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Respiratory Medicine 2024Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs)... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
BACKGROUND
Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs) offer an alternative, but concerns exist whether DPIs provide an effective relief during an obstructive event.
OBJECTIVE
We aimed to show non-inferiority of Salbutamol Easyhaler DPI compared to pMDI with spacer in treating methacholine-induced bronchoconstriction. Applicability of Budesonide-formoterol Easyhaler DPI as a reliever was also assessed.
METHODS
This was a randomized, parallel-group trial in subjects sent to methacholine challenge (MC) test for asthma diagnostics. Participants with at least 20 % decrease in forced expiratory volume in 1 s (FEV) were randomized to receive Salbutamol Easyhaler (2 × 200 μg), Ventoline Evohaler with spacer (4 × 100 μg) or Budesonide-formoterol Easyhaler (2 × 160/4.5 μg) as a reliever. The treatment was repeated if FEV did not recover to at least -10 % of baseline.
RESULTS
180 participants (69 % females, mean age 46 yrs [range 18-80], FEV%pred 89.5 [62-142] %) completed the trial. Salbutamol Easyhaler was non-inferior to pMDI with spacer in acute relief of bronchoconstriction showing a -0.083 (95 % LCL -0.146) L FEV difference after the first dose and -0.032 (-0.071) L after the last dose. The differences in FEV between Budesonide-formoterol Easyhaler and Salbutamol pMDI with spacer were -0.163 (-0.225) L after the first and -0.092 (-0.131) L after the last dose.
CONCLUSION
The study confirms non-inferiority of Salbutamol Easyhaler to Ventoline Evohaler with spacer in relieving acute bronchoconstriction, making Easyhaler a sustainable and safe reliever for MC test and supports its use during asthma attacks.
Topics: Humans; Methacholine Chloride; Female; Bronchoconstriction; Male; Adult; Asthma; Middle Aged; Albuterol; Dry Powder Inhalers; Forced Expiratory Volume; Bronchodilator Agents; Young Adult; Administration, Inhalation; Metered Dose Inhalers; Adolescent; Bronchial Provocation Tests; Treatment Outcome; Aged; Inhalation Spacers; Budesonide, Formoterol Fumarate Drug Combination
PubMed: 38851404
DOI: 10.1016/j.rmed.2024.107693 -
Turkish Journal of Medical Sciences 2023Propofol is a positive allosteric modulator of GABAA receptor (GABAAR) and has potent antioxidant activity. The aim of this study was to investigate the effect of...
Propofol mitigates brain injury and oxidative stress, and enhances GABAA receptor α1 subunit expression in a rat model of lithium chloride-pilocarpine induced status epilepticus.
BACKGROUND/AIM
Propofol is a positive allosteric modulator of GABAA receptor (GABAAR) and has potent antioxidant activity. The aim of this study was to investigate the effect of propofol on damage to the cerebral cortex and hippocampus in a lithium chloride (LiCl)-pilocarpine animal model of status epilepticus (SE).
MATERIALS AND METHODS
Adult male Sprague Dawley rats were injected with LiCl-pilocarpine to induce SE. They were then randomized and injected 30 min later with vehicle saline (SE+saline), propofol (SE+PPF, 50 mg/kg), Diazepam (SE+DZP, 10 mg/kg), Scopolamine (SE+SCOP, 10 mg/kg), or MK-801 (SE+MK-801, 2 mg/kg). Another group of rats received saline only and served as the naïve control (BLK). The levels of superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) in the serum, cortex and hippocampus were analyzed 2 and 24 h posttreatment. The degree of tissue damage in the cortex and hippocampus of individual rats was assessed 24 h posttreatment, together with expression of the GABAAR α1 subunit.
RESULTS
The propofol group showed reduced levels of tissue damage in the cerebral cortex and hippocampus, decreased levels of MDA, and increased levels of GSH compared to the SE+saline group. No changes in SOD level were observed in serum and tissue samples from the cortex and hippocampus of SE+saline rats. Immunohistochemistry and Western blot assays showed that propofol treatment significantly increased the expression of GABAR α1 subunit in the cortical and hippocampal tissues of SE rats.
