Antidotal therapy of severe acute organophosphate poisoning: A multihospital study

Finkelstein, Yoram; Kushnir, Amir; Raikhlin-Eisenkraft, Bianca; Taitelman, U

doi:10.1016/0892-0362(89)90044-5

Cited by 53 publications

(23 citation statements)

References 9 publications

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“…However, in others, oxime concentrations as high as 14.6 mg.l À1 did not produce an effect. These workers concluded that the therapeutic effect of oximes seemed to depend on the plasma concentration of the OP agent, with the benefits being minimal at high blood levels of OP [146]. A high incidence of arrhythmia was observed in patients who received large cumulative doses of atropine and obidoxime.…”

Section: Oximesmentioning

confidence: 99%

Organophosphorus poisoning and anaesthesia

1999

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SummaryOrganophosphorus compounds, used as insecticides and agents of chemical warfare, are a major global cause of health problems. These irreversible inhibitors of cholinesterase produce three wellrecognised clinical entities: the initial cholinergic phase, which is a medical emergency often requiring management in an intensive care unit; the intermediate syndrome, during which prolonged ventilatory care is necessary; and delayed polyneuropathy. In addition, disturbances of body temperature and endocrine function, electrolyte imbalances, immunological dysfunction and disorders of reproduction have been reported in animals and man. Vocal cord paralysis, pancreatitis, cardiac arrhythmias and a wide range of neuropsychiatric disorders are known to follow acute and chronic exposure to organophosphorus compounds. As a result of the inhibition of plasma cholinesterase, there can be increased sensitivity to drugs hydrolysed by this enzyme, e.g. suxamethonium and mivacurium. The inhibition of acetylcholinesterase causes dysfunction at the neuromuscular junction which can produce altered responses to nondepolarising neuromuscular blockers. Anaesthetists may encounter patients exposed to organophosphorus compounds either following acute poisoning, trauma (warfare) or as patients with a wide range of nonspecific disorders presenting for surgery. The traditional use of oximes and atropine in treatment has failed to reduce the morbidity and mortality associated with poisoning. The roles of agents that have reduced the toxicity of organophosphorus compounds in animal experiments are discussed as potential therapeutic agents. There is an urgent need for accurate information on the problems associated with exposure to organophosphorus compounds. This would best be achieved by collaborative research between technologically advanced countries and developing countries, where organophosphorus compounds are a leading cause of ill health.

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Section: Oximesmentioning

confidence: 99%

Organophosphorus poisoning and anaesthesia

1999

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“…Our reference oxime Toxogonin has been used extensively as an antidote against organophosphorus poisoning in various species including humans. 15 The reported therapeutic doses of Toxogonin are 10.8 mg kg −1 (30 µmol kg) The process of determination of CED for other oximes was based on a dose-response curve that was obtained from the experimentally observed clinical-toxicological symptoms (Tables 1-3). Evaluation of the therapeutic efficacy of a drug is related to doses that are included in the range defined by the therapeutic window.…”

Section: Discussionmentioning

confidence: 99%

“…11,13,14 In some countries, Toxogonin serves as part of the clinical antidotal treatment against insecticide and nerve agent poisoning in humans. 15 The therapeutic dose of Toxogonin used in large animals (30 µmol kg −1 in dogs and 41.7 µmol kg −1 in monkeys) may serve as a reference value for the assessment of therapeutic doses of newly developed oximes. Quaternary oximes could induce cholinergic toxic signs such as salivation, dispnoea, fasiculations and twitching of limb and facial muscles in dogs 16 that may lead to death only at extremely large doses.…”

Section: Introductionmentioning

confidence: 99%

Determination of therapeutic doses of bisquaternary oximes in large animals

Chen

Raveh

Zomber

et al. 2001

J of Applied Toxicology

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This report presents a non-lethal method for estimating a range of therapeutic doses of bisquaternary oximes that serve as antidotes against organophosphorus poisoning. We have estimated therapeutic oxime doses that are equivalent in their relative toxicity rather than selecting arbitrary fractions of their LD(50). Thus, toxic signs of the oximes HI-6, HLö-7, Toxogonin, AB-8 and AB-13 were monitored quantitatively in baboon monkeys and beagle dogs. Using Toxogonin as a reference oxime, a calculated unit of equivalent dose (CED) was defined as the oxime dose equal to the ratio between its minimal toxic dose (MTD) and the therapeutic ratio (TR) of Toxogonin i.e. CED = MTD/TR. Assuming that the tails of dose-response curves of toxicity for bisquaternary oximes are shallow and similar to one another, one could substitute the ED(10) for the MTD. The ED(10) values for bisquaternary oximes were estimated using the log-log model following experimental observations and quantitative scoring of toxic signs in dogs and monkeys. The MTD values then were calculated using the ED(10) values and the experimental therapeutic dose of the reference oxime Toxogonin. The following CED values were obtained for AB-8, AB-13, Toxogonin, HI-6 and HLö-7 in dogs (d) and monkeys (m): 98.7, 74.2, 30.0, 14.5 and 12.1 (d) and 281.9, 232.1, 41.7, 192.9 and 92.9 (m) micromol kg(-1), respectively. The antidotal efficacy of these oximes against poisoning by the nerve agent tabun was determined in dogs and monkeys. These dose-dependent efficacy data were obtained at 0.3 x CED, 1 x CED and 3 x CED of oximes in combination with atropine. These data provide comparative therapeutic values using oxime doses based on their relative toxicity. The highest antidotal efficacy against tabun in dogs was obtained for toxogonin, whereas HLö-7 and AB-13 were most efficacious in monkeys.

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“…Basically, the specific treatment of OP-poisoning is a combination of an anticholinergic drug, mostly atropine, and an oxime which is intended to reactivate OP-inhibited AChE 2 . The antidotal therapy is supplemented by benzodiazepines, catecholamines, antibiotics, and further drugs depending on the clinical signs and symptoms [3][4][5][6] . Apart from pralidoxime, only few oximes have been used in human OP-poisoning in the past 50 years 7 .…”

Section: Introductionmentioning

confidence: 99%