Mirtazapine is an atypical antidepressant employed clinically for the treatment of major depression. As a multipotent antagonist it acts at α2a-adrenergic receptors (α2a -ARs). serotonin type-2A receptors (5-HT2a-Rs) and histamine type-I receptors (H1-Rs). Its actions at the α2a-AR have been proposed to play a role in its putative earlier onset of action. However, it is not known whether mirtazapine is a neutral antagonist or inverse agonist at α2a- ARs. The current study aimed to determine the mode of α2a-AR antagonism by mirtazapine, as well as to investigate in vitro the modulatory effects of mirtazapine pre-treatments on β-adrenergic receptor (β-AR), muscarinic acetylcholine receptor (mAChR) and α2a-AR functions. Chinese hamster ovary (CHO-K1) cells expressing the porcine α2a-AR at high numbers (α2a-H), a constitutively active mutant α2a-AR (α2a--CAM), or mock-transfected control cells (neo) were radio-labelled with [3H]-adenine and concentration-effect curves of mirtazapine, yohimbine, mianserin or idazoxan were constructed, measuring [3H]-cAMP accumulation. In addition human neuroblastoma SH-SY5Y cells and CHO-K1 cells expressing the porcine α2a- AR at low numbers (am-L) were used to investigate the effect of mirtazapine pre-treatments on mAChRs and β-ARS or α2a-ARs respectively. After radio-labelling with myo-[2-3H]-inositol or [2-%]-adenine, radio-label uptake was measured and receptor function was investigated by constructing concentration-effect curves, measuring [3H]-IPx or [3H]-cAMP accumulation respectively. The results from the current study show that mirtazapine binds to the α2a-AR with an affinity value in the lower micromolar range (K1≈ 0.32 µM; pK1 = 6.50 ± 0.07). Mirtazapine is not a partial agonist at α2a-ARs as it does not affect [3H]-cAMP accumulation in α2a-H cells. Preliminary results suggest that mirtazapine displays partial inverse agonism in α2a-CAM cells, while mianserin displays neutral antagonism. Mirtazapine pre-treatment in SH-SY5Y cells does not alter muscarinic receptor function (different from fluoxetine and imipramine), but reduces I-isoproterenol-induced increase in [3H]-cAMP accumulation in SH-SY5Y cells (typically associated with chronic antidepressant activity). Although inconclusive, the data also suggests that mirtazapine may reduce α2a-AR function. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

In the present study alpha-receptor modulation of coronary flow and cardiac function was examined in exercising dogs, chronically instrumented to measure: circumflex blood flow velocity (CFV), heart rate (HR), global left ventricular function (LVP and dP/dt Max) and regional left ventricular function (%SL and dL/dt (s)max). During exercise, local adrenergic blockade was produced by intracoronary injection of 1.0 mg phentolamine ( anon-specific alpha-antagonist) or .5 mp prazosin. Exercise significantly increased HR, LVP, dP/dt max, CFV, %SL and dL/dt (s)max. Neither alpha-antagonist produced changes in HR, LVP or %SL; however, both phentolamine and prazosin produced significant increses in dP/dtmax, CFV and dL/dt(s)max of the alpha-blocked region, when compared to their exercise level before alpha-blockade. It is suggested that an alpha1-adrenergic vasoconstriction limits coronary vasodilation and, thereby, cardiac function during exercise.

No / A sensitive and rapid high performance liquid chromatography method has been developed and used for the simultaneous determination of formoterol and budesonide in Symbicort Turbuhaler when assessing the aerodynamic characteristics of the emitted dose using Pharmacopoeial methods. This capability results in both time and cost saving. The mobile phase composition was acetonitrile-5 mM sodium dihydrogen orthophosphate, pH 3 (60: 40% v/v), and was passed at 1.5 ml min-1 through a C18 column with a UV detection (wavelength 214 nm). The method was shown to give good analytical performance in terms of linearity, precision (using phenylpropanolamine as an internal standard), sensitivity and solution stability. The intra-day precision for both formoterol and budesonide were 0.75% and 1.11%, respectively (n = 10). The limit of quantitation for formoterol was 10 ¿g L-1 and for budesonide was 120 ¿g L-1, and the limit of detection were 3 and 30 ¿g L-1, for both formoterol and budesonide, respectively. The method has been applied to determine the content of the emitted dose and the fine particle dose of Symbicort Turbuhaler.

