Critical Reviews in Toxicology

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Treating organophosphates poisoning:

management challenges and potential solutions

Maria Alozi & Mutasem Rawas-Qalaji

To cite this article: Maria Alozi & Mutasem Rawas-Qalaji (2020): Treating organophosphates
poisoning: management challenges and potential solutions, Critical Reviews in Toxicology, DOI:
10.1080/10408444.2020.1837069

To link to this article: https://doi.org/10.1080/10408444.2020.1837069

Published online: 13 Nov 2020.

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CRITICAL REVIEWS IN TOXICOLOGY
https://doi.org/10.1080/10408444.2020.1837069

REVIEW ARTICLE

Treating organophosphates poisoning: management challenges and

potential solutions
Maria Alozia
and Mutasem Rawas-Qalajia,b,c

a
College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates; bResearch Institute for Medical and Health Sciences, University of
Sharjah, Sharjah, United Arab Emirates; cDr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale,
FL, USA

ABSTRACT ARTICLE HISTORY

Organophosphorus agents (OP) are widely used as pesticides due to their cost effectiveness, yet they Received 7 July 2020
present a significant public health risk owing to their high toxicity, especially in cases of occupational Revised 11 October 2020
exposure in agriculture, during suicide attempts using pesticides, and as nerve agents in warfare. Their Accepted 11 October 2020
vigorous permeability through inhalation, ingestion, and dermal exposure results in a high number of
KEYWORDS
reported OP poisoning cases and alarming mortality rates. Initial first-aid management involves decon- Atropine sulfate; nerve
tamination, ventilation, and hemodialysis. Additionally, current treatment guidelines recommend agent; organophosphates;
prompt administration of atropine as a first-line antidote, oximes as a follow-up, benzodiazepines for pesticides; poisoning; sarin;
seizure control, and pyridostigmine for prophylaxis. Nevertheless, current treatment options are associ- soman; tabun
ated with several challenges. Thus, recent research has focused on investigating novel approaches for
their potential in improving current management strategies. This article intends to review recent
advances in OP poisoning treatment, including agents investigated for their use as an alternative or
adjunctive therapy, novel formulations such as nasal drops or sublingual tablets for emergency admin-
istration of atropine, as well as innovative strategies for enhanced oximes delivery and overall efficacy.
However, two major barriers may limit these innovations, ethical issues associated with their clinical
assessment in emergencies, and limited profitability in countries where most cases occur.

Abbreviations: 2-PAM: 2-pralidoxime chloride; ABC: airway, breathing and circulation; ACC: acute cho-
linergic crisis; ACh: acetylcholine; AChE: acetylcholinesterase; ADECh: acetyldiethylcholine; AMECh: ace-
tylmonoethylcholine; ATNAA: antidote treatment nerve agent auto-injector; BBB: blood–brain barrier: ;
BuChEs: butyrylcholinesterase; CEs: carboxylesterases; CNS: central nervous system; EEG: electroenceph-
alogram; FDA: US Food and Drug Administration; HI-6: asoxime; ICU: intensive care unit; IM: intramus-
cular; IMS: intermediate syndrome; IV: intravenous; MgSO4: magnesium sulfate; M Receptors: muscarinic
receptors; NA: nerve agents; NaHCO3: sodium bicarbonate; N Receptors: nicotinic receptors; OP: organo-
phosphorus agents; OPIDN: OP-induced delayed neuropathy; TMB4: trimedoxime; USSR: Union of
Soviet Socialist Republics

Table of contents
1. Introduction ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...
2. The toxic agents: organophosphorus compounds ... ...
3. The toxic effects: organophosphorus poisoning ... ... ...
4. Management of acute toxicity ... ... ... ... ... ... ... ... ... ... ...
4.1. Supportive treatment ... ... ... ... ... ... ... ... ... ... ... ... ... ...
4.1.1. Resuscitation and airway management ... ... ...
4.1.2. Decontamination ... ... ... ... ... ... ... ... ... ... ... ... ...
4.1.3. Hemodialysis ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...
4.2. FDA-approved pharmacological treatment ... ... ... ...
4.2.1. Antidote: atropine ... ... ... ... ... ... ... ... ... ... ... ... ...
4.2.2. Follow-up: oximes ... ... ... ... ... ... ... ... ... ... ... ... ...
4.2.3. Seizure control: benzodiazepines ... ... ... ... ... ...
4.2.4. Prophylaxis: pyridostigmine bromide ... ... ... ...
4.3. Potential investigational agents ... ... ... ... ... ... ... ... ...
4.3.1. Alternative antidotes ... ... ... ... ... ... ... ... ... ... ... ...
2 4.3.2. Prophylactic agents ... ... ... ... ... ... ... ... ... ... ... ... 8
2 4.3.3. Supportive agents for neuroprotection ... ... ... 8
4 4.3.4. Adjunctive agents ... ... ... ... ... ... ... ... ... ... ... ... 10
5 4.4. Limitations of current treatment options and poten-
5 tial solutions ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 10
5 4.4.1. Intermittent IV infusion ... ... ... ... ... ... ... ... ... 10
6 4.4.2. Restrictions of auto-injectors ... ... ... ... ... ... ... 12
6 4.4.3. Penetration of BBB by oximes ... ... ... ... ... ... 12
6 4.4.4. Narrow-spectrum of oximes activity ... ... ... ... 13
6 Conclusions ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 13
6 Acknowledgements ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 14
6 Declaration of interest ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 13
8 ORCID ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 13
8 References ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 14
8

CONTACT Mutasem Rawas-Qalaji mqalaji@sharjah.ac.ae College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates

Equally contributing first authors.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group
2 M. ALOZI AND M. RAWAS-QALAJI
1. Introduction
Organophosphorus agents (OP), also known as
“organophosphates,” are the leading cause of poisoning in
developing countries, as they account for 50 percent of hos-
pital admissions resulting from poisoning (Mohapatra and
Rath 2014). Due to the wide-ranging application of OP from
their ubiquitous presence in agricultural pesticides to their
use as nerve agents, OP presents a significant hazard to pub-
lic health and safety (Costanzi et al. 2018). Three million indi-
viduals are exposed to OP each year, and among them, an
estimated 300 000 deaths are recorded, resulting in five mil-
lion deaths over the last three decades alone (Eddleston and
Chowdhury 2016; Robb and Barker 2020).
OP is absorbed efficiently through all routes of exposure,
including the gastrointestinal, respiratory, and even the der-
mal route (Kumar et al. 2018). They act as inhibitors of serine
esterases, with especially high affinity for acetylcholinesterase
(AChE), a vital enzyme responsible for controlling levels of
acetylcholine (ACh) at neural synaptic junctions. The over-
stimulation of muscarinic (M) and nicotinic (N) receptors
resulting from AChE inhibition and subsequent ACh accumu-
lation leads to several toxic effects including excessive secre-
tions, miosis, emesis, bronchoconstriction, and fatal
respiratory depression (Peter et al. 2014; Jacob et al. 2016)
For the first-aid treatment of acute OP poisoning, atropine
is the antidote of choice in clinical guidelines, as it antago-
nizes ACh binding at M receptors to counteract the initial
symptoms of toxicity (Kumar et al. 2018). Oximes are also
used clinically to reverse AChE inhibition through the
hydrolysis of the bond created with OP (Abou-Donia et al.
2016). Both atropine and oxime products are available as
auto-injector dosage forms for out-of-hospital emergency
administration (Food and Drug Administration 2019).
Furthermore, midozolam is the anticonvulsant of choice for
seizure control while pyridostigmine is the only prophylactic
agent approved by the FDA (Pyridostigmine Bromide Tablets,
USP 2003; Reddy and Reddy 2015). Although management
strategies have barely improved since atropine and oximes
first came into use (Eddleston and Chowdhury 2016),
researchers have recently started developing novel formula-
tions and investigating innovative approaches to overcome
numerous challenges associated with available treat-
ment options.
In this article, a brief summary of OP and OP poisoning
will be presented along with a comprehensive review of cur-
rent management strategies, therapeutic agents, as well as
promising agents under research. Furthermore, this article
will draw particular attention to the challenges associated
with the available treatment options and the recent advances
developed to overcome these challenges.
2. The toxic agents: organophosphorus compounds
OP are highly toxic compounds produced in the form of
ester, amide or thiol derivatives of phosphoric, phosphonic,
or phosphinic acids (Carullo et al. 2015) (Figure 1). Most OP
pesticides are phosphorothioates with a P¼S bond that is
bioactivated in vivo to a P¼O bond, while nerve agents (NA)
Figure 1. General chemical structure of organophosphorus compounds. Each
organophosphorus agent (OP) has different alkyl substituents. The leaving
group (X) is displaced upon binding of the OP to the active site of the acetyl-
cholinesterase (AChE) enzyme.
mostly exist in the active form with a native P¼O bond
(Costa 2018). OP compounds are classified into 13 subcatego-
ries depending on their chemical structures. However, these
structural similarities do not necessarily translate to similar
toxicological properties (Table 1) (Gupta 2005). The US
Environmental Protection Agency has classified different OP
as highly toxic or moderately toxic based on their oral LD50
values in rats regardless of their chemical structures (Roberts
and Routt 2013).
OP pesticides are still the most commonly used pesticides
for agricultural pest control despite the high risks associated
with their use. In addition to occupational exposure, many
cases of intentional harm using OP pesticides have been
reported in developing countries. This is mainly attributed to
the fact that large quantities of pesticides are readily access-
ible on farms (Eddleston 2019). Although acute high-level
exposure to OP pesticides has been long-known to cause
neurotoxicity, the toxicity of chronic exposure to moderate
levels was controversial, until recent meta-analyses suggested
its connection with a decline in neurological functions (Ross
et al. 2013; Mun ~ oz-Quezada et al. 2016).
Lethal exposure to OP has been noted in several wars and
domestic terrorist attacks where OP-based NA, such as sarin,
soman, tabun, and VX, were used (Costanzi et al. 2018). To
ensure safe handling and storage of these deadly NA, some
of them were produced in a binary form, where two precur-
sors are produced and stored to be mixed just before use
(Rice et al. 2015). Although the Geneva Protocol of 1925
advocated for prohibiting the use of all weapons of mass
destruction (Abou-Donia et al. 2016), around 100 000 soldiers
were exposed to low-levels of sarin after the demolition of a
storage facility in Iraq following the Gulf War. Later, several
studies reported that these soldiers were at higher risk of
developing brain cancer (Abou-Donia et al. 2016; Barth
et al. 2017).
The continued use of NA throughout several terrorist attacks
culminated in the signing of the Chemical Weapons Convention
in 1997, which called for a ban on the development, produc-
tion, stockpiling, and use of chemical weapons and mandated
their destruction (Abou-Donia et al. 2016). Eventually, the
Organization for the Prohibition of Chemical Weapons was
believed to be successful in eliminating NA until evidence of
their use surfaced during the Syrian Civil War in 2013, where
the use of sarin gas resulted in 13 000 injuries and 3415 deaths
 CRITICAL REVIEWS IN TOXICOLOGY 3

Table 1. Classification of OP compounds and associated toxicological properties.

Oral LD50 in Dermal LD50 in
Classification Chemical structure Examples rat (mg/kg) rabbit (mg/kg)
Phosphates Chlorfenvinphos** 12 3200
Dichlorvos** 25 59
Monocrotophos** 8 354
Paraoxon (active metabolite of Parathion)** 1.8 0.23

Phosphonates Trichlorfon 630 >2100

Phosphinates Glufosinate 2000 >4000

Phosphorothioates Bromophos 1600 2188

(S5) Diazinon* 300 379
Fenthion* 255 330
Parathion** 3 6.8

Phosphonothioates EPN** 7 30
(S¼) Leptophos** 19 800

Phosphorothioates Demeton-S-methyl NA NA
(S-substituted) Echothiophate

Phosphonothioates VX NA NA
(S-substituted)

Phosphorodithioates Azinphos-ethyl** 13 250

Azinphos-methyl** 5 220
Dimethoate* 250 400
Disulfoton** 2 6
Malathion 885 4000
Methidathion** 25 200
Phosphorotrithioates DEF (tribufos) NA NA

Phosphoramidates Fenamiphos** 15.3 NA

Phosphoramidothioates Methamidophos** 13 110

Isofenphos** 32 162

Phosphorofluoridates Diisopropyl phosphorofluoridate (DFP) NA NA

Phosphonofluoridates Cyclosarin NA NA
Sarin** 0.55 0.925
Soman NA NA

NA: information on LD50 not available for the corresponding compound; **“Highly toxic” includes compounds with oral LD50 values (rats) less than 50 mg/kg;
*“Moderately toxic” includes compounds with oral LD50 values (rats) between 50 and 500 mg/kg.
4 M. ALOZI AND M. RAWAS-QALAJI

Figure 2. Role of acetylcholinesterase (AChE) in the hydrolysis of acetylcholine (ACh).

Figure 3. Mechanism of action of organophosphate toxicity. The OP group (O ¼ P) is attacked by the free electron pairs of the nucleophilic (–OH) element of the
acetylcholinesterase (AChE), leading to the formation of a covalent bond between the two molecules. This bond is strengthened when it releases an H2O molecule;
in a process known as “aging.”

over the course of 7 years of war (Brooks et al. 2018). In 2018, a
newly developed class of NA named “Novichok” or “newcomer”
agents originally created by the USSR from 1971–1993 were
made known to the public. They are thought to be more
potent compared to VX gas and can be employed in either uni-
tary or binary forms (Chai et al. 2018).
Despite their high toxicity profiles, smaller doses of certain
OP have shown some therapeutic benefits. As a long-acting
inhibitor, echothiophate iodide (PhospholineV) eye drop for-
R
schistosomiasis led researchers to investigate its efficacy for
treating dementia by enhancing central cholinergic neuro-
transmission. Despite its proven efficacy, its long-term use
during phase III clinical trials was found to induce respiratory
paralysis and led to the discontinuation of the clinical trial
and subsequent FDA withdrawal (Sharma 2019).