CONCLUSION
Propofol treatment protected against SE-induced tissue injury in the cortex and hippocampus of rats. This was due at least in part to its antioxidant activity and to its induction of GABAAR α1 subunit expression in the brain.
Topics: Animals; Propofol; Receptors, GABA-A; Status Epilepticus; Pilocarpine; Male; Rats, Sprague-Dawley; Lithium Chloride; Oxidative Stress; Rats; Disease Models, Animal; Hippocampus; Brain Injuries; Malondialdehyde; Cerebral Cortex
PubMed: 38813010
DOI: 10.55730/1300-0144.5670 -
Scientific Reports May 2024We studied the inhibitory actions of docosahexaenoic acid (DHA) on the contractions induced by carbachol (CCh), angiotensin II (Ang II), and bradykinin (BK) in guinea...
We studied the inhibitory actions of docosahexaenoic acid (DHA) on the contractions induced by carbachol (CCh), angiotensin II (Ang II), and bradykinin (BK) in guinea pig (GP) gastric fundus smooth muscle (GFSM), particularly focusing on the possible inhibition of store-operated Ca channels (SOCCs). DHA significantly suppressed the contractions induced by CCh, Ang II, and BK; the inhibition of BK-induced contractions was the strongest. Although all contractions were greatly dependent on external Ca, more than 80% of BK-induced contractions remained even in the presence of verapamil, a voltage-dependent Ca channel inhibitor. BK-induced contractions in the presence of verapamil were not suppressed by LOE-908 (a receptor-operated Ca channel (ROCC) inhibitor) but were suppressed by SKF-96365 (an SOCC and ROCC inhibitor). BK-induced contractions in the presence of verapamil plus LOE-908 were strongly inhibited by DHA. Furthermore, DHA inhibited GFSM contractions induced by cyclopiazonic acid (CPA) in the presence of verapamil plus LOE-908 and inhibited the intracellular Ca increase due to Ca addition in CPA-treated 293T cells. These findings indicate that Ca influx through SOCCs plays a crucial role in BK-induced contraction in GP GFSM and that this inhibition by DHA is a new mechanism by which this fatty acid inhibits GFSM contractions.
Topics: Animals; Guinea Pigs; Docosahexaenoic Acids; Bradykinin; Muscle, Smooth; Carbachol; Muscle Contraction; Angiotensin II; Gastric Fundus; Verapamil; Calcium; Male; Humans; Calcium Channels; HEK293 Cells; Calcium Channel Blockers; Imidazoles
PubMed: 38778154
DOI: 10.1038/s41598-024-62578-y -
BMJ Open Respiratory Research May 2024Methods used to assess ventilation heterogeneity through inert gas washout have been standardised and showed high sensitivity in diagnosing many respiratory diseases. We... (Observational Study)
Observational Study Comparative Study
BACKGROUND
Methods used to assess ventilation heterogeneity through inert gas washout have been standardised and showed high sensitivity in diagnosing many respiratory diseases. We hypothesised that nitrogen single or multiple breath washout tests, respectively nitrogen single breath washout (NSBW) and nitrogen multiple breath washout (NMBW), may be pathological in patients with clinical suspicion of asthma but normal spirometry. Our aim was to assess whether NSBW and NMBW are associated with methacholine challenge test (MCT) results in this population. We also postulated that an alteration in S at NSBW could be detected before the 20% fall of forced expiratory volume in the first second (FEV) in MCT.
STUDY DESIGN AND METHODS
This prospective, observational, single-centre study included patients with suspicion of asthma with normal spirometry. Patients completed questionnaires on symptoms and health-related quality-of-life and underwent the following lung function tests: NSBW (S), NMBW (Lung clearance index (LCI), S, S), MCT (FEV and sGeff) as well as NSBW between each methacholine dose.
