Tesi sul tema "Propranolol"

Infantile hemangioma (IH) is a vascular neoplasm that affects 4-10 percent of infants. Propranolol, a non-selective beta-adrenergic receptor (AR) antagonist, was serendipitously discovered to accelerate regression of IH in 2008; however, its mechanism in IH is unclear.

Orientador: Marcia Carneiro Valera
Coorientadora: Renata Falchete do Prado
Banca: Eduardo Bresciani
Banca: Mariella Vieira Pereira Leão
Resumo: Os objetivos deste estudo são: 1) Esclarecer a possível associação entre o estresse crônico e a estimulação do Sistema Nervoso Simpático (SNS) e investigar sua interferência no desenvolvimento e progressão da lesão periapical; 2) Avaliar a quantidade de receptores para os neurotransmissores na região periapical; 3) Elucidar uma via farmacológica de modulação inflamatória através do uso de bloqueadores adrenérgicos. Trinta e dois ratos Wistar foram submetidos à modelo animal de lesão periapical através da exposição da cavidade pulpar e em seguida foram aleatoriamente divididos em 4 grupos: sem estresse (NS); estresse + solução salina (SS); estresse + β-bloqueador (Sβ); estresse + α-bloqueador (Sα). Os grupos SS, Sβ e Sα foram submetidos à modelo animal de estresse crônico durante 28 dias e receberam injeções diárias de solução salina, propranolol (β bloqueador adrenérgico) e fentolamina (α bloqueador adrenérgico), respectivamente. Após 28 dias os animais foram eutanasiados e procedeu-se as seguintes análises: a) dos níveis séricos de corticosterona através de Radioimunoensaio; b) histomorfométrica por coloração com hematoxilina e eosina; c) da estrutura óssea periapical através de microtomografia computadorizada (micro-CT); d) expressão de receptores β e α adrenérgicos; e) da atividade osteoclástica através de histoquímica para fosfatase ácida resistente ao tartarato (TRAP). Os resultados obtidos mostram um aumento do nível sérico de corticosterona dos animais do grupo SS send... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The objectives of this study are: 1) To clarify the possible association between chronic stress (CS) and stimulation of the Sympathetic Nervous System (SNS) and to investigate its interference in the development and progression of periapical lesion; 2) To evaluate the amount of receptors for neurotransmitters in the periapical region; 3) To elucidate a pharmacological pathway of inflammatory modulation through the use of adrenergic blockers. Thirty- two Wistar rats were submitted to animal model of periapical lesion through exposure of the pulp cavity and were then randomly divided into 4 groups: no stress (NS); stress + saline solution (SS); stress + β-blocker (Sβ); stress + α-blocker (Sα). The SS, Sβ and Sα groups were submitted to animal model of CS for 28 days and received daily injections of saline solution, propranolol (β blocker adrenergic) and phentolamine (α adrenergic blocker), respectively. After 28 days the animals were euthanized and the following analysis were carried out: a) serum corticosterone levels through Radioimmunoassay; b) histomorphometric by staining with hematoxylin and eosin; c) periapical bone structure through micro computed tomography; d) expression of β and α adrenergic receptors; e) osteoclast activity by histochemistry for tartrate resistant acid phosphatase (TRAP). The results obtained show an increase in the seric corticosterone level of the animals of the SS group being statistically significant compared to the NS group animals (without str... (Complete abstract click electronic access below)
Mestre

Die therapeutische Beeinflußbarkeit einer Leberverfettung gilt weltweit als unbefriedigend ge-löst, so daß ein letaler Ausgang besonders bei Wiederkäuern teilweise nicht zu verhindern ist. Die Nutzung von beta-Rezeptorenblockern hat bisher mit dieser Indikation keinen Eingang in die Veterinärmedizin gefunden. In den vorliegenden Untersuchungen wurden deshalb die Auswirkungen einer unspezifischen Blockade der beta-adrenergen Rezeptoren auf die Lipolyse, die klinischen und hämatologi-schen Funktionen sowie Leber-, Eiweiß- und Mineralstoffwechsel bei fastenden Schafen ge-prüft. Insbesondere wurde dabei die Wirkung einer Propranololapplikation auf die Lipolyse in der frühen Phase des Fastens untersucht. Zu diesem Zweck wurden insgesamt 15 weiblichen, klinisch gesunden, güsten Schafen der Rasse Merino-Fleisch während eines dreitägigen Futterentzuges mit Hilfe einer Dauertropfinfu-sion mit zwei 8stündigen Pausen 0,5 bzw. 1 mg Propranolol/kg KM/d bzw. den Tieren der Kontrollgruppe ein vergleichbares Volumen einer NaCl-Lösung appliziert. Neben der klini-schen Kontrolle von Puls- und Atemfrequenz, Körpertemperatur und Pansenaktivität erfolgte über die wiederholte Gewinnung von Blutproben aus der Vena jugularis externa eine Erfassung der Konzentrationen von Glucose, FFS, Bilirubin, BHB, K, Na, Mg, Gesamteiweiß und Albu-min im Blutserum. Zur Kontrolle der Leberfunktion wurden die Aktivitäten der GLDH und ASAT bestimmt. Die Wirkung des beta-Rezeptor-Antagonisten Propranolol auf die hämatolo-gischen Parameter wurde durch die Kontrolle der Leukozyten-, Erythrozyten- und Hämoglo-binkonzentrationen und den Hämatokrit der Schafe im Versuchsverlauf überprüft. In Übereinstimmung mit bisherigen Untersuchungen an Wiederkäuern und Nichtwiederkäuern kam es aufgrund der dreitägigen Futterdeprivation in allen Tiergruppen zu einer signifikanten Verminderung des Körpergewichtes um bis zu 9,8 %. Die Zahl der Pansenbewegungen redu-zierte sich bei allen Tieren signifikant bereits innerhalb der ersten 48 Stunden der Futterdepri-vation. Der stärkste Abfall der Pansenaktivität ließ sich bei den Schafen, denen 1 mg Propra-nolol/kg KM/d infundiert wurde, nachweisen. Puls- und Atemfrequenz, die Konzentrationen von Na, K, Mg, Gesamteiweiß und Albumin sowie die Aktivitäten von GLDH und ASAT im Blutserum blieben im Versuchsverlauf ohne signifikante Veränderungen. Eine Beeinflussung der hämatologischen Parameter ließ sich we-der bei den Schafen der Kontrollgruppe noch bei denen der Versuchsgruppen nachweisen. Während der Futterentzug in allen Tiergruppen zu einer tendenziellen Abnahme der Blut-serumkonzentration an Glucose führte, stiegen die Konzentrationen an FFS, Bilirubin und BHB im Blutserum aller Tiere an. Damit weisen die Veränderungen in den Konzentrationen von FFS, BHB und Bilirubin im Blutserum der Schafe der Kontrollgruppe die typischen Merkmale einer Fastenstoffwechsellage auf. In beiden Versuchsgruppen fielen diese Konzen-trationserhöhungen gegenüber denen der Kontrollgruppe statistisch gesichert niedriger aus. Unter Berücksichtigung der dabei erreichten Niveaus ließ sich für die Versuchsgruppen eine geringere Belastung von Energie- und Leberstoffwechsel als in der Kontrollgruppe feststellen. Der Übergang von der ersten in die zweite Phase des Fastenstoffwechsels ist in allen Tiergrup-pen, besonders deutlich in beiden Versuchsgruppen, zum Zeitpunkt um 48 h nach Versuchsbe-ginn an der Erhöhung der Körpertemperatur sowie den stärkeren Anstiegen der FFS-Konzentrationen erkennbar. Die besondere klinische und labordiagnostische Bedeutung der Änderungen der FFS-Konzentration im Blutserum zeigte sich in der zeitlich früheren und ausgeprägteren Reaktion als die Konzentrationsänderungen von Bilirubin und BHB. Bereits nach 24stündigem Fasten waren in allen Schafgruppen signifikant gegenüber den Ausgangswerten erhöhte FFS-Konzentrationen nachweisbar. In beiden Versuchsgruppen war bis zum Erreichen der Maxi-malwerte 48 h nach Beginn des Fastens ein geringerer Anstieg der FFS-Konzentration im Blut-serum als in der Kontrollgruppe nachzuweisen. Nach dem Erreichen der Maximalkonzentration kam es unter dem Propranololeinfluß in beiden Versuchsgruppen zu einem raschen, signifi-kantem Abfall der FFS-Konzentration um 44,7 bzw. 63,5 %. Die Abnahme der FFS-Konzentration im Blutserum vom Maximalwert bis zum Versuchsende betrug in der Kontroll-gruppe lediglich 8,6 %. und lag damit signifikant unter den Vergleichswerten der Versuchstie-re. Für die Konzentration der FFS fanden sich zum Versuchsende zwischen allen Gruppen si-gnifikante Unterschiede. Damit läßt sich eine dosisabhängige Wirkung einer Propranololappli-kation auf die Freisetzung von FFS aus den körpereigenen Fettdepots ableiten. Als Besonderheit war zu beobachten, daß sich die Konzentration der FFS in der Kontrollgrup-pe in den Zeiträumen der Infusion der NaCl-Lösung vermindert. Möglicherweise spielt hierbei der säuernde Einfluß des NaCl auf den pH-Wert im Blut eine Rolle. Unter dem Einfluß einer pH-Verminderung kommt es dabei zu einer Absenkung der Lipolyserate. Der zwischen den Infusionszeiten starke Konzentrationsanstieg der FFS in der Kontrollgruppe führt in dieser zu signifikant höheren FFS-Konzentrationen als in den Versuchsgruppen. Die Konzentrationsänderungen von direkt reagierendem und Gesamtbilirubin fielen bei den Schafen der Kontrollgruppe höher aus als bei den Tieren der Versuchsgruppen. Während die Maximalkonzentrationen für das Gesamtbilirubin in den Versuchsgruppen mit Dosierungen von 0,5 bzw. 1 mg Propranolol/kg KM/d 48 h nach Versuchsbeginn erreicht werden, ließen sich die maximalen Gesamtbilirubinkonzentrationen in der Kontrollgruppe erst 56 h nach Versuchsbe-ginn nachweisen. Die dabei vorhandenen Konzentrationsunterschiede zwischen den einzelnen Gruppen weisen auf eine geringere Belastung der Leber bei den Schafen der Versuchsgruppen hin. Auch die BHB-Konzentrationen im Blutserum der Schafe der Versuchsgruppen lagen zum Versuchsende unter denen der Tiere in der Kontrollgruppe. Damit liegt ein weiterer Indikator auf eine geringere Leberbelastung der Tiere in den Versuchsgruppen gegenüber den Schafen der Kontrollgruppe vor. Die absolut niedrigsten BHB-Konzentrationen waren bei den Schafen der Versuchsgruppe mit einer Propranololgabe von 1 mg/kg KM/d nachweisbar. In dieser Gruppe wurde die maximale BHB-Konzentration 32 h nach Fastenbeginn erreicht. Die vorliegenden Ergebnisse zeigen, daß sich mit Propranololgaben in Höhe von 0,5 bzw. 1 mg/kg KM/d beim Schaf eine Hemmung der Lipolyse innerhalb der ersten 64 Stunden eines Futterentzuges erreichen läßt, ohne dabei nachweisbaren Einfluß auf hämatologische Parameter auszuüben. Insbesondere weisen die zwischen Versuchs- und Kontrollgruppe vergleichbaren Anstiege der FFS-Konzentrationen in den infusionsfreien Zeiträumen auf den Einfluß des beta-adrenergen Antagonisten auf die Lipolyse während der Infusion hin. Die Konzentrationsände-rungen von Bilirubin und BHB in den Versuchsgruppen erfolgen in deutlich geringerem Um-fang als in der Kontrollgruppe. Damit läst sich auf eine geringere Belastung von Energie- und Leberstoffwechsel bei den Versuchstieren schließen. Die nicht signifikanten Veränderungen der Enzymaktivitäten von GLDH und ASAT bestätigen, daß durch die Anwendung von Propra-nolol keine negative Beeinflussung der Leberfunktion erfolgt. Aufgrund der stärkeren Reduzie-rung der Zahl der Pansenbewegungen und des verminderten Konzentrationsanstieges von FFS im Blutserum der Schafe, denen 1 mg Propranolol/kg KM/d appliziert wurde, gegenüber denen die 0,5 mg Propranolol/kg KM/d erhielten, ist von einer Dosisabhängigkeit der Propranolol-wirkung auszugehen. Die Applikation von Propranolol in einer Dosis von 0,5 bzw. 1 mg/kg KM/d stellt beim Schaf eine geeignete Methode dar, frühzeitig eine Verminderung der fasten-induzierten Lipolyse zu erreichen
The treatment of the fatty liver disease is world-wide regarded as unsatisfactory, so that death of the affected ruminants is partly unavoidable. The administration of beta receptor blockers in such cases has not found its way into veterinary medicine until now. In this study, the effects of a nonspecific blockade of the beta adrenoceptors on lipolysis, clinical and hematological parameters as well as on the metabolism of the liver, proteins and minerals in fasting sheep were therefore tested. Especially, the effect of a Propranolol administration on the lipolysis in the early stage of fasting was examined. During a three-day period of food deprivation, 15 female, clinically healthy and non-pregnant sheep (Merino-Fleisch) were given 0.5 or 1 mg Propranolol/kg body weight per day via a continuous infusion with two interruptions of eight hours. During the experiment, pulse, respiration rate, body temperature and rumen activity were checked. The serum concentrations of glucose, FFA, bilirubin, beta-hydroxybutyrate, potassium, sodium, magnesium, total protein and albumin were controlled by repeatedly taking blood samples from the vena jugularis externa. The activity of the enzymes GLDH and AST were determined to check the liver function. The effect of the beta-receptor antagonist Propranolol on the hematological parameters was checked by examining the WBC, RBC, the hemoglobin concentrations and the packed cell volume. All test groups showed significant decrease in body weigth of up to 9.8 %, due to the three-day food deprivation. Even within the first 48 hours of food deprivation, rumen motility of all animals was decreasing significantly. Those sheep which received 1 mg Propranolol/kg body weight per day showed the strongest decrease in rumen activity. Pulse and respiration rate, the concentrations of potassium, sodium, magnesium, total protein and albumin as well as the activity of GLDH and AST in blood serum remained without significant changes during the experiment. Neither the sheep of the control group nor those of the experimental groups showed any influence on the hematological parameters. While the blood glucose concentration tended to be lower during the food deprivation in all groups, the concentrations of FFA, bilirubin and beta-hydroxybutyrate in blood serum were increasing. Thus, the changes of FFA, bilirubin and beta-hydroxybutyrate concentrations in the control group showed the typical characteristics of fasting metabolism. These absolute increases in concentrations were significantly lower in both experimental groups than those in the control group. With regard to the levels reached and compared to the control group, a smaller load of energy and liver metabolism could be determined in the experimental groups. The transition from the first to the second stage of the fasting metabolism in all groups (but especially in the experimental groups) was clearly discernible in the rises of body temperature and in the stronger increases of the FFA concentrations approximately 48 hours after the experiment started. The special clinical and diagnostic importance of the FFA concentration was indicated in an earlier and stronger change of the FFA concentration in the blood serum, compared to the changes of bilirubin and beta-hydroxybutyrate. As early as 24 hours after the beginning of the fasting, a significant rise of the FFA concentration in comparison to the initial concentration could be proved. In contrast to the control group the two experimental groups showed a smaller increase in the FFA concentration. All groups reached their maxima of FFA concentration 48 hours after the beginning of the experiment. Afterwards FFA concentrations in the two experimental groups were sinking fast and significantly by 44.7 % and 63.5 % respectively. In the control group, the decrease of the FFA concentration from the maximum until the end of the experiment was only 8.6 % and thus significantly lower than the comparative results. At the end of the experiment, significant differences in FFA concentrations between all groups could be proved. So, it can be assumed that there is a dose-dependent effect of Propranolol on the FFA release from the bodyŽs own fat depots. The FFA concentration in the control group was decreasing during the NaCl-infusion. This could be due to NaClŽs influence on the pH value of the blood. The reduction of the pH causes a decreasing rate of the lipolysis. The strong rise of FFA concentration between the infusion in the control group, lead to significantly higher results compared to the experimental groups. The changes of total and direct reacting bilirubin in the control group were higher than in the experimental groups. While maximum concentrations of total bilirubin acid in the experimental groups (which got 0.5 and 1 mg Propranolol/kg body weigth per day respectively) could be determined 48 hours after the experimentŽs start, maximum concentrations in the control group could be found only 56 hours after beginning of the fasting. Beta-hydroxybutyrate concentrations in the experimental groups were also lower than in the control group. These differences between the groups indicate a smaller strain of the liver in the experimental groups. The lowest beta-hydroxybutyrate concentrations could be proved in the experimental group with a dose of 1 mg Propranolol/kg body weight per day. In this group, the maximum beta-hydroxybutyrate concentration was reached 32 hours after the beginning of the fasting. These results suggest that by the administration of Propranolol at doses of 0.5 mg and 1 mg/kg body weigth per day respectively it is possible to inhibit the lipolysis within the first 64 hours after a food deprivation without effecting the hematological parameters. Particularly, the comparable increases in FFA concentrations in the experimental and control groups between the infusions indicate a direct effect of the beta-adrenergic antagonist on the lipolysis during the infusions. The changes of bilirubin and beta-hydroxybutyrate concentrations in the experimental groups were smaller than those in the control group. This suggests a smaller strain on the energy and liver metabolism in the experimental groups compared to the control group. The nonsignificant changes of the activity of GLDH and AST indicate no negative influence on the liver function after applicating Propranolol. The stronger reduction of rumen motility and the smaller increase of the FFA concentration in the group with 1 mg Propranolol/kg body weigth per day compared to the group with 0.5 mg Propranolol/kg body weigth per day shows the dose-dependent effect of Propranolol. The application of Propranolol at a dose of 0.5 mg or 1 mg/kg body weigth per day is a suitable method to early inhibit fasting-induced lipolysis in sheep

