ALIMENTAZIONE, STILI DI VITA E SALUTE

Dopo un breve excursus sulla fisiopatologia della Sindrome Metabolica (SM), viene posta attenzione sul ruolo centrale dell’insulinoresistenza quale fattore eziopatogenetico comune a molte delle componenti della sindrome stessa. Il trattamento nutrizionale diviene il punto cardine dell’approccio terapeutico della SM, per cui viene suggerito dagli AA uno schema idoneo da fornire alla maggior parte dei pazienti e si sottolinea poi, la necessità di promuovere il potenziamento dell’attività fisica che assume oggi un ruolo terapeutico assai rilevante. Gli AA infine, passano in rassegna i fattori di rischio e le comorbilità associate alla SM e concludono sottolineando la necessità di attuare programmi di osservazione epidemiologica e di intervento multifattoriale che si incentrino sulla modificazione dello “stile di vita” oltre che sull’intervento terapeutico farmacologico, riducendo così gran parte dei rischi correlati alla Sindrome Metabolica

Abecarnil enhances recovery from diazepam tolerance.

Treatment with diazepam (25 mg/kg; p.o., twice-daily for 17 days) induced tolerance to the anticonvulsant effect of diazepam against bicuculline-induced convulsions in mice. Cross-tolerance was observed to the anticonvulsant action of clonazepam, imidazenil but not abecarnil. While substitution of clonazepam (12 mg/kg; p.o., twice-daily for 15 days) for diazepam did not affect tolerance to diazepam, substitution of imidazenil (17 mg/kg; p.o., twice-daily for 15 days) for diazepam significantly increased sensitivity to the anticonvulsant effect of diazepam, although tolerance was not abolished. Tolerance to diazepam progressively decreased either after suspension of diazepam administration or replacement treatment with abecarnil (20 mg/kg; p.o., twice-daily). Complete recovery of diazepam efficacy was detected after 8 and 15 days of administration of abecarnil and vehicle, respectively. Binding experiments using [H-3]-flumazenil showed that K-d values did not differ among treatment groups. A significant decrease in B-max (-42%) was observed in the cortex of diazepam-tolerant mice whether or not also treated with imidazenil and clonazepam. Conversely, chronically diazepam-treated mice, that further received abecarnil for either 8 or 15 days or vehicle for 15 days showed B-max values similar to those of vehicle-treated mice never exposed to diazepam. Results suggest that repeated abecarnil administration to diazepam-tolerant mice can facilitate re-adaptation of receptors to the diazepam-free state. It is proposed that replacement therapy with abecarnil after long-term treatment with conventional benzodiazepines (BDZs) may provide a novel approach for reducing tolerance to their anticonvulsant effects. (C) 1999 Elsevier Science Ltd. All rights reserved

Conditioned place preference: no tolerance to the rewarding properties of morphine.

The effect of repeated morphine administration on conditioned place preference (CPP) using a novel treatment schedule, i.e., drug treatment was always contingent with the conditioned environmental stimuli, was investigated. We also examined whether changes in the mu- and kappa-opioid receptor binding occurred in the brain of morphine-treated animals. Intraperitoneal (i.p.) administration of morphine (2 and 10 mg/kg) induced a place preference after 8 daily conditioning trials (4 morphine injections on alternate trials), the level of preference being the same with the two doses of the opiate. No change in place preference was observed in the morphine-treated rats at 2 mg/kg, when animals were further trained up to a total of 32 conditioning trials (16 morphine injections). Conversely, after 20 conditioning trials (10 morphine injections), a stronger CPP response developed in the morphine-treated rats at 10 mg/kg. Signs of morphine withdrawal were never detected in morphine-treated rats during the experiment. Loss of body weight (index of opiate dependence) was not observed either 24 h or 48 h after the last morphine administration. mu- and kappa-opioid receptor density and affinity were not affected by repeated morphine administrations at either dose. The results demonstrate that no tolerance develops to the rewarding properties of morphine. Indeed, a sensitisation effect may occur at increasing doses of the opiate. Furthermore, changes in the rewarding effect of morphine are not dependent upon alterations in opioid receptors involved in the reinforcing mechanisms

Abecarnil, a beta-carboline derivative, does not exhibit anticonvulsant tolerance or withdrawal in mice.

Development of tolerance and dependence has been reported to occur upon chronic administration of traditional benzodiazepines (BZDs). We compared the effect of chronic treatment with abecarnil, a beta-carboline derivative with high affinity for central BDZ receptors, and diazepam, the BDZ prototype, in mice. After acute administration, abecarnil was as potent and effective as diazepam in protecting from bicuculline-induced convulsion. The time-course analysis of two peak equieffective doses of abecarnil (1.9 mg/kg p.o.) and diazepam (2.7 mg/kg p.o.) showed a similar duration of action. The anticonvulsant potency of diazepam was reduced in mice given chronic diazepam (25 mg/kg p.o., 2 times a day for 17 days). No tolerance to abecarnil was apparent when the drug was administered for the same period using a comparable dose (20 mg/kg p.o.). Severe symptoms of precipitated withdrawal were observed upon administration of the BDZ partial inverse agonist Ro 15-3505 in mice treated chronically with diazepam but not abecarnil. In mice made tolerant to diazepam, maximum [3H]-flumazenil binding sites were reduced in both cerebral cortex (-50%) and cerebellum (-55.2%). No changes in [3H]-flumazenil binding were measured in chronic abecarnil-treated mice. These data indicate that abecarnil possesses a very low tolerance/dependence liability and does not affect BZD receptor density after chronic administration

