Neuroleptic-like effects of the l-isomer of fenfluramine on striatal dopamine release in freely moving rats

l-Fenfluramine (l-F) was studied for its ability to release dopamine (DA) and its metabolites in freely moving rats through the trans-striatal dialysis technique. l-F's effect on striatal DA release was also studied in animals made tolerant to the effect of haloperidol by chronic treatment (1 mg/kg i.p. twice daily for 11 days and 48 hr wash-out) with the neuroleptic or pretreated with 300 mg/kg i.p. gamma-butyrolactone (GBL). Five and 10 mg/kg l-F dose-dependently increased the release of DA and its metabolites with a pattern of effects similar to that observed with neuroleptic drugs. The dose of 20 mg/kg l-F had the same effect as 10 mg/kg. Repeated haloperidol treatment reduced the basal release of DA and its metabolites and a much smaller amount of DA and metabolites was released by l-F (10 mg/kg i.p.) and haloperidol (0.1 mg/kg i.p.) in animals treated with haloperidol than in controls. GBL 300 mg/kg i.p. reduced basal DA release by about 50%. When 10 mg/kg l-F, 0.1 mg/kg haloperidol and 0.25 mg/kg d-amphetamine were injected i.p. 40 min after GBL, l-F and haloperidol did not significantly raise DA release in GBL-treated rats whereas a significant effect was observed at various times after d-amphetamine. The data show that l-F resembles haloperidol in its ability to release DA and its metabolites from the corpus striatum of freely moving rats. The cross-tolerance between haloperidol and l-F for their effect on DA release suggests that a common site is involved in the mechanism of these drugs.     

Differential modulation of [3H]flunitrazepam binding in female rat brain by sex steroid hormones

Quantitative autoradiographic analysis revealed changes in [3H]flunitrazepam (a benzodiazepine agonist) binding in the anterior hypothalamus nucleus, the medial preoptic area and the cortico-medial amygdala nucleus following in vivo estradiol. The administration of 4 mg of progesterone, but not 1 mg, increased the binding of [3H]flunitrazepam in the basolateral amygdaloid nucleus and in the oriens-pyramidalis CA1 layer of the hippocampus. Exposure of brain sections in vitro to the potent, naturally occurring progesterone metabolite, 3 alpha-hydroxy-5 alpha-dihydroprogesterone, induced GABA-dependent changes in flunitrazepam binding, similar to the changes induced by progesterone, thus suggesting that different steroid mechanisms are implicated in the control of flunitrazepam binding.     

Cholinomimetics effects of carnitine on isolated and denervated rat stomach preparations

According to various suggestions in the literature of cholinomimetic effects of carnitine on nervous structures, and experimental results of previous work on vascular smooth muscle, we studied the influence of this substance on the rat isolated and denervated stomach responses to acetylcholine (Ach). We found that Ach invariably induces contraction of the preparation, this effect being abolished by means of atropine or prifinium bromide or reduced by means of fendiline or flunarizine. We found also that carnitine invariably enhances the contractile responses of the preparation to Ach, and this effect is not modified by indomethacin or lysine acetylsalicylate, but usually abolished by fendiline and flunarizine. Our opinion is that the potentiation of stomach contractile responses to Ach by carnitine, is not due to prostaglandin mediation but it is due to sensitisation of the muscarinic receptors, which are stimulating contraction (here and in vascular smooth muscle) by means of: facilitation of calcium transit across the cellular membrane; intracellular deposit site release activation.     

Life-threatening tachyarrhythmias in athletes.

The arrhythmias in competitive athletes may be classified as "benign," "paraphysiological" due to prolonged athletic training, or "pathological" due to hemodynamic effects on the athletic performance-risk-arrhythmogenic substratum. Pathological arrhythmias include life-threatening forms that are severe enough to produce symptoms (presyncope, syncope, cardiac arrest) during athletic activity. These forms are in particular rapid VT, VF, torsades de pointes, preexcited atrial fibrillation, sinus atrial and AV block. Our study population includes 766 competitive athletes, mean age 21.1 years (74 top international level), investigated with a cardioarrhythmological work-up for symptoms and for arrhythmias from 1974 to June 30, 1991. Three leading categories, represented by 16 aborted sudden death, 8 sudden death, and 7 induced VF (by EES or TAP) athletes, are described. All athletes with life-threatening arrhythmias, previously as asymptomatic or with minor symptoms had an arrhythmogenic substratum due to underlying silent cardiopathy or primary arrhythmic disorders. Athletic activity can be regarded as a trigger of electrical destabilization.     

