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Dr Mehra Haghi

Biography

Dr Mehra Haghi graduated with a Doctor of Pharmacy degree from Azad University of Tehran (2007). She received her PhD in Pharmaceutical Sciences from the Faculty of Pharmacy, University of Sydney in 2012 in the area of applied respiratory cell biology.

She was then employed as postdoctoral research scientist at the university of Sydney (2012-2013) and later at The Woolcock Institute of Medical Research (2013-2014) where she was appointed as Honorary Associate Lecturer in the Discipline of Pharmacology, Sydney Medical School, University of Sydney.

In 2014 she joined the Faculty of Pharmacy at the University of Technology, Sydney as lecturer in Pharmaceutics. Dr Haghi was awarded the Alexander von Humboldt fellowship to pursue her research in the area of applied respiratory cell biology at the Department of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research (HIPS) in Saarbrücken, Germany during the second semester of 2014 and 2015.

She has authored more than 20 peer reviewed papers and conference proceedings involving international collaborators, from academia and industry: University of Groningen (Netherlands), Chiesi Ltd. and King’s College London (UK), University of Parma and University of Ferrara (Italy) and was selected as invited speaker and contributed oral presentations at SutEN (Sydney University tissue Engineering Network) in 2010, The Bosch Young Investigators 2012, Respiratory Drug Delivery Europe 2013 and seminars at The Woolcock Institute of Medical Research in 2012, Faculty of Pharmacy- University of Parma (Italy), Helmholz Research Institute (Germany), TSANZ (Thoracic Society of Australia & New Zealand) (NSW) Branch - Annual Scientific Meeting 2013 and TSANZSRS annual scientific meeting 2014.

Dr haghi has acted as reviewer for a number of research journals in the field of pharmaceutical sciences (Int. J. Pharm., Eur. J. Pharm. Biopharm., J. Pharm. Sci. etc.).

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Lecturer, Pharmacy
PHARMACY/PHARMACEUTICAL STUDIES, PHILOSOPHY
 

Research Interests

Dr Mehra Haghi’s research interests have been devoted to understanding and treatment of respiratory diseases encompassing epithelial cell biology, molecular pharmacology, respiratory technology and the development of representative in vitro models that mimic healthy and diseased lung tissue.  Specifically her team focus on understanding the complex mechanisms that occur when inhaled micro-particles are deposited at the lung epithelia; with a view to create new and more effective approaches to treat a range of respiratory diseases.

Can supervise: Yes

Dr Haghi welcomes research degree enquiries via a formal expression of interest (please do not email directly).

