AMPAKINE drugs may provide protection from drug-induced respiratory depression

Jun 5 2007

Drug-induced respiratory depression is a life-threatening condition caused by analgesic, hypnotic, and anesthesia medications.

Although it is a leading cause of death from the overdose of some classes of abused drugs, respiratory depression also arises during normal, physician-supervised procedures such as surgical anesthesia, post-operative analgesia, and as a result of normal out-patient management of pain from cancer, accidents, or illnesses.

The majority of adverse events occurring with these drugs take place during the dose adjustment period, when two or more central nervous depressants are taken together, or when patients take prescribed drugs in ways not intended by their physician.

Although only 0.5%-1.2% of total adverse drug events caused by prescription medications are respiratory in nature, these serious side effects account for 25%-30% of drug-induced deaths. Opiates and barbiturates are the primary drugs classes responsible for these effects. Opiates include the standard pain-killing drugs morphine, fentanyl, and codeine, as well as related products vicodin, hydrocodone, and oxycontin. Barbituates comprise the sedative drugs amobarbital, aprobarbital, butabarbital, pentobarbital, and others. Sleeping disorders are another common predisposing factor for respiratory depression, in this case known as sleep apnea.

Currently, the only way to counter opiate-induced respiratory depression is to administer opiate receptor antagonists, drugs that block the effectiveness of opiate analgesia. While this approach may prevent a serious side effect or even death, it dramatically reduces the effectiveness of drugs administered for management of severe pain.

Researchers at the University of Alberta (Edmonton, AB) and Cortex Pharmaceuticals (Irvine, CA) believe that AMPAKINE drugs may provide protection from drug-induced respiratory depression, while simultaneously allowing the sedative or analgesic to continue working as it was intended.

The drug tested in this study belongs to a novel class of molecules known as AMPAKINE compounds being developed by Cortex Pharmaceuticals, Inc. located in Irvine, California. AMPAKINE compounds act on the most common excitatory receptor in the brain, the AMPA "Glutamate type receptor," which has been shown in rodent models to boost the brain's own protein for improving age-related deficits in memory mechanisms. In primate models AMPAKINE compounds have replicated the studies in rodents and in adults patients suffering from Attention Deficit Hyperactivity Disorder, significant clinical and statistical improvement in increase attention and decrease hyperactivity have been observed. The U. Alberta research provide evidence that another important AMPAKINE indication is to stimulate primitive areas of the brain called the pre-Botzinger Complex responsible for breathing, without causing side effects. The pre-Botzinger Complex generated respiratory-related oscillations similar to those generated by the whole brainstem in vitro, and neurons with voltage-dependent pacemaker-like properties that have been identified in this brain region.

In a study published in 2006, Dr. John J. Greer of U. Alberta demonstrated that certain AMPAKINE compounds enhance the respiratory drive and breathing rhythm at the brain-stem level containing the pre-Botzinger Complex in laboratory rats whose respiration rates were purposely suppressed by administration of central nervous system depressants.

Dr. Greer found that respiratory depression induced by these agents can be reversed or prevented in test animals with an experimental AMPAKINE drug, without a reduction of pain relief or sedation.

Greer and coworkers treated rats with the opioids analgesic fentanyl or the barbiturate sedative Phenobarbital, both commonly prescribed in the United States. Greer used a technique known as plethysmography, which measures blood flow throughout the body, to determine the level of respiratory distressed caused by the drugs. When drugged rats were treated with the AMPAKINE , the respiratory distress quickly resolved. The drug worked in both newborn and adult rats. Interestingly, the drug on its own did not affect blood flow in animals not treated with the sedative drugs, nor did administration of the drug cause noticeable arousal in the animals.

Greer concluded, in a study published in the September 20, 2006 issue of the American Journal of Respiratory Critical Care Medicine, that CX546, "effectively reverses opioid- and barbiturate-induced respiratory depression without reversing the analgesic response."

"These results open up the real possibility of combining an ampakine compound with commonly prescribed barbiturates or opiates to reduce the likelihood that life-threatening respiratory depression will occur," noted explained Roger G. Stoll, Ph.D., Chairman, President, and CEO of Cortex.

Cortex Pharmaceuticals has entered into a Patent Licensing Agreement with the University of Alberta for this new respiratory application for the use of AMPAKINE compounds. Under terms of the license Cortex will evaluate a number of novel low and high impact AMPAKINE compounds for a range of new respiratory applications, such as, respiratory depression induced by opiates and barbiturates to start and others to be named at a future time. In return, Cortex will provide the University with an undisclosed upfront payment, milestone compensation, and royalties from the commercialization of specific AMPAKINE drugs approved for any therapeutic and/or prophylactic indication associated with respiratory depression . Dr. Greer, who has successfully filed a patent for the use of AMPAKINE drugs for these respiratory indications, will receive multiple years of research support funding from Cortex.

Cortex focuses on novel drug therapies for neurological and psychiatric disorders. Its lead compounds belong to two classes of ampakines, which act on the brain's AMPA receptor. Approximately 85% of neurons that handle brain electrical activity do so through this receptor, which controls traffic of the neurotransmitter glutamate. Ampakine molecules bind to the AMPA receptor, causing its glutamate channel to remain open for a longer time period, thereby allowing more glutamate to enter the cell. As a result, ampakines cause amplification of signals at connections between brain cells.

The loss of these connections may be, in part, responsible for memory and behavior problems in Alzheimer's disease, neurological disorders, and even aging. Research data suggests that ampakine molecules may improve neurotransmitter deficiencies implicated in schizophrenia, Huntington's disease, fragile X syndrome, and Rhett's syndrome.

Cortex is developing two classes of AMPAKINE drugs: Low and High impact compounds. , CX717 is an example of a Low impact AMPAKINE drugs, which is currently in human clinical trials, and high-impact molecules which are currently in lead optimization and are currently being tested in transgenic animal models for a variety of neurodegenerative diseases . The two classes of AMPAKINE drugs operate at different binding sites on the AMPA_type glutamate receptor.

Cortex has partnered with several leading pharmaceutical companies for specific therapeutic applications of ampakines. The company has an alliance with Organon Biosciences (soon to be part of Schering-Plough) for AMPAKINE -based treatment of schizophrenia and depression, and with Les Laboratoires Servier.

The study of AMPAKINE drugs in respiratory depression opens a new chapter in the development of this class of therapeutics, and a potentially significant breakthrough in how medication for pain, analgesia, and sedation are used. "Ampakines may allow for improved safety and a more effective use of opiate analgesics and barbiturate sedatives," Dr. Stoll of Cortex observes, "two important classes of central nervous system drugs."