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Drug Metabolism and Disposition: the... May 2024This study investigated an association between the cytochrome P450 (CYP) 2C8*3 polymorphism with asthma symptom control in children and changes in lipid metabolism and...
The Cytochrome P450 (CYP) 2C8*3 Variant (rs11572080) is Associated with Improved Asthma Symptom Control in Children and Altered Lipid Mediator Production and Inflammatory Response in Human Bronchial Epithelial Cells.
This study investigated an association between the cytochrome P450 (CYP) 2C8*3 polymorphism with asthma symptom control in children and changes in lipid metabolism and pro-inflammatory signaling by human bronchial epithelial cells (HBECs) treated with cigarette smoke condensate (CSC). CYP genes are inherently variable in sequence and while such variations are known to produce clinically relevant effects on drug pharmacokinetics and pharmacodynamics, the effects on endogenous substrate metabolism and associated physiological processes are less understood. In this study, CYP2C8*3 was associated with improved asthma symptom control among children: Mean asthma control scores were 3.68 [n=207] for patients with one or more copies of the CYP2C8*3 allele vs. 4.42 [n=965] for CYP2C8*1/*1 (p=0.0133). , CYP2C8*3 was associated with an increase in montelukast 36-hydroxylation and a decrease in linoleic acid (LA) metabolism despite lower mRNA and protein expression. Additionally, CYP2C8*3 was associated with reduced mRNA expression of interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL-8) by HBECs in response to CSC, which was replicated using the soluble epoxide hydrolase inhibitor, AUDA. Interestingly, 9(10)- and 12(13)-DiHOME, the hydrolyzed metabolites of 9(10)- and 12(13)-EpOME, increased the expression of IL-6 and CXCL-8 mRNA by HBECs. This study reveals previously undocumented effects of the CYP2C8*3 variant on the response of HBECs to exogenous stimuli. These findings suggest a role for CYP2C8 in regulating the EpOME:DiHOME ratio leading to a change in cellular inflammatory responses elicited by environmental stimuli that exacerbate asthma.
PubMed: 38772712
DOI: 10.1124/dmd.124.001684 -
Minerva Surgery May 2024
PubMed: 38713181
DOI: 10.23736/S2724-5691.24.10297-3 -
Cureus Apr 2024A black box warning, signaling potential life-threatening adverse effects of medications or medical devices, is crucial for public and healthcare professional awareness.... (Review)
Review
A black box warning, signaling potential life-threatening adverse effects of medications or medical devices, is crucial for public and healthcare professional awareness. Comprehending and adhering to these warnings can prevent serious harm. This review aims to elucidate their significance. Data on drugs with black box warnings were collected from the Food and Drug Administration's (FDA's) official website using the search term 'Boxed warnings' from January 1, 2015, to January 31, 2024. A Microsoft Excel spreadsheet (Microsoft Corporation, Redmond, WA, USA) containing black box warnings for this period was downloaded from the FDA's website. Additional parameters, such as drug class and whether the warnings were new or existing, were added to the downloaded spreadsheet. The collected data were organized by year, categorizing new and existing warnings, along with details on the evidence source, system-wise classification, and black box warnings for commonly used drugs, including their clinical significance. Results show that in the past decade, 40% of black box warnings were issued in 2023, followed by 12% in 2022. Most warnings (67%) comprised existing ones with minor revisions while 29% were new. Nine existing warnings were removed during the period. Post-marketing studies predominantly provided evidence for these warnings. Neuropsychiatric concerns like addiction potential (31%), suicidal tendency (7%), and hypersensitivity reactions (12%) were the frequently encountered black box warnings. Black box warnings play a crucial role in highlighting the serious adverse effects of medications. Neuropsychiatric warnings have been frequent over the past decade. Awareness of these warnings is essential to prevent adverse effects and enhance patient care, especially concerning drugs like guaifenesin/hydrocodone bitartrate, zolpidem, and montelukast commonly encountered in clinical practice.
PubMed: 38706997
DOI: 10.7759/cureus.57597 -
American Journal of Veterinary Research Jun 2024To examine the potential of galangin in a mouse model of ovalbumin (OVA)-induced allergic rhinitis (AR), as chronic AR, induced by immunoglobulin-E (IgE), leads to...
