Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.

Made available in DSpace on 2014-06-11T19:29:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-11-24Bitstream added on 2014-06-13T19:37:58Z : No. of bitstreams: 1 moro_et_me_botfm.pdf: 465770 bytes, checksum: 4a10047a2171b9c6542fe3eba27f15c5 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / Justificativa e Objetivos: o início de ação dos agentes bloqueadores neuromusculares pode ser influenciado por fatores que incluem a distância do músculo ao coração, o fluxo sangüíneo muscular e o débito cardíaco. O propofol pode causar hipotensão arterial, principalmente quando associado a um opióide, o que diminuiria o fluxo sangüíneo muscular e, portanto tem sido citado como um fator responsável pelo aumento do tempo de latência dos bloqueadores neuromusculares. O objetivo deste estudo foi avaliar a eficácia da efedrina na prevenção dos efeitos hipotensores arteriais induzidos pela associação do propofol e do remifentanil, assim como os efeitos sobre o tempo de latência do cisatracúrio. Método: foram selecionados 60 pacientes com idade entre 18 e 52 anos, estado físico ASA I ou II, que seriam submetidos à cirurgia eletiva sob anestesia geral e divididos em 3 grupos, de modo aleatório. A distribuição dos pacientes foi realizada de acordo com a solução empregada durante a indução da anestesia como segue: G I (n=20) - Propofol 1 %; G II (n=20) - Propofol 1% + efedrina 0,5 mg.ml-1 e G III (n=20) - Propofol 1% + efedrina 1,0 mg.ml-1. Após a pré-oxigenação com O2 a 100% em máscara facial, foi administrado remifentanil em infusão contínua, por via venosa (0,5 mg.kg-1.min-1), por 90 segundos. Em seguida foi administrado o propofol 1% (associado ou não à efedrina), com velocidade de infusão igual a 180 ml.h-1, até a perda da resposta ao estímulo auditivo e dos reflexos palpebral e corneano e cisatracúrio na dose de 0,15 mg.kg-1 . Foram registrados os dados demográficos, os sinais vitais (PAS, PAM, PAD, FC e SpO2) e o tempo de latência do cisatracúrio pelo método da aceleromiogarfia (T1< 5% do controle). O nível de significância utilizado foi de 5%. Resultados: os grupos foram homogêneos com relação aos dados demográficos. Houve diminuição... / Justification and Objectives: the beginning of action of neuromuscular blocking agents may be influenced by factors including the distance from the muscle to the heart, muscle blood flow and cardiac output. Propofol may cause systemic hypotension, particularly when associated with an opioid, which would decrease muscle blood flow and, hence, it has been cited as a factor responsible for the increase in the onset time of neuromuscular blocking agents. This study aimed at evaluating the efficacy of ephedrine in the prevention of systemic hypotensive effects induced by the association of propofol and remifentanil as well as the effects on the onset time of cisatracurium. Method: sixty patients were selected. They were 18 to 52 years old, exhibited ASA physical status I or II and would be submitted to elective surgery under general anesthesia. The patients were randomly allocated into three groups. The distribution of patients was carried out according to the solution used during anesthesia induction, as follows: G I (n=20) - 1% propofol; G II (n=20) - 1% propofol + 0.5 mg.ml-1 ephedrine and G III (n=20) - 1% propofol + 1.0 mg.ml-1 ephedrine. Following pre-oxygenation with O2 at 100% by facial mask, remifentanil was administered by venous continuous infusion (0.5 mg.kg-1.min-1) for 90 seconds. Next, 1% propofol was administered (associated with ephedrine or not), at an infusion rate equal to 180 ml.h-1 until the response to auditory stimuli and palpebral and corneal reflexes could not be detected; a dose of 0.15 mg.kg-1 of cisatracurium was also administered. Demographic data, vital signs (SBP, MBP, DBP, HR and SpO2) and the onset time of cisatracurium were recorded by the acceleromiography method (T1< 5% of the control). The level of significance used was of 5%.Results: the groups were homogeneous as regards the demographic data. There was a statistically significant... (Complete abstract click electronic access below)

