A comparison of reactivating and therapeutic efficacy of bispyridinium acetylcholinesterase reactivator KR-22934 with the oxime K203 and commonly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice

Article · March 2011with79 Reads
DOI: 10.3109/15376516.2010.538750 · Source: PubMed
Abstract
The potency of bispyridinium acetylcholinesterase reactivator KR-22934 in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with the oxime K203 and commonly used oximes. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in rats showed that the reactivating efficacy of KR-22934 was slightly higher than the reactivating efficacy of K203 and roughly corresponded to the reactivating efficacy of obidoxime and trimedoxime in blood and diaphragm. On the other hand, the oxime KR-22934 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied approximately corresponded to their reactivating efficacy. Based on the results, one can conclude that the oxime KR-22934 is not suitable for the replacement of commonly used oximes for the antidotal treatment of tabun poisoning in spite of its potency to reactivate tabun-inhibited acetylcholinesterase in the peripheral compartment (blood, diaphragm).
Figures
Introduction
Nerve agents are considered to be the most dangerous
chemical warfare agents. eir acute toxic eects are based
on the phosphonylation of the enzyme acetylcholinesterase
(AChE, EC 3.1.1.7), leading to the irreversible inhibition of its
active site and subsequent over-stimulation of post-synaptic
cholinergic receptors due to the accumulation of the neu-
rotransmitter acetylcholine in synapses of the central and
peripheral nervous systems (Marrs 1993; Lotti 2000). One of
the most important representatives of nerve agents is tabun
(O-ethyl-N,N-dimethylphosphoramidocyanidate). It diers
from other nerve agents in its chemical structure and by the
fact that commonly used antidotes are not able to suciently
prevent tabun-induced acute toxic eects. Tabun-induced
acute toxic eects are extraordinarily dicult to antagonize
due to the changes in hydrogen bonding and the conforma-
tional changes of AChE-tabun complex prior aging process in
AChE active site that make the nucleophilic attack of oxime
almost impossible (Cabal and Bajgar 1999; Ekström et al.
2006).
A current standard treatment for the poisoning with
tabun usually consists of a combined administration of an
anti-cholinergic drug (preferably atropine) and an oxime
(preferably pralidoxime or obidoxime). e anti-cholinergic
drug blocks the eects of over-stimulation by acetylcholine
accumulated at the muscarinic receptor sites, while oxime
(compound with nucleophilic oximate anion) repairs bio-
chemical lesions by dephosphonylating tabun-inhibited
(Received 06 August 2010; revised 11 October 2010; accepted 24 October 2010)
ISSN 1537-6516 print/ISSN 1537-6524 online © 2011 Informa Healthcare USA, Inc.
DOI: 10.3109/15376516.2010.538750 http://www.informahealthcare.com/txm
RESEARCH ARTICLE
A comparison of reactivating and therapeutic ecacy of
bispyridinium acetylcholinesterase reactivator KR-22934
with the oxime K203 and commonly used oximes
(obidoxime, trimedoxime, HI-6) in tabun-poisoned rats
and mice
Jiri Kassa1, Jana Zdarova Karasova1, Ruzena Pavlikova1, Kamil Musilek1, Kamil Kuca2, Jiri Bajgar1, and
Young-Sik Jung3
1Department of Toxicology, 2Center of Advanced Studies, Faculty of Military Health Sciences, Hradec Kralove, Czech
Republic, and 3Medicinal Science Division, Korea Research Institute of Chemical Technology, Yusong, Daejeon, Korea
Abstract
The potency of bispyridinium acetylcholinesterase reactivator KR-22934 in reactivating tabun-inhibited acetylcho-
linesterase and reducing tabun-induced lethal toxic effects was compared with the oxime K203 and commonly
used oximes. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholineste-
rase in rats showed that the reactivating efficacy of KR-22934 was slightly higher than the reactivating efficacy
of K203 and roughly corresponded to the reactivating efficacy of obidoxime and trimedoxime in blood and dia-
phragm. On the other hand, the oxime KR-22934 was not able to reactivate tabun-inhibited acetylcholinesterase in
the brain. The therapeutic efficacy of all oximes studied approximately corresponded to their reactivating efficacy.
