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.

[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.

[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.

[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.

Research on psychotropic agents. III. Antidepressant activity and neuropsychobehavioural effects of new 5H-Pyrrolo[1,2-b][1,2,5]benzotriazepine derivatives.

The synthesis of 5H-pyrrolo[1,2-b][1,2,5]benzotriazepine derivatives related to imipramine and aptazepine antidepressant agents is reported. Pharmacological screening on new tricyclic derivatives showed that in some cases antidepressant effects at equimolecular dose with imipramine are associated with sedative-muscle relaxant activities and antinociception.

Synthesis, neuropsychopharmacological effects and analgesic-antiinflammatory activities of pyrrole analogues of lefetamine.

The synthesis of pyrrole analogues of the analgesic drug lefetamine is reported. These derivatives bear the 1-phenyl-2-(1H-pyrrol-1-yl)ethylamino moiety. Compounds were evaluated for analgesic activities in mice by the hot plate and Randall-Selitto tests. Antiinflammatory activity was tested by the carrageenan-induced rat paw edema method. General neuropsychopharmacological effects were also screened. The most interesting compound, N,N-dimethyl-1-phenyl-2-(1H-pyrrol-1-yl)ethylamine, showed an analgesic effect comparable to that of lefetamine, but devoid of the neurotoxicity of this drug.

[5-Aroyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepin-4-carboxylic acids: synthesis and analgesic and neurobehavioral activity]. / Acidi 5-aroil-5,6-diidro-4H-pirrolo[1,2-a][1,4]benzodiazepin-4-carbossilici: sintesi ed attività analgesica e neurocomportamentale.

Reaction between 1-(2-aminomethylphenyl)-1H-pyrrole hydrochloride and methyl 2-methoxyglicolate in methanol afforded methyl 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepin-4-carboxylate. Aroylation at the 5-position and subsequent hydrolysis of the ester function led to 5-aroyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepin-4-ca rboxylic acids. The pharmacological profile of these acids has been studied with regard to analgesic, antiinflammatory and neuropsychobehavioural effects.

Effects of maternal exposure to polychlorobiphenyls (PCBs) on F1 generation behavior in the rat.

The effect of Fenclor 42 (PCB) exposure of female rats (Fischer 344 strain) was studied through assessment of the behavioral development of their F1 progeny. Female rats were exposed to PCB according to the following treatment schedule: (A) (5 days) 2 weeks prior to mating, (B) during gestation (Days 6-15 of pregnancy), (C) during lactation (Days 1-21 after delivery). Behavioral endpoints of motor reflexes, motor coordination, activity (preweaning behaviors), and learning (postweaning behavior) were evaluated for PCB ip dosages of 5-10 mg/kg/day for 5 days (preconception exposure), and PCB oral dosages of 2-4 mg/kg/day for 10 days (in utero exposure) and of 1-2 mg/kg/day for 20 days (during lactation exposure). Dosage-dependent differences in the evaluated behaviors were found in the offspring of the PCB-exposed females when compared to the offspring of corn-oil (vehicle)-exposed females. Significant differences in the development of cliff avoidance reflexive behavior, swimming ability, and open field activity were particularly evident. Furthermore the PCB exposure of female rats during gestation and lactation resulted in impaired acquisition of the active avoidance behavior while preconceptional PCB exposure significantly affected active avoidance performance as reflected in increased number of avoidance responses to reach criterion for extinction. These results show that Fenclor 42 does possess a significant risk to the offspring of exposed females, and further illustrate the sensitivity of progeny behavioral assessment in detecting suspected functional teratogenesis.

[Nonsteroidal anti-inflammatory agents. V. Synthesis of 1-aryl-5-(1-pyrryl)-pyrazolyl-4-acetic acids with potential anti-inflammatory action]. / Agenti antiinfiammatori non-steroidei. Nota V. Sintesi di acidi 1-aril-5-(1-pirril)pirazolil-4-acetici a potenziale attività antiinfiammatoria.

The synthesis of 1-aryl-5-(1-pyrryl)pyrazoles bearing at position 4 an acetic or alpha-propionic chain is described. The new compounds can be structurally related to lonazolac and its analogues with analgesic-antiinflammatory activities. When tested pharmacologically in comparison with tolmetin and indomethacin none of the above derivatives showed any appreciable activity.