The Experts below are selected from a list of 201 Experts worldwide ranked by ideXlab platform
Maria F. M. Braga - One of the best experts on this subject based on the ideXlab platform.
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Acetylcholinesterase inhibitors (nerve agents) as weapons of mass destruction: History, mechanisms of action, and medical countermeasures.
Neuropharmacology, 2020Co-Authors: Vassiliki Aroniadou-anderjaska, Taiza H. Figueiredo, James P. Apland, Marcio De Araujo Furtado, Maria F. M. BragaAbstract:Abstract Nerve agents are organophosphorus acetylcholinesterase inhibitors. Acute exposure to nerve agents can cause rapid death. In this review, we summarize the history of nerve agent development and use in warfare, the mechanisms by which these agents cause death or long-term brain damage, and the treatments for preventing death or long-term morbidity. The G-series nerve agents, tabun, sarin, soman, ethyl sarin, and cyclosarin, were developed by the Nazis. VX, the best-known of the V-series agents, was synthesized in the 1950's by a British scientist. Little is known about the development of the novichoks (the “A-series”) by the former Soviet Union. Nerve agents were used for the first time in the battlefield by the Iraqi government in the Iran–Iraq War, in the 1980s. The Chemical Weapons Convention, in 1993, banned all chemical weapons production and use, yet, sarin was subsequently used not only in terrorist attacks in Japan, but also recently in the war in Syria. Pyridostigmine has been used as a prophylactic treatment, and bioscavengers are presently investigated as a better alternative. Atropine, along with an oxime, can prevent rapid death from the nerve agent-induced peripheral cholinergic crisis. Treatment with diazepam or midazolam for the cessation of nerve agent-induced status epilepticus cannot protect against brain damage, and, therefore, these benzodiazepines should be replaced by novel anticonvulsants and neuroprotectants. The AMPA/GluK1 receptor antagonist LY293558 (tezampanel) has shown superior antiseizure and neuroprotective efficacy against soman, particularly when administered in combination with Caramiphen, an antagonist of muscarinic and NMDA receptors.
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Electroencephalographic analysis in soman‐exposed 21‐day‐old rats and the effects of midazolam or LY293558 with Caramiphen
Annals of the New York Academy of Sciences, 2020Co-Authors: Marcio De Araujo Furtado, Taiza H. Figueiredo, Vassiliki Aroniadou-anderjaska, James P. Apland, Maria F. M. BragaAbstract:Acute nerve agent exposure induces status epilepticus (SE), which can cause brain damage or death. Research aiming at developing effective therapies for controlling nerve agent-induced SE is commonly performed in adult rats. The characteristics of nerve agent-induced SE in young rats are less clear; relevant knowledge is necessary for developing effective pediatric therapies. Here, we have used electroencephalographic (EEG) recordings and analysis to study seizures in postnatal day 21 rats exposed to 1.2 × LD50 of soman, and compared the antiseizure efficacy of midazolam (MDZ)-currently considered by the Food and Drug Administration to replace diazepam for treating SE in victims of nerve agent exposure-with that of LY293558, an AMPA/GluK1 receptor antagonist, administered in combination with Caramiphen, an antimuscarinic with N-methyl-d-aspartate receptor antagonistic properties. Prolonged SE developed in 80% of the rats and was reflected in behavioral seizures/convulsions. Both MDZ and LY293558 + Caramiphen stopped the SE induced by soman, but there was a significant recurrence of seizures within 24 h postexposure only in the MDZ-treated group, as revealed in the raw EEG data and their representation in the frequency domain using a fast Fourier transform and in spectral analysis over 24 hours. In contrast to the high efficacy of LY293558 + Caramiphen, MDZ is not an effective treatment for SE induced by soman in young animals.
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electroencephalographic analysis in soman exposed 21 day old rats and the effects of midazolam or ly293558 with Caramiphen
Annals of the New York Academy of Sciences, 2020Co-Authors: Marcio De Araujo Furtado, Taiza H. Figueiredo, James P. Apland, Vassiliki Aroniadouanderjaska, Maria F. M. BragaAbstract:Acute nerve agent exposure induces status epilepticus (SE), which can cause brain damage or death. Research aiming at developing effective therapies for controlling nerve agent-induced SE is commonly performed in adult rats. The characteristics of nerve agent-induced SE in young rats are less clear; relevant knowledge is necessary for developing effective pediatric therapies. Here, we have used electroencephalographic (EEG) recordings and analysis to study seizures in postnatal day 21 rats exposed to 1.2 × LD50 of soman, and compared the antiseizure efficacy of midazolam (MDZ)-currently considered by the Food and Drug Administration to replace diazepam for treating SE in victims of nerve agent exposure-with that of LY293558, an AMPA/GluK1 receptor antagonist, administered in combination with Caramiphen, an antimuscarinic with N-methyl-d-aspartate receptor antagonistic properties. Prolonged SE developed in 80% of the rats and was reflected in behavioral seizures/convulsions. Both MDZ and LY293558 + Caramiphen stopped the SE induced by soman, but there was a significant recurrence of seizures within 24 h postexposure only in the MDZ-treated group, as revealed in the raw EEG data and their representation in the frequency domain using a fast Fourier transform and in spectral analysis over 24 hours. In contrast to the high efficacy of LY293558 + Caramiphen, MDZ is not an effective treatment for SE induced by soman in young animals.