Molecular imprinted polymers (MIPs), prepared to propranolol, were evaluated as solid phase extraction (SPE) phases. Monolithic MIPs were converted to particulate SPE materials by crushing, sieving, and sedimentation to remove fines. A high proportion (85%) of template propranolol was recovered with initial washes of the MIPs. Template leaching diminished with successive washes though low level leachings till compromised analysis of propranolol at trace levels (<5ng/mL). It was possible to retain propranolol on the MIPs following application in aqueous solution, biological matrices and organic solvent. In reversed and normal phase mode it was necessary to include an acid or base to achieve elution of basic compounds. In reversed phase mode, propranolol-imprinted MPs showed a degree of selectivity when using methanol:water:triethylamine but not methanol:water:trifluoroacetic acid elution solvents. This selectivity was related to structure when structurally-diverse compounds were assessed. Selectivity was very limited when assessed using compounds structurally similar to propranolol. In normal phase mode, MIPs retained amino-alcohols more strongly than a non-imprinted polymer though there was no evidence of a structure-related selectivity. A non-imprinted polymer and one prepared to an alternative template (tamoxifen) were assessed as reference polymers by which to assess the selectivity of propranolol-imprinted MIPs. Both materials were suitable references in reversed-phase mode though little selectivity was evident. The non-imprinted polymer was a poor comparator in normal phase mode as it appeared to show lesser non-specific binding than the imprinted MIP. Reversed and normal phase SPE methods were successfully developed for compounds structurally-simila to propranolol from human plasma. A protein precipitation step ahead of SPE was necessary. The MEP-based asays showed no advantage over conventional SPE and solvent extraction assay approaches. Although MIP-based extracts were clean, accuracy was poor at low concentrations (2 and 5 ng/mL) due to interference from template impurities leaching from the MJP.

Infantile hemangiomas (IH) are the most common soft-tissue tumours of infancy. Although propranolol has been shown to treat IH effectively, there are a few cases of propranolol-resistant IH (PRIH) are mentioned in the literature. The incidence of PRIH in different studies is 0-9%. The objective of this study is to describe and analyze the clinical cases of PRIH. This prospective study was conducted in the department of Pediatric surgery at Sumy Region Children's Clinical Hospital (Ukraine) between September 2012 and January 2016.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Diversos estudos tem mostrado que memorias aversivas antigas, ja consolidadas, quando reativadas, retomam em um estado fragil, necessitando de uma nova rodada de consolidacao para que ela tome-se novamente estavel. Este fenomeno e denominado de reconsolidacao, sendo dependente tanto da sintese proteica quanto do sistema noradrenergico. A tarefa da preferencia condicionada pelo lugar e um tipo de condicionamento pavloviano no qual o animal aprende a associar pistas ambientais com uma recompensa, sendo amplamente utilizado para o estudo das propriedades recompensadoras dos alimentos e das drogas de abuso. A amigdala basolateral e uma estrutura relacionada com o aprendizado aversivo, como o condicionamento do medo ao som e ao contexto. Esta estrutura esta tambem envolvida com o aprendizado apetitivo, incluindo a preferencia condicionada pelo lugar. Diversos trabalhos com farmacologia, inativacao e lesao tem mostrado que esta estrutura esta envolvida com a aquisicao, a consolidacao, a expressao e o restabelecimento dessa tarefa. Como a infusao de um inibidor de sintese proteica (anisomicina) na amigdala basolateral bloqueou a reconsolidacao em uma tarefa aversiva, e como esta estrutura tambem esta envolvida na expressao da preferencia condicionada pelo lugar, a primeira parte deste estudo investigou se a infusao da anisomicina bloqueou a reconsolidacao desta tarefa. Os resultados deste estudo mostraram que a anisomicina, quando infundida na amigdala basolateral imediatamente apos a reativacao(teste), nao prejudicou o desempenho dos animais em um teste posterior, indicando que nao houve reconsolidacao dependente de sintese proteica nesta estrutura para a tarefa de preferencia condicionada pelo lugar. A segunda parte deste estudo teve por objetivo verificar se o propranolol, um antagonista β-noradrenergico, quando injetado sistemicamente, bloquearia a reconsolidacao da tarefa de preferencia condicinada pelo lugar induzida pela morfina, uma vez que diversos estudos verificaram que essa droga bloqueia a reconsolidacao, tanto de tarefas aversivas, quanto de apetitivas. Novamente, a adminsitracao sistemica do propranolol apos a reativacao(teste), nao prejudicou o desempenho dos animais, sugerindo que nao houve reconsolidacao dependente do sistema noradrenergico na tarefa de preferencia pelo lugar desta tarefa. Os resultados deste estudo mostraram que a anisomicina, quando infundida na amigdala basolateral imediatamente apos a reativacao (teste), nao prejudicou o desempenho dos animais em um teste posterior, indicando que nao houve reconsolidacao dependente de sintese proteica nesta estrutura para a tarefa de preferencia condicionada pelo lugar. A segunda parte deste estudo teve por objetivo verificar se o propranolol, um antagonista β-noradrenergico, quando injetado sistemicamente, bloquearia a reconsolidacao da tarefa de preferencia condicionada pelo lugar induzida pela morfina, uma vez que diversos estudos verificaram que essa droga bloqueia a reconsolidacao, tanto de tarefas aversivas, quanto de apetitivas. Novamente, a administracao sistemica do propranolol apos a reativacao (teste), nao prejudicou o desempenho dos animais, sugerindo que nao houve reconsolidacao dependente do sistema noradrenergico na tarefa de preferencia pelo lugar
BV UNIFESP: Teses e dissertações

