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Availability, stability, and sterility of pralidoxime for mass casualty use.

STUDY OBJECTIVE: Pralidoxime is indicated to treat patients poisoned with nerve agents. It is available in intravenous formulation for more seriously ill hospitalized patients and intramuscular formulation for field treatment and less seriously ill patients. Our study describes a method to convert the intramuscular formulation for intravenous use and determines the stability and sterility of the resulting formulation over time and under various environmental conditions. METHODS: An inventory was taken of all intravenous (Protopam) and intramuscular (Mark I Autoinjector kits) pralidoxime available in Franklin County, Ohio hospitals, and out-of-hospital stockpiles. A method was devised to safely convert the intramuscular pralidoxime to an intravenous formulation, which was then tested for stability and sterility under a variety of environmental temperatures over time. RESULTS: In Franklin County, Ohio (population 1.1 million), the 10 acute care hospitals and out-of-hospital community have 36 g of intravenous pralidoxime and 4,398 g (7,270 Mark I kits) of intramuscular pralidoxime. The reformulated pralidoxime retained greater than 90% stability and remained sterile at all environmental temperatures through day 28. CONCLUSION: Available pralidoxime in Franklin County is predominantly in the intramuscular preparation. Conversion of intramuscular to intravenous pralidoxime results in a stable and sterile solution for up to 28 days under a variety of environmental conditions and should be considered in a mass casualty situation in which additional intravenous supplies are needed.

Antidotes↗

The comparison of therapeutic effects of atropine and pralidoxime on cardiac signs in rats with experimental organophosphate poisoning.

Organophosphate poisoning causes disturbances in cardiac conduction and potentially fatal severe cardiac rhythm abnormalities. This study investigated the cardiac effects of atropine and pralidoxime in the treatment of organophosphate poisoning in rats. Three groups of 10 adult male Wistar rats were anesthetized with an intraperitoneal injection of ketamine 100 mg/kg and xylazine 10 mg/kg and connected to a computerized electrocardiographic monitor. Each rat was then injected intraperitoneally with the pesticide dichlorvos 70 mg/kg. Sixty seconds after the injection, 10 rats were injected with saline, 10 with pralidoxime mesylate 20 mg/kg, and 10 with atropine 10 mg/kg. During the computerized electrocardiographic monitoring, each rat's heart rate and QT(c) intervals were recorded and analyzed as the injections were administered. The heart rates in all 3 groups did not differ before the dichlorvos was administered, nor at 60 seconds afterward, but in the atropine group, the time elapsed before the first decline in heart rate was significantly longer than that in the control group (P<.05). In addition, the interval before death was significantly longer in the atropine group than in either the control group or the pralidoxime group (P<.05 for both). The QT(c) was almost identical in each of the groups. Atropine has beneficial effects on the heart rate, prolongs the time before the heart rate declines, and delays death but has no effect on the QT(c) interval. Further research about the toxic effects of organophosphate compounds on myocardial cells is warranted.

Animals↗

Prompt recovery from severe cholinesterase-inhibitor poisoning--remarks on classification and therapy of organophosphate poisoning.

In organophosphate intoxication the assessment of both the degree of severity of poisoning and the initial dose of pralidoxime and atropine are as yet based only on clinical symptoms. We present three patients with clinically severe organophosphate poisoning in whom a prompt recovery from central nervous symptoms occurred after the administration of low doses of atropine and pralidoxime. It is suggested that the true severity of organophosphate intoxication as well as the initial therapy should be determined by the amount ingested, the propensity for aging, and the pharmacodynamic properties of the organophosphorus compound, as well as by the time interval between exposure and initiation of appropriate treatment, as far as these data can be verified in the individual patient.

Acetylcholinesterase↗

Aggressive atropinisation and continuous pralidoxime (2-PAM) infusion in patients with severe organophosphate poisoning: experience of a northwest Indian hospital.

