Medical treatment of acute poisoning with organophosphorus and carbamate pesticides.
ABSTRACT Organophosphorus compounds (OPs) are used as pesticides and developed as warfare nerve agents such as tabun, soman, sarin, VX and others. Exposure to even small amounts of an OP can be fatal and death is usually caused by respiratory failure. The mechanism of OP poisoning involves inhibition of acetylcholinesterase (AChE) leading to inactivation of the enzyme which has an important role in neurotransmission. AChE inhibition results in the accumulation of acetylcholine at cholinergic receptor sites, producing continuous stimulation of cholinergic fibers throughout the nervous systems. During more than five decades, pyridinium oximes have been developed as therapeutic agents used in the medical treatment of poisoning with OP. They act by reactivation of AChE inhibited by OP. However, they differ in their activity in poisoning with pesticides and warfare nerve agents and there is still no universal broad-spectrum oxime capable of protecting against all known OP. In spite of enormous efforts devoted to development of new pyridinium oximes as potential antidotes against poisoning with OP only four compounds so far have found its application in human medicine. Presently, a combination of an antimuscarinic agent, e.g. atropine, AChE reactivator such as one of the recommended pyridinium oximes (pralidoxime, trimedoxime, obidoxime and HI-6) and diazepam are used for the treatment of OP poisoning in humans. In this article the available data related to medical treatment of poisoning with OP pesticides are reviewed and the current recommendations are presented.
- SourceAvailable from: Esra Sağlam[Show abstract] [Hide abstract]
ABSTRACT: Dioxacarb (Elecron, Famid) is a phenyl methylcarbamate insecticide and in vitro cytotoxic and genotoxic effects of this pesticide on human peripheral blood lymphocytes and Allium root meristematic cells were investigated by chromosomal aberrations (CAs) and Allium test. Human lymphocytes were treated with 62.5, 125, 250 and 500 ppm doses of dioxacarb for CAs. CA/cell, abnormal cell % and mitotic index % (MI %) data were obtained from these concentrations in 24 and 48 h treatment periods. Dioxacarb did not increase the CA/cell frequency significantly, so this insecticide was not identified as genotoxic. But it was found cytotoxic especially at 250 and 500 ppm concentrations because of the reduced the MI % and increased the abnormal cell %. In Allium test, 25 ppm (EC50/2), 50 ppm (EC50) and 100 ppm (EC50 × 2) concentrations were used for root growth inhibition (EC50 determination) and Allium mitotic index (MI) determination tests. The used concentrations of dioxacarb induced dose-dependent inhibition of MI and root growth on root meristems. Mitotic inhibition of dioxacarb was found significantly higher than for the positive control. These Allium results indicated the high cytotoxicity of dioxacarb. The present study is the first research on cytotoxicity and genotoxicity of dioxacarb by human lymphocyte CAs and Allium test.Cytotechnology 05/2014; · 1.32 Impact Factor
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ABSTRACT: Organophosphorus compounds (OP) are bound to human butyrylcholinesterase (BChE) and endogenous or exogenous BChE may act as a stoichiometric scavenger. Adequate amounts of BChE are required to minimize toxic OP effects. Simultaneous administration of BChE and oximes may transfer the enzyme into a pseudo-catalytic scavenger. The present study was initiated to determine the reactivation kinetics of 31 structurally different bispyridinium oximes with paraoxon-, tabun- and cyclosarin-inhibited human BChE. Human plasma was incubated with OP and the reactivation of inhibited BChE was tested with multiple oxime concentrations followed by nonlinear regression analysis for the determination of reactivity, affinity and overall reactivation constants. The generated data indicate that the tested oximes have a low-to-negligible reactivating potency with paraoxon- and tabun-inhibited human BChE. Several oximes showed a moderate-to-high potency with cyclosarin-inhibited BChE. Thus, the present study indicates that bispyridinium oximes are obviously not suitable to serve as reactivators of human BChE inhibited by different OP and it is doubtful whether further modifications of the bispyridinium template will lead to more potent reactivators. In the end, novel structures of oxime and non-oxime reactivators are urgently needed for the development of human BChE into an effective pseudo-catalytic scavenger.Archives of Toxicology 06/2014; · 5.22 Impact Factor
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ABSTRACT: Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer's disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a "cholinergic anti-inflammatory pathway" which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system.International Journal of Molecular Sciences 01/2014; 15(6):9809-9825. · 2.46 Impact Factor
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Author's personal copy
Toxicology Letters 190 (2009) 107–115
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/toxlet
Medical treatment of acute poisoning with organophosphorus and
Milan Jokanovi´ ca,b,∗
aFaculty of Medicine, University of Nish, Nish, Serbia
bAcademy of Sciences and Arts of Republic Srpska, Banja Luka, Republic Srpska, Bosnia and Herzegovina
a r t i c l ei n f o
Received 13 July 2009
Accepted 27 July 2009
Available online 3 August 2009
Warfare nerve agents
a b s t r a c t
Organophosphorus compounds (OPs) are used as pesticides and developed as warfare nerve agents
such as tabun, soman, sarin, VX and others. Exposure to even small amounts of an OP can be fatal and
death is usually caused by respiratory failure. The mechanism of OP poisoning involves inhibition of
acetylcholinesterase (AChE) leading to inactivation of the enzyme which has an important role in neuro-
transmission. AChE inhibition results in the accumulation of acetylcholine at cholinergic receptor sites,
producing continuous stimulation of cholinergic fibers throughout the nervous systems.
