No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Vergiftung mit Diisopropylfluorphosphat (DFP)
Abstract
Es wird ber Symptomatik und Verhalten der Esteraseaktivitt bei 3 akzidentellen DFP-Vergiftungen berichtet. Die Verabreichung des Fermentreaktivators PAM hatte nur innerhalb der ersten Stunden einen gewissen Erfolg. Trotz einer nur geringen Reaktivierbarkeit der durch DFP blockierten Cholinesterase kann die PAM-Behandlung eine lebensrettende Ma\nahme darstellen, wie aus ergnzenden Tierversuchen hervorgeht.
Contents Introduction Nature and Physiologic Function of Cholinesterase Symptoms of Organic Phosphorus Poisoning Mechanism of Inhibition of Cholinesterase Measurement of Cholinesterase Activity and Its Relationship to Symptomatology Measurement of Metabolites and Their Relationship to Symptomatology Use and Action of Atropine and Other Nonspecific Antidotes Development of Specific Antidotes Chemical and Physiologic Properties of Oximes Antidotal Efficacy of Oximes in Poisoned Experimental Animals Application of 2-P AM in Poisoning in Man Suggestions for Treatment Prevention of Poisoning Comment and Summary Introduction Organic phosphorus compounds are of considerable interest and importance by virture of their widespread use as insecticides; their effectiveness in the treatment of myasthenia gravis, glaucoma, and abdominal distention; and their potential application as war gases. These compounds owe their pharmacologic effect primarily, if not entirely, to their ability to inhibit the enzyme cholinesterase with a resultant overstimulation of the parasympathetic nervous system by the acetylcholine which accumulates. Atropine has been the drug of choice for the treatment of organophosphorus poisoning. This therapy produces relief of symptoms based on blocking the action of excess acetylcholine.
Bei Untersuchungen ber das Verhalten von Serumcholinesterase und Acetylcholinesterase nach der Vergiftung mit Paraoxon bzw. DFP in vitro wurden folgende Befunde erhoben:1.
Durch DFP inaktivierte Serum-ChE zeigt keine Spontanreaktivierung. Paraesteratisch vorliegende DFP-Mengen werden abgebaut.
2.
Weder die durch DFP noch die durch Paraoxon inaktivierte AChE zeigten Anzeichen einer Spontanreaktivierung. Eine spontane Wiederherstellung der Esteraseaktivitt ist im Falle der Paraoxon-Vergiftung allerdings dann zu erreichen, wenn durch Dialyse berschssige Alkylphosphatmengen entfernt werden.
3.
Unter den gewhlten Bedingungen lassen sich die durch die geprften Alkylphosphate Paraoxon und DFP blockierten Esterasetypen (Serum-ChE und AChE) noch nach vielen Tagen durch das Antidot PAM deutlich reaktivieren.
Einige unerwartete Nebenbefunde erklren sich mglicherweise daraus, da die Alkylphosphate zeitweilig adsorptiv (reversibel) an Trgerstoffe der verwendeten Esteraseprparate gebunden werden knnen.
Es wird ber eine schwere DFP-Vergiftung berichtet, die sich nach dem klinischen Bild nicht von anderen Alkylphosphatintoxikationen abtrennen l\t. In der spezifischen Therapie ist das Toxogonin dem PAM vorzuziehen, da es im Gegensatz zum PAM auch die Hirncholinesterase zu reaktivieren vermag.
A fatal case of poisoning with phosphamidon, a recently developed organophosphate insecticide, is described. A second, probable case of mild phosphamidon poisoning is also reported. The clinical picture in both cases resembled that seen in poisoning with other organophosphate compounds. The first patient was an 18-year-old girl who had swallowed about 50 ml. of a 50% solution of phosphamidon and developed jaundice, bronchopneumonia, and pulmonary oedema. She died on the sixth day in hospital despite prolonged respiratory support and treatment with massive doses of atropine, PAM, and antibiotics. Post-mortem examination revealed a fatty liver, congestion of the internal organs, and brain damage of the type seen in anoxia. The second patient was a 50-year-old agricultural worker, who was engaged in uprooting and cutting shrubs which had been sprayed two weeks earlier with phosphamidon. He was admitted to hospital in a state of confusion and recovered within several hours. The importance of securing a free airway and of artificial ventilation as first-aid measures in organophosphate poisoning is stressed, and the value of early massive dosage of PAM is emphasized.