Based on the results, one can conclude that the oxime KR-22934 is not suitable for the replacement of commonly
used oximes for the antidotal treatment of tabun poisoning in spite of its potency to reactivate tabun-inhibited
acetylcholinesterase in the peripheral compartment (blood, diaphragm).
Keywords: Tabun; acetylcholinesterase; oximes; reactivation
Toxicology Mechanisms and Methods, 2010, 1–5, Early Online
Toxicology Mechanisms and Methods
2010
1
5, Early Online
06 August 2010
11 October 2010
24 October 2010
1537-6516
1537-6524
© 2011 Informa Healthcare USA, Inc.
10.3109/15376516.2010.538750
Address for Correspondence: Professor Jiri Kassa, MD, CSc, Trebesska 1575, Faculty of Military Health Sciences, 500 01 Hradec Kralove, Czech Republic. Tel: +420
973 255150. Fax: +420 495518094. Email: kassa@pmfhk.cz
TXM
538750
UTXM
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2 J. Kassa et al.
AChE and restoring its activity (Kassa 2002; Bajgar 2004).
While the anti-cholinergic drugs such as atropine are able
to counteract the eects of tabun at the peripheral cholin-
ergic receptors (Bajgar 2004), commonly used reactivators
of tabun-inhibited AChE based on monopyridinium (e.g.
pralidoxime) and bispyridinium oximes (e.g. obidoxime,
trimedoxime) are not able to suciently counteract the
acute toxic eects of tabun because of their low reactivat-
ing ecacy (Marrs et al. 2006; Jokanovic and Prostran
2009). In addition, the oxime HI-6, which is relatively eca-
cious against adverse eects of other nerve agents (Kassa
and Cabal 1999a; b; c), is not able to suciently reactivate
tabun-inhibited AChE (Worek et al. 1998; Lundy et al. 2006).
erefore, the replacement of commonly used oximes (pra-
lidoxime, obidoxime) as well as H-oximes (the oxime HI-6)
with a more eective oxime has been a long-standing goal for
the treatment of tabun poisoning. For this reason, the new
bispyridinium oxime K203 [1-(4-carbamoylpyridinium)-4-
(4-hydroxyiminomethylpyridinium)-but-2-ene-dibromide]
(Figure 1) was synthesized at our department several years
ago (Musilek et al. 2008) to improve the ecacy of the anti-
dotal treatment in reactivating tabun-inhibited AChE and
eliminating tabun-induced lethal toxicity. e oxime K203
was considered to be a promising reactivator of tabun-
inhibited AChE; nevertheless, the dierences between the
reactivating and therapeutic ecacy of K203 and some com-
monly used bispyridinium oximes (obidoxime, trimedoxime)
are relatively small (Kassa et al. 2008). Another bispyridin-
ium oxime, KR-22934 [1-(4-carbamoylpyridinium)-3-(4-
hydroxyiminomethylpyridinium)-2-oxapropan-dichloride]
(Figure 1) was synthesized in Korea to improve the reactivat-
ing and therapeutic ecacy of antidotal treatment of tabun
poisoning.
e main aim of this study was to compare the reactivat-
ing and therapeutic ecacy of the oxime KR-22934 with the
oxime K203 and the currently available oximes (obidoxime,
trimedoxime, the oxime HI-6) against tabun using in vivo
methods.
Material and methods
Animals
Male albino Wistar rats weighing 180–210 g and NMRI
male mice weighing between 20–25 g were purchased
from VELAZ (Prague, Czech Republic). ey were kept in
an air-conditioned room with light from 07:00 to 19:00 h
and were allowed access to standard food and tap water
ad libitum. ey were divided into groups of eight animals.
