Perspectives in Pharmacology Experimental Treatments for Cocaine

Transcription

1521-0103/347/2/251–257$25.00
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright ª 2013 by The American Society for Pharmacology and Experimental Therapeutics
http://dx.doi.org/10.1124/jpet.113.206383
J Pharmacol Exp Ther 347:251–257, November 2013
Perspectives in Pharmacology
Experimental Treatments for Cocaine Toxicity: A Difficult
Transition to the Bedside
Nicholas J. Connors and Robert S. Hoffman
Division of Medical Toxicology, Department of Emergency Medicine, New York University School of Medicine, Bellevue Hospital
Center, New York, New York
ABSTRACT
Cocaine is a commonly abused illicit drug that causes significant
morbidity and mortality. Although there is no true antidote to
cocaine toxicity, current management strategies address the
life-threatening systemic effects, namely hyperthermia, vasospasm, and severe hypertension. Clinicians rely on rapid cooling,
benzodiazepines, and a-adrenergic antagonists for management,
with years of proven benefit. Experimental agents have been
developed to more effectively treat acute toxicity. Pharmacodynamic approaches include antipsychotics that are thought to
interfere with cocaine’s actions at several neurotransmitter receptors. However, these medications may worsen the consequences of cocaine toxicity as they can interfere with heat dissipation,
cause arrhythmias, and lower the seizure threshold. Pharmacokinetic approaches use cocaine-metabolizing enzymes, such as
butyrylcholinesterase (BChE), cocaine hydrolase (CocH), and
For at least 30 years, cocaine has remained a major public
health concern. In 2010, there were 1.5 million cocaine users
in the United States alone (Substance Abuse and Mental
Health Services Administration, 2011). The molecular actions
of cocaine are numerous and defy a simple treatment to
mitigate its toxic effects. Cocaine use predisposes to diffuse
central nervous system (CNS) excitation. It inhibits the transporter proteins responsible for the reuptake of epinephrine,
norepinephrine, serotonin, and dopamine into presynaptic
neurons, allowing repeated activation of the postsynaptic neuron through a- and b-adrenergic, serotonergic, and dopaminergic receptors (Williams and Lacey, 1988). However,
cocaine’s toxic effects cannot simply be explained by reuptake
inhibition, because other agents with similar effects on reuptake do not cause the same clinical manifestations as cocaine
toxicity. Concentrations of glutamate and aspartate, excitatory amino acids, increase significantly in animals exposed
to cocaine and may play a crucial role in acute toxicity and
neuromodulation resulting in addiction (Smith et al., 1995;
dx.doi.org/10.1124/jpet.113.206383.
bacterial cocaine esterase (CocE). Experimental models with
these therapies improve survival, primarily when administered
before cocaine, although newer evidence demonstrates beneficial effects shortly after cocaine toxicity has manifested. CocE,
a foreign protein, can induce an immune response with antibody formation. When enzyme administration was combined
with vaccination against the cocaine molecule, improvement in
cocaine-induced locomotor activity was observed. Finally, lipid
emulsion rescue has been described in human case reports as an
effective treatment in patients with hemodynamic compromise
because of cocaine, which correlates well with its documented
benefit in toxicity due to other local anesthetics. A pharmaceutical
developed from these concepts will need to be expedient in onset
and effective with minimal adverse effects while at the same time
being economical.
Kasanetz et al., 2013). Morbidity and mortality largely result
from acute cardiovascular and neurologic complications. Hyperthermia, vasospasm, and severe hypertension are produced by catecholamine excess and psychomotor agitation.
General management with rapid cooling and fast-acting
benzodiazepines is usually sufficient to decrease the risk
of permanent disability or death. a-Adrenergic antagonists
and the potential use of calcium channel antagonists and
sedatives have proven to be of clinical use when the first-line
measures are inadequate. The numerous biochemical actions of cocaine with effects on various cellular receptors
make development of an antidote difficult. Newer agents
such as antipsychotics that antagonize dopamine receptors,
enzymes-metabolizing cocaine, and vaccines against cocaine
have been developed. Preliminary results hold promise,
although significant barriers may prevent these therapies
from achieving practical utility in acutely cocaine-toxic
patients. In this article, we will review several recent advances in the treatment of acute cocaine toxicity and discuss
the difficulties facing their clinical implementation.
