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Introduction En 2016, 2017 et 2018 les associations de patients (France-Rein et l’AFD), les reseaux regionaux thematiques et les services de sante volontaires (106, 108 et 95 structures respectivement) ont organise en partenariat avec l’ARS d’Ile-de-France des semaines de co-depistage regional du diabete, de l’obesite et d’une maladie renale et de leurs facteurs de risque en population generale. Description claire et complete de l’experience L’objectif est de rapporter les principaux resultats du co-depistage et les facteurs ayant conduit a conseiller certaines personnes de consulter leur medecin traitant. Methodes Le depistage a porte au total sur 16 597 personnes. Ont ete recueillies des donnees socio-demographiques, les antecedents medicaux et des donnees cliniques (IMC, tour de taille, pression arterielle, proteinurie a la bandelette, Findrisk calcule en 2017–2018). Une regression logistique sur les donnees de 2017 a determine les raisons principales d’orientation vers le medecin traitant. Resultats obtenus ou attendus Dans la population totale, l’âge median etait de 51 ans, femmes 67,8 %, 52,3 % avaient au moins une maladie connue : hypertension 21 %, diabete 7,9 %, maladie renale 13 %, maladie cardiovasculaire 8,6 % ; 34,2 % etaient en surpoids, 20,4 % obeses. Parmi les personnes sans diabete connu, 20 % avaient un Findrisk ≥ 12 (risque de diabete modere a tres eleve) et seulement 2,5 % avaient une glycemie capillaire elevee. La prevalence de la proteinurie ≥ 0,3 g/L etait de 15,4 %. Il a ete conseille a 51,3 % des personnes de voir leur medecin traitant. Selon les modeles de regression multiple, les 3 principaux facteurs d’orientation vers le medecin traitant etaient la proteinurie, l’IMC ou le Findrisk et une pression arterielle elevee, expliquant 75 % des orientations. Conclusion Lors de ces campagnes de co-depistage la proportion de personnes a risque de diabete et de maladie renale. Plus de 50 % des personnes ont ete orientees vers leur medecin traitant pour des raisons conformes aux criteres initialement definis. more...

Resume La table ronde intitulee «Modeles de Partenariats Public-Prive en Europe, Comparaison France-pays europeens » reunissait des representants du secteur academique et industriel, de programmes scientifiques nationaux ou europeens dans le domaine de la Sante, d’acteurs regionaux et nationaux du partenariat public-prive et des biotechnologies, et bien entendu de representants d’institutions ou de programmes Europeens ou extraeuropeens dans le domaine de le recherche en Sante, avec pour objectifs: • le partage d’une vision sur les besoins, attentes et enjeux du Partenariat Public-Prive • a partir de l’analyse de cas concrets et originaux, ou d’initiatives nouvelles de partenariats Public-Prive • en tirer des enseignements - Facteurs clefs du succes. • identifier des axes de progres - Recommandations. L’actualite dans ce secteur est actuellement dominee par une initiative de partenariat public-prive a l’echelle de l’Union europeenne entre l’industrie du medicament (EFPIA) et la Commission europeenne (DG Recherche - Sciences de la Vie), sous la forme du projet de Plate-forme technologique Europeenne « Innovative Medicines Initiative » (IMI), dont l’architecture repose sur l’identification des principaux obstacles au developpement de medicaments innovants (pharmacologie et toxicologie predictives, identification et validation des biomarqueurs, recrutement de patients, evaluation du risque et cooperation avec les instances reglementaires) Simultanement, un certain nombre d’initiatives a l’echelle nationale ou regionale viennent complementer le maillage geographique du partenariat: la constitution de poles de competitivite a l’echelle regionale, ou l’appel d’offres du reseau Innovation Biotechnologie (RIB) de l’ANR sont autant d’incitations au partenariat public-prive, capables de structurer des consortia aptes a repondre secondairement a des appels d’offres de plus grande envergure a l’echelle europeenne, realisant un escalier du partenariat. En depit de mesures incitatives et de cadres regionaux et nationaux du partenariat, les difficultes decrites au niveau national reposent en partie sur la multiplicite des acteurs - multiples agences de valorisation, multiples organismes de recherche (operateur ou agence de moyens) qui peuvent compliquer la passation de contrats - rendant souhaitable une structuration plus lisible avec un referent unique par domaine (sante, technologie, etc.). Ces partenariats seront aussi facilites par un travail concernant les statuts, le recrutement et la mobilite, par un support aux scientifiques dans le pilotage des projets, et par un soutien permettant d’accompagner (sans les maintenu’ artificiellement en vie) des entreprises emergentes depuis le concept jusqu’au stade du developpement clinique. Concernant le developpement clinique, des pistes ont ete avancees quant a l’organisation de la recherche clinique en France et en Europe, necessairement structuree au sein du secteur public, et supposant un couplage entre infrastructures integrees a l’echelle de l’Europe et reseaux thematiques. Comme le souligne le volet « Efficacite » d’IMI, la qualite des infrastructures publiques europeennes sera un element cle de sa competitivite et de son attractivite pour le secteur academique comme industriel. more...