OBJECTIVE: The aim of the study was to find whether continuous pralidoxime (2-PAM) infusion along with aggressive atropinisation improves the outcome in patients with severe organophosphate poisoning who require assisted ventilation. METHODS: Sixteen patients admitted to the respiratory intensive care unit (RICU) with severe organophosphate poisoning and requiring assisted ventilation were included in the study. The compounds involved were phorate (six), dichlorvos (four), oxydimeton methyl (one), monocrotophos (one), methyl parathion (one) and in three it was unknown. After decontamination, they were given intravenous (iv) bolus atropine 5 mg at onset and then 2.5 mg every 5-10 min till atropinisation was achieved, and then maintained either by intermittent bolus doses or by continuous infusion if the required dose was large. They were also given continuous iv infusion of 2-PAM in dose of 7.5 mg/ kg body weight/h (maximum 500 mg/h) after an initial bolus dose of 2 g. RESULTS: The mean (+/-S.D.) dose of atropine was 735.02 +/- 742.98 mg (range 85-3000 mg) with maximum dose on day 1. The mean (+/-S.D) duration of 2-PAM infusion was 96.4+/-49.4 h (range 10-216 h). The mean (+/-S.D) duration of mechanical ventilation (MV) was 131.5 +/- 95.65 h (range 4-336 h). Fourteen patients could be successfully extubated and two died of bronchopneumonia and sepsis (mortality 12.5%). CONCLUSION: Continuous 2-PAM infusion along with aggressive atropinisation after initial decontamination improved the outcome but not the duration of MV in severely intoxicated patients with organophosphate compounds who required assisted ventilation in this case series.

Adolescent↗

Sarin intoxication elevates plasma pralidoxime.

Groups of guinea pigs were injected with a range of dosages for sarin (0, 140, 279, 557 micrograms/kg) followed by pralidoxime (2-PAM) and atropine sulfate (16 mg/kg). Poisoning by sarin in these animals elevated plasma pralidoxime content in a dose-dependent manner within 10 min of intoxication. Plasma levels after administration of 3.12 mg/kg of 2-PAM were elevated from a control mean of 6.18 micrograms/ml to a maximum of 13.78 micrograms/ml in animals given 557 micrograms/kg of sarin at 2 min after the injection of the therapeutic compounds. This suggests that pathophysiological changes following intoxication by potent inhibitors of cholinesterase result in a decrease in the rate and extent of distribution of therapeutic compounds. This effect is most likely a consequence of changes in cardiovascular functions influencing blood flow to various organs.

Animals↗

Effects of HI-6 and pralidoxime on neuronal RNA in thalamic cholinergic sites.

Quantitative azure B-RNA cytophotometry was employed to compare effects of the oximes HI-6 and pralidoxime (2-PAM) to those of atropine sulfate (AS) on neuronal RNA metabolism in the thalamic ventrobasal nuclear complex (VBC) and nucleus reticularis (NR). The ability of these compounds to mitigate soman (pinacolyl methylphosphonofluoridate)-induced neuronal RNA alterations (i.e., VBC-RNA depletion/NR-RNA elevation) in these muscarinic cholinergic sites was also determined. Generally, HI-6 (125 mg/kg, i.p.) and 2-PAM (43.2 mg/kg, i.m.) elicited similar patterns of neuronal RNA changes, i.e., diminution of VBC-RNA and NR-RNA with oximes alone; partial amelioration of soman (1.5 LD50, s.c.)-induced VBC-RNA loss; and slight or no effect on soman induced NR-RNA accumulation. HI-6 produced more severe RNA reduction than 2-PAM in both brain regions of non-poisoned rats, whereas 2-PAM was more effective in reversing the effects of soman in these two regions. The muscarinic antagonist, AS, also produced VBC-RNA depletion and partially counteracted the VBC-RNA loss in soman intoxicated rats. Unlike the oximes, however, AS resulted in NR-RNA accumulation and it also antagonized soman induced NR-RNA elevation. Neither oxime reactivated soman inhibited brain acetylcholinesterase but HI-6 did reactivate appreciable plasma cholinesterase. The overall data suggest that HI-6 and 2-PAM do exert pharmacologic actions on cholinergic neurons in the rat CNS. However, the greater effectiveness of HI-6 over 2-PAM in countering lethal actions of soman does not appear to be correlated with oxime mediated restoration of neuronal RNA levels in these two cholinergic regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Intensive care management of organophosphate insecticide poisoning.