During more than five decades, pyridinium oximes have been developed as therapeutic agents used in
the medical treatment of poisoning with OP. They act by reactivation of AChE inhibited by OP. However,
they differ in their activity in poisoning with pesticides and warfare nerve agents and there is still no
universal broad-spectrum oxime capable of protecting against all known OP. In spite of enormous efforts
devoted to development of new pyridinium oximes as potential antidotes against poisoning with OP
only four compounds so far have found its application in human medicine. Presently, a combination of
an antimuscarinic agent, e.g. atropine, AChE reactivator such as one of the recommended pyridinium
oximes (pralidoxime, trimedoxime, obidoxime and HI-6) and diazepam are used for the treatment of OP
poisoning in humans. In this article the available data related to medical treatment of poisoning with OP
pesticides are reviewed and the current recommendations are presented.
© 2009 Elsevier Ireland Ltd. All rights reserved.
Interaction of cholinesterases with organophosphorus and carbamate compounds............................................................... 108
Clinical presentation of acute poisoning with organophosphorus compounds..................................................................... 108
Antidotes in the treatment of human poisoning with organophosphorus pesticides .............................................................. 109
4.1. Atropine ......................................................................................................................................
4.2. Diazepam ..................................................................................................................................... 109
4.3.Pyridinium oximes ...........................................................................................................................
Medical treatment of acute poisoning with organophosphorus pesticides......................................................................... 111
5.1.General measures ............................................................................................................................
5.2.Specific therapy............................................................................................................................... 111
5.2.2. Pyridinium oximes .................................................................................................................
5.2.3.Clinical experience with pyridinium oximes....................................................................................... 112
Clinical aspects of medical treatment of poisoning with carbamate pesticides ....................................................................
Conflict of interest ...................................................................................................................................
∗Correspondence address: Experta Consulting, Nehruova 57, 11070 Belgrade, Serbia. Tel.: +381 11 1779560.
E-mail addresses: email@example.com, firstname.lastname@example.org.
0378-4274/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
Author's personal copy
M. Jokanovi´ c / Toxicology Letters 190 (2009) 107–115
Organophosphorus compounds (OPs) have been used as pesti-
cides and developed as warfare nerve agents such as soman, sarin,
tabun, VX and others. OP pesticide self-poisoning is an important
clinical problem in rural regions of the developing world that kills
an estimated 200,000 people every year. Unintentional poisoning
kills far fewer people but is an apparent problem in places where
highly toxic OP pesticides are available. Medical management is
difficult, with case fatality generally more than 15% (Eddleston et
al., 2008). Carbamates (CBs) are used as pesticides and some of
them (e.g. physostigmine, pyridostigmine) have been registered
as human drugs. Exposure to even small amounts of an OP com-
pound can be fatal; death is usually caused by respiratory failure
resulting from paralysis of the diaphragm and intercostal mus-
cles, depression of the brain respiratory center, bronchospasm, and
excessive bronchial secretions. The mechanism of OP poisoning
essential enzyme which has an important role in neurotransmis-
sion. The CB also act by carbamylating the same site on AChE which
reversibly inhibits the enzyme activity. AChE inhibition results in
the accumulation of acetylcholine at cholinergic receptor sites,
producing continuous stimulation of cholinergic fibers throughout
the central and peripheral nervous systems. Presently, a combi-
nation of an antimuscarinic agent, e.g. atropine, AChE reactivator
such as one of the recommended pyridinium oximes (pralidoxime,
trimedoxime, obidoxime and HI-6) and diazepam are used for the
treatment of OP poisoning in humans. Both atropine and oximes
for either therapy. This article reviews the mechanisms of action of
OP, CB, and antidotes used in current medical treatment of human
poisonings with OP and CB pesticides.
2. Interaction of cholinesterases with organophosphorus
and carbamate compounds
There are different types of cholinesterases in the human body,
iological function. The principal ones are acetylcholinesterase (EC
184.108.40.206, AChE), found in the nervous system and also present in
the outer membrane of erythrocytes, and plasma cholinesterases
(EC 220.127.116.11, ChE), which are a group of enzymes present in plasma,
conditions, AChE performs the breakdown of acetylcholine (ACh),
not serve any known physiological function. It was proposed that
ChE may have roles in cholinergic neurotransmission and involved
in other nervous system functions (cellular proliferation and neu-
rite growth during the development of the nervous system) and in
neurodegenerative disorders (Darvesh et al., 2003).
The function of AChE is termination of action of ACh at the junc-
tions of the various cholinergic nerve endings with their effector
organs or post-synaptic sites. OP and CB are the most important
AChE inhibitors and often called anticholinesterases. In the pres-
ence of inhibitors, AChE becomes progressively inhibited and is
not further capable of hydrolyzing ACh to choline and acetic acid
(Jokanovi´ c and Maksimovi´ c, 1997). Consequently, ACh accumu-
lates at cholinergic receptor sites and produces effects equivalent
to excessive stimulation of cholinergic receptors throughout the
central and peripheral nervous system.
