Neurochemical and behavioural effects of chronic aldicarb administration in rats.

Changes in neurochemical parameters, behavioural and memory performances due to aldicarb (a carbamate pesticide) treatment was investigated after chronic oral administration in rats. Rats received water, or aldicarb 1 ppb (= 0.12 g/kg/day), aldicarb 10 ppb (= 1.2 g/kg/day) and aldicarb 100 ppb (= 12 g/kg/day) for 4 months. The locomotor and explorative activities were reduced, and aldicarb significantly decreased brain AChE activity while an increase was found in the passive avoidance and water-maze performance. In the striatum, aldicarb 10 ppb and 100 ppb, significantly reduced DOPA but not DOPAC concentrations, while the 10 ppb and 100 ppb doses significant increased DA levels. Aldicarb did not affect DA, DOPA and DOPAC levels in the accumbens. The neuropharmacologic effects of chronic dosing with aldicarb, AChE inhibition and dopaminergic modulation could be useful for treatment of memory deficits related to CNS disorders.

Mucosal 5-aminosalicylic acid concentration inversely correlates with severity of colonic inflammation in patients with ulcerative colitis.

BACKGROUND AND AIM: The treatment of ulcerative colitis (UC) with 5-aminosalicylic acid (5-ASA) does not have the same therapeutic effect in all patients. We tested the hypothesis that the effectiveness of the drug is related to its mucosal concentration. PATIENTS: Twenty one UC patients receiving oral 5-ASA (2.4-3.2 g/day) were enrolled in the study. Four were also receiving topical treatment (2 g/day). METHODS: Six endoscopic biopsies were taken from the rectum for measurement of 5-ASA concentrations (ng/mg) by HPLC; soluble interleukin 2 receptor (sIL-2R) concentrations (U/ml) were measured by ELISA and histology. Endoscopic and histological appearance was graded on a four point scale (0-3). The Wilcoxon's rank test and Pearson's correlation coefficient were used for statistical analysis. RESULTS: Mucosal concentrations of 5-ASA were significantly higher (p=0.03) in patients with endoscopic scores of 0-1 compared with those with scores of 2-3 (16.1 (range 10.2-45) v 5. 5 (3.5-17.4), respectively) and in patients with lower histological inflammation compared with those with more severe scores (17.4 (10. 5-45) v 8.9 (3.5-17.2), respectively) (p<0.01). In contrast, mucosal sIL2-R concentrations were significantly lower in patients with slight endoscopic and histological lesions than in those with more severe disease. A significative inverse correlation (r=-0.85) was found between 5-ASA and sIL-2R mucosal concentrations (p=0.00008). CONCLUSIONS: In patients with UC, in the same area of the intestinal tract, we found that the higher the 5-ASA mucosal concentrations, the lower the IL-2R levels and endoscopic and histological scores. We hypothesise that maintenance of high mucosal 5-ASA concentrations in all colonic segments could contribute to improve clinical outcome in UC patients.

[Leukocyanidines and collagenases: in vitro enzyme inhibition activity]. / Leucocianidine e collagenasi: inibizione dell'attività enzimatica "in vitro".

OBJECTIVE: The matrix metalloproteinases (MMPs) play a key role in the extracellular matrix turnover. This protein family has been involved in some ocular pathologies such as glaucoma, diabetic retinopathy, macular degeneration, vitreous degeneration and corneal stroma ulceration cleaving all the matrix components. In the present study we evaluated the action of leucocyanidin from Vitis vinifera seeds as non toxic inhibitor of these proteinases. MATERIALS AND METHODS: To this purpose we used a fluorimetric method to evaluate the effect of this substance on the collagenase activity. We evaluated "in vitro" the inhibitory potency of the tested drug on type III collagenase activity, and the recover of the metalloprotease activity upon removal by dialysis of the inhibitor. RESULTS: The leucocyanidines extract (minimum procyanidines value of 95.0) resulted to be a good collagenase activity inhibitor showing an inhibition constant value, Ki, of 82 microM, evident index of affinity between the extract and the enzyme. Furthermore, the dialysis experiments demonstrated that the inhibitory effect persisted 24 h later, probably because the extract forms a stable complex with the enzyme. CONCLUSIONS: These results should be related to the pharmacokinetic profile of leucoanthocyanins, a family of natural polyphenols belonging to the class of bioflavonoids of grape seds extract (Vitis vinifera L.).

[Metalloproteinase inhibition: therapeutic application in rheumatic diseases]. / L'inibizione delle metalloproteasi: applicazioni terapeutiche nelle patologie reumatiche.

