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Biomedical subjects

Michel Burnier

Publications and source records attributed to Michel Burnier.

At least 73 records · Page 4Linked to original sources
PubMed2003

Recent clinical trials with omapatrilat: new developments.

Omapatrilat belongs to the vasopeptidase inhibitors, ie, drugs that possess the ability to inhibit simultaneously the membrane-bound zinc metalloproteases, angiotensin-converting enzyme (ACE), and the neutral endopeptidase EC 3.4.24.11 (NEP). Omapatrilat was targeted to treat patients with hypertension and congestive heart failure. The preclinical and early clinical studies conducted with omapatrilat were very promising. Indeed, omapatrilat appeared to be a very potent antihypertensive agent with very favorable effects on cardiac function in heart failure patients. In contrast to these early studies, the large clinical trials were more disappointing. The results of the OCTAVE trial confirmed the antihypertensive efficacy of omapatrilat, but at the price of an angioedema rate more than threefold higher than that of an ACE inhibitor in the overall population (2.17% vs 0.68%), and close to fourfold higher in the black population. In OVERTURE, a large randomized control trial in heart failure, angioedema was also more common with omapatrilat, but the incidence was much lower (0.8% with omapatrilat vs 0.5% with enalapril). However, omapatrilat was not convincingly superior to the ACE inhibitor. Because angioedema is probably a class side effect of vasopeptidase inhibitors, the higher incidence of this potentially life-threatening complication with omapatrilat has likely stopped the development of this new class of agents. The future of vasopeptidase inhibitors will depend on the ability to improve the risk/benefit ratio either by developing agents that produce less angioedema, or by defining more precisely a high-risk population that could take advantage of dual ACE/NEP inhibition.

Angioedema↗
PubMed2003

Renal hemodynamic and tubular responses to salt in women using oral contraceptives.

BACKGROUND: The use of oral contraceptives is associated with an increased risk of developing hypertension but the mechanisms of this hypertensive effect are not completely defined. The purpose of the present study was to assess prospectively the systemic and renal hemodynamic and tubular responses to salt in women taking oral contraceptives. METHODS: Twenty seven young healthy normotensive women taking oral contraceptives containing monophasic combination of 30 microg ethynilestradiol and 150 microg desogestrel for>6 months were enrolled. All women were assigned at random to receive a low (40 mmol/day) or a high (250 mmol/day) sodium diet for 1 week on two consecutive menstrual cycles during the active oral contraceptive phase. At the end of each diet period, 24-hour ambulatory blood pressure, renal hemodynamics, sodium handling, and hormonal profile were measured. RESULTS: The blood pressure response to salt on oral contraceptives was characterized by a salt-resistant pattern with a normal circadian rhythm. Salt loading results in an increase in glomerular filtration rate (GFR) (P < 0.05 vs. low salt), with no change in the renal plasma flow, thus leading to an increase in the filtration fraction (P < 0.05). At the tubular level, women on oral contraceptives responded to a low salt intake with a marked increased in proximal sodium conservation (P < 0.01 vs. high salt) and with an almost complete reabsorption of sodium reaching the distal tubule. After sodium loading, both the proximal and the distal reabsorption of sodium decreased significantly (P < 0.01). CONCLUSION: The use of oral contraceptives is not associated with an increased blood pressure response to salt in young normotensive women. However, oral contraceptives affect the renal hemodynamic response to salt, a high salt intake leading to an increase in GFR and filtration fraction. This effect is possibly mediated by the estrogen-induced activation of the renin-angiotensin system. Oral contraceptives also appear to increase the tubular responsiveness to changes in sodium intake. Taken together, these data point out evidence that synthetic sex steroids have a significant impact on renal function in women. The renal effects of oral contraceptives should be taken into account when managing young women with renal diseases.

Adult↗
PubMed2003

Electronic monitoring of long-term use of the nicotine nasal spray and predictors of success in a smoking cessation program.

This study evaluated the efficacy of prolonged administration (18 months) of a nicotine nasal spray in smoking cessation and attempted to characterize the pattern of use of the nasal spray with a specially developed electronic monitor in an effort to assess the factors associated with cessation success or failure. Study participants were 92 patients in a smoking cessation unit of a medical outpatient clinic in Switzerland. Participants were daily smokers who had smoked for more than 5 years and were highly motivated to quit. The main outcome measure was the number of abstainers at 12 and 24 months. Their use of the spray was monitored using a microchip (MDILog) that recorded the date and time of every actuation. Success rates were 17.4% at 12 months and 9.8% at 24 months. During the first month of study, median use was 12 puffs/day in abstainers and 6 puffs/day in failures (p=.049). Abstainers used the spray less in the morning compared with failures (26.6% vs. 32.8% of the total median daily dose; p=.028). By contrast, abstainers used the spray more in the evening/night compared with failures (35.3% vs. 26.7% of the total median daily dose; p=.007). Abstinence during the first two weeks was associated significantly with cessation success at 6 months (OR=17.10) and 24 months (OR=11.09). Although the pattern of use of the nasal spray differed between successful quitters and failures (used in higher doses by the successful quitters), mean daily consumption during the first month was not predictive of success. Mean daily consumption of the nicotine nasal spray remained lower than expected in most participants, particularly in failures.

