Reversion of methacholine induced bronchoconstriction with inhaled diazepam in patients with asthma

Mirić, Mirjana; Ristić, Siniša; Joksimović, Bojan; Medenica, Snežana; Račić, Maja; Ristić, Slavica; Joksimović, Vedrana; Skipina, Mirjana

doi:10.4067/s0034-98872016000400003

Cited by 2 publications

(3 citation statements)

References 27 publications

(36 reference statements)

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“…These results are in agreement with studies performed for orally administrated MIDD0301 and diazepam . Interestingly, a recent clinical study with inhaled diazepam confirmed bronchodilation for patients with asthma . The authors proposed that diazepam acted on the peripheral nervous system regulating the airway smooth-muscle tone rather than directly relaxing contracted airway smooth muscle, which was demonstrated for MIDD0301 using ex vivo human lung tissue .…”

Section: Resultssupporting

confidence: 84%

“…6 Interestingly, a recent clinical study with inhaled diazepam confirmed bronchodilation for patients with asthma. 30 The authors proposed that diazepam acted on the peripheral nervous system regulating the airway smooth-muscle tone rather than directly relaxing contracted airway smooth muscle, which was demonstrated for MIDD0301 using ex vivo human lung tissue. 10 To show that bronchodilation by MIDD0301 is limited to constricted airways (e.g., in the presence of methacholine or caused by lung inflammation), we iteratively treated nai ̈ve mice with nebulized MIDD0301 followed by airway measurements using a whole-body plethysmograph (Figure 6C).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Nebulized MIDD0301 Reduces Airway Hyperresponsiveness in Moderate and Severe Murine Asthma Models

Zahn

Mikulsky²,

Roni

et al. 2020

ACS Pharmacol. Transl. Sci.

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We report the relaxation of methacholine-constricted airways with nebulized MIDD0301, a positive allosteric γ-aminobutyric acid type A receptor (GABA A R) modulator. The therapeutic efficacy of nebulized MIDD0301 in reducing airway resistance was investigated in spontaneous breathing mice using a whole-body plethysmograph and in unconscious mice using a forced oscillation technique. Prophylactic nebulized MIDD0301 reduced subsequent methacholine-induced bronchoconstriction in ovalbumin and house dust mite allergic asthma models and in normal mice. Nebulized MIDD0301 exhibited comparable or better therapeutic potency compared to nebulized albuterol and oral montelukast. Prophylactic nebulized MIDD0301 was also effective in reducing bronchoconstriction, comparable to nebulized albuterol or fluticasone, in a steroid resistant asthma mouse model induced by intratracheal installation of lipopolysaccharide and interferon-gamma. Oral dexamethasone was ineffective in this model. Nebulized MIDD0301 was also effective in reversing bronchospasm when dosed after methacholine challenge comparable to albuterol. Pharmacokinetic studies showed that about 0.06% of nebulized MIDD0301 entered the mouse lung when using a whole body plethysmograph and therapeutic levels were sustained in the lung for at least 25 min. Consistent with previous reports on orally dosed MIDD0301, high doses of nebulized MIDD0301 resulted in minimal brain exposure and thus no observable adverse sensorimotor or respiratory depression effects occurred. In addition, no adverse cardiovascular effects were observed following 100 mg/kg i.p. dosing. These results further demonstrate that charged imidazodiazepine MIDD0301 can selectively target lung GABA A R without adverse motor, cardiovascular, or respiratory effects and inhaled dosing is effective in reducing bronchoconstriction in allergen and infectious lung inflammation.

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Section: Resultssupporting

confidence: 84%

Section: ■ Results and Discussionmentioning

confidence: 99%

Nebulized MIDD0301 Reduces Airway Hyperresponsiveness in Moderate and Severe Murine Asthma Models

Zahn

Mikulsky²,

Roni

et al. 2020

ACS Pharmacol. Transl. Sci.

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“…2-hydroxyglutarate is involved in the butanoate metabolism pathway, which regulates the GAD (Glutamic Acid Decarboxylase)-mediated decarboxylation of L-glutamate into GABA. GABA, an inhibitory neurotransmitter, is known to participate in regulation of contractility of airway smooth muscle [10]. GABA has a number of positive effects on lung function, including relaxing airway smooth muscle, inhibiting muscle conduction, decreasing resistance in airway breathing channels, decreasing contractility of trachea muscle, reducing neurogenic extravasation, reducing anticholinergic bronchoconstriction, and regulating mucus hypersecretion [10,11].…”

Section: Discussionmentioning

confidence: 99%

Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions

et al. 2019

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The role of metabolism in modifying age-related differential responses to asthma medications is insufficiently understood. The objective of this study was to determine the role of the metabolome in modifying the effect of age on bronchodilator response (BDR) in individuals with asthma. We used longitudinal measures of BDR and plasma metabolomic profiling in 565 children with asthma from the Childhood Asthma Management Program (CAMP) to identify age by metabolite interactions on BDR. The mean ages at the three studied time-points across 16 years of follow-up in CAMP were 8.8, 12.8, and 16.8 years; the mean BDRs were 11%, 9% and 8%, respectively. Of 501 identified metabolites, 39 (7.8%) demonstrated a significant interaction with age on BDR (p-value < 0.05). We were able to validate two significant interactions in 320 children with asthma from the Genetics of Asthma in Costa Rica Study; 2-hydroxyglutarate, a compound involved in butanoate metabolism (interaction; CAMP: β = −0.004, p = 1.8 × 10−4; GACRS: β = −0.015, p = 0.018), and a cholesterol ester; CE C18:1 (CAMP: β = 0.005, p = 0.006; GACRS: β = 0.023, p = 0.041) Five additional metabolites had a p-value < 0.1 in GACRS, including Gammaminobutyric acid (GABA), C16:0 CE, C20:4 CE, C18.0 CE and ribothymidine. These findings suggest Cholesterol esters and GABA may modify the estimated effect of age on bronchodilator response.

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Reversion of methacholine induced bronchoconstriction with inhaled diazepam in patients with asthma

Cited by 2 publications

References 27 publications

Nebulized MIDD0301 Reduces Airway Hyperresponsiveness in Moderate and Severe Murine Asthma Models

Nebulized MIDD0301 Reduces Airway Hyperresponsiveness in Moderate and Severe Murine Asthma Models

Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions

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