Effects of bepridil and CERM 4205 (ORG 30701) on the relation between cardiac cycle length and QT duration in healthy volunteers.

Bepridil is a calcium antagonist that prolongs the duration of ventricular repolarization, whereas CERM 4205, another calcium antagonist, seems to be devoid of any effect on QT interval. The aim of this study was to compare the effects of bepridil and CERM 4205 on the QT-RR relation at different heart rates during rest and exercise and the results of pharmacologic tests designed to vary neurovegetative tone. Twelve healthy men (21 to 37 years) participated in a placebo-controlled, randomized, crossover, double-blind study and received either bepridil (200 mg/day twice daily) or CERM 4205 (200 mg/day twice daily), or matching placebo during three 14-day treatment periods at 2-week intervals. Bepridil, but not CERM 4205, caused a significant prolongation of resting QT interval. The RR-QT relation was monoexponential for all subjects during resting and exercising physiologic conditions and remained unchanged after 14 days with placebo or CERM 4205. Bepridil significantly shifted the relation upward, resulting in a rate-dependent QT prolongation that predominated during bradycardia. After isoprenaline, QT no longer adapted to changes in heart rate, whereas atropine resulted in a rate-dependent shortening in QT. These results suggest that bepridil and CERM 4205 exert different effects on ventricular repolarization, since only bepridil significantly prolonged QT duration. Bepridil-induced prolongation of QT increased at slow heart rates, which could explain the greater incidence of torsades de pointes in bradycardia.

Life survival and cardiovascular structures following selective beta-blockade in spontaneously hypertensive rats.

The aim of this study was to assess life survival, and arterial and cardiac structural changes following chronic selective beta-blockade in spontaneously hypertensive rats (SHR). Twenty-two SHR aged 3 months and 20 SHR aged 18 months were treated with the beta 1-blocking agent bisoprolol (10 mg/kg/day) or placebo for a period of 2 months. At the end of this period left and right ventricular weight and morphometric parameters of five different arterial segments (thoracic and abdominal aorta, renal, mesenteric, and carotid arteries) were evaluated. In younger SHR, systolic blood pressure (tail-cuff method) was significantly lower in drug-treated animals (225 +/- 15 v 185 +/- 10 mm Hg in placebo-treated animals; P < .001); left ventricular weight was significantly lower in drug-treated rats (0.845 +/- 0.02 v 0.932 +/- 0.03 g; P < .05); medial thickness was significantly lower in the bisoprolol-treated rats at the site of the thoracic (-22%) and abdominal (-17%) aorta, and mesenteric artery (-29%); in the renal and carotid arteries, no change in medial thickness was observed. In older SHR, cardiovascular morbidity and mortality were significantly higher (P < .01) in the placebo group. In bisoprolol-treated animals, systolic blood pressure did not change and was even significantly higher than in controls. Heart weight and medial thickness of the thoracic aorta and the renal arteries were significantly lower in the Bisoprolol group. These results provide evidence that 2 months of selective beta-blockade in adult SHR has an important antihypertrophic cardiac and vascular effect.(ABSTRACT TRUNCATED AT 250 WORDS)

[Stress, blood pressure reactivity and arterial hypertension: not an unambiguous relation]. / Stress, réactivité tensionnelle et hypertension artérielle: une relation non univoque.

UNLABELLED: In order to determine the different ways the hypertensives' blood pressure would react during mental stress, 49 patients, 27 women and 22 men, were submitted at the Stroop Word Colour Conflict Test. Their haemodynamic parameters were recorded by finger photoplethysmography (Finapres device), with equidistant sampling (2 Hz). Temporal and spectral analysis showed evidence of: a quick and short elevation of BP and HR and a greater variability of SBP, as shown by the increase of the MF (66-128 mHZ) module. Patients can be divided into 3 clusters according to the reactivity of SBP. Group I (N, mean +/- sigma) 13, + 32.7 +/- 8 mmHg; group II 24, + 10.3 +/- 6; group III 12, -10.2 +/- 7. They were comparable on anxiety level and on any demographic and clinical feature. In group III, the higher NA at rest, the bigger the fall of SBP when stressed. The cognitive efficiency of these patients is increased by stress. Spectral analysis: Mid frequency (66-128 mHz) components are markedly higher in group III, before, during and after SWCCT showing a higher sympathetic tonus. CONCLUSION: The reactivity of BP is not homogeneous. One fourth of our patients showed a decrease of SBP during the cognitive treatment stage of the test without showing a decrease of sympathetic tone. Anxiety level is not predictive of BP's response.

