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Biomedical subjects

A J Puech

Publications and source records attributed to A J Puech.

At least 37 records · Page 2Linked to original sources
PubMed1995

Evaluation of the alpha 2-adrenoceptor blocking properties of buspirone and ipsapirone in healthy subjects. Relationship with the plasma concentration of the common metabolite 1-(2-pyrimidinyl)-piperazine.

1. Because the 5-HT1A agonist anxiolytic azapirones have a common alpha 2-adrenoceptor antagonist metabolite, 1-(2-pyrimidinyl)-piperazine (1PP), we measured central and peripheral alpha 2-adrenoceptor dependent responses before and after intravenous administration of 0.15 mg clonidine when healthy subjects were taking buspirone (30 mg day-1 for 4 days and 10 mg on day 5), ipsapirone (15 mg day-1 for 4 days and 5 mg on day 5) or placebo. 2. Clonidine decreased blood pressure, heart rate, oral body temperature, salivary excretion, plasma noradrenaline, 3,4-dihydroxyphenylglycol (DHPG) concentrations, increased plasma growth hormone but did not modify plasma insulin and C-peptide concentrations. Treatments tended to modify only the effect of clonidine on growth hormone (P = 0.07). 3. The azapirones reduced clonidine induced prolongation of choice reaction time (P = 0.015) and tended to antagonise clonidine induced fall in critical flicker fusion frequency (P = 0.066). 4. Only buspirone reduced total reaction time and increased critical flicker fusion threshold measured 12 h after the evening dose and these effects were correlated with the residual plasma 1PP concentration which was higher on buspirone than on ipsapirone (2.76 micrograms l-1, 95% CI:1.3-4.22 vs 0.65 microgram l-1, 95% CI: 0.32-0.98, P = 0.006). 5. Mean AUC of the 1PP plasma concentrations after the last dose of treatments were 3.7 times greater with buspirone than with ipsapirone (P = 0.0011). The AUC ipsapirone/AUC 1PP ratio was 6.45 and the AUC buspirone/AUC 1PP ratio was 0.076.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1995

Treatment of negative symptoms in schizophrenia with amisulpride.

BACKGROUND: The efficacy of low doses of certain neuroleptics in improving negative symptoms is still controversial. This study assessed the efficacy of amisulpride, a benzamide which increases dopaminergic transmission at low doses via presynaptic dopamine receptor blockade, on negative symptoms of schizophrenia. METHOD: The study was designed as a parallel-group, double-blind, placebo-controlled trial. Patients had to fulfil DSM-III criteria for schizophrenia, Andreasen's criteria for negative schizophrenia, and to have a total score of at least 75 on the SANS; those treated with neuroleptics or antidepressants underwent a six-week placebo wash-out. One hundred and four in-patients were randomly assigned to amisulpride 100 mg/d, amisulpride 300 mg/d, or placebo for six weeks; 85 patients completed the study. RESULTS: Both amisulpride doses were significantly more effective than placebo on the primary evaluation criterion (SANS total score, MANOVA P < 0.02). No significant changes were found in positive symptoms or in extrapyramidal symptoms. CONCLUSIONS: Negative symptoms can be improved by low doses of amisulpride, favouring the hypothesis of dopaminergic hypofunction as one of the causes of negative symptoms.

Adult↗
PubMed1995

[Biological factors and resistance to antidepressive agents].

Concerning depressive disorders, biological factors remain relatively unknown. However, they might first be risk factors for depressive disorders and secondly could decrease the response to antidepressants. We studied hypothyroidism, diabetes and hypothalamic-pituitary-adrenal axis disorders. In terms of neurotransmitters, beta-adrenergic dysfunction may be involved in hypothyroidism and diabetes whereas a serotonergic dysfunction may be involved in hypothalamic-pituitary-adrenal axis disorders.

Animals↗
PubMed1994

Effects of 5-HT1A receptor ligands on a safety signal withdrawal procedure of conflict in the rat.

