Biomedical subjects

G Blanchet

Publications and source records attributed to G Blanchet.

At least 19 recordsLinked to original sources

PubMed2000

Stability study of a new antidote drug combination (Atropine-HI-6-Prodiazepam) for treatment of organophosphate poisoning.

The main purpose of this study was to investigate the chemical stability of a new antidote combination for the treatment of organophosphate poisoning. The antidote combination was packed (enclosed) in two plastic compartments separated by a barrier film. One of them contained a powder oxime cholinesterase reactivator (HI-6-monohydrate 1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydro xyimino)meth yl]-pyridinium dichloride). The other contained an anticholinergic (Atropine) and an anticonvulsant (Prodiazepam or Avizafone (L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-glycinamide dihydrochloride) drug in a liquid mixture. The plastic compartments were mounted in an autoinjector device to study the dissolution of HI-6 by ejection of the solution. Drug analysis was performed by high-performance liquid chromatography. The results obtained after 6 months show that this new antidote combination is stable. The amount of each antidote is unchanged during the study. Some known degradation products can be detected in small amounts. The autoinjector mechanism used, gives a complete dissolution of HI-6 powder in the liquid mixture throughout the study.

Antidotes↗

PubMed1997

Efficacy of atropine/pralidoxime/diazepam or atropine/HI-6/prodiazepam in primates intoxicated by soman.

We performed an experiment to characterize the toxicity of soman in cynomolgus monkeys when the organophosphorus intoxication was followed by a treatment with either the three-drug therapy atropine/pralidoxime/diazepam or the association atropine/HI-6/prodiazepam. Clinical, electrophysiological and histological approaches were combined. Our data demonstrate that the protection afforded against soman toxicity was better with the combination atropine/HI-6/prodiazepam compared to atropine/pralidoxime/diazepam. This was observed transiently in term of vigilance and respiratory function of intoxicated animals, but particularly in term of their EEG- and ECG disturbances. Moreover, compared to those treated with atropine/pralidoxine/diazepam, animals treated with atropine/ HI-6/prodiazepam recovered slightly sooner and did not exhibit prostration 2 days after intoxication although their rapidity of movements was not totally restored. The final recovery observed 3 weeks after intoxication was similar for the two groups. The value of the combination of atropine/HI-6/prodiazepam vs atropine/pralidoxime/diazepam to counteract soman toxicity was also confirmed in term of brain neuroprotection since greater lesions were observed with the second three drug treatment three weeks after intoxication.

Animals↗

PubMed1995

Compared toxicity of the potassium channel blockers, apamin and dendrotoxin.

The central toxicities of two potassium ion channel blockers, apamin and alpha-dendrotoxin (DTx), have been compared. Both apamin and dendrotoxin injected intracerebroventricularly produced signs of poisoning, including tremor and ataxia; however, only DTx produced changes in brain electrical activity, with high voltage spikes and epileptiform activity and subsequent brain damage. DTx, but not apamin, increased the amplitude of evoked field potentials and caused repetitive firing of neurones in hippocampal slices. Signs of poisoning following peripheral (intraperitoneal) administration of apamin were similar to those following central administration, including dramatic haemorrhagic effects on the lungs of decedent animals. These results are consistent with dendrotoxin being a centrally-active neurotoxin producing epileptiform activity and brain damage, whilst apamin produces its most significant pathology in the lung, possibly involving a neurogenic mechanism.

Animals↗

PubMed1995

Involvement of non-muscarinic receptors in phosphoinositide signalling during soman-induced seizures.

Previous investigations have indicated that soman-induced convulsions involve the inositol lipid signalling system. We previously reported that 10 min after the onset of seizures, inositol 1,4,5-triphosphate (IP3) build-up was coupled to activation of non-muscarinic receptor subtypes. In the present study, we demonstrate that (1) in addition to muscarinic receptors, histamine H1 subtypes and glutamate metabotropic receptors contribute to the first IP3 increase (first 10 min of seizures) and (2) the histamine H1 subtype and glutamate metabotropic receptors are also involved in the second step of inositol phosphate response (after 10 min of seizures). alpha 1-adrenoceptor and 5-HT2 receptors, known to be coupled to phosphoinositide turnover, did not participate in soman-induced IP3 response. Neurochemical interactions between cholinergic, histamine H1 and glutamate metabotropic systems, responsible of the phosphoinositide hydrolysis under soman are envisaged.

Animals↗

PubMed1994

Modulation of soman-induced neuropathology with an anticonvulsant regimen.