INTRODUCTION: Organophosphate (OP) insecticides inhibit both cholinesterase and pseudo-cholinesterase activities. The inhibition of acetylcholinesterase causes accumulation of acetylcholine at synapses, and overstimulation of neurotransmission occurs as a result of this accumulation. The mortality rate of OP poisoning is high. Early diagnosis and appropriate treatment is often life saving. Treatment of OP poisoning consists of intravenous atropine and oximes. The clinical course of OP poisoning may be quite severe and may need intensive care management. We report our experience with the intensive care management of serious OP insecticide poisonings. METHODS: A retrospective study was performed on the patients with OP poisoning followed at our medical intensive care unit. Forty-seven patients were included. Diagnosis was performed from the history taken either from the patient or from the patient's relatives about the agent involved in the exposure. Diagnosis could not be confirmed with serum and red blood cell anticholinesterase levels because these are not performed at our institution. Intravenous atropine and pralidoxime was administered as soon as possible. Pralidoxime could not be given to 16 patients: 2 patients did not receive pralidoxime because they were late admissions and 14 did not receive pralidoxime because the Ministry of Health office was out of stock. Other measures for the treatment were gastric lavage and administration of activated charcoal via nasogastric tube, and cleansing the patient's body with soap and water. The patients were intubated and mechanically ventilated if the patients had respiratory failure, a depressed level of consciousness, which causes an inability to protect the airway, and hemodynamic instability. Mechanical ventilation was performed as synchronized intermittent mandatory ventilation + pressure support mode, either as volume or pressure control. Positive end expiratory pressure was titrated to keep SaO2 above 94% with 40% FIO2. Weaning was performed using either T-tube trials or pressure support weaning. The chi-square test was used for statistical analysis. Data are presented as mean +/- standard deviation. RESULTS: There were 25 female and 22 male patients. Thirty-two (68%) were suicide attempts and 15 (32%) were accidental exposure. The gastrointestinal route was the main route in 44 (93.6%) patients. The mortality rates for the patients who did and did not receive pralidoxime were 32 and 18.7%, respectively, and were not statistically different. The most frequent signs were meiosis, change in mental status, hypersalivation and fasciculations. Ten patients (21.2%) required mechanical ventilation. The mortality rate for the patients who required mechanical ventilation was 50%, but the rate was 21.6% for the patients who were not mechanically ventilated. Intermediate syndrome was observed in 9 (19.1%) patients. Complications were observed in 35 (74.4%) patients. These complications were respiratory failure (14 patients), aspiration pneumonia (10 patients), urinary system infection (6 patients), convulsion (4 patients) and septic shock (1 patient). The duration of the intensive care stay was 5.2 +/- 3.0 days. DISCUSSION: Ingestion of OP compounds for suicidal purposes is a major problem, especially in developing countries. Thirty-two (68%) of our patients used the OP insecticide for suicide. Two patients did not receive pralidoxime because of delayed admission and they were successfully treated with atropine alone. Three of the patients who did not receive pralidoxime because of unavailability died. The mortality rate was no different between the patients treated with pralidoxime or those without pralidoxime. De Silva and coworkers have also reported that the mortality rate was not different between each group. Three patients with intermediate syndrome died due to delay for endotracheal intubation. The average respiratory rate of these patients increased from 22 to 38 breaths/min, which is an important sign of respiratory distress. The nurse to patient ratio was increased after these events. Early recognition of respiratory failure resulting in intubation and mechanical ventilation is a life-saving intervention for patients with OP poisoning. Respiratory failure is the most troublesome complication, which was observed in 35 (74.4%) patients. Patients with OP poisoning may have respiratory failure for many reasons, including aspiration of the gastric content, excessive secretions, pneumonia and septicemia complicating acute respiratory distress syndrome. CONCLUSIONS: OP insecticide poisoning is a serious condition that needs rapid diagnosis and treatment. Since respiratory failure is the major reason for mortality, careful monitoring, appropriate management and early recognition of this complication may decrease the mortality rate among these patients.

Accidents↗

Cholinesterase inhibition by aluminium phosphide poisoning in rats and effects of atropine and pralidoxime chloride.