Administration, Inhalation↗
PubMed2003

Assessing the prevalence of hypertension in populations: are we doing it right?

BACKGROUND: Although it is well recognized that the diagnosis of hypertension should be based on blood pressure (BP) measurements taken on several occasions, notably to account for a transient elevation of BP on the first readings, the prevalence of hypertension in populations has often relied on measurements at a single visit. OBJECTIVE: To identify an efficient strategy for assessing reliably the prevalence of hypertension in the population with regards to the number of BP readings required. DESIGN: Population-based survey of BP and follow-up information. SETTING AND PARTICIPANTS: All residents aged 25-64 years in an area of Dar es Salaam (Tanzania). MAIN OUTCOME MEASURES: Three BP readings at four successive visits in all participants with high BP (n = 653) and in 662 participants without high BP, measured with an automated BP device.RESULTS BP decreased substantially from the first to third readings at each of the four visits. BP decreased substantially between the first two visits but only a little between the next visits. Consequently, the prevalence of high BP based on the third reading--or the average of the second and third readings--at the second visit was not largely different compared to estimates based on readings at the fourth visit. BP decreased similarly when the first three visits were separated by 3-day or 14-day intervals. CONCLUSIONS: Taking triplicate readings on two visits, possibly separated by just a few days, could be a minimal strategy for assessing adequately the mean BP and the prevalence of hypertension at the population level. A sound strategy is important for assessing reliably the burden of hypertension in populations.

Adult↗
PubMed2003

Monitoring compliance in resistant hypertension: an important step in patient management.

Poor compliance with antihypertensive drug regimens is one recognized cause of inadequate blood pressure control. Compliance is difficult to measure, so poor adherence to treatment remains largely undiagnosed in clinical practice. When the therapeutic response to a drug is not the one expected, it is a major challenge for many physicians to decide whether the patient is a non-responder or a non-complier. Poor compliance is therefore often incorrectly interpreted as a lack of response to treatment. Not detecting non-compliance can lead to the wrong measures being taken. Electronic monitoring of compliance provides important longitudinal information about drug-intake behaviour that cannot be obtained in the clinic. Such monitoring can improve both compliance and blood pressure control, and help physicians to make more rational therapeutic decisions. A reliable assessment of compliance could have a great impact on medical costs by preventing unnecessary investigations or dose adaptations in patients who are not taking their drugs adequately, or potentially reducing the number of hospitalizations. Side-effects and lack of effectiveness are two frequent causes of poor compliance. The right choice of antihypertensive drug can therefore contribute to compliance. In this respect, it is important to find a drug regimen that is effective, long-acting and well tolerated. Long-acting antihypertensive drugs that provide good blood pressure control beyond the 24-h dosing period should perhaps be considered as drugs of choice in non-compliant patients with hypertension because they help to prevent the consequences of occasional drug omissions.

Antihypertensive Agents↗
PubMed2003

Angiotensin II receptor blockade: is there truly a benefit of adding an ACE inhibitor?

We assessed the blockade of the renin-angiotensin system (RAS) achieved with 2 angiotensin (Ang) antagonists given either alone at different doses or with an ACE inhibitor. First, 20 normotensive subjects were randomly assigned to 100 mg OD losartan (LOS) or 80 mg OD telmisartan (TEL) for 1 week; during another week, the same doses of LOS and TEL were combined with 20 mg OD lisinopril. Then, 10 subjects were randomly assigned to 200 mg OD LOS and 160 mg OD TEL for 1 week and 100 mg BID LOS and 80 mg BID TEL during the second week. Blockade of the RAS was evaluated with the inhibition of the pressor effect of exogenous Ang I, an ex vivo receptor assay, and the changes in plasma Ang II. Trough blood pressure response to Ang I was blocked by 35+/-16% (mean+/-SD) with 100 mg OD LOS and by 36+/-13% with 80 mg OD TEL. When combined with lisinopril, blockade was 76+/-7% with LOS and 79+/-9% with TEL. With 200 mg OD LOS, trough blockade was 54+/-14%, but with 100 mg BID it increased to 77+/-8% (P<0.01). Telmisartan (160 mg OD and 80 mg BID) produced a comparable effect. Thus, at their maximal recommended doses, neither LOS nor TEL blocks the RAS for 24 hours; hence, the addition of an ACE inhibitor provides an additional blockade. A 24-hour blockade can be achieved with an angiotensin antagonist alone, provided higher doses or a BID regimen is used.