Rat hippocampus and piriform cortex were examined for pathological changes 48 hours after exposure to a convulsant dose of soman. Animals were treated with a low dose of atropine just after soman and were then injected, after 10 or 40 minutes of seizures, with both the anticonvulsant drugs NBQX and TCP. Atropine given alone counteracted the extensive neuronal loss due to soman in both areas without prevention of neuronal suffering. Comparatively, the complete anticonvulsant regimen, given before 40 minutes of seizures, totally prevented hippocampal soman-induced neuropathology. Neurones of piriform cortex were still suffering whatever the time of injection of the drugs. This emphasizes the need for a rapid and definitive anticonvulsant treatment just after soman intoxication to block the subsequent neurotoxic effect of nerve-agent exposure.

Animals↗

PubMed1994

Coadministration of atropine, NBQX and TCP against soman-induced seizures.

The ability of relatively low doses of atropine, NBQX and TCP administered in combination to prevent or stop seizures induced by soman, was studied in rats. While these drugs injected together early after soman prevented the onset of seizures, their delayed concomitant administration after 5 or 30 min of epileptic activity only mildly attenuated the intensity of seizures. Conversely, a total arrest of epileptic activity was observed in 80 to 100% of animals when NBQX and TCP were given together after 5 to 50 min of seizures to atropine pretreated rats. The large time-window for antiepileptic effectiveness of this 'three drug treatment', provided that atropine is administered early after soman, is discussed in relation to reciprocal potentiations of the antiepileptic effects of atropine, NBQX and TCP in combination.

Animals↗

PubMed1994

Antiepileptic effects of NBQX against soman-induced seizures.

The ability of NBQX, a potent antagonist of AMPA glutamatergic receptors, to prevent or stop seizures induced by the organophosphate soman, an irreversible inhibitor of AChE, was studied in rats. NBQX administered concomitantly with soman prevents the onset of seizures (ED50: 29.2 mg kg-1, i.p.). Administered 5 min after the onset of seizures, NBQX greatly reduces the intensity of the epileptic activity. The same decrease of epileptic activity is observed, in the presence of atropine, when the administration of NBQX is delayed 15 min after the onset of seizures. NBQX thus appears as a promising antiepileptic candidate against soman-induced seizures. The roles of AMPA and muscarinic receptors in the onset and propagation of soman-induced epileptic activity are discussed.

Animals↗

PubMed1994

Anticonvulsant and antilethal effects of the phencyclidine derivative TCP in soman poisoning.

The protection afforded by TCP (thienylcylohexylpiperidine), a non-competitive blocker of N-methyl-D-aspartate (NMDA) receptors, against the seizures and lethality produced by 2 x LD50 of soman (62 micrograms/kg, sc), an irreversible inhibitor of cholinesterase, was studied in guinea-pigs. In the presence of additional anticholinergic medication (pyridostigmine: 0.2 mg/kg, sc, 30min prior to soman; atropine sulphate: 5mg/kg, im, 1 min post-soman), TCP pretreatment (2.5mg/kg, im, 30 or 15 min prior to soman) did not generally prevent the appearance of soman-induced status epilepticus but did arrest it after 30-40 min in 80% (TCP-30min) or 100% (TCP-15min) of the convulsing subjects. Moreover, in all subjects treated curatively, TCP was able to interrupt ongoing status epilepticus in approximately 20, 10 or 8 min when it was administered 5, 30 or 60min respectively after the onset of epileptiform tracings on EEG. All of these curatively administered animals survived and recovered remarkably well. On every criteria examined (latency-to-seizure arrest, 24hr-survival rate, clinical recovery), injection of 2.5mg/kg TCP after 90min of seizures appeared slightly less efficient compared to earlier curative administration. Therefore, our study (a) establishes that the previously reported capacity of MK-801 (dibenzocyclohepneimine) to counteract soman toxicity is not unique and could be extended to other non-competitive inhibitors of NMDA receptors; (b) shows that TCP could easily prevent and, above all, interrupt soman-induced seizures; furthermore, TCP appears the first compound ever tested on soman poisoning that still displays satisfactory anticonvulsant activity after such a long duration of initial status epilepticus (90min); therefore, TCP might be of special value for the delayed therapy for soman poisoning; (c) confirms that NMDA receptors are involved in the maintenance of seizures and play an important role in other processes implicated in the overall toxicity (including the lethal respiratory effects) of soman poisoning.

Animals↗

PubMed1994

[Prevention and treatment of status epilepticus induced by soman].