OBJECTIVE
To examine the potential of galangin in a mouse model of ovalbumin (OVA)-induced allergic rhinitis (AR), as chronic AR, induced by immunoglobulin-E (IgE), leads to histamine release and nasal inflammation, and although galangin exhibits antiasthmatic and anti-inflammatory potential, its effect on AR is yet to be investigated.
ANIMALS
126 BALB/c mice.
METHODS
AR induction involved sensitizing female mice with OVA (5%, 500 µL, IP) for 14 days. Post OVA challenge, the mice were divided into 7 groups (n = 18/group), including normal, AR control, montelukast (10 mg/kg), galangin (5, 10, and 20 mg/kg), and per se (galangin [20 mg/kg] treatment. Various outcomes were evaluated, including nasal symptoms, histopathology, biochemistry, and nasal lavage fluid inflammatory cytokines and signaling pathways in nasal mucosal to assess galangin potential in AR.
RESULTS
In AR mice, galangin (10 and 20 mg/kg) significantly (P < .05) reduced sneezing, rubbing, and nasal discharge post-OVA challenge. Galangin treatment attenuated (P < .05) elevated serum histamine, β-hexosaminidase, IgE, and Immunoglobulin G1 levels in AR control mice. Additionally, galangin significantly (P < .05) decreased OVA-induced alterations in IL-4, IL-6, IL-13, and interferon-γ levels in nasal lavage fluid compared to AR control mice. Western blot analysis demonstrated that galangin lowered OVA-induced AR by significantly (P < .05) downregulating the phosphorylated protein kinase B and mammalian target of rapamycin-protein expressions while markedly (P < .05) upregulating the glycogen synthase kinase-3β protein expressions in nasal mucosal. Galangin also significantly ameliorated (P < .05) the OVA-induced histological aberrations in the nasal mucosa, reflected by reduced eosinophil infiltration, hyperplasia, and edema.
CLINICAL RELEVANCE
Galangin exhibits antihistaminic and anti-inflammatory effects in AR mice by regulating IgE-mediated histamine and inflammatory release and modulating the phosphatidylinositol 3-kinase/Ak strain transforming/mammalian target of rapamycin pathways.
Topics: Animals; Ovalbumin; Mice, Inbred BALB C; Flavonoids; Mice; Female; Rhinitis, Allergic; Phosphatidylinositol 3-Kinases; Signal Transduction; Proto-Oncogene Proteins c-akt; Disease Models, Animal; Quinolines; Cytokines; Nasal Mucosa; Immunoglobulin E; Acetates; Cyclopropanes; Sulfides
PubMed: 38697189
DOI: 10.2460/ajvr.24.02.0031 -
Multiple Sclerosis (Houndmills,... May 2024Effective and safe treatment options for multiple sclerosis (MS) are still needed. Montelukast, a leukotriene receptor antagonist (LTRA) currently indicated for asthma...
Montelukast as a repurposable additive drug for standard-efficacy multiple sclerosis treatment: Emulating clinical trials with retrospective administrative health claims data.
BACKGROUND
Effective and safe treatment options for multiple sclerosis (MS) are still needed. Montelukast, a leukotriene receptor antagonist (LTRA) currently indicated for asthma or allergic rhinitis, may provide an additional therapeutic approach.
OBJECTIVE
The study aimed to evaluate the effects of montelukast on the relapses of people with MS (pwMS).
METHODS
In this retrospective case-control study, two independent longitudinal claims datasets were used to emulate randomized clinical trials (RCTs). We identified pwMS aged 18-65 years, on MS disease-modifying therapies concomitantly, in de-identified claims from Optum's Clinformatics Data Mart (CDM) and IQVIA PharMetrics Plus for Academics. Cases included 483 pwMS on montelukast and with medication adherence in CDM and 208 in PharMetrics Plus for Academics. We randomly sampled controls from 35,330 pwMS without montelukast prescriptions in CDM and 10,128 in PharMetrics Plus for Academics. Relapses were measured over a 2-year period through inpatient hospitalization and corticosteroid claims. A doubly robust causal inference model estimated the effects of montelukast, adjusting for confounders and censored patients.