L'hémangiome capillaire infantile (IH) est une tumeur vasculaire bénigne courante. Les formes sévères sont traitées depuis 2008 par propranolol bien que le mécanisme d’action reste à ce jour inexpliqué. La 1ère partie de ma thèse est une étude de tolérance chez les enfants traités par propranolol dans le cadre de l'ATU française. L'analyse de cette base de données prospective de 922 enfants a permis de confirmer la bonne tolérance du propranolol dans la population pédiatrique, et de cibler les situations à risque de complication. La 2e partie est une étude de la signalisation adrénergique à partir des tissus d'IH opérés. Tout d'abord, nous avons identifié par immunofluorescence les cellules exprimant les récepteurs béta-adrénergiques ADRB1, 2 et 3 : Nous avons observé une forte expression d'ADRB2 sur le mastocyte, et de manière plus modérée d'ADRB1 et 2 sur les vaisseaux. Ce profil d'expression était retrouvé quel que soit le degré d'involution de la tumeur, et était également observé sur des tumeurs vasculaires contrôles qui elles ne répondent pas au propranolol. Nous avons donc envisagé une activation des récepteurs ADRB propre aux IH prolifératifs. Cette hypothèse a été confirmée par la mise en évidence, de l'expression d'enzymes de synthèse des catécholamines et de marqueurs neuroendocrines sur les péricytes des IH prolifératifs, sur tissus inclus en paraffine et également péricytes d’IH mis en culture. La surexpression de HIF1-a sur ces cellules a conduit à tester l’effet du propranolol en hypoxie. Nous n’avons pas mis en évidence d'effet sur la prolifération cellulaire, mais par contre une inhibition de la sécrétion de VEGF induite par l’hypoxie
Capillary infantile haemangioma (IH) is a common benign vascular tumour of infants. Severe forms are treated since 2008 by propranolol. However, its dramatic efficacy remains until now unexplained.The first part of my thesis is a safety study of children treated with propranolol as part of the French Compassionate Use Program. The prospective vigilance database, including 922 children, confirmed the safety of propranolol among the paediatric patients, and highlighted the circumstances at risk of complications.The second part is a study of adrenergic signaling in IH tissues. First, we identified by immunofluorescence the expression of beta-adrenergic receptors on IH cells. We observed a strong expression of ADRB2 on mast cells, and a moderate ADRB1 and 2 expression on vessels. This expression pattern was the same regardless of the degree of involution of the tumour, and has also been observed on tumour vascular controls which did not respond to propranolol. We therefore hypothesized that ADRB receptors may be activated in proliferative IH. We indeed detected the expression of catecholamine synthesis enzymes and of neuro-endocrine markers on pericytes in paraffin-embedded tissues, and also in IH pericytes in culture. We also detected HIF1-alpha overexpression and therefore explored propranolol effect during hypoxia. Propranolol had no effect on cell proliferation, but reduced hypoxia-induced secretion of VEGF-A

Touchant près de 3 à 10 % des nouveau-nés, les hémangiomes infantiles (HI) sont des tumeurs vasculaires bénignes, les plus fréquentes chez les nourrissons. Les HI sévères sont actuellement traités par un bêtabloqueur, le propranolol, dont l’efficacité a été découverte de manière fortuite. Ainsi, son mécanisme d’action est méconnu. Le propranolol se fixe sur les récepteurs beta-adrénergiques et empêche leur activation par les catécholamines comme la noradrénaline. Nous nous sommes donc interrogés sur la relation entre le propranolol et la noradrénaline dans cette tumeur. Nous avons montré une forte expression de la noradrénaline et des enzymes de synthèse des catécholamines dans les HI, comparés aux hémangiomes congénitaux, qui diminuent lorsque la tumeur involue ou est traitée par le propranolol. Nous avons ensuite réalisé un modèle in vitro ressemblant à l’HI à partir de cellules isolées d’HI capables de synthétiser les catécholamines : les cellules endothéliales et les péricytes. Ce modèle nous permettra d’étudier l’impact de la noradrénaline et du propranolol sur ces cellules. Parallèlement, notre équipe a réalisé un modèle in vivo qui a permis de mettre en évidence le rôle clé de la protéine quaporine-1 (AQP1) dans la réponse antitumorale du propranolol. Nous avons également étudié l’expression de l’AQP1 dans les HI et les hémangiomes congénitaux et découvert un type cellulaire adventitiel exprimant l’AQP1 dans les HI, le télocyte. Au total, notre travail sur l’HI a mis en évidence d’une part une possibilité de production endogène accrue de noradrénaline, probablement antagonisée avec succès par le propranolol, et la découverte de télocytes AQP1+ qui pourraient avoir un rôle dans la spécificité de la réponse des HI au propranolol
Affecting nearly 3 to 10 % of newborns, infantile hemangiomas (HI) are the most common benign vascular tumors in infants. Severe HIs are currently treated with a beta-blocker, propranolol, whose efficacy was discovered by serendipidity. Propranolol binds to beta-adrenergic receptors and prevents their activation by catecholamines such as noradrenaline. We therefore wondered about the relationship between propranolol and noradrenaline in this tumor. We showed a strong expression of noradrenaline and catecholamine synthesis enzymes in HI, compared to congenital hemangiomas, which decrease when the tumor involutes or is treated with propranolol. We then realize an in vitro model resembling HI from cells isolated from HI capable of synthesizing catecholamines: endothelial cells and pericytes. This model will permit to study the impact of noradrenaline and propranolol on these cells. At the same time, our team created an in vivo model that highlighted the key role of aquaporin-1 protein (AQP1) in the antitumor response to propranolol. We have also studied the expression of AQP1 in HI and congenital hemangiomas, and discovered an adventitious cell type expressing AQP1 in HI, the telocyte. Altogether, our work on HI has revealed firstly the possibility of increased endogenous production of norepinephrine, probably successfully antagonized by propranolol, and secondly the presence of AQP1 + cells which could have a central role central in the specificity of HI response to propranolol

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Receptores adrenérgicos são amplamente expressos em diferentes tecidos, incluindo na pele. Recentemente foi descoberto que bloqueadores dos receptores β-adrenérgicos são capazes de modular o processo de reparo tecidual. O propranolol é um β-bloqueador não seletivo largamente utilizado na prática clínica para o tratamento de doenças cardiovasculares, parecendo apresentar propriedades antioxidantes. O objetivo desse estudo foi avaliar a resposta de diferentes doses de propranolol durante a lesão isquêmica cutânea em roedores. Ratos Wistar foram tratados com propranolol nas concentrações de 3 e 6 mg/kg. O grupo controle recebeu apenas o veículo e o grupo controle positivo recebeu vitamina E (50 mg/kg/dia). A administração do propranolol iniciou-se no dia da lesão, sendo realizada diariamente até o sacrifício. Incisões bilaterais foram feitas no dorso de cada animal. O flap foi suturado e foram realizadas lesões excisionais totais entre as lesões incisionais. A contração das lesões foi avaliada e os cortes histológicos foram corados com hematoxilina e eosina e vermelho de picrosirius. Foram utilizadas também as seguintes técnicas: Dopplerfluxometria, análises bioquímicas, análise estereológica e expressão de PECAM-1. O grupo tratado com 3 mg de propranolol apresentou uma maior redução na área total da lesão quando comparado ao grupo controle. Da mesma forma, este grupo apresentou um aumento na densidade de vasos sanguíneos, uma maior expressão de PECAM-1 e aumento na perfusão sanguínea na pele isquêmica e no sítio da lesão quando comparado ao grupo controle. Não observamos efeito antioxidante do propranolol neste modelo. Em resumo, nós sugerimos que o propranolol quando administrado na dose de 3 mg/kg/dia foi capaz de modular a angiogênese e melhorar o fechamento da lesão em modelo de roedores
Adrenoceptors are highly expressed in a wide variety of tissues, including skin. Recently, it was discovered that β-blockers agents are able to modulate the wound healing process. Propranolol is a nonselective β1 and β2-blocker widely used in clinical practice for treating diseases of cardiovascular system. Moreover, this drug has been shown to have antioxidant properties. The aim of this study was to evaluate the response of different propranolol doses during cutaneous ischemic wound in rodents. Wistar rats were treated with propranolol at concentrations of 3 and 6 mg/kg/day, control group received only vehicle and positive control group received vitamin E (50 mg/kg/day). Propranolol administration began on the day of injury, and was administered daily until euthanasia. Bilateral incisions were performed the dorsum of each animal. The flap was sutured and a full-thickness wound was made between the incisional lesions. Wound contraction was evaluated and sections were stained with H&E and Sirius red. Laser Doppler flowmetry, biochemical analysis, stereological analysis, and protein expression of PECAM-1 were also measured. Propranolol treated with 3 mg group showed a reduction in total wound area when compared to control group. Also, propranolol treated with 3 mg group showed an increased of density of blood vessels, highest PECAM-1 expression and highest blood perfusion in ischemic skin and in the wound bed when compared to control group. In summary, we suggest that propranolol administered at 3 mg/day was able to modulate angiogenesis and improved closure of the lesion in this rodent model

