New challenges in the disease management of hypertension.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
S Laurent
Publications and source records attributed to S Laurent.
Clinical benefit of very-low-dose perindopril-indapamide combination in hypertension.
OBJECTIVE: To review the efficacy and safety of the very-low-dose combination of 2 mg perindopril and 0.625 mg indapamide in essential hypertension. STUDY SELECTION: The five main studies from the European registration file were performed in hypertensive outpatients and included two phase II double-blind randomised dose-ranging studies, and three phase III double-blind randomised studies (one study comparing placebo with each of the components, one long-term study over 15 months and one study comparing the combination and losartan). MAIN OUTCOME MEASURES: Decreases in systolic (SBP) and diastolic (DBP) blood pressures measured at trough with a mercury sphygmomanometer, an automatic device (Omron), and 24 h ambulatory blood pressure measurements (ABPM). RESULTS: The combination 2 mg perindopril and 0.625 mg indapamide was selected from the dose-finding studies. Twelve weeks after participants in the randomised studies were allocated to groups, the reductions in SBP, measured with an Omron device, were 12.3 +/- 15.0 mmHg with the combination, 8.0 +/- 16.5 mmHg with 2 mg perindopril (P = 0.001), 9.4 +/- 14.3 mmHg with 0.625 mg indapamide (P = 0.023), and 2.1 +/- 16.8 mmHg with placebo (P < 0.001) (mean +/- SD; all P values are for comparisons with the combination). The reductions in DBP were 6.8 +/- 9.2 mmHg, 5.0 +/- 9.5 mmHg (P = 0.02), 4.7 +/- 8.2 mmHg (P = 0.004), and 2.4 +/- 9.6 mmHg (P < 0.001) in the combination, 2 mg perindopril, 0.625 mg indapamide and placebo groups, respectively. During the long-term study, among 235 patients who achieved initial blood pressure normalisation with the fixed combination, 79.8% sustained their normalisation over 1 year, with no significant difference regarding safety criteria: the occurrence of adverse drug reactions per patient per year was 0.37 and 0.28 in the combination and placebo groups, respectively. A significantly (P < 0.05) larger blood pressure decreasing effect on nocturnal mean SBP (by ABPM) was demonstrated for the combination compared with that achieved with losartan, with no difference in safety. CONCLUSIONS: The proven efficacy on DBP and SBP, and the good safety profile, confirm that the new low-dose combination of 2 mg perindopril and 0.625 mg indapamide is a valuable option in the first-line treatment of hypertension.
Antihypertensive Agents↗
Local pulse pressure and regression of arterial wall hypertrophy during long-term antihypertensive treatment.
BACKGROUND: Local pulse pressure (PP) is an independent determinant of carotid artery wall thickness, stronger than mean blood pressure (BP). The present study was designed to assess whether a beta-adrenoceptor antagonist-based or an ACE inhibitor-based treatment was able to reduce carotid artery wall hypertrophy through a reduction in carotid PP rather than by lowering mean BP and whether the influence of local PP reduction could also be detected at the site of a muscular artery, the radial artery. METHODS AND RESULTS: Ninety-eight essential hypertensive patients were randomized to 9 months of double-blind treatment with either celiprolol or enalapril. Arterial parameters were determined with high-resolution echo-tracking systems. PP was measured locally with applanation tonometry and independently of mean BP. After 9 months of treatment, mean BP, carotid PP, and intimal-medial thickness (IMT) decreased significantly, with no difference between the 2 groups. The reduction in carotid PP but not in mean BP was a major independent determinant of the reduction in carotid IMT. Radial artery IMT and PP decreased significantly with both treatments. However, the reduction in radial artery IMT was not related to the changes in radial artery PP. CONCLUSIONS: The regression of carotid artery wall hypertrophy during long-term antihypertensive treatment was dependent on the reduction in local PP rather than on the lowering of mean BP. The effect of PP lowering on IMT reduction was observed at the site of an elastic artery but not at the site of a muscular artery.
Adult↗
[Auditing of drug use practices in anesthesia].