in essentially the same manner, because acetylation of the ser-
ine residue at AChE catalytic site is analogous to phosphorylation
or carbamylation. In contrast to the acetylated enzyme which
rapidly separates acetic acid and restores the catalytic site, the
phosphorylated enzyme is stable (Fig. 1). Inhibited enzyme can
be spontaneously reactivated at different rates depending on the
inhibitor—for CB it occurs very rapidly with half-time of an hour or
less, while for OP having branched alkyl groups it may occur at a
very slow rate. In addition, for OP pesticides containing dimethyl
phosphate groups the half-time of spontaneous reactivation of
phosphorylated AChE in vitro is 1–1.3h, in vivo 2.1h and the
neous reactivation is slower (31–57h in vitro) as well as the rate of
aging (31h) (Reiner and Pleˇ stina, 1979; Worek and Diepold, 1999;
phates are recognized as reversible AChE inhibitors, while other
OP having branched alkyl groups are practically irreversible AChE
The variations in the acute toxicity of OP are the result of their
and aging. Aged form of phosphorylated AChE is resistant to both
spontaneous and oxime-induced reactivation. The aging reaction,
although appearing with many phosphorylated AChE complexes,
has the only major clinical importance and an imperative problem
occurs so fast that no clinically relevant spontaneous reactivation
of AChE can occur before aging has taken place. Hence, recovery
of function depends on relatively slow resynthesis of AChE. It is
important to immediately administer atropine and oximes so that
some extent of AChE reactivation occurs before all AChE has aged.
in the case of OP insecticides and other nerve agents, early oxime
administration is clinically important particularly in patients poi-
soned with these agents.
3. Clinical presentation of acute poisoning with
Signs and symptoms of acute poisoning with anticholinesterase
agents are predictable from their biochemical mechanism of action
and are directly related to the levels of AChE activity. In cases
of human intoxication, general acute symptoms of peripheral
nicotinic and muscarinic intoxication are clearly apparent (World
Health Organization, 1986). These symptoms include miosis (unre-
active to light); sweating, rhinorrhea, lacrimation, and salivation;
abdominal cramps and other gastrointestinal symptoms; respi-
ratory difficulties and cough; dyspnea, constriction sensation in
the chest, wheezing; twitching of facial muscles and tongue,
tremors, and fasciculations; bradycardia and ECG changes, pallor,
urination and defecation. These signs and symptoms are accom-
panied by central effects such as dizziness, tremulousness, and
confusion; ataxia; headache, fatigability, and paresthesia. Finally,
seizures, convulsions, twitching, coma, and respiratory failure may
occur. If the subject survives past the day of poisoning, there are
personality changes, mood swings, aggressive events and psy-
chotic episodes including schizoid reactions, paranoid delusions,
and exacerbations of preexisting psychiatric problems. Sleep is
poor from nightmares and hallucinations; disturbances or deficits
in memory and attention, and additional delayed effects also occur
(Karchmar, 2007; World Health Organization, 1986; IPCS, 1989;
Marrs and Vale, 2006).
The first 4–6h are the most critical in acute poisoning with OP
pesticides. If there is improvement in symptoms after initial treat-
Author's personal copy
M. Jokanovi´ c / Toxicology Letters 190 (2009) 107–115
Fig. 1. Physiological role (a) and interaction of acetylcholinesterase (AChE) and other esterases (E) with organophosphorus (b) and carbamate (c) compounds. Reaction 1
shows interaction of organophosphate molecule with the serine hydroxyl group at the active site of AChE via formation of an intermediate Michaelis Menten complex leading
to phosphorylated enzyme (Reaction 2). Reaction 3 is a spontaneous reactivation of inhibited AChE which occurs very slowly for most OP and very rapidly for carbamates.
Reaction 4, called “aging”, represents non-enzymatic time-dependent loss of one alkyl group (R) bound to the phosphorus. The aging reaction depends on the chemical
structure of the inhibitor and leads to a stable non-reactivatable form of phosphorylated AChE.
is continued (IPCS, 1989). The duration of effects is determined
mainly by the properties of the compound: its liposolubility, the
stability of the OP–AChE complex and whether it is reactivatable
after the use of cholinesterase reactivators (such as oximes). It is
important to note that only OP containing P O bond (known as
direct inhibitors) are potent AChE inhibitors; those having a P S
group (indirect inhibitors) must be metabolically activated to P O
direct inhibitors appear quickly during or after exposure, while
those with indirect inhibitors appear slowly and last longer, even
up to several days after cessation of exposure.
Clinical diagnosis is relatively simple and is based on medi-
cal history, circumstances of exposure, clinical presentation, and
laboratory tests. Confirmation of diagnosis can be made by mea-
surement of erythrocyte AChE or plasma ChE. Activities of these
enzymes are accepted as biomarkers of exposure and/or toxicity of
OP and CB. Erythrocyte AChE is identical to the enzyme present in
the target synapses and its levels are assumed to reflect the effects
the above assumption is only correct when the inhibitor has equal
access to blood and synapses. It is difficult to know, due to phar-
macokinetic reasons, how closely AChE inhibition in erythrocytes
reflects that in the nervous system since access to blood is always
easier than access to brain. Thus, the inhibition of AChE in ery-
throcytes may be overestimated relative to that in brain (Jokanovi´ c
and Maksimovi´ c, 1997). In addition, AChE in brain is restored by
de novo synthesis more rapidly than in erythrocytes where AChE
activity is recovered via erythropoesis. The level of activity of ChE
should be carefully interpreted since the normal range in healthy
subjects is relatively wide, rendering interpretation in individual
patients difficult unless the results of previous estimations in the
patient are available. Inhibition of ChE does not provide accurate
information related to clinical severity of the poisoning. Many OP
insecticides (e.g. chlorpyrifos, demethon and malathion) appear to
be more potent inhibitors of ChE than they are of erythrocyte AChE
and, as the consequence, ChE inhibition might occur to a greater
extent than AChE inhibition.
The rate of spontaneous reactivation (Fig. 1, Reaction 3) can be
accelerated by pyridinium oximes that have a chemical structure
be of benefit as long as inhibited AChE is not completely converted
to the aged form.