Orientador: Norma Sueli Pinheiro Módolo / Banca: Eliana M. Ganem / Banca: Angélica de Fátima Assunção Braga / Resumo: Justificativa e Objetivos: o início de ação dos agentes bloqueadores neuromusculares pode ser influenciado por fatores que incluem a distância do músculo ao coração, o fluxo sangüíneo muscular e o débito cardíaco. O propofol pode causar hipotensão arterial, principalmente quando associado a um opióide, o que diminuiria o fluxo sangüíneo muscular e, portanto tem sido citado como um fator responsável pelo aumento do tempo de latência dos bloqueadores neuromusculares. O objetivo deste estudo foi avaliar a eficácia da efedrina na prevenção dos efeitos hipotensores arteriais induzidos pela associação do propofol e do remifentanil, assim como os efeitos sobre o tempo de latência do cisatracúrio. Método: foram selecionados 60 pacientes com idade entre 18 e 52 anos, estado físico ASA I ou II, que seriam submetidos à cirurgia eletiva sob anestesia geral e divididos em 3 grupos, de modo aleatório. A distribuição dos pacientes foi realizada de acordo com a solução empregada durante a indução da anestesia como segue: G I (n=20) - Propofol 1 %; G II (n=20) - Propofol 1% + efedrina 0,5 mg.ml-1 e G III (n=20) - Propofol 1% + efedrina 1,0 mg.ml-1. Após a pré-oxigenação com O2 a 100% em máscara facial, foi administrado remifentanil em infusão contínua, por via venosa (0,5 mg.kg-1.min-1), por 90 segundos. Em seguida foi administrado o propofol 1% (associado ou não à efedrina), com velocidade de infusão igual a 180 ml.h-1, até a perda da resposta ao estímulo auditivo e dos reflexos palpebral e corneano e cisatracúrio na dose de 0,15 mg.kg-1 . Foram registrados os dados demográficos, os sinais vitais (PAS, PAM, PAD, FC e SpO2) e o tempo de latência do cisatracúrio pelo método da aceleromiogarfia (T1< 5% do controle). O nível de significância utilizado foi de 5%. Resultados: os grupos foram homogêneos com relação aos dados demográficos. Houve diminuição... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Justification and Objectives: the beginning of action of neuromuscular blocking agents may be influenced by factors including the distance from the muscle to the heart, muscle blood flow and cardiac output. Propofol may cause systemic hypotension, particularly when associated with an opioid, which would decrease muscle blood flow and, hence, it has been cited as a factor responsible for the increase in the onset time of neuromuscular blocking agents. This study aimed at evaluating the efficacy of ephedrine in the prevention of systemic hypotensive effects induced by the association of propofol and remifentanil as well as the effects on the onset time of cisatracurium. Method: sixty patients were selected. They were 18 to 52 years old, exhibited ASA physical status I or II and would be submitted to elective surgery under general anesthesia. The patients were randomly allocated into three groups. The distribution of patients was carried out according to the solution used during anesthesia induction, as follows: G I (n=20) - 1% propofol; G II (n=20) - 1% propofol + 0.5 mg.ml-1 ephedrine and G III (n=20) - 1% propofol + 1.0 mg.ml-1 ephedrine. Following pre-oxygenation with O2 at 100% by facial mask, remifentanil was administered by venous continuous infusion (0.5 mg.kg-1.min-1) for 90 seconds. Next, 1% propofol was administered (associated with ephedrine or not), at an infusion rate equal to 180 ml.h-1 until the response to auditory stimuli and palpebral and corneal reflexes could not be detected; a dose of 0.15 mg.kg-1 of cisatracurium was also administered. Demographic data, vital signs (SBP, MBP, DBP, HR and SpO2) and the onset time of cisatracurium were recorded by the acceleromiography method (T1< 5% of the control). The level of significance used was of 5%.Results: the groups were homogeneous as regards the demographic data. There was a statistically significant... (Complete abstract click electronic access below) / Mestre

Orientadores: Angelica de Fatima de Assunção Braga, Franklin Sarmento da Silva Braga / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-12T22:04:04Z (GMT). No. of bitstreams: 1 Carvalho_VanessaHenriques_M.pdf: 2016873 bytes, checksum: ed79870ad9763d6497595ceb7fdcf4ba (MD5) Previous issue date: 2009 / Resumo: Os anestésicos locais podem interagir com os bloqueadores neuromusculares e modificar as suas propriedades farmacocinéticas e farmacodinâmicas, no entanto o mecanismo dessa interação é controverso. Este estudo experimental, realizado em preparação nervo frênico - diafragma de ratos e musculo biventer cervicis de pintainhos, teve por objetivo avaliar o efeito de diferentes anestésicos locais na transmissão neuromuscular e sua influência no bloqueio produzido pelo rocurônio. Foram avaliados os seguintes parâmetros: efeito dos anestésicos locais (lidocaína, bupivacaína racêmica, mistura em excesso enantiomérico de bupivacaína) e do rocurônio empregados isoladamente, na transmissão neuromuscular; o bloqueio produzido pelo rocurônio em preparações expostas aos anestésicos locais; a ação dos anestésicos locais na resposta contraturante da acetilcolina; seus efeitos nos potenciais de membrana e nos potenciais de placa terminal em miniatura. Os resultados foram expressos em médias e desvios padrão e analisados através dos testes t de Student, Mann-Whitney , Wilcoxon, Kruskall-Wallis e Anova com teste para comparação múltipla de Tukey. Adotou-se um nível de significância