Brain site-specific regulation of hedonic intake by orexin and DYN peptides: role of the PVN and obesity.

The orexin peptides promote hedonic intake and other reward behaviors through different brain sites. The opioid dynorphin peptides are co-released with orexin peptides but block their effects on reward in the ventral tegmental area (VTA). We previously showed that in the paraventricular hypothalamic nucleus (PVN), dynorphin and not orexin peptides enhance hedonic intake, suggesting they have brain-site-specific effects. Obesity alters the expression of orexin and dynorphin receptors, but whether their expression across different brain sites is important to hedonic intake is unclear. We hypothesized that hedonic intake is regulated by orexin and dynorphin peptides in PVN and that hedonic intake in obesity correlates with expression of their receptors. Here we show that in mice, injection of DYN-A1-13 (an opioid dynorphin peptide) in the PVN enhanced hedonic intake, whereas in the VTA, injection of OXA (orexin-A, an orexin peptide) enhanced hedonic intake. In PVN, OXA blunted the increase in hedonic intake caused by DYN-A1-13. In PVN, injection of norBNI (opioid receptor antagonist) reduced hedonic intake but a subsequent OXA injection failed to increase hedonic intake, suggesting that OXA activity in PVN is not influenced by endogenous opioid activity. In the PVN, DYN-A1-13 increased the intake of the less-preferred food in a two-food choice task. In obese mice fed a cafeteria diet, orexin 1 receptor mRNA across brain sites involved in hedonic intake correlated with fat preference but not caloric intake. Together, these data support that orexin and dynorphin peptides regulate hedonic intake in an opposing manner with brain-site-specific effects.

Plasma peroxiredoxin changes and inflammatory cytokines support the involvement of neuro-inflammation and oxidative stress in Autism Spectrum Disorder.

BACKGROUND: It has been established that children with Autism Spectrum Disorders (ASD) are affected by oxidative stress, the origin of which is still under investigation. In the present work, we evaluated inflammatory and pro-oxidant soluble signature in non-syndromic ASD and age-matched typically developing (TD) control children. METHODS: We analyzed leukocyte gene expression of inflammatory cytokines and inflammation/oxidative-stress related molecules in 21 ASD and 20 TD children. Moreover, in another-comparable-group of non-syndromic ASD (N = 22) and TD (N = 21) children, we analyzed for the first time the protein expression of the four members of the antioxidant enzyme family of peroxiredoxins (Prx) in both erythrocyte membranes and in plasma. RESULTS: The gene expression of IL6 and of HSP70i, a stress protein, was increased in ASD children. Moreover, gene expression of many inflammatory cytokines and inflammation/oxidative stress-related proteins correlated with clinical features, and appeared to be linked by a complex network of inter-correlations involving the Aryl Hydrocarbon Receptor signaling pathway. In addition, when the study of inter-correlations within the expression pattern of these molecules was extended to include the healthy subjects, the intrinsic physiological relationships of the inflammatory/oxidative stress network emerged. Plasma levels of Prx2 and Prx5 were remarkably increased in ASD compared to healthy controls, while no significant differences were found in red cell Prx levels. CONCLUSIONS: Previous findings reported elevated inflammatory cytokines in the plasma of ASD children, without clearly pointing to the presence of neuro-inflammation. On the other hand, the finding of microglia activation in autoptic specimens was clearly suggesting the presence of neuro-inflammation in ASD. Given the role of peroxiredoxins in the protection of brain cells against oxidative stress, the whole of our results, using peripheral data collected in living patients, support the involvement of neuro-inflammation in ASD, and generate a rational for neuro-inflammation as a possible therapeutic target and for plasma Prx5 as a novel indicator of ASD severity.

Spontaneous regression of low-grade cervical intraepithelial lesions is positively improved by topical bovine colostrum preparations (GINEDIE®). A multicentre, observational, italian pilot study.

