[Hepatonephritis during the treatment of malaria by the therapeutic combinations from a pharmacovigilance database]. / Hépatonéphrites au cours du traitement du paludisme par les combinaisons thérapeutiques à partir d'une base de données de pharmacovigilance.

INTRODUCTION: Prior studies have shown an association between the onset of hepatonephritis and the use of arteminisin-based combination therapy (ACT) during the treatment of uncomplicated malaria. The objective of this study was to identify the risk factors of hepatonephritis occurrence because of the uncertainty regarding the appearance and the aggravation of this syndrome. METHODS: A case-non case study was carried out on 428 notifications of pharmacovigilance extracted from the database of the clinical pharmacology department of the teaching hospital of Cocody from 2008 to 2012. Twenty-two cases of hepatonephritis were identified. Univariate analysis and multivariate logistic regression were performed to identify the risk factors and an adjusted odds ratio (AOR) was calculated for each factor. The cut-off for significant association was set at 0.05. RESULTS: The average age of cases was comparable with that of non-cases (34.04±3.68 years versus 33.94±3.92 years) with a median duration of therapy of 5 days and 6 days respectively. Male (AOR: 6.71; P<0.0001), toxic antecedents, traditherapy (AOR: 6.25; P<0.0001), consumption of CTA (AOR: 1.25; P<0.0001), betalactam (AOR: 0.46; P<0.0001), fluoroquinolone and self-medication (AOR: 2.89; P<0.0001) would be the majors risk factors associated with hepatonephritis onset. The risk increased with the number of antimalarial drugs taken. The evolution towards the offset was less frequent (AOR: 0.078; P<0.02). CONCLUSION: The risk factors of hepatonephritis were the consumption of malarial drugs and connected molecules, self-medication and misuse. The outcome was generally unfavourable. Both the general population and health professionals should be trained on the good use of the antimalarial drugs.

Sodium and blood pressure in Africa.

In the pathophysiology of hypertension, the profile hemodynamic is modified by the relation between the increased sodium intake and blood pressure (BP) level. An increased sodium diet is related not only on the amount of fluid volume within the organism but also to the elasticity of the cardiovascular system. In humans, age and salt excess reduced elasticity is linked to BP level and to stiffness material within the vascular wall of larges arteries. Actions of vasoactives hormones such as angiotensin II, antidiuretic hormone, and aldosterone are also linked. The purpose of this article is : (i) to report existing work in Africa relating to "salt and hypertension", (ii) to determine the characteristic of hypertension among black populations, and for epidemiologic study in Ivory Coast, (iii) to determine the various characteristics of hypertension, prevention of cardiovascular risk, and to show usual antihypertensive drugs for reduce rigidity and vascular fibrosis.

Comparison of the effects of semicarbazide and beta-aminopropionitrile on the arterial extracellular matrix in the Brown Norway rat.

To investigate a putative role for semicarbazide-sensitive amine oxidase (SSAO) in arterial extracellular matrix (ECM) organization, we compared arteries of growing Brown Norway (BN) rats after chronic administration of semicarbazide (SCZ) and beta-aminopropionitrile (BAPN), two inhibitors with different properties and relative specificities for SSAO and lysyl oxidase (LOX). The BN model is particularly well adapted to evaluating effects of toxic compounds on the arterial elastic network. We measured aortic LOX and SSAO activities and quantified several ECM parameters. After a pilot study comparing doses previously studied and testing for additivity, we studied low and high equimolar doses of SCZ and BAPN. Both compounds similarly inhibited LOX, whereas SCZ inhibited SSAO far more effectively than BAPN. Both decreased carotid wall rupture pressure, increased tail tendon collagen solubility, decreased aortic insoluble elastin (% dry weight) and dose-dependently increased defects in the internal elastic lamina of abdominal aorta, iliac and renal arteries. Our results suggest that either these effects are mediated by LOX inhibition, SCZ being slightly more effective than BAPN in our conditions, or SSAO acts similarly to and in synergy with LOX on ECM, the greater SCZ effect reflecting the simultaneous inhibition of both enzymes. However, the high SCZ dose increased aortic collagen and ECM proteins other than insoluble elastin markedly more than did equimolar BAPN, possibly revealing a specific effect of SSAO inhibition. To discriminate between the two above possibilities, and to demonstrate unequivocally a specific effect of SSAO inhibition on ECM formation or organization, we must await availability of more specific inhibitors.