Adult↗
PubMed2003

AT1-receptor antagonism in hypertension: what has been learned with irbesartan?

Irbesartan is a long-acting angiotensin II antagonist acting specifically at the level of the Type 1-receptor subtype (AT1-receptor). This compound lowers blood pressure dose-dependently in hypertensive patients and has a placebo-like tolerability. The antihypertensive efficacy of irbesartan is greatly enhanced by the coadministration of a diuretic, and fixed-dose combinations of irbesartan and hydrochlorothiazide are now available. Irbesartan-based treatment appears especially effective for high-risk patients, such as those with diabetes, renal disease and cardiac hypertrophy. In patients with Type 2 diabetes, irbesartan delays the development of nephropathy as well as the progression of renal failure. Irbesartan may have antiatherosclerotic properties beyond those expected from blood pressure lowering per se: this AT1-blocker decreases the vascular oxidative stress and prevents the procoagulant as well as the pro-inflammatory effects of angiotensin II. Irbesartan given alone or in combination with a diuretic therefore represents a rational approach to treat hypertensive patients.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2002

Renal segmental tubular response to salt during the normal menstrual cycle.

BACKGROUND: It has been suggested that women gain weight and develop peripheral edema during the luteal phase of the menstrual cycle because they tend to retain sodium and water. However, there is actually no clear evidence for physiological, cyclic variations in renal sodium handling during the menstrual cycle. We prospectively assessed the changes in segmental renal sodium handling occurring during the menstrual cycle in response to changes in salt intake. METHODS: Thirty-five normotensive women were enrolled. Seventeen women were randomized and studied in the follicular and 18 in the luteal phases of their menstrual cycle. All women were assigned at random to receive a low (40 mmol/day) or a high (250 mmol/day) sodium diet for seven days on two consecutive menstrual cycles. Renal sodium handling and hemodynamics were measured at the end of each diet period. RESULTS: The changes in sodium intake induced comparable variations in sodium excretion in both phases of the menstrual cycle. In the follicular phase, the increase in salt intake was associated with no change in renal hemodynamics, an increased fractional excretion of lithium (FELi) and a decreased fractional distal reabsorption of sodium (FDRNa), suggesting that sodium reabsorption is reduced both in the proximal and the distal tubules. In contrast, in the luteal phase, the renal response to salt was characterized by a significant renal vasodilation and a marked salt escape from the distal nephron, compared to the women investigated in the follicular phase (P < 0.01). Sodium reabsorption by the proximal nephron was not reduced as indicated by the unchanged FELi. CONCLUSIONS: These results show that the segmental renal handling of sodium differs markedly in the two phases of the menstrual cycle. They suggest that the female hormones modulate the renal handling of sodium at the proximal and distal segments of the nephron in young normotensive women.

Adult↗
PubMed2002

Hyperuricemia, hypertension, and proteinuria associated with high-altitude polycythemia.

Chronic exposure to high altitude is associated with the development of erythrocytosis, proteinuria, and, in some cases, hyperuricemia. We examined the relationship between high-altitude polycythemia and proteinuria and hyperuricemia in Cerro de Pasco, Peru (altitude, 4,300 m). We studied 25 adult men with hematocrits less than 65% and 27 subjects with excessive erythrocytosis (EE; hematocrit > 65%) living in Cerro de Pasco, Peru and compared them with 28 control subjects living in Lima, Peru (at sea level) and after 48 hours of exposure to high altitude. Serum urate levels were significantly elevated in patients with EE at altitude, and gout occurred in 4 of 27 of these subjects. Urate level strongly correlated with hematocrit (r = 0.71; P < 0.0001). Urate production (24-hour urine urate excretion and urine urate-creatinine ratio) was increased in this group compared with those at sea level. Fractional urate excretion was not increased, and fractional lithium excretion was reduced, in keeping with increased proximal reabsorption of filtrate. Significantly higher blood pressures and decreased renin levels in the EE group were in keeping with increased proximal sodium reabsorption. Serum urate levels correlated with mean blood pressure (r = 0.50; P < 0.0001). Significant proteinuria was more prevalent in the EE group despite normal renal function. Hyperuricemia is common in subjects living at high altitude and associated with EE, hypertension, and proteinuria. The increase in uric acid levels appears to be caused by increased urate generation secondary to systemic hypoxia, although a relative impairment in renal excretion also may contribute.