OBJECTIVES: Human papillomavirus (HPV) is the causal agent of cervical cancer. The great majority of abnormal Pap test results - almost 90% - is referrable to either atypical squamous intraepithelial lesion or CIN1. For these lesions, worldwide agreement exists concerning the high rate - ranging from 40% to 70% - of spontaneous regression over a period of 1-5 years. Host's immune response is a key point influencing the natural history of these conditions. Bovine colostrum is a natural agent positively promoting several immune activities against bacterial and viral agents. The aim of this report was to evaluate the potential positive effect of bovine colostrum-containing vaginal tablets administered to CIN1 diagnosed patients in a prospective trial in regards to spontaneous regression rate. PATIENTS AND METHODS: A series of 256 consecutive patients with histologically proven CIN1 recruited in a multicentre, observational, Italian study. Patients have been enrolled in a 24-weeks protocol of treatment and re-tested at the end of the study. Rates of regression have been recorded. RESULTS: Overall regression rate to a negative histology at the end of the 6 month follow up was 75.5%. CONCLUSIONS: Regression to normal histology was observed in a very high rate of cases in a very short period compared to the natural history of these lesions. CIN1 patients could benefit from bovine colostrum topical administration in terms of significantly shortening the regression time.

Long-term outcome of radiofrequency thermal ablation (RFA) of liver metastases from colorectal cancer (CRC): size as the leading prognostic factor for survival.

PURPOSE: The aim of this study was to review some prognostic factors for survival after radiofrequency ablation (RFA) of metastases from colorectal cancer (CRC). MATERIALS AND METHODS: From 1996 to 2009, 262 patients with metastases from CRC were treated with RFA. Fourteen were lost to follow-up. The following predictors were analysed in the remaining 248: synchronous/metachronous metastases, single/multiple metastases, diameter of largest metastasis and absence/presence of extrahepatic metastases. Survival was measured from the date of metastasis diagnosis and from the date of RFA. RESULTS: Survival at 1, 2, 3 and 5 years was 93%, 78%, 62% and 35% from metastasis diagnosis, and 84%, 59%, 43% and 23% from the date of RFA. Median survival was 41 months in patients with largest metastasis ≤3 cm and 21.7 months for those with metastases >3 cm (p=0.0001); survival increased to 45.2 months in patients with largest metastasis ≤2.5 cm and fell to 18.5 months in those with metastasis >3.5 cm. Median survival of patients with extrahepatic metastases was significantly lower than that of patients without extrahepatic disease (23.3 vs. 32.6 months, p=0.018). CONCLUSIONS: In light of our long-term results obtained with commonly used equipment, small lesion size (diameter of largest lesion ≤3 or 2.5 cm) proved to be the most favourable prognostic factor for survival in patients with CRC metastases to the liver treated with RFA. This conclusion is probably related to the possibility of obtaining radical ablation and points to the usefulness of devices allowing ablation of larger volumes. In the presence of extrahepatic metastases, RFA has less impact on survival, even though it is potentially useful in patients at a higher risk of death due to hepatic rather than extrahepatic metastases.

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells.

Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells (CSCs), unraveling differences with respect to their normal counterparts. Expansion of mammospheres (MS) is a valuable tool for the in vitro study of normal and cancer mammary gland stem cells. Here, we expanded MSs from human breast cancer and normal mammary gland tissues, as well from tumorigenic (MCF7) and non-tumorigenic (MCF10) breast cell lines. We observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells. This phenomenon is paralleled by the hampering of pro-inflammatory Nuclear Factor-κB (NF-κB)/Interleukin-6 (IL6) axis that is hyperactive in breast cancer-derived MS. The hindrance of such pathway associates with the downregulation of MS regulatory genes (SLUG, Notch3, Jagged1) and with the upregulation of the differentiation markers estrogen receptor-α and keratin18. At variance, the PPARα agonist Wy14643 promotes MS formation, upregulating NF-κB/IL6 axis and MS regulatory genes. These data reveal that nuclear receptors agonists (6-OH-11-O-hydroxyphenanthrene, RA, PGZ) reduce the inflammation dependent survival of breast CSCs and that PPARα agonist Wy14643 exerts opposite effects on this phenotype.

The basal-like breast carcinoma phenotype is regulated by SLUG gene expression.

