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Inhalable lipid microparticle and spray dried formulations based on polyphenolic compounds
No full textL’infiammazione acuta e cronica di alveoli e/o bronchi sta alla base della patogenesi e dello sviluppo di malattie infiammatorie croniche polmonari come asma e broncopneumopatia cronico ostruttiva (BPCO) [1]. L’asma è una malattia infiammatoria caratterizzata da un’ostruzione generalmente reversibile, ma a volte irreversibile, delle vie aeree inferiori, caratterizzata da una sintomatologia variabile e ricorrente, come ostruzione delle vie aeree e broncospasmo [2]. La BPCO è una delle principali cause di morbilità e mortalità in tutto il mondo [3, 4], ed è caratterizzata da infiammazione cronica, dalla limitazione del flusso aereo, da ipersecrezione di muco, enfisema e broncocostrizione che portano ad una diminuzione dell’attività respiratoria fino alla morte. La terapia farmacologica per il trattamento di queste patologie ha diversi target farmacologici, diversi tipi di farmaci e vie di somministrazione. Ad oggi, non esiste una terapia in grado di ripristinare le normali funzioni polmonari, poiché tutti i trattamenti farmacologici mirano a rallentare la progressione di queste malattie e a ridurne i sintomi [5]. L’infiammazione e lo stress ossidativo stanno alla base della patogenesi di queste malattie [6]. Infatti, studi precedenti hanno dimostrato come lo stress ossidativo svolga un ruolo importante nella patogenesi di malattie polmonari in quanto causa un’ infiammazione irreversibile delle vie aeree attraverso il rilascio di mediatori dell’infiammazione. Di conseguenza, l'identificazione di composti ad attività antiossidante e anti-infiammatoria, quali i polifenoli (quercetina e resveratrolo), può essere una via terapeutica vantaggiosa in quanto queste molecole riescono a modulare vari aspetti biochimici delle malattie infiammatorie croniche polmonari. I polifenoli, presentano numerose attività benefiche, ma ad oggi il loro utilizzo risulta essere limitato dalla loro bassa biodisponibilità a causa della loro scarsa solubilità in acqua, rapida metabolizzazione e instabilità chimica [7]. Per questi motivi, la mia attività di ricerca si è focalizzata sullo sviluppo di sistemi microparticellari da somministrare per via inalatoria al fine di avere una consegna sito-specifica a livello polmonare, migliorando così la biodisponibilità dei polifenoli studiati.
Il lavoro sperimentale è stato diviso in tre sezioni:
I. SEZIONE A: Inhalable dry powder based on quercetin-loaded lipid microparticles for pulmonary delivery;
II. SEZIONE B: Inhalable resveratrol spray dried formulation to improve the treatment of chronic inflammatory lung diseases; III. SEZIONE C: In vitro activities of co-spray dried resveratrol and budesonide inhalable formulations in alveolar macrophages.
I. SEZIONE A La quercetina, è una molecola appartenente ai polifenoli, che grazie alla sua attività anti-ossidante e anti-infiammatoria presenta diverse attività farmacologiche rispetto a diverse malattie. Specificamente per le malattie polmonari, studi in vitro e in vivo dimostrano come questo flavonoide presenta delle proprietà favorevoli per il trattamento dell’asma [8, 9]. Nonostante le sue attività siano favorevoli rispetto a diverse patologie, il suo utilizzo risulta essere limitato dal rapido metabolismo, scarsa permeazione cellulare e dalla sua instabilità nei fluidi biologici [8, 10, 11]. Per questo motivo, in diversi studi è riportata l’incapsulazione della quercetina in sistemi micro- e nanoparticelle [9, 12]. Le microparticelle lipidiche (LM) rappresentano un ottimo sistema di per veicolare la quercetina direttamente a livello polmonare, avendo così un aumento della sua concentrazione nel sito di azione [13]. In questo studio la quercetina è stata incapsulata all’interno delle ML, ottenendo così una formulazione di polvere secca da somministrare per via inalatoria. Le ML ottenute sono state caratterizzate sia da un punto di vista morfologico che come caratteristiche chimico-fisiche, ed inoltre è stata valutata l’efficienza di incapsulazione del flavonoide nella matrice lipidica. Con lo scopo di valutare l’effetto delle ML sull’attività in vitro della quercetina sono stati condotti studi in vitro utilizzando linee cellulari epiteliali alveolari A549 per valutare la permeazione del flavonoide. Le ML sono state ottenute mediante la tecnica della fusione-emulsione ed i componenti che hanno permesso di ottenere le condizioni