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Biomedical subjects

J Ménard

Publications and source records attributed to J Ménard.

At least 109 records · Page 6Linked to original sources
PubMed1992

Improving hypertension treatment. Where should we put our efforts: new drugs, new concepts, or new management?

Despite the availability of numerous antihypertensive agents, a concerted research effort to develop new approaches to hypertension treatment is necessary. Published results of large multicenter trials emphasize the benefits of available treatments in highly selected patients. A critical look at the results shows that treatment failure is frequent and side effects are common. In the Systolic Hypertension in the Elderly Program, 28 to 35% of patients did not reach the goal blood pressure, 13% stopped treatment because of side effects, and 21% required medication other than a diuretic and a beta-blocker. Basic research may bring forth novel concepts of treatment, such as neutral endopeptidase inhibition, renin inhibition, or new techniques such as gene therapy. In the meantime, among many other lines of research, type 1 angiotensin II-receptor antagonists represent a promising new group of agents for the vast majority of hypertensive patients who are renin-dependent. A different global approach to hypertension management is also needed. Because hypertension is a heterogeneous disease, individual sequential monotherapy or the "N of 1" trial aim to select the most effective drug for each patient. To achieve the accurate assessment of drug efficacy that is a prerequisite for this approach, the number of blood pressure measurements before and during drug administration must be increased. For this purpose, self-blood pressure measurement and teletransmission of results to the physician will provide a major treatment advance.

Angiotensin Receptor Antagonists↗
PubMed1992

Unmasking of the hypotensive effect of nifedipine in normotensives by addition of the angiotensin converting enzyme inhibitor benazepril.

OBJECTIVE: To study the pharmacological interaction between a dihydropyridine derivative (nifedipine slow release 20 mg) and inhibition of the renin-angiotensin system (benazepril 10 mg). DESIGN: Single application at intervals of 2 weeks in an open-label three-way cross-over design. SETTING: Institutional pharmacological unit. PARTICIPANTS: Nine healthy male volunteers. MAIN OUTCOME MEASURES(S): Blood pressure and heart rate were recorded in the supine position for 24 h as well as plasma drug levels, plasma angiotensin converting enzyme activity and active plasma renin concentration. RESULTS: Nifedipine increased active plasma renin two-fold and benazepril increased it five-fold. The combination of the two drugs accelerated the increase of active renin during the first 2 h after drug intake. Whereas no hypertensive effect could be detected after nifedipine or benazepril alone, a significant fall in systolic and diastolic blood pressure was observed for up to 9 to 12 h after the combination. The increase in heart rate induced by nifedipine was minimized by the addition of benazepril. There was no interaction between the pharmacokinetics of benazeprilate and nifedipine which would explain these pharmacodynamic effects. CONCLUSION: These results demonstrate that, in normotensive volunteers, the renin-angiotensin system contributes to mask the hypotensive effect of a single oral dose of dihydropiridine. The concomitant administration of a converting enzyme inhibitor discloses the hypotensive effect and limits the baroreflex-mediated increase in heart rate secondary to vasodilation.

Adult↗
PubMed1991

[Validation of Oscillomat, a device for self-measurement of blood pressure. Comparison with mercury sphygmomanometers].

Self-measurement of arterial blood pressure (BP) is a valuable aid in the follow-up of hypertensive patients. Unfortunately, the devices utilized are not subject to certification and therefore must be validated. In this study, the accuracy and precision of BP measurement with the Oscillomat device were measured and simultaneously compared with those of a standard mercury sphygomomanometer in 60 subjects and with a random zero mercury sphygmomanometer in 44 subjects. The Oscillomat device correctly explored systolic and diastolic BP within a 55 to 210 mmHg range. Compared with the auscultatory method, it tended to underestimate systolic BP values by + 3 to -15 mmHg and diastolic B.P. values by + 1 to -15 mmHg.

Adult↗
PubMed1991

Arterial and endocrine effects of a combination of an angiotensin converting enzyme inhibitor and a vasodilator in normotensive healthy volunteers.

