Nerve agent poisoning in primates: antilethal, anti-epileptic and neuroprotective effects of GK-11

 Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD₅₀) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. Received: 16 June 1997 / Accepted: 23 September 1997     

Altered Mental Status and End Organ Damage Associated with the use of Gacyclidine: A Case Series

Introduction

Over the past decade, there has been a sharp increase in the number of newly identified synthetic drugs. These new drugs are often derivatives of previously abused substances but have unpredictable toxicity. One of these drugs is gacyclidine, a derivative of phencyclidine (PCP). Gacyclidine has been studied as a neuroprotective agent in trauma and as a therapy of soman toxicity. There are no previous reports of its use as a drug of abuse.

Case Reports

During a two-month period in the summer of 2013, a series of patients with severe agitation and end-organ injury were identified in an urban academic Emergency Department (ED). A urine drug of abuse screen was performed on all patients, and serum samples were sent for comprehensive toxicology analysis. A total of five patients were identified as having agitation, rhabdomyolysis, and elevated troponin (Table 1). Three of the five patients reported use of methamphetamine, and all five patients had urine drug screens positive for amphetamine. Comprehensive serum analysis identified methamphetamine in three cases, cocaine metabolites in one case, and a potential untargeted match for gacyclidine in all five cases. No other drugs of abuse were identified.

Discussion

This is the first series of cases describing possible gacyclidine intoxication. The possible source of the gacyclidine is unknown but it may have been an adulterant in methamphetamine as all patients who were questioned reported methamphetamine use. These cases highlight the importance of screening for new drugs of abuse when patients present with atypical or severe symptoms. Gacyclidine has the potential to become a drug of abuse both by itself and in conjunction with other agents and toxicity from gacyclidine can be severe. It is the role of the medical toxicology field to identify new agents such as gacyclidine early and to attempt to educate the community on the dangers of these new drugs of abuse.     

Interaction of gacyclidine enantiomers with 'non-NMDA' binding sites in the rat central nervous system

Gacyclidine, a channel blocker of N-methyl-D-aspartate receptors (NMDAR), exhibits potent neuroprotective properties and a low self-neurotoxicity. Preventing its interaction with NMDARs we demonstrate, through the use of its enantiomers, that gacyclidine also interacts with other ('non-NMDA') binding sites. The autoradiographic study showed that these sites displayed a uniform specific binding in the forebrain and a more discrete distribution in the molecular layer of the cerebellum. The 'non-NMDA' binding sites could exert a modulatory control on glutamatergic neurotransmission.     

Binding properties of [H]gacyclidine (cis(pip/me)-1-[1-(2-thienyl)-2-methylcyclohexyl]piperidine) enantiomers in the rat central nervous system

Gacyclidine (cis(pip/me)-1-[1-(2-thienyl)-2-methylcyclohexyl]piperidine) is a TCP derivative, which exhibits potent neuroprotective properties against glutamate-induced neurotoxicity in vitro and in vivo. In order to better understand gacyclidine pharmacological properties, the binding parameters of its enantiomers ((−) and (+)[³H]GK11) were determined in the rat central nervous system (CNS). An autoradiographic study has shown that their binding distributions are correlated with those of N-methyl- -aspartate (NMDA) receptors throughout the CNS. Globally, the labeling was the highest with (−)[³H]GK11. In the cerebellum, both radioligands similarly labeled the molecular layer. For both radioligands, on telencephalic, cerebellum and spinal cord homogenates, the association and dissociation kinetics were accounted for by multiphasic process. In all regions, (−)[³H]GK11 exhibited the highest affinity in the nanomolar range. The pharmacological study revealed that both enantiomers labeled both high and low affinity sites in all regions. The pharmacological profile of high affinity sites was correlated with those of NMDA receptors. Those of low affinity sites were different in telencephalic and cerebellar homogenates. Overall, this study showed that low affinity sites might constitute a heterogeneous population, which could include σ receptors in the cerebellum. The autoradiographic study has shown that these sites may be located in the molecular layer. The contribution of low affinity sites to the neuroprotective properties of gacyclidine remains to be investigated.     

