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Indian Journal of Dermatology 2021Leukotriene antagonists constitute an important group of drugs in the therapeutic armamentarium of all dermatologists. It has been quite valuable in the management of...
Leukotriene antagonists constitute an important group of drugs in the therapeutic armamentarium of all dermatologists. It has been quite valuable in the management of various types of urticaria and atopic dermatitis. Recently, the role of zileuton in the management of acne has been elaborated, and in the near future it could be used as a first-line agent for the same, thereby preventing adverse effects and antibiotic resistance encountered following antibiotic use. This review will throw light on the dermatologic aspects of leukotriene antagonists.
PubMed: 35068536
DOI: 10.4103/ijd.IJD_557_18 -
Clinical and Experimental Dermatology May 2006In vitro and in vivo clinical and experimental data have suggested that leukotrienes play a key role in inflammatory reactions of the skin. Antileukotriene drugs, i.e.... (Review)
Review
In vitro and in vivo clinical and experimental data have suggested that leukotrienes play a key role in inflammatory reactions of the skin. Antileukotriene drugs, i.e. leukotriene receptor antagonists and synthesis inhibitors, are a new class of anti-inflammatory drugs that have shown clinical efficacy in the management of asthma. We searched the MedLine database and carried out a manual search on journals specializing in allergy and dermatology for the use of antileukotriene drugs in urticaria. Montelukast might be effective in chronic urticaria associated with aspirin or food additive hypersensitivity or with autoreactivity to intradermal serum injection when taken with an antihistamine but not in moderate chronic idiopathic urticaria. Evidence for the effectiveness of zafirlukast and the 5-lipoxygenase inhibitor, zileuton, in chronic urticaria is mainly anecdotal. In addition, there is anecdotal evidence of effectiveness of antileukotrienes in primary cold urticaria, delayed pressure urticaria and dermographism. No evidence exists for other physical urticarias, including cholinergic, solar and aquagenic urticarias, vibratory angio-oedema, and exercise-induced anaphylaxis.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Clinical Trials as Topic; Drug Therapy, Combination; Food Additives; Histamine H1 Antagonists; Humans; Leukotriene Antagonists; Leukotrienes; Urticaria
PubMed: 16681569
DOI: 10.1111/j.1365-2230.2006.02127.x -
International Journal of Molecular... Oct 2022Metastases are the main cause of death in cancer patients, and platelets are largely known for their contribution in cancer progression. However, targeting platelets is...
Metastases are the main cause of death in cancer patients, and platelets are largely known for their contribution in cancer progression. However, targeting platelets is highly challenging given their paramount function in hemostasis. Using a high-throughput screening and platelet-induced breast tumor cell survival (PITCS) assay as endpoint, we identified the widely used anti-asthmatic drugs and cysteinyl leukotriene receptor 1 (CysLT1R) antagonists, zafirlukast and montelukast, as new specific blockers of platelet protumoral action. Here, we show that human MDA-B02 breast cancer cells produce CysLT through mechanisms involving microsomal glutathione-S-transferase 1/2/3 (MGST1/2/3) and that can modulate cancer cell-platelet interactions via platelet-CysLT1R. CysLT1R blockade with zafirlukast decreased platelet aggregation and adhesion on cancer cells and inhibited PITCS, migration, and invasion in vitro. Zafirlukast significantly reduced, by 90%, MDA-B02 cell dissemination to bone in nude mice and reduced by 88% 4T1 spontaneous lung metastasis formation without affecting primary tumor growth. Combined treatment of zafirlukast plus paclitaxel totally inhibited metastasis of 4T1 cells to the lungs. Altogether, our results reveal a novel pathway mediating the crosstalk between cancer cells and platelets and indicate that platelet CysLT1R represents a novel therapeutic target to prevent metastasis without affecting hemostasis.
