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Cocrystals, prodrugs, microparticles, cyclodextrins and nasal administration of active pharmaceutical substances: innovative strategies to modulate their oral bioavailability or their action site targeting
No full textThe experimental work presented in this Thesis involves new strategies focused during my Ph.D. activity to improve drug oral bioavailability, avoid side effects or promote the targeting of therapeutic agents to their action site. The co-crystallization strategy was applied to increase the dissolution rate and the permeability across the intestinal barrier of nitrofurantoin (NITRO), an antibiotic characterized by low aqueous solubility and low oral bioavailability. In particular, NITRO dissolution rate and permeability were compared with those of its cocrystals containing isoniazid (ISO), bipyridyl (BIP), or phenanthroline (PHE) as coformers, and their parent mixtures. NITRO dissolution profiles were evaluated via High-Performance Liquid Chromatography (HPLC), whereas permeation studies were performed by using an in vitro model of the small intestine based on rat intestine epithelial cells (IEC-6).
The research activity was then focused on D-limonene, eugenol and cinnamaldehyde, natural compounds derived from essential oils promising in the prevention and protection of neurodegenerative diseases. In particular, I contributed to perform a systematic in vivo study to elucidate their pharmacokinetic profile, oral bioavailability, and aptitude to permeate the central nervous system from the bloodstream. Based on obtained data, eugenol was recruited for in vitro studies of viability and time/dose-dependent dopamine release in neuronal differentiated PC12 cells, a recognized cellular model mimicking dopaminergic neurons. The prodrug approach was considered to study self-assemble nanomicelles consisting in amphiphilic inulin-D-α-tocopherol succinate bioconjugates (INVITE) and loaded with an antioxidant compound, curcumin (INVITE C), to enhance curcumin biopharmaceutical properties and induce its targeting to the retina from the bloodstream. Transport experiments on polarized monolayers of human retinal pigment epithelium (HRPE) cells were performed, evaluating the transepithelial electrical resistance of the HRPE monolayer in physiologic and diabetic conditions. The prodrug approach for nasal formulations and brain targeting was then focused on ferulic acid (Fer), known for its antioxidant and anti-inflammatory activities, potentially useful against neurodegenerative diseases. A prodrug of Fer (methyl ferulate, Fer-Me) was synthesised and loaded in tristearin or stearic acid solid lipid microparticles (SLMs) as sustained delivery and targeting systems for Fer. In vitro pharmacokinetic studies were performed via HPLC to evaluate the prodrug behaviour of Fer-Me. The ability of SLMs to control the prodrug release and the dissolution rate were observed via dissolution and release from SLMs studies and quantification via HPLC. The prodrug approach on Fer was further developed and a conjugate of Fer itself methylated on the carboxylic moiety, without the use of linkers, was synthesised (Fer-Fer-Me). Fer-Fer-Me and its potential hydrolysis products, namely the non-methylated homologous (Fer-Fer-OH), Fer-Me and Fer, after appropriate purification of blood samples, were quantified via HPLC. The prodrug behaviour of Fer-Fer-Me was evidenced by in vitro pharmacokinetic studies, then it was loaded in tristearin and stearic acid SLMs. The results obtained by their characterization allowed to select the stearic acid SLMs loaded with Fer-Fer-Me for a nasal administration in rats, quantifying the prodrug in the cerebrospinal fluid of rats (CSF). A further approach related to nasal administration and brain targeting was studied considering the use of cyclodextrins focusing on geraniol (GER), a natural compound derived from essential oils that may exert anti-inflammatory effects in neurodegenerative diseases. Inclusion complexes with β-cyclodextrin (βCD) and its hydrophilic derivative hydroxypropyl-β-cyclodextrin (HPβCD) were formulated and the biocompatibility with nasal mucosae and drug bioavailability into CSF were studied in rats.Nuove strategie per migliorare la biodisponibilità