OBJECTIVES: Internal pharmaceutical practice guidelines were produced in a department of anaesthesia of a University hospital in 1995, after a preliminary evaluation showing controversial and expensive practices. After approval, these recommendations were circulated to all members of the department. Phase I of this study was started 18 months later, to evaluate the compliance of anaesthetists with these guidelines. STUDY DESIGN: Prospective survey. METHOD: An audit was performed by a research assistant pharmacist, previously trained, who compared anaesthetic agents and fresh gas flows used during anaesthetics with those recommended in the internal guidelines. RESULTS: Implementation of guidelines was observed in more than 90% of cases for all agents studied, except for non-depolarizing neuromuscular relaxants. Relaxants of intermediate duration were used in 52% of cases with an expected surgery duration of more than 90 min, in opposition to the guidelines stating that pancuronium should have been administered in such circumstances. These results were presented and discussed. Slight changes in the guidelines (especially concerning monitoring of neuromuscular blockade) were made and evaluated again, using the same method (Phase II). A small but significant improvement was seen with induction agents (use of propofol in non-approved situations: 5 versus 0%, P = 0.03), while a non significant trend toward better implementation of guidelines was seen with non-depolarizing agents (use of pancuronium in surgery of expected duration > 90 min: phase I vs phase II = 47 vs 52%, NS; use of pancuronium in surgery of expected duration < 90 min: phase I vs phase II = 3.5 vs 0%, NS). CONCLUSION: This study suggests that implementation of internal guidelines is easy when clinical indications of the agents are not controversial.
Anesthetics↗
Subfulminant hepatitis requiring liver transplantation following ibuprofen overdose.
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Anti-Inflammatory Agents, Non-Steroidal↗
Early down-regulation of cytochrome P450 3A and 2E1 in the regenerating rat liver is not related to the loss of liver mass or the process of cellular proliferation.
AIMS/BACKGROUND: Conflicting data have been reported concerning the modification of cytochrome P450 expression in the regenerating liver. Ligation of branches of the portal vein (PBL) perfusing 70% of the liver parenchyma, which produces regeneration and atrophy within the same liver, constitutes an ideal model to study the relative specificity of the early events in the regenerating liver and their relationship to the loss of liver mass. METHODS: In this PBL model and in sham models, we studied the expression and the metabolic activities of two major cytochromes, CYP3A and CYP2E1, and the expression of inducible nitric oxide synthase protein (iNOS). They were simultaneously measured in the atrophying and regenerating liver lobes following PBL using Western Blot and HPLC methods. RESULTS: The metabolic activities of both cytochromes were transiently and simultaneously down-regulated in the regenerating and atrophying lobes during the first 2-5 h after PBL. No significant modification was observed at the protein level. In contrast, iNOS protein was significantly induced in both lobes. Similar results were observed after sham operation. CONCLUSIONS: The reduction of these CYP activities in both lobes after PBL and in sham livers suggests that other mechanisms than the regenerating process itself or the reduction of the liver mass might account for such down-regulation during the early phase of liver regeneration. The activation of nitric oxide (NO) and/or pro-inflammatory cytokine production provides clues to pathways liable to affect the CYP activities in the regenerating liver.
Animals↗
Association between the apolipoprotein E polymorphism and arterial wall thickness in asymptomatic adults.
OBJECTIVES: The polymorphism of the apolipoprotein E gene (epsilon2, epsilon3, epsilon4) affects plasma cholesterol but the relationship with artery wall thickness has indicated contradictory results. This study investigated the relationship between apolipoprotein E polymorphism and vascular phenotypes of the carotid and radial arteries, two arterial sites differently affected by atherosclerosis. METHODS: We studied a cohort of 320 Caucasian subjects (age 49 +/- 12 years) without evidence of cardiovascular disease. Structural (internal diameter and wall thickness) and functional phenotypes (compliance, distensibility) were evaluated for the common carotid and the radial arteries using high resolution echo-tracking devices. Genotypes of apolipoprotein E were determined by allele-specific oligonucleotides hybridization. Because of the relative low frequency of some apolipoprotein E genotypes, they were designated as E2 (epsilon2/epsilon2, epsilon2/epsilon3), E3 (epsilon3/epsilon3), and E4 (epsilon4/epsilon4, epsilon3/epsilon4). RESULTS: Apolipoprotein E allele frequencies were epsilon2 = 0.08, epsilon3 = 0.79, epsilon4 = 0.13. Subjects with epsilon4 allele had the highest levels of total serum cholesterol and low density lipoprotein cholesterol; subjects with epsilon2 allele had the lowest levels (P < 0.001). Considering carotid hypertrophy as intima-media thickness > 660 microm, and radial hypertrophy as intima-media thickness > 260 microm, a logistic regression model testing determinants of arterial hypertrophy (age, gender, weight, systolic blood pressure, smoking habits, and total serum cholesterol) observed a significant and positive association between carotid hypertrophy and epsilon2 allele carriers (P= 0.03). In contrast, no association was found between hypertrophy and apolipoprotein E genotypes for the radial artery. No association was observed between the apolipoprotein E genotypes and functional artery parameters. CONCLUSIONS: In subjects without any evidence of cardiovascular disease, the presence of the epsilon2 allele is related to wall hypertrophy in carotid artery despite favourable effect on the lipid profile.
