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Biomedical subjects

M Morre

Publications and source records attributed to M Morre.

At least 19 recordsLinked to original sources
PubMed1992

Effect of propranolol on growth hormone response to GH releasing hormone (GHRH 1-44) in the dog.

The present study was undertaken to examine whether beta-adrenergic blockade with propranolol might influence and make less variable the growth hormone (GH) response to exogenous GH releasing hormone (GHRH) 1-44 in the dog. On four separate occasions eight healthy beagles, one to two years old, randomly received either propranolol (40 micrograms kg-1 intravenously) or an equivalent volume of saline, 30 minutes before either GHRH 1-44 (1 microgram kg-1 intravenously) or vehicle was injected. After propranolol alone, GH secretion did not differ from saline (area under the curve [AUC]: 649.5 +/- 128.3 v 633.2 +/- 87.7 ng min ml-1, respectively). GHRH alone elicited a significant increase in GH secretion (AUC: 1230.5 +/- 210.5 ng min ml-1) with a peak concentration of 16.7 +/- 4.8 ng ml-1. When GHRH was injected after propranolol the mean peak (59.1 +/- 14.7 ng ml-1) and secretory area (AUC: 2631.0 +/- 474.4 ng min ml-1) were greater than those observed after GHRH alone. However, from a clinical point of view propranolol pretreatment does not modify the great individual variability of the GH response to GHRH.

Animals↗
PubMed1992

Treatment with growth hormone-releasing hormone (GHRH) 1-44 in children with idiopathic growth hormone deficiency: a randomized double-blind dose-effect study. The GHRH European Multicenter Study (GEMS) Group.

One hundred and eleven pre-pubertal children (70 boys, 41 girls, aged 2.5 to 14.3 years) with growth failure (height 2 SD below the mean for chronological age (CA) and height velocity (HV) below the 10th percentile for bone age) due to idiopathic growth hormone deficiency (peak plasma GH < 20 mUI/1 to two standard provocative tests) were treated with GHRH 1-44 NH2. Patient stratification in two classes was performed according to body weight; in each class, patients were randomly allocated to one of seven GHRH doses, from 30 to 300 micrograms/day. GHRH was injected subcutaneously, every evening, for six months in a double-blind fashion. No relationship was found between the absolute or incremental HV during treatment and the dose (range from 1.3-23.1 micrograms/kg/day) of GHRH. However, HV (cm/year) increased from 3.8 +/- 0.1 (mean +/- SEM) before treatment to 6 +/- 0.2 during six months treatment and 47 patients (42%) increased their HV up to at least the mean normal HV for bone age (catch-up growth). Low titer antibodies to GHRH were found in 19 patients (17.1%) at six months; no adverse effect was observed. Our results suggest that patients showing catch-up growth were older, had a height closer to the mean for chronological age and a slower pre-treatment height velocity. Failure to demonstrate a relationship between GHRH dose and changes in growth velocity might be explained by the combination of a placebo effect, insufficient frequency of GHRH administration and heterogeneity of the population.

Adolescent↗
PubMed1989

High affinity binding sites for basic fibroblast growth factor in rat hepatic plasma membranes.

The binding of [125I]-recombinant basic FGF (rec bFGF) to rat hepatic plasma membranes was investigated. [125I] rec bFGF bound to an apparent single class of high affinity binding sites (KD = 69 pM; Bmax = 9.61 fmoles/mg proteins). The absence of low affinity sites was confirmed by the inability of sulphated polysaccharides and heparinase to interfere with FGF binding. A good correlation existed between the ability of bovine pituitary-derived bFGF, rec bFGF and bovine brain-derived aFGF to displace [125I]rec bFGF from these binding sites and their in vitro potency on bovine aortic endothelial cell proliferation.

Animals↗
PubMed1989

Growth hormone response induced by synthetic human growth hormone-releasing factor (1-44) in healthy dogs.

The growth hormone (GH) secretory response to varying doses (1, 5 and 25 micrograms/kg) of intravenous (i.v.) human GH releasing factor (GRF) (1-44) was measured in four, 16-month-old female dogs and compared to the GH response to placebo (vehicle solubilizing GRF) and standard clonidine test (10 micrograms/kg i.v.). The three doses of GRF had no apparent clinical side effects and were capable of eliciting a rapid increase in the mean plasma GH level. The rise in plasma GH occurred within 5 minutes with a peak response at 15-30 minutes. However inter-subject variability of the GH response was large in terms of magnitude and time course. By analysis of the areas under the response curves it was shown that GRF 1-44 was as effective in stimulating GH release as clonidine and that a dose of 1 microgram/kg GRF 1-44 could be a good choice for use as a standard test dose in the dog.

