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A comparison of cholinergic effects of HI-6 and pralidoxime-2-chloride (2-PAM) in soman poisoning☆
Abstract
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 increased the time-todeath, while 2-PAM had no effect; a combination of HI-6 and ATS provided the most significant increase in time-to-death. Cholinesterase (ChE) activity was not altered in any tissue by ATS, HI-6 or 2-PAM treatment individually, but was markedly inhibited in all tissues by 100 μg/kg of soman. In soman-poisoned rats, the HI-6, but not the 2-PAM, group had significantly higher levels of ChE in blood and other peripheral tissues than did the group given soman alone. Neither HI-6 nor 2-PAM affected soman-inhibited ChE in the brain. Additional ATS treatment had no effect on ChE activity. HI-6 and 2-PAM neither modified baseline brain acetylcholine (ACh) or choline (Ch) levels nor protected against soman-induced ACh or Ch elevation. 2-PAM exhibited a 4-fold more potent in vitro inhibition of 3 H-quinuclidinyl benzilate ( 3 H-QNB) binding and sodium-dependent high-affinity Ch uptake (HACU) than did HI-6 in brain tissues. The findings that 2-PAM is a more potent in vitro inhibitor of muscarinic receptor binding and HACU than HI-6, and yet neither elevates ChE activity in the periphery nor protects rats against soman poisoning, indicate the importance of higher ChE activity in the periphery of HI-6-treated rats. Maintenance by HI-6 of a certain amount of active ChE in the periphery appears to be important for survival after soman exposure.
  • References (66)
  • Cited By (54)
W. Hauser1
Estimated H-index: 1
,
N. Weger1
Estimated H-index: 1
Therapeutic properties of various combinations of the bispyridinium salts HGG-12 and HGG-42 against soman and sarin poisoning were investigated in male beagles.
Cited 21
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Meeter E1
Estimated H-index: 1
,
Wolthuis Ol1
Estimated H-index: 1
,
van Benthem Rm1
Estimated H-index: 1
Abstract Cholinesterase inhibitors that can pass the blood—brain barrier produce hypothermia when injected intravenously in just sublethal doses. From a comparison of the hypothermia-reducing effects of five cholinesterase-reactivating oximes when injected intraperitoneally or subarachnoidally into rats pretreated with DFP or soman it was possible to distinguish central and peripheral actions of the oximes. The comparative efficacy of the five oximes and the effectiveness of cholinesterase inhib...
Cited 23
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1986 in Biochemical Pharmacology [IF: 4.58]
Cheryl J. Flynn2
Estimated H-index: 2
(University Medical Center New Orleans),
Lynn Wecker29
Estimated H-index: 29
(University Medical Center New Orleans)
Abstract The role of cholinergic and non-cholinergic mechanisms in mediating organophosphate cholinesterase (ChE) inhibitor-induced elevations in choline levels in brain was investigated. The nerve agents soman and sarin, when administered to rats at doses greater than the ic 50 for acetylChE inhibition, significantly increased the levels of choline and acetylcholine in both the striatum and hippocampus. The elevation in choline levels was evident 1 hr after injection with a maximal increase at ...
Ref 29Cited 46
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Howard S. Tong2
Estimated H-index: 2
,
James L. Way13
Estimated H-index: 13
Prophylactic protection by intraperitoneally administered l-methyl-2-formylpyridinium iodide oxime (2-PAM) against tetraethylpyrophosphate, paraoxon and diisopropyl phosphorofluoridate intoxication in mice was markedly enhanced by intracerebral administration of this antagonist into the central nervous system. Potency ratios and LD50 values of these alkylphosphates were compared in groups of mice premedicated with 2-PAM and/or atropine. The 2-PAM was administered by the intraperitoneal, intracer...
Cited 9
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J.G. Clement1
Estimated H-index: 1
Abstract The efficacy of Pro-PAM ( N -methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride) was compared to pyridine-2-aldoxime chloride (PAM) as a prophylaxis against organophosphate poisoning in mice and guinea pigs. Pro-PAM was generally less toxic than PAM in mice and pH of the vehicle did not appear to alter the toxicity of Pro-PAM. Pro-PAM alone and combined with atropine improved the protective ratio (PR) against DFP and sarin in mice, whereas it improved very slightly the PR against s...
Ref 26Cited 38
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1961 in Biochemical Pharmacology [IF: 4.58]
George L. Ellman9
Estimated H-index: 9
(University of California, San Francisco),
K.Diane Courtney1
Estimated H-index: 1
(University of California, San Francisco),
Valentino Andres1
Estimated H-index: 1
(University of California, San Francisco)
... more
Abstract A photometric method for determining acetylcholinesterase activity of tissue extracts, homogenates, cell suspensions, etc., has been described. The enzyme activity is measured by following the increase of yellow color produced from thiocholine when it reacts with dithiobisnitrobenzoate ion. It is based on coupling of these reactions: The latter reaction is rapid and the assay is sensitive (i.e. a 10 μ1 sample of blood is adequate). The use of a recorder has been most helpful, but is not...
