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1.
Ann Oncol ; 34(4): 397-409, 2023 04.
Article in English | MEDLINE | ID: mdl-36709040

ABSTRACT

BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI) and overall survival (OS). RESULTS: Younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and CN amplifications (CNAs) (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Additionally, they had significantly higher frequencies of features suggestive of HRD (27% versus 21%) and a higher proportion of PIK3CA mutations with concurrent CNAs (23% versus 11%). Genomic features suggestive of HRD, PIK3CA mutations with CNAs, and CNAs were associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% aged ≥40 years. Poor prognostic features [n = 584 (46%)] versus none [n = 692 (54%)] had an 8-year DRFI of 84% versus 94% and OS of 88% versus 96%. Younger women (<40 years) had the poorest outcomes: 8-year DRFI 74% versus 85% and OS 80% versus 93%, respectively. CONCLUSION: These results provide insights into genomic alterations that are enriched in young women with HR+HER2- EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.


Subject(s)
Breast Neoplasms , Humans , Female , Aged , Breast Neoplasms/drug therapy , Receptor, ErbB-2/metabolism , Prognosis , Genomics , Class I Phosphatidylinositol 3-Kinases/genetics
2.
J Hum Nutr Diet ; 32(4): 468-479, 2019 08.
Article in English | MEDLINE | ID: mdl-30663156

ABSTRACT

BACKGROUND: The influence of nutrition on breast cancer prognosis is still inconclusive and therefore dietary interventions incorporating dietary biomarkers are needed to confirm compliance with dietary goals and clarify biological mechanisms. The present study assessed whether a lifestyle intervention in breast cancer survivors could affect dietary biomarkers of fruit and vegetables and fatty acids. METHODS: In this phase II single-arm trial, 37 overweight/obese early stage breast cancer patients completed a 12-week diet and exercise intervention. The intervention involved 1-h weekly diet sessions delivered by a dietician and 75-min bi-weekly physical activity sessions of moderate-to-high intensity led by trained monitors. Before and after the intervention, three 24-h dietary recalls were carried out to calculate nutrient intakes and, in addition, blood samples were taken to measure plasma carotenoids, vitamin E and retinol concentrations and erythrocyte membrane fatty acid (EFA) composition. Wilcoxon signed rank tests were used to assess changes in dietary and biomarkers measurements over the intervention period. RESULTS: After the intervention, there was a significant increase in the intake of dietary carotenoids (+15.1% compared to baseline) but not plasma carotenoids levels (+6.3%). Regarding the EFA levels, we observed a significant decrease in percentage of saturated fatty acids (-1.4%) and n-6 polyunsaturated fatty acids (-2.9%) and an increase in monounsaturated fatty acids (1.7%) and total and long-chain n-3 polyunsaturated fatty acids (by 13.1% and 13.7%, respectively). A favourable decrease in the ratio of long-chain n-6 to n-3 polyunsaturated fatty acids (-9.1%) was also observed. CONCLUSIONS: After a short-term diet and exercise intervention in overweight/obese breast cancer survivors, we observed significant changes in dietary nutrients and fatty acid biomarkers, suggesting positive dietary changes that could be relevant for breast cancer prognosis.


Subject(s)
Breast Neoplasms/blood , Carotenoids/blood , Diet/methods , Erythrocyte Membrane/metabolism , Fatty Acids/analysis , Life Style , Adult , Biomarkers/blood , Breast Neoplasms/complications , Cancer Survivors/psychology , Diet/psychology , Energy Intake , Exercise , Female , Humans , Middle Aged , Obesity/blood , Obesity/complications , Obesity/therapy , Overweight/blood , Overweight/complications , Overweight/therapy , Patient Compliance , Treatment Outcome , Young Adult
3.
Breast Cancer Res Treat ; 151(3): 597-606, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25981896

