Evaluation of HIV-1 resistance to antiretroviral drugs among 150 patients after six months of therapeutic interruption

Most of the antiretroviral (ARV) studies in Brazil have been reported in treatment-experienced and naive patients rather than in the setting of treatment interruption (TI). In this study, we analysed reasons given for TI and resistance mutations occurring in 150 HIV-1-infected patients who underwent TI. Of the patients analysed, 110 (73.3%) experienced TI following medical advice, while the remaining patients stopped antiretroviral therapy (ART) of their own accord. The main justifications for TI were: ARV-related toxicities (38.7%), good laboratory parameters (30%) and poor adherence (20%). DNA sequencing of the partial pol gene was successful in 137 (91.3%) patients, of whom 38 (27.7%) presented mutations conferring ARV resistance. A higher viral load prior to TI correlated with drug resistance (P < 0.05). Our results demonstrate that there are diverse rationales for TI and that detection of resistant strains during TI most likely indicates a fitter virus than the wild type. High viral loads coupled with unprotected sex in this group could increase the likelihood of transmission of drug-resistant virus. Thus, treating physicians should be alerted to this problem when the use of ARVs is interrupted.

Neuronal NOS Inhibitor and Conventional Antidepressant Drugs Attenuate Stress-induced Fos Expression in Overlapping Brain Regions

Recent evidence indicates that the administration of inhibitors of neuronal nitric oxide synthase (nNOS) induces antidepressant-like effects in animal models such as the forced swimming test (FST). However, the neural circuits involved in these effects are not yet known. Therefore, this study investigated the expression of Fos protein, a marker of neuronal activity, in the brain of rats submitted to FST and treated with the preferential nNOS inhibitor, 7-nitroindazole (7-NI), or with classical antidepressant drugs (Venlafaxine and Fluoxetine). Male Wistar rats were submitted to a forced swimming pretest (PT) and, immediately after, started receiving a sequence of three ip injections (0, 5, and 23 h after PT) of Fluoxetine (10 mg/kg), Venlafaxine (10 mg/kg), 7-NI (30 mg/kg) or respective vehicles. One hour after the last drug injection the animals were submitted to the test session, when immobility time was recorded. After the FST they were sacrificed and had their brains removed and processed for Fos immunohistochemistry. Independent group of non-stressed animals received the same drug treatments, or no treatment (naive). 7-NI, Venlafaxine or Fluoxetine reduced immobility time in the FST, an antidepressant-like effect. None of the treatments induce significant changes in Fos expression per se. However, swimming stress induced significant increases in Fos expression in the following brain regions: medial prefrontal cortex, nucleus accumbens, locus coeruleus, raphe nuclei, striatum, hypothalamic nucleus, periaqueductal grey, amygdala, habenula, paraventricular nucleus of hypothalamus, and bed nucleus of stria terminalis. This effect was attenuated by 7-NI, Venlafaxine or Fluoxetine. These results show that 7-NI produces similar behavioral and neuronal activation effects to those of typical antidepressants, suggesting that these drugs share common neurobiological substrates.

Use of alcohol and other drugs among Brazilian college students: effects of gender and age

Objective: To assess the frequency of drug use among Brazilian college students and its relationship to gender and age. Methods: A nationwide sample of 12,721 college students completed a questionnaire concerning the use of drugs and other behaviors. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST-WHO) criteria were used to assess were used to assess hazardous drug use. A multivariate logistic regression model tested the associations of ASSIST-WHO scores with gender and age. The same analyses were carried out to measure drug use in the last 30 days. Results: After controlling for other sociodemographic, academic and administrative variables, men were found to be more likely to use and engage in the hazardous use of anabolic androgenic steroids than women across all age ranges. Conversely, women older than 34 years of age were more likely to use and engage in the hazardous use of amphetamines. Conclusions: These findings are consistent with results that have been reported for the general Brazilian population. Therefore, these findings should be taken into consideration when developing strategies at the prevention of drug use and the early identification of drug abuse among college students.