RESULTS
182 patients were screened and 106 were included in the study, with mean age of 41.8±14 years. The majority were never-smokers (58%) and women (61%). MCT was abnormal in 48% of participants, NSBW was pathological in 10.6% at baseline and NMBW abnormality ranged widely (LCI 81%, S 18%, S 43%). The dose response rate of the MCT showed weak to moderate correlation with the subsequent NSBW measurements during the provocation phases (ρ 0.34-0.50) but no correlation with NMBW.
CONCLUSIONS
Both MCT and N washout tests are frequently pathological in patients with suspicion of asthma with normal spirometry. The weak association and lack of concordance across the tests highlight that they reflect different but not interchangeable pathological pathways of the disease.
Topics: Humans; Asthma; Methacholine Chloride; Female; Male; Prospective Studies; Adult; Spirometry; Breath Tests; Middle Aged; Nitrogen; Bronchial Provocation Tests; Forced Expiratory Volume; Respiratory Function Tests; Lung; Bronchoconstrictor Agents
PubMed: 38697675
DOI: 10.1136/bmjresp-2023-001919 -
Scientific Reports Apr 2024Selective activation of individual subtypes of muscarinic receptors is a promising way to safely alleviate a wide range of pathological conditions in the central nervous...
Selective activation of individual subtypes of muscarinic receptors is a promising way to safely alleviate a wide range of pathological conditions in the central nervous system and the periphery as well. The flexible G-protein interface of muscarinic receptors allows them to interact with several G-proteins with various efficacy, potency, and kinetics. Agonists biased to the particular G-protein mediated pathway may result in selectivity among muscarinic subtypes and, due to the non-uniform expression of individual G-protein alpha subunits, possibly achieve tissue specificity. Here, we demonstrate that novel tetrahydropyridine-based agonists exert specific signalling profiles in coupling with individual G-protein α subunits. These signalling profiles profoundly differ from the reference agonist carbachol. Moreover, coupling with individual Gα induced by these novel agonists varies among subtypes of muscarinic receptors which may lead to subtype selectivity. Thus, the novel tetrahydropyridine-based agonist can contribute to the elucidation of the mechanism of pathway-specific activation of muscarinic receptors and serve as a starting point for the development of desired selective muscarinic agonists.
Topics: Muscarinic Agonists; Receptors, Muscarinic; Animals; Signal Transduction; Humans; Pyridines; Carbachol; CHO Cells; Cricetulus; GTP-Binding Proteins; GTP-Binding Protein alpha Subunits
PubMed: 38671143
DOI: 10.1038/s41598-024-60259-4 -
Cell Reports May 2024The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows...
The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.
Topics: Animals; Male; Mice; Apoptosis; Mice, Inbred C57BL; Neurons; Phosphorylation; Pilocarpine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Pyrimidines; Seizures; Status Epilepticus
PubMed: 38656874
DOI: 10.1016/j.celrep.2024.114144 -
Respiratory Physiology & Neurobiology Jul 2024Eight pig tracheal strips were stimulated to contract with log increments of methacholine from 10 to 10 M. For each strip, the concentration-response was repeated four...
Eight pig tracheal strips were stimulated to contract with log increments of methacholine from 10 to 10 M. For each strip, the concentration-response was repeated four times in a randomized order to measure isometric force, isotonic shortening against a load corresponding to either 5 or 10 % of a reference force, and average force, stiffness, elastance and resistance over one cycle while the strip length was oscillating sinusoidally by 5 % at 0.2 Hz. For each readout, the logEC50 was calculated and compared. Isotonic shortening with a 5 % load had the lowest logEC50 (-7.13), yielding a greater sensitivity than any other contractile readout (p<0.05). It was followed by isotonic shortening with a 10 % load (-6.66), elastance (-6.46), stiffness (-6.46), resistance (-6.38), isometric force (-6.32), and average force (-6.30). Some of these differences were significant. For example, the EC50 with the average force was 44 % greater than with the elastance (p=0.001). The methacholine sensitivity is thus affected by the contractile readout being measured.