migliori sono state la tristearina come lipide e fosfatidilcolina come tensioattivo. Il contenuto di quercetina nelle ML e l’efficienza di incapsulazione sono stati di 11.8 ± 0.3% (p/p) e 72,4 % rispettivamente. Informazioni riguardo morfologia e dimensioni delle ML sono state ottenute da osservazioni al microscopio ottico e con la microscopia a scansione elettronica (SEM), le cui immagini hanno mostrato morfologia sferica delle ML con dimensioni adatte alla somministrazione a livello polmonare. Dagli studi di rilascio si evince che la quercetina è stata incapsulata all’interno della matrice lipidica in quanto la cinetica di rilascio della quercetina incapsulata è inferiore rispetto alla velocità di dissoluzione della quercetina libera. Per valutare l’effetto delle microparticelle su linee cellulari sono state utilizzate le cellule epiteliali alveolari A549. I risultati ottenuti mostrano che dopo 4h di incubazione il quantitativo di quercetina nelle cellule A549 è stato significativamente maggiore rispetto al flavonoide non incapsulato. L’
aumento del quantitativo di quercetina permeata è dovuto al fatto che le ML impediscono la metabolizzazione del flavonoide e che quindi modulandone il rilascio nel tempo ne permettono l’assorbimento a livello cellulare. In conclusione, i risultati ottenuti mostrano come le ML rappresentano un buon sistema di veicolazione della quercetina a livello polmonare come nuovo approccio terapeutico per il trattamento di malattie infiammatorie delle vie aeree.
II: SECTION B: Il resveratrolo, è un composto polifenolico di origine naturale che viene prodotto da diverse specie di piante e che presenta diverse attività benefiche, tra cui le attività anti-infiammatoria e antiossidante [14, 15]. La formulazione del resveratrolo come polvere secca rappresenta una buona via per veicolarlo a livello polmonare, in quanto l’utilizzo di questo polifenolo in soluzione non è possibile data la sua instabilità, la sua rapida degradazione per ossidazione e la sua scarsa solubilità in acqua [16]. Lo scopo di questo lavoro è stato quello di formulare il resveratrolo in una formulazione di polvere secca da somministrare per via inalatoria per il trattamento della BPCO utilizzando la tecnica dello spray drying. Nello specifico è stata valutata l’efficacia del resveratrolo come inalabile polvere secca (spray dried resveratrolo) e la sua attività anti-infiammatoria e anti-ossidante nelle linee cellulari bronchiali Calu-3. Sono state valutate le caratteristiche morfologiche e chimico fisiche della formulazione. L’ efficienza di aerosolizzazione è stata determinata utilizzando l’Andersen Cascade Impactor (ACI). Successivamente sono stati valutati la deposizione, il trasporto e l’uptake cellulare dello spray dried resveratrolo utilizzando le linee cellulari Calu-3 inserite in un ACI modificato. Infine è stata valutata l’attività anti-ossidante e anti-infiammatoria del resveratrolo nelle cellule Calu-3. I risultati ottenuti mostrano come le particelle ottenute con lo spray drying hanno morfologia sferica e diametro inferiore a 5 μm. La frazione di particelle fini (FPF) e il diametro aerodinamico mediano di massa (MMAD) della formulazione spray dried sono stati di 39.9 ± 1.1% e 3.7 ± 0.1 μm, rispettivamente, utilizzando l’ACI a 60 l/min. Gli studi in vitro indicano che il resveratrolo non causa effetti tossici significativi nelle cellule Calu-3 anche ad alte concentrazioni (fino a 160 μM). Dagli studi di trasporto si è visto come l’80% del resveratrolo è in grado di permeare le Calu-3 dopo 4h dalla deposizione della polvere sulle cellule. Lo spray dried resveratrolo presenta attività antiinfiammatoria nei confronti delle cellule Calu-3 in quanto l’espressione di interleuchina-8 (IL-8) è stata significativamente ridotta dopo aver favorito l’infiammazione cellulare con il fattore di necrosi tumorale alpha (TNF-α), fattore di crescita trasformante beta-1 (TGF-β1) e il lipopolisaccaride
(LPS). Infine lo spray dried resveratrolo ha mostrato di possedere attività anti-ossidante sulle cellule Calu-3. Questi dati mostrano come il resveratrolo presenti delle attività terapeutiche per le malattie polmonari, come asma e BPCO e che la formulazione spray dried rappresenta un ottimo sistema per veicolare il resveratrolo direttamente a livello polmonare. In conclusione , i risultati dimostrano come il resveratrolo può essere formulato come polvere secca da somministrare per via inalatoria nel trattamento di malattie infiammatorie croniche polmonari, come la BPCO.