Basal-like breast carcinoma is an aggressive form of breast cancer, characterized by the absence of oestrogen receptor and HER2 expression, the presence of cytokeratin 5 and epidermal growth factor receptor expression, and by the up-regulation of stem cell regulatory genes. We show here that tumour tissues expressing high levels of SLUG mRNA show a basal-like breast carcinoma phenotype and that such tumours also express high levels of stem cell-regulatory genes, ie CD133, Bmi1. Further, we show that stem/progenitor cells, isolated from ductal breast carcinoma and from normal mammary gland as mammospheres, express SLUG, CD133, and Bmi1 mRNA and show a phenotype similar to that of basal-like breast carcinoma. We also report that SLUG expression in tumour tissues correlates with that of the hypoxia survival gene carbonic anhydrase IX. In this regard, we report that the exposure of SLUG-negative/luminal-like MCF-7 cells to a hypoxic environment promotes the onset of the basal-like breast carcinoma phenotype, together with up-regulation of the SLUG gene, which in turn blunts oestrogen receptor-alpha and boosts carbonic anhydrase IX gene expression. Finally, we show that SLUG expression promotes the invasiveness of MCF-7 cells exposed to hypoxia and sustains the in vivo aggressiveness of hypoxia-selected, MCF-7-derived cells in xenografts. These data indicate that SLUG gene expression is part of a hypoxia-induced genetic programme which sets up a basal/stem cell-like, aggressive phenotype in breast cancer cells.

Knockdown of caveolin-1 by antisense oligonucleotides impairs angiogenesis in vitro and in vivo.

Knock-out of the gene coding for caveolin-1, the main organizer of caveolae, has not yet been performed. We devised a strategy to knock-down caveolin-1 gene expression using antisense oligodeoxynucleotides (ODNs). Seven ODNs, covering different regions of caveolin-1 mRNA, were screened by Western blot analysis of caveolin-1 levels. The most active and specific was found to reduce caveolin-1 protein levels by 70% at 1 microM concentration and its action, as demonstrated by a marked reduction (about 50%) in caveolin-1 mRNA levels, was due to a true antisense mechanism. In HUVEC treated with the active ODN, caveolae were undetectable by confocal and electron microscopy, while their number was not affected when cells were treated with a scrambled ODN. Using the fibrin gel 3 D angiogenesis test we established that the active (but not the scrambled) ODN strongly suppressed capillary-like tube formation. Moreover, an antisense tailored against chicken caveolin-1 mRNA, when tested using the chorio-allantoic membrane technique, dramatically reduced vessel formation at doses (10-20 microg) under which control ODNs were ineffective and devoid of toxicity. Thus, it is likely that caveolin-1 down regulation, followed by caveolae disruption, impairs angiogenesis in vitro and in vivo.

Intravenous antiarrhythmic regimens with focus on amiodarone for prophylaxis of atrial fibrillation after open heart surgery.

Atrial fibrillation commonly occurs after coronary bypass surgery. Most studies suggest that atrial fibrillation develops in approximately 20% to as many as 50% of patients undergoing coronary artery bypass surgery. Over the years, a number of prophylactic regimens have been utilized to prevent atrial fibrillation after coronary bypass surgery. The majority of these studies have used oral agents in various combinations. Few studies have used intravenous agents, and most of these studies have used either beta blockers, calcium antagonists, or class I antiarrhythmic drugs. Recent evidence suggests that intravenous amiodarone may provide safe and effective prophylaxis against atrial fibrillation in many patients undergoing coronary bypass surgery. The evolving data that support such an approach are discussed in this article.

Intravenous amiodarone for the prevention of atrial fibrillation after open heart surgery: the Amiodarone Reduction in Coronary Heart (ARCH) trial.

OBJECTIVES: This study was designed to test whether intravenous (i.v.) amiodarone would prevent atrial fibrillation and decrease hospital stay after open heart surgery. BACKGROUND: Atrial fibrillation commonly occurs after open heart procedures and is thought to be a significant determinant for prolongation of hospitalization. Oral amiodarone given preoperatively appears to reduce the incidence of atrial fibrillation. This study was designed to test whether the more rapid-acting i.v. formulation of amiodarone given postoperatively would reduce the incidence of atrial fibrillation. METHODS: Three hundred patients undergoing standard open heart surgery were randomized in a double-blind fashion to i.v. amiodarone (1 g/day for 2 days) versus placebo immediately after open heart surgery. The primary end points of the trial were incidence of atrial fibrillation and length of hospital stay. Baseline clinical variables and mortality and morbidity data were collected. RESULTS: Atrial fibrillation occurred in 67/142 (47%) patients on placebo versus 56/158 (35%) on amiodarone (p = 0.01). Length of hospital stay for the placebo group was 8.2 +/- 6.2 days, and 7.6 +/- 5.9 days for the amiodarone group (p = 0.34). No differences were noted in baseline variables, morbidity or mortality. CONCLUSIONS: Low-dose i.v. amiodarone was safe and effective in reducing the incidence of atrial fibrillation after heart surgery, but did not significantly alter length of hospital stay.

