[Knowledge of the human body. At the 450th anniversary of the first edition of Andreas Vesalius' life work. "De Humani Coporis Fabrica Libri Septem"]. / De kennis van het menselijk lichaam. Bij de 450e verjaring van de editio princeps van het levenswerk van Andreas Vesalius. "De Humani Corporis Fabrica Libri Septem".

As an introduction to the symposium we pay attention successively: firstly, to the "Magister divinus", to Andreas Vesalius' personality, according to the testimony of his pupil Fallopius; secondly, to his ingenious lifework, the "De Humani Corporis Fabrica", according to the opinion of Sir William Osler, "the greatest medical book ever written", finally, to the historical evolution leading to the Vesalian way of thinking and working. All this proves that Vesalius' work is a fundamental turning point in the development of medicine as well as in the evolution of scientific practice in a general sense. It is also one of the highlights in the construction of mankind's intellectual patrimony.

[Clinical pharmacology: current status and perspectives]. / Klinische farmacologie: vaststellingen en vooruitzichten.

In view of the ever increasing complexity of individualized pharmacotherapy, the study of new and potent drugs in man and the misuse and abuse of drugs, WHO-Study Group reports and a recent enquiry in Belgium, France and W. Germany stress that the development of clinical pharmacology is an absolute necessity for patients, physicians, health authorities, the pharmaceutical industry and society at large. It seems this development could be optimally achieved by setting up, within Services of General Medicine or Internal Medicine of University Hospitals and large Public Hospitals, autonomous Units of Clinical Pharmacology with the responsibility to take an active part: a) at the service level: 1) in patient care, either directly in general medical services or drug problem oriented consultations, or indirectly through consultative functions and pharmacotherapeutic conferences; 2) in drug monitoring services, management of cases of overdose, drug information, drug utilization surveys, pharmaco-epidemiology, ethical committees, formulary committees, drug regulatory agencies and studies of Phase I, II and III; b) at the teaching level: 1) in courses of clinical pharmacology sui generis, to undergraduates, in close collaboration with the University Department of Pharmacology; 2) at the postgraduate level, as a specialty in se, and as part of the training in medical specialties and at the level of continuing education of general practitioners and specialists; c) at the research level: 1) in clinical pharmacokinetic studies, with special attention to interindividual variability and genetic factors, to drug concentration/effect studies, to drug interactions, and in pharmacodynamic studies, in view of the development of new approaches in the study of drug-receptor interactions; 2) in the design, realization and evaluation of Phase I, II and III studies, clinical trials and multicenter drug studies.

Risks and benefits in the trial of the European Working Party on High Blood Pressure in the Elderly.

Hypertensive patients over the age of 60 years were admitted to a double-blind placebo-controlled trial. Patients in the actively treated group received a combined potassium-losing and -sparing diuretic (triamterene 50 mg plus hydrochlorothiazide 25 mg; n = 416); this dose could be doubled and methyldopa (up to 2 g, daily) was added in 35% of patients when blood pressure remained high. The placebo group (n = 424) received matching capsules and tablets. Adverse effects were assessed in the double-blind period of the trial by calculating the incidence of abnormal biochemical results, investigator reports of diseases and prescriptions of concomitant therapy and a self-administered symptom questionnaire completed by patients. In 1000 hypertensive subjects over 60 years of age, 1 year of active treatment would prevent 11 fatal cardiac events, 6 fatal and 11 non-fatal strokes and 8 cases of severe congestive heart failure. No unexpected adverse treatment effects were observed. A significant excess incidence rate (per 1000 person years) was found in the active group compared with placebo for: (1) impaired renal function, a serum creatinine greater than 180 mumol/l (2.0 mg/dl); (2) mild hypokalaemia, a serum potassium less than 3.5 mmol/l; (3) reports of gout; and (4) an elevated serum uric acid greater than 0.52 mmol/l in men or greater than 0.46 in women. Elevated blood sugar and prescriptions for hypoglycaemic drugs tended to be more frequent in the actively treated group, but this difference was not statistically significant. In both groups, there was a low incidence (less than 7 per 1000 person years) of anaemia and depression and diseases of the liver, gall bladder or pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related effects of placebo and active treatment in patients beyond the age of 60 years: the need for a proper control group.

The age-related response to placebo and active antihypertensive treatment was evaluated in 742 elderly hypertensive patients who were followed in the double-blind placebo-controlled trial conducted by the European Working Party on High blood pressure in the Elderly (EWPHE). In the two treatment groups, the fall in systolic and diastolic blood pressures after 3 months was negatively correlated with age (P less than 0.02), indicating that the hypotensive effect of placebo and active treatment was more pronounced in older patients. Further comparison of the two treatment groups failed to demonstrate any statistical differences in the slopes of the hypotensive effect on age. These conclusions were not altered by cumulative adjustments for baseline blood pressure, pulse rate, serum creatinine and the presence of cardiovascular complications at entry. In conclusion, in the present study, a similar blood-pressure-lowering action which increased with age was observed on active and placebo treatment; thus, proof that an observed age-related hypotensive effect is caused by a particular drug requires comparison with a control group on placebo.