The present study evaluated in the rat the ability of various 5-HT1A receptor agonists to exert an "anxiolytic-like" release of the suppression of lever pressing for food induced by the withdrawal of a conditioned signal for safety without presentation of a conditioned signal for punishment. During the period associated with the safety signal withdrawal (Saf.CS-/Pun.CS-), control rats exhibited a typical pattern of responding with an initial strong blockade of responding that lessened over the period as presses were rewarded and shocks omitted. The 5-HT1A receptor partial agonists buspirone (0.125-0.5 mg/kg) and 8-(2-[2,3-dihydro-1,4-benzodioxin-2-yl- methylamino]ethyl)-8-azaspiro[4,5]decane-7,9-dione methyl sulfonate (MDL 73005EF; 0.5-2 mg/kg) and the full agonist (+)-4-[N-(5-methoxy-chroman-3-yl)-N-propylamino]-butyl-8- azaspiro[4,5]decane-7,9-dione (S 20499; 0.125-1 mg/kg) produced a robust and dose-related release of pressing during the Saf.CS-/Pun.CS- period. This effect was less marked with ipsapirone (0.125-1 mg/kg). Conversely, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.06-0.25 mg/kg), a full agonist, was completely inactive and did not prevent MDL 73005EF (1-2 mg/kg) or diazepam (0.125 mg/kg) from releasing the suppressed behavior. The specific 5-HT1A antagonist (+)-N-tert-butyl-3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenylpr opa namide [(+)-WAY 100135; 0.25-8 mg/kg] and the beta-adrenoceptor/5-HT1A antagonist (-)-tertatolol (2-8 mg/kg) did not modify the behavioral blockade, nor did (+)-WAY 100135 (2-4 mg/kg) reduce the ability of buspirone (0.25 mg/kg) to enhance responding during the Saf.CS-/Pun.CS- period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Reduction of hyperglycemia after oral glucose load by the new alpha 2-adrenergic receptor antagonist SL 84.0418 in healthy subjects.

OBJECTIVE: To assess the antihyperglycemic activity of a new peripherally acting alpha 2-adrenergic receptor antagonist, SL 84.0418 in healthy volunteers METHODS: This was a randomized, double-blind crossover study. The effects of 10, 50, and 100 mg SL 84.0418 on blood glucose, plasma insulin, C-peptide, glucagon, epinephrine, and norepinephrine were investigated in comparison with placebo and 5 mg glipizide before and after an oral glucose challenge (75 gm). RESULTS: Peak blood glucose and area under the blood-glucose curve were dose-dependently reduced by SL 84.0418; the extent of this reduction was similar with 100 mg SL 84.0418 and glipizide. Glipizide but not SL 84.0418 decreased nadir blood glucose. Plasma insulin and C-peptide were increased by glipizide but not by SL 84.0418. Treatments did not modify plasma glucagon. Plasma epinephrine increased during glipizide treatment and plasma norepinephrine increased during treatment with 50 and 100 mg SL 84.0418. Systolic and diastolic blood pressure were moderately enhanced by 50 and 100 mg SL 84.0418. Adverse effects reflecting alpha 2-adrenergic receptor blockade occurred more frequently with 100 mg SL 84.0418. The adverse effect profile of 50 mg SL 84.0418 was not different from that observed with glipizide. CONCLUSION: The alpha 2-adrenergic receptor antagonist SL 84.0418 dose dependently reduced the increase in blood glucose after glucose load without modification of plasma insulin. It may represent an alternative to sulfonylureas in the treatment of non-insulin-dependent diabetes mellitus. Further studies are needed to assess its efficacy and tolerability in non-insulin-dependent patients.

Administration, Oral↗
PubMed1994

Suspected postprandial hypoglycemia is associated with beta-adrenergic hypersensitivity and emotional distress.

