Oxime Treatment Research Articles

Carbamate Poisoning and Oxime Treatment in Children: A Clinical and Laboratory Study

(1) Retrospective evaluation of the clinical course of carbamate poisoning and the effect of oxime therapy in children. (2) In vitro study of the effect of oximes on the reactivation of carbamylated cholinesterase. (1) Clinical survey: The records of 26 children intoxicated with carbamates were examined retrospectively. The poisoning agents in all cases were positively identified as methomyl or aldicarb by gas chromatography-mass spectrometry. (2) Laboratory study: The direct effect of obidoxime and of pralidoxime on acetylcholinesterase activity in vitro was investigated in normal human packed red blood cells pretreated with an organophosphate (paraoxon) or a carbamate (aldicarb or methomyl). Pediatric intensive care unit of a teaching hospital. Twenty-six infants and young children (aged 1 to 8 years) admitted to the pediatric intensive care unit with severe carbamate intoxication. All cases had been treated with repeated doses of atropine sulfate (0.05 mg/kg) administered every 5 to 10 minutes until muscarinic symptoms disappeared. Obidoxime chloride (Toxogonin, 6 mg/kg) was administered on admission, and again after 4 to 5 hours. Predominant symptoms were related to central nervous system and nicotinic effects. All the patients showed marked improvement within several hours and recovered completely within 24 hours. None of the children deteriorated and none showed exacerbation of cholinergic symptoms after obidoxime treatment. In vitro, oximes reactivated acetylcholinesterase inhibited with paraoxon, whereas no significant effect of oximes on carbamylated enzyme activity was observed. Based on the recovery of all cases, as compared with other reports of carbamate poisoning treated with atropine alone, it is concluded that, in the case of aldicarb or methomyl poisoning, oxime therapy apparently does not contribute to the recovery of poisoned patients. In cases of poisoning by an unknown pesticide or of mixed poisoning, oxime therapy can prove beneficial because no negative effects of the therapy can be discerned.

Effect of pyridostigmine pretreatment, HI-6 and Toxogonin treatment on rat tracheal smooth muscle response to cholinergic stimulation after organophosphorus inhalation exposure.

The ex vivo contraction response of the rat tracheal smooth muscle was examined after 10 min in vivo inhalation of soman and/or pretreatment with pyridostigmine and/or post-exposure treatment with HI-6 ([[[(4-aminocarbonyl)pyridinio]methoxy]methyl]-2[(hydroxy imino) methyl]pyridinium dichloride) or Toxogonin (1,1'-[oxybis-(methylene)]bis[4-[(hydroxyimino)methyl]-py rid inium] dichloride). In vivo pretreatment with pyridostigmine was achieved by subcutaneous (s.c.) implantation of an osmotic pump that delivered pyridostigmine continuously (0.01 mg/h) in the neck region of the rat 18 h before soman exposure. The ex vivo cholinergic tracheal smooth muscle response increased during the first 60 min after soman exposure in animals pretreated with pyridostigmine. The amplitude of the contraction response in pyridostigmine pretreated animals was about 60% of control, compared to 15% of control without pyridostigmine pretreatment. Pyridostigmine pretreatment also produced significant recovery of the total cholinesterase (ChE) activity in plasma, but not in trachea and lung. Intraperitoneal (i.p.) injection of HI-6 or Toxogonin (50 mg/kg), immediately after 10 min inhalation exposure to soman, also significantly improved the ex vivo cholinergic contraction response of the trachea (decapitation 15 min after oxime administration). The recovery of the physiological response with Toxogonin was, however, not stable. HI-6 was superior to Toxogonin with respect to the initial airway contraction response, and the response increased up to a stable level not significantly different from control. There was no significant reactivation of the ChE activity after treatment with the oximes. Combination of pyridostigmine pretreatment and oxime treatment enhanced the recovery of the tracheal contraction response and the ChE activity in the trachea compared to treatment with oximes alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Atropine and Oxime Treatment in Lethal Soman Poisoning of Anaesthetized Guinea‐pigs: HLö 7 Dimethanesulfonate Versus HI 6 Dichloride