Liquid-phase microextraction for simultaneous chromatographic analysis of three antidepressant drugs in plasma

A method using Liquid Phase Microextraction for simultaneous detection of citalopram (CIT), paroxetine (PAR) and fluoxetine (FLU), using venlafaxine as internal standard, in plasma by high performance liquid chromatography with fluorescence detection was developed. The linearity was evaluated between 5.0 and 500 ng mL-1 (r > 0.99) and the limit of quantification was 2.0, 3.0 and 5.0 ng mL-1 for CIT, PAR and FLU, respectively. Therefore, it can be applied to therapeutic drug monitoring, pharmacokinetics or bioavailability studies and its advantages are that it necessary relatively inexpensive equipment and sample preparation techniques.

Using fluid bed granulation to improve the dissolution of poorly water-soluble drugs

In this study, fluid bed granulation was applied to improve the dissolution of nimodipine and spironolactone, two very poorly water-soluble drugs. Granules were obtained with different amounts of sodium dodecyl sulfate and croscarmellose sodium and then compressed into tablets. The dissolution behavior of the tablets was studied by comparing their dissolution profiles and dissolution efficiency with those obtained from physical mixtures of the drug and excipients subjected to similar conditions. Statistical analysis of the results demonstrated that the fluid bed granulation process improves the dissolution efficiency of both nimodipine and spironolactone tablets. The addition of either the surfactant or the disintegrant employed in the study proved to have a lower impact on this improvement in dissolution than the fluid bed granulation process.

Modeling global pricing and launching of new drugs

Doctorado en Economía: Aplicaciones a las finanzas y seguros, a la economía sectorial, al medio ambiente y a las infraestructuras.

Advergaming e In-game advertising: Attori e contesti di una forma emergente di Internet marketing

Due nuove mode che si stanno propagando sempre più tra gli innumerevoli tentativi di realizzare nuovi formati di pubblicità on-line sono la pubblicità che diventa videogame gratuito, giocabile on-line o scaricabile, chiamata advergame, e la collocazione di pubblicità, oramai nella stragrande maggioranza dinamiche, nei videogames sopratutto di grandi software house, chiamata in-game advertising. Infatti nella società odierna i pubblicitari devono camuffare i consigli per gli acquisti per fare in modo che non vengano rifiutati. L'advergame in passato è stato lodato per il suo metodo innovativo di fare pubblicità. La sua caratteristica è la capacità di divertire e intrattenere l'utente ottenendo una connotazione non intrusiva e un effetto fidelizzante, peculiarità che fa di questo mezzo uno strumento potenzialmente molto valido. Si tratta, in parole povere, di videogames spesso multiplayer, nei quali gli scenari, gli oggetti e i personaggi evocano determinati brand o prodotti. Per quello che invece riguarda l'in-game advertising, si tratta di una forma particolarmente efficace di pubblicità che permette di ottenere dei tassi di ricordo rilevanti e che consente un elevato coinvolgimento emotivo. E' a livello della creazione degli spazi pubblicitari che si scatena la fantasia degli sviluppatori: se nei giochi sportivi basta trasporre in 3D gli spazi pubblicitari presenti solitamente nella realtà, in altre tipologie di gioco è necessario sfruttare parti dell'ambientazione o creare degli intermezzi atti allo scopo. Esempio tipico è quello di manifesti pubblicitari inseriti in spazi di gioco come le locande, soprattutto nei giochi di ruolo e nelle avventure grafiche. Gli investimenti in queste particolari forme di comunicazione, crescono a tassi elevatissimi e il business è molto allettante, non a caso le principali agenzie specializzate in materia sono state acquisite da grandi colossi: AdScape Media da Google e Massive Inc. da Microsoft. L'advergame e l'in-game advertising possono essere usati per lanciare un nuovo prodotto sul mercato, per rafforzare l'immagine del brand e per ottenere un database di utenti disposti ad essere sollecitati per ottenere in modo facile e non dispendioso riscontri su future attività di marketing. Perciò mi sono proposto di analizzare la situazione odierna del marketing, in particolare la parte che riguarda la pubblicità, i vantaggi ottenuti da questa scienza dallo sviluppo tecnologico, fattore che ha determinato la nascita dei due formati pubblicitari in esame e analizzati in seguito. Inoltre effettuerò l'analisi del fenomeno che vede i grandi colossi dell'IT tentare l'inserimento come agenzie intermediarie fra le software house da una parte e le grandi multinazionali dall'altra, queste ultime alla ricerca di nuovi canali più profittevoli dove sponsorizzare le proprie attività. Cercherò infine di capire le scelte di tutti gli attori che girano attorno a questi formati pubblicitari e i benefici che ne traggono per ipotizzare quale sarà il contesto che si andrà a delineare.