3. The toxic effects: organophosphorus poisoning

mulation is approved for treating glaucoma. PhospholineV
R

helps treat glaucoma by sustaining ACh levels to mitigate
intraocular pressure (Phospholine IodideV Ophthalmic 2018).
R
Additionally, the short-term safety of metrifonate for treating
OP is known to inhibit several esterase enzymes including
carboxylesterases (CEs), a class of enzymes that play a signifi-
cant role in the metabolism of various types of drugs (Casey

Figure 4. Functions of acetylcholine (ACh) as a neurotransmitter.
Laizure et al. 2013), as well as butyrylcholinesterases
(BuChEs), a class of “orphan enzymes” thought to have no
specific physiological function but were later discovered to
affect emotional behaviors (Brimijoin et al. 2016). Since the
major toxic effects of OP are attributed to AChE inhibition,
CEs and BuChEs can be administered exogenously as biosca-
vangers to protect against AChE inhibition as will be dis-
cussed later in this article (Iyer et al. 2015).
AChE enzyme hydrolyzes ACh through the nucleophilic
attack of ACh’s carbonyl (C¼O) group by the serine residue
in the esteratic site of AChE (Figure 2) (Agency for Toxic
Substances and Disease Registry 2010). Because OP is struc-
turally similar to ACh, it also can bind at AChE’s esteratic site
(Figure 3) (Agency for Toxic Substances and Disease Registry
2010). The resulting OP-AChE complex may then be stabilized
through dealkylation in a process known as “aging,” which
leads to the formation of a double bond that cannot be
hydrolyzed, and makes the AChE resistant to reactivation by
oximes (Abou-Donia et al. 2016; Zhuang et al. 2016).
Regrettably, different OP age at different rates requiring
divergent approaches for treatment. The abrupt aging of
soman makes it one of the deadliest OP compared to the 5,
35, and 45 h for sarin, VX, and tabun to age, respectively
(Balali-Mood et al. 2016; Stone 2018). Once aging occurs, real-
kylators should be used to destabilize AChE and enable the
effects of oximes. Otherwise, more complicated approaches
such as the upregulation of AChE expression and administra-
tion of exogenous AChE should be employed (Zhuang
et al. 2016).
Since ACh is an essential neurotransmitter involved in vari-
ous chemical pathways (Brady et al. 2011) (Figure 4), a myr-
iad of toxic effects can result from its accumulation in OP
poisoned individuals. The first symptoms observed within the
first few hours occur collectively as a part of the acute cholin-
ergic crisis (ACC) and include salivation, lacrimation, emesis,
CRITICAL REVIEWS IN TOXICOLOGY 5
miosis, bradycardia, hypotension, bronchoconstriction, and
convulsions (Peter et al. 2014). These signs may be followed
by an intermediate syndrome (IMS) phase, which typically
occurs within 24–96 h in 10–40% of affected individuals and
is characterized by muscle weakness, respiratory insufficiency,
and decreased deep tendon reflexes. If appropriate therapy is
provided, recovery from IMS may occur within 5–18 days
(Bird 2020). Unfortunately, some patients can also develop
painful paresthesias and even permanent disabilities during
the OP-induced delayed neuropathy (OPIDN) phase, which
typically occurs within 1–3 weeks after ingesting certain types
of OP, such as chlorpyrifos (Bird 2020).
4. Management of acute toxicity
Clinical guidelines identified two main components for the
initial management of OP poisoned individuals: prompt
administration of the antidote in addition to support ventila-
tion. Ventilation is mainly required as respiratory failure rep-
resents the most life-threatening consequence of OP
poisoning and in many cases is usually associated with fatal
outcomes. The first few steps performed as soon as OP poi-
soning symptoms are recognized are the most critical in the
successful management of OP poisoning. Follow up treat-
ment is also important in specific cases where severe compli-
cations arise, and a prophylaxis option is available to aid in
the prevention of recurrence (World Health Organization
2008; Balali-Mood and Saber 2012).
4.1. Supportive treatment
4.1.1. Resuscitation and airway management
Patients with OP poisoning should be immediately admitted
to the general ICU and treated as a medical emergency. The
ABCs of cardiopulmonary resuscitation should be initially
6 M. ALOZI AND M. RAWAS-QALAJI
performed to allow the patient to regain consciousness and
restore their normal physiological functions. In addition,
100% oxygen should be supplied through an oxygen mask
along with fluid replenishment to improve the delivery of
oxygen to tissues and prevent further damage (Bird 2020).
4.1.2. Decontamination
Another essential approach is dermal, ocular, and gastric
decontamination. Because OP dissolve in alkaline aqueous
solutions, the patient’s body should be washed with water
and soap after removing all clothing and accessories, to clear
remaining OP residues. The patient’s eyes should then be
washed with water or normal saline. Finally, gastric decon-
tamination is strongly recommended within the first 1–2 h of
OP ingestion to prevent aspiration but can still be effective
up to 12 h from OP ingestion in case the patient arrives late
to the emergency department. Gastric decontamination is
advised to be repeated three times separated by 4 h intervals
and followed by a dose of 50 g activated charcoal at the end
(World Health Organization 2008; Balali-Mood and
Saber 2012).
4.1.3. Hemodialysis
Direct removal of OP from the bloodstream can enhance the
therapeutic efficacy of conventional agents used. The utiliza-
tion of hemofiltration and hemoperfusion methods were pre-
viously reported in a few OP poisoning cases. Several studies
including retrospective analyses (Dong et al. 2017; Jiang et al.
2019) and a non-randomized controlled trial (Peng et al.
2004) assessing the clinical efficacy of hemoperfusion alone
and hemoperfusion combined with hemodialysis have dem-
onstrated several advantages for these procedures. Their use
was associated with reduced incidence rates of poisoning
complications and medication-related adverse reactions,
shortened AChE reactivation time as well as shortened venti-
lation time, improved clinical outcomes, and elevated overall
survival rates.
4.2. FDA-approved pharmacological treatment
4.2.1. Antidote: atropine
The antidote of choice for OP poisoning is atropine, as it
works by competitively inhibiting the binding of ACh at M
receptors to reverse the first signs of OP toxicity. For treat-
ment in a hospital emergency department, intravenous (IV)
administration is usually available and is considered the pre-
ferred route of administration, while intramuscular (IM) auto-
injectors are dispensed for out-of-hospital self-administration
(Bird 2020). However, IM auto-injectors are mainly available
for use by soldiers on the battlefield and were designed spe-
cifically to penetrate “nuclear biological chemical” suits
(Vijayaraghavan 2020). The recommended initial dose for
adults is 2 mg, which is equivalent to one auto-injector.
Further doses may be administered every 5–10 min depend-
ing on the responsiveness of the patient and a maximum of
three auto-injectors can be used. Drying of secretions marks
the beginning of atropinization and the endpoint of atropine
dosing (Bird 2020). For severe cases where patients are
unable to inject themselves multiple times using the auto-
injector, a single dose of 6 mg is advisable. Smaller doses of
atropine as 0.25, 0.5, and 1 mg auto-injectors are also manu-
factured for administration to children (AtropenV Auto-
R
Injector 2017).
4.2.2. Follow-up: oximes
After the patient is stabilized by an initial dose of atropine,
follow up procedures begin mainly by identifying the causal
OP agent if possible, in addition to continuous monitoring of
physiological functions. Oximes are then administered as
reversal agents to restore the activity of AChE and act by
binding to the phosphate moiety of OP and displacing it
from the active sites of AChE, which further aid in restoring
the nervous and muscular functions (Buckley et al. 2011).
Currently, the only oxime derivative approved by the FDA
is 2-pralidoxime chloride (2-PAM) as it is a safe and potent
drug that counters the effects of most nerve agents if admin-
istered correctly. Like atropine, an IM auto-injector of 2-PAM
is available for out-of-hospital treatment in a dose of 600 mg/
2 ml (Pralidoxime Chloride Auto-Injector 2016), while IV is the
preferred route of administration used in hospital settings.
An initial IV dose, 30 mg/kg, for infusion for 30 min after dilu-
tion in 5% dextrose solution, and thereafter an infusion of
8 mg/kg/h is recommended (Buckley et al. 2011).
Alternatively, there are few other oxime compounds that
are commercially available including obidoxime, methoxime,
trimedoxime (TMB4), and asoxime (HI-6). Although obidoxime
and trimedoxime are considered the most promising agents,
their use is limited due to their high toxicity profiles.
Asoxime (HI-6), on the other hand, demonstrated high poten-
tial due to its broad-spectrum of activity against commonly
used OP (Kuca et al. 2018).
Oximes are also added to atropine to potentiate its effects
for out-of-hospital emergency administration. Antidote
Treatment Nerve Agent Auto-injector (ATNAA) is an FDA
approved auto-injector that was developed by the US mili-
tary. ATNAA contains a combination of atropine at a dose of
2.1 mg/0.7 ml along with 2-PAM at a dose of 600 mg/2 ml in
two separate chambers, and the two doses are sequentially
administered through a single needle upon activation
(ATNAA Auto-Injector 2017). In contrast, an alternative IM
auto-injector combining 2 mg of atropine with 220 mg of obi-
doxime chloride is supplied outside the US by Emergent
BioSolutions Inc (Emergent BioSolutions 2017).
4.2.3. Seizure control: benzodiazepines
In cases where OP-induced seizures are not controlled prop-
erly, serious consequences such as permanent brain damage
can develop. Although diazepam has long been the drug of
choice for persistent acute seizures, midazolam in recent ani-
mal studies has demonstrated more favorable pharmacoki-
netic properties and the onset of action as a replacement
anticonvulsant. Midazolam can be administered as either IV
or IM injections at the onset of seizures. However, delaying
its administration may result in reduced potency, leading to