Adult↗
Gene transfer using recombinant rabbit hemorrhagic disease virus capsids with genetically modified DNA encapsidation capacity by addition of packaging sequences from the L1 or L2 protein of human papillomavirus type 16.
The aim of this study was to produce gene transfer vectors consisting of plasmid DNA packaged into virus-like particles (VLPs) with different cell tropisms. For this purpose, we have fused the N-terminally truncated VP60 capsid protein of the rabbit hemorrhagic disease virus (RHDV) with sequences which are expected to be sufficient to confer DNA packaging and gene transfer properties to the chimeric VLPs. Each of the two putative DNA-binding sequences of major L1 and minor L2 capsid proteins of human papillomavirus type 16 (HPV-16) were fused at the N terminus of the truncated VP60 protein. The two recombinant chimeric proteins expressed in insect cells self-assembled into VLPs similar in size and appearance to authentic RHDV virions. The chimeric proteins had acquired the ability to bind DNA. The two chimeric VLPs were therefore able to package plasmid DNA. However, only the chimeric VLPs containing the DNA packaging signal of the L1 protein were able efficiently to transfer genes into Cos-7 cells at a rate similar to that observed with papillomavirus L1 VLPs. It was possible to transfect only a very limited number of RK13 rabbit cells with the chimeric RHDV capsids containing the L2-binding sequence. The chimeric RHDV capsids containing the L1-binding sequence transfer genes into rabbit and hare cells at a higher rate than do HPV-16 L1 VLPs. However, no gene transfer was observed in human cell lines. The findings of this study demonstrate that the insertion of a DNA packaging sequence into a VLP which is not able to encapsidate DNA transforms this capsid into an artificial virus that could be used as a gene transfer vector. This possibility opens the way to designing new vectors with different cell tropisms by inserting such DNA packaging sequences into the major capsid proteins of other viruses.
Animals↗
Intrinsic stiffness of the carotid arterial wall material in essential hypertensives.
We have previously shown that the decrease in large artery distensibility observed in patients with essential hypertension (HT group) was primarily due to an increase in distending pressure and not to hypertension-associated structural modifications of the artery, suggesting a functional adaptation of the wall material. To evaluate the elastic properties of the wall material of the common carotid artery, we determined Young's incremental elastic modulus (Einc) in the HT group and in normotensive subjects (NT group) as a function of blood pressure and circumferential wall stress. In 102 HT patients with never-treated essential hypertension and 40 age- and gender-matched NT subjects, the Einc-pressure and Einc-stress curves were calculated from intima-media thickness and from diameter and pressure waveforms, determined with echo tracking and aplanation tonometry, respectively. The "effective" stiffness of the wall material, determined through Einc calculated at mean blood pressure, was significantly higher in the HT than in the NT group. The "intrinsic" stiffness of the wall material, determined through Einc calculated at a common circumferential wall stress, did not differ between the 2 groups. However, when each group (HT and NT) was analyzed according to tertiles of age, the "intrinsic" stiffness of the arterial wall material was increased only in younger HT patients. In middle-aged and older HT patients, the intrinsic mechanical properties of the carotid arterial wall material were unchanged, and the increased stiffness of the common carotid artery in the HT group was due primarily to the increased level of blood pressure. These results also indicate that the deleterious effects of aging and hypertension on "intrinsic" stiffness are not additive.