ABSTRACT

Anthracycline and taxane-based primary chemotherapy (PCT) is the standard treatment for high-risk breast cancer (HRBC). However, conventional anthracyclines are not commonly used in elderly patients or those prone to cardiotoxicity. Pegylated liposomal doxorubicin, (PLD) has comparable efficacy, but less cardiotoxicity than conventional anthracyclines. We conducted a phase II single-arm trial to assess the efficacy and safety of PCT based on PLD followed by paclitaxel (PTX) in a HRBC population usually undertreated. Fifty patients with stage II-IIIB breast cancer and at least one risk factor for developing cardiotoxicity initiated PLD 35 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 4 weeks for four cycles, followed by 80 mg/m(2) weekly PTX for 12. Close cardiac monitoring was performed. Primary endpoint was the pathological complete response rate (pCR) in the breast. Treatment delivery and toxicities were assessed. Eighty-four per cent of patients were older than 65 years, 64 % suffered from hypertension, and 10 % had prior cardiac disease. In an intention-to-treat analysis, breast pCR was 32 % (95 % CI 19.5-46.7 %) and pCR in breast and axilla was 24 % (95 % CI 12.1-35.8 %). At diagnosis only, 26 % of patients were candidates for breast conservative surgery, which increased to 58.7 % after PCT. No significant decrease in left ventricular ejection fraction was seen. PLD followed by PTX was feasible in a fragile population of patients who were not candidates for conventional doxorubicin. Moreover, it achieved a pCR similar to standard therapy and could therefore be an option for elderly patients or cardiotoxicity-prone who present HRBC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adult , Age Factors , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cardiotoxicity , Comorbidity , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Female , Heart Diseases/diagnosis , Heart Diseases/etiology , Heart Diseases/physiopathology , Humans , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Polyethylene Glycols/administration & dosage , Risk Factors , Treatment Outcome
6.
Ann Oncol ; 24(5): 1163-70, 2013 May.
Article in English | MEDLINE | ID: mdl-23165977

ABSTRACT

Management of the axilla in early breast cancer (EBC) patients has dramatically evolved in recent years from more radical to increasingly conservative approaches. Classically, the EBC patients with a clinically positive axilla are offered axillary lymph node dissection (ALND) and those with a clinically negative axilla (cN0) are offered sentinel lymph node (SLN) biopsy, which obviates the complications related to ALND and provides adequate surgical staging and comparable locoregional control and survival. The need for performing ALND when the SLN is positive and contemporary adjuvant treatment is delivered has been questioned in recent years. On the other hand, ongoing trials are testing whether node-positive patients can be spared chemotherapy, based on intrinsic primary tumor biology. Because the integration of novel surgical management and tumor biology is needed, this article provides an overview of the current challenges that a more detailed knowledge of tumor biology has brought to EBC staging and treatment. We propose that breast cancer oncologists (surgeons, radiation therapists, and medical oncologists) should focus their efforts on offering therapy tailored to each patient's needs in such a way that no matter which treatment is used, no overtreatment occurs.


Subject(s)
Breast Neoplasms/pathology , Lymph Node Excision , Sentinel Lymph Node Biopsy , Axilla , Breast Neoplasms/surgery , Female , Humans , Lymph Nodes/surgery , Lymphatic Metastasis , Neoplasm Recurrence, Local/surgery , Treatment Outcome
7.
Ann Oncol ; 23(4): 897-902, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21828361

ABSTRACT

BACKGROUND: Elderly breast cancer patients are usually excluded from clinical trials. Nevertheless, with the increasing use of trastuzumab, there is a need to address trastuzumab-related cardiotoxicity in this population. PATIENTS AND METHODS: Records for patients ≥ 70 years treated with trastuzumab since 2005 were reviewed. New York Heart Association classification was used to document symptomatic cardiotoxicity. Asymptomatic cardiotoxicity was defined as an absolute drop ≥ 10% with a final left ventricular ejection fraction < 50% or an absolute drop > 20%. RESULTS: Forty-five patients, median age 75.9 years (range 70-92), were identified. Three of 24 (12.5%) early breast cancer patients and 5 of 21 (23.8%) with advanced disease experienced asymptomatic cardiotoxicity. Four of 45 patients (8.9%), all with advanced breast cancer, developed symptomatic congestive heart failure. All but one of them recovered in a median time of 5 weeks (range 3-21). Patients with trastuzumab-related cardiotoxicity presented more often with cardiovascular risk factors, such as history of cardiac disease (33% versus 9.1%, P = 0.017) and diabetes (33.3% versus 6.1%, P = 0.010), compared with those without. CONCLUSIONS: Elderly breast cancer patients with a history of cardiac disease and/or diabetes treated with trastuzumab have an increased incidence of cardiotoxicity. Continuous cardiac monitoring is especially advised in this population.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents/adverse effects , Breast Neoplasms/drug therapy , Carcinoma, Ductal, Breast/drug therapy , Heart Failure/chemically induced , Aged , Aged, 80 and over , Breast Neoplasms/complications , Carcinoma, Ductal, Breast/complications , Diabetes Complications/chemically induced , Female , Humans , Multivariate Analysis , Risk Factors , Trastuzumab
8.
Ann Oncol ; 23(5): 1130-1137, 2012 May.
Article in English | MEDLINE | ID: mdl-21976387