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Targeting the glutamatergic system to counteract organophosphate poisoning: A novel therapeutic strategy.
Neurobiology of disease, 2019Co-Authors: Vassiliki Aroniadou-anderjaska, Taiza H. Figueiredo, James P. Apland, Maria F. M. BragaAbstract:Abstract One of the devastating effects of acute exposure to organophosphates, like nerve agents, is the induction of severe and prolonged status epilepticus (SE), which can cause death, or brain damage if death is prevented. Seizures after exposure are initiated by muscarinic receptor hyperstimulation—after inhibition of acetylcholinesterase by the organophosphorus agent and subsequent elevation of acetylcholine—but they are reinforced and sustained by glutamatergic hyperexcitation, which is the primary cause of brain damage. Diazepam is the FDA-approved anticonvulsant for the treatment of nerve agent-induced SE, and its replacement by midazolam is currently under consideration. However, clinical data derived from the treatment of SE of any etiology, as well as studies on the control of nerve agent-induced SE in animal models, have indicated that diazepam and midazolam control seizures only temporarily, their antiseizure efficacy is reduced as the latency of treatment from the onset of SE increases, and their neuroprotective efficacy is limited or absent. Here, we review data on the discovery of a novel anticonvulsant and neuroprotectant, LY293558, an AMPA/GluK1 receptor antagonist. Treatment of soman-exposed immature, young-adult, and aged rats with LY293558, terminates SE with limited recurrence of seizures, significantly protects from brain damage, and prevents long-term behavioral deficits, even when LY293558 is administered 1 h post-exposure. More beneficial effects and complete neuroprotection is obtained when LY293558 administration is combined with Caramiphen, which antagonizes NMDA receptors. Further efficacy studies may bring the LY293558 + Caramiphen combination therapy on the pathway to approval for human use.
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Full Protection Against Soman-Induced Seizures and Brain Damage by LY293558 and Caramiphen Combination Treatment in Adult Rats
Neurotoxicity Research, 2018Co-Authors: James P. Apland, Taiza H. Figueiredo, Vassiliki Aroniadou-anderjaska, Marcio De Araujo Furtado, Maria F. M. BragaAbstract:Acute exposure to nerve agents induces status epilepticus (SE), which causes brain damage or death. LY293558, an antagonist of AMPA and GluK1 kainate receptors is a very effective anticonvulsant and neuroprotectant against soman; however, some neuronal damage is still present after treatment of soman-exposed rats with LY293558. Here, we have tested whether combining LY293558 with an NMDA receptor antagonist can eliminate the residual damage. For this purpose, we chose Caramiphen (CRM), an antimuscarinic compound with NMDA receptor antagonistic properties. Adult male rats were exposed to 1.2 × LD_50 soman, and at 20 min after soman exposure, were injected with atropine + HI-6, or atropine + HI-6 + LY293558 (15 mg/kg), or atropine + HI-6 + LY293558 + CRM (50 mg/kg). We found that (1) the LY293558 + CRM treatment terminated SE significantly faster than LY293558 alone; (2) after cessation of the initial SE, seizures did not return in the LY293558 + CRM-treated group, during 72 h of monitoring; (3) power spectrum analysis of continuous EEG recordings for 7 days post-exposure showed increased delta and decreased gamma power that lasted beyond 24 h post-exposure only in the rats who did not receive anticonvulsant treatment; (4) spontaneous recurrent seizures appeared on day 7 only in the group that did not receive anticonvulsant treatment; (5) significant neuroprotection was achieved by LY293558 administration, while the rats who received LY293558 + CRM displayed no neurodegeneration; (6) body weight loss and recovery in the LY293558 + CRM-treated rats did not differ from those in control rats who were not exposed to soman. The data show that treatment with LY293558 + CRM provides full antiseizure and neuroprotective efficacy against soman.
Lily Raveh - One of the best experts on this subject based on the ideXlab platform.
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Caramiphen edisylate: An optimal antidote against organophosphate poisoning
Toxicology, 2014Co-Authors: Lily Raveh, Arik Eisenkraft, Ben Avi WeissmanAbstract:Abstract Potent cholinesterase inhibitors such as sarin, induce an array of harmful effects including hypersecretion, convulsions and ultimately death. Surviving subjects demonstrate damage in specific brain regions that lead to cognitive and neurological dysfunctions. An early accumulation of acetylcholine in the synaptic clefts was suggested as the trigger of a sequence of neurochemical events such as an excessive outpour of glutamate and activation of its receptors. Indeed, alterations in NMDA and AMPA central receptors’ densities were detected in brains of poisoned animals. Attempts to improve the current cholinergic-based treatment by adding potent anticonvulsants or antiglutamatergic drugs produced unsatisfactory results. In light of recent events in Syria and the probability of various scenarios of military or terrorist attacks involving organophosphate (OP) nerve agent, research should focus on finding markedly improved countermeasures. Caramiphen, an antimuscarinic drug with antiglutamatergic and GABAergic facilitating properties, was evaluated in a wide range of animals and experimental protocols against OP poisoning. Its remarkable efficacy against OP exposure was established both in prophylactic and post-exposure therapies in both small and large animals. The present review will highlight the outstanding neuroprotective effect of Caramiphen as the optimal candidate for the treatment of OP-exposed subjects.