Adult↗
Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin and angiotensin-converting enzyme, in rats and humans.
The aim of this study was to assess the antihypertensive activity of fasidotril, a dual inhibitor of neprilysin (NEP) and angiotensin I-converting enzyme (ACE), in various models of hypertension in rats (spontaneously hypertensive rats [SHR]; renovascular Goldblatt 2-kidney, 1-clip rats; and deoxycorticosterone acetate [DOCA]-salt hypertensive rats) and in patients with mild-to-moderate essential hypertension. Fasidotril treatment (100 mg/kg PO twice daily for 3 weeks) resulted in a progressive and sustained decrease in systolic blood pressure (-20 to -30 mm Hg) in SHR and Goldblatt rats compared with vehicle-treated rats and prevented the progressive rise in blood pressure in DOCA-salt hypertensive rats. After a 4-week placebo run-in period, 57 patients with essential hypertension were included in a randomized double-blind, placebo-controlled, parallel-group study and received orally either fasidotril (100 mg twice daily) or placebo for 6 weeks. Blood pressure was measured during the 6 hours after the first intake and then at trough (12 hours after the last intake) on days 7, 28, and 42. The first dose of fasidotril had no significant effect on blood pressure. After 42 days, compared with placebo, fasidotril lowered supine systolic and diastolic blood pressures by 7.4/5.4 mm Hg and standing blood pressure by 7.6/6.8 mm Hg. Fasidotril, a dual NEP/ACE inhibitor, was an effective oral antihypertensive agent during chronic treatment in high-renin renovascular rats, normal-renin SHR, and low-renin DOCA-salt hypertensive rats and in patients with essential hypertension.
Alanine↗
[Local pulse pressure and regression of arterial wall hypertrophy during antihypertensive treatment. CELIMENE study. The Celiprolol Intima-Media Enalapril Efficacy study].
BACKGROUND: Local Pulse Pressure (PP) is an independent determinant of carotid artery wall thickness, stronger than mean BP. The present study was designed to assess whether a beta-adrenoceptor antagonist or an ACE inhibitor-based treatment was able to reduce carotid artery wall hypertrophy through the reduction in carotid PP rather than by lowering mean BP, and whether the influence of local PP reduction could also be detected at the site of a muscular artery, the radial artery. METHODS AND RESULTS: Ninety-eight essential hypertensive patients were randomised to 9 months of double-blind treatment with either celiprolol or enalapril. Arterial parameters were determined with high resolution echotracking systems. PP was measured locally with PP applanation tonometry, and independently of mean BP. After 9 month's treatment, mean BP, carotid PP and intima-media thickness (IMT) decreased significantly, with no difference between the tow groups. The reduction in carotid pression pulsée, but not in mean BP, was a major independent determinant of the reduction in carotid IMT. Radial artery IMT and PP decreased significantly with both treatments. However, the reduction in radial artery IMT was not related to the changes in radial artery PP. CONCLUSION: The regression of carotid artery wall hypertrophy during long-term antihypertensive treatment was dependent on the reduction in local PP rather than on the lowering of mean BP. The effect of PP lowering on IMT reduction was observed at the site of an elastic artery but not at the site of a muscular artery.
Adrenergic beta-Antagonists↗
[Assessment of the management of arterial hypertension in a population of (type 2) diabetic patients undergoing hospitalization. Diabetes and prognostic factors in the control of arterial hypertension].
The control of hypertension in diabetic hypertensive patients prevents micro and macroangiopathy complications. Our prospective study was designed to evaluate the level of treatment of hypertension in type II diabetic patients at the time of referral to our endocrinology unit and after a mean follow-up of 9.2 months. Five hundred and sixty four patients (sex ratio: 1.15, mean age of 56 +/- 13, mean BMI of 28 +/- 15, mean duration of diabetes of 11.3 +/- 9.9) were referred to our unit. Among these, 42% had an antihypertensive drug (58% under monotherapy, 42% under combinations) and 92% had a documented history of CHD. Glycemic and blood pressure controls were stable during follow-up. HbA1c remained unchanged (8.95% at admission, 8.8% at 9 months) BP decreased from 143/84 +/- 26/13 mmHg to 142/82 +/- 23/13 mmHg. Fifty six percent reached a BP goal of 140/90 mmHg whereas 42% achieved a BP goal of 130/85 mmHg at 9 months compared to respectively 56% and 39% at admission. A multivariate logistic regression analysis showed that initial value of SBP (p < 0.0001), age (p < 0.0001), BMI (p = 0.006), HbA1c (p = 0.018) were independent factors of non control of hypertension. In conclusion, follow-up of hypertension diabetic patients would be focussed on identified and modifiable factors.