Meccanismi d'asta per on-line advertising: modelli, equilibri ed efficienza

Il seguente lavoro di tesi tratta l'argomento delle aste in modo tecnico, ovvero cerca di descriverne i modelli e le caratteristiche principali, spesso ignorate dagli stessi fruitori. Nel capitolo 1 si introduce brevemente il concetto di asta, descrivendone i principali elementi costitutivi. Si ripercorrono poi le origini di questa procedura ed alcuni suoi utilizzi. Nel capitolo 2 si presentano inizialmente le principali tipologie di aste conosciute e si accenna al processo di valutazione dell'oggetto d'asta. Si introduce poi il concetto di Private Value, analizzandolo per ogni tipo di asta e confrontando queste sotto l'aspetto della rendita. Si enuncia in seguito un principio fondamentale, quale quello dell'equivalenza delle rendite, rilassandone alcuni assunti basilari. Infine si passa al concetto di valori interdipendenti all'interno delle aste, valutandone equilibri, rendite ed efficienza, accennando nel contempo al problema denominato Winner's curse. Nel capitolo 3 si parla dei meccanismi di asta online, ponendo l'attenzione su un loro aspetto importante, ovvero la veridicità, ed analizzandoli attraverso l'analisi del caso peggiore e del caso medio in alcuni esempi costruiti ad-hoc. Nel capitolo 4 si descrivono in particolare le sponsored search auctions, narrandone inizialmente la storia, e successivamente passando all'analisi di equilibri, rendite ed efficienza; si presenta, infine, un modello di tali aste mettendone in rapporto la computabilità con quella dei meccanismi offline conosciuti.

The problems of equivalence in advertising translation: examples from English and Russian

Abstract The academic environment has recently recognized the importance and benefits that an extensive research on the translation of advertising can have for translation studies. Despite the growing interest and increasing research activity in the field it is still difficult to speak about a theory of advertising translation in general. There is a need for further study encompassing different languages and both heterogeneous and homogenous cultures that will give the possibility to receive a more complete map of what the translation of advertising is and should be. Previous studies have been concentrated, for the most part, on Western European language pairs. This study is a research into perfume and cosmetics print advertisements translated from English into Russian where both visual and verbal elements are considered. Three broad translation approaches have been identified in what concerns the verbal message: Translated message, parallel translation, recreated adverts, and three approaches in dealing with the image: similar images, modified images, completely different images. The thesis shows that where Russian advertisements for perfume products tend to have a message, or create one, this is often lacking in the English copy. The article ends by suggesting that perfume advertisements favor the standardization approach when entering Russian market. The attempts to localize the advert have also been noticed although they are obviously less numerous in perfume adverts and are rather instances of adaptation - a mix between the localization and standardization approaches since they keep drawing on the same globally accepted universals about female beauty and concern for ‘woman’s identity’ (we focused our analysis on products designed for female consumers). This study, complementing previous studies, aims to be a contribution to the description of laws and strategies that guide the translation of advertising texts into Russian.

Development of Original Analytical Methods for the Determination of Drugs of Abuse in Biological Samples

Drug abuse is a major global problem which has a strong impact not only on the single individual but also on the entire society. Among the different strategies that can be used to address this issue an important role is played by identification of abusers and proper medical treatment. This kind of therapy should be carefully monitored in order to discourage improper use of the medication and to tailor the dose according to the specific needs of the patient. Hence, reliable analytical methods are needed to reveal drug intake and to support physicians in the pharmacological management of drug dependence. In the present Ph.D. thesis original analytical methods for the determination of drugs with a potential for abuse and of substances used in the pharmacological treatment of drug addiction are presented. In particular, the work has been focused on the analysis of ketamine, naloxone and long-acting opioids (buprenorphine and methadone), oxycodone, disulfiram and bupropion in human plasma and in dried blood spots. The developed methods are based on the use of high performance liquid chromatography (HPLC) coupled to various kinds of detectors (mass spectrometer, coulometric detector, diode array detector). For biological sample pre-treatment different techniques have been exploited, namely solid phase extraction and microextraction by packed sorbent. All the presented methods have been validated according to official guidelines with good results and some of these have been successfully applied to the therapeutic drug monitoring of patients under treatment for drug abuse.