The Italian Group for the Study of Streptokinase in Myocardial Infarct: Study of arrhythmias

The purpose of the trial "Arrhythmias" was to evaluate all the arrhythmic events in the control and treated patients by considering, in the latter, the chronological relation to the infusion of Streptokinase (SK). This was done in order to determine if the presence of arrhythmias was significantly greater in the treated patients, and if these arrhythmias could be considered as possible markers of reperfusion. 10 Centres participated by recording and evaluating all the hyperkinetic and hypokinetic arrhythmic events in the treated and control patients for an observation period of 2 hours including infusion of SK. The recording method used was computerised UCIC or Holter recording. The centre for data handling carried out storage and statistical elaboration of the data. The Lown and the Italian Modified Lown classifications were used. When appropriate, the statistical significance of observed differences was assessed with chi-square and t tests. 433 patients, 227 treated and 206 controls, were randomised. No statistically significant differences were observed between the two groups as regards the quantity and quality of the hyperkinetic or hypokinetic arrhythmias. On the contrary, on dividing the patients into two groups in accordance with the incidence of Hyperkinetic Ventricular Arrhythmias (HVA), more serious HVA were observed in the controls both in absolute value and in relation to those with better functional class, younger patients (less than 65 yrs.) and with multiple site infarct. The results of the search for arrhythmias which can be markers of reperfusion, show that the Slow Ventricular Tachycardia is the only arrhythmia which can be used as such.     

The site of tumor development determines immunogenicity via temporal mobilization of antigen‐laden dendritic cells in draining lymph nodes

The elimination of solid tumors largely depends on effective T‐cell priming by dendritic cells (DCs). For decades, studies focusing on antitumoral immune responses have been performed with tumors transplanted subcutaneously (s.c.). These studies however do not take into account the heterogeneous tissue distribution and functionality of the different DC subsets. Given the crucial role of DCs in inducing protective immune response, we postulated that the anatomic location of tumor development may greatly impact tumor immunogenicity. We therefore implanted tumor cells either in the DC‐rich dermis environment or in the s.c. tissue that mainly contains macrophages and monocytes. We showed that intradermal (i.d.), but not s.c. tumors are rapidly rejected in a T‐cell‐dependent manner and induce protective T‐cell responses. The rejection of i.d. tumors correlates with rapid recruitment of dermal DCs presenting the tumor antigen to both CD4 and CD8 T cells in the draining lymph nodes (dLNs). The same DC subsets were mobilized upon s.c. tumor transplantation but with delayed kinetics. Altogether, our results show that the anatomical site of tumor development influences tumor immunogenicity, notably by controlling the kinetics of DC mobilization in the draining LNs.     

Association of tumor necrosis factor a-2 and a-8 microsatellite alleles with human papillomavirus and squamous intraepithelial lesions among women in Brazil

Infection with oncogenic human papillomavirus (HPV) is considered to be the major risk factor for cervical cancer. Tumor necrosis factor (TNF) is a pluripotent cytokine that plays an important role in inhibiting the action of microbial agents, and TNF microsatellite polymorphisms have been associated with several diseases, including cancer and viral infections. This study analyzed the associations between TNFa to -e microsatellite polymorphisms and the severity of squamous intraepithelial lesions (SIL), according to the presence of the oncogenic HPV16 and HPV18 types. Samples from 146 HPV-positive women with low-grade SIL (LSIL) and high-grade SIL (HSIL) and samples from 101 healthy women were studied. TNF microsatellite polymorphism typing and HPV detection and typing were performed using PCR-amplified DNA hybridized with sequence-specific primers. Data were analyzed by Fisher's exact test using the GENEPOP software. Significant associations were observed between LSIL and the TNFa-8 allele (4/166; P = 0.04), as well as between TNFa-2 with HPV18 only (16/44; P = 0.002) and TNFa-2 with HPV18 coinfection with HPV16 (16/44; P = 0.001). Patients exhibiting the TNFa-2 allele and harboring HPV18, in the presence or absence of coinfection with HPV16, had an increased risk of HSIL occurrence (13/38; P = 0.04; 5/10; P = 0.04) compared to patients with other HPV types. These results suggest that the TNFa-8 allele is associated with increased susceptibility to the occurrence of LSIL and that despite the presence of a high TNF-alpha production allele, the ability of HPV18 to resist the inhibitory effects of TNF-alpha may contribute to the occurrence of infection and consequently to HSIL in women with cervical HPV18 infection.     

Influence of layer position on in vitro and in vivo release of levodopa methyl ester and carbidopa from three-layer matrix tablets.

A versatile oral controlled release system for the simultaneous delivery of levodopa methyl ester and carbidopa, consisting of a three-layer matrix tablet, has been studied and developed. Each individual layer of the matrix exhibited a different release mechanism, i.e. the first layer was swellable (S), the second one was erodible (E) and the third one was disintegrating (D). The three layers have been assembled in the monolithic matrix in different relative positions. It was found that in the monolith the three layers could interact, producing in vitro release profiles depending on their relative position. The monoliths having the configurations DSE and SDE were administered to human volunteers in order to determine the plasma profiles. The pharmacokinetic data showed a significant difference between the early time plasma curves: the monolith DSE, having the fast release profile, gave rise to a rapid appearance of a high levodopa plasma level, whereas the slower releasing monolith SDE produced a smoothed plasma concentration profile.