Oculomotor palsy and supraclinoid internal carotid artery aneurysms. Personal experience and review of the literature.

Oculomotor palsy related to the presence of an intracranial aneurysm arising from the supraclinoid internal carotid artery (ICA) is a well known and described clinical condition. Recent microanatomical and clinical evidences seem to demonstrate that the pathophysiology of the aneurysm-related III nerve palsy could be interpreted as that of any other cranial nerve's neurovascular compression syndrome. The authors review their personal experience with supraclinoid ICA aneurysms related to oculomotor palsy and the data of the literature, aiming to elucidate a better clinical, therapeutic and prognostic correlation to these factors.

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.

L-arginine prevents bone loss and bone collagen breakdown in cyclosporin A-treated rats.

Cyclosporin A is implicated in the pathogenesis of post-transplantation bone disease. Because of recent evidence that cyclosporin A may cause renal and cardiovascular toxicity by inhibiting nitric oxide (NO) activity, and that NO slows bone remodeling and bone loss in animal and human studies, we investigated a possible link between NO production and beneficial effects on bone health in cyclosporin A-treated rats. Thirty-six 10-week-old male rats were assigned to six groups of six animals each, and treated for 4 weeks with: vehicle; cyclosporin A; L-arginine; N(G)-nitro-L-arginine methylester (L-NAME, a general inhibitor of NO synthase activity); a combination of cyclosporin A+L-arginine; and a combination of cyclosporin A+L-NAME. Whole body and regional (spine and pelvis) bone mineral content of rats were measured under basal conditions and at the end of the treatment period by dual-energy X-ray absorptiometry (DXA) scanning. Femur weights and serum concentrations of pyridinoline, a reliable marker of bone resorption, were measured at the end of the study period. Cyclosporin A-, L-NAME-, and cyclosporin A+L-NAME-treated rats had significantly lower bone mineral content and femur weights, and significantly higher pyridinoline levels than did control animals. The administration of L-arginine appeared to prevent bone loss caused by cyclosporin A, suggesting that this amino acid, which can be converted to produce NO, might prove useful in preventing disturbed bone modeling and inhibition of bone growth associated with cyclosporin A therapy.

Synthesis of new [1,3,4]thiadiazolo[3,2-a]thieno[2,3-d]pyrimidinone derivatives with antiinflammatory activity.

New thiadiazolothienopyrimidinones were synthesized in continuation of efforts to prepare thienopyrimidine derivatives with analgesic and antiinflammatory activities. In this study, the effect of various substituents in the thiophene ring on the pharmacological activity of the compounds was investigated.

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.

Involvement of DA1 and DA2 receptors in the gastroprotective activity of amylin in the rat.

Peripheral administration of amylin (40 microg kg-1) exerts gastroprotective effects in the reserpine-induced gastric lesions in the rat. This activity is decreased by pretreatment (30 min before) with (-)-sulpiride (0.1 mg kg-1 s.c.) or domperidone (0.1-2.5 mg kg-1 per os), dopamine DA2 antagonists. Pretreatment with SCH 23390 (0.5-4 mg kg-1 s.c.), a DA1 antagonist, at the maximal dose used, also significantly decreased the gastroprotective activity of the peptide. Amylin does not exert any gastroprotective effect in indomethacin-pretreated rats (7.5 mg kg-1 s.c., 30 min before), as well as in the aspirin-induced ulcer test (200 mg kg-1 per os at the time of amylin administration). Our data confirm that the gastroprotective effect of amylin in reserpine-induced gastric lesions involves, at least in part, the dopaminergic transmission, interfering with both the DA1 and DA2 receptor subtypes.

Synthesis and pharmacological evaluation of 1-methyl-5-[substituted-4 (3H)-oxo-1,2,3-benzotriazin-3-yl]-1H-pyrazole-4-acetic acid derivatives.

Several new 1-methyl-5-[substituted-4-oxo-1,2,3-benzotriazin-3-yl] -1H-pyrazole-4-acetic acids and their ethyl ester derivatives were prepared. The compounds were tested for analgesic and antiinflammatory activities, acute toxicity, ulcerogenic effect, and as in vitro inhibitors of 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), since it is claimed that the inhibition of such an enzyme predicts in vivo antiinflammatory activity. Some compounds were more active than phenylbutazone in the phenylbenzoquinone and acetic acid peritonitis tests, and equiactive to the same drug in the carrageenin paw edema test. All the compounds inhibited the 3 alpha-HSD, but no correlation was observed with the paw edema inhibition values. The compounds proved to possess marginal or no ulcerogenic effect, as well as low systemic toxicity.

Synthesis of new thieno [2,3-d]pyrimidine-2,4(1H,3H)-diones with analgesic and anti-inflammatory activities.

A series of new 1,3-disubstituted thieno[1,3-d]pyrimidine-2,4(1H,3H)-diones were prepared to investigate their analgesic and anti-inflammatory properties. The analgesic and anti-inflammatory activities of synthesized compounds were investigated by the phenylquinone-induced writhing syndrome test, carrageenan rat paw oedema test and acetic acid-induced peritonitis assay. Most of the new compounds were found to be superior to mefenamic acid, as they were devoid of any ulcerogenic activity.