Correlation between arterial mechanical properties, vascular biomaterial and tissue engineering.

This review presents some of the recent technological developments in biomaterials used for the construction of synthetic cardiovascular vessels that are capable of simulating specific biological responses. However, with respect to the problems of stiffness, a major hypertensive risk factor, it is necessary to underline the important role of mechanical properties, such as vessel strength and composition, in vascular reconstructive surgery. Biomaterials occupy a central place in many cardiovascular disease treatments and they depend on the chemical nature of the polymers, on the biotechnology used, and also on cellular and gene therapy. Several methodologies using animal or human cells have emerged for constructing blood vessel replacements. Tissue-engineered blood vessel (TEBV) substitutes begin to motivate much work and have contributed to the restoration, maintenance, and/or improvement in tissue and organ function. Each methodology has it benefits, its promises, and holds many challenges in future biological, biomaterial and clinical research.

Carotid arterial stiffness, elastic fibre network and vasoreactivity in semicarbazide-sensitive amine-oxidase null mouse.

OBJECTIVE: We examined the arterial phenotype of semicarbazide-sensitive amine-oxidase null mouse (SSAO -/-) using various techniques including high resolution echotracking. METHODS AND RESULTS: SSAO -/- mice showed no change in arterial pressure under anesthesia. The in vivo arterial diameter, only measured in the carotid artery (CA), was higher in SSAO -/- than in SSAO +/+ animals. Elastic modulus-wall stress curves and CA rupture pressure were similar between SSAO -/- and +/+ mice, indicating no change in arterial wall stiffness or mechanical strength. There was no significant difference in insoluble elastin, total collagen content and elastic lamellar morphology between the two genotypes. No alteration in vascular reactivity was observed in aortic rings and mesenteric arteries from SSAO -/- mice. Aortic lysyl oxidase (LO) activity remained unaltered, indicating that SSAO invalidation is not accompanied by a compensatory increase in LO activity. CONCLUSION: This is the first functional study of arteries lacking SSAO. Our results indicate that SSAO -/- mice present an increased arterial diameter associated with normal arterial mechanical properties, suggesting that SSAO deficiency might contribute to arterial wall remodeling. However, these results argue against the hypothesis that SSAO intervenes in elastic fibre organization, elastin cross-linking processes and vasoreactivity.

Pathophysiology, genetic, and therapy of arterial stiffness.

Stiffening of large arteries is considered as an independent predictor of cardiovascular events. This article summarizes recent theories on the mechanisms contributing to arterial stiffness involving extracellular matrix proteins, endothelial and smooth muscle cells, cell-matrix interactions, and genetic background. Despite the important role of genetic factors in essential hypertension, little is known about the genetic of arterial stiffness. In the future, candidate genes approaches will allow to determine the cellular and molecular mechanisms of arterial stiffness. A review of different strategies aimed at lowering arterial stiffness and potentially reducing cardiovascular risk are presented. Lifestyle changes and antihypertensive drugs have showed beneficial effects in reversing stiffness. New emerging tools as gene therapy and molecules involved in matrix attachments or crosslink of collagen may be promising. Therapeutic trials using such strategies will be necessary to demonstrate their impact on morbidity and mortality.

[Clinical trials using medicinal plants: bibliographical review and methodological analysis]. / Essais cliniques des medicaments à base de plantes: revue bibliographique.

BACKGROUND: The importance of traditional medicine, one of the fundamentals of the cultural heritage of African, Asian and South American peoples, is evident in that such medicine is practised by more than 80% of these populations. METHODS: To analyse the methodology of clinical trials using medicinal plants, we reviewed articles published on this topic between 1980 and 2000. RESULTS: Forty-eight clinical trials were identified. Most were carried out in developed countries. Standard methodological principles were applied in almost all the trials: randomisation (85.4%), comparison (87.5%) versus placebo (95.2%), and blinded design (81.3%). The duration of the studies was short. Sample sizes were generally small, ranging from 30 to 99 subjects; statistical tests were used in 90% of the trials. Adverse effects were infrequently collected. CONCLUSION: Most clinical trials included in this survey were conducted in accordance with WHO guidelines. Respect for methodological principles and the implementation of a legislative framework are important in obtaining credibility and international recognition of the traditional pharmacopoeia.