orale dei farmaci, limitare effetti collaterali o promuovere il direzionamento di agenti terapeutici al loro sito di azione sono state presentate in questa Tesi. I cocristalli sono stati sfruttati per aumentare la velocità di dissoluzione e la permeabilità attraverso la barriera intestinale della nitrofurantoina (NITRO), antibiotico caratterizzato da bassa solubilità acquosa e biodisponibilità orale. NITRO è stata confrontata, in termini di velocità di dissoluzione e permeazione, con i cocristalli contenenti isoniazide, bipiridile o fenantrolina come coformeri e con le miscele fisiche. I profili di dissoluzione della NITRO sono stati valutati via cromatografia liquida ad alta prestazione (HPLC), gli studi di permeazione sono stati eseguiti su un modello in vitro basato su cellule epiteliali di intestino di ratto. Ho contribuito ad effettuare uno studio in vivo per valutare il profilo farmacocinetico, biodisponibilità orale e tendenza a permeare nel sistema nervoso centrale dal sangue di D-limonene, eugenolo e cinnamaldeide, composti naturali derivati da oli essenziali promettenti nella prevenzione e protezione di patologie neurodegenerative. In base ai risultati, l’eugenolo è stato selezionato per studi in vitro su vitalità e rilascio tempo/dose-dipendente della dopamina in cellule PC12 differenziate a fenotipo neuronale, un modello di neuroni dopaminergici. Sono state studiate nanomicelle self-assemblanti costituite da bioconiugati anfifilici di inulina-D-α-tocoferolo succinato caricate con un composto antiossidante (INVITE C), la curcumina, per migliorarne le proprietà biofarmaceutiche e indurne il direzionamento alla retina. Sono stati effettuati esperimenti di trasporto su monostrati polarizzati di cellule di epitelio pigmentato umano, valutandone la resistenza elettrica transepiteliale e il beneficio di INVITE C in condizioni diabetiche simulate. Sono stati progettati e sintetizzati profarmaci dell’acido ferulico (Fer), noto per le attività antiossidanti e antinfiammatorie, potenzialmente utili contro patologie neurodegenerative. È stato sintetizzato un profarmaco di Fer (metil ferulato, Fer-Me). Fer-Me è stato caricato in microparticelle solide lipidiche (SLM) di tristearina o acido stearico come sistema di trasporto e di direzionamento per Fer. Studi farmacocinetici in vitro sono stati condotti via HPLC per valutare se Fer-Me fosse un profarmaco. La capacità delle SLM di controllare il rilascio del profarmaco e la velocità di dissoluzione sono stati osservati attraverso studi di dissoluzione e rilascio dalle SLM, quantificando via HPLC. Inoltre, è stato sintetizzato un coniugato di Fer con se stesso senza l’uso di linkers, metilato sul carbossile (Fer-Fer-Me). Fer-Fer-Me e i suoi potenziali prodotti di idrolisi, ovvero l’omologo non metilato (Fer-Fer-OH), Fer-Me e Fer, sono stati quantificati via HPLC in seguito ad appropriate procedure di estrazione da fluidi fisiologici. Studi farmacocinetici in vitro hanno dimostrato che Fer-Fer-Me è un profarmaco di Fer, ed è stato caricato in SLM di tristearina e acido stearico. I risultati ottenuti dalla caratterizzazione hanno permesso di selezionare le SLM di acido stearico per una somministrazione nasale a ratti, quantificando il profarmaco nel liquido cerebrospinale (CSF) per dimostrare la capacità della formulazione di indurre il direzionamento nel sistema nervoso centrale. È stato studiato un ulteriore approccio relativo alla somministrazione nasale e al direzionamento centrale utilizzando ciclodestrine e geraniolo (GER), un composto naturale derivato dagli oli essenziali che potrebbe esercitare effetti antinfiammatori in patologie neurodegenerative. Sono stati formulati complessi di inclusione con β-ciclodestrina (β-CD) e il suo derivato idrofilico idrossipropil-β-ciclodestrina (HP-β-CD), studiando la biocompatibilità con la mucosa nasale e la biodisponibilità di GER nel CSF nei ratti
Circadian and dopaminergic influence on chlorogenic acid intestinal permeability
No full textChlorogenic acid (CGA) is a natural polyphenol potentially health promoting along the gut-brain axis, even if limited by poor oral bioavailability. As components of therapeutic drugs or functional food, polyphenols can influence each other their absorption from the gut according to circadian rhythms.
