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Biomedical subjects

G Perrault

Publications and source records attributed to G Perrault.

At least 91 records · Page 5Linked to original sources
PubMed1992

Workers' exposure to isocyanates.

A model of exposure to isocyanates, based on knowledge of industrial processes and starting materials and the results of industrial hygiene surveys, is proposed. This model of exposure suggests the concentration and physical form of airborne isocyanate monomers and oligomers. A new sampling and analytical system was developed that is capable of determining the physical and chemical characteristics of occupational exposure to a variety of aliphatic and aromatic isocyanates as required by the exposure model. The sampling system consisted of a dual-filter 37-mm cassette, in which the first filter captured aerosol phase contaminants and the second captured vapor phase isocyanates through derivatization with 9-(N-methylaminomethyl) anthracene (MAMA). Urea derivative recovery by the sampling system, isocyanate-MAMA reactivity, and linearity of the calibration curve were evaluated in the laboratory. The practicality of the system was evaluated during field trials. Sampling times are reduced to 15 min, and the detection limit for TDI, HDI, and MDI was 1.0 micrograms/m3. A partial validation of the new sampling system was performed for HDI vapor by comparison to a standard method in field trials and for TDI vapor in a controlled test atmosphere. The analytical system may also be used to measure the concentration of oligomeric isocyanates. Airborne concentrations of isocyanates were measured in two foam plants, nine paint shops, and two foundries to verify the usefulness of the model. Exposure in foam plants was predominantly to gaseous monomeric isocyanates. Exposure to oligomer isocyanates was higher than expected in paint shops. Both monomer and oligomer isocyanates were undetectable in foundries.

Air Pollutants, Occupational↗
PubMed1992

Pulmonary clearance of fibrous and angular SiC particulates in the sheep model of pneumoconiosis.

Both angular and fibrous SiC (carborundum) particulates can be emitted by SiC production operations. Carborundum pneumoconiosis is now recognized as an occupational lung disease with specific pathological features. These were previously reproduced in the sheep model of pneumoconiosis with fibrous SiC but not with angular SiC. To further document this question, the pulmonary retention in the sheep of the two morphological types was studied. Animals were injected in the tracheal lobe with equal mass (100 mg) of particulates prepared from SiC materials taken in the field. Particles were measured by analytical transmission electron microscopy in samples of bronchoalveolar lavage fluids (BAL) obtained at months 2, 4, 6 and 8 after the injection. They were also measured in samples of lung parenchyma obtained at month 8. Measurements in BAL and in lung samples both indicated a much lower retention for fibrous than for angular SiC. The retention rate in lung parenchyma at month 8 was 30 times lower for fibrous SiC. The half-life of decrease of concentrations was 3.4 times shorter for fibrous SiC. Other data in the literature support the notion that fine fibres are cleared more effectively than coarser angular particles.

Animals↗
PubMed1992

Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem.

Zolpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors]. The present study investigated whether tolerance and physical dependence develop after repeated treatment with zolpidem as is observed with benzodiazepines. Mice were given zolpidem or the benzodiazepine midazolam (2 x 30 mg/kg, p.o.) for 10 consecutive days. Tolerance to central depressant effects (evaluated by recording spontaneous locomotor activity) and to anticonvulsant effects (measured against pentylenetetrazole-, electroshock- and isoniazid-induced convulsions) was assessed 42 hr after the last administration. A decrease in the latency to isoniazid-induced convulsions was taken as an index of physical dependence and was evaluated 3, 6, 14, 24, 42 and 67 hr after the end of chronic drug treatment. Repeated treatment with midazolam produced tolerance to its sedative and anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3 to 5. Fourteen hr after discontinuation of treatment, spontaneous withdrawal was observed and lasted 3 days. When flumazenil was given 3 or 6 hr after the final midazolam injection, precipitated withdrawal was observed. In contrast, after repeated treatment with zolpidem, there was no change in its ability to produce sedative and anticonvulsant effects. Moreover, neither spontaneous nor flumazenil-induced precipitated withdrawal was observed in zolpidem-treated mice.