Neuroprotective effects of a novel NMDA antagonist, Gacyclidine, after experimental contusive spinal cord injury in adult rats

The aim of this study was to analyze the optimal time-window for neuroprotection by a novel NMDA antagonist, Gacyclidine, after experimental spinal cord injury, in terms of its functional, histopathological and electrophysiological effects. This molecule has already demonstrated its capacity for reducing the extent of an ischemic lesion and is currently experimented in a clinical trial of spinal cord injury. In this study, the spinal cord of rats was damaged by a contusive method and the animals were treated by saline or 1 mg/kg of Gacyclidine i.v., 10, 30, 60 and 120 min after injury. The time-course of the motor score was evaluated on days 1, 7 and 18 after injury, and somatosensory evoked potentials were determined on day 20. The animals were then killed and the cross-sectional area of the spinal cord (at the epicenter of the injury, above and below the injury), was measured. Walking recovery was better (P<0.0125) in the group treated 10 min after injury than in the untreated injured animals after 18 days of injury. Motor performances were related to the preservation of a larger undamaged area of spinal cord at the level of the injury (P<0.0125). Somatosensory evoked potential amplitudes were also higher in this group. These results confirm that Gacyclidine attenuates spinal cord damage after an experimental spinal cord lesion. Recovery was better within the group treated 10 min after injury compared with the other groups, which certainly confirms that the acute time-course of glutamate release requires rapid pharmacological intervention to achieve good results.     

Acute soman poisoning in primates neither pretreated nor receiving immediate therapy: value of gacyclidine (GK-11) in delayed medical support

Organophosphorus (OP) nerve agents are still used as warfare and terrorism compounds. Classical delayed treatment of victims of organophosphate poisoning includes combined i.v. administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the above therapy against organophosphate poisoning. Gacyclidine was injected (i.v.) in combination with atropine/diazepam/pralidoxime at man-equivalent doses after a 45- or 30-min latency period to intoxicated primates (2 LD₅₀). The effects of gacyclidine on the animals' survival, electroencephalographic (EEG) activity, signs of toxicity, recovery after challenge and central nervous system histology were examined. The present data demonstrated that atropine/diazepam/pralidoxime alone or combined with gacyclidine did not prevent signs of soman toxicity when treatment was delayed 45 min after poisoning. Atropine/diazepam/pralidoxime also did not control seizures or prevent neuropathology in primates exhibiting severe signs of poisoning when treatment was commenced 30 min after intoxication. However, in this latter case, EEG recordings revealed that additional treatment with gacyclidine was able to stop soman-induced seizures and restore normal EEG activity. This drug also totally prevented the neuropathology observed 5 weeks after soman exposure in animals treated with atropine/diazepam/pralidoxime alone. Overall, in the case of severe OP-poisoning, gacyclidine represents a promising adjuvant therapy to the currently available polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. However, it should always be kept in mind that, in the case of severe OP-poisoning, medical intervention must be conducted as early as possible. Received: 30 November 1998 / Accepted: 12 January 1999     

Update On Pharmaceutical Trials In Acute Spinal Cord Injury

Abstract

Objective: To review the major pharmacological trials in acute spinal cord injury (SCI) that have been conducted over the past 25 years.

Methods: Review article.

Results: The publication of the firstNational Acute Spinal Cord lnjury (NASCIS) trial in 1 9 84 ushered in the era of pharmacological tri als of therapies intended to improve neurologic outcome in acute SC I. Subsequent trials of methylprednisolone sodium succinate (MPSS) and GM-1 have added to the evidence basis that informs the current management practices for acute SCI.

Conclusion: The last 50 years have seen a conceptual shift from the pessimism of the past to a cautious optimism that the meager prognosis for neurologic recovery in acute SCI will yield to the progress of medical science. Major advances in the understanding of primary and secondary injury mechanisms have led to the preclinical study of many promising pharmacological therapies, all with the goal of improving neurologic outcome. A few of these drugs have stood the test of animal model experiments and have made it to the forum of human clinical tri als. The NASCIS tri als of methylprednisolone have been acknowledged widely as the firsthuman studies to claim improved neurologic outcome. Although the results of these trials remain controversial, the MPSS therapy that they reported has been adopted widely by clinicians around the world as the best currently available, even if not a consensus “standard of care.” Clearly, the challenge for medical science remains. The search for effective treatment has only begun.

J Spinal Cord Med. 2004;27:319-–325