The oxime HI 6 is considered to be effective in soman poisoning and less effective in tabun poisoning. Recently, HLö 7 was shown to reactivate acetylcholinesterase (AChE) inhibited by soman and tabun. Therefore, the efficacy of HLö 7 and HI 6 was compared in soman poisoned guinea-pigs. Female Pirbright-white guinea-pigs were anaesthetized with urethane (1.8 g/kg) and the a. carotis, v. jugularis and trachea were cannulated. After base line measurements soman 0.08 mg/kg (= 5 x LD50) or 0.16 mg/kg (= 10 x LD50) was injected intravenously, 2 min. later the antidotes were applied intravenously: HLö 7 0.03 or 0.1 mmol/kg, HI 6 0.03 or 0.1 mmol/kg, atropine 10 mg/kg, or a combination of atropine and an oxime. Respiratory and circulatory parameters were recorded for 60 min. or until the death of the animal. The injection of 5 x LD50 soman resulted in a rapid respiratory arrest followed by circulatory failure in the soman and soman plus oxime groups (survival time about 7 min). Atropine restored the circulatory parameters to base line but was unable to provide a sufficient respiratory function (survival time 26 min.). The combination therapy with atropine plus HLö 7 or HI 6 improved the respiration sufficiently, restored the circulation completely, and prolonged the survival time to about 50 min. Atropine treatment was insufficient in animals poisoned with 10 x LD50 soman. The combination of atropine and HLö 7 or HI 6 improved respiration, circulation, and survival time to various extent. Despite of the striking therapeutic effect no reactivation of erythrocyte AChE by the antidotes was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Reductive Beckmann's Type Fragmentation of α-Amino Oximes by Sodium Borohydride: A New Synthetic Pathway to ω-Amino Nitriles

Treatment of cyclic α-amino oximes with sodium borohydride in acetonitrile is a new convenient route to ω-amino nitriles.

Evaluation of the toxicity, pathology, and treatment of cyclohexylmethylphosphonofluoridate (CMPF) poisoning in rhesus monkeys.

Cyclohexylmethylphosphonofluoridate (CMPF) is an organophosphate cholinesterase inhibitor with military significance. The purpose of these studies was 1) to determine the acute toxicity of CMPF in the male rhesus monkey, 2) to evaluate the efficacy of pyridostigmine (PYR) pretreatment plus atropine and oxime (2-PAM or H16) treatment, and 3) to evaluate the pathological consequences of acute poisoning. An i.m. LD50 of CMPF was estimated using an up-and-down dose selection procedure and 12 animals. The 48-h and 7-day LD50 was 46.6 micrograms/kg, i.m. In the protection experiments, pyridostigmine (0.3-0.7 mg/kg/24 h) was administered by surgically implanted osmotic minipumps for 3-12 days resulting in 21-65% inhibition of erythrocyte acetylcholinesterase activity. Animals were challenged with 5 x L50 CMPF (233 micrograms/kg) and treated with atropine (0.4 mg/kg) and either 2-PAM (25.7 mg/kg) or HI6 (37.8 mg/kg) at the onset of signs or 1 min after challenge. Osmotic pumps were removed within 30 min after agent challenge. Pyridostigmine, atropine, and either 2-PAM or H16 were completely effective against CMPF, saving ten of ten animals in each group. In comparison, three of five animals challenged with 5 x LD50 of soman and treated with atropine and 2-PAM survived 7 days. The primary histologic lesions in the acute toxicity group were neuronal degeneration/necrosis and spinal cord hemorrhage. The CMPF treated groups (total of 20 animals) had minimal nervous system changes with no significant lesion difference resulting from the different oxime therapies. The primary non-neural lesions were degenerative cardiomyopathy and skeletal muscle degeneration which occasionally progressed to necrosis and mineralization.(ABSTRACT TRUNCATED AT 250 WORDS)

HI-6 in Man: Efficacy of the Oxime in Poisoning by Organophosphorus Insecticides

The efficacy of the oxime HI-6 was studied as a treatment for organophosphorus poisoning. HI-6 was given four times daily as a single intramuscular injection of 500 mg accompanied by atropine and diazepam therapy. Oxime treatment was started on admission and continued for a minimum of 48 h and a maximum of 7 d. HI-6 rapidly reactivated human blood acetylcholinesterase inhibited by dimethoxy organophosphorus compounds, while the dimethoxy-inhibited enzyme was mainly resistant to the treatment by HI-6. Although both HI-6 and pralidoxime chloride reactivated the red blood cell cholinesterase in quinalphos-poisoned subjects, the return of enzyme activities was more rapid following the use of HI-6. The general improvement of poisoned patients, which was sometimes more rapid than the rise of acetylcholinesterase activity, pointed to direct pharmacological effects of HI-6. No undesirable side-effects were noted in patients when HI-6 plasma concentrations were maintained at levels far above the 'therapeutic' concentration for up to 7 d.

