Ziprasidone, Diazepam, or the Combination for Prevention of Cocaine Toxicity in a Mouse Model

Abstract

This study suggests that diazepam and ziprasidone have efficacy for preventing lethality from cocaine poisoning in an animal model but that the combination offers little addition to either therapy alone. However, the combination may be more effective for prevention of cocaine-induced seizures.

Experimental Treatments for Cocaine Toxicity: A Difficult Transition to the Bedside

“…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).…”

Mechanisms of Acute Cocaine Toxicity

“…They bind to a unique allosteric site on the GABA A receptor and increase the frequency of GABA-mediated chloride channel opening and GABAergic inhibitory neurotransmission. There are at least six rodent studies that support their use for treatment of cocaine poisoning [78][79][80][81][82][83]. One studied reported a non-significant trend toward increased survival and a marked decrease in seizures [78], while others have reported decreased mortality without a change in the proportion of animals that have cocaine-induced seizures [82,84].…”

“…For example, patients have been resuscitated from severe cocaine toxicity using a combination of benzodiazepines to treat CNS toxicity and sodium bicarbonate to reverse antagonism of sodium channels [75,76]. The combination of diazepam and ziprasidone dramatically decreases the incidence of seizures compared to either treatment alone [83]. Benzodiazepines act on GABA while ziprasidone block dopaminergic and serotonergic receptors.…”

Presumptive cocaine toxicosis in 19 dogs: 2004–2012

“…Diazepam has been shown to decrease the risk of seizures, and may attenuate adverse cardiovascular signs by reducing central stimulation. 28,38 Both of the dogs with refractory seizures were sedated with propofol. However, IV levetiracetam r has since become available, and is a safe, effective, rapidly acting parenteral anticonvulsant that is thought to directly modulate release of neurotransmitters and thus may be particularly useful in these patients.…”