The inactivation by oximes of sarin and soman in plasma from various species. I. The influence of diacetylmonoxime on the hydrolysis of sarin.
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Protection from quinidine or physostigmine against in vitro inhibition by sarin of acetylcholinesterase activity.
We have studied the relative effectiveness of quinidine and physostigmine in protecting against the inhibition of acetylcholinesterase (AChE) by sarin, an organophosphate (OP) compound. The protective effects of these compounds were studied in vitro in both synaptosomal and soluble samples obtained from various regions of sarin-administered or control isolated, perfused canine brain. Although AChE activities in the sarin-administered brain were substantially lower than in the control brain, we observed regional differences in the AChE activity in both. The AChE in the control brain and the AChE remaining in sarin-administered brain had different susceptibilities to inhibition from OP compounds in vitro and, therefore, have different properties. Quinidine partially protected AChE from the inhibitory effects of sarin in vitro possibly by altering the sarin binding sites. Addition of sarin to physostigmine-treated control brain samples allowed partial recovery of the AChE activity. The protective effects of quinidine or physostigmine were lost when samples from sarin-administered brain were treated in vitro with these compounds and then again exposed to sarin. Therefore, both quinidine and physostigmine provided partial protection against the inhibitory effects of sarin in vitro if they were added prior to sarin.
Animals↗
Pharmacokinetics and pharmacodynamics of obidoxime in sarin-poisoned rats.
The pharmacokinetics and pharmacodynamics of the oxime obidoxime (Toxogonin, 50 mg/kg iv) were investigated in anesthetized normal rats and in sarin-poisoned (50 micrograms/kg iv) rats. The kinetics were described by a two-compartment open model. The elimination half-life ranged from 35 min in normal rats to 86 min in sarin-poisoned rats. Obidoxime excretion occurred predominantly by the renal route, amounting to 4.6% of the administered dose in normal rats and to 0.9% in sarin-poisoned rats within the first hour of administration. The significantly diminished glomerular filtration rate confirmed the retardation of obidoxime excretion in sarin poisoning. The mean arterial blood pressure (MAP) response to obidoxime, measured in normal rats, was a transient hypotension, but to sarin an immediate hypertension. In sarin-poisoned rats the therapeutic sequence of administration of obidoxime and atropine (5 mg/kg iv) seemed to be important: the administration of atropine 10 min after and of obidoxime 20 min after sarin poisoning exerted a stabilizing effect on MAP. No serum albumin binding was found for obidoxime. Competition experiments at the isolated nicotinic receptor demonstrated the anticholinergic activity of obidoxime. The affinity of obidoxime was 1000 times smaller than that of acetylcholine. It is concluded that obidoxime, due to its prolonged residence time in the organism in sarin poisoning, exerts a "curare-like" inhibition and protection of the nicotinic acetylcholine receptor and, combined with atropine, a synergistic effect on blood pressure normalization.
Acetylcholine↗
Tissue disposition of [3H]sarin and its metabolites in mice.
The biodisposition and metabolic fate of [3H]sarin was investigated in mice after iv administration of a sublethal dose (80 micrograms/kg). Within 1 min of administration, all tissues contained substantial quantities of radioactivity of which less than 10% represented [3H]sarin. The major portion of radioactivity corresponded to free [3H]isopropyl methylphosphonic acid (IMPA), the pharmacologically inactive hydrolytic product of [3H]sarin. Somewhat lesser quantities were present as bound [3H]IMPA which resulted from phosphorylation of protein. Plasma contained high concentrations of bound [3H]IMPA, consistent with sarin's very reactive nature, which were sustained throughout the time course. Plasma concentrations of free [3H]IMPA diminished rather quickly. The high concentrations of metabolites in kidneys implied that this organ played a major role in the detoxification and excretion of [3H]sarin. Large quantities of free and bound [3H]IMPA were also found in lung which suggested an important site for toxicity. Only trace quantities of [3H]sarin were found in brain after 15 min. The major portion of radioactivity was present as either free and bound [3H]IMPA or as nonextractable material which presumably was [3H]methylphosphonic acid. Examination of the time course of sarin-induced motor hypoactivity and hypothermia revealed an immediate onset of action that lasted for 24 hr. However, substantial quantities of bound [3H]IMPA remained in brain at 24 hr which suggested that only a small portion of phosphorylation in brain accounted for these pharmacological effects.
