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Journal of Pharmaceutical and... Sep 2023Recent studies presented the crucial role of montelukast (MON, a leukotriene receptor antagonist) against gouty arthritis and its protective effect on drug-induced liver...
A feasible HPTLC method for concurrent quantitation of allopurinol-montelukast co-therapy in plasma and evaluation of their hepatic and renal effects in rats: Analytical, biochemical, and histopathological study.
Recent studies presented the crucial role of montelukast (MON, a leukotriene receptor antagonist) against gouty arthritis and its protective effect on drug-induced liver and kidney injury. Allopurinol (ALO, a selective xanthine oxidase inhibitor) is also used for treatment of hyperuricemia, however, it induces hepatotoxicity and acute kidney injury. Therefore, this study introduces the first analytical/biochemical/histopathological assay for MON-ALO co-therapy and aims to: inspect the hepatic and renal impacts of ALO, MON and their combination in rats via biochemical and histopathological examinations, propose and validate a facile HPTLC method for concurrent estimation of ALO-MON binary mixture in human plasma, and employ this method to attain the targeted drugs in real rat plasma. First, the cited drugs in human plasma were simultaneously separated utilizing silica gel G 60 F-TLC plates. The separated bands were scanned at 268 nm demonstrating appropriate linearities (50.0-2000.0 ng band for each drug) and correlations (0.9986 and 0.9992 for ALO and MON, correspondingly). The calculated detection and quantitation limits, as well as recoveries confirmed the method's reliability. This procedure was validated, and the stability studies were achieved according to Bioanalytical Method Validation Guideline. This work was extended to investigate the possible hepatic and renal effects of ALO, MON and their co-therapy in rats. Using rat's gastric tube, the following was administered to four groups of male Wistar rats: Group Ia and Ib as control (received either saline or DMSO), Groups II, III, and IV were given MON, ALO, and MON+ALO, respectively. Good correlation between the measured biochemical parameters and the observed histopathological changes was encountered. Considerable drop in aspartate transaminase and alanine transaminase levels, in addition to lower liver damage changes were observed in the combination group compared to MON or ALO-treated groups. Regarding renal changes, ALO-MON co-therapy caused elevation in the serum creatinine and blood urea nitrogen levels when compared to controls and MON- or ALO-treated groups. Severe proteinaceous casts accumulation in kidney tubular lumen, severe congestion, and severe tubular necrosis were also noticed in the combination group. Lastly, this study suggests ALO-MON co-treatment not only as a preventive therapy against gouty arthritis but also as a new line to minimize ALO-induced hepatic injury. However, co-administration of ALO and MON should be further studied to assess the benefits and risks in various tissues, adjust the MON dosing, and monitor its nephrotoxic effect.
Topics: Humans; Rats; Male; Animals; Rats, Wistar; Allopurinol; Arthritis, Gouty; Reproducibility of Results; Kidney; Liver
PubMed: 37186992
DOI: 10.1016/j.jpba.2023.115439 -
Journal of Affective Disorders Jul 2024Post-market monitoring has shown a potential link between the use of leukotriene-modifying agents (LTRAs) and an increased risk of neuropsychiatric events, such as...
INTRODUCTION
Post-market monitoring has shown a potential link between the use of leukotriene-modifying agents (LTRAs) and an increased risk of neuropsychiatric events, such as depression. However, observational studies have produced inconsistent findings, offering no definitive conclusions.
OBJECTIVE
To assess the potential correlation between LTRAs exposure and depression in US adults.
METHOD
This cross-sectional study, based on population data from the National Health and Nutrition Examination Survey (NHANES) 2007-2016 cycle. The Patient Health Questionnaire-9 was used to assess depression. Multivariable regression was used to evaluate the association between LTRAs exposure and depression. Sensitivity and subgroup analyses were conducted, with the calculation of the E-value. Network pharmacology was employed to investigate the influence of LTRAs on mechanisms of depression.
RESULTS
Among the 9414 participants, 595 (6.3 %) were classified as having depression. LTRAs exposure was associated with a higher prevalence of depression (16.9 % vs. 6.0 %). The multivariable logistic regression results showed that LTRAs use increased the risk of depression (OR = 1.70; 95 % CI, 1.05-2.75). An association between LTRAs exposure and depression was found in sensitivity analyses conducted regardless of multivariable linear regression with the PHQ-9 score as a continuous variable (β = 0.97; 95 % CI, 0.44-1.50) or multivariable logistic regression with the PHQ-9 cut-off of 5 (OR = 1.52; 95 % CI, 1.08-2.14). The association between LTRAs and depression was stable in the different subgroups.
