Indian Journal of Experimental Biology

Vol 48, July 2010, pp. 642-650

Review Article

Pharmacological agents in the prophylaxis/treatment of organophosphorous

pesticide intoxication
Kazim Husain1*, Rais A Ansari2 & Leon Ferder1
1

Department of Physiology, Pharmacology and Toxicology, Ponce School of Medicine, Ponce, PR 00732, USA
Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA

Organophosphorus pesticide poisoning causes tens of thousands of deaths each year across the world. Poisoning includes
acute cholinergic crisis as a result of AChE inhibition, intermediate syndrome (IMS) due to neuromuscular necrosis and
organophosphate-induced delayed neuropathy (OPIDN) due to inhibition of neuropathy target esterase (NTE). Standard
treatment for acute poisoning involves administration of intravenous atropine, oxime 2-PAM to counter AChE inhibition and
diazepam for CNS protection. However clinical trials showed ineffectiveness of the standard therapy regimen. Although new
oximes that can reactivate both peripheral and cerebral AChE and other prophylactic agents such as human serum
butyrylcholinesterase (Hu BChE), sodium bicarbonate, huperzine A (a reversible ChE inhibitor) with imidazenil (a GABAA
receptor modulator) have been proved effective in animal models, systematic clinical trials in patients are warranted. For IMS
which is non-responsive to standard therapy, supportive therapy specifically artificial respiration followed by recovery is
indicated. For OPIDN which has a different target (NTE) than AChE, standard therapy is ineffective. However neuroprotective
drugs such as corticosteroids proved partially effective. Pretreatment with protease inhibitor PMSF has been shown to protect
the aging of NTE and prevent the development of delayed symptoms in hens. Since the biology of NTE is being explored, new
pharmacological agents should be developed in future. OP pesticide poisoning is a serious condition that needs rapid diagnosis
and treatment. Since respiratory failure is the major reason for mortality, artificial respiration, careful monitoring, appropriate
treatment and early recognition of OP pesticide poisoning may decrease the mortality rate among these patients.
Keywords: Antidote, OPIDN, Organophosphorus pesticide, Prophylatic agents

Introduction
Organophosphorus (OP) pesticides were first
synthesized and discovered by German chemist Gerhard
Schrader at company IG Farben in the 1930s. After
World War II, American companies began synthesizing
organophosphate pesticides in large quantities. Parathion
was among the first marketed, followed by Malathion.
The popularity of these insecticides increased after many
of the organochlorine insecticides like DDT, dieldrin,
and heptachlor were banned in the 1970s. In 1944 two
well-known organophosphorus insecticides, diethyl-pnitrophenylphosphate (paraoxon) and diethyl-pnitrophenylthiophosphate (parathion) were synthesized.
Currently more than 100 different OP pesticides are
used mainly as insecticides in agriculture and
gardening1,2. The commonly used OP pesticides are
given in Table 1. The number of intoxications with
organophosphorus pesticides (OPs) is estimated at
some 3 millions per year, and the number of deaths
and casualties some 300,000 per year worldwide1. In
_________________
*Correspondent author-Telephone: 001 787-840-2575 x 2192
Fax: 001 787-259-7085
E-mail: khusain@psm.edu

developing countries, the most common cause of

pesticide poisonings is due to occupational exposure.
However, a review of poisoning studies in developing
countries reveals that pesticide poisonings associated
with high mortality rates are usually the result of selfpoisoning. Particularly, a great number of victims
were present in rural regions due to the widespread
availability of acutely toxic pesticides used in
agriculture3,4. While some of these intoxications may
be attributed to accidental exposure, the majority of
Table 1 List of commonly used organophosphorus pesticides
Pesticides
Chlorpyrifos*
Diazinon
Dimethoate
Fenitrothion
Glyphosate
Isofenphos-methyl
Malathion
Mipafox*
Paraoxon
Parathion-methyl
Phorate
Trichlorphos

Pesticides
Chlorpyrifos-methyl
Dichlorvos*
Disulfoton
Fenthion*
Isocarbophos
Leptophos*
Methamidophos*
Omethoate*
Parathion*
Phenthoate
Trichlorfon*
Tri-O-cresyl phosphate*

*Pesticides known to induce OPIDN.

