Showing papers by "Achille P. Caputi published in 1993"

Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects.

Abstract: SummaryThe effect of the selective serotonin reuptake inhibitor fluvoxamine (100 mg/day for 10 consecutive days) on the kinetics of a single oral dose of imipramine (50 mg) and desipramine (100 mg) was investigated in 12 healthy subjects. Compared with a control session, treatment with fluvoxamine c

Effects of zileuton, a new 5-lipoxygenase inhibitor, in experimentally induced colitis in rats

Abstract: The efficacy of zileuton, a new 5-lipoxygenase inhibitor, was investigated in comparison with sulphasalazine in an experimental model of rat colitis. Under light anaesthesia with ether, male rats were subjected to intracolonic administration of trinitrobenzene sulfonic acid (TNB) in 50% ethanol and were then sacrificed 2, 4 and 7 days after colitis induction. Untreated rats exhibited elevated colonic levels of leukotriene B4 (LTB4) and 6-keto-PGF1 alpha, and an increase in colonic myeloperoxidase (MPO) activity (investigated as an index of leukocyte adhesion and accumulation). Moreover, ulceration and inflammation of the distal colon with formation of granuloma and pathologic connections were observed. Treated rats received zileuton or sulphasalazine (50 mg/kg per os twice a day) 24 h before the induction of colitis until they were sacrificed. Treatment with the specific 5-lipoxygenase inhibitor, zileuton, resulted in significant reductions of colonic leukotriene B4 and 6-keto-PGF1 alpha synthesis, macroscopic and histological colonic damage and colonic inflammation as assessed by the measurement of MPO activity. In contrast, sulphasalazine had a lower effect than zileuton on LTB4 and MPO levels (p < 0.05), while it was able to reduce colonic damage and 6-keto-PGF1 alpha levels as well as zileuton. This study shows, therefore, that zileuton is effective in attenuating the lesions in an experimental model of colitis. Furthermore, the results are consistent with the hypothesis that leukotrienes play an important role in the pathogenesis of intestinal bowel diseases (IBD).

Carbamazepine coadministration with fluoxetine or fluvoxamine.

Abstract: To study the potential interaction between carbamazepine (CBZ) and selective serotonin reuptake inhibitors, fluoxetine (20 mg/day) and fluvoxamine (100 mg/day) were administered for 3 weeks to eight and seven epileptic patients, respectively, on chronic CBZ treatment. No significant changes in steady-state plasma concentrations of CBZ and its active metabolite, carbamazepine-10,11-epoxide (CBZ-E) occurred, suggesting that CBZ metabolism is probably not affected by fluoxetine or fluvoxamine administration.

Fluvoxamine-induced alterations in plasma concentrations of imipramine and desipramine in depressed patients.

Abstract: The effect of fluvoxamine maleate, 100 mg/day for 10 days, on plasma concentrations of tricyclic antidepressants was studied in 15 depressed patients on maintenance therapy with imipramine (7 pts.) or desipramine (8 pts.). In the subgroup treated with imipramine, plasma levels of imipramine increased significantly (p < 0.001) during fluvoxamine coadministration, while levels of desipramine were not modified. Addition of fluvoxamine to patients on a stable desipramine dosage regimen resulted in a slight, but statistically not significant, increase in desipramine plasma concentrations. These results suggest that fluvoxamine is a potent inhibitor of imipramine demethylation, while it has a weak effect on the hydroxylation of desipramine.

Prevalence of acute dystonic reactions associated with neuroleptic treatment with and without anticholinergic prophylaxis.

Abstract: The occurrence of acute dystonic reactions was intensively monitored in a population of 646 patients, 379 males and 267 females, aged 18-87 years, consecutively admitted to different psychiatric units and treated with neuroleptics alone or in combination with anticholinergic drugs. Thirty-four patients experienced acute dystonic reactions yielding a total incidence of 5.3%. There was a tendency towards a higher frequency of dystonia in males than in females, and in young patients than in older ones. Patients without anticholinergic medication had a higher frequency of the reaction than those receiving anticholinergic drugs (8.5% vs. 2.8%; p < 0.02). Neuroleptic-induced dystonia was more common in patients treated with butyrophenones than in those receiving phenothiazines or substituted benzamides.

Platelet activating factor interaction with tumor necrosis factor in myocardial ischaemia-reperfusion injury.

