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Nerve Agent–Induced Seizures and Status Epilepticus: Neuroprotective Strategies
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Frederic Doreu, Karine Thibault, Nina Dupuis
Combinations of drugs acting on different targets as well as multifunctional molecules are also considered, mainly antimuscarinics with anti-NMDA properties such as aprophen, azaprophen, benactyzine, biperiden, procyclidine, and trihexyphenidyl (McDonough et al., 1995), and appear to be more effective in blocking NA-induced seizure activity (McDonough and Shih, 1997; Myhrer et al., 2006; Raveh et al., 2003; Shih and McDonough, 2000; Shih et al., 1993, 1999). All of these compounds are antispasmodic, and some (biperiden, procyclidine, and trihexyphenidyl) are clinically used as antiparkinsonian drugs (McDonough and Shih, 1997). Egyptian troops in 1973 were reported to have been equipped with an antidote containing benactyzine, and benactyzine is a component of the Czech military pretreatment Panpal (Kassa, 2006) and the Israeli autoinjector (TAB).
Comparative evaluation of antidotal efficacy of 2-PAM and HNK-102 oximes during inhalation of sarin vapor in Swiss albino mice
Published in Inhalation Toxicology, 2018
Devyani Swami, Ruchi Yadav, A.S.B. Bhaskar, A. Soni, D.P. Nagar, J. Acharya, H.N. Karade, K.P. Singh, Pravin Kumar
Having established better antidotal efficacy of new bis-pyridinium acetamide derivatives (HNK series oximes; HNK-102) over standard antidote 2-PAM against diisopropylphosphorofluoridate (DFP) (Kumar et al., 2014), sarin (Swami et al., 2017), dichlorvos (DDVP) (Kumar et al., 2017), soman and tabun (Kumar et al., 2017) poisoning following subcutaneous route of intoxication, this study was focused to examine HNK-102 vis-a-vis 2-PAM against poisoning induced by inhalation of sarin vapor. Treatment with HNK-102 shifted LCt50 of sarin by 6.54 times upwards; in other words, PI or survival was found to be 6.54 fold compared to 1.58 of 2-PAM. Thus, HNK-102 was found to be four times better antidote against acute inhalation poisoning induced by sarin vapor in the mice, compared to 2-PAM. As reported earlier, a combination therapy of 2-PAM, atropine and benactyzine when administered within 20 s post sarin vapor exposure, increased the survival rate up to 4 × LD50 of sarin dose (Levy et al., 2004) and aerosolized treatment with MMB-4 in combination with atropine, 30 s post sarin vapor exposure, protected the guinea pigs up to 1.2 × LCt50 of sarin (Perkins et al., 2012). In the present study, administration of oxime after one min sarin exposure and again exposing these moribund but treated mouse to sarin vapors for next 14 min, created a real exposure condition where the individual encounter lethal doses of nerve agent at varying period of time and first aid is to be taken as soon as the nerve agent exposure is felt. In actual scenario, once the individual(s) take self-aid of oxime and atropine, the exposure continues until rescued. The present study showed that HNK-102 oxime (if taken) in combination with atropine can act as a savior drug for the next 15 min, may be more, in sarin contaminated environment. The better protection of HNK-102 over 2-PAM, explicitly proves it as a better antidote against acute inhalation poisoning of sarin vapor, in vivo.
Comparative effects of scopolamine and phencynonate on organophosphorus nerve agent-induced seizure activity, neuropathology and lethality
Published in Toxicology Mechanisms and Methods, 2019
Tsung-Ming Shih, Jeffrey A. Koenig, Cindy Acon Chen
In the past several decades, the effects of numerous anticholinergic compounds alone or in conjunction with other treatments after NA poisoning have been evaluated (Wills 1963; Coleman et al. 1962, 1968; Brimblecombe et al. 1970). Using a mouse model, Jovic and Milosevic (1970) examined the efficacy of twelve anticholinergic drugs to determine if atropine was the most effective cholinolytic following exposure to different OP compounds including the NAs soman (GD), tabun (GA), and sarin (GB). They determined that caramiphene and benactyzine had activities comparable or greater than that of atropine after NA exposure. Furthermore, they concluded that the use of atropine as a treatment for OP poisoning could be enhanced with the use of other anticholinergics. Ketchum et al. (1973) evaluated the relative potency and effects of belladonnoid compounds (e.g. atropine and scopolamine) in 158 US Army enlisted men and found that compared to scopolamine (SCP), atropine displays 8–9 times less central potency. Atropine also displayed a slower onset of action than SCP or other synthetic anticholinergics (Ketchum et al. 1973). These studies exposed the limitations of using atropine alone and revealed the need to research additional anticholinergics. In subsequent decades, researchers assessed the effects of purely anticholinergic SCP against GD intoxication using rat or guinea pig models, demonstrating this drug’s efficacy to improve behavioral symptoms and terminate seizure activity (Capacio and Shih 1991; Anderson et al. 1994; Harris et al. 1994; Wetherell 1994; McDonough et al. 1999; Philippens et al. 2000; Meshulam et al. 2001; Wetherell et al. 2002). This efficacy in the rat model, however, was shown to be ablated if SCP treatment was withheld until 40 min after seizure onset (McDonough and Shih 1993). This is the time point associated with a shift of seizure maintenance from the cholinergic to excitatory amino acid neurotransmitter system. SCP was chosen as a testing candidate for our study, not only because it has previously shown efficacy against GD, but also because it has attained FDA approval as a transdermal extended release film for use as a motion sickness medication, smooth muscle spasmodic, and surgical preanesthetic (Clissold and Heel 1985; Nachum et al. 2006).