III.SECTION C: Il trattamento farmacologico per la BPCO è sintomatico e include l’utilizzo farmaci corticosteroidi da somministrare per via inalatoria (es. budesonide). I corticosteroidi sono molecole che sono in grado di diminuire il rilascio di mediatori dell’infiammazione a livello dei macrofagi alveolari, ma questa loro attività diminuisce in pazienti con BPCO in quanto viene inibita l’attività dell’istone deacetilasi (HDAC2) [17]. C’è il bisogno di un nuovo approccio terapeutico per la BPCO in quanto vi è un aumento della resistenza ai corticosteroidi nei pazienti con BPCO ed inoltre perché il trattamento farmacologico non è in grado di bloccare questa patologia [18]. L’infiammazione sistemica e lo stress ossidativo sono gli elementi centrali che stanno alla base della BPCO ed inoltre sono i bersagli terapeutici [19]. La combinazione di una composto ad attività anti-ossidante con uno ad attività antiinfiammatoria può essere investigato come nuovo approccio terapeutico per la BPCO. Questo studio ha avuto come scopo quello di preparare e caratterizzare una inalabile formulazione, co-spray dried contenente resveratrolo e budesonide. Sono state prodotte diverse formulazioni che sono state caratterizzate da un punto di vista chimico-fisico e ne sono state valutate le proprietà aerosolizzanti. L’attività biologica è stata studiata utilizzando linee cellulari di macrofagi alveolari, nello specifico è stata valutata la citotossicità, l’attività anti-infiammatoria e anti-ossidante delle diverse formulazioni preparate. Tutte le co-spray dried formulazioni contenenti resveratrolo e budesonide hanno mostrato morfologia e dimensioni appropriate per la somministrazione polmonare. L’analisi dei dati di efficienza di aerosolizzazione hanno mostrato un aumento di capacità di proprietà aerosolizzanti proporzionale alla concentrazione della budesonide. I macrofagi alveolari hanno mostrato di tollerare resveratrolo e budesonide nel range di concentrazioni investigato. Inoltre, resveratrolo e budesonide, presentano attività anti-infiammatoria nei macrofagi dopo aver indotto l’infiammazione con LPS perché in grado di diminuire e livelli di TNF-α e interleuchina-6. La capacità anti
ossidante delle formulazioni è stata misurata come la loro capacità di ridurre il quantitativo di ossido nitrico nei macrofagi alveolari stimolati con LPS. I risultati ottenuti mostrano un’attività anti-ossidante che è concentrazione dipendente per i singoli composti, ma la riduzione è stata maggiore quando resveratrolo e budesonide sono stati utilizzati in combinazione. In conclusione, in questo studio sono state prodotte delle formulazioni co-spray dried di resveratrolo e budesonide che presentano morfologia e proprietà aerosolizzanti appropriate per la loro somministrazione per via inalatoria. Queste formulazione non hanno effetti tossici significativi nei macrofagi alveolari ed inoltre presentano attività anti-infiammatoria e anti-ossidante dopo aver indotto l’infiammazione cellulare con LPS.Acute and chronic alveolar and/or bronchial inflammation is thought to be central to the pathogenesis of many lung disorders such as asthma and chronic obstructive pulmonary disease (COPD) [1]. Asthma is a common chronic inflammatory disease of the airways characterise by variable and recurring symptoms, such as reversible airflow obstruction and bronchospasm [2]. COPD is one of the leading causes of morbidity and mortality worldwide [3, 4] , characterised by chronic inflammation, airflow limitation, hyper mucous production, emphysema, bronchoconstriction, a decline of respiratory activity and eventual death. Pharmacotherapy for asthma and COPD could have different target and also different types of drugs and administration routes. There is no cure for restore the normal lungs function because the treatments can help slow the progression of the condition and reduce the symptoms [5]. In literature is show that inflammation and oxidation are the principle markers in the pathogenesis of these disease [6]. Moreover previous studies have shown that oxidative stress play an important role in the pathogenesis of the inflammatory lungs diseases, because is implicated in the pathogenesis and in irreversible airway inflammation by release of inflammatory mediators. Consequently, the identification of various anti-oxidant agents such as polyphenols (quercetin and resveratrol) have made it possible to modulate various biochemical aspects of inflammatory lungs diseases such as COPD and asthma. However, these molecules have a very low solubility in water, chemical stability, rapid metabolization and consequently they exhibit low bioavailability [7]. To overcome these problems and enhance the beneficial properties of quercetin and resveratrol, multiparticulate forms, have been developed in the course of this thesis, specifically inhalation powder using intelligent drug carriers and site-specific delivery in order to protect and enhance the bioavailability of the studied polyphenols.