An experiment was conducted using forty-one Bonsmara steers (age ± 7 months) to determine the effect of zilpaterol hydrochloride (ZH) on the growth performance and carcass characteristics. The trial was structured using a completely randomized design with two treatments, control and ZH group. The steers were fed ZH for 28 consecutive days at the end of the finishing period and ZH was withdrawn from the diet 2 days prior to slaughter of the animals. The steers were placed in individual pens and weighed fortnightly throughout the 4 months trial. Zilpaterol hydrochloride (ZH) was included in the diet at a rate of 8.3 mg/kg of DM. Feeding of ZH increased (P< 0.05) body weight (BW) gain and ADG (1.102 vs. 1.444) and tended to increase (P = 0.067) feed efficiency (F:G) during the last month of the finishing period. There were no significant differences (P> 0.05) in daily dry matter intakes (DMI). For the control group, high treatment weight gains were significantly associated with high initial weight (r = 0.424, P = 0.049) and also high pre-treatment body weight (r = 0.678, P= 0.001). Treatment weight gain increased as the initial and pre-treatment weight gain increased in the control group. For the steers that were fed ZH, there was no significant correlation between the treatment body weight gain with initial weight (r = 0.097, P = 0.694) and also pre- treatment live weight (r = 0.393, P = 0.096). Supplementation of ZH significantly increased (P < 0.0001) the dressing percentage (56.4% vs. 58.4%) and had no significant (P>0.05) effect on the carcass weight. The outcome of the study suggest that supplementation of ZH in the diet during the last month of the finishing period enhances growth performance and shows the repartitioning capacity of the feed additive as a beta- agonist. / Agriculture and  Animal Health / M. Sc. (Agriculture (Animal Science)

An experiment was conducted using forty-one Bonsmara steers (age ± 7 months) to determine the effect of zilpaterol hydrochloride (ZH) on the growth performance and carcass characteristics. The trial was structured using a completely randomized design with two treatments, control and ZH group. The steers were fed ZH for 28 consecutive days at the end of the finishing period and ZH was withdrawn from the diet 2 days prior to slaughter of the animals. The steers were placed in individual pens and weighed fortnightly throughout the 4 months trial. Zilpaterol hydrochloride (ZH) was included in the diet at a rate of 8.3 mg/kg of DM. Feeding of ZH increased (P< 0.05) body weight (BW) gain and ADG (1.102 vs. 1.444) and tended to increase (P = 0.067) feed efficiency (F:G) during the last month of the finishing period. There were no significant differences (P> 0.05) in daily dry matter intakes (DMI). For the control group, high treatment weight gains were significantly associated with high initial weight (r = 0.424, P = 0.049) and also high pre-treatment body weight (r = 0.678, P= 0.001). Treatment weight gain increased as the initial and pre-treatment weight gain increased in the control group. For the steers that were fed ZH, there was no significant correlation between the treatment body weight gain with initial weight (r = 0.097, P = 0.694) and also pre- treatment live weight (r = 0.393, P = 0.096). Supplementation of ZH significantly increased (P < 0.0001) the dressing percentage (56.4% vs. 58.4%) and had no significant (P>0.05) effect on the carcass weight. The outcome of the study suggest that supplementation of ZH in the diet during the last month of the finishing period enhances growth performance and shows the repartitioning capacity of the feed additive as a beta- agonist. / Agriculture and  Animal Health / M. Sc. (Agriculture (Animal Science)

Whereas first line therapy for chronic obstructive pulmonary disease (COPD) usually includes a short-acting bronchodilator, there are suggestions that these agents may increase the risk of cardiac arrhythmias. In this thesis, we first assessed the risks associated with short-acting beta-agonists (SABA), long-acting beta-agonists (LABA), ipratropium bromide (IB), and methyl xanthines (MX) within a cohort of COPD patients using the health databases of Saskatchewan. In order to confirm these findings and to address some methodological issues we then replicated this analysis within a larger cohort of patients using the health databases of Quebec. / Our first study cohort consisted of 6,018 adults aged 55 and older, newly treated with bronchodilator medications. We found that new users of both IB and LABA increased the risk of arrhythmia (RR 2.39 [95% CI 1.42-4.05] and (RR 4.55 [95% CI 1.43-14.45] respectively). When the cohort was restricted by excluding subjects who had recently either been hospitalised or experienced an exacerbation, the elevated risk associated with the new use of IB persisted (RR 3.65 [95% CI 1.72-7.74]), an effect was detected with new use of MX (RR 5.17 [95% CI 1.38-19.30]), but there was insufficient power to detect an effect associated with the new use of LABA. / Due to both power issues and the limited availability of LABA within the Saskatchewan data, we replicated the analysis in a larger new-user cohort of 76,661 Quebec adults aged 67 and over. This study confirmed our earlier results, with an elevated risk of arrhythmia associated with the new use of both IB and LABA (RR 1.43 [95% CI 1.08-1.88]) and (RR 1.54 [95% CI 1.00-2.36]) respectively, as well as with new use of SABA (RR 1.28 [95% CI 1.02-1.61]). Finally, using marginal structural models, we demonstrated that both exacerbations of COPD as well as minor non-event arrhythmias were moderate time-dependent confounders within this setting. / In conclusion, we found that new use of bronchodilators in COPD, particularly IB and LABA, was associated with an increase in the risk of cardiac arrhythmias. We also demonstrated the method by which the time-dependent confounder status of specific model covariates may be evaluated.

