Bloch-Shilderman E


Full name : Bloch-Shilderman Eugenia

First name : Eugenia

Mail : Dept. of Pharmacology\; Israel Institute for Biological Research\; Lerer 17 st\; POB 19\; Ness Ziona\; 74100

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Country : Israel

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Phone : 97289381611

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References (10)

Title : Catch-up therapy: combining antidotal treatment with dermal application of AHA following percutaneous VX poisoning in the domestic swine - Bloch-Shilderman_2023_Arch.Toxicol__
Author(s) : Bloch-Shilderman E , Nili U , Nahum V , Smolkin B , Ashkenazi N
Ref : Archives of Toxicology , : , 2023
Abstract : Low-volatility organophosphorus chemical warfare agents (OP CWAs) are cholinesterase inhibitors which easily absorb into the skin, leading to the formation of a dermal depot from which they slowly enter the bloodstream. This leads to sustained cholinergic hyperstimulation, which if untreated may lead to death. However, current available countermeasures are not adequate to neutralize the agent residing in the dermal depot. Accordingly, we evaluated the efficacy of the potassium salt of acetohydroxamic acid (880 mg/ml in DMSO/H(2)O 1:4, AHAK), as a potential "catch-up" therapy lotion intended to neutralize the dermal depot, by penetrating the skin and decomposing it before it reaches the bloodstream. To that end, we compared the clinical outcome following skin surface decontamination combined with antidotal treatment, to that following the same antidotal treatment combined with dermal application of AHAK at the site of VX exposure, against percutaneous poisoning by a lethal neat dose (4 mg/kg) of the low-volatility nerve agent VX, in an unanesthetized swine model. Following skin surface decontamination and antidotal treatment, recurrence of intoxication signs and a prolonged recovery time were observed. In contrast, similar antidotal treatment combined with dermal application of AHAK significantly reduced intoxication signs recurrences and accordingly medical supervision duration needed, paralleled by a significantly faster recovery of whole blood cholinesterase activity. An initial evaluation demonstrated the safety of prolonged whole-body AHAK application. Hence, the AHAK lotion may act as an efficient "catch-up" therapy against percutaneous poisoning by low-volatility OP CWAs, improving the clinical outcome and reducing the burden on medical staff.
ESTHER : Bloch-Shilderman_2023_Arch.Toxicol__
PubMedSearch : Bloch-Shilderman_2023_Arch.Toxicol__
PubMedID: 37610476

Title : Repetitive antidotal treatment is crucial in eliminating eye pathology, respiratory toxicity and death following whole-body VX vapor exposure in freely moving rats - Bloch-Shilderman_2019_Arch.Toxicol_93_1365
Author(s) : Bloch-Shilderman E , Yacov G , Cohen L , Egoz I , Gutman H , Gez R , Rabinovitz I , Nili U
Ref : Archives of Toxicology , 93 :1365 , 2019
Abstract : Exposure to the chemical warfare nerve agent VX is extremely toxic, causing severe cholinergic symptoms. If not appropriately treated, death ultimately ensues. Based on our previously described whole-body vapor exposure system, we characterized in detail the clinical outcome, including respiratory dynamics, typical of whole-body exposure to lethal doses of VX vapor in freely moving rats. We further evaluated the efficacy of two different antidotal regimens, one comprising a single and the other repeated administration of antidotes, in countering the toxic effects of the exposure. We show that a 15 min exposure to air VX concentrations of 2.34-2.42 mg/m(3) induced a late (15-30 min) onset of obvious cholinergic signs, which exacerbated over time, albeit without convulsions. Marked eye pathology was observed, characterized by pupil constriction to pinpoint, excessive lacrimation with red tears (chromodacryorrhea) and corneal damage. Respiratory distress was also evident, characterized by a three-fourfold increase in Penh values, an estimate of lung resistance, and by lung and diaphragm histological damage. A single administration of TAB (the oxime TMB-4, atropine and the anticholinergic and antiglutamatergic benactyzine) at the onset of clinical signs afforded only limited protection (66% survival), with clinical deterioration including weight loss, chromodacryorrhea, corneal damage, increased airway resistance and late death. In contrast, a combined therapy of TAB at the onset of clinical signs and repeated administration of atropine and toxogonin (ATOX) every 3-5 h, a maximum of five i.m. injections, led to 100% survival and a prompt recovery, accompanied by neither the above-described signs of eye pathology, nor by bronchoconstriction and respiratory distress. The necessity of recurrent treatments for successful elimination of VX vapor toxicity strongly supports continuous penetration of VX following termination of VX vapor exposure, most likely from a VX reservoir formed in the skin due to the exposure. This, combined with the above-described eye and respiratory pathology and absence of convulsions, are unique features of whole-body VX vapor exposure as compared to whole-body vapor exposure to other nerve agents, and should accordingly be considered when devising optimal countermeasures and medical protocols for treatment of VX vapor exposure.
ESTHER : Bloch-Shilderman_2019_Arch.Toxicol_93_1365
PubMedSearch : Bloch-Shilderman_2019_Arch.Toxicol_93_1365
PubMedID: 30729277