ABBREVIATIONS: ALT, alanine aminotransferase; BChE, butyrylcholinesterase; BE, benzoylecgonine; CNS, central nervous system; CocH,
cocaine hydrolase; CocE, bacterial cocaine esterase; EME, ecgonine methyl ester.
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Received May 20, 2013; accepted August 26, 2013
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Connors and Hoffman
Current Clinical Management
Cooling
Benzodiazepines
Generalized suppression of central nervous system activity
antagonizes the sympathomimetic effects of cocaine. In
animal models of cocaine toxicity, sedation with a benzodiazepine increases the mean lethal and convulsive doses of
cocaine (Guinn et al., 1980) and improves survival (Guinn
et al., 1980; Catravas and Waters, 1981; Yuksel et al., 2013).
Through their action on the g-aminobutyric acid receptors in
the amygdala and reticular activating system, benzodiazepines function as anxiolytics, sedatives, and antiepileptics.
Additionally, benzodiazepines may enhance the effect of
endogenous adenosine on the myocardium by inhibiting
the nucleoside transporter responsible for adenosine reuptake with resultant coronary vasodilation from A2A receptor
agonism (Seubert et al., 2000). Benzodiazepines also relieve
tachycardia, hypertension, and vasoconstriction, thereby decreasing the metabolic demands of the myocardium. Finally,
when high doses of ligands to the translocator protein,
formerly known as the peripheral benzodiazepine receptor,
are administered in vivo to rabbits and ex vivo to rat and
Adrenergic Receptor Antagonists
Cocaine inhibits norepinephrine reuptake in central presynaptic nerves. Excess norepinephrine causes stimulation of
both a-and b-adrenergic receptors. Studies of b-adrenergic
antagonists in acute cocaine toxicity have shown decreases in
the mean convulsive and mean lethal cocaine doses in animals
(Guinn et al., 1980) and worsened coronary vasoconstriction in humans (Lange et al., 1990). Clinically, the use of a
b-adrenergic antagonist in an acutely cocaine toxic patient
has resulted in death (Fareed et al., 2007). Alternatively,
a-adrenergic antagonists, such as phentolamine, can mitigate
the vasoconstrictive effects of cocaine toxicity, suggesting the
mechanism is cocaine-induced elevation in a-adrenergic tone
(Lange et al., 1989). Mean arterial pressure and coronary
vasospasm can be relieved, reducing afterload and improve
myocardial perfusion. The clinical use of phentolamine
has resulted in the resolution of chest pain and electrocardiographic changes consistent with coronary ischemia
(Hollander et al., 1992).
Finally, calcium channel antagonists and neuromuscular
blockers have been used to treat refractory cases of cocaine
toxicity. Myocardial injury due to cocaine-induced vasoconstriction was decreased with verapamil in a clinical trial
(Negus et al., 1994). Although little clinical evidence exists
supporting use in acute cocaine toxicity, the mechanism of
action of calcium channel antagonists makes them a reasonable second-line agent. Neuromuscular blockade is the last
resort in the treatment of hyperthermia and agitated delirium associated with cocaine toxicity. After paralysis,
locomotor activity is abolished and behavior is controlled,
allowing passive and active cooling and administration of
benzodiazepines.
Therapies under Development
Pharmacodynamic Approaches
Treatments that antagonize receptors stimulated by cocaine can be categorized as pharmacodynamic approaches to
the treatment of cocaine toxicity. Among the antagonists
Among the most dangerous effects of cocaine toxicity is its
ability to raise core temperature and cause life-threatening
hyperthermia (Roberts et al., 1984; Daras et al., 1995).