Table 2. Recent advances in the utilization of atropine for OP poisoning treatment.
Treatment under investigation
Adjunct and alternative antidotes
Diphenhydramine alone
Chlorpheniramine alone
Glycopyrrolate þ atropine
Glycopyrrolate alone
Diphenhydramine alone
Glycopyrrolate þ atropine
Anisodamine (follow up
after atropine)
Promethazine alone
Alternative emergency formulations
Nasal spray
Nasal drops
Dry powder inhaler of atropine
nanocrystals
MicroDose dry powder inhaler
Fast disintegrating
sublingual tablets
Alternative to hospital iv infusion
Continuous IV infusion of
atropine using micropumps
Study Study type
Yavuz et al. (2008) In vivo study (fenthion
poisoned rats)
Mousa (2009) In vivo study
(dichlorvos poisoned chicks)
Arendse and Irusen (2009) Retrospective analysis
(n ¼ 53)
Anju et al. (2010) Retrospective analysis
(n ¼ 33)
Mohammad et al. (2012) In vivo study
(dichlorvos poisoned chicks)
Bhandarkar (2014) Retrospective analysis
(n ¼ 199)
Wang et al. (2014) Retrospective analysis
(n ¼ 64)
Nurulain et al. (2015) In vivo study
(paraxon-methyl or dicrotophos
poisoned rats)
Kumar and Vijayaraghavan (2001) Animal study (dichlorvos
poisoned rats)
Rajpal et al. (2009) Pilot study – not controlled, nor
dose-ranged
(n ¼ 6)
Ali et al. (2009) Pilot study – not controlled, nor
dose-ranged
(n ¼ 6)
Corcoran et al. (2013) Randomized cross-over study
(n ¼ 17)
Aodah et al. (2019) Ex vivo study (porcine
sublingual membrane)
Jiang et al. (2019) Retrospective analysis
(n ¼ 136)
CRITICAL REVIEWS IN TOXICOLOGY 7
Outcomes and comments
Provided effective control of cardiac
toxic effects, compared to the control
group receiving normal saline.
Provided similar control over OP toxic
effects and similar survival rates
compared to atropine.
Decreased mortality rates significantly
compared to atropine alone, yet the
anticholinergic toxic effects
remained unchanged.
Provided similar control over OP toxic
effects compared to atropine,
minimized anticholinergic toxic effects
as it only acts peripherally, but was
associated with higher costs.
Provided similar control over OP toxic
effects compared to atropine as it
acts both peripherally and centrally.
Provided lower control over OP toxic
effects compared to atropine.
Patients who were switched to
anisodamine after 12 h of atropine
use without reaching atropinization,
showed shorter atropinization times
and over hospital stay, compared to
patients who continued on atropine.
Provided higher protection against OP
toxic effects and lower cardiac toxicity
compared to atropine, although AChE
reactivation levels did not vary
significantly, indicating the possibility
of multi-pharmacological actions.
One puff from atropine nasal aerosol
spray (2 mg/puff) provided faster
absorption and was equivalent to
intraperitoneal atropine (10 mg/kg) in
controlling toxic cardiac effects.
1% atropine sulfate–0.5% chitosan
intranasal drops (6 mg) reached
therapeutic concentrations within 5
mins, indicating significantly faster
absorption and higher bioavailability
leading to earlier atropinization
compared to IM injection.
One capsule of dry powder inhaler
(6 mg/capsule) resulted in an initial
plasma concentration peak at 15 min
and another one at 60 mins, due to
absorption from GIT.
Six inhalations using MicroDose inhalers
(0.4 mg/inhalation) were required to
provide a pharmacokinetic profile
similar to a single 2 mg IM auto-
injector, showing a peak at around
15 mins.
Six different formulations were
investigated (2, 4, and 8 mg) and
achieved disintegration times of less
than 30 s. Ex vivo sublingual
permeability profiles were similar to
that of 1 mg/1 ml atropine solution.
Achieved more stable vital signs,
reduced total atropine dose, and
therefore reduced atropine poisoning
rates. It was also associated with
lower rates of atropinism, lower
recurrence rates, and have
significantly decreased mortality rates
when compared to normal IV infusion.
8 M. ALOZI AND M. RAWAS-QALAJI
chronic epilepsy in certain cases. The suggested dose based
on these studies is 2.2 mg/kg, which can vary depending on
the type of causal OP and how soon midazolam was adminis-
tered from the onset of the seizure (Reddy and Reddy 2015;
Wu et al. 2018).
The use of three-chambered auto-injectors consisting of
appropriate doses of atropine, an oxime, and a benzodiazep-
ine was also suggested as an alternative for the use of mul-
tiple auto-injectors to provide more practical utilization,
especially on battlefields (Bajgar 2010).
4.2.4. Prophylaxis: pyridostigmine bromide
Along with the protection provided by using masks and
hoods on the battlefield, the administration of a prophylactic
agent hours before an anticipated exposure to OP can be
highly beneficial in preventing ACC from ever occurring. The
only FDA approved prophylactic agent for OP poisoning is
pyridostigmine bromide. Studies proved its effectiveness
against the nerve agent soman provided that atropine and 2-
PAM are immediately administered after exposure. It revers-
ibly inhibits a significant number of AChE enzymes, thus pro-
tecting them from being irreversibly inhibited by OP. The
recommended dose is a 30 mg oral tablet every 8 h to be
started several hours prior to anticipated exposure (Federal
Drug Administration 2003).
4.3. Potential investigational agents
4.3.1. Alternative antidotes
Although standard treatment provides sufficient control of
symptoms and reduces mortality, it only attenuates OP-
induced convulsions when atropine is given in high doses at
an extremely early stage of toxicity (Myhrer et al. 2015).
Therefore, the potential of several investigational adjunctive
and alternative antidotes was explored (Table 2). The poten-
tial action of the antimuscarinic agent glycopyrrolate against
OP poisoning was tested alone and in combinations with
atropine. In one study, glycopyrrolate was combined with
atropine in equivalent doses and was assumed to provide
potent control for poisoning symptoms while reducing the
anticholinergic CNS toxicity since its effects are restricted to
peripheral receptors. Results showed that the use of this
combination resulted in lower mortality rates without causing
any changes in the anticholinergic toxic effects (Arendse and
Irusen 2009). Additionally, a clinical study involving 33
patients investigated the clinical efficacy of using glycopyrro-
late alone. Glycopyrrolate showed similar efficacy and lower
CNS toxicity when compared to atropine, but was associated
with a higher treatment cost (Anju et al. 2010). In contrast, a
retrospective analysis performed between 2012 and 2013
demonstrated less OP-induced complications in patients
treated with atropine alone compared to patients treated
with both atropine and glycopyrrolate (Bhandarkar 2014).
On another note, diphenhydramine, which is an antihista-
mine with strong antimuscarinic action commonly used to
treat animals exposed to dichlorvos, was able to provide a
similar efficacy profile to atropine (Mohammad et al. 2012).
Also, it effectively attenuated OP-induced cardiac toxicity,
which constitutes one of the most severe complications of
OP poisoning (Yavuz et al. 2008). Other antihistamines with
central antimuscarinic activity like chlorpheniramine and pro-
methazine have also shown promising antidotal efficacy in
animal models. Several other advantages were associated
with their use including the amelioration of edema, higher
availability in clinical settings, and lower costs (Mousa 2009;
Ojha et al. 2014; Nurulain et al. 2015).
4.3.2. Prophylactic agents
Several reversible cholinesterase inhibitors were compared
against pyridostigmine for their prophylactic activity with
varying outcomes (Table 3). Physostigmine is still under
investigation with current efforts aiming to enhance its phar-
macokinetic profile to achieve better efficacy while rivastig-
mine demonstrated high inter-patient variability owing to its
complicated pharmacological profile (Lavon et al. 2015; Park
et al. 2018). Tiapride, a reversible cholinesterase inhibitor,
also failed to show similar efficacy and cause fewer side
effects when compared to pyridostigmine in rat studies
(Petroianu et al. 2007; Lorke and Petroianu 2019). In preclin-
ical studies, galantamine, another potentially reversible cho-
linesterase inhibitor, showed promising efficacy against OP
poisoning with potent anticonvulsant activity and a low tox-
icity profile (Indu et al. 2016).
The use of bioscavengers capable of binding and deacti-
vating OP is an alternative approach for prophylaxis against
OP. HuBChE is a recombinant plasma protein that strongly
binds to OP molecules and blocks their action (Iyer et al.
2015). A recent animal study demonstrated the effectiveness
and safety of HuBChE following its IM administration (Myers
2019). As a stoichiometric scavenger, only one molecule of
protein can bind to another molecule of OP, and effective
utilization requires a large initial dose or adjunct replenish-
ment of AChE. Hence, several other alternative catalytic scav-
engers that require a smaller initial dose are currently under
investigation, such as paraoxonase (Mata et al. 2014; Iyer
et al. 2015).
4.3.3. Supportive agents for neuroprotection
The addition of a neuroprotective agent to the standard ther-
apy of OP poisoning is highly recommended and had been
investigated (Table 3), as benzodiazepines are limited in their
therapeutic benefit as they can only provide sufficient control
when administered before the onset of seizures (Balali-Mood
and Saber 2012). Memantine, an antiglutamatergic agent
with potential neuroprotective effects, showed enhanced and
prolonged protection against soman poisoning when com-
pared to pyridostigmine and physostigmine in vivo, however,
its narrow therapeutic index limits its potential use
(Stojiljkovic et al. 2019). Furthermore, the adjunct use of keta-
mine with midazolam was effective in providing neuroprotec-
tive effects in sarin-poisoned rats. Also, fewer
electroencephalographic (EEG) abnormalities were recorded
with the combined treatment compared to treatment with
either therapeutic alone (Lewine et al. 2018).
 CRITICAL REVIEWS IN TOXICOLOGY 9