Animals↗
PubMed1988

Tetrazepam: a benzodiazepine which dissociates sedation from other benzodiazepine activities. I. Psychopharmacological profile in rodents.

In the 1,4-benzodiazepine (BZD) series the nature of the C(5) substituent is critical for activity. In tetrazepam this substituent is a cyclohexenyl ring, in all other clinically effective 1,4-BZD derivatives it is a phenyl ring. The activities of tetrazepam and diazepam, whose chemical structures differ only by the nature of the C(5) substituent, were compared in rodent models which are predictive of anticonvulsant, anxiolytic, muscle relaxant and sedative effects. In mice, tetrazepam and diazepam antagonized pentylenetetrazol (PTZ)-induced seizures, increased novel food consumption, decreased rearing behavior in the Staircase test and impaired performance in the Traction test. The effects of both drugs were abolished by Ro 15-1788. In rats, both drugs antagonized PTZ-induced seizures, released punished responding in an approach-avoidance conflict procedure and blocked the PTZ discriminative cue. In mice and rats, and with both BZDs, maximal activity occurred 15 to 30 min after drug administration. In mice and rats, the overall anxiolytic and muscle relaxant potencies of tetrazepam were one-fourth and one-sixth those of diazepam, respectively. The anticonvulsant potency of tetrazepam varied from one-half (rats) to one-twentieth (mice) that of diazepam. In rats and mice, the sedative potency of tetrazepam (Rotorod test; locomotor activity) was approximately one-sixteenth that of diazepam. Finally, tetrazepam induced a loss of righting reflex in mice, with an ED50 value which was approximately 70-times greater than that of diazepam. It is concluded that replacing the 5-phenyl ring by a 5-cyclohexenyl ring leads to a relative dissociation of the pharmacological actions of the 1,4-BZDs.

Animals↗
PubMed1988

Tetrazepam: a benzodiazepine which dissociates sedation from other benzodiazepine activities. II. In vitro and in vivo interactions with benzodiazepine binding sites.

Tetrazepam is a 1,4-benzodiazepine (BZD) derivative which, in rodents, appears to have very little sedative and ataxic effects. In an attempt to identify the molecular mechanisms underlying this particular pharmacological profile we examined the interaction of tetrazepam with BZD binding sites. Tetrazepam interacted competitively with "central" and "peripheral" BZD binding sites and exhibited comparable affinities for both sites. Tetrazepam was approximately one-seventh as potent as diazepam at the central receptor and as potent as diazepam at the peripheral binding site. Tetrazepam did not distinguish type I from type II central BZD receptors, as evidenced by comparable affinities for the cerebellar and hippocampal receptors. In vitro autoradiographic studies showed that tetrazepam displaced [3H]flunitrazepam from rat brain membranes without any clear regional specificity. Like all BZD receptor agonists, tetrazepam exhibited a gamma-aminobutyric acid shift, a photoaffinity shift and potentiated the binding of 35S-t-butyl-bicyclophosphorothionate to rat brain membranes. However, the latter effect was observed at relatively high concentrations of tetrazepam. In vivo, tetrazepam displaced specifically bound [3H]flunitrazepam from mouse brain (ID50, 37 mg/kg p.o. vs 3.5 mg/kg p.o. for diazepam) and from mouse kidney (ID50, 38 mg/kg p.o. vs. 21 mg/kg p.o. for diazepam). It is concluded that tetrazepam is a BZD receptor agonist; the molecular mechanisms which underly the low sedative potential of the drug cannot at present be explained by a particular interaction with either central or peripheral BZD binding sites, but may be related to the drug's relatively weak effect on 35S-t-butyl-bicyclophosphorothionate binding.

Animals↗
PubMed1987

Results of 1-year growth hormone (GH)-releasing hormone-(1-44) treatment on growth, somatomedin-C, and 24-hour GH secretion in six children with partial GH deficiency.

