Anti-Alcohol and Anxiolytic Properties of a New Chemical Entity, GET73

N-[(4-trifluoromethyl)benzyl]4-methoxybutyramide (GET73) is a newly synthesized compound structurally related to the clinically used, alcohol-substituting agent, gamma-hydroxybutyric acid (GHB). The present study was designed to assess whether GET73 may share with GHB the capacity to reduce alcohol intake in rats. Additionally, the effect of treatment with GET73 on anxiety-related behaviors and cognitive tasks in rats was investigated. A series of in vitro binding assays investigated the capacity of GET73 to bind to the GHB binding site and multiple other receptors. GET73 (10−9–10−3 M) failed to inhibit [3H]GHB binding at both high- and low-affinity GHB recognition sites in rat cortical membranes. GET73 displayed minimal, if any, binding at dopamine, serotonin, GABA, and glutamate receptors in membranes from different rat brain areas. Acute treatment with low-to-moderate, non-sedative doses of GET73 (5–50 mg/kg, i.g. or i.p.) (a) reduced alcohol intake and suppressed “alcohol deprivation effect” (a model of alcohol relapse) in selectively bred, Sardinian alcohol-preferring (sP) rats, (b) exerted anxiolytic effects in Sprague-Dawley (SD) and sP rats exposed to the Elevated Plus Maze test, and (c) tended to induce promnestic effects in SD rats exposed to a modified water version of the Hebb–Williams maze test. Although the mechanism of GET73 action is currently unknown, the results of the present study suggest that GET73 has a multifaceted pharmacological profile, including the capacity to reduce alcohol drinking and anxiety-related behaviors in rats

Efficacy and safety of growth hormone treatment in children with short stature: the Italian cohort of the GeNeSIS clinical study

Purpose: We examined auxological changes in growth hormone (GH)-treated children in Italy using data from the Italian cohort of the multinational observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) of pediatric patients requiring GH treatment. Methods: We studied 711 children (median baseline age 9.6 years). Diagnosis associated with short stature was as determined by the investigator. Height standard deviation score (SDS) was evaluated yearly until final or near-final height (n = 78). Adverse events were assessed in all GH-treated patients. Results: The diagnosis resulting in GH treatment was GH deficiency (GHD) in 85.5 % of patients, followed by Turner syndrome (TS 6.6 %). Median starting GH dose was higher in patients with TS (0.30 mg/kg/week) than patients with GHD (0.23 mg/kg/week). Median (interquartile range) GH treatment duration was 2.6 (0.6\u20133.7) years. Mean (95 % confidence interval) final height SDS gain was 2.00 (1.27\u20132.73) for patients with organic GHD (n = 18) and 1.19 (0.97\u20131.40) for patients with idiopathic GHD (n = 41), but lower for patients with TS, 0.37 ( 120.03 to 0.77, n = 13). Final height SDS was > 122 for 94 % of organic GHD, 88 % of idiopathic GHD and 62 % of TS patients. Mean age at GH start was lower for organic GHD patients, and treatment duration was longer than for other groups, resulting in greater mean final height gain. GH-related adverse events occurred mainly in patients diagnosed with idiopathic GHD. Conclusions: Data from the Italian cohort of GeNeSIS showed auxological changes and safety of GH therapy consistent with results from international surveillance databases

GET73 MODULATES RAT HIPPOCAMPAL GLUTAMATE TRANSMISSION: EVIDENCE FOR A FUNCTIONAL INTERACTION WITH mGluR5.

In the present study, the effects of the γ-Hydroxybutyrate (GHB) analogue, GET73, on hippocampal glutamate transmission have been evaluated by combining in vivo microdialysis with an in vitro tissue slices approach. The microdialysis results indicated that the local perfusion (60 min) with GET73 (10 nM-1 mM), concentration-dependently increased extracellular glutamate levels in CA1 region of the hippocampus of freely moving rat. In rat hippocampus slices, GET73 (1 µM-10 µM) did not affect l-[3H]glutamate uptake, whereas at 1 µM concentration, significantly increased K+-evoked, but not spontaneous, glutamate efflux. The GHB analogue did not affect NMDA (100 µM and 300 µM)-induced increase of glutamate efflux. On the contrary, at a concentration by itself ineffective (500 nM), GET73 partially, but significantly, counteracted the increase of K+-evoked glutamate efflux induced by the mGluR5 agonist CHPG (100 µM). When GET73 (500 nM) was co-perfused with MPEP (100 µM), it amplified the decrease of K+-evoked glutamate efflux induced by the mGluR5 antagonist. Interestingly, the GET73 (1 μM)-induced increase of K+-evoked glutamate efflux was counteracted by co-perfusion with a low (10 μM) concentration of MPEP, by itself ineffective. Finally, GET73 (500 nM) did not affect the reduction of K+-evoked glutamate efflux induced by the mGluR2/3 agonist LY379268. These findings demonstrate that the GHB analogue, GET73, significantly affects hippocampus glutamate transmission and its profile of action differs from that of parent compound