RESULTS
pwMS treated with montelukast demonstrated a statistically significant 23.6% reduction in relapses compared to non-users in 67.3% of emulated RCTs.
CONCLUSION
Real-world evidence suggested that montelukast reduces MS relapses, warranting future clinical trials and further research on LTRAs' potential mechanism in MS.
Topics: Humans; Sulfides; Cyclopropanes; Quinolines; Acetates; Adult; Middle Aged; Female; Male; Retrospective Studies; Leukotriene Antagonists; Multiple Sclerosis; Young Adult; Case-Control Studies; Adolescent; Aged; Administrative Claims, Healthcare; Recurrence
PubMed: 38660773
DOI: 10.1177/13524585241240398 -
Frontiers in Cellular and Infection... 2024Chronic obstructive pulmonary disease (COPD) is a prevalent condition that significantly impacts public health. Unfortunately, there are few effective treatment options...
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a prevalent condition that significantly impacts public health. Unfortunately, there are few effective treatment options available. Mendelian randomization (MR) has been utilized to repurpose existing drugs and identify new therapeutic targets. The objective of this study is to identify novel therapeutic targets for COPD.
METHODS
Cis-expression quantitative trait loci (cis-eQTL) were extracted for 4,317 identified druggable genes from genomics and proteomics data of whole blood (eQTLGen) and lung tissue (GTEx Consortium). Genome-wide association studies (GWAS) data for doctor-diagnosed COPD, spirometry-defined COPD (Forced Expiratory Volume in one second [FEV1]/Forced Vital Capacity [FVC] <0.7), and FEV1 were obtained from the cohort of FinnGen, UK Biobank and SpiroMeta consortium. We employed Summary-data-based Mendelian Randomization (SMR), HEIDI test, and colocalization analysis to assess the causal effects of druggable gene expression on COPD and lung function. The reliability of these druggable genes was confirmed by eQTL two-sample MR and protein quantitative trait loci (pQTL) SMR, respectively. The potential effects of druggable genes were assessed through the phenome-wide association study (PheWAS). Information on drug repurposing for COPD was collected from multiple databases.
RESULTS
A total of 31 potential druggable genes associated with doctor-diagnosed COPD, spirometry-defined COPD, and FEV1 were identified through SMR, HEIDI test, and colocalization analysis. Among them, 22 genes (e.g., MMP15, PSMA4, ERBB3, and LMCD1) were further confirmed by eQTL two-sample MR and protein SMR analyses. Gene-level PheWAS revealed that ERBB3 expression might reduce inflammation, while GP9 and MRC2 were associated with other traits. The drugs Montelukast (targeting the MMP15 gene) and MARIZOMIB (targeting the PSMA4 gene) may reduce the risk of spirometry-defined COPD. Additionally, an existing small molecule inhibitor of the APH1A gene has the potential to increase FEV.
CONCLUSIONS
Our findings identified 22 potential drug targets for COPD and lung function. Prioritizing clinical trials that target these identified druggable genes with existing drugs or novel medications will be beneficial for the development of COPD treatments.
Topics: Pulmonary Disease, Chronic Obstructive; Humans; Mendelian Randomization Analysis; Drug Repositioning; Quantitative Trait Loci; Genome-Wide Association Study; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide
PubMed: 38660492
DOI: 10.3389/fcimb.2024.1386506 -
Journal of Epidemiology and Global... Apr 2024This study examines incidence, mortality, medical expenditure and prescription patterns for asthma on a national scale, particularly in Asian countries for asthma is...
BACKGROUND
This study examines incidence, mortality, medical expenditure and prescription patterns for asthma on a national scale, particularly in Asian countries for asthma is limited. Our aim is to investigate incidence, mortality, prescription patterns and provide a comprehensive overview of healthcare utilization trends for asthma from 2009 to 2018.