Abstract: The role played by platelet-activating factor (PAF) and tumor necrosis factor (TNF-alpha) in myocardial ischaemia-reperfusion injury was investigated. Pentobarbital anaesthetized rats were subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham-operated rats were used as controls (Sham MI/R). Myocardial ischaemia-reperfusion injury produced a marked myocardial injury (necrotic area/area-at-risk = 60 +/- 5%; necrotic area/total area = 50 +/- 6%), high serum creatine phosphokinase activity (Sham MI/R = 25 +/- 10 U/ml; MI/R = 190 +/- 12 U/ml), a severe leukopenia (Sham MI/R = 10367 +/- 630 WBC x mm3; MI/R = 4123 +/- 120 WBC x mm3) and elevated myocardial myeloperoxidase activity (investigated as an index of leukocytes adhesion and accumulation) in the area-at-risk (6.2 +/- 0.5 U x 10(-3)/g tissue) and in necrotic area (6.6 +/- 0.7 U x 10(-3)/g tissue. Plasma PAF and serum TNF-alpha were significantly increased only during reperfusion. The peak of PAF plasma levels (6.5 +/- 1.2 pmol/ml) occurred earlier (15 min of reperfusion) than the peak of serum TNF-alpha (150 U/ml at 30 min of reperfusion). At the end of reperfusion, macrophage TNF-alpha was also enhanced (Sham MI/R = undetectable; MI/R = 148 +/- 12 U/ml). The administration of CV 6209, a specific PAF receptor antagonist (5 mg/kg, 5 min after occlusion), significantly reduced myocardial injury (necrotic area/area-at-risk = 27 +/- 3%, P < 0.001; necrotic area/total area = 10 +/- 2%, P < 0.001), blunted the increase in serum creatine phosphokinase (70 +/- 12 U/ml), partially restored leukopenia (8234 +/- 143 WBC x mm3) and lowered myeloperoxidase activity in area-at-risk (2.3 +/- 0.3 U x 10(-3)/g tissue; P < 0.001) and in necrotic area (2.8 +/- 0.5 U x 10(-3)/g tissue). In addition, administration of CV 6209 reduced the serum and macrophage levels of TNF-alpha. The results of this study, therefore, suggest that PAF and TNF-alpha are key mediators of myocardial ischaemia-reperfusion injury and that PAF plays a permissive role in inducing the release of other factor(s) relevant to reperfusion injury.

Reduction of myocardial leukocyte accumulation and myocardial infarct size following administration of BAY u3405, a thromboxane A2 receptor antagonist, in myocardial ischaemia-reperfusion injury.

Abstract: We investigated the effect of BAY u3405, a thromboxane A2 receptor antagonist in pentobarbital anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham operated rats were used as controls (Sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase activity were studied. Ischaemia-reperfusion injury significantly reduced the survival rate (45%), caused a marked myocardial necrosis, increased serum creatine phosphokinase activity (Sham MI/R=26±10.2 U/ml; MI/R=213±19 U/ml) and produced a rise in myocardial myeloperoxidase activity in the area-at-risk and in the necrotic area (6.1±0.4 U×10−3/g tissue and 6.7±0.9 U×10−3/g of tissue, respectively). The administration of BAY u3405 (30 and 60 mg/kg/i.v., 30 min before occlusion) significantly increased survival rate, lowered the area of myocardial necrosis, blunted the increase in serum creatine phosphokinase activity and reduced the increase in myeloperoxidase activity in both the area-at-risk and the necrotic area. Furthermore, the protective effect of BAY u3405 was dose-dependent. These data are consistent with an involvement of TXA2 in myocardial ischaemia-reperfusion injury and suggest that BAY u3405 may represent a novel therapeutic approach to the treatment of acute ischaemia-reperfusion injury.

G619, a dual thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, reduces myocardial damage and polymorphonuclear leukocyte accumulation following coronary artery occlusion and reperfusion in rats.

Abstract: We investigated the effect of G 619, a dual thromboxane synthase inhibitor and thromboxane A2 (TxA2) receptor antagonist, in pentobarbital-anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham-operated rats were used as controls (sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase (MPO) activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase (CPK) activity were studied. MI/R injury significantly reduced survival rate (45%), caused a marked myocardial necrosis, increased serum CPK activity (sham MI/R = 35 +/- 12 U/ml; MI/R = 205 +/- 13 U/ml) and produced an increase in myocardial MPO activity in the area at risk and in the necrotic area (6.3 +/- 0.5 and 6.6 +/- 0.9 U x 10(-3)/g tissue, respectively). The administration of G 619 significantly increased survival rate, lowered the area of necrosis, blunted the increase in serum CPK activity and reduced the increase in MPO activity in both the area at risk and the necrotic area. These data are consistent with an involvement of TxA2 in MI/R injury and suggest that G 619 may represent a novel therapeutic approach to the treatment of acute myocardial infarction.