Orientador: Cláudia Herrera Tambeli / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-24T16:27:32Z (GMT). No. of bitstreams: 1 Favaro-Moreira_NadiaCristina_D.pdf: 14440949 bytes, checksum: 19ac7e9f7196c13dfd756bd4150b1456 (MD5) Previous issue date: 2014 / Resumo: Disfunção temporomandibular (DTM) é um termo coletivo que abrange uma série de problemas clínicos que envolvem os músculos mastigatórios e a articulação temporomandibular (ATM) e está comumente associada à inflamação. Apesar de medicamentos anti-inflamatórios não esteróides (AINEs) serem frequentemente utilizados no controle de dor inflamatória, sabe-se que a dor inflamatória possui um componente simpático que pode predominar em casos menos responsivos a tratamentos com AINEs. Portanto, os objetivos deste estudo foram: (i) avaliar se os hormônios gonadais modulam a resposta antinociceptiva ao bloqueio dos ?-adrenoreceptores (ARs) na ATM de ratos, (ii) avaliar se um e três dias de tratamento com o ?-bloqueador não seletivo para AR ?1 e ?2 nadolol reduzem a dor em pacientes com DTM significativamente mais do que o placebo, (iii) avaliar se as mulheres experimentam relativamente maior benefício com o tratamento com nadolol que os homens dependendo do seu estado hormonal, e (iv ) comparar o efeito do nadolol com o efeito do ibuprofeno. O primeiro objetivo foi desenvolvido em ratos machos e fêmeas, intactos ou gonadectomizados (com ou sem reposição hormonal) através da coadministração de formalina e antagonista específico para AR ?1 , ?2 e ?3 na região da ATM. O comportamento nocieptive foi quantificado e utilizado para a análise estatística. Para o segundo objetivo Nadolol (40 mg/dia), ibuprofeno (400 mg/dia) ou placebo foi administrado em 27 mulheres que não usam contraceptivo oral (CO), 28 mulheres usando CO e 29 homens, que estavam de acordo com os Critérios Diagnósticos para Pesquisa (Research Diagnostic Chriteria) para DTM. Eles completaram um estudo cruzado, aleatorizado, duplo-cego e com controle placebo. As mulheres participaram durante três meses (durante a fase menstrual e durante a fase peri-ovulatória em mulheres que não usam CO, e durante a fase menstrual e durante a fase de uso do CO em mulheres usando CO), em um total de 6 etapas de análise ( 2 por mês), e homens participaram durante um mês com três etapas de análise com um período de 6 dias entre cada etapa. Cada etapa consistiu de uma avaliação de basal e duas avaliações durante o tratamento, uma no primeiro e o outra no terceiro dia de tratamento. A dor foi avaliada por meio da utilização da escala visual analógica (VAS) e as comparações foram feitas através do pré-tratamento (basal), o primeiro e o terceiro dia de intervenção (pós-tratamento). O bloqueio dos ARs ? reduz significativamente a nocicepção da ATM em ratos machos e fêmeas, mas as fêmeas são mais sensíveis. Os hormônios gonadais reduziram a resposta ao bloqueio de ARs ? na ATM de machos e fêmeas. No estudo em humanos um e três dias de tratamento com nadolol ou ibuprofeno produz uma analgesia em mulheres e homens significativamente maior que placebo, mas as mulheres são mais sensíveis independente do estado hormonal. Em resumo, estes dados demonstram que os hormonios sexuais podem modular o efeito analgésico de bloqueadores de ARs ? dependendo dos níveis séricos dos hormonios gonadais, do subtipo de ARs ? ativado e da dose de droga administrada. A maior eficácia no tratamento da dor em mulheres é clinicamente relevante uma vez que a DTM é mais prevalente e mais severa em mulheres do que em homens / Abstract: Temporomandibular disorder (TMD) is a collective term embracing a number of clinical problems that involve the masticatory muscles, and the temporomandibular joint (TMJ), commonly associated with inflammation. Despite anti-inflammatory drugs (NSAIDs) are frequently used in the control of inflammatory pain, it is well known that inflammatory pain has a sympathetic component that might predominate in the cases less responsive to NSAIDs treatments. Therefore, the aims of this study were: (i) to evaluate whether gonadal hormones modulate the antinociceptive responsiveness to the blockade of ?-adrenoreceptors (ARs) in the TMJ of rats, (ii) to evaluate whether one and three days of treatment with the nonselective ?1 and ?2-AR antagonist nadolol would reduce clinical pain symptoms in TMD patients significantly more than placebo, (iii) to evaluate whether women would experience relatively greater benefit from nadolol than men depending on their hormonal status, and (iv) compared the effect of nadolol with the effect of ibuprofen. The first aim was developed in male and female rats, intact or gonadectomized (with or without hormone replacement), by coadministration of formalin and specific antagonist for ?1, ?2 and ?3-ARs in the TMJ region. The nocieptive behavior was quantified and used for estatistical analysis. For the second aim Nadolol (40 mg/day), ibuprofen (400 mg/day) or placebo was administrated in 27 women not using oral contraceptive (OC), 28 women using OC, and 29 men which met the Research Diagnostic Criteria for TMD. They completed a randomized, crossover, double¿blind, placebo controlled study. Women participated for three months (during menstrual phase and during peri-ovulatory phase in women not using OC, and during menstrual phase and during OC using phase in women using OC) in a total of 6 stages of analysis (2 per month), and men participated for one month whith three stages of analysis and 6 days of wash out. Each stage consisted of a baseline evaluation and two evaluations during treatment, one on the first and the other on the third day of treatment. Clinical pain ratings were obtained by Visual Analog Scale (VAS) and comparisons were made across the pre-treatment (baseline), the first and the third day of intervention (post-treatment). Blockade of ?-ARs significantly reduce the TMJ nociception in male and female rats, but females are more responsive. The gonadal hormones reduce the responsiveness to the blockade of ?-ARs in the TMJ of males and females rats. In the human study one and three days of treatment with nadolol or ibuprofen produces analgesia in TMD women and men significantly more than placebo, but women are more responsive independent of their hormonal status. In summary, these data demonstrate that gonadal hormones can modulate the analgesic effect of ?-ARs blockers depending on the gonadal hormones serum levels, on the ?-ARs activated subtype and on the dose of drug administered. The greater treatment efficacy in women is of clinical relevance since TMD is more prevalent and severe in women than in men / Doutorado / Fisiologia Oral / Doutora em Odontologia