Topics: Mice; Animals; Humans; Female; Breast Neoplasms; Mice, Nude; Lung; Anti-Asthmatic Agents; Paclitaxel; Transferases; Glutathione
PubMed: 36293074
DOI: 10.3390/ijms232012221 -
Polskie Archiwum Medycyny Wewnetrznej Mar 2010Antileukotriene medications that have been implemented into clinical practice of bronchial asthma and allergic rhinitis include specific leukotriene receptor antagonists... (Review)
Review
Antileukotriene medications that have been implemented into clinical practice of bronchial asthma and allergic rhinitis include specific leukotriene receptor antagonists (montelukast, zafirlukast, pranlukast) and leukotriene biosynthesis inhibitors (zileuton). The current GINA (Global Initiative for Asthma) guidelines, the PRACTALL (Practicing Allergology) report on asthma treatment in children, and ARIA (Allergic Rhinitis and its Impact on Asthma) recommendations classify antileukotriene therapeutic agents as a group of drugs controlling the course of the disease. However, inhaled glucocorticosteroids still remain the first-line treatment in chronic asthma. According to current guidelines, antileukotriene drugs are recommended as alternative treatment to low-dose inhaled glucocorticosteroids in the second level of asthma severity and as complementary treatment to inhaled and/or oral glucocorticosteroids, starting from the third level of asthma severity. Recently, clinical efficacy of antileukotriene drugs has been suggested in the treatment of isolated allergic rhinitis, chronic cough in the course of asthma, as a sole symptom of the disease, and as the therapy for episodes of wheezing caused by viral infections.
Topics: Anti-Asthmatic Agents; Asthma; Humans; Leukotriene Antagonists; Severity of Illness Index; Treatment Outcome
PubMed: 20332717
DOI: No ID Found -
Journal of Immunology Research 2014Cysteinyl leukotrienes (cysLTs) are produced predominantly by cells of the innate immune system, especially basophils, eosinophils, mast cells, and... (Review)
Review
Cysteinyl leukotrienes (cysLTs) are produced predominantly by cells of the innate immune system, especially basophils, eosinophils, mast cells, and monocytes/macrophages. Notwithstanding potent bronchoconstrictor activity, cysLTs are also proinflammatory consequent to their autocrine and paracrine interactions with G-protein-coupled receptors expressed not only on the aforementioned cell types, but also on Th2 lymphocytes, as well as structural cells, and to a lesser extent neutrophils and CD8(+) cells. Recognition of the involvement of cysLTs in the immunopathogenesis of various types of acute and chronic inflammatory disorders, especially bronchial asthma, prompted the development of selective cysLT receptor-1 (cysLTR1) antagonists, specifically montelukast, pranlukast, and zafirlukast. More recently these agents have also been reported to possess secondary anti-inflammatory activities, distinct from cysLTR1 antagonism, which appear to be particularly effective in targeting neutrophils and monocytes/macrophages. Underlying mechanisms include interference with cyclic nucleotide phosphodiesterases, 5'-lipoxygenase, and the proinflammatory transcription factor, nuclear factor kappa B. These and other secondary anti-inflammatory mechanisms of the commonly used cysLTR1 antagonists are the major focus of the current review, which also includes a comparison of the anti-inflammatory effects of montelukast, pranlukast, and zafirlukast on human neutrophils in vitro, as well as an overview of both the current clinical applications of these agents and potential future applications based on preclinical and early clinical studies.
Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acetates; Anti-Asthmatic Agents; Arachidonate 5-Lipoxygenase; Asthma; Chromones; Cyclopropanes; Gene Expression Regulation; Humans; Immunity, Innate; Immunologic Factors; Indoles; Leukotriene Antagonists; Monocytes; NF-kappa B; Neutrophils; Phenylcarbamates; Quinolines; Receptors, Leukotriene; Sulfides; Sulfonamides; Tosyl Compounds
PubMed: 24971371
DOI: 10.1155/2014/608930 -
Canadian Family Physician Medecin de... May 1999To review new treatments for allergic rhinitis. (Review)
Review
OBJECTIVE
To review new treatments for allergic rhinitis.