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Anticholinergic and Antiglutamatergic Agents Protect against Soman- Induced Brain Damage and Cognitive Dysfunction
2013Co-Authors: Lily Raveh, David Alkalay, Eran Gilat, Ishai Rabinovitz, Hagar Sonego, Giora Cohen, Ben Avi WeissmanAbstract:Soman, a powerful inhibitor of acetylcholinesterase, causes an array of toxic effects in the central nervous system including convulsions, learning and memory impairments, and, ultimately, death. We report on the protection afforded by postexposure antidotal treatments, combined with pyridostigmine (0.1 mg/kg) pretreatment, against these consequences associated with soman poisoning. Scopolamine (0.1 mg/kg) or Caramiphen (10 mg/kg) were administered 5 min after soman (1.2 LD 50), whereas TAB (i.e., TMB4, atropine, and benactyzine, 7.5, 3, and 1 mg/kg, respectively) was injected in rats concomitant with the development of toxic signs. Atropine (4 mg/kg) was given to the two former groups at the onset of toxic symptoms. Caramiphen and TAB completely abolished electrographic seizure activity while scopolamine treatment exhibited only partial protection. Additionally, no significant alteration in the density of peripheral benzodiazepin
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Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity
Archives of Toxicology, 2013Co-Authors: Shahaf Katalan, Ishai Rabinovitz, Rachel Brandeis, Inbal Egoz, Shlomi Lazar, Ettie Grauer, Eugenia Bloch-shilderman, Lily RavehAbstract:Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions. Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage. Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension and was shown to block kainate-induced convulsions. Magnesium sulfate was evaluated herein as an anticonvulsant against sarin poisoning and its efficacy was compared with the potent anticonvulsants midazolam (MDZ) and Caramiphen (CRM). Rats were exposed to a convulsant dose of sarin (96 μg/kg, im) and 1 min later treated with the oxime TMB4 and atropine to increase survival. Five minutes after initiation of convulsions, MGS, CRM, or MDZ were administered. Attenuation of tonic–clonic convulsions was observed following all these treatments. However, radio-telemetric electro-corticography (ECoG) monitoring demonstrated sustained seizure activity in MGS-injected animals while this activity was completely blocked by MDZ and CRM. This disrupted brain activity was associated with marked increase in brain translocator protein levels, a marker for brain damage, measured 1 week following exposure. Additionally, histopathological analyses of MGS-treated group showed typical sarin-induced brain injury excluding the hippocampus that was partially protected. Our results clearly show that MGS demonstrated misleading features as an anticonvulsant against sarin-induced seizures. This stems from the dissociation observed between overt convulsions and seizure activity. Thus, the presence or absence of motor convulsions may be an unreliable indicator in the assessment of clinical status and in directing adequate antidotal treatments following exposure to nerve agents in battle field or terror attacks.
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Multifunctional drugs as novel antidotes for organophosphates' poisoning.
Toxicology, 2011Co-Authors: Ben Avi Weissman, Lily RavehAbstract:Some organophosphorus compounds (OPs) are nerve agents that continue to concern military personnel and civilians as potential battlefield and terrorist threats. Additionally, OPs are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants induce an array of deleterious effects including respiratory distress, convulsions and ultimately death. A mechanism involving a rapid and potent inhibition of peripheral and central cholinesterases leading to a massive buildup of acetylcholine in synaptic clefts was suggested as the underlying trigger of the toxic events. Indeed, therapy comprised of an acetylcholinesterase reactivator (i.e., oxime) and a cholinergic antagonist (e.g., atropine) is the accepted major paradigm for protection. This approach yields a remarkable survival rate but fails to prevent neurological and behavioral deficits. Extensive research revealed a complex picture consisting of an early activation of several neurotransmitter systems, in which the glutamatergic plays a pivotal role., Data accumulated in recent years support the concept that multi-targeting of pathways including glutamatergic and cholinergic circuits is required for an effective treatment. Drugs that demonstrate the ability to interact with several systems (e.g., Caramiphen) were found to afford a superior protection against OPs as compared to specific antimuscarinic ligands (e.g., scopolamine). Compounds that potently block muscarinic receptors, interact with the NMDA ion channel and in addition are able to modulate σ(1) sites and/or GABAergic transmission seem to represent the emerging backbone for novel antidotes against OP poisoning. Several multifunctional drugs are already used for complex diseases e.g., cancer and depression.
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Therapy against organophosphate poisoning: the importance of anticholinergic drugs with antiglutamatergic properties.
Toxicology and applied pharmacology, 2008Co-Authors: Ben Avi Weissman, Lily RavehAbstract:Potent cholinesterase inhibitors (e.g., soman, sarin), induce a wide range of deleterious effects including convulsions, behavioral impairments and ultimately, death. Due to the likelihood of various scenarios of military or terrorist attacks by these and other chemical weapons, research has to be aimed at finding optimal therapies. Early accumulation of acetylcholine in synaptic clefts was suggested to trigger an array of toxic events including an excessive release of glutamate, culminating in the activation of its receptors. Stimulation of the N-Methyl-D-Aspartate (NMDA) subtype of these receptors was associated with the neuronal injury that initiates organophosphate-induced brain damage. The notion of a stepwise mechanism yielded treatments based on a combination of an immediate administration of enzyme reactivators and anticholinergic drugs. This strategy dramatically increased survival rates but did not abolish convulsions and failed to prevent the ensuing cognitive dysfunction. Efforts to improve this paradigm by adding anticonvulsants or antiglutamatergic drugs with anti-epileptic characteristics produced dubious results. Under these conditions, benactyzine and Caramiphen, agents with anticholinergic and antiglutamatergic properties, provided improved protection when introduced as adjunct agents to oximes, reversible cholinesterase inhibitors and/or specific antimuscarinic drugs such as atropine. In contrast, the specific antimuscarinic drug scopolamine failed to block soman-induced changes in glutamatergic and behavioral parameters even when given prophylactically. These findings along with a large number of additional reports led towards the conclusion that the therapeutic advantage of drugs such as benactyzine and Caramiphen could derive from their ability to modulate central cholinergic and glutamate neurotransmission.