PURPOSE: Matrix metalloproteinases (MMPs) play an important role in the degradation of articular cartilage in several diseases, including osteorthritis and rheumatoid arthritis. Aiming at developing new drugs with selective inhibiting action against enzyme damaging the extracellular matrix, research is mainly directed towards the: 1) development of new drugs with specific inhibitory effect on MMPs; 2) better understanding of the pharmacologic profile of drugs already used in the treatment of rheumatic diseases, in order to identify those having an inhibiting action on degradative enzymes. MATERIALS AND METHODS: The interaction between rifamycins and collagenase type XI were studied using a fluorogenic substrate MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2. RESULTS: In our experimental conditions rifamycins showed a marked inhibition capacity with a IC50 ranging from 13 to 20.7 microM. This inhibition was reversible after extensive dialysis. CONCLUSIONS: Our results indicate that the effects of rifamycins in rheumatoid arthritis may correlate to the inhibitory activity of these molecules on collagenase activity.

Rectal and colonic mesalazine concentration in ulcerative colitis: oral vs. oral plus topical treatment.

AIM: To measure mucosal concentrations of mesalazine in ulcerative colitis patients treated with oral mesalazine alone, compared to patients treated with both topical and oral mesalazine. METHODS: Twenty-two patients with mild to moderate ulcerative colitis were randomized to receive 2.4 g/day of oral mesalazine (11 patients) or 2.4 g/day oral plus 4 g/day of topical mesalazine (11 patients). After 2 weeks of treatment, endoscopic biopsies specimens were taken from the rectum and in descending colon just distal of the splenic flexure and stored to -80 degrees C for later assay (HPLC). Wilcoxon's rank sum test for unpaired data was used for the statistical analysis. RESULTS: Mucosal levels of mesalazine in the rectum were significantly higher in patients who received oral plus topical treatment than in those who had oral treatment alone (52.1 ng/mg, range: 13.6-122.1 vs. 0.2 ng/mg, range: 0.2-9.7, respectively; P < 0.0001). Similarly, in the descending colon, the mucosal concentrations of mesalazine were significantly higher in patients who had oral plus topical treatment than in those receiving oral treatment alone (46.6 ng/mg, range: 6-112.6 vs. 15.9 ng/mg, range: 2.3-42.4, respectively; P=0.01). CONCLUSIONS: Topical treatment of mesalazine significantly increases mucosal concentrations of mesalazine up to the splenic flexure, supporting the rationale to treat left-sided ulcerative colitis with topical formulations of mesalazine.

Pharmacokinetic of intraarterial mitomycin C with extra corporeal detoxification in humans.

PURPOSE: A study has been performed in 15 patients with liver metastases from colorectal cancer to evaluate the pharmacokinetic of mitomycin C and the effectiveness of drug removal techniques during high-dose locoregional chemotherapy. PATIENTS AND METHODS: Haemofiltration and/or haemodialysis of post-hepatic venous blood were performed during 22 intra-arterial infusions of mitomycin C by the use of a double lumen catheter surgically introduced in the inferior vena cava. Mitomycin C levels were measured by high performance liquid chromatography in the extracorporeal circuit blood, in the peripheral venous blood and ultrafiltrate. RESULTS: The mean reduction of mitomycin C bioavailability in the extracorporeal circuit blood was 42.3 per cent using haemofiltration, 58.9 per cent using haemofiltration plus haemodialysis and 59.3 per cent with haemodialysis alone. The resulting mean mitomycin C plasmatic half-life was 40.2 minutes using haemofiltration, 24.9 minutes using haemofiltration plus haemodialysis and 24.1 minutes using haemodialysis alone. CONCLUSIONS: The detoxification of posthepatic venous blood during intra-arterial hepatic chemotherapy is an effective method to increase mitomycin C concentrations and oncological response and limit extra hepatic toxicity.

Can non-steroidal anti-inflammatory drugs act as metalloproteinase modulators? An in-vitro study of inhibition of collagenase activity.

The in-vitro effects of some non-steroidal anti-inflammatory drugs and some analgesic drugs on collagenase activity were studied by use of a self-quenched fluorogenic esapeptide as substrate. The increased fluorescence signal arising as a result of peptide cleavage by collagenase was recorded and related to the inhibitory potency of the drugs. The effective concentrations in collagenase modulation were also correlated with the levels of the drugs in the plasma and synovial fluids of patients receiving therapeutic doses. Six of the tested drugs, nimesulide, piroxicam, tolmetin, meloxicam, sulindac and sodium meclofenamate, inhibited enzyme activity with IC50 values (concentrations resulting in 50% inhibition) ranging from 1.9 to 28.2 microM and Ki (apparent inhibition constant) ranging from 0.83 to 21.8 microM. Much of the activity was restored after dialysis of the enzyme-drug complex, demonstrating the reversibility of the effect. Although these results indicate that some anti-inflammatory drugs could modulate enzymatic activity involved in the degradation of the extracellular matrix, their possible pharmacological involvement as collagenase inhibitors in collagen degradative diseases remains to be assessed by clinical studies.

[Hydrogels in medicine. Origin and clinical use]. / Idrogeli per medicina. Origini ed uso clinico.

Hydrogels are a new revolutionary method used to dress wounds without using gauzes and cotton wool. Our hydrogels were produced by irradiation and are perfectly sterile and biocompatible. The innovation of this topical treatment permits direct contact of hydrogels on wounds and results in complete repair of wounds and ulcers that do not heal easily. The fundamental advantage are: disappearance of local pain, very good protection of wounds, easy removal of necrotic tissue, total adhesion on wounds and simple removal without pain, faster tissue repair.