Three patients with organophosphate insecticide poisoning are described. The first patient with Diazinon® poisoning and the second with parathion poisoning illustrate the acute manifestations, the criteria for diagnosis, and treatment with pralidoxime and atropine in organophosphate poisoning. The diagnosis of acute organophosphate poisoning is based on a history of exposure to organophosphates, manifestations including miosis and fasciculations, improvement following administration of pralidoxime and atropine (increased tolerance to atropine), and reduction in blood cholinesterase activity. Pralidoxime has been effective in management of many patients with poisoning by parathion and methyl parathion, and in a smaller number with poisoning by Diazinon, EPN, DFP, TEPP; probably Bidrin, carbophenthion, dichlorvos and dimethoate; and possibly mevinphos. The effectiveness of pralidoxime in the management of poisoning in man by malathion, methyl demeton, phosphamidone and azinphosmethyl has not been established. Pralidoxime is effective in reactivating organophosphate-inhibited cholinesterase at the cholinergic synapses, including the central nervous system.The third patient with polyneuropathy illustrates the possibility of persistent manifestations of organophosphate poisoning. He had been exposed as a chemist to organophosphates and their intermediates, which appear to be the cause of polyneuropathy. In animal experiments some organophosphates caused polyneuropathy. In man, polyneuropathy has been caused frequently by triorthocresyl phosphate and less often by mipafox, but rarely by commercially available organophosphate insecticides, and the cause-result relationship has not been established. The other main persistent effect of organophosphate poisoning has been central nervous system symptoms, which usually follow acute poisoning inconsistently and are mainly of emotional origin.
Neben der Verwendung von Insecticiden zur Seuchenverhütung (Entlausung, Mücken- und Wanzenbekämpfung u. a.) ist die Schädlingsbekämpfung in der landwirtschaftlichen Produktion und bei Transport- und Speicherungsaufgaben in der ganzen Welt ein wirtschaftliches Problem ersten Ranges. Man hat einmal spöttisch gesagt: „Wir ernten nur das, was die Schädlinge uns übriglassen“. Auf dem Internationalen Pflanzenschutzkongreß Hamburg 1957 wies man darauf hin, daß etwa 1/5 der Welternte als Opfer von Pflanzenschädlingen und -krankheiten verloren gehe.
Ein 29jähriger Mann trank 12 ccm des Pflanzenschutzmittels E 605 forte, das entspricht 6 g Diäthyl-p-nitrophenyl-thiophosphat und ist die 10—20fache letale Dosis. 15 Minuten danach wurde er in die Klinik eingeliefert, und es traten Erbrechen, Bewußtlosigkeit, gepreßte Atmung, Zyanose und Muskelzuckungen auf, die sich zu einem tonisch-klonischen Krampfzustand ausweiteten. Innerhalb von 15 Minuten werden 7mal 2 mg des symptomatisch wirkenden Antidots Atropin intravenös injiziert. Jede Dosis bewirkt eine kurzfristige Besserung der Atmung, der Zyanose, die Krämpfe verschwinden. Eine erneute Verschlechterung nach 1 Stunde wurde wiederum durch Injektion von 2 mg Atropin aufgehalten. Diese Atropingaben wirkten bis zur Beschaffung des spezifischen Antidots PAM (Pyridin-aldoxim-(2)-methojodid) nach 2 Stunden lebensrettend. 10 Minuten nach i.v. Gabe von 0,5 g PAM in 50 ccm 1%iger Lösung tritt eine entscheidende Besserung ein. Die drohende Atemlähmung wird aufgehoben. Der Patient kommt zu Bewußtsein, die PAM-Injektion wird nach 2 Stunden wegen der Nachresorption von E 605 wiederholt. Die kombinierte Behandlung mit Atropin und PAM, möglichst bei gleichzeitiger künstlicher Beatmung, stellt heute die optimale Behandlung bei Vergiftungen mit Alkylphosphaten dar. An Hand des Verhaltens der Blutesterase-Aktivität im Verlaufe der Vergiftung konnten Erfolg und Grenzen der spezifischen Behandlung erklärt werden.
