Stewart JR

References (5)

Title : A comparison of the efficacy of HI6 and 2-PAM against soman, tabun, sarin, and VX in the rabbit - Koplovitz_1994_Toxicol.Lett_70_269
Author(s) : Koplovitz I , Stewart JR
Ref : Toxicology Letters , 70 :269 , 1994
Abstract : This study compared the efficacy of HI6 and 2-PAM against nerve agent (soman, tabun, sarin, and VX)-induced lethality in the atropinesterase-free rabbits pretreated with vehicle (controls) or pyridostigmine. Treatment was administered at signs or 2 min after agent challenge and consisted of oxime (100 mumol/kg) + atropine (13 mg/kg) (alone or together with diazepam). Twenty-four-h LD50 values were calculated for soman- and tabun-intoxicated animals, whereas 24-h survival was noted in animals given 10 LD50s of sarin or VX. In pyridostigmine and control rabbits intoxicated with soman and treated with oxime + atropine (alone or together with diazepam), HI6 was 3-5 times more effective than 2-PAM. In contrast, HI6 was less effective than 2-PAM against tabun poisoning. In pyridostigmine-pretreated animals exposed to tabun, efficacy was increased more than 3-fold when compare to tabun-challenged animals treated with atropine + HI6 alone. Both oximes were highly effective against sarin and VX. These findings suggest that HI6 could replace 2-PAM as therapy for nerve agent poisoning, because it is superior to 2-PAM against soman, and when used in pyridostigmine-pretreated animals, it affords excellent protection against all four nerve agents when used in combination with atropine (alone or together with diazepam) therapy.
ESTHER : Koplovitz_1994_Toxicol.Lett_70_269
PubMedSearch : Koplovitz_1994_Toxicol.Lett_70_269
PubMedID: 8284794

Title : Efficacy of oxime plus atropine treatment against soman poisoning in the atropinesterase-free rabbit - Koplovitz_1992_Drug.Chem.Toxicol_15_117
Author(s) : Koplovitz I , Stewart JR
Ref : Drug & Chemical Toxicology , 15 :117 , 1992
Abstract : The oximes pralidoxime chloride (2-PAM), MMB4, and HI-6 were evaluated in combination with atropine as treatments against soman poisoning in atropinesterase-free rabbits. Animals were challenged i.m. with 2 x LD50 soman and treated at the onset of toxic signs with 50 mumols/kg of oxime and 5 or 13 mg/kg atropine. Survival and time to death were compared at 48 hours post-soman challenge. Survival rates in MMB4 and HI-6 treated animals were higher than in 2-PAM-treated animals. The increase in survival was significant at the 13 mg/kg dose of atropine. MMB4 and HI-6 also significantly delayed time to death after soman compared to 2-PAM. The results suggest that MMB4 and HI-6 have potential as useful oximes for treating soman poisoning.
ESTHER : Koplovitz_1992_Drug.Chem.Toxicol_15_117
PubMedSearch : Koplovitz_1992_Drug.Chem.Toxicol_15_117
PubMedID: 1597126

Title : Reduction by pyridostigmine pretreatment of the efficacy of atropine and 2-PAM treatment of sarin and VX poisoning in rodents - Koplovitz_1992_Fundam.Appl.Toxicol_18_102
Author(s) : Koplovitz I , Harris LW , Anderson DR , Lennox WJ , Stewart JR
Ref : Fundamental & Applied Toxicology , 18 :102 , 1992
Abstract : This study concerned the effect of pyridostigmine pretreatment on (a) the antidotal efficacy of atropine and 2-PAM in sarin, tabun, and VX poisoning in mice and guinea pigs and on (b) the oxime-induced reactivation of VX-inhibited whole blood acetylcholinesterase (AChE) of guinea pigs. One hour prior to organophosphate (OP) challenge with sarin, tabun, or VX, animals were given oral doses of pyridostigmine to induce approximately 30 and 60% inhibition of whole blood AChE; controls received vehicle. Mice were challenged im and guinea pigs sc with the OP compounds. Treatment with atropine (11.2 mg/kg to mice; 32 mg/kg to guinea pigs) plus 2-PAM (25 mg/kg) was given im at 10 sec postchallenge in mice and 1 min postchallenge in guinea pigs. In the reactivation experiments, pyridostigmine or saline was given im to guinea pigs 30 min prior to VX (8.24 micrograms/kg, sc), atropine (16 mg/kg) was given im at 1 min, and 2-PAM (25 mg/kg) at 16 min postchallenge. Pyridostigmine significantly enhanced the efficacy of atropine and 2-PAM against tabun in both species. In contrast, pyridostigmine reduced or did not increase the efficacy of atropine and 2-PAM against sarin or VX in both species. Recovery of VX-inhibited AChE by 2-PAM was decreased significantly in pyridostigmine pretreated animals. The results suggest that pyridostigmine pretreatment may adversely effect the efficacy of atropine and 2-PAM as antidotes for VX and sarin intoxication.
ESTHER : Koplovitz_1992_Fundam.Appl.Toxicol_18_102
PubMedSearch : Koplovitz_1992_Fundam.Appl.Toxicol_18_102
PubMedID: 160120

Title : Evaluation of the toxicity, pathology, and treatment of cyclohexylmethylphosphonofluoridate (CMPF) poisoning in rhesus monkeys - Koplovitz_1992_Arch.Toxicol_66_622
Author(s) : Koplovitz I , Gresham VC , Dochterman LW , Kaminskis A , Stewart JR
Ref : Archives of Toxicology , 66 :622 , 1992
Abstract : 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.
ESTHER : Koplovitz_1992_Arch.Toxicol_66_622
PubMedSearch : Koplovitz_1992_Arch.Toxicol_66_622
PubMedID: 1482284

Title : Pharmacokinetics and pharmacodynamics of oximes in unanesthetized pigs - Stemler_1991_Fundam.Appl.Toxicol_16_548
Author(s) : Stemler FW , Tezak-Reid TM , McCluskey MP , Kaminskis A , Corcoran KD , Shih ML , Stewart JR , Wade JV , Hayward IJ
Ref : Fundamental & Applied Toxicology , 16 :548 , 1991
Abstract : The pharmacokinetics and cardiovascular pharmacodynamics of two oximes were studied in unanesthetized pigs. Effects of 2-[(hydroxyimino)methyl]-1-methylpyridinium chloride (pralidoxime chloride; 2-PAM Cl; 50 mumol/kg) were compared with those of 1,1-methylene bis[4(hydroxyiminomethyl) pyridinium] dichloride (methoxime; MMB-4; 100 mumol/kg). Cardiopulmonary parameters were monitored and plasma concentrations of oximes were determined from arterial blood samples taken at intervals over a period of 5 hr postinjection. Plasma concentrations for both oximes were fitted to standard pharmacokinetic models using the computer program PCNONLIN. Average pharmacokinetic parameters were determined for each oxime. Only mild to moderate physiological side effects were detected following intramuscular administration. 2-PAM Cl was more rapidly absorbed and distributed in the blood than MMB-4. Although the latter had a slight lag time to attain detectable levels in the blood, retention time was longer than that of 2-PAM Cl.
ESTHER : Stemler_1991_Fundam.Appl.Toxicol_16_548
PubMedSearch : Stemler_1991_Fundam.Appl.Toxicol_16_548
PubMedID: 1855625