de 5% (p<0,05). Nas preparações nervo frênico -diafragma de rato, os anestésicos locais nas concentrações empregadas, não alteraram a amplitude das respostas musculares mas, potencializaram o efeito do rocurônio. Nas preparações biventer cervicis de pintainho os anestésicos locais promoveram diminuição na resposta contraturante da acetilcolina evidenciando um efeito pós-juncional. Não causaram alteração significativa nos potenciais de membrana, não demonstrando ação despolarizante na fibra muscular. A lidocaína promoveu um aumento inicial dos potenciais de placa terminal em miniatura (pptm) seguida de bloqueio e, a bupivacaína nas duas formulações causou diminuição na amplitude e na freqüência dos pptm, caracterizando um efeito pré-juncional. Os resultados obtidos neste estudo demonstram um sinergismo entre as drogas comprovado por efeitos pré e pós-juncionais / Abstract: Local anesthetics can interact with neuromuscular blockers and modify their pharmacokinetics and pharmacodynamics properties but this mechanism of interaction is very controversial. This experimental study performed in rat phrenic nerve diaphragm preparation and chick biventer cervicis muscle, had the objective to evaluate the effect of different local anesthetics in neuromuscular transmission and their influence in the block promoted by rocuronium. The parameters evaluated were that: the effect of local anesthetics (lidocaine, racemic bupivacaine, enantiomeric mixture of bupivacaine) and the rocuronium isolated in neuromuscular transmission; the block promoted by rocuronium in local anesthetics exposed preparations; the action of local anesthetics in contracture response of acetylcholine; their effects in membrane potentials and miniature end plate potentials. The results were expressed in average and standard deviation and analysed using T Student test, Mann-Whitney, Wilcoxon, Kruskall-Wallis and Anova with Tukey multiple comparative test. We adopted a level of significance of 5% (p<0,05). In rat phrenic nerv diaphragm preparation, local anesthetics in the concentrations employed did not caused alterations in the amplitude of muscle responses but potentialized the effect of rocuronium. In chick biventer cervicis preparations local anesthetics promoted a decrease in acetylcholine contracture response indicating a postjunctional effect. They did not cause significant alterations in membrane potential so they did not demonstrate depolarizing action in muscle fiber. Lidocaine promoted an initial increase in miniature end plate potentials (meps) followed by block and bupivacaine in the two formulations caused a decrease in the amplitude and frequency of meps, characterizing a prejunctional effect. The results obtained in this study demonstrate a synergism of the drugs confirmed by pre and postjunctional effects / Mestrado / Mestre em Farmacologia

A selective a2-adrenergic agonist, lofexidine, significantly reduced intraocular pressure (lOP) in intact ocular normotensive NZW rabbits, producing a differential dose-dependent decrease in IOP in'the ipsilateral and contralateral eye. Contralateral IOP reduction was most observable at low doses. Unilateral superior cervical ganglionectomy and extraocular muscle excision studies were undertaken to elucidate the factors influencing differential IOP reduction by lofexidine. Similar significant contralateral decreases in IOP were noted when the agent was applied to either the intact or operated eye. Biochemical studies demonstrated that lofexidine inhibited isoproterenol-stimulated adenylcyclase in isolated iris-ciliary body preparations. Yohimbine, an α2-adrenergic antagonist, blocked this inhibitory response. Hence, these observations suggested that lofexidine's site of IOP reduction was probably at the cellular level.

Drugs used in the pharmaceutical industry often occur as a mixture of several isomers with a different biological activity. In a case that some isomer provides an undesirable side effect, it is important to separate it from the mixture and check the chiral purity of a drug. Capillary zone electrophoresis plays a significant role in chiral separations. A different affinity of isomers to complexation reagent is used for their separation from each other. The extent of their interaction is characterized by the complexation constant. Most commonly the cyclodextrins are used for the chiral separations of β-blockers and they could be in neutral or charged form. They probably interact with them through the creation of inclusion complexes. A successful baseline enantioseparation of all the β-blockers that have been studied, labetalol, pindolol, alprenolol and atenolol, was provided by using the background electrolyte containing charged cyclodextrins. The highest resolution of peaks was observed using sulfated cyclodextrins.