ABSTRACT

BACKGROUND: Bevacizumab is a monoclonal antibody against vascular endothelial growth factor with the ability to increase progression-free survival in metastatic breast cancer (MBC). A systematic review and meta-analysis was conducted to determine the risk of the most clinically relevant adverse outcomes associated with the use of bevacizumab in the treatment of breast cancer. PATIENTS AND METHODS: We included phase III clinical trials that used bevacizumab alone or in combination with chemotherapy as for MBC or locally recurrent. Statistical analyses were conducted to calculate summary odds ratio (OR) of the eight most relevant adverse outcomes related with bevacizumab. RESULTS: Five clinical trials were included in the meta-analysis. Summary odds ratios obtained showed a statistically significant bevacizumab-associated increased risk in four of the adverse outcomes studied: proteinuria (OR = 27.68), hypertension (OR = 12.76), left ventricular dysfunction (LVD) (OR = 2.25), and hemorrhagic events (OR = 4.07). No statistically significant differences were found for gastrointestinal (GI) perforation, vascular events, fatal events, or febrile neutropenia. CONCLUSIONS: Bevacizumab did increase the risk of LVD and hemorrhagic events. The addition of bevacizumab to chemotherapy in patients with metastatic breast cancer was not associated with a significant increase in grade ≥ 3 arterial or venous thromboembolic events, GI perforation, or fatal events.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Carcinoma/drug therapy , Drug-Related Side Effects and Adverse Reactions/epidemiology , Algorithms , Antibodies, Monoclonal, Humanized/administration & dosage , Bevacizumab , Breast Neoplasms/epidemiology , Carcinoma/epidemiology , Clinical Trials, Phase III as Topic/statistics & numerical data , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Humans , Risk Factors
9.
Rev Mal Respir ; 24(6): 691-701, 2007 Jun.
Article in French | MEDLINE | ID: mdl-17632430

ABSTRACT

INTRODUCTION: Neonatal screening for cystic fibrosis (CF) leads to early dedicated specialist care for all patients. BACKGROUND: Pulmonary function tests (PFT) are mandatory for routine monitoring of CF patients. The aim of this article is to review the current guidelines for PFTs in CF, particularly the type of test, the age and the clinical status of the patient. VIEWPOINT: The regular use of spirometry is generally accepted. Many other tests are used but their clinical value in the routine follow-up of CF patients remains to be established. CONCLUSION: Further efforts should be made to evaluate the value of PFTs in CF, particularly in very young children.


Subject(s)
Cystic Fibrosis/diagnosis , Respiratory Function Tests , Age Factors , Cystic Fibrosis/classification , Follow-Up Studies , Humans , Pulmonary Gas Exchange/physiology , Respiratory Function Tests/classification , Spirometry , Work of Breathing/physiology
10.
J BUON ; 12(1): 105-11, 2007.
Article in English | MEDLINE | ID: mdl-17436410