HUSAIN et al.: PHARMACOLOGICAL AGENTS IN TREATMENT OF OP PESTICIDE INTOXICATION

casualties result from suicidal attempts with ingestion

of multiple lethal doses. Therefore, the indiscriminate
use of these pesticides results in a toxicity risk to nontarget organisms and environmental pollution. This
communication reviews the current understanding and
future perspectives of the management and
pharmacological treatment of human poisoning with
OP pesticides.
Mechanism of action of organophosphorus pesticides
The basic chemical structure of all OP pesticides is
depicted in Fig. 1. The structural diversity of OP
pesticides is due to different substituents at the
phosphorus atom. Substituents at R1 and R2 are alkyl,
alkoxy, alkylthio or amino groups, and substituent at X
is a labile acyl residue (halide, cyano, phenol or thiol
group), known as the leaving group. The reactivity of
OP pesticides varies upon chemical structure.
Electrophilicity of the phosphorus atom is crucial for
the biological actions. OP pesticides that have double
bonds between phosphorus and oxygen atoms (P=O)
are highly electrophilic at the phosphorus atom and
accordingly are highly reactive. Groups that enhance
the reactivity of the phosphorus atom are nitro, cyano,
halogen, ketone and carboxylic ester. Deactivating
groups include hydroxyl and carboxylic acid.
Organophosphates share a common mode of action,
exerting their toxic effects primarily via
acetylcholinesterase (AChE) inhibition5,6 (Fig. 2).
Cholinesterases are hydrolytic enzymes, the
butyrylcholinesterase (BuChE) and AChE are both
blocked by OP pesticides. Although both
cholinesterases hydrolyze acetylcholine (ACh) and
other choline esters, they differ in their relative affinity
for some substrates. A single enzyme molecule is
capable of hydrolyzing 6 105 molecules of
acetylcholine (ACh)/min. Muscle and nerve AChE are
only present in the synaptic cleft and cannot be
measured directly. Since erythrocyte AChE has a
similar structure as the synaptic enzyme, it appears to
be a suitable parameter to reflect various reactions at
the synaptic site7. Therefore, its measurement is of
high value for therapeutic management, especially
oxime administration, during the course of
intoxication8.

Fig. 1 General chemical structure of organophosphorus (OP) pesticides

643

Clinical presentation of poisoning with

organophosphorus pesticides
Exposure to OP pesticides can induce four different
clinical syndromes:
(1) Acute cholinergic crisis as a result of AChE inhibition
(2) Intermediate syndrome (IMS) whose underlying
mechanism(s) is still unclear
(3) Organophosphate-induced delayed neuropathy
(OPIDN) that has been explained by the
inhibition of neuropathy target esterase
(4) Chronic organophosphate induced neuropsychiatric
disorder due to long-term low-level exposure.
Acute cholinergic crisis that immediately follows
exposure to OP pesticides includes hyperstimulation
of muscarinic receptors (e.g., bradycardia, bronchoconstriction, bronchorrhoea, hypotension, increased
gastrointestinal motility, abdominal cramps, miosis,
hyper salivation), nicotinic receptors (e.g.,
hypertension, tachycardia, fibrillation, fasciculation,
necrosis of striated muscles), and both central
muscarinic and nicotinic receptors (e.g., tremor,
movement in coordination, seizures, central
depression of respiration, coma, death). Although the
immediate cause of death could also be cardiac arrest

Fig. 2 Interaction of OP pesticide with serine hydroxyl group of

AChE enzyme active site. (A) Inhibition by an ageable OP
pesticide produces cholinergic toxicity which is treateable by
atropine and oximes. Aging does not alter the type of toxicity but
it obviates oxime therapy. (B) Inhibition by a no-ageable OP
pesticide produces cholinergic toxicity which is treateable worth
atropine and oxime. R, R': substituted or unsubstituted alkyl or
aryl groups. X: primary leaving group displaced by AChE active
site serine. 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

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INDIAN J EXP BIOL, JULY 2010

or heart failure, central respiratory failure due to loss

of respiratory drive is by far the most frequent cause
of death after intoxication with OP pesticides9.
Antidotes in the treatment of acute poisoning with
organophosphorus pesticides
The current view of the treatment of OP pesticide
poisoning includes three strategies:
(1) Anticholinergic drug (e.g., atropine)
(2) Cholinesterase-reactivating agents (e.g., oximes)
(3) Anticonvulsant drugs (e.g., benzodiazepines)
Anticholinergic drug (e.g., atropine)

