Letteratura scientifica selezionata sul tema "Propranolol"

At present, the issue of creating and introducing into medical practice domestically produced drugs, the quality of man-ufacture of which is established using objective, highly sensitive optical physical and chemical methods, becomes relevant. Objective: to develop a spectrophotometric method for analysis of propranololol in the ointment "Propranozol" made on the basis of "Tizol" gel. Materials and methods. Pharmaceutical substance propranolol, gel "Tizol", soft dosage form "Propranosol" containing 0.5% of beta-adrenoblocker in titanium-containing base were used in the study. The analysis was carried out by spectropho-tometric method in the near ultraviolet region using a domestic device SF-2000. The method was validated according to State Pharmacopoeia of the Russian Federation, XIV edition, General Pharmacopeia Article 1.1.0012.15 "Validation of analytical methods". The developed method was validated according to the following metrological characteristics: specificity, linearity, reliability and precision. Statistical processing of the measurement results was performed according to the requirements of SPh RF XIV edition by methods of modern mathematical statistics (regression analysis), using a personal computer and MSOffice application package. Results. When studying propranolol absorption spectra in the ultraviolet region it was found that spectrophotometric analysis of this compound is rationally performed at a wavelength of 290 nm. The content of propranolol in the soft dosage form, found by the equation of the calibration graph, is within the range of 0.0470-0.0582 g, which corresponds to the allow-able standards of deviation given in the regulatory documentation. Conclusion. During the experimental study optimal conditions were chosen and the method of spectrophotometric quantitative determination of propranololol in the ointment "Propranozol" was developed with the relative error not exceed-ing ± 1.60 %.

This study assesses the therapeutic effect of propranolol on cervical cancer and its mechanism. Propranolol’s effect on cervical cancer was evaluated by MTT, Western blotting, flow cytometry and colony formation. By searching Drug Bank and String, cGMP/PKG signaling might be downstream targets of propranolol for subsequent analysis. Our results found that propranolol could significantly inhibit Hela and SiHA cell vitality and clone formation in a dose dependent manner. Further, Annexin V-PE/7-AAD Apoptosis Detection assay showed that propranolol could increase Hela and SiHA cell apoptosis. Finally, propranolol attenuated the phosphorylation level of VASP at Ser239 which is critical for PKG activation. In conclusion, propranolol suppressed cervical cancer cell proliferation via inhibition of cGMP/PKG signaling, which provides an affordable and effective method for cervical cancer remedy.

We conducted an open‐label study to determine the impact of cytochrome P‐4502D6 (CYP2D6) on propranolol pharmacokinetics and response in 12 healthy men with CYP2D6 extensive metabolizer (EM) phenotype and 3 healthy men with CYP2D6 poor metabolizer (PM) phenotype. Subjects received R,S‐propranolol hydrochloride 80 mg every 8 hours for 16 doses. After the sixteenth dose, blood and urine samples were collected for 24 hours, and serum propranolol and urine metabolite concentrations were determined by chiral high‐performance liquid chromatography. Heart rate response to treadmill exercise was measured serially over 24 hours. Apparent oral clearance of propranolol and partial metabolic clearance values of propranolol to 4‐hydroxypropranolol (HOP), propranolol glucuronide, and naphloxylactic acid (NLA) were estimated. Apparent oral clearance and elimination half‐life of propranolol were not different between EMs and PMs. Partial metabolic clearance of propranolol to HOP was significantly higher and to NLA was significantly lower in EMs than in PMs. No differences in percentage reductions in exercise heart rate were observed between EMs and PMs. The CYP2D6 PM phenotype has no effect on propranolol blood concentrations and does not alter response to propranolol. Our data also suggest that CYP2D6 mediates approximately 65% and 70% of S‐ and R‐propranolol's 4‐hydroxylation, respectively.