ABSTRACT

PURPOSE: To evaluate serum changes of matrix metalloproteinases (MMPs) 2 and 9, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) levels in patients with advanced non-small cell lung cancer (NSCLC) and their association with main clinicopathological parameters during chemotherapy with cisplatin and gemcitabine. PATIENTS AND METHODS: In this prospective study, consecutive patients with stage III and IV NSCLC were enrolled. Serum MMP2 and 9, VEGF and EGFR levels were monitored in blood samples taken on day 1 of starting chemotherapy (baseline 1st), and after 3 cycles of chemotherapy (2nd) using commercial sandwich ELISA method. RESULTS: 116 patients were evaluated. Males / females 100 / 6, ECOG performance status (PS) 0/1/2: 47/65/4, stage III / IV: 49/67, squamous /adeno/large cell carcinoma 41/31/19. Forty-two (36%) patients achieved partial response (PR), 32 (28%) stable disease (SD) and 42 (36%) showed progressive disease (PD). Mean serum values -/+ standard deviation (SD) of the analyzed markers at baseline/at response evaluation were: EGFR 86 -/+ 87/96 -/+ 47 fmol/ml; MMP9 236 -/+ 156/162 -/+ 133 ng/ml ; MMP2 525 -/+ 189/569 -/+ 201 ng/ml; VEGF 555 -/+ 476/599 -/+ 611 pg/ml; VEGF adjusted for platelets (PLT) 1.9 -/+ 1.45/2.4 -/+ 2.78 pg/10(6). In logistic regression model for response rate adjusted for stage, the increase in MMP9 levels during chemotherapy (mean = 74 ng/ml -/+ SD 140) was predictive for progression (p=0.041) with 5% increase in the odds of progression for an increase of 10 ng. CONCLUSION: MMP9 level increase was found to be predictive of disease progression. EGFR levels could refl ect extracellular domain (ECD) loss from resistant cells and its shedding into the circulation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/blood , Lung Neoplasms/drug therapy , Matrix Metalloproteinase 2/blood , Matrix Metalloproteinase 9/blood , Receptors, Vascular Endothelial Growth Factor/blood , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Humans , Logistic Models , Lung Neoplasms/blood , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Odds Ratio , Predictive Value of Tests , Prognosis , Prospective Studies , Survival Analysis , Treatment Outcome , Gemcitabine
11.
Arch Pediatr ; 12(9): 1338-43, 2005 Sep.
Article in French | MEDLINE | ID: mdl-16023842

ABSTRACT

INTRODUCTION: To take in charge of an asthmatic child it is necessary to evaluate the lung function. METHODS: In this study, the Negative Expiratory Pressure (NEP) has been used for the first time in children with asthma. After lung spirometry by plethysmography, we have used the NEP to assess the prevalence of expiratory flow limitation (FL) during resting breath in 27 asthmatic children (mean age: 11 +/- 2,5 years) 3-4 days after a crisis in both sitting and supine positions. RESULTS: All the children presented an obstructive defect (FEV 1: 63 +/- 13% med) and a dynamic hyperinflation (FRC: 128 +/- 25% med). According to the NEP, 11 children presented an expiratory flow limitation (FL). Asthma was more severe in the FL than in non-FL children (GINA 2002 classification). Among the 11 FL children, 5 were FL in both sitting and supine position and 6 only in supine. Nine of the 27 children were FL with the conventional method. NEP seems a more accurate method to assess the clinical gravity of asthma than FEV 1. The reduction of FRC in the supine position probably explains the greater incidence of FL in supine position. CONCLUSION: Because of its easy execution, NEP seems to be well adapted for children. Links between FL detected by NEP and clinical signs of asthma has to be assessed by furthers studies including more patients.


Subject(s)
Asthma/diagnosis , Adolescent , Asthma/physiopathology , Child , Exhalation/physiology , Forced Expiratory Volume/physiology , Functional Residual Capacity/physiology , Humans , Inspiratory Capacity/physiology , Lung Diseases, Obstructive/physiopathology , Maximal Expiratory Flow-Volume Curves/physiology , Plethysmography , Posture , Prospective Studies , Pulmonary Ventilation/physiology , Residual Volume/physiology , Spirometry , Status Asthmaticus/physiopathology , Supine Position , Total Lung Capacity/physiology , Vital Capacity/physiology
12.
J Hypertens ; 5(5): 599-604, 1987 Oct.
Article in English | MEDLINE | ID: mdl-3429863

ABSTRACT

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.