Suspected postprandial (reactive or idiopathic) hypoglycemia is characterized by predominantly adrenergic symptoms appearing after meals rich in carbohydrates and by their rare association with low blood glucose level (< 2.77 mmol/L). We studied heart rate, blood pressure, plasma insulin, C-peptide, and catecholamine responses during a 5-h oral glucose tolerance test in eight patients with suspected postprandial hypoglycemia and eight age-, sex-, and body mass index-matched healthy controls. We also evaluated beta-adrenergic sensitivity by using the isoproterenol sensitivity test. Psychological profile was assessed by the Symptom Checklist (SCL-90R) self-report symptom inventory. Patients with suspected postprandial hypoglycemia had higher beta-adrenergic sensitivity (defined as the dose of isoproterenol required to increase the resting heart rate by 25 beats/min) than controls (mean +/- SEM, 0.8 +/- 0.13 vs. 1.86 +/- 0.25 microgram isoproterenol; P = 0.002). After administration of glucose (75 g) blood glucose, plasma C-peptide, plasma epinephrine, and plasma norepinephrine responses were identical in the two groups, but plasma insulin was higher in the patients (group effect, P = 0.02; group by time interaction, P = 0.0001). Both heart rate and systolic blood pressure were significantly higher (but remained in the normal range) after glucose administration in patients with suspected postprandial hypoglycemia than in controls (group by time interactions, P = 0.004 and 0.0007, respectively). After glucose intake, seven patients had symptoms (palpitations, headache, tremor, generalized sweating, hunger, dizziness, sweating of the palms, flush, nausea, and fatigue), whereas in the control group, one subject reported flush and another palpitations, tremor, and hunger. Analysis of the SCL-90R questionnaire revealed that patients had emotional distress and significantly higher anxiety, somatization, depression, and obsessive-compulsive scores than controls. We may conclude that patients with suspected postprandial hypoglycemia have normal glucose tolerance, increased beta-adrenergic sensitivity, and emotional distress.

Adult↗
PubMed1993

Beta-adrenoceptor blockade potentiates acute exercise-induced release of atrial natriuretic peptide by increasing atrial diameter in normotensive healthy subjects.

The role of atrial distension and/or adrenergic mechanisms in the regulation of atrial natriuretic peptide (ANP) secretion, plasma immunoreactive ANP, norepinephrine (NE), epinephrine (E) and left atrial diameter at rest, during and after graded bicycle exercise has been studies in 8 healthy male subjects after single doses of placebo, tertatolol 5 mg (a non-selective beta-adrenoceptor blocker), prazosin 1 mg (an alpha 1-adrenoceptor antagonist) and their combination. Systolic and diastolic left atrial diameters were measured before, during and just after exercise by bidimensional echocardiography. Exercise caused an increase in plasma ANP, which was greater after tertatolol alone, and tertatolol plus prazosin, than after placebo or prazosin alone; the mean area under the plasma ANP concentration curve was increased by 35% after tertatolol alone, by 45% after tertatolol and prazosin compared to placebo, and by 82% and 94%, respectively when compared to prazosin alone. The rise in plasma ANP was more marked during the post-exercise period: 80% after tertatolol alone, 67% after tertatolol and prazosin compared to placebo, and 133% and 115%, respectively, compared to prazosin alone. The rise in plasma ANP was accompanied by an increase in both the systolic and diastolic atrial diameter, which was also significantly greater after tertatolol alone and the combination than placebo, or after prazosin alone. beta-Adrenoceptor blockade alone did not affect the plasma catecholamine concentrations, but the exercise-induced increase in plasma norepinephrine was significantly potentiated by prazosin and by prazosin plus tertatolol, and that of plasma epinephrine by the drug combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1993

Potentiation by low doses of selected neuroleptics of food-induced conditioned place preference in rats.

Numerous data support the hypothesis that dopamine (DA) plays a crucial role in reward-related processes and in incentive learning in animals and man. The possibility that various neuroleptics exhibiting a high affinity for the dopaminergic D2 (and D3) receptors could reinforce DA transmission was studied using the conditioned place preference paradigm (CPP) in rats. This was done by examining the ability of these compounds to potentiate the reinforcing properties of food in hungry rats subjected to a version of the CPP paradigm which consisted of repeated pairings of food with a single environmental cue, the floor texture of an open field. During the test session when food was no longer available in the open field, the increase in the time spent by drug-free rats on the food-paired texture was assumed to indicate the perceived rewarding value of the food. This time was significantly lengthened when the specific D2 (D3)-receptor antagonists sulpiride (4 mg/kg), amisulpride (0.5, 1 mg/kg) or pimozide (0.03, 0.06 mg/kg) were administered before the food conditioning sessions. Larger doses of these compounds as well as haloperidol, metoclopramide and the non-specific D1-D2 antagonist, chlorpromazine, regardless of the doses tested, did not exhibit this effect, but rather reduced the food-induced CPP, an action usually associated with neuroleptics. The positive effects of amisulpride was reversed by a D1 receptor antagonist, SCH 23390 (0.01 mg/kg). These results suggest that, as with amphetamine (0.5 mg/kg), some D2-specific neuroleptics enhance the incentive value of food in a narrow range of low doses, an effect proposed to reflect a "prohedonic" property.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

A randomized double-blind placebo-controlled study of tropisetron in the treatment of outpatients with generalized anxiety disorder.