The development of treatment against OP pesticide

poisoning started with recognition of the efficacy of
atropine as an antidote for their parasympathomimetic
effects. This is mainly due to the fact that atropine, as
an antimuscarinic drug, is not capable of
counteracting effects provoked by nicotinic
hyperstimulation, while at the same time, possesses
only limited antimuscarinic action in the central
nervous system (CNS). Also, convulsions can be
blocked by atropine only for a very limited time after
exposure to OP pesticides since other transmitter
systems have become involved in cholinergic
overstimulation in the brain (e.g., -amino butyric acid,
glutamate). Nevertheless, atropine is the initial drug of
choice in acute organophosphate poisoning.
Cholinesterase-reactivating agents (e.g., oximes)

The first successful destruction of phosphylated

AChE was accomplished by hydroxylamine in 1951. In
the following years, development of specific antidotes
such as pralidoxime (PAM-2), the first pyridinium
oxime was developed. Pralidoxime reactivates the
phosphylated enzyme about a million times faster than
hydroxylamine10. PAM-2 was first used against
parathion poisoning in Japan11. Further investigations in
this area resulted in synthesis of bispyridinium oximes:
trimedoxime (TMB-4), obidoxime (LH-6), HI-6, and
HL-7. PAM-2 (pyridinium-2-aldoxime) and TMB-4
Cl2 [1, 3-Bis (4-hydroxyiminomethyl-1-pyridinio)
propane dichloride] were synthesized in the United
States. LH-6 Cl2 a 1, 3-Bis (4-hydroxyiminomethyl-1pyridinio) -2-oxapropane dichloride was synthesized in
Germany and introduced into the medical practice12. An
oxime HI-6 Cl2 [1-(2-hydroxyiminomethyl-1-pyridinio)3-(4-carbamoyl-1-pyridinio)-2-oxapropane dichloride]
was also synthesized by Germans13. The most recent
oxime of importance (after LH-6 and HI-6) was HL-7,
synthesized by Germans. Its chemical name is
1-(4-(aminocarbonyl) pyridinio) methoxy) methyl)-2,4-

bis (hydroxyimino)methyl) pyridinium diiodide14.

Quaternary pyridinium oximes do not cross the blood
brain barrier hence unable to reactivate the central
cholinesterase enzyme. However tertiary oximes such as
monoisonitrosoacetone (MINA) and diacetyl-monoxime
(DAM) have been shown effective in the reactivation of
brain AChE and abolition of convulsions in OP pesticide
intoxicated animals15-17. Numerous attempts have also
been made to improve the antidotal properties of the
conventional mono- and bis-pyridinium mono (di)oximes by modifying their structure8-21. Indians have
developed new derivatives of bispyridinium and 1-alkyl
pyridinium oximes which reactivated both blood and
brain AChE in DFP intoxicated animals21-23. The
efficacy of these new oximes is far better than 2-PAM
and warrant for testing in patients in the clinic.
Mechanism of action of oximesReactivation of
inhibited AChE by removal of the phosphyl moiety from
the AChE active site serine is considered to be the
primary mechanism of action for oximes. Clinical data
obtained in organophosphorus pesticide-poisoned patients
provide evidence for the validity of this assumption24-26.
The oxime is oriented proximally to exert a nucleophilic
attack on the phosphorus of the enzyme-inhibitor
complex. Intermediate in the reactivation is a complex
between the phosphylated enzyme and the reactivator.
The enzyme-inhibitor-oxime complex is then split off,
leaving the regenerated enzyme (Fig. 3). Mechanistic

Fig. 3 Oxime (2-PAM) catalyzed reactivation of an OP

pesticide inhibited molecule of AChE, showing the release of
active enzyme and the formation of oxime-phosphate complex