AIM: To investigate the cholinesterase inhibition and effect of atropine and pralidoxime (PAM) treatment on the survival time in the rat model of aluminium phosphide (AlP) poisoning. METHODS: The rats were treated with AlP (10 mg/kg; 5.55 x LD50; ig) and the survival time was noted. The effect of atropine (1 mg/kg, ip) and PAM (5 mg/kg, ip) was noted on the above. Atropine and PAM were administered 5 min after AlP. Plasma cholinesterase levels were measured spectrophotometrically in the control and AlP treated rats 30 min after administration. RESULTS: Treatment with atropine and PAM increased the survival time by 2.5 fold (1.4 h+/-0.3 h vs 3.4 h+/-2.5 h, P < 0.01) in 9 out of 15 animals and resulted in total survival of the 6 remaining animals. Plasma cholinesterase levels were inhibited by 47 %, (438+/-74) U/L in AlP treated rats as compared to control (840+/-90) U/L (P < 0.01). CONCLUSION: This preliminary study concludes that AlP poisoning causes cholinesterase inhibition and responds to treatment with atropine and PAM.

Aluminum Compounds↗

Efficacy of pralidoxime iodide and obidoxime dichloride as antidotes in diazinon-poisoned goslings.

The antidotal efficacy of pralidoxime iodide and obidoxime dichloride was investigated in goslings poisoned by a supralethal dose of the organophosphorus insecticide diazinon. Various doses of both drugs were administered by intramuscular injection when the poisoned birds were unable to walk. Pralidoxime at 100 mg/kg brought about a complete and speedy clinical recovery. Fifty mg/kg induced recovery in 4 of 6 poisoned goslings, and 25 mg/kg successfully trated only 1 of 6 birds. Obidoxime at 25 mg/kg showed no therapeutic properties whereas 50 and 100 mg/kg delayed the death of some birds by several hours. At 100 mg/kg, all goslings had transient signs of intoxication, which precluded the use of this compound as an antidote at higher doses. The mode of action of these antidotes in diazinon-poisoned goslings is discussed.

Animals↗

Plasma concentrations of the oxime Pralidoxime Mesylate (P2S) after repeated oral and intramuscular administration.

The use of the oxime P2S as intravenous therapy for organophosphorus anticholinesterase poisoning is well known. In emergency situations this route of administration may prove impractical due to severe symptoms of anticholinesterase poisoning and therefore the intramuscular route is to be preferred. The absolute intramuscular dose of P2S per man, recommended as necessary for adequate therapy of anticholinesterase poisoning, is 500 mg. In practical situations this dose may have to be repeated at intervals resulting in overdosage, and therefore, the clinical side-effects which this regimen might have on normal subjects has been determined. It has also been suggested that where organophosphorus anticholinesterase compounds are handled continuously for many months in the year, for example, in crop spraying and in industry, P2S might be taken prophylactically.

Administration, Oral↗

Estimation of oxime efficacy in nerve agent poisoning: a kinetic approach.

Standard treatment of poisoning by organophosphorus compounds (OP) includes the administration of an anti-muscarinic, e.g. atropine, and of an acetylcholinesterase (AChE) reactivator (oxime). Two oximes, obidoxime and pralidoxime (2-PAM), are presently commercially available, yet, these compounds are considered to be of insufficient efficacy against certain nerve agents, e.g. soman and cyclosarin. In the past decades, numerous new oximes were synthesized and tested for their antidotal efficacy. The available data indicate that two Hagedorn oximes, HI 6 and HLö 7, are promising antidotes against various nerve agents. The efficacy of antidotes against nerve agent poisoning cannot be investigated in humans for ethical reasons. Therefore, it is necessary to use surrogate parameters for the evaluation of oxime efficacy. Reactivation of inhibited AChE is considered to be the main mechanism of action of oximes. Clinical data indicate that changes in erythrocyte AChE activity correlate to neuromuscular function indicating that interactions between AChE, inhibitor and oximes can be investigated in vitro with human erythrocyte AChE. Different theoretical models were used for the evaluation of reactivating efficacy of oximes with nerve agent-inhibited human AChE and for estimating effective oxime concentrations. The calculations demonstrate the marked differences between oximes in dependence of the inhibitor and provide a basis for the estimation of the required oxime dose as well as of dosing intervals.

Acetylcholinesterase↗

Reactivation and aging kinetics of human acetylcholinesterase inhibited by organophosphonylcholines.

