Cholinergic stimulation with pyridostigmine, hemodynamic and echocardiographic analysis in healthy subjects

OBJECTIVE: Growing evidence suggests that sudden death after an acute myocardial infarction (AMI) correlates with autonomic nervous system imbalance. Parasympathomimetic drugs have been tested to reverse these changes. However, their effects on ventricular function need specific evaluation. Our objective was to analyze pyridostigmine's (PYR) effect on hemodynamic and echocardiographic variables of ventricular function. METHODS: Twenty healthy volunteers underwent Doppler echocardiographic evaluations, blood pressure (BP), and heart rate (HR) assessment at rest, before and 120 min after ingestion of 30 mg PYR or placebo, according to a double-blind, placebo-controlled, crossed and randomized protocol, on different days. RESULTS: PYR was well tolerated and did not cause alterations in BP or in ventricular systolic function. A reduction in HR of 10.9±1.3% occurred (p<0,00001). There was an A wave reduction in the mitral flow (p<0.01) and an E/A ratio increase (p<0.001) without changes in the other diastolic function parameters (p>0.05). CONCLUSION: PYR reduces HR and increases E/A ratio, without hemodynamic impairment or ventricular function change.

Brazilian multicenter study on efficacy and tolerability of trandolapril in mild-to-moderate essential arterial hypertension. EMBATHE substudy with ambulatory blood pressure monitoring

OBJECTIVE: A double-blind, placebo-controlled multicenter study involving 34 centers from different Brazilian regions was performed to evaluate the antihypertensive efficacy and tolerability of trandolapril, an angiotensin I converting enzyme inhibitor, in the treatment of mild-to-moderate systemic arterial hypertension. METHODS: Of 262 patients enrolled in this study, 127 were treated with trandolapril 2 mg/day for 8 consecutive weeks, and the remaining 135 patients received placebo for the same period of time. Reduction in blood pressure (BP) and the occurrence of adverse events during this period were evaluated in both groups. RESULTS: Significant reductions in both systolic and diastolic pressures were observed in patients treated with trandolapril when compared with those on placebo. Antihypertensive efficacy was achieved in 57.5% of the patients on trandolapril and in 42% of these normal values of BP were obtained. The efficacy of trandolapril was similar in all centers, regardless of the area of the country. In a subset of 30 patients who underwent ABPM, responders showed a significant hypotensive effect to trandolapril throughout the 24 hour day. The adverse event profile was similar in both trandolapril and placebo groups. CONCLUSION: Our results demonstrate, for the first time in a large group of hypertensive patients from different regions in Brazil, good efficacy and tolerability of trandolapril during treatment of mild-to-moderate essential systemic hypertension.

Reduction of QTc interval dispersion. Potential mechanism of cardiac protection of pyridostigmine bromide

OBJECTIVE: Parasympathetic dysfunction is an independent risk factor in individuals with coronary artery disease, and cholinergic stimulation is a potential therapeutical option. We determined the effects of pyridostigmine bromide, a reversible anticholinesterase agent, on electrocardiographic variables of healthy individuals. METHODS: We carried out a cross-sectional, double blind, randomized, placebo-controlled study. We obtained electrocardiographic tracings in 12 simultaneous leads of 10 healthy young individuals at rest before and after oral administration of 45 mg of pyridostigmine or placebo. RESULTS: Pyridostigmine increased RR intervals (before: 886±27 ms vs after: 1054±37 ms) and decreased QTc dispersion (before: 72±9ms vs after: 45±3ms), without changing other electrocardiographic variables (PR segment, QT interval, QTc, and QT dispersion). CONCLUSION: Bradycardia and the reduction in QTc dispersion induced by pyridostigmine may effectively represent a protective mechanism if these results can be reproduced in individuals with cardiovascular diseases.

Effects of chlorthalidone and diltiazem on myocardial ischemia in elderly patients with hypertension and coronary artery disease