Adult↗
PubMed2002

Comparative angiotensin II receptor blockade in healthy volunteers: the importance of dosing.

OBJECTIVES: We have reported previously that 80 mg valsartan and 50 mg losartan provide less receptor blockade than 150 mg irbesartan in normotensive subjects. In this study we investigated the importance of drug dosing in mediating these differences by comparing the AT(1)-receptor blockade induced by 3 doses of valsartan with that obtained with 3 other antagonists at given doses. METHODS: Valsartan (80, 160, and 320 mg), 50 mg losartan, 150 mg irbesartan, and 8 mg candesartan were administered to 24 healthy subjects in a randomized, open-label, 3-period crossover study. All doses were given once daily for 8 days. The angiotensin II receptor blockade was assessed with two techniques, the reactive rise in plasma renin activity and an in vitro radioreceptor binding assay that quantified the displacement of angiotensin II by the blocking agents. Measurements were obtained before and 4 and 24 hours after drug intake on days 1 and 8. RESULTS: At 4 and 24 hours, valsartan induced a dose-dependent "blockade" of AT(1) receptors. Compared with other antagonists, 80 mg valsartan and 50 mg losartan had a comparable profile. The 160-mg and 320-mg doses of valsartan blocked AT(1) receptors at 4 hours by 80%, which was similar to the effect of 150 mg irbesartan. At trough, however, the valsartan-induced blockade was slightly less than that obtained with irbesartan. With use of plasma renin activity as a marker of receptor blockade, on day 8, 160 mg valsartan was equivalent to 150 mg irbesartan and 8 mg candesartan. CONCLUSIONS: These results show that the differences in angiotensin II receptor blockade observed with the various AT(1) antagonists are explained mainly by differences in dosing. When 160-mg or 320-mg doses were investigated, the effects of valsartan hardly differed from those obtained with recommended doses of irbesartan and candesartan.

Adult↗
PubMed2002

Postischemic forearm skin reactive hyperemia is related to cardovascular risk factors in a healthy female population.

OBJECTIVE: To examine whether forearm postischemic skin reactive hyperemia (SRH) measured by laser Doppler flowmetry (LDF) can be used to explore microvascular function and whether LDF response is related to cardiovascular (CV) risk in a population study. METHODS: SRH of the forearm defined as the percentage increase in cutaneous blood flow from resting conditions to peak dilation following a 2 min upper arm occlusion and CV risk factors were measured prospectively in 862 healthy females screened for cardiovascular risk factors in the context of a campaign designed to promote the 'control' of CV risk factors in women. RESULTS: The Framingham risk score was constructed from age, sex, systolic and diastolic blood pressure, diabetes, total and high-density lipoprotein-cholesterol and left ventricular hypertrophy (Cornell product. The Cornell product for women was calculated as the QRS duration (ms) (R aVL + S V3 + 6 mV)). Although the score was low in this female population (CV event risk at 10 years 7.89) (95% confidence interval, 7.49-8.30) aged 40 to 75 years, we observed an inverse correlation between SRH of the forearm and the CV risk score ( P<0.001). Hormonal replacement therapy (39.4% of the study population was on hormone replacement therapy) had no significant influence on forearm postischemic SRH in this particular population. CONCLUSIONS: This study shows that in a very low CV risk female population, a significant correlation can be observed between the weight of CV risks and the impairment of postischemic forearm SRH. Thus, skin laser Doppler flowmetry may represent a valuable, simple and non-invasive tool to assess and monitor microvascular function in future prospective observational and interventional studies.

Adult↗
PubMed2002

Blood pressure, cardiac, and renal responses to salt and deoxycorticosterone acetate in mice: role of Renin genes.

