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- Cysteinyl leukotriene-receptor-1 antagonists interfere with PGE2 synthesis by inhibiting mPGES-1 activity. [JOURNAL ARTICLE]
- Biochem Pharmacol 2013 May 14.
Because of their favourable safety profile and beneficial anti-inflammatory properties, the CysLT1 receptor antagonists (LTRA), montelukast, zafirlukast and pranlukast are approved for the treatment of asthma and are frequently prescribed as add-on therapeutics to reduce the amount of inhaled glucocorticoids and β2-agonists. There is evidence that some of these anti-inflammatory properties might be of a secondary nature and therefore, unrelated to the CysLT1 antagonism. Here, we show that LTRA inhibit PGE2 formation in cytokine- stimulated Hela and A549 carcinoma cells and in lipopolysaccharide (LPS)-stimulated human leukocyte preparations (IC50∼ 20μM). Neither expression of enzymes involved in PGE2 synthesis nor arachidonic acid release and COX activities were inhibited by the compounds. In contrast, mPGES-1 activity was suppressed at low micromolar levels (IC50 between 2-4μM). This suppression was specific for PGE2 synthesis, since PGD2 and PGI2 levels in LPS- stimulated leukocyte preparations were not negatively affected. PGF2α levels were concomitantly inhibited, probably due to its direct synthesis from PGE2. Several major conclusions can be drawn from this study: (A) Clinical trials investigating elevated doses of the compounds are helpful to confirm suppression of PGE2 synthesis in vivo; (B) Studies investigating the role of CysLTs in cell culture or animal models of inflammation and cancer have to be reassessed carefully, if higher doses of LTRA were applied or serum levels in cell culture assays were low; (C) LTRA may serve as new scaffolds for the development of potent, selective and well tolerated mPGES-1 inhibitors.
- Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549 - Role of the 5-lipoxygenase. [JOURNAL ARTICLE]
- Am J Physiol Cell Physiol 2013 Mar 13.
Pathophysiological conditions challenge cell volume homeostasis and perturb cell volume regulatory mechanisms leading to alterations of cell metabolism, active transepithelial transport, cell migration and death. We report that inhibition of the 5-lipoxygenase (5-LO) with AA861 or ETH 615-139, the cysteinyl leukotriene 1 receptor (CysLT1) with the anti-asthmatic drug Zafirlukast, or the volume-sensitive organic anion channel (VSOAC) with DIDS, blocks the release of organic osmolytes (taurine, meAIB) and the concomitant cell volume restoration following hypoosmotic swelling of human type II-like lung epithelial cells (A549). Reactive oxygen species (ROS) are produced in A549 cells upon hypotonic cell swelling by a diphenylene iodonium sensitive NADPH oxidase. The swelling-induced taurine release is suppressed by ROS scavenging (butylated hydroxytoluene, N-acetyl cysteine) and potentiated by H2O2. Ca(2+) mobilization with ionomycin or ATP stimulates the swelling-induced taurine release whereas calmodulin inhibition (W7) inhibits the release. Chelation of the extracellular Ca(2+) (EGTA) had no effect on swelling-induced taurine release but prevented ATP-induced stimulation. H2O2, ATP and ionomycin were unable to stimulate the taurine release in the presence of AA861 or Zafirlukast, placing 5-LO and CysLT1 as essential elements in the swelling-induced activation of VSOAC with ROS and Ca(2+) as potent modulators. Inhibition of tyrosine kinases (genistein, cucurbitacin) reduces volume-sensitive taurine release, adding tyrosine kinases (Janus kinase) as regulators of VSOAC activity. Caspase 3 activity during hypoxia is unaffected by inhibition of 5-LO/CysLT1 but reduced when swelling-induced taurine loss via VSOAC is prevented by DIDS excess extracellular taurine, indicating a beneficial role of taurine under hypoxia.
- Zafirlukast Inhibits Complexation of Lsr2 with DNA and Growth of Mycobacterium tuberculosis. [Journal Article]
- Antimicrob Agents Chemother 2013 May; 57(5):2134-40.
The mycobacterial nucleoid-associated protein Lsr2 is a DNA-bridging protein that plays a role in condensation and structural organization of the genome and acts as a global repressor of gene transcription. Here we describe experiments demonstrating that zafirlukast inhibits the complexation between Lsr2 and DNA in vitro. Zafirlukast is shown to inhibit growth in two different species of mycobacteria tested but exhibits no growth inhibition of Escherichia coli. The Lsr2 inhibitory activity is reflected in vivo as determined by monitoring of transcription levels in Mycobacterium tuberculosis. These data suggest that zafirlukast inhibits Lsr2 function in vivo, promoting dysregulation of the expression of an array of genes typically bound by Lsr2 and hindering growth. Since zafirlukast likely operates by a mechanism distinct from current M. tuberculosis drugs and is currently used as a prophylactic treatment for asthma, it offers an intriguing lead for development of new treatments for tuberculosis.