Animals↗
PubMed1991

Animal models of anxiety and the development of novel anxiolytic drugs.

1. The behavioural effects of classical anxiolytics such as barbiturates and benzodiazepines have been well characterised. However, recent research has been aimed at the development of novel anxiolytics without problems of sedation, muscle relaxation, amnesia and dependence. 2. A number of novel omega (benzodiazepine) receptor ligands with anxiolytic properties have been described including alpidem, bretazenil, suriclone and abecarnil. Although these compounds share some behavioural effects with older anxiolytic drugs, such as increasing punished drinking, they also show many differences. Their novel profiles may be related to low intrinsic activity or to selectivity for omega receptor subtypes. 3. The possibility that novel anxiolytics may be found among compounds active at serotonin receptors remains a strong hypothesis. Compounds, which, like buspirone, are active at 5HT1A receptors may be anxiolytic as may be antagonists at 5HT2 and 5HT3 receptors. All these compounds have behavioural effects which differ from those of benzodiazepines. 4. In order more effectively to screen for and develop novel anxiolytics it will be necessary to refine behavioural models in the light of feedback from the clinic.

Animals↗
PubMed1990

Differences in pharmacological profiles of a new generation of benzodiazepine and non-benzodiazepine hypnotics.

The hypnotics, quazepam (a benzodiazepine), brotizolam (a thienotriazolodiazepine), zopiclone (a cyclopyrrolone) and zolpidem (an imidazopyridine) have a common ability to bind to the benzodiazepine recognition site (omega receptor) within the GABAA receptor. For this reason we compared their pharmacological profiles in mice. All compounds shared anticonvulsant and central depressant effects. However, the sedative activity of zolpidem appeared at much lower doses than did the anticonvulsant and myorelaxant effects but the opposite was observed with the other hypnotics. In contrast to brotizolam, quazepam and zopiclone, zolpidem did not increase food intake in mice placed in a novel environment, indicating that this drug lacks disinhibitory activity. Moreover the efficacy of zolpidem at the GABAA receptor, as indicated by its activity against convulsions induced by the GABA synthesis inhibitor, isoniazid, was much greater than that of other hypnotics. These results suggest that the hypnoselective properties observed with zolpidem might be related to a high selectivity for the omega 1 recognition site of the GABAA receptor coupled with a very high intrinsic activity.

Animals↗
PubMed1990

Pharmacological and behavioral profile of alpidem as an anxiolytic.

Pharmacological and behavioral studies in mice and rats have shown that the imidazopyridine alpidem possesses anxiolytic activity with a profile which is substantially different from that of benzodiazepines. Thus, in mice, alpidem inhibited marble-burying behavior and enhanced feeding under stressful conditions, as did benzodiazepines; in contrast to these drugs, however, alpidem was inactive against shock-induced fighting and shock-suppressed exploration. In rats, alpidem exerted anticonflict activity in the punished drinking test, but failed to antagonize punishment-induced inhibition of operant behavior. Moreover, in rats trained to discriminate chlordiazepoxide from saline, alpidem did not produce a benzodiazepine-like interoceptive stimulus. Alpidem also produced anticonvulsant effects in a variety of tests sensitive to benzodiazepines. However, the order of potencies against convulsions induced by different convulsive agents was different from that of the benzodiazepines. Alpidem decreased motor performance in the rotarod test and only produced a deficit in muscle strength at doses which were more than 20 times higher than the doses active in anxiolytic tests. Moreover, alpidem did not interfere with the acquisition of conditioned fear, except at very high doses, indicating a weak potential to impair memory. The effects of alpidem were antagonized by flumazenil, indicating that central omega receptors are involved in the action of this drug. The weak sedative effects of alpidem may be attributed to its low intrinsic activity, as demonstrated by its low efficacy in increasing latency to isoniazid-induced convulsions.

Animals↗
PubMed1989

Carborundum pneumoconiosis. Fibers in the mineral activate macrophages to produce fibroblast growth factors and sustain the chronic inflammatory disease.