THE EFFECT OF AN ENKEPHALIN ANALOG ON ALDOSTERONE SECRETION IN NORMAL SUBJECTS

The effect of FK33 824, a stable analogue of methionine-enkephalin, on aldosterone (A), plasma renin activity (PRA) and cortisol (F) secretion were studied in 4 normal subjects. A significantly increased while PRA was unaffected and F decreased afted the drug adrninistration. We suggest that enkephalins may play a role in the control of A secretion by a mechanism of action independent on angiotensin II and ACTH

Prolactinomas in children and adolescents. Clinical presentation and long-term follow-up

In this study, we report the clinical presentation, response to medical treatment, and long-term follow-up of 26 patients with prolactinoma (15 macro- and 11 micro-adenomas) diagnosed at the age of 7-17 yr. All patients were first treated with bromocriptine (BRC) at doses ranging from 2.5-20 mg/day orally. BRC was discontinued for intolerance and/or resistance to the drug and was replaced by quinagolide (CV) at doses ranging from 0.075-0.6 mg/day or by cabergoline at doses ranging from 0.5-3.5 mg/week orally. Two patients received external conventional radiotherapy after surgery. In 7 prepubertal males and 6 females with macroprolactinoma, headache and/or visual defects were the first symptoms. All females presented with primary or secondary amenorrhea. Growth arrest was observed in a male patient with microadenoma, whereas all the remaining patients had normal heights, and pubertal development was appropriate for their age. Spontaneous or provocative galactorrhea was observed in 12 patients (3 males and 9 females) and gynecomastia in 4 males. Mean serum PRL concentration (+/-SE) at the time of diagnosis was 1080 +/- 267 microg/L in patients with macroadenoma and 155 +/- 38 microg/L in patients with microadenoma. In 10 patients, BRC normalized PRL levels and caused variable, but significant, tumor shrinkage. CV normalized PRL concentrations and reduced tumor size in 5 patients. Cabergoline normalized PRL concentrations in 7 of 10 patients resistant to CV. Pregnancy occurred in 2 patients while on treatment. Pregnancies were uncomplicated, and the patients delivered normal newborns at term. Only 4 patients are still moderately hyperprolactinemic. Impairment of other pituitary hormone secretion was documented at the time of diagnosis in 7 patients, 5 of whom underwent surgery. Four patients became GH deficient in adult age. In conclusion, the medical treatment with dopaminergic compounds is effective and safe in patients with prolactinoma with onset in childhood, allowing preservation of the anterior pituitary function

In vitro functional characterization of GET73 as possible negative allosteric modulator of metabotropic glutamate receptor 5

The present study was aimed to further characterize the pharmacological profile of N-[4-(trifluoromethyl) benzyl]-4-methoxybutyramide (GET73), a putative negative allosteric modulator (NAM) of metabotropic glutamate subtype 5 receptor (mGluR5) under development as a novel medication for the treatment of alcohol dependence. This aim has been accomplished by means of a series of in vitro functional assays. These assays include the measure of several down-stream signaling [intracellular Ca++levels, inositol phosphate (IP) formation and CREB phosphorylation (pCREB)] which are generally affected by mGluR5 ligands. In particular, GET73 (0.1 nM-10 μM) was explored for its ability to displace the concentration-response curve of some mGluR5 agonists/probes (glutamate, L-quisqualate, CHPG) in different native preparations. GET73 produced a rightward shift of concentration-response curves of glutamate- and CHPG-induced intracellular Ca++levels in primary cultures of rat cortical astrocytes. The compound also induced a rightward shift of concentration response curve of glutamate- and L-quisqualate-induced increase in IP turnover in rat hippocampus slices, along with a reduction of CHPG (10 mM)-induced increase in IP formation. Moreover, GET73 produced a rightward shift of concentration-response curve of glutamate-, CHPG- and L-quisqualate-induced pCREB levels in rat cerebral cortex neurons. Although the engagement of other targets cannot be definitively ruled out, these data support the view that GET73 acts as an mGluR5 NAM and support the significance of further investigating the possible mechanism of action of the compound

Dataset for Phase I randomized clinical trial for safety and tolerability of GET 73 in single and repeated ascending doses including preliminary pharmacokinetic parameters

The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled âPhase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteersâ (Haass-Koffler et al., 2017) [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted. The next series of tables provided includes Pharmacokinetic (PK) parameters for GET 73 and its main metabolite MET 2. This set of data is comprised by two experiments: Experiment 1 references a single ascending dose administration of GET 73 and Experiment 2 references a repeated ascending dose administration of GET 73. Keywords: Glutamate receptor subtype 5 (mGlu5), Allosteric modulator, GET 73, Safety, Tolerabilit