The aim of the present study was to look for possible additive or synergistic effects of the combined oral administration of a single dose of an angiotensin converting enzyme (ACE) inhibitor, benazepril (10 mg) (B), and a long-acting vasodilator, cadralazine (5 mg) (C), on blood pressure, arterial parameters, and active plasma renin. The study was carried out in eight normotensive subjects according to a double-blind, randomized, placebo-controlled, crossover design. Blood pressure (BP), heart rate, humeral artery diameter (D), carotid-femoral pulse-wave velocity (PWV), finger-pulse ratio (FPR), and plasma active renin (PAR) were measured at baseline and every 2 h over 8 h. A significant treatment effect was observed for supine and tilted BP, FPR, PWV, and PAR. The largest decrease in supine systolic and diastolic BP was observed with the combination (10.0 +/- 6.9/7.2 +/- 3.7 mm Hg). Six hours after drug intake, the mean changes in FPR were 0.05 +/- 0.24 (P), -0.06 +/- 0.30 (C), 0.13 +/- 0.32 (B), and 0.28 +/- 0.34 (B + C), and the mean changes in PWV were 0.14 +/- 0.66 m/s (P), 0.09 +/- 0.54 m/s (C), -0.29 +/- 0.50 m/s (B), and -0.55 +/- 0.48 m/s (B + C). PAR was more markedly augmented with the combination of the two drugs (142 +/- 40 pg/ml) than with benazepril alone (90 +/- 62 pg/ml). It was concluded that a single noneffective dose of a vasodilator administered together with an ACE inhibitor in normotensives can lower blood pressure and increase arterial compliance and plasma active renin.

Administration, Oral↗
PubMed1991

Renin release regulation during acute renin inhibition in normal volunteers.

Blockade of the renin-angiotensin system by an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II (Ang II) antagonist is accompanied by a reactive rise in renin release. This rise is generally attributed to interruption of the short feedback loop between Ang II and renin release. Similarly, after the administration of a renin inhibitor, the plasma concentrations of active and total renin are increased and plasma renin activity is suppressed. The aim of the present study was to investigate if a fall in the plasma Ang II level is the unique determinant of the rise in the active renin (AR) level that follows renin inhibition. Six normal male volunteers participated in three successive 240-minute experiments at weekly intervals according to a single-blind randomized Latin square design. For experiment 1, Ang II was infused at 2 ng/kg/min from 0 to 60 minutes and at 4 ng/kg/min from 60 to 120 minutes. For experiment 2, 0.3 mg/kg of the new potent renin inhibitor Ro 42-5892 was injected at 30 minutes followed by infusion at 0.1 mg/kg/hr from 30 to 240 minutes. For experiment 3, Ang II and Ro 42-5892 were administered simultaneously at the same doses as described above. The mean +/- SEM Ang II concentration increased from 10.2 +/- 1.6 to 33.7 +/- 11.2 pg/ml after infusion of exogenous peptide. It decreased from 9.5 +/- 0.9 to 1.4 +/- 0.3 pg/ml after the injection of Ro 42-5892 and increased from 15.6 +/- 2.9 to 37.1 +/- 11.8 pg/ml after the simultaneous infusion of both compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1991

Effects of purified Pasteurella multocida dermonecrotoxin on the nasal ventral turbinates of fattening pigs: histological observations.

Fattening specific pathogen-free derived pigs were injected intramuscularly with dermonecrotoxin of Pasteurella multocida, capsular type D. Ten days later, the nasal ventral turbinates and liver were examined histologically. A moderate turbinate atrophy was observed due to an increased number of osteoclasts and the absence of intramembranous bone apposition. Liver lesions were limited to some hepatocyte necrosis, sinusoid neutrophil infiltration and Kupffer cell hypertrophy. This study demonstrated that adult pigs are sensitive to P. multocida dermonecrotoxin.

Animals↗
PubMed1990

[Intraluminal angioplasty in renovascular arterial hypertension. 104 cases].

Between January 1, 1985 and January 1, 1988, 104 patients with arterial hypertension and renal artery stenosis were treated by percutaneous transluminal angioplasty (PTA). The procedure was justified by the resistance of hypertension to other treatments in 50 patients with atheromatous stenosis and 38 patients with fibrodysplasic stenosis. In the remaining 16 patients, who had severe atheroma, PTA was made necessary by ischaemic renal failure. Out of 52 PTAs (including 2 bilateral in one stage) performed in atheroma patients without renal failure, 48 (92 per cent) were immediate technical successes. In 44 patients arterial pressure measurements after 7.5 months (2-24) showed cure in 6 cases (13 per cent), improvement in 29 cases (66 per cent) and failure in 9 cases (21 per cent). Control arteriography of 40 arteries showed success in 28 cases (70 per cent), residual stenosis in 9 (22 per cent) and restenosis in 3 cases (8 per cent) (2 secondary successes of PTA). In patients with fibrodysplastic stenosis, 42 PTAs (4 bilateral) resulted in immediate angiographic success in 81 per cent. In 34 patients arterial pressure measurements after 8.2 months (2-35) showed cure in 2 cases (65 per cent), improvement in 10 cases (29 percent) and failure in 2 cases. Angiography of 34 arteries showed success in 31 (91 per cent) and restenosis in 3 (2 bypasses). In 13 of the 16 patients with renal failure, the renal function was stabilized by PTA, but 5 patients needed surgery and 2 were put on chronic dialysis. It is concluded that the immediate and medium term success rates of renal angioplasty confirm the value of this recanalization procedure in fibrodysplasia and atheroma.