Emphasizing the dangerous relationship between cocaineinduced hyperthermia and mortality, there is a 33% increase
in mean cocaine-related mortality on days where the ambient
temperature is above 88°F (Marzuk et al., 1998). In addition
to protein denaturation that occurs at elevated body temperatures, the cardiovascular system, which is likewise being
stimulated by the sympathomimetic effects of cocaine, is
further taxed to maintain cardiac output in the face of
temperature-induced vasodilation. In this setting, rapid resolution of hyperthermia is of utmost importance. In a canine
model of cocaine toxicity, limiting hyperthermia by reducing
the ambient temperature to 25°C was more protective
against mortality than prevention of acidosis with sodium
bicarbonate, prevention of convulsions with antiepileptics, or
inhibition of dopamine with a dopamine antagonist. Cocaine
administration caused dogs to become more hypothermic at
25°C than a control group, indicating that cocaine may have
an effect in enhancing the response to hypothermia, which is
actually protective (Catravas and Waters, 1981). In humans,
cocaine-induced hyperthermia is mediated by increased
locomotor activity (Rosenberg et al., 1986). As the ambient
temperature rises, cocaine augments elevations in core temperature, attenuates cutaneous vascular conductance and
sweating, and decreases the perception of elevated temperature (Crandall et al., 2002). Rats given intravenous cocaine
have increases in brain temperature that do not correlate
with temporal muscle temperature (Kiyatkin, 2013). Patients
with cocaine-induced hyperthermia often recover if rapidly
cooled (Menaker et al., 2011), although the risks of prolonged
elevations of core body temperature include death and
permanent neurologic disability. Ice water immersion and
paralysis are useful (Roberts et al., 1984; Rosenberg et al.,
1986), and data suggest cold water immersion is the most
practical treatment modality, effectuating rapid cooling at
a rate of about 0.2°C/min (Armstrong et al., 1996).
rabbit hearts, the area of myocardial infarction is decreased
after an ischemic stress. The mechanism of protection is
potentially reduced cardiac mitochondrial membrane permeability that results in decreased apoptosis and prevents
release of mitochondrial cytochrome c (Leducq et al., 2003;
Obame et al., 2007). Success using short-onset benzodiazepines such as midazolam or diazepam has been a cornerstone
of the treatment of acute cocaine toxicity since the 1980s.
Large human trials assessing their efficacy are lacking, but
recent meta-analysis data demonstrate a 51.7% improvement
in survival in cocaine-poisoned animals treated with benzodiazepines compared with animals receiving placebo (Heard
et al., 2011). In humans, a beneficial effect of benzodiazepine
treatment is best demonstrated for patients with cocainerelated chest pain. In randomized trials, patients treated with
a parenteral benzodiazepine plus sublingual nitroglycerin
had more rapid and substantial improvement in their subjective pain scores than those receiving nitroglycerin alone
(Honderick et al., 2003). In addition, those who received
benzodiazepines alone did no worse than those treated with
only nitroglycerin (Baumann et al., 2000).
Experimental Treatments for Cocaine Toxicity
Pharmacokinetic Approaches
Pharmacokinetic approaches to the treatment of cocaine
overdose aim to prevent its entry into, enhance its diffusion
from, and mitigate subsequent action within the CNS. This
mechanism aims to neutralize or metabolize cocaine rather
than countering its clinical effects. Examples of this approach
are the use of cocaine metabolizing enzymes, vaccines, and
lipid emulsion.
Enzymes. Cocaine metabolism is complex. In addition to
spontaneous hydrolysis, in humans, liver carboxylesterase
hydrolyzes the methyl ester of approximately 45% of cocaine
to form benzoylecgonine (BE) and butyrylcholinesterase
(BChE) hydrolyzes the benzoyl ester of 45% of cocaine to
produce ecgonine methyl ester (EME). Approximately 5% of
cocaine also undergoes N-demethylation by BChE to form
norcocaine (see Fig. 1) (Dean et al., 1991). In isolated cerebral
arteries from cats and fetal sheep, BE was a more potent
vasoconstrictor than cocaine, norepinephrine, and norcocaine.