Selective reduction of heart rate by ivabradine: effect on the visco-elastic arterial properties in rats.

BACKGROUND: The heart rate (HR) reduction obtained by ivabradine is associated in rats with a decrease in diastolic blood pressure (DBP) and mean blood pressure (MBP), and with an increased pulsatile carotid arterial diameter. OBJECTIVE: To determine, in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, whether acute reductions of the HR in response to ivabradine induced changes in the carotid visco-elastic behavior, as assessed by echo-tracking techniques. METHODS: The hysteresis of the carotid diameter/pressure curve was used to determine the dissipated energy per cardiac cycle, a classical index of arterial viscosity. Four doses of 1 mg/kg intravenous ivabradine were repeated in anesthetized rats to obtain subsequent HR reductions. RESULTS: In WKY, repeated administration of ivabradine produced reduction of MBP, DBP and HR, without change of systolic blood pressure (SBP). In SHR, ivabradine produced a higher reduction in DBP, SBP and HR than in WKY rats, but the increase in pulse pressure was similar in both strains. In SHR and WKY rats, ivabradine did not modify the incremental elastic modulus-stress curves, and shifted the distensibility-pressure curves through changes in blood pressure, indicating no modification in isobaric carotid stiffness. In both strains, ivabradine produced an identical increase of the energy dissipated per cardiac cycle. CONCLUSION: In WKY rats and SHR, acute ivabradine reduces MBP and DBP and increases pulse pressure, but without change in arterial stiffness. In both strains, the HR reduction due to ivabradine induces an identical increase of the energy dissipation of the arterial wall.

Selective reduction of central pulse pressure under angiotensin blockage in SHR: role of the fibronectin-alpha5beta1 integrin complex.

BACKGROUND: Meta-analyses of antihypertensive therapy suggest that, independently of blood pressure (BP) level, stroke prevention is influenced mainly by calcium-entry blockers (CEB) and cardiac risk prevention by angiotensin-converting enzyme inhibitors (ACEIs). The possibility that central systolic and pulse pressure (PP) reduction differs between the two drug classes for the same mean BP (MBP) has never been explored. Our aim was to compare carotid PP at the same MBP obtained with the CEB, amlodipine, and the ACEI, trandolapril, in spontaneously hypertensive rats (SHR), and to evaluate the resulting changes of fibronectin (Fn) and its integrin alpha5beta1 receptor on central PP and arterial stiffness. METHODS: Amlodipine and trandolapril were administered chronically to achieve the same MBP. Carotid arterial systolic BP (SBP) and PP, diameter and incremental elastic modulus (E(inc)) were determined using echo Doppler techniques, and complemented with vascular histomorphometry, and Fn and alpha5beta1-integrin immunolabeling. RESULTS: Both drugs produced the same MBP, carotid wall thickness, and stress. Trandolapril reduced PP and E(inc) significantly more than amlodipine, while both agents comparably lowered EIIIA-Fn. Total Fn and alpha-subunit were lowered significantly by trandolapril, but unaffected by amlodipine, indicating that ACEI alone contributed to both diminished carotid stiffness and decrease of the Fn-integrin complex. CONCLUSIONS: Results showed that amlodipine and trandolapril have different effects on carotid mechanical properties for comparable MBP reduction. Changes in Fn-integrin complex not only modify consistently ACEI mechanotransduction but also are associated with selective central PP reduction. Whether this property has consequences on cardiovascular (CV) risk remains to be investigated.

Role of alpha1beta1-integrin in arterial stiffness and angiotensin-induced arterial wall hypertrophy in mice.