Topics: Animals; Muscle, Smooth; Methacholine Chloride; Swine; Trachea; Bronchoconstrictor Agents; Muscle Contraction; Dose-Response Relationship, Drug; Elasticity; Isometric Contraction
PubMed: 38599345
DOI: 10.1016/j.resp.2024.104264 -
Frontiers in Immunology 2024Hemorrhagic shock is characterized by derangements of the gastrointestinal microcirculation. Topical therapy with nitroglycerine or iloprost improves gastric tissue... (Comparative Study)
Comparative Study
INTRODUCTION
Hemorrhagic shock is characterized by derangements of the gastrointestinal microcirculation. Topical therapy with nitroglycerine or iloprost improves gastric tissue oxygenation but not regional perfusion, probably due to precapillary adrenergic innervation. Therefore, this study was designed to investigate the local effect of the parasympathomimetic carbachol alone and in combination with either nitroglycerine or iloprost on gastric and oral microcirculation during hemorrhagic shock.
METHODS
In a cross-over design five female foxhounds were repeatedly randomized into six experimental groups. Carbachol, or carbachol in combination with either nitroglycerine or iloprost were applied topically to the oral and gastric mucosa. Saline, nitroglycerine, or iloprost application alone served as control groups. Then, a fixed-volume hemorrhage was induced by arterial blood withdrawal followed by blood retransfusion after 1h of shock. Gastric and oral microcirculation was determined using reflectance spectrophotometry and laser Doppler flowmetry. Oral microcirculation was visualized with videomicroscopy. Statistics: 2-way-ANOVA for repeated measurements and Bonferroni post-hoc analysis (mean ± SEM; p < 0.05).
RESULTS
The induction of hemorrhage led to a decrease of gastric and oral tissue oxygenation, that was ameliorated by local carbachol and nitroglycerine application at the gastric mucosa. The sole use of local iloprost did not improve gastric tissue oxygenation but could be supplemented by local carbachol treatment. Adding carbachol to nitroglycerine did not further increase gastric tissue oxygenation. Gastric microvascular blood flow remained unchanged in all experimental groups. Oral microvascular blood flow, microvascular flow index and total vessel density decreased during shock. Local carbachol supply improved oral vessel density during shock and oral microvascular flow index in the late course of hemorrhage.
CONCLUSION
The specific effect of shifting the autonomous balance by local carbachol treatment on microcirculatory variables varies between parts of the gastrointestinal tract. Contrary to our expectations, the improvement of gastric tissue oxygenation by local carbachol or nitroglycerine application was not related to increased microvascular perfusion. When carbachol is used in combination with local vasodilators, the additional effect on gastric tissue oxygenation depends on the specific drug combination. Therefore, modulation of tissue oxygen consumption, mitochondrial function or alterations in regional blood flow distribution should be investigated.
Topics: Animals; Dogs; Female; Carbachol; Hemorrhage; Iloprost; Microcirculation; Nitroglycerin; Shock, Hemorrhagic
PubMed: 38566995
DOI: 10.3389/fimmu.2024.1369617 -
Immunity, Inflammation and Disease Mar 2024The dosage of ovalbumin (OVA) during the sensitization stage is considered a crucial factor in the development of airway hyperresponsiveness (AHR). However, the...
BACKGROUND
The dosage of ovalbumin (OVA) during the sensitization stage is considered a crucial factor in the development of airway hyperresponsiveness (AHR). However, the inconsistent dosages of sensitizing OVA used in current studies and the lack of research on their impact on AHR are notable limitations.