Animals↗
Comparison of cholinergic and neuromuscular toxicity following acute exposure to sarin and VX in rat.
Male Sprague-Dawley rats injected with a sublethal sc dosage of 110 micrograms/kg of sarin (isopropyl methylphosphonofluoridate), or 12 micrograms/kg of VX (S-(2-diisopropylaminoethyl) O-ethyl methylphosphonothioate), developed severe toxic signs within 5-15 min after sarin and 20-50 min after VX lasting for 5 to 7 hr. Myonecrotic lesions were seen in soleus and diaphragm muscles within 1 hr. A maximum number of lesions had developed after 24 hr, and lesions were also present in extensor digitorum longus (EDL) at this time. Regeneration of muscle fibers was slow since lesions were still evident past 7 days of treatment. Within 1 hr following VX, AChE activity was reduced to 8, 12, and 17% of control activity in soleus, diaphragm, and EDL, respectively, whereas with sarin the enzyme activity was reduced to 23, 48, and 82% of control. A still greater inhibition was seen 24 hr after sarin when AChE activity was reduced to 19, 13, and 43% in these muscles. In skeletal muscles the different molecular forms of AChE, such as 16 S, 12 S, 10 S, and 4 S vary in location and functional importance with the 16 S form highly concentrated at the neuromuscular junction. All forms in a given muscle were equally sensitive to the inhibitors. In EDL, sarin was the least effective in reducing AChE or its molecular forms. In the brain structures (cortex, brain stem, striatum, and hippocampus), AChE activity was reduced to 1-6% of control by sarin and VX with the exception that following VX striatal AChE was reduced to only 41% of control activity. AChE activity in the brain cortex following either of the agents was maximally affected (1%). A slow but significant recovery of brain AChE was evident after 24 hr and more so after Day 7. Butyrylcholinesterase (BuChE) activity was less sensitive to inhibition by both inhibitors compared to AChE activity and showed a rapid recovery. Based on the equitoxic doses (toxic signs of similar magnitude), VX was found to be 10 times more toxic than sarin. The mechanisms of this disparity may be due to differences in rate of uptake, circulation, susceptibility to hydrolysis, and reactivity with nonspecific binding sites.
Acetylcholinesterase↗
Sarin transport across excised human skin I: Permeability and adsorption characteristics.
The transport rates and permeability coefficients for the transport of sarin in solution across both hydrous and anhydrous excised human skin were determined quantitatively. An activation energy was determined from study of the temperature influence on the transport of sarin in solution across anhydrous callus membranes. The transport of pure sarin and of sarin as a water-soluble and water-insoluble gel was studied also. The adsorption characteristics of sarin on powdered keratin were studied to determine their role in permeation. Both equilibrium and nonequilibrium measurements were made, which allowed calculation of the heat of adsorption, the heat of activation for adsorption, and the heat of activation for desorption. The results show that interaction between the membrane and penetrant plays a significant role in sarin transport across human skin.
Humans↗
The reversible carbamate, (-)physostigmine, reduces the size of synaptic end plate lesions induced by sarin, an irreversible organophosphate.
