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International Journal of Molecular... Oct 2021Characterization of new pharmacological targets is a promising approach in research of neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently...
Characterization of new pharmacological targets is a promising approach in research of neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently been proposed as an interesting pharmacological target, e.g., in neuroregenerative processes. Using the well-established model of organotypic slice co-cultures of the mesocortical dopaminergic system (prefrontal cortex (PFC) and substantia nigra/ventral tegmental area (SN/VTA) complex), the influence of GPR17 ligands on neurite outgrowth from SN/VTA to the PFC was investigated. The growth-promoting effects of Montelukast (MTK; GPR17- and cysteinyl-leukotriene receptor antagonist), the glial cell line-derived neurotrophic factor (GDNF) and of two potent, selective GPR17 agonists (PSB-16484 and PSB-16282) were characterized. Treatment with MTK resulted in a significant increase in mean neurite density, comparable with the effects of GDNF. The combination of MTK and GPR17 agonist PSB-16484 significantly inhibited neuronal growth. qPCR studies revealed an MTK-induced elevated mRNA-expression of genes relevant for neuronal growth. Immunofluorescence labelling showed a marked expression of GPR17 on NG2-positive glia. Western blot and RT-qPCR analysis of untreated cultures suggest a time-dependent, injury-induced stimulation of GPR17. In conclusion, MTK was identified as a stimulator of neurite fibre outgrowth, mediating its effects through GPR17, highlighting GPR17 as an interesting therapeutic target in neuronal regeneration.
Topics: Acetates; Animals; Animals, Newborn; Coculture Techniques; Cyclopropanes; Drug Evaluation, Preclinical; Female; Leukotriene Antagonists; Male; Nerve Regeneration; Neuronal Outgrowth; Quinolines; Rats; Receptors, G-Protein-Coupled; Sulfides
PubMed: 34769111
DOI: 10.3390/ijms222111683 -
Drug Design, Development and Therapy 2021The aim of this study was to assess and compare the pharmacokinetic (PK) properties and bioequivalence of montelukast sodium chewable tablets prepared by two different... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The aim of this study was to assess and compare the pharmacokinetic (PK) properties and bioequivalence of montelukast sodium chewable tablets prepared by two different manufacturers in healthy Chinese volunteers to obtain adequate PK evidence for the registration approval of the test formulation.
PATIENTS AND METHODS
A randomized-sequence, single-dose, open-label, 2-period crossover study was conducted in fasted and fed healthy Chinese volunteers (Chinese Clinical Trials Registry identifier: CTR20182362). Eighteen subjects each were selected for a fasted study and a fed study. Eligible participants were randomly assigned in a 1:1 ratio to receive a single dose of the reference formulation or the test formulation, followed by a 5-day washout period and the administration of the alternate formulation. Plasma samples were collected over a 24-hour period following tablet administration and analyzed for montelukast contents by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The PK parameters, such as maximum serum concentration (C), area under the curve (AUC) from t = 0 to the last quantifiable concentration (AUC), AUC from t = 0 to infinity (AUC), half-life (t), time to C (T), and terminal elimination rate constant (λ), were evaluated. The safety assessment included changes in vital signs (blood pressure, pulse, and temperature) or laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) and the incidence of adverse events (AEs).
RESULTS
The geometric mean ratios (GMRs) between the two formulations for the primary pharmacokinetic parameters (C, AUC, and AUC ) and the corresponding 90% confidence intervals (Cis) were all within the range of 80.00-125.00% for both the fasting and fed states. The safety profiles for both treatments were comparable.
CONCLUSION
The PK analysis revealed that the test and reference formulations of montelukast sodium chewable tablets were bioequivalent and well-tolerated by healthy Chinese subjects.
Topics: Acetates; Administration, Oral; Adolescent; Adult; Asian People; Cross-Over Studies; Cyclopropanes; Drug Compounding; Fasting; Female; Healthy Volunteers; Humans; Male; Middle Aged; Quinolines; Sulfides; Tablets; Therapeutic Equivalency; Young Adult
PubMed: 33727797
DOI: 10.2147/DDDT.S298355 -
Pharmaceutics Jul 2023Earlier studies with montelukast (M) and telmisartan (T) have revealed their potential antiviral properties against SARS-CoV-2 wild-type (WT) but have not assessed their...
