The reversal by oximes and their de oximinomethyl analogues of neuromuscular block produced by soman

French, Mark; Wetherell, Janet R.; White, Phillip D.T.

doi:10.1016/0014-2999(83)90164-4

Cited by 12 publications

(6 citation statements)

References 21 publications

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“…action, and TMB-4 and SAD-128 the largest. French et al (1983), however, reported a higher ranking for BPE and HS-6, and a lower ranking for BPT, than was found in the present experiments. These discrepancies are probably due to the much higher concentrations of the drugs which they used and the time of application, which was only 1 min after soman in their study.…”

Section: Diaphragm Recoverycontrasting

confidence: 92%

“…This was expected, since the half time of aging for somaninhibited AChE in the guinea-pig is 6-8 min (Harris et al, 1971;Talbot et al, 1988). Previous studies on guinea-pig muscle in vitro have also demonstrated direct therapeutic actions of oximes, but generally at higher concentrations than those used here (Smith et al, 1981;French et al, 1983). French et al (1983 used the compounds at previously-determined optimum concentrations, which were usually higher than those tested in the present study.…”

Section: Diaphragm Recoverymentioning

confidence: 68%

“…The therapeutic effects of some oximes against soman poisoning can be demonstrated in vitro with the guinea-pig phrenic nerve-hemidiaphragm preparation Smith et al, 1981;French et al, 1983). The neuromuscular recovery produced in these experiments is reversed by washing out the oxime and thus appears to be due to a direct pharmacological action.…”

Section: Introductionmentioning

confidence: 96%

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Ion channel blockade by oximes and recovery of diaphragm muscle from soman poisoning in vitro

Tattersall

1993

British J Pharmacology

113

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1 The actions of oximes and related compounds on the nicotinic acetylcholine receptor ion channel at the adult mouse muscle endplate were investigated by use of single-channel recording techniques. The aim of the study was to determine whether the channel-blocking properties of the compounds could contribute to their therapeutic effectiveness against soman poisoning in vitro. 2 Therapeutic effectiveness was assessed in guinea-pig phrenic nerve-hemidiaphragm preparations by measuring the degree of recovery of neuromuscular function produced by the compounds following poisoning by soman. A number of the compounds, including some which lacked the oxime group, produced a significant recovery of neuromuscular function which was unrelated to acetylcholinesterase (AChE) reactivation; this was reversed by washing off the compound, and was therefore attributed to a direct pharmacological action on the muscle. 3 Single channel recordings showed that some of the compounds blocked open nicotinic receptor ion channels in preparations of mouse muscle fibres. The compounds which showed the greatest direct pharmacological actions in diaphragms produce a very fast, flickering blockade of the channels. Several quantitative measures of channel-blocking activity correlated very well with the direct pharmacological action. Furthermore, for two compounds studied in greater detail, the direct action and channelblocking showed similar concentration-response relationships. 4 The results of this study indicate that the direct pharmacological action of oximes and their analogues against neuromuscular blockade by soman in vitro is due to their channel-blocking activity. The direct action does not correlate well with protection against soman poisoning in vivo, however, which suggests that additional non-reactivating properties of these compounds, at sites other than the neuromuscular junction, may also be important for their therapeutic effectiveness.

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Section: Diaphragm Recoverycontrasting

confidence: 92%

Section: Diaphragm Recoverymentioning

confidence: 68%

Section: Introductionmentioning

confidence: 96%

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Ion channel blockade by oximes and recovery of diaphragm muscle from soman poisoning in vitro

Tattersall

1993

British J Pharmacology

113

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“…Direct actions of oxime compounds through the inhibition of postsynaptic nicotinic receptor sites have been proposed to contribute to their antidotal effectiveness in cases of organophosphate poisoning (Lundy and Tremblay 1979;Clement 1981;Kitsch and Weger 1981;French et al 1983). …”

Section: Mechanisms Of Protectionmentioning

confidence: 98%

“…In cases of organophosphate poisoning, oxime compounds are administered in order to restore the function of the inhibited enzyme (French et al 1983;Schoene et al 1983;Bo~covi6 et al 1984;Suet al 1986).…”