OBJETIVE: Antihypertensive therapy with thiazides decreases coronary events in elderly patients. However, the influence of diuretics on myocardial ischemia has not been fully investigated. The aim of this study was to compare the effect of chlorthalidone and diltiazem on myocardial ischemia. METHODS: Following a randomized, double-blind, crossover protocol, we studied 15 elderly hypertensive patients aged 73.6±4.6 years with myocardial ischemia. All patients had angiographically documented coronary artery disease. We measured patients using 48- hour ambulatory electrocardiogram monitoring and exercise testing. After a 2-week period using placebo, patients received chlorthalidone or diltiazem for 4 weeks. RESULTS: Both treatments lowered systolic and diastolic blood pressures. The number of ischemic episodes on ambulatory electrocardiogram recordings was reduced with the use of chlorthalidone (2.5±3.8) and diltiazem (3.2±4.2) when compared with placebo (7.9±8.8; p<0.05). The total duration of ischemic episodes was reduced in both treatments when compared with placebo (chlorthalidone: 19.2±31.9min; diltiazem: 19.3±29.6min; placebo: 46.1±55.3min; p<0.05). CONCLUSION: In elderly hypertensive patients with coronary artery disease, chlorthalidone reduced myocardial ischemia similarly to diltiazem. This result is consistent with epidemiological studies and suggests that reduction of arterial blood pressure with thiazide therapy plays an important role in decreasing myocardial ischemia.

Exercise stress testing in healthy subjects during cholinergic stimulation after a single dose of pyridostigmine

OBJETIVE: The evaluation, by exercise stress testing, of the cardiorespiratory effects of pyridostigmine (PYR), a reversible acetylcholinesterase inhibitor. METHODS: A double-blind, randomized, cross-over, placebo-controlled comparison of hemodynamic and ventilation variables of 10 healthy subjects who underwent three exercise stress tests (the first for adaptation and determination of tolerance to exercise, the other two after administration of placebo or 45mg of PYR). RESULTS: Heart rate at rest was: 68±3 vs 68±3bpm before and after placebo, respectively (P=0.38); 70±2 vs 59±2bpm, before and after pyridostigmine, respectively (P<0.01). During exercise, relative to placebo: a significantly lower heart rate after PYR at, respectively, 20% (P=0.02), 40% (P=0.03), 80% (P=0.05) and 100% (P=0.02) of peak effort was observed. No significant differences were observed in arterial blood pressure, oxygen consumption at submaximal and maximal effort, exercise duration, respiratory ratio, CO2 production, ventilation threshold, minute ventilation, and oxygen pulse. CONCLUSION: Pyridostigmine, at a dose of 45mg, decreases heart rate at rest and during exercise, with minimal side effects and without interfering with exercise tolerance and ventilation variables.

Manidipina no tratamento da hipertensão arterial essencial estágio I e II do paciente com sobrepeso ou obesidade andróide. Estudo multicêntrico brasileiro de eficácia, tolerabilidade e efeitos metabólicos

OBJETIVO: Avaliar a eficácia anti-hipertensiva, efeitos metabólicos e tolerabilidade da manidipina no tratamento de hipertensos essenciais estágio I e II com sobrepeso ou obesidade do tipo andróide. MÉTODOS: Em estudo aberto, não comparativo, realizado em 11 centros brasileiros de pesquisa, 102 pacientes de ambos os sexos com sobrepeso ou obesidade central, foram tratados por 12 semanas com manidipina em dose única diária de 10 a 20mg e avaliadas pressão arterial, freqüência cardíaca e a presença de eventos adversos. Ao final dos períodos placebo e de droga ativa foram obtidos os valores plasmáticos da glicemia de jejum, colesterol total e frações e triglicérides. Em 12 pacientes foi avaliada a sensibilidade à insulina. RESULTADOS: A manidipina reduziu a pressão arterial de 159±15 / 102±5mmHg para 141±15 / 90±8mmHg sem acarretar aumento da freqüência cardíaca. A taxa de eficácia foi de 71,9% com 51,1% de normalização pressórica. Não foram observadas alterações significativas dos parâmetros metabólicos. A tolerabilidade da manidipina foi muito boa e no final do estudo 87,1% estavam livres de qualquer reação adversa. CONCLUSÃO: A manidipina constitui opção adequada, altamente eficaz, livre de efeitos metabólicos e segura para tratamento de hipertensos estágios I e II com sobrepeso ou obesidade andróide.

Effects of Sibutramine on the Treatment of Obesity in Patients with Arterial Hypertension

OBJECTIVE: To assess the effects of weight reduction with 10mg of sibutramine or placebo on blood pressure during 24 hours (ambulatory blood pressure monitoring), on left ventricular mass, and on antihypertensive therapy in 86 obese and hypertensive patients for 6 months. METHODS: The patients underwent echocardiography, ambulatory blood pressure monitoring, and measurement of the levels of hepatic enzymes prior to and after treatment with sibutramine or placebo. RESULTS: The group using sibutramine had a greater weight loss than that using placebo (6.7% versus 2.5%; p<0.001), an increase in heart rate (78.3±7.3 to 82±7.9 bpm; p=0.02), and a reduction in the left ventricular mass/height index (105±29.3 versus 96.6±28.58 g/m; p=0.002). Both groups showed similar increases in the levels of alkaline phosphatase and comparable adjustments in antihypertensive therapy; blood pressure, however, did not change. CONCLUSION: The use of sibutramine caused weight loss and a reduction in left ventricular mass in obese and hypertensive patients with no interference with blood pressure or with antihypertensive therapy.