Handling of the experimental animals was done under the
supervision of the Ethics Committee of the Faculty of Military
Health Sciences, Czech Republic.
Chemicals
Tabun was obtained from the Technical Institute in Brno
(Czech Republic) and was 96.5% pure as assayed by acidi-
metric titration. All oximes with the exception of KR-22934
(obidoxime, trimedoxime, HI-6, K203) of 97.5% purity were
synthesized at our Department of Toxicology of the Faculty
of Military Health Sciences (Czech Republic). e oxime
KR-22934 of 98% purity was synthesized in Medicinal Science
Division of Korea Research Institute of Chemical Technology.
e purity of oximes was analyzed using a HPLC technique.
All other drugs and chemicals of analytical grade were
obtained commercially and used without further purication.
All substances were administered intramuscularly (i.m.) at a
volume of 1 ML/kg body weight (b.w.) in rats and 10 ML/kg
b.w. in mice.
Evaluation of acute toxicity of oximes
Before starting the evaluation of reactivating and therapeutic
ecacy of oximes, the acute toxicity of tested oximes was eval-
uated in rats and mice by the assessment of their LD50 values
and their 95% condence limits using probit-logarithmical
analysis of death occuring within 24 h after i.m. administra-
tion of each oxime at ve dierent doses with eight animals
per dose (Tallarida and Murray 1987).
Evaluation of reactivating ecacy of oximes
To evaluate the reactivating ecacy of the oximes, the rats
were injected i.m. with either atropine (21 mg/kg) alone or
atropine (21 mg/kg) in combination with one of the oximes
studied in equimolar doses (50 µmol/kg) 5 min before the rats
received tabun i.m. at a dose of 160 µg/kg (LD50). e pro-
phylactic administration of antidotes was used because this
procedure is suitable for a mechanistic study that compares
the reactivating ecacy of various oximes. is approach
should give better results than the treatment of animals after
poisoning and reduce the inuence of aging of nerve agent-
AChE complex (Clement et al. 1992). Moreover, some oximes
are planned to be used prophylactically in certain chemical
warfare scenarios (Bajgar 2004). e rats were decapitated
and exsanguinated to obtain the blood 30 min subsequent
to tabun poisoning. e blood was hemolyzed in Tris-HCl
buer (0.02 mol/L, pH 7.6, 1:20). e tissues, diaphragm,
and brain were removed and homogenized in Tris-HCl
buer (0.02 mol/L, pH 7.6, 1:10) to determine AChE activity
by the standard spectrophotometric method described by
Ellman et al. (1961). Acetylthiocholine was used as a substrate
(Tris-HCl buer, 0.1 mol/L, pH 7.6). Helios Alpha, the spec-
trophotometer, was used for determination of absorbancy
at 436 nm. e AChE activity was expressed as µkat/kg or L
(µmol substrate hydrolyzed/kg wet tissue or L blood within
1 s). e untreated control values for blood, diaphragm, and
brain AChE activity were obtain from rats administered with
saline instead of tabun and antidotes (saline control). e
reactivation percentage extent was calculated using the AChE
activity values: {1 [((saline control) – (oxime + atropine))/
((saline control) – (atropine control))]} × 100 (Clement et al.
1992).
