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Newly emerging roles of LRRC8 volume-regulated anion channels (VRAC) raise important questions about the therapeutic potential of VRAC in the treatment of epilepsy, type 2 diabetes, and other human diseases. A critical barrier to evaluating whether VRAC represents a viable drug target is the lack of potent and specific small-molecule inhibitors and activators of the channel. Here we review recent progress in developing the molecular pharmacology of VRAC made by screening a library of FDA-approved drugs for novel channel modulators. We discuss the discovery and characterization of cysteinyl leukotriene receptor antagonists Pranlukast and Zafirlukast as novel VRAC inhibitors, and zinc pyrithione (ZPT), which apparently activates VRAC through a reactive oxygen species (ROS)-dependent mechanism. These ongoing efforts set the stage for developing a pharmacological toolkit for probing the integrative physiology, molecular pharmacology, and therapeutic potential of VRAC.

Docetaxel-associated liver injury has become a serious public health problem, resulting in therapy discontinuation, liver failure, and death. Zafirlukast is a typical leukotriene receptor antagonist used for prophylaxis and chronic treatment of asthma. In this study, we investigate whether treatment with Zafirlukast could alleviate Docetaxel-induced cytotoxicity in hepatocytes. Our results indicate that Zafirlukast mitigated Docetaxel-induced toxicity in LO-2 hepatocytes. Firstly, Zafirlukast reduced the production of 8-hydroxy-2p-deoxyguanosine (8-OHdG) and increased the levels of reduced glutathione (GSH) against Docetaxel. Secondly, Zafirlukast elevated the levels of mitochondrial membrane potential (ΔΨm) and adenosine triphosphate (ATP). Thirdly, Zafirlukast prevented Docetaxel-induced release of lactate dehydrogenase (LDH) and increased cell viability of LO-2 hepatocytes against Docetaxel. We also found that Zafirlukast ameliorated Docetaxel-induced apoptosis by reducing Caspase-3 and Caspase-9 activity. Mechanistically, our results demonstrate that Zafirlukast inhibited the activation of NOD-like receptor protein 3 (NLRP3), mediated by SIRT1. Based on these findings, we conclude that the administration of Zafirlukast might have a protective effect against Docetaxel-induced cytotoxicity in hepatocytes.

The coronavirus helicase is an essential enzyme required for viral replication/transcription pathways. Structural studies revealed a sulphate moiety that interacts with key residues within the nucleotide-binding site of the helicase. Compounds with a sulphoxide or a sulphone moiety could interfere with these interactions and consequently inhibit the enzyme. The molecular operating environment (MOE) was used to dock 189 sulphoxide and sulphone-containing FDA-approved compounds to the nucleotide-binding site. Zafirlukast, a leukotriene receptor antagonist used to treat chronic asthma, achieved the lowest docking score at -8.75 kcals/mol. The inhibitory effect of the compounds on the SARS-CoV-2 helicase dsDNA unwinding activity was tested by a FRET-based assay. Zafirlukast was the only compound to inhibit the enzyme (IC50 = 16.3 µM). The treatment of Vero E6 cells with 25 µM zafirlukast prior to SARS-CoV-2 infection decreased the cytopathic effects of SARS-CoV-2 significantly. These results suggest that zafirlukast alleviates SARS-CoV-2 pathogenicity by inhibiting the viral helicase and impairing the viral replication/transcription pathway. Zafirlukast could be clinically developed as a new antiviral treatment for SARS-CoV-2 and other coronavirus diseases. This discovery is based on molecular modelling, in vitro inhibition of the SARS-CoV helicase activity and cell-based SARS-CoV-2 viral replication.

The aim of the present study was to formulate the novel pediatric suspension containing nanoparticulate Zafirlukast (ZFR) for the treatment of pediatric asthma. The ZFR loaded nanoparticles (NPs) were formulated by ionotropic external gelation method using tripolyphosphate (TPP) and Tween 80. NPs were characterized for drug loading, encapsulation efficiency, surface morphology, saturation solubility, particle size, zeta potential and polydispersity index (PDI). The optimized NP formulation was used for the development of suspension. The suspensions were characterized for pH, viscosity, sedimentation volume, dissolution and drug content. The encapsulation efficiency of NPs was found between 93.24% and 98.57% with drug loading in the range of 26.50–35.90%. All formulations were found of nanosized in nature (150–220 nm) with zeta potential (19.18–21.41 mV). PDI of all NP formulations was found less than 0.3. The NPs were spherical and smooth in nature. The saturation solubility of ZFR was enhanced nearly 16 times as compared to pure ZFR. The optimized suspension showed almost 100% ZFR release within the period of 30 min. The reduction in lung resistance (RI) was found nearly four fold as compared to the control group animals. The study supported the efficacy of suspension containing nanoparticulate ZFR in asthmatic animals.

International audience; 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.

Lung diseases, including asthma, pose a serious global health issue. Loss of mitochondrial function and decreased mitochondrial biogenesis play pivotal roles in the initiation and progression of chronic lung diseases. Thus, maintaining mitochondrial function and homeostasis is an important treatment goal. Zafirlukast is a CysLTR1 antagonist that is widely used as an adjuvant treatment for asthma. In the present study, we investigated the effects of zafirlukast in vitro using human bronchial epithelial cells (BECs). We performed measurements of oxygen consumption and bioenergetics and found that zafirlukast increased mitochondrial respiration and biogenesis in human BECs as evidenced by increased mitochondrial mass and mtDNA/nDNA. Through real-time PCR and western blot analysis, we found that zafirlukast significantly increased the expression of PGC-1α, NRF1, and TFAM at both the mRNA and protein levels. Finally, we determined that these effects are mediated through CREB signaling and that inhibition of CREB with its specific inhibitor H89 abolished the effects of zafirlukast described above. Thus, zafirlukast might have potential in enhancing mitochondrial function by promoting mitochondrial biogenesis in human bronchial epithelial cells through upregulating the expression of PGC-1α and activating the CREB pathway.

Chen XG, Hua F, Wang SG, Xu YY, Yue HT, Sun J. DrugDes Devel Ther. 2018;12:2389–2402The authors have advised Figures 1 (on page 2393),Figure 3 (on page 2394), Figure 5 (on page 2395),Figure 7 and Figure 8 (on page 2396) are incorrect dueto a fault in their microscope camera. The correct Figuresare shown below:Read the original article &nbsp

The retinal pigment epithelium (RPE), which is among the tissues in the body that are exposed to the highest levels of phagocytosis and oxidative stress, is dependent on autophagy function. Impaired autophagy and continuous cellular stress are associated with various disorders, such as dry age-related macular degeneration (AMD), a disease for which effective therapies are lacking. Cysteinyl leukotriene receptor (CysLTR) 1 is a potential modulator of autophagy; thus, the aim of this study was to investigate the role of CysLTR1 in autophagy regulation in the RPE cell line ARPE-19. The polarized ARPE-19 monolayer exhibited expression of CysLTR1, which was colocalized with β-tubulin III. In ARPE-19 cells, autophagic activity was rhythmically regulated and was increased upon CysLTR1 inhibition by Zafirlukast (ZK) treatment. H2O2 affected the proautophagic regulatory effect of ZK treatment depending on whether it was applied simultaneously with or prior to ZK treatment. Furthermore, mRNA levels of genes related to the leukotriene system, autophagy and the unfolded protein response were positively correlated. As CysLTR1 is involved in autophagy regulation under basal and oxidative stress conditions, a dysfunctional leukotriene system could negatively affect RPE functions. Therefore, CysLTR1 is a potential target for new treatment approaches for neurodegenerative disorders, such as AMD.