The experimental work was divided in three section, as listed below: I. SECTION A: Inhalable dry powder based on quercetin-loaded lipid microparticles for pulmonary delivery II. SECTION B: Inhalable resveratrol spray dried formulation to improve the treatment of chronic inflammatory lung diseases
III. SECTION C: In vitro activities of co-spray dried resveratrol and budesonide inhalation formulations in alveolar macrophages
I. SECTION A Quercetin has been shown to have several beneficial pharmacological properties against different diseases due its ant-oxidant activity and specifically to pulmonary pathologies, published in vitro and in vivo studies have demonstrated that this flavonoid had a good properties as potential compound that could be potentially useful for asthma treatment [8, 9]. However, the therapeutic application of quercetin is hampered by its low bioavailability due to the extensive metabolism, poor cell permeability and high chemical instability in physiological fluids [8, 10, 11]. For this reason, the encapsulation of quercetin into micro- and nano-particles has been reported [9, 12]. Specifically, solid lipid microparticles (SLM) represent a suitable carrier to delivery the flavonoid directly to the lung thereby increasing its concentration at the site of action [13]. In this study quercetin-loaded lipid microparticles for pulmonary delivery as a dry powder. The morphology and physico-chemical characterization of the SLM coupled with the entrapment efficiency of quercetin in SLM were evaluated. Moreover, the effect of the flavonoid-loaded SLM on the uptake in A549 lung alveolar epithelial cells were examine. A melt emulsification technique was employed to prepare the quercetin loaded SLM and the components that achieved the more suitable condition for SLM preparation were tristearin and phosphatidylcholine , as lipid and emulsifier, respectively. The quercetin content of the microparticles and the encapsulation efficiency were 11.8 ± 0.3% (w/w) and 72.4%, respectively. In order to charactherise the microparticles in term of both, morphology and release, different studies were performed. Preliminary analysis of the microparticles by optical and scanning electron microscopy indicated a particles size and morphology to be delivery to the lungs. The flavonoid release profiles show that the SLM produced a quercetin release significantly lower than the dissolution of the pure flavonoid drug. This indicated that quercetin was encapsulated in the lipid matrix, the diffusion through this matrix producing an efficient modulation of quercetin release. In order to investigate if the SLM are able to influence the in vitro activity of quercetin, alveolar epithelial cells A549 were selected for the study and the uptake of free and microencapsulated quercetin by lung alveolar A549 cells was investigated. Data obtained show that after 4-h incubation, the accumulation of quercetin in the A549 cells was significantly higher for the microparticles entrapped flavonoid when compare to non-encapsulated
quercetin. The enhanced intracellular delivery of quercetin achieved by the SLM is likely due to the flavonoid stabilization after encapsulation. In conclusion the data obtained in this study suggest that SLM could represents a promising system for inhalation delivery of quercetin as a new potential therapeutic approach for the treatment of airways inflammatory diseases.
