-
Annals of Medicine and Surgery (2012) Jun 2024Kidney damage can result from various factors, leading to structural and functional changes in the kidney. Acute kidney injury (AKI) refers to a sudden decline in kidney... (Review)
Review
INTRODUCTION
Kidney damage can result from various factors, leading to structural and functional changes in the kidney. Acute kidney injury (AKI) refers to a sudden decline in kidney function, while chronic kidney disease involves a gradual deterioration lasting more than 3 months. Mechanisms of renal injury include impaired microcirculation, inflammation, and oxidative stress. Cysteinyl-leukotrienes (CysLTs) are inflammatory substances contributing to tissue damage. Montelukast, a leukotriene receptor antagonist, has shown potential renoprotective effects in experimental models of kidney injury.
METHODS
The authors conducted a scoping review using PubMed, Scopus, and Web of Science databases to identify relevant studies investigating the impact of montelukast on renal diseases. Articles published until 2022 were included and evaluated for quality. Data extraction and analysis were performed based on predetermined inclusion criteria.
RESULTS
The scoping review included 30 studies from 8 countries. Montelukast demonstrated therapeutic effects in various experimental models of nephrotoxicity and AKI induced by agents such as cisplatin, lipopolysaccharide, diclofenac, amikacin, , cyclosporine, methotrexate, cobalt-60 gamma radiation, doxorubicin, and cadmium. Studies involving human subjects with nephrotic syndrome, pyelonephritis, and other renal diseases also reported positive outcomes with montelukast treatment. Montelukast exhibited anti-inflammatory, anti-apoptotic, antioxidant, and neutrophil-inhibiting properties, leading to improved kidney function and histopathological changes.
CONCLUSIONS
Montelukast shows promise as a renoprotective medication, particularly in early-stage kidney injury. Its ability to mitigate inflammation, oxidative stress, and neutrophil infiltration contributes to its therapeutic effects. Further research is needed to explore the clinical applications and mechanisms underlying the renoprotective action of montelukast.
PubMed: 38846849
DOI: 10.1097/MS9.0000000000002085 -
Frontiers in Immunology 2024Schistosomiasis remains the most devastating neglected tropical disease, affecting over 240 million people world-wide. The disease is caused by the eggs laid by mature...
Schistosomiasis remains the most devastating neglected tropical disease, affecting over 240 million people world-wide. The disease is caused by the eggs laid by mature female worms that are trapped in host's tissues, resulting in chronic Th2 driven fibrogranulmatous pathology. Although the disease can be treated with a relatively inexpensive drug, praziquantel (PZQ), re-infections remain a major problem in endemic areas. There is a need for new therapeutic drugs and alternative drug treatments for schistosomiasis. The current study hypothesized that cysteinyl leukotrienes (cysLTs) could mediate fibroproliferative pathology during schistosomiasis. Cysteinyl leukotrienes (cysLTs) are potent lipid mediators that are known to be key players in inflammatory diseases, such as asthma and allergic rhinitis. The present study aimed to investigate the role of cysLTR1 during experimental acute and chronic schistosomiasis using cysLTR1 mice, as well as the use of cysLTR1 inhibitor (Montelukast) to assess immune responses during chronic infection. Mice deficient of cysLTR1 and littermate control mice were infected with either high or low dose of to achieve chronic or acute schistosomiasis, respectively. Hepatic granulomatous inflammation, hepatic fibrosis and IL-4 production in the liver was significantly reduced in mice lacking cysLTR1 during chronic schistosomiasis, while reduced liver pathology was observed during acute schistosomiasis. Pharmacological blockade of cysLTR1 using montelukast in combination with PZQ reduced hepatic inflammation and parasite egg burden in chronically infected mice. Combination therapy led to the expansion of Tregs in chronically infected mice. We show that the disruption of cysLTR1 is dispensable for host survival during schistosomiasis, suggesting an important role cysLTR1 may play during early immunity against schistosomiasis. Our findings revealed that the combination of montelukast and PZQ could be a potential prophylactic treatment for chronic schistosomiasis by reducing fibrogranulomatous pathology in mice. In conclusion, the present study demonstrated that cysLTR1 is a potential target for host-directed therapy to ameliorate fibrogranulomatous pathology in the liver during chronic and acute schistosomiasis in mice.