Is a high serum cholesterol level associated with longer survival in elderly hypertensives?

The relationship between serum total cholesterol, measured at randomization, and mortality was investigated in 822 patients, who were followed for an average of 3.1 years in a double-blind trial, conducted by the European Working Party on High Blood Pressure in the Elderly. Serum cholesterol, measured at randomization, was 0.54 mmol/l higher in women than in men, and declined with increasing age in both men (0.028 mmol/l per year) and women (0.036 mmol/l per year). During follow-up on randomized treatment, cholesterol fell by a similar amount with placebo (0.11 mmol/l per year) and with active treatment (0.14 mmol/l per year). Active treatment consisted of hydrochlorothiazide (25-50 mg/day) plus triamterene (50-100 mg/day) with the addition of alpha-methyldopa (0.5-2.0 g/day) in one-third of the patients. Serum total cholesterol, measured at randomization, was independently and inversely correlated with total (P = 0.03), non-cardiovascular (P = 0.03) and cancer (P = 0.04) mortality during follow-up on double-blind treatment. Total and non-cardiovascular mortality were also negatively correlated with haemoglobin and body weight at randomization.

Diuretics--a risk in the long-term treatment of hypertensive patients?

The trial of the European Working Party on High blood pressure in the Elderly (EWPHE) revealed an overall decrease in cardiovascular mortality and morbidity in the actively treated patients. They received as first-line drugs a combination of hydrochlorothiazide and triamterene; methyldopa was added as necessary. The present post hoc analysis examined the effect of the diuretic treatment on cardiovascular events, both when given alone and in conjunction with methyldopa, by calculating the relative hazard rates (RHR) for cardiovascular mortality and morbidity. Using the Cox proportional hazard model, compared with placebo, a 34% reduction in cardiovascular mortality in the intention-to-treat analysis was demonstrated in the diuretic (hydrochlorothiazide and triamterene) group with an RHR of 0.66 and a 95% confidence interval (CI) of 0.44-0.97; the 16% decrease in the group treated with diuretics and methyldopa was not significant (RHR, 0.84; 95% CI, 0.56-1.25). The effect of treatment in the latter combined group became significant (RHR, 0.62; 95% CI, 0.40-0.95) when all cardiovascular study terminating events were considered; they were reduced by 38%. No effect of treatment on mortality from all causes was detected.

Effects of felodipine and metoprolol on blood pressure, plasma renin, angiotensin II, aldosterone and catecholamines in hypertensive patients.

Oral administration of felodipine to 10 patients with mild essential hypertension acutely reduced the brachial artery pressure by 15/13mm Hg. The tachycardia which occurred was sustained for 90 minutes together with an elevated plasma noradrenaline concentration. Addition of intravascular metoprolol after 90 minutes decreased heart rate. The felodipine-induced increase of plasma renin activity (100%; p less than 0.001) was completely reversed by metoprolol. Plasma angiotensin II (PA II) rose by 15% (p less than 0.05) during felodipine, whereas plasma aldosterone concentration was not significantly affected.

Influence of antihypertensive drug treatment on morbidity and mortality in patients over the age of 60 years. European Working Party on High blood pressure in the Elderly (EWPHE) results: sub-group analysis on entry stratification.

The European Working Party on High blood pressure in the Elderly (EWPHE) trial was a double-blind randomized placebo-controlled trial of antihypertensive treatment in patients over the age of 60 years. Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range of 90-119 mmHg and a systolic blood pressure in the range of 160-239 mmHg. Eight-hundred and forty patients were randomly assigned either to active treatment (hydrochlorothiazide + triamterene) or a matching placebo. If blood pressure remained elevated methyldopa was added to the active regimen and matching placebo to the placebo regimen. Before randomization, the patients were stratified in eight strata according to sex, age groups between 60 and 69 years or 70 years and over, and the presence or absence of cardiovascular complications of hypertension. Both the intention-to-treat and 'on randomized treatment' analyses suggested a benefit from active treatment in men and women. Formal statistical significance was achieved for male cardiovascular mortality (intention-to-treat analyses) and for cardiovascular events in females. Although the event rates were greater for patients with previous cardiovascular events and patients over the age of 70 years, the percentage reduction in cardiovascular events was similar in these groups to those without complications and in patients between 60 and 69 years of age. However, little benefit from treatment could be demonstrated in patients over the age of 80 years. The presence or absence of smoking had no influence on response to treatment in these elderly patients.

Glucose intolerance during diuretic therapy in elderly hypertensive patients. A second report from the European Working Party on high blood pressure in the elderly (EWPHE).

Five hundred and seven elderly hypertensive patients were followed for 1 year, 371 for 2 years and 270 for 3 years in a double-blind, randomized, controlled trial in which they received either placebo or 25-50 mg hydrochlorothiazide and 50-100 mg of triamterene daily. One third of the active treatment group also received 250 mg to 2 g methyldopa daily. After 1 year the active treatment group had an average increase in fasting blood sugar of 2.5 mg/dl compared with an average fall of 1.4 mg/dl in the placebo group (P = 0.01). The increase in blood sugar 1 hour and 2 hours after 50 g oral glucose tended to be greater in the actively treated group but these increases did not achieve statistical significance. The effects of diuretic treatment were established after one year and did not increase further over the next 2 years. Overall there was an increase in fasting blood sugar of 5 mg/dl in the active treatment group which occurred mainly in the first year. The hyperglycaemic effect of diuretics appeared to be partly or wholly related to potassium loss since, in both groups, impairment of glucose tolerance was most marked in those in whom serum potassium decreased. The measures of blood sugar were also positively related to systolic pressure before and after treatment.

