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Biomedical subjects

M Bellet

Publications and source records attributed to M Bellet.

At least 19 recordsLinked to original sources
PubMed2026

Impact of BRCA2 pathogenic variants on outcomes to first-line CDK4/6 inhibitors plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Currently, three cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are approved in combination with endocrine therapy (ET) as first-line treatment of patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). The impact of homologous recombination repair (HRR) pathogenic variants (PV) on outcomes with first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC remains uncertain. PATIENTS AND METHODS: We conducted a multicenter, real-world, case-control study including 233 patients with HR-positive/HER2-negative MBC treated with first-line CDK4/6i and ET. Among them, 116 presented HRR PVs and 117 were matched controls with negative germline testing. The primary objective was to compare progression-free survival (PFS) and overall survival among germline-BRCA2 PV carriers, other HRR PV carriers, and controls. To minimize baseline differences in prognostic factors between PV carriers and controls, inverse probability of treatment weighting was applied. Molecular analyses in pre-CDK4/6i samples among patients with BRCA2 PV were carried out, including RAD51-foci, PAM50 intrinsic subtype, and RB1 loss of heterozygosity (LOH). RESULTS: Among the included 233 patients, median age at diagnosis was 45 years (interquartile range 39-56) and 33% had de novo metastatic disease. Primary resistance to adjuvant ET was present in 10% and secondary resistance in 27%. After a median follow-up of 44 months, patients with germline-BRCA2 PVs (n = 67) had significantly shorter PFS [11 versus 27 months; adjusted hazard ratio (aHR) 2.73, 95% confidence interval (CI) 1.65-4.51, P < 0.001] compared with controls. Among patients with endocrine-sensitive disease, germline BRCA2 PV carriers had markedly shorter PFS (median PFS 12 versus 39 months; aHR 4.04; 95% CI 1.82-8.98, P < 0.001). Exploratory analyses revealed RB1 LOH before CDK4/6i-treatment in most evaluable BRCA2 tumors. CONCLUSIONS: BRCA2 PVs were independently associated with poorer outcomes to first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC compared with controls, especially relevant among patients with endocrine-sensitive disease. These findings suggest that patients with a germline PV in BRCA2 may require alternative first-line strategies.

Humans↗
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

[3-dimensional reconstruction of x-ray computed tomographic views in fractures of the acetabulum].

In 21 cases of acetabulum fractures of 19 patients, the authors compare the findings given by three dimensional reconstructions of axial CT scan cuts with the plain films. The number of CT scan cuts is reasonable for each patient. Working time is about 20 to 30 minutes for the technician. In the cases of complex and displaced fractures, three dimensional imaging brings often decisive informations for the therapeutic management of these patients. Unusual views are often allowed but completely adapted to each type of fracture.

Acetabulum↗
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

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

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↗
PubMed1989

Need for plasma angiotensin measurements to investigate converting-enzyme inhibition in humans.

Since only a minute proportion of total angiotensin-converting enzyme (ACE) is present in plasma, the reliability of conventional in vitro measurements of ACE activity has been questioned. Data presented here demonstrate that the definition of ACE inhibition depends on the methodology used, with different results obtained with different substrates. We have developed a method that provides accurate and precise determinations of "true" angiotensin levels and in vivo ACE activity was estimated by measuring the plasma angiotensin II/angiotensin I ratio. Since the initial interruption of angiotensin II production by an ACE inhibitor stimulates renal renin release, the response can be quantitated by measuring changes in plasma levels of angiotensin I. The actual state of the renin-angiotensin system during ACE inhibition is represented by the plasma angiotensin II level. When ACE inhibition is no longer complete, increased angiotensin I levels bring the system back toward initial angiotensin II concentrations.

Administration, Oral↗
PubMed1989

Crossover design for the dose determination of an angiotensin converting enzyme inhibitor in hypertension.

