No abstract

1 In vitro studies with human erythrocyte acetylcholin esterase (AChE) and the mouse diaphragm model were performed to unravel the various microscopic reaction parameters that contribute to the dynamic equilibrium of AChE inhibition, ageing and reactivation. These data may help to define more precisely the indications and limitations of oxime therapy in organophosphate (OP) poisoning. 2 Diethylphosphoryl-AChE resulting from intoxications with parathion, chlorpyrifos, chlorfenvinphos, diazi non and other OPs is characterized by slow sponta neous reactivation and low propensity for ageing. This kind of phosphorylated enzyme is particularly sus ceptible to reactivation by oximes. 3 None of the oximes tested (pralidoxime, obidoxime, HI 6 and HLö 7) can be regarded as a universally suitable reactivator. Obidoxime turned out to be the most potent and most efficacious oxime in reactivating AChE inhibited by various classes of OP insecticides and tabun. Obidoxime, however, was inferior to HI 6 against soman, sarin, cyclosarin and VX. Pralidoxime was generally less potent. 4 The kinetic data of reactivation established for diethylphosphoryl-AChE of human red cells indicate that the usually recommended dosage to attain a plasma concentration of 4 μg/ml does not permit exploitation of the full therapeutic potential of the oximes, in particular of pralidoxime. However, in suicidal mega-dose poisoning, oximes, even at optimal plasma concentrations, may be unable to cope with the fast re-inhibition of reactivated AChE in the first days following intoxication. 5 It is suggested that oximes be administered by continuous infusion following an initial bolus dose as long as reactivation can be expected and until permanent clinical improvement is achieved.

1 The effectiveness of oxime therapy in organophos phate poisoning is still a matter of debate. It appears, however, that the often cited ineffectiveness of oximes may be due to inappropriate dosing. By virtue of in vitro findings and theoretical considerations we concluded in the preceding paper that oximes should preferably be administered by continuous infusion following an initial bolus dose for as long as reactiva tion of inhibited acetylcholinesterase (AChE) can be expected. This conclusion has called for a clinical trial to evaluate such oxime therapy on the basis of objective parameters. 2 Before transfer to the intensive care unit (ICU), 5 patients received primary care by an emergency physician. In the ICU, atropine sulphate was adminis tered IV upon demand according to the endpoints: no bronchorrhoea, dry mucous membranes, no axillary sweating, heart rate of about 100/min. Obidoxime (Toxogonin®) was given as an IV bolus (250 mg) followed by continuous infusion of 750 mg/24 h. 3 Intoxication and therapy were monitored by determin ing erythrocyte AChE (eryAChE) activity, reactivat ability of the patient's eryAChE ex vivo, plasma cholinesterase activity, the presence of AChE inhibit ing compounds, as well as the concentrations of obidoxime and atropine in plasma. 4 Obidoxime was effective in life-threatening parathion poisoning, in particular when the dose absorbed was comparably low. In mega-dose poisoning, net reacti vation was not achieved until several days after ingestion, when the concentration of active poison in plasma had declined. Reactivatability in vivo lasted for a longer period than expected from in vitro experiments. 5 Obidoxime was quite ineffective in oxydemeton- methyl poisoning, when the time elapsed between ingestion and oxime therapy was longer than 1 day. When obidoxime was administered shortly after ingestion (1 h) reactivation was nearly complete. 6 Obidoxime levels of 10-20 μM were achieved by our regimen, and atropine could rapidly be reduced to approx. 20 nM, as attained by continuous infusion of 1 mg atropine sulphate/h. Maintenance of the desired plasma levels was not critical even when renal function deteriorated. 7 Signs of transiently impaired liver function were observed in patients who showed transient multi- organ failure. In the present stage of knowledge, we feel it advisable to keep the plasma concentration of obidoxime at 10 - 20 μM, although the full reactivating potential of obidoxime will not then be exploited. Still, the reactivation rate, with an apparent half-time of some 3 min, is twice that estimated for a tenfold higher pralidoxime concentration.