We examined the arterial phenotype of mice lacking alpha(1)-integrin (alpha(1)(-/-)) at baseline and after 4 wk of ANG II or norepinephrine (NE) administration. Arterial mechanical properties were determined in the carotid artery (CA). Integrin expression, MAPK kinases, and focal adhesion kinase (FAK) were assessed in the aorta. No change in arterial pressure was observed in alpha(1)(-/-) mice. Elastic modulus-wall stress curves were similar in alpha(1)(-/-) and alpha(1)(+/+) animals, indicating no change in arterial stiffness. The rupture pressure was lower in alpha(1)(-/-) mice, demonstrating decreased mechanical strength. Lack of alpha(1)-integrin was accompanied by an increase in beta(1)-, alpha(v)-, and alpha(5)-integrins but no change in alpha(2)-integrin. ANG II increased medial cross-sectional area of the CA in alpha(1)(+/+), but not alpha(1)(-/-), mice, whereas equivalent pressor doses of NE did not produce a significant increase in either group. In alpha(1)(+/+) mice, ANG II induced alpha(1)-integrin expression and smooth muscle cell (SMC) hypertrophy in the CA in association with increased aortic expression of alpha-smooth muscle actin and smooth muscle myosin heavy chain and phosphorylation of ERK1/2, p38 MAPK, and FAK. ANG II did not induce SMC hypertrophy or phosphorylation of p38 MAPK and FAK in alpha(1)(-/-) mice. A functional anti-alpha(1)-integrin antibody inhibited in vitro the ANG II-induced phosphorylation of FAK and p38 MAPK. In conclusion, alpha(1)(-/-) mice exhibit a reduced mechanical strength at baseline and a lack of ANG II-induced SMC hypertrophy. These results emphasize the importance of alpha(1)beta(1)-integrin in p38 MAPK and FAK phosphorylation during vascular hypertrophy in response to ANG II.

Early activation of internal medial smooth muscle cells in the rabbit aorta after mechanical injury: relationship with intimal thickening and pharmacological applications.

1. Smooth muscle cells (SMC) participate in both inflammatory and dedifferentiation processes during atherosclerosis, as well as during mechanical injury following angioplasty. In the latter, we studied medial SMC differentiation and inflammation processes implicated early after de-endothelialization in relation to mechanical stresses. We hypothesized that activation of a subpopulation of SMC within the media plays a crucial role in the early phase of neointimal formation. 2. For this purpose, we used a rabbit model of balloon injury to study activation and differentiation of medial SMC in the early time after denudation and just before neointima thickening. Inflammation was evaluated by the expression of vascular cell adhesion molecule (VCAM)-1, integrin alpha4beta1 and nuclear factor (NF)-kB. Myosin isoforms and 2P1A2 antigen, a membrane protein expressed by rabbit dedifferentiated SMC, were used as markers of differentiation. 3. On day 2 after de-endothelialization, VCAM-1, alpha4beta1 and NF-kB were coexpressed by a well-defined subpopulation of SMC of the internal part of the media, in the vicinity of the blood stream. At the same time, the majority of SMC throughout the media expressed non-muscle myosin heavy chain-B (nm-MHC-B) and 2P1A2 antigen. On day 7, when intimal thickening appeared, SMC of the media were no longer activated, whereas some intimal SMC expressed the activation markers. Thus, after de-endothelialization, early dedifferentiation occurs in most of the medial SMC, whereas activation concerned only a subpopulation of SMC located in the internal media. Using the T-type voltage-operated calcium channel blocker mibefradil (0.1-1 micromol/L) in SMC culture, we showed that this agent exhibited an antiproliferative effect in a dose-dependent manner only on undifferentiated cells. 4. In conclusion, the results suggest that the activated SMC represent cells that are potentially able to migrate and participate in the intimal thickening process. Thus, the medial SMC inflammatory process, without any contribution of inflammatory cells, may represent a major mechanism underlying the development of intimal thickening following mechanical stress. In humans, inhibition of T-type calcium channels may be a tool to prevent the early proliferation step leading to neointimal formation.

Carotid and brachial blood pressure–measurements in hypertensive subjects

Physiologically, central pulse pressure is lower than peripheralpulse pressure for the same mean arterial pressure. Thissituation protects the heart from an increase in post load asa consequence of mechanisms related to wave reflectionsand/or arterial stiffness. Nowadays, non-invasive measurementsenable to evaluate this physiological particularity.One of the methods enabling to minor measurement errorsis to calculate the difference between brachial and carotidpulse pressure, so called amplification (mmHg). When thisprocedure is used, errors are limited to those of brachialblood pressure measurements. Amplification is reducedwith age, but augmented by tachycardia, mostly in women.Amplification is poorly modified by drug treatment, exceptthrough drug-induced changes in heart rate. Longitudinalstudies are needed to evaluate the role of amplification incardiovascular epidemiology and therapeutics.