Several studies have demonstrated that mice are polymorphic for the number of renin genes, with some inbred strains harboring one gene (Ren-1(c)) and other strains containing two genes (Ren-1(d) and Ren-2). In this study, the effects of 1% salt and deoxycorticosterone acetate (DOCA)/salt were investigated in one- and two-renin gene mice, for elucidation of the role of renin in the modulation of BP, cardiac, and renal responses to salt and DOCA. The results demonstrated that, under baseline conditions, mice with two renin genes exhibited 10-fold higher plasma renin activity, 100-fold higher plasma renin concentrations, elevated BP (which was angiotensin II-dependent), and an increased cardiac weight index, compared with one-renin gene mice (all P < 0.01). The presence of two renin genes markedly increased the BP, cardiac, and renal responses to salt. The number of renin genes also modulated the responses to DOCA/salt. In one-renin gene mice, DOCA/salt induced significant renal and cardiac hypertrophy (P < 0.01) even in the absence of any increase in BP. Treatment with losartan, an angiotensin II AT(1) receptor antagonist, decreased BP in two-renin gene mice but not in one-renin gene mice. However, losartan prevented the development of cardiac hypertrophy in both groups of mice. In conclusion, these data demonstrate that renin genes are important determinants of BP and of the responses to salt and DOCA in mice. The results confirm that the Ren-2 gene, which controls renin production mainly in the submaxillary gland, is physiologically active in mice and is not subject to the usual negative feedback control. Finally, these data provide further evidence that mineralocorticoids promote cardiac hypertrophy even in the absence of BP changes. This hypertrophic process is mediated in part by the activation of angiotensin II AT(1) receptors.

Animals↗
PubMed2002

In vitro and in vivo characterization of the activity of telmisartan: an insurmountable angiotensin II receptor antagonist.

In vitro studies have shown that telmisartan is an insurmountable angiotensin II subtype-1 (AT1) receptor antagonist. Herein, the molecular basis of this insurmountable antagonism has been investigated in vitro, and the effect of telmisartan has been compared in vivo with that of irbesartan and candesartan. Association and dissociation kinetics of telmisartan to AT1 receptors have been characterized in vitro on rat vascular smooth muscle cells (RVSMC) expressing solely the AT1 receptor subtype. In a second set of experiments, the antagonistic efficacy of single intravenous doses (0.1, 0.3, and 1 mg/kg) of telmisartan was compared with that of irbesartan (0.3, 1.0, 3.0, and 10.0 mg/kg) and candesartan (0.3 and 1 mg/kg) in conscious, normotensive, male Wistar rats. The results show that the specific binding of [(3)H]telmisartan to the surface of living RVSMC is saturable and increases quickly to reach equilibrium within 1 h. Telmisartan dissociates very slowly from the receptor with a dissociation half-life (t(1/2)) of 75 min, which is comparable with candesartan and almost 5 times slower than angiotensin II (AngII). In vivo, telmisartan blunts the blood pressure response to exogenous AngII dose dependently. The blockade is long lasting and remains significant at 24 h at doses >0.1 mg/kg. Ex vivo assessment of the AT1 receptor blockade using an in vitro AngII receptor binding assay shows similar results. When administered intravenously in rats, telmisartan is 10-fold more potent than irbesartan and comparable to candesartan. Taken together, our in vitro data show that the insurmountable antagonism of telmisartan is due at least in part to its very slow dissociation from AT1 receptors.

Angiotensin II↗
PubMed2002

Renal hemodynamic and natriuretic effects of concomitant Angiotensin-converting enzyme and neutral endopeptidase inhibition in men.

This double-blind placebo-controlled study was designed to investigate the acute and sustained hormonal, renal hemodynamic, and tubular effects of concomitant ACE and neutral endopeptidase (NEP) inhibition by omapatrilat, a vasopeptidase inhibitor, in men. Thirty-two normotensive subjects were randomized to receive a placebo, omapatrilat (40 or 80 mg), or the fosinopril/hydrochlorothiazide (FOS/HCTZ; 20 and 12.5 mg, respectively) fixed combination for 1 week. Blood pressure, renal hemodynamics, urinary electrolytes and atrial natriuretic peptide excretion, and several components of the renin-angiotensin system were measured for 6 hours on days 1 and 7 of drug administration. When compared with the placebo and the FOS/HCTZ combination, omapatrilat induced a significant decrease in plasma angiotensin II levels (P<0.001 versus placebo; P<0.05 versus FOS/HCTZ) and an increase in urinary atrial natriuretic peptide excretion (P<0.01). These hormonal effects were associated with a significant fall in blood pressure (P<0.01) and a marked renal vasodilatation, but with no significant changes in glomerular filtration rate. The FOS/HCTZ markedly increased urinary sodium excretion (P<0.001). The acute natriuretic response to FOS/HCTZ was significantly greater than that observed with omapatrilat (P<0.01). Over 1 week, however, the cumulative sodium excretion induced by both doses of omapatrilat (P<0.01 versus placebo) was at least as great as that induced by the dose of FOS/HCTZ (P=NS versus FOS/HCTZ). In conclusion, the results of the present study in normal subjects demonstrate that omapatrilat has favorable renal hemodynamic effects. Omapatrilat combines potent ACE inhibition with a sustained natriuresis, which explains its well-documented potent antihypertensive efficacy.

Adult↗