Session 6

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73

COMPARISON OF NIFEDIPINE IMMEDIATE RELEASE AND SLOW RELEASE ON SYMPATHETIC ACTIVATION IN HUMAN HYPERTENSION

C. Bussy, P. Boutouyrie. M. Azizi #, E. Billaud. A. Vincent

, H. Kolski *, S. Laurent.

Service de Pharmacologie, # CIC, Hôpital Broussais, 96 rue Didot, Paris,

CIC Lille, * Bayer Pharma, Puteaux, France; France.

Short-acting calcium antagonists induce a baroreflex activation of the sympathetic system in response to their powerful vasodilatating effect. Sympathetic activation induced by these drugs has been recognized as potentially harmful. Whether such effect is observed with long-acting calcium antagonists remains discussed. We therefore conducted a double blind cross-over study comparing long-acting nifedipine (nifedipine GITS) with short-acting nifedipine (nifedipine IR) or placebo during a short term treatment in 12 essential hypertensive patients. A run-in single-blind placebo washout period of 29 days was followed by 3 therapeutic periods during which active treatments or placebo was administrated in random order. These therapeutic periods were separated by 1 week wash-out periods under placebo. This study was conducted during a 36 H stay in hospital, in a neutral emotional environment. Active treatments were beginned the day before and measurements were performed at HO (8 am), HO 5, H1.5, H4, H6, H12, H24 on the second day of treatment. Sympathetic activation was evaluated indirectly from mean heart rate (ECG-Holter7 HO to H4, primary end-point), and during the maximal blood pressure decrease measured with ambulatory BP monitoring, and repeated spectral analysis of heart rate and blood pressure (Finapres) before and during active orthostatism. Sympathetic activation was further directly evaluated directly through repeated dosage of catecholamines in peripheral blood, and methoxylated compounds in 24 H urine. Full results will be presented after opening of the randomization code.

74

TROUGH/PEAK RATIOS OF ONCE DAILY BETA-BLOCKERS AND DIURETICS COMPLY WITH FDA RECOMMENDATIONS

Carole Salvio, Faiez Zannad

Centre d’Investigation Clinique, INSERM – CHU, Nancy, France.

Once daily (o.d) regimen may increase patient compliance. However this regimen can be recommended only for drugs with long duration of action. Duration of action may be prolonged by increasing the dosage but this is achieved only at the expense of exagerate peak effect. Thus trough/peak ratio seems to be a relevant way to evaluate the optimal therapeutic coverage. In order to estimate the therapeutic coverage of once daily beta-blockers and diuretics, we performed a literature analysis (Medline 85-97 + Exerpta Medica 89-97) of all the published studies with the following criteria: (1) unselected mild to moderate hypertensive patients, (2) monotherapy by o.d betablockers or o.d diuretics

Despite many theorical limitations, our literature analysis suggests that diuretics and beta-blockers that play an important and well-recognized role in preventing cardiovascular mortality and morbidity in hypertension, are characterized by trough/peak ratios > 50%, a standard figure recommended by the FDA for once daily administered drugs.

75

COMBINATION OF 2 ANTIHYPERTENSIVE AGENTS POTENTIATE THE MAGNITUDE AND THE DURATION OF ACTION OF EFFECTS ON BLOOD PRESSURE

Carole Salvio, Faiez Zannad.

Centre d’lnvestigation Clinique, INSERM – CHU, Nancy, France.

The most important reason for combining 2 antihypertensive drugs is to use low doses of each compound in order to obtain less adverse events and an improved antihypertensive effect. This potentiated effect has always been studied in terms of magnitude of blood pressure decrease. We wanted to determine whether the combination could potentiate the duration of action of each compound. The trough/peak ratio (T/P) seems to be a relevant way to evaluate the optimal therapeutic coverage of once daily administered antihypertensive drugs.

We performed a literature analysis (Medline 85-97 + Excerpta Medica 88-97) of all the published studies on fixed combination of an angiotensin converting enzyme inhibitor (ACE i) and a diuretic and their separate compounds with the following criteria: (I) unselected mild to moderate hypertensive patients, (2) monotherapy by o.d ACEi or o.d diuretics

2-4 weeks (4) evaluation by 24-hrs ambulatory blood pressure monitoring.

The database search permitted to select 12 studies for the combinations and 19 studies for the diuretics (hydrochlorothiazide, HCTZ) and ACE i, (captopril, quinapril, benazepril, lisinopril, enalapril) which complied with our criteria. The mean T/P were computed for DBP (trough=mean BP lowering during the 24th hr after drug intake, peak=maximum mean hourly lowering during the first 8 hrs post-dosing).

Fixed combination of 2 agents which separately could present a short duration of action could nevertheless offer an optimal therapeutic coverage over 24 hr with a T/P > 50%. This suggests that the combination treatment potentiates the duration of action of the separate compounds.

76

MORE EFFECTIVE BLOOD PRESSURE CONTROL WITH FELODIPINE-METOPROLOL COMBINATION THAN WITH AMLODIPINE. 24-HOUR AMBULATORY BLOOD PRESSURE MONITORING

Faiez Zannad, Laurence Fluckiger for the French Multicenter Group

Centre d’Investigation Clinique, INSERM CHU, Nancy, France.

The study was aimed to compare the antihypertensive efficacy over 24 hrs of the combination tablet felodipine-metoprolol (Logimax

; FM) 5/50 mg o.d. and amlodipine (AML) 5 mg o.d. in patients with mild-to-moderate primary hypertension. In this multicentre, double-blind, parallel group study 245 patients (90 men, 155 women, mean age 54.8 yrs) with a sitting DBP 95-115 mmHg inclusive were randomized to FM 5/50 mg or AML 5 mg after a 4-week placebo run-in period. 24-hr ABPM was performed at the end of placebo run-in (baseline) and after 6 weeks active treatment. Overall 212 patients (102 in FM, 110 in AML group) were eligible for analysis. All unfavorable events, whether or not considered causally related to study medication, were recorded as adverse events (AE).

Both treatments controlled blood pressure in the majority of patients. The average 24-hour, day-time (6.00-22.00 h) and night time (22.00-6.00 h) DBP, SBP and HR were significantly more reduced from baseline to after 6-week treatment in FM than in AML group. Estimates, 95% confidence intervals and p-values of difference in change in BP and HR between the treatment groups are given below:

* p