Background: Leukotrienes are powerful mediators of inflammation and interact with specific receptors in target cell membrane to initiate an inflammatory response. Thus, Leukotrienes (LTs) are considered to be potent mediators of inflammatory diseases including allergic rhinitis, inflammatory bowel disease and asthma. Leukotriene B4 and the series of cysteinyl leukotrienes (C4, D4, and E4) are metabolites of arachidonic acid metabolism that cause inflammation. The cysteinyl LTs are known to increase vascular permeability, bronco-constriction and mucus secretion. Objectives: To review the published data for leukotriene inhibitors of plant origin and the recent patents for leukotriene inhibitors, as well as their role in the management of inflammatory diseases. Methods: Published data for leukotrienes antagonists of plant origin were searched from 1938 to 2019, without language restrictions using relevant keywords in both free text and Medical Subject Headings (MeSH terms) format. Literature and patent searches in the field of leukotriene inhibitors were carried out by using numerous scientific databases including Science Direct, PubMed, MEDLINE, Google Patents, US Patents, US Patent Applications, Abstract of Japan, German Patents, European Patents, WIPO and NAPRALERT. Finally, data from these information resources were analyzed and reported in the present study. Results: Currently, numerous anti-histaminic medicines are available including chloropheneremine, brompheniramine, cetirizine, and clementine. Furthermore, specific leukotriene antagonists from allopathic medicines are also available including zileuton, montelukast, pranlukast and zafirlukast and are considered effective and safe medicines as compared to the first generation medicines. The present study reports leukotrienes antagonistic agents of natural products and certain recent patents that could be an alternative medicine in the management of inflammation in respiratory diseases. Conclusion: The present study highlights recent updates on the pharmacology and patents on leukotriene antagonists in the management of inflammation respiratory diseases.

[Image: see text] Porphyromonas gingivalis is a Gram-negative anaerobic pathogen that can trigger oral dysbiosis as an early event in the pathogenesis of periodontal disease. The FDA-approved drug zafirlukast (ZAF) was recently shown to display antibacterial activity against P. gingivalis. Here, 15 novel ZAF derivatives were synthesized and evaluated for their antibacterial activity against P. gingivalis and for their cytotoxic effects. Most derivatives displayed superior antibacterial activity against P. gingivalis compared to ZAF and its first generation derivatives along with little to no growth inhibition of other oral bacterial species. The most active compounds displayed bactericidal activity against P. gingivalis and less cytotoxicity than ZAF. The superior and selective antibacterial activity of ZAF derivatives against P. gingivalis along with an increased safety profile compared to ZAF suggest these new compounds, especially 14b and 14e, show promise as antibacterials for future studies aimed to test their potential for preventing/treating P. gingivalis-induced periodontal disease.

In the current scenario of pharmaceutical research much attention has been focused on patients health in terms of therapeutic efficacy and economical standards (price factor).The formulation design consist of core tablets designed by direct compression method. Core tablets were coated with an naturally occurring swelling agent (carbopol & Karaya gum). Evaluation studies were performed for prepared pulsatile tablets hardness. In in vitro release profile of 6 hours study in first 5 hours it shows minimum drug release and at the end of six hours rapid and transient release was observed. Stability studies proved that coating of tablets seems to decrease the effect of temperature and moisture on degradation of Zafirlukast. The pulsatile release has been achieved from tablet over a 7-8 hour period.

Purpose Capsular contracture (CC) is a troublesome complication after breast surgery with breast implants, and the risk increases in breast cancer patients after radiotherapy. Studies investigating leukotriene antagonists (eg, montelukast, zafirlukast) found that the acellular dermal matrix (ADM) can help prevent CC. We aimed to compare the effects of ADM and montelukast on CC after irradiation. Methods Eighteen New Zealand white rabbits were randomly divided into 3 groups of 6 each. Miniature cohesive gel implants were inserted into the pocket under the latissimus dorsi muscle. The lateral part was uncovered by the latissimus dorsi muscle. Six animals were included in the control group. In experimental group A (EG-A) (n = 6), the site was partially wrapped with ADM but not covered with muscle. Montelukast (Singulair, 0.2 mg/kg) was administered in experimental group B (EG-B) (n = 6) daily. Groups were irradiated at postoperative day 21 with Co-60 γ rays (25 Gy, single fraction) at the peri-implant area. Rabbits were sacrificed 12 weeks after surgery; implants with peri-implant capsule were harvested. Capsule thickness, collagen pattern, myofibroblast, and transforming growth factor (TGF) β1/2 levels in the peri-implant capsule were evaluated. Results On histological evaluation, the capsule was thinner on the lateral aspect (covered with ADM) in EG-A (P = 0.004) and the entire capsule in EG-B (P = 0.004) than in the control group. However, there was no significant difference between EG-A and EG-B (P = 0.073). The collagen distribution pattern was more parallel with low density in the lateral capsular aspect in EG-A, but in the entire capsule in EG-B. The myofibroblast amount (EG-A, P = 0.031; EG-B, P = 0.016) and levels of TGF-β1 and TGF-β2 were reduced in the experimental groups (TGF-β1, EG-A, P = 0.019; TGF-β1, EG-B, P = 0.045; TGF-β2, EG-A, P = 0.018; TGF-β2, EG-B, P = 0.022). There was no significant difference between EG-A and EG-B (myofibroblast, P = 0.201; TGF-β1, P = 0.665; TGF-β2, P = 0.665). Conclusions Acellular dermal matrix and montelukast have a prophylactic effect for CC even when the breast is irradiated. There was no significant difference between ADM and montelukast in preventing capsular formation. The difference is that ADM will only have the effect of covering the capsular formation with ADM and montelukast can cause systemic effects or complications.

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.