A great number of structurally different organophosphorus compounds (OPs) was synthesized in the past decades to be used as pesticides or chemical warfare agents. Methyl-fluorophosphonylcholines were found to be highly toxic OPs and the acetylcholinesterase (AChE) reactivator pralidoxime was shown to be unable to reactivate inhibited AChE. In the course of the development of more effective AChE reactivators, we have determined the reactivation rate constants of various oximes with human AChE inhibited by methylfluorophosphonylcholine (MFPCh), methylfluoro-beta-phosphonylcholine (MFP beta Ch) and methylfluorophosphonylhomocholine (MFPhCh). In addition, we investigated the potential influence of aging phenomena on the oxime efficacy. Human AChE inhibited by MFPCh, MFP beta Ch or MFPhCh was extremely resistant towards reactivation by oximes. Nevertheless, the newer compounds, HLö 7 and HI 6, were substantially more potent reactivators than obidoxime and pralidoxime. The low oxime efficacy was not due to rapid aging since no decrease in reactivatability was found over 96 h at 37 degrees C. Within this period a substantial spontaneous reactivation was observed, with MFPCh >MFP beta Ch >MFPhCh, which did not follow pseudo-first-order kinetics. In conclusion, the unexpected results, i.e., high resistance of inhibited AChE towards oxime reactivation and aging, and much lower resistance towards spontaneous reactivation, calls for further experiments at a molecular level for a better understanding of the interactions among AChE, its inhibitors and reactivators.

Acetylcholinesterase↗

O-Substituted derivatives of pralidoxime: muscarinic properties and protection against soman effects in rats.

O-Substituted aldoximes of the cholinesterase reactivator pralidoxime (O-methyl 1, O-benzyl 2, O-propynyl 3 and O-butynyl 4 derivatives) were synthesized and found to exhibit strong binding affinities for muscarinic receptors in rat brain, heart and submandibulary glands. The aldoximes were noncompetitive antagonists of acetylcholine-induced contraction of the guinea pig ileum. A good correlation was observed between binding affinity and pK(B). Weak anticholinesterase activities were observed for these compounds. When given intracerebroventricularly into conscious rats before soman administration (0.9 LD(50), subcutaneously), the aldoximes, like atropine but not pralidoxime, protected against respiratory depression (3,4) and bradycardia (2). No protection against soman-induced pressor effects was noted. The protective effects of these aldoximes may be the outcome of compensatory mechanisms, of which the cholinergic receptor agonist and antagonist properties of these compounds may be important.

Acetylcholinesterase↗

Effect of pyridostigmine, pralidoxime and their combination on survival and cholinesterase activity in rats exposed to the organophosphate paraoxon.

Pyridostigmine (PSTG) is a carbamate inhibitor of cholinesterases. Carbamates are known to confer some protection from the lethal effects of (some) organophosphorus compounds. Recently, based on animal data, the FDA approved oral PSTG for pre-exposure treatment of soman. The purpose of the study was to quantify in vivo the effect of PSTG pre-treatment on survival in rats exposed to the organophosphate paraoxon (POX) with and without subsequent reactivator (pralidoxime) treatment. POX is a highly toxic non-neuropathic ethyl organophospate. Pralidoxime (PRX) is the enzyme reactivator used by some NATO armies. The prospective, controlled animal (rat) study included Group 1 that received 1 micromol POX ( approximately LD(75)); Group 2 that received 1 micromol PSTG followed 30 min later by 1 micromol POX; Group 3 that received 1 micromol PSTG followed 30 min later by 1 micromol POX and 50 micromol PRX; Group 4 that received 1 micromol POX and 50 micromol PRX; Group 5 that received 1 micromol PSTG; Group 6 that received 50 micromol PRX and Group 7 that received 1 micromol PSTG followed 30 min later by 50 micromol PRX. Each group contained six rats. The experiment was repeated twelve times (12 cycles). All substances were applied i.p. From surviving animals of eight cycles tail blood was taken for red blood cell acetylcholinesterase (RBC-AChE) measurements. The animals were monitored for 48 h and mortality (survival time) was recorded. RBC-AChE activities were determined. Mortality was analysed using Kaplan-Meier plots. Both PSTG and PRX statistically significantly decreased organophosphate induced mortality in the described model. While the same applies to their combination the decrease in mortality when using both PSTG and PRX is less than that achieved with their single use (but not significantly so). While certainly further work using different organophosphorus compounds and animal species are needed before a final conclusion is reached, the animal data presented does not support the combined use of PSTG and PRX.

Animals↗

Evaluation of two treatment regimens of pralidoxime (1 gm single bolus dose vs 12 gm infusion) in the management of organophosphorus poisoning.

