title: Two studies on reversal of opioid-induced respiratory depression by BK-channel blocker GAL021 in human volunteers.
abstract: BACKGROUND
  Opioid-induced respiratory depression is potentially lethal. GAL021 is a calcium-activated potassium (BKCa) channel blocker that causes reversal of opioid-induced respiratory depression in animals due to a stimulatory effect on ventilation at the carotid bodies. To assess in humans whether GAL021 stimulates breathing in established opioid-induced respiratory depression and to evaluate its safety, a proof-of-concept double-blind randomized controlled crossover study on isohypercapnic ventilation (study 1) and subsequent double-blind exploratory study on poikilocapnic ventilation and nonrespiratory end points (study 2) was performed.
  
  
  METHODS
  In study 1, intravenous low- and high-dose GAL021 and placebo were administrated on top of low- and high-dose alfentanil-induced respiratory depression in 12 healthy male volunteers on two separate occasions. In study 2, the effect of GAL021/placebo on poikilocapnic ventilation, analgesia, and sedation were explored in eight male volunteers. Data are mean difference between GAL021 and placebo (95% CI).
  
  
  RESULTS
  Study 1: Under isohypercapnic conditions, a separation between GAL021 and placebo on minute ventilation was observed by 6.1 (3.6 to 8.6) l/min (P < 0.01) and 3.6 (1.5 to 5.7) l/min (P < 0.01) at low-dose alfentanil plus high-dose GAL021 and high-dose-alfentanil plus high-dose GAL021, respectively. Study 2: Similar observations were made on poikilocapnic ventilation and arterial pCO2. GAL021 had no effect on alfentanil-induced sedation, antinociception and no safety issues or hemodynamic effects became apparent.
  
  
  CONCLUSIONS
  GAL021 produces respiratory stimulatory effects during opioid-induced respiratory depression with containment of opioid-analgesia and without any further increase of sedation. Further studies are needed to confirm these preliminary data.
authors.affiliation: From the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands (A.D., M.R., R.v.d.S.); Centre for Human Drug Research, Leiden, The Netherlands (P.O., J.H.); and Galleon Pharmaceuticals Corp., Horsham, Pennsylvania (J.F.M.).
authors.forename: Margot
authors.initials: M
authors.lastname: Roozekrans
authors.forename: Rutger
authors.initials: R
authors.lastname: van der Schrier
authors.forename: Pieter
authors.initials: P
authors.lastname: Okkerse
authors.forename: Justin
authors.initials: J
authors.lastname: Hay
authors.forename: James F
authors.initials: JF
authors.lastname: McLeod
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000293:Adolescent; D000328:Adult; D015760:Alfentanil / Q000009:adverse effects / Q000627:therapeutic use; D000698:Analgesia; D000701:Analgesics, Opioid / Q000009:adverse effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004315:Doxapram / Q000627:therapeutic use; D064368:Healthy Volunteers; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000188:drug therapy; D014227:Triazines / Q000627:therapeutic use*
chemical_list: D000701:Analgesics, Opioid; D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D014227:Triazines; D015760:Alfentanil; C000593146:GAL021; D004315:Doxapram