Efficacy of antihypertensive drug treatment according to age, sex, blood pressure, and previous cardiovascular disease in patients over the age of 60.

Results of the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial have been analysed in relation to age, sex, blood pressure, and previous cardiovascular disease. Cardiovascular mortality and the cardiovascular study-terminating events were significantly and independently related to treatment, age, cardiovascular complications at randomisation, and systolic but not diastolic blood pressure. The benefits of treatment observed in the trial seemed to be independent of entry blood pressure and the presence or absence of cardiovascular complications at entry. There was some evidence that treatment effect decreases with advancing age. Little or no benefit from treatment could be demonstrated in patients over the age of 80 years, the great majority of whom were women.

In-vitro study of the enkephalinergic hypothesis for non-adrenergic, non-cholinergic innervation in the cat stomach.

It has been suggested that enkephalins are involved in the gastric relaxation induced by stimulation of the non-adrenergic, non-cholinergic vagal fibres in the cat stomach. Experiments were therefore performed on strips of cat stomach. With longitudinal and circular gastric fundus and corpus strips from reserpinized cats, non-adrenergic, non-cholinergic relaxatory responses could be elicited by transmural electrical stimulation in Tyrode solution containing atropine and 5-hydroxytryptamine. Morphine, leu-enkephalin and met-enkephalin did not influence the tone of the strips or the relaxation evoked by stimulation at 8 Hz, and neither did the opioid antagonist, naloxone. These results do not support the enkephalinergic hypothesis for the non-adrenergic, non-cholinergic vagal fibres in the cat stomach.

Influence of hypotensive drug treatment in elderly hypertensives: study terminating events in the trial of the European Working Party on High Blood Pressure in the Elderly.

The European Working Party on High Blood Pressure in the Elderly (EWPHE) trial was a double-blind randomized placebo-controlled trial of antihypertensive treatment in patients over the age of 60 years. Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range 90-119 mmHg and a systolic blood pressure in the range of 160-239 mmHg. The patients (n = 840) were randomized either to active treatment (hydrochlorothiazide + triamterene) or matching placebo. If the blood pressure remained elevated, methyldopa was added to the active regimen and matching placebo in the placebo group. An overall intention-to-treat analysis, combining the double-blind part of the trial and all subsequent follow-up, revealed a non-significant change in total mortality rate (-9%, P = 0.41) but a significant reduction of cardiovascular mortality rate (-27%, P = 0.037). The latter was due to a reduction of cardiac mortality (-38%, P = 0.036) and to a non-significant decrease of cerebrovascular mortality (-32%, P = 0.16). In the double-blind part of the trial, total mortality rate was not significantly reduced (-26%, P = 0.077). Cardiovascular mortality was reduced in the actively treated group (-38%, P = 0.023), due to a reduction of cardiac deaths (-47%, P = 0.048) and to a non-significant decrease of cerebrovascular mortality (-43%, P = 0.15). Deaths from myocardial infarction were reduced (-60%, P = 0.043). Study-terminating morbid cardiovascular events were significantly reduced by active treatment (-60%, P = 0.0064). In the patients randomized to active treatment there were 14 fewer cardiovascular deaths per 1000 patient-years during the double-blind part of the trial. Version 3.

The nature of opioid involvement in the hemodynamic respiratory and humoral responses to exercise.

After 30 min rest in the lying position, 12 healthy male volunteers (average age 22 years) received, in a randomized double-blind cross-over protocol, either saline or naloxone (10 mg iv followed by a continuous infusion of 10 mg/hr). Thereafter they rested for a further 30 min in the recumbent position and for 15 min sitting on a bicycle ergometer; they then exercised to exhaustion. At rest plasma levels of adrenocorticotropin (ACTH), cortisol, and aldosterone increased during infusion of naloxone, while body temperature decreased. During exercise the difference in plasma ACTH between naloxone and saline periods was abolished, while the differences in plasma cortisol and aldosterone lost statistical significance. Intra-arterial pressure, heart rate, ventilation, O2 uptake, and CO2 output were continuously monitored throughout the experiment and were not affected by naloxone. This was also the case for several hormonal and biochemical measurements, including those of plasma renin, angiotensin II, norepinephrine, 13,14-dihydro-15-keto-prostaglandin F2 alpha, glucose and lactate, and serum insulin and growth hormone. Exercise performance was not changed by naloxone. In conclusion (1) during exhaustive graded exercise of short duration opioidergic inhibition of the pituitary-adrenocortical axis is probably not sustained, (2) apart from the latter mechanism, the present study does not support the hypothesis that endogenous opioids are involved in various hemodynamic, respiratory, and hormonal responses to this type of exercise.