Organophosphorus (OP) poisoning is most frequently encountered among our community. Treatment of poisoning is primarily aimed at reversing the effects of the compound by administration of atropine. Oximes have been shown to be efficacious in case reports. The dose of this drug in these reports varies from 1 gm which is a very low dose and physiologically no dose, to doses upto 16 gm. This is also a very expensive imported drug which causes the nation considerable loss of foreign exchange. We report our experience with the use of two treatment regimens of Pralidoxime (P2AM) in the management of patients with OP poisoning in a prospective trial. Seventy-two adult patients presenting to a large university affiliated teaching institution with a history of consumption of OP compounds and requiring intensive care were entered into the trial. Patients were randomized using a block randomisation to receive either a single bolus dose of 1 gm P2AM at admission (Low dose group) followed by placebo infusion over the next 4 days or a single placebo bolus at admission followed by P2AM 12 gm as a continuous infusion over the next 4 days. Outcome measures analyzed were mortality, duration of ICU stay, need for ventilation and duration of ventilation, time to recovery of consciousness, development of intermediate syndrome and infections. A higher prevalence of intermediate syndrome (p = 0.08) was observed in the high dose group. Ventilatory requirement was also more in the high dose group (p = 0.09). Since this was an equivalence study designed to show that the low dose was as effective as the high dose, these results attain greater significance as the low dose group fared better than the high dose group, even though the pre-test hypothesis was in the reverse direction. Subgroup analysis of patients who received at least 1 gm of P2AM within 12 hours of ingestion of the OP poison with those who received P2AM after 12 hours, showed that there was a significant reduction of intermediate syndrome (p = 0.05) but no significant difference was noted in number ventilated. High dose P2AM infusion has no role in the routine management of patients with OP poisoning. These results also suggest that the time of administration of P2AM after the ingestion of the poison mabe a crucial factor which determines response to therapy. A prospective double blind placebo controlled trial is now justified in the light of the above findings.

Adult↗

Synthesis of asymmetrical bispyridinium compounds bearing cyano-moiety and evaluation of their reactivation activity against tabun and paraoxon-inhibited acetylcholinesterase.

Three asymmetrical AChE reactivators with cyano-moiety and propane linker were synthesized using modification of currently known synthetic pathways. Their potency to reactivate AChE inhibited by nerve agent tabun and insecticide paraoxon was tested in vitro and compared to pralidoxime, HI-6, obidoxime, K027, and K048. According to the results, three compounds seem to be promising against paraoxon-inhibited AChE. Better results were obtained for bisquaternary substances at least with one oxime group in position four. None of tested substances was able to satisfactorily reactivate tabun-inhibited AChE at concentration applicable for in vivo experiments.

Cholinesterase Inhibitors↗

Current understanding of the application of pyridinium oximes as cholinesterase reactivators in treatment of organophosphate poisoning.

This paper reviews the mechanisms of interaction of organophosphorus compounds with cholinesterases and clinical signs of acute poisoning. Further, we describe the current understanding of the mechanisms of action of pyridinium oximes pralidoxime (PAM-2), trimedoxime (TMB-4), obidoxime (LüH-6, Toxogonin), HI-6 and HLö-7 which are used as cholinesterase reactivators in the treatment of poisoning with organophosphorus compounds. We also review the most important literature data related to the efficacy of these oximes in the treatment of poisoning with warfare nerve agents soman, sarin, tabun, VX and cyclosarin and organophosphorus insecticides. Finally, we discuss the criteria for selection of oximes intended for further development as antidotes in poisoning with organophosphorus compounds and auto-injectors for their application in urgent situations.

Animals↗

A new H-oxime restores rat diaphragm contractility after esterase inhibition in vitro.

Acetylcholine esterase inhibitors block cholinergic neurotransmission. This blockade can be reversed by oximes. However, a universally effective esterase reactivator does not exist. A new H-oxime, HLö 7, was tested on rat diaphragm strips. Electrically evoked contractions were blocked by di-2-propyl fluorophosphate (DFP), tabun, sarin and soman. Whereas pralidoxime, obidoxime and HI 6 reversed the blockade induced by three of these organophosphorus compounds, HLö 7 restored the contractions after short blockade induced by all four organophosphorus compounds tested.

Animals↗