Topics: Animals; Receptors, Leukotriene; Mice; Disease Models, Animal; Cyclopropanes; Acetates; Sulfides; Schistosomiasis mansoni; Mice, Knockout; Quinolines; Female; Schistosoma mansoni; Chronic Disease; Leukotriene Antagonists; Liver; Mice, Inbred C57BL; Praziquantel; T-Lymphocytes, Regulatory
PubMed: 38840916
DOI: 10.3389/fimmu.2024.1279043 -
Journal of Affective Disorders Sep 2024Post-marketing surveillance found montelukast use was associated with an increased risk of depression. However, results of observational studies are inconsistent.
BACKGROUND
Post-marketing surveillance found montelukast use was associated with an increased risk of depression. However, results of observational studies are inconsistent.
OBJECTIVE
This study aimed to assess whether montelukast exposure is associated with depression and elucidate the possible molecular mechanism.
METHOD
We conducted a cross-sectional study of 9508 adults from the National Health and Nutrition Examination Survey (NHANES) 2007-2016. Multivariable regression was used to evaluate the association between montelukast exposure and depression. Network pharmacology was conducted to identify the mechanisms of montelukast on depression.
RESULTS
Montelukast exposure had a higher prevalence of depression (37.4 %). In a multivariable logistic regression model adjusted for sociodemographic, behavioural, and health characteristics, montelukast exposure was associated with depression (odds ratio [OR]: 1.61; confidence interval [CI]: 1.18-2.19). Network pharmacology was identified 69 key targets of montelukast on depression. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested montelukast mainly works through multiple pathways in endocrine resistance, chemical carcinogenesis-receptor activation, estrogen signaling pathway, etc. LIMITATIONS: Cross-sectional data.
CONCLUSIONS
The study implies a potential positive association between long-term montelukast exposure and depression through multi-faceted mechanisms. It is suggested that attention be given to the possibility of depression in patients undergoing prolonged montelukast therapy.
Topics: Humans; Acetates; Quinolines; Female; Male; Sulfides; Cyclopropanes; Cross-Sectional Studies; Adult; Middle Aged; Depression; Nutrition Surveys
PubMed: 38824963
DOI: 10.1016/j.jad.2024.05.130 -
The Primary Care Companion For CNS... May 2024
Topics: Humans; Sulfides; Cyclopropanes; Acetates; Quinolines; Male; Psychoses, Substance-Induced; Child; Female; Adolescent; Asthma
PubMed: 38815271
DOI: 10.4088/PCC.23cr03694 -
MedRxiv : the Preprint Server For... May 2024The effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain.
IMPORTANCE
The effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain.
OBJECTIVE
To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19.
DESIGN SETTING AND PARTICIPANTS
The ACTIV-6 platform randomized clinical trial aims to evaluate the effectiveness of repurposed medications in treating mild to moderate COVID-19. Between January 27, 2023, and June 23, 2023, 1250 participants ≥30 years of age with confirmed SARS-CoV-2 infection and ≥2 acute COVID-19 symptoms for ≤7 days, were included across 104 US sites to evaluate the use of montelukast.
INTERVENTIONS
Participants were randomized to receive montelukast 10 mg once daily or matched placebo for 14 days.
MAIN OUTCOMES AND MEASURES
The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID clinical progression scale; and difference in mean time unwell.
RESULTS
Among participants who were randomized and received study drug, the median age was 53 years (IQR 42-62), 60.2% were female, 64.6% identified as Hispanic/Latino, and 56.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR] 1.02; 95% credible interval [CrI] 0.92-1.12; P(efficacy) = 0.63]). Unadjusted median time to sustained recovery was 10 days (95% confidence interval 10-11) in both groups. No deaths were reported and 2 hospitalizations were reported in each group; 36 participants reported healthcare utilization events (a priori defined as death, hospitalization, emergency department/urgent care visit); 18 in the montelukast group compared with 18 in the placebo group (HR 1.01; 95% CrI 0.45-1.84; P(efficacy)=0.48). Five participants experienced serious adverse events (3 with montelukast and 2 with placebo).