Pretreatment of rats with atropine and the reversible esterase inhibitor physostigmine [-)PHY), prior to injection of a lethal dose of the irreversible organophosphate sarin (0.13 mg/kg), protects 100% of the animals from lethality. We have used quantitative light and qualitative electron microscopy to show that damage to the end plate region of voluntary muscles is also strikingly limited by the same pretreatment. Drug effects on soleus motor end plates detectable 1 hr after treatment were (1) a single sublethal dose of sarin (0.08 mg/kg) produced large, blistered, and severely disrupted subjucntional regions. Damage extended from the end plate, in the form of myofiber necrosis and subsequent phagocytosis; (2) (-)PHY (0.1 mg/kg) itself had a selective effect in inducing irregularities of the subjunctional sarcomere band without any gross vacuolization; (3) the morphometric analysis done with light microscopy indicated that the combination of atropine (0.5 mg/kg) and (-)PHY (0.1 mg/kg) prior to a lethal dose of sarin (0.13 mg/kg) offered 86% reduction in the average area of the lesions, relative to the dimensions of damage induced by atropine/sarin alone. In most lesions induced by (-)PHY, recognizable changes were markedly less severe in degree and extent than those seen in sarin myopathy; there were few instances of extensive muscle damage and myofiber necrosis. The relationship of the (-)PHY dose to the level of protection against sarin suggested that (-)PHY pretreatment almost completely prevents the characteristic sarin-induced myopathy and, instead, imposes the characteristic PHY-induced subjunctional swelling. In all three experimental groups examined, the myopathic changes located extrajuctionally were reversible. The mechanism by which (-)PHY acts as a protective agent is discussed.
Animals↗
Effects of soman and sarin on high affinity choline uptake by rat brain synaptosomes.
Synaptosomes were incubated at various time intervals following injection of 120 micrograms/kg SC of soman or sarin or with various concentrations (10(-8) to 10(-2) M) of soman or sarin in vitro. Total cholinesterase (ChE) activities in each brain region were also measured. Following soman injection, sodium-dependent, high affinity choline uptake (SDHACU) was decreased from 1 to 4 hr in the cortex and from 1 to 2 hr in the hippocampus, but increased from 2 to 24 hr in the striatum. Similarly, following sarin injection SDHACU was decreased at 0.5 hr in the cortex and from 1 to 4 hr in the hippocampus, but increased at 1 hr in the striatum. Injection of soman severely inhibited (83-99%) total ChE activity in the cortex, hippocampus and striatum from 1 to 24 hr. In contrast, sarin did not severely inhibit ChE activity in these regions and maximal inhibition (40-60%) did not occur until 24 hr after injection. With both compounds, by 168 hr ChE activity in all regions had partially recovered. Incubation of synaptosomes with soman or sarin in vitro at concentrations below 10(-4) M did not affect SDHACU in any of the brain regions. These data demonstrated that acute soman and sarin injection produced similar effects upon SDHACU in different brain regions, although the time-course of these effects was different for the two compounds. These effects were probably neither due to a direct action of these compounds on the uptake process nor dependent on ChE inhibition.
Acetylcholinesterase↗
Cyclopentolate in treatment of sarin miosis.
1. Six young male volunteers were exposed to sarin vapour (isopropyl methyl phosphonofluoridate) at a concentration of 0.5 mg/m(3) for 30 min (concentration time (Ct) 15 (mg min)/m(3)).2. The resulting clinical syndrome was treated by instilling 0.06 ml of a 1% solution of cyclopentolate into the conjunctival sac.3. Visual acuity, retinoscopy, objective and subjective refraction and pupil sizes were noted before the trial, after exposure to sarin and after treatment with cyclopentolate.4. No appreciable difference was demonstrated between the control objective retinoscopy values and those obtained after cyclopentolate treatment of the clinical syndrome induced by sarin. Reduced near visual acuity was observed in some subjects treated with cyclopentolate as compared with acuity after exposure to sarin alone, considered to be due to the partial cycloplegia produced by treatment. Visual acuity after exposure to sarin alone was improved in some instances by the miosis produced.5. It is suggested that unless full dark adaptation is a consideration, treatment of the ophthalmic condition resulting from exposure to this dosage of sarin should be reserved for those experiencing distressing ocular symptoms.