Treatment of the convulsive and neuropathologic actions of organophosphates comprise the major unsolved problem in defending against this class of chemical nerve agents. Understanding and preventing these central actions are important goals of chemical defense research. It is generally accepted that inhibition of acetylcholinesterase results in an accumulation of acetylcholine (ACh) which may be responsible for the acute toxic effects of nerve agents. Although atropine has long been used in the treatment of poisoning, it does not significantly reduce convulsions and seizures nor does it drastically alter the acute toxicity. Inasmuch as antimuscarinic agents do not provide sufficient antidotal activity, it follows that ACh may not be the only transmitter involved in the CNS actions of organophosphates. Benzodiazepines, the most potent of the clinically available anticonvulsants are potentially useful as antidote against nerve agent poisoning. However, significant disadvantages are associated with the im administration of benzodiazepines particularly diazepam the now anticonvulsant fielded drug. The present report was undertaken to compare the effectiveness of thienyl phencyclidine (TCP), a non-competitive antagonist at N-methyl-D-aspartate (NMDA) glutamate receptors, to diazepam both administered im for protection against soman toxicity (convulsions, seizures, incidence on death, brain damage). In a first set of experiments, male wistar rats were pretreated with diazepam (1 mg/kg) given im. Fifteen minutes later 1 x LD50 of soman was injected sc and the incidence of seizures and death were recorded for 24 hr. The therapeutic efficacy of a post-poisoning treatment of diazepam was also studied. In this case diazepam was administered 45 min after the onset of seizures. In a second set of experiments, guinea-pigs were pretreated with pyridostigmine (0.2 mg/kg, sc) in combination with atropine (5 mg/kg, im) 30 min before soman (62 micrograms/kg, sc) and the protective effect of TCP (2.5 mg/kg, im) evaluated when the drug was administered either before soman (15 or 30 min) or after the onset of EEG seizures (5, 30 or 60 min). Pretreatment with diazepam alone did reduce soman-induced seizures but did not reduce mortality of rats. Neuropathology was not observed in non-seizuring rats. When given 45 min after the onset of seizures, diazepam failed to protect against status epilepticus and neuropathology. Thus, diazepam was more effective when given before, rather than after, seizure initiation. Systemic injection of TCP blocked the seizures induced by 2 x LD50 of soman in guinea-pigs pretreated by pyridostigmine and atropine. The anticonvulsant potency of TCP was particularly obvious when the compound was administered curatively.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1993

Transient impairment of the gabaergic function during initiation of soman-induced seizures.

The changes in extracellular gamma-aminobutyric acid (GABA) levels, the modifications in binding capacities of GABA-receptor subtypes A and B and of the Cl- ionophore sites localized in the ionic-channel associated to the GABAA receptors were studied in hippocampus of rats subjected to a convulsive dose of the acetylcholinesterase inhibitor soman. Whereas extracellular GABA levels, just as binding on GABAA and GABAB receptors, were not modified under soman, a significant transient decrease in the binding capacities of the Cl- ionophore site of the GABAA receptor complex occurred within the first 10 min of seizures in CA1, CA3 areas, and in the dentate gyrus with return to basal values after 30 min. Accordingly, a transient decrease of the brain muscimol-gated Cl- influx was observed after 10 min of seizures. An increased ability of diazepam to potentiate the GABAA gated Cl- influx occurred at the same time. Altogether, these data demonstrated that an impairment of the GABAA receptor function occurs at the beginning of seizures. This suggests that a temporary decrease of GABAAergic function may contribute to the onset of seizures.

Animals↗

PubMed1993

Cholinergic activation of phosphoinositide metabolism during soman-induced seizures.

In the present study we investigated the role of the cholinergic pathway in phosphoinositide metabolism activation observed during soman-induced convulsions. We thus studied the effect of atropine sulphate, a muscarinic antagonist (20 mg kg-1, i.p.), on IP3 levels in rat hippocampus. We demonstrated that initially, the increase of IP3 is closely seizure-related. On the other hand, after 10 min of seizures, the IP3 enhancement and the seizure activity are no longer correlated. After 20 min of seizures, atropine failed to inhibit soman-induced IP3 enhancement, suggesting that the activation of another neurotransmitter system(s) linked to PPI turnover succeeds the cholinergic stimulation.

Animals↗

PubMed1993

Neuroprotective activity of glutamate receptor antagonists against soman-induced hippocampal damage: quantification with an omega 3 site ligand.