CONCLUSIONS AND RELEVANCE
Among outpatients with mild to moderate COVID-19, treatment with montelukast does not reduce duration of COVID-19 symptoms.
TRIAL REGISTRATION
ClinicalTrials.gov ( NCT04885530 ).
PubMed: 38798524
DOI: 10.1101/2024.05.16.24307115 -
Medicina (Kaunas, Lithuania) Apr 2024: The influence of montelukast (MK), an antagonist of cysLT1 leukotriene receptors, on lung lesions caused by experimental diabetes was studied. : The study was...
: The influence of montelukast (MK), an antagonist of cysLT1 leukotriene receptors, on lung lesions caused by experimental diabetes was studied. : The study was conducted on four groups of six adult male Wistar rats. Diabetes was produced by administration of streptozotocin 65 mg/kg ip. in a single dose. Before the administration of streptozotocin, after 72 h, and after 8 weeks, the serum values of glucose, SOD, MDA, and total antioxidant capacity (TAS) were determined. After 8 weeks, the animals were anesthetized and sacrificed, and the lungs were harvested and examined by optical microscopy. Pulmonary fibrosis, the extent of lung lesions, and the lung wet-weight/dry-weight ratio were evaluated. : The obtained results showed that MK significantly reduced pulmonary fibrosis (3.34 ± 0.41 in the STZ group vs. 1.73 ± 0.24 in the STZ+MK group < 0.01) and lung lesion scores and also decreased the lung wet-weight/dry-weight (W/D) ratio. SOD and TAS values increased significantly when MK was administered to animals with diabetes (77.2 ± 11 U/mL in the STZ group vs. 95.7 ± 13.3 U/mL in the STZ+MK group, < 0.05, and 25.52 ± 2.09 Trolox units in the STZ group vs. 33.29 ± 1.64 Trolox units in the STZ+MK group, respectively, < 0.01), and MDA values decreased. MK administered alone did not significantly alter any of these parameters in normal animals. : The obtained data showed that by blocking the action of peptide leukotrienes on cysLT1 receptors, montelukast significantly reduced the lung lesions caused by diabetes. The involvement of these leukotrienes in the pathogenesis of fibrosis and other lung diabetic lesions was also demonstrated.
Topics: Sulfides; Cyclopropanes; Animals; Quinolines; Acetates; Rats, Wistar; Diabetes Mellitus, Experimental; Male; Rats; Lung; Pulmonary Fibrosis; Leukotriene Antagonists; Streptozocin; Blood Glucose
PubMed: 38792932
DOI: 10.3390/medicina60050749 -
Medicina (Kaunas, Lithuania) Apr 2024The guidelines for chronic urticaria in children contain recommendations that are often based on adult studies. The diagnostic pathway has not been standardized and the... (Observational Study)
Observational Study
The guidelines for chronic urticaria in children contain recommendations that are often based on adult studies. The diagnostic pathway has not been standardized and the effectiveness of anti-H1, omalizumab, montelukast, and systemic glucocorticoids is rarely reported in the pediatric population. There is a wide variation in the rate of remission of chronic urticaria between studies. The aim of this study is to enhance our understanding of pediatric chronic urticaria. This study enrolled 37 children with chronic urticaria aged from 0 to 18 years. Demographic parameters, medical history, clinical features, laboratory data and treatment information were collected. Children were treated with the recommended dosage of second-generation H1-antihistamines, which was increased by up to twofold. Omalizumab was added for refractory anti-H1 patients. A three-day course with systemic glucocorticoids was administered for severe exacerbations. Montelukast was administered to some children. : Wheals without angioedema were common. Chronic urticaria was spontaneous in 32 children (86.48%), inducible in 2 (5.41%), induced by a parasite in 1 and vasculitic in 2. Treatment of the potential causes of chronic urticaria was of no benefit, except for eradication of Dientamoeba fragilis. Chronic urticaria was resolved within three years in 45.9% of cases. Allergic diseases were present in nine children (24.32%) and autoimmune diseases were present in three (8.11%). All children were treated with anti-H1 at the licensed dose or at a higher dose. A partial or complete response to anti-H1 was observed in 29 (78.38%) patients. Montelukast showed no benefit. All children treated with omalizumab responded. Systemic glucocorticoids were successfully used to treat exacerbations. Our findings indicate that laboratory tests should not be routinely performed in children with chronic urticaria without clinical suspicion. However, comorbidities such as thyroid autoimmune disease and coeliac disease are suggested to be monitored over the chronic urticaria course. These clinical conditions could be diagnosed from the diagnostic framework of chronic urticaria. Increasing the dosage of anti-H1 and omalizumab was effective in children resistant to standard treatment but we still need further studies to generate a standard patient-centered treatment.