4. Antidotes in the treatment of human poisoning with
Atropine acts by blocking the effects of excess concentrations
of acetylcholine at muscarinic cholinergic synapses following OP
inhibition of AChE. Atropine is the initial drug of choice in acute
OP poisoning. Atropine sulphate in combination with an oxime
has been used in traditional therapy for OP intoxications includ-
ing insecticides. Atropine can relieve the following symptoms of
OP poisoning: sweating, salivation, rhinorrhoea, lacrimation, nau-
circulatory depressions, dilating the bronchi and abolishing bron-
relieve nicotinic effects in OP poisoning.
It has been shown that atropine may have anticonvulsant
effects and prevent development of convulsions and brain dam-
age induced by certain OP (McDonough et al., 1987). Other authors
have stated that atropine can only partly block convulsions after
exposure to these agents since other transmitter systems (GABA,
(Zilker, 2005; Antonijevi´ c and Stojiljkovi´ c, 2007). The effects of
atropine in OP poisoning are far more complex than muscarinic
blokade. In a study in rats it was found that atropine treatment
reduced local use of cerebral glucose and brain damage during
seizures induced with soman (Pazdernik et al., 1986).
Although the clinical efficacy of atropine in OP poisoning is well
established, no controlled studies have been published. Atropine
dosing is discussed later in this text.
Benzodiazepines are CNS depressants, anxiolytics and muscle
relaxants. Their main site of action is at the gamma-aminobutyric
acid (GABA) receptor. The GABAAreceptor is a ligand gated chlo-
ride ion channel and part of a superfamily of receptors which
also includes the nicotinic acetylcholine receptor and the glycine
receptor. GABA is the major inhibitory neurotransmitter in the
mammalian central nervous system. Benzodiazepines, including
fashion, but do not directly activate the receptors (Sellström, 1992;
Currently, the most important anticonvulsant is diazepam. The
combination of atropine and diazepam is more effective in reduc-
ing mortality than atropine or oxime alone. It was also shown
that diazepam enhanced the efficacy of low doses of atropine. In
the cholinergic nervous system, diazepam appears to decrease the
zodiazepines in CNS is hyperpolarization of neurons making them
significantly less susceptible to cholinergically induced depolariza-
tion. The ultimate result is cessation of propagation of convulsions
(Sellström, 1992; Marrs, 2004; Antonijevi´ c and Stojiljkovi´ c, 2007).
effect in reducing anxiety and restlessness, reducing muscle fasci-
culation, arresting seizures, convulsions, controlling apprehension
and agitation and possibly reducing morbidity and mortality when
Author's personal copy
M. Jokanovi´ c / Toxicology Letters 190 (2009) 107–115
used in conjunction with atropine and an oxime. Diazepam should
be given to patients poisoned with OP whenever convulsions or
pronounced muscle fasciculation are present. In severe poison-
ing, diazepam administration should be considered even before
these complications develop. The recommended dose of diazepam
in cases of OP poisoning is 5–10mg intravenously in the absence
of convulsions and 10–20mg intravenously in cases with convul-
sions, which may be repeated as required (Johnson and Vale, 1992;
Antonijevi´ c and Stojiljkovi´ c, 2007). WHO recommends the dose
of diazepam of 5–10mg intravenously slowly over 3min which
may be repeated every 10–15min (maximum 30mg) in adults and
0.2–0.3mg/kg intravenously slowly over 3min in children (maxi-
than 5 years) (IPCS, 1989).
4.3. Pyridinium oximes
Extensive studies over the past decades have investigated the
mechanism of action of pyridinium oximes. There is convincing
evidence that the antidotal potency of pyridinium oximes is pri-
marily attributed to their ability to reactivate the phosphorylated
by displacing the phosphoryl moiety from the enzyme by virtue of
their high affinity for the enzyme and their powerful nucleophilic-
ity. Reactivation proceeds as a two-step reaction via formation of
of the enzyme, the structure and concentration of oxime which is
known as aging. Phosphorylated oximes are formed during reacti-
vation reaction and some of them appear to be potent inhibitors
of AChE (Luo et al., 1999; Ashani et al., 2003; Worek et al., 2007).
The structure–activity relationship for pyridinium oximes devel-
oped as AChE reactivators was recently discussed by Jokanovi´ c and
In addition to performing AChE reactivation in OP poison-
ing, pyridinium oximes also show direct pharmacological effects
that are discussed in detail in other publications (Jokanovi´ c and
Stojiljkovi´ c, 2006; Jokanovi´ c and Prostran, 2009).
Pyridinium oximes are effective against OP-inhibited AChE in
the peripheral nervous system, but have a limited penetration
across the blood–brain barrier due to their pharmacokinetic pro-
file and the presence of quaternary nitrogen atom(s) in their
structure. However, it appears that oxime penetration through
blood–brain barrier is underestimated since soman can cause
seizure-related opening of the blood–brain barrier (Carpentier et
tribute to better penetration of oximes through the blood–brain
barrier: the induction of local inflamatory processes and increase
of brain–blood flow (Shrot et al., 2009). It was shown that 0.5–1.0
LD50 of sarin caused a dose-dependent increase in permeability
of blood–brain barrier in midbrain, brainstem, cerebrum and cere-
bellum in rats 24h after poisoning (Abdel-Rahman et al., 2002).