Summary
The case is reported of a 29-year-old man who drank 12 ml. of the insecticide E 605 forte (this amount corresponds to 6 Gm. of diethyl-p-nitrophenyl-thiophosphate), 10 to 20 times the lethal dose. He was admitted to hospital 15 minutes later. There was vomiting, unconsciousness, depressed respiration, cyanosis, and muscle twitching, which changed into tonic-clonic spasms. Within 15 minutes atropine was injected intravenously 7 times 2 mg. Each dose caused a short-lived improvement in respiration, the cyanosis and the cramps ceased. Deterioration after one hour was again successfully treated with 2 mg. of atropine. Atropine administration was successful until the administration of the specific antidote P.A.M. (2-hydroxyimino-methyl-N-methyl pyridinium iodide) 2 hours later. 10 minutes after intravenous administration of 0.5 Gm. P.A.M. in 50 ml. there occurred a decisive improvement. Consciousness was regained. P.A.M. injection was repeated after 2 hours when there was delayed absorption of E 605. The combined administration of atropine and P.A.M. in conjuction with artificial ventilation is considered to be the optimal treatment today of poisoning by alkyl phosphates. — E 605 acts as an inhibitor of cholinesterase. The enzyme activity of cholinesterase in whole blood was followed in the course of the poisoning; in vivo and in vitro experiments showed its reactivation by P.A.M.
Resumen
El tratamiento positivo de una intoxicación de E 605 fuerte con Atropina y el reactivador de esterasa PAM
Un hombre de 29 años había bebido 12 cms.³ del insecticida E 605 fuerte, que corresponden a 6 grs. de dietilo-p-nitrofenil-tiofosfato, representando 10—20 veces la dosis mortal. 15 minutos después ingresó en la clínica, presentándose vómitos, inconsciencia, respiración dificultosa, cianosis y sacudidas musculares, desembocando en un estado convulsivo tónico-clónico. En 15 minutos se inyectaron por vía intravenosa, 7 veces, 2 mgrs. de Atropina, antídoto de efecto sintomático. Cada dosis produce una mejoría breve de la respiración y cianosis, desapareciendo las convulsiones. Un empeoramiento pasajero, después de 1 hora, fué parado inyectando nuevamente 2 mgrs. de Atropina. Estas dosis de Atropina salvaron la vida del enfermo hasta conseguir el antídoto específico PAM (piridina-aldoxima-(2)-metoyoduro), 2 horas después. 10 minutos después de la administración intravenosa de 0,5 gr. de PAM en 50 cms.³ de solución al 1% se inició una mejoría decisiva. El enfermo recuperó el conocimiento. La inyección de PAM es repetida a las 2 horas en atención a la resorción postrera de E 605. — El tratamiento combinado con Atropina y PAM, simultáneamente con la respiración artificial, representa en la actualidad la terapia óptima en los casos de intoxicación con fosfatos alquílicos. El E 605 motiva una inhibición de la colinesterasa. Su actividad fermentativa en la sangre total fué perseguida en el transcurso de la intoxicación, demostrándose la reactivación por PAM en ensayos «in vivo» e «in vitro», respectivamente.
The prompt antidotal effect of PAM (pyridine-2-aldoxime methiodide) in alkylphosphate poisoning was demonstrated in five cases here reported. The patients were all farm workers who had been spraying fields with parathion. Cholinesterase determinations in both serum and erythrocytes were carried out and clearly showed the inhibitory effect of the parathion upon the enzyme. Intravenous administration of PAM relieved some of the symptoms instantly, and cholinesterase determinations demonstrated the reactivation of the enzyme. PAM was effective after either oral or parenteral administration and could be given in adequate doses without disagreeable side-effects. It also relieved certain symptoms, such as muscular fasciculation, that are not relieved by atropine.