Previous investigations have indicated that the measurement of omega 3 (peripheral-type benzodiazepine) binding site densities could be of widespread applicability in the localization and quantification of neural tissue damage in the central nervous system. In the first step of the present study, the suitability of this approach for the assessment of soman-induced brain damage was validated. Autoradiographic study revealed marked increases of omega 3 site densities in several brain areas of convulsing rats 2 days after soman challenge. These increases were well-correlated with the pattern and the amplitude of neuropathological alterations due to soman and closely related to both glial reaction and macrophage invasion of the lesioned tissues. We then used this marker to assess, in mouse hippocampus, the neuroprotective activity against soman-induced brain damage of NBQX and TCP which are respective antagonists of non-NMDA and NMDA glutamatergic receptors. Injection of NBQX at 20 or 40 mg/kg 5 min prior to soman totally prevented the neuronal damage. Comparatively, TCP had neuroprotective efficacy when administered at 1 mg/kg 5 min prior to soman followed by a reinjection 1 h after. These results demonstrate that both NBQX and TCP afford a satisfactory neuroprotection against soman-induced brain damage. Since it is known that the neuropathology due to soman is closely seizure-related, the neuroprotective activities of NBQX and TCP are discussed in relation with the respective roles of non-NMDA and NMDA receptors in the onset and maintenance of soman-induced seizures.

Animals↗

PubMed1993

[Evaluation of the anticonvulsant and neuroprotective efficacy of propentofylline during soman poisoning].

The objective of the present study was to evaluate the anticonvulsant and neuroprotective activities of propentofylline against soman, an irreversible acetylcholinesterase inhibitor. In a first step, the ability of propentofylline to inhibit in vitro the hippocampal evoked release of acetylcholine (ACh) and glutamate (Glu), the two major neurotransmitters involved during soman intoxication, was demonstrated. Propentofylline was then given either at single doses from 0.5 to 25 mg/kg or with repetitive injections at 10 mg/kg to mice subjected to soman. Neither tonic-clonic convulsions induced by soman nor subsequent hippocampal damage were reduced in propentofylline-treated mice. This observation suggested that propentofylline did not inhibit the long-lasting hippocampal release of ACh and Glu under soman.

Acetylcholine↗

PubMed1993

Somatotopical effects of local microinjection of GABAergic agents in Deiters nucleus on the posturokinetic responses to cortical stimulation.

The postural adjustments that accompany the limb flexion following stimulation of the motor cortex in the cat are in part at least mediated by the lateral vestibular nucleus (LVN). In fact, inactivation of vestibulospinal (VS) neurons by unilateral injection of GABA agonists into the LVN decreased the early component of the responses in all of the postural limbs without modifying the threshold, latency, or amplitude of the cortically induced flexion movement. Just the opposite result was obtained after injection into the same structure of GABA antagonists. Experiments were performed to find out whether these VS influences were somatotopically organized. Microinjection of 0.25 microL of the GABA-A agonist muscimol or the GABA-B agonist baclofen (at 1.5 to 4 micrograms/microL saline) into the rostroventral part of the LVN (rvLVN) of one side produced hypotonia in the ipsilateral and hypertonia in the contralateral forelimb. The same injection also reduced the early component of the postural responses to cortical stimulation in both forelimbs, but not in the hindlimbs. On the other hand, unilateral injection of the same agents into the dorsocaudal part of the LVN (dcLVN) produced similar effects, but they were limited to the hindlimbs. The results obtained, which lasted for about 2 to 3 h, were not only site-specific but were also dose-dependent. Injection into the rvLVN or dcLVN of 0.25 microL of the GABA-A antagonist bicuculline or the GABA-B antagonist phaclofen (at 8 or 5 micrograms/microL saline) produced localized changes in posture as well as in the post-urokinetic responses to cortical stimulation. These were opposite in sign to those elicited by the corresponding agonists. In conclusion, it appears that: 1) the motor cortex utilizes descending volleys passing through the LVN in order to elicit the early postural adjustments during a cortically induced limb movement; 2) the resulting VS influences are somatotopically organized; 3) the amplitude of these postural responses can be affected by inhibitory influences probably exerted by Purkinje cells of the cerebellar vermis on the related VS neurons through both GABA-A and GABA-B receptors.

Animals↗

PubMed1992

Influence of medial septal cholinoceptive cells on c-Fos-like proteins induced by soman.

