), a BK channel blocker, is currently in early clinical trials. GAL-021 is a new chemical entity designed based on our understanding of the structure–activity relationship and structure-tolerability limitations of almitrine. GAL-021 does not contain the fluorinated piperazine ring, which causes lipidosis in dorsal root ganglia in rat leading to peripheral neuropathy and hindlimb dysfunction (Yamanaka et al., 1997). GAL-021 was extensively profiled in mice, rats, dogs, and cynomolgus monkeys preclinically. In brief, GAL-021 stimulates ventilation and attenuates opiate-induced respiratory depression but not morphine analgesia (Baby et al.,

2012a and Golder et al., 2012d). GAL-021 also reverses drug-induced respiratory depression elicited by isoflurane, propofol, and midazolam (Galleon Pharmaceuticals, unpublished data). Ventilatory stimulation is accompanied by enhanced carotid sinus Alectinib supplier nerve afferent and phrenic nerve efferent activity (Baby et al., 2012b). Carotid sinus nerve transection almost completely abolishes (∼85% reduction) GAL-021-induced respiratory stimulation (Baby et al., 2012b). The residual stimulation was blocked when the cervical vagi were transected in addition

to the carotid sinus nerve (Galleon Pharmaceuticals, unpublished data). Thus, some of the effects of GAL-021 on ventilation are mediated from other peripheral sites, most likely aortic chemoreceptors. In healthy human subjects, GAL-021 administration caused statistically significant increases in V˙E (AUE0–1 h) with reciprocal suppression of ETCO2 during 1-h continuous infusions. The BMS-777607 manufacturer half-maximal effect on V˙E and ETCO2 occurred rapidly (<10 min). Drug concentration rose rapidly during the infusion and declined rapidly initially with a distribution t1/2 of 30 min and then more slowly with a terminal Dapagliflozin t1/2 of 5–7 h. Thus, in humans GAL-021 has pharmacodynamic and pharmacokinetic

characteristics consistent with an acute care medication. A Proof-of-Concept study using opioids in a hypercapnic clamp setting is on-going in humans to determine the clinical utility of GAL-021 and to validate the BK channel as a therapeutic target. Further clinical development with phase 2 studies in patients with post-operative respiratory depression is planned for late 2014. It is clear that there is an unmet medical need for a safe and effective respiratory stimulant, especially during sleep, in post-operative patients receiving potent respiratory depressants. Doxapram and almitrine illustrates the potential utility of a carotid body stimulant in the treatment of drug-induced respiratory depression, and possibly exacerbated sleep disordered breathing in the perioperative setting. However, the widespread use of both drugs is limited by their side effect profiles and toxicities. In the case of doxapram, the primary limitation is in its pressor effects.