Conferences

Stigliani, M., Haghi, M., Russo, P., Young, P. & Traini, D. 2014, 'Evaluation of Antibiotic Transepithelial Transport Across Calu-3 Human Airway Cells', Respiratory Drug Delivery 2014, Davis Healthcare Int.
Haghi, M., Traini, D., Lewis, D.A., Forbes, B., Colombo, P. & Young, P.M. 2014, 'Effect of Particle Size and Excipients on the Uptake of Beclomethasone Dipropionate-Pressurized Metered Dose Inhalers After Deposition on Calu-3 Respiratory Epithelia', Respiratory Drug Delivery 2014, Davis Healthcare Int, Puerto Rico.
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Haghi, M., Traini, D., Bebawy, M. & Young, P. 2013, 'Uptake of Salmeterol Xinafoate and Fluticasone Propionate from Single and Combination Dry Powder Inhalers After Deposition on Calu-3 Respiratory Epithelia.', Respiratory Drug Delivery Europe 2013, Respiratory Drug Delivery, Berlin, Germany, pp. 445-448.
Haghi, M., Traini, D., Bebawy, M. & Young, P. 2011, 'Comparison of albuterol sulphate and base dry powder particulate deposition using the Calu-3 lung epithelial model', RDD Europe 2011, Respiratory Drug Delivery Europe 2011, Virginia Commonwealth University, Germany, pp. 519-522.
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To effectively predict the fate of formulated inhalation compounds delivered to the lung, a model of the airway epithelium should reflect drug permeability and transport characteristics in vivo. Most cell-based system established for this purpose, study drug transport using wet models and thus do not necessarily represent in vivo conditions. Recently, air-interface models have been established that increase the relevance of in vitro transport studies to the in vivo state. The aim of our study was to elucidate the dissolution and diffusion process of deposited dry drug particulates (albuterol) after aerosolization onto the epithelial surface and compare these to conventional in vitro `glass models. Two forms of albuterol were investigated (albuterol base and albuterol sulphate), to evaluate the effects of lipophilicity and aqueous solubility on the mechanism of transport.
Haghi, M., Young, P., Traini, D. & Bebawy, M. 2010, 'Characterization of P-gp Expression and Function vs. Time and Passage in the Calu-3 Air-Interface Model for Drug Delivery to the Lung', Proceedings of Respiratory Drug Delivery 2010, Respiratory Drug Delivery 2010, Davis Healthcare Int', Orlando, Florida, pp. 875-878.
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Calu-3, a sub-bronchial epithelial cell line, cultured at the air-interfaced, has been shown to be a very reliable model for the in vitro investigation of inhalation drug delivery to the upper airways. It has been found to be superior with respect to morphology and function when compared to the liquid covered culture model (1, 2), but the Calu-3 air-interface model has not been fully investigated for P-glycoprotein (P-gp) expression (3, 4) a parameter that could influence predicted drug delivery in the lung. P-gp is a plasma membrane drug transporter, actively involved in `carrying a wide range of structurally and functionally unrelated drugs out of cells (5). P-gp has been shown to interact with some drugs routinely used in respiratory therapy (1). Another factor that may affect drug transport across the epithelium is the presence of mucus; which, in healthy lungs, aids mucociliary clearance of deposited particulate matter, acts as an antibacterial substance and prevents loss of excessive fluid from the airway due to evaporation (6). The aim of this investigation was to characterize mucus secretion and cell surface P-gp expression and function in the Calu-3 air-interface model.