The effects of intraseptal application of atropine on c-fos proto-oncogene expression related to soman treatment were studied by immunohistochemistry for c-Fos-like proteins. In control rats, 2 h after the onset of convulsion, c-Fos-like immunoreactivity was intense in the piriform and entorhinal cortices, but also in the cingulate, frontoparietal and retrosplenial cortices. In addition, the staining was moderate in the hypothalamus, amygdala and fascia dentata. The intraseptal application of atropine, which prevented soman-induced convulsions, reduced or even blocked c-Fos-like protein production related to soman treatment. This inhibition of Fos induction was significant in most of the limbic structures but also in non-limbic areas. The data in this study strongly suggest that the cholinergic cells of the medial septal area play a key role in soman-induced seizures, and confirm that c-Fos-like protein induction is closely related to neuronal hyperactivity.

Animals↗

PubMed1992

Changes in hippocampal acetylcholine and glutamate extracellular levels during soman-induced seizures: influence of septal cholinoceptive cells.

The changes in extracellular acetylcholine and glutamate levels were determined, during the course of seizures induced by soman, an irreversible inhibitor of acetylcholinesterase, in the CA1 hippocampal area of rats previously injected with atropine or normal saline into septum. The marked increases observed in soman-treated animals were abolished in rats receiving atropine. These data strongly suggest that, during soman intoxication, septal cholinoceptive cells play a key role in controlling the release of acetylcholine and glutamate in hippocampus. The mechanisms underlying this phenomenon are discussed.

Acetylcholine↗

PubMed1992

Effects of paraldehyde on the convulsions induced by administration of soman in rats.

The ability of paraldehyde, a potent central nervous system depressant, to prevent the convulsions induced by the organophosphate soman, an irreversible inhibitor of acetylcholinesterase, was studied in rats. Paraldehyde (0.1-500 mg/kg, im) administered 10 min before soman (100 micrograms/kg, sc) did not protect against seizures. Co-administered with atropine sulfate (10 mg/kg, im), paraldehyde produced a clear dose-dependent anticonvulsant response. Although this pre-treatment could delay the occurrence of death, it did not produce any change in the soman-induced 24 h mortality rate. Thus, co-administration of paraldehyde and atropine sulfate might constitute a valuable tool to be used against the convulsant consequences of soman poisoning. However, supplementary pre-medication, in addition to paraldehyde and atropine sulfate, remains necessary to improve the antilethal capacity of the pre-treatment.

Animals↗

PubMed1992

GABA receptors in Deiters nucleus modulate posturokinetic responses to cortical stimulation in the cat.

The early component of the postural responses which accompany the limb flexion during unilateral stimulation of the motor cortex in the cat is not of reflex origin, but results from a central command. These postural adjustments are characterized by a decreased force under the limb diagonally opposite to the moving one and an increased force under the other two. Since the lateral vestibular nucleus (LVN) exerts an excitatory influence on ipsilateral limb extensor motoneurons, experiments were performed in cats to establish whether the cortical-induced postural changes were mediated through the LVN. This structure is tonically inhibited by GABAergic synapses originating from Purkinje cells of the cerebellar vermis, so that local microinjection into the LVN of GABA agonists or antagonists should either decrease or increase the spontaneous discharge of their neurons. Unilateral microinjection of 0.25 microliters of the GABA-A agonist muscimol or the GABA-B agonist baclofen (at 2-4 micrograms/microliters saline) into the LVN produced a short-lasting episode of ipsilateral postural hypotonia and contralateral hypertonia, during which the cats were unable to stand on the measurement platform. When, shortly after, some recovery of the postural activity appeared, no changes in threshold, latency or amplitude of the cortical-induced flexion movement were observed; however, the early component of the postural responses decreased in the other three limbs. Moreover, the slope of the response curve of the moving limb remained unmodified, while that of the early component of the postural responses, which involved the remaining limbs, decreased following stimulation of the motor cortex at different stimulus intensities. These effects started a few min after the injection and lasted for about 2-3 h. The effects described above were dose-dependent. Moreover, histological controls indicated that the structure responsible for these postural changes corresponded to the middle part of the LVN. The specificity of the results was shown by the fact that unilateral microinjection of 0.25 microliters of the GABA-A antagonist bicuculline or the GABA-B antagonist phaclofen (at 5-8 micrograms/microliter saline) into the LVN produced a postural asymmetry opposite in sign to that elicited in the same experiments by the corresponding agonists. These injections did not modify the amplitude of the cortical-induced limb flexion, but rather enhanced the amplitude of the early component of the postural responses in the other three limbs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