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GAL‐160 is a potent orally bioavailable ventilatory stimulant in rats (873.3)
Author(s) -
Hewitt Matthew,
Gruber Ryan,
Ideo Courtney,
Puskovic Veljko,
Mardirosian Saro,
Peng Sean,
Golder Francis,
MacIntyre D
Publication year - 2014
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.28.1_supplement.873.3
Subject(s) - tidal volume , respiratory minute volume , pharmacodynamics , heart rate , anesthesia , respiratory rate , mean arterial pressure , pharmacokinetics , bioavailability , stimulant , bolus (digestion) , blood pressure , stimulation , respiratory system , plethysmograph , ventilation (architecture) , medicine , pharmacology , chemistry , endocrinology , mechanical engineering , engineering
GAL‐160 is a novel chemoreceptor modulator entering early clinical development as a therapeutic for sleep‐disordered breathing. Here, we describe GAL‐160’s properties as a ventilatory stimulant in rats. The effects of bolus GAL‐160 (0.01 – 10 mg/kg IV) on breathing, mean arterial pressure (MAP) and heart rate (HR, as inferred from pulse rate) were measured using whole‐body plethysmography and blood pressure telemetry in conscious rats. GAL‐160 dose‐dependently increased minute volume (Emax ~400% above baseline; ED 50 0.05 mg/kg) by increasing tidal volume and respiratory rate. At the highest dose tested, and in comparison to vehicle‐treated controls GAL‐160 produced no significant changes in mean arterial MAP (7.1 ± 2.3%) or HR (‐8.3 ± 5.7%). GAL‐160 (20 mg/kg PO) increased minute volume (Emax ~ 100% above vehicle) which remained elevated for up to 75 minutes post‐gavage with no effect on MAP (0.1 ± 0.5%) or HR (7.6 ± 0.7%) compared to vehicle. The pharmacokinetic‐pharmacodynamic relationship for GAL‐160 was evaluated following IV infusion and using changes in PaCO 2 as a marker for ventilatory stimulation. The GAL‐160 plasma concentration associated with a statistically significant reduction in PaCO 2 (10% decrease relative to baseline) was 380 ng/ml. Collectively, these data demonstrate that GAL‐160 is a potent, orally bioavailable ventilatory stimulant with negligible effects on cardiovascular function.