Inhaled Remimazolam Potentiates Inhaled Remifentanil in Rodents.

BACKGROUND: Remimazolam is an ester-based short-acting benzodiazepine currently in clinical trials for IV administration. This study explored the feasibility of delivering remimazolam alone and as an adjunct to remifentanil via inhalation in rodent models. METHODS: Mice were exposed to remimazolam via inhalation; sedation was assessed using time to movement outside a set perimeter. Rats were also exposed to remimazolam aerosol alone and in combination with inhaled remifentanil, and analgesia was quantified by using a tail flick meter. Pulmonary injury was assessed in mice using mechanics measurements. RESULTS: Mice showed significantly increased time to movement outside a set perimeter after 5-minute exposure to increasing concentrations (10-25 mg/mL solutions) of inhaled remimazolam aerosols. Differences in mean (95% confidence interval) time to movement from pretest baseline group (0.05 [0.01-0.09] minutes) were 11 (4-18), 15 (5-26), 30 (19-41), and 109 (103-115) minutes after exposure to remimazolam aerosol of 10, 15, 20, and 25 mg/mL, respectively (P = .007 - P < .0001). Exposure of rats to remimazolam aerosols alone failed to produce sedation or analgesia after a 5-minute exposure. When remimazolam (10 or 25 mg/mL) was administered in combination with 250 µg/mL remifentanil, there was a significant difference in time to tail flick (P < .0001) consistent with a strong analgesic effect. Mean (95% confidence interval) differences in time to tail flick from the pretest baseline group (3.2 [2.5-3.9] seconds) were 14 (10-18) seconds when 250 µg/mL remifentanil was administered with either 10 or 25 mg/mL remimazolam. Remimazolam alone or in combination with remifentanil did not cause lung irritation, bronchospasm, or other adverse pulmonary events to the respiratory tract of mice as assessed by Flexi-Vent pulmonary function tests. CONCLUSIONS: Remimazolam can significantly potentiate the analgesic effect of remifentanil when concurrently delivered via inhalation.

Inhaled Remifentanil in Rodents.

BACKGROUND: Remifentanil is an injectable opioid that is metabolized rapidly at a constant rate by plasma esterases. This supports its use as an analgesic for short-term, but painful, procedures in a wide range of patients. The aim of this study was to explore the feasibility and safety of administering remifentanil via inhalation. Our hypothesis was that inhaled remifentanil would be absorbed rapidly, pharmacologically active, rapidly cleared, and noninjurious to rodent airways and lungs. METHODS: Rats were exposed to remifentanil aerosol (100-2000 µg/mL) for varying times (1-5 minutes). Analgesia was quantified as a function of dose and time by measuring time to tail flick in response to a painful stimulus. Remifentanil was measured in blood using liquid chromatography-tandem mass spectrometry. Pulmonary mechanics and histology were assessed in mice for the evidence of adverse effects after acute and repeated (subacute) dosing. RESULTS: Exposure of rats to remifentanil aerosols produced dose-dependent analgesia within 2 minutes, which was sustained for the exposure period. Subsequently, the rats experienced rapid and complete recovery with a return to baseline tail flick response to a painful stimulus within 5 minutes. Analgesia mirrored the concentration profile of remifentanil in blood, and the animals were not affected adversely by repeated dosing. Pulmonary mechanics measurements in mice indicated that remifentanil was nonirritating and that the nasal and respiratory tissues of rats were free of significant morphological changes. CONCLUSIONS: Remifentanil delivered by inhalation is rapidly absorbed, pharmacologically active, rapidly cleared, and noninjurious to respiratory tissues in rodents.

Activation of Transient Receptor Potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma.

Inhaled irritants activate transient receptor potential ankyrin-1 (TRPA1), resulting in cough, bronchoconstriction, and inflammation/edema. TRPA1 is also implicated in the pathogenesis of asthma. Our hypothesis was that particulate materials activate TRPA1 via a mechanism distinct from chemical agonists and that, in a cohort of children with asthma living in a location prone to high levels of air pollution, expression of uniquely sensitive forms of TRPA1 may correlate with reduced asthma control. Variant forms of TRPA1 were constructed by mutating residues in known functional elements and corresponding to single-nucleotide polymorphisms in functional domains. TRPA1 activity was studied in transfected HEK-293 cells using allyl-isothiocynate, a model soluble electrophilic agonist; 3,5-ditert butylphenol, a soluble nonelectrophilic agonist and a component of diesel exhaust particles; and insoluble coal fly ash (CFA) particles. The N-terminal variants R3C and R58T exhibited greater, but not additive, activity with all three agonists. The ankyrin repeat domain-4 single nucleotide polymorphisms E179K and K186N exhibited decreased response to CFA. The predicted N-linked glycosylation site residues N747A and N753A exhibited decreased responses to CFA, which were not attributable to differences in cellular localization. The pore-loop residue R919Q was comparable to wild-type, whereas N954T was inactive to soluble agonists but not CFA. These data identify roles for ankyrin domain-4, cell surface N-linked glycans, and selected pore-loop domain residues in the activation of TRPA1 by insoluble particles. Furthermore, the R3C and R58T polymorphisms correlated with reduced asthma control for some children, which suggest that TRPA1 activity may modulate asthma, particularly among individuals living in locations prone to high levels of air pollution.