Growth hormone releasing activity by intranasal administration of a synthetic hexapeptide (hexarelin)

OBJECTIVE Hexarelin is a new synthetic growth hormone releasing peptide. We have tested the efficacy of intranasal (i.n.) administration of hexarelin to stimulate plasma GH and have compared this to the intravenous (i.v.) administration of the peptide. PATIENTS Ten children with familial short stature (FSS) aged 5·5-15·5 years and two known GH deficient patients aged 24 and 28 years without GH treatment. METHODS All 12 subjects were submitted to i.v. (1 μg/kg) and i.n. (20 μg/kg) hexarelin tests with a one-week interval between tests. Blood samples for GH, TSH, fT4 and T3 were obtained at 0, 15, 30, 60, 90 and 120 minutes. The hormone determinations were made by standard radio-immunoassays (RIA). RESULTS Both the i.n. and i.v. administration of hexarelin induced a large GH response, the mean (±SD) being 72·2± 35·5 mU/l for the i.n. test and 79·6 ± 53·0 mU/l for the i.v. test. The peak GH in the i.v. test occurred at 15–30 minutes and in the i.n. test between 30 and 60 minutes. The GH deficient patients showed no GH response In either test. Plasma TSH decreased in the FSS children from a mean (±SD) of 1.0 ± 0·26 to 0·64±0 2 mU/l (P<0 005) during the i.n. test and from 1·0±0·3 to 0·7±0·3mU/l (P> 0 05) during the I.v. test. In the isolated GH deficient patient, plasma TSH decreased from 1·06±0·38 mU/l to 0·86±0·17 during the i.v. test and from 1·60±0·01 to 1·11±0·06mU/l during the i.n. test. There were no significant changes in plasma fT4 or T3 in any of the tests. CONCLUSIONS The synthetic hexapeptide hexarelin is a potent pituitary GH stimulator when administered intra-nasally. The GH response was similar to that observed after intravenous hexarelin. Simultaneously, there was a significant decrease in plasma TSH but the concentrations remained in the normal range. These findings appear to be of theoretical and practical relevance to the investigation and management of short children.     

Dominant negative DISC1 mutant mice display specific social behaviour deficits and aberration in BDNF and cannabinoid receptor expression

Objectives. Disrupted in schizophrenia 1 (DISC1) is considered the most prominent candidate gene for schizophrenia. In this study, we aimed to characterize behavioural and brain biochemical traits in a mouse expressing a dominant negative DISC1mutant (DN-DISC1). Methods. DN-DISC1 mice underwent behavioural tests to evaluate object recognition, social preference and social novelty seeking. ELISA was conducted on brain tissue to evaluate BDNF levels. Western blot was employed to measure BDNF receptor (TrkB) and cannabinoid receptor CB1. Results. The mutant DISC1 mice displayed deficits in preference to social novelty while both social preference and object recognition were intact. Biochemical analysis of prefrontal cortex and hippocampus revealed a modest reduction in cortical TrkB protein levels of male mice while no differences in BDNF levels were observed. We found sex dependent differences in the expression of cannabinoid-1 receptors. Conclusions. We describe novel behavioural and biochemical abnormalities in the DN-DISC1 mouse model of schizophrenia. The data shows for the first time a possible link between DISC1 mutation and the cannabinoid system.     

The effect of acute and repeated electroconvulsive treatment on plasma β-endorphin,growth hormone,prolactin and cortisol secretion in depressed patients

The effects of single and repeated electroconvulsive treatment (ECT) on β-endorphin (β-EP), cortisol, growth hormone (GH) and prolactin (Prl) plasma levels were investigated in nine depressed patients. Blood samples were monitored a day before ECT, the day of the first and sixth ECT (0, 30, 60 and 90 min after seizures), the day afterwards and 4 weeks after termination of the ECT course. A significant elevation of β-EP levels was achieved immediately with and 24 h after the first and the sixth ECT. A transient increase in basal β-EP was observed 1 day following the sixth ECT in comparison with pre-treatment level. Peak and 30 min levels of cortisol were increased compared with baseline by the first ECT. The former (peak) but not the latter (30 min) were increased also at the sixth treatment. GH levels were decreased the day after the first ECT in comparison with the pre-treatment levels and immediately following each ECT in comparison with baseline. A trend toward elevation of Prl was observed immediately after the first and sixth ECT, although the rise did not reach significant levels. ECT administration stimulated β-EP and cortisol secretion and suppressed human GH release, possibly by activation of endorphinergic and/or serotonergic systems. These mechanisms might be involved in the beneficial effect of ECT in depression.     

Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases

Certain selective serotonin reuptake inhibitors (SSRIs) induce the clinical and biochemical manifestations of a metabolic syndrome by as yet unknown mechanism. Here we demonstrate that incubation (1 h) of rat hepatoma Fao cells with the SSRIs paroxetine and sertraline, but not with the atypical antipsychotic drug olanzapine, inhibited the insulin-stimulated Tyr phosphorylation of the insulin receptor substrate-1 (IRS-1) with half-maximal effects at approximately 10 microM. This inhibition correlated with a rapid phosphorylation and activation of a number of Ser/Thr IRS-1 kinases including JNK, S6K1, ERK and p38 MAPK, but not PKB (Akt). JNK appears as a key player activated by SSRIs because specific JNK inhibitors partially eliminated the effects of these drugs. The SSRIs induced the phosphorylation of IRS-1 on S307 and S408, which inhibits IRS-1 function and insulin signaling. These results implicate selected SSRIs as inhibitors of insulin signaling and as potential inducers of cellular insulin resistance.     

Attenuating effect of reboxetine on appetite and weight gain in olanzapine-treated schizophrenia patients: a double-blind placebo-controlled study

Rationale Search for safe and effective strategies to diminish weight gain associated with second generation antipsychotics (SGAs) is imperative. In the present study, we sought to replicate our preliminary findings, which indicated that coadministration of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Materials and method Fifty-nine patients hospitalized for first-episode DSM-IV schizophrenic disorder participated in this randomized double-blind study. Reboxetine (4 mg/day; 31 patients) or placebo (29 patients) was coadministered with olanzapine (10 mg/day) for 6 weeks. Analysis was by intention-to-treat. Results Nine patients in each group prematurely discontinued the trial. Olanzapine/reboxetine-treated patients showed a significantly lower increase in body weight (mean = 3.31 kg, SD = 2.73) than their olanzapine/placebo-treated counterparts (mean = 4.91 kg, SD = 2.45). Significantly fewer olanzapine/reboxetine-treated patients gained at least 7% of their initial weight, the cutoff for clinically significant weight gain (6 [19.4%] of 31 patients vs 13 [46.4%] of 28 patients). Seven (22.6%) olanzapine/reboxetine-treated patients compared to only one patient (3.6%) in the olanzapine/placebo group revealed no weight change or even modest weight loss. Appetite increase was significantly lower in the olanzapine/reboxetine than olanzapine/placebo group and was correlated with attenuation of weight gain. Reboxetine addition was safe and well tolerated. Conclusions The results confirm that coadministration of reboxetine promotes a clinically meaningful attenuation of olanzapine-induced weight gain in schizophrenia patients. If substantiated in long-term studies, along with behavioral management and diet counseling, reboxetine may have a clinical utility in controlling SGA-induced weight gain.     

Platelet imipramine binding and plasma cortisol levels in Israeli civilians during the Gulf War.

[3H] Imipramine binding to platelets and plasma cortisol levels were measured in nine Israeli civilians before, during, and after repeated missile attacks. Hamilton Anxiety Rating Scale (HARS), and Beck Depression Inventory (BDI) were similar before and during the war and decreased significantly after the war. A trend toward increase in platelet imipramine binding values was observed during the war when compared with the postwar values (19%; p = 0.056), and/or when compared with prewar values (26%; p = 0.063). However, one-way analysis of variance with repeated measures did not reveal a significant statistical difference [F (2,6) = p = 2.07; NS] among the three time points. A significant correlation was found between HARS score, but not BDI, and imipramine binding values in the prewar and postwar time points (r = 0.87; 0.71, respectively). Plasma cortisol levels did not alter significantly during the study period.     

Growth hormone releasing activity of thyrotropin-releasing hormone in rats with hypothalamic lesions.