Sakurada et al. (2003) have determined the amount of PAM-2 pass-
ing across the blood–brain barrier at approximately 10% of the
given dose which may be effective in reactivation of OP-inhibited
AChE in brain. Additional data indicate that in OP poisoning, when
given with atropine, PAM-2 can pass blood–brain barrier at higher
Some clinicians from Asia have reported that pralidoxime is
not sufficiently effective in treatment of OP pesticide poisoning
and their opinion is based on poorly designed studies (suboptimal
dose, short duration of treatment, long delay before pralidoxime is
given, studies did not follow WHO recommendations, the chemical
1992; Singh et al., 1995; Johnson et al., 1996; Cherian et al., 2005).
Possible reasons why oximes may not be effective in OP poisoning
were discussed by Johnson et al. (2000), Eyer (2003) and Milatovi´ c
a. The oxime dose may be inadequate to produce the optimal con-
centration required to achieve the desired reactivation and it
may not be present at target sites when mostly needed (i.e.
when AChE inhibition reaches its maximum and when OP is
present in blood at high concentrations). Proposed minimum-
effective plasma levels for oximes of 4mg/L were also supported
by other scientists (Bokonji´ c et al., 1987; Shiloff and Clement,
1987; Kuˇ si´ c et al., 1991). In severe cases of OP pesticide poison-
ing, higher oxime concentrations may be necessary, especially
in the case of pralidoxime. However, Eyer (2003) disagrees
with the 4mg/L concept suggesting necessity of a higher oxime
concentration. He proposed that for the most frequently used
OP, pralidoxime plasma concentrations of around 80?mol/L
(13.8mg/L pralidoxime chloride) or 10?mol/L of obidoxime
(3.6mg/L obidoxime chloride) should be adequate and main-
tained for as long as the OP is present in the body. Oxime
treatment may be required for up to 10 days.
b. In addition to an inadequate initial dose, subsequent treatment
cleared from the body and although some reactivation may
be achieved, another cycle of inhibition and eventually aging
of inhibited AChE, due to continuing presence of OP in blood,
may follow. This is particularly possible in the case of massive
overdose where residual OP pesticide may persist in the body
for several days. In such cases only persistent administration
of oximes, by means of continuous infusion or repeated oxime
administration, can be expected to result in permanent clinical
improvement. Eyer (2003) suggests that the most appropriate
dosing regimen consists of a bolus short infusion followed by a
maintenance dosage. For pralidoxime chloride a 1g bolus over
30min followed by an infusion of 0.5g/h appears appropriate
to maintain the concentration of 13mg/L. For obidoxime chlo-
ride the proposed dosing regimen is a 0.25g bolus followed by
an infusion of 0.75g/24h. It is important that the concentrations
were well tolerated and effective in keeping the active levels of
c. Treatment with oxime may be started too late or terminated too
tal treatment as soon as possible and to maintain the treatment
as long as needed. In cases of poisoning with persistent OP pes-
ticides it is appropriate to start oxime therapy at adequate dose
levels up to 10 days after exposure or even later. Eddleston et al.
120h for diethyl OP poisoning and 12h for dimethyl OP poison-
needed and the decision about this can be made on the basis of
clinical status of the patient, relatively high AChE activity in ery-
throcytes when compared to control values and the absence of
OP and/or OP metabolites in urine.
Observational studies of pralidoxime and obidoxime suggest
that the ability to reverse AChE inhibition with oximes varies
with the pesticide ingested. AChE inhibited by diethyl OP pesti-
cides, such as parathion and quinalphos, seems to be effectively
reactivated by oximes, but AChE inhibited by dimethyl OP, such
as dimethoate, monocrotophos and oxydemeton-methyl, appar-
ently responds poorly. AChE inhibited by S-alkyl-linked OP, such
as profenofos, is not reactivated by oximes at all. This difference is
Author's personal copy
M. Jokanovi´ c / Toxicology Letters 190 (2009) 107–115
induced by different OP pesticides.
5. Medical treatment of acute poisoning with
5.1. General measures
Treatment of OP pesticide poisoning should begin with decon-
tamination and resuscitation if needed. Decontamination is vital
in reducing the dose of the pesticide absorbed, but care must be
taken not to contaminate others, such as medical and paramedi-
cal workers. In the case of ingestion, lavage can be performed, and
activated charcoal administered. The patient should be observed
carefully during the early stages of treatment because respiratory
arrest may occur. Solvent vehicles and other components of the
formulated OP pesticides may complicate the clinical picture and
should be taken into consideration (IPCS, 1989).
Supportive measures should be directed towards the cardiores-
piratory system with particular emphasis on maintenance of
ventilation, cardiac rhythm and blood pressure; the removal by
suction of respiratory and oral secretions which may cause res-
piratory distress; and the oxygenation of the patient. Severely
poisoned patients disconnected from the ventilator when the
general condition improves, must be carefully watched for rapid
deterioration and development of the intermediate syndrome dur-
ing the following few days in the Intensive Care Unit (IPCS, 1989).
In addition, the patients should be warned to report to hospital if
2–3 weeks after exposure.
Ingested organophosphates should be removed by early gas-
tric aspiration and then lavage, with protection of the airway
because they are mostly dissolved in aromatic hydrocarbons;
this may be the best remedy in unconscious patients. Gastric
lavage is most effective within 30min of ingestion, but might be
still effective up to 4h post-ingestion, as organophosphates are
rapidly absorbed from the gastrointestinal tract (World Health
may be considered for reducing further absorption of some OP pes-
ticides (World Health Organization, 1986). This recommendation
was supported by Peng et al. (2004) who conducted a random-
ized controlled clinical trial involving 108 patients aimed to assess
the efficacy of hemoperfusion with charcoal in treatment of acute
severe dichlorvos poisoning. The authors concluded that the rapid
gest that hemoperfusion with charcoal is effective in the treatment
of acute severe dichlorvos poisoning.
