RESUMEN
Evaluation of safety and efficacy of new drugs is based largely on data from clinical trials involving a limited number of patients. This approach does not necessarily detect the rare adverse events that may only be observed when very large numbers of patients are studied. Consequently, we designed a double-blind 12-week trial comparing the new angiotensin-converting enzyme (ACE) inhibitor, quinapril (n = 5,053), with a well-established beta-adrenergic receptor blocker, metoprolol (n = 506). Essentially hypertensive patients (diastolic blood pressure 95-114 mm Hg) received either 10 mg quinapril or 50 mg metoprolol once daily, and the doses were doubled at 4-week intervals to a maximum of 40 and 200 mg, respectively, in nonresponders. Responder rates were similar under both regimens. Adverse events were assessed by interview as well as by a standard questionnaire. The overall prevalence of adverse events reported by standard questionnaire was higher than that reported spontaneously during interviews. With respect to typical ACE inhibitor adverse reactions (e.g. cough and taste disturbances), there was no difference between quinapril and metoprolol independent of the mode of reporting. In summary, both drugs showed comparable overall tolerance and safety. The discrepancy between spontaneously reported and questionnaire-reported adverse events was noteworthy, and this finding prevailed in a volunteer group of 327 patients who were treated with quinapril for 52 weeks. Thus, a questionnaire is of great significance in addition to the patient history/interview in a large-scale, double-blind study designed to learn about details of drug safety.
Asunto(s)
Antagonistas Adrenérgicos beta/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Hipertensión/tratamiento farmacológico , Isoquinolinas/efectos adversos , Metoprolol/efectos adversos , Tetrahidroisoquinolinas , Adolescente , Adulto , Factores de Edad , Anciano , Método Doble Ciego , Tolerancia a Medicamentos , Femenino , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Calidad de Vida , Quinapril , Encuestas y CuestionariosRESUMEN
Early treatment with ACE inhibitors of even moderate heart failure is clinically beneficial, even though haemodynamic measurements cannot adequately quantitate such improvement. Neurohumoral assessment is, however, supposed to be more accurate. In 55 patients with moderate heart failure (ejection fraction < or = 35%), we investigated the dose-dependent effects of ACE inhibition with quinapril taken orally (2.5, 5 or 10 mg b.i.d.) following a placebo-controlled, parallel design protocol over 12 weeks. Plasma components of the renin angiotensin system, catecholamines and ANF were measured together with haemodynamics both at rest and during exercise. Before ACE inhibitor treatment, median PRA, Ang I and II and catecholamines were normal, while ANF was increased. All these parameters, including ACE activity, rose during exercise. Chronic inhibition of ACE activity was dose-dependent and the maximal fall in Ang II occurred with quinapril 20 mg.day-1. Humoral changes appeared more assessible than haemodynamic alterations even though many of these changes were reasonably correlated. The effects of chronic ACE inhibition on circulating neurohumoral components in patients with moderate heart failure are small and dose-dependent. Since humoral changes are related to haemodynamics they should account for the clinical benefit. Appropriately high doses of ACE inhibitors should be chosen for treatment of heart failure.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Hemodinámica/efectos de los fármacos , Isoquinolinas/administración & dosificación , Tetrahidroisoquinolinas , Administración Oral , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Prueba de Esfuerzo/efectos de los fármacos , Femenino , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/fisiología , Humanos , Isoquinolinas/efectos adversos , Masculino , Persona de Mediana Edad , Neurotransmisores/sangre , Quinapril , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiologíaRESUMEN
The effect of the angiotensin-converting enzyme (ACE) inhibitor quinapril on myocardial ischaemia was tested in a randomized double-blind cross-over study of 16 men (mean age 62 [44-75] years) with angiographically demonstrated coronary heart disease, exercise-induced ST-segment depression and stable angina. Exercise ECGs were recorded before and 4 hours after a single dose of 10 mg quinapril and after a 14-day course of 10 mg quinapril twice daily. The single dose decreased the average ST-segment depression from 1.12 mV (placebo) to 0.74 mV (P less than 0.05); after 14 days on quinapril the ST-segment depression decreased from 0.91 mV (placebo) to 0.72 mV (P less than 0.05). While heart rate remained unchanged the average resting arterial blood pressure fell from 136/80 to 120/74 mmHg (P less than 0.05) after a single dose and from 141/83 to 127/78 mmHg (P less than 0.05) after 14 days on the drug. These data indicate that ACE inhibitors should be considered as a means of treating coronary heart disease and angina.
