Interventional catheterization decreases plasma levels of atrial natriuretic peptide (ANP) in children with congenital heart defects

Atrial natriuretic peptide (ANP) is one of the cardiac peptides implicated in volume and sodium homeostasis. We investigated the effect of interventional catheterization on plasma levels of ANP, aldosterone, and cortisol in 28 children with various congenital heart defects (CHD). Patients were divided by age into two groups: group A - infants and children over 3 months of age (n = 22), and group B - newborns (n = 6). These were compared to age-matched control groups. In group A, interventions included pulmonic valvotomy (n = 8), aortic valvotomy (n = 4), balloon angioplasty of native coarctation of the aorta (n = 3), balloon dilatation of the mitral valve (n = 1), and Rashkind double umbrella closure of patent ductus arteriosus (n = 6). Group B interventions included pulmonic valvotomy (n = 3), aortic valvotomy (n = 1), and balloon atrial septosomy (n = 2). In group A, mean ANP levels were markedly higher than in age-matched controls (125.2 ± 15.8 vs. 24.6 ± 4.6 pg/ml) (P <0.0001), and decreased immediately after intervention (75.6 ± 11.4 pg/ml, P <0.02), and more markedly on follow-up (42.9 ± 5.0 pg/ml, P <0.0001). In group B (newborns), mean basal plasma levels were high before and after intervention and were not different from age-matched controls (243 ± 42.1 vs. 220.8 ± 16.2 pg/ml). There was a significant decrease on follow-up measurement (62.1 ± 12.7 pg/ml, P <0.005). In both groups, plasma cortisol levels increased significantly immediately following catheterization (P <0.02), and normalized on follow-up. Basal aldosterone levels were normal in group A and high in Group B (9.9 ± 3.8 vs. 167.6 ± 16.9 ng/dl) (P <0.001). It is suggested that plasma ANP levels are increased in children with CHD, without overt heart failure, and decrease significantly following successful intervention. In newborns with CHD, the physiological high ANP levels obscure the effect of the CHD. Cathet. Cardiovasc. Diagn. 45:27–32, 1998. © 1998 Wiley-Liss, Inc.     

Evaluation of the potential anti-cancer activity of the antidepressant sertraline in human colon cancer cell lines and in colorectal cancer-xenografted mice

Evidence has been provided of the anti-proliferative activity of certain antidepressants, mainly the selective serotonin reuptake inhibitors (SSRIs). We tested the effect of different antidepressants on cell viability and proliferation of human colorectal carcinoma cell lines HT29 and the multi-drug resistant (MDR) LS1034. The SSRIs, paroxetine and sertraline, induced a dose-dependent inhibition of cell viability and proliferation in the two cell lines (IC50 8-15 micro M). When compared to cytotoxic agents e.g. doxorubicin, vincristine and 5-fluorouracil, the SSRIs showed comparable activity (HT29) or a superior effect (LS1034). Using flow cytometry analysis, we found that the two SSRIs arrested cells at the G0/G1 stage and stimulated DNA fragmentation in a dose-dependent manner. The SSRIs (10 and 20 microM) increased caspase-3 activation. Western blot analysis showed an increase after 24 h in c-Jun and a decrease in the expression of the anti-apoptotic protein Bcl-2. The results suggest a proapoptotic activity for the active SSRIs accompanied by mitogen-activated protein kinase cascade activation and Bcl-2 inhibition. In vivo, we used CD1 nude mice xenografted subcutaneously with HT29 cells. On day 8, after cell inoculation sertraline or paroxetine (15 mg/kg x3/week i.p.) were administered to animals (6/group), which were monitored weekly (for 5 weeks) for tumor volume and body weight. At 5 weeks, the animals survived, with no significant difference in body weight. Sertraline, though not paroxetine, significantly inhibited tumor growth. Collectively, our results suggest that the widely-used antidepressant, sertraline, possesses a potential anti-tumor activity, which circumvents the MDR mechanism. Since SSRI therapy is frequently indicated in cancer patients, the use of sertraline in colon cancer patients with co-morbidity of depression seems attractive.     