Title : Determining a threshold sub-acute dose leading to minimal physiological alterations following prolonged exposure to the nerve agent VX in rats - Bloch-Shilderman_2018_Arch.Toxicol_92_873
Author(s) : Bloch-Shilderman E , Rabinovitz I , Egoz I , Yacov G , Allon N , Nili U
Ref : Archives of Toxicology , 92 :873 , 2018
Abstract : VX, a potent inhibitor of cholinesterase (ChE), is considered as one of the most toxic, persistent and least volatile nerve agents. VX is absorbed in various environmental surfaces and is gradually released long after its initial dispersal. Its toxicity is mainly caused by disrupting central and peripheral cholinergic nervous system activity, leading to potential long-term detrimental effects on health. The primary objective of the present study was to assess the threshold VX dose leading to minimal physiological alterations following prolonged VX exposure. Characterization of such a threshold is crucial for dealing with unresolved operative dilemmas such as when it is safe enough to resettle a population that has been evacuated from a VX-contaminated area. Rats, continuously exposed to various doses of VX (0.225-45 microg/kg/day) for 4 weeks via implanted mini-osmotic pumps, showed a dose-dependent and continuous decrease in ChE activity in whole blood, brain and muscles, ranging between 20 and 100%. Exposure to 13.5 microg/kg/day led to a stable low ChE activity level (~ 20%), accompanied by transient and negligible electrocorticogram spectral power transformations, especially in the theta and alpha brain wave frequencies, and a significant decrease in total brain M2 receptor density. These changes were neither accompanied by observable signs of intoxication nor by changes in motor function, circadian rhythm or TSPO level (a reliable marker of brain damage). Following exposure to lower doses of 2.25 and 0.225 microg/kg/day, the only change measured was a reduction in ChE activity of 60 and 20%, respectively. Based on these results, we delineate ChE inhibition as the physiological measure most susceptible to alterations following prolonged VX exposure, and determine for the first time the threshold sub-acute VX dose for minimal physiological effects (up to 20% reduction in ChE activity) in the rat as 0.225 microg/kg/day.
ESTHER : Bloch-Shilderman_2018_Arch.Toxicol_92_873
PubMedSearch : Bloch-Shilderman_2018_Arch.Toxicol_92_873
PubMedID: 29127449

Title : Propagation of damage in the rat brain following sarin exposure: Differential progression of early processes - Lazar_2016_Toxicol.Appl.Pharmacol_310_87
Author(s) : Lazar S , Egoz I , Brandeis R , Chapman S , Bloch-Shilderman E , Grauer E
Ref : Toxicol Appl Pharmacol , 310 :87 , 2016
Abstract : Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80mug/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6h post exposure while TSPO receptor density increased only at 24h. In all brain regions tested, bax mRNA decreased 1h post exposure followed by an increase 24h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous "first response" mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention.
ESTHER : Lazar_2016_Toxicol.Appl.Pharmacol_310_87
PubMedSearch : Lazar_2016_Toxicol.Appl.Pharmacol_310_87
PubMedID: 27639427