Eficiência dos Ésteres de Fitoesteróis Alimentares na Redução dos Lípides Plasmáticos em Hipercolesterolêmicos Moderados

OBJETIVO - Avaliar o efeito dos ésteres de fitoesteróis (FE) da dieta, em função dos diferentes genótipos de apo E, sobre os lípides plasmáticos em indivíduos moderadamente hipercolesterolêmicos. MÉTODOS - Pacientes moderadamente hipercolesterolêmicos (20 a 60 anos de idade; 50 mulheres e 10 homens), mantidos em dieta habitual, receberam margarina (20g/dia) enriquecida com fitoesteróis (2,8g/dia=1,68g de FE), ou margarina normal (placebo), por dois períodos de quatro semanas cada, em estudo duplo cego e cruzado. RESULTADOS - Fitoesteróis reduziram significativamente o colesterol total e o LDL-colesterol, respectivamente, em 10% e 12% quando comparado à fase basal de admissão ao programa, e 6% e 8% quando comparado à fase placebo. O HDL-colesterol e a trigliceridemia não se modificaram. CONCLUSÃO - Ésteres de fitoesteróis da dieta reduziram a colesterolemia e a redução do LDL-colesterol foi mais pronunciada nos indivíduos que apresentavam valores maiores de LDL-colesterol, quando admitidos no estudo. Em relação ao sinótipo de apo E não houve diferença significativa entre apo E 3/3 e apo E 3/4.

A multicenter, open-label study of the efficacy and safety of telmisartan in mild to moderate hypertensive patients

OBJECTIVE: To evaluate the efficacy and tolerability of telmisartan, given once a day to patients with mild to moderate hypertension, as well as to assess the 24-hour blood pressure profile with ABPM. METHODS: Initially, 163 patients over 18 were selected, regardless of sex, with blood pressure levels >140/90mmHg at visit 1, which was confirmed at visit 2. One hundred thirty-four patients completed the study. After a 4-week placebo run-in phase, telmisartan 40mg/daily was given for 6 weeks. In those patients whose blood pressure (BP) levels were lower than 140/90mmHg, the same dosage was kept for an additional period of 6 weeks. For those who had BP higher than 140/90mmHg, the dosage was increased to 80mg/daily. Sixty-two patients were included in a subgroup that underwent ABPM 3 different times during the study. RESULTS: In the overall group, blood pressure reduction ranged from 162.3±14.5/101.3±5.75 mmHg (baseline) to 147.3±20.1/90.8±10.9 mmHg (week 12) (p<0.05). Mean blood pressure decreases were 14.4mmHg for systolic BP and 10.3mmHg for diastolic BP, after 12 weeks of active treatment. A subanalysis showed that 47 (35%) patients took telmisartan 40mg throughout the study and 81 (65%) had the dosage increased to 80mg daily. Using ABPM, an 8-mmHg reduction in systolic BP as well as a 5-mmHg reduction in diastolic BP were observed, when compared with baseline values in the final 6 hours (18-24 hours after the last dose of study medication). CONCLUSION: Our results confirm that telmisartan given once a day is effective in reducing blood pressure levels in mild to moderate hypertensive patients. This reduction occurs in a sustained and gradual manner during a 24-hour period confirmed by ABPM.

Mildly symptomatic chronic mitral regurgitation. Analysis of left ventricular systolic function and mitral regurgitant fraction under pharmacological influence: echocardiographic study