- Novel therapies in asthma: leukotriene antagonists, biologic agents, and beyond. [Journal Article]
- Am J Ther 2013 Jan; 20(1):79-103.
Asthma is one of the most common conditions seen in clinical practice and carries both a significant disease burden in terms of patient morbidity and a high economic burden in both direct and indirect costs. Despite this, it remains a comparatively poorly understood disease, with only modest advances in treatment over the past decade. Corticosteroids remain the cornerstone of therapy. Both patient compliance with medications and physician adherence to evidence-based guidelines are often poor, and a high percentage of patients continue to have inadequately controlled disease even with optimal therapy. Following a contextual overview of the current treatment guidelines, this review focuses on novel asthma therapies, beginning with the introduction of the leukotriene receptor antagonist zafirlukast in the 1990s, continuing through advanced endoscopic therapy and into cytokine-directed biologic agents currently in development. Along with clinically relevant biochemistry and pharmacology, the evidence supporting the place of these therapies in current guidelines will be highlighted along with data comparing these agents with more conventional treatment. A brief discussion of other drugs, such as those developed for unrelated conditions and subsequently examined as potential asthma therapies, is included.
- Effects of zafirlukast on capsular contracture: long-term results. [Journal Article]
- Int J Immunopathol Pharmacol 2012 Oct-Dec; 25(4):935-44.
Capsular contracture is a distressing complication after breast augmentation for both the patient and surgeon. Although capsular contracture is a multifactorial process, one common denominator in the successful treatment of this complication is believed to be the abatement of inflammation. Leukotriene antagonists have recently emerged as effective prophylactic agents in reactive airway diseases. A prospective study was carried out on 60 female patients (120 prostheses implanted) with mild/severe capsular contracture in at least one breast. The hardness of capsular contracture was assessed by means of the mammary compliance method. Patients received zafirlukast (Accolate®) for a 6-month period. Mammary compliance was assessed at the start of the study and thereafter monthly, during drug intake and for one year after drug withdrawal. The results show a significant decrease in breast compliance values in the first 6 months, followed by a significant increase one year after the end of drug intake. Indeed, zafirlukast-treated patients displayed a 6.93 percent reduction in mammary compliance after 1 month, 14.42 percent after 3 months, 22.05 percent after 6 months and 22.52 percent after 7 months (1 month after the withdrawal of the drug). Thereafter, mammary compliance values gradually increased. A 5.47 percent reduction in mammary compliance was observed 1 year after drug withdrawal. The present study suggests that zafirlukast may be effective in reducing breast capsule distortion in patients with long-standing contracture, though reduced capsular contracture values are strictly related to the duration of drug intake.
- The effect of bariatric surgery in the difficult asthma-obesity phenotype: a case report. [Journal Article]
- J Asthma 2013 Feb; 50(1):52-5.
Obesity and asthma have become increasingly prevalent conditions in recent years; they often coexist and place a significant burden on the National Health Service. Asthma in the obese is more difficult to treat than in those with a normal body mass index (BMI) and is associated with resistance to traditional asthma therapies and increased use of healthcare resources. Weight loss can improve asthma control in such patients. The degree of weight loss achieved through dietary strategies, however, is often only modestly successful in this group. Bariatric surgery is increasingly used to achieve sustained significant weight loss in morbid obesity. It may offer under-recognized benefit in the difficult asthma-obesity phenotype.We describe the case of a 32-year-old female with difficult asthma who had a BMI of 45 kg/m(2) at the time of referral to our clinic. Her asthma was uncontrolled despite maximal inhaled therapy, oral therapy with Zafirlukast, and daily high-dose (25 mg) oral prednisolone. Additional therapies (subcutaneous Terbutaline and the steroid-sparing agent Methotrexate) had little impact on asthma control and she remained morbidly obese. She underwent gastric bypass surgery and, over the following 18 months, her BMI dropped to 27.7 kg/m(2), her corticosteroid dose was reduced to 7.5 mg (adrenal insufficiency proven), and maintenance inhaled therapy and oral medications were stopped as she maintained good asthma control.This case demonstrates the dramatic improvement that bariatric surgery can have on asthma symptoms and medication use in morbidly obese patients with very difficult to control asthma.
- Chapter 16: Asthma in pregnancy. [Journal Article, Review]
- Allergy Asthma Proc 2012 May-Jun.:S55-7.