Evaluation of therapeutic ecacy of oximes
e potency of oximes in combination with atropine to elimi-
nate tabun-induced lethal eects in mice was determined
as follows. e LD50 value of tabun and its 95% condence
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Reactivating ecacy of oximes against tabun 3
limit in non-treated tabun-poisoned mice was assessed using
probit-logarithmical analysis of death occuring within 24 h
after i.m. administration of tabun at ve dierent doses with
eight mice per dose (Tallarida and Murray 1987). en, tabun-
poisoned mice were treated i.m. with one of the tested oximes
at equitoxic doses (5% LD50) in combination with atropine
(21 mg/kg) at 1 min after i.m. challenge of tabun. e LD50
values of tabun and their 95% condence limits in the treated
tabun-poisoned mice were assessed by the same method. e
ecacy of tested antidotes was expressed as a protective ratio
(LD
50
value of tabun in protected mice/LD
50
value of tabun in
unprotected mice). Statistical signicance was determined
by the use of one-way ANOVA test and dierences were con-
sidered signicant when p < 0.05. Statistical evaluation was
determined with the relevant computer programs (Tallarida
and Murray 1987).
Results
e acute i.m. toxicity of tested oximes is summarized in
Table 1. e results show that the acute toxicity of the oxime
KR-22934 in mice is signicantly lower than the acute toxic-
ity of obidoxime, trimedoxime, and K203. Unfortunately, we
were not able to calculate the LD50 value for KR-22934 in rats
due to the limitation of its solubility. According to our results,
the oxime HI-6 can be considered to be the least toxic for both
animal species.
e ability of oximes to reactivate tabun-inhibited AChE in
rat blood, diaphragm, and brain in vivo is shown in Table 2.
e oxime KR-22934 seems to be the most eective reacti-
vator of tabun-inhibited AChE in blood, but the dierences
between the reactivating ecacy of KR-22934 and other
oximes studied (with the exception of HI-6) are not signi-
cant. In the diaphragm, its reactivating ecacy corresponds
to the potency of obidoxime, trimedoxime, and the oxime
K203 to reactivate tabun-inhibited AChE. On the other
hand, the oxime KR-22934 is not able to reactivate tabun-
inhibited AChE in the brain, where the rectivating ecacy of
all oximes studied is generally very low. Only the oxime K203,
obidoxime, and trimedoxime were able to slightly reactivate
tabun-inhibited AChE in the brain but their reactivating
eects are not signicant. us, the reactivating ecacy of
KR-22934 is slightly higher than the potency of the oxime
K203 to reactivate tabun-inhibited AChE in blood and dia-
phragm, but it is lower compared to the oxime K203 in brain.
e oxime HI-6 is completely inefective to reactivate tabun-
inhibited AChE in peripheral as well as central compartment
(Table 2).
ese results roughly correlate with the therapeutic
potency of the oximes tested against lethal tabun poison-
ing in mice (Table 3). Tabun-poisoned mice showed a wide
spectrum of clinical signs of poisoning including muscarinic
(salivation) and niconitic (tonic-clonic convulsions) signs
within a few minutes regardless of the type of antidotes.
ey died within 20–30 min after poisoning with tabun. All
oximes studied, with the exception of the oxime HI-6, were
able to decrease the acute toxicity of tabun by more than two
times, and the dierences between their therapeutic ecacy
were relatively small. Obidoxime was found to be the most
eective to reduce the acute toxicity of tabun. In addition,
the oxime HI-6 showed signicantly lower potency to reduce
acute lethal toxic eects of tabun in mice in comparison with
all other oximes studied. When atropine was used alone for
the treatment of acute tabun poisonings, practically no thera-
peutic ecacy was found (Table 3).
Discussion
e currently used monopyridinium and bispyridinium oxi-
mes seem to be relatively poor reactivators of tabun-inhibited
AChE. e values of kinetic parameters of the tested oximes
for the reactivation of tabun-inhibited AChE in vitro showed
N
+N
+
OH2N
2Cl
HON
N
CH2OCH2
CH2OCH2
+N
+
HON NOH
2Cl
N
CH2CH2CH2
+
N
+
HONNOH
2Br
Trimedoxime
2 Br
NN
HON=HC
CONH2
N
CONH2
ON
2 Cl
HON=HC
KR-22934
HI-6 Obidoxime
K 203
Figure 1. Chemical structure of oximes.
Table 1. LD50 values of oximes following i.m. administration in rats and
mice.