Pyrrolobenzodiazepines and related systems. 2. Synthesis and biological properties of isonoraptazepine derivatives.

The synthesis of some derivatives and analogues of 12,13,14,14a-tetrahydro-9H,11H-pyrazino-[2,1-c]pyrrolo[1,2- a][1,4]benzodiazepine (isonoraptazepine) is reported. The new derivatives have been subjected to pharmacological tests for evaluation of antidepressant effects. Neurobehavioral assays were also carried out to acquire data on neurotoxicity and sedative action. Isonoraptazepine analogues and derivatives lacked the pharmacological activity of mianserin and aptazepine and showed properties similar to imipramine. Molecular modeling studies revealed structural similarities between isonoraptazepine derivatives and imipramine, thus explaining the similar pharmacological profile found in some of the tests employed. Based on pharmacological data the title compounds cannot be regarded as alpha 2 presynaptic adrenoceptors antagonists. In vitro studies for receptor binding gave support to this observation. The above studies lead us to conclude that isonoraptazepine derivatives are conformationally restricted analogues of imipramine, but their antidepressant activity cannot be correlated to inhibition of 5HT uptake. Among the derivatives tested, 7b and 8e show some affinity for the d-fenfluramine receptor site, a serotonin presynaptic site connected with anorectic activity.

Researches on psychotropic agents. IV. Synthesis and neuropsychopharmacological effects of 1,3,4,14 b-tetrahydro-10-methyl-2H,10H- pyrazino[2,1-d] pyrrolo[1,2-b][1,2,5]benzotriazepine and its derivatives.

The synthesis and neuropsychopharmacological properties of new 1,3,4,14b-tetrahydro-2H,10H-pyrazino [2,1-d] pyrrolo [1,2-b] [1,2,5] benzotriazepine derivatives related to antidepressant agent aptazepine are reported. The new derivatives displayed sedative-miorelaxant activity in mice, but no significant antagonist effect on clonidine blockade of phenylquinone-induced abdominal constriction. Among test compounds 4a, 4l and 4n showed high antinociceptive effect on the hot-plate test and compound 4e protected from death and convulsion all the electroshocked animals.

Pyrrylphenylethanones related to cathinone and lefetamine: synthesis and pharmacological activities.

The synthesis of various pyrrylphenylethanones resembling cathinone and lefetamine is described starting from 2-chloro-1-(1-methyl-1H-pyrrol-2-yl)-2-phenylethan-1-one. Some derivatives showed good antinociceptic activity, comparable to that of morphine. The neuropsychopharmacological profile of title compounds has been also studied to explore their action on C.N.S.

Ferning test in Down's syndrome.

The tear film was evaluated by the ferning test. We tested tear film in right and left eye on 28 subjects (total 56 eyes), of whom 14 were affected by Down's syndrome, age range 18 to 35 years. The results obtained show that there exists an alteration of the tear ferning in subjects affected by Down's syndrome. We did not find any difference between the right or left eye in each individual. This anomaly could be responsible for frequent infectious pathologies found in the anterior eye segment in these subjects.

[Polyunsaturated fatty acids and atherosclerosis]. / Acidi grassi poliinsaturi ed aterosclerosi.

The major aspects of the antithrombogenic and antiatherogenic effects of polyunsaturated fatty acids (PUFA) have been outlined. After briefly relating on the biochemistry, the essentiality concept has been defined. Some of the many evidences of their effects both on men and animals have been reported. Eicosanoid metabolism is discussed and eicosanoid compounds derived from omega-6 and omega-3 fatty acids are compared with regard to their effects concerning atherosclerosis. Considerations about the correct amount of PUFA are reported as tentative strategies for a cardiovascular protective diet.

Pyrrolobenzodiazepine and related systems. I. Synthesis and pharmacological evaluation of new 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine derivatives.

Some new 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine derivatives substituted at the 5 position have been synthesized and tested to evaluate their antidepressant and neuropsychopharmacological activities. The antinociceptic action of these compounds has been also assayed. The introduction of an ethoxycarbonyl group at the 4 position generally decreased the antidepressant effect.

Non-steroidal antiinflammatory agents. VII. Synthesis and antiinflammatory activity of 5-methyl-10,11-dihydro-5H-pyrrolo [1,2-b] [1,2,5]benzotriazepine-11-acetic acid and its 10-aroyl derivatives.

The synthesis of 5-methyl-10,11-dihydro-5H-pyrrolo [1,2-b] [1,2,5]benzotriazepine-11-acetic acid and its 10-aroyl derivatives is reported. Compounds were evaluated for antiinflammatory activity by the carrageenin-induced rat paw edema method. Antinociceptic activity was tested by the hot plate and Randall-Selitto tests. General neuropsychopharmacological effects were also screened. All test compounds showed antiinflammatory effect comparable to that of tolmetin.