Two recent clinical trials designed to evaluate the effectiveness
results. A randomized controlled trial of single and multiple doses
of activated charcoal in Sri Lanka failed to find a significant benefit
with pesticides (Eddleston et al., 2005a). In addition, Eddleston
et al. (2008) conducted an open-label, parallel group, random-
ized, controlled trial in three Sri Lankan hospitals aimed to assess
whether routine treatment with multiple-dose activated charcoal
offers benefit compared with no charcoal. Among 2338 patients
who ingested pesticides (1310 cases of poisoning with OP and car-
bamate pesticides) there were no differences in mortality between
patients treated with or no charcoal. The authors concluded that
they cannot recommend the routine use of multiple dose activated
charcoal in poisonings with OP and carbamate pesticides and sug-
gest that further studies of early charcoal administration might be
Fig. 2. Chemical structure of pyridinium oximes used in medical treatment of
human OP poisoning. X stands for an anion (chloride or methylsulphate).
5.2. Specific therapy
According to IPCS (1989) an initial trial dose of atropine,
1–2mg (0.05mg/kg) intravenously, should be given slowly over
3min, and then repeated every 5–10min if there is no observ-
able adverse effect. In symptomatic children, intravenous dose of
0.015–0.05mg/kg atropine should be administered every 15min
as needed. Atropine may then be repeated or increased in incre-
ments at 15–30min intervals until bronchosecretion is cleared
and the patient is atropinized (dilated pupils, dry skin, and skin
flushing) which should be maintained during further treatment.
Repeated evaluations of the quantity of the secretions through
regular auscultation of the lungs is the only adequate measure of
atropinization in the severely poisoned patient. The dose may be
tant to toxic effects of atropine and may require relatively large
OP poisoning total dose of atropine given during 5 weeks of treat-
ment can be as high as 30,000mg (IPCS, 2002).
5.2.2. Pyridinium oximes
Among the many classes of oximes investigated so far, those
with clinical application can be divided in two groups—the
monopyridinium and bispyridinium oximes. Currently, the only
used monopyridinium oxime is pralidoxime (PAM-2), while the
most significant bispyridinium oximes comprise: trimedoxime
(TMB-4), obidoxime (LüH-6, Toxogonin) and asoxime (HI-6), and
national consensus on the choice of most effective oxime and on
18.104.22.168. Pralidoxime. Pralidoxime administered to human volun-
teers at a dose of 10mg/kg by intramuscular route, produced a
plasma concentration of >4mg/L within 5–10min and maintained
levels above this threshold for an hour (Sidell and Groff, 1971).
Adverse effects of PAM-2 iodide in volunteers include dizziness,
and headache (Jagger and Stagg, 1958; Sidell and Groff, 1971).
atropine and diazepam, in the treatment of the victims of Tokyo
sarin attack victims in 1995 was extremely favourable (Stojiljkovi´ c
and Jokanovi´ c, 2005). However, PAM-2 should not be recom-
mended as the drug of choice in poisoning with warfare nerve
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M. Jokanovi´ c / Toxicology Letters 190 (2009) 107–115
agents due to its lack of efficacy against tabun and soman (Kassa,
In poisoning with OP pesticides pralidoxime chloride should
be administered to adults in a dose of 500mg/h, continuously
maintained until clinical improvement is obtained, or 30mg/kg
body weight bolus intravenously over 4–6h or 8–10mg/kg/h
intravenously until full recovery occurs. In children, pralidoxime
chloride should be administered in a dose of 25mg/kg intra-
venously for 15–30min, followed by a continuous infusion of
10–20mg/kg/h. The therapy can continue for 18h or longer,
depending on the clinical status (IPCS, 1989).
for pralidoxime 20–40mg/L and for obidoxime about 4mg/L. This
concentration is usually attained by a daily dose of 10–15g PAM-
2 Cl and 0.75–1.0g obidoxime, respectively, either given divided
in 4–6 single bolus doses or, preferably, by continuous intravenous
obidoxime, respectively) (IPCS, 1989).
22.214.171.124. Obidoxime. When administered to human volunteers by
intramuscular route obidoxime 5mg/kg produced a plasma con-
centration >4mg/L, from 5min after injection to 3h (Sidell and
Groff, 1970). Adverse effects of obidoxime in male volunteers were
described as pallor, nausea, burning sensation, headache, gener-
alized weakness, sore throat, and paresthesia of the face (Simon
and Pickering, 1976; Eyer, 2003; Marrs and Vale, 2006). Following
high doses of obidoxime (several grams per day) in severely OP-
poisoned patients, hepatotoxic effects were occasionally observed
including increased serum transaminases, jaundice and cholestasis
Obidoxime should be administered in adults at dose of 250mg
given by slow intravenous injection followed by continuous infu-
sion of 750mg/24h (0.4mg/kg/h) to reach plasma concentrations
of 10–20?mol/L. Intramuscular dosing is possible when the intra-
venous route is inaccessible. In children, the dose of obidoxime is
3–6mg/kg slowly administered intravenously over at least 5min
126.96.36.199. Asoxime (HI-6). Clinical studies showed that HI-6 dosed at
either 250mg or 500mg by intramuscular route reached plasma
concentrations >4mg/L in 4–6min. This concentration was main-
tained for 125min following the lower dose (250mg) and 200min
following the higher dose (500mg) (Kuˇ si´ c et al., 1985, 1991).
These authors have administered HI-6 four times a day as a sin-
gle intramuscular injection of 500mg with atropine and diazepam
treatment. Oxime therapy was started on admission and continued
for 2–7 days.