Table 3. Potential investigational agents for use in OP poisoning treatment.

Treatment under investigation Study Study type Outcomes and comments
Prophylactic agents
Tiapride Petroianu et al. (2007) In vivo study Provided similar protection to
(paraoxon poisoned rats) pyridostigmine when either agent were
followed by a dose of 2-PAM, yet it also
provided lower protection when either
agent were used alone.
Galantamine alone/ Perera et al. (2009) In vivo study Provided sufficient protection against OP
galantamine þ atropine (soman poisoned guinea pigs) toxic effects and lethality when
administered alone, with survival rates
reaching up to 100% when atropine was
also used.
Paraoxonase Mata et al. (2014) In vivo study Out of four engineered paroaxonase
(paraoxon poisoned mice) variants, one candidate provided
complete asymptomatic protection below
a paraoxon-to-enzyme ratio of 8:1.
Rivastigmine Lavon et al. (2015) Randomized controlled trial in 1.5 and 3 mg rivastigmine capsules provided
healthy volunteers non-linear pharmacokinetics, high inter-
(n ¼ 19) patient variability, and mild adverse
reactions compared to the placebo
control group.
Physostigmine Park et al. (2018) In vivo study In an attempt to enhance pharmacokinetics
(rats) of physostigmine, PEG-liposomes of
physostigmine provided lower but
sustained inhibition of AChE, compared
to an equivalent dose of
physostigmine solution.
Human Myers (2019) In vivo study A large dose of IM HuBChE (13.1 mg/kg)
butyrylcholinesterase (HuBChE) (soman poisoned monkeys) was able to provide effective protection
against neurobehavioral dysfunctions as
no behavioral disruptions were observed,
even in monkeys injected with another
lethal dose of soman a day after.
Neuroprotective agents
Ketamine þ midozolam Lewine et al. (2018) In vivo study Provided a significant improvement in
(sarin poisoned rats) neuroprotection compared to midozolam
alone. While 90% of animals showed
abnormalities in EEG after midozolam
was used alone, only 10% of those
administered with the combination did.
Memantine alone/ Stojiljkovic et al. (2019) In vivo study Provided an improvement of AChE activity
memantine þ standard treatment (soman poisoned rats) in brain and diaphragm compared to
control untreated group, and a higher
protective ratio compared to
pyridostigmine and physostigmine.
Potential is limited due to the narrow
therapeutic index.
Adjunctive agents
Blood alkalization with sodium Roberts and Buckley (2005) Cochrane database systematic All five studies either did not satisfy
bicarbonate (NaHCO3) review inclusion criteria or had significant
(n ¼ 5) heterogeneity between treatment and
control group. Hence, data is insufficient
to recommend the routine use
of NaHCO3.
Clonidine Perera et al. (2009) Dose finding, open-label, 0.15 or 0.3 mg clonidine bolus and 0.5 mg/
multicentre, phase II pilot 24 h infusion were well tolerated. Higher
clinical trial doses were associated with hypotension
(n ¼ 48) requiring intervention.
Clonidine El-Ebiary et al. (2016) Open-label, phase II pilot clinical No significant improvement in clinical
trial outcomes was provided compared to
(n ¼ 60) standard treatment alone. It was also
associated with a high incidence of
hypotension, although moderate doses
were used (0.1 mg tablets)
Magnesium sulfate (MgSO4) Afify et al. (2016) Randomized controlled trial 4 g of MgSO4 IV infusion in a dose of 1 g/
(n ¼ 100) 6 h significantly decreased mortality rates
compared to standard treatment with
added placebo.
Magnesium sulfate (MgSO4) Harsha et al. (2017) Randomized controlled trial 4 g of MgSO4 IV infusion over 4 h
(n ¼ 50) significantly decreased total atropine,
required ventilation, ICU stay and
associated mortality rates compared to
standard treatment with added placebo.
Magnesium sulfate (MgSO4) Vijayakumar et al. (2017) Randomized controlled trial 4 g of 20% MgSO4 IV infusion over 30 mins
(n ¼ 100) significantly decreased total atropine
required compared to standard treatment
with added placebo.
(continued)
10 M. ALOZI AND M. RAWAS-QALAJI