Carborundum is a synthetic abrasive manufactured through fusion of high grade silica sand and finely ground carbon in an electric furnace at 2,400 degrees C. It had been considered an inert dust until recently. Two recent epidemiologic studies in Quebec have documented an excess of interstitial lung disease in plant workers and some 30 workers have received workman compensation. Histopathologic lesions have been described in four of the workers. To further investigate the carborundum pneumoconiosis, nine groups of eight sheep were exposed once in the tracheal lobe to either 100 ml saline, 100 mg latex beads in 100 ml saline, 100 mg graphite in 100 ml saline, 100 mg carborundum particles in 100 ml saline, 100 mg ashed carborundum particles in 100 ml saline, 100 mg of quartz (Minusil-5) in 100 ml saline, 100 mg crocidolite fibers in 100 ml saline, 100 mg carborundum fibers in 100 ml saline, and 100 mg ashed carborundum fibers in 100 ml saline solutions. The animals had BAL at two-month intervals and autopsy at month 8. The BAL analyses of cellularity, cytotoxicity and fibrogenicity, in association to necropsy histopathology, documented that all particles except for quartz were inert. The two-carborundum fiber samples produced a similar sustained nodular fibrosing alveolitis and crocidolite asbestos fibers produced a peribronchiolar fibrosing alveolitis of comparable severity. Thus, the major bioactive dusts in the carborundum manufacturing process are quartz particles and the carborundum fibers generated in the process. The latter have fibrogenic activities comparable to asbestos fibers of similar size and are likely to contribute to the pathogenesis of the interstitial lung disease of carborundum workers.

Animals↗
PubMed1988

The interaction between zolpidem and beta-CMC: a clue to the identification of receptor sites involved in the sedative effect of zolpidem.

The interaction of beta-CMC, an amino beta-carboline recently described as a selective antagonist of the sedative effect of diazepam, with zolpidem, an imidazopyridine hypnotic, which like beta-CMC binds preferentially to the omega 1 (BZ-1) site of the GABA benzodiazepine chloride channel receptor complex, was investigated. In mice, beta-CMC antagonized the effect of zolpidem against isoniazid-induced convulsions without affecting its activity against convulsions induced by pentylenetetrazole or electroshock. beta-CMC also antagonized the decrease in locomotor activity and the impairment in muscle strength provoked by zolpidem. In rats trained to discriminate zolpidem, beta-CMC antagonized both the interoceptive stimulus and the decrease in the rate of lever pressing produced by zolpidem. This selective antagonism, inhibition of effects of zolpidem exerted by low doses (locomotor activity and isoniazid-induced convulsions) as well as effects produced by high doses (muscle strength) but not those provoked by intermediate doses (pentylenetetrazole and electroshock-induced convulsions), could not be explained by a receptor occupancy hypothesis. These results suggest that the anticonvulsant and sedative effects of zolpidem do not involve the same receptor subtype and that the hypnoselective properties of zolpidem may be linked to its selectivity for the omega 1 (BZ-1) site of the GABAA receptor.

Animals↗
PubMed1988

In vivo interaction of zolpidem with central benzodiazepine (BZD) binding sites (as labeled by [3H]Ro 15-1788) in the mouse brain. Preferential affinity of zolpidem for the omega 1 (BZD1) subtype.

Zolpidem is a novel hypnotic drug which possesses preferential affinity, under in vitro conditions, for the omega 1 (BZD1) subtype of BZD binding sites. In the present study the in vivo interaction of zolpidem with mouse brain BZD binding sites, as labeled by i.v. injection of [3H]Ro 15-1788, has been investigated. Intraperitoneal administration of zolpidem (30 min before sacrifice) decreased in a dose-dependent manner, the retention of [3H]Ro 15-1788 in the cerebral cortex (ED50 = 8.9 mg/kg i.p.); the inhibition by zolpidem was maximal (70%) at 5 to 10 min postinjection and of only 10% 1 hr later. These kinetics are in agreement with its short lasting hypnotic properties. CGS 9896, CL 218,872 and flunitrazepam also prevented the cortical accumulation of [3H]Ro 15-1788 with ED50 values of 12.5, 24 and 0.17 mg/kg i.p., respectively. Zolpidem, like flunitrazepam, diminishes exploratory activity and possesses anticonvulsant and myorelaxant effects in the mouse. However, in contrast to flunitrazepam, the sedative action of zolpidem can be evidenced at a much lower recognition site occupancy (35%) than that needed for myorelaxant or anticonvulsant effects (50-56%). The regional selectivity of zolpidem as an inhibitor of [3H]Ro 15-1788 in vitro and in vivo binding in the mouse brain has been assessed by quantitative autoradiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

