Sahar R

References (4)

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

Title : A topical skin protectant against chemical warfare agents - Kadar_2003_Isr.Med.Assoc.J_5_717
Author(s) : Kadar T , Fishbine E , Meshulam J , Sahar R , Amir A , Barness I
Ref : Isr Med Assoc J , 5 :717 , 2003
Abstract : BACKGROUND: Sulfur mustard and VX are potent chemical warfare agents that penetrate rapidly through the skin, causing severe prolonged injuries and sometimes death. OBJECTIVES: To develop a topically applied pretreatment that will act as a barrier and prevent the absorption of these agents through the skin, reducing morbidity and saving life.
METHODS: Several formulations were developed and tested in preclinical animal studies in pigs. The protecting cream was applied as a single application (0.5-1 ml/100 cm2) prior to exposure (10 minutes to 12 hours) to sulfur mustard or VX. Assessment of sulfur mustard-induced skin damage was based on clinical and histologic evaluations. When tested against VX, clinical signs and blood cholinesterase activity were monitored. At the final stage of development, safety studies were conducted in animals and in human volunteers.
RESULTS: The formulation that gave the best results, coded IB1 (under patent application), provided significant protection against a 1 hour exposure to sulfur mustard (droplets or vapor). All the pigs pretreated with IB1 cream survived a 1-4 hour challenge of 2xLD50 VX and did not exhibit any overt clinical signs. Protection was exhibited even when the cream was applied 12 hours (single application) prior to exposure. IB1 was found to be non-irritating in animals and humans. No adverse effects were found in a Phase I clinical study in young healthy volunteers when the cream was applied to around 20% of the skin surface (results presented elsewhere).
CONCLUSIONS: IB1 cream has been shown to be a safe and effective topical skin protectant against the chemical warfare agents sulfur mustard and VX.
ESTHER : Kadar_2003_Isr.Med.Assoc.J_5_717
PubMedSearch : Kadar_2003_Isr.Med.Assoc.J_5_717
PubMedID: 14719467

Title : QTc prolongation and cardiac lesions following acute organophosphate poisoning in rats - Abraham_2001_Proc.West.Pharmacol.Soc_44_185
Author(s) : Abraham S , Oz N , Sahar R , Kadar T
Ref : Proc West Pharmacol Soc , 44 :185 , 2001
Abstract : Sarin and soman induced the following similar effects prolongation of QT interval duration cardiac lesions and immediate and statistically significant decrease in body weight However animals exposed to soman remained underweight and suffered delayed death Thus as sarin produced both cardiac lesions and QT prolongation without exhibiting late death it is unlikely that the late death observed in soman-poisoned rats are attributable to QT prolongation and the occurrence of life-threatening arrhythmias It is postulated that low body weight may precipitate late mortality in soman-exposed rats It is well documented that QT prolongation in the rat is explained in terms of blockade of the Ito potassium channels and the Na+/Ca+2 exchanger Soman and sarin may exert their effect on QT interval duration through non-specific action on these sites As drug-induced QT prolongation in man is mediated by blockade of Ikr potassium channels the data presented in this study may not predict late death in humans in cases of organophosphate intoxication
ESTHER : Abraham_2001_Proc.West.Pharmacol.Soc_44_185
PubMedSearch : Abraham_2001_Proc.West.Pharmacol.Soc_44_185
PubMedID: 11793977

Title : Sarin-induced neuropathology in rats - Kadar_1995_Hum.Exp.Toxicol_14_252
Author(s) : Kadar T , Shapira S , Cohen G , Sahar R , Alkalay D , Raveh L
Ref : Hum Exp Toxicol , 14 :252 , 1995
Abstract : Sarin, a highly toxic cholinesterase (ChE) inhibitor, administered at near 1 LD50 dose causes severe signs of toxic cholinergic hyperactivity in both the peripheral and central nervous systems (CNS). The present study evaluated acute and long-term neuropathology following exposure to a single LD50 dose of sarin and compared it to lesions caused by equipotent doses of soman described previously. Rats surviving 1 LD50 dose of sarin (95 micrograms/kg; IM), were sacrificed at different time intervals post exposure (4 h-90 days) and their brains were taken for histological and morphometric study. Lesions of varying degrees of severity were found in about 70% of the animals, mainly in the hippocampus, piriform cortex, and thalamus. The damage was exacerbated with time and at three months post exposure, it extended to regions which were not initially affected. Morphometric analysis revealed a significant decline in the area of CA1 and CA3 hippocampal cells as well as in the number of CA1 cells. The neuropathological findings, although generally similar to those described following 1 LD50 soman, differed in some features, unique to each compound, for example, frontal cortex damage was specific to soman poisoning. It is concluded that sarin has a potent acute and long-term central neurotoxicity, which must be considered in the design of therapeutic regimes.
ESTHER : Kadar_1995_Hum.Exp.Toxicol_14_252
PubMedSearch : Kadar_1995_Hum.Exp.Toxicol_14_252
PubMedID: 7779455