Recruitment of polymorphonuclear neutrophils (PMNs) into the vaginal lumen is the hallmark of an acute immunopathologic inflammatory response during vulvovaginal candidiasis (VVC) caused by Candida albicans. Recurrent VVC (RVVC) remains a chronic health burden in affected women worldwide despite the use of antifungal therapy. Based on the role leukotrienes (LTs) play in promoting inflammation, leukotriene receptor antagonists (LTRAs) targeted for LTB4 (etalocib) or LTC4, LTD4, and LTE4 (zafirlukast or montelukast) have been shown to reduce inflammation of epithelial tissues. An open-label pilot study using long-term regimens of zafirlukast in women with RVVC indicated the potential for some relief from recurrent episodes. To investigate this clinical observation further, we evaluated the effects of LT antagonistic agents and LT deficiency on the immunopathogenic response in a mouse model of VVC. Results showed that mice given daily intraperitoneal injections of individual LTRAs, starting 2days prior to vaginal inoculation with C. albicans and continuing through 14days post-inoculation, had no measurable reduction in PMN migration. The LTRAs were also ineffective in reducing levels of the hallmark vaginal inflammatory markers (S100A8, IL-1β) and tissue damage (LDH) associated with the immunopathogenic response. Finally, LT-deficient 5-lipoxygenase knockout mice showed comparable levels of vaginal fungal burden and PMN infiltration to wild-type mice following inoculation with a vaginal (ATCC 96113) or laboratory (SC5314) C. albicans isolate. These results indicate that despite some clinical evidence suggestive of off-target efficacy of LTRAs in RVVC, LTs and associated signaling pathways appear to be dispensable in the immunopathogenesis of VVC.

Background Capsular contracture (CC) is the most common long-term complication of breast surgery with prosthesis. Leukotriene receptor antagonists (LRAs) have been tested as a potential treatment; however, mixed results have been observed. Objectives The aim of this study was to undertake a meta-analysis to clarify the treatment and prophylactic capabilities of LRAs in the management of CC. Methods A systematic literature search of the most popular English-language databases was performed to identify relevant primary publications. We included all studies that used the Baker scale to evaluate the treatment and preventive capabilities of LRAs. Results Six eligible studies were included based on predefined inclusion and exclusion criteria, totalling 2276 breasts, of which 775 did not receive LRAs and 1501 did. Final pooled results showed that LRAs could help manage CC with a risk difference (RD) of –0.38 with a corresponding 95% CI of –0.69 to –0.08, showing statistical significance at a Z value of 2.48, P = 0.01. Subgroup analysis based on the type of drug showed that only montelukast yielded statistical significance (RD = –0.27, 95% CI = –0.51 to –0.03, Z = 2.20, P = 0.03). Zafirlukast did not seem to influence CC. Further subgroup analysis based on treatment timing showed that prophylaxis was ineffective and only treatment for ongoing CC yielded statistically significant improvements. Conclusions The current meta-analysis proved that LRAs could be used in the management of CC. Only treatment for ongoing CC showed statistically significant improvements. Montelukast seemed to be more efficient with a safer profile for adverse effects, whereas zafirlukast yielded no statistically significant results. Level of Evidence: 4

Introduction: Intra-abdominal adhesions’ main etiology is surgical procedures that commonly require reintervention. Oral treatments with sildenafil, zafirlukast, and pirfenidone have yielded decreased severity of fibrotic phenomena secondary to the introduction of foreign material. This study aimed to evaluate the efficacy of oral zafirlukast, sildenafil, or pirfenidone treatment on reducing or preventing intra-abdominal adhesions in an experimental rat model. Methods: Four groups, each of 10 male Wistar rats weighing 250–300 g, were used. A midline laparotomy was used to excise an area of 1.5 × 1.5 cm and reconstructed with polypropylene mesh fixed to the abdominal wall. After 12 h, oral doses of zafirlukast (1.25 mg/kg, group B), sildenafil (15 mg/kg, group C), or pirfenidone (500 mg/kg, group D) were given every day for 8 days. The control group, A, received no treatment. At day 9, animals were reoperated. The implant was resected after ethically approved euthanasia, and specimens were fixed in 10% formaldehyde for histopathology. Results: Control group A yielded adhesions with greater fibrovascular density and neighboring organ involvement than the other groups (p = 0.001), as well as intense inflammatory infiltrates and numerous granulomas (p = 0.04). Adhesions in group C had less fibrovascular density (p = 0.03) with decreased serosal injuries (p = 0.001) and less organ involvement. Group D had reduced adhesions without organ involvement (p < 0.01) and less inflammatory infiltrates, collagen fibers, and foreign body granulomas than group B or C (p < 0.01). Conclusions: Oral administration of these agents did not prevent adhesions but ameliorated them. Oral pirfenidone offered the best performance and could be recommended for human use.

BACKGROUND Zafirlukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLTR1). Advanced glycation end-products (AGEs) are formed by the glycation of lipids and proteins in hyperglycemia, including diabetes mellitus. Zafirlukast has not previously been studied in diabetic nephropathy. This study aimed to investigate the effects of zafirlukast on rat renal mesangial cells cultured with AGEs in vitro. MATERIAL AND METHODS Mesangial cells were cultured in AGEs (0, 20, 50, 100 μg/ml), and with AGEs (100 μg/ml) and zafirlukast (2.5 μm, 5 μm, and 100 μm). An enzyme-linked immunoassay (ELISA) was used to measure the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1s (IL-1s), IL-6, and monocyte chemoattractant protein-1 (MCP-1). Reactive oxygen species (ROS) were assessed by intracellular fluorescence measurement of 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA), and detection kits were used to measure malondialdehyde (MDA), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD). Cell apoptosis was assessed by flow cytometry, and Western blot was used to measure protein levels. RESULTS In mesangial cells cultured with AGEs, markers of inflammation, oxidative stress, and apoptosis and levels of CysLTR1 increased, and these effects were reduced by zafirlukast in a dose-dependent manner. The effects of zafirlukast as a CysLTR1 antagonist protected mesangial cells from the effects of AGE in vitro. CONCLUSIONS Zafirlukast, a CysLTR1 antagonist, reduced the levels of inflammatory cytokines, markers of oxidative stress, and cell apoptosis induced by AGE in mesangial cells in a dose-dependent way. Future in vivo studies are needed to investigate the potential role for zafirlukast in models of diabetic nephropathy.

Volume-regulated anion channels (VRACs) encoded by the leucine-rich repeat containing 8 ( LRRC8) gene family play critical roles in myriad cellular processes and might represent druggable targets. The dearth of pharmacological compounds available for studying VRAC physiology led us to perform a high-throughput screen of 1,184 of US Food and Drug Administration-approved drugs for novel VRAC modulators. We discovered the cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, pranlukast, as a novel inhibitor of endogenous VRAC expressed in human embryonic kidney 293 (HEK293) cells. Pranlukast inhibits VRAC voltage-independently, reversibly, and dose-dependently with a maximal efficacy of only ~50%. The CysLT1R pathway has been implicated in activation of VRAC in other cell types, prompting us to test whether pranlukast requires the CysLT1R for inhibition of VRAC. Quantitative PCR analysis demonstrated that CYSLTR1 mRNA is virtually undetectable in HEK293 cells. Furthermore, the CysLT1R agonist leukotriene D4 had no effect on VRAC activity and failed to stimulate Gq-coupled receptor signaling. Heterologous expression of the CysLT1R reconstituted LTD4-CysLT1R- Gq-calcium signaling in HEK293 cells but had no effect on VRAC inhibition by pranlukast. Finally, we show the CysLT1R antagonist zafirlukast inhibits VRAC with an IC50 of ~17 µM and does so with full efficacy. Our data suggest that both pranlukast and zafirlukast are likely direct channel inhibitors that work independently of the CysLT1R. This study provides clarifying insights into the putative role of leukotriene signaling in modulation of VRAC and identifies two new chemical scaffolds that can be used for development of more potent and specific VRAC inhibitors.