It has recently been discovered that propranolol—a beta-blocker traditionally used to treat cardiac arrhythmias and hypertension—might disrupt the formation of the emotionally disturbing memories that typically occur in the wake of traumatic events and consequently prevent the onset of trauma-induced psychological injuries such as Post-traumatic Stress Disorder. One context in which the use of propranolol is generating interest in both the popular and scientific press is sexual violence. Nevertheless, feminists have so far not weighed in on propranolol. I suggest that the time is ripe for a careful feminist analysis of the moral and political implications of propranolol use in the context of sexual violence. In this paper, I map the feminist issues potentially raised by providing propranolol to victims of sexual assault, focusing in particular on the compatibility of propranolol use and availability with an understanding of the social and systematic dimensions of rape's harms. I do not deliver a final verdict on propranolol; in fact, I show that we do not yet have enough information about propranolol's effects to do so. Rather, I provide a feminist framework for evaluating the possibilities and perils opened up by therapeutic memory manipulation in the context of sexual violence against women.

The development of bacterial resistance is an increasing global concern that requires discovering new antibacterial agents and strategies. Bacterial quorum sensing (QS) systems play important roles in controlling bacterial virulence, and their targeting could lead to diminishing bacterial pathogenesis. In this context, targeting QS systems without significant influence on bacterial growth is assumed as a promising strategy to overcome resistance development. This study aimed at evaluating the anti-QS and anti-virulence activities of the β-adrenoreceptor antagonist propranolol at sub-minimal inhibitory concentrations (sub-MIC) against two Gram-negative bacterial models Pseudomonas aeruginosa and Serratia marcescens. The effect of propranolol on the expression of QS-encoding genes was evaluated. Additionally, the affinity of propranolol to QS receptors was virtually attested. The influence of propranolol at sub-MIC on biofilm formation, motility, and production of virulent factors was conducted. The outcomes of the propranolol combination with different antibiotics were assessed. Finally, the in vivo protection assay in mice was performed to assess propranolol’s effect on lessening the bacterial pathogenesis. The current findings emphasized the significant ability of propranolol at sub-MIC to reduce the formation of biofilms, motility, and production of virulence factors. In addition, propranolol at sub-MIC decreased the capacity of tested bacteria to induce pathogenesis in mice. Furthermore, propranolol significantly downregulated the QS-encoding genes and showed significant affinity to QS receptors. Finally, propranolol at sub-MIC synergistically decreased the MICs of different antibiotics against tested bacteria. In conclusion, propranolol might serve as a plausible adjuvant therapy with antibiotics for the treatment of serious bacterial infections after further pharmacological and pharmaceutical studies.

Background: Pharmaceutical scientists are exploring transdermal route for treatment of various systemic diseases nowadays. Transdermal nanocarrier systems show various advantages like bioavailability enhancement of drugs, avoidance of first pass hepatic metabolism, and reduction of dosing frequency of bioactive therapeutic molecules. Objective: The objective of the present research work was to encapsulate Propranolol hydrochloride into oleic acid vesicles and carry out in-vitro and in-vivo evaluation of oleic acid vesicular gel containing Propranolol hydrochloride. Method: Propranol hydrochloride loaded oleic acid vesicles were prepared by exploring thin film hydration method. Developed vesicles were evaluated for morphology, size, zeta potential and polydispersity index (PDI). Thermal behavior of drug loaded vesicles was checked using differential scanning calorimetry (DSC) and depth of skin penetration was determined using confocal laser scanning microscopy (CLSM). Oleic acid vesicles dispersed in Carbopol 934R gel were subjected to in-vivo evaluation in male Sprague Dawley rats through measurement of plasma concentration and tissue distribution of Propranolol hydrochloride. Results: Optimized formulation having oleic acid : Propranol hydrochloride in the ratio 7 : 3 showed highest entrapment (56.1 ± 0.7%), acceptable size (291.3 ± 2.2 nm), the optimum value of PDI (0.219 ± 0.043) and zeta potential (-27.13 ± 0.25 mV). The results of DSC analysis showed effective encapsulation of drug inside the vesicles and CLSM analysis revealed penetration of vesicles upto stratum spinosum layer of skin. The results of in-vivo study revealed capability of vesicular gel to prolong the release of Propranolol hydrochloride upto 24 h with a Cmax value of 83.6 ± 3.0 ng/mL which was higher compared to the marketed tablet of Propranolol hydrochloride [InderalR (40 mg), Abbott India Ltd.] (45.6 ± 3.1 ng/mL). Tissue distribution studies revealed higher percentage of Propranolol hydrochloride in various organs after 24 h of administration of vesicular gel compared to marketed tablet. Conclusion: Developed oleic acid vesicular gel could be effective to reduce dosing frequency and avoid side effects of oral Propranol hydrochloride.