Journal articles

Kota, A., Deshpande, D., Haghi, M., Oliver, B. & Sharma, P. 2017, 'Autophagy and airway fibrosis: Is there a link?', F1000 Research, vol. 6, no. 409, pp. 1-10.
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In the past decade, an emerging process named 'autophagy has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital cellular processes, including tissue remodeling. This review will discuss some of the recent advancements made in understanding the role of this fundamental process in airway fibrosis with emphasis on airway remodeling, and how autophagy can be exploited as a target for airway remodeling in asthma and chronic obstructive pulmonary disease.
Arora, S., Haghi, M., Young, P.M., Kappl, M., Traini, D. & Jain, S. 2016, 'Highly respirable dry powder inhalable formulation of voriconazole with enhanced pulmonary bioavailability.', Expert opinion on drug delivery, vol. 13, no. 2, pp. 183-193.
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To develop and characterize a highly respirable dry powder inhalable formulation of voriconazole (VRZ).Powders were prepared by spray drying aqueous/alcohol solutions. Formulations were characterized in terms of particle size, morphology, thermal, moisture responses and aerosolization performance. Optimized powder was deposited onto an air-interface Calu-3 model to assess their uptake across Calu-3 lung epithelia. Optimized formulation was evaluated for stability (drug content and aerosol performance) for 3 months. Additionally, Calu-3 cell viability, lung bioavailability and tissue distribution of optimized formulation were evaluated.Particle size and aerosol performance of dry powder containing 80% w/w VRZ and 20% w/w leucine was appropriate for inhalation therapy. Optimized formulation showed irregular morphology, crystalline nature, low moisture sensitivity and was stable for 3 months at room temperature. Leucine did not alter the transport kinetics of VRZ, as evaluated by air-interface Calu-3 model. Formulation was non-cytotoxic to pulmonary epithelial cells. Moreover, lung bioavailability and tissue distribution studies in murine model clearly showed that VRZ dry powder inhalable formulation has potential to enhance therapeutic efficacy at the pulmonary infection site whilst minimizing systemic exposure and related toxicity.This study supports the potential of inhaled dry powder VRZ for the treatment of fungal infections.
Stigliani, M., Haghi, M., Russo, P., Young, P.M. & Traini, D. 2016, 'Antibiotic transport across bronchial epithelial cells: Effects of molecular weight, LogP and apparent permeability.', European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, vol. 83, pp. 45-51.
The first step in developing a new inhalable formulation for the treatment of respiratory diseases is to understand the mechanisms involved in the absorption of drugs after lung deposition. This information could be important for the treatment of bacterial infection in the lung, where low permeability would probably be beneficial, or a systemic infection, where high permeability would be desirable. The goal of this study was to evaluate the transport of several antibiotics (ciprofloxacin, azithromycin, moxifloxacin, rifampicin, doxycycline and tobramycin) across human bronchial airway epithelium and to study the influence of molecular weight and LogP on the apparent permeability.The experiments were conducted using Calu-3 cells seeded in the apical compartment of 24-well Transwell® inserts. The antibiotics transport was measured in both apical to basolateral (A-B) and basolateral to apical (B-A) directions and the apparent permeability of each antibiotic was calculated.The A-B transport of ciprofloxacin and rifampicin was independent of the initial concentration in the donor compartment, suggesting the involvement of active transporters in their absorption. Moxifloxacin, doxycycline, azithromycin and tobramycin presented a low absorptive permeation in the A-B direction, indicating that these substances could be substrate for efflux pumps. Generally, all antibiotics studied showed low permeabilities in the B-A direction.These findings suggest that the inhalation route would be favorable for delivering these specific antibiotics for the treatment of respiratory infection, compared with present oral or intravenous administration.
Arora, S., Kappl, M., Haghi, M., Young, P.M., Traini, D. & Jain, S. 2016, 'An investigation of surface properties, local elastic modulus and interaction with simulated pulmonary surfactant of surface modified inhalable voriconazole dry powders using atomic force microscopy', RSC Advances, vol. 6, no. 31, pp. 25789-25798.