Introduction: Asthma is a chronic inflammatory disease of the airways with a large heterogeneity of clinical phenotypes. There has been increasing interest regarding the role of cysteinyl leukotriene (LT) and leukotriene receptor antagonists (LTRA) in asthma treatment.Areas covered: This review summarized the data (published in PubMed during 1984-2019) regarding LTRA treatment in asthma and LTs-related airway inflammation mechanisms. Involvement of LTs C4/D4/E4 has been demonstrated in the several aspects of airway inflammation and remodeling. Novel pathways related to LTE4, the most potent mediator, and its respective receptors have recently been studied. Antagonists against cysteinyl leukotriene receptor (CysLTR) type 1, including montelukast, pranlukast and zafirlukast, have been widely prescribed in clinical practices; however, some clinical trials have shown insignificant responses to LTRAs in adult asthmatics, while some phenotypes of adult asthma showed more favorable responses to LTRAs including aspirin-exacerbated respiratory disease, elderly asthma, asthma associated with smoking, obesity and allergic rhinitis.Expert opinion: Further investigations are needed to understand the role of LTs in airway inflammation and remodeling of the asthmatic airways. There is a lack of biomarkers to predict responsiveness to LTRA, especially in adult asthmatics. Besides CysLTR1 antagonists, targets aiming other LT pathways should be considered.

Vascular dementia is considered a vascular cognitive impairment disease caused by neuronal degeneration in the brain. Several studies have supported the hypothesis that oxidative stress and endothelial dysfunction are the main pathogenic factors in vascular dementia. This current study aims to determine the possible neuroprotective effects of zafirlukast, piracetam and the combination of piracetam and zafirlukast on L-methionine-induced vascular dementia in rats. Male Wistar albino rats were divided into five groups. Group I was the normal control, and group II received L-methionine (1700 mg/kg, P.O.) for 32 days. The remaining groups received zafirlukast (20 mg/kg, P.O.), piracetam (600 mg/kg, P.O.) or their combination (zafirlukast 20 mg/kg + piracetam 600 mg/kg, P.O.) for 32 days after L-methionine administration. Afterwards, the cognitive and memory performances of the rats were investigated using the novel object recognition (NOR) test; rats were then sacrificed for histopathological and biochemical analyses. L-methionine-induced vascular dementia altered rats' behaviours and the brain contents of different neurotransmitters and acetylcholinesterase activity while increasing levels of oxidative stress and causing notable histopathological alterations in brain tissues. The treatment of vascular dementia with zafirlukast and the combination improved neurochemical, behavioural and histological alterations to a comparable level to those of piracetam. Thus, zafirlukast, piracetam and the combination of both drugs can be considered as potential therapeutic strategies for the treatment of vascular dementia induced by L-methionine. To the best of our knowledge, this study is the first to explore the neuroprotective effects of zafirlukast and piracetam on L-methionine-induced vascular dementia.

Zafirlukast, a leukotriene receptor antagonist, has been shown to exert a wide range of effects including anti-asthmatic, anti-inflammatory and oral anti-bacterial. Osteoarthritis is one of the most prevalent age-related public health burdens in the modern world. In the present study, we applied zafirlukast in the treatment of human primary chondrocytes and found that it exerts potent anti-osteoarthritic effects. Zafirlukast inhibited AGEs-induced degradation of the articular extracellular matrix by suppressing expression of MMPs, ADAMTS, NOX-4, generation of ROS, and activation of NF-κB via the IκBα/JNK/AP-1 pathway through targeted inhibition of CysLTR1. These findings suggest that zafirlukast possesses a protective effect against AGEs- induced damage and dysfunction in human chondrocytes.

Periodontal disease is an oral chronic immune-inflammatory disease highly prevalent worldwide that is initiated by specific oral bacterial species leading to local and systemic effects. The development of new preventive/therapeutic strategies to specifically target oral periodontopathogens without perturbing oral microbiome species normally colonizing the oral cavity is needed. The fast and affordable strategy of repositioning of already FDA-approved drugs can be an answer to the development of novel treatments against periodontal pathogens such as Porphyromonas gingivalis. Herein, we report the synthesis and antibacterial activity of novel zafirlukast derivatives, their bactericidal effect, and their cytotoxicity against oral epithelial cell lines. Many of these derivatives exhibited superior antibacterial activity against P. gingivalis compared to the parent drug zafirlukast. The most promising compounds were found to be selective against P. gingivalis and they were bactericidal in their activity. Finally, we demonstrated that these potent derivatives of zafirlukast provided a better safety profile against oral epithelial cells compared to zafirlukast.

Worldwide, obesity rates have doubled since the 1980s and in the USA alone, almost 40% of adults are obese, which is closely associated with a myriad of metabolic diseases such as type 2 diabetes and arteriosclerosis. Obesity is derived from an imbalance between energy intake and consumption, therefore balancing energy homeostasis is an attractive target for metabolic diseases. One therapeutic approach consists of increasing the number of brown-like adipocytes in the white adipose tissue (WAT). Whereas WAT stores excess energy, brown adipose tissue (BAT) can dissipate this energy overload in the form of heat, increasing energy expenditure and thus inhibiting metabolic diseases. To facilitate BAT production a high-throughput screening approach was developed on previously known drugs using human Simpson–Golabi–Behmel Syndrome (SGBS) preadipocytes. The screening allowed us to discover that zafirlukast, an FDA-approved small molecule drug commonly used to treat asthma, was able to differentiate adipocyte precursors and white-biased adipocytes into functional brown adipocytes. However, zafirlukast is toxic to human cells at higher dosages. Drug-Initiated Activity Metabolomics (DIAM) was used to investigate zafirlukast as a BAT inducer, and the endogenous metabolite myristoylglycine was then discovered to mimic the browning properties of zafirlukast without impacting cell viability. Myristoylglycine was found to be bio-synthesized upon zafirlukast treatment and was unique in inducing brown adipocyte differentiation, raising the possibility of using endogenous metabolites and bypassing the exogenous drugs to potentially alleviate disease, in this case, obesity and other related metabolic diseases.