Therefore, we have evaluated, via HPLC-UV analysis, how the permeability of CGA across IEC-6 cell monolayers, as a model of intestinal barrier, is influenced by the presence of arbutin, gallic, caffeic and ferulic acids and by circadian cycles entrainment by horse serum shock. Moreover, dopaminergic neuronal influence on CGA intestinal permeability was investigated by co-culture with rat pheochromocytoma PC12 cell line mimicking dopaminergic component of enteric nervous system (ENS).
Our results indicate the presence of a circadian-dependent active efflux for CGA permeation across IEC-6 monolayers, suggesting its higher bioavailability in the evening rather than in the morning. Among the natural polyphenols tested, only gallic acid was able to influence the CGA permeation, causing its reduction. Finally, (60 mM KCl)-evoked dopamine release from PC12 cells induced a significant CGA permeation increase across IEC-6 monolayers, probably by downregulation of efflux transporters expression/activity. Dopamine ENS-evoked may therefore enhance the CGA oral bioavailability dependence on circadian rhythms.
Although this is a preliminary study in this field, the results obtained allow us to suggest that the absorption of CGA from an oral administration of a food supplement is not influenced by arbutin, caffeic acid and ferulic acid, whereas it can be enhanced in the absence of gallic acid and by evening intake
In vitro cell models merging circadian rhythms and brain waves for personalized neuromedicine
No full textNew evidence is emerging about the dynamics of interaction between circadian rhythms and brain waves, whose coordination occurs through the entrainment process. The so-called “oscillopathies” or dysfunctions in synchronization of neuronal oscillation in key brain networks lead to the onset of neurodegenerative diseases. A typical example of alteration is insomnia, a risk factor for the oscillopathies, increasingly widespread worldwide. Recently, synchronization of circadian rhythms in cell cultures has allowed an improvement in the physiological relevance of responses to stimuli. Furthermore, brain organoids and neurons cultured in microfluidic systems are the latest frontiers for in vitro reproduction of rhythmic electrical signals. In this review, the combination of these in vitro experimental approaches is proposed as suitable for a more direct investigation on the common mechanisms and neurophysiological substrates underlying brain waves and circadian oscillations, and useful to evaluate the effects of “oscillotherapeutic” drugs for personalized neuromedicine
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Nasal administration of microencapsulated dimeric conjugate of ferulic acid: towards a new approach for neurodegenerative diseases.
No full textFerulic acid (Fer) displays antioxidant/anti-inflammatory properties useful for neurodegenerative disease therapy. To increase Fer uptake and residence time in the central nervous system, a dimeric prodrug, optimizing the Fer loading on nasally administrable solid lipid microparticles (SLMs), was developed.
The prodrug was synthesized as Fer dimeric conjugate, then methylated on the carboxylic moiety. Antioxidant/anti-inflammatory properties of the prodrug and its ability to release Fer in physiologic environments were evaluated. Tristearin or stearic acid SLMs were obtained by hot emulsion technique. In vivo pharmacokinetics were quantified by HPLC.
The prodrug displayed by itself in vitro antioxidant/anti-inflammatory properties similar to those of Fer. Moreover, the prodrug ability to release Fer in physiologic environments, such as whole blood and brain homogenates, was demonstrated. Stearic acid SLMs exhibited the highest prodrug loading and dissolution rate and were selected as nasal formulation to rats for pharmacokinetic studies. Intranasal administration of SLMs allowed to obtain high prodrug bioavailability and prolonged residence in the cerebrospinal fluid of rats, showing values up to 30 times higher than that of Fer, following its intravenous/nasal administration at the same doses.
Nasal administration of prodrug-loaded SLMs can be proposed as a non-invasive approach for neurodegenerative disease therapy
Variations on the Author
Get PDF“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
Get PDFWe 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
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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