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&copy; The Royal Society of Chemistry 2016. l-Leucine is used as the most common force control agent used in the inhaled dry powder formulations. In this study, the effect of l-leucine on the surface morphology, surface energy and the Young's modulus of the composite spray dried particles was studied. In addition, how l-leucine modifies the interaction of particles with a simulated pulmonary surfactant is also studied. Voriconazole (VRZ) was spray dried with different concentrations of l-leucine from hydroalcoholic solutions. Formulations were found to possess irregular morphology. Surface concentration of l-leucine was increased with increasing feed concentration and plateaued at about 20% w/w l-leucine. Atomic force microscopy (AFM) coupled with drug colloid probe enabled measurement of cohesion forces between the prepared formulations and found cohesion to be reduced significantly (p < 0.05) with the increase of l-leucine concentration. Peak Force Tapping enabled characterization of nanomechanical properties (elasticity and deformation) of formulations. Co-spray drying l-leucine with VRZ does not seem to have any influence on the Young's modulus of the formulations. Lastly, AFM revealed that the surface chemistry of the drug particle and pulmonary surfactant, as well as the contact geometry of the interacting surfaces, plays an important role in determining nature and extent of interaction between inhaled drug particles and pulmonary surfactant.
Haghi, M., Saadat, A., Zhu, B., Colombo, G., King, G., Young, P.M. & Traini, D. 2015, 'Immunomodulatory Effects of a Low-Dose Clarithromycin-Based Macrolide Solution Pressurised Metered Dose Inhaler', PHARMACEUTICAL RESEARCH, vol. 32, no. 6, pp. 2144-2153.
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Haghi, M., Traini, D., Wood, L.G., Oliver, B., Young, P.M. & Chrzanowski, W. 2015, 'A 'soft spot' for drug transport: modulation of cell stiffness using fatty acids and its impact on drug transport in lung model', JOURNAL OF MATERIALS CHEMISTRY B, vol. 3, no. 13, pp. 2583-2589.
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Haghi, M., van den Oetelaar, W., Moir, L.M., Zhu, B., Phillips, G., Crapper, J., Young, P.M. & Traini, D. 2015, 'Inhalable tranexamic acid for haemoptysis treatment', EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 93, pp. 311-319.
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Arora, S., Haghi, M., Loo, C.-.Y., Traini, D., Young, P.M. & Jain, S. 2015, 'Development of an Inhaled Controlled Release Voriconazole Dry Powder Formulation for the Treatment of Respiratory Fungal Infection', MOLECULAR PHARMACEUTICS, vol. 12, no. 6, pp. 2001-2009.
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Zhu, B., Haghi, M., Goud, M., Young, P. & Traini, D. 2015, 'The formulation of a pressurized metered dose inhaler containing theophylline for inhalation.', European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, vol. 76, pp. 68-72.
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BACKGROUND: Theophylline (TP) is a bronchodilator used orally to treat chronic obstructive pulmonary disease (COPD) that has been associated with multiple side effects, tempering its present use. This study aims to improve COPD treatment by creating a low-dose pressurized metered dose inhaler (pMDI) inhalable formulation of TP. METHODS: Aerosol performance was assessed using Andersen Cascade Impaction (ACI). Solubility of TP in HFA 134/ethanol mixture was measured and morphology of the particles analyzed with a scanning electron microscope (SEM). Calu-3 cell viability, epithelial cell transport and inflammatory-response assays were conducted to study the impact of the formulation on lung epithelial cells. RESULTS: The mass deposition profile of the formulation showed an emitted dose of 250.04&plusmn;14.48g per 5 actuations, achieving the designed nominal dose (50g/dose). SEM showed that the emitted particles were hollow with spherical morphology. Approximately 98% of TP was transported across Calu-3 epithelial cells and the concentration of interleukin-8 secreted from Calu-3 cells following stimulation with tissue necrosis factor- (TNF-) resulted in significantly lower level of interleukin-8 released from the cells pre-treated with TP (1.92&plusmn;0.77ngml(-1) TP treated vs. 8.83&plusmn;2.05ngml(-1) TNF- stimulated, respectively). CONCLUSIONS: The solution pMDI formulation of TP developed in present study was shown to be suitable for inhalation and demonstrated anti-inflammatory effects at low doses in Calu-3 cell model.
Trotta, V., Lee, W.H., Loo, C.Y., Haghi, M., Young, P., Scalia, S. & Traini, D. 2015, 'In vitro biological activity of resveratrol using a novel inhalable resveratrol spray-dried formulation.', International journal of pharmaceutics.