Ref 8Cited 15442
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Joseph H. Fleisher10
Estimated H-index: 10
,
Larrel W. Harris10
Estimated H-index: 10
,
Gail R. Miller1
Estimated H-index: 1
... more
Abstract Intramuscular atropine-oxime therapy for sarin poisoning in rats and guinea pigs was evaluated. Injection of 7.5 mg/kg of pyridinium aldoxime methochloride (2-PAMCl) plus 16 mg/kg of atropine 1 min after poisoning rats with sarin subcutaneously raised the LD50 of the organophosphorous compound 2.5-fold. Toxogonin (7.5 mg/kg) gave somewhat less protection when substituted for 2-PAMCl. Atropine-oxime therapy was more successful in sarin-poisoned guinea pigs, the LD50 being increased 18.5-...
Ref 12Cited 50
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Joseph O. Owasoyo4
Estimated H-index: 4
(University of Ibadan),
Anthony D. Okonmah5
Estimated H-index: 5
(Florida A&M University),
Karam F.A. Soliman26
Estimated H-index: 26
(Florida A&M University)
... more
Abstract Acetylcholinesterase (AChE) activity of the adenohypophysis, cerebellum, cerebral cortex, hypothalamus, amygdala, hippocampus, midbrain, pons, medulla oblongata and caudate nucleus was determined by a spectro‐photometric method in adult, male rats adapted toan LD 12:12cycle. Results of the study show that AChE activity is highest during the light phase and lowest during the dark phase of the cycle in all the brain areas studied except the adenohypophysis, cerebellum, hippocampus and hyp...
Ref 10Cited 17 Source Cite this paper
1970 in Science [IF: 37.20]
I. Hanin1
Estimated H-index: 1
,
R. Massarelli1
Estimated H-index: 1
,
E. Costa1
Estimated H-index: 1
A diurnal oscillation of acetylcholine concentrations in rat brain has been demonstrated by gas chromatography. Peak concentrations occur at 2 hours of light, and a trough is seen at 6 hours of darkness. This pattern is observed only in grouped rats, and emerges after at least 18 days of prior conditioning in an environment with controlled light, humidity, and temperature.
Ref 12Cited 115
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John G. Clement2
Estimated H-index: 2
Abstract The effect of HS-6 [1-(2-hydroxyiminomethylpyridinium)-1-(3-carboxamidopyridinium)-dimethyl ether] on neuromuscular (NM) transmission was investigated using chick biventer cervicis (CBC), rat diaphragm (RD) and guinea pig ileum longitudinal muscle strip (GPLS) preparations. In the CBC preparation HS-6 did not cause a contraction, whereas it produced a dose-related contraction of the GPLS preparation. HS-6 produced a hemicholinium- like NM blockade in the CBC and RD preparations. This wa...
Ref 18Cited 36
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  • References (66)
  • Cited By (54)
Jiří Kassa16
Estimated H-index: 16
(Military Medical Academy),
Jiří Cabal10
Estimated H-index: 10
(Military Medical Academy)
The purpose of this study was to compare the therapeutic efficacy of a new acetylcholinesterase reactivator. designated BI-6 (1-(2-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)-2-butene dibromide), with presently used oximes (pralidoxime, obidoxime, methoxime) and H-oximes (Hl-6. HLo-7) by in vitro and in vivo methods. In vitro, methoxime seems to be the most efficacious reactivator of GF agent-inhibited acetylcholinesterase because the phosphonylation of acetylcholinesterase by GF age...
Ref 21Cited 64 Source Cite this paper
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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Tsung-Ming Shin1
Estimated H-index: 1
,
Thomas A. Koviak1
Estimated H-index: 1
,
Ben R. Capacio1
Estimated H-index: 1
Exposure to high doses of organophosphorus nerve agents such as soman, even with carbamate pretreatment, produces a variety of toxic cholinergic signs, including secretions, convulsions and death. Evidence suggests that soman-induced convulsions may be associated with postexposure brain neuropathology. The purpose of this study was to investigate the pharmacologic mechanism of action of soman-induced convulsions and of anticonvulsant drugs. Various classes of compounds were evaluated for their e...