HLö 7 dimethanesulfonate (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2,4-bis [(hydroxyimino)methyl]pyridinium dimethanesulfonate) is a broad-spectrum reactivator against highly toxic organophosphorus compounds. The compound was synthesized by a new route with the carcinogenic bis(chloromethyl)ether being substituted by the non-mutagenic bis(methylsulfonoxymethyl)ether. The very soluble dimethanesulfonate of obidoxime was also prepared by this way. HLö 7 dimethanesulfonate is the first water-soluble salt of HLö 7 that should be suitable for the wet/dry autoinjector technology, because aqueous solutions of HLö 7 are not very stable (calculated shelf-life 0.2 years when stored at 8 degrees C, 1 M solution, pH 2.5). The crystalline preparation contains 96% of the syn/syn-isomer, less than 2% of the syn/anti-isomer and some minor identified by-products. HLö 7 was very efficient in reactivating acetylcholinesterase (AChE) blocked by organophosphates as long as ageing did not prevent dephosphylation. HLö 7 was superior to HI 6 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2- [(hydroxyimino)methyl]pyridinium dichloride) in reactivating soman and sarin-inhibited AChE from erythrocytes, and literature data indicate that HLö 7 exceeds HI 6 by far in reactivating tabun-inhibited AChE. In atropine-protected, soman-poisoned mice HLö 7 was three times more potent than HI 6 (protective ratio 5 versus 2.5), and in sarin-poisoned mice HLö 7 was 10 times more potent than HI 6 (protective ratio 8 for both oximes). In atropine-protected guinea-pigs HLö 7 was less effective than HI 6 (protective ratio: 2.3 versus 5.2 for soman; 5.2 versus 6.8 for sarin; 4.3 versus 3.8 for tabun). The mean survival time of anaesthetized guinea-pigs exposed to 5 LD50 soman (6.3 min) was increased by atropine (27 min) and atropine + HLö (57 min). HLö 7 alone did not prolong the survival. The most impressive effect of HLö 7 was on respiration: 3 min after i.v. injection of HLö 7 and atropine, the depressed respiration increased rapidly to 60% of control and remained at that level during the observation period (60 min). With atropine alone, respiration recovered only slowly. Behavioural and physiologic parameters were determined in atropine-protected mice exposed to a sublethal soman dose. The running performance was significantly improved by HLö 7. Even central symptoms, e.g. hypothermia and convulsions, were decreased markedly by HLö 7 (evaluation 60 min after poisoning). The pharmacokinetic data for HLö 7 in male beagle dogs are similar to those of HI 6.(ABSTRACT TRUNCATED AT 400 WORDS)

The cyanide antidote 4-dimethylaminophenol . HCl (DMAP) was administered orally, i.v., or i.m. to man and dog. Ferrihemoglobin formation and changes of several parameters in human blood were investigated to obtain information on damage to liver, kidney, muscle, and red blood cells; in addition, the metabolism of DMAP was studied. In dogs, the initial rate of ferrihemoglobin production (DMAP, 3.25 mg/kg i.v. or i.m., 15 mg/kg orally) amounted to 28%, 3.5%, and 2% of the total hemoglobin per min; the corresponding values for man were 9%, 2%, and 2% per min. The dogs behaved normally while CPK increased after i.m. injection. In man, only i.m. injection of DMAP (3.25 mg/kg) was followed by increases in LDH, GOT, and CPK of 110, 260, and 490%, resp.; while total bilirubin, conjugated bilirubin, and iron concentration rose by 270, 120, and 50%, respectively. Bilirubin and iron concentration increased also after DMAP i.v. (3.25 mg/kg) or when it was taken orally (600 or 900 mg). The lactate concentration was not influenced while the pyruvate concentration increased by 50%. DMAP produced hemolysis in vitro. Generally, the values determined in vivo approached the starting level within 1 week. Intramuscular injection of DMAP induced reversible subjective and objective symptoms, e.g., local pain, swollen buttock, fever reaction. The urine showed no pathological changes. About 54% of DMAP taken orally was excreted as metabolites in the urine, 41% as glucuronide, 7% as sulfate, and 6% as thioethers. After i.v. administration the total of metabolites was somewhat higher, and the thioether proportion was 15%. The results indicate that DMAP is readily absorbed after oral administration but undergoes significant first pass effect in the liver. Therefore, the 4-fold i.v. dose must be administered orally to achieve the same ferrihemoglobin formation.