Adult↗
PubMed1990

From the parallel group design to the crossover design, and from the group approach to the individual approach.

The consequences of heterogeneity in response to antihypertensive drugs for the clinical development programs of new antihypertensive drugs and for the care of the individual hypertensive patient have not previously been sufficiently recognized. They play a role in the inappropriate choice of too-high daily doses of some antihypertensive drugs at the end of extensive international development programs. They are also implicated in the insufficient control of blood pressure observed in the long-term multicenter trials in hypertension, where some patients have been treated for several years with drugs that were not the most appropriate for their disease and which did not adequately control their blood pressure. In addition to the parallel group studies, the use of double-blind two-period or multiple period crossover designs can provide valid data for the dose-finding of new antihypertensive drugs and their comparative evaluation. At the end of the trial, these designs also offer each patient the opportunity to be treated with the right dose of the drug most appropriate for his or her disease.

Antihypertensive Agents↗
PubMed1990

Computer-assisted techniques for evaluation and treatment of hypertensive patients.

An integrated approach, progressively implemented in the ARTEMIS system since 1975, is described for the computerized management of hypertensive patients. From a medical point of view, computerized programs can be used to memorize patients' individual records and profiles, to facilitate patient management and follow-up, to store medical knowledge about hypertension and to provide facilities for decision making at the level either of the individual patient or of the population followed up. From a technical point of view, the methodology used integrates data and knowledge management facilities into the same software. Five hypertension clinics are presently using the system in France and more than 22,000 records have been registered. Answer rates to 12 mandatory questions regarding past history and examination at first visit were superior to 95% in 19,601 records created between January 1976 and December 1987. Patient database interrogation can be used to evaluate the sensitivity and specificity of various signs and symptoms for the diagnosis of secondary hypertension, and to predict, for each patient, his/her cardiovascular risk, the risk of drop-out, the risk of insufficient blood pressure control and the probable blood pressure level. It also serves to test the content and validity of the associated expert system which is progressively built up. A prospective evaluation of the performance of the expert system on 80 cases of hypertension showed overall agreement between the specialists and the expert system ranging from 58 to 91% depending on the decision.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Treating the individual hypertensive patient: considerations on dose, sequential monotherapy and drug combinations.

For the general practitioner to be able to prescribe optimal therapy to his individual hypertensive patients, he needs accurate information on the therapeutic agents he is going to administer and practical treatment strategies. The information on drugs and drug combinations has to be applicable to the treatment of individual patients and not just patient study groups. A basic requirement is knowledge of the dose-response relationship for each compound in order to choose the optimal therapeutic dose. Contrary to general assumption, this key information is difficult to obtain and often not available to the physician for many years after marketing of a drug. As a consequence, excessive doses are often used. Furthermore, the physician needs comparative data on the various antihypertensive drugs that are applicable to the treatment of individual patients. In order to minimize potential side effects due to unnecessary combinations of compounds, the strategy of sequential monotherapy is proposed, with the goal of treating as many patients as possible with monotherapy at optimal doses. More drug trials of a crossover design and more individualized analyses of the results are badly needed to provide the physician with information that he can use in his daily practice. In this time of continuous intensive development of new antihypertensive agents, much could be gained in enhanced efficacy and reduced incidence of side effects by taking a closer look at the drugs already available and using them more appropriately in individual patients.

Antihypertensive Agents↗
PubMed1990

Influence of acetylator status on the haemodynamic effects and pharmacokinetics of cadralazine in healthy subjects.

1. Cadralazine is a new antihypertensive agent which causes peripheral vasodilation, probably mediated by a hydrazinopyridazine metabolite. 2. The possible influence of acetylator status on the pharmacokinetics and haemodynamics of the drug was studied in six fast and six slow acetylators over a period of 24 h after administration of a single 10 mg oral dose. 3. There were no differences between the two groups in AUC and Cmax values of cadralazine and apparent metabolite, the latter defined as the sum of the free and conjugated hydrazinopyridazine. Peak plasma concentrations of these compounds were reached after 1 h. Thereafter, the concentration of the metabolite declined more slowly than that of cadralazine. 4. No effects on blood pressure were noted. Changes in heart rate and plasma renin were delayed by 3-5 h with respect to the time-course of drug and metabolite in plasma; maximum responses occurred at 4-6 h after drug administration. The extent of the increase in plasma renin activity was slightly greater in slow than in fast acetylators, but the difference was not significant statistically.

Acetylation↗
PubMed1990

Effect of bradykinin and kininogens in isolated rat kidney vasoconstricted by angiotensin II.