Subject(s)
Blood Pressure/drug effects , Hypertension/drug therapy , Nicardipine/administration & dosage , Administration, Sublingual , Adult , Aged , Blood Pressure Determination/methods , Delayed-Action Preparations , Double-Blind Method , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Nicardipine/blood , Random Allocation
13.
J Hypertens ; 10(9): 1045-51, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1328364

ABSTRACT

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.


Subject(s)
Benzazepines/pharmacology , Blood Pressure/drug effects , Heart Rate/drug effects , Nifedipine/pharmacology , Renin-Angiotensin System/drug effects , Adult , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Benzazepines/pharmacokinetics , Delayed-Action Preparations , Drug Interactions , Humans , Male , Nifedipine/pharmacokinetics , Reference Values , Renin/blood
14.
J Hypertens ; 8(1): 3-11; discussion 13-9, 1990 Jan.
Article in English | MEDLINE | ID: mdl-2157754

ABSTRACT

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.


Subject(s)
Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Antihypertensive Agents/administration & dosage , Clinical Trials as Topic , Dose-Response Relationship, Drug , Drug Combinations , Drug Therapy, Combination , Humans
15.
J Hypertens ; 7(12): 1005-12, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2697728

ABSTRACT

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)


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Benzazepines/administration & dosage , Hypertension/drug therapy , Adult , Aged , Aldosterone/blood , Angiotensin II/blood , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Benzazepines/adverse effects , Blood Pressure Determination , Double-Blind Method , Drug Administration Schedule , Female , Humans , Hypertension/blood , Male , Middle Aged , Patient Compliance , Renin/blood
16.
Am J Cardiol ; 56(15): 927-31, 1985 Dec 01.
Article in English | MEDLINE | ID: mdl-3000160

ABSTRACT

Fifteen patients who had undergone cardiac transplantation and who had hypertension (164 +/- 14/112 +/- 13 mm Hg), aged 16 to 57 years (mean 39), were treated with cyclosporine, 8 +/- 3 mg/kg/day, and prednisolone, 0.27 +/- 0.1 mg/kg/day, for 63 to 788 days (mean 288) after transplantation. They were not given antihypertensive drugs. Before treatment, the mean urinary sodium level was 104 +/- 48 mEq/day. Two discrete abnormalities accompanied their high blood pressure (BP): an increase in serum creatinine levels (p less than 0.05) to values exceeding those measured just before transplantation (2.1 +/- 1.0 vs 1.35 +/- 0.54 mg/dl) with low creatinine clearance (61 +/- 28 ml/min X 1.73 m2), and a 15% increase in plasma volume (+445 +/- 686 ml, p less than 0.02). Urinary excretion of vanilmandelic acid and total metanephrines was normal. Supine plasma renin activity was also normal (0.78 +/- 0.32 nmol/ml/hour). The stimulation of renin release after acute inhibition of converting enzyme by captopril was less marked than is usual in hypertensive subjects (0.86 +/- 0.54 nmol/liter/hour). Captopril induced a smaller drop in BP than nifedipine (-8 +/- 13/-6 +/- 10 mm Hg vs -14 +/- 11/-15 +/- 10 mm Hg). Levels of plasma aldosterone, angiotensinogen and converting enzyme activity were all normal, 308 +/- 147 pmol/liter, 712 +/- 164 nmol/ml and 30 +/- 6 mU/ml, respectively. It is concluded that hypertension is common in cardiac transplantation patients treated with cyclosporine, since 13 of our 15 subjects were normotensive before transplant.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Cyclosporins/pharmacology , Heart Transplantation , Hypertension/chemically induced , Renin-Angiotensin System/drug effects , Adolescent , Adult , Angiotensin-Converting Enzyme Inhibitors , Blood Pressure/drug effects , Cyclosporins/adverse effects , Female , Heart Rate/drug effects , Humans , Male , Middle Aged , Renin/blood
17.
Br J Pharmacol ; 71(2): 365-9, 1980.
Article in English | MEDLINE | ID: mdl-6110456