James P. Apland - One of the best experts on this subject based on the ideXlab platform.
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Acetylcholinesterase inhibitors (nerve agents) as weapons of mass destruction: History, mechanisms of action, and medical countermeasures.
Neuropharmacology, 2020Co-Authors: Vassiliki Aroniadou-anderjaska, Taiza H. Figueiredo, James P. Apland, Marcio De Araujo Furtado, Maria F. M. BragaAbstract:Abstract Nerve agents are organophosphorus acetylcholinesterase inhibitors. Acute exposure to nerve agents can cause rapid death. In this review, we summarize the history of nerve agent development and use in warfare, the mechanisms by which these agents cause death or long-term brain damage, and the treatments for preventing death or long-term morbidity. The G-series nerve agents, tabun, sarin, soman, ethyl sarin, and cyclosarin, were developed by the Nazis. VX, the best-known of the V-series agents, was synthesized in the 1950's by a British scientist. Little is known about the development of the novichoks (the “A-series”) by the former Soviet Union. Nerve agents were used for the first time in the battlefield by the Iraqi government in the Iran–Iraq War, in the 1980s. The Chemical Weapons Convention, in 1993, banned all chemical weapons production and use, yet, sarin was subsequently used not only in terrorist attacks in Japan, but also recently in the war in Syria. Pyridostigmine has been used as a prophylactic treatment, and bioscavengers are presently investigated as a better alternative. Atropine, along with an oxime, can prevent rapid death from the nerve agent-induced peripheral cholinergic crisis. Treatment with diazepam or midazolam for the cessation of nerve agent-induced status epilepticus cannot protect against brain damage, and, therefore, these benzodiazepines should be replaced by novel anticonvulsants and neuroprotectants. The AMPA/GluK1 receptor antagonist LY293558 (tezampanel) has shown superior antiseizure and neuroprotective efficacy against soman, particularly when administered in combination with Caramiphen, an antagonist of muscarinic and NMDA receptors.
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Electroencephalographic analysis in soman‐exposed 21‐day‐old rats and the effects of midazolam or LY293558 with Caramiphen
Annals of the New York Academy of Sciences, 2020Co-Authors: Marcio De Araujo Furtado, Taiza H. Figueiredo, Vassiliki Aroniadou-anderjaska, James P. Apland, Maria F. M. BragaAbstract:Acute nerve agent exposure induces status epilepticus (SE), which can cause brain damage or death. Research aiming at developing effective therapies for controlling nerve agent-induced SE is commonly performed in adult rats. The characteristics of nerve agent-induced SE in young rats are less clear; relevant knowledge is necessary for developing effective pediatric therapies. Here, we have used electroencephalographic (EEG) recordings and analysis to study seizures in postnatal day 21 rats exposed to 1.2 × LD50 of soman, and compared the antiseizure efficacy of midazolam (MDZ)-currently considered by the Food and Drug Administration to replace diazepam for treating SE in victims of nerve agent exposure-with that of LY293558, an AMPA/GluK1 receptor antagonist, administered in combination with Caramiphen, an antimuscarinic with N-methyl-d-aspartate receptor antagonistic properties. Prolonged SE developed in 80% of the rats and was reflected in behavioral seizures/convulsions. Both MDZ and LY293558 + Caramiphen stopped the SE induced by soman, but there was a significant recurrence of seizures within 24 h postexposure only in the MDZ-treated group, as revealed in the raw EEG data and their representation in the frequency domain using a fast Fourier transform and in spectral analysis over 24 hours. In contrast to the high efficacy of LY293558 + Caramiphen, MDZ is not an effective treatment for SE induced by soman in young animals.
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electroencephalographic analysis in soman exposed 21 day old rats and the effects of midazolam or ly293558 with Caramiphen
Annals of the New York Academy of Sciences, 2020Co-Authors: Marcio De Araujo Furtado, Taiza H. Figueiredo, James P. Apland, Vassiliki Aroniadouanderjaska, Maria F. M. BragaAbstract:Acute nerve agent exposure induces status epilepticus (SE), which can cause brain damage or death. Research aiming at developing effective therapies for controlling nerve agent-induced SE is commonly performed in adult rats. The characteristics of nerve agent-induced SE in young rats are less clear; relevant knowledge is necessary for developing effective pediatric therapies. Here, we have used electroencephalographic (EEG) recordings and analysis to study seizures in postnatal day 21 rats exposed to 1.2 × LD50 of soman, and compared the antiseizure efficacy of midazolam (MDZ)-currently considered by the Food and Drug Administration to replace diazepam for treating SE in victims of nerve agent exposure-with that of LY293558, an AMPA/GluK1 receptor antagonist, administered in combination with Caramiphen, an antimuscarinic with N-methyl-d-aspartate receptor antagonistic properties. Prolonged SE developed in 80% of the rats and was reflected in behavioral seizures/convulsions. Both MDZ and LY293558 + Caramiphen stopped the SE induced by soman, but there was a significant recurrence of seizures within 24 h postexposure only in the MDZ-treated group, as revealed in the raw EEG data and their representation in the frequency domain using a fast Fourier transform and in spectral analysis over 24 hours. In contrast to the high efficacy of LY293558 + Caramiphen, MDZ is not an effective treatment for SE induced by soman in young animals.
