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GAL‐021 acts as a novel respiratory stimulant in non‐human primates
Author(s) -
Golder Francis John,
Wardle Robert L,
Van Scott Michael R,
Hoskins Paul A,
Dax Scott L,
Peng Sean,
MacIntyre D Euan,
Mannion James C
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.704.27
Subject(s) - morphine , opioid , anesthesia , medicine , respiratory system , respiration , bolus (digestion) , isoflurane , respiratory minute volume , ketamine , tidal volume , pharmacology , receptor , anatomy
Opioid‐induced respiratory depression (OIRD) is a common side effect of opioid‐induced analgesia and can be life‐threatening, especially during the perioperative period and sleep. Current therapy for OIRD includes administering opioid antagonists and/or decreasing subsequent opioid doses, both of which can compromise analgesia. We have demonstrated that GAL‐021, a novel respiratory stimulant, increases minute ventilation (Vmin) and reverses OIRD in rats, without diminishing opioid‐induced analgesia. Here, we describe the effects of GAL‐021 in Cynomolgus monkeys. In isoflurane‐anesthetized opioid‐naïve monkeys, GAL‐021 administered by IV bolus (0.01 – 0.3 mg/kg) or infusion (0.02 – 0.1 mg/kg/min) increased Vmin, tidal volume, and respiratory frequency. In conscious animals, OIRD was induced by morphine (2.4 – 3.2 mg/kg, slow IV bolus), titrated in each animal to decrease Vmin by 20 to 30% and increase ETCO 2 by 10 mmHg. Administration of GAL‐021 15‐min post‐morphine diminished OIRD in a dose‐dependent manner. Loading GAL‐021 at 0.1 mg/kg/min × 5 min and maintaining infusion at 0.05 mg/kg/min × 10 min reduced OIRD by 75%. In contrast, loading at 0.2 mg/kg/min × 5 min and maintaining infusion at 0.1 mg/kg/min × 10 min returned ETCO 2 to pre‐morphine levels. These data demonstrate that GAL‐021 stimulates respiration in conscious and anesthetized monkeys and is capable of reversing OIRD in non‐human primates.