The selective 5HT3 antagonist tropisetron was studied in 91 outpatients meeting DSM-III criteria for Generalized Anxiety Disorder. Following a placebo washout period of up to 1 week, one of three active treatments (tropisetron 0.5 mg, 5 mg, or 25 mg daily) or placebo was given for a further 3 weeks. After 7 days treatment termination rates due to inefficacy showed a statistically significant dose-related therapeutic effect of tropisetron. Similar effects were seen on the Hopkins Symptom Check List total score and the Global Impression Scale. The Hamilton Anxiety Scale showed a similar trend which, however, failed to reach statistical significance. At day 21 tropisetron showed significant dose-dependent effects on all anxiety-related outcome measures. The incidence of adverse events was low and the severity generally mild. Most frequent complaints were headache, nausea, constipation and nervousness. Laboratory tests and physical examination performed at baseline and study end showed no significant treatment effects.

Adolescent↗
PubMed1993

Benzodiazepines reverse the anti-immobility effect of antidepressants in the forced swimming test in mice.

The present study provides evidence that, in mice subjected to the forced swimming test, the anti-immobility effect of the tricyclic antidepressants, desipramine and imipramine (16-32 mg/kg) was antagonized by the acute co-administration of a benzodiazepine, diazepam (0.25-2 mg/kg) and lorazepam (0.125 mg/kg). This effect cannot be accounted for by variations in plasma and/or brain levels of each compound since brain and plasma concentrations of desipramine and plasma levels of diazepam and desmethyldiazepam, measured immediately after the swimming test, were not significantly modified by the co-administration. Diazepam (2 mg/kg) also counteracted the reduction of time spent immobile induced by the MAO inhibitors, toloxatone (256 mg/kg) and selegiline (4 mg/kg) and the 5-HT1A receptor agonist, 8-OH-DPAT (1 mg/kg), but not by the psychostimulant, caffeine (32 mg/kg). The sedative neuroleptic, thioridazine (4 mg/kg) was also found to reverse the anti-immobility effect of desipramine whereas the non-benzodiazepine anxiolytics, alpidem (8 mg/kg) and buspirone (0.5 mg/kg) did not. These results indicate that the observed interactions were unlikely to be accounted for by a reduction of the stressful aspect of the situation whereas the participation of some motor or sedative component could not be totally ruled out.

Analysis of Variance↗
PubMed1993

How to improve the risk-benefit ratio of antidepressants.

To improve the risk associated with present antidepressant drugs, it is necessary to choose drugs that are selective and well tolerated in overdose, to look for contraindications, to adapt the dose progressively, to inform and supervise patients adequately, and to deal with risks due to the main pharmacological effects (anxiety, nervousness, sleep disturbances, suicide). With new drugs, risk improvement will probably be the result of greater selectivity. Improvements in efficacy could emerge during the development of new drugs, based on the monoaminergic and non-monoaminergic hypotheses. Much progress could be made, however, by questioning present practices. Optimizing dose, duration of treatment, co-medication, strategies for non-responders, and compliance, decreasing onset of action and targeting patients may help improve the efficacy of present antidepressant drugs.

Antidepressive Agents↗
PubMed1993

Tertatolol potentiates exercise-induced atrial natriuretic peptide release by increasing atrial diameter in healthy subjects.

