatory activity in the model characterized by a vascular component. This effect involves CGRP receptors and appears to be mediated by nitric oxide system.

Synthesis and pharmacological activities of novel 3-(isoxazol-3-yl)-quinazolin-4(3H)-one derivatives.

Several new 3-(isoxazol-3-yl)-quinazolin-4(3H)-one derivatives were synthesized and tested for their analgesic and antiinflammatory activities, as well as for their acute toxicity and ulcerogenic effect. A few compounds were as active as phenylbutazone in the writhing and acetic acid peritonitis tests. They had a very low ulcerogenic effect.

Effects of centrally of peripherally injected adrenomedullin on reserpine-induced gastric lesions.

Adrenomedullin intracerebroventricularly administered (0.1 to 20 ng/rat i.c.v.), showed significant gastroprotective activity in a dose-dependent manner. When the peptide was intravenously administered (1 to 1000 ng/kg i.v.) it did not show significant gastroprotective activity in the same test. The gastroprotective effect of the peptide (10 ng/rat) was abolished by bilateral adrenalectomy, by pretreatment with the beta-adrenoceptor antagonist, propranolol (1 mg/kg i.p.), or by a calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8-37) fragment (1 or 10 ng/rat i.c.v.). This study showed that adrenomedullin is protective against reserpine-induced gastric lesions, that the action involves sympathetic nerve activity, and moreover interferes with CGRP receptors.

[Effects of modulation of the redox system on endogenous lipoperoxidation in the rat central nervous system]. / Effetti della modulazione del sistema redox sulla lipoperossidazione endogena nel sistema nervoso centrale del ratto.

In this study we have measured malonaldehyde (MDA) as an index of endogenous lipoperoxidation, the latter being a relevant aspect of oxidative stress that occurs in different neuronal systems. Our results clearly demonstrate that in physiological conditions specific neuronal systems exhibit a different rate of MDA formation among which substantia nigra neurons show a particular vulnerability to oxidative stress. Chronic ethanol treatment significantly enhances MDA production, particularly at the level of cholinergic structures (septum) as well as in the dopaminergic system (substantia nigra) and cortex. On the other hand, treatment with glutathione is able to decrease MDA formation, pointing out the possibility of an exogenous modulation of redox balance in brain cells.