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Targeting the glutamatergic system to counteract organophosphate poisoning: A novel therapeutic strategy.
Neurobiology of disease, 2019Co-Authors: Vassiliki Aroniadou-anderjaska, Taiza H. Figueiredo, James P. Apland, Maria F. M. BragaAbstract:Abstract One of the devastating effects of acute exposure to organophosphates, like nerve agents, is the induction of severe and prolonged status epilepticus (SE), which can cause death, or brain damage if death is prevented. Seizures after exposure are initiated by muscarinic receptor hyperstimulation—after inhibition of acetylcholinesterase by the organophosphorus agent and subsequent elevation of acetylcholine—but they are reinforced and sustained by glutamatergic hyperexcitation, which is the primary cause of brain damage. Diazepam is the FDA-approved anticonvulsant for the treatment of nerve agent-induced SE, and its replacement by midazolam is currently under consideration. However, clinical data derived from the treatment of SE of any etiology, as well as studies on the control of nerve agent-induced SE in animal models, have indicated that diazepam and midazolam control seizures only temporarily, their antiseizure efficacy is reduced as the latency of treatment from the onset of SE increases, and their neuroprotective efficacy is limited or absent. Here, we review data on the discovery of a novel anticonvulsant and neuroprotectant, LY293558, an AMPA/GluK1 receptor antagonist. Treatment of soman-exposed immature, young-adult, and aged rats with LY293558, terminates SE with limited recurrence of seizures, significantly protects from brain damage, and prevents long-term behavioral deficits, even when LY293558 is administered 1 h post-exposure. More beneficial effects and complete neuroprotection is obtained when LY293558 administration is combined with Caramiphen, which antagonizes NMDA receptors. Further efficacy studies may bring the LY293558 + Caramiphen combination therapy on the pathway to approval for human use.
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Full Protection Against Soman-Induced Seizures and Brain Damage by LY293558 and Caramiphen Combination Treatment in Adult Rats
Neurotoxicity Research, 2018Co-Authors: James P. Apland, Taiza H. Figueiredo, Vassiliki Aroniadou-anderjaska, Marcio De Araujo Furtado, Maria F. M. BragaAbstract:Acute exposure to nerve agents induces status epilepticus (SE), which causes brain damage or death. LY293558, an antagonist of AMPA and GluK1 kainate receptors is a very effective anticonvulsant and neuroprotectant against soman; however, some neuronal damage is still present after treatment of soman-exposed rats with LY293558. Here, we have tested whether combining LY293558 with an NMDA receptor antagonist can eliminate the residual damage. For this purpose, we chose Caramiphen (CRM), an antimuscarinic compound with NMDA receptor antagonistic properties. Adult male rats were exposed to 1.2 × LD_50 soman, and at 20 min after soman exposure, were injected with atropine + HI-6, or atropine + HI-6 + LY293558 (15 mg/kg), or atropine + HI-6 + LY293558 + CRM (50 mg/kg). We found that (1) the LY293558 + CRM treatment terminated SE significantly faster than LY293558 alone; (2) after cessation of the initial SE, seizures did not return in the LY293558 + CRM-treated group, during 72 h of monitoring; (3) power spectrum analysis of continuous EEG recordings for 7 days post-exposure showed increased delta and decreased gamma power that lasted beyond 24 h post-exposure only in the rats who did not receive anticonvulsant treatment; (4) spontaneous recurrent seizures appeared on day 7 only in the group that did not receive anticonvulsant treatment; (5) significant neuroprotection was achieved by LY293558 administration, while the rats who received LY293558 + CRM displayed no neurodegeneration; (6) body weight loss and recovery in the LY293558 + CRM-treated rats did not differ from those in control rats who were not exposed to soman. The data show that treatment with LY293558 + CRM provides full antiseizure and neuroprotective efficacy against soman.
Ben Avi Weissman - One of the best experts on this subject based on the ideXlab platform.
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Caramiphen edisylate: An optimal antidote against organophosphate poisoning
Toxicology, 2014Co-Authors: Lily Raveh, Arik Eisenkraft, Ben Avi WeissmanAbstract:Abstract Potent cholinesterase inhibitors such as sarin, induce an array of harmful effects including hypersecretion, convulsions and ultimately death. Surviving subjects demonstrate damage in specific brain regions that lead to cognitive and neurological dysfunctions. An early accumulation of acetylcholine in the synaptic clefts was suggested as the trigger of a sequence of neurochemical events such as an excessive outpour of glutamate and activation of its receptors. Indeed, alterations in NMDA and AMPA central receptors’ densities were detected in brains of poisoned animals. Attempts to improve the current cholinergic-based treatment by adding potent anticonvulsants or antiglutamatergic drugs produced unsatisfactory results. In light of recent events in Syria and the probability of various scenarios of military or terrorist attacks involving organophosphate (OP) nerve agent, research should focus on finding markedly improved countermeasures. Caramiphen, an antimuscarinic drug with antiglutamatergic and GABAergic facilitating properties, was evaluated in a wide range of animals and experimental protocols against OP poisoning. Its remarkable efficacy against OP exposure was established both in prophylactic and post-exposure therapies in both small and large animals. The present review will highlight the outstanding neuroprotective effect of Caramiphen as the optimal candidate for the treatment of OP-exposed subjects.