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A ocorrência de fármacos no meio ambiente tem se tornado um assunto de interesse nos últimos anos. Grande número desses compostos tem sido detectado em efluentes de estações de tratamento de esgoto (ETE) municipais, águas superficiais e, menos frequentemente, em águas subterrâneas e água potável em todo o mundo. Alguns dos efeitos adversos causados por fármacos incluem toxicidade aquática, desenvolvimento de resistência em bactérias patogênicas, genotoxicidade, e desregulação endócrina. Diferentes fontes podem ser indicadas para explicar o aparecimento de fármacos no ambiente aquático. Atualmente, é amplamente reconhecido que a principal fonte de poluição são os efluentes de ETE. Portanto, o descarte de resíduos farmacêuticos nos efluentes de ETE deve ser minimizado o máximo possível. A remoção de poluentes orgânicos recalcitrantes como fármacos na água e em efluentes pode ser obtida utilizando processos oxidativos avançados (POA). O objetivo deste trabalho é avaliar a eficiência de remoção de Propranolol por meio de POA, avaliar a toxicidade dos produtos de degradação durante os tratamentos bem como realizar um estudo cinético de degradação do composto. O fármaco usado neste estudo foi o Propranolol fornecido pelo LAFEPE. Foi utilizada solução modelo a 20 mgL-1 . Os tratamentos por meio de POA (H2O2/UV, Fenton e foto-Fenton) além de radiação UV (fotólise) e H2O2 foram realizados em escala laboratorial em um reator ao longo de 60 minutos. A radiação UV foi obtida por uma lâmpada a vapor de mercúrio de média pressão de 30 W. A agitação do sistema foi feita utilizando um agitador magnético. Sulfato ferroso heptahidratado foi utilizado como fonte de íons de ferro para o processo Fenton e foto-Fenton. A determinação e a quantificação do fármaco após tratamento por POA, foram realizadas em um espectrofotômetro UV-Vis. Em relação aos resultados obtidos pelo tratamento utilizando POA, o propranolol se mostrou pouco sensível a oxidação com peróxido de hidrogênio. O tratamento Foto-Fenton apresentou melhor eficiência de remoção e o Fenton o melhor resultado de toxicidade. A cinética de oxidação do fármaco foi discutida e verificou-se que o modelo cinético de pseudo-primeira ordem pode descrever melhor a oxidação do fármaco. As principais vantagens e desvantagens de cada processos e a complexidade de comparação dos vários processos de oxidação foram discutidos. O processo Foto-Fenton foi o que removeu mais de 80% do propranolol a 20 mg L-1 em 15 minutos.
The occurrence of pharmaceuticals in the environment has become a subject of interest in recent years. A vast number of these compounds have been detected in sewage treatment plant (STP) effluents, surface waters and, less frequently, in groundwater and drinking water, all over the world. Some of the adverse effects caused by pharmaceuticals include aquatic toxicity, resistance development in pathogenic bacteria, genotoxicity and endocrine disruption. Different sources can be indicated to explain the appearance of pharmaceuticals in the aquatic environment. Nowadays, it is widely accepted that the main source of pollution are STP effluents. Therefore, the discharge of pharmaceutical residues to the environment in STP effluents should be minimized. Removal of recalcitrant organic pollutants such as pharmaceuticals in water and wastewater can be achieved using advanced treatment technologies such as advanced oxidation processes (AOP). The objective of this study is to evaluate the removal efficiency of Propranolol by AOP to identify the degradation products toxicity as well as to perform a degradation kinetic study of these compounds. The pharmaceutical used in this study was Propranolol were purchased from LAFEPE. The pharmaceutical were spiked daily at a concentration of 20 mgL-1 were treated by AOP. The treatments by AOP (H2O2/UV, Fenton and photo-Fenton) and photolysis (UV radiation) and peroxide, were performed in a reactor along 60 minutes. UV radiation was provided by a medium pressure mercury lamp of 30 W. The agitation of the system was realized by a magnetic bar. Ferrous sulfate heptahydrate was used as source of iron for the Fenton and photo-Fenton process. The determination and quantification of the pharmaceutical present during the treatment by AOP were performed with UV-Vis spectrophotometer. With regard to the results obtained by using AOP treatment, the propranolol was less sensitive to hydrogen peroxide. Despite photo-fenton treatment presented the highest removal efficiency and Fenton the best treatment toxicity. The kinetics of oxidation of propranolol has been discussed and it was found that the pseudo-first order kinetic model can describe the oxidation. The main advantages and disadvantages of each process and the complexity of comparing the various advanced oxidation processes (AOP) was discussed. In the photo-fenton process it was possible to remove more than 80% from propranolol concentration of 20 mg L-1 in 15 minutes.

There has been a change in the management of infantile haemangioma with the introduction of propranolol. The aim of this study is to retrospectively evaluate a simple treatment for infantile haemangioma at the Red Cross War Memorial Children’s Hospital (RCWMCH) and document the results. While it is known that all haemangiomas undergo involution at some stage, some haemangiomas pose certain problems. These relate mainly to visual axis obstruction and aesthetics. Subjects are children in the first two years of life presenting with haemangiomas. All patients were treated with oral propranolol in conjunction with haemangioma size documentation, using a simple radiological modality, i.e. ultrasound imaging. Patients are followed up and clinical and radiological evaluations are undertaken to observe changes in size and appearance. Propranolol is non-selective β-adrenergic antagonist that is used extensively for the treatment of a multitude of disorders, mainly cardiovascular indications. The main adverse effects include bradycardia, hypotension and bronchospasms. For the purposes of this study, all subjects were routinely examined, especially with regard to the cardiopulmonary systems. Any perceived anomaly was referred to the cardiorespiratory physicians at RCWMCH for further evaluation, which includes all the necessary investigations such as electrocardiograms(ECG) and echocardiograms. Therefore, only fit healthy patients were selected for this study. Patients are educated and fully informed regarding the adverse effect profile of propranolol, and advised of the appropriate route of management.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
A equivalÃncia farmacÃutica entre dois medicamentos relaciona-se à comprovaÃÃo de que ambos contÃm o mesmo fÃrmaco na mesma dosagem e forma farmacÃutica, o que pode ser avaliado por meio de testes in vitro. No Brasil, os medicamentos alopÃticos sÃo divididos em trÃs categorias quanto ao registro junto à AgÃncia Nacional de VigilÃncia SanitÃria: medicamentos novos, medicamentos similares e medicamentos genÃricos. A legislaÃÃo atual dispÃe que para o registro de novos medicamentos genÃricos e similares à necessÃria a comprovaÃÃo da equivalÃncia farmacÃutica e a bioequivalÃncia em relaÃÃo ao medicamento de referÃncia. Produtos registrados antes de 2003 tÃm um perÃodo de adaptaÃÃo garantido, de modo que os resultados dos testes de equivalÃncia farmacÃutica e perfil de dissoluÃÃo sejam incluÃdos ao seu registro atà 2014. O Programa FarmÃcia Popular do Brasil à uma nova polÃtica de AssistÃncia FarmacÃutica, dentro do Sistema Ãnico de SaÃde que tem como objetivo facilitar o acesso da populaÃÃo aos medicamentos considerados bÃsicos e essenciais, diminuindo assim, o impacto dos preÃos dos medicamentos no orÃamento familiar. O objeivo deste trabalho foi avaliar a EquivalÃncia FarmacÃutica de comprimidos de Captopril 25 mg e Cloridrato de Propranolol 40 mg comercializados no Programa FarmÃcia Popular do Brasil, comparando-o com medicamentos de ReferÃncia e GenÃrico, visando discutir a importÃncia da qualidade dos medicamentos para a saÃde pÃblica. Realizaram-se testes fÃsicos e fÃsico-quÃmicos como: identificaÃÃo, determinaÃÃo de peso, desintegraÃÃo, dureza, friabilidade, teor, uniformidade de conteÃdo, pureza e perfil de dissoluÃÃo, segundo a FarmacopÃia Brasileira, 4a ediÃÃo. Os resultados indicaram uma baixa dureza nos comprimidos de cloridrato de propranolol da FarmÃcia Popular. Os perfis de dissoluÃÃo, analisados por ANOVA e teste de Tukey demonstraram diferenÃas significativas (p<0,001) entre os perfis de dissoluÃÃo da FarmÃcia popular em relaÃÃo ao GenÃrico e ReferÃncia nos tempos avaliados dos dois fÃrmacos em estudo. Compararam-se os perfis de dissoluÃÃo dos comprimidos da FarmÃcia Popular com os medicamentos ReferÃncia e GenÃrico atravÃs da EficiÃncia de DissoluÃÃo (ED%). A extensÃo do fÃrmaco dissolvido do medicamento FarmÃcia Popular foi significativamente menor (P < 0,001) do que o ReferÃncia para Captopril e Propranolol. O Captopril da FarmÃcia Popular, apesar de ter cumprido as exigÃncias da legislaÃÃo, foi reprovado no ensaio de ED%. Portanto, os comprimidos de Cloridrato de Propranolol e Captopril da FarmÃcia Popular nÃo foram considerados equivalentes farmacÃuticos em relaÃÃo aos medicamentos ReferÃncia e GenÃrico.
The pharmaceutical equivalence between two medicines is based on the confirmation that both contain the same active drug on the same dosage and dosage form, wich is assessed by in vitro tests. In Brazil, the National Health Surveillance Agency defines that allopathic medicines can be registered in three categories: innovator, generic and similar drugs. The actual legislation determines that to register new generic and similar medicines it is necessary to prove its pharmaceutical equivalence and bioequivalence with a reference drug. Products registered before 2003 have until 2014 to present these equivalence results. The Popular Pharmacy Program in Brazil is a new strategy of pharmaceutical assistance of the Health Sistem with the purpose to facilitate the populationâs access to medicines considered basic and essential, lowering the price impact of these medicines in the family budgets. The objective of this study was to assess the pharmaceutical equivalence of captopril 25 mg and propranolol hydrochloride 40 mg tablets sold in the Popular Pharmacy Program in Brazil, comparing them to a reference and generic drug, debating the importance of the quality of drugs for the public health. Physical and physicochemical tests such as identification, weight variation, disintegration, hardness, friability, purity, dosage, content uniformity, and dissolution profile, were performed according to the Brazillian Pharmacopeia 4th edition. The results showed a low hardness of propranolol hydrochloride tablets originated from the Popular Pharmacy Program. The dissolution profiles analised by analysis of variance (ANOVA) and Tukey test demonstrated significant differences between the dissolution profiles of both drugs originated from the Popular Pharmacy Program and their respective reference and generic drugs (p<0,001). The dissolution profiles were compared by the Dissolution Efficiency method. The extention of the active drug dissolved from the Popular Pharmacy medicine was significantly lower than the dissolution from the reference and generic drugs (P < 0,001) for both captopril and propranolol hydrochloride. Even though captopril would fulfill the requirements of the National Health Surveillance Agency to be considered equivalent, it was not approved on the dissolution efficiency test. Therefore, the assessed tablets originated from the Popular Pharmacy Program in Brazil were not considered pharmaceutical equivalents when compared to their respective reference and generic drugs.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado.
El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado.
Hematohidrosis is a condition that presents with the excretion of blood from intact skin. Reported cases suggest emotional stress reactions as the most common inciting events. The pathogenesis of the condition is not well understood. We describe a 9-year old boy and his 6-month old half-sister with a history of bleeding episodes from the ears, eyes, and scalp, as well as other sites. Symptoms in both children have shown a positive response to propranolol, with decreased frequency and severity of bleeding. There are no prior reports of siblings with hematohidrosis, suggesting a possible genetic predisposition.
Revisión por pares