Oximes
LD50 (mg/kg) ± 95% condence limit
Rats Mice
Obidoxime 211.1 (176.4–252.6) 188.4 (156.3–208.0)
HI-6 781.3 (738.4–826.6) 671.3 (627.4–718.3)
Trimedoxime 150.5 (142.1–159.4) 149.3 (124.1–184.5)
K203 326.4 (285.4–373.2) 95.0 (88.4–102.2)
KR-22934 > 500 415.4 (312.8– 496.4)
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4 J. Kassa et al.
that the dissociation constants and the rate constants are
lower compared to the kinetic parameters describing the
reactivation of sarin, soman, or cyclosarin-inhibited AChE
by these oximes (Kassa and Cabal 1999a; b; c). erefore, a
lot of new structural analogues of currently available oximes
have been developed to increase the potency of oximes to
reactivate tabun-inhibited AChE (Musilek et al. 2007; Laufer
et al. 2010).
Generally, the reactivating ecacy of oximes depends
upon the chemical structure of a bridge connecting both
pyridinium rings (in the case of bispyridinium oximes), the
position of the oxime group, the chemical structure, and a
position of a functional group situated on the second pyrid-
inium ring (Cabal et al. 2004; Kuca et al. 2006). To reach suf-
cient reactivating ecacy against tabun, both substituents
should be situated on the position 4. e replacement of sub-
stituents to another usual position decreases the reactivating
ecacy of tested AChE reactivators against tabun (Kuca et al.
2006). is fact can explain relatively low ecacy of the oxime
HI-6, which is eective against uorophosphonates (Kassa
and Cabal 1999a; b; c), because the oxime HI-6 contains a
dimethylether bridge and the oxime group in position 2.
e chemical structure of the oxime HI-6 compared to other
oximes studied is disadvantageous for the reactivation of
tabun-inhibited AChE (Cabal et al. 2004).
e oxime K203 was synthesized according to the
above-mentioned structural requirements (Musilek et al.
2008), and the results dealing with the evaluation of its
reactivating, therapeutic, and neuroprotective ecacy
showed that it can be considered to be a relatively prom-
ising reactivator of tabun-inhibited AChE (Kassa et al.
2008; 2009; Kovarik et al. 2009). However, the dierences
of reactivating and therapeutic ecacy between the oxime
K203 and some currently available oximes are rather small
(Kassa et al. 2008; 2009). erefore, another bispyririnium
oxime (KR-22934) was synthesized based on the structural
requirements in the Korea Research Institute of Chemical
Technology. It structurally corresponds to the oxime
HJ 2 (Schoene and Oldiges 1973) and diers from K203
by the chemical structure of a bridge connecting both
pyridinium rings (oxapropan instead of but-2-ene). Our
results showed that the potency of the oxime KR-22934 to
reactivate tabun-inhibited AChE is relatively satisfactory
in the peripheral compartment, but, unfortunately, it is
not able to reactivate tabun-inhibited AChE in the brain,
probably due to the poor penetration through the blood–
brain barrier. us, the change of bridge connecting both
pyridinium rings does not bring a signicant increase
in the reactivating and therapeutic ecacy of antidotal
treatment of tabun poisoning and, therefore, the oxime
KR-22934 is not a suitable candidate for the replacement
of commonly used oximes for the antidotal treatment of
acute tabun poisoning..
Among currently available oximes, the oxime HI-6 is
not able to suciently reactivate tabun-inhibited AChE in
vivo nor protect rats poisoned with lethal doses of tabun,
when it is administered at human-relevant doses (Lundy
et al. 2006; Marrs et al. 2006; Jokanovic and Prostran 2009).