A novel tertiary pyridostigmine derivative [3-( N, N-dimethylcarbamyloxy)-1-methyl-Δ 3-tetrahydropyridine]: Anticholinesterase properties and efficacy against soman

In an effort to develop an effective centrally acting pretreatment compound against organophosphorus poisons, the tertiary pyridostigmine (Pyr) derivative 3-( N, N-dimethylcarbamyloxy)-1-methyl-Δ 3-tetrahydropyridine (THP) was synthesized and studied for its anticholinesterase properties, as well as its efficacy against soman intoxication in guinea pigs. Injection of THP (262 μg/kg, im) into adult male guinea pigs caused inhibition of blood (30%) and brain (25%) acetylcholinesterase (AChE), showing that THP penetrates the blood-brain barrier. Pyr (131 μg/kg, im) caused AChE inhibition in the blood (59%), but not in the brain. The inhibitory potencies of THP and Pyr were compared by determining their IC50 values for in vitro inhibition of both AChE (brain, erythrocyte) and pseudo-cholinesterase (plasma) in three mammalian species (guinea pig, rat, rabbit). THP, although effective in inhibiting both types of cholinesterase, was in general less potent than Pyr. Pretreatment of guinea pigs with THP 9262 μg/kg, im) plus Pyr (131 μg/kg, im), 30 min prior to subcutaneous soman challenge, with no antimuscarinic or oxime treatment, protected 60% of the animals against 2 × LD50 of soman. Neither THP nor Pyr alone was effective. The protective pretreatment regimen did not prevent convulsions, but shortened the recovery time in surviving animals (median recovery time 1.6 hr, compared to 24 hr in control and other groups of animals pretreated with THP or Pyr alone). A combination of THP and Pyr thus appears to provide a means of evaluating the relative importance of selective peripheral plus central vs peripheral AChE protection against soman.

Organophosphate poisoning: a method to test therapeutic effects of oxamines other than acetylcholinesterase activation in the rat

A method was developed to study exlusively those therapeutic effects of oximes that are not related to reactivation of organophosphate-inhibited acetylcholinesterase (AChE). The model uses the organophosphorus compound crotylsarin (CRS), which proved to be a potent, irreversible, peripherally and centrally active AChE inhibitor with a very short biological half-life. CRS inhibited AChE appeared to age very rapidly, because in vitro addition of oximes immediately following inbition, did not result in any AChE reactivation. Anesthetized, atropinized and artificially ventilated rats were intoxicated with 3 × LD 50 CRS and treated 5 min later with the bipysridinuime HI-6. Fifty percent of these animals survived more than 24 h following termination of artificial ventilation at 10 min after oxime treatment. The mean survival time of the remaining was 66 min, whereas all untreated animals died within 4 min HI-6, when added in vitro to isolated intact hemidiaphragms of brain homogenates from rat which had been killed 1 min following 3 × LD 50 CRS, failed to reactive the inhibited AChE. If blood was sampled (before and) after HI-6 administration to CRS-intoxicated rats. no HI-6 induced AChE ractviation was observed. Yet, a clear improvement of molecular of the neuromuscular transmission in the hindleg muscles of these animals was found following HI-6 injection. With this model, decisive evidence is obtained that non-reactivating effects of HI-6 by themselves are therapeutically relevant.

ChemInform Abstract: Thermal Reactions of Arylamidoximes.

AbstractIn contrast to previous work, which demonstrated the need for an acid in the transformation of arylamidoximes to bis‐aryl‐oxadiazoles, it is shown now that the thermal treatment of oximes, e.g. (I), also leads to the desired oxadiazoles such as (II).