Adult↗
Neurobehavioral toxicity with low doses of sarin and soman.
The acute effects of single subtoxic doses (1/48-1/9 of LD50) of two potent organophosphates (OPs), sarin (12.5 and 50 micrograms/kg i.p.) and soman (4 and 20 micrograms/kg i.p.), were studied on behavior, motor performance and nociception in male Wistar rats. On the elevated plus-maze with two open + two closed arms, higher doses of soman and sarin decreased the proportion of entries made onto open arms (p less than 0.05), while the total number of entries onto open + closed arms was unchanged. On the narrow elevated horizontal bridge, the latencies to reach the safe platform were prolonged with the higher dose of sarin (p less than 0.05) but not with that of soman. On the broad and rod bridges, the latencies of OP-treated rats did not differ significantly from those of controls. OPs did not significantly impair either learning frequency in one-trial passive avoidance test, rotarod performance or nociception in hot plate test. The results suggest that in acutely nontoxic doses sarin and soman affect the behavior of rats, and that the action profiles of the OPs differ from each other. Both soman and sarin change the behavior of rats in the plus-maze test but only sarin seems likely to impair motor coordination/balance.
Animals↗
The acute toxicity of sarin in marmosets (Callithrix jacchus): a behavioral analysis.
In marmosets, the clinical signs of poisoning following the administration of sarin and the effects of sarin upon performance in three behavioral test models were investigated. The sensitivity of marmosets to the lethal action of sarin was shown to be greater than that of rodent species and rabbits but very similar to that of the rhesus monkey. Doses of sarin ranging from 33 to 55% LD50, resulting in erythrocyte acetylcholinesterase inhibitions of 88% or more, were shown to disrupt the performance of a food-reinforced visually guided reaching response. However, the pattern of disruption did not suggest a specific action of sarin upon visuomotor coordination and could not be explained on the basis of an indirect effect of this agent upon either feeding motivation or changes in gross mobility. It was suggested that possible changes in animals' perception of the reaching task and/or their own drugged ability may be relevant to any interpretation of sarin-induced changes in visuomotor coordination in this species.
Acetylcholinesterase↗
Neuropathy target esterase in hens after sarin and soman.
To estimate the potential of small doses of sarin (types I and II) and soman to cause delayed neuropathic effects, 400, 200, 61, and 0 micrograms/kg of sarin-I, 280, 140, 70, and 0 micrograms/kg of sarin-II, and 14.2, 7.1, 3.5, and 0 micrograms/kg of soman by gavage were compared with 510 mg/kg tri-o-cresyl phosphate (TOCP) in 14- to 18-month-old SPF white leghorn hens (4/dose) protected with atropine (100 mg/kg). The neuropathy target esterase (NTE) activity 24 hr after dosing was determined in brain, spinal cord, and lymphocytes and in plasma and brain for cholinesterase and carboxylesterase. None of the compounds showed statistically significant NTE decreases. Sarin-II showed a dose-related trend in the lymphocyte NTE (to 33% of control at 280 micrograms/kg), suggesting that longer exposure to lower doses might cause a cumulative neurotoxic insult. All of the agents decreased the activity of plasma and brain cholinesterase and carboxylesterase. Using more than 70% inhibition of brain NTE as a biochemical predictor of delayed neuropathy, sarin and soman appear unable to cause delayed neuropathy at nonlethal doses within this protocol.
Animals↗
Comparison of serum concentrations of the acetylcholinesterase oxime reactivators HI-6, obidoxime, and PAM to efficacy against sarin (isopropyl methylphosphonofluoridate) poisoning in rats.