Title : Efficacy assessment of a combined anticholinergic and oxime treatment against topical sarin-induced miosis and visual impairment in rats - Gore_2014_Br.J.Pharmacol_171_2364
Author(s) : Gore A , Bloch-Shilderman E , Egoz I , Turetz J , Brandeis R
Ref : British Journal of Pharmacology , 171 :2364 , 2014
Abstract : BACKGROUND AND PURPOSE: Eye exposure to the organophosphorus (OP) irreversible cholinesterase inhibitor sarin results in long-term miosis and impaired visual function. We have previously shown that tropicamide is better at ameliorating this insult than topical atropine or cyclopentolate. However, to minimize side effects associated with repeated tropicamide applications and high treatment doses, we evaluated the effects of oximes (ChE re-activators) alone and combined with tropicamide at ameliorating OP-induced ocular impairments. EXPERIMENTAL APPROACH: Rats were topically exposed to sarin, followed by topical treatment with various oximes alone or in combination with tropicamide. Pupil width and light reflex were measured by an infrared-based digital photograph system, while visual performance was assessed by employing the cueing version of the Morris water maze (MWM). KEY
RESULTS: Oxime treatment following sarin ocular exposure induced a slow persistent pupil widening with efficacy in the order of HLo-7 > HI-6 > obidoxime = TMB-4(Trimedoxime) = MMB-4. In the light reflex test, the ability of the iris to contract following oxime treatment was mostly impaired at 1 h and was back to normal at 4 h following sarin exposure. All oxime treatments ameliorated the sarin-induced visual impairment as tested in the visual task (MWM). The combined topical treatment of tropicamide with an oxime induced a rapid improvement in pupil widening, light reflex and visual performance, and enabled a reduction in tropicamide dose. CONCLUSIONS AND IMPLICATIONS: The use of tropicamide combined with an oxime should be considered as the topical treatment of choice against the toxic effects of ocular OP exposure.
ESTHER : Gore_2014_Br.J.Pharmacol_171_2364
PubMedSearch : Gore_2014_Br.J.Pharmacol_171_2364
PubMedID: 24428128

Title : Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity - Katalan_2013_Arch.Toxicol_87_347
Author(s) : Katalan S , Lazar S , Brandeis R , Rabinovitz I , Egoz I , Grauer E , Bloch-Shilderman E , Raveh L
Ref : Archives of Toxicology , 87 :347 , 2013
Abstract : 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 mug/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.
ESTHER : Katalan_2013_Arch.Toxicol_87_347
PubMedSearch : Katalan_2013_Arch.Toxicol_87_347
PubMedID: 23052190

Title : Efficacy assessment of various anticholinergic agents against topical sarin-induced miosis and visual impairment in rats - Gore_2012_Toxicol.Sci_126_515
Author(s) : Gore A , Brandeis R , Egoz I , Peri D , Turetz J , Bloch-Shilderman E
Ref : Toxicol Sci , 126 :515 , 2012
Abstract : Eye exposure to the organophosphorus (OP) irreversible acetylcholinesterase inhibitor sarin results in long-term miosis and reduction in visual function. Anticholinergic drugs, such as atropine or homatropine, which are used topically in order to counter these effects may produce mydriasis and partial cycloplegia, which may worsen visual performance. This study was aimed to test the efficacy of short-acting anticholinergic drugs against sarin-induced miosis and visual impairment, which will minimally insult vision. Long-Evans rats, exposed topically to various sarin doses from 0 to 10 ug, showed a dose-dependent miosis, which returned to pre-exposure levels within 24-48 h. Tropicamide treatment rapidly widened the miotic effect to a different extent depending on time following treatment and dosage given. Cyclopentolate, however, showed a delayed response that finally widened the pupils in a dose-dependent manner. Atropine treatment showed a rapid widening of the pinpoint pupils exceeding baseline level finally causing mydriasis. Light reflex test showed that the contraction ability of the iris following atropine treatment was impaired, as opposed to the use of tropicamide which facilitated the iris contraction, similar to control. Finally, tropicamide and atropine treatments ameliorated the visual impairment, as opposed to cyclopentolate, which worsened visual performance. Considering that tropicamide treatment against sarin exposure did not cause mydriasis nor did it impair the iris contraction flexibility as a response to light, the use of this drug should be taken into consideration as a first-choice topical treatment against OP intoxication.
ESTHER : Gore_2012_Toxicol.Sci_126_515
PubMedSearch : Gore_2012_Toxicol.Sci_126_515
PubMedID: 22247005

Title : Subchronic exposure to low-doses of the nerve agent VX: physiological, behavioral, histopathological and neurochemical studies - Bloch-Shilderman_2008_Toxicol.Appl.Pharmacol_231_17
Author(s) : Bloch-Shilderman E , Rabinovitz I , Egoz I , Raveh L , Allon N , Grauer E , Gilat E , Weissman BA
Ref : Toxicol Appl Pharmacol , 231 :17 , 2008
Abstract : The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 microg/kg/day, 0.05 LD(50)) for three months via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition (approximately 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction (approximately 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures.
ESTHER : Bloch-Shilderman_2008_Toxicol.Appl.Pharmacol_231_17
PubMedSearch : Bloch-Shilderman_2008_Toxicol.Appl.Pharmacol_231_17
PubMedID: 18485435