Graphical abstract, Drug solubility is a key parameter controlling oral absorption, but intestinal solubility is difficult to assess in vitro. Human intestinal fluid (HIF) aspirates can be applied but they are variable, difficult to obtain and expensive. Simulated intestinal fluids (SIF) are a useful surrogate but multiple recipes are available and the optimum is unknown. A recent study characterised fasted HIF aspirates using a multi-dimensional approach and determined nine bioequivalent SIF media recipes that represented over ninety percent of HIF compositional variability. In this study these recipes have been applied to determine the equilibrium solubility of twelve drugs (naproxen, indomethacin, phenytoin, piroxicam, aprepitant, carvedilol, zafirlukast, tadalafil, fenofibrate, griseofulvin, felodipine, probucol) previously investigated using a statistical design of experiment (DoE) approach. The bioequivalent solubility measurements are statistically equivalent to the previous DoE, enclose literature solubility values in both fasted HIF and SIF, and the solubility range is less than the previous DoE. These results indicate that the system is measuring the same solubility space as literature systems with the lower overall range suggesting improved equivalence to in vivo solubility, when compared to DoEs. Three drugs (phenytoin, tadalafil and griseofulvin) display a comparatively narrow solubility range, a behaviour that is consistent with previous studies and related to the drugs’ molecular structure and properties. This solubility behaviour would not be evident with single point solubility measurements. The solubility results can be analysed using a custom DoE to determine the most statistically significant factor within the media influencing solubility. This approach has a lower statistical resolution than a formal DoE and is not appropriate if determination of media factor significance for solubilisation is required. This study demonstrates that it is possible to assess the fasted intestinal equilibrium solubility envelope using a small number of bioequivalent media recipes obtained from a multi-dimensional analysis of fasted HIF. The derivation of the nine bioequivalent SIF media coupled with the lower measured solubility range indicate that the solubility results are more likely to reflect the fasted intestinal solubility envelope than previous DoE studies and highlight that intestinal solubility is a range and not a single value.

Aims Over the past few years, AI has been considered as potential important area for improving drug development and in the current urgent need to fight the global COVID-19 pandemic new technologies are even more in focus with the hope to speed up this process. The purpose of our study was to identify the best repurposing candidates among FDA-approved drugs, based on their predicted antiviral activity against SARS-CoV-2. Materials and methods This article describes a drug discovery screening based on a supervised machine learning model, trained on in vitro data encoded in chemical fingerprints, representing particular molecular substructures. Predictive performance of our model has been evaluated using so-called scaffold splits offering a state-of-the-art setup for assessing model's ability to generalize to new chemical spaces, critical for drug repurposing applications. Key findings Our study identified zafirlukast as the best repurposing candidate for COVID-19. Significance Zafirlukast could be potent against COVID-19 both due to its predicted antiviral properties and its ability to attenuate the so called cytokine storm. Thus, these two critical mechanisms of action may be combined in one drug as a novel and promising pharmacotherapy in the current pandemic., Highlights • AI drug screening discovers zafirlukast as a repurposing candidate for COVID-19. • Predicted antiviral and cytokine-storm-attenuating mechanisms combined in one drug. • Molecular property prediction-based drug discovery screening of FDA-approved drugs. • Reaffirmed utility of leukotriene receptor antagonists (LTRA) against SARS-CoV-2. • Research driven by the current severe acute respiratory syndrome CoV-2 pandemic.

Covid-19 is an infectious disease that has rattled the world. Although several new vaccines are being administered to prevent infections, there is a large unmet need for antiviral drugs to ameliorate disease progression. In this study, structures of endogenous proteins were modelled using the genome browser and screened for molecular docking of drugs with spike protein of SARS COV-2 binding to ACE2 receptor using bioinformatics approaches such as structure-assisted drug design (SBDD), virtual drug screening (VS), and high-throughput screening (HTS). We have screened 150 drugs that were shortlisted from extensive literature data, 110 of these have been approved by the US-FDA for various diseases. We have developed a molecule assessment process from which we have identified fifteen drugs that have the potential for repurposing towards blocking SARS-COV2 proteins with endogenous proteins. Using these approaches, we have identified asthma drugs such as Cromolyn sodium, Ciclesonide and Zafirlukast.

TNFR1 is a crucial regulator of NF-ĸB-mediated proinflammatory cell survival responses and programmed cell death (PCD). Deregulation of TNFα- and TNFR1-controlled NF-ĸB signaling underlies major diseases, like cancer, inflammation, and autoimmune diseases. Therefore, although being routinely used, antagonists of TNFα might also affect TNFR2-mediated processes, so that alternative approaches to directly antagonize TNFR1 are beneficial. Here, we apply quantitative single-molecule localization microscopy (SMLM) of TNFR1 in physiologic cellular settings to validate and characterize TNFR1 inhibitory substances, exemplified by the recently described TNFR1 antagonist zafirlukast. Treatment of TNFR1-mEos2 reconstituted TNFR1/2 knockout mouse embryonic fibroblasts (MEFs) with zafirlukast inhibited both ligand-independent preligand assembly domain (PLAD)-mediated TNFR1 dimerization as well as TNFα-induced TNFR1 oligomerization. In addition, zafirlukast-mediated inhibition of TNFR1 clustering was accompanied by deregulation of acute and prolonged NF-ĸB signaling in reconstituted TNFR1-mEos2 MEFs and human cervical carcinoma cells. These findings reveal the necessity of PLAD-mediated, ligand-independent TNFR1 dimerization for NF-ĸB activation, highlight the PLAD as central regulator of TNFα-induced TNFR1 oligomerization, and demonstrate that TNFR1-mEos2 MEFs can be used to investigate TNFR1-antagonizing compounds employing single-molecule quantification and functional NF-ĸB assays at physiologic conditions.

The lipid-derived autacoids like prostaglandins, thromboxanes, leukotrienes, and platelet-activating factors play a major role in inflammation. Derived from a common source—arachidonic acid, these lipid-derived autacoids produce a myriad of physiological action. Prostaglandins are considered as housekeeper biomolecule in vast number of tissues, where they maintain the homeostasis via their specific receptors like IP, FP, EP, and DP receptors. In general, PGE and PGI have the opposite physiological functions to PGF, TXA2, and leukotrienes. Based on their physiological action, numerous prostaglandin analogs like misoprostol, alprostadil, latanoprost, travoprost, and others have been developed and are extensively used to treat various clinical conditions. Prostaglandin analogs are nowadays recommended as the first drugs of choice for open-angle glaucoma. Similarly, leukotriene antagonists like zafirlukast and montelukast are being used in asthma for a long time. Recently, compounds related to prostaglandins like levuglandins (isoketals), prostamides, and esterified prostaglandins have been identified. The receptors for such compounds are under study and their role in maintaining homeostasis and in certain diseases like asthma, Alzheimer’s disease, and others have been studied in depth currently.

The purpose of this study was to evaluate the use of the leukotriene modifiers (LTMs), zafirlukast and montelukast, in children with asthma managed by an inner city pediatric pulmonary practice. A retrospective chart review was done of children 6 years of age with persistent asthma seen at Connecticut Children's Medical Center and prescribed LTM drugs. Eighty-three children whose asthma control was adequately assessed both before and after addition of a LTM to his/her treatment regimen was included in the study. There were statistically significant improvements in several parameters of asthma control following initiation of LTM use, including provider assessment score (p = 0.0005), number of hospitalizations and unscheduled visits (clinic or emergency department; p < 0.0001), use of oral corticosteroids (p = 0.0015), spirometry severity score (p = 0.0015), and spirometry test results (FEV1, FEV1/FVC, FEF, FEF25-75%; p < 0.005 for all). These results suggest that montelukast and zafirlukast help to improve asthma control in young patients with persistent asthma.