Opposite modulatory effects of ovarian hormones on rat brain dopamine and serotonin transporters

The present study was designed to investigate the modulatory effect of gonadal steroids on brain dopamine (DA) and serotonin (5-HT) presynaptic transporters in female and male rats. Female and male rats were castrated and treated with either vehicle or gonadal hormones. The pharmacodynamic characteristics of the DA and 5-HT transporters were analyzed by [³H]BTCP and [³H]imipramine binding respectively. Ovariectomy (OVX) resulted in an upregulation of the striatal DA transporter and this alteration was prevented by estradiol (E₂) or E₂+progesterone (P) treatment but not by P alone. In contrast to the DA transporter, the hypothalamic 5-HT transporter was down-regulated by OVX in female rats and this decrease was reversed by the administration of E₂, P or their combination. The striatal DA transporter and the hypothalamic 5-HT transporter in male rat were not affected by orchidectomy or by administration of testicular hormone. Our findings indicate that ovarian, but not testicular, steroid hormones may play an important role in the regulation of brain DA and 5-HT transporters. It appears that ovarian hormones modulate rat brain 5-HT and DA transporters in opposite directions. These interactions between ovarian steroids and presynaptic transporters may be relevant to DA- and 5-HT-related neuropsychiatric disorders.     

Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth

Phenothiazines and related antipsychotics were reported to have an antiproliferative effect in several tissue cultures. The aims of this study were: a) to screen in vitro, the potential anti-cancer activity of phenothiazines in wild-type and multi-drug resistant (MDR) B16 mouse melanoma cell lines; and b) to determine the in vivo anti-tumor effect of an in vitro selected highly potent phenothiazine (thioridazine) in a murine melanoma model. The following phenothiazines were evaluated: perphenazine, fluphenazine, thioridazine trifluoperazine and chlorpromazine. All agents induced a dose-dependent decrease in cell viability in wild-type and in MDR B16 melanoma cells. Thioridazine displayed the highest antiproliferative activity. Flow cytometric analyses of 24-h treated B16 melanoma cells revealed an increase in fragmented DNA (16.3 vs 71.3% and 87.2% in controls, 25 microM and 50 microM thioridazine-treated, respectively). Apoptosis was confirmed by co-staining of thioridazine-treated B16 cells (12.5 microM) with propidium iodide and Hoechst 33342 reagents. Caspase-3 expression, a typical mediator of apoptosis, was markedly increased following a 4-h exposure of B16 cells to thioridazine (25 microM and 50 microM). This increase could be blocked by a specific caspase-3 inhibitor. In vivo studies were performed using female C57/Bl mice. Animals were inoculated with wild-type B16 cells by i.v. injection into the tail vein. Mice were treated with thioridazine (10 and 15 mg/kg x3/week i.p. or 15, and 25 mg/kg/day p.o.) and control animals received saline. Mice were monitored for 21-30 days. Body weight was recorded. After autopsy, the lung weight and number of pulmonary melanoma colonies were determined. Thioridazine administration (i.p. or p.o.) resulted in the reduction of lung tumor burden and an increase in mice survival. In conclusion, several phenothiazines, and particularly thioridazine, induced apoptosis of B16 melanoma cells and demonstrated in vivo anti-tumor activity.     

Haloperidol – induced neurotoxicity – possible implications for tardive dyskinesia

Summary. Tardive dyskinesia (TD) is one of the major side effects of long – term neuroleptic treatment. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. The traditional concept of supersensitivity of striatal dopamine receptors as the mechanism involved in the development of TD is not satisfying, and current studies have focused on the role of neuroleptic – induced neuronal toxicity in the development of TD. We performed a series of experiments to gain a better understanding on the mechanisms involved in induction of TD. We have evaluated the direct neurotoxic effect of haloperidol (HP), a widely – used neuroleptic drug, and its three metabolites, in mouse neuronal cultures and in PC-12 cells. We found that the features of HP-induced cell death were apoptotic rather than necrotic, as indicated by different DNA-staining methods and specific caspases inhibitors. Moreover, cotreatment with antioxidants such as vitamin E and N-acetylcysteine (NAC) significantly protected the cultures. Further studies on the mechanisms underlying HP-induced toxicity may lead to the development of new neuroprotective therapeutic strategies. Received May 10, 1999; accepted September 6, 1999     