The hemodynamic and endocrine effects of bradykinin and kininogens were investigated using a closed-circuit isolated rat kidney perfused with angiotensin II (ANG II). ANG II induced vasoconstriction, stimulation of urinary kallikrein release, and inhibition of renin secretion. Bradykinin markedly increased renal perfusate flow (RPF) and produced a slight but significant diuresis and natriuresis. The inhibitory effect of ANG II on renin secretion was delayed. Urinary kallikrein secretion was unchanged. The effect of bradykinin was suppressed by the competitive kinin antagonist [DArg,Hyp3,Thi5,8,DPhe7]bradykinin. Kallikrein-sensitive rat high-molecular-weight kininogen produced a progressive rise in renal perfusate flow. Exocrine function and renin and kallikrein secretions were unchanged. Immunoreactive kinins, identified as bradykinin by high-pressure liquid chromatography, were liberated into the perfusate. Perfusate immunoreactive high-molecular-weight kininogen decreased in parallel as a result of consumption. The kalikrein-resistant T-kininogen was not hydrolyzed to release a kinin, had no effect on renal function, and its concentration in the perfusate remained constant. These results suggest that kinin can be produced in the renal circulation from kallikrein-sensitive circulating kininogens and can antagonize the vasoconstrictor effect of ANG II and alter renal hemodynamics. They provide evidence that the kallikrein-kinin system can participate with the renin-angiotensin system in the control of renal blood flow.

Angiotensin II↗
PubMed1990

Determinants of angiotensin II generation during converting enzyme inhibition.

The reaction of the renin-angiotensin system to acute angiotensin converting enzyme inhibition was investigated in a single-blind, crossover study in nine normal volunteers receiving two out of three regimens in random order: the new converting enzyme inhibitor benazepril (20 mg once or 5 mg four times at 6-hour intervals) or enalapril (20 mg). Plasma converting enzyme activity, drug levels, angiotensin I and angiotensin II, active renin, and aldosterone were measured before and 1-4 hours and 14-30 hours after drug intake. Baseline in vitro plasma converting enzyme activity was 97 +/- 15 nmol/ml/min (mean +/- SD) when Hip-Gly-Gly was used as substrate, but with carbobenzoxy-Phe-His-Leu (Z-Phe-His-Leu) or angiotensin I as substrate it was only 20 +/- 4 and 1.7 +/- 0.3 nmol/ml/min, respectively. Discriminating power at peak converting enzyme inhibition was enhanced with the two latter substrates. In vivo converting enzyme activity was estimated by the plasma angiotensin II/angiotensin I ratio, which correlated well with in vitro converting enzyme activity using Z-Phe-His-Leu as substrate (r = 0.76, n = 252). Angiotensin II levels returned to baseline less than 24 hours after drug administration, whereas in vitro and in vivo converting enzyme activity remained considerably inhibited and active renin together with angiotensin I levels were still elevated. A close linear relation was found between plasma angiotensin II and the angiotensin I/drug level ratio (r = 0.91 for benazeprilat and r = 0.88 for enalaprilat, p less than 0.001). Thus, plasma angiotensin II truly reflects the resetting of the renin-angiotensin system at any degree of converting enzyme inhibition. The ratio of plasma angiotensin II to angiotensin I represents converting enzyme inhibition more accurately than in vitro assays, which vary considerably depending on substrates and assay conditions used.

Angiotensin I↗
PubMed1990

Use of crossover trials to obtain antihypertensive dose-response curves and to study combination therapy during the development of benazepril.

When a new drug is developed, one of the first requirements is to establish the correct dose. Unfortunately, in dose-determination studies, not enough lessons have been learned from the past. Pilot studies are often planned without sufficient statistical power, due to an insufficient number of patients and highly variable blood pressure measurements. In the development of the new angiotensin converting enzyme (ACE) inhibitor benazepril, crossover trials were used to obtain useful information. At the end of phase II of the benazepril development, a double-blind crossover study was carried out with 25 patients, and the results made it possible to redefine the 12- and 24-h effects of benazepril in comparison with placebo. Moreover, the crossover trial allowed an investigation of the biological effects of the treatment. In further work, the efficacy of 10 mg benazepril, administered once a day, was confirmed in comparison with captopril and enalapril, with a beta-risk of less than 20%. Since this crossover study yielded reliable data, and there was no carryover effect, a similar crossover design was used to study the interaction between benazepril and nifedipine. In the past, mistakes were made and many antihypertensive drugs were administered in high doses, with no further beneficial effect on blood pressure and an increased risk of side effects. Work described in this paper shows that fewer but better designed and implemented studies can improve the efficiency and value of dose-finding studies for antihypertensive drugs.

Antihypertensive Agents↗