Els sistemes de separació mitjançant membranes han guanyat importància com a tècniques de separació enantiomèrica. S'han investigat distintes configuracions de membranes.
Per a la separació enantiomèrica de SR-propranolol, fàrmac usat per al tractament d'algunes anomalies cardiovasculars, s'han estudiat diferents transportadors selectius: N-alquil-hidroxiprolines i dialquil tartrats en membranes líquides, i el norbornadiè com a polímer quiral. Malgrat tots aquest sistemes mostraven resultats prometedors, cap d'ells ha estat investigat detalladament.
La finalitat d'aquesta tesi ha consistit a desenvolupar i caracteritzar diferents sistemes de membrana per a la separació del fàrmac SR-propranolol. S'han investigat quatre sistemes distints de membranes: membranes líquides suportades (SLM), membranes compòsit activades (ACM), membranes activades quirals (CAM) i membranes basades en polisulfona quiral (CPS). En la majoria dels casos s'ha emprat com a transportador selectiu l'N-hexadecil-L-hidroxiprolina (HHP).
L'estudi i la caracterització de cada sistema s'ha dut a terme mitjançant tècniques microscòpiques i experiments de transport usant quatre mòduls de membrana diferents: una cel·la de diàlisi, un mòdul micro espiral , un mòdul que permet el modelatge del transport i un mòdul de filtració frontal.
L'estudi del sistema de SLM va permetre elucidar els dos mecanismes de transport implicats en aquest sistema de separació, així com discriminar els principals paràmetres que governen (en termes de flux i selectivitat) el comportament del sistema de membranes. En condicions òptimes de treball (fase de càrrega ajustada a pH 8 i concentració de transportador de C/A = 3) es va detectar un excés enantiomèric del 5.6%.
Les membranes compòsit activades, formades per una capa porosa de polisulfona pel·liculada sobre un paper no teixit, i una capa densa superficial de poliamida, foren caracteritzades mitjançant distintes tècniques: microscòpia de força atòmica, transport de soluts, mesures d'angle de contacte, ressonància electrònica d'espí, i microscòpia electrònica d'escombratge. L'ús d'aquestes tècniques complementàries va permetre obtenir informació de la morfologia interna i superficial de les membranes, i alhora va confirmar la presència de transportador a l'interior de les membranes. Tot i així, al ser aplicades per a la separació enantiomèrica de propranolol no es va observar transport enantioselectiu.
Les CAM, formades per un capa porosa de polisulfona pel·liculada sobre un paper no teixit, si que van permetre el transport enantioselectiu del fàrmac d'estudi. En aquest cas es va estudiar la influència sobre el sistema de la concentració de transportador selectiu en la membrana i del valor de pH de la solució receptora. L'estudi va revelar la relació entre el flux i la enantioselectivitat i va contribuir a proposar les preferències d'afinitat del transportador vers ambdós enantiòmers del fàrmac propranolol. Els bons resultats van esperonar el desenvolupament d'un nou sistema de membranes CAM emprant didodeciltartrat com a transportador selectiu. La comparació dels dos sistemes de CAM es va dur a terme mitjançant el modelatge del transport ambdós enantiòmers implicats. Els resultats mostraren que el segon sistema posseeix millors propietats per al transport enantioselectiu de propranolol.
Per últim es van investigar les membranes basades en polisulfona quiral, que contenen el selector quiral enllaçat covalentment a la matriu polimèrica. La polisulfona fou derivatitzada seguint dues rutes sintètiques distintes, i van obtenir-se dos productes diferents: CPSA i CPSB. Ara bé, sols la CPSA va resultar adequada com a polímer. Les membranes obtingudes a partir de CPSA van ser caracteritzades. L'aplicació d'aquest tipus de membranes van donar lloc a resultats prometedors tan pel que fa al flux com a la enantioselectivitat, i van permetre confirmar la major afinitat del selector per a l'enantiòmer S-propranolol. En aquest cas, quan es va incorporant la quantitat més gran possible de transportador en la membrana es va obtenir un factor de separació de 1,1a les 96h d'experimentació.
Membrane systems have been gaining importance as enatioseparation techniques.
Various membrane configurations, have been proposed to attain enantioseparation. Liquid membrane processes were firstly proposed, however they exhibit a rapid selectivity decrease with operating time and show low stability and short lifetime when tested under industrial separation conditions. Therefore, solid polymeric membranes have also been developed.
For the case of SR-propranolol, a β-blocking drug used for treating certain cardiovascular anomalies different enantioselective carriers have been studied. N-n-alkyl-hydroxyprolines, and dialkyl tartrate were used in liquid membrane configurations, and norbornadiene was considered as chiral polymer. Although all these membrane systems showed promising results, none of them was investigated in detail.
The purpose of the present work was the characterisation and development of membrane systems for the enantioselective separation of SR-propranolol. Four different membrane systems, based in supported liquid membranes (SLM), activated composite membranes (ACM), chiral activated membranes (CAM) and chiral polysulfone (CPS) membranes, have been investigated. In most of them, N-hexadecyl-L-hydroxyproline (HHP) was applied as chiral carrier.
The study and characterization of each membrane type was carried out using microscopy techniques and transport experiments. The latest were conducted with four different membrane modules: a dialysis cell, a micro spiral module, a module capable of well-defining hydrodynamics conditions for transport modelling and a dead-end filtration module.
The study of SLM, permitted the elucidation of the two transport mechanisms involved in these separation systems and allowed discriminating the principal parameters governing the performance of the membrane system, either in terms of flux as in terms of selectivity. Under operating conditions showing the best performance results (feed at pH 8, and carrier concentration up to C/A = 3) a 5.6% of enantiomeric excess was reached.
Activated composite membranes (ACM) consisted of a porous polysulfone support casted on a none-woven fabric, with a top dense polyamide layer. ACM were characterized by different techniques, such as atomic force microscopy, solute transport, contact angle measurements, electron spin resonance, and scanning electron microscopy. The use of all these complementary techniques provided an extensive and concise description of ACM internal and surface morphology, together with the confirmation of the presence of the chiral carrier inside the membranes. However, when applied to the enantioseparation of propranolol enantioselectivity was not observed.
CAM consisted in a porous polysulfone film, also casted on a non-woven fabric. This membrane type permitted the enantioselective transport of propranolol across the membranes. In that case, the influence of carrier concentration in the membrane as well as the striping phase pH were studied. These studies revealed the relationship between transport rate and enantioselectivity and contributed to propose the affinity preferences of the carrier by the two enantiomers. The good results obtained, motivated the development of another CAM system containing the chiral carrier didodecyltartrate. The comparison of the two equivalent systems was carried out by conveniently modelling the transport of both propranolol enantiomers. Results showed that the last system possesses better properties for the enantioseparation of propranolol.
The last type of polymeric membranes assayed were based in chiral polysulfones CPS, containing the chiral carrier covalently bonded to the polysulfone polymeric structure. PS was chiraly derivatised following two different sysnthetic routes, and two corresponding chiral polysulfones were obtained, namely CPSA and CPSB. However when preparing the membranes, only CPSA was suitable as polymer. CPS membranes, obtained from CPSA were prepared and characterised. The application of these polymeric membranes showed promising results regarding both the transport rate and enantioselectivity, and confirmed the higher affinity of the carrier by the S-propranolol enantiomer. In that case, with membranes containing the highest CPSA amount, a separation factor of 1.1 was encountered at 96h of experiment.

Propõe-se que a angiogênese represente um importante passo no processo de adesão, implantação, invasão e crescimento das células endometriais, visto que, semelhante aos tumores metastáticos, implantes endometrióticos dependem de neovascularização para se proliferarem. Tal constatação sugere que a supressão do desenvolvimento de vasos sanguíneos por meio da inibição de fatores angiogênicos específicos pode ser uma nova oportunidade terapêutica na abordagem da endometriose. Estudos demonstram um efeito antiangiogênico do propranolol anticancerígeno em diferentes tipos de tumores. Tal achado sugere que o propranolol pode contribuir clinicamente exercendo papel sobre a inibição de neoangiogênese, e tal efeito resultar em um impacto sobre as lesões de endometriose. Foi estudado o efeito do propranolol sobre marcadores de diferenciação (Metalotioneínas MT1 e MT2), invasão (MMP9 e TIMP2), proliferação celular (PCNA) e apoptose (CASP8 - caspase 8) por coloração imunohistoquímica, e também a influência sobre a adesão, motilidade e angiogênese das lesões de endometriose por quantificação da expressão relativa (RQ) por PCR em tempo real dos genes Vegf, Cald1, Pcna, Tnf e Sparc. Foram utilizadas 30 ratas adultas Wistar, fêmeas, virgens que foram submetidas a laparotomia para indução de lesões de endometriose. As ratas foram separadas em três grupos, e sacrificados após 14 dias de tratamento de dose baixa (PB, n = 10) e dose elevada (PA, n = 10) de propranolol; e o grupo de controlo (C, n = 10) sem tratamento. As lesões foram excisadas para análise histológica com o corno uterino contralateral, com confirmação da presença de tecido glandular e estroma endometrial. No presente estudo foi observada uma redução na marcação imunohistoquímica para Metalotioneínas, com 60% de positividade no grupo controle, 10% e 11,1% para o PA, PB, respectivamente (p <0,05). Também observamos uma diminuição na expressão do gene de Pcna (C = 1,04; PA = 0,32; PB = 0,69). Em outros marcadores de imunohistoquímica e quantificação da expressão gênica nas lesões e no tecido uterino não foram observadas diferenças significativas. O tratamento com drogas antiangiogênicas como propranolol oferece novas perspectivas de abordagem terapêutica para pacientes com endometriose.
Since endometrial implants rely on neovascularization to proliferate, in a similar way to metastatic tumors, it is proposed that angiogenesis represents an important step in the process of adhesion, implantation, invasion and growth of ectopic endometrial cells. These findings suggest that the suppression of the development of blood vessels by inhibition of specific angiogenic factors may be a new therapeutic opportunity in endometriosis approach. Studies demonstrate an antiangiogenic anticancer effect of propranolol in different types of tumors. This drug can play a role in the inhibition of neoangiogenesis, which could interfere on the growth of endometriotic lesions. The effect of propranolol on markers of differentiation (Metallothionein, MT1 and MT2), invasion (MMP9 and TIMP2), cell proliferation (PCNA) and apoptosis (CASP8 - caspase 8) was evaluated by immunohistochemical staining, as well as the influence of propranolol on adhesion, motility and angiogenesis of both endometriotic lesions and endometrial tissue through quantification of relative expression (RQ) by real-time PCR of the genes Vegf, Cald1, Pcna, Tnf and Sparc. Thirty Wistar adult rats, females, virgins who underwent laparotomy for induction of endometriosis lesions were used. The rats were divided into three groups, and sacrificed after 14 days of low (BP, n = 10) and high dose treatment (AP, n = 10) of propranolol; and the control group (C, n = 10), untreated. The lesions were excised for histological analysis with the contralateral uterine horn, with confirmation of the presence of glandular tissue and endometrial stroma. In the present study we observed a reduction in immunostaining for Metallothioneins, with 60% positive in the control group, in comparison to 10% and 11.1% for PA and PB, respectively (p <0.05). Furthermore, there was a decrease in expression of Pcna gene (C = 1.04; PA = 0.32; PB = 0.69) which was statistically significant (p<0.05). However, quantification of gene expression regarding other immunohistochemical markers evaluated both in the endometriotic lesions and uterine tissue showed no statistically significant difference. In conclusion, antiangiogenic drugs like propranolol may offer new perspectives for the therapeutic approach of patients with endometriosis.