The growth hormone (GH)-releasing effect of thyrotropin-releasing hormone (TRH) was investigated in rats in which central nervous system (CNS)-anterior pituitary (AP) connections had been experimentally interrupted. Sprague-Dawley (SD) female and male rats, underwent bilateral electrolytic lesions in the median eminence (ME) or the ventromedial nuclei (VMN) or were sham-operated (sham-op). Fifteen days after surgery, 0.9% NAACl or TRH was injected iv into sham-op rats or those with lesions in the CNS, anesthetized with urethane, and blood was drawn at 5 and 10 min posttreatment. In the rats with ME lesions, TRH at all the doses used (0.1, 0.4 and 0.8 microng/100 g BW) induced a marked, although not dose-related GH rise, which was not present in sham-op rats after TRH, or after NaCl administration to either rats with ME lesions or sham-op rats. In SD male rats lesioned in the VMN, TRH at doses of 0.4 and 0.8 microng/100 g BW induced significant GH rises, while the lowest TRH dose (0.1 microng/100 g BW) was ineffective; again, TRH was ineffective at all doses used in sham-op rats. Concomitant evaluation of the prolactin (PRL)-releasing effect of TRH (0.1-0.8 microng/100 g BW), showed a striking elevation of plasma PRL in both female and male sham-op controls, but no PRL rise in the rats with ME lesions. The results reveal that in the rat with surgical separation of the anterior pituitary from the CNS, a direct GH-releasing effect of TRH can be obtained, whereas its PRL-releasing effect is no longer observed, and suggest that, by analogy, the GH-releasing effect of TRH present in some disease states of the human may be due to an impairment of CNS-AP connections.     

Intravenous administration of recombinant IGF-I lowers serum GHRH and TSH

Recombinant IGF-I was administered as an iv bolus of 75 micrograms/kg to 10 patients with Laron type dwarfism (3 children aged 9, 11 and 12 years and 7 adults aged 30.6 +/- 3.5 years) and to 8 healthy subjects (mean age 19.9 +/- 12.1 years) and determinations of IGF-I, GHRH, hGH, TSH, and glucose were made before and at 2, 5, 15, 30, 60, 90, and 120 min. The following effects were observed: a. an immediate, marked and sustained drop in blood glucose (p less than 0.001), more prolonged in the patients; b. in both groups, a dramatic rise in plasma hGH (p less than 0.01) which peaked at 60-90 min; in the patients this occurred after an initial immediate fall in plasma hGH (p less than 0.01); c. a progressive decrease of plasma GHRH and TSH (p less than 0.05, 0.02) in both patients and healthy controls. An hypothesis is put forward that acute and time-limited release of somatostatin by IGF-I is the main cause of the hormonal changes registered. As the IGF-I bolus also suppressed circulating insulin levels, the hypoglycemia is considered to be a direct effect of IGF-I.     

The effect of reboxetine co-administration with olanzapine on metabolic and endocrine profile in schizophrenia patients

Rationale

We previously demonstrated that the addition of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Using the same study sample, we also sought to determine whether reboxetine’s weight-attenuating effect was accompanied by a beneficial effect on metabolic and endocrine parameters relevant to antipsychotic-induced weight gain and obesity.

Method

Blood samples at baseline and at the end of the 6-week trial were available for 54 participants who participated in previous double-blind, placebo-controlled studies of reboxetine (4 mg BID) addition to olanzapine-treated schizophrenia patients. Fasting glucose, lipid profile, insulin, leptin, cortisol, dehydroepiandrosterone (DHEA), prolactin, and thyroid-stimulating hormone (TSH) were analyzed.

Results

In contrast to the olanzapine/placebo group, the olanzapine/reboxetine group exhibited a reduction in blood triglyceride (p?<?0.05) and leptin (p?<?0.05) levels, and elevation in cortisol (p?<?0.05) and DHEA (p?<?0.008) levels. No significant between-group differences were detected in the changes in cholesterol, glucose, insulin, TSH, and prolactin.

Conclusions

Reboxetine addition resulted in meaningful improvement of some metabolic and endocrine measures associated with olanzapine-induced weight gain. The potential role of reboxetine in the prevention of olanzapine-induced weight gain and cardio–metabolic morbidity merits further large-scale, long-term investigation.