Novel Compounds May Help Protect Against Respiratory Depression
Source Newsroom: Cortex Pharmaceuticals
Newswise — A paper that appears in the June 2009 issue of Anesthesiology details how AMPAKINE CX717, a Phase II compound created by Irvine, California-based neuroscience company Cortex Pharmaceuticals, demonstrated the rescue of fentanyl-induced respiratory depression and sleep apnea in rats. In this same study, CX717 demonstrated equal efficacy with the opioid antagonist Naloxone, a drug used to counter the effects of opioids on suppression of breathing. CX717 did not, however, interfere with the action of pain-killing opiates. This offers a distinct advantage compared with Naloxone and could provide a novel therapeutic means of treating those patients who are particularly prone to breathing depression with opiates while achieving maximum pain relief.
"The paper focuses on how CX717 enhances the safety of opiate analgesic use during surgery," explains University of Alberta professor Dr. John J. Greer, who led the animal study. "Patients are usually given an opiate to mediate pain during surgery. Typically, opiates cause respiratory depression in about ten to fifteen percent of patients, which is usually countered by decreasing the amount of opiate. The problem then becomes patients awakening from surgery into pain. The study's hypothesis was that the AMPAKINE molecule can stimulate breathing without interfering with the ameliorative effects of analgesics."
AMPAKINE compounds act on the most common excitatory receptor in the brain, the AMPA-type glutamate receptor. Dr. Greer's research team demonstrated that certain AMPAKINE compounds stimulate primitive areas of the brain called the pre-Botzinger Complex that controls breathing, without causing side effects. In animal models, the compounds were shown to enhance the respiratory drive and breathing rhythm in laboratory rats whose respiration rates were purposely suppressed by administration of central nervous system depressants.
"We tested this hypothesis with adult Sprague-Dawley rats, which were given the potent opioid fentanyl," Dr. Greer explains. "When these rats were administered AMPAKINE CX717 after taking the opiate, their breathing came back very strong. During the study, CX717 was shown not only to protect breathing rates; it also demonstrated the potential to prevent upper airways from collapsing. We then co-administered the AMPAKINE with the opiate as a cocktail, and found that the rats did not experience respiratory depression."
These results suggest that high-risk post-operative surgical patients, including people sixty-five years and older, those suffering from a history of sleep apnea, patients struggling with obesity, those with a history of respiratory disease such as Chronic Obstructive Pulmonary Disease (COPD), and patients on a regimen of heavy background opiates for the treatment of chronic pain, might be given AMPAKINE preemptively in order to reduce the risk of respiratory depression during surgery.
"CX717 appears to allow clinicians to reduce the incidents of respiratory depression during surgery in some cases, and, in other cases, be used as a rescue for people overdosing on opiates," says Dr. Greer. "CX717 also generalized across families of drugs not limited to opioids. Combinations of alcohol and barbiturates can cause severe instances of respiratory depression, and CX717 was shown to work in these cases as well. This may lead the way in turning these compounds into rescue therapies."
These animal studies were later replicated in two Phase II respiratory depression clinical studies involving forty human volunteers in Germany. The next step will be the development of CX717 in intravenous form, with repeated Phase II tests in human trials via intravenous dosing.
"These advances will help patients whose pain cannot be treated effectively with opioids due to the unwanted side effect of a depression of breathing," says Dr. Greer. "Administration of AMPAKINE compounds can overcome this problem and lead to a significant improvement in pain management, as well as guard against deaths caused by opioid overdose."
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