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Biomedical subjects

B Waeber

Publications and source records attributed to B Waeber.

424 records · Page 24Linked to original sources
PubMedDate not supplied

Does pharmacological profiling of a new drug in normotensive volunteers provide a useful guideline to antihypertensive therapy?

Similar pressor mechanisms should be active in hypertensive and normotensive subjects since hypertension is a quantitative rather than qualitative disorder. Consequently, if an antihypertensive drug is designed to specifically block a well-defined mechanism involved in blood pressure regulation, it should be possible to evaluate its efficacy rather precisely in normotensive volunteers before even administering the compound to a hypertensive patient. That this is indeed the case is illustrated by the example of angiotensin-converting-enzyme inhibitors. The magnitude of blockade that can be obtained in humans, the minimal does needed for maximal efficacy, and the onset and duration of action of the agents have all been precisely determined in normotensive volunteers. Subsequent administration to hypertensive patients merely confirmed these findings. Moreover, if the antihypertensive effect of converting-enzyme inhibitors could not be predicted in an individual hypertensive patient, this is not related to some unknown action of the drug that cannot be assessed in normal volunteers but rather to our lack of understanding of the precise mixture of pathogenetic mechanisms prevailing in any particular patient. Only the safety evaluation and the search for side-effects still has to be carried out in nonspecific fashion, thus requiring long-term observations in large numbers of patients. If the tolerance of new converting-enzyme inhibitors were more predictable, the number of studies in hypertensive patients could be drastically reduced since the antihypertensive profile of any new converting-enzyme inhibitor can probably be precisely determined in normotensive volunteers.

Aldosterone↗
PubMedDate not supplied

Does renin determine the blood pressure response to calcium entry blockers?

Male Wistar rats with one-kidney, one clip renal hypertension were maintained on either a regular or a low salt diet for 3 weeks after clipping. At that time mean blood pressure in the unanesthetized rats was equally elevated in sodium-depleted (n = 17) and in sodium-replete rats (n = 19), but plasma renin activity was significantly higher in the former (p less than 0.05). Infusion of the calcium entry blocker verapamil at a rate of 0.05 mg/kg/minute decreased blood pressure within 60 minutes to a similar extent in rats kept on a salt-deficient diet and in rats fed a regular salt diet. In all rats taken as a group, there was a close, direct correlation (r = 0.87, p less than 0.001) between the magnitude of the blood pressure response to verapamil and the pretreatment blood pressure levels. Verapamil markedly accelerated heart rate and stimulated renin release in all rats. In additional groups of sodium-depleted (n = 8) and sodium-replete renal hypertensive rats (n = 7), nifedipine administration (4 micrograms/kg/min i.v.) within a 45-minute observation period caused a blood pressure fall (p less than 0.001) and heart rate acceleration (p less than 0.001) that were comparable in both groups. These findings suggest that in the rat with renal hypertension the short-term blood pressure response to the calcium antagonists verapamil and nifedipine is not influenced by the state of sodium balance and plasma renin activity. In this experimental model of hypertension, the magnitude of the blood pressure lowering effect of calcium entry blockers appears to be proportional to pretreatment blood pressure levels.

Animals↗
PubMedDate not supplied

True versus immunoreactive angiotensin II in human plasma.

To measure specifically angiotensin-(1-8)octapeptide, peptides were extracted from 2 ml of plasma by reversible adsorption to bonded-phase silica. The angiotensin-(1-8)octapeptide was then isolated by isocratic reversed-phase high-performance liquid chromatography and quantified by radioimmunoassay. The extraction recovery of 125I-angiotensin II added to 2 ml of plasma was 99 +/- 2% (mean +/- SD). The overall recovery of 5, 10, and 20 fmol unlabeled angiotensin II added to 1 ml of plasma was 80 +/- 10%. The coefficient of variation for within-assay precision was 0.06 and for between-assay precision 0.13. The detection limit was 0.4 fmol/ml. Buffer and plasma blanks were below the detection limit. Normal subjects on a free diet in supine position averaged 4.2 +/- 1.7 fmol/ml angiotensin-(1-8)octapeptide. Furosemide (40 mg p.o.) and standing increased these values to 22 +/- 7.6 fmol/ml. In four volunteers, immunoreactive "angiotensin II" (more or less angiotensin-like material) was measured serially before and after converting-enzyme inhibition (Hoe 498) with conventional Dowex extraction. At peak inhibition, plasma immunoreactive "angiotensin II" levels decreased by only 44%. In contrast, angiotensin-(1-8)-octapeptide isolated by high-performance liquid chromatography completely disappeared. In hypertensive patients receiving long-term treatment with enalapril, plasma levels of angiotensin-(1-8)octapeptide fell from 2.7 +/- 0.9 to 0.9 +/- 0.3 fmol/ml (mean +/- SEM) 2 hours after the morning dose, whereas levels of immunoreactive "angiotensin II" were not significantly changed. We found that this sensitive method specifically measured angiotensin-(1-8)octapeptide and demonstrated that true angiotensin II virtually disappears during converting-enzyme inhibition.

Adult↗
PubMedDate not supplied

Compliance with antihypertensive therapy.