EME actually demonstrated vasodilatory properties and was
protective in mice (Madden and Powers, 1990). Norcocaine
easily crosses the blood-brain barrier, whereas BE and EME
are more restricted. Findings of BE in the brains of cocaine
users days after last exposure, together with cocaine’s short
half-life and clinical effects that last hours, suggest that cerebrovascular effects may be due to BE (Madden and Powers,
1990).
Three enzyme types have been studied as potential antidotal therapies to acute cocaine toxicity. Wild-type human
BChE, also referred to as pseudocholinesterase, hydrolyses
cocaine to EME (Misra et al., 1975). In humans, decreased
BChE activity is associated with life-threatening reactions to
cocaine, and it has been postulated that phenotypes with low
BChE activity are more susceptible to cocaine (Hoffman et al.,
1992). In rats pretreated with BChE and then exposed to
cocaine, blood pressure elevation was mitigated and the lethal
dose was increased. In rats administered cocaine 80 mg/kg
Fig. 1. Three primary pathways of cocaine metabolism and
the relative production of each metabolite.
being explored are antipsychotics that affect multiple receptors where cocaine has actions.
Antipsychotics. The use of atypical antipsychotics in
cocaine toxicity exploits their mechanisms as dopamine, serotonin, and muscarinic inhibitors. Animal studies show
antipsychotics as a class increase survival by 27% over
placebo (Heard et al., 2011). Olanzapine, specifically, is an
antagonist at the dopamine D1, D2, muscarinic, and serotonin
5HT2A receptors. In mice pretreated with olanzapine, only
10.5% developed irreversible cocaine toxicity (and were
euthanized) compared with 46.2% of those pretreated with
placebo (Heard et al., 2009). Ziprasidone, an antagonist at
dopamine and serotonin receptors, reduces cocaine induced
lethality in pretreated mice by 51% (Cleveland et al., 2005),
although in a more recent investigation using similar doses,
ziprasidone failed to prevent lethality but did delay the onset
of seizure (Cleveland et al., 2007). There are concerns whether
antipsychotics should be used at all in the setting of cocaine
toxicity (Wu et al., 2008). Conflicting data exist regarding
antipsychotics that may be agent and or species specific. In
dogs, pimozide showed no benefit in convulsions or lethality
compared with controls, although a group treated with chlorpromazine had improved mortality and a slight increase in
the mean convulsive dose (Catravas and Waters, 1981). In
a small cynomologus monkey trial, there was an increased
mean convulsive dose and fewer convulsions in those treated
with chlorpromazine compared with controls, but a greater
proportion of subjects with convulsions compared with those
treated with diazepam (Guinn et al., 1980). Additionally,
haloperidol pretreatment in rats did not improve cocaineinduced mortality (Witkin et al., 1989). Associated anticholinergic effects causing impaired heat dissipation, decreased
seizure threshold, and prolongation of the QT interval are all
potentially catastrophic to a cocaine-toxic patient. We conclude, for now, that data are insufficient to support the use of
antipsychotics for patients with cocaine toxicity.
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acute cocaine toxicity has the potential to be curative,
although significant caveats to its administration will apply.
More than 40% of patients who present to the emergency
department with cocaine toxicity do so more than 1 hour after
cocaine use (Gitter et al., 1991). More concerning is another
analysis that shows patients suffering an acute myocardial
infarction after cocaine use presented after more than
18 hours (Amin et al., 1990). It is unknown whether enzymatic
therapy will be effective in these late presenters. Pharmacoeconomically, enzymatic therapy will be costly. Unless there is
significant benefit of enzymatic treatment in terms of patient
mortality, major adverse events, or reductions in hospital
resource utilization compared with current clinical management, it will be difficult to justify the significant cost. Given
these hurdles, it is difficult to imagine enzymatic therapy
supplanting cooling and benzodiazepines in the treatment of
cocaine toxic patients.