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The aim of the study was to prepare inhalable resveratrol by spray drying for the treatment of chronic obstructive pulmonary disease (COPD). Resveratrol, with a spherical morphology and particle diameter less than 5m, was successfully manufactured. Fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of spray-dried resveratrol was 39.9&plusmn;1.1% and 3.7&plusmn;0.1m, respectively when assessed with an Andersen cascade impactor (ACI) at 60l/min. The cytotoxicity results of spray-dried resveratrol on Calu-3 revealed that the cells could tolerate high concentration of resveratrol (up to 160M). In addition, in transport experiments using Snapwells, it was observed that more than 80% of the deposited dry powder was transported across the Calu-3 cells to the basal chamber within four hours. The expression of interleukin-8 (IL-8) from Calu-3 induced with tumor necrosis factor alpha (TNF-), transforming growth factor beta (TGF-1) and lipopolysaccharide (LPS) were significantly reduced after treatment with spray-dried resveratrol. The antioxidant assay (radical scavenging activity and nitric oxide production) showed spray-dried resveratrol to possess an equivalent antioxidant property as compared to vitamin C. Results presented in this investigation suggested that resveratrol could potentially be developed as a dry powder for inhalation for the treatment of inflammatory lung diseases like COPD.
Haghi, M., Hittinger, M., Zeng, Q., Oliver, B.G., Traini, D., Young, P., Huwer, H., Schneider-Daum, N. & Lehr, C.M. 2015, 'Mono- and Cocultures of Bronchial and Alveolar Epithelial Cells Respond Differently to Proinflammatory Stimuli and Their Modulation by Salbutamol and Budesonide.', Mol Pharm, vol. 12, no. 8, pp. 2625-2632.
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The aim of this study was to investigate the changes in transport and effectiveness of salbutamol sulfate (SAL) and budesonide (BD) following stimulation with transforming growth factor- (TGF-) in mono- and coculture models of bronchial and alveolar epithelium. Primary bronchial and alveolar epithelial cells, grown at air interface on filters, either as monocultures or in coculture with airway smooth muscle cells or alveolar macrophages, respectively, were stimulated with TGF-. The biological response was modulated by depositing aerosolized SAL and BD on bronchial and alveolar models, respectively. Barrier integrity, permeability to fluorescein-Na, transport of the deposited drug, and the pharmacological response to SAL (cAMP and IL-8 levels) or BD (IL-6 and -8 levels) were measured. While stimulation with TGF- did not have any significant effect on the transepithelial electrical resistance and permeability to fluorescein-Na in mono- and coculture models, transport of SAL and BD were affected in cultures from some of the patients (6 out of 12 for bronchial and 2 out of 4 for alveolar cells). The bronchial coculture showed a better responsiveness to SAL in terms of cAMP release than the monoculture. In contrast, the difference between alveolar mono- and cocultures to TGF- mediated interleukin release and its modulation by BD was less pronounced. Our data point to intrinsic differences in the transport of, and responsiveness to, SAL and BD when epithelial cell cultures originate from different patients. Moreover, if the biological responses (e.g., IL-8, cAMP) involve communication between different cell types, coculture models are more relevant to measure such effects than monocultures.
Zhu, B., Haghi, M., Nguyen, A., Goud, M., Yeung, S., Young, P.M. & Traini, D. 2015, 'Delivery of theophylline as dry powder for inhalation', Asian Journal of Pharmaceutical Sciences, vol. 10, no. 6, pp. 520-527.
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&copy; 2015 The Authors. Theophylline (TP) is a very well established orally or intravenously delivered antiasthma drug with many beneficial effects. This study aims to improve asthma treatment by creating a dry powder inhalable (DPI) formulation of TP to be delivered directly to the lung, avoiding the side effects associated with conventional oral delivery. The DPI TP formulation was investigated for its physico-chemical characteristics using scanning electron microscopy, laser diffraction, thermal analysis and dynamic vapour sorption. Furthermore, aerosol performance was assessed using the Multi Stage Liquid Impinger (MSLI). In addition, a Calu-3 cell transport assay was conducted in vitro using a modified ACI to study the impact of the DPI formulation on lung epithelial cells. Results showed DPI TP to be physico-chemically stable and of an aerodynamic size suitable for lung delivery. The aerosolisation performance analysis showed the TP DPI formulation to have a fine particle fraction of 29.70 &plusmn; 2.59% (P < 0.05) for the TP formulation containing 1.0% (w/w) sodium stearate, the most efficient for aerosolisation. Regarding the deposition of TP DPI on Calu-3 cells using the modified ACI, results demonstrated that 56.14 &plusmn; 7.62% of the total TP deposited (13.07 &plusmn; 1.69 g) was transported across the Calu-3 monolayer over 180 min following deposition, while 37.05 &plusmn; 12.62% of the deposited TP was retained in the cells. This could be due to the presence of sodium stearate in the current formulation that increased its lipophilicity. A DPI formulation of TP was developed that was shown to be suitable for inhalation.