Elevated circulatory level of GABA(A)--antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder

BACKGROUND: Post-traumatic stress disorder (PTSD) is a multisystem neurobiological disorder with chronic alterations in various neurochemical systems. Levels of the GABA(A)--antagonistic neurosteroids plasma dehydroepiandrosterone (DHEA) and its sulphate derivate, dehydroepiandrosterone sulphate (DHEAS) may be relevant to depressive and anxiety disorders, including PTSD. METHODS: We assessed the circulatory levels of morning plasma DHEA and DHEAS in 21 male outpatients with untreated chronic combat-related PTSD (CR-PTSD), and 18 healthy control male subjects. RESULTS: Compared with the control subjects, the PTSD patients showed significantly higher plasma DHEA and DHEAS levels. CONCLUSIONS: Chronic CR-PTSD may be associated with increased circulatory level of neuroactive steroids with inhibitory activity at the GABA(A) receptors. Neurosteroid-induced decreased GABAergic tone may be relevant to the symptomatology and pathophysiology of chronic PTSD, as well as to the frequent co-morbidity of PTSD with depression and anxiety disorders.     

The effect of famotidine addition on olanzapine-induced weight gain in first-episode schizophrenia patients: a double-blind placebo-controlled pilot study.

Olanzapine treatment is associated with substantial weight gain. In this double-blind placebo-controlled study we evaluated whether the H2 antagonist famotidine may prevent/attenuate olanzapine-induced weight gain. Fourteen first-episode DSM-IV schizophrenia patients were randomly allocated to receive either famotidine (40 mg/day, n=7) or placebo (n=7) in addition to olanzapine (10 mg/day) for 6 weeks. All patients completed the trial. Patients in both groups showed a similar increase in body weight (olanzapine/famotidine: 4.8 (3.2) kg and olanzapine/placebo: 4.9 (1.6) kg, respectively; a between-group difference of 0.14 (1.3) kg). Four of seven (57.1%) patients in the olanzapine/famotidine group and three of seven (42.9%) in the olanzapine/placebo group gained at least 7% of their initial body weight, a cut-off for clinically significant weight gain. Famotidine addition was safe and well tolerated and did not interfere with olanzapine's therapeutic effect. In conclusion, famotidine (40 mg/day for 6 weeks) is not effective in preventing/attenuating weight gain in olanzapine-treated first-episode schizophrenia patients.     

Neuroendocrinological response to standardized mixed meal in female anorectic patients during active and refeeding phases

To evaluate the neuroendocrinological dysfunction in anorexia nervosa, plasma somatostatin, glucose, insulin, and growth hormone were monitored in ten patients with anorexia nervosa in the active and refeeding (remission) phases of the disorder and in nine age-matched healthy control subjects. Somatostatin levels were significantly higher in the anorectic patients in both the active and refeeding phases than in the controls at baseline (mean+/-SD 27.4 +/-5.5 and 31.1+/-2.6 vs 21.3+/-1.9 pg/ml; p<0.001), and significantly higher in the anorectic patients in the active phase compared to the refeeding phase and to the controls in response to a mixed meal (p<0.05). Insulin levels were significantly lower in the anorectic patients in both the active and refeeding phases compared to the controls at baseline (9.3+/-1.1, 7.6+/-1.0 vs 14.7+/-3.5 microU/ml; p<0.0001) and after a mixed meal (p<0.05). An attenuated glucose response discriminated the anorectic patients in the active state from the same patients in the refeeding state and the controls (p<0.0001). There was no significant difference in growth hormone response between the anorectic patients and the controls. These findings suggest that there is an augmented response of somatostatin and an attenuated response of insulin to mixed meal stimulation in active anorexia. The diminished insulin response persists during the refeeding phase. It seems that central and peripheral alterations in endocrine function occur in anorexia nervosa.     