The course of asthma during pregnancy may be affected by maternal physiological changes and triggers of asthma such as viral infections, exposure to allergens, and nonadherence with therapy. If asthma is uncontrolled, there are recognized harmful effects not only to the mother but also to the fetus. However, with effective asthma control, most women have outcomes, at or near that of the general population. Many medications are considered appropriate for use in pregnancy including inhaled corticosteroids (ICSs) such as budesonide, beclomethasone dipropionate, and fluticasone and the leukotriene receptor antagonists montelukast and zafirlukast. When ICSs or ICS/long-acting beta(2)-adrenergic agonist combinations are not effective during exacerbations of asthma, short courses of oral corticosteroids should be administered earlier rather than later. Spirometry and flow volume loop tracings are useful measures of pulmonary function for gravidas. Results may be compared with nonpregnant reference values. Vocal cord dysfunction may be suspected when the inspiratory loop is truncated. The gravida does not reject the fetus because of lack of vascular continuity, a trophoblast layer causing separation, and suppressive mechanisms at the placental interface. The secretion of IL-10 increases in pregnancy and is lower in women with recurrent spontaneous abortions. Only immunoglobulin G (IgG) subclasses are transported across the placenta, especially IgG1, IgG3, and IgG4. Fetal B cells can produce endogenous IgE by 20 weeks of gestation.
- Lipofilling in skin affected by radiodermatitis: clinical and ultrasound aspects. Case report. [Journal Article]
- G Chir 2012 May; 33(5):186-90.
In recent years, lipofilling has established itself as one of the most effective and least invasive techniques to treat connective dystrophy subsequent to radiotherapy. We report the case of a patient diagnosed with intraductal carcinoma of the right breast in 1996, at the age of 41. The patient underwent quadrantectomy with ipsilateral axillary lymph node dissection and adjuvant chemotherapy and radiotherapy. Four years later, a recurrence led the patient to undergo a subcutaneous mastectomy and immediate reconstruction, involving the submuscular insertion of a permanent implant. In 2007 the patient suffered both radiodermatitis and capsular contracture around the implant, causing constant pain and significant functional limitation. She first took a leukotriene inhibitor (Zafirlukast, 20 mg daily for 8 months) to reduce the capsular contracture. She then underwent lipofilling (Coleman's technique) of the area affected by radiodermatitis, in which the skin was considerably thinned and visibly ischemic. A second session followed four months later. Clinical, photographic and ultrasound examination revealed clear and lasting thickening of the superficial tissues, increased coverage of the implant, and reduced skin discoloration and tension.
- Development of a stability-indicating RP-LC method for the separation of a critical pair of impurities and their degradants in zafirlukast. [Journal Article]
- J Chromatogr Sci 2012 Nov-Dec; 50(10):945-52.
A high-throughput reverse-phase liquid chromatographic (RP-LC) method is developed for the quantification of zafirlukast and its related impurities in drug substance. The separation of known impurities is accomplished using a short (50 mm) LC column with sub-2-µm particle size in a relatively short run-time. A linear gradient elution involves ammonium formate and acetonitrile as mobile phase. The critical impurity pair is the meta and para isomers of zafirlukast, which are known to be potential impurities of zafirlukast, whose resolution is sensitive to pH. The stability-indicating capability of the developed method is demonstrated using forced degradation samples from stress conditions such as hydrolysis, oxidation, thermal and photolytic degradation. The developed RP-LC method is validated in accordance with International Conference on Harmonization requirements. The results from the validation study indicate that this RP-LC method can be used for the determination of synthetic and degradation impurities in regular quality control analysis for the drug substance.
- Zafirlukast antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Anticancer Drugs 2012 Sep; 23(8):865-73.
ATP-binding cassette (ABC) transporters are present in the majority of human tumors and are involved in multidrug resistance (MDR). Therefore, compounds that inhibit the function of ABC transporters may improve the efficacy of anticancer agents. Previous research has shown that zafirlukast is a reversal drug for multidrug resistance protein (MRP) 1-mediated MDR. In the present study, we assessed whether zafirlukast could be a reversal agent for other ABC transporter-mediated MDR. Using the MTT assay, we found that zafirlukast enhanced the cytotoxicity of several anticancer drugs that are substrates of breast cancer resistance proteins (BCRP/ABCG2), including mitoxantrone and SN-38. Furthermore, zafirlukast could partially reverse P-glycoprotein-mediated (P-gp/ABCB1) and MRP7 (ABCC10)-mediated MDR at nontoxic doses. Studies on [(3)H]-mitoxantrone accumulation and efflux have shown that zafirlukast increases the intracellular accumulation of [(3)H]-mitoxantrone by directly inhibiting ABCG2-mediated drug efflux. Western blot analysis indicated that zafirlukast did not alter the expression of ABCG2. In addition, a docking model predicted the binding conformation of zafirlukast within the transmembrane region of homology-modeled human ABCG2. Our findings suggest a possible strategy to potentially enhance the activity of anticancer drugs using a clinically approved drug with known side effects and drug-drug interactions.