In order to determine the dose regimen of new antihypertensive compounds, between-patient trials are usually performed. However, the combined use of a crossover design and a precise methodology to measure blood pressure (BP) and biological effects can provide relevant data with a minimal number of patients, if there is no carryover effect which invalidates the experiment. Such goals were successfully achieved with just 25 hypertensive patients who were randomly allocated in double-blind fashion every 2 weeks to a new angiotensin converting enzyme (ACE) inhibitor, benazepril [10 mg once a day (o.d.), 20 mg o.d., 10 mg twice a day (b.i.d.) and 20 mg b.i.d.], or a placebo. The mean BP fall [systolic (SBP)/diastolic (DBP), measured in mmHg] just before drug intake was significantly greater with benazepril: -14/-9 (10 mg o.d.); -15/-8.5 (20 mg o.d.); -22.5/-14 (10 mg b.i.d.), and -21/-13 (20 mg b.i.d.) in comparison with placebo (-3/-3). Mean active plasma renin (measured in pg/ml), assessed by an immunoradiometric assay based on two monoclonal antibodies, increased significantly in a dose-dependent manner, by +0.7 (placebo), +15.0 (10 mg o.d.), +23.4 (20 mg o.d.), +44.4 (10 mg b.i.d.) and +78.8 (20 mg b.i.d.), whereas plasma ACE decreased (by 67 and 78% after 10 and 20 mg o.d., respectively, and by 91-92% after 10 and 20 mg b.i.d.). In the clinical development of an antihypertensive drug, the earlier use of such within-patient studies, with the random insertion of one placebo period between the active periods, should help in the dose-response curve search.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Predictive factors of the blood pressure fall induced by intravenous nicardipine.

The effect on blood pressure of the dihydropyridine derivative nicardipine was studied in 87 essential hypertensive patients aged 25-77 years. A total cumulative dose of 8.75 mg nicardipine was administered over a 30-min period by continuous intravenous infusion. The dose was doubled every 10 min from 1.25 to 5.0 mg. The mean blood pressure fall and the heart rate rise were both dose-related. At 30 min, mean blood pressure fell by 18.9 +/- 7.5% vs. baseline values (p less than 0.001), heart rate increased by 28.0 +/- 11.8% (p less than 0.001), and the renin level by 20.7 +/- 32.5% (p less than 0.001). The blood pressure fall was correlated positively with age (r = 0.521; p less than 0.001) and negatively with the rise in heart rate (r = -0.308; p less than 0.01) and renin level (r = -0.205; p = 0.05). After eliminating the linear effects of age by the partial correlation method, blood pressure fall and the initial renin level were no longer correlated (r = -0.046, NS), whereas the positive correlation between age and blood pressure fall persisted after eliminating the effect of renin (r = 0.464; p less than 0.001). The slope of the regression line for the heart rate rise vs. the blood pressure fall was taken to reflect the baroreflex sensitivity. This sensitivity was negatively correlated to age (r = -0.515; n = 51; p less than 0.001) in the 51 of the 87 patients for whom it could be calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

[The value of echography in the early diagnosis of renal lesions in the Laurence-Moon-Bardet-Biedl syndrome. Apropos of a case].

The Laurence-Moon-Bardet-Biedl syndrome (LMBB) is characterized by the association of obesity, hypogonadism, polydactyly, mental retardation and pigmentary retinitis. Symptomatic or asymptomatic renal dysplasia (calyceal diverticula, precalyceal tubular ectasia, cysts) is frequently associated with LMBB. The authors consider renal sonography as the convenient investigation for an early detection of such dysplasia as in the case they reported here.

Child↗
PubMed1988

[Chondrodysplasia punctata. Report of four cases in two sibships].

Chondrodysplasia punctata has very diverse clinical and radiological features. Its diagnosis may be suggested as early as in the neonatal period in front of an abnormal facial appearance, sometimes associated with bone and vertebrae defects. Radiological exams will assert it. Its subsequent course depends on the accompanying visceral abnormalities. Genetics advice is closely related to these. Ultrasonography is the only actual possibility of prenatal diagnosis. However our attitude must be guided by the clinical course (of the disease) of the initial case in the sibship.

Chondrodysplasia Punctata↗
PubMed1987

Measurement of irradiation doses secondary to bedside radiographs in a medical intensive care unit.

The authors prospectively studied the radiation doses to radio-sensitive organs secondary to bedside radiographs in intensive care patients and in a control phantom. Dosimeters were taped on different organs during each bedside X-ray. The mean radiation doses, expressed in 10(-5) Gy (m-rad), for an "average patient" who was hospitalized 9 days and had 6 chest X-rays were respectively: 292 to the sternal bone marrow; 239 to the thyroid gland; 3 to the testes; 1 to the ovaries; 605 to the eye for 2 maxillary sinus X-rays. No diffused irradiation was measured during a 2-month period in the intensive care unit nor on dosimeters worn by four nurses.

Adult↗
PubMed1987

Evaluation of slow release nicardipine in essential hypertension by casual and ambulatory blood pressure measurements. Effects of acute versus chronic administration.