[Blood pressure variability and stimulation tests: value of the Stroop word color conflict test]. / Variabiilité tensionnelle et tests de stimulation; intérêt du Stroop word color conflict test.

OBJECTIVES: To study the modifications of the BP and its short-term variability in hypertensives patients submitted at to a psychological stress test. DESIGN AND METHODS: Fourty nine hypertensive subjects (27 women and 22 men, aged 46 +/- 9, SBP 164 +/- 10, DBP 97 +/- 6 mmHg after a 15 days placebo run-in period) were studied. We used the original version of Stroop Word Color Conflict Test (SWCCT) to induce mental stress. Haemodynamic parameters (SBP, DBP, MPB and HR) were measured continuously by a non invasive method (Finapres) with data acquisition every 0.5 second allowing spectral analysis of SBP variability at rest, during and after SWCCT (FFT algorithm on 256 point time series Anapres 1.2). RESULTS: All haemodynamic parameters increased during stress test (p = 0.001). The mean value and the variability (V) of SBP standard deviation (SD) increased during SWCCT (p = 0.001 and p = 0.003 respectively). Two minutes after the test, SPB returned to the rest level, while the overall variability of SPB remained elevated (p = 0.007). Spectral analysis: the total area under the curve and the mid frequency component (MFC) (66-128 mHz) increased during and after SWCCT (p = 0.001). [table: see text] CONCLUSION: Short-term variability of SBP is increased in hypertensives when submitted to a SWCCT appears to induce sustained orthosympathetic stimulation as suggested by the increase of mid frequency component (Mayer waves).

[Comparative study of bisoprolol and celiprolol in to moderate hypertension using casual as well as ambulatory blood pressure measurements]. / Etude comparative du bisoprolol et du céliprolol dans l'hypertension artérielle légère à modérée par la mesure casuelle et ambulatoire de la pression artérielle.

A randomised, parallel, double-blind trial was undertaken in 80 patients to compare the efficacy of bisoprolol with that of celiprolol, using causal (BPc) as well as ambulatory (AMBP) blood pressure measurement. After a two week wash-out and two week placebo run-in, patients in whom diastolic blood pressure (DBP) was between 95 and 114 mmHg were given either bisoprolol (10 mg/day) or celiprolol (200 mg/day) for 12 weeks. When efficacy was insufficient (DBP > 95 mmHg), the dose could be doubled after 4 weeks and a diuretic added after 8 weeks. BPc was measured at each visit and an AMBP obtained the day before the start of active treatment and at its end. Six patients dropped out of the trial because of adverse events. Clinical safety/acceptability of both drugs was good. Demographic data, and blood pressure and heart rate figures in both groups were comparable at the end of the placebo period. Mean fall in BPc in the bisoprolol group was 32.5/20.3 mmHg and 23/17.4 mmHg in the celiprolol group, with a significant difference between the two groups concerning systolic pressure (SBP). Ambulatory measurement showed evidence during the periods 24 hours (H), day and night, of a greater fall with bisoprolol (10.7/8.9 mmHg; 13.9/10.8 mmHg; 7.3/7.2 mmHg) than in the celiprolol group (4.9/21.6; 7.3/3.8; 2.9/2 mmHg), the difference being significant for diastolic blood pressure (DBP: p < 0.01; p < 0.05; p < 0.05. Thus bisoprolol was more effective than celiprolol in mild to moderate hypertension, but the difference was significant for SBP by casual measurement and for DBP by ambulatory measurement.

[Comparative study of verapamil LI 120 mg 3 times a day and verapamil LP 120 mg twice a day in stable exertion-induced angina. A multicenter study]. / Etude comparative du vérapamil LI 120 mg 3 fois par jour et du vérapamil LP 120 mg 2 fois par jour dans l'angor d'effort stable. Etude multicentrique.