Topics: Humans; Child; Female; Male; Child, Preschool; Adolescent; Chronic Urticaria; Infant; Sulfides; Cyclopropanes; Quinolines; Acetates; Omalizumab; Histamine H1 Antagonists; Glucocorticoids; Anti-Allergic Agents; Infant, Newborn; Chronic Disease; Urticaria
PubMed: 38792886
DOI: 10.3390/medicina60050704 -
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 -
British Journal of Pharmacology May 2024Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss and consequent muscle atrophy, for which no...
BACKGROUND AND PURPOSE
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss and consequent muscle atrophy, for which no effective therapies are available. Recent findings reveal that disease progression is fuelled by early aberrant neuroinflammation and the loss of oligodendrocytes with neuroprotective and remyelinating properties. On this basis, pharmacological interventions capable of restoring a pro-regenerative local milieu and re-establish proper oligodendrocyte functions may be beneficial.
EXPERIMENTAL APPROACH
Here, we evaluated the in vivo therapeutic effects of montelukast (MTK), an antagonist of the oligodendroglial G protein-coupled receptor 17 (GPR17) and of cysteinyl-leukotriene receptor 1 (CysLTR) receptors on microglia and astrocytes, in the SOD1 ALS mouse model. We chronically treated SOD1 mice with MTK, starting from the early symptomatic disease stage. Disease progression was assessed by behavioural and immunohistochemical approaches.
KEY RESULTS
Oral MTK treatment significantly extended survival probability, delayed body weight loss and ameliorated motor functionalityonly in female SOD1 mice. Noteworthy, MTK significantly restored oligodendrocyte maturation and induced significant changes in the reactive phenotype and morphological features of microglia/macrophages and astrocytes in the spinal cord of female SOD1 mice, suggesting enhanced pro-regenerative functions. Importantly, concomitant MN preservation has been detected after MTK administration. No beneficial effects were observed in male mice, highlighting a sex-based difference in the protective activity of MTK.
CONCLUSIONS AND IMPLICATIONS
Our results provide the first preclinical evidence indicating that repurposing of MTK, a safe and marketed anti-asthmatic drug, may be a promising sex-specific strategy for personalized ALS treatment.
PubMed: 38751168
DOI: 10.1111/bph.16408 -
Spectrochimica Acta. Part A, Molecular... Sep 2024A green, sensitive and rapid spectrofluorimetric method for quantitative assay of an anti-allergic medication composed of montelukast and fexofenadine mixture in raw...
A green, sensitive and rapid spectrofluorimetric method for quantitative assay of an anti-allergic medication composed of montelukast and fexofenadine mixture in raw materials and dosage form was developed. The method was based on measuring the synchronous fluorimetric peak without interference, pre-separation or pre-extraction procedures. Montelukast was analyzed at 360 nm while fexofenadine was measured at 263 nm using Δλ = 20 nm for both drugs using ethanol as diluting solvent and acetate buffer of pH 4. The assay was rectilinear over the concentration range of 1.0-10.0 μg/mL for fexofenadine and 0.1-0.6 μg/mL for montelukast. The method was full validated according to ICH guidelines. The applicability of the method enables the assay of both drugs in raw materials, synthetic mixture as well as combined tablets. Moreover, the greenness of the method was assessed using different methods including; analytical eco-scale, GAPI and AGREE. All of these methods confirm that the proposed method is an eco-friendly method.
Topics: Cyclopropanes; Spectrometry, Fluorescence; Terfenadine; Quinolines; Acetates; Sulfides; Anti-Allergic Agents; Green Chemistry Technology; Tablets; Reproducibility of Results; Limit of Detection; Dosage Forms; Hydrogen-Ion Concentration
PubMed: 38728846
DOI: 10.1016/j.saa.2024.124371