HUSAIN et al.: PHARMACOLOGICAL AGENTS IN TREATMENT OF OP PESTICIDE INTOXICATION

studies of oxime (a reversible ligand) action have shown

that it may bind to cholinesterases either at the catalytic
site or at the allosteric site, or at both sites of the enzymes,
thus explaining the mechanism of protection afforded by
oxime administration27. Therefore the stereo chemical
arrangements of oximes can play an important role in the
difference in their therapeutic efficacy. The direct
pharmacological effects such as direct reaction with OP
pesticides, anticholinergic and sympathomimetic effects
and a decrease in the amount of liberated acetylcholine
into the synaptic cleft, may also be relevant for the
interpretation of antidotal potency of oximes28-32. It is
possible to administer oximes prophylactically before the
poisoning occurs. Oximes protect cholinesterases from
phosphylation by OP pesticides33. Oximes may be able to
reactivate the enzyme before a significant amount of aging
to occur. This approach has been tried by the British who
used P2S tablets as a pretreatment drug34. But due to short
elimination half-lives of the oximes make them
inappropriate for prophylactic use25,26,35-37. Another
prophylactic approach is a combination of cholinesterase
and an oxime pre-treatment that has been explored as a
pseudo-catalytic bioscavenger, such that the catalytic
activity of inhibited cholinesterase can rapidly and
continuously be restored in the presence of an oxime38.
Anticonvulsant drugs (e.g., benzodiazepines)

The most important anticonvulsant in present use is

diazepam39,40. The combination of atropine and
diazepam is more effective than atropine or oxime
alone in reducing mortality41. Basically, the
benzodiazepines potentiate the action of the inhibitory
-aminobutyric acid at its
neurotransmitter
receptors42-45. In the cholinergic nervous system,
diazepam probably decreases the synaptic release of
ACh46. The main consequence of the action of
benzodiazepines in CNS is hyper polarization of
neurons which makes them significantly less
susceptible to cholinergically-induced depolarization.
The ultimate result is cessation of propagation of
convulsions47. Diazepam is of benefit in
organophosphate poisoned patients by reducing
anxiety, restlessness and muscle fasciculations,
terminating convulsions, and reducing morbidity and
mortality when used in conjunction with atropine and
oxime. Diazepam should be given to patients poisoned
with OP pesticides whenever convulsions or
pronounced muscle fasciculation are present. In severe
poisoning, diazepam administration should be
considered even before these complications develop48.
Sivilotti et al.49 have used multiple centrally acting

645

antidotes (diazepam, xylazine, morphine and

ketamine) in animals intoxicated with OP pesticide
and observed protection from severe poisoning. These
findings suggest new possibilities for prophylaxis or
therapy against OP pesticide poisoning.
Other prophylactic agents

Several adjunct and alternative therapies have been

explored in animal and human studies other than
standard therapy and summarized in Table 2. In
animal studies sodium bicarbonate addition to
standard therapy improved the protective efficacy
against dichlorvos poisoning50. NMDA receptor
antagonist dizocilpine alone or in combination with
atropine blocked the convulsion caused by acute dose
of dichlorvos in mice51. Oxidative stress seems to be
one of the important components of the mechanism of
OP pesticide toxicity. Animal studies have shown
protective effects of antioxidants such as
N-acetylcysteine and melatonin against acute OP
pesticide-induced oxidative tissue damage52,53.
Interleukin-10, a cytoprotective agent protected the
peripheral tissue damage in rats caused by poisoning
with OP pesticide54. Efficacy of an adenosine A1
receptor agonist phenylisopropyl adenosine (PIA)
against standard therapy in rat intoxicated with OP
pesticide showed partial protection in the abolition of
acute symptoms and tissue damage55. Pibiri et al.56
have shown that a combination of huperzine A
(a reversible ChE inhibitor) with imidazenil
(a GABAA receptor modulator) is a prophylactic,
potent, and safe therapeutic strategy to overcome OP
toxicity. Clinical studies in humans have been
conducted using scopolamine, a competitive inhibitor
of acetylcholine which can cross the blood-brain
barrier and prove effective against chloropyrifos
Table 2 Adjuncts and other prophylactic agents used against
OP pesticide poisoning in animal and human studies other than
standard therapy.
Agents

Agents

Clonidine*
Human serum
butyrylcholinesterase
(Hu BChE)*
Imidazenil
Ketamine
Melatonin
N-acetylcysteine
Scopolamine*
Xylazine