CONCLUSION
LTRAs exposure is positively associated with depression in US adults. Therefore, the risk for depression in patients receiving long-term LTRAs treatment should be considered.
Topics: Humans; Cross-Sectional Studies; Male; Female; Middle Aged; Adult; Depression; Nutrition Surveys; United States; Leukotriene Antagonists; Prevalence; Risk Factors; Aged
PubMed: 38663558
DOI: 10.1016/j.jad.2024.04.095 -
Cureus Sep 2023Progesterone hypersensitivity (PH) is a rare hypersensitivity reaction to either endogenous or exogenous progesterone. There are around 200 reported cases of...
Progesterone hypersensitivity (PH) is a rare hypersensitivity reaction to either endogenous or exogenous progesterone. There are around 200 reported cases of progesterone hypersensitivity in the medical literature. We present the case of a 31-year-old female who presented with cyclical urticaria and angioedema after exogenous progesterone exposure. Her symptoms would begin a few days before her menstrual cycle began and resolve after menstruation. She only had partial recovery of her symptoms with antihistamines, steroids, montelukast, and omalizumab. She needed treatment with oral contraceptives and had a resolution of symptoms, but subsequently developed a recurrence again. Given the rarity of this condition, the diagnosis is often delayed. This diagnosis should be considered for women of reproductive age who present with cyclic hypersensitivity or allergic symptoms.
PubMed: 37680259
DOI: 10.7759/cureus.44776 -
Chirality Dec 2023Montelukast sodium (MLS) is a leukotriene receptor antagonist that relieves asthma, bronchospasm, allergic rhinitis, and urticaria. A simple, robust, and...
Separation and quantitative estimation of stereo-selective enantiomers of montelukast in pharmaceutical drug substance and tablets dosage forms by using stability-indicating normal phase-HPLC method.
Montelukast sodium (MLS) is a leukotriene receptor antagonist that relieves asthma, bronchospasm, allergic rhinitis, and urticaria. A simple, robust, and stability-indicating normal phase high-performance liquid chromatography method was developed to separate and quantitatively estimate the S-enantiomer of MLS. The chiral separation was achieved using USP L51 packing material along with a mobile phase consisting of a solvent mixture (n-hexane, ethanol, and propionic acid), a flow rate of 1.0 mL/min, a detection wavelength of 284 nm, a column temperature of 30°C and an injection volume of 20 μL. The enantiomers peaks were well separated from the peaks of the placebo, diluting solvent, MLS, and its known impurities with a resolution of more than 2.2 and with no interference. Accuracy and linearity were studied in a range of 0.36-3.597 μg/mL (0.03%-0.30%), with good recoveries between 92.5% and 96.8% and a linear regression coefficient above 0.996. The suggested chiral chromatography method is being considered as an alternative and equivalent method to the United States Pharmacopeia and European Pharmacopeia monographs. The developed method was effectively employed for the study of release and stability samples of MLS. This HPLC method is also capable of separating and estimating the stereo-selective isomers (R- and S-enantiomers) of sulfoxide impurity of MLS in pharmaceutical medicine.
Topics: Chromatography, High Pressure Liquid; Stereoisomerism; Tablets; Solvents; Acetates; Cyclopropanes; Quinolines; Sulfides
PubMed: 37461225
DOI: 10.1002/chir.23610 -
CNS & Neurological Disorders Drug... Sep 2023Alzheimer's disease (AD) is an overwhelming neurodegenerative disease with progressive loss of memory. AD is characterized by the deposition of the senile plaques mainly...
Montelukast Ameliorates Scopolamine-induced Alzheimer's Disease: Role on Cholinergic Neurotransmission, Antioxidant Defence System, Neuroinflammation and Expression of BDNF.
BACKGROUND
Alzheimer's disease (AD) is an overwhelming neurodegenerative disease with progressive loss of memory. AD is characterized by the deposition of the senile plaques mainly composed of β-amyloid (Aβ) fragment, BDNF decline, Cholinergic system overactivity and neuroinflammation. Montelukast (MTK), a leukotriene receptor antagonist, showed astounding neuroprotective effects in a variety of neurodegenerative disorders.
OBJECTIVE
This study aims to investigate the ameliorative effects of Montelukast in the scopolamineinduced Alzheimer's disease (AD) model in rats and evaluate its activity against neuroinflammation.