Haghi, M., Bebawy, M., Colombo, P., forbes, B., Lewis, D., Salama, R., Traini, D. & Young, P. 2014, 'Towards the bioequivalence of pressurised metered dose inhalers 2. Aerodynamically equivalent particles (with and without glycerol) exhibit different biopharmaceutical profiles in vitro', European Journal of Pharmaceutics and Biopharmaceutics, vol. Online.
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Two solution-based pressurised metered dose inhaler (pMDI) formulations were prepared such that they delivered aerosols with identical mass median aerodynamic diameters, but contained either beclomethasone dipropionate (BDP) alone (glycerol-free formulation) or BDP and glycerol in a 1:1 mass ratio (glycerol-containing formulation). The two formulations were deposited onto Calu-3 respiratory epithelial cell layers cultured at an air interface. Equivalent drug mass (~1000ng or ~2000ng of the formulation) or equivalent particle number (1000ng of BDP in the glycerol-containing versus 2000ng of BDP in the glycerol-free formulation) were deposited as aerosolised particles on the air interfaced surface of the cell layers. The transfer rate of BDP across the cell layer after deposition of the glycerol-free particles was proportional to the mass deposited. In comparison, the transfer of BDP from the glycerol-containing formulation was independent of the mass deposited, suggesting that the release of BDP is modified in the presence of glycerol. The rate of BDP transfer (and the extent of metabolism) over 2h was faster when delivered in glycerol-free particles, 465.01ng&plusmn;95.12ng of the total drug (20.99&plusmn;4.29%; BDP plus active metabolite) transported across the cell layer, compared to 116.17ng&plusmn;3.07ng (6.07&plusmn;0.16%) when the equivalent mass of BDP was deposited in glycerol-containing particles. These observations suggest that the presence of glycerol in the maturated aerosol particles may influence the disposition of BDP in the lungs.
Saadat, A., Zhu, B., Haghi, M., King, G., Colombo, G., Young, P.M. & Traini, D. 2014, 'The formulation, chemical and physical characterisation of clarithromycin-based macrolide solution pressurised metered dose inhaler', JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 66, no. 5, pp. 639-645.
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Haghi, M., Ong, H.X., Traini, D. & Young, P. 2014, 'Across the pulmonary epithelial barrier: Integration of physicochemical properties and human cell models to study pulmonary drug formulations', PHARMACOLOGY & THERAPEUTICS, vol. 144, no. 3, pp. 235-252.
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Haghi, M., Traini, D. & Young, P. 2014, 'In Vitro Cell Integrated Impactor Deposition Methodology for the Study of Aerodynamically Relevant Size Fractions from Commercial Pressurised Metered Dose Inhalers', PHARMACEUTICAL RESEARCH, vol. 31, no. 7, pp. 1779-1787.
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Lewis, D.A., Young, P., Buttini, F., Church, T., Colombo, P., Forbes, B., Haghi, M., Johnson, R., O'Shea, H., Salama, R. & Traini, D. 2014, 'Towards the bioequivalence of pressurised metered dose inhalers 1: Design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient', EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 86, no. 1, pp. 31-37.
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Saadat, A., Haghi, M., Zhu, B., King, G., Colombo, G., Young, P. & Traini, D. 2014, 'THE FORMULATION OF A NOVEL MACROLIDE SOLUTION PRESSURISED METERED DOSE INHALER: THE USE OF CLARITHROMYCIN AS AN ANTI-INFLAMMATORY FOR BRONCHIECTASIS THERAPY', JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY, vol. 27, no. 4, pp. A3-A3.
Haghi, M., Chrzanowski, W., Traini, D., Wood, L., Oliver, B. & Young, P. 2014, 'THE ROLE OF DIETARY FATTY ACIDS IN TRANSPORT OF SALBUTAMOL ACROSS CALU-3 EPITHELIA', RESPIROLOGY, vol. 19, pp. 38-38.
Zeng, Q., Haghi, M., Rimmer, J., Black, J., Shi, J., Oliver, B. & Ge, Q. 2014, 'THE TRANSPORT OF SALBUTAMOL SULFATE THROUGH CALU-3 AND DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL CELL', RESPIROLOGY, vol. 19, pp. 63-63.
Trotta, V., Haghi, M., Lee, W.-.H., Scalia, S., Young, P.M. & Traini, D. 2014, 'RESVERATROL, A NOVEL SPRAY DRIED INHALATION POWDER FOR COMPLEMENTARY THERAPY IN THE TREATMENT OF COPD', JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY, vol. 27, no. 6, pp. A8-A9.