Web advertising. Le comunicazioni commerciali on-line.

La tesi ha ad oggetto lo studio e l’approfondimento delle forme di promozione commerciale presenti in Rete caratterizzate, più che da una normale evoluzione, da continue metamorfosi che ridefiniscono ogni giorno il concetto di pubblicità. L’intento è quello di analizzare il quadro giuridico applicabile alla pubblicità via Web, a fronte della varità di forme e di modalità che essa può assumere. Nel lavoro vengono passate in rassegna le caratteristiche che differenziano la pubblicità commerciale on-line rispetto a quella tradizionale; tra le quali, particolare rilievo assume la capacità d’istaurare una relazione – diretta e non mediata – tra impresa e consumatore. Nel prosieguo viene affrontato il problema dell’individuazione, stante il carattere a-territoriale della Rete, della legge applicabile al web advertising, per poi passare ad una ricognizione delle norme europee ed italiane in materia, senza trascurare quelle emanate in sede di autodisciplina. Ampio spazio è dedicato, infine, all’esame delle diverse e più recenti tecniche di promozione pubblicitaria, di cui sono messi in evidenza gli aspetti tecnico-informatici, imprescindibili ai fini di una corretta valutazione del tema giuridico. In particolare, vengono approfonditi il servizio di posizionamento a pagamento offerto dai principali motori di ricerca (keywords advertising) e gli strumenti di tracciamento dei “comportamenti” on-line degli utenti, che consentono la realizzazione di campagne pubblicitarie mirate (on-line behavioural advertising). Il Web, infatti, non offre più soltanto la possibilità di superare barriere spaziali, linguistiche o temporali e di ampliare la propria sfera di notorietà, ma anche di raggiungere l’utente “interessato” e, pertanto, potenziale acquirente. Di queste nuove realtà pubblicitarie vengono vagliati gli aspetti più critici ed esaminata la disciplina giuridica eventualmente applicabile anche alla luce delle principali decisioni giurisprudenziali nazionali ed europee in materia, nonché delle esperienze giuridiche nord-americane e di tipo autoregolamentare.

Design and synthesis of multipotent drugs: application to Alzheimer's disease and benign prostatic hyperplasia

The aim of this thesis was to synthesize multipotent drugs for the treatment of Alzheimer’s disease (AD) and for benign prostatic hyperplasia (BPH), two diseases that affect the elderly. AD is a neurodegenerative disorder that is characterized, among other factors, by loss of cholinergic neurons. Selective activation of M1 receptors through an allosteric site could restore the cholinergic hypofunction, improving the cognition in AD patients. We describe here the discovery and SAR of a novel series of quinone derivatives. Among them, 1 was the most interesting, being a high M1 selective positive allosteric modulator. At 100 nM, 1 triplicated the production of cAMP induced by oxotremorine. Moreover, it inhibited AChE and it displayed antioxidant properties. Site-directed mutagenesis experiments indicated that 1 acts at an allosteric site involving residue F77. Thus, 1 is a promising drug because the M1 activation may offer disease-modifying properties that could address and reduce most of AD hallmarks. BPH is an enlargement of the prostate caused by increased cellular growth. Blockade of α1-ARs is the predominant form of medical therapy for the treatment of the symptoms associated with BPH. α1-ARs are classified into three subtypes. The α1A- and α1D-AR subtypes are predominant in the prostate, while α1B-ARs regulate the blood pressure. Herein, we report the synthesis of quinazoline-derivatives obtained replacing the piperazine ring of doxazosin and prazosin with (S)- or (R)-3-aminopiperidine. The presence of a chiral center in the 3-C position of the piperidine ring allowed us to exploit the importance of stereochemistry in the binding at α1-ARs. It turned out that the S configuration at the 3-C position of the piperidine increases the affinity of the compounds at all three α1-AR subtypes, whereas the configuration at the benzodioxole ring of doxazosin derivatives is not critical for the interaction with α1-ARs.