Development of Keap1–Nrf2 interaction inhibitors is a promising strategy for the discovery of therapeutic agents against oxidative stress-mediated diseases. Two motifs of Nrf2, ETGE and DLG motif, are responsible for Keap1-Nrf2 binding. Previously, ETGE peptide or ETGE-derived peptide-based approaches were used to detect Keap1-Nrf2 interaction; however, these approaches are not able to monitor Keap1-DLG motif binding. We first report here a novel Enzyme-linked Immunosorbent Assay (ELISA) approach to detect the protein-protein interaction of full length Keap1 and Nrf2. In our assay, the test compounds can target either ETGE or DLG binding site, therefore facilitating the exploration of diverse Keap1-Nrf2 inhibitors. Three FDA-approved drugs, zafirlukast, dutasteride and ketoconazole, were found to inhibit the Keap1-Nrf2 interaction with IC50 of 5.87, 2.81 and 1.67 μM, respectively. Additionally, these three drugs also activated Nrf2 pathway in neuroblasts and lipopolysaccharide (LPS)-challenged mice. The results presented here indicate that the ELISA approach has the capacity to identify Keap1-Nrf2 inhibitors., Graphical abstract Image 1, Highlights • We established a novel Enzyme-linked Immunosorbent Assay for Keap1-Nrf2 interaction inhibitors identification. • This ELISA is the first approach to detect the protein-protein interaction of full length Keap1 and Nrf2. • In this assay, the test compounds can target either ETGE or DLG binding site, therefore facilitating the exploration of diverse Keap1-Nrf2 inhibitors. • Zafirlukast, dutasteride and ketoconazole have been identified as inhibitors of the Keap1-Nrf2 interaction.

Background and purpose Multiple members of the thiol isomerase (TI) family of enzymes are present in, and released by platelets. Inhibition of these enzymes results in diminished platelet responses including aggregation, adhesion and thrombus formation. In recent years, the therapeutic potential of TI inhibition has been recognised and drug-development technologies used to identify selective small molecule inhibitors. To date, few pan-TI inhibitors have been characterised and the most studied, bacitracin is known to be nephrotoxic which prohibits its systemic therapeutic usage. Experimental approach We therefore sought to identify novel broad-spectrum inhibitors of these enzymes and test their effects in vivo. 3641 compounds were screened for inhibitory effects on the redox activity of ERp5, PDI, ERp57, ERp72 and thioredoxin (TRX) in an insulin turbidity assay. Of the lead compounds identified, zafirlukast (ZFL) was selected for further investigation. Key results When applied to platelets, ZFL diminished platelet responses in vitro. ZFL was antithrombotic in murine models of thrombosis but did not impair responses in a model of haemostasis. Since thiol isomerases are known to modulate adhesion receptor function, we explored the effects of ZFL on cell migration. This was inhibited independently of cysteinyl leukotriene receptor expression and was associated with modulation of cell-surface free thiol levels consistent with alterations in redox activity on the cell surface. Conclusion and implications We identify zafirlukast to be a novel, potent, broad-spectrum TI inhibitor, with wide ranging effects on platelet function, thrombosis and integrin-mediated cell migration. ZFL is antithrombotic but does not cause bleeding.

Introduction: Asthma is one of the most common respiratory disorders in clinical practice, affecting up to 13% of people worldwide. Leukotriene antagonists have long been used in the treatment of asthma. This study was conducted to compare the effectiveness of the montelukast and zafirlukast treatment in children diagnosed with asthma. Methods: Sixty-one patients diagnosed with asthma in the age group of 6-14 years were included in the study. Patients were consecutively divided into 2 groups, and the first group was given 5 mg of montelukast before sleep and the second group received 10 mg/day of zafirlukast in two doses. The patients were followed up monthly for 6 months. Short acting beta agonist and inhaled corticosteroid use, daytime symptoms, night awakenings, admission to the emergency department andFEV1 value were compared before and after the treatment and between two groups. Results: Significant improvement was observed in both groups during post-treatment period when compared to the pre-treatment period in terms of the short acting beta agonist and inhaled corticosteroid use, daytime symptoms, night awakenings, mean FEV I. However, no statistical difference was determined between two groups. Discussion and Conclusion: It was found that monteluksat and zafirlukast were effective in asthma treatment and there was no difference between their effects.

Xiao-Gang Chen,1 Fu Hua,2 Shou-Guo Wang,1 Yong-Yi Xu,1 Hai-Tao Yue,1 Jin Sun1 1Department of Orthopedics, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of China; 2Department of Gynaecology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of China Background: Biosynthesis of leukotriene (LT) by arachidonic acid involves 5-lipoxygenase (5-LO) as an important precursor. Here, we evaluated the role of pseudohypericin (PHP) for its postulated 5-LO inhibitory activity along with a Cys-LT receptor antagonist zafirlukast (ZFL) against inflammatory response and tissue injury in mice. Materials and methods: The spinal injury was induced by two-level laminectomy of T6 and T7 vertebrae. The inflammation was assessed by histology, inflammatory mediators by enzyme-linked immunosorbent assay, apoptosis by Annexin-V, FAS staining, terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL) assay and expression of Bax and Bcl-2 by Western blot. Effect on motor recovery of hind limbs was evaluated for 10days postinjury. Results: The spinal injury resulted in tissue damage, apoptosis, edema, infiltration of neutrophils with increased expression of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). The spinal tissue showed elevated levels of prostaglandin E2 (PGE2), and LTB4 and increased phosphorylation of injured extracellular signal-regulated kinase-1/2 (ERK1/2). The PHP, ZFL and combination decreased inflammation, tissue injury and infiltration of neutrophils. Treatment also decreased the levels of PGE2, phosphorylation of extracellular signal-regulated kinase-1/2 (pERK 1/2), LT, TNF-α and COX-2 with a marked reduction in apoptosis and improved the motor function. Conclusion: The present study confirmed 5-LO antagonist activity of PHP and established its neuroprotective role along with ZFL. Keywords: pseudohypericin, zafirlukast, 5-lipoxygenase, Cys-LT, mice

Glioblastoma is the most aggressive type of brain cancer with the highest proliferation, invasion, and migration. Montelukast and zafirlukast, 2 widely used leukotriene receptor antagonists (LTRAs) for asthma treatment, inhibited invasion and migration of glioblastoma cell lines. Montelukast induces apoptosis and inhibits cell proliferation of various cancer cells. Herein, apoptotic and antiproliferative effects of montelukast and zafirlukast were investigated in 2 glioblastoma cell lines, A172 and U-87 MG. Both LTRAs induced apoptosis and inhibited cell proliferation of glioblastoma cells in a concentration-dependent manner. Montelukast was more cytotoxic and induced higher levels of apoptosis than zafirlukast in A172 cells, but not in U-87 MG cells. Both drugs decreased expression of B-cell lymphoma 2 (Bcl-2) protein without affecting Bcl-2-associated X (Bax) levels. LTRAs also reduced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). In contrast, zafirlukast showed a greater antiproliferative effect than montelukast and induced G0/G1 cell cycle arrest by upregulating p53 and p21 expression. These results suggested the therapeutic potential of LTRAs in glioblastoma.

