- Biorelevant dissolution testing of a weak base: Interlaboratory reproducibility and investigation of parameters controlling in vitro precipitation. [Journal Article]
- EJEur J Pharm Biopharm 2019; 140:141-148
- Following a previous study which aimed to determine the interlaboratory reproducibility of biorelevant dissolution testing in the USP 2 apparatus for commercial formulations of two weak acids (ibupro…
Following a previous study which aimed to determine the interlaboratory reproducibility of biorelevant dissolution testing in the USP 2 apparatus for commercial formulations of two weak acids (ibuprofen and zafirlukast), this study attempts to determine the interlaboratory reproducibility using a similar protocol for a commercially available formulation of a weak base, indinavir. Fourteen partners including twelve industrial and two academic partners participated in this study. To ensure uniformity, all partners were provided with a standardized protocol to perform (i) a single medium dissolution test in fasted state simulated gastric and intestinal fluids (FaSSGF and FaSSIF, respectively) and (ii) a two-stage dissolution experiment simulating gastrointestinal transfer. Optionally, partners could run a single-stage dissolution test in fed state simulated intestinal fluid (FeSSIF). For each dissolution test, one Crixivan® capsule (containing 400 mg indinavir as its sulfate salt) was added as dose of interest. For the single medium dissolution test in FaSSIF, all partners observed rapid release of indinavir resulting in supersaturated concentrations, followed by precipitation to equilibrium solubility. The degree and period of supersaturation varied among the participating laboratories. Average dissolution profiles in FeSSIF appeared to be highly reproducible with dissolved concentrations remaining lower than the thermodynamic solubility of indinavir in FeSSIF. For the two-stage dissolution test, most partners observed supersaturated concentrations in the intestinal compartment; two partners observed no supersaturation due to immediate precipitation. Given the fact that a high interlaboratory but low intralaboratory variability was observed when supersaturation/precipitation occurred, an undefined factor was hypothesized as a potential cause of the variability in precipitation. Hence, the impact of several experimental factors on the supersaturation and precipitation behavior of indinavir was investigated in a next step. The investigation indicated that variability is likely attributable to a combination of factors, especially, the time elapsed between sampling and dilution of the sample with the mobile phase. Therefore, when designing a test in which supersaturation and precipitation is anticipated, stringent control of the test methodology, especially regarding sampling and dilution, is needed.
- Neuroprotective effects of zafirlukast, piracetam and their combination on L-Methionine-induced vascular dementia in rats. [Journal Article]
- FCFundam Clin Pharmacol 2019 Apr 18
- 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 endotheli…
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 Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor γ. [Journal Article]
- FPFront Pharmacol 2019; 10:263
- 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…
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 IC50 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 EC50 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.
- Zafirlukast attenuates advanced glycation end-products (AGEs)-induced degradation of articular extracellular matrix (ECM). [Journal Article]
- IIInt Immunopharmacol 2019; 68:68-73
- 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 …
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.
- Cysteinyl leukotriene receptor type 1 (CysLT1R) antagonist zafirlukast protects against TNF-α-induced endothelial inflammation. [Journal Article]
- BPBiomed Pharmacother 2019; 111:452-459
- Endothelial dysfunction induced by chronic inflammation has been considered one of the most important mechanisms behind a variety of cardiovascular diseases. Extensive efforts have been made in past …
Endothelial dysfunction induced by chronic inflammation has been considered one of the most important mechanisms behind a variety of cardiovascular diseases. Extensive efforts have been made in past decades to explore the underlying mechanisms of endothelial dysfunction and to develop new therapeutic agents for the treatment of cardiovascular diseases. Zafirlukast, a selective antagonist of CysLT receptor 1 (CysLT1R), has been licensed by the U.S. Food and Drug Administration (FDA) for the treatment of asthma. In this study, we found that zafirlukast possesses beneficial protective effects on endothelial cells from TNF-α-induced inflammatory response and injury. Our results indicate that TNF-α treatment induces CysLT1R expression. The addition of zafirlukast to culture media suppressed TNF-α-induced expression of endothelial vascular adhesion molecules, such as ICAM-1, VCAM-1, and induction of cytokines, including IL-1β, IL-6, and IL-8. Zafirlukast also ameliorated production of reactive oxygen species (ROS) and adhesion of monocytes to endothelial cells induced by TNF-α. Mechanistically, we demonstrate that zafirlukast suppresses MAPK kinase p38 and NF-κB activation to inhibit inflammatory mediators. Collectively, our findings provide insights into the mechanisms of a potential therapeutic strategy for endothelial dysfunction-related diseases and shed light on the possible application of zafirlukast in cardiovascular diseases such as atherosclerosis.
