Proposals for European Commission guidelines in the use of ambulatory blood pressure monitoring to evaluate antihypertensive drugs.

Different national authorities have different requirements before antihypertensive drugs can be approved for clinical use. Traditionally, antihypertensive treatment is evaluated by blood pressure measurements made by standardized casual readings. Twenty-four-hour ambulatory blood pressure monitoring provides additional information on the antihypertensive profile of a drug. In antihypertensive drug studies, this technique reduces the sample size required, has no placebo effect and provides more detailed information on first-dose effects, the duration of action and dose-response relationships. Accordingly, proposals are being made that might form the basis of European Commission (EC) guidelines for ambulatory blood pressure monitoring, thus standardizing the present different national requirements.

Blood pressure profile and cardiac risk in hypertensive patients with left ventricular hypertrophy.

A study of normotensive volunteers and patients with primary hypertension demonstrated the superiority of a single 24-h mean systolic and diastolic ambulatory blood pressure monitoring (SpaceLabs 90207 ABPM) over standardized sphygmomanometric casual readings. In contrast to the casual blood pressure measurement there was a significant correlation between both 24-h mean systolic and diastolic blood pressures and left ventricular hypertrophy as assessed by two-dimensional M-mode echocardiography. Although no significant differences between daytime and night-time blood pressure were demonstrated in normotensive or hypertensive subjects with or without target organ damage, larger prospective trials are required to confirm this finding.

Antihypertensive and metabolic effects of diltiazem and nifedipine.

The antihypertensive effect of diltiazem (180-270 mg/day) and nifedipine (40-60 mg/day) in slow-release forms was assessed over 8 weeks in a double-blind parallel study in 40 subjects with essential hypertension at rest and during exercise. Blood pressure was comparably reduced in both groups at rest as well as during exercise. The responder rates (greater than or equal to 10% reduction in diastolic blood pressure) after 8 weeks of therapy were 53% at rest and 75% during exercise in the diltiazem group and 78% and 50%, respectively, in the nifedipine group. Diltiazem decreased heart rate by 8% (p less than 0.01), while nifedipine did not affect it. As a consequence, myocardial oxygen consumption, as judged by the pressure-rate product, was reduced by diltiazem. Resting plasma norepinephrine levels were increased significantly after 8 weeks of diltiazem therapy. Plasma epinephrine, renin, aldosterone, glucose, insulin, and lactate and routine laboratory parameters were unchanged at the end of the study. No significant changes in total cholesterol and triglyceride levels were observed after 8 weeks. Whereas therapy with diltiazem resulted in an 8% fall in low density lipoprotein cholesterol after 8 weeks (p less than 0.05), nifedipine induced a drop in very low density lipoprotein cholesterol (p less than 0.05) after 8 weeks of therapy. We conclude that both diltiazem and nifedipine are effective antihypertensive agents lacking undesirable metabolic side effect. Diltiazem, however, had the advantage of lowering heart rate and myocardial oxygen consumption.

Specific alpha-adrenoceptor-mediated vasoconstriction in human veins and interaction with the calcium entry blockers nifedipine and diltiazem.

In order to characterize the pharmacological properties of post-junctional alpha-adrenoceptors, the vasoconstricting effects of the non-specific alpha-adrenoceptor agonist noradrenaline, of the specific alpha 1-adrenoceptor agonist phenylephrine and of the specific alpha 2-adrenoceptor agonist azepexole and the interaction with the calcium entry blockers nifedipine and diltiazem were studied in hand veins of eight healthy volunteers. Both subtypes of alpha-adrenoceptors could be demonstrated in human hand veins in vivo. The alpha 1-subtype seemed to prevail. Vasoconstriction induced by stimulation of either post-synaptic alpha 1- or alpha 2-adrenoceptors was reduced by the calcium entry blockers diltiazem and nifedipine.

Long-term administration of vitamin D steroles in incipient and advanced renal failure: effect on bone histology.

In 36 patients with incipient and advanced renal failure (CCr 80--30 ml/min X 1.73 m2), serum chemistry including ionized Ca, serum PTH and fractional intestinal absorption of Ca (whole body counter; two-dose-technique; 47Ca p.o. and i.v. to correct for urinary and endogenous fecal loss were measured. Quantitative bone histology after in vivo tetracycline double labeling was evaluated from undecalcified sections before and 18 months after therapy with vitamin D3 or 5,6-trans-25-OH-CC in a dose sufficient to raise intestinal absorption and/or urinary excretion of Ca. Intestinal absorption of Ca was impaired in some patients at a GFR of 60 ml/min/1.73 m2. After up to 10000 U/d 5,6-trans-25-OH-CC and 8000 IU/d vitamin D3, respectively, fractional intestinal absorption of Ca rose and was normalized in all patients. There was a concomitant rise in urinary Ca. Serum PTH fell, but did not always return into the normal range. Ionized Ca rose in all patients. Bone histology was evaluated in 17 of these 36 patients after informed consent was obtained. The mass of mineralized bone (Vv) rose in 7/17 patients, pointing to a positive calcium balance. Volumetric density of osteoid (Vvos) and surface density of osteoid (Svos) fell in 10/17 patients concomitant with an increase in the fraction of mineralizing seams and a decrease in the number of lamellae in osteoid seams. Osteoclastic resorption (OCl) fell as did the fraction of woven osteoid seams. However, woven osteoid failed to disappear completely and osteoclastic resorption stayed elevated in some patients. 5,6-trans-25-OH-CC and vitamin D3, in doses that normalized intestinal absorption of Ca, failed to restore completely bone histology to normal although mineralization and collagen texture of osteoid were consistently improved. The dose response characteristics to vitamin D of different abnormalities of Ca metabolism appear to be non-uniform.