Table 3. Continued.
Treatment under investigation
N-acetylcysteine þ blood
alkalization with sodium
bicarbonate (NaHCO3)
Magnesium sulfate (MgSO4)
Rocuronium
N-acetylcysteine
Analagous of ACh (AMECh
and ADECh)
Study Study type
Motawei and Elbiomy (2017) Randomized controlled trial
(n ¼ 140)
Jamshidi et al. (2018) Randomized controlled trial
(n ¼ 80)
Dhanarisi et al. (2020) Randomized three-arm dose-
response phase II pilot clinical
trial
(n ¼ 45)
Rambabu et al. (2020) Systematic review
(n ¼ 17 studies including 2
randomized controlled trials)
Whitmore et al. (2020) In vitro study
(diaphragm preparation from
soman poisoned guinea pigs)
Outcomes and comments
Improved clinical outcomes and significantly
reduced length of hospital stay
compared to standard treatment alone.
2 g of 50% MgSO4 IV infusion over 30 mins
provided better control over toxic cardiac
effects, reduced hospital stay, mortality
rates, and therapeutic costs compared to
standard treatment with added placebo.
No evidence of added benefit, as clinical
outcomes and mortality rates were
similar to the control group receiving
standard treatment alone. In fact, higher
ventilation was required when
rocuronium was added.
Provided improvement of clinical outcomes
in animal studies, while the sample size
of human studies was too small to
recommend the use of N-acetylcysteine.
Administration of precursors MECh and
DECh that act as antagonists improved
neuromuscular function.

4.3.4. Adjunctive agents of glutathione, an endogenous antioxidant. However, the

Several adjunctive agents have been investigated as potential
antidotes for OP poisoning (Table 3). Recently, two natural
analogs of ACh, acetylmonoethylcholine (AMECh) and acetyl-
diethylcholine (ADECh) were investigated in vitro and were
shown to be associated with a decrease in the overstimula-
tion of ACh receptors as they are partial agonists and exhibit
lower binding activity at the receptor relative to ACh
(Whitmore et al. 2020). On another note, the use of magne-
sium sulfate (MgSO4) as a calcium channel blocker was also
recommended by several researchers as it can decrease the
release of ACh at cholinergic synapses (Brvar et al. 2018). A
phase II study confirmed the safety of MgSO4 administration
to OP poisoned patients (Basher et al. 2013), and several
other trials recommended the infusion of 1 g of MgSO4 every
6 h within the first 24 h of admission (Afify et al. 2016; Harsha
et al. 2017; Vijayakumar et al. 2017; Jamshidi et al. 2018).
Adjunctive MgSO4 was also shown to reduce the dose of
atropine needed for intubation and the overall time spent in
the ICU and associated mortality rates were reduced as well.
Additionally, the antidotal activity of clonidine was demon-
strated in animal studies via the inhibition of ACh release by
an unknown mechanism, which can provide synergism to atro-
pine’s antidotal effect (Perera et al. 2009). However, two pilot
studies investigating the use of clonidine against OP showed
no significant improvement when compared to the standard
treatment and was associated with a higher incidence of
hypotension (Perera et al. 2009; El-Ebiary et al. 2016)
Moreover, researchers suggested the use of nicotinic
antagonists to aid in maintaining adequate respiration by
minimizing the inhibition of N receptors at neuromuscular
junctions (Ring et al. 2015). However, a recent clinical trial
using rocuronium failed to show any benefits over standard
therapy and resulted in a worsening of neuromuscular junc-
tion function (Dhanarisi et al. 2020).
Since oxidative stress has been recognized as an import-
ant factor in OP poisoning, a recent systematic review cover-
ing 17 studies of which two were randomized clinical trials
suggested the use of acetylcysteine, as it increases the levels
small sample size of these clinical trials prevents any defini-
tive conclusion regarding the therapeutic benefit of using
acetylcysteine (Rambabu et al. 2020). Anisodamine is another
promising muscarinic and nicotinic antagonist with notable
antioxidant activity and less toxic effects compared to atro-
pine that may qualify as an add-on to current standard treat-
ment (Eisenkraft and Falk 2016).
Blood alkalization with sodium bicarbonate (NaHCO3) has also
been recommended. Several hypotheses had been proposed to
explain its mechanism of action including improving OP excretion
through pH-mediated hydrolysis, enhancing the potency of
oximes as well as its direct effects on improving neuromuscular
function. However, older studies did not provide enough evi-
dence to recommend its routine clinical use due to the critical
flaws in their study designs (Roberts and Buckley 2005).
Recently, the use of both acetylcysteine and NaHCO3 for
blood alkalization as a combination therapy was investigated
in a randomized controlled trial performed with 140 enrolled
patients. Results demonstrated an improvement in clinical
outcomes and a significant reduction in hospital stay when
the two approaches were added to standard treatment simul-
taneously (Motawei and Elbiomy 2017).
In clinical settings, broad-spectrum antibiotics are usually
used following the treatment of OP poisoning as prophylaxis
against nosocomial infections. Nevertheless, recent studies
challenged their clinical benefits and suggested increased
risks of superinfections, antimicrobial resistance, and a higher
treatment cost (Priyendu et al. 2017). In contrast, diuretics
such as furosemide and mannitol are effectively utilized in
clinical settings with the aim of promoting OP excretion in
addition to controlling OP-induced edema (Jiang et al. 2019).
4.4. Limitations of current treatment options and
potential solutions
4.4.1. Intermittent IV infusion
Due to difficulties in maintaining equilibrium between the
input rate and elimination rate using intermittent IV infusion,