ABSTRACT

1. The cardiovascular effects of morphine, fentanyl, [D-Ala2]-met-enkephalinamide were analyzed after intracisternal injection in anaesthetized rats. PaO2 was measured as an index of respiratory function. 2. At low doses in spontaneously breathing rats, morphine, fentanyl and [D-Ala2]-met-enkephalinamide induced a pressor response with slight tachycardia and no significant change in PaO2. 3. The pressor response appeared to be due to activation of opiate receptors and mediated through the sympathetic nervous system. 4. High doses of morphine and [D-Ala2]-met-enkephalinamide induced a biphasic effect with a secondary hypotension associated with bradycardia in spontaneously breathing rats. A marked reduction in PaO2 was found during the depressor phase. 5. High doses of [D-Ala2]-met-enkephalinamide produced only a pressor response in artificially-ventilated rats with no signs of secondary hypotension. 6. Our data support the idea that morphinomimetic agents are centrally pressor at low doses in the rat. The respiratory depression observed with high doses may be the cause of hypotension.


Subject(s)
Analgesics, Opioid/pharmacology , Endorphins/pharmacology , Enkephalins/pharmacology , Hemodynamics/drug effects , Animals , Autonomic Nervous System/drug effects , Blood Pressure/drug effects , Fentanyl/pharmacology , Heart Rate/drug effects , Male , Morphine/pharmacology , Oxygen Consumption/drug effects , Rats
18.
Am J Hypertens ; 3(10): 815-9, 1990 Oct.
Article in English | MEDLINE | ID: mdl-2222948

ABSTRACT

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.


Subject(s)
Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Randomized Controlled Trials as Topic/methods , Antihypertensive Agents/administration & dosage , Blood Pressure/drug effects , Evaluation Studies as Topic , Humans , Multicenter Studies as Topic/standards , Patient Education as Topic/methods
19.
Intensive Care Med ; 13(1): 60-3, 1987.
Article in English | MEDLINE | ID: mdl-3558937

ABSTRACT

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.


Subject(s)
Intensive Care Units , Radiation Dosage , Radiography , Thermoluminescent Dosimetry , Adult , Aged , Aged, 80 and over , Bone Marrow/radiation effects , Eye/radiation effects , Female , Humans , Male , Middle Aged , Models, Structural , Ovary/radiation effects , Prospective Studies , Radiation Monitoring/instrumentation , Testis/radiation effects , Thyroid Gland/radiation effects
20.
Eur J Radiol ; 5(1): 17-23, 1985 Feb.
Article in English | MEDLINE | ID: mdl-4006947

ABSTRACT

To evaluate the frequency of right ventricular dysfunction following recovery from myocardial infarction (MI) and the relationship of segmental right ventricular (RV) wall motion abnormalities to left ventricular (LV) function or location of coronary arterial stenosis, biplane right and left ventricular cineangiograms were obtained in 100 consecutive patients (4 +/- 3 months post MI). Thirty (group A) had anterior MI and significant stenosis or obstruction of left anterior descending artery (LAD). The remaining 70 patients had inferior MI. They were divided into three groups according to the site of the main coronary stenosis or obstruction and corresponding LV akinesia: right coronary artery (RCA) proximal to the acute marginal artery (RMA), (group B: 32 patients), RCA distal to the RMA (group C: 18 patients), left circumflex artery (LCF), (group D: 18 patients). RV and LV end-diastolic volume index (EDV), end-systolic volume index (ESV), stroke volume (SV) and ejection fraction (EF) have been determined. RV segmental wall motion was assessed in RAO and LAO projection by determining the percentage of systolic shortening (+ delta R) along 11 hemiaxes. Mean axial shortening (delta R) of the RV inferior and free walls were considered. When compared with that in 10 normal subjects, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV) were increased and RV ejection fraction (RVEF) was lower in patients with anterior or inferior MI. Inferior delta R exhibited comparable sequential changes in the three groups of inferior MI and similar LVEF alteration.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Heart/physiopathology , Myocardial Infarction/physiopathology , Adult , Angiography , Cardiac Catheterization , Coronary Angiography , Coronary Vessels/physiopathology , Female , Heart/diagnostic imaging , Hemodynamics , Humans , Male , Middle Aged , Myocardial Contraction , Stroke Volume
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