Earlier studies with montelukast (M) and telmisartan (T) have revealed their potential antiviral properties against SARS-CoV-2 wild-type (WT) but have not assessed their efficacy against emerging Variants of Concern (VOCs) such as Omicron. Our research fills this gap by investigating these drugs' impact on VOCs, a topic that current scientific literature has largely overlooked. We employed computational methodologies, including molecular mechanics and machine learning tools, to identify drugs that could potentially disrupt the SARS-CoV-2 spike RBD-ACE2 protein interaction. This led to the identification of two FDA-approved small molecule drugs, M and T, conventionally used for treating asthma and hypertension, respectively. Our study presents an additional potential use for these drugs as antivirals. Our results show that both M and T can inhibit not only the WT SARS-CoV-2 but also, in the case of M, the Omicron variant, without reaching cytotoxic concentrations. This novel finding fills an existing gap in the literature and introduces the possibility of repurposing these drugs for SARS-CoV-2 VOCs, an essential step in responding to the evolving global pandemic.
PubMed: 37514075
DOI: 10.3390/pharmaceutics15071891 -
Plastic and Reconstructive Surgery Jul 2022Burns are severe injuries often associated with impaired wound healing. Impaired healing is caused by multiple factors, including dysregulated inflammatory responses at...
BACKGROUND
Burns are severe injuries often associated with impaired wound healing. Impaired healing is caused by multiple factors, including dysregulated inflammatory responses at the wound site. Interestingly, montelukast, an antagonist for cysteinyl leukotrienes and U.S. Food and Drug Administration approved for treatment of asthma and allergy, was previously shown to enhance healing in excision wounds and to modulate local inflammation.
METHODS
In this study, the authors examined the effect of montelukast on wound healing in a mouse model of scald burn injury. Burn wound tissues isolated from montelukast- and vehicle-treated mice at various times after burn injury were analyzed for wound areas ( n = 34 to 36), reepithelialization ( n = 14), inflammation ( n = 8 to 9), and immune cell infiltration ( n = 3 to 6) and proliferation ( n = 7 to 8).
RESULTS
In contrast to previously described beneficial effects in excision wounds, this study shows that montelukast delays burn wound healing by impairing the proliferation of keratinocytes and endothelial cells. This occurs largely independently of inflammatory responses at the wound site, suggesting that montelukast impairs specifically the proliferative phase of wound healing in burns. Wound healing rates in mice in which leukotrienes are not produced were not affected by montelukast.
CONCLUSION
Montelukast delays wound healing mainly by reducing the proliferation of local cells after burn injury.
CLINICAL RELEVANCE STATEMENT
Although additional and clinical studies are necessary, our study suggests that burn patients who are on montelukast may exhibit delayed healing, necessitating extra observation.
Topics: Acetates; Animals; Burns; Cyclopropanes; Endothelial Cells; Inflammation; Leukotrienes; Mice; Quinolines; Sulfides; Wound Healing
PubMed: 35536768
DOI: 10.1097/PRS.0000000000009228 -
Journal of Analytical Methods in... 2021In this study, we present a new, green electrochemical method for potentiometric estimation of desloratadine and montelukast sodium in their pure and binary dosage form....
In this study, we present a new, green electrochemical method for potentiometric estimation of desloratadine and montelukast sodium in their pure and binary dosage form. For that, three pencil graphite sensors were fabricated; the first one was prepared to analyse desloratadine drug (DES) by coating the graphite bar with the coating membrane, which comprises the ion pair of desloratadine and ammonium reineckate reagent (RNK), the polymer poly vinyl chloride (PVC), and the plasticizers dibutyl phthalate (DBP). The second one, which was used to analyse montelukast (MON), was constructed by using the ion pair of cadmium chloride reagent (Cd.) with montelukast and the same earlier named polymer and plasticizer. As a trial to analyse both of the drugs by the same sensor consecutively, we have constructed a combined pencil graphite electrode, which contains the two earlier suggested ion pairs, that is, we can use this electrode to selectively analyse for each drug. The proposed electrodes were effectively used for analysis of DES and MON as a single dosage form and as combined pharmaceutical preparation, without any need for prior separation that was performed depending on the difference in the efficient pH range for each sensor. The proposed sensors exhibited a Nernstian equation slopes of -30.11, 27.70, (-29.16, 29.79) mv. decade in the linearity range 5.00 × 10-1.00 × 10 and 1.00 × 10 - 1.00 × 10 M, respectively. The sensors exhibit high sensitivity according to LOD values ((0.036-0.018) - (0.025-0.026) M), respectively, and important selectivity toward the studied drugs in presence of interfering ions and excipients. The optimum circumstances were studied, and the method was validated by application of ICH rules. Finally, the method was compared with a documented method, and the required statistical values were calculated.