Celiachia nell'adulto: rassegna della letteratura e recenti strategie terapeutiche

Il presente articolo passa in rassegna i più recenti dati della letteratura concernenti le novità sulla patogenesi e sulla terapia della malattia celiaca, patologia la cui prevalenza ed incidenza sono in continuo aumento. Viene perciò proposto uno schema dietetico per celiaci adulti di circa 1800 Kcal/die, col 54% di Glucidi, il 20% di Protidi ed il 26% di Lipidi, quindi moderatamente ipocalorico, ipoglucidico, iperproteico e normolipidico e con un adeguato apporto di nutrienti acalorici (minerali e vitamine); ci si sofferma poi sui limiti insiti al trattamento dietetico, ovvero le difficoltà nell’aderenza alla dieta. Infine, vengono presi in considerazione i più innovativi ed interessanti trattamenti farmacologici e non, derivati dalle attuali conoscenze sulla patogenesi della malattia celiaca e dall'utilizzo di modelli sperimentali

Catecholamines do not induce fibrinolytic activity increase in cultured bovine endothelial cells.

This study has investigated the catecholamine involvement in the fibrinolytic modulation of cultured bovine aortic endothelial cells (BAEC). Adrenaline and isoproterenol, at concentrations ranging from 10 to 100 microM, were unable to modulate the fibrinolytic response of these cells. beta-Adrenergic binding studies using 3H-CGP 12177 as radioligand evidenced the presence of about 23,113 +/- 2,065 sites/cell, with a KD of 1.23 +/- 0.29 nM. Isoproterenol stimulated cAMP accumulation at concentrations ranging from 1 to 100 microM, with a maximal accumulation of 30 pmol/10(6) cell. Hence, in our experimental conditions BAEC, although possessing functional beta-adrenergic receptors, were unable to increase any fibrinolytic activity in response to catecholamines

Reduction of beta-adrenergic receptors by tertatolol: an additional mechanism for beta-adrenergic blockade.

Tertatolol is a potent new beta-blocker with no intrinsic sympathomimetic activity or beta 1/beta 2-receptor subtype selectivity. When given at therapeutic doses (5 mg/day) to human subjects it induced a reduction in the beta-adrenergic receptor number measured by 3H-CGP 12177 specific binding, without any change in the affinity on intact lymphocytes. This reduction was seen 7 hours (54%), 24 hours (35%), and 48 hours (30%) after a single drug dose. A similar receptor reduction was observed 7 hours (42%), 24 hours (37%), and 48 hours (15%) after 14 doses of the drug. In parallel, the pharmacologic efficacy of the drug was evident from the reduction in supine and upright heart rates and after submaximal exercise; heart rate was reduced to the same extent after single or repeated drug doses. The reduction of receptor number correlated well with the reduction in heart rate in the supine (P less than 0.001) and upright (P less than 0.01) positions and after exercise (P less than 0.02). In in vitro competitive binding experiments tertatolol was found to be a competitive inhibitor of beta-adrenergic receptors. However, on intact human lymphocytes preincubated with this drug, tertatolol reduced the density of beta-adrenergic receptors. We conclude that tertatolol, besides competitively inhibiting beta-adrenergic receptors, induced a marked and lasting decrease in the beta-adrenergic receptor number. This effect may be important for its beta-blocking effects

A Computational Study of the Electrophysiological Substrate in Patients Suffering From Atrial Fibrillation

In the context of cardiac electrophysiology, we propose a novel computational approach to highlight and explain the long-debated mechanisms behind atrial fibrillation (AF) and to reliably numerically predict its induction and sustainment. A key role is played, in this respect, by a new way of setting a parametrization of electrophysiological mathematical models based on conduction velocities; these latter are estimated from high-density mapping data, which provide a detailed characterization of patients' electrophysiological substrate during sinus rhythm. We integrate numerically approximated conduction velocities into a mathematical model consisting of a coupled system of partial and ordinary differential equations, formed by the monodomain equation and the Courtemanche-Ramirez-Nattel model. Our new model parametrization is then adopted to predict the formation and self-sustainment of localized reentries characterizing atrial fibrillation, by numerically simulating the onset of ectopic beats from the pulmonary veins. We investigate the paroxysmal and the persistent form of AF starting from electro-anatomical maps of two patients. The model's response to stimulation shows how substrate characteristics play a key role in inducing and sustaining these arrhythmias. Localized reentries are less frequent and less stable in case of paroxysmal AF, while they tend to anchor themselves in areas affected by severe slow conduction in case of persistent AF

Biochemical effects of minaprine on striatal dopaminergic neurons in rats.

The biochemical effects of minaprine, a new psychotropic drug, were investigated on striatal dopaminergic neurons in the rat. Minaprine did not displace [3H]spiperone in-vitro binding from striatal membranes but had clear effects on dopamine (DA) metabolites. Homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly decreased in a dose-dependent manner after intraperitoneal administration of minaprine 30 min before killing. In rats injected with minaprine 15 mg kg-1 i.p. at different intervals, the decrease in striatal HVA and DOPAC was time-dependent and a concomitant rise in 3-methoxytyramine (3-MT) concentrations was observed. The maximum of these effects was reached 30 min after minaprine. When administered 5 min after a monoamineoxidase (MAO) inhibitor (pargyline, 100 mg kg-1 i.p.) and 30 min before killing, minaprine did not affect pargyline-induced changes in HVA, DOPAC and 3-MT levels. This together with other data suggests that minaprine affects DA metabolism by acting, at least partially, at presynaptic level through in-vivo inhibition of MAO activity