Six children with short stature and partial GH deficiency in response to two pharmacological tests received GHRH for 12 months (10 micrograms/kg X day, sc) each evening. Twenty-four-hour GH secretion was studied before and after 3 and 12 months of treatment, and GHRH tests (2 micrograms/kg, iv) were done before and after 6 months of treatment. Plasma somatomedin-C was measured before and after 1.5, 3, 6, 9, and 12 months of treatment. Statural growth was measured at 3-month intervals. Mean growth velocity increased from 4.2 to 8.6 cm/yr, with a good result in five children and no response in the other. The growth response was substantial during the first 3 months. It was maintained during the following 6 months, and then decreased during the last 3 months. The peak plasma GH level in response to GHRH increased from 34.5 +/- 14.2 (+/-SD) ng/mL before treatment to 47.8 +/- 3.4 ng/mL after 6 months of treatment. Twenty-four-hour GH secretion increased in all parameters at 3 months (maximum peak, area under the curve, integrated concentration, and number of peaks) and at 12 months (with the exception of the maximum peak). Nycthemeral secretory profiles became normal, with reappearance of secretory pulses in two children, slight increases in three children, and no change in one child. Plasma somatomedin-C levels rose from 0.8 +/- 0.3 U/mL before treatment to 2.0 +/- 1.0 U/mL at 3 months, then decreased to 1.3 +/- 0.6 U/mL at 12 months. These results indicate that GHRH administered by sc injection for a 1-yr period stimulated growth and GH secretion. However, a decrease in activity was noted during the last 3 months of treatment. Tests for anti-GHRH antibodies were positive in the only child who did not respond to treatment.

Adolescent↗
PubMed1987

Growth hormone (GH) response to a single intravenous injection of synthetic GH-releasing hormone in prepubertal children with growth failure.

In this collaborative study involving 27 European medical centers, the plasma GH response to a single iv bolus dose of 2 micrograms/kg BW synthetic GHRH-(1-44)NH2 was determined in 574 children with growth failure of various etiologies. Analysis of the plasma GH response to GHRH was performed in 394 validated prepubertal children; these children were subdivided into 3 groups according to the degree of GH deficiency assessed within 6 months by conventional provocative tests (insulin, arginine, etc.): normal GH status (n = 210), partial GH deficiency (n = 73), or severe GH deficiency (n = 111). The mean peak GH values (+/- 2 SEM) after GHRH treatment in the three groups were 45.8 +/- 4.8, 29.2 +/- 6.3, and 16.8 +/- 3.1 microU/mL, respectively, and were greater than those after the conventional tests. The GH responses were consistent with the degree of GH deficiency based on the responses to the conventional tests. In addition, the areas under the GH response curves in the three groups were significantly different (P less than 0.0001). Among children with severe idiopathic GH deficiency 77% had a peak plasma GH level after GHRH above 10.0 microU/mL and 39% had a peak GH above 20.0 microU/mL. In these children, a single GHRH injection provides information on both their GH secretory capacity and the putative supresellar etiology of their GH deficiency, and may be of potential therapeutic value.

Adolescent↗
PubMed1986

In vivo evaluation by differential pulse voltammetry of the effect of thyrotropin-releasing hormone (TRH) on dopaminergic and serotoninergic synaptic activity in the striatum and nucleus accumbens of the rat.

In vivo differential pulse voltammetry was used to determine the effect of thyrotropin-releasing hormone (TRH) on dopaminergic and serotoninergic synaptic activity in the striatum and nucleus accumbens of the rat. Thyrotropin releasing hormone (TRH) produces marked stimulatory effects on behaviour, which have been attributed to the release of dopamine in the nucleus accumbens. Other studies indicate a close relationship between the peptide and serotonin in the brain. We have thus used an improved differential pulse voltammetry technique to evaluate the effects of TRH on the extracellular content of the dopamine and serotonin metabolites. Dihydroxyphenylacetic acid (DOPAC) and 5-Hydroxy-indoleacetic acid (5HIAA) in the nucleus accumbens and striatum of the rat in vivo. TRH rapidly increased extracellular DOPAC, reaching a maximum after 60 min in the nucleus accumbens, and after 40 min in the striatum. There was also a slower increase in extracellular 5-HIAA content in both areas, reaching a plateau after 100 min. The delayed time course of the increase in 5-HIAA suggested that the increase in 5-HIAA content might be secondary to the increase in dopamine turnover produced by TRH. These results suggest that doses of TRH which produce behavioural stimulation increase the release of both dopamine and serotonin in the nucleus accumbens and striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Anaesthesia abolishes the effect of valproate on extracellular 5-HIAA, DOPAC and ascorbate as measured in rat striatum by differential pulse voltammetry.