A clinical study performed on 22 healthy human volunteers did
not reveal any adverse effects when HI-6 was given in doses up
to 500mg by oral route (Jovanovi´ c et al., 1990). HI-6 is considered
to be a very promising bispyridinium oxime in medical treatment
following exposure to most nerve agents. A disadvantage of HI-6
compared to other available oximes is its lack of stability in aque-
ous solutions. HI-6 was considered to be an effective antidote (in
combination with atropine and diazepam) in treatment of patients
poisoned with OP insecticides (Kuˇ si´ c et al., 1991).
as aspiration pneumonia or hypoxic brain injury before treatment.
Such complications take place with fast-acting pesticides such as
parathion and dichlorvos (Eddleston et al., 2008).
5.2.3. Clinical experience with pyridinium oximes
A particular problem in interpreting the beneficial role and
efficacy of oximes in clinical practice is a deficiency of published
data, especially those evaluated in controlled clinical trials. Stud-
ies related to the efficacy of oximes in clinical setting showed the
heterogeneity of therapeutic approaches (i.e. dose regimen, oxime
choice and final outcome of the treatment). In most reports cited
in this section chemical structure of OP pesticides was identified in
Eddleston et al. (2005b) reported the results of a prospective
study on 802 patients self-poisoned with chlorpyrifos, dimethoate,
or fenthion. Compared with chlorpyrifos (8.0%), the proportion
dying was significantly higher with dimethoate (23.1%) or fenthion
(16.2%) as was the proportion requiring endotracheal intubation
(chlorpyrifos, 15.0%; dimethoate, 35.2%; fenthion, 31.3%). Patients
poisoned by diethyl OP pesticide (chlorpyrifos) responded well to
pralidoxime, whereas those poisoned by two dimethyl OP pes-
ticides (dimethoate, fenthion) responded poorly. Poor efficacy of
pralidoxime in treatment of human dimethoate and fenthion poi-
sonings was in agreement with experimental studies conducted
by Jokanovi´ c and Maksimovi´ c (1995) who found that antidotal
efficacy of obidoxime, trimedoxime, pralidoxime and HI-6 (given
with atropine and diazepam) in rats dosed with 2 LD50 of the
dimethoate, was low. However, there was a discrepancy between
fenthion-poisoned patients and animals in that pralidoxime was
considerable efficacy in rats.
Kuˇ si´ c et al. (1991) have tested the oxime HI-6 in OP pesticide
poisoning in 60 patients. HI-6 was administered four times a day
as a single intramuscular injection of 500mg with atropine and
diazepam treatment. Oxime therapy was started on admission and
continued for 2–7 days. Most patients were treated with HI-6 and
PAM-2 chloride (1000mg four times per day). HI-6 rapidly reacti-
pyridaphenthion, quinalphos) as well as that inhibited by dichlor-
to 3.5h. AChE inhibited with other dimethoxy OPs (dimethoate,
phosphamidon) was reported to be resistant to HI-6 treatment,
whereas reactivation with malathion was slow (reactivation half-
time 10h). Both HI-6 and PAM-2 successfully reactivated AChE in
quinalphos-poisoned patients, with HI-6 acting as a faster AChE
reactivator than PAM-2. No adverse effects were seen in patients
treated with the oximes.
Nine patients intoxicated with OP pesticides were treated with
PAM-2 methylsulphate (Contrathion) using a dose of 4.42mg/kg
as a bolus injection followed by continuous infusion 2.14mg/kg/h.
In patients with ethylparathion and methylparathion poisonings,
enzyme reactivation could be obtained in some patients at oxime
concentrations as low as 2.88mg/L. In others, however, oxime con-
centration as high as 14.6mg/L were ineffective. The therapeutic
of ethyl parathion and methyl parathion. Due to AChE reinhibition,
reactivation was absent as long as these concentrations remained
above 30?g/L (Aragao et al., 1996).
Willems et al. (1993) reported that ethyl parathion and methyl
parathion could be effectively treated with PAM-2 methylsulphate
(plasma concentrations 4mg/L) and atropine when pesticide con-
centrations in plasma were relatively low. In severe poisoning with
pesticide levels in plasma above 30?g/L, high PAM-2 concentra-
tions in plasma (14.6mg/L) did not provide any improvement. In
addition, PAM-2 at concentrations of 6.3mg/L was not effective in
AChE reactivation in dimethoate poisoning where AChE was inhib-
ited with its active metabolite omethoate.
It was reported that in cases of life-threatening parathion
poisoning obidoxime (Toxogonin) (250mg administered intra-
venously as a bolus followed by infusion of 750mg per day) was
effective (Thiermann et al., 1997, 1999). However, AChE reactiva-
tion did not occur until the concentration of paraoxon in plasma
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M. Jokanovi´ c / Toxicology Letters 190 (2009) 107–115
was low. Oxydemeton methyl poisoning responded to obidoxime
therapy only when the oxime was instituted shortly after poison-
ing. In cases when obidoxime treatment started too late there was
no reactivation of erythrocyte AChE and one out of six treated
In a clinical study of 63 patients poisoned with OP pesticides,
patients were divided into three groups: one was treated with
atropine only, while the other two received atropine and either
2mg/kg/h, respectively, for obidoxime. The major clinical findings
significant differences among the groups. Although the severity of
intoxications (based on respiratory complications and duration of
hospitalization) was higher in the atropine plus oxime groups, 12%
and 50% of patients in the atropine and atropine plus obidoxime
groups died, respectively. No mortality was found in the PAM-2
plus atropine group. Incidence of recurrent twitching and convul-
sions, repeated respiratory arrest, required mechanical respiration,
required intensive care unit therapy and duration of hospitaliza-
tion were lower in the atropine plus obidoxime group than in the
atropine plus PAM-2 group. Three of the patients who received the
obidoxime combination therapy developed hepatitis and two of
them died due to hepatic failure, which may indicate overdosage
of obidoxime (Balali-Mood and Shariat, 1998).
