title: GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers.
abstract: BACKGROUND
  Potassium-channels in the carotid body and the brainstem are important regulators of ventilation. The BKCa-channel contains response elements for CO, O2, and CO2. Its block increases carotid body signalling, phrenic nerve activity, and respiratory drive. GAL-021, a new BKCa-channel blocker, increases minute ventilation in rats and non-human primates. This study assessed the single-dose safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GAL-021 in healthy volunteers.
  
  
  METHODS
  Thirty subjects participated in a nine-period, randomized, double-blinded, placebo-controlled, crossover, ascending dose, first-in-human study with i.v. infusions of 0.1-0.96 mg kg(-1) h(-1) for 1 h and intermediate doses up to 4 h.
  
  
  RESULTS
  Adverse event rates were generally similar among dose levels and between placebo- and GAL-021-treated subjects. At higher GAL-021 doses, a mild/moderate burning sensation at the infusion site occurred during the infusion. No clinically significant changes in vital signs or clinical chemistries were noted. Minute ventilation increased (AUE0-1 h ≈ 16%, P<0.05) and end-tidal carbon dioxide ([Formula: see text]) decreased (AUE0-1 h ≈ 6%, P<0.05) during the first hour at 0.96 mg kg(-1) h(-1) with 1/2-maximal [Formula: see text] and [Formula: see text]-change occurring by 7.5 min. Drug concentration rose rapidly during the infusion and decreased rapidly initially (distribution t1/2 of 30 min) and then more slowly (terminal t1/2 of 5.6 h).
  
  
  CONCLUSIONS
  GAL-021 was safe and generally well tolerated with adverse events comparable with placebo except for an infusion site burning sensation. GAL-021 stimulated ventilation at the highest doses suggesting that greater infusion rates may be required for maximum PD effects. GAL-021 had PK characteristics consistent with an acute care medication.
authors.affiliation: Galleon Pharmaceuticals Corporation, 213 Witmer Road, Horsham, PA 19044, USA jmcleod@galleonpharma.com james@mcleod.bz.
authors.forename: J F
authors.initials: JF
authors.lastname: McLeod
authors.affiliation: SGS Life Science Services, Lange Beeldekensstraat 267, Antwerpen B-2060, Belgium.
authors.forename: J M
authors.initials: JM
authors.lastname: Leempoels
authors.affiliation: Galleon Pharmaceuticals Corporation, 213 Witmer Road, Horsham, PA 19044, USA.
authors.forename: S X
authors.initials: SX
authors.lastname: Peng
authors.affiliation: Galleon Pharmaceuticals Corporation, 213 Witmer Road, Horsham, PA 19044, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Dax
authors.affiliation: Vivonoetics, 27 Dorian, Newport Coast, CA, 92657, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Myers
authors.affiliation: Galleon Pharmaceuticals Corporation, 213 Witmer Road, Horsham, PA 19044, USA.
authors.forename: F J
authors.initials: FJ
authors.lastname: Golder
mesh_terms: D000328:Adult; D002245:Carbon Dioxide / Q000097:blood; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors*; D008297:Male; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D015656:Respiratory Mechanics / Q000187:drug effects; D014227:Triazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D026902:Potassium Channel Blockers; D014227:Triazines; D002245:Carbon Dioxide; C000593146:GAL021
keywords: BKCa channel; EudraCT: 2011-003371-11; KCNMA1; breathing; carotid body; pharmacokinetics; potassium channel; respiratory stimulant; ventilatory function