Table 4. Recent advances in the utilization of oximes for OP poisoning treatment.
Treatment under investigation
Strategies to enhance BBB penetration
Sugar-oxime conjucates
Chemical modification of 2-PAM
Zwitterionic amidine-oximes
Intranasal obidoxime
Phenoxyalkyl substituted
pyridinium oximes
Inhibition of p-glycoprotein (by
adding tariquidar or
cyclosporine A)
Encapsulation in nanoparticles
Phenoxyalkyl substituted
pyridinium oximes
Zwitterionic acetamido bis-oximes
Encapsulation in cucurbit[7]uril
Combinations to broaden the spectrum of activity
HI-6 þ obidoxime and HI-6 þ K203
HI-6 þ trimedoxime and
HI-6 þ K203
2-PAM þ obidoxime
Alternative to hospital iv infusion
Continuous IV infusion of both
atropine and 2-PAM
using micropumps
Study
Garcia et al. (2010)
Karasova et al. (2010)
Okolotowicz et al. (2014)
Krishnan et al. (2016)
Chambers et al. (2016)
Joosen et al. (2016)
Pashirova et al. (2017)
Dail et al. (2019)
Gorecki et al. (2020)
Zdarova Karasova et al. (2020)
Kassa et al. (2009)
Caisberger et al. (2018)
Bohnert et al. (2020)
Liu et al. (2015)
CRITICAL REVIEWS IN TOXICOLOGY 11
Study type Outcomes and comments
In vitro study Out of 14 synthesized sugar-oxime
(human OP-AChE complex) conjugates, the highest achievable AChE
reactivation level was 80% of that
achieved by 2-PAM.
In vitro study Between 2-PAM, 3-PAM, and 4-PAM, the
(screening of BBB penetration) highest penetration was achieved in 4-
PAM as the substitution of oxime in the
para position of the pyridinium ring
decreased polar surface area.
In vivo study Proved to be nontoxic and provided higher
(rats) penetration levels to the brain compared
to 2-PAM.
In vivo study Provided effective reduction of AChE
(paraoxon poisoned rats) inhibition in the brain along with a
decrease in seizure severity and duration
and complete prevention of mortality
and neurodegeneration when compared
to saline.
In vivo study A number of phenoxyalkyl substituted
(rats subjected to lethal doses of pyridinium oximes were successful in
sarin and VX surrogates) achieving 25% reactivation of AChE
within the first 30 mins in the brain,
compared to 2-PAM showing no activity
in brain.
In vivo study Provided double the levels of AChE
(rats) reactivation activity in the brain
compared to that achieved with HI-
6 alone.
In vivo study 2-PAM loaded nanoparticles achieved 15 %
(paraoxon poisoned rats) AChE reactivation in the brain compared
to no reactivation achieved by free
2-PAM.
In vivo study Three candidates were administered at the
(subjected to lethal doses of onset of seizures, to compare effects on
paraoxon or sarin surrogate) neuropathology with 2-PAM. A lead
candidate was selected as it showed the
lowest damage in the hippocampus and
this was mostly attributed to its
increased lipophilicity and higher
penetration to the brain.
In vitro study Provided enhanced logP values and faster
(human OP-AChE complex) AChE reactivation rates compared to a
centrally acting agent, yet slower rates
compared to 2-PAM.
In vivo study Encapsulated K027 did not provide any
(sarin poisoned mice) enhancement in AChE reactivation levels
in the brain compared to free K027.
In vivo study Provided significantly higher AChE
(tabun poisoned rats) reactivation levels in the blood and
diaphragm, but similar levels in the
brains when compared to treatment by
any of the agents administered
individually.
In vivo study Significantly reduced mortality rates and
(sarin poisoned rats) slightly reduced brain damage compared
to the administration of HI-6 alone.
In vivo study Enhanced AChE reactivation and improved
(sarin poisoned guinea pigs) seizure control, as it provided a similar
activity to the individual oximes
administered in two equivalent doses
using autoinjectors.
Retrospective analysis Significantly decreased AChE recovery time,
(n ¼ 60) a dose of atropine supplied upon
atropinization, and overall mortality
compared to intermittent injections.
12 M. ALOZI AND M. RAWAS-QALAJI
Table 5. Comparison of oximes and their effectiveness in countering specific
OP nerve agents.
Oxime Sarin Tabun Soman VX
2-PAM þþ/þþþ 0 þþ þþ/þþþ
Obidoxime þþ þþ þ/þþþ þþþ
HI-6 þþþ þ/þþ þ þþþ þþþ
Trimedoxime NA þþ NA NA
Plus signs indicate relative effectiveness; 0 means no appreciable effect; NA
means information on activity not available for the correspond-
ing compound.
fluctuations in plasma levels of atropine may occur causing
symptoms of atropinization at peak levels and symptoms of
atropinism at low levels. A recent retrospective analysis sug-
gested that continuous infusion using micropumps can
ensure a stable equilibrium between input rate and elimin-
ation rate, minimizing fluctuations, and ensuring more stable
vital signs (Table 2). In addition, micropumps offer advan-
tages in terms of providing a more convenient method of
administration, easier dose adjustments when required, and
reduced mortality and recurrence rates due to better case
control (Jiang et al. 2019).
It has been shown that the use of micropumps for both
atropine and 2-PAM in 60 patients resulted in a significant
decrease in AChE recovery time, time to atropinization, and
reduced the atropine dose needed to achieve atropinization,
which led to better-controlled plasma concentrations and
decreased mortality rates (Table 4) (Liu et al. 2015).
4.4.2. Restrictions of auto-injectors
Several limitations have led to the underutilization of IM
auto-injectors as a device designed for self-administration
during emergencies, including delayed administration due to
the fear of needles (Chad et al. 2013), a lack of proper train-
ing for correct administration (Prince et al. 2018), the poten-
tial risks of the device malfunctioning and the need for
multiple injections (Guerlain et al. 2010). Hence, several
research groups investigated alternative novel formulations
to overcome most of these hurdles associated with the use
of auto-injectors in OP poisoning emergencies (Table 2).
Nasal atropine sprays were developed and tested in rat
models. These sprays provided similar efficacy to parenteral
atropine, fast systemic absorption, administration conveni-
ence, and a greater safety margin (Kumar and Vijayaraghavan
2001). Nasal drops of atropine-chitosan formulation were
investigated in six healthy individuals. Chitosan as a mucoad-
hesive and permeability enhancer was proposed to enhance
atropine nasal absorption. However, the study was not con-
trolled nor dose-ranged and resulted in a single peak at
30 min (Rajpal et al. 2009).
Dry powder inhalers using a formulation consisting of
atropine nanocrystals were investigated in six healthy individ-
uals but were unable to produce sufficiently rapid, high
plasma concentrations. The clinical study was not controlled
nor dose-ranged as well and resulted in an initial small
plasma peak at 15 min and a second larger peak at 60 min
mainly due to absorption from the GIT (Ali et al. 2009). The
administration of atropine using a MicroDose dry powder
inhaler was also tested on 17 healthy volunteers as a second-
line treatment after the initial use of atropine and 2-PAM. Six
inhalations using the MicroDose inhaler (0.4 mg/inhalation)
were required to produce a similar pharmacokinetic profile
achieved with a single 2 mg IM injection using an auto-
injector (Corcoran et al. 2013).
Recently, a fast-disintegrating sublingual tablet of atropine
was proposed as a convenient alternative dosage form. The
tablets had a very short disintegration time and resulted in a
sublingual permeability comparable to the control which
consisted of an atropine solution. However, further in vivo
testing is required to determine the potential bioequivalent
sublingual atropine dose (Aodah et al. 2017, 2019; Bafail
et al. 2019).
4.4.3. Penetration of BBB by oximes
OP are lipophilic molecules that can easily cross blood–brain
barrier (BBB). However, the IV or IM administration of oximes
does not antagonize the central effects of OP due to their
poor BBB permeability, and researchers have explored various
alternative delivery methods as well as chemical modifica-
tions to oximes to amend this limitation (Table 4). An intra-
nasal obidoxime formulation was developed and was able to
provide effective protection to the brain and reduce mortality
in rats (Krishnan et al. 2016). Several other approaches were
investigated to enhance BBB permeation but were proven
unsuccessful, including attachment to sugar ligands (Garcia
et al. 2010; Kobrlova et al. 2019). However, loading drugs
into nanoparticles or their co-administration with inhibitors
of efflux transporters were shown to be more promising
(Joosen et al. 2016; Pashirova et al. 2017; Kobrlova
et al. 2019).
Other means of chemical modification have also been
attempted to enhance the lipophilicity of oximes and subse-
quently increase their BBB penetration. In a rat study, a series
of newly developed phenoxy alkyl substituted pyridinium
oximes resulted in higher levels of central AChE reactivation
in comparison to 2-PAM (Chambers et al. 2016; Dail et al.
2019). Variations in the charge of the oxime structure have
also been investigated and two classes of zwitterionic com-
pounds, amidine-oximes, and acetamido bis-oximes have
been proven promising and resulted in a greater degree of
BBB penetration (Okolotowicz et al. 2014; Gorecki
et al. 2020).
Another research group attempted different chemical
modifications to 2-PAM itself and monitored the extent of
in vitro BBB penetration of the different analogs. Results sug-
gested that the highest level of penetration was achieved by
4-PAM in which the oxime substituent was placed on the
para position of the pyridinium ring (Karasova et al. 2010).
The encapsulation of oximes in cucurbit[7]uril, a biocom-
patible rigid hydrophobic macrocycle, was also investigated
in an attempt to increase their brain bioavailability. In vitro
investigations showed that the encapsulated molecules were
not only associated with higher and faster BBB penetration
but also their release was sustained and was protected from
rapid renal clearance. This approach needs further in vivo
testing to be validated for its potential in enhancing the
delivery of oxime compounds (Zdarova Karasova et al. 2020).