OBJECTIVE: To study echocardiographic parameters of left ventricular systolic function and valvar regurgitation under pharmacological influence in mildly symptomatic patients with chronic mitral regurgitation (MR). METHODS: We carried out a double-blind placebo controlled study in 12 patients with MR, mean aged 12.5 years old, who were randomized in 4 phases: A) digoxin; B) enalapril; C) digoxin + enalapril; D) placebo. The medication was administered for 30 days in each phase, and the following variables were analyzed: shortening and ejection fractions, wall stress index of left ventricle, left ventricular meridional end-systolic wall stress, Doppler-derived mean rate of left ventricular pressure rise (mean dP/dt), stroke volume and MR jet area. The clinical variables analysed were heart rate and systemic arterial pressure. RESULTS: No significant variation was observed in the clinical variables analysed. The shortening and ejection fraction, the mean dP/dt and stroke volume significantly increased and the wall stress index of left ventricle, the meridional left ventricular end systolic wall stress and the mitral regurgitation jet area decreased in the phases with medication as compared with that in the placebo phase. CONCLUSION: The parameters of left ventricular systolic function improved significantly and the degree of MR decreased with the isolated administration of digoxin or enalapril in mildly symptomatic patients with chronic MR. The combination of the drugs, however, did not show better results.

Comparative study of the use of diltiazem as an antispasmodic drug in coronary angiography via the transradial approach

OBJECTIVE: To evaluate the impact of the use, prior to the procedure, of injectable diltiazem to prevent complications. METHODS: Between September 2000 and July 2001, 50 patients underwent transradial coronary angiography and were randomized to receive placebo (GI) or diltiazem (GII) through a catheter inserted into the radial artery. All patients received isosorbide mononitrate. Ultrasound analyses of the radial artery were performed before examination, 30 minutes afterwards, and 7 days afterwards to evaluate the flow, the diameter, and the artery output. RESULTS: The radial artery diameter of GI was 2.4± 0.5 mm before the procedure and 2.3±0.5 mm after 30 minutes (NS), whereas in GII the diameter was 2.2±0.3 mm before the examination and 2.5±0.4 mm 30 minutes after it (P<0.001). Radial artery output in group 1 was 7.3±5.l2 mL/min before the examination and 6.1±3.5 mL/min 30 minutes after the examination (NS), and GII had an increase of 5.9±2.5 mL/min before examination to 9.05± 7.78 mL/min after the examination (P=0.04). Complications (spasm, occlusion, and partial obstruction) occurred in 4 patients (17.4%) in GI and did not occur in GII (P=0.04). CONCLUSION: The study suggests a decrease in vascular complications through the transradial access for coronary angiography with the use of diltiazem as an antispasmodic drug, resulting in the significant increase in the diameter of the radial artery and radial artery output.

Efeitos agudos dos estrogênios associados a progestogênios sobre a trigliceridemia e reatividade vascular pós-prandial

OBJETIVO: Avaliar se a terapia de reposição hormonal com estrogênios e progestogênios, em mulheres hipertensas na pós-menopausa, modifica a trigliceridemia e a reatividade vascular pós-prandial. MÉTODOS: Estudo controlado, duplo cego, cruzado contra placebo em 15 mulheres na pós-menopausa (idade de 50 a 70, média = 61,6 ± 6 anos), sorteadas para 2 semanas de placebo ou ingestão oral de 0,625 mg de estrogênios conjugados eqüinos e 2,5 mg de medroxiprogesterona e alimentadas com refeição rica em gorduras (897 calorias; 50,1% de gorduras). Foi medida a reatividade vascular (RV - % de variação dos diâmetros do vaso entre o jejum e 2h após a alimentação), usando-se método ultra-sonográfico automatizado. Foram também determinados o perfil lipídico e a glicose, em jejum e 2h após a alimentação rica em gorduras. RESULTADOS: Com o placebo, a reatividade vascular (RV) diminuiu de 3,20 ± 17% em jejum para -2,1 ± 30%, 2h após a alimentação (p = 0,041), e com terapia de reposição hormonal, a reatividade vascular diminuiu de 6,14 ± 27% em jejum para -0,05±18%, 2h após a alimentação (p=NS). A trigliceridemia pós-prandial aumentou, 35 ± 25% com o placebo, e 12 ± 10% com a terapia de reposição hormonal (P < 0,05). CONCLUSÃO: Em mulheres hipertensas, na pós-menopausa, 2 semanas de reposição hormonal com uma associação de estrogênios e progestogênios, diminuiu a hipertrigliceridemia após uma refeição com alto teor de gorduras, efeito que pode melhorar a disfunção endotelial existente no período pós-prandial.