No description available.

No / The electrophoretic mobilities of three beta-blocker drug practolol, timolol and propranolol, have been measured in electrolyte systems with mixed binary and ternary water-methanol-ethanol solvents with acetic acid/sodium acetate as buffer using capillary electrophoresis. The highest mobilities for the analytes studied have been observed in pure aqueous. the lowest values in ethanolic buffers The measured electrophoretic mobilities have been used to evaluate the accuracy of a mathematical model based on a mixture response surface method that expresses the mobility as a function of the solvent composition. Mean percentage error (MPE) has been computed considering experimental and calculated mobilities as an accuracy criterion. The obtained MPE for practolol, timolol and propranolol in the binary mixtures are between 0.9 and 2.6%, in the ternary water-methanol-ethanol solvent system the MPE was about 2.7%. The MPE values resulting from the proposed equation lie within the experimental relative standard deviation values and can he considered as an acceptable error.

No / A novel high-performance liquid chromatography (HPLC) assay for the estimation of formoterol in urine samples was developed and validated. A solid phase extraction (SPE) using Oasis HLB was optimised to isolate formoterol from a urine matrix followed by HPLC with UV detection. This extraction procedure concentrated the final analyte forty times so that UV detection can be used to determine even a low concentration of formoterol in urine samples. The urinary assay was performed in accordance with FDA and ICH regulations for the validation of bioanalytical samples. The samples were injected onto a C18 Spherisorb® (250 mm x 4.6 mm x 5 ¿m) analytical column maintained at 30 °C. The mobile phase consisted of 5 mM of potassium dihydrogen orthophosphate buffer (adjusted to pH 3 with ortho phosphoric acid):acetonitrile (ACN) (70:30, v/v), and the formoterol peak was detected at wavelength 214 nm. The extraction recovery of formoterol from the urine sample was >95%. The calibration curve was linear (r2=0.99) over formoterol concentrations ranging from 1.5 to 25 ng/mL (n=6). The method had an accuracy of >92% and intra and inter-day precision CV% of <3.9% and <2.2%, respectively, at three different concentrations low, medium and high (10, 15, 20 ng/mL). The limit of quantification (LOQ) for formoterol was found to be 1.50 ng/mL. The accuracy and precision at the LOQ level were 95% and %CV <3.7% (n = 10), respectively. The method reported is simple, reliable, precise, and accurate and has the capacity to be used for determination of formoterol in urine samples.