METHODS
We included patients diagnosed with asthma between 2009 and 2018. We excluded patients with missing demographic data. Our analysis covered comorbidities, including diabetes mellitus, hypertension, allergic rhinitis, eczema, atopic dermatitis, coronary artery disease, congestive heart failure, chronic kidney disease, chronic hepatitis, stroke, and cancer. Investigated medications comprised oral and intravenous steroids, short-acting beta-agonists, inhaled corticosteroids (ICS), combinations of ICS and long-acting beta-agonists, long-acting muscarinic antagonists, and leukotriene receptor antagonists montelukast. We also assessed the number of outpatient visits, emergency visits, and hospitalizations per year, as well as the average length of hospitalization and average medical costs.
RESULTS
The study included a final count of 88,244 subjects from 1,998,311 randomly selected samples between 2000 and 2019. Over the past decade, there was a gradual decline in newly diagnosed asthma patients per year, from 10,140 to 6,487. The mean age annually increased from 47.59 in 2009 to 53.41 in 2018. Over 55% of the patients were female. Eczema was diagnosed in over 55% of the patients. Around 90% of the patients used oral steroids, with a peak of 97.29% in 2018, while the usage of ICS varied between 86.20% and 91.75%. Intravenous steroids use rose from 40.94% in 2009 to 54.14% in 2018. The average annual hospital stay ranged from 9 to 12 days, with a maximum of 12.26 days in 2013. Lastly, the average medical expenses per year ranged from New Taiwan dollars 5558 to 7921.
CONCLUSIONS
In summary, both asthma incidence and all-cause mortality rates decreased in Taiwan from 2009 to 2018. Further analysis of medical expenses in patients with asthma who required multiple hospitalizations annually revealed an increase in outpatient and emergency visits and hospitalizations, along with longer hospital stays and higher medical costs.
PubMed: 38656730
DOI: 10.1007/s44197-024-00230-8 -
Frontiers in Medicine 2024This network meta-analysis was to analyze and rank the efficacy and safety of different systemic drugs in the treatment of uremic pruritus (UP) among hemodialysis...
Efficacy and safety of different systemic drugs in the treatment of uremic pruritus among hemodialysis patients: a network meta-analysis based on randomized clinical trials.
AIM
This network meta-analysis was to analyze and rank the efficacy and safety of different systemic drugs in the treatment of uremic pruritus (UP) among hemodialysis patients.
METHOD
PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception to 10 July 2023 for randomized controlled trials (RCTs) investigating different drugs in the treatment of UP among hemodialysis patients. Drugs including cromolyn sodium, dexchlorpheniramine, difelikefalin, gabapentin, hydroxyzine, ketotifen, melatonin, montelukast, nalbuphine, nalfurafine, nemolizumab, nicotinamide, pregabalin, sertraline, thalidomide, and placebo were assessed. Outcome measures, including pruritus relief, response, and adverse events, were analyzed. Network plots, forest plots, league tables, and the surface under the cumulative ranking (SUCRA) probabilities were depicted for each outcome.
RESULTS
The network meta-analysis retrieved 22 RCTs. Gabapentin (69.74%) had the highest likelihood to be the most effective drug for pruritus relief in UP patients receiving hemodialysis, followed by cromolyn sodium and hydroxyzine. Thalidomide (60.69%) and gabapentin (58.99%) were associated with significantly more drug responses for treating UP among patients receiving hemodialysis. Patients who were treated with gabapentin (40.01%) were likely to have risks of adverse events and dizziness. Lower risks of adverse events, nausea, and diarrhea were found in patients who received cromolyn sodium and lower risks of somnolence.
CONCLUSION
This study suggests considering gabapentin treatment when facing a patient suffering from UP. This study provides a reference for the selection of drug therapy for UP patients receiving hemodialysis.
PubMed: 38646551
DOI: 10.3389/fmed.2024.1334944 -
International Journal of Biological... 2024Cysteinyl leukotriene receptor 1 (CYSLTR1) is observed to increase in psoriatic skin lesions. Montelukast, a CYSLTR1 antagonist, effectively treats inflammatory...