Trimedoxime and obidoxime are more eective oximes for
the treatment of acute tabun poisonings than the oxime HI-6,
but their potency to eliminate tabun-induced lethal eects
is also limited, when they are administered at low, human-
relevant doses (Kassa 2002; Marrs et al. 2006; Jokanovic and
Prostran 2009). us, the recently developed oxime K203 still
seems to be the most promising candidate for the replace-
ment of commonly used oximes for the treatment of acute
tabun poisoning.
Acknowledgements
e authors wish to thank Mrs Jana Uhlirova for her skilful
assistance.
Table 2. Percentage reactivation of tabun-inhibited AChE by oximes in rat blood, diaphragm, and brain in vivo.
Treatment
AChE activity (µkat/L or µkat/kg)
Blood Diaphragm Brain
Atropine 6.73 ± 0.84a4.19 ± 0.79a9.93 ± 2.18a
Atropine + obidoxime (% reactivationb)8.66 ± 0.60 (30.2*x) 7.02 ± 1.35 (23.4*)11.13 ± 2.61 (1.1)
Atropine + HI-6 (% reactivation) 6.52 ± 0.84 (0) 4.13 ± 1.29 (0) 9.40 ± 2.56 (0)
Atropine + trimedoxime (% reactivation) 8.68 ± 0.92 (30.5*x) 7.27 ± 0.73 (24.8*x)14.19 ± 1.32 (3.8)
Atropine + K203 (% reactivation) 8.40 ± 0.76 (26.2x)5.94 ± 0.85 (14.1*)14.50 ± 1.97 (4.1)
Atropine + KR-22934 (% reactivation) 9.03 ± 0.94 (35.9*x) 6.85 ± 1.65 (21.5*x)9.50 ± 2.72 (0)
a Means ± SEM, n = 8. e untreated control value for rat blood AChE activity was 13.13 ± 1.02 µkat/L, for diaphragm AChE activity 16.57 ± 0.70 µkat/kg,
and for brain AChE activity 121.3 ± 7.40 µkat/kg.
b Percentage reactivation was determined using the AChE activity values: {1 [((saline) – (oxime + atropine))/((saline) – (atropine control))]} × 100.
* Signicantly dierent from the atropine group at a level of p < 0.05, x signicantly dierent from the atropine + HI-6 group at a level of P < 0.05 as deter-
mined by one-way ANOVA test.
Table 3. e inuence of the type of oxime on the potency of antidotal
treatment to eliminate acute lethal eects of tabun in mice.
Treatment LD50 (µg/kg) ± 95% IS Protective ratio
248.7 (219.7–305.8)
Atropine 280.7 (249.0–316.3) 1.13
Obidoxime + atropine 586.9 (528.0–666.2)*x2.36
HI-6 + atropine 396.0 (338.6–463.1)*1.59
Trimedoxime + atropine 569.0 (524.0–598.4)*x2.29
K203 + atropine 524.1 (479.9–606.2)*x2.11
KR-22934 + atropine 538.9 (491.8–589.9)*x2.17
* signicantly dierent from the untreated group at a level of p < 0.05; x
signicantly dierent from the group treated with HI-6 at a level of p < 0.05
as determined by one-way ANOVA test.
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Reactivating ecacy of oximes against tabun 5
Declaration of interest
e study was supported by the grant of Ministry of Defence,
No. MO0FVZ0000501. e authors report no conicts of
interest. e authors alone are responsible for the content
and writing of the paper.
References
Bajgar J. 2004. Organophosphate/nerve agent poisoning: mechanism of action,
diagnosis, prophylaxis, and treatment. Adv Clin Chem 38:151–216.
Cabal J, Bajgar J. 1999. Tabun – reappearance 50 years later. Chem Listy 93:27–31
[in Czech].
Cabal J, Kuca K, Kassa J. 2004. Specication of the structure of oximes able
to reactivate tabun-inhibited acetylcholinesterase. Pharmacol Toxicol
95:81–86.
Clement JG, Hansen AS, Boulet CA . 1992. Ecacy of HLö-7 and pyrimi-
doxime as antidotes of nerve agent poisoning in mice. Arch Toxicol 66:
216–219.