Activation of the ornithine decarboxylase-polyamine system and induction of c-fos and p53 expression in relation to excitotoxic neuronal apoptosis in normal and microencephalic rats.

Microencephalic rats obtained by gestational treatment with the DNA alkylating agent methylazoxymethanol, show a remarkable lack of sensitivity to excitotoxic neuropathology caused by systemic injections of the convulsant neurotoxin kainic acid. Taking advantage of this, we have studied in these rats, as well as in normal rats, the relationship between the induction of cellular signals supposedly related to cell death and the neuronal apoptosis consequent to kainic acid administration. While normal rats responded to the excitatory insult with a large and relatively long lasting increase of the activity of the enzyme ornithine decarboxylase and of the concentration of putrescine in some brain regions, these alterations were much smaller in microencephalic rats. Expression of c-fos in brain regions sensitive to kainic acid was quicker but lasted a noticeably shorter time in microencephalic rats as compared to normal animals. A profusion of apoptotic neurons, labeled by an in situ technique, were observed in the olfactory cortex, amygdala and hippocampus of normal rats injected with kainic acid, in particular 48 h and 72 h after drug administration. At corresponding time intervals and with similar topographic localization, neurons expressing p53 protein were observed. By contrast, microencephalic rats displayed only in a few cases and in a small number apoptotic neurons in restricted areas of the ventral hippocampus and entorhinal cortex. Noticeably, in these cases small populations of p53-expressing neurons were also present in the same areas. The present observations clearly show that oncogenes such as c-fos and p53, as well as ornithine decarboxylase which behaves as an immediate-early gene in the brain under certain circumstances, undergo noticeably lower and/or shorter induction in microencephalic rats exposed to excitotoxic stimuli. In these rats, therefore, the cellular signalling pathways studied here and related to excitotoxic sensitivity and commitment to cell death are downregulated as a probable consequence of altered brain wiring.

Changes in NADPH-diaphorase expression induced by excitotoxicity in the goldfish retina: relation with some morphological and biochemical aspects.

We report alterations in the pattern of NADPH-diaphorase staining, a marker of nitric oxide, in the goldfish retina after kainic acid administration. The heavily stained ellipsoids of the photoreceptors, the heavily stained neurons of the inner plexiform layer and the labeled neurons of the ganglion cell layer are spared by excitotoxic insult, while the faintly medium sized neurons of the inner plexiform layer disappear after kainic acid administration. Furthermore, in the bipolar and in the horizontal retinal neurons we observe an induction of NADPH-diaphorase expression. The kainic acid-induced neurotoxicity evaluated by morphological observations and by measuring the levels of choline acetyltranferase in retinal homogenates, is not prevented by the administration of a nitric oxide synthase inhibitor.

Alteration of neuronal nitric oxide synthase activity and expression in the cerebellum and the forebrain of microencephalic rats.

Microencephalic rats were obtained through gestational (for the forebrain) or neonatal (for the cerebellum) administration of the DNA-alkylating agent methylazoxymethanol acetate (MAM), which selectively kills dividing cells during neurogenesis. In the microencephalic cerebellum the specific activity of calcium-dependent nitric oxide synthase (NOS) was decreased by 35-40% at 12, 28 and 70 days of age. Other neurochemical markers not related to granule cells (the neuronal population selectively compromised by neonatal MAM treatment), choline acetyltransferase (ChAT) and glutamate decarboxylase (GAD) were not decreased, but actually increased when determined as specific activity. In agreement with the decreased catalytic activity measured in the tube, the expression of neuronal NOS protein was attenuated as judged from immunohistochemistry and Western blotting. In the microencephalic forebrain, the specific calcium-dependent NOS activity measured in homogenates of the whole hemisphere was significantly increased as compared to normal animals. Accordingly, immunohistochemistry for neuronal NOS, as well as NADPH-diaphorase histochemistry revealed an apparent increase in the density of strongly reactive neurons in the underdeveloped cortex and striatum of microencephalic rats. The results reported here demonstrate that permanent alterations of neuronal NOS activity and expression occur when the development of the brain and its neuronal circuits are severely compromised. Furthermore, the permanent downregulation of neuronal NOS in the cerebellum of microencephalic rats may be exploited for the study of the role of NO in mechanisms of synaptic plasticity such as long term depression (LTD).

Apoptosis is induced by excitotoxicity in goldfish retina.