Age Factors↗
Association between local pulse pressure, mean blood pressure, and large-artery remodeling.
BACKGROUND: The aim of the present study was to determine the respective influences of local pulse pressure and mean blood pressure on arterial remodeling in humans at 2 arterial sites: a central, predominantly elastic artery (the common carotid artery) and a peripheral muscular artery (the radial artery). METHODS AND RESULTS: Forty-three healthy subjects and 124 never-treated hypertensive patients were included in the study. Intima-media thickness and internal diameter of the carotid and radial arteries were noninvasively determined with high-definition echo-tracking devices. Pulse pressure was measured locally with applanation tonometry. Multivariate regression models including mean blood pressure and local pulse pressure were established in the whole population. Carotid internal diameter and intima-media thickness were strongly influenced (P<0.0001) by carotid pulse pressure but not by mean blood pressure or brachial pulse pressure, independently of age and sex. Radial artery internal diameter was correlated with age but not with mean blood pressure or radial pulse pressure. Radial artery intima-media thickness was correlated with mean blood pressure (P<0.001) but not with radial pulse pressure. CONCLUSIONS: Carotid pulse pressure was a strong independent determinant of carotid artery enlargement and wall thickening, whereas mean blood pressure and brachial pulse pressure were not, indicating the prominent influence of local pulsatile mechanical load on arterial remodeling. These relationships were observed at the site of an elastic artery but not at the site of a muscular artery, suggesting the contribution of cyclic stretching to the pulse pressure-induced arterial remodeling.
Adult↗
Central pulse pressure is a major determinant of ascending aorta dilation in Marfan syndrome.
BACKGROUND: In patients with Marfan syndrome (MFS), brachial pulse pressure (PP) has been recognized as a risk factor for aortic dilatation, leading to aortic dissection, the main cause of premature death. However, the relationships between aortic PP, aortic stiffness, and aortic root dilation have not been investigated. Our main objective was to determine whether central PP, which takes into account wave reflections and aortic stiffness, is a better determinant of ascending aorta diameter than brachial PP in MFS patients. METHODS AND RESULTS: Twenty patients with confirmed MFS and 20 age- and sex-matched control subjects were included in this cross-sectional, noninvasive study. Elastic properties of the abdominal aorta and common carotid, common femoral, and radial arteries were calculated from the pulsatile changes in arterial diameter and pressure. The ascending aorta diameter, measured with conventional echocardiography, was 37% larger in MFS than in control subjects (P<0.001). Arterial distensibility was 38% lower in MFS than in control subjects at the site of the abdominal aorta (P<0.01) but not at other sites (common carotid, common femoral, and radial arteries). Independently of age and body surface area, ascending aorta diameter was positively correlated with carotid PP in MFS (P<0. 01) and negatively in control subjects (P<0.01) but was not correlated with brachial PP and mean blood pressure. CONCLUSIONS: In patients with MFS, local PP, estimated from carotid PP, was a major determinant of ascending aorta diameter, whereas brachial PP was not. Increased arterial stiffness was confined to the aorta.
Adult↗
Incremental conductance levels of GABAA receptors in dopaminergic neurones of the rat substantia nigra pars compacta.