Ekström F, Akfur C, Tunemalm AK, Lundberg S. 2006. ářčáářStructural changes
of phenylalanine 338 and histidine 447 revealed by the crystal struc-
tures of tabun-inhibited murine acetylcholinesterase. Biochemistry 45:
74–81.
Ellman GL, Courtney DK, Andres V, Jr, Feartherstone RM. 1961. A new and rapid
colorimetric determination of acetylcholinesterase activity. Biochem
Pharmacol 7:88–93.
Jokanovic M, Prostran M. 2009. Pyridinium oximes as cholinesterase reac-
tivators. Structure-activity relationship and ecacy in the treatment
of poisoning with organophosphorus compounds. Curr Med Chem
16:2177–2188.
Kassa J. 2002. Review of oximes in the antidotal treatment of poison-
ing by organophosphorus nerve agents. J Toxicol Clin Toxicol 40:
803–816.
Kassa J, Cabal J. 1999a. A comparison of the ecacy of a new asymmetric
bispyridinium oxime BI-6 with currently available oximes and H oxi-
mes against soman by in vitro and in vivo methods. Toxicology 132:
111–118.
Kassa J, Cabal J. 1999b. A comparison of the ecacy of a new asymmetric
bispyridinium oxime BI-6 with presently used oximes and H oxi-
mes against sarin by in vitro and in vivo methods. Hum Exp Toxicol
18:560–565.
Kassa J, Cabal J. 1999c. A comparison of the ecacy of acetylcholinesterase
reactivators against cyclohexylmethylphosphonouoridate (GF agent) by
in vitro and in vivo methods. Pharmacol Toxicol 84:41–45.
Kassa J, Karasova J, Musilek K, Kuca K. 2008. An evaluation of therapeutic and
reactivating eects of newly developed oximes (K156, K203) and com-
monly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned
rats and mice. Toxicology 243:311–316.
Kassa J, Karasova J, Vasina L, Bajgar J, Kuca K, Musilek K. 2009. A comparison
of neuroprotective ecacy of newly developed oximes (K203, K206) and
commonly used oximes (obidoxime, HI-6) in tabun-poisoned rats. Drug
Chem Toxicol 32:128–138.
Kovarik Z, Vrdoljak AL , Berend S, Catalinic M, Kuca K, Musilek K, Radic B.
2009. Evaluation of oxime K203 as antidote in tabun poisoning. Arh Hig
Rada Toksikol 60:19–26.
Kuca K, Jun D, Musilek K. 2006. Structural requirements of acetylcholinesterase
reactivators. Mini-Rev Med Chem 6:109–120.
Laufer R, Kalasz H, Musilek K, Szegi P, Darvas F, Kuca K, Tekes K. 2010. Synthesis,
antidotal eects and HPLC behavior of some novel pyridinium aldoximes.
Curr Org Chem 14:447–456.
Lotti M. 2000. Organophosphorus compounds. In: Spencer PS, Schaumburg
HH, editors. Experimental and clinical neurotoxicology. New York: Oxford
University Press. pp 898–925.
Lundy PM, Raveh L, Amitai G. 2006. Development of the bisquaternary oxime
HI-6 toward clinical use in the treatment of organophosphate nerve agent
poisoning. Toxicol Rev 25:231–243.
Marrs TC. 1993. Organophosphate poisoning. Pharmacol er 58:51–66.
Marrs TC, Rice P, Vale JA. 2006. e role of oximes in the treatment of nerve
agent poisoning in civilian casualties. Toxicol Rev 25:297–323.
Musilek K, Holas O, Kuca K, Jun D, Dohnal V, Opletalova V, Dolezal M. 2008.