QUALITY OF EVIDENCE
Most studies supporting the principles in this paper are double-blind, placebo-controlled trials. Good evidence supports use of antihistamines, nasal steroid sprays, and immunotherapy. Fewer trials have been done on the new antileukotrienes.
MAIN MESSAGE
Allergic rhinitis causes significant morbidity, which can be successfully treated. Newer antihistamines, developed to replace terfenadine and astemizole which have potential side effects, include loratadine, cetirizine, and the newest, fexofenadine. Intranasal steroid sprays are also effective, particularly for people with nasal stuffiness. One study showed some growth retardation in children using beclomethasone over a prolonged period (1 year). The newer steroid sprays, such as fluticasone, budesonide, and mometasone furoate aqueous, however, have not been studied in the same way and are usually recommended for shorter periods. The newest group of medications showing real promise are the antileukotrienes, including zafirlukast and montelukast. Taken orally, these medications avoid the discomfort of nasal sprays and seem to have few side effects. Immunotherapy offers a new option: a short-course, preseasonal series of six to 11 injections that reduces the burden on patients for year-round therapy. Combinations of these therapies are also possible.
CONCLUSIONS
With new medications and immunotherapy options, family physicians can offer effective treatment to patients with allergic rhinitis.
Topics: Administration, Topical; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Child; Controlled Clinical Trials as Topic; Double-Blind Method; Glucocorticoids; Histamine Antagonists; Humans; Immunotherapy; Leukotriene Antagonists; Middle Aged; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Time Factors
PubMed: 10349070
DOI: No ID Found -
Therapeutic Advances in Respiratory... Oct 2009Asthma is one of the most common respiratory disorders in clinical practice, affecting up to 13% of people worldwide. Inflammation is the most important component of... (Review)
Review
Asthma is one of the most common respiratory disorders in clinical practice, affecting up to 13% of people worldwide. Inflammation is the most important component of asthma and inhaled corticosteroids (ICS) are recommended as the first line controller treatment for patients of all ages. Treatment with corticosteroids is often unable to fully control asthma symptoms and progression. Recently, leukotrienes have come to the forefront of research as they have been found play a pivotal role in the airway inflammatory process, and specific drugs have been developed to target them. Cysteiny leukotriene antagonists (LTRAs) have recently emerged as important therapeutic options that show a large potential clinical utility. Three specific LTRAs are licensed for clinical use: montelukast, zafirlukast and pranlukast, although montelukast is the only drug approved in the paediatric age range. It is well tolerated (although adverse effects such as headaches, abdominal pain, rashes, angioedema, pulmonary eosinophilia and arthralgia have been reported) and shows many positive effects in asthmatic patients. Current Global Initiative for Asthma guidelines recommend LTRAs as: (1) a second choice treatment to ICS for patients with mild persistent asthma, (2) an add-on therapy to reduce the dose of ICS in patients with moderate or severe asthma, due to the different and complementary mechanisms of action of these agents. LTRAs may be particularly appropriate choices in a number of clinical situations, including the following: patients with concomitant rhinitis; patients with viral-induced wheeze; patients with exercise-induced bronchoconstriction (EIB) and, in children aged 2-5 years, to reduce the frequency of asthma exacerbations.