II: SECTION B: Resveratrol, is a natural polyphenolic compound, synthesized in a large number of plant species that exhibits several beneficial effects, including anti-inflammatory and anti-oxidative action [14, 15]. The delivery of resveratrol as solution is not suitable due to its instability, propensity for rapid oxidative degradation in water and to its low solubility in water [16], for this reason the dry powder could be a suitable formulation to delivery the polyphenol directly to the lungs. The aim of the study was to prepare inhalable resveratrol by spray drying for the treatment of COPD. Specifically was investigated the potential of resveratrol as dry powder for inhalation and its anti-inflammatory and anti-oxidant activity in Calu-3 bronchial cell lines. The inhalable microparticles were produced using the spray drying technique. The physicochemical characteristics of spray dried resveratrol formulation were investigated and the aerosol performance evaluated using andersen cascade impactor (ACI). After that, the deposition, transport and cell uptake of spray dried resveratrol were investigated using the Calu-3 cell line incorporated onto a modified ACI. Finally, the anti-inflammatory and antioxidant activities of resveratrol on Calu-3cell were studied. Resveratrol, with a spherical morphology and particle diameter less than 5 μm, was successfully manufactured. Fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of spray-dried resveratrol was 39.9 ± 1.1% and 3.7 ± 0.1 μm, respectively when assessed with an ACI at 60 l/min. The cytotoxicity results of spray-dried resveratrol on Calu-3 revealed that the cells could tolerate high concentration of resveratrol (up to 160 μM). 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-α), transforming growth factor beta (TGF-β1) 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 antioxidant activity on Calu-3 cells. Hence, resveratrol could be of high therapeutic value in diseases like asthma and COPD where inflammation and oxidation is
present and the spray dried formulation could be an appropriate formulation to delivery this polyphenol directly to the lungs. In conclusion, the 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.
III. SECTION C: Current pharmacotherapy of COPD is symptomatic and includes the use of inhaled antiinflammatory agents, such as corticosteroids (e.g. budesonide). Corticosteroid molecules are able to suppress the release of these inflammatory mediators in alveolar macrophages but these drugs are relatively ineffective in COPD patients due to the inhibition of the histone deacetylases (HDAC2) activities [17]. The increase in patients developing resistance to corticosteroids therapies coupled with the ineffective cure to stop COPD progression signals for alternative therapeutic approaches [18]. Systemic inflammation and oxidative stress are the central hallmark for the pathogenesis of COPD; and therefore are often the molecular targets in therapy [19]. A combination therapy containing anti-oxidant compound and antiinflammatory molecule could be explored as novel approach to target the key mediators in COPD pathogenesis. This study aims to prepare and characterise inhalable co-spray dried microparticles containing resveratrol and budesonide. Different series of co-spray dried formulations were prepared and the physico-chemical characteristics and in vitro aerosol performance were investigated. The biological responses of alveolar macrophages cell lines in terms of cell viability, anti-inflammatory and anti-oxidant activities were evaluated with the prepared spray dried formulations. The co-spray dried microparticles of all formulations exhibited morphologies appropriate for inhalation administration.
Pulmonary delivery systems for polyphenols
No full textThis review reports on the beneficial pharmacological properties of naturally occurring polyphenols for the treatment of inflammatory pulmonary diseases. In addition, it presents an overview of the different types of inhalable formulations which have been developed in order to achieve efficient delivery of polyphenols to the respiratory tract. The main biological activities of polyphenols (anti-oxidant and anti-inflammatory) are covered, with particular emphasis on the studies describing their therapeutic effects on different factors and conditions characteristic of lung pathologies. Special focus is on the technological aspects which influence the pulmonary delivery of drugs. The various polyphenol-based inhalable formulations reported in the literature are examined with specific attention to the preparation methodologies, aerosol performance, lung deposition and in vitro and in vivo polyphenol uptake by the pulmonary epithelial cells
In vivo human skin penetration of (–)-epigallocatechin-3-gallate from topical formulations
Full text linkThe aim of the study was to examine the effect of topical vehicles on the in vivo human stratum corneum penetration of the antioxidant and skin photoprotective agent (–)-epigallocatechin-3-gallate (EGCG). Model oil-in-water (o/w) emulsion and gel formulations containing 1 % (m/m) EGCG were prepared and subjected to photodegradation studies in order to select excipients that minimize the light instability of EGCG. The optimized emulsion and gel were applied to human volunteers and the EGCG percutaneous permeation was evaluated in vivo by the tape-stripping technique. No significant differences in the percentage of the applied EGCG dose diffused into the stratum corneum were observed between the o/w emulsion (36.1 ± 7.5 %) and gel (35.5 ± 8.1 %) preparations. However, the amount of EGCG permeated into the deeper region of human stratum corneum was significantly larger for the o/w emulsion compared to the gel. Therefore, the emulsion represents a suitable vehicle for topical delivery of EGCG
Enhancement of trans-resveratrol photostability by encapsulation in lipid microparticles: in vitro and in vivo studies
No full textLipid microparticles (LMs) loaded with the antioxidant polyphenol, trans-resveratrol were developed in order to
enhance its photostability in topical formulations. The LMs were prepared by the melt emulsification technique,
using tristearin as the lipidic material and hydrogenated phosphatidylcholine as the surfactant. The obtained
microparticles were characterized by optical microscopy and release studies. The trans-resveratrol loading was
10.8% (w/w). Free or microencapsulated trans-resveratrol was introduced in model topical formulations (cream
and hydrogel) and irradiated with a solar simulator. The light-induced degradation of trans-resveratrol was significantly
reduced by incorporation into the LMs both in the cream (the trans-resveratrol loss decreased from 34.3%
to 19.9%) and in the hydrogel (the trans-resveratrol decomposition decreased from 15.4% to 9.4%) vehicles.