The purpose of my study was to determine and compare the effects of three calcium antagonists on systemic hemodynamics, ECG, blood flow distribution, tissue conductance and venous tone of the rat. The effects of a representative drug from Spedding's (1985) three subclasses of calcium antagonists on systemic hemodynamics, ECG, cardiac output and the distribution of blood flow were investigated by the microsphere technique in pentobarbital-anesthetized rats. The representative drugs were: I, nifedipine (12 and 35 µg/kg/min); II, verapamil (43 and 83 µg/kg/min) and III, flunarizine (174 and 275 µg/kg/min). Low and high doses were selected to give a decrease in mean arterial pressure of 10 and 20 mmHg, respectively, compared with control rats. At equal depressor levels, all the drugs similarly decreased total peripheral resistance while slightly but not significantly increasing cardiac output (CO) and stroke volume. Heart rate was decreased by verapamil and flunarizine, but increased by nifedipine. The high dose of nifedipine decreased contractility as measured by dP/dt and had no effect on PR-interval, while verapamil decreased dP/dt and prolonged the PR-interval. The low dose of nifedipine and both doses of flunarizine slightly but not significantly decreased dP/dt and had no effect on PR-interval. All three drugs similarly affected the distribution of blood flow. Blood flow to lungs, liver, and heart was increased while flow to the intestine, kidneys, spleen and skin was decreased. Arterial conductances in lungs, liver, heart and skeletal muscle were increased by the three drugs. These results show that representative drugs from the three subclasses of calcium antagonists had similar effects on the distribution of blood flow and arterial conductances but different chronotropic, dromotropic and inotropic effects. A final set of experiments were designed to evaluate calcium antagonist actions on venous tone, as venous tone is a primary determinant of CO and the calcium antagonists generally increase CO. The effects of three calcium antagonists, verapamil, nifedipine and flunarizine on mean arterial pressure (MAP), heart rate (HR) and mean circulatory filling pressure (MCFP), an index of total body venous tone, were investigated in the. conscious rat. Infusions of all three drugs caused a dose-dependent decrease in MAP and an increase in MCFP, compared with the corresponding values in control rats. HR was decreased by verapamil and flunarizine and slightly increased by nifedipine. Further experiments investigated whether the increase in MCFP by verapamil was indirectly caused by reflex activation of the autonomic nervous system. Rats were pretreated with a continuous infusion of the ganglionic blocker hexamethonium prior to infusion of verapamil. After treatment with hexamethonium, verapamil did not increase the MCFP. In fact the highest dose of verapamil significantly decreased MCFP. The results suggest that calcium antagonists have greater dilator effects in arterioles compared to veins. It appears that any direct venodilator effects of verapamil in conscious rats are masked due to reflex activation of the autonomic nervous system. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Background: Amiodarone (AM) is a widely used anti-arrhythmic medication. Its utility is, however, limited by adverse side effects. The mechanism of amiodarone-induced toxicity (APT) in the lungs is attributed primarily to stimulation of the angiotensin enzyme system leading to lung cell apoptosis and cell death. This mechanism has been demonstrated by in vitro and in vivo experimental animal studies. To date, however, no in vivo human studies have confirmed this mechanism for APT. Purpose: This study was undertaken to determine whether angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) offer a protective effect against APT in humans. Demonstration of a protective effect of an ACE-I or ARB would suggest that stimulation of the angiotensin enzyme system may be a key process in APT. Design: An 8-year retrospective analysis of all patients on AM therapy at the James H. Quillen Veterans Affairs Medical Center was undertaken. Results: A total of 1000 patients on AM were identified. One-hundred-and-seventeen were excluded from the study. Five-hundred-and-twenty-four patients were simultaneously on an ACE-I or ARB. The remaining 359 patients were not. Pulmonary toxicity attributed to AM was identified in five and 14 patients with and without concomitant ACE-I or ARB therapy, respectively. The APT rate for the entire patient sample was 2.2%. APT occurred in 1% of patients on an ACE-I or ARB and in 3.9% of patients not taking an ACE-I or ARB. This observed difference in percentage of APT was statistically significant. Conclusion: The concomitant use of ACE-I or ARB in patients taking AM appears to offer a protective effect against APT. This observation suggests that the stimulation of the angiotensin enzyme system may play an important role in APT in humans.