METHODS
Thirty rats were split into five groups: Control group (1 mL/kg normal saline, i.p.), Montelukast perse (10 mg/kg, i.p.), Disease group treated with Scopolamine (3 mg/kg, i.p.), Donepezil group (3 mg/kg, i.p.), Montelukast treatment group (10 mg/kg, i.p.) and behavioural and biochemical tests were carried out to assess the neuro protective effect.
RESULTS
Scopolamine treatment led to a significant reduction in learning and memory and an elevation in cholinesterase levels when compared with the control group (p < 0.01). Additionally, elevated oxidative stress and Amyloid-β levels were associated with enhanced neuroinflammation (p < 0.05, p < 0.01). Furthermore, the decline in neurotrophic factor BDNF is also observed when compared with the normal control group (p < 0.01). Montelukast pre-treatment significantly attenuated learning and memory impairment and cholinesterase levels. Besides, Montelukast and standard drug donepezil administration significantly suppressed the oxidative stress markers (p < 0.01), Amyloid-β levels, neuroinflammatory mediators (p < 0.05) and caused a significant increase in BDNF levels (p < 0.05) Conclusion: Montelukast bestowed ameliorative effects in scopolamine-induced AD animal models as per the previous studies via attenuation of memory impairment, cholinesterase neurotransmission, oxidative stress, Amyloid-β levels, neuroinflammatory mediators and enhanced BDNF levels.
PubMed: 37779395
DOI: 10.2174/0118715273258337230925040049 -
American Journal of Translational... 2023This study was designed to determine the effects of montelukast sodium combined with budesonide on pulmonary function, serum immunoglobulin (Ig)E levels, and eosinophil...
OBJECTIVE
This study was designed to determine the effects of montelukast sodium combined with budesonide on pulmonary function, serum immunoglobulin (Ig)E levels, and eosinophil (EOS) percentage in children comorbid with allergic rhinitis (AR) and asthma.
METHODS
The medical records of 114 children comorbid with AR and asthma treated in the Guizhou Provincial People's Hospital from February 2020 to September 2022 were collected and analyzed retrospectively. Among them, 54 children treated with budesonide were assigned to a control group, and the remaining 60 children treated with montelukast sodium combined with budesonide were assigned to an observation group. The efficacy was compared between the two groups. Additionally, the changes in pulmonary function, serum IgE levels, and EOS percentage were compared between the two groups before and after treatment (one month). The adverse reactions during the treatment and the recurrence of AR within 3 months were recorded. Logistics regression was conducted to analyze the risk factors affecting the efficacy in children.
RESULTS
The observation group showed a significantly higher overall response rate than the control group (P<0.05). After treatment, the observation group showed significantly higher levels of forced expiratory volume in 1 second (FEV1)%, FEV1/forced vital capacity (FVC), and peak expiratory flow (PEF) than the control group (P<0.05), and significantly lower IgE levels and EOS percentage than the control group (P<0.05). No significant difference was found between the two groups in terms of the total incidence of adverse reactions (P>0.05). According to the follow-up results of prognosis, the observation group presented a greatly lower recurrence rate of AR within 3 months than the control group (P<0.05). Multivariate logistics regression analysis showed that therapeutic regimen, IgE, and EOS were independent risk factors affecting the efficacy in the patients (P<0.05).
CONCLUSION
Montelukast sodium combined with budesonide can substantially improve the pulmonary function in children with comorbid AR and asthma, alleviate their symptoms of asthma and rhinitis, and lower the IgE level and EOS percentage. In addition, therapeutic regimen, IgE and EOS are independent risk factors affecting the efficacy in patients.
PubMed: 38186993
DOI: No ID Found -
Odontology Oct 2023Bone metabolism and repair are directly regulated by arachidonic acid metabolites. At present, we analyzed the dose-response effects of a selective cysteinyl leukotriene...
