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A comparison of the efficacy of HI6 and 2-PAM against soman, tabun, sarin, and VX in the rabbit
Abstract
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 μmol/kg) + atropine (13 mg/kg) (alone or together with diazepam). Twenty-four-h LD 50 , values were calculated for soman- and tabun-intoxicated animals, whereas 24-h survival was noted in animals given 10 LD 50 s 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.
  • References (14)
  • Cited By (87)
Paul I. Feder10
Estimated H-index: 10
(Battelle Memorial Institute),
David W. Hobson6
Estimated H-index: 6
(Battelle Memorial Institute),
Carl T. Olson9
Estimated H-index: 9
(Battelle Memorial Institute)
... more
A principal design objective of many dose-response studies is to estimate extreme percentiles of a dose-response distribution, e.g., the ED 95 dose for a particular drug therapy, as precisely as feasible using the smallest number of experimental subjects possible. Such a design requirement necessitates that allocation of subjects to drug doses be carried out in a stagewise fashion to maximize the information obtained from each subsequent experimental observation in light of what has previously b...
Ref 3Cited 37
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1991 in Toxicology Letters [IF: 3.86]
Shih Tsung-Ming2
Estimated H-index: 2
,
Christopher E. Whalley4
Estimated H-index: 4
,
James J. Valdes26
Estimated H-index: 26
Abstract The effects of HI-6 and pralidoxime chloride (2-PAM) on soman-induced lethality, time to death and several cholinergic parameters in rats were compared to understand the beneficial action of HI-6. Treatment with atropine sulfate (ATS) or HI-6 alone protected against 1.2 and 2.5 LD 50 s of soman respectively, whereas 2-PAM or methylated atropine (AMN) alone afforded no protection. Addition of ATS, but not AMN, to HI-6-treated rats enhanced the protection from 2.5 to 5.5 LD 50 s. HI-6 inc...
Ref 66Cited 54
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1992 in Drug and Chemical Toxicology [IF: 1.73]
Irwin Koplovitz13
Estimated H-index: 13
(United States Army Medical Research Institute of Chemical Defense),
James R. Stewart2
Estimated H-index: 2
(United States Army Medical Research Institute of Chemical Defense)
ABSTRACTThe 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 × LD50 soman and treated at the onset of toxic signs with 50 μmol/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 ...
Ref 17Cited 13
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Larry A. Kepner2
Estimated H-index: 2
,
Otto L. Wolthuis7
Estimated H-index: 7
The bisquaternary mono-oximes HS-6 and HI-6 may both be considered as potential therapeutic agents for soman intoxication. It has been found that HI-6 was superior to an equal dose of HS-6 in the treatment of soman intoxication in mice and rats. Not only did HI-6 protect against higher levels of soman, but also fewer 'delayed deaths' were seen following HI-6. In anesthetized atropinized rats, the administration of HI-6 resulted in a longer duration of spontaneous breathing and a higher degree of...
Ref 4Cited 78
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I. W. Coleman2
Estimated H-index: 2
,
G. E. Patton2
Estimated H-index: 2
,
R. A. B. Bannard2
Estimated H-index: 2
The effectiveness of Parpanit in the treatment of organophosphorus poisoning was examined and compared with that of atropine sulfate. The potency of Parpanit was assessed in the mouse, rat, hamster, guinea pig, and rabbit against sarin, tabun, soman, CMPF, and DSDP in treatments in which the oximes P2S and TMB4 were used both singly and together. The effectiveness of the treatments utilizing both cholinolytics varied with the species used for assay, with the oxime used in combination, and with t...
Cited 24
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Paul I. Feder10
Estimated H-index: 10
(Battelle Memorial Institute),
Carl T. Olson9
Estimated H-index: 9
(Battelle Memorial Institute),
David W. Hobson6
Estimated H-index: 6
(Battelle Memorial Institute)
... more
The use of stagewise, group sequential experimental designs with dichotomous responses in toxicity or drug screening programs is discussed. Such designs represent a compromise between the standard, fixed sample size designs and fully sequential designs. Stagewise group sequential designs place specified numbers of animals on test at each stage, up to a maximum number of stages. The greatest increases in sample size efficiency occur with small numbers of stages, particularly when going from one s...
Ref 5Cited 28
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1989 in Archives of Toxicology [IF: 5.90]
Murray G. Hamilton12
Estimated H-index: 12
,
Paul M. Lundy15
Estimated H-index: 15
The bis-pyridinium oxime HI-6, in conjunction with atropine, was found to offer significant protection against multiple LD50 challenges with the organophosphorus compounds soman and tabun. In adult rhesus macaques, the therapeutic administration of HI-6 with atropine and diazepam protected three of four animals from the lethal effects of 5 × LD50 of soman and three of three animals from 5 × LD50 of tabun. However, when toxogonin was substituted for HI-6 in the therapeutic mixture, all three anim...
Ref 21Cited 109
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1984 in Toxicological Sciences [IF: 4.08]
B Bokovi1
Estimated H-index: 1
Cited 74 Source Cite this paper
  • References (14)
  • Cited By (87)
ii ACKNOWLEDGEMENTS iii TABLE OF CONTENTS iv LIST OF TABLES ix LIST OF FIGURES xii LIST OF ABBREVIATIONS xvii
Ref 103
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R K Kan1
Estimated H-index: 1
,
C P Tompkins1
Estimated H-index: 1
,
D M Kniffin1
Estimated H-index: 1
... more
Abstract : The present study evaluated promethazine, an FDA-approved antihistamine, for treating the toxic effects of soman (GD). Male Sprague-Dawley rats, weighing 240-300 g, were pretreated 30 minutes prior to or treated less than or equal 1 minute after GD administration (180 mg/kg, sc) with promethazine alone (40 mg/kg, ip) or in combination with oxime reactivator HI-6 (125 mg/kg, ip) and atropine methylnitrate (AMN; 2.0 mg/kg, im). The incidence of convulsions, percentage of mortality, and ...