Synthesis of monooxime-monocarbamoyl bispyridinium compounds
bearing (E)-but-2-ene linker and evaluation of their reactivation activity
against tabun- and paraoxon-inhibited acetylcholinesterase. J Enzyme
Inhib Med Chem 23:70–76.
Musilek K, Kuca K, Jun D, Dolezal M. 2007. Progress in synthesis of new acetyl-
cholinesterase reactivators during the period 1990–2004. Curr Org Chem
11:229–238.
Schoene K, Oldiges H. 1973. Ecacy of pyridinium salts in tabun and sarin
poisoning. Arch Int Pharmacodyn er 204:110–123.
Tallarida RJ, Murray RB. 1987. Manual of pharmacological calculation with
computer programs. New York: Springer-Verlag.
Worek F, Widmann R, Knop O, Szinicz L. 1998. Reactivating potency of obi-
doxime, pralidoxime, HI-6 and HLö-7 in human erythrocyte acetylcho-
linesterase inhibited by highly toxic organophosphorus compounds. Arch
Toxicol 72:237–243.
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    • In this study, we have tested three currently used AChE reactivators (pralidoxime, obidoxime, and HI-6) in comparison with our newly developed AChE reactivators (K033 and K027) [11,12]. We have previously tested their potencies on rat brain homogenate [13,14]. The use of different animal species makes the effects of AChE reactivators in humans more predictable [15,25].
    [Show abstract] [Hide abstract] ABSTRACT: The mechanism of intoxication with organophosphorus compounds, including highly toxic nerve agents, is based on the formation of irreversibly inhibited acetylcholinesterase (AChE; EC 3.1.1.7) that could be followed by a generalized cholinergic crisis. Nerve agent poisoning is conventionally treated using a combination of a cholinolytic drug (atropine mostly) to counteract the accumulation of acetylcholine at muscarinic receptors and AChE reactivators (pralidoxime or obidoxime) to reactivate inhibited AChE. At the Department of Toxicology, the strategy of the development of new more potent AChE reactivators consists of several steps: description of the nerve agent intoxication mechanism on the molecular basis (molecular design), prediction of the biological active structure of AChE reactivators (artificial neural networks), their synthesis, in vitro evaluation of their potencies (potentiometric titration and Ellman's method), in vivo studies (therapeutic index, LD(50) of newly synthesized reactivators, reactivation in different tissues, neuroprotective efficacy).
    Full-text · Article · Jan 2006
  • [Show abstract] [Hide abstract] ABSTRACT: Reactivation potency of three newly developed oximes K027, K033 and K048 was tested using standard in vitro and in vivo reactivation tests. K027 and K048 seem to be efficacious reactivators of tabun-inhibited acetylcholinesterase. K033 is sufficient reactivator of cyclosarin-inhibited AChE. However, its potency is poor compared with current "gold standard" oxime HI-6.
    Article · Jan 2006
  • [Show abstract] [Hide abstract] ABSTRACT: The therapeutical efficacies of eleven oxime-based acetylcholinesterase reactivators were compared in an in vivo (rat model) study of treatment of intoxication caused by tabun. In this group there were some currently available oximes (obidoxime, trimedoxime and HI-6) and the rest were newly synthesized compounds. The best reactivation efficacy for acetylcholinesterase in blood (expressed as percent of reactivation) among the currently available oximes was observed after administration of trimedoxime (16%) and of the newly synthesized K127 (22432) (25%). The reactivation of butyrylcholinesterase in plasma was also studied; the best reactivators were trimedoxime, K117 (22435), and K127 (22432), with overall reactivation efficacies of approximately 30%. Partial protection of brain ChE against tabun inhibition was observed after administration of trimedoxime (acetylcholinesterase 20%; butyrylcholinesterase 30%) and obidoxime (acetylcholinesterase 12%; butyrylcholinesterase 16%).
    Full-text · Article · Dec 2008
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March 2010 · Journal of Enzyme Inhibition and Medicinal Chemistry · Impact Factor: 2.33
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