Es wird eine neue Methode zum Nachweis des Fermentes, das Acetylcholin in Cholin und Essigsure hydrolysiert, die Cholinesterase, beschrieben. Das Verfahren ist nach derWarburgschen Methode aufgebaut.Versuche mit Zusatzkrpern zeigen, da das Physostigmin, Prostigmin und Gynergen, die die schon mit anderen biologischen Methoden nachgewiesene fermentative Acetylcholinhydrolyse total hemmen, auerordentlich starke Hemmungskrper fr die Cholinesterase sind. Das Muscarin hat von den untersuchten vegetativ wirksamen Krpern auch einen stark hemmenden Einflu auf das Ferment. Eine Reihe anderer Stoffe hemmen die Acetylcholinspaltung erst in hheren Konzentrationen (Milligrammdosen).Einige Versuche mit Esteraseprparaten verschiedenster Herkunft legen die Vermutung nahe, die Cholinesterase als ein besonderes Ferment anzusprechen.
1.1. The origin, nature and function of the serum cholinesterase is discussed.2.2. Values for serum cholinesterase activity in 120 healthy individuals, as determined by Michel's simple electrometric method, are presented.3.3. Changes in serum cholinesterase activity are described in a variety of disease states. In general, low levels are found in patients ill with liver disease, malnutrition and chronic debilitating diseases, acute infectious diseases and anemias. Normal levels are observed in patients ill with uncomplicated obstructive jaundice, myasthenia gravis, hyperthyroidism, asthma, hypertension, epilepsy, diabetes mellitus and many other diseases. High levels occur in the nephrotic syndrome.4.4. Changes in serum cholinesterase activity following administration of a variety of drugs are described.5.5. Evidence is presented to support the concept that the serum cholinesterase molecule is synthesized in the liver in parallel with the albumin molecule and that it has a life span of approximately twenty-eight days.
The mechanism responsible for the protection against lethal organophosphate poisoning by pyridine-2-aldoxime methiodide (P-2-AM) was studied in the mouse. Two types of organophosphates were used: ethyl pyrophosphate (TEPP), E 600, Ro 3–0340, and Ro 3–0422 which form with true cholinesterase a diethylphosphoryl enzyme (1) and DFP, D 600 and Ro 3–0351 which form with true cholinesterase a diisopropylphosphoryl enzyme (2).
In vitro and under the experimental conditions used more than 50% reactivation of (1) was obtained within 1 hr. by concentrations of P-2-AM ranging from 0.5 to 1 × 10−6m; 30 times higher concentrations of the oxime were required to achieve the same effect with (2). In vivo reactivation of phosphorylated true cholinesterases in blood amounted to 10 to 24% within the first 30 min. if 25 mg./kg. P-2-AM was injected (i.p.) 5 min. before a sublethal dose of TEPP, E 600, Ro 3–0340, or Ro 3–0422 and reactivation reached a maximum within 1 to 2 hr. after the injection of the oxime. P-2-AM was more effective when given 30 min. after the organophosphate. The effect of 25 mg./kg. P-2-AM on the phosphorylated true cholinesterase in brain (experiments with TEPP and E 600) was negligible. A dose of 25 mg./kg. P-2-AM had no consistent effect on the phosphorylated true cholinesterases in blood and brain of mice injected with sublethal doses of DFP, D 600, or Ro 3–0351.
The protection by 25 mg./kg. P-2-AM against lethal doses of TEPP, E 600, Ro 3–0422, and Ro 3–0340 was greater than that obtained with 50 mg./kg. atropine sulphate, but the degree of protection was determined by the organophosphate itself and not its dialkylphosphoryl group. Protection by 25 mg./kg. P-2-AM against lethal doses of DFP, D 600, and Ro 3–0351 was negligible. The antidotal effect of P-2-AM was potentiated by atropine. Mice which were injected with atropine and P-2-AM were protected to a greater extent against DFP than against Ro 3–0422, and protection against DFP was only slightly less than protection against TEPP. This is difficult to reconcile with a specific action of P-2-AM on phosphorylated cholinesterases.
Ebaugh: Use of diisopropylfluorophosphate32 for determination of in vivo red cell survival and plasma cholinesterase turnover rates
- J R Bove
- J. R. Bove
Robins: The reversal by oximes of neuromuscular block produced by anticholinesterases
- R Holmes
- R. Holmes