Apoptosis is an important mechanism of cell death that occurs physiologically during development. Recently, it has been shown that the selective pattern of neuronal degeneration in some brain disorders or in excitotoxic animal models, can reveal signs of apoptosis. This work produces evidence that kainic acid, a non-NMDA receptor agonist, induces apoptotic cell death in the goldfish retina. DNA breaks are in situ detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL). This reaction shows a large number of positive cells in the inner nuclear layer 48 hours after intravitreal kainic acid administration. TUNEL staining of apoptotic death was prevented by the non-NMDA glutamate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) but not by the NMDA receptor antagonist MK-801 administration. Ultrastructural changes that occur in kainic acid affected retinal neurons (hypercondensation and clumping of the chromatin and shrinkage of the cytoplasm) are consistent with those described in programmed cell death. Our results indicate that the excitotoxicity of intravitreally injected kainic acid causes the degeneration of those neurons in the goldfish retina, that underwent apoptotic death.

Localization of nitric oxide synthase in the goldfish retina.

The localization of nitric oxide synthase and NADPH-diaphorase was studied in the goldfish retina by means of immunohistochemistry or tetrazolium salt technique. Nitric oxide synthase was found in some small neurons of the inner nuclear layer and in large neurons of the ganglion cell layer. The reaction product was localized in the outer plexiform layer and a diffuse labeling was also observed in the inner plexiform layer. In addition to the outer segments of photoreceptors, NADPH-diaphorase labeled several neurons of the inner nuclear layer and some neurons scattered in the ganglion cell layer. Both outer and inner plexiform layers were labeled. Ultrastructural observations showed that the reaction product was found to be bound to the endoplasmic membranes of positive neurons. In the outer plexiform layer the formazan precipitate labeled prevailingly the presynaptic terminals of rods and cones, in the inner plexiform layer both pre- and postsynaptic profiles showed the reaction product.

Telencephalo-habenulo-interpeduncular connections in the goldfish: a DiI study.

The telencephalo-habenulo-interpeduncular system has been anatomically and neurochemically characterized in mammals. However, little is known about these important forebrain-midbrain connections in non-mammalian vertebrates, although available data suggest that they are evolutionarily relatively conservative. Previous ultrastructural studies in the goldfish confirmed the presence of massive telencephalohabenular and habenulointerpeduncular projections and demonstrated a minor direct telencephalointerpeduncular connection. Here we report the anterograde and retrograde transport of lipophilic fluorescent carbocyanine dye from the interpeduncular nucleus and the habenular nuclei in the fixed goldfish brain. The application of dye into the interpeduncular nucleus resulted in massive labeling of the fasciculus retroflexus and of the habenular neurons. A few scattered neurons were also seen in the dorsal nucleus of area ventralis telencephali. Application of dye into the habenulae resulted in anterograde transport through the medial and lateral olfactory tracts to some cell bodies in the anterior and posterior zone of area ventralis telencephali and in perikarya of the bed nucleus and in the entopeduncular nucleus. These results demonstrate the origin of the direct telencephalointerpeduncular projection in the goldfish and confirm some important homologies with forebrain-midbrain projections in land vertebrates.

Neurotoxic effects of DSP-4 on the noradrenergic system of the goldfish brain.

The substance N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a neurotoxin with selective and long-lasting effects on the noradrenergic (NA) neurons of mammalian brains. The present study examines the effects of this toxin on the noradrenergic system of the goldfish brain. Single doses (50 mg/kg body weight) of DSP-4 reduce the immunoreactivity of the NA synthesizing enzyme dopamine-beta-hydroxylase (DBH), as revealed by immunohistochemistry 7 and 12 days after toxin administration. The depletion involves the DBH-positive fibres and spares the DBH-positive cell bodies. Dopamine-beta-hydroxylase immunoreactivity, 40 days after toxin administration, showed a complete recovery. Ultrastructural investigations confirmed that DSP-4 toxicity affects only nervous fibres and terminals, sparing cell bodies. Administration of DSP-4 also produced a marked decrease of noradrenaline (NA) levels in the goldfish brain, seven days later, while dopamine (DA) and serotonin (5-HT) levels were unaffected by toxin injection. The reduction of NA levels induced by DSP-4 was prevented by the concomitant administration of the NA uptake inhibitor desipramine. Noradrenaline levels measured 40 days after toxin administration show that DSP-4 toxicity was completely reversed. The results suggest a pronounced plasticity of the noradrenergic system in the goldfish brain.