Mamlouk, M., Young, P., Bebawy, M., Haghi, M., Mamlouk, S., Mulay, V. & Traini, D. 2013, 'Salbutamol Sulfate Absorption Across Calu-3 Bronchial Epithelia Cell Monolayer is Inhibited in the Presence of Common Anionic NSAIDs', Journal Of Asthma, vol. 50, no. 4, pp. 334-341.
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The aim of this study was to characterize the permeability kinetics of salbutamol sulfate, a commonly used 2-agonist in the treatment of asthma exacerbation, across Calu-3 respiratory epithelial cell monolayers in the presence of non-steroidal anti-inflammatory drugs (NSAIDs), as they have been implicated to be able to modulate organic cation transporters (OCTs). Methods. Calu-3 cell monolayers were grown in a liquid covered culture (LCC) configuration on 0.33 cm2 Transwell polyester cell culture supports. Monolayers, cultured between 11 and 14 days were evaluated for epithelial resistance, tight junction integrity, and expression of OCT using Western blot analysis. The transport of salbutamol across the monolayer was studied as a function of concentration. Directional transport was investigated by assessing apical-basal (a-b) and basal-apical (b-a) directions. The influence of a non-specific OCT inhibitor (tetraethylammonium, TEA) and three NSAIDs (aspirin, ibuprofen, and indomethacin) on the uptake of salbutamol was studied. Results. The flux of salbutamol sulfate increased with increasing concentration before reaching a plateau, suggesting the involvement of a transport-mediated uptake mechanism. Western blot analysis detected the presence of OCT1-3 and N1 and N2 sub-types, suggesting the presence of functioning transporters. The apparent permeability (Papp) of 0.1 mM salbutamol across the epithelial monolayer displayed directional transport in the a-b direction which was inhibited by ~70% in the presence of TEA, suggesting OCT-mediated uptake. Likewise, the uptake of 0.1 mM salbutamol was decreased in the presence of all the three NSAIDs, supporting a mechanism whereby NSAIDs inhibit absorption of salbutamol across the bronchial epithelium via effects on the OCT transporters. Conclusion. This study demonstrates that NSAIDs influence the uptake kinetics of salbutamol in an in vitro Calu-3 cell system.
Marin, L., Traini, D., Bebawy, M., Colombo, P., Buttini, F., Haghi, M., Ong, H.X. & Young, P. 2013, 'Multiple dosing of simvastatin inhibits airway mucus production of epithelial cells: Implications in the treatment of chronic obstructive airway pathologies', European Journal of Pharmaceutics and Biopharmaceutics, vol. 84, no. 3, pp. 566-572.
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Background Chronic obstructive pulmonary disease (COPD) is characterised by mucus hyper-production. This pathology, together with other inflammatory contributions, leads to airway obstruction and breathing complications. Newer therapeutic approaches are of increased interest, including the use of HMG-CoA reductase inhibitors. Retrospective studies have shown that statins are effective in reducing patient mortality and blood cytokines levels. These findings suggest statins may also provide a new therapeutic approach in COPD treatment. Purpose The aim of the present work was to study the transport of simvastatin (SV) across Calu-3 epithelial cells and to investigate its pharmacological action with respect to reduction in mucus production. Methods Calu-3 cells were grown under liquid covered culture (LCC) conditions for transport studies in order to demonstrate the ability of SV to transport across the monolayer. For mucus detection, cells were grown under air interface culture (AIC) conditions. Samples collected for microscope analysis were stained with alcian blue; images of the stained cell surface were acquired and the mucus was quantified as the RGBB ratio.
haghi, M., Traini, D., Postma, D.S., Bebawy, M. & Young, P.M. 2013, 'Fluticasone uptake across Calu-3 cells is mediated by salmeterol when deposited as a combination powder inhale', Respirology, vol. 18, no. 8, pp. 1197-1201.
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BACKGROUND AND OBJECTIVE: We assessed whether co-deposition of a long-acting 2 -agonist and a corticosteroid affects their respective transport rates across epithelial cells. METHODS: Drug particles were deposited on the air-interface culture of Calu-3 cells using a twin-stage impinger. We compared the transport rate of salmeterol and fluticasone across the epithelial cells using commercially available formulations (Serevent, Flixotide and Seretide). The transepithelial resistance of Calu-3 cells was measured before and after each deposition to monitor epithelial resistance. RESULTS: The codeposition of salmeterol and fluticasone had no significant effect on transport of salmeterol through the cell layer. In contrast, the rate of fluticasone propionate transport in presence of salmeterol xinofoate was significantly lower (0.53 &plusmn; 0.20%) compared with the single fluticasone formulation (2.36 &plusmn; 0.97%). Furthermore, the resistance of the epithelial cells was significantly increased after salmeterol deposition from both single and combination products. CONCLUSIONS: Our data demonstrate that salmeterol may decrease the permeability of epithelial cells, resulting in slower fluticasone transport across Calu-3 epithelial monolayers. The subsequent increased residence time of fluticasone in the airways could prolong its anti-inflammatory effects.