Efeito do estradiol sobre as respostas cardiopulmonar e metabólica em mulheres normotensas após a menopausa submetidas à cicloergoespirometria

OBJETIVO: Avaliar pela cicloergoespirometria as respostas cardiopulmonar e metabólica, em 30 usuárias de estrogênio após a menopausa, durante exercício físico máximo, sendo que 25 completaram o estudo. MÉTODOS: Em estudo prospectivo, duplo-cego, randomizado, controlado por placebo foram avaliados dois grupos de mulheres: um, constituído por 14 mulheres (57,6±4,8 anos) após a menopausa, usuárias de estradiol na dose de 2 mg/dia por via oral durante 90 dias, e, outro, por 11 mulheres (55,8±6,7 anos) usuárias de placebo no mesmo período. Ambos os grupos foram submetidos a testes cicloergoespirométricos e analisadas as variáveis: volume de oxigênio consumido por kg/min no pico do exercício (VO2 pico), limiar anaeróbio (LA), volume de oxigênio consumido por Kg/min no limiar anaeróbio (VO2 no LA), ponto de descompensação respiratória (PDR), tempo de exercício (TE), carga máxima atingida (CM), freqüência cardíaca máxima (FC), pressão arterial sistólica (PAS), pressão arterial diastólica (PAD), antes e após administração dos medicamentos. RESULTADOS: Constataram-se reduções estatisticamente significantes em VO2 pico (p=0,002), LA (p=0,01), VO2 no LA (p=0,001) e TE (p=0,05) somente no grupo de usuárias de estradiol. As outras variáveis não sofreram alterações. CONCLUSÃO: O estradiol não promoveu melhora nas respostas cardiopulmonar e metabólica, quando comparado ao placebo.

Resposta cronotrópica ao teste cardiopulmonar após o uso de cimetidina

OBJETIVO: Testar a hipótese, por meio de ensaio clínico randomizado, de que a administração de cimetidina altera a resposta cronotrópica ao exercício. MÉTODOS: Foram selecionados 24 indivíduos saudáveis, com idade entre 20 e 68 anos, não-atletas, os quais concordaram em ser submetidos a testes cardiopulmonares, após uso de placebo e de cimetidina, 400 mg, duas vezes ao dia, durante uma semana. Os testes foram realizados em esteira rolante, com protocolo de rampa com análises diretas dos gases expirados. Foi avaliada freqüência cardíaca máxima atingida, além da freqüência cardíaca de repouso e do limiar anaeróbico. RESULTADOS: Os indivíduos estudados foram igualmente distribuídos por sexo, com idade média (± desvio padrão) de 43 ±11 anos. Os exames com placebo e com cimetidina tiveram igual duração (578±90 seg vs 603±131 seg) e igual VO2 pico (35±8 ml/kg.min vs 35±8 ml/kg.min). A administração de cimetidina não apresentou efeito significativo na freqüência cardíaca de repouso (75±10 vs 74±8 bpm), no pico do esforço (176±12 vs 176±11 bpm) e, da mesma forma, também não houve diferença entre as variações das freqüências cardíacas (pico - repouso), nos dois estudos (101±14 vs 101±13 bpm). CONCLUSÃO: A administração de cimetidina por sete dias não altera a resposta cronotrópica ao exercício.

Alta dose de amiodarona em curto período reduz incidência de fibrilação atrial e flutter atrial no pós-operatório de cirurgia de revascularização miocárdica

OBJETIVOS: Avaliar se a administração de amiodarona, em doses altas e curso rápido, reduz a incidência de fibrilação ou flutter atrial, após cirurgia de revascularização miocárdica e se reduz, também, o tempo de internação hospitalar. MÉTODOS: A amostra se constituiu de 93 pacientes randomizados, em estudo duplo-cego, para receberem amiodarona (46 pacientes) ou placebo (47 pacientes). A terapia consistia na aplicação de 600mg de amiodarona, três vezes ao dia, iniciada no mínimo 30 horas e no máximo 56 horas antes da cirurgia. RESULTADOS: Fibrilação ou flutter atrial no pós-operatório ocorreu em 8 dos 46 pacientes no grupo amiodarona (17,4%) e em 19 dos 47 pacientes no grupo placebo (40,4%) (p=0,027). A dose média de amiodarona foi de 2,8g. Os pacientes do grupo amiodarona ficaram hospitalizados por 8,9±3,1 dias, enquanto a internação dos pacientes do grupo placebo foi de 11,4± 8,7 dias (p=0,07). O tempo de internação foi significativamente prolongado nos pacientes que desenvolveram fibrilação ou flutter atrial após a cirurgia, independente do grupo randomizado. CONCLUSÃO: Esta nova alternativa de administração de amiodarona em alta dose e por um curto período, antes da cirurgia de revascularização miocárdica, reduz a incidência de fibrilação ou flutter atrial no pós-operatório desta cirurgia.