Asunto(s)
Angina de Pecho/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Isoquinolinas/uso terapéutico , Tetrahidroisoquinolinas , Administración Oral , Anciano , Angina de Pecho/diagnóstico , Presión Sanguínea/efectos de los fármacos , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/tratamiento farmacológico , Método Doble Ciego , Electrocardiografía/efectos de los fármacos , Prueba de Esfuerzo , Humanos , Masculino , Persona de Mediana Edad , Quinapril , Factores de TiempoRESUMEN
Twelve healthy volunteers received single oral doses of propranolol (80 mg), metoprolol (100 mg), L-bunolol (2 mg), and placebo in a four-way crossover study. Blood pressure, ventricular rate, and echocardiographically determined ejection fraction, ejection time, and mean rate of circumferential fiber shortening (mVcf) were measured before dosing and at multiple time points during 10 hours after each dose, with subjects maintained in the supine position. Reductions in systolic and diastolic blood pressure following administration of each of the beta blockers were greater than those observed with placebo, but differences among the four treatments were not significant. Heart rate reductions with the beta blockers differed significantly from placebo (P less than .001), but differences among the three beta blockers were not significant. Differences among the four treatments in mVcf decrement did not attain significance at the 5% level (.05 less than P less than .1), and there were no significant differences in ejection-time prolongation or ejection-fraction reduction. Thus, reduced blood pressure, heart rate slowing, and reduced cardiac contractility may be associated with placebo treatment and may indicate the need for placebo controls in studies of the cardiovascular effects of beta blockers. Despite differing secondary pharmacologic properties, the three beta blockers reduced heart rate to a similar extent. Other effects of the beta blockers on blood pressure and cardiac contractility could not be consistently distinguished from those associated with placebo.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Presión Sanguínea/efectos de los fármacos , Ecocardiografía , Femenino , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Levobunolol/farmacología , Masculino , Metoprolol/farmacología , Propranolol/farmacologíaRESUMEN
Ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)acetate (etozolin, Gö 687, Elkapin) is a diuretic with a new chemical structure. Animal experiments with etozolin showed low toxicity, potent diuretic and saluretic properties with a mild onset of action. A marked antihypertensive effect was found in long-term experiments in hypertensive rats. In investigations concerning general pharmacology etozolin showed no effects which stand against its use as a diuretic.
Asunto(s)
Diuréticos/farmacología , Tiazoles/farmacología , Animales , Bilis/metabolismo , Presión Sanguínea/efectos de los fármacos , Diuresis/efectos de los fármacos , Diuréticos/uso terapéutico , Diuréticos/toxicidad , Perros , Vesícula Biliar/fisiología , Hipertensión/tratamiento farmacológico , Piperidinas/farmacología , Ratas , Tiazoles/uso terapéutico , Tiazoles/toxicidad , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
Xipamide (4-chloro-5-sulfamoyl-2',6'-salicyloxylidide, Aquaphor), a new compound is a derivate of salicylic acid with marked sodium and water excreting potency. Its effect is dosage dependent. Dosages as low as 0.001 mg/kg p.o. in rats and 0.04 mg/kg p.o. in dogs lead to a statistically significant increase of sodium and water excretion. Potassium excretion was less affected and showed to be rather constant in a dosage range between 0.01 and 10.0 mg/kg. In rats a maximum of sodium and water excretion could be reached by a dose of 200 mg/kg duration of action in rats was approximately 10 h. In dogs a statistically significant sodium and chloride excretion could be detected after oral application of 0.04 mg/kg. Xipamide increased diuresis started with an oral dose of 0.1 mg/kg. Intravenous application of xipamide in a dose of 0.2 mg/kg in dogs accompanied by permanent infusion of 5 per cent mannit solution clearly showed the diuretic profile of the substance: increased diuresis started within 40 min. A peak was reached within 40-60 min post injectionem. Then excretion decreased slowly. Even 120 min post injectionem a diuretic action could be detected. Diuresis and sodium excretion could be demonstrated in rats with experimentally predamaged kidneys and with steroid dependent sodium retention. As could be demonstrated in hypertensive rats xipamide had a hypotensive effect, normotensive rats were not affected. In animal studies xipamide was excellently tolerated. The therapeutic range of the substance was high in single doses as well as when the drug administered over 6 weeks.