Section: Introductionmentioning

confidence: 97%

Bispyridinium (oxime) compounds antagonize the “ganglion blocking” effect of pyridostigmine in isolated superior cervical ganglia of the rat

1990

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The "antidotal effectiveness" of several bispyridinium compounds (HGG 12, HGG 65, HGG 70, HI 6, HLö and HLö 12) against the acetylcholinesterase (AChE) inhibitor pyridostigmine was evaluated in isolated superior cervical ganglia of the rat. Compound action potential amplitudes were inhibited by pyridostigmine in a concentration-dependent manner. HI 6 and atropine proved to be the most effective compounds in antagonizing the "ganglion blocking" action of pyridostigmine. Their relative effectiveness (PE value) was 5.4 and 4.2, respectively. All of the six bispyridinium compounds inhibited carbachol-induced, nicotinic, ganglionic surface depolarizations. The antinicotinic potencies of HI 6 and HLö 7 were about one order of magnitude lower (apparent KI values: 294 and 330 mumol/l) than the antinicotinic potencies of HGG 12, HGG 65, HGG 70 and HLö 12 (apparent KI values ranging from 19 to 41 mumol/l). The antinicotinic potencies of the bispyridinium compounds did not correlate with their in vitro protection of synaptic transmission in sympathetic ganglia. Moreover, the effectiveness of atropine points to the importance of antimuscarinic properties of possible "antidotes" for the maintenance of ganglionic transmission in cases of AChE poisoning.

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Chemical Stability of the Hagedorn Oximes HGG‐12 and HI‐6

Eyer

Hell

1985

Archiv der Pharmazie

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The chemical stability of the soman antidotes HGG-12 and HI-6 was studied over the pH range 2-9 at various temperatures. Maximum stability for both oximes was found at pH 2. From Arrhenius plots the predicted shelf life (10 % decomposition) was 2.6 years at 25°C and 60years at 4°C for both oximes. The apparent energy of activation was 113 kJ/mol. The decay rate of both oximes apparently was not influenced by oxime concentration, buffer composition, light, and oxygen. By ion-pair HPLC the following degradation products were indentified: pyridine-2-carbaldoxime, pyridine-2-carbonitrile, 2-pyridone, formaldehyde and 3-benzoylpyridine (for HGG-12) or isonicotinamide and isonicotinic acid (for HI-6). Two additional pyridinium compounds have not yet been identified. The pattern of degradation products varied considerably with pH. Die chemische Stabilitat der Hagedorn-Oxime HGG-12 und HI-6Die chemische Stabilitat der Soman-Antidote HGG-12 und HI-6 wurde irn pH-Bereich zwischen 2 und 9 untersucht. Beide Oxime waren bei pH 2 am stabilsten. Die Bestandigkeit beider Oxime (10% Zerfall) wurde nach der Arrhenius-Gleichung mit 2,6 Jahren bei 25", mit 60 Jahren bei 4" errechnet. Die scheinbare Aktivierungsenergie des Zerfalls betrug 113 kJ/mol. Die Zerfallsgeschwindigkeit beider Oxime scheint weder von der Oximkonzentration, noch von der Pufferzusammensetzung, von Licht oder von Sauerstoff abzuhangen.Durch Ionen-Paar HPLC wurden folgende Zerfallsprodukte identifiziert: 2-Pyridincarbaldoxim, 2-Cyanopyridin, 2-Pyridon, Formaldehyd und 3-Benzoylpyridin (HGG 12) bzw. Isonicotinamid und Isonicotinsaure (HI-6). Zwei weitere Pyridinium-Verbindungen wurden bisher noch nicht identifiziert. Das Muster der Zerfallsprodukte ist stark pH-abhangig.

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The reversal by oximes and their de oximinomethyl analogues of neuromuscular block produced by soman

Cited by 12 publications

References 21 publications

Ion channel blockade by oximes and recovery of diaphragm muscle from soman poisoning in vitro

Ion channel blockade by oximes and recovery of diaphragm muscle from soman poisoning in vitro

Bispyridinium (oxime) compounds antagonize the “ganglion blocking” effect of pyridostigmine in isolated superior cervical ganglia of the rat

Chemical Stability of the Hagedorn Oximes HGG‐12 and HI‐6

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