Ref 125Cited 156
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Zibo Zhang2
Estimated H-index: 2
(Peking Union Medical College),
Qinglin Zhang1
Estimated H-index: 1
(Academy of Military Medical Sciences),
Hongtao Jin5
Estimated H-index: 5
(Peking Union Medical College)
... more
Abstract Penequine hydrochloride, a novel anticholinergic agent, was developed as an effective treatment for organophosphorus intoxication. The potential for penequine hydrochloride to induce fertility and early embryonic developmental toxicity was evaluated in AMMS-1 mice. Totally 320 healthy, sexual mature and nulliparous AMMS-1 mice were orally treated with the chemical in drinking water at dose levels of 0, 2.5, 12.5 and 62.5 mg/L from 60 days before cohabitation to successful copulation in ...
Ref 41
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Miroslav Pohanka26
Estimated H-index: 26
,
Daniel Jun32
Estimated H-index: 32
(University of Defence),
Kamil Kuca43
Estimated H-index: 43
(University of Defence)
Abstract Amperometric biosensors containing enzymes butyrylcholinesterase or acetylcholinesterase were prepared. The biosensors were employed for studying of cholinesterase reactivator: HI‐6. Competitions between HI‐6 and acetylthiocholine as enzyme substrate were used for determination of IC50 value. Biosensors with butyrylcholinesterase from human serum determined IC50 as (1.00±0.02)×10−6 M; the biosensor with acetylcholinesterase from human erythrocytes performance provided IC50 (3.31±0.13)×1...
Ref 21Cited 19 Source Cite this paper
Michael Adler19
Estimated H-index: 19
,
Donald M. Maxwell2
Estimated H-index: 2
,
Margaret G. Filbert7
Estimated H-index: 7
... more
Abstract The actions of the bispyridinium oxime HI-6 ([[[(4-aminocarbonyl)pyridino]-methoxy]methyl]-2-[(hydroxyimino)methyl]-pyridinium dichloride) were investigated in vitro on rat phrenic nerve-hemidiaphragm preparations. Isometric twitch and tetanic tensions were elicited at 37°C with supramaximal nerve stimulation at frequencies of 20 and 50 z. To approximate normal respiration patterns, trials consisting of 30 successive 0.55 s trains were alternated with 1.25 s rest periods. Under control ...
Ref 32Cited 4
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M.K. Schultz1
Estimated H-index: 1
,
L.K.M. Wright1
Estimated H-index: 1
,
M. de Araujo Furtado1
Estimated H-index: 1
(Walter Reed Army Institute of Research)
... more
Abstract The progression of epileptiform activity following soman (GD) exposure is characterized by a period of excessive cholinergic activity followed by excessive glutamatergic activity resulting in status epilepticus , which may lead to neuropathological damage and behavioral deficits. Caramiphen edisylate is an anticholinergic drug with antiglutamatergic properties, which conceptually may be a beneficial therapeutic approach to the treatment of nerve agent exposure. In the present study, rat...
Ref 49Cited 12
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Tsung-Ming Shih18
Estimated H-index: 18
,
Jacob W. Skovira8
Estimated H-index: 8
,
John C O'Donnell5
Estimated H-index: 5
... more
The capability of several oximes (HI-6, HLo7, MMB-4, TMB-4, carboxime, ICD 585, ICD 692, ICD 3805, and 2-PAM) to reactivate in vivo AChE inhibited by the nerve agents sarin, cyclosarin, VX, or VR in blood, brain regions, and peripheral tissues in guinea pigs was examined and compared. Animals were injected subcutaneously with 1.0 LD50 of sarin, cyclosarin, VR, or VX, and treated intramuscularly 5 min later with one of these compounds. Toxic signs and lethality were monitored, and tissue AChE act...
Ref 45Cited 30
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Alessandro Barelli5
Estimated H-index: 5
,
Immacolata Biondi1
Estimated H-index: 1
,
Maurizio Soave1
Estimated H-index: 1
... more
Medical management of victims of chemical incidents includes supportive therapy, decontamination and antidote administration. Chemical weapons of mass destruction are available to many countries and are a possible alternative to conventional weapons for terrorist groups. During the last 5 years, some Italian institutions have made big efforts to establish a national system of antidote stockpiling and distribution. Little or no efforts have been addressed to other aspects of the medical managemen...
Ref 20Cited 8
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Brian R. Coleman1
Estimated H-index: 1
(Walter Reed Army Institute of Research),
Ruthie H. Ratcliffe5
Estimated H-index: 5
(Walter Reed Army Institute of Research),
Samuel Oguntayo11
Estimated H-index: 11
(Walter Reed Army Institute of Research)
... more
Abstract The toxicity of organophosphorous (OP) nerve agents is attributed to their irreversible inhibition of acetylcholinesterase (AChE), which leads to excessive accumulation of acetylcholine (ACh) and is followed by the release of excitatory amino acids (EAA). EAAs sustain seizure activity and induce neuropathology due to over-stimulation of N -methyl- d -aspartate (NMDA) receptors. Huperzine A (Hup A), a blood–brain barrier permeable selective reversible inhibitor of AChE, has been shown to...
Ref 48Cited 36
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