Ultrastructural localization of NADPH-diaphorase in the goldfish brain.

The ultrastructural localization of NADPH-diaphorase was studied in the goldfish brain by means of the tetrazolium salt technique. The reaction product was found to be bound to the endoplasmic membranes of neurons in different brain areas. In the synaptic structures both pre and post-synaptic profiles showed the reaction product. Furthermore non-neuronal structures were intensely labeled. Endothelial cells revealed the membranous localization of NADPH-diaphorase and the glial cells of the hypothalamic nuclei and of the paraventricular organ were labeled. In some cases the reaction product was seen also in oligodendrocytes and in microglial cells.

6,7-Dinitroquinoxaline-2,3-dione but not MK-801 exerts a protective effect against kainic acid neurotoxicity in the goldfish retina.

Recent findings indicated that the excitotoxicity of glutamate analogues was prevented in the mammalian nervous system by N-methyl-D-aspartate (NMDA) antagonists. The neurodegenerative effects of kainic acid, and the putative protection of MK-801 and 6,7-dinitroquinoxaline-2,3-dione (DNQX), were investigated by morphological studies showing the toxicity of kainic acid to the neurons of the inner nuclear layer, and measuring choline acetyltransferase and glutamate decarboxylase activities in the retina. In addition, the proliferation of Müller retinal cells was assumed as an index of neuronal degeneration and was quantified by counting glial fibrillary acidic protein immunopositive cells. Our observations suggest that the non-NMDA receptor antagonist DNQX exerted a protective effect on goldfish retinal neurons, while MK-801 did not prevent the neurotoxicity induced by kainic acid in the goldfish retina. This finding is in agreement with previous work on kainic acid toxicity in the goldfish optic tectum.

Localization of NADPH-diaphorase in the goldfish brain.

The distribution of NADPH-diaphorase positive neurons was studied by using the enzyme histochemical method. Numerous neurons were labeled in different brain areas of the goldfish and their distribution showed some differences in comparison with other studied teleosts, indicating a species-specific pattern of NADPH-diaphorase distribution as observed in mammals. The localization of NADPH-diaphorase in the thalamic nuclei, in the paraventricular organ, in the inferior hypothalamic lobe, in the periventricular neurons of the optic tectum, in the nucleus isthmi and in the mesencephalic reticular formation was comparable to the one observed in other teleosts. In addition in the goldfish the telencephalic neurons of the pars centralis and lateralis of the area dorsalis, the habenular neurons, the bipolar neurons of the central grey layer of the optic tectum and the motor neurons of the hypertrophied vagal lobe were labeled. The localization of NADPH-diaphorase positive neurons, compared to the distribution of cholinergic neurons described in fish, indicated that the production of nitric oxide was prevailing in the brain areas where cholinergic circuits are active.

Flecainide acetate for paroxysmal supraventricular tachyarrhythmias. The Flecainide Supraventricular Tachycardia Study Group.

Flecainide has been shown to be effective in short-term, controlled studies for prevention of paroxysmal supraventricular tachycardia (SVT) and paroxysmal atrial fibrillation (AF). However, it is unknown whether this beneficial response is maintained during long-term chronic therapy. Forty-nine patients were studied who enrolled in double-blind, placebo-controlled, short-term studies of safety and efficacy and subsequently received long-term, open-label therapy for > or = 6 months (mean duration of therapy, 17 months). To evaluate chronic efficacy, events during long-term therapy were documented by a transtelephonic monitor for either 4 or 8 weeks, comparable to the corresponding 4- or 8-week placebo-baseline periods in the same patients. Results during chronic therapy were compared with those at baseline and after the initial (short-term) treatment period. Compared with placebo-baseline results, the number of patients free of arrhythmic attacks increased significantly for both patients with SVT (from 24% to 82%, p = 0.013, n = 17) and patients with AF (from 12% to 68%, p < 0.001, n = 25). Mean time to first attack and mean number of days between attacks also showed significant and parallel increases during the chronic efficacy period. In patients with paired short- and long-term efficacy evaluations with the same dose of flecainide, end points were maintained at equivalent levels or showed further improvement (i.e., mean rate of AF attacks decreased further with chronic therapy, p = 0.036). No proarrhythmic events, death, or myocardial infarction occurred.(ABSTRACT TRUNCATED AT 250 WORDS)