Vaccine and Enzyme Combinations. Vaccines that actively immunize against cocaine can result in innate production of anti-cocaine antibodies that yield immune-mediated
degradation of the cocaine molecule. Although more suited
to treat cocaine addiction by preventing the entry of cocaine
into the CNS and the resultant reinforcing effects, it has also
shown some promise in acute toxicity, reducing sequelae in
mice and humans (Fox et al., 1996; Martell et al., 2009). Anticocaine antibody binding allows for rapid sequestration of the
toxin in plasma. As discussed above, enzymatic degradation
enhances elimination of active cocaine; in combination, it is
believed that enzymatic treatment and prior vaccination work
synergistically to prevent cocaine toxicity. Data show higher
plasma cocaine and cocaine metabolite concentrations in mice
treated with vaccine and CocH, suggesting endogenously produced antibodies trap cocaine in the plasma, possibly preventing entry into the CNS, and allow greater metabolism
by CocH (Brimijoin et al., 2013). When the administration
of cocaine vaccine [8100-1 KLH SNC vaccine (norcocaine
hapten-conjugated keyhole limpet hemocyanin)] is compared
with pretreatment with a quadruple mutant CocH (A199S/
S287G/A328W/Y332G), each agent alone was not sufficient to
prevent decreased grip strength or increased locomotor
activity in cocaine-toxic mice (Carroll et al., 2012; Gao et al.,
2013). Combination treatment of CocH and vaccine resulted
in no loss of grip strength and greatly reduced locomotor
activity (Carroll et al., 2012). Furthermore, this combination
afforded almost total protection from alanine aminotransferase (ALT) elevation, suggesting that the liver cells were
protected from injury when hepatotoxic doses (120 mg/kg i.p.)
were administered (Gao et al., 2013). The protection from ALT
elevation was equivalent to that when cocaine antibody was
given, suggesting that the mice who received the vaccine went
on to produce antibody and reaped the same benefit. Of note,
cocaine-induced hepatotoxicity is specific to rodents and does
not typically occur in humans. Mice treated with adenoassociated viral vector pAAVio-CASI-CocH C-W-SV40 encoding
cDNA for C-terminally truncated CocH developed significant
CocH activity and normal serum ALT after treatment with
cocaine 120 mg/kg i.p. compared with mean ALT concentration of 18,000 units/ml in untreated subjects 3 months after
vector administration (Gao et al., 2013). The use of an effective vaccine against cocaine has the potential to reduce
toxicity substantially, although issues regarding bioethics
and public health resource utilization must be considered.
and then given BChE 3 minutes later, a smaller proportion
suffered convulsions or expired in a dose-dependent manner
than controls (Lynch et al., 1997). After cocaine administration, a pretreated rat had significantly decreased plasma
concentrations of cocaine, BE, and norcocaine and significant
increases in EME compared with a control (Mattes et al.,
1997). Similar results are reported in pretreated squirrel
monkeys in vivo and human plasma in vitro (Carmona et al.,
2000). Interestingly, rat brain concentrations of cocaine and
BE were not altered by BChE, although brain EME concentrations were increased in a dose-dependent manner after
BChE pretreatment (Carmona et al., 2005).
A major limitation of native BChE is the inherent
inefficiency of the enzyme: kcat 5 0.07/s and Km 5 4.5 mM. It
would require massive doses to detoxify cocaine in a human
(Sun et al., 2002a). Guided by molecular modeling, two amino
acid substitutions, Ala328Trp/Tyr332Ala, were introduced
into wild-type BChE to allow better orientation of (2)-cocaine
for enzymatic hydrolysis after it has bound to the enzyme
active site. The recombinant enzyme, CocH, is also primarily
tetrameric, and similar to wild-type BChE, is not rapidly
degraded as are monomeric or dimeric enzymes and has a 40fold increase in catalytic activity. CocH has a kcat 5 2.6/s and
Km 5 18 mM. After CocH pretreatment, decreased cocaine concentrations were found in rat tissue, and increased locomotor
activity induced by cocaine was abolished in mice (Sun et al.,
2002a). Rats pretreated with CocH showed no major change in
the concentration of BE generated, but EME concentration
was 8-fold greater than controls (Sun et al., 2002b). When rats
with cocaine-induced hypertension were treated with 3 mg/kg
CocH after an average of 108 seconds after cocaine administration, they had rapid reversal of blood pressure abnormalities (Gao and Brimijoin, 2004). Development of additional
mutants of CocH, such as A199S/S287G/A328W/Y332G and
A199S/F227A/S287G/A328W/Y332G, has yielded catalytic
efficiency with hundreds to thousands times that of native
BChE (Zheng et al., 2008). Investigators have fused A199S/
S287G/A328W/Y332G with albumin to provide a longer halflife. When given as pretreatment or as a rescue after administration of 100 mg/kg cocaine, albumin-CocH resulted in
improved mortality and prevention or resolution of convulsions. When given after cocaine, brain cocaine concentrations
in treated rats were 4-fold less compared with controls
(Brimijoin et al., 2008).