Xiao-Gang Chen,1 Fu Hua,2 Shou-Guo Wang,1 Yong-Yi Xu,1 Hai-Tao Yue,1 Jin Sun1 1Department of Orthopedics, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of China; 2Department of Gynaecology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of China Background: Biosynthesis of leukotriene (LT) by arachidonic acid involves 5-lipoxygenase (5-LO) as an important precursor. Here, we evaluated the role of pseudohypericin (PHP) for its postulated 5-LO inhibitory activity along with a Cys-LT receptor antagonist zafirlukast (ZFL) against inflammatory response and tissue injury in mice. Materials and methods: The spinal injury was induced by two-level laminectomy of T6 and T7 vertebrae. The inflammation was assessed by histology, inflammatory mediators by enzyme-linked immunosorbent assay, apoptosis by Annexin-V, FAS staining, terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL) assay and expression of Bax and Bcl-2 by Western blot. Effect on motor recovery of hind limbs was evaluated for 10days postinjury. Results: The spinal injury resulted in tissue damage, apoptosis, edema, infiltration of neutrophils with increased expression of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). The spinal tissue showed elevated levels of prostaglandin E2 (PGE2), and LTB4 and increased phosphorylation of injured extracellular signal-regulated kinase-1/2 (ERK1/2). The PHP, ZFL and combination decreased inflammation, tissue injury and infiltration of neutrophils. Treatment also decreased the levels of PGE2, phosphorylation of extracellular signal-regulated kinase-1/2 (pERK 1/2), LT, TNF-α and COX-2 with a marked reduction in apoptosis and improved the motor function. Conclusion: The present study confirmed 5-LO antagonist activity of PHP and established its neuroprotective role along with ZFL. Keywords: pseudohypericin, zafirlukast, 5-lipoxygenase, Cys-LT, mice

Multitarget design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist zafirlukast that simultaneously inhibits soluble epoxide hydrolase and activates peroxisome proliferator-activated receptor g. The triple modulator exhibits robust anti-inflammatory activity in vivo and highlights the therapeutic potential of designed multitarget agents.

Aims This study investigated the hepatoprotective effects of both zafirlukast and vincamine and their possible role in the treatment of tamoxifen-induced liver injury in rats. Materials and methods Female Wistar rats were divided into five groups (10 rats each). Groups I and II received 1% Tween 80 and served as normal and tamoxifen controls, respectively. Groups III, IV and V were treated with zafirlukast (80 mg/kg), vincamine (10 mg/kg) and a combination of zafirlukast (80 mg/kg) and vincamine (10 mg/kg), respectively for 10 successive days. Tamoxifen was given orally to all groups, except for 1st group, in the dose of 45 mg/kg for 10 days to induce liver injury. Subsequently, rats were sacrificed for biochemical, histopathological, Immunohistochemistry, PCR and western blot assessment. Key findings Tamoxifen-induced liver injury was reflected by alterations in estimated biochemical parameters, activation of JNK/ERK pathway, increased expression of NF-κB, liver oxidative stress and inflammatory markers parallel to histopathological changes in liver tissue. Treatment of rats with zafirlukast and vincamine ameliorated tamoxifen induced hepatic cell injury via suppressing oxidative stress, inflammatory markers, caspases-3, p-JNK/p-ERK and NF-κB pathways. Significance Zafirlukast and vincamine may be regarded as potential therapeutic strategies with antioxidant and anti-inflammatory activities against tamoxifen-induced oxidative damage in rat liver.

Through regulating the expression of hundreds of genes, hypoxia-inducible factor -1(HIF-1) plays a critical role in hypoxic adaption of cancer cells and is considered as a target for cancer therapy. Here we show that montelukast, a clinical leukotriene receptor antagonist for the treatment of asthma, inhibits hypoxia or CoCl(2)-induced HIF-1α activation and reduces its protein expression in prostate cancer cells. However, the other two leukotriene receptor antagonists, pranlukast and zafirlukast, cannot decrease HIF-1α protein, which indicates that montelukast-induced downregulation of HIF-1α is not mediated by leukotriene receptor. Neither proteasome inhibitor MG132 nor the lysosomal inhibitor chloroquine (CQ) can block montelukast-induced downregulation of HIF-1α protein. Interestingly, GSK2606414, a PKR-like endoplasmic reticulum kinase (PERK) inhibitor, abrogates montelukast-induced downregulation of HIF-1α under hypoxic conditions. However, montelukast increases phosphorylation of eIF-2α at Ser51. Moreover, montelukast inhibits the proliferation of prostate cancer cells, which can be reversed by overexpression of HIF-1α protein. In conclusion, we identify montelukast may be used as a novel agent for the treatment of prostate cancer by decreasing HIF-1α protein translation.

The FDA-approved drug for the treatment of asthma, zafirlukast, is synthesized engaging multiple catalytic reactions including a new method for the construction of 3-aroylindoles via oxidative cyclization. The highlights include transition-metal and peroxide free C–H bond activation using the stoichiometric amount of sodium persulfate as an oxidizing agent in the construction of 3-aroylindole, avoiding transition metal, with over 28% overall yield. The complete process has a turnaround time of 28 h to get the target molecule starting from substituted aniline, with practically no protecting groups.

Cocrystals have been identified as a method for ensuring the delivery of poorly soluble drugs. Development of cocrystal phases presents many challenges, with the in vivo drug delivery benefits difficult to predict robustly. Additional to this, many of the benefits seen in the literature do not use formulation strategies which are representative of the clinical dosage form. Zafirlukast has been shown to possess poor development properties. It is poorly soluble and difficult to manufacture. Here we present a case study highlighting the benefits of cocrystals in this context, outlining the discovery, formulation and improved pharmacokinetics of mixed stoichiometry cocrystals of zafirlukast. This case study outlines methods, which could be broadly applied to other drug molecules, for determination of the properties of cocrystals through a suite of in vitro experiments that display a predictive pathway from physical form discovery to enhanced in vivo activity in animal models.

