, 2006). Given that therapeutic plasma concentration of doxapram is in the order of 4–5 μM (see below), these studies suggest that doxapram may increase ventilatory drive via inhibition of TASK channels and to a lesser extent the BK channel. The effects of almitrine on ionic currents from isolated rat type 1 glomus cells have been reported (Lopez-Lopez et al., 1998 and Peers and O’Donnell, 1990). Almitrine inhibits BK currents (IC50 ∼ 200 nM) without altering voltage Rigosertib datasheet dependent K+, Na+, or calcium currents. To our knowledge, the effect of almitrine on TASK channels has not been tested. Doxapram was first identified as an analeptic agent with ventilatory

stimulant properties in the 1960s (Ward and Franko, 1962) and AG-014699 manufacturer was used clinically for more than

40 years. In recent years, the use of doxapram has declined considerably due to its side-effect profile that includes hypertension, anxiogenesis, and dyspnea (see below). Doxapram (Dopram®) is still licensed for human use with three primary indications (as per the Dopram package insert, FDA.gov, 2013): (1) to stimulate respiration in the postoperative patient and in patients with drug-induced post-anesthesia respiratory depression or apnea, (2) to stimulate respiration, hasten arousal, and return airway protective reflexes in patients with respiratory and CNS depression due to drug overdosage, and (3) to stimulate respiration in chronic pulmonary disease patients with acute respiratory insufficiency. Doxapram also is used off-label to decrease post-operative shivering in adults (Singh et al., 1993), though this effect may be minimal (Komatsu et al., 2005), and apnea of prematurity in human neonates

Epothilone B (EPO906, Patupilone) (Bairam et al., 1992). In veterinary medicine, doxapram is licensed for use in dogs, cats and horses (Dopram-V®, Respiram®), and is used off-license in other species. In animals, doxapram is primarily used to stimulate respiration and speed awakening after general anesthesia, diagnose laryngeal paralysis, and initiate and stimulate respiration in neonates following cesarean section or dystocia. However, in both human and veterinary medicine, the need for an analeptic to hasten arousal from anesthesia has declined considerably because of the introduction of shorter-acting anesthetic agents (e.g., sevoflurane and propofol). Doxapram elicits respiratory stimulation as evidenced by increased minute volume ( V˙E) in a broad range of species (Bairam et al., 1990, Bleul et al., 2010, Bleul and Bylang, 2012, Burki, 1984, Calverley et al., 1983, Forster et al., 1976, Gregoretti and Pleuvry, 1977, Khanna and Pleuvry, 1978, Murphy et al., 2010 and Wilkinson et al., 2010). The increase in V˙E is predominantly due to an increase in tidal volume (V  T) with little effect on respiratory rate (RR), although a few studies report an increase in both.