Poor compliance with antihypertensive therapy is a major cause of unsatisfactory blood pressure control. The doctor has a key role in all steps that lead the patient to adopt a treatment and to take it as prescribed lifelong. Compliance with therapy is a parameter which is difficult to assess. There is often an important mismatch between the subjective views of physicians and patients regarding long-term drug taking. Electronic monitoring of compliance represents a valuable method to evaluate the "real time" compliance of the patient. Discussing a compliance recording with a patient may help to identify and solve problems linked with everyday adherence to antihypertensive treatment. Improving compliance is an important task not only for the doctors, but also for all healthcare providers.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Improved blood pressure control by monitoring compliance with antihypertensive therapy.

Compliance with antihypertensive therapy was monitored for three months using an electronic medication dispenser in 35 patients remaining hypertensive despite the once-daily administration of a blood pressure lowering drug (either as monotherapy or as fixed-dose combination therapy). During the monitoring of compliance, the treatment was unchanged but blood pressure decreased significantly (p < 0.001) from 167.9/100.4 +/- 16.3/7.2 mmHg (mean +/- SD) to 152.5/90.9 +/- 20.9/11.5 mmHg. The percentage of days with one opening per day was 80.8 +/- 20.5. Thus, discussing with the patient about compliance with the prescribed drug regimen and monitoring compliance for a few months allows better control of blood pressure. This most likely reflects increased compliance with antihypertensive drug therapy.

Adult↗
PubMedDate not supplied

Antihypertensive therapy with MK 421: angiotensin II--renin relationships to evaluate efficacy of converting enzyme blockade.

Nineteen hypertensive patients were treated with increasing doses of the new angiotensin-converting enzyme inhibitor MK 421. Twenty milligrams orally reduced blood pressure from 180/112 +/- 6.8/3.6 (mean +/- SEM) to 160/100 +/- 6.5/3.3 mm Hg (p less than 0.005) while heart rate increased from 75 +/- 2 to 87 +/- 3 beats/min (p less than 0.005). Plasma converting enzyme activity was still markedly reduced 24 h following 2.5, 5, 10, or 20 mg MK 421 p.o. (p less than 0.001). In nine patients treated with 20 mg b.i.d. for up to 10 months, blood pressure was controlled, with the association of hydrochlorothiazide 50 mg q.d. in five. However, 12 to 16 h following the preceding drug administration, plasma angiotensin II and aldosterone were back to base-line levels. Analysis of plasma angiotensin II-renin relationships strongly suggests that converting enzyme blockade is not complete even 4 h after 20 mg MK 421 and starts to wear off already at 12 h. Thus, MK 421 20 mg taken orally twice daily, effectively reduces blood pressure, but does not constantly suppress plasma angiotensin II and aldosterone. Whether its long duration of action makes once daily administration possible has not yet been established.

Adult↗
PubMedDate not supplied

Ambulatory blood pressure recordings. Reproducibility and unpredictability.

The accuracy of blood pressure readings taken by the portable semiautomatic blood pressure recorder Remler M 2000 was investigated in 101 unselected, untreated volunteers. On the average, pressures recorded during usual daily activities were lower by approximately 10 mm Hg than pressures measured in the office. However, individual ambulatory pressures could not be predicted from office readings, and the difference varied among the volunteers from +14 to -43 mm Hg. The reproducibility of office and ambulatory pressures was investigated in 84 subjects. There was a highly significant correlation between pressure levels determined at a 3- to 4-month interval with both the conventional auscultatory method in the office and the Remler ambulatory recorder. These data demonstrate that the Remler M 2000 ambulatory blood pressure recorder, when used properly, provides reproducible blood pressure profiles during customary daily activities. The ambulatory pressure recorder seems particularly useful for a baseline evaluation of the usual daily blood pressure, which in the individual subject differs in a highly unpredictable manner from the blood pressure measured at the physician's office.

Adult↗
PubMedDate not supplied

Ambulatory blood pressure recordings. Reproducibility and unpredictability.

The accuracy of blood pressure readings taken by the portable semiautomatic blood pressure recorder Remler M 2000 was investigated in 101 unselected, untreated volunteers. On the average, pressures recorded during usual daily activities were lower by approximately 10 mm Hg than pressures measured in the office. However, individual ambulatory pressures could not be predicted from office readings, and the difference varied among the volunteers from +14 to -43 mm Hg. The reproducibility of office and ambulatory pressures was investigated in 84 subjects. There was a highly significant correlation between pressure levels determined at a 3- to 4-month interval with both the conventional auscultatory method in the office and the Remler ambulatory recorder. These data demonstrate that the Remler M 2000 ambulatory blood pressure recorder, when used properly, provides reproducible blood pressure profiles during customary daily activities. The ambulatory pressure recorder seems particularly useful for a baseline evaluation of the usual daily blood pressure, which in the individual subject differs in a highly unpredictable manner from the blood pressure measured at the physician's office.

Adolescent↗
PubMedDate not supplied

Angiotensin II antagonists: a new class of antihypertensive agent.

Losartan is an orally active angiotensin II antangonist that selectively blocks effects mediated by the stimulation of the AT1 subtype of the angiotensin II receptor. This agent, at doses of 50-150mg/day, is as effective at lowering blood pressure as chronic angiotensin converting enzyme (ACE) inhibitors. Losartan is generally well tolerated and has an incidence of adverse effects very similar, in double-blind controlled trials, to that of placebo. It does not cause coughing, the most common side-effect of the ACE inhibitors, most probably because angiotensin II antagonism has no impact on ACE, an enzyme known to process bradykinin and other cough-inducing peptides. Losartan is a promising antihypertensive agent with the potential to become a first-line option for the treatment of patients with high blood pressure.

Angiotensin Receptor Antagonists↗