To evaluate the contribution of atrial distension and/or adrenergic mechanisms in the regulation of atrial natriuretic peptide (ANP) secretion, plasma immunoreactive ANP, norepinephrine (NE), epinephrine (E), and left atrial diameter were measured at rest, during, and after graded upright standardised bicycle exercise in 8 healthy male subjects after single-dose administration of placebo, tertatolol (5 mg), prazosin (1 mg), or combination of tertatolol (5 mg) and prazosin (1 mg). Systolic and diastolic left atrial diameters were measured before, during, and just after exercise by bidimensional echocardiography. Exercise raised plasma ANP concentrations. This rise was greater on tertatolol alone and tertatolol and prazosin than on placebo or prazosin alone: mean area under the plasma ANP concentration curve increased by 35% on tertatolol alone, 45% on tertatolol and prazosin when compared with placebo (p < 0.01), and by 82 and 94%, respectively, when compared with prazosin alone (p < 0.01). The rise in plasma ANP was greater during the postexercise period: 80% for tertatolol alone, 67% for tertatolol and prazosin when compared with placebo (p < 0.01) and 133 and 115%, respectively, when compared with prazosin alone (p < 0.01). The rise in plasma ANP was accompanied by an increase in both systolic and diastolic atrial diameters which was significantly greater on tertatolol alone and on the tertatolol and prazosin combination than on placebo or prazosin alone (p < 0.001). Beta-blockade alone did not affect plasma catecholamine concentrations but exercise-induced increase in plasma NE was significantly potentiated by prazosin and the prazosin and tertatolol combination, and that of plasma E by the prazosin and tertatolol combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1993

Comparison of the effects of zolpidem and triazolam on memory functions, psychomotor performances, and postural sway in healthy subjects.

Zolpidem is a rapid-onset, short-duration imidazopyridine hypnotic drug and is specific agonist of the omega-1 (BZD1) receptors. Its hypnotic characteristics resemble those of triazolam. The aims of this study were to assess the effects of zolpidem on memory (the main objective), psychomotor performances, and postural sway (secondary objectives) in 18 healthy subjects and to compare them with those of triazolam and placebo. Short- and long-term memory (paired words associate and pictures test), psychomotor performances (critical flicker fusion frequency, choice reaction time, digit symbol substitution test), and postural sway were evaluated before and 1.5, 4, 6, and 8 h after the administration of a single dose of zolpidem (10 mg), triazolam (0.25 mg), and placebo. For each assessment, the maximal effect for both hypnotic drugs occurred 1.5 hour after intake. Both drugs decreased psychomotor performance, impaired memory, and increased postural sway. The effects of both hypnotic agents were short lasting, and no alterations were found 6 and 8 hours, respectively, after drug intake. No clinically relevant differences were found between zolpidem and triazolam for memory, psychomotor performance, postural sway, or adverse effects. It may be concluded that zolpidem, like triazolam, impairs short- and long-term memory, psychomotor performances, and postural sway and that these effects are of short duration.

Adult↗
PubMed1992

5-HT3 receptor antagonists reverse helpless behaviour in rats.

The effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and ICS 205-930, were investigated in an animal model of depression, the learned helplessness test. Rats previously subjected to a session of 60 inescapable foot-shocks exhibited a deficit of escape performance in three subsequent shuttle-box sessions. The 5-HT3 receptor antagonists administered i.p. twice daily on a chronic schedule (zacopride 0.03-2 mg/kg per day; ondansetron and ICS 205-930: 0.125-2 mg/kg per day) reduced the number of escape failures at low to moderate daily doses. This effect was not observed with the highest dose(s) of zacopride, ondansetron and ICS 205-930 tested. These results indicate that 5-HT3 antagonists may have effects like those of conventional antidepressants in rats.

Analysis of Variance↗
PubMed1992

Comparative investigation of the effect of moclobemide and toloxatone on monoamine oxidase activity and psychometric performance in healthy subjects.

The effects of moclobemide and toloxatone, two reversible monoamine oxidase-A inhibitors, on biochemical parameters that reflect monoamine metabolism and on psychomotor performance parameters were investigated in a study in 12 healthy volunteers. Treatments were given double-blind in a randomized, placebo-controlled cross-over design, with 1 week wash-out between the treatments. Drugs were given thrice daily in the following doses: moclobemide 150-150-150 mg and toloxatone 400-200-400 mg. All assessments were performed on day 8 under standardized conditions. There was no difference with regard to adverse events between moclobemide and toloxatone: both drugs induced a slight decrease in both supine and standing heart rate. Judged on the basis of the area under the curve, the two MAO-inhibitors reduced the plasma levels of DHPG and HVA, with more pronounced effects for moclobemide than for toloxatone. After moclobemide MAO-A inhibition was almost constant over 24 h, whereas the effect of toloxatone was short lasting after each dose. The same differences were reflected in plasma 5-HIAA concentrations and urinary excretion of 3-methoxytyramine and normetanephine. Neither of the compounds tested had any influence on the memory, vigilance, mood, or sleeping habits of the subjects.

Adult↗