A CocE found in Rhodococcus spp. catalyzes cocaine
hydrolysis with a kcat 5 7.8/s and Km 5 0.64 mM. CocE is
effective in preventing convulsions and mortality and rescues
mice from convulsions when given after a lethal dose of cocaine (Ko et al., 2009). CocE (1 mg i.v.) given to rats 1 minute
after cocaine administration produced a 10-fold rightward
shift in the cocaine-toxicity dose-response curve. Notably,
when CocE is administered to rats up to 6 minutes after
cocaine, there is still a significantly reduced mortality rate
(Cooper et al., 2006). However, an immune response was
noted with repeated administrations of CocE, and as antiCocE antibodies increased, the clinical response to treatment
declined (Ko et al., 2009). Double mutant CocE (T172R/
G173Q) given to rhesus monkeys 10 minutes after cocaine
improved mean arterial pressure, heart rate, and locomotor
activity, even as anti-double mutant CocE antibody titers
increased in the animals after repeated administrations
(Collins et al., 2011, 2012). Effective enzymatic therapy for
Conclusion
The perfect cocaine antidote must be easily deliverable to
a patient manifesting signs and symptoms of severe cocaine
toxicity, namely cerebral, coronary, or peripheral vasoconstriction, or life-threatening hyperthermia. This substance would rapidly halt the actions of cocaine centrally by
neutralizing cocaine in the plasma before it has traversed
the blood-brain barrier, traversing the barrier itself, or
creating a diffusion gradient to pull cocaine from the CNS
into the plasma. This substance should perform better than
symptomatic treatments to such a great degree that this
product would be economically viable against generic benzodiazepines. This ideal has proven elusive though because
of the complexity of cocaine’s pathophysiologic effects.
The preponderance of preclinical studies evaluating antidotal therapies for cocaine are elegant experiments that help
further elucidate cocaine’s actions at receptors and the ability
of enzymes to catalyze its hydrolysis. The majority are proof of
concept studies that pretreat subjects with the investigational
agent before administration of cocaine. Excitement for a potential contender is enhanced by the studies that show clinical
improvement with a delay of several minutes between cocaine
and antidote administration. Currently, 10 minutes is the
longest delay to treatment with retained benefit. Several
potentially harmful active metabolites of cocaine, such as
norcocaine and BE, may be present in greater concentrations
relative to cocaine by the time a patient develops symptoms,
presents to an emergency department, and is treated. The
efficacy of experimental treatments on these metabolites or
when given after a delay between cocaine administration and
treatment is unknown. With regards to non-human-derived
proteins, antibody formation and the resultant immune response will have to be considered because an acutely cocainetoxic patient may be extremely susceptible to significant
immune-mediated reactions. This is not likely an issue the
first time a patient is treated, but the addictive nature of the
drug suggests that patients may require treatment several
times. These patients are also those from whom an accurate
history of prior treatments would be very difficult to obtain.