The behavioral profile of zolpidem, a novel hypnotic drug of imidazopyridine structure.

The imidazopyridine zolpidem has previously been shown to displace benzodiazepines from their receptors, with a preferential activity at BZ1 sites, and to exert hypnotic activity in man. Zolpidem's pharmacological profile includes anticonvulsant, antipunishment and behavioral depressant actions. However, unlike benzodiazepines, zolpidem exerts sedative actions at relatively low doses. In drug discrimination experiments differences between the internal stimuli produced by chlordiazepoxide and zolpidem were identified. These differences appeared to be qualitative rather than quantitative with the stimulus properties of zolpidem being related to the drug's sedative action. In condition where tolerance developed rapidly to the depressant activity of benzodiazepines little tolerance was seen with zolpidem. The behavioral profile of consistent with the suggestion that this compound may have selective sedative action produced by activity at a sub-type of benzodiazepine receptor.

Animals↗
PubMed1987

Evaluation of occupational exposure to mixed dusts and polycyclic aromatic hydrocarbons in silicon carbide plants.

Workers in the silicon carbide industry have experienced occupational health diseases, particularly lung disorders such as silicosis. The silicon carbide production process mainly employs petroleum coke, sawdust, pure crystalline silica and graphite. Since crystalline silica is present in the occupational environment, the airborne dust content of various polymorphs of silica, especially quartz, cristobalite and tridymite, was determined by X-ray diffraction analysis. The analytical method was modified to eliminate graphite, since it overlaps with the main diffraction plane of quartz. Exploratory field surveys were conducted to identify the minerals present in that occupational environment and to evaluate the validity of the analytical method. The surveys provided information on the mineralogical nature of the dust, its respirable content and the concentration of silica polymorphs. Polycyclic aromatic hydrocarbons also were measured, and the effect of their adsorption on graphite was evaluated.

Air Pollutants, Occupational↗
PubMed1987

Evaluation of worker exposure to polycyclic aromatic hydrocarbons.

A sampling and analytical method was selected to determine the physical and chemical nature of worker exposure to polycyclic aromatic hydrocarbons (PAH). It consists of filter and sorbent tube sampling followed by benzene extraction and analysis of 12 different PAHs with a gas chromatograph connected to a mass spectrometer. This method has undergone extensive field trials. Sampling temperature, inorganic and organic interferences have an effect on the results as they do on the standard gravimetric method of benzene-solubles. A combination of the gravimetric method and the particulate and gaseous concentration profile of 12 PAHs is necessary to obtain an informative evaluation of worker exposure. This approach was used to demonstrate that workers in paving and roofing operations and on some worksites in the steel and silicon carbide industries show an exposure profile that suggests minimal health risk and is largely different from the exposure of workers in aluminum refineries, refractory brick laying and most other worksites in the silicon carbide industry.

Environmental Exposure↗
PubMed1986

Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects.

Zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate] is reported to be a rapid onset, short duration hypnotic that interacts at the benzodiazepine recognition site. The present report establishes the neuropsychopharmacological profile of zolpidem and compares it with those of benzodiazepine hypnotics. Although in mice the effects of zolpidem are qualitatively similar to those of midazolam, triazolam and flunitrazepam, sedation with zolpidem occurs at doses 10 and 20 times lower than those inducing anticonvulsant and myorelaxant effects, respectively. In contrast, the benzodiazepines studied induce sedation at doses causing myorelaxation and which are 2 to 6 times superior to those antagonizing pentetrazole-induced convulsions. In the rat, zolpidem induces sleep (as indicated behaviorally and electrocorticographically) and displays anticonflict activity in a punished drinking paradigm, as do the benzodiazepines. However, whereas benzodiazepine hypnotics induce EEG sleep patterns in curarized rats at doses similar or inferior to those active in the conflict test (in freely moving animals), the hypnotic effect of zolpidem is seen at doses 10 times lower than those producing an anticonflict effect. Moreover, a qualitative difference between the effects of zolpidem and benzodiazepines is observed in electrocorticographic recordings obtained in curarized rats: electrocorticographic hypersynchronization induced by zolpidem is dominated by the energy increase within the 2 to 4 Hz band whereas the benzodiazepines increase predominantly energy levels within the 12 to 14 Hz band. Studies of the sleep-wakefulness cycle in the rat and the cat revealed that hypnotic doses of zolpidem do not alter the pattern of physiological sleep, although elevated doses of the drug decrease paradoxical sleep and increase slow wave sleep. In rats trained to discriminate chlordiazepoxide, zolpidem fails to generalize with the chlordiazepoxide-associated lever indicating that the compound and benzodiazepines do not share the same discriminative stimulus properties. Nevertheless, the anticonvulsant, hypnotic, myorelaxant and anticonflict effects of zolpidem are antagonized by benzodiazepine receptor antagonist Ro 15-1788 and CGS 8216 indicating an involvement of the benzodiazepine recognition site in the action of this drug. The highly selective sedative effect of zolpidem (as compared to myorelaxant and anticonvulsant effects) suggests that it may possess a specificity for certain subtypes of benzodiazepine receptors.

Animals↗
PubMed1985

[Implications of GABAergic synapses in neuropsychiatry].

The use of a multidisciplinary approach--laboratory and clinical pharmacology and experimental and human neurochemistry--has demonstrated that GABA neurons and receptors play a variety of functional roles in the mammalian brain. The present synopsis has been limited to some of the newer aspects of GABA neuron function. Thus there is strong evidence that GABA neurons are involved in the control of cerebral excitability (cf. tables I, II) and in the genesis of at least some seizures states, including certain types of human epilepsy (table III). Furthermore GABA receptor activation can be used to control seizures of diverse etiology and at least one GABA agonist, progabide, is effective in human epilepsy. There is a foundation for the belief that GABA neurons function in the control of affect and emotion. The most convincing evidence is from laboratory and clinical pharmacology studies in depression and models for the development of new antidepressant drugs. GABA agonists act as antidepressants not only in animal models such as learned helplessness, olfactory bulbectomy and the sleep-cycle but also demonstrate an antidepressant action in man. Additionally, the recent studies showing that chronic treatment by antidepressants, induce an increase in 3H-GABA "B" binding strongly support a GABAergic contribution in the mechanism of antidepressant drugs (cf. table IV). There is also some evidence for the hypothesis that GABA neurons and receptors participate in the biology of anxiety, or at least the mechanism of action of anxiolytics. This is based mainly on the known molecular pharmacology of the benzodiazepine receptor and the evidence in animal models for anxiety (table V). However in clinical trials the GABA agonist progabide is only a weak anxiolytic. A major function of GABA neurons and receptors is the regulation of the nigro-striatal dopamine pathway (table VI) and the expression of dopamine receptor mediated events (table VII). This modulation probably occurs via at least 3 mechanisms: a tonic inhibition of dopamine neuron activity regulating dopamine synthesis, turnover and release; a long term modulation controlling striatal dopamine receptor numbers, modification of the expression of dopaminergic transmission distal to the dopaminergic synapse.

4-Aminobutyrate Transaminase↗
PubMed1979

[Perturbation of glycoregulation in irradiated rabbits].

Acute whole body gamma irradiation of the rabbit can induce a latent diabetes revealed by the stimulated hyperglycemia test. The manifestations of this state, and in particular the assimilation coefficient and the development of an insulino-resistance, vary greatly according to sex.

Animals↗