Cysteinyl leukotriene receptor 1 (CYSLTR1) is observed to increase in psoriatic skin lesions. Montelukast, a CYSLTR1 antagonist, effectively treats inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis, and atopic dermatitis. Thus, blocking CYSLTR1 may be a promising strategy for psoriasis immunotherapy. We prepared a montelukast sodium cream and solution and investigated their effects on psoriasis-like skin lesions induced by imiquimod (IMQ). After the treatment, serum, skin, and spleen samples were collected for evaluation. We treated human T helper (Th) 17 cells with montelukast to study its effect on Th17 differentiation and nuclear factor kappa-B (NF-κB) signaling. We also created a keratinocyte proliferation model induced by M5 cytokines and assessed the influence of montelukast on key psoriasis-related genes. We induced psoriasis in CYSLTR1 knockout (KO) mice using IMQ to explore the role of CYSLTR1 in psoriasis development. Montelukast sodium cream and solution effectively reduced the psoriasis area and severity index (PASI) and alleviated disease symptoms in IMQ-induced mice. Furthermore, reduced infiltration of inflammatory cells (Th1, Th17, and T follicular helper [Tfh] cells), decreased mRNA expression of cytokines in the skin (interleukin [IL]-17/F and IL-23), and lower serum concentrations of various cytokines (IL-2, IL-6, IL-13, and IL-17A/F) were observed. Montelukast cream and solution also decreased spleen size and the proportion of Th17 and Tfh cells, and significantly inhibited NF-κB signaling-related genes after application. Moreover, montelukast inhibited Th17 cell differentiation and suppressed NF-κB signaling . CYSLTR1 KO mice induced with IMQ showed improvement in PASI scores, serum IL-17A/F levels, and lower Th1 and Th17 cells in the spleen and skin compared to wild-type mice. Montelukast also suppressed the proliferation and inflammatory response of keratinocytes by regulating NF-κB signaling. Collectively, our results strongly indicate that inhibition of CYSLTR1 signaling to target the Th17 response holds significant promise as a therapeutic approach to manage psoriasis.
Topics: Humans; Animals; Mice; NF-kappa B; Interleukin-17; Th17 Cells; Psoriasis; Cell Differentiation; Cytokines; Acetates; Cyclopropanes; Quinolines; Sulfides
PubMed: 38617532
DOI: 10.7150/ijbs.92514 -
Animal Models and Experimental Medicine Apr 2024Adenoid hypertrophy (AH) is a common pediatric disease that significantly impacts the growth and quality of life of children. However, there is no replicable and valid...
BACKGROUND
Adenoid hypertrophy (AH) is a common pediatric disease that significantly impacts the growth and quality of life of children. However, there is no replicable and valid model for AH.
METHODS
An AH rat model was developed via comprehensive allergic sensitization, chronic inflammation induction, and chronic intermittent hypoxia (CIH). The modeling process involved three steps: female Sprague-Dawley rats (aged 4-5 weeks) were used for modeling. Allergen sensitization was induced via intraperitoneal administration and intranasal provocation using ovalbumin (OVA); chronic nasal inflammation was induced through intranasal lipopolysaccharide (LPS) administration for sustained nasal irritation; CIH akin to obstructive sleep apnea/hypopnea syndrome was induced using an animal hypoxia chamber. Postmodel establishment, behaviors, and histological changes in nasopharynx-associated lymphoid tissue (NALT) and nasal mucosa were assessed. Arterial blood gas analysis and quantification of serum and tissue levels of (interleukin) IL-4 and IL-13, OVA-specific immunoglobulin E (sIgE), eosinophil cationic protein (ECP), tumor necrosis factor (TNF-α), IL-17, and transforming growth factor (TGF)-β were conducted for assessment. The treatment group received a combination of mometasone furoate and montelukast sodium for a week and then was evaluated.
RESULTS
Rats exhibited notable nasal symptoms and hypoxia after modeling. Histopathological analysis revealed NALT follicle hypertrophy and nasal mucosa inflammatory cell infiltration. Elevated IL-4, IL-13, IL-17, OVA-sIgE, ECP, and TNF-α levels and reduced TGF-β levels were observed in the serum and tissue of model-group rats. After a week of treatment, the treatment group exhibited symptom and inflammatory factor improvement.
CONCLUSION
The model effectively simulates AH symptoms and pathological changes. But it should be further validated for genetic, immunological, and hormonal backgrounds in the currently used and other strains and species.
PubMed: 38572767
DOI: 10.1002/ame2.12396