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Híbridos Siloxano-PPO obtidos pela síntese sol-gel foram utilizados como matrizes carreadoras do fármaco cloridrato de propranolol com interesse de se aumentar a disponibilidade do fármaco em meio aquoso. Foram preparados amostras contendo teores de 5 e 30% do fármaco. A eficiência na formação da rede híbrida foi confirmada por análises FTIR, RMN e SAXS. A cinética de liberação mostrou que ela ocorre de forma prolongada (superior a 1200 h) com regimes intermitentes de aceleração e desaceleração da taxa de liberação. Foram aplicados ajustes matemáticos a cada regime utilizando a equação de Korsmayer-Peppas que demonstraram que a saída do fármaco ocorre por diferentes mecanismos. Observou-se que o acesso da água na amostra durante a liberação não é homogêneo, mas sim gradual da superfície ao centro. Devido a esses fenômenos as caracterizações foram feitas em diferentes regiões da amostra (periferia e centro) e em diferentes períodos da liberação, visando acompanhar a difusão da água para o interior da amostra e a cinética de saída do fármaco. As análises estruturais de DRX e as térmicas por TGA e DSC mostraram que o fármaco é incorporado na matriz híbrida na forma solubilizada e na forma cristalina. As medias realizadas em função do tempo mostraram que a velocidade de saída do fármaco e de entrada da água na matriz híbrida é maior na superfície em relação ao volume, confirmando o acesso gradual da água. Essas análises indicam a correlação entre as fases cristalina do fármaco com os primeiros regimes e da parte solubilizada com a liberação mais lenta. As medidas de DSC mostraram que o acesso da água em regiões mais internas da amostra resultaram no comportamento de confinamento da água, indicado pelo fenômeno de super congelamento. Foi detectado por medias de SAXS a existência de espalhadores secundários presentes em todas as amostras, inclusive nas matrizes híbridas sem a adição de fármaco, que foram atribuídos a agregados formados por domínios com maior densidade de nanopartículas de sílica. A evolução no tamanho desses agregados foi correlacionada aos regimes de liberação. Conclui-se, que a cinética de liberação tem uma forte dependência da evolução da matriz híbrida causadas por mudanças estruturais favorecidas pela mobilidade da cadeia polimérica e pela interação do fármaco com a água.
Siloxane-PPO hybrids obtained by sol-gel synthesis have been used as drug delivery systems for propranolol hydrochloride with the intent to increase the drug availability in the aqueous medium. Samples with 5% and 30% of drug have been prepared. The efficiency related to the formation of the hybrid network has been confirmed by means of FTIR, RMN and SAXS analyses. The drug delivery kinetics showed that it occurs in a prolonged form (more that 1200h) with increasing and decreasing intermediate release rates. The Korsmayer-Peppas equation has been used for each release rate with mathematical adjustments that displayed how the drug release occurred through different mechanisms. It has been observed that the water intake inside the sample during the drug release was not homogeneous but gradual, from the surface to the centre. Due to these phenomena, the characterizations have been carried out in different regions of the samples (exterior and interior) and at different drug delivery periods, aiming at accompanying the water diffusion to the sample centre and the drug release kinetics. The XRD structural analyses and the thermal analyses by means of TGA and DSC showed that the drug is incorporated in the hybrid matrix in a solubilized form and in a crystalline form. The tests done as function of time displayed that the drug release velocity and water intake inside the hybrid matrix is greater at the surface in relation to its volume, confirming the gradual access of water. These analyses point to the correlation between the drug crystalline phase with the first release regimes and between the solubilized form with the slower release. The DSC tests showed that the water intake inside more internal regions of the sample resulted in the water confinement, demonstrated by the super-cooling phenomenon. By means of SAXS, the existence in all the samples, including those without drug, of secondary scatterings has been observed and these have been attributed to aggregates formed by domains with a higher silica nanoparticle density. The size evolution of these aggregates has been correlated to the drug release regimes. It has been concluded that the drug release kinetics has a strong dependence with the hybrid matrix evolution caused by structural changes facilitated by polymer chain mobility and by drug/water interaction.

Magister Pharmaceuticae - Mpharm
Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality in both developed and developing countries; and account for around 30% of all deaths worldwide. Reports indicate that nanoparticle (NP) based drug systems are likely to meet the urgent demand for breakthrough innovation in CVDs therapy and diagnosis. NPs have the potential to improve pharmacokinetics and efficacy and reduce the toxicity of cardiovascular drugs. Propranolol is a non-selective beta blocker, and has long been used in the treatment of hypertension, angina and other CVDs. Propranolol has a short half-life (between 2-3 h) and exhibits toxicity, including bronchospasm, due to non-selective beta receptor stimulation. The aim of this study was to develop an NP drug delivery system for propranolol; studying the parameters around formulation of the NPs and their performance in-vitro.

La migraine constitue un problème de santé publique ayant un impact négatif majeur dans la vie quotidienne des patients. Douze pour cent de la population mondiale souffre de migraine et son coût est évalué à 18 milliards d'euros par an dans la communauté européenne. La fréquence des crises peut augmenter au cours du temps chez certains migraineux, faisant ainsi évoluer une migraine épisodique (0 à 14 jours de crises par mois) en migraine chronique (plus de 15 jours de crises par mois). Ce processus est qualifié de transformation de la migraine. La fréquence des crises semble être un facteur important dans ce processus. Utilisant des approches comportementales, électrophysiologiques, immunohistologiques(expression de la protéine Fos), nous avons identifié une partie des mécanismes neurobiologiques impliqués dans la transformation des céphalées. En effet, en développant un modèle animal de stimulation chimique répétée des méninges nous avons évalué (1) le rôle de l'intensité et de lafréquence sur la sensibilité cutanée (2) la sensibilisation des neurones de la corne dorsale spinale et trigéminale (3) l'efficacité du traitement de fond de référence de la crise, le propranolol (4) l’implication du tronc cérébral (le locus coeruleus (LC) et la substance grise periacqueducale (PAG)) dans la sensibilisation des neurones trigéminaux et spinaux (5) l'implication du LC dans les modifications de la sensibilité cutanée induite par la stimulation chimique des méninges. Notre étude comportementale révèle que la topographie (céphalique et/ou extracéphalique) et la nature (statique ou dynamique) de l'allodynie induite par la stimulation chimique des méninges est sous l'influence de deux facteurs : l'intensité et la fréquence de la stimulation, qui peuvent entraîner sa persistance. Nos études électrophysiologiques et comportementales confirment que l'allodynie cutanée céphalique et extracéphalique est le reflet de la sensibilisation des neurones trigéminaux cervicaux et spinaux, qui peut devenir persistante. Le propranolol, permet de prévenir la modification de la sensibilité cutanée ainsi que l'altération de l'activité des neurones trigéminaux et spinaux. Nous avons également observé la sensibilisation de deux structures du tronc cérébral : la PAG et la PAG qui se traduisent par une altération persistante des CIDN. Cependant le propranolol semble prévenir l'altération de tous ces phénomènes via l'inhibition d'une seule structure le LC et non la PAG. En effet, nos microinjections de propranolol dans le LC permettent de prévenir toutes les modifications induites par la stimulation chimique des méninges. En conclusion ces résultats suggèrent que la fréquence et l'intensité des crises de migraine sont deux facteurs de risque endogène de transformation des céphalées. Un marqueur de cettetransformation est l'allodynie, qui est le reflet clinique de la sensibilisation centrale des neurones de la corne dorsale. Cette sensibilisation centrale est due à l'arrivée directe d'information provenant des méninges mais également à une altération de l'activité neuronale du LC. Nous pouvons également dire que le propranolol constitue un excellent choix dans le traitement de la crise migraineuse étant donné qu'il prévient toutes les modifications induites par la stimulation chimique des méninges et qu'il agit via le LC
Migraine is a public health problem having a major negative impact on the daily lives of patients. Twelve percent of the world population suffers from migraine and its cost is estimated at $ 18 billion per year in the European Community. The frequency of attacks may increase over time in some migraineurs, thus evolve episodic migraine (0-14 days crises by month) in chronic migraine (more than 15 days of attacks by month). This process is called transformation of migraine. Frequency of headache attacks at baseline appears to be an important risk factor for this process. Using behavioral electrophysiological, and immunohistochemical (expression of Fos protein) approaches, we have identified some of the neurobiological mechanisms involved in the transformation of migraine. Indeed, developing an animal model of repeated chemical stimulation of the dura, we evaluated (1) the role of the intensity and frequency of chemical stimulation (crisis) on skin sensitivity (2) sensitization of second order trigeminal and spinal neurons (3) the effectiveness of font treatment reference of the crisis, propranolol (4) the involvement of the brainstem (locus coeruleus (LC) and periacqueductal grey matter (PAG)) in the sensitization of trigeminal and spinal neurons and (5) the involvement of LC changes in skin sensitivity induced by chemical stimulation of the dura. Our behavioral study reveals that topography (cephalic and / or extracephalic) and nature (static or dynamic) of allodynia induced by chemical stimulation of the dura is under the influence of two factors: intensity and frequency of stimulation, which may lead to its persistence. Our electrophysiological and behavioral studies confirm that the cephalic and extracephalic cutaneous allodynia reflects awareness of trigeminal and spinal neurons, respectively, which may become persistent. Propranolol permits to prevent changes in cutaneous allodynia, and trigeminal and spinal sensitization. We also observed the awareness of two brainstem structures: the PAG and LC which result in a persistent alteration of DNIC. However propranolol appears to prevent the alteration of these phenomena via inhibition of a single structure LC and not the PAG. Indeed, our microinjection of propranolol in the LC can prevent any changes induced by chemical stimulation of the dura. In conclusion these results suggest that the frequency and intensity of migraine attacks are two endogenous risk factors of migraine transformation. A marker of transformation is allodynia, which is the clinical expression of central sensitization of the dorsal horn neurons. This central sensitization is due to the direct arrival of information from the dura but also to an alteration of neuronal activity in LC. Based on these findings, one can suggest that patients with frequent and/or severe migraine attacks take as early as possible a migraine prophylactic treatment. This treatment should prevent the cumulative adverse functional consequences on the central nervous system of the activation of dural nociceptors

Propranolol (PROP) is a β-blocker prescribed mainly to treat human cardiac diseases but with its wide usage it often makes its way into the aquatic environment. This study examined whether PROP alters developmental patterns and catecholamine (CA)-regulated processes in the zebrafish (Danio rerio) and if exposure during early life alters the stress response and behaviors of adults. The 48 h LC50 was 21.6 mg/L, well above environmental levels (0.00059 mg/L). Embryos/larvae continuously PROP-exposed had decreased and increased transcript levels of the β1-adrenoceptor at 1 dpf and 5 dpf, respectively. Stressed, PROP-exposed zebrafish had reduced testosterone and estradiol levels and exhibited less anxiety behaviours than control fish. Furthermore, adults previously PROP-exposed as embryos/larvae had decreased growth in terms of body length (0.0006 mg/L PROP) and mass (20 mg/L PROP). Changes in cholesterol and testosterone levels occurred in PROP-exposed fish. Thus PROP-exposure alters developmental patterns and CA-regulated process that are essential for normal behaviours and responses to stress, and at least some of these changes persist in the adult zebrafish.