Moreover, the in vitro (i.e., antioxidant action) and in vivo (i.e., anti-inflammatory action) biological activities of
trans-resveratrol in the cream preparation were not altered by the encapsulation proces
Enhancement of in vivo human skin penetration of resveratrol by chitosan-coated lipid microparticles
Full text linkIn this study, lipid microparticles (LMs) uncoated or coated with chitosan, and containing the
antioxidant polyphenol, resveratrol were developed in order to enhance its in vivo skin permeation.
The LMs loaded with resveratrol were prepared by melt emulsification and sonication, using tristearin
as lipidic material and hydrogenated phosphatidylcholine as the surfactant. Two different methods
were examined for the coating of the LMs: chitosan addition during LM preparation or treatment of
already formed LMs with a chitosan solution. The latter method achieved a better modulation of the in
vitro release of resveratrol and hence was used for subsequent studies.
The resveratrol loading and mean diameter of the LMs were 4.1 ± 0.3% (w/w) and 5.7 μm and 3.8±0.2
% (w/w) and 6.1 μm for the uncoated and the chitosan-coated LMs, respectively. Chitosan coating
changed the LM surface charge, from a negative zeta potential value (- 17.8 ± 4.8mV) for the uncoated
particles, to a higher positive values (+ 64.2 ± 4.4 mV) for the chitosan-coated ones.
Emulsions containing resveratrol free, encapsulated in the uncoated or chitosan-coated LMs were
applied to the forearm of human volunteers and the penetration of the polyphenol in the stratum
corneum was investigated in vivo by the tape stripping technique. Uncoated LMs did not produce any
significant increase in the fraction of the applied resveratrol dose diffused in the stratum corneum
(32.8 ± 8.9 %) compared to the control emulsion containing the non-encapsulated polyphenol (26.2 ±
5.6 % of the applied dose). On the other hand, application of the emulsion containing the chitosancoated
LMs produced a significant enhancement in the in vivo permeation of resveratrol to 49.3 ±
5.9% of the applied dose, the effect being more marked in the superficial region of the horny layer. The
observed improvement in the human stratum corneum penetration of resveratrol achieved by the LMs
coated with chitosan should favour the efficiency of its topical application
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Co-spray dried resveratrol and budesonide inhalation formulation for reducing inflammation and oxidative stress in rat alveolar macrophages
No full textOxidative stress is instrumental in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Novel therapeutic strategies that target macrophages, based on the use of antioxidant compounds, could be explored to improve corticosteroids responses in COPD patients. In this study, inhalable microparticles containing budesonide (BD) and resveratrol (RES) were prepared and characterized. This approach was undertaken to develop a multi-drug inhalable formulation with anti-oxidant and anti-inflammatory activities for treatment of chronic lung diseases. The inhalable microparticles containing different ratio of BD and RES were prepared by spray drying. The physico-chemical properties of the formulations were characterized in terms of surface morphology, particle size, physical and thermal stability. Additionally, in vitro aerosol performances of these formulations were evaluated with the multi-stage liquid impinger (MSLI) at 60 and 90 l/min, respectively. The cytotoxicity effect of the formulations was evaluated using rat alveolar macrophages. The biological responses of alveolar macrophages in terms of cytokine expressions, nitric oxide (NO) production and free radical scavenging activities were also tested. The co-spray dried (Co-SD) microparticles of all formulations exhibited morphologies appropriate for inhalation administration. Analysis of the deposition profiles showed an increase in aerosol performance proportional to BD concentration. Cell viability assay demonstrated that alveolar macrophages could tolerate a wide range of RES and BD concentrations. In addition, RES and BD were able to decrease the levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS) induced alveolar macrophages.
This study has successfully established the manufacture of Co-SD formulations of RES and BD with morphology and aerosol properties suitable for inhalation drug delivery, negligible in vitro toxicity and enhanced efficacy to control inflammation and oxidative stress in LPS-induced alveolar macrophages
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