Modulation of brain insulin-like growth factor I (IGF-I) binding sites and hypothalamic GHRH and somatostatin levels by exogenous growth hormone and IGF-I in juvenile rats

The effect of exogenous growth hormone (GH) and insulin-like growth factor I (IGF-I) on brain IGF-I binding sites (IGF-IR), and on the levels of growth hormone-releasing hormone (GHRH) and somatostatin was studied in hypophysectomized and intact juvenile male rats. Animals were injected subcutaneously twice daily (n=5 each) with recombinant GH (rGH) (2.5 U/kg per day) or rIGF-I (500 μg/kg per day). In the hypophysectomized rats, serum GH and IGF-I levels were markedly suppressed and IGF-I levels were partially restored by GH treatment. There was a significant increase in IGF-IR binding capacity in the IGF-I-treated hypophysectomized rats compared to the saline-treated hypophysectomized animals (150.61 ± 45.66 vs 41.32±12.42 fmol/mg, p<0.05) but no significant difference in IGF-IR mRNA levels. GHRH levels in the saline-treated hypophysectomized group were significantly lower than in the saline-treated intact rats (31.2±11.2 vs 140.6±48.1 pg/mg tissue, respectively, p<0.01); no effect was induced by GH or IGF-I (37.5±26.8 and 53.8±22.5 pg/mg tissue, respectively). However, in the intact rats, GH and IGF-I injection led to a decrease in GHRH content, which was significant in the GH-treated compared to the saline-treated animals (33.1±16.2 vs 140.6±48.1 pg/mg tissue, p<0.01). No difference was found in somatostatin levels between intact and hypophysectomized rats (631.2±81.2 and 625.0±62.5 pg/mg tissue, respectively). However, in the hypophysectomized animals, GH and IGF-I treatment induced a significant increase in somatostatin levels (1300±193.7 pg/mg tissue, p<0.01, and 912.5±81.2 pg/mg tissue, p<0.05, respectively). Our findings suggest that the bioavailability of exogenous IGF-I is greater than that of GH-stimulated endogenous IGF-I. Because IGF-I is a potent neurotrophic agent, this effect may have important implications for states of neurodegenerative diseases.     

Insulin, insulin-like growth factors-I and -II and insulin-like growth factor binding protein-3 in newborn serum: association with normal fetal head growth and head circumference

The insulin-like growth factors (IGF) and their binding proteins (IGFBP) have been implicated in the regulation of fetal weight and length. The aim of our study was to determine the relationship between head circumference at birth and serum levels of IGF-I, IGF-II, IGFBP-3 and insulin in full-term appropriate-for-gestational age (AGA) infants. Serum samples were obtained from 77 singleton full-term neonates, 69 AGA and 8 small-for-gestational age (SGA). The AGA infants were divided into three groups by head circumference: Group 1: < or = 3rd percentile; Group 2: at 50th percentile; Group 3: > or = 97th percentile. Serum levels of IGF-I, IGF-II, IGFBP-3 and insulin were determined with commercial kits and immunometric methods. There were no statistically significant differences in mean serum levels of IGF-I, IGF-II and IGFBP-3 between the groups. A significantly higher mean serum insulin level was noted in the AGA infants with a head circumference > or = 97th percentile compared to those with a head circumference < or = 3rd percentile (4.6 +/- 0.3 vs 3.3 +/- 0.6 microU/ml; p = 0.04), and in AGA infants with a head circumference above the 50th percentile compared to those with a head circumference below the 50th percentile (4.4 +/- 0.4 vs 3.3 +/- 0.3 microU/ml; p = 0.01). AGA infants with a head circumference above or below the 50th percentile did not differ statistically in their mean IGF-II and IGFBP-3 serum level, while IGF-I differed statistically between the groups (18 +/- 2.7 vs 11.6 +/- 1.6 ng/ml, respectively; p = 0.045). Using univariate analysis, head circumference correlated positively with insulin (r = 0.29; p = 0.016) and with IGF-I (r = 0.26; p = 0.03). A stepwise multivariate linear regression analysis, however, did show statistically significant correlation of head circumference with birth weight (f = 36; p = 0.0001), and only marginally with birth length (f = 4.7; p = 0.06) and insulin (f = 3.4; p = 0.07). No correlations were found between head circumference and IGF-I, IGF-II or IGFBP-3. These data suggest that apart from genetic and nutritional factors, insulin may play a role in promoting intrauterine head growth, as reflected by head circumference at birth.