1. Molecular and biophysical properties of GABAA receptors of dopaminergic (DA) neurones of the pars compacta of the rat substantia nigra were studied in slices and after acute dissociation. 2. Single-cell reverse transcriptase-multiplex polymerase chain reaction confirmed that DA neurones contained mRNAs encoding for the alpha3 subunit of the GABAA receptor, but further showed the presence of alpha4 subunit mRNAs. alpha2, beta1 and gamma1 subunit mRNAs were never detected. Overall, DA neurones present a pattern of expression of GABAA receptor subunit mRNAs containing mainly alpha3/4beta2/3gamma3. 3. Outside-out patches were excised from DA neurones and GABAA single-channel patch-clamp currents were recorded under low doses (1-5 microM) of GABA or isoguvacine, a selective GABAA agonist. Recordings presented several conductance levels which appeared to be integer multiples of an elementary conductance of 4-5 pS. This property was shared by GABAA receptors of cerebellar Purkinje neurones recorded in slices (however, with an elementary conductance of 3 pS). Only the 5-6 lowest levels were analysed. 4. A progressive change in the distribution of occupancy of these levels was observed when increasing the isoguvacine concentration (up to 10 microM) as well as when adding zolpidem (20-200 nM), a drug acting at the benzodiazepine binding site: both treatments enlarged the occupancy of the highest conductance levels, while decreasing that of the smallest ones. Conversely, Zn2+ (10 microM), a negative allosteric modulator of GABAA receptor channels, decreased the occupancy of the highest levels in favour of the lowest ones. 5. These properties of alpha3/4beta2/3gamma3-containing GABAA receptors would support the hypothesis of either single GABAA receptor channels with multiple open states or that of a synchronous recruitment of GABAA receptor channels that could involve their clustering in the membranes of DA neurones.
Animals↗
[Impact of essential hypertension on the arteries].
Arterial remodeling has emerged as a key-concept in the pathophysiology of hypertension and its vascular damage. In any given arterial territory, hypertension-induced remodeling is characterized by an increased intima-media thickness, independently of the lumen and wall cross-sectional areas. Functional consequences of hypertension-induced arterial remodeling depend upon the caliber of the artery, and thus upon its function. In essential hypertension, the 2 major functional consequences of large artery remodeling are the long-term enhancement of atherosclerosis and the shorter-term preservation of elastic properties. The functional consequences of resistive arteries remodeling can be either deleterious (structural increase in peripheral vascular resistances, hyperreactivity to vasomotor stimuli, and decrease in perfusion reserve of target organs) or rather compensatory (changes in the autoregulation of regional perfusions).
Arteries↗
Sub-Tenon's block: the effect of hyaluronidase on speed of onset and block quality.
The role of hyaluronidase on the onset time and quality of single quadrant sub-Tenon's block was studied in a prospective, randomized, double-blind controlled manner. One hundred and twenty consecutive patients undergoing cataract surgery under local anaesthesia received a sub-Tenon's block with either of two local anaesthetic solutions. One consisted of 2% plain lignocaine 3 ml with 0.5% plain bupivacaine 2 ml. The other consisted of 2% lignocaine 1 ml containing 150 i.u. per ml of hyaluronidase with 2% plain lignocaine 2 ml and 0.5% plain bupivacaine 2 ml. The development of akinesia and the resulting block quality were assessed. Akinesia scores were lower at all time intervals and were significantly lower (P < 0.05) up to 9 minutes after block in the hyaluronidase group. However, block quality as assessed by the surgeon was not significantly different between the groups. The addition of 150 IU hyaluronidase significantly speeds up the onset of surgical anaesthesia produced by a sub-Tenon's block.
Aged↗
[Hypertrophy of the arterial wall and arterial rigidity].
The purpose of this article is to review the relations between hypertension-induced hypertrophy and stiffness of the arterial wall. Arterial remodeling was assessed based on the geometrical (lumen and arterial wall thickness) and functional (distensibility and Young's elastic modulus) properties of large and medium-sized arteries in hypertensive and normotensive subjects. Several clinical and animal studies have shown that arterial wall hypertrophy, which normalizes circumferential wall stress, does not increase the elastic modulus of arterial wall material during chronic essential hypertension. The structural changes associated with hypertension and those associated with aging have opposite effects on arterial distensibility at a given transmural pressure (isobaric distensibility): arterial distensibility increases with hypertension and decreases with aging. Thus, hypertension cannot be considered equivalent to aging. The structural and functional changes in arterial wall material associated with hypertension-induced hypertrophy may explain why medium-sized arteries maintain their distensibility characteristics despite a distending pressure increase; these changes may not be associated with an intrinsic (isobaric) decrease in the distensibility of large arteries.
Animals↗