Background: Essential tremor, the world’s most prevalent movement disorder, lacks a clear understanding of its pathophysiology. Propranolol, a non-specific beta-blocker capable of crossing the blood-brain barrier, is a primary choice for essential tremor treatment. While its tremor-reducing effects are generally attributed to peripheral actions, various uses hint at central adrenergic effects. Nevertheless, propranolol’s precise impact on the central nervous system in essential tremor subjects remains unexplored. Methods: In this study, we employed transcranial magnetic stimulation to assess the influence of propranolol on the excitability of the primary motor cortex (M1) in patients with essential tremor, compared to an age- and sex-matched control group. Cortical excitability parameters were measured following placebo and propranolol administration, encompassing resting and active motor thresholds, motor evoked potential characteristics, cortical silent period, and the input/output curve. Results: Distinct effects were observed across the two cortical hemispheres. Essential tremor patients displayed inhibition of the left M1 cortex and heightened excitability in the right M1 cortex four hours after propranolol administration, but not following placebo. Conclusions: These findings suggest potential differential noradrenergic excitatory and inhibitory modulation. However, comprehensive understanding necessitates further investigations, including left-handed participants and more diverse essential tremor subpopulations. This study underscores the need for continued exploration to unravel propranolol’s complex effects on motor cortex excitability in essential tremor.

Pharmacotherapy of portal hypertension in patients with cirrhosis includes beta-blockers, nitrates, somatastain analogues, alpha-blockers like prazocin. These drugs differ widely in their effectiveness, adverse effects and patient compliance. Beta-blockers particularly propranolol are the most commonly used drugs. Of late, carvedilol has been used and found to be superior to propranolol. The present study was aimed at assessing the effect of propranolol, carvedilol, iso-sorbide dinitrate; combination of “propranolol and iso-sorbide-dinitrate” and carvedilol and isosorbide dinitrate” on portal venous pressure in cirrhosis of liver. 40 consecutive patients with cirrhosis were subjected to hepatic venous catheterization. Baseline free and wedged hepatic venous pressures were recorded. Patients were randomly assigned to receive propranolol. 40 mgm PO (n=8); carvedilol 25mg PO (n=8); iso-sorbide dinitrate 20 mg PO (n-8); propranol plus iso-sorbide dinitrate (40 mg and 20 mg) (n=8) and carvedilol plus iso-sorbide dinitrate (25 mg and 20 mg PO) (n=8). Hemodynamic values were repeated 90 minutes after drug administration. All drugs significantly decreased the hepatic venous pressure gradient. Combination of carvedilol and iso-sorbide dinitrate was found to be most effective. The mean ± SD drop in hepatic venous pressure gradient was: propranolol 4.3 ± 1.4 mmHg (27%); Carvedilol 4.4 ± 1.8 mmHg (30%); iso-sorbide dinitrate 2.8 ± 1.4 mmHg (17%); propranolol plus iso-sorbide dinitrate” 5.1 ± 1.0 mmHg (31%) and “Carvedilol plus iso-sorbide dinitrate” 5.5 ± 1.2 mmHg (36%). Conclusion: combination of carvedilol and iso-sorbide dinitrate is the most effective anti-portal hypertensive regimen in patients of cirrhosis. JMS 2013;16(2):80-85