AChE inhibited by several OP pesticides, including dimethoate,
demethon, triamiphos, ethoprophos, profenofos, fenamiphos and
pyridafenthion, resists any attempt of reactivation with any oxime,
probably due to variations in phosphoryl moiety and distribution
of electronic charge (Jokanovi´ c and Maksimovi´ c, 1995; Bismuth et
In a randomized controlled trial, Pawar et al. (2006) studied the
effect of very-high dose pralidoxime iodide (2g loading dose, then
1g either every hour or every 4h for 48h, then 1g every 4h until
recovery) in 200 patients with moderate OP poisoning (excluding
severely ill patients). Among OP pesticides involved there were
chlorpyrifos (diethyl OP) and dimethoate (dimethyl OP). The high-
of pneumonia, and reduced time on mechanical ventilation. This
study suggests that large doses of pralidoxime could have benefit
if patients are treated early and have good supportive care.
6. Clinical aspects of medical treatment of poisoning with
Cases of accidental overexposure to or suicide attempts with
various CB pesticides have followed similar clinical courses char-
acteristic of cholinergic poisoning like that in poisoning with OP.
Differences in severity, duration, and outcome have corresponded
to differences in effective doses and in promptness and appro-
priateness of treatment. Spontaneous recovery without medical
treatment has occurred generally within 4h of exposures pro-
ducing symptoms of headache, dizziness, weakness, excessive
salivation, nausea, or vomiting. More severe symptoms have gen-
erally prompted medical treatment. Following treatment with
sufficient atropine, individuals have recovered from poisoning that
abdominal pain, incoordination, fasciculations, breathing difficul-
ties, or changes in pulse rate. Recovery has been complete in some
cases within 2h and in all cases within 1 day. CB poorly pene-
trate the blood–brain barrier and effects on central nervous system
seen in OP poisoning are absent or minimal. Deaths have resulted
in severe cases where treatment was delayed and/or insufficient
atropine was administered. It is important to note, however, that
treatment with atropine combined with general supportive treat-
ment, such as artificial respiration and administration of fluids, has
resulted in recovery even in cases where symptoms progressed to
pulmonary edema or coma (Baron, 1991; Rotenberg et al., 1995).
as CB are reversible AChE inhibitors that spontaneously reacti-
vate with a half-life in the order of an hour or less. Although the
immediate clinical picture of CB poisoning is similar to that of
OP, reversible inhibition with spontaneous hydrolysis of the car-
bamylated AChE moiety results in less severe and less prolonged
toxicity. Dimethyl compounds are a special case: they produce a
carbamylated AChE, which may be reactivated with oximes. How-
ever, oximes are harmful when employed in animals poisoned
with monomethyl carbamate, and a man who ingested carbaryl
died 6h after a PAM-2 treatment (Karchmar, 2007). The use of
oximes in the case of CB poisoning is controversial and considered
contraindicated by some authors. Lieske et al. (1992) have found
that pyridinium oximes (obidoxime, trimedoxime, pralidoxime,
and HI-6) enhance inhibition of both eel AChE and human serum
ChE induced by carbaryl. The authors have proposed that oximes
act as allosteric effectors of cholinesterases in carbaryl poisoning
resulting in enhanced inhibition rates and potentiation of carbaryl
toxicity. In spite of this, some authors have reported beneficial
effects of pralidoxime in aldicarb poisoning in humans (Garber,
1987; Burgess et al., 1994). In experimental studies, oximes have
been shown to be beneficial, alone and/or with atropine, in coun-
tering the toxicity of the carbamates isolan, thimetilan, pyramat,
dimetilan, aldicarb, neostigmine, physostigmine, pyridostigmine
and others (Boˇ skovi´ c et al., 1976; Sterri et al., 1979; Dawson, 1995).
It appears that the only CB whose toxicity was increased by an
oxime was carbaryl (Dawson, 1995).
includes general (decontamination and supportive measures) and
specific treatment with atropine, oximes (pralidoxime, trime-
doxime, obidoxime, and HI-6) and diazepam. About a half of the
century has passed since the introduction of the antidotes to med-
ical treatment of patients poisoned with OP compounds and there
is still no agreement on how these substances should best be given.
While the use of atropine and diazepam in human OP poisoning
has been widely accepted throughout the world, there are appar-
ently conflicting results related to the importance of pralidoxime
treatment. When given with atropine and diazepam, pyridinium
oximes were successful in the treatment of most cases of OP
poisoning in European toxicology clinics where the recommen-
dations proposed by World Health Organization were followed.
On the other hand, reports from developing countries indicated
that pralidoxime treatment was not sufficiently beneficial in their
patients, but their studies were not designed according to the
recommendations. These problems of effectiveness of oxime treat-
ment may be solved in randomized clinical trial(s) comparing the
WHO-recommended regimen with a placebo to assess the value of
as well, in acute OP poisoning. The trial(s) will have to be carefully
designed and take into account many factors that may have impact
on their results.
Conflict of interest
The research of M.J. was supported by grants from the Serbian
Ministry of Science (Projects 145030 and 145035).
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