Bone metabolism and repair are directly regulated by arachidonic acid metabolites. At present, we analyzed the dose-response effects of a selective cysteinyl leukotriene receptor type-1 antagonist during bone repair after tooth extraction and on non-injured skeleton. Sixty-three 129 Sv/Ev male mice composed the groups: C-Control (saline solution); MTK2-2 mg/Kg of Montelukast (MTK) and MTK4-4 mg/Kg of MTK, daily administered by mouth throughout all experimental periods set at 7, 14, and 21 days post-operative. Dental sockets were analyzed by computed microtomography (microCT), histopathology, and immunohistochemistry. Femurs, L5 vertebra and organs were also removed for observation. Blood was collected for plasma bone and liver markers. Histopathology and microCT analysis revealed early socket repair of MTK2 and MTK4 animals, with significant increased BV/TV at days 14 and 21 compared to C. Higher plasma calcium was detected at days 7 and 21 in MTK4 in comparison to C, while phosphate was significantly increased in MTK2 in the same periods in comparison to C and MTK4. No significant differences were found regarding plasma ALP and TRAP, neither for local TRAP and Runx2 immunolabeling at the healing sockets. Organs did not present histological abnormalities. Increased AST levels have been detected in distinct groups and periods. In general, femur phenotype was improved in MTK treated animals. Collectively, MTK promoted early bone formation after tooth extraction and increased bone quality of femurs and vertebra in a time-dose-dependent manner, and should be considered as an alternative therapy when improved post-extraction socket repair or skeleton preservation is required.
Topics: Male; Mice; Animals; Tooth Socket; Wound Healing; Tooth Extraction; Acetates
PubMed: 36920595
DOI: 10.1007/s10266-023-00800-5 -
Molecular Medicine Reports Aug 2024Montelukast and zafirlukast, cysteinyl leukotriene receptor antagonists (LTRAs), trigger apoptosis and inhibit cell proliferation of triple‑negative breast cancer...
Differential effects of montelukast and zafirlukast on MDA‑MB‑231 triple‑negative breast cancer cells: Cell cycle regulation, apoptosis, autophagy, DNA damage and endoplasmic reticulum stress.
Montelukast and zafirlukast, cysteinyl leukotriene receptor antagonists (LTRAs), trigger apoptosis and inhibit cell proliferation of triple‑negative breast cancer MDA‑MB‑231 cells. By contrast, only zafirlukast induces G/G cell cycle arrest. The present study compared the effects of these drugs on proteins regulating cell proliferation, apoptosis, autophagy, and endoplasmic reticulum (ER) and oxidative stress using reverse transcription‑quantitative PCR, western blotting and flow cytometry. The expression of proliferating markers, Ki‑67 and proliferating cell nuclear antigen, was decreased by both drugs. Zafirlukast, but not montelukast, decreased the expression of cyclin D1 and CDK4, disrupting progression from G to S phase. Zafirlukast also increased the expression of p27, a cell cycle inhibitor. Both drugs decreased the expression of anti‑apoptotic protein Bcl‑2 and ERK1/2 phosphorylation, and increased levels of the autophagy marker LC3‑II and DNA damage markers, including cleaved PARP‑1, phosphorylated (p)‑ATM and p‑histone H2AX. The number of caspase 3/7‑positive cells was greater in montelukast‑treated cells compared with zafirlukast‑treated cells. Montelukast induced higher levels of the ER stress marker CHOP compared with zafirlukast. Montelukast activated PERK, activating transcription factor 6 (ATF6) and inositol‑requiring enzyme type 1 (IRE1) pathways, while zafirlukast only stimulated ATF6 and IRE1 pathways. GSK2606414, a PERK inhibitor, decreased apoptosis mediated by montelukast, but did not affect zafirlukast‑induced cell death. The knockdown of CHOP by small interfering RNA reduced apoptosis triggered by montelukast and zafirlukast. In conclusion, the effects on cell cycle regulator proteins may contribute to cell cycle arrest caused by zafirlukast. The greater apoptotic effects of montelukast may be caused by the higher levels of activated caspase enzymes and the activation of three pathways of ER stress: PERK, ATF6, and IRE1.
Topics: Humans; Sulfides; Cyclopropanes; Quinolines; Apoptosis; Acetates; Endoplasmic Reticulum Stress; Cell Line, Tumor; Autophagy; Sulfonamides; Indoles; Female; DNA Damage; Phenylcarbamates; Tosyl Compounds; Cell Proliferation; eIF-2 Kinase; Endoribonucleases; Cell Cycle Checkpoints; Transcription Factor CHOP; Cell Cycle; Leukotriene Antagonists; Protein Serine-Threonine Kinases
PubMed: 38904207
DOI: 10.3892/mmr.2024.13265 -
Heliyon Jan 2024Montelukast, an approved leukotriene receptor 1 (Cys-LT 1) antagonist with anti-inflammatory properties is used for the treatment of asthma and allergic rhinitis. In the...
Anti-enzymatic and DNA docking studies of montelukast: A multifaceted molecular scaffold with investigations, molecular expression analysis and molecular dynamics simulations.
