Session Speaker

Development of AMPAKINE Therapy to Alleviate Drug-Induced Respiratory Depression
John J. Greer
Canada

AHFMR Scientist, Professor, Department of Physiology, Centre for Neuroscience, University of Alberta, Edmonton, AB, Canada. john.greer@ualberta.ca
Suppression of central respiratory drive by opiate analgesics, anaesthetics and drugs of substance abuse are a clinical problem. A pharmacological approach to alleviate respiratory depression without loss of analgesia and sedation is an unmet clinical need. Based on the past identification of glutamatergic mediated drive via AMPA receptors as being critical for driving respiratory rhythmogenesis (Greer et al., 1992), I hypothesized that AMPAKINES would be a potential therapy for respiratory depression. AMPAKINES are a class of compounds being investigated as a novel approach for treating psychiatric and neurological disorders (www.cortexpharm.com). They function by allosterically binding to AMPA-type glutamate receptors and modulating the kinetics of deactivation, transmitter dissociation and desensitization. We performed a comprehensive series of studies examining the efficacy of AMPAKINES in countering opiate-induced respiratory depression using in vitro and in vivo rodent models, including mechanistic studies at the neuronal level with whole-cell patch recordings. Those data demonstrate that AMPAKINES are very effective in countering respiratory depression induced by ?-opiate receptor agonists. Further, we extended the rodent studies to demonstrate that AMPAKINES reduce respiratory depression induced by propofol or a mixture of alcohol and barbiturates. Importantly, AMPAKINES counter drug-induced respiratory depression without significantly altering the baseline frequency or amplitude of breathing under control conditions, the inhibition of analgesia and sedation, or noticeably affecting the animals’ behavior. The pre pre-clinical data on opiates provided the basis for a subsequent Phase IIA clinical trial that clearly demonstrated that the AMPAKINE CX717 countered alfentanil-induced respiratory depression without altering analgesia in human subjects (Oertel et al., 2009). In summary, data from a series of preclinical studies in conjunction with an early phase clinical trial demonstrate the significant potential for the use of AMPAKINES in respiratory medicine.


References

1. Greer JJ, Smith JC, Feldman JL. The role of excitatory amino acids in the generation and transmission of respiratory drive in the neonatal rat. J Physiol 1991; 437:727-749.

2. Oertel, B.G., Felden, L., Tran, P.V., Bradshaw, M., Angst, M.S., Schmidt, H., Johnson, S., Greer, J.J., Geisslinger, G, Varney, M.A. and Lotsch, J. (2009). Selective antagonism of opioid-induced respiratory depression by an AMPAKINE molecule in humans without loss of opioid analgesia. Clin Pharmacol Ther. In press

3. Ren, J., Poon, B.Y., Tang Y, Funk, G.D. and Greer, J.J. (2006) Ampakines alleviate respiratory depression in rats. American Journal of Respiratory and Critical Care Medicine. 174: 1384-1391

4. Ren, J., Ding, X., Funk, G.D. and Greer J.J. (2009) Ampakine CX717 protects against fentanyl-induced respiratory depression and lethal apnea in rats. Anesthesiology. 110(6):1364-70.