Dizocilpine
Huperzine A

*Used clinically in humans

Interleukin-10
Magnesium sulfate*
Morphine
Phenylisopropyl adenosine (PIA)
Sodium bicarbonate

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INDIAN J EXP BIOL, JULY 2010

poisoning, specifically CNS toxicity57. A phase II

clinical trial was conducted using clonidine in patients
within acute OP pesticide poisoning prove effective at
moderate doses but hypotension was associated with
high dose as a side effect58. Beneficial effect of
magnesium sulfate at a dose of 4g/day concurrent
with standard therapy, in OP acute human poisoning
has been reported59. Several studies over the last two
decades have demonstrated that exogenously
administered human serum butyrylcholinesterase (Hu
BChE) can be used prophylactically to counteract the
toxicity of OP pesticides60-62. A recent report suggests
the suitability of human butyrylcholinesterase as
therapeutic marker and pseudo catalytic scavenger in
organophosphate poisoning by a kinetic analysis63.
Since oxime-induced reactivation of cholinesterase is
too slow to accomplish pseudo catalytic function,
BChE would be effective as a stoichiometric
scavenger.
Antidotes for OP pesticide-induced intermediate syndrome

Intermiate syndrome (IMS) has been considered as

a major contributing factor of organophosphaterelated morbidity and mortality because of its frequent
occurrence and probable consequence of respiratory
failure. Despite a high incidence, the pathophysiology
that underlies IMS remains unclear. Proposed
mechanisms of IMS include muscle necrosis,
prolonged acetylcholinesterase inhibition, down
regulation or desensitization of postsynaptic
acetylcholine receptors, failure of postsynaptic
acetylcholine release, and oxidative stress-related
myopathy. The clinical manifestations of IMS
typically occur within 24 to 96 h, affecting conscious
patients without cholinergic signs, and involve the
muscles of respiration, proximal limb muscles, neck
flexors, and muscles innervated by motor cranial
nerves64. A 33 year old female ingested an unknown
quantity of malathion in a suicide attempt.
Cholinergic signs consistent with severe organ,
phosphate intoxication developed and were treated
within 6 h of ingestion. Intravenous atropine and a
continuous infusion of pralidoxime (400 mg/h) were
administered. Prolonged depression of plasma and red
blood cell cholinesterases were documented. Despite
an initial clinical improvement and the presence of
plasma pralidoxime concentrations exceeding 4
g/mL, the patient developed profound motor
paralysis consistent with the diagnosis of IMS65. The
use of conventional antidotes atropine and oximes are
ineffective in IMS patients. With appropriate therapy

that commonly includes artificial respiration;

complete recovery develops 5-18 days later. The
treatment of IMS is mainly supportive.
Antidotes for organophosphate-induced delayed neuropathy
(OPIDN)

Organophosphate-induced delayed neurotoxicity

(OPIDN) or organophosphate-induced delayed
polyneuropathy (OPIDP) is a toxicity syndrome
caused by certain OP pesticides (Table 1). It is
characterized by distal muscular weakness in the hand
and feet, ataxia and paralysis due to degeneration of
axons in the central and peripheral nervous system
that appear about 4-21 days after OP pesticide
exposure66,67. The molecular target for OPIDN is
considered to be an enzyme in the nervous system
known as neuropathy target esterase (NTE)68,69. NTE
is also present in peripheral lymphocytes and platelets
which can be used as biochemical marker of
OPIDN70,71.The ability of a NTE inhibitor to cause
OPIDN, besides its affinity for the enzyme, is related
to its chemical structure and the residue left attached
to the NTE. If such residues undergo the aging
reaction i.e. the loss of an alkyl group bound to the
enzyme, those OP pesticides usually have a high
likelihood of causing OPIDN (Fig. 4). Atropine and
oximes are ineffective in the treatment of OPIDN72,73.
,Protection from neuropathic doses of OP inhibitors is

Fig. 4 Interaction of OP pesticide with serine hydroxyl group of

NTE enzyme active site. (A) Inhibition by an ageable OP
pesticide produces a negative charge phosphoryl moiety results in
OPIDN. (B) Inhibition by a no-ageable OP pesticide produces no
OPIDN but provides protection against NTE inhibitors. R, R':
substituted or unsubstituted alkyl or aryl groups. X: primary
leaving group displaced by NTE active site serine

