cx717 and Respiratory-Insufficiency

Ventilatory depression is a significant risk associated with the use of opioids. We assessed whether opioid-induced ventilatory depression can be selectively antagonized by an ampakine without reduction of analgesia. In 16 healthy men, after a single oral dose of 1,500 mg of the ampakine CX717, a target concentration of 100 ng/ml alfentanil decreased the respiratory frequency by only 2.9 +/- 33.4% as compared with 25.6 +/- 27.9% during placebo coadministration (P < 0.01).Blood oxygenation and the ventilatory response to hypercapnic challenge also showed significantly smaller decreases with CX717 than with placebo. In contrast, CX717 did not affect alfentanil-induced analgesia in either electrical or heat-based experimental models of pain. Both ventilatory depression and analgesia were reversed with 1.6 mg of naloxone. These results support the use of ampakines as selective antidotes in humans to counter opioid-induced ventilatory depression without affecting opioid-mediated analgesia.

Topics: Administration, Oral; Adult; Alfentanil; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Humans; Hypercapnia; Isoxazoles; Male; Naloxone; Narcotic Antagonists; Oxygen; Pain; Respiratory Insufficiency; Young Adult

Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol's disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea.. The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem-spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heart-brainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats.. In vitro, respiratory depression caused by propofol (2 μM, n = 11, mean ± SEM, 41 ± 5% of control frequency, 63 ± 5% of control duration) was alleviated by CX717 (n = 4, 50-150 μM). In situ, a decrease in respiratory frequency (44 ± 9% of control), phrenic burst duration (66 ± 7% of control), and amplitude (78 ± 5% of control) caused by propofol (2 μM, n = 5) was alleviated by coadministration of CX717 (50 μM, n = 5). In vivo, pre- or coadministration of CX717 (20-25mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20mg/kg) and propofol-induced lethal apnea (n = 6; 30 mg/kg).. Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death.

Topics: Anesthetics, Intravenous; Animals; Animals, Newborn; Apnea; Disease Models, Animal; Drug Therapy, Combination; Isoxazoles; Male; Mice; Plethysmography; Propofol; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency

Topics: Anesthetics, Intravenous; Animals; Apnea; Isoxazoles; Male; Propofol; Respiratory Insufficiency

Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive/synergistic actions were unresolved. Current management of ethanol-barbiturate-induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression, we hypothesized that ampakine compounds may provide a treatment for other types of drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline, and the ampakine CX717, alone and in combination, were measured via 1) ventral root recordings from newborn rat brain stem-spinal cord preparations and 2) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g/kg ip). Pentobarbital induced an ∼50% reduction in respiratory frequency in vitro (50 μM) and in vivo (28 mg/kg for pups and 56 mg/kg for adult rats ip). However, severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABA(A) receptors, which was exacerbated by hypoxic (8% O(2)) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50-150 μM) and in vivo (30 mg/kg ip). Bicuculline also alleviated ethanol-/pentobarbital-induced respiratory depression but caused seizure activity, whereas CX717 did not. These data demonstrated that ethanol and pentobarbital together caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia and hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression.

Topics: Animals; Apnea; Barbiturates; Brain Stem; Ethanol; Hypercapnia; Hypoxia; Isoxazoles; Male; Oxygen; Plethysmography; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Respiratory Insufficiency; Spinal Cord

Opioid analgesics are the most widely used and effective pharmacological agents for the treatment of acute, postoperative and chronic pain. However, activation of opiate receptors leads to significant depression of respiratory frequency in a subpopulation of patients. Here we test the hypothesis that the AMPAKINE CX717 is effective for alleviating fentanyl-induced respiratory depression without interfering with analgesia. Ampakines are a relatively new class of compounds that are in Phase II clinical trials as potential treatments for cognitive disorders and the enhancement of memory and attentiveness. They function by allosterically binding to amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPA)-type glutamate receptors and modulating the kinetics of channel closing, transmitter dissociation and desensitization. AMPA receptor mediated conductances play a central role in controlling respiratory rhythmogenesis and drive to motoneurons. Here, we demonstrate that CX717 counters fentanyl-induced respiratory depression without significantly altering analgesia and sedation, or noticeably affecting the animals' behavior. Collectively, the preclinical data demonstrate the significant potential for the use of ampakines in respiratory medicine.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Drug Administration Schedule; Fentanyl; Heart Rate; Hyperalgesia; Isoxazoles; Male; Pain Measurement; Phrenic Nerve; Plethysmography; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, AMPA; Respiratory Insufficiency; Time Factors