-
Anticholinergic and Antiglutamatergic Agents Protect against Soman- Induced Brain Damage and Cognitive Dysfunction
2013Co-Authors: Lily Raveh, David Alkalay, Eran Gilat, Ishai Rabinovitz, Hagar Sonego, Giora Cohen, Ben Avi WeissmanAbstract:Soman, a powerful inhibitor of acetylcholinesterase, causes an array of toxic effects in the central nervous system including convulsions, learning and memory impairments, and, ultimately, death. We report on the protection afforded by postexposure antidotal treatments, combined with pyridostigmine (0.1 mg/kg) pretreatment, against these consequences associated with soman poisoning. Scopolamine (0.1 mg/kg) or Caramiphen (10 mg/kg) were administered 5 min after soman (1.2 LD 50), whereas TAB (i.e., TMB4, atropine, and benactyzine, 7.5, 3, and 1 mg/kg, respectively) was injected in rats concomitant with the development of toxic signs. Atropine (4 mg/kg) was given to the two former groups at the onset of toxic symptoms. Caramiphen and TAB completely abolished electrographic seizure activity while scopolamine treatment exhibited only partial protection. Additionally, no significant alteration in the density of peripheral benzodiazepin
-
Multifunctional drugs as novel antidotes for organophosphates' poisoning.
Toxicology, 2011Co-Authors: Ben Avi Weissman, Lily RavehAbstract:Some organophosphorus compounds (OPs) are nerve agents that continue to concern military personnel and civilians as potential battlefield and terrorist threats. Additionally, OPs are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants induce an array of deleterious effects including respiratory distress, convulsions and ultimately death. A mechanism involving a rapid and potent inhibition of peripheral and central cholinesterases leading to a massive buildup of acetylcholine in synaptic clefts was suggested as the underlying trigger of the toxic events. Indeed, therapy comprised of an acetylcholinesterase reactivator (i.e., oxime) and a cholinergic antagonist (e.g., atropine) is the accepted major paradigm for protection. This approach yields a remarkable survival rate but fails to prevent neurological and behavioral deficits. Extensive research revealed a complex picture consisting of an early activation of several neurotransmitter systems, in which the glutamatergic plays a pivotal role., Data accumulated in recent years support the concept that multi-targeting of pathways including glutamatergic and cholinergic circuits is required for an effective treatment. Drugs that demonstrate the ability to interact with several systems (e.g., Caramiphen) were found to afford a superior protection against OPs as compared to specific antimuscarinic ligands (e.g., scopolamine). Compounds that potently block muscarinic receptors, interact with the NMDA ion channel and in addition are able to modulate σ(1) sites and/or GABAergic transmission seem to represent the emerging backbone for novel antidotes against OP poisoning. Several multifunctional drugs are already used for complex diseases e.g., cancer and depression.
-
Therapy against organophosphate poisoning: the importance of anticholinergic drugs with antiglutamatergic properties.
Toxicology and applied pharmacology, 2008Co-Authors: Ben Avi Weissman, Lily RavehAbstract:Potent cholinesterase inhibitors (e.g., soman, sarin), induce a wide range of deleterious effects including convulsions, behavioral impairments and ultimately, death. Due to the likelihood of various scenarios of military or terrorist attacks by these and other chemical weapons, research has to be aimed at finding optimal therapies. Early accumulation of acetylcholine in synaptic clefts was suggested to trigger an array of toxic events including an excessive release of glutamate, culminating in the activation of its receptors. Stimulation of the N-Methyl-D-Aspartate (NMDA) subtype of these receptors was associated with the neuronal injury that initiates organophosphate-induced brain damage. The notion of a stepwise mechanism yielded treatments based on a combination of an immediate administration of enzyme reactivators and anticholinergic drugs. This strategy dramatically increased survival rates but did not abolish convulsions and failed to prevent the ensuing cognitive dysfunction. Efforts to improve this paradigm by adding anticonvulsants or antiglutamatergic drugs with anti-epileptic characteristics produced dubious results. Under these conditions, benactyzine and Caramiphen, agents with anticholinergic and antiglutamatergic properties, provided improved protection when introduced as adjunct agents to oximes, reversible cholinesterase inhibitors and/or specific antimuscarinic drugs such as atropine. In contrast, the specific antimuscarinic drug scopolamine failed to block soman-induced changes in glutamatergic and behavioral parameters even when given prophylactically. These findings along with a large number of additional reports led towards the conclusion that the therapeutic advantage of drugs such as benactyzine and Caramiphen could derive from their ability to modulate central cholinergic and glutamate neurotransmission.
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Efficacy of antidotal treatment against sarin poisoning: the superiority of benactyzine and Caramiphen.