HUSAIN et al.: PHARMACOLOGICAL AGENTS IN TREATMENT OF OP PESTICIDE INTOXICATION

obtained when NTE is inhibited with nonageable

inhibitors (Fig. 4). Promotion affects either the
progression or expression of OPIDN after the initial
biochemical effect on NTE. Some recent observations
suggest that development of OPIDN in hens can be
influenced by PMSF and methylprednisolone when
they are given before or soon after neuropathic OP
pesticides. Administration of PMSF prior to or
following the administration of leptophos can
significantly modify not only clinical signs of OPIDN
but also changes of several biochemical indices
accompanied by OPIDN. Furthermore, it is possible
to expect that these biochemical indices can provide
some valuable clues for exploring the modification of
OPIDN by PMSF treatment74. Results of a recent
study demonstrated that the pretreatment with PMSF
could inhibit TOCP-induced NF degradation while it
protected hens against the development of OPIDN,
which suggested the inhibition of NF-associated
protease in peripheral nerves that might be an
underlying protective mechanism of PMSF against
OPIDN75. Modification of OPIDN development has
also been reported using calcium channel blockers
such as verapamil and ganglioside mixture76-78.
Because of the use of corticosteroids and vitamin B
complex in the neurological diseases, these drugs
have also been evaluated against OPIDN. It was
observed that delayed neuropathy induced by OP
pesticides could not be resisted completely by the
treatment with prednisolone or vitamin B complex,
but clinical signs of OPIDN and pathological changes
in hens that received these two protective agents after
OP pesticides were less severe than those in hens that
received only OP pesticides79,80. There are
controversial reports regarding use of corticosteroids
against OPIDN in hens; it was beneficial against
TOTP-induced delayed neurotoxicity but was
ineffective
against
DFP-induced
delayed
neurotoxicity81,82.
Medical treatment (clinical trials)
organophosphorus pesticides poisoning

in

patients

647

the severity of the organophosphate poisoning. No

adverse effects were noted in patients treated with
oximes24.
Nine
patients
intoxicated
with
organophosphorus insecticides were treated with
PAM-2 methylsulphate (Contrathion) using a dose of
4.42 mg/kg as a bolus injection followed by
continuous infusion (2.14 mg/kg/h)83. In a series of
five case reports, LH-6 (Toxogonin) 250 mg was
given as an intravenous bolus followed by continuous
infusion of 750 mg/24 h in cases of life-threatening
parathion poisoning. This dose was effective,
especially when the dose of parathion absorbed was
relatively low25. In a clinical study of 63 patients
poisoned with organophosphorus insecticides, patients
were divided into three groups: one was treated with
atropine only, while the other two received atropine
and either PAM-2 or LH-6. Three of the patients
who received the LH-6 combination therapy
developed hepatitis and two of them died due to liver
failure, which may indicate over dosage of LH-684.
Clinical trials in India and Iran carried out in OP
pesticide poisoning using pralidoxime were also not
very much effective85-88 A systematic review of
clinical trials by Eddleton et al.89 concluded that a
large clinical trial is required to compare the current
WHO-recommended pralidoxime regimen (>30mg/kg
bolus followed by >8mg/kg/hr infusion) with placebo
to determine definitively the role of oxime therapy in
OP pesticide poisoning. A recent clinical trial
concluded that despite clear reactivation of RBC
AChE in diethyl OP pesticide poisoned patients, no

with

A pathway that either increases the toxicity or

decreases the toxicity of OP pesticides in humans is
depicted in Fig. 5. Beneficial role and efficacy of
oximes drugs in clinical practice especially those
evaluated in controlled clinical trials against OP
pesticides are described here. Patients (60) acutely
poisoned with various organophosphorus insecticides
were treated with atropine, diazepam and HI-6
(500 mg every 6 h, im) for 2 to 7 days, depending on

Fig. 5 Pathways that either increases the toxicity or decreases

the toxicity of OP pesticides in humans. AChE enzyme inhibition
either reversible or irreversible and reactivation of enzyme
spontaneously or with oxime drug

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INDIAN J EXP BIOL, JULY 2010

evidence of improved survival with 2-PAM or

reduces need for intubation in patients with OP
pesticide poisoning90. Further studies of different dose
regimen and different oximes are required.
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