Orientador: Aparecido Antonio Camacho
Resumo: O uso de betabloqueadores tem mostrado implicações significativas na terapia de neoplasias através do bloqueio de adrenoreceptores em tecidos tumorais. O sistema nervoso autônomo simpático apresenta um perfil pró-inflamatório e por estímulo das catecolaminas ocorre à ativação de macrófagos teciduais com liberação de citocinas inflamatórias. Estudos recentes sugerem que estímulos inflamatórios crônicos podem acelerar a progressão do câncer, fato este relacionado à ativação do sistema beta adrenérgico. Assim, o objetivo do presente estudo foi avaliar a influência do emprego do propranolol sobre a evolução macroscópica dos nódulos mamários assim como a monitoração da função cardíaca. O estudo foi prospectivo, randomizado e longitudinal. Para tanto, 06 cadelas portadoras de tumores de mama (G1) receberam cloridrato de propranolol (0.2 mg/kg/BID, VO, 30 dias) e, outras 08 cadelas também com neoplasia mamária (G0) receberam apenas medicação placebo (BID, VO, 30 dias). Foram realizados exames ecocardiográfico, eletrocardiográficos convencional e Holter, paquimetria tumoral e exame histopatológico. A análise estatística foi baseada em um estudo experimental, cujos resultados foram submetidos à análise de variância (ANOVA) com medidas repetidas no tempo e em seguida Teste de Tukey. O uso do fármaco mostrou segurança sobre os parâmetros cardíacos avaliados e controle sobre o crescimento tumoral quando comparado com o grupo placebo.
Abstract: The use of beta-blockers has shown significant implications in the therapy of neoplasias through the blockade of adrenoreceptors in tumor tissues. The autonomic sympathetic nervous system presents a pro-inflammatory profile and by stimulating the catecholamines occurs to the activation of tissue macrophages with the release of inflammatory cytokines. Recent studies suggest that chronic inflammatory stimuli may accelerate the progression of cancer, a fact related to activation of the beta adrenergic system. Thus, the objective of the present study was to evaluate the influence of the use of propranolol on the macroscopic evolution of the mammary nodes as well as the monitoring of the cardiac function. The study was prospective, randomized, and longitudinal. For this, 06 bitches bearing breast tumors (G1) received propranolol hydrochloride (0.2 mg / kg / BID, VO, 30 days) and another 08 female mammary glanders (G0) received only placebo medication (BID, VO , 30 days). Echocardiographic, conventional electrocardiographic and Holter tests, tumor pachymetry and histopathological examination were performed. The statistical analysis was based on an experimental study, whose results were submitted to analysis of variance (ANOVA) with measures repeated in time and then Tukey's test. The use of the drug showed safety over the evaluated cardiac parameters and control over tumor growth when compared to the placebo group.
Mestre

A saúde do meio ambiente vem sendo comprometida devido ao descarte incorreto de produtos e seus subprodutos. Dentre os contaminantes emergentes encontram-se os fármacos, causadores de problemas ambientais por serem descartados no meio ambiente através dos efluentes. As técnicas convencionais de tratamento são insuficientes na remoção de diversos fármacos, por apresentarem resíduos resistentes e baixa biodegradabilidade. Sendo assim os processos oxidativos avançados vêm sendo estudados como alternativa para o tratamento de diferentes tipos de efluentes. O objetivo desse trabalho foi aplicar o processo de irradiação com feixe de elétrons para reduzir os efeitos tóxicos do propranolol, e de sua mistura com cloridrato de fluoxetina, em solução aquosa. Foram realizados ensaios ecotoxicológicos com o fármaco propranolol, e de sua mistura com o cloridrato de fluoxetina, utilizando como organismos-teste o microcrustáceo Daphnia similis, e a bactéria Vibrio fischeri. Observamos que o organismo D. similis mostrou-se mais sensível as amostras de fármacos quando comparado à bactéria V.fischeri. Após serem submetidas ao tratamento com radiação ionizante, todas as doses aplicadas para o propranolol e a mistura, mostraram significativa redução de toxicidade, tendo como organismo-teste D. similis. Para a bactéria V. fischeri apenas na dose de 5,0 kGy foi verificada a redução da toxicidade para o fármaco propranolol. Quanto à mistura dos fármacos, apenas as doses de 2,5 e 5,0 kGy apresentaram eficiência de remoção da toxicidade. A dose 5,0 kGy mostrou-se a melhor, apresentando redução de 79,94% para D. similis, e 15,64% para V. fischeri, quando expostas ao fármaco propranolol. Quanto à mistura, apresentou 81,59% e 26,93%, para D.similis e V.fischeri, respectivamente.
Environmental health has been damage due to incorrect disposal of products and by-products. Among emerging pollutants it is possible to account with several pharmaceuticals, causing those problems when disposed in the environment by effluents. Conventional processing techniques are insufficient in removal of the pharmaceuticals, for having resistant waste and low biodegradability. Thus the advanced oxidation processes have been studied as an alternative for the treatment of different types of effluents. The objective of this study was to apply the process of irradiation with electron beam in order to reduce the toxic effects of propranolol, and the mixture with fluoxetine hydrochloride in aqueous solution. Ecotoxicological tests conducted with propranolol, and the mixture with fluoxetine hydrochloride, for Daphnia similis microcrustacean, and the Vibrio fischeri bacterium. It was observed that D. similis was more sensitive to propranolol drug and to the mixture, when compared to bacterium V.fischeri. After being subjected to the treatment with ionizing radiation, all applied doses to the propranolol and the mixture, showed significant reduction of toxicity, for D. similis. Different were the results for V. fischeri, when only 5.0 kGy reduced toxicity to propranolol. The mixture of pharmaceuticals required 2.5 and 5.0 kGy for reducing toxicity. 5.0 kGy showed the best removal efficiency for toxicity: 79.94 % for D. similis and 15.64 % for V. fischeri, when exposed to propranolol. The mixture reduction eficacy were 81.59 % and 26.93 % for D.similis and V.fischeri, respectively.

Class of 2007 Abstract
Objectives: To compare the cost-effectiveness of amitriptyline, divalproex, propranolol, and topiramate in the prophylactic treatment of migraine headaches based on published data. Methods: A MEDLINE search was done to identify all randomized, controlled clinical trials evaluating the efficacy of amitriptyline, divalproex, propranolol, and topiramate in the prophylactic treatment of migraine headaches. Results from these studies were then combined with drug cost and health care service costs related to treatment failure and adverse events to assess the relative cost-effectiveness of each medication. A decision tree model was created and Monte Carlo simulation was done to determine each products cost-effectiveness. Results: Amitriptyline was both most effective and least costly of the four treatment regimens studied. The mean costs for a 90 day treatment of each of the four respective medications were found to be: amitriptyline $62, divalproex $450, propranolol $91, and topiramate $802. An acceptability curve demonstrated that amitriptyline was most cost-effective 90% of the time, propranolol 10% of the time, and divalproex and topiramate were never the most cost-effective treatment. Conclusions: Among the most common medications used for migraine prophylaxis are amitriptyline, divalproex, propranolol, and topiramate. Based upon this analysis, amitriptyline was found to be the most cost-effective medication. Therefore, it is logical from the perspective of a managed-care organization to recommend amitriptyline as a first-line agent for migraine prophylaxis.

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A migrânea é uma cefaléia primária comum, sendo a queixa mais freqüente nos serviços de atendimento em Neurologia. A fisiopatologia da migrânea ainda não foi completamente elucidada e as principais estruturas envolvidas podem ser o sistema trigeminovascular, fibras autonômicas e os vários agentes vasoativos locais. Aspectos peculiares do óxido nítrico (NO) e a presença da sintase do óxido nítrico (NOS) tanto a nível periférico (endotélio, fibras nervosas ao redor dos grandes vasos cerebrais e dura-máter), como no tronco cerebral e áreas hipotalâmicas, tornam esse composto um bom candidato a mediador dos mecanismos das crises de cefaléias vasculares, especialmente a migrânea. O NO provavelmente participa da inflamação neurogênica e da ativação das fibras perivasculares que conduzem os impulsos nociceptivos para o gânglio trigeminal. Terapias com estatinas melhoram a viabilidade do NO e possuem propriedades antiinflamatórias. O presente estudo é um ensaio clínico, aberto, prospectivo e comparativo, cujos objetivos foram avaliar a ação preventiva do propranolol, amitriptilina ou sinvastatina no controle dos ataques de migrânea; e correlacionar a produção plasmática de NO com a redução do índice de cefaléia (obtido através do cálculo do produto da freqüência de crises por mês X duração da dor em horas X intensidade da dor). Um total de 357 pacientes com diagnóstico de migrânea participou do estudo no período de novembro de 2004 a março de 2006. As pacientes receberam propranolol, amitriptilina ou sinvastatina por três meses e amostras de sangue foram coletadas para a determinação plasmática do NO. Em relação ao índice de cefaléia e número de dias com migrânea, as pacientes que usaram propranolol (60 mg; 80 mg; 120 mg), amitriptilina (12,5 mg; 25 mg; 50 mg) ou sinvastatina (10 mg; 20 mg; 40 mg) apresentaram redução significativa desde o segundo mês de tratamento (p<0,001), com exceção das usuárias de amitriptilina, que apresentaram redução a partir do primeiro mês (p<0,001). Aumento significativo no nitrato plasmático (p<0,001) foi detectado nas pacientes com dor (31 ± 1 μM, n=357) quando comparadas no período sem dor (28 ± 1μM, n=357). A redução ≥50% no número de dias com migrânea ao final do terceiro mês foi significativa para os três tratamentos instituídos, porém não houve diferença na eficácia entre os mesmos. Os nitratos plasmáticos analisados na fase livre de migrânea diminuiram significativamente entre as avaliações no controle e no terceiro mês, para as pacientes tratadas com propranolol 60 mg/dia (28,1 ± 1,0 vs 20,3 ± 1,0 μM, p<0,01), 80 mg/dia (28,1 ± 1,0 vs 22,3 ±1,2 μM, p<0,05) e 120 mg/dia (28,1 ± 1,0 vs, 21,5 ± 1,5 μM, p<0,01); para as pacientes que utilizaram a amitriptilina 12,5 mg/dia (30,1 ± 1,7 vs 22,3 ± 1,2 μM, p<0,05), 25 mg/dia (30,1 ± 1,7 vs 23,0 ± 1,3 μM, p<0,05) e 50 mg/dia (30,1 ± 1,7 vs 21,3 ± 1,0 μM; p<0,01); e para as migranosas tratadas com sinvastatina 10mg/dia (24,82 ± 1,0 vs 16,5 ± 1,0 μM, p<0,01), 20 mg/dia (24,82 ± 1,0 vs 19,9 ±1,0 μM, p<0,05) e 40 mg/dia (24,82 ± 1,0 vs 20,0 ±1,0 μM, p<0,05). Concluimos que a sinvastatina foi eficaz como medicação profilática na migrânea, assim como o propranolol e a amitriptilina e a redução no índice de cefaléia ocorreu paralelamente com a diminuição da produção do NO