Toxicology and applied pharmacology, 2008Co-Authors: Lily Raveh, Eran Gilat, Ishai Rabinovitz, Ben Avi Weissman, Inbal Egoz, Joseph Kapon, Ziv Stavitsky, Rachel BrandeisAbstract:Sarin, a potent cholinesterase inhibitor, induces an array of toxic effects including convulsions and behavioral impairments. We report here on the protection provided by post-exposure antidotal treatments against a lethal dose of sarin (1.2xLD50) by scopolamine, benactyzine, trihexyphenidyl or Caramiphen, administered 5, 10 or 20 min after the initiation of convulsions. A mixture of the oxime TMB4 and atropine (TA) was injected 1 min following poisoning a paradigm that may represent a scenario reminiscent of a terror incident. Surviving TA-treated rats exhibited marked tonic-clonic convulsions, weight loss, poor clinical status and abnormal cognitive performance as assessed by the Morris water maze. Additionally, a dramatic increase in the density of peripheral benzodiazepine receptors (PBRs), a faithful marker for neuronal damage, was noted. Animals treated 5 min after the development of toxic signs with benactyzine, trihexyphenidyl or Caramiphen demonstrated control levels of PBR values, whereas scopolamine produced binding densities significantly above basal levels. Examined at the 10-min time point, scopolamine and trihexyphenidyl afforded no protection against brain damage and did not differ from TA-injected rats. All four drugs failed to significantly prevent the alterations when applied 20 min after onset of convulsions. Assessment of learning processes yielded similar results, where Caramiphen exibited some protection at the 20-min time point. Our results show that Caramiphen and benactyzine, agents with combined anticholinergic and antiglutamatergic pharmacological profiles, offer considerable shielding against sarin, even when their administration is delayed.
Taiza H. Figueiredo - One of the best experts on this subject based on the ideXlab platform.
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Acetylcholinesterase inhibitors (nerve agents) as weapons of mass destruction: History, mechanisms of action, and medical countermeasures.
Neuropharmacology, 2020Co-Authors: Vassiliki Aroniadou-anderjaska, Taiza H. Figueiredo, James P. Apland, Marcio De Araujo Furtado, Maria F. M. BragaAbstract:Abstract Nerve agents are organophosphorus acetylcholinesterase inhibitors. Acute exposure to nerve agents can cause rapid death. In this review, we summarize the history of nerve agent development and use in warfare, the mechanisms by which these agents cause death or long-term brain damage, and the treatments for preventing death or long-term morbidity. The G-series nerve agents, tabun, sarin, soman, ethyl sarin, and cyclosarin, were developed by the Nazis. VX, the best-known of the V-series agents, was synthesized in the 1950's by a British scientist. Little is known about the development of the novichoks (the “A-series”) by the former Soviet Union. Nerve agents were used for the first time in the battlefield by the Iraqi government in the Iran–Iraq War, in the 1980s. The Chemical Weapons Convention, in 1993, banned all chemical weapons production and use, yet, sarin was subsequently used not only in terrorist attacks in Japan, but also recently in the war in Syria. Pyridostigmine has been used as a prophylactic treatment, and bioscavengers are presently investigated as a better alternative. Atropine, along with an oxime, can prevent rapid death from the nerve agent-induced peripheral cholinergic crisis. Treatment with diazepam or midazolam for the cessation of nerve agent-induced status epilepticus cannot protect against brain damage, and, therefore, these benzodiazepines should be replaced by novel anticonvulsants and neuroprotectants. The AMPA/GluK1 receptor antagonist LY293558 (tezampanel) has shown superior antiseizure and neuroprotective efficacy against soman, particularly when administered in combination with Caramiphen, an antagonist of muscarinic and NMDA receptors.
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Electroencephalographic analysis in soman‐exposed 21‐day‐old rats and the effects of midazolam or LY293558 with Caramiphen
Annals of the New York Academy of Sciences, 2020Co-Authors: Marcio De Araujo Furtado, Taiza H. Figueiredo, Vassiliki Aroniadou-anderjaska, James P. Apland, Maria F. M. BragaAbstract:Acute nerve agent exposure induces status epilepticus (SE), which can cause brain damage or death. Research aiming at developing effective therapies for controlling nerve agent-induced SE is commonly performed in adult rats. The characteristics of nerve agent-induced SE in young rats are less clear; relevant knowledge is necessary for developing effective pediatric therapies. Here, we have used electroencephalographic (EEG) recordings and analysis to study seizures in postnatal day 21 rats exposed to 1.2 × LD50 of soman, and compared the antiseizure efficacy of midazolam (MDZ)-currently considered by the Food and Drug Administration to replace diazepam for treating SE in victims of nerve agent exposure-with that of LY293558, an AMPA/GluK1 receptor antagonist, administered in combination with Caramiphen, an antimuscarinic with N-methyl-d-aspartate receptor antagonistic properties. Prolonged SE developed in 80% of the rats and was reflected in behavioral seizures/convulsions. Both MDZ and LY293558 + Caramiphen stopped the SE induced by soman, but there was a significant recurrence of seizures within 24 h postexposure only in the MDZ-treated group, as revealed in the raw EEG data and their representation in the frequency domain using a fast Fourier transform and in spectral analysis over 24 hours. In contrast to the high efficacy of LY293558 + Caramiphen, MDZ is not an effective treatment for SE induced by soman in young animals.