We conducted a randomized placebo-controlled double-blind study in 40 hypertensive subjects to assess the antihypertensive effect of a new galenic form of nicardipine administered at a dosage of 50 mg twice daily for 3 weeks. Regardless of whether blood pressure was measured by standard mercury sphygmomanometer, non-ambulatory automatic oscillometry or a Remler ambulatory blood pressure recorder, it dropped by a significantly larger amount in the nicardipine group than in the placebo group. In the control group, a placebo effect was observed with the ambulatory diastolic blood pressure recording, whereas it was not observed with hospital blood pressure measurements, especially when using the serial measurements performed for 30 min by an automatic recorder. The fall in blood pressure measured with the Remler recorder was correlated with the fall measured 10-20 min during one acute intravenous nicardipine perfusion before the trial, although the correlation coefficients do not suggest clinically relevant predictability of nicardipine efficacy at the individual level. The present findings support the need for controlled double-blind trials with careful office blood pressure measurements.

Administration, Sublingual↗
PubMed1987

Converting-enzyme inhibition buffers the counter-regulatory response to acute administration of nicardipine.

1. To investigate the interaction of angiotensin-converting-enzyme (ACE) inhibitor and calcium antagonist, we conducted a double-blind randomized, placebo-controlled crossover study of a new ACE inhibitor (CGS 14824 A, 20 mg) during intravenous administration (i.v.) of nicardipine in eight normotensive healthy subjects. Nicardipine was infused to give cumulative doses of 1.25, 3.75, and 8.75 mg after 10, 20 and 30 min. 2. ACE inhibition was demonstrated 24 h after the first CGS 14 824 A intake (61%). Three hours after the second dose this inhibition was more marked (98%). 3. I.v. nicardipine administration induced a significant and similar fall in systolic or diastolic blood pressure with and without ACE activity (-3/-6 vs -2/-8%), while tachycardia was significantly decreased by CGS 14 824 A (+14 vs +30%, P less than 0.02). The increase of plasma noradrenaline was also significantly blunted (+1.8 +/- 0.3 vs +3.1 +/- 0.7 pmol ml-1, P less than 0.05). 4. Active and total plasma renin increased at the end of nicardipine infusion in the presence or absence of ACE inhibition. Inactive renin did not increase after nicardipine infusion under placebo. It was higher 3 h after the second intake of CGS 14 824 A and then increased after nicardipine infusion. 5. The rise in plasma aldosterone during i.v. calcium antagonist infusion was diminished after ACE inhibition (126 +/- 39 vs 277 +/- 120 pmol l-1, P less than 0.02). 6. In conclusion, converting-enzyme inhibition buffers the rise in heart rate, plasma noradrenaline and plasma aldosterone induced by acute calcium blockade.

Adult↗
PubMed1987

[Hemodynamic effects of a new iso-osmotic contrast medium in selective left ventriculography].

To evaluate the myocardial hemodynamic effects of a new iso-osmotic contrast agent (Hexabrix 160: H 16) a randomized cross-over study was performed comparing Hexabrix 160 with Sodium Meglumine diatrizoate (Radioselectan 76: R 76) in 20 patients with ischemic heart disease. H 16 produced substantially smaller (p less than 0.001) increases in heart rate (68 +/- 11 to 73 +/- 12) than R 76 (69 +/- 12 to 88 +/- 15) and smaller decreases in left systolic ventricular pressure (131 +/- 15 to 128 +/- mmHg) than R 76 (132 +/- 14 to 94 +/- 15 mmHg). Both contrast media resulted in an increase in contractility beginning three to five seconds after the onset of the injection and reached its maximum at 45 seconds. However the increases in contractility was smaller with H 16 than R 76: H 16 caused a significantly smaller (p less than 0.01) increases in V max. (0.1 CIRC/s) than R 76 (0.35 CIR/s). The hemodynamic effects of H 16 were probably in relation with the Frank-starling mechanism. The lowest variation of preload observed (left ventricle end-diastolic pressure: 12 +/- 4 to 14 +/- 5 mmHg) showed that this contrast medium appeared to behave like isotonic serum. These results suggest that H 16 may preferable for digital left ventriculography.

Blood Pressure↗
PubMed1987

[A simple method for measuring anteversion of the acetabulum from a frontal radiograph of the hip].

A simple, reproducible and reliable method is proposed for measurement of cotyloid version. Using a standing frontal image of hip, the cotyloid borders are identified and a single-plane geometric projection determines the precise degree of version. This study can also be made from a conventional frontal pelvic image with bipodalic weight bearing. Knowledge of spatial orientation allows a better approach to head-cotyle biomechanical phenomena and thus improved understanding of the genesis of certain hip diseases.

Acetabulum↗