Topics: Asthma; Child; Humans; Leukotriene Antagonists
PubMed: 19822630
DOI: 10.1177/1753465809348014 -
Canadian Respiratory Journal 1999Leukotrienes (LTs), lipid mediators of inflammation, have proved to be important biochemicals involved in the symptoms and physiological changes of asthma. In the past... (Comparative Study)
Comparative Study Review
Leukotrienes (LTs), lipid mediators of inflammation, have proved to be important biochemicals involved in the symptoms and physiological changes of asthma. In the past year and a half, the development of three new drugs that modulate the LT pathway has been completed. The first subclass of these drugs, leukotriene receptor antagonists (LTRA) (zafirlukast and montelukast), blocks the interaction of the cysteinyl form of the LTs with the cell type bearing the receptor. The second subclass, the 5-lipoxygenase (5-LO) inhibitors (zileuton) inhibits the 5-LO enzyme, which prevents the formation of both cysteinyl LTs and LTB4. The LT modulators have shown efficacy in inhibiting the physiological changes occurring after allergen, acetylsalicylic acid and exercise challenge in asthmatics. In addition, they have shown efficacy in improving symptoms, beta-agonist use and forced expiratory volume in 1 s (FEV1) in chronic, 'day-to-day' asthma in patients with mild disease. Comparison studies with low doses of inhaled corticosteroids suggest that LT modulators may have similar effects on symptom scores and beta-agonist use, but have lesser effects on FEV1. Finally, emerging data suggest that these drugs are beneficial in decreasing the dose of inhaled corticosteroids necessary to control more moderate to severe asthma. While long term studies will be helpful in determining the 'disease modifying' effects of these drugs, data suggest that these drugs are useful in the treatment of a broad range of asthmatic patients.
Topics: Acetates; Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Cyclopropanes; Forced Expiratory Volume; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Leukotriene B4; Lipoxygenase Inhibitors; Phenylcarbamates; Quinolines; Receptors, Leukotriene; Sulfides; Sulfonamides; Tosyl Compounds
PubMed: 10322101
DOI: 10.1155/1999/676798 -
European Journal of Pharmaceutics and... Jul 2022Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro...
Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro simulated intestinal fluids have been developed, but there are multiple recipes and the optimum is unknown. This situation creates difficulties during drug discovery and development research. A recent study characterised sampled fasted intestinal fluids using a multidimensional approach to derive nine bioequivalent fasted intestinal media that covered over 90% of the compositional variability. These media have been applied in this study to examine the equilibrium solubility of twenty one exemplar drugs (naproxen, indomethacin, phenytoin, zafirlukast, piroxicam, ibuprofen, mefenamic acid, furosemide, aprepitant, carvedilol, tadalafil, dipyridamole, posaconazole, atazanavir, fenofibrate, felodipine, griseofulvin, probucol, paracetamol, acyclovir and carbamazepine) to determine if consistent solubility behaviour was present. The bioequivalent media provide in the majority of cases structured solubility behaviour that is consistent with physicochemical properties and previous solubility studies. For the acidic drugs (pKa < 6.3) solubility is controlled by media pH, the profile is identical and consistent and the lowest and highest pH media identify the lowest and highest solubility in over 70% of cases. For weakly acidic (pKa > 8), basic and neutral drugs solubility is controlled by a combination of media pH and total amphiphile concentration (TAC), a consistent solubility behaviour is evident but with variation related to individual drug interactions within the media. The lowest and highest pH × TAC media identify the lowest and highest solubility in over 78% of cases. A subset of the latter category consisting of neutral and drugs non-ionised in the media pH range have been identified with a very narrow solubility range, indicating that the impact of the simulated intestinal media on their solubility is minimal. Two drugs probucol and atazanavir exhibit unusual behaviour. The study indicates that the use of two appropriate bioequivalent fasted intestinal media from the nine will identify in vitro the maximum and minimum solubility boundaries for drugs and due to the media derivation this is probably applicable in vivo. These media could be applied during discovery and development activities to provide a solubility range, which would assist placement of the drug within the BCS/DCS and rationalise drug and formulation decisions.
Topics: Administration, Oral; Atazanavir Sulfate; Hydrogen-Ion Concentration; Intestinal Absorption; Pharmaceutical Preparations; Probucol; Solubility
PubMed: 35605926
DOI: 10.1016/j.ejpb.2022.05.010 -
Frontiers in Pharmacology 2019Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown...
Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.
PubMed: 30949053
DOI: 10.3389/fphar.2019.00263