Effect of amylin in various experimental models of gastric ulcer.

Subcutaneous administration of amylin (20-40 micrograms/kg) prevented, in a dose-dependent manner, reserpine- and serotonin-induced gastric damage, but the anti-ulcer effect was not present when lesions were induced by pylorus ligation. The protective effect of amylin was inhibited by pretreatment with capsicin as well as CGRP-(8-37), a calcitonin gene-related peptide (CGRP) and amylin receptor antagonist, and was significantly reduced by domperidone, a dopamine D2 receptor antagonist, or neostigmine, an inhibitor of acetylcholinesterase. Our data suggest that the gastroprotective activity of amylin in some experimental models of gastric ulcers involves capsaicin-sensitive fibers and CGRP receptors. Moreover, the peptide interferes, at least in part, with the dopaminergic and parasympathetic systems.

Protective action of epidermal growth factor and a fraction from Triticum vulgare extract in mouse tail necrosis.

Several peptide growth factors, including EGF, are known to protect endothelium from oxygen-related damage or ischemia-reperfusion, in vitro experiments show that such protective effect involves endogenous endothelium-related factors like nitric oxide and prostanoids. However, in vivo demonstrations of a possible role in related vascular diseases are lacking. In our experiments, human EGF and fraction C, a 3-10 kDa oligosaccharidic fraction from an aqueous extract of Triticum vulgare, known as growth promoters for several cell types including endothelial cells, were found protective against ischemic necrosis of the mouse tail induced by i.v. k-carrageenin plus endothelin-1. After i.p. injection, peak activities were observed at 10 micrograms/kg EGF and 2 mg/kg fraction C. Pretreatment with L-NAME reduced protection in a dose-dependent manner. Addition of indomethacin increased the effect of L-NAME, suggesting that both nitric oxide and eicosanoids are involved in the protective effect of EGF and fraction C.

Amylin given by central or peripheral routes decreases gastric emptying and intestinal transit in the rat.

The effect of rat amylin on gastric emptying and intestinal transit in the rat was examined. Amylin administered intracerebroventricularly (1, 2, 2.5 or 4 micrograms/rat) produced the maximal decrease in gastric emptying and intestinal transit at the dose of 2.5 micrograms/rat. Higher doses produced a lower effect. Peripheral administration (25, 50 or 100 micrograms/kg) produced dose-dependent effects. Pre-treatment with neostigmine blocked the effect of amylin when it was centrally injected, while the effect of amylin given peripherally was partially reduced. Pre-treatment with domperidone decreased the inhibitory effect of peripherally injected amylin, but no effect was observed when the peptide was centrally injected.

Synthesis and pharmacological evaluation of thieno[2,3-d]pyrimidin-2,4-dione and 5H-pyrimido [5,4-b]indol-2,4-dione derivatives.

Two series of novel derivatives based on the thienopyrimidine and pyrimidoindole ring systems, both N-substituted in position 3, have been synthesized. The compounds were obtained by reaction of N-amino groups of 5,6-dimethyl-thieno[2,3-d]pyrimidin-2,4-dione and of 5H-pyrimido[5,4-b]indol-2,4-dione with aromatic aldehydes. Some of these substances showed an appreciable analgesic activity, a good antiinflammatory activity, a low acute toxicity with an optimal gastric tolerance.

Synthesis and pharmacological properties of thieno[2',3':4,5]pyrimido [2,1-b][1,3,4]thiadiazine derivatives.

A new series of 2-substituted-7,8-dimethyl-3H,9H-thieno[2',3':4,5]pyrimido[2,1- b][1,3,4]thiadiazin-9-ones 5a-d and 6a,b was synthesized through the hydrazinium(1+) salt of 3-amino-2,3-dihydro-5,6-dimethyl-2-thioxo- thieno[2,3-d]pyrimidin-4(1H)-one, 2. These derivatives and two analogs 10a,b were tested for their analgesic and antiinflammatory properties. The pharmacological results are discussed in comparison with those of related compounds previously tested.

Protective effect of propionyl-L-carnitine against PAF-induced rat paw oedema.

Recent reports from our laboratory gave evidence showing that propionyl-L-carnitine (PLC), unlike L-carnitine (LC) and acetyl-L-carnitine (ALC), has anti-inflammatory activity in some models of vascular inflammation in rodents. The present paper shows that PLC (50 to 200 mg kg-1 i.p.) inhibits rat paw oedema induced by platelet activating factor (PAF), while LC and ALC, as well as indomethacin and phenylbutazone, are ineffective. The extent of the maximal inhibition produced by PLC at 200 mg kg-1 was comparable to that of betamethasone 0.05 mg kg-1 or sodium salicylate 100 mg kg-1. PLC inhibited also the early phase (1-2 h) of carrageenin-induced rat paw oedema, which is partly dependent on PAF release, but it was ineffective in the eicosanoid-dependent late phase (3-4 h) of the carrageenin oedema. We suggest that such anti-inflammatory activity of PLC may be due to various mechanisms converging on a stabilizing action upon biomembranes.