Cancer remains a leading cause of death worldwide, despite many advances being made in recent decades. Changes in the tumor microenvironment, including dysregulated immunity, may contribute to carcinogenesis and cancer progression. The cysteinyl leukotriene (CysLT) pathway is involved in several signal pathways, having various functions in different tissues. We summarized major findings of studies about the roles of the CysLT pathway in cancer. Many in vitro studies suggested the roles of CysLTs in cell survival/proliferation via CysLT1 receptor (CysLT1R). CysLT1R antagonism decreased cell vitality and induced cell death in several types of cancer cells, such as colorectal, urological, breast, lung and neurological malignancies. CysLTs were also associated with multidrug resistance of cancer, and CysLT1R antagonism might reverse chemoresistance. Some animal studies demonstrated the beneficial effects of CysLT1R antagonist in inhibiting tumorigenesis and progression of some cancer types, particularly colorectal cancer and lung cancer. The expression of CysLT1R was shown in various cancer tissues, particularly colorectal cancer and urological malignancies, and higher expression was associated with a poorer prognosis. The chemo-preventive effects of CysLT1R antagonists were demonstrated in two large retrospective cohort studies. In summary, the roles of the CysLT pathway in cancer have been delineated, whereas further studies are still warranted.

Leukotriene-modifying agents (LTMAs) including montelukast, zafirlukast, and zileuton are approved by the US Food and Drug Administration (FDA) for the treatment of asthma and allergic rhinitis. Various neuropsychiatric events (NEs) have been reported; however, the evidence of the association is conflicting. This systematic review investigates the association between NEs and LTMAs by assessing the relevant published literature. PubMed, EMBASE, MEDLINE, and Cochrane Library were searched using keywords. Studies designed to investigate the association were eligible for inclusion without restriction to any study design or language. The primary outcome was defined as suicidal conditions, while secondary outcomes included all other NEs. Thirty-three studies were included for a narrative review. Four observational studies did not find a significant association, while ten pharmacovigilance studies using different global databases detected the signals. Notably, some studies suggest that the FDA warning issued in 2008 might have influenced the reporting rate of NEs as a result of increased awareness. The risk of NEs was not quantified, because of the lack of randomized controlled trials and observational studies investigating the association. Many pharmacovigilance studies have been conducted to determine the association between NEs and LTMAs, but there is limited evidence from observational studies. High-quality epidemiological studies should be conducted to evaluate the association and quantify the risk, not only in children, but also in adults.

Glioblastoma is one of the most malignant and aggressive types of brain tumors. 5-lipoxygenase and cysteinyl leukotriene receptor 1 (CysLT1) play a role in human carcinogenesis. Leukotriene receptor antagonists (LTRAs), anti-asthmatic drugs with mild side effects, have anti-metastatic activity in epidermoid carcinoma, lung carcinoma, and colon cancers as well as neuroprotective effects. Herein, anti-migratory effects of two LTRAs, montelukast and zafirlukast, were investigated in glioblastoma cells. The level of CysLT1 in A172 cells was increased by 3.13 folds after IL-1β treatment. The median toxic concentration of LTRAs in A172, U373, and primary astrocytes ranged from 7.17 to 26.28 μM at 24-h post-exposure. Both LTRAs inhibited migration and invasion of glioma. Additionally, both drugs significantly inhibited the expression and activities of MMP-2 and MMP-9 in A172 and U373 glioblastoma cells and primary human astrocytes, suggesting that CysLT1 plays a role in migration and invasion of glioma, and LTRAs are potential drugs to reduce migration and invasion.

SD Glockler-Lauf, Y Finkelstein, J Zhu, LY Feldman, T To. J Pediatr. 2019;209:176–182.e4 To assess the association between montelukast prescription and neuropsychiatric events in children with asthma. Ontario children aged 5–18 years with an index neuropsychiatric event between April 1, 2004, and March 31, 2016, were identified as cases within a study cohort of children with physician-diagnosed asthma prescribed an asthma maintenance medication. Patients with pre-existing mental health conditions or a dispensed prescription for zafirlukast were excluded. Each case was matched based on sex, asthma diagnosis date, and birthdate to a maximum of four control patients without a neuropsychiatric event from the same study cohort. …

The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non‐alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti‐NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti‐asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver‐related metabolic diseases., Changing targets: The anti‐asthma drug Zafirlukast was used as a lead to develop dual farnesoid X receptor activators/soluble epoxide hydrolase inhibitors. Systematic structural modification produced the desired polypharmacological profile and depleted the drug's original on‐target activity while conserving the favorable molecular scaffold. Optimized compounds engaged the desired targets in cellular settings. The designed multi‐target profile may generate synergies in treating liver‐related metabolic diseases.

VEGFR2, vascular endothelial growth factor receptor 2, plays an important role in anti-angiogenesis and is an effective target for inhibiting tumor cell proliferation and metastasis. Many small molecule inhibitors have so far exhibited fine therapeutic effects but do not rule out some adverse reactions. From the perspective of the new use of old drugs, we use a combination of two different docking methods, molecular dynamics simulations and quantum-chemical calculations to acquire potential anti-angiogenesis inhibitors from the library of FDA-approved drugs. We attain five FDA-approved old drugs from Drugbank as potential inhibitors against VEGFR2. Therein, the anti-tumor effects of three compounds, including vilazodone (psychiatric drug), pranlukast and zafirlukast (asthma drugs), have been reported by previous experiments but no anti-tumor data is available for the other two compounds, including antrafenine (analgesic and anti-inflammatory drug) and iloperidone (psychiatric drug). These five compounds exhibit more stable interaction than sorafenib as a market-oriented drug targeting VEGFR2. In parallel, there is a most stable interaction for zafirlukast while a weakest interaction for iloperidone with VEGFR2. We show that these five compounds bind with the hydrophobic cavity of VEGFR2, then forming hydrogen bond interactions with three key residues, Glu-885, Cys-919 and Asp-1046. Lys-868 and Phe-1047 play an important role in stabilizing the interaction conformation. The binding poses of pranlukast and vilazodone are similar to that of sorafenib, whereas antrafenine and zafirlukast act differently from sorafenib, focusing on the direction difference of the respective ring structure. This work may help to develop new and effective anti-angiogenic inhibitors.

Stroke has been considered the second leading cause of death worldwide, and ischemic stroke accounts for the vast majority of stroke cases. Some of the main features of ischemic stroke are increased brain permeability, ischemia/reperfusion injury, oxidative stress, and acute inflammation. Antagonism of cysLT1R has been shown to provide cardiovascular and neural benefits. In the present study, we investigated the effects of the cysLT1R antagonist zafirlukast both in vivo and in vitro using a middle cerebral artery occlusion (MCAO) mouse model and human brain microvascular endothelial cells (HBMVECs). In vivo, we found that zafirlukast pretreatment could reduce MCAO-induced increased brain permeability by rescuing the expression levels of the tight junction proteins occludin and ZO-1. In vitro, we found that zafirlukast could suppress the increase in endothelial monolayer permeability induced by OGD/R via rescue of occludin and ZO-1 expression; additionally, we found that zafirlukast prevented OGD/R-induced degradation of the extracellular matrix via inhibition of MMP-2 and MMP-9 expression. Finally, we found that zafirlukast could also inhibit OGD/R-induced activation of the critical proinflammatory regulator NF-κB by preventing phosphorylation and nuclear translocation of p65 protein. Together, our findings demonstrate a promising role for zafirlukast in preventing damage induced by ischemic stroke and reperfusion injury.