Montelukast, an approved leukotriene receptor 1 (Cys-LT 1) antagonist with anti-inflammatory properties is used for the treatment of asthma and allergic rhinitis. In the present studies, montelukast was subjected to inhibitory assays followed by kinetic and investigations. Montelukast demonstrated inhibitory activity against yeast α-glucosidase (IC 44.31 ± 1.21 μM), jack bean urease (JB urease, IC 8.72 ± 0.23 μM), human placental alkaline phosphatase (hPAP, IC 17.53 ± 0.19 μM), bovine intestinal alkaline phosphatase (bIAP, IC 15.18 ± 0.23 μM) and soybean 15-lipoxygenase (15-LOX, IC 2.41 ± 0.13 μM). Kinetic studies against α-glucosidase and urease enzymes revealed its competitive mode of inhibition. Molecular expression analysis of montelukast in breast cancer cell line MCF-7 down-regulated AP by a factor of 0.27 (5 μM) compared with the 0.26 value for standard inhibitor levamisole (10 μM). Molecular docking estimated a binding affinity ranging -8.82 to -15.65 kcal/mol for the enzymes. Docking against the DNA dodecamer (ID: 1BNA) observed -9.13 kcal/mol via minor groove binding. MD simulations suggested stable binding between montelukast and the target proteins predicting strong inhibitory potential of the ligand. Montelukast features a chloroquinoline, phenyl ring, a cyclopropane group, a carboxylic group and a sulfur atom all of which collectively enhance its inhibitory potential against the said enzymes. These and computational investigations demonstrate that it is possible and suggested that the interactions of montelukast with more than one targets presented herein may be linked with the side effects presented by this drug and necessitate additional work. The results altogether suggest montelukast as an important structural scaffold possessing multitargeted features and warrant further investigations in repurposing beyond its traditional pharmacological use.
PubMed: 38298631
DOI: 10.1016/j.heliyon.2024.e24470 -
Clinical Drug Investigation Aug 2023Montelukast's new boxed warning for neuropsychiatric events questions its use in the setting of coronavirus disease 2019 (COVID-19) due to increased risk for new-onset... (Observational Study)
Observational Study
Evaluating the Association of Montelukast Use on Neuropsychiatry-Related Healthcare Utilization and Depression in COVID-19-Hospitalized Veterans: A Nationwide VA Observational Cohort Study.
BACKGROUND
Montelukast's new boxed warning for neuropsychiatric events questions its use in the setting of coronavirus disease 2019 (COVID-19) due to increased risk for new-onset psychiatric diagnoses.
OBJECTIVE
We aim to evaluate the impact of using montelukast in patients hospitalized with COVID-19 on neuropsychiatry-related healthcare utilization and depression.
METHODS
This retrospective nationwide observational cohort study using the Veterans Health Administration database included patients from January 1, 2020, through July 1, 2021. The treatment cohorts consisted of patients with and without montelukast use prior to COVID-19 hospitalization and matched using propensity score (PS) to two control cohorts: patients with COVID-19-related hospitalization without prior montelukast use and patients with prior montelukast use who were hospitalized for reasons other than COVID-19. The primary outcome of psychiatric hospitalizations at 90 days and 180 days and mental health visits at 180 days were compared using Poisson or negative binomial regression. Secondary outcomes of new-onset depression and new use of antidepressants were analyzed using multivariable logistic regression.
RESULTS
After PS matching, a total of 415 patients were included in COVID-19 with and without montelukast matched cohort and 409 patients in montelukast with and without COVID-19-related hospitalization matched cohorts. For the primary outcomes, inpatient psychiatric hospitalization at 90 days [incidence rate ratio (IRR) 95% CI 1.79 (1.36-2.36)] and 180 days [IRR 95% CI 1.79 (1.32-2.25)] and mental health visits at 180 days [IRR 95% CI 1.72 (1.45-2.03)] were significantly higher in the montelukast with COVID-19 hospitalization group compared with those hospitalized without COVID-19. No difference in primary outcomes were noted in patients hospitalized with COVID-19 with and without use of montelukast. No significant difference was found in the secondary outcomes between either comparator group.
CONCLUSIONS
Patients with prior montelukast use who were hospitalized with COVID-19 appeared to have increased rate of neuropsychiatry-related healthcare utilization.
Topics: Humans; Retrospective Studies; COVID-19; Veterans; Depression; Neuropsychiatry; Cohort Studies; Hospitalization; Patient Acceptance of Health Care
PubMed: 37498493
DOI: 10.1007/s40261-023-01292-5