A comparison of serum concentrations of the oximes HI-6 [1-(((4-aminocarbonyl)-pyridino)methoxy)methyl)-2(hydroxy imino)methyl- pyridinium dichloride], PAM [2-[hydroxyimino)methyl-1-methylpyridinium chloride], and obidoxime [1,1'-(oxybis(methylene]bis(4-((hydroxyimino) methyl)-pyridinium dichloride] to the efficacy against sarin (350 micrograms/kg; sc) lethality was evaluated in rats. The oximes were administered prophylactically by means of Alzet osmotic minipumps. Atropine (17.4 mg/kg; im) was administered immediately following sarin (350 micrograms/kg; sc) administration. At serum concentrations of 3.6, 3.6, and 3.3 micrograms/ml for HI-6, obidoxime, and PAM, respectively, the 24-hr mortality following sarin poisoning was 0, 90, and 20%. The serum oxime concentrations (ED50 values) for HI-6, obidoxime, and PAM against a 3 LD50 dose of sarin were 0.72, 9.05, and 2.56 micrograms/ml, respectively. HI-6 was determined to be the most efficacious oxime when combined with atropine against sarin poisoning followed in order by PAM and obidoxime.
Acetylcholinesterase↗
Electrophysiological changes in the primary sensory neuron following subchronic soman and sarin: alterations in sensory receptor function.
Cats were administered soman or sarin either in a single high dose (1 mg/kg) with pretreatment or in multiple sublethal doses to determine whether these potent organophosphorus agents could produce a delayed neurotoxicity and what, if any, pathophysiological changes occurred in peripheral sensory receptors. Neither soman nor sarin, when administered as a single high dose, produced a delayed neurotoxicity as observed behaviorally for up to 60 days. There were also no observable signs of delayed neurotoxicity when these agents were administered in multiple doses. Functional tests of proprioceptors and mechanoreceptors were performed on the cats which received multiple sublethal doses of either soman or sarin. It was found that the discharge rates of muscle spindle primary endings were depressed while the discharge rates of secondary endings were facilitated following the administration of either soman or sarin. The discharge rates of slowly adapting type 1 mechanoreceptors were also depressed. The total number of identified mechanoreceptors was reduced in both the soman- and sarin-treated animals. Conduction velocities of several of the muscle spindle and mechanoreceptor afferents were significantly decreased. The alterations in muscle spindle function may be due to changes in the muscle resulting from acetylcholinesterase inhibition. Another explanation for the changes in both muscle spindle and mechanoreceptor function may be the direct effect of the organophosphorus agents on the afferents themselves, thus altering their excitability.
Animals↗
Studies on low dose sub-acute administration of soman, sarin and tabun in the rat.
The effects of low-dose administration of the organophosphate cholinesterase inhibitors, soman, sarin and tabun, on growth rates over 85 days were studied in rats. Acetylcholinesterase (AChE) activity was determined in the striatum and the remainder of the brain 24 hrs following the last exposure to these agents. Further, the cumulative mortality of daily administration of several doses of soman, sarin and tabun for 25 days was studied. The animals treated with 25 micrograms/kg of soman or sarin for 85 days demonstrated reduced growth rates which returned to control levels after 30 days. The animals which received 50 micrograms/kg of sarin also grew at reduced rates which returned to control levels after 35 days, while the tabun-treated (100 micrograms/kg) animals required 38 days to return to control growth rates. The striatal AChE activity of the soman-treated group was reduced to 36% of control while the AChE activities of the high-dose sarin-treated group were reduced to 66% of control. The striatal AChE activity of the tabun-treated group was only 13% of control. It is suggested that growth rates may be used to monitor the development of tolerance to low-dose administration of organophosphate cholinesterase inhibitors.
Acetylcholinesterase↗
Interaction of obidoxime with sarin in aqueous solution.