METHODS
We examined the impact of increasing sensitizing doses of OVA in a murine asthma model, which entailed initial sensitization with OVA followed by repeated exposure to OVA aerosols. BALB/c mice were primed with doses of OVA (0, 10, 20, 50, and 100 μg) plus 1 mg Alum on Days 0 and 7, and were challenged with OVA aerosols (10 mg/mL for 30 min) between Days 14 and 17. Antigen-induced AHR to methacholine (MCh), as well as histological changes, eosinophilic infiltration, and epithelial injury were assessed.
RESULTS
The result indicated that there are striking OVA dose-related differences in antigen-induced AHR to MCh. The most intense antigen-induced AHR to MCh was observed with sensitization at 50 μg, while weaker responses were seen at 10, 20, and 100 μg. Meanwhile, there was a significant increase in eosinophil count with sensitization at 50 μg. The changes of AHR were correlated with total cells count, lymphocytes count, eosinophils count, and basophils count in bronchoalveolar lavage fluid; however, it did not correlate with histological changes such as cellular infiltration into bronchovascular bundles and goblet cell hyperplasia of the bronchial epithelium.
CONCLUSION
Overall, this study demonstrated that sensitization with 50 μg of OVA resulted in the most significant AHR compared to other dosages. These findings may offer valuable insights for future research on mouse asthma modeling protocols.
Topics: Animals; Mice; Ovalbumin; Bronchial Hyperreactivity; Respiratory Aerosols and Droplets; Asthma; Respiratory Hypersensitivity; Methacholine Chloride
PubMed: 38533918
DOI: 10.1002/iid3.1225 -
Cell and Tissue Research Jun 2024Status epilepticus (SE), the most severe form of epilepsy, leads to brain damage. Uncertainty persists about the mechanisms that lead to the pathophysiology of epilepsy...
Status epilepticus (SE), the most severe form of epilepsy, leads to brain damage. Uncertainty persists about the mechanisms that lead to the pathophysiology of epilepsy and the death of neurons. Overloading of intracellular iron ions has recently been identified as the cause of a newly recognized form of controlled cell death called ferroptosis. Inhibiting ferroptosis has shown promise as a treatment for epilepsy, according to recent studies. So, the current study aimed to assess the possible antiepileptic impact of CoQ10 either alone or with the standard antiepileptic drug sodium valproate (SVP) and to evaluate the targeted effect of COQ10 on hippocampal oxidative stress and ferroptosis in a SE rat model. Using a lithium-pilocarpine rat model of epilepsy, we evaluated the effect of SVP, CoQ10, or both on seizure severity, histological, and immunohistochemical of the hippocampus. Furthermore, due to the essential role of oxidative stress and lipid peroxidation in inducing ferroptosis, we evaluated malonaldehyde (MDA), reduced glutathione (GSH), glutathione peroxidase 4 (GPX4), and ferritin in tissue homogenate. Our work illustrated that ferroptosis occurs in murine models of lithium-pilocarpine-induced seizures (epileptic group). Nissl staining revealed significant neurodegeneration. A significant increase in the number of astrocytes stained with an astrocyte-specific marker was observed in the hippocampus. Effective seizure relief can be achieved in the seizure model by administering CoQ10 alone compared to SVP. This was accomplished by lowering ferritin levels and increasing GPX4, reducing MDA, and increasing GSH in the hippocampus tissue homogenate. In addition, the benefits of SVP therapy for regulating iron stores, GPX4, and oxidative stress markers were amplified by incorporating CoQ10 as compared to SVP alone. It was concluded that CoQ10 alone has a more beneficial effect than SVP alone in restoring histological structures and has a targeted effect on hippocampal oxidative stress and ferroptosis. In addition, COQ10 could be useful as an adjuvant to SVP in protecting against oxidative damage and ferroptosis-related damage that result from epileptic seizures.
Topics: Animals; Ferroptosis; Status Epilepticus; Ubiquinone; Hippocampus; Disease Models, Animal; Rats; Male; Oxidative Stress; Pilocarpine; Rats, Sprague-Dawley; Valproic Acid; Lipid Peroxidation
PubMed: 38499882
DOI: 10.1007/s00441-024-03880-z