Title : Transient and reversible nephrotoxicity of sarin in rats - Bloch-Shilderman_2007_J.Appl.Toxicol_27_189
Author(s) : Bloch-Shilderman E , Levy A
Ref : J Appl Toxicol , 27 :189 , 2007
Abstract : Organophosphate (OP) poisoning, which inhibits cholinesterase activity, leads to severe cholinergic symptoms. Effective and quick management of these symptoms is considered critical to the clinical outcome. Acute renal damage following exposure to OP insecticides has been reported. Similar complications might occur following exposure to OP nerve agents, however, this subject has been studied only sporadically. In the present study, the effect of the nerve agent sarin on renal function was examined in rats. A single dose of sarin ( approximately 0.9 LD(50)) led to a significant reduction (of 45%) in renal function during the first 2 days post exposure, as exhibited by evaluation of the glomerular filtration rate, through measuring the clearance of ( 99m)Tc-DTPA. The urine volume was reduced by 50%, the urine specific gravity increased to 104% of the control value and massive hematuria and glucosuria were recorded 24-48 h post exposure. In addition, around 60% decrease in urine electrolytes was monitored during the first 2 days following exposure, with a recovery after 8 days. Post mortem gross inspection of the bladder, 24 h post exposure, revealed severe edema and hemorrhage. Treatment with the muscarinic antagonist atropine and the oxime TMB-4, at excessive doses administered 1 min post exposure, did not prevent most renal impairments. It has been concluded that sarin caused an acute renal dysfunction, possibly accompanied by bladder damage. These impairments were reversible, recovered spontaneously within 3-8 days, and were probably related to the state of shock and hypovolemia caused by the poisoning. However, if renal impairments are left unattended, they might contribute to the overall toxic manifestation and as a result aggravate the clinical state of intoxicated casualties.
ESTHER : Bloch-Shilderman_2007_J.Appl.Toxicol_27_189
PubMedSearch : Bloch-Shilderman_2007_J.Appl.Toxicol_27_189
PubMedID: 17154277

Title : Subcellular alterations of protein kinase C isozymes in the rat brain after organophosphate poisoning - Bloch-Shilderman_2005_J.Pharmacol.Exp.Ther_313_1082
Author(s) : Bloch-Shilderman E , Kadar T , Levy A , Sahar R , Rabinovitz I , Gilat E
Ref : Journal of Pharmacology & Experimental Therapeutics , 313 :1082 , 2005
Abstract : The protein kinase C (PKC) signaling pathway has been associated with modulation of N-metyl-D-aspartate receptor activity, motor behavior, learning, and memory, all of which are severely impaired in organophosphate (OP) intoxication. Nevertheless, the role of PKC in OP intoxication is largely unknown. The present study attempted to characterize alterations in the immunoreactivity levels of PKC isozymes expressed in different brain areas in the rat following exposure to the nerve agent sarin (1x LD(50)). Furthermore, possible neuroprotective effect of selective PKC regulating peptide after such insult was evaluated. The results indicated that a significant reduction in the immunoreactivity level of the conventional betaII-PKC and the atypical zeta-PKC was observed in frontal cortex up to 24 h postsarin and in the striatum up to 5 days postsarin exposure. This reduction was in contrast to the increase in the immuno-reactivity level of both isozymes seen in the hippocampus or thalamus. Treatment with the anticonvulsant midazolam (0.5 mg/kg) 10 min postsarin exposure markedly reduced zeta-PKC immunoreactivity level and betaII-PKC in the membrane fractions in the hippocampus. betaII-PKC peptide (380 ng/kg), known to inhibit PKC translocation and activation, attenuated sarin-induced neuropathology. These observations suggest a role for both conventional and atypical PKC isozymes in OP-induced neuropathy in the rat and further support their involvement in cell death.
ESTHER : Bloch-Shilderman_2005_J.Pharmacol.Exp.Ther_313_1082
PubMedSearch : Bloch-Shilderman_2005_J.Pharmacol.Exp.Ther_313_1082
PubMedID: 15716382