Ref 29Cited 2
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Milan Jokanović18
Estimated H-index: 18
Organophosphorus (OP) compounds have been used as pesticides and have been developed as warfare nerve agents such as tabun, soman, sarin, VX, and others. Exposure to even small amounts of an OP compound can be fatal and death is usually caused by respiratory failure resulting from paralysis of the diaphragm and intercostal muscles, depression of the brain respiratory center, bronchospasm, and excessive bronchial secretions. The mechanism of OP poisoning involves phosphorylation of the serine hyd...
Ref 126Cited 2
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Jiří Cabal10
Estimated H-index: 10
(Military Medical Academy),
Kamil Kuca43
Estimated H-index: 43
(Military Medical Academy),
Jiří Kassa16
Estimated H-index: 16
(Military Medical Academy)
Abstract: The efficacy of various oximes to reactivate acetylcholinesterase phosphorylated by tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) was tested by in vitro and in vivo methods. The oximes commonly used for the treatment of acute poisonings with highly toxic organophosphates appeared to be almost ineffective (HI-6, pralidoxime, methoxime) or just slightly effective (obidoxime) against tabun. On the other hand, trimedoxime seemed to be a significantly more efficacious reactivator than...
Ref 31Cited 94
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Joel L. Sussman76
Estimated H-index: 76
(Weizmann Institute of Science),
Israel Silman58
Estimated H-index: 58
Abstract : The acute toxicity of organophosphate (OP) compounds in mammals in general, and in humans in particular, is generally ascribed to their irreversible inhibition of acetyicholinesterase (AChE), the enzyme that terminates the action of acetylcholine (ACh) at cholinergic synapses by its rapid hydrolysis (1). Current medical protection against OPs involves anticholinergic drugs to counteract the accumulation of ACh (2), and quatemary oximes to reactivate OP-inhibited AChE (3). Since some O...
Ref 74
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2012 in Drug Testing and Analysis [IF: 3.47]
Reinhard Bogan2
Estimated H-index: 2
,
Franz Worek37
Estimated H-index: 37
,
Marianne Koller12
Estimated H-index: 12
... more
HI-6 exhibits superior efficacy in the therapy of intoxication by different highly toxic organophosphorus nerve agents. Therefore HI-6 is a promising candidate for the development of new antidotes against nerve agents. For ethical and safety reasons antidotes containing HI-6 should get marketing authorization. Active pharmaceutical ingredients of medicinal products have to fulfil regulatory conditions in terms of purity and stability. Photostability is an essential parameter in this testing stra...
Ref 29Cited 3
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2012 in Drug Testing and Analysis [IF: 3.47]
Reinhard Bogan2
Estimated H-index: 2
,
Marianne Koller12
Estimated H-index: 12
,
Bernd Klaubert2
Estimated H-index: 2
As reactivators of inhibited acetylcholinesterase, oximes are essential antidotes in poisoning by organophosphorus compounds. Due to its superior efficacy in cases of soman, cyclosarin, and sarin poisoning, the oxime HI-6 represents a promising option for an active pharmaceutical ingredient (API) in the further development of antidote therapy for nerve agent poisoning. Developmental lots of HI-6 DMS (dimethanesulfonate) provided by different manufacturers were examined with respect to their cont...
Ref 17Cited 4
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Jiri Bajgar15
Estimated H-index: 15
(Military Medical Academy)
Publisher Summary Organic compounds of phosphorus show a broad variety of biological properties. They can be irritating, mutagenic, teratogenic or carcinogenic, nephrotoxic, myelotoxic, or pneumotoxic. Some of these compounds damage the pancreas and testes, others can influence the nervous system psychotomimetically or in a depressive manner, or they have delayed neurotoxic effects. Organic phosphorus (OP)/nerve agents are still considered important chemicals acting on living organisms and are w...
Ref 260Cited 471
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2015 in Toxicology in Vitro [IF: 2.87]
Franz Worek37
Estimated H-index: 37
,
Nadja M. Herkert8
Estimated H-index: 8
,
Marianne Koller12
Estimated H-index: 12
... more
Tabun-inhibited acetylcholinesterase (AChE) is rather resistant towards reactivation by oximes in vitro while in vivo experiments showed some protection of animals poisoned by this chemical warfare nerve agent after treatment with an oxime and atropine. In addition, AChE inhibited by close tabun analogues, N,N-diethyltabun and N,N-di-n-propyltabun was completely resistant towards reactivation by oximes. In order to get more insight into potential mechanisms of this oxime resistance experiments w...
Ref 50Cited 1
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R. Pita1
Estimated H-index: 1
,
Arturo Anadón24
Estimated H-index: 24
,
M.R Martínez Larrañaga1
Estimated H-index: 1
El bromuro de piridostigmina (bromuro de 3-dimetilaminocarboniloxi-N-metilpiridinio) se utiliza como pretratamiento en escenarios en los que existe riesgo de utilizacion de agentes neurotoxicos de guerra. De hecho, este pretratamiento fue utilizado por las tropas Aliadas durante la Guerra del Golfo Persico. Desde su vuelta a casa muchos veteranos de esta guerra se han quejado de padecer sintomas debidos a lesiones que afectan al sistema nervioso. Las causas de estos sintomas son aun desconocidas...
Ref 43Cited 2
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