4.4.4. Narrow-spectrum of oximes activity
Different oxime derivatives exhibit variable degrees of effect-
iveness depending on the type of intoxicating OP (Table 5)
(Moshiri et al. 2012). However, the prompt identification of
the causal OP before the OP-AChE complex is aged and no
longer liable for reactivation by oximes is nearly impossible
and may hinder or limit their use.
Therefore, oxime combinations are being investigated for
their effectiveness and safety in order to provide effective
protection against a broader range of OP (Table 4). In a
recent study, 2-PAM and obidoxime were combined and
tested in guinea pigs exposed to sarin. The combined oximes
were more effective in reactivating AChE and had better seiz-
ure control while maintaining the same level of safety as
individualized therapy (Bohnert et al. 2020).
In another in vivo study performed on rats exposed to
tabun, two combinations of oximes were tested (HI-
6 þ obidoxime and HI-6 þ K203), each of which produced
reactivation levels higher than those achieved with the indi-
vidual oximes in the blood and diaphragm, but had similar
reactivation levels in the brain (Kassa et al. 2009).
Furthermore, another similar study in rats poisoned with sarin
used two combinations (HI-6 þ trimedoxime and HI-6 þ K203)
which similarly resulted in lower mortality rates and lower
levels of brain damage (Caisberger et al. 2018), confirming
the greater efficacy of combination oxime therapy.
Conclusions
OP poisoning is a global health issue recognized by the
WHO, which reported high annual toxicity cases and mortal-
ity rates due to exposure to various OP molecules. Several
approaches were investigated and various novel formulations
have been developed to overcome the limitations of conven-
tional therapy.
Standard therapy of OP poisoning compromises of two
main stages, supportive treatment including resuscitation,
mechanical ventilation, decontamination, and hemodialysis if
required, as well as pharmacological treatment. The only
FDA-approved products for the treatment of OP poisoning
are atropine as the first-line antidote, oximes as AChE reacti-
vators used as a follow-up or in combination with atropine,
benzodiazepines as anticonvulsants, and pyridostigmine as
the primary prophylactic agent.
Newer antidotes were investigated, such as glycopyrrolate
which demonstrated potential benefit when added to atro-
pine due to its lower toxicity profile. Additionally, several bio-
scavangers were evaluated for their potential use as
prophylactic agents with HuBChE being the primary com-
pound with the highest potential. Furthermore, numerous
agents were reported to provide beneficial effects as adjunct-
ive agents added to standard therapy, including neuroprotec-
tive agents, analogs of ACh, and diuretics among
several others.
Moreover, efforts have been directed toward developing
novel ways to deliver and administer the currently approved
agents to maximize their effectiveness and minimize toxicity.
For instance, micropumps have been suggested for the IV
CRITICAL REVIEWS IN TOXICOLOGY 13
administration of atropine and oximes to better control drugs
within therapeutic levels for a prolonged time. For out-of-
hospital emergency administration, various novel atropine
formulations have been tested in animals and in pilot human
studies for their high potential as alternatives to auto-injec-
tors. Examples of these formulations include nasal sprays,
mucoadhesive nasal drops, dry powder inhalers, and fast-dis-
integrating sublingual tablets.
The potential of increasing the penetration of oximes into
the brain was also investigated. Various novel formulations
including intranasal, nanonization, encapsulation in hydro-
phobic carriers and administration with efflux inhibitors were
shown to remarkably enhance the delivery of oximes to the
brain. Furthermore, combining oximes together was found to
enhance their effectiveness against a wider range of OP com-
pounds without compromising their safety when compared
to their individual delivery.
In conclusion, the prevalence and severity of OP poisoning
should encourage on-going research into innovating new
treatment strategies and more convenient drug delivery that
focuses on maximizing the effectiveness of treatments while
reducing complications. However, a few, yet very sturdy bar-
riers are preventing most of these innovations from being
advanced to reach the affected individuals. The most domin-
ant one is the ethical concerns associated with conducting
clinical trials for most emergency and life-saving medications.
The majority of these clinical trials are being performed in
healthy volunteers. In addition, developing new drugs or dos-
age forms for the treatment of OP poising may not be finan-
cially rewarding for the pharmaceutical industry since the
majority of these cases occur in areas with lower socioeco-
nomic status, such as in rural and agricultural areas or eco-
nomically impacted war-zones or countries.
Acknowledgements
The authors thank the anonymous peer reviewers for their constructive
criticism and suggested additions. Their comments and suggestions were
helpful to improve and clarify this publication.
Declaration of interest
The authors report no conflict of interest. The author’s affiliations are as
shown on the cover page. The institutions with which the authors are
affiliated are academic institutions, and the authors take sole responsibil-
ity for the writing and content of the manuscript. None of the authors
have been involved in legal or regulatory matters related to the contents
of the paper.
M. Rawas-Qalaji was the first inventor for multiple related patent
applications and one granted European patent. These patent applications
were for the development of atropine sublingual fast-disintegrating tab-
lets for the emergency treatment of organophosphates toxicities.
ORCID
Mutasem Rawas-Qalaji http://orcid.org/0000-0001-8890-3818
14 M. ALOZI AND M. RAWAS-QALAJI
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