ChemInform Abstract: REGENERATION OF KETONES FROM HYDRAZONES, OXIMES, AND SEMICARBAZONES BY BENZENESELENINIC ANHYDRIDE

AbstractDie Steroid‐Ketone (I)‐(IV) werden durch Behandlung ihrer Hydrazone, Oxime und Semicarbazone mit dem Anhydrid (V) in Tetrahydrofuran bei 50‐60°C in guten Ausbeuten erhalten.

Regeneration of ketones from hydrazones, oximes, and semicarbazones by benzeneseleninic anhydride

Treatment of ketone hydrazones, oximes, and semicarbazones with benzeneseleninic anhydride readily affords the parent carbonyl compound in good yields, even in cases resistant to known methodology.

ChemInform Abstract: AN IMPROVED SYNTHESIS OF 13‐EPI‐STEROIDS

Treatment of oximes of 17-keto steroids with refluxing acetic anhydride and pyridine, and acid hydrolysis of the resulting enamides, constitutes an efficient route to 13-epi-17-keto-steroids; this observation is evidence that the former reaction proceeds by a freeradical pathway.

An improved synthesis of 13-epi-steroids

Treatment of oximes of 17-keto steroids with refluxing acetic anhydride and pyridine, and acid hydrolysis of the resulting enamides, constitutes an efficient route to 13-epi-17-keto-steroids; this observation is evidence that the former reaction proceeds by a freeradical pathway.

The effect of oximes on isolated organs intoxicated with organophosphorus anticholinesterases

The oxime concentration needed for “complete functional recovery” of the isolated diaphragm treated with organophosphorus anticholinesterases, varies considerably with the inhibitor used. After Soman “aging” of the inhibitor—cholinesterase combination product is completed in about 60 min. With the other anticholinesterases used, “aging” cannot be observed within 4–6 hr. The degree of functional recovery observed can be correlated with the percentage reactivation of the acetylcholinesterase in the diaphragm. The marked variation in the oxime concentration needed to counteract the effect of different anticholinesterases, was confirmed using the isolated rat hind-quarter preparation perfused with blood and using the isolated rat ileum. In contrast to this the dose of atropin needed to counteract various inhibitors in the rat ileum shows very little variation. It is concluded that two factors are important in the oxime treatment of anticholinesterase poisoning, i.e. the effective oxime concentration and the “aging” rate. The relative preponderance of these factors varies with the anticholin-esterase used.

THE INDUCTION OF METHEMOGLOBINEMIA AS AN ADJUNCT TO THERAPY FOR TABUN POISONING

The protective and therapeutic effectiveness of p-aminopropiophenone (PAPP) against tabun poisoning in the rat has been examined. The relationship between dosage of PAPP and percentage of methaemoglobin in the blood of the rat has been determined.Treatment of rats with PAPP both alone and in conjunction with atropine gave no evidence of protection against tabun poisoning. In combination with oxime treatment, PAPP improved protection against the use of monoisonitrosoacetone (MINA) by a factor of 4, but was less effective with diacetylmonoxime (DAM) and N-methylpyridinium-2-aldoxime methanesulphonate (P-2-S). The highest net protection from oxime and PAPP therapy was obtained with two members of the bisquaternary pyridinium-4-aldoxime alkanes, one member of which in the presence of PAPP protected rats from 23 LD50's of tabun.

THE INDUCTION OF METHEMOGLOBINEMIA AS AN ADJUNCT TO THERAPY FOR TABUN POISONING

The protective and therapeutic effectiveness of p-aminopropiophenone (PAPP) against tabun poisoning in the rat has been examined. The relationship between dosage of PAPP and percentage of methaemoglobin in the blood of the rat has been determined.Treatment of rats with PAPP both alone and in conjunction with atropine gave no evidence of protection against tabun poisoning. In combination with oxime treatment, PAPP improved protection against the use of monoisonitrosoacetone (MINA) by a factor of 4, but was less effective with diacetylmonoxime (DAM) and N-methylpyridinium-2-aldoxime methanesulphonate (P-2-S). The highest net protection from oxime and PAPP therapy was obtained with two members of the bisquaternary pyridinium-4-aldoxime alkanes, one member of which in the presence of PAPP protected rats from 23 LD50's of tabun.