The current recommendations by the American Heart Association for health promotion are that all persons should partake in regular physical activity in order to reduce the risk of cardiovascular disease. Regular physical exercise reduces blood pressure and is an important component of the management of hypertension. It is therefore important that patients with hypertension participate in habitual physical exercise. Many hypertensive patients who exercise will require anti-hypertensive medication. However, some antihypertensive agents cause fatigue during exercise. In order for patients to gain the full benefits of an active lifestyle, it is important that the prescribed antihypertensive agent does not prevent them performing and enjoying sustained exercise. It has been well documented that β-blockers cause premature fatigue during physical exercise. The effects on exercise performance of other first line antihypertensive medications, such as calcium channel antagonists have not been extensively investigated. In particular, the effects of these agents on prolonged submaximal exercise endurance have not been well studied. The object of this thesis was to compare the effects of isradipine, a dihydropyridine calcium channel antagonist, to those of atenolol, a β₁-selective antagonist, on maximal and submaximal exercise performance and on short duration high-intensity exercise in physically active hypertensive patients. The study design was a crossover trial where drug treatments were double blinded and randomised. Physically active volunteers with mild to moderate hypertension were recruited. 11 subjects performed i) progressive exercise to exhaustion for determination of maximal oxygen consumption (VO₂max), maximal work load and cardiorespiratory responses to maximal exercise, ii) prolonged submaximal exercise for determination of exercise endurance, cardiorespiratory responses and ratings of perceived exertion (APE), and iii) short duration, high intensity exercise consisting of a 30 second maximal exercise test (Wingate test) to determine skeletal muscle power output, following 4 weeks ingestion of isradipine (2.5mg bd), atenolol (50mg bd) or placebo. Diastolic blood pressure at rest was reduced by both atenolol and isradipine, but was lowered to a greater extent by atenolol (83.3 vs 89.0 vs 96.1 mmHg, atenolol vs isradipine vs placebo, p<.0005). Systolic blood pressure at rest tended to be similarly reduced by both agents, but was significantly reduced during maximal and submaximal exercise by atenolol only (p<.001, atenolol vs isradipine, placebo). Heart rate at rest and during maximal and submaximal exercise was decreased by atenolol only (p<.0005, atenolol vs isradipine, placebo). Maximal exercise performance was reduced after atenolol ingestion compared to placebo but not after isradipine ingestion. Peak workload achieved during the maximal exercise test was decreased after atenolol but unchanged after isradipine ingestion (214 vs 243 W, atenolol vs placebo, p<.01). Similarly, VO₂max was reduced after atenolol compared to placebo but was unchanged after isradipine ingestion (33.6 vs 36.4, 33.6 vs 36.1 mlO₂/kg/min, atenolol vs placebo, atenolol vs isradipine, p<.05). Both atenolol and isradipine ingestion reduced submaximal endurance time compared to placebo (27.8 vs 46.4, 34.4 vs 46.4 min, atenolol vs placebo, isradipine vs placebo, p<.005), and increased rating of perceived exertion (APE) after 30 min of submaximal exercise (p<.05). Submaximal oxygen consumption (VO₂), ventilation, respiratory exchange ratio (REA) and blood lactate, glucose and free fatty acid concentrations were not altered after the ingestion of either agent. Neither agent influenced peak skeletal muscle power, total work done, or rate of fatigue during the Wingate test compared to placebo. The results of these studies indicate that impaired performance and increased RPE during submaximal exercise after ingestion of either atenolol or isradipine is not due to alterations of ventilation, VO₂, RER, or blood lactate, glucose and free fatty acid concentrations during prolonged submaximal exercise. Similarly, reduced submaximal exercise performance after atenolol or isradipine ingestion is not due to factors which would also limit the ability of skeletal muscle to perform short duration, high intensity exercise before a bout of prolonged exercise. This study demonstrates that prolonged submaximal exercise testing can reveal an impairment in exercise performance after ingestion of antihypertensive medication which is not evident during maximal exercise testing. This finding is important as prolonged submaximal exercise is the form of exercise which most hypertensive patients actually perform. Further research is required on the effects of anti-hypertensive medications on submaximal exercise performance before firm recommendations can be made regarding medications most suitable for the physically active hypertensive patient. The results of these and other studies indicate that it is not yet possible to make claims that the calcium channel antagonist agents are without effect on physical exercise performance in physically active hypertensive patients.

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