- A mometasone-eluting sinus implant (Sinuva) for nasal polyps. [Review]
- MLMed Lett Drugs Ther 2018 Sep 10; 60(1555):151-152
- Breathing new life into West Nile virus therapeutics; discovery and study of zafirlukast as an NS2B-NS3 protease inhibitor. [Journal Article]
- EJEur J Med Chem 2018 Sep 05; 157:1202-1213
- The West Nile virus (WNV) has spread throughout the world causing neuroinvasive diseases with no treatments available. The viral NS2B-NS3 protease is essential for WNV survival and replication in hos…
The West Nile virus (WNV) has spread throughout the world causing neuroinvasive diseases with no treatments available. The viral NS2B-NS3 protease is essential for WNV survival and replication in host cells and is a promising drug target. Through an enzymatic screen of the National Institute of Health clinical compound library, we report the discovery of zafirlukast, an FDA approved treatment for asthma, as an inhibitor for the WNV NS2B-NS3 protease. Zafirlukast was determined to inhibit the protease through a mixed mode mechanism with an IC50 value of 32 μM. A structure activity relationship study of zafirlukast revealed the cyclopentyl carbamate and N-aryl sulfonamide as structural elements crucial for NS2B-NS3 protease inhibition. Replacing the cyclopentyl with a phenyl improved inhibition, resulting in an IC50 of 22 μM. Experimental and computational docking analysis support the inhibition model of zafirlukast and analogs binding at an allosteric site on the NS3 protein, thereby disrupting the NS2B cofactor from binding, resulting in protease inhibition.
- Zafirlukast in combination with pseudohypericin attenuates spinal cord injury and motor function in experimental mice. [Journal Article]
- DDDrug Des Devel Ther 2018; 12:2389-2402
- CONCLUSIONS: The present study confirmed 5-LO antagonist activity of PHP and established its neuroprotective role along with ZFL.
- Drugs and Lactation Database (LactMed): Zafirlukast [BOOK]
- BOOKNational Library of Medicine (US): Bethesda (MD)
- No published information is available on the use of zafirlukast during breastfeeding; however, manufacturer's data indicate that the dose in milk is low. If zafirlukast is required by the mother, it …
No published information is available on the use of zafirlukast during breastfeeding; however, manufacturer's data indicate that the dose in milk is low. If zafirlukast is required by the mother, it is not a reason to discontinue breastfeeding. However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Zafirlukast has been used in children as young as 12 months of age.
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- Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the Streptococcus agalactiae Respiratory Chain and Is a Potential Drug Target. [Journal Article]
- MBIOMBio 2018 07 03; 9(4)
- The opportunistic pathogen Streptococcus agalactiae is the major cause of meningitis and sepsis in a newborn's first week, as well as a considerable cause of pneumonia, urinary tract infections, and …
The opportunistic pathogen Streptococcus agalactiae is the major cause of meningitis and sepsis in a newborn's first week, as well as a considerable cause of pneumonia, urinary tract infections, and sepsis in immunocompromised adults. This pathogen respires aerobically if heme and quinone are available in the environment, and a functional respiratory chain is required for full virulence. Remarkably, it is shown here that the entire respiratory chain of S. agalactiae consists of only two enzymes, a type 2 NADH dehydrogenase (NDH-2) and a cytochrome bd oxygen reductase. There are no respiratory dehydrogenases other than NDH-2 to feed electrons into the respiratory chain, and there is only one respiratory oxygen reductase to reduce oxygen to water. Although S. agalactiae grows well in vitro by fermentative metabolism, it is shown here that the absence of NDH-2 results in attenuated virulence, as observed by reduced colonization in heart and kidney in a mouse model of systemic infection. The lack of NDH-2 in mammalian mitochondria and its important role for virulence suggest this enzyme may be a potential drug target. For this reason, in this study, S. agalactiae NDH-2 was purified and biochemically characterized, and the isolated enzyme was used to screen for inhibitors from libraries of FDA-approved drugs. Zafirlukast was identified to successfully inhibit both NDH-2 activity and aerobic respiration in intact cells. This compound may be useful as a laboratory tool to inhibit respiration in S. agalactiae and, since it has few side effects, it might be considered a lead compound for therapeutics development.IMPORTANCES. agalactiae is part of the human intestinal microbiota and is present in the vagina of ~30% of healthy women. Although a commensal, it is also the leading cause of septicemia and meningitis in neonates and immunocompromised adults. This organism can aerobically respire, but only using external sources of heme and quinone, required to have a functional electron transport chain. Although bacteria usually have a branched respiratory chain with multiple dehydrogenases and terminal oxygen reductases, here we establish that S. agalactiae utilizes only one type 2 NADH dehydrogenase (NDH-2) and one cytochrome bd oxygen reductase to perform respiration. NADH-dependent respiration plays a critical role in the pathogen in maintaining NADH/NAD+ redox balance in the cell, optimizing ATP production, and tolerating oxygen. In summary, we demonstrate the essential role of NDH-2 in respiration and its contribution to S. agalactiae virulence and propose it as a potential drug target.