Other modalities such as antipsychotics predispose to anticholinergic effects that are potentially additive to the most
severe risks of cocaine toxicity, namely hyperthermia, arrhythmia, and seizures. The last issue in the development of
new pharmaceuticals is their potentially exorbitant cost,
especially for enzymes or other complex proteins. Any new
antidotal therapy would have to be far more efficacious than
generic benzodiazepines and phentolamine to be a costeffective care strategy. Given these cost issues, clinical studies
proving efficacy will need to be powered to show superiority to
current treatment modalities, which will require more patients than studies performed to show noninferiority. Cocaine
toxicity remains a significant cause of death and permanent
disability. Cooling, high dose, rapid-acting benzodiazepines,
and adrenergic antagonists are the foundation of current
clinical management. Lipid emulsion has been effective in
managing refractory cases and may be an economical rescue
treatment of patients with severe cocaine toxicity. Experimental agents hold promise, although there are many issues
to contend with before these are available at the bedside.
These agents must not predispose the patient to arrhythmia
or interfere with normal neurotransmitter function. They also
need to be effective after a significant delay between cocaine
exposure and presentation. Immunogenicity must be minimal, as such critically ill patients would fare poorly with
additional anaphylactoid or anaphylactic reactions. Even
considering the significant and numerous hurdles, the ideal
agent may be on the horizon and for that we can wait and hope.
For now, years of treating cocaine toxicity have supported the
Would this vaccine be offered broadly or to those who abuse
and are psychologically addicted to cocaine? Could it become
mandated in some cases, and what effects would that have on
patient autonomy? Finally, there is the potential for riskier
behavior; some may try to overcome the vaccine with higher
doses whereas others may experiment with cocaine with the
perception that there is an easy and effective treatment
(Young et al., 2012). Significant more development of this
modality and the evaluation of bioethical issues surrounding
its use are required before this is a reasonable treatment
option.
Lipid Emulsion. Use of an intravenous 20% lipid emulsion was initially described as a rescue therapy for toxicity to
local anesthetics (Weinberg et al., 1998; Rosenblatt et al.,
2006), although it has now shown benefit in refractory cases of
various overdoses (Jamaty et al., 2010). Case reports describe
the effective use of intravenous lipid emulsion bolus followed
by infusion in patients with hemodynamic compromise secondary to cocaine toxicity (Jakkala-Saibaba et al., 2011; Arora
et al., 2013). The precise mechanism of lipid emulsion in
overdose is not fully elucidated. Theories including the formation of a “lipid sink” with sequestration of a lipophilic
xenobiotic, such as cocaine, in the plasma, creating a gradient
off the target organs and possibly enhancing elimination have
been proposed (Weinberg et al., 1998). The partition coefficient (log P) and the volume of distribution are properties
of chemicals found to be predictive of in vitro reductions of
drug concentrations after lipid emulsion treatment. The more
positive the log P and the greater the volume of distribution,
the more likely a drug is to be highly lipid soluble and
therefore more likely that lipid emulsion will be effective
(French et al., 2011). The distribution constant (log D)
correlates well with the log P and is a more precise estimate
of lipid solubility because it takes pH into account (Samuels
et al., 2012). Cocaine has a log D of 1.14 (Wilson et al., 2004)
and volume of distribution of 1.96 l/kg (Chow et al., 1985),
suggesting that lipid emulsion may be helpful in cases
refractory to conventional management. Additionally, lipid
emulsion is a component common in parenteral feeding preparations, is already present in many hospitals, and its cost is
almost negligible relative to innovative pharmaceuticals.
Although it has been used clinically, the paucity of evidence
precludes lipid emulsion from being considered a conventional
therapy, although its use is far more available to the clinician
at the bedside. Lipid emulsion treatment of toxic exposures is
in its infancy, and there remain significant questions regarding its efficacy and potential harm. Concerns include
impairment of therapeutic medications via the same mechanism as inactivation of the toxin [log D for diazepam and
midazolam is 3.86 and 3.68, respectively (Wilson et al., 2004)],
inducement of pancreatitis, and interference with the laboratory analysis of serum constituents such as lactate. Lipid emulsion remains an investigational final treatment option available
to providers when patients are acutely decompensating.
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safe and effective use of cooling and benzodiazepines in these
critically ill patients.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Connors,
Hoffman.
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Address correspondence to: Nicholas J. Connors, 455 First Ave, Room 123,
New York, NY 10016. E-mail: [email protected]

Perspectives in Pharmacology Experimental Treatments for Cocaine

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