PubMed: 34035974
DOI: 10.1155/2021/5540907 -
Annals of Translational Medicine Jan 2023The oral soluble film (OSF) is a new drug delivery system. Whether montelukast sodium OSF has similar pharmacokinetic (PK) properties and bioequivalence to chewable...
Pharmacokinetics and bioequivalence study of montelukast sodium oral soluble film and chewable tablet in healthy Chinese volunteers: randomized trials under fasting and fed conditions.
BACKGROUND
The oral soluble film (OSF) is a new drug delivery system. Whether montelukast sodium OSF has similar pharmacokinetic (PK) properties and bioequivalence to chewable tablet (CT) should be investigated.
METHODS
This study, conducted at Haikou People's Hospital, consisted of two trials: a randomized, open-label, single-dose, 3-sequence, 3-period crossover trial under fasting conditions and a randomized, open-label, single-dose, 2-sequence, 2-period crossover trial under fed conditions. Healthy volunteers were randomized 1:1:1 to receive single-dose oral montelukast sodium OSF without water, OSF, or CT with water in the fasting trial, and 1:1 to receive OSF or CT with water in the fed trial in each period, with a 7-day washout period. Randomization was performed according to random number tables generated using computer. Blood samples were collected over a 24-h period. Plasma drug concentrations were tested using high-performance liquid chromatography-tandem mass spectrometry. The primary PK parameters were maximum plasma drug concentration (C), area under the plasma drug concentration-time curve (AUC) from t=0 to the last quantifiable concentration (AUC), and AUC from t=0 to infinity (AUC). The other PK parameters included time to C (T), terminal elimination rate constant (λ), and half-life (t). Safety was also assessed. Analysis of variance on log-transformed primary PK parameters was applied to analyze the bioequivalence between the OSF and CT. The bioequivalence margin was 80-125%.
RESULTS
From November 2018 to January 2019, 30 subjects were included in each trial. The PK parameters between OSF and CT were numerically similar. All 90% confidence intervals (CIs) of the geometric mean ratio (GMR) for the primary PK parameters fell within 80-125%, confirming the bioequivalence of montelukast sodium OSF and CT under fasting and fed conditions. In the fasting trial, 6 (20%) adverse events (AEs) were reported, including 3 (10%) cases after OSF administration without water and 3 (10%) after OSF administration with water, with no serious AEs. No AEs were recorded in the fed trial.
CONCLUSIONS
Montelukast sodium OSF is bioequivalent to CT, with acceptable safety. The OSF is an alternative option of CT.
TRIAL REGISTRATION
ClinicalTrials.gov identifiers: NCT05528198 (the fasting trial) and NCT05531994 (the fed trial).
PubMed: 36819512
DOI: 10.21037/atm-22-6485 -
Brazilian Journal of Medical and... 2016Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals...
Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals and changes in CysLT receptor expression after pentylenetetrazol (PTZ)-induced kindling have not been investigated. In this study, we evaluated whether the CysLT1 inverse agonist montelukast, and a classical anticonvulsant, phenobarbital, were able to reduce seizures in PTZ-kindled mice and alter CysLT receptor expression. Montelukast (10 mg/kg, sc) and phenobarbital (20 mg/kg, sc) increased the latency to generalized seizures in kindled mice. Montelukast increased CysLT1 immunoreactivity only in non-kindled, PTZ-challenged mice. Interestingly, PTZ challenge decreased CysLT2 immunoreactivity only in kindled mice. CysLT1 antagonists appear to emerge as a promising adjunctive treatment for refractory seizures. Nevertheless, additional studies are necessary to evaluate the clinical implications of this research.
Topics: Acetates; Animals; Anticonvulsants; Blotting, Western; Convulsants; Cyclopropanes; Kindling, Neurologic; Leukotriene Antagonists; Male; Mice; Pentylenetetrazole; Phenobarbital; Quinolines; Receptors, Leukotriene; Seizures; Sulfides; Time Factors; Treatment Outcome
PubMed: 26909785
DOI: 10.1590/1414-431X20155031 -
Pakistan Journal of Medical Sciences 2021Generally, the blockage of upper respiratory tract in children is seen with the hypertrophy of adenoids and tonsils. Normally for patients with adenoid hypertrophy (AH),...
BACKGROUND & OBJECTIVES
Generally, the blockage of upper respiratory tract in children is seen with the hypertrophy of adenoids and tonsils. Normally for patients with adenoid hypertrophy (AH), Adenoidectomy with or without Tonsillectomy is carried out, however it has its own complications like haemorrhage and recurrence of adenoid tissue. Consequently, therapeutic approach has increased extraordinary consideration rather than surgical procedure. The inflammatory process proposed for AH has prompted the utilization of anti-inflammatory drugs to treat this issue. The objective of this study was to assess the impacts of Montelukast sodium in children with enlarged adenoids.
