Some special respiratory effects of CO2 in pigeons

Injections of CO₂-gas have been made into an abdominal air-sac of pigeons. The resulting alterations of respiratory rate and of breathing efforts are dose-dependent and easily reproducible. The receptive zones for these effects do not seem to be located in the air-way system itself; they may be in the respiratory center.Some data provide further evidence for the assumption that the ventilation of the abdominal air-sacs is mainly one-directional, from outside to gas-exchange compartments.Panting increases the ventilation of the abdominal air-sacs.     

Pre-operative gastric ultrasound in patients at risk of pulmonary aspiration: a prospective observational cohort study

Point-of-care gastric sonography offers an objective approach to assessing individual pulmonary aspiration risk before induction of general anaesthesia. We aimed to evaluate the potential impact of routine pre-operative gastric ultrasound on peri-operative management in a cohort of adult patients undergoing elective or emergency surgery at a single centre. According to pre-operative gastric ultrasound results, patients were classified as low risk (empty, gastric fluid volume ≤ 1.5 ml.kg^-1 body weight) or high risk (solid, mixed or gastric fluid volume > 1.5 ml.kg^-1 body weight) of aspiration. After sonography, examiners were asked to indicate changes in aspiration risk management (none; more conservative; more liberal) to their pre-defined anaesthetic plan and to adapt it if patient safety was at risk. We included 2003 patients, 1246 (62%) of which underwent elective and 757 (38%) emergency surgery. Among patients who underwent elective surgery, 1046/1246 (84%) had a low-risk and 178/1246 (14%) a high-risk stomach, with this being 587/757 (78%) vs. 158/757 (21%) among patients undergoing emergency surgery, respectively. Routine pre-operative gastric sonography enabled changes in anaesthetic management in 379/2003 (19%) of patients, with these being a more liberal approach in 303/2003 (15%). In patients undergoing elective surgery, pre-operative gastric sonography would have allowed a more liberal approach in 170/1246 (14%) and made a more conservative approach indicated in 52/1246 (4%), whereas in patients undergoing emergency surgery, 133/757 (18%) would have been managed more liberally and 24/757 (3%) more conservatively. We showed that pre-operative gastric ultrasound helps to identify high- and low-risk situations in patients at risk of aspiration and adds useful information to peri-operative management. Our data suggest that routine use of pre-operative gastric ultrasound may improve individualised care and potentially impact patient safety.     

NVP-QBE170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia

Background and Purpose

Inhaled amiloride, a blocker of the epithelial sodium channel (ENaC), enhances mucociliary clearance (MCC) in cystic fibrosis (CF) patients. However, the dose of amiloride is limited by the mechanism-based side effect of hyperkalaemia resulting from renal ENaC blockade. Inhaled ENaC blockers with a reduced potential to induce hyperkalaemia provide a therapeutic strategy to improve mucosal hydration and MCC in the lungs of CF patients. The present study describes the preclinical profile of a novel ENaC blocker, NVP-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia.

Experimental Approach

The in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and a newer ENaC blocker, P552-02, in primary human bronchial epithelial cells (HBECs) by short-circuit current. In vivo efficacy and safety were assessed in guinea pig (tracheal potential difference/hyperkalaemia), rat (hyperkalaemia) and sheep (MCC).

Key Results

In vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo, intratracheal (i.t.) instillation of NVP-QBE170 attenuated ENaC activity in the guinea pig airways with greater potency and duration of action than that of amiloride without inducing hyperkalaemia in either guinea pig or rat. Dry powder inhalation of NVP-QBE170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action.

Conclusions and Implications

NVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds.     

Selective inhibition by nicotine of shock-induced fighting in the rat

The frequency of shock-induced fighting, posturing and “no reaction” (running/ jumping or freezing), after acute SC injections of 0, 0.1, 0.2 and 0.4 mg/kg nicotine, was measured in 38 pairs of male and 12 pairs of female rats. Sensitivity of footshock was also measured, at the same nicotine doses, in males. Nicotine inhibited shock-induced fighting in 32 pairs of high-frequency fighting males in a dose-dependent fashion, with fighting being gradually replaced by posturing at the 0.1 and 0.2 mg/kg doses. There was a significant increase in the “no reaction” category (especially freezing behavior) only at 0.4 mg/kg, indicating that reduced activity may have been partly responsible for the reduction in fighting seen at that dose. None of the doses had a significant effect on sensitivity to footshock. Nicotine had no effect on shock-induced fighting in the six low-frequency fighting male pairs, and affected the female pairs only at the 0.4 mg/kg level, where fighting was also decreased due to an increase in the “no reaction” category. It could be concluded that small doses of nicotine, under favorable conditions, were capable of inhibiting shock-induced fighting in rats without altering shock sensitivity or depressing activity.     

Inspiratory versus expiratory efforts in pigeons: A search for selective drug influence

Respiratory activity of anaesthetized pigeons was stimulated by occluding the trachea. Inspiratory and expiratory efforts were measured in an early and in the agonal period of prolonged tracheal occlusions.In the early period the mean change in intratracheal pressure amounted to –0.79 cm H₂O and +0.73 cm H₂O per breath. These mean pressures are considered to represent an equivalent of the mean inspiratory and expiratory activity of that period. The corresponding figures in the agonal period were –1.18 and +2.48 cm H₂O, respectively.A palette of 10 drugs was tested to see whether they could alter respiratory efforts. None of the drugs, including the CNS-stimulants, was able to increase the efforts in either of the two periods. Some of the drugs (ethylurethane, pentobarbitone, codeine and 37059¹)) led to an impairment of the efforts performed in the early period, to about the same extent in both inspiration and expiration. One drug (37059) led to an impairment of the expiratory efforts in the agonal period and to an increase of the inspiratory efforts at the same time.     

Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes.

In 26 hospitalized patients with depression, a combined pharmacogenetic test with dextromethorphan, a substrate of cytochrome P450IID6, and mephenytoin, the S-form of which is hydroxylated by a P450IIC isozyme, was carried out before amitriptyline therapy. Metabolites were determined in 24-hour urine samples collected on treatment day 8, and the contributions of individual compounds, including the four isomers of 10-hydroxyamitriptyline and 10-hydroxynortriptyline to total excretion were calculated. Formation of (-)-E-10-hydroxyamitriptyline and (-)-E-10-hydroxynortriptyline apparently depends on the activity of cytochrome P450IID6 because negative correlations existed between the log metabolic ratio of dextromethorphan and the relative quantities of these enantiomers. In contrast, correlations were positive for nortriptyline, (+)-E-10-hydroxynortriptyline, (-)-Z-10-hydroxynortriptyline, and (+)-Z-10-hydroxynortriptyline. The mephenytoin hydroxylase seems to participate in side-chain demethylation to the secondary and primary amines, because the log metabolic ratio of mephenytoin correlated negatively with the relative quantity of E-10-hydroxydidesmethylamitriptyline and positively with that of amitriptyline and its N-glucuronide.