Scalia, S., Haghi, M., Losi, V., Trotta, V., Young, P.M. & Traini, D. 2013, 'Quercetin solid lipid microparticles: A flavonoid for inhalation lung delivery', EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 49, no. 2, pp. 278-285.
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Haghi, M., Salama, R., Traini, D., Bebawy, M. & Young, P. 2012, 'Modification of disodium cromoglycate passage across lung epithelium in vitro via incorporation into polymeric microparticles', The AAPS Journal, vol. 14, no. 1, pp. 79-86.
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Two microparticle systems containing disodium cromoglycate (DSCG) alone or with polyvinyl alcohol (DSCG/PVA) were produced via spray drying and compared in terms of their physicochemical characteristics, aerosol performance and drug uptake across a pulmonary epithelial cell line (Calu-3), cultured under air interface conditions. The particle size distribution of DSCG and DSCG/PVA were similar, of spherical geometry, amorphous and suitable for inhalation purposes. Aerosolisation studies using a modified twin-stage impinger showed the DSCG/PVA to have greater aerosol performance than that of DSCG alone. Aerosol particles of DSCG and DSCG/PVA were deposited onto the surface of the Calu-3 air interface epithelium monolayer and the drug uptake from apical to basal directions measured over time. Drug uptake was measured across a range of doses to allow comparison of equivalent drug and powder mass deposition. Analysis of the data indicated that the percentage cumulative drug uptake was independent of the mass of powder deposited, but dependent on the formulation. Specifically, with the formulation containing DSCG, the diffusion rate was observed to change with respect to time (indicative of a concentration-dependent diffusion process), whilst DSCG/PVA showed a time-independent drug uptake (suggesting a zero-order depot release).
Haghi, M., Traini, D., Bebawy, M. & Paul, Y.M. 2012, 'Deposition, Diffusion and Transport Mechanism of Dry Powder Microparticulate Salbutamol, at the Respiratory Epithelia', Molecular Pharmaceutics, vol. 9, no. 6, pp. 1717-1726.
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The deposition, dissolution and transport of salbutamol base (SB) and salbutamol sulfate (SS) inhalation powders were investigated using the Calu-3 air interface cell culture model and Franz diffusion cell. Drug uptake by cells was studied with respect to deposited dose, drug solubility and hydrophobicity. Furthermore, the role of active transport via organic cationic transporters (OCTs) was studied. SB and SS were processed to have similar diameters (3.09 &plusmn; 0.06 &micro;m and 3.07 &plusmn; 0.03 &micro;m, respectively) and were crystalline in nature. Analysis of drug wetting, dissolution and diffusion using a conventional in vitro Franz cell (incorporating a cell culture support Transwell polyester membrane) showed diffusion of SB to be slower than that of SS (98.57 &plusmn; 4.23 &micro;g after 4 h for SB compared to 98.57 &plusmn; 4.01 &micro;g after 15 min for SS). Such observations suggest dissolution to be the rate-limiting step. In comparison, the percentage transfer rate using the air interface Calu-3 cell model suggested SB transport to be significantly faster than SS transport (92.02 &plusmn; 4.47 &micro;g of SB compared to 63.76 &plusmn; 8.84 &micro;g of SS transported over 4 h), indicating that passive diffusion through the cell plays a role in transport. Furthermore, analysis of SB and SS transport, over a range of deposited doses, suggested the transport rate in the Franz diffusion cell to be limited by wetting of the particle and dissolution into the medium.
Haghi, M., Traini, D., Jaiswal, R., Gong, J. & Bebawy, M. 2010, 'Time- and passage-dependent characteristics of a Calu-3 respiratory epithelial cell model', Drug Development And Industrial Pharmacy, vol. 36, no. 10, pp. 1207-1214.
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Background: Although Standard Protocols For The Study Of Drug Delivery In The Upper Airways Using The Sub-Bronchial Epithelial Cell Line Calu-3 Model, Particularly That Of The Air-Liquid Interface Configuration, Are Readily Available, The Model Remains U