The effect of sodium valproate (VPA, 400 mg kg-1, i.p.) on extracellular ascorbate, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum was examined by differential pulse voltammetry in anaesthetized and freely-moving rats. In rats anaesthetized with chloral hydrate (400 mg kg-1, i.p.) pentobarbitone (50 mg kg-1, i.p.) or phenobarbitone (60 mg kg-1, i.p.), VPA produced no significant changes in peak 1 (extracellular ascorbate) or peak 2 (extracellular DOPAC), but produced a slight but statistically significant reduction in the height of peak 3 (extracellular 5-HIAA). In contrast, in freely-moving rats the same dose of VPA greatly reduced extracellular ascorbate and DOPAC concentrations, and increased that of 5-HIAA. These results suggest that VPA may reduce the release or turnover of dopamine, and increase that of 5-hydroxytryptamine in conscious rats. Our data also suggest that caution may be required in the interpretation of the effects of VPA in anaesthetized animals, as the results obtained may not always reflect the situation in the absence of anaesthesia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Effect of overnight constant infusion of human growth hormone (GH)-releasing hormone-(1-44) on 24-hour GH secretion in children with partial GH deficiency.

A continuous infusion (0.5 or 1 microgram/kg X h) of GH-releasing factor-(1-44) [GHRH-(1-44)] was administered from 2000-0800 h to 16 children with GH deficiency, defined as a maximum peak plasma GH less than 11 ng/ml in response to 2 provocative tests [first test; mean, 7.4 +/- 2.6 (+/- SD) ng/ml; second test; mean, 8.4 +/- 2.4 ng/ml]. Eight were boys and 8 girls; their average age was 10 yr, 5 months; and growth was retarded in all [mean, -3 +/- 0.6 (+/- SD)]. Polygraphic monitoring was carried out during the night, and blood samples for plasma GH measurements were drawn every 20 min during the night and the following day. A control study had been carried out in the preceding months with the same children. During GHRH infusion, a significant increase in nocturnal GH secretion occurred; the mean maximum peak increased from 17.5 +/- 3.4 (+/- SD) to 38.7 +/- 3.2 ng/ml, the mean area under the curve from 2243 +/- 459 to 5348 +/- 710 ng/ml, the mean integrated concentration from 4.2 +/- 0.8 to 9.9 +/- 1.3 ng/ml X min, and the mean number of peaks above 5 ng/ml from 2.7 +/- 0.3 to 4.7 +/- 0.4. During GHRH infusion, the 16 children had 2 peaks during the first 4 h of sleep and a third peak at the end of the night. Plasma GH levels the day after the infusions were not significantly increased. We conclude that continuous nocturnal GHRH infusion increases pulsatile sleep GH secretion throughout the night in children with partial GH deficiency.

Adolescent↗
PubMed1985

Growth hormone-releasing factor modifies dopaminergic but not serotonergic activity in the arcuate nucleus of hypothalamus in the rat, as recorded in vivo by differential pulse voltammetry.

Parenteral (i.v.) injection of growth hormone-releasing factor (GRF) increases the height of the 3,4-dihydroxyphenylacetic acid oxidation peak (peak 2) but does not change 5-hydroxyindole extracellular content (peak 3) in the arcuate nucleus of the hypothalamus, both peaks being recorded by the differential pulse voltammetry technique using a single specifically pretreated monopyrolytic carbon fibre electrode. Conversely, no significant changes are observed in the peak 2 and peak 3 heights recorded in the medial or in the lateral nucleus of the hypothalamus. These data suggest a specific interaction between GRF and the dopaminergic system.

Animals↗
PubMed1985

Allosteric effects of diprobutine on acetylcholine receptors.