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electroencephalographic analysis in soman exposed 21 day old rats and the effects of midazolam or ly293558 with Caramiphen
Annals of the New York Academy of Sciences, 2020Co-Authors: Marcio De Araujo Furtado, Taiza H. Figueiredo, James P. Apland, Vassiliki Aroniadouanderjaska, Maria F. M. BragaAbstract:Acute nerve agent exposure induces status epilepticus (SE), which can cause brain damage or death. Research aiming at developing effective therapies for controlling nerve agent-induced SE is commonly performed in adult rats. The characteristics of nerve agent-induced SE in young rats are less clear; relevant knowledge is necessary for developing effective pediatric therapies. Here, we have used electroencephalographic (EEG) recordings and analysis to study seizures in postnatal day 21 rats exposed to 1.2 × LD50 of soman, and compared the antiseizure efficacy of midazolam (MDZ)-currently considered by the Food and Drug Administration to replace diazepam for treating SE in victims of nerve agent exposure-with that of LY293558, an AMPA/GluK1 receptor antagonist, administered in combination with Caramiphen, an antimuscarinic with N-methyl-d-aspartate receptor antagonistic properties. Prolonged SE developed in 80% of the rats and was reflected in behavioral seizures/convulsions. Both MDZ and LY293558 + Caramiphen stopped the SE induced by soman, but there was a significant recurrence of seizures within 24 h postexposure only in the MDZ-treated group, as revealed in the raw EEG data and their representation in the frequency domain using a fast Fourier transform and in spectral analysis over 24 hours. In contrast to the high efficacy of LY293558 + Caramiphen, MDZ is not an effective treatment for SE induced by soman in young animals.
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Targeting the glutamatergic system to counteract organophosphate poisoning: A novel therapeutic strategy.
Neurobiology of disease, 2019Co-Authors: Vassiliki Aroniadou-anderjaska, Taiza H. Figueiredo, James P. Apland, Maria F. M. BragaAbstract:Abstract One of the devastating effects of acute exposure to organophosphates, like nerve agents, is the induction of severe and prolonged status epilepticus (SE), which can cause death, or brain damage if death is prevented. Seizures after exposure are initiated by muscarinic receptor hyperstimulation—after inhibition of acetylcholinesterase by the organophosphorus agent and subsequent elevation of acetylcholine—but they are reinforced and sustained by glutamatergic hyperexcitation, which is the primary cause of brain damage. Diazepam is the FDA-approved anticonvulsant for the treatment of nerve agent-induced SE, and its replacement by midazolam is currently under consideration. However, clinical data derived from the treatment of SE of any etiology, as well as studies on the control of nerve agent-induced SE in animal models, have indicated that diazepam and midazolam control seizures only temporarily, their antiseizure efficacy is reduced as the latency of treatment from the onset of SE increases, and their neuroprotective efficacy is limited or absent. Here, we review data on the discovery of a novel anticonvulsant and neuroprotectant, LY293558, an AMPA/GluK1 receptor antagonist. Treatment of soman-exposed immature, young-adult, and aged rats with LY293558, terminates SE with limited recurrence of seizures, significantly protects from brain damage, and prevents long-term behavioral deficits, even when LY293558 is administered 1 h post-exposure. More beneficial effects and complete neuroprotection is obtained when LY293558 administration is combined with Caramiphen, which antagonizes NMDA receptors. Further efficacy studies may bring the LY293558 + Caramiphen combination therapy on the pathway to approval for human use.
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Full Protection Against Soman-Induced Seizures and Brain Damage by LY293558 and Caramiphen Combination Treatment in Adult Rats
Neurotoxicity Research, 2018Co-Authors: James P. Apland, Taiza H. Figueiredo, Vassiliki Aroniadou-anderjaska, Marcio De Araujo Furtado, Maria F. M. BragaAbstract:Acute exposure to nerve agents induces status epilepticus (SE), which causes brain damage or death. LY293558, an antagonist of AMPA and GluK1 kainate receptors is a very effective anticonvulsant and neuroprotectant against soman; however, some neuronal damage is still present after treatment of soman-exposed rats with LY293558. Here, we have tested whether combining LY293558 with an NMDA receptor antagonist can eliminate the residual damage. For this purpose, we chose Caramiphen (CRM), an antimuscarinic compound with NMDA receptor antagonistic properties. Adult male rats were exposed to 1.2 × LD_50 soman, and at 20 min after soman exposure, were injected with atropine + HI-6, or atropine + HI-6 + LY293558 (15 mg/kg), or atropine + HI-6 + LY293558 + CRM (50 mg/kg). We found that (1) the LY293558 + CRM treatment terminated SE significantly faster than LY293558 alone; (2) after cessation of the initial SE, seizures did not return in the LY293558 + CRM-treated group, during 72 h of monitoring; (3) power spectrum analysis of continuous EEG recordings for 7 days post-exposure showed increased delta and decreased gamma power that lasted beyond 24 h post-exposure only in the rats who did not receive anticonvulsant treatment; (4) spontaneous recurrent seizures appeared on day 7 only in the group that did not receive anticonvulsant treatment; (5) significant neuroprotection was achieved by LY293558 administration, while the rats who received LY293558 + CRM displayed no neurodegeneration; (6) body weight loss and recovery in the LY293558 + CRM-treated rats did not differ from those in control rats who were not exposed to soman. The data show that treatment with LY293558 + CRM provides full antiseizure and neuroprotective efficacy against soman.