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
The presence of drug residues has been found in aquatic environments, such as; lakes and rivers and in most cases this type contaminant is found in sewers. This type of pharmaceutical waste may contain an antihypertensive drug class, and one of its main representatives is propranolol (PRO). As a result, this study aimed to apply the advanced oxidation processes (AOPs) as an alternative to removal of this drug in synthetic effluent (SE) and real (RE). This study employed in a photochemical reactor, homogeneous systems of type photolysis, UV/H2O2, Fenton, photo-Fenton, like that TiO2 and ZnO as methods based on heterogeneous catalysis. The parameters for optimization of these methods were evaluated with the assistance of full factorial design. The evaluation of the optimal methods was performed based on the values of the rate of degradation, chemical oxygen demand (COD) and the germination index (GI). The results of better rate degradation (98,3 and 88.6%), reduction of COD (47 and 29.4%) and germination rate (62,2 and 47.2%), were achieved employing a UVC lamp 60W in the method photo-Fenton with a H2O2 concentration of 6 mmol L-1 and a Fe2+ concentration of 0.2 mmol L-1 for the synthetic and real effluent.
ambientes aquáticos, tais como; lagos e rios, e na maioria dos casos esse tipo de contaminante é encontrado em esgotos. Este tipo de efluentes das indústrias farmacêuticas pode conter uma classe de fármaco antihipertensivos, e um de seus principais representantes é o propranolol (PRO). Em vista disso, o presente trabalho visou aplicar processos oxidativos avançados (POAs) como alternativa na remoção desse fármaco em efluente sintético (ES) e real (ER). Nesse estudo foram empregados, em um reator fotoquímico, sistemas homogêneos do tipo fotólise, UV/H2O2, Fenton, foto-Fenton, bem como TiO2 e ZnO, como semicondutores para a catálise heterogênea. Os parâmetros para otimização desses métodos foram avaliados com o auxílio de planejamentos fatoriais completos. A avaliação dos métodos otimizados foi realizada com base nos valores da taxa de degradação, DQO e índice de germinação. Os melhores resultados de taxa de degradação (98,3 e 88,6%), redução de DQO (47 e 29,4%) e índice de germinação (62,2 e 47,0%) foram alcançados com o método foto-Fenton empregando lâmpada UVC com 60W de potência, concentração de H2O2 4 mmolL-1 e concentração de Fe2+ 0,12 mmolL-1, para o efluente sintético e real.

L’objectif de cette étude était d’examiner chez la rate les effets osseux d’un agoniste et d‘un antagoniste b adrénergiques utilisés respectivement dans le milieu du dopage et médical. Deux niveaux d’études ont été établis : (1) effet d’une dose dopante de salbutamol chez des rates soumises ou non à un protocole d’entraînement et (2) effet préventif du propranolol couplé ou non à un exercice physique chez des rates ovariectomisées. Ces études ont comporté une analyse qui va de la microarchitecture aux propriétés biomécaniques de l’os trabéculaire et cortical en passant par une analyse du métabolisme osseux. Un effet délétère du salbutamol a été noté sur la densité, la microarchitecture trabéculaire, l‘épaisseur et la porosité corticales que les animaux soient sédentaires ou entraînés. La répercussion majeure est une altération des propriétés biomécaniques extrinsèques et intrinsèques du tissu osseux. L’analyse du propranolol a permis de mettre en avant un effet dose avec une efficacité préventive de l’ostéopénie plus grande avec une dose faible de 0. 1mg/kg. De plus malgré une absence d’effet synergique du propranolol et de l’exercice physique sur la structure corticale, un effet synergique a été mis en évidence sur les propriétés biomécaniques intrinsèques du tissu osseux. Ces études soulignent l’importance du système nerveux sympathique dans la régulation de l’os et laissent discerner une possible implication thérapeutique dans l'ostéoporose.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em Farmacologia.
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Experiências de medo podem estabelecer memórias emocionais que resultam em mudanças comportamentais. Muitos neurotransmissores parecem estar envolvidos com a aquisição, consolidação e expressão do medo e de suas respostas defensivas. O condicionamento de medo Pavloviano tem sido amplamente utilizado para o estudo das bases neuroanatômicas, celulares e moleculares do medo. Este paradigma é fundamentado na associação entre um estímulo emocionalmente neutro e um estímulo incondicionado aversivo (EI). Após um ou alguns pareamentos, o estímulo condicionado (EC), que inicialmente era neutro, adquire a capacidade de gerar respostas defensivas que tipicamente ocorrem na presença de perigo. Em roedores, as respostas condicionadas parecem ocorrer de forma mais pronunciada frente a estímulos olfatórios, uma vez que a olfação é o principal sentido destes animais. O objetivo principal do presente estudo foi avaliar o efeito do midazolam, do propranolol e da escopolamina sobre as etapas de aquisição, consolidação e expressão da memória de medo utilizando o odor de café como estímulo olfatório no modelo de condicionamento de medo. Para este propósito, foi realizada inicialmente a padronização do modelo dentro das condições experimentais do laboratório. Em seguida, foi avaliado o papel da neurotransmissão GABAérgica, beta-adrenérgica e colinérgica no modelo de condicionamento olfatório de medo. Nestas etapas, foram utilizados um benzodiazepínico, midazolam, um antagonista beta-adrenérgico, propranolol e um antagonista muscarínico, escopolamina, todos com ações farmacológicas centrais. Os resultados demonstraram que a utilização de cinco associações entre o odor de café (EC) e o choque elétrico nas patas (EI) promoveu a expressão de uma robusta resposta condicionada de medo quando os animais foram reapresentados ao estímulo condicionado e ao ambiente onde ocorreu esta re-exposição. A aquisição do medo condicionado olfatório foi prejudicada pela administração de midazolam e escopolamina, ao passo que, a consolidação da memória de medo foi atenuada apenas pelo midazolam. As respostas defensivas frente ao odor de café condicionado e ao contexto foram expressivamente reduzidas quando a escopolamina foi administrada antes da re-exposição ao estímulo olfatório. A administração de propranolol atenuou o padrão comportamental defensivo frente ao odor de café condicionado e ao contexto, prejudicando as etapas de formação e expressão do medo condicionado com pista olfatória e a formação do medo condicionado contextual. A fearful experience can establish an emotional memory that results in behavioral changes. Several neurotransmitters seem to be involved in acquisition, consolidation and expression of fear and related defensive responses. Pavlovian fear conditioning has been widely used to study the anatomical, cellular and molecular bases of fear. Fear conditioning occurs when an emotionally neutral stimulus is presented in conjunction with an aversive unconditioned stimulus (US). After one or several pairings, the conditioned stimulus (CS), previously neutral, acquires the capacity to elicit responses that typically occur in the presence of danger. In rodents, conditioned responses are more pronounced toward olfactory stimulus, since olfaction is a dominant sense in these animals. The aim of the present study is to evaluate the effects of midazolam, propranolol and scopolamine in acquisition, consolidation and expression of fear memory using coffee odor as an olfactory stimulus in the conditioning fear model. For this purpose, the standardization of the olfactory fear conditioning was realized in accordance to the experimental conditions of the laboratory. Next, the role of GABAergic, beta-adrenergic and cholinergic system in olfactory fear conditioning was evaluated. In order to examine the effects of these neurotransmission systems, rats were given midazolam, a benzodiazepine, propranolol, a beta-blocker and scopolamine, a cholinergic antagonist, all drugs with action in central nervous system. It was found that five pairings of coffee odor and footshock resulted in robust conditioned responses to subsequent presentation of CS alone and to the context where this exposition took place. The acquisition of olfactory fear conditioning was impaired by midazolam and scopolamine administration, while the consolidation of fear memory was disrupted only by midazolam. Defensive responses toward conditioned coffee odor and context were strongly reduced when scopolamine was injected before the re-exposition to the olfactory stimulus. Propranolol reduced defensive behaviors toward conditioned coffee odor and context, producing impairment in the acquisition, consolidation and expression of fear conditioning paradigm with olfactory cue.

In this work calibration multivariate models were developed with the use of the technique of partial least scores (PLS) for the dosage of tablets of propranolol hydrochloride using infrared spectroscopy. Samples were ground and homogenized in cryogenic mill in order to have all the samples in the same conditions in relation to the particle size and to avoid problems related to the samples heterogeneity. Sample masses of 45.0 ± 2.0 mg of tablets were used and the concentration of reference tablets were between 0.1 and 0.45 mg of propranolol hydrochloride for mg of tablet. Eighteen calibration samples and 8 validation samples were used, for which were obtained spectra in 5 replicatas. The 3 more similar replicates were chosen by the analysis of HCA. The pre-processing and used pre-treatments were: autoscaling of the data, multiplicative scatter correction and first and second derivatives. Five models were obtained with good capacity of prediction of the concentrations of propranolol hydrochloride in the tablets. These models presented the coefficient of linear correlation higher than 0.92 and the root mean standard error of cross validation (RMSECV) smaller than 0.020. By the ANOVA test was verified that there was not significant difference between the models with a confidence level of 95%. The proposed procedure was fast, cheap, allowing good accuracy and it can be easily adapted to the quality control of the pharmaceutical industry. In addition, the proposed methodology doesn't generate dangerous chemical residues, because it is a technique non destructive and it doesn't use solvents for your application.
Neste trabalho foram desenvolvidos modelos de calibração multivariada com o uso da técnica dos mínimos quadadros parciais (PLS) para o doseamento de comprimidos de cloridrato de propranolol utilizando espectroscopia no infravermelho. As amostras foram moídas e homogeneizadas em moinho criogênico a fim de ter-se todas as amostras nas mesmas condições em relação a granulometria e evitar problemas de heterogeneidade das amostras. Foram utilizadas massas de amostra de 45,0 ± 2,0 mg de comprimidos e a concentração dos padrões ficou entre 0,1 e 0,45 mg de cloridrato de propranolol por mg de comprimido. Foram utilizadas 18 amostras de calibração e 8 amostras de validação, para as quais foram obtidos espectros em 5 replicatas. Fez-se a escolha de 3 replicatas mais semelhantes pela análise de HCA. Os pré-processamentos e pré-tratamentos utilizados foram: autoescalamento dos dados, correção de espalhamento de luz (MSC, do inglês, multiplicative scatter correction) e primeira e segunda derivadas. Após os testes realizados, foram obtidos 5 modelos com boa capacidade de predição das concentrações de cloridrato de propranolol nos comprimidos. Estes modelos apresentaram os coeficientes de correlação linear maiores que 0,92 e erro quadrático padrão de validação cruzada (RMSECV) menor que 0,020. Realizou-se o teste de ANOVA e verificou-se que não havia diferença significativa entre os modelos com um grau de confiança de 95%. A metodologia proposta mostrou-se rápida, barata, exata e pode ser facilmente adaptada ao controle de qualidade da indústria farmacêutica. Ademais, a metodologia proposta não gera resíduos químicos perigosos, pois é um técnica não destrutiva e não utiliza solventes para sua realização.