A multicentre, open, crossover study in 27 patients with exertional angina compared the efficacy of verapamil LP 120 mg twice a day (VP LP 120) with that of verapamil LI 120 mg 3 times a day (VP LI 120) by means of stress tests. The study procedure was as follows: 7-day selection period during which the patient received placebo, and two 21-day treatment periods by VP LI 120 or VP LP 120 according to the crossover principle. At the end of each treatment phase, a stress test was performed at the trough serum concentration for each substance. VP LP 120 mg and VP LI 120 mg both improved exercise capacity compared to placebo. Comparison of VP LP 120 and VP LI 120 did not reveal any significant difference for stress test parameters (total duration of effort: 12 +/- 3.2 min with placebo, 13.3 +/- 3.7 min for the VP LI phase, 13.9 +/- 3.2 min for the VP LP phase; % FMT reached: 87.2% +/- 7.2 for VP LI, 89% +/- 7.3 for VP LP; time to onset of significant ST depression: 10 min +/- 2.9 for VP LI, 11 min 3.6 for VP LP). The efficacy of VP LP 120 in exertional angina is therefore identical to that of VP LI 120, despite a reduction of the total dose and serum levels.

[Multifactorial and typological analysis of frailty in uncontrolled hypertensives. The Eclat survey]. / Approche multifactorielle et typologique du concept de fragilité chez les patients hypertendus non contrôlés. Enquête Eclat.

OBJECTIVE: The aim of the Eclat survey was to evaluate the frequency of frailty in uncontrolled hypertensives and to individualize different frailty profiles. PATIENTS AND METHODS: This was an observational, prospective, longitudinal survey conducted in the cohort of uncontrolled hypertensive patients aged 55 years or more. Morbid events having occurred between two visits at a 6-month interval were reported. Patients with at least one event were considered to be frail. Predictive factors of at least one event were identified (logistic regression). The analysis was completed by a typological analysis (principal components analysis and clustering). RESULTS: At least one event occurred in 211 (9%) of 2306 patients (males 55%, 67+/-9 years old, blood pressure [BP]=160+/-11/93+/-8 mmHg, diabetes 23%): cardiovascular (1.7%), gerontological (5.5%), onset of diabetes (1.3%), worsening of renal impact (2%). Three frailty profiles were identified: patients at low risk (n=1507, event rate=6%), with neither cardiovascular risk factors nor target organ damage; patients at moderate risk (n=335, event rate=12%) with numerous risk factors but no target organ damage and patients at high risk (n=243, event rate=23%), the older ones, in bad general condition, with target organ damage, sensorial deficits and cognitive disorders. In a population of uncontrolled hypertensives aged 55 years or more, 9% could be considered as frailty. CONCLUSION: Therapeutic measures might be adapted according to the frailty profile of the patient. With respect to treatment management, healthcare behaviour could differ depending on these frailty profiles.

Assessment of antihypertensive effect by blood pressure monitoring: applications to bisoprolol and lisinopril in a double-blind study.

The aim of this study was to evaluate the antihypertensive effect of drugs according to the initial ambulatory blood pressure (BP) level. After a 15-day placebo run-in period, 105 patients with moderate essential hypertension (mean age, 52 years) underwent 24-h BP monitoring (spacelabs: 1 measure/15 min). Patients were subdivided into two groups: the "High" group, with 24-h mean values of systolic BP (SBP) > 137 or diastolic BP (DBP) > 87 mm Hg, and the "Low" group, with SBP < or = 137 and DBP < or = 87 mm Hg. All patients received, in a random and double-blind design, either bisoprolol (10 mg q.d.) or lisinopril (20 mg q.d.) for 8 weeks. At the end of this active treatment period, office and ambulatory BP measurements were performed. Casual measurements revealed similar BP decreases in all subgroups receiving bisoprolol and lisinopril; BP monitoring showed that the antihypertensive effect depended on the baseline mean 24-h value; -15/-12 mm Hg for bisoprolol and -18/-13 mm Hg for lisinopril in the High group; -7/-6 mm Hg for bisoprolol and -6/-6 mm Hg for lisinopril in the Low group. This study shows that the antihypertensive effect depended on initial ambulatory BP values, with a lower BP decrease in the Low group. Assessment of the antihypertensive effect on ambulatory BP is useful in clinical trials.