METHODS
A randomized controlled trail was performed from April 2018 to March 2019 in the Otorhinolaryngology clinic of Dr. Akbar Niazi Teaching Hospital, Islamabad. In this randomized, placebo treatment-controlled trial, 60 children aged 4-12 years meeting inclusion criteria were isolated into two groups. The study group was treated with Montelukast sodium 5mg consistently for three months while the control group got placebo treatment for a similar timeframe. A questionnaire was filled by parents/ guardians of every child before and after the intervention to evaluate the severity of sleep discomfort, snoring and mouth breathing.
RESULTS
Following 3 months of treatment, significant reduction in size of the adenoids was seen in 76% of study group compared with just 3% of control group getting placebo treatment.
CONCLUSION
Montelukast sodium seems to be effective in the reduction of the size of adenoids and improvement in clinical manifestations. It can be viewed as a viable option in contrast to surgical treatment in children with hypertrophy of adenoids.
PubMed: 33679914
DOI: 10.12669/pjms.37.2.2670 -
Drug Safety Jun 2022Montelukast is a medicine indicated for use in asthma. Psychiatric disorders including nightmares have not been described in clinical trials but during recent years have...
INTRODUCTION
Montelukast is a medicine indicated for use in asthma. Psychiatric disorders including nightmares have not been described in clinical trials but during recent years have been included in the product information as having been reported post-marketing, without further description of the events. Previous descriptions in the scientific literature were based on limited numbers of reports or lacked detailed case information.
OBJECTIVE
The study aim was to further characterise post-marketing adverse drug reactions for nightmares, suspected to be induced by montelukast, to facilitate safer use of the medicine by providing additional information to patients and healthcare professionals.
METHODS
We clinically reviewed reports of nightmares with montelukast present in VigiBase, World Health Organization's global database of suspected adverse reactions to medicinal products, developed and maintained by the Uppsala Monitoring Centre, until 3 May, 2020.
RESULTS
There were 1118 reports of nightmares with montelukast in VigiBase, which provided valuable descriptions of the nightmares as well as information about the impact on the daily lives, with many cases describing a severe impact of the nightmares. About half of the reports were classified as serious. Two thirds concerned children, with the largest age group represented being children aged 5-10 years. In most cases, the nightmares disappeared upon discontinuation of the drug but for some patients it took a long time until the nightmares ceased.
CONCLUSIONS
The nature and potential severity of this adverse drug reaction, as described in these reports, present important knowledge for patients and healthcare providers that could help reduce drug-induced harm. This study highlights the value of post-marketing reports for further characterisation of known adverse drug reactions. The benefit-risk balance should be continuously monitored while patients are taking montelukast.
Topics: Acetates; Adverse Drug Reaction Reporting Systems; Child; Cyclopropanes; Dreams; Drug-Related Side Effects and Adverse Reactions; Humans; Quinolines; Sulfides
PubMed: 35650509
DOI: 10.1007/s40264-022-01183-2 -
Naunyn-Schmiedeberg's Archives of... Feb 2024The microbiome is increasingly implicated in playing a role in physiology and pharmacology; in this review, we investigate the literature on the possibility of bacterial... (Review)
Review
The microbiome is increasingly implicated in playing a role in physiology and pharmacology; in this review, we investigate the literature on the possibility of bacterial influence on the pharmacology of anti-asthmatic drugs, and the potential impact this has on asthmatic patients. Current knowledge in this area of research reveals an interaction between the gut and lung microbiome and the development of asthma. The influence of microbiome on the pharmacokinetics and pharmacodynamics of anti-asthmatic drugs is limited; however, understanding this interaction will assist in creating a more efficient treatment approach. This literature review highlighted that bioaccumulation and biotransformation in the presence of certain gut bacterial strains could affect drug metabolism in anti-asthmatic drugs. Furthermore, the bacterial richness in the lungs and the gut can influence drug efficacy and could also play a role in drug response. The implications of the above findings suggest that the microbiome is a contributing factor to an individuals' pharmacological response to anti-asthmatic drugs. Hence, future directions for research should follow investigating how these processes affect asthmatic patients and consider the role of the microbiome on drug efficacy and modify treatment guidelines accordingly.
Topics: Humans; Anti-Asthmatic Agents; Microbiota; Asthma; Lung; Bacteria
PubMed: 37650889
DOI: 10.1007/s00210-023-02681-5