Tumor cell metabolism differs from that of normal cells, conferring tumors with metabolic advantages but affording opportunities for therapeutic intervention. Accordingly, metabolism-targeting therapies have shown promise. However, drugs targeting singular metabolic pathways display limited efficacy, in part due to the tumor’s ability to compensate by using other metabolic pathways to meet energy and growth demands. Thus, it is critical to identify novel combinations of metabolism-targeting drugs to improve therapeutic efficacy in the face of compensatory cellular response mechanisms. Our lab has previously identified that the anti-cancer activity of propranolol, a non-selective beta-blocker, is associated with inhibition of mitochondrial metabolism in head and neck squamous cell carcinoma (HNSCC). In response to propranolol, however, HNSCC exhibits heightened glycolytic activity, which may limit the effectiveness of propranolol as a single agent. Thus, we hypothesized that propranolol’s metabolic effects promote a state of enhanced glucose dependence, and that propranolol together with glycolytic inhibition would provide a highly effective therapeutic combination in HNSCC. Here, we show that glucose deprivation synergizes with propranolol for anti-cancer activity, and that the rational combination of propranolol and dichloroacetate (DCA), a clinically available glycolytic inhibitor, dramatically attenuates tumor cell metabolism and mTOR signaling, inhibits proliferation and colony formation, and induces apoptosis. This therapeutic combination displays efficacy in both human papillomavirus-positive (HPV(+)) and HPV(−) HNSCC cell lines, as well as a recurrent/metastatic model, while leaving normal tonsil epithelial cells relatively unaffected. Importantly, the combination significantly delays tumor growth in vivo with no evidence of toxicity. Additionally, the combination of propranolol and DCA enhances the effects of chemoradiation and sensitizes resistant cells to cisplatin and radiation. This novel therapeutic combination represents a promising treatment strategy which may overcome some of the limitations of targeting individual metabolic pathways in cancer.

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

Propranolol, ((R,S)-1-iso-propylamino-3-(1-naphthoxy)-2-propanol), is a β-adrenergic antagonist and is commercially available as a racemic mixture. Only the S-enantiomer has the desired therapeutic effect. Therefore, many researchers have been working on strategies to obtain S-propranolol with high enantiomeric purity. One approach to carry out the acetylation of (R,S)-Propranolol using Candida antarctica lipase B, CalB. This reaction leads to an enantiomeric purity of 96% at a relatively low conversion rate of 30 %. In our research group, we have been studying this reaction. The CalB active site is composed by the triad catalytic (ASP 187, HIS 224 and SER 105) and oxyanion hole (GLN 106 and THR 40). In a previous work, a QM/MM (Quantum Mechanics / Molecular Mechanics) study was carried out, using a QM region consisting only of the catalytic triad of CalB and (R,S)-propranolol [1]. In the present study, we investigate the effect of expanding the quantum region to include the oxyanion hole and to comprehend the effect of intermolecular hydrogen bonds present between the (R,S)-propranolol and the CalB active site. The electronic structure was analyzed using the Quantum Theory of Atoms In Molecules, QTAIM. Our results show that: 1. the studied reactions are more exothermic with the inclusion of the oxyanion hole than with only the catalytic triad. 2. the intermolecular interactions between (R,S)-propranolol and the CalB active site are dominated by hydrogen bonds (HB). Among those HBs, only one between propranolol and HIS 224, and another one between THR 40 and the carbonyl oxygen of acetylated SER 105 play an important role.

We investigated the effect of the acyl group size in the enantioselectivity of the acylation of propranolol, an amino alcohol used as β-adrenergic blocking agent. We applied a methodology frequently used to model enantioselectivity that is based on the hydrogen bonds present in the tetrahedral intermediate, which occurs in lipase-catalyzed reactions. We sampled the conformations of the tetrahedral intermediate corresponding to the esterification of both enantiomers of propranolol with ethanoyl and butanoyl, employing molecular dynamics simulation together with a quantum mechanics/molecular mechanics approach. We found that the population of these hydrogen bonds provides insight into the mechanism of the reaction. However, they are not conclusive about the role of the acyl group in the enantioselectivity. For both acyl groups, we found that the reaction from the Michaelis complex to the tetrahedral intermediate is more favorable for (R)-propranolol and the reaction from the tetrahedral intermediate to the enzyme/product complex is more favorable for (S)-propranolol.