The nicotinic effects of a novel antiparkinsonian compound, diprobutine were investigated on the acetylcholine receptor (AChR) from Torpedo marmorata electric organ and on rat brain membranes by a variety of techniques including stopped flow measurements. On the nicotinic AChR from Torpedo, diprobutine behaved as a typical noncompetitive blocker: it inhibited the agonist-regulated 22Na+ efflux from excitable microsacs; it shifted in the ms-s time-range the conformation of the AChR towards a high affinity state for agonists; it competed with [3H]PCP bound to its high affinity 'allosteric' site. On rat brain membrane, it displaced [3H]PCP bound to its high affinity site. The pharmacological properties of diprobutine are discussed in the context of its biochemical effects.

Allosteric Site↗
PubMed1985

EEG effects of i.v. infusion of pentylenetetrazol in rats: a model for screening and classifying antiepileptic compounds.

In order to validate a new animal model predictive of the profile of antiepileptic drugs, we studied the antagonism by standard antiepileptics of the EEG modifications induced by low-speed IV infusion of pentylenetetrazol (PTZ) in rats. The activity of the drugs was measured by their effects on temporal characteristics of the PTZ-induced EEG paroxysms. Most compounds had moderate to potent anti-PTZ effects, as shown by the changes in the EEG temporal parameters. However, these effects depended on the drugs and doses. Cluster analysis showed that drugs and doses which evoked similar changes were closely related and were included in separate clusters with respect to one another. In particular, the present results showed that benzodiazepines and antiepileptics cluster differently in their effects. Thus, this model could be a useful tool for assessing new antiepileptic drugs.

Animals↗
PubMed1985

Effect of valproate on brain GABA: comparison with various medium chain fatty acids.

The antiepileptic valproic acid increases brain GABA levels, and interferes with intermediate metabolism. We have therefore evaluated the effects of a number of other medium chain fatty acids on brain GABA. Propionate, isovalerate, pent-4-enoate and diallylacetate all increased whole-brain GABA levels in mice, but only diallylacetate possessed some anticonvulsant activity. Hyperammonaemia is a common side effect observed with these acids, but artificially induced hyperammonaemia through injections of ammonium chloride did not alter brain GABA. These results suggest that high doses of valproate may increase brain GABA by interfering with intermediate metabolism, possibly at the level of medium chain acyl CoA. However alterations in brain GABA did not correlate with anticonvulsant activity.

Ammonia↗
PubMed1985

Comparison of the pharmacological and biochemical profiles of valproic acid (VPA) and its cerebral metabolite (2-en-VPA) after oral administration in mice.

The pharmacological and biochemical profiles of valproate (VPA) and its cerebral metabolite (2-en-VPA) have been compared in order to determine the potential therapeutic value of the latter. After oral administration, 2-en-VPA was approximately half as potent as VPA in a number of chemical seizure models (pentylenetetrazol, B-mercaptopropionic acid, bicuculline, picrotoxinin), but more potent in tests of sedative activity (rotarod and loss of righting reflex). Whereas VPA possessed anxiolytic activity in mice, 2-en-VPA appeared to be inactive. The anticonvulsant activity of 2-en-VPA was shorter-lasting than that of VPA. The activity of 4 mmol/kg 2-en-VPA lasted less than 2 hours, while the same dose of VPA provided protection for over 5 hours. Both molecules increased brain GABA content to a similar extent, but again the action of 2-en-VPA was short-lasting. The low potency, poor ratio of sedative:anticonvulsant activity, and short-lived action of 2-en-VPA suggest that the molecule is poorly adapted for use as an antiepileptic agent.

Administration, Oral↗
PubMed1984

An improved differential pulse voltammetry technique allows the simultaneous analysis of dopaminergic and serotonergic activities in vivo with a single carbon-fibre electrode.

Differential pulse voltammetry has successfully been employed to study either 5-hydroxyindoles, or ascorbic acid and catechols in the brain of anaesthetised or freely moving rats. A new electrochemical pretreatment of pyrolytic carbon-fibre electrodes has been developed, enabling the simultaneous recording of all three compounds in the striatum of anaesthetised rats, using a Tacussel polarography. Furthermore, a fourth peak was recorded at +450 mV. Pharmacological treatments performed to define the nature of the four peaks recorded in the striatum confirmed that peak 1 corresponds to ascorbic acid, peak 2 to dihydroxyphenylacetic acid, peak 3 to 5-hydroxyindoleacetic acid and peak 4 to homovanillic acid.

3,4-Dihydroxyphenylacetic Acid↗