The interaction of obidoxime (Toxogonin) with sarin was shown by different analytical methods. The UV spectrum of obidoxime at pH 7.4 yields two absorption maxima, lambda 1 = 284 nm and lambda 2 = 353 nm. The peak at lambda 2 = 353 nm is representative for the amount of zwitter-ionic obidoxime, i.e. the active form of obidoxime. By addition of sarin, lambda 1 shifts immediately to 278 nm and the intensity at lambda 2 decreases, thus indicating an interaction. TLC and 31P-NMR evidence shows that both mono-phosphonylated and diphosphonylated obidoximes are present. Decomposition of phosphonylated obidoxime in MOPS (3-[N-morpholino] propanesulfonic acid) buffered D2O at pH 7.4 occurs with t1/2 = 13.3 min at 24 degrees C. Decomposition of di-phosphonylated obidoxime is faster. It is suggested that decomposition of di-phosphonylated obidoxime occurs through the mono-phosphonylated form. Formation and decomposition of mono- and di-phosphonylated obidoxime is pH dependent. We conclude that obidoxime exerts a detoxifying effect by capturing free sarin molecules and thus increasing its polarity. Thereby the transition of sarin through the blood-brain barrier is restricted and its renal elimination facilitated.
Chromatography, Thin Layer↗
Segmental synaptic depression caused by diisopropylphosphorofluoridate and sarin is reversed by thyrotropin-releasing hormone in the neonatal rat spinal cord.
The organophosphorus compounds diisopropylphosphorofluoridate (DFP) and isopropylmethylphosphonofluoridate (sarin) depressed the monosynaptic reflex (MSR) in spinal cords from 7- to 9-day-old male rats. The concentrations of DFP and sarin which depressed the MSR by nearly 50% were 100 microM and 100 nM, respectively. Simultaneous superfusion of the cords with thyrotropin-releasing hormone (TRH) with either DFP or sarin resulted in a reversal of the depression. The depression caused by DFP was reversed to 95% of control by 100 nM TRH whereas similar reversal of sarin-induced depression required a 10-fold greater concentration of TRH. The potentiating effect of TRH was not affected by atropine even at a high concentration (1 microM) although atropine easily reversed organophosphorus-induced depression of the MSR. It appears that reversal of organophosphorus-induced depression by TRH might occur through a noncholinergic, TRH-sensitive receptor mechanism and may be unrelated to acetylcholinesterase activity. This action represents a possible utility of TRH as an adjunct in organophosphorus toxicity.
Animals↗
Acute inhalation toxicity of soman and sarin in baboons.
Adult baboons (Papio sp.; 8-12 kg) were anesthesized with sodium pentobarbital (20 mg/kg iv). The animals were instrumented for measurement of mean blood pressure (MBP), pulmonary artery pressure (PAP), ECG, arterial and mixed venous blood gases, lung volumes, lung pressures, and efferent phrenic nerve activity. Bronchoalveolar lavage (BAL) was performed. Studies were done prior to exposure, at intervals during the first 4 hr postexposure, and at 4 and 28 days after exposure. Control animals received a sham exposure to 2-propanol (N = 5). Soman (pinacolyl methylphosphonofluoridate) at 13.14 micrograms/kg (2 X LD50) was vaporized into the upper airway in a second group of animals (N = 5), and sarin (isopropyl methylphosphonofluoride) 30 micrograms/kg (2 X LD50) was vaporized into a third group of animals (N = 4). Controls showed no change in any parameter either immediately after diluent exposure or during the monitoring period. Soman and sarin produced a decline in MBP and bradyarrhythmias that were reversed with atropine. Apnea occurred in all soman- and sarin-exposed animals within 5 min postexposure, and was associated with absence of phrenic nerve signal. Ventilation was mechanically supported until the animal could maintain normal arterial blood gases during spontaneous breathing. BAL studies revealed an increase in total white cell population and neutrophils at 4 hr in all three groups. There were signs of impaired hemodynamics and persistent lung injury for 4 days that resolved by 28 days after exposure. In conclusion, inhalation of soman and sarin in the baboon is associated with cardiac arrhythmias, development of apnea, and a significant decrease in MBP. Inhalation exposure also resulted in a persistent influx of neutrophils and hypoxemia.
Administration, Inhalation↗