The workshop entitled "Public-Private partnerships models in Europe-- comparison between France and European countries" brought together representatives of academia and industry, of national or European health research programs, of regional or national public-private partnership (PPP) initiatives, and of biotechnology with the following objectives: sharing a common vision on the needs, expectations and challenges of public-private partnership, based on the analysis of actual and original cases, and of new initiatives on public-private partnership, drawing conclusions and identifying key success factors, identifying trails for progress and drawing recommendations. The major event in this field is a European public-private partnership initiative between pharmaceutical industry (European Federation of Pharmaceultical Industry and Associations, EFPIA) and the European Commission (DG Research--health priority) resulting in the European Technology Platform project "Innovative Medicines Initiative" (IMI). Its architecture is based on the identification of the main bottlenecks to the development of innovative treatments (predictive pharmacology and toxicology, identification and validation of biomarkers, patients' recruitment, risk evaluation, and cooperation with the regulatory authorities). Simultaneously, initiatives both at the national and regional levels also foster PPP in the therapeutic field. Regional competitivity clusters acting in the biomedical sector, and national PPP calls such as the ANR (National Research Agency) RIB (Research and Innovation in Biotechnology) call are incentives for PPP projects. These regional and national PPP levels help public and private partners to further build consortia able to compete for EU-level calls, thus acting as incubators for EU PPP projects. In spite of incentives and of the regional and national structuring of PPP, weaknesses in the French system are linked to its fragmentation--multiple transfer agencies, multiple research organisations (operator or funding agency)--making contracts more difficult. This requires a simplified organisation, with a single referent per area (health, technology...). Improvement may also result from adaptation in the carreer, recruitment and mobility, from support to scientists in the management of projects, and from consistent support (without maintaining them artificially alive) to emerging companies from concept through clinical development. Pathways have been proposed to improve the efficiency of clinical research in France and Europe, involving the public hospital sector, and this requires the connection of disease-oriented networks and integrated infrastructures in Europe. As stated in the IMI strategic research agenda on efficacy, the quality of public infrastructures in Europe will be a key factor for its competitiveness and attractiveness for both academic and industry projects. more...

Aims Family-based studies suggest a genetic basis for nephropathy in Type 2 diabetes. The angiotensin-I-converting enzyme (ACE) gene is a candidate gene for Type 1 diabetes nephropathy. We assessed the association between high urinary albumin concentration and ACE insertion/deletion (I/D) polymorphism, in French Type 2 diabetes patients. Methods We studied 3139 micro/macroalbuminuric French patients recruited in the DIABHYCAR Study, an ACE inhibition trial in Type 2 diabetes patients with renal and cardiovascular outcomes. The main inclusion criteria were age ≥ 50 years, urinary albumin concentration ≥ 20 mg/l assessed centrally during two consecutive screening visits, and plasma creatinine concentration ≤ 150 µmol/l. These patients were compared with 605 normoalbuminuric (NA; urinary albumin concentration more...

The increase in renin secretion and the induction of the converting enzyme (ACE) observed during treatment by ACE inhibitors (CEIs) could result in increased angiotensin II (ang II) synthesis when the treatment is stopped. The object of this study was to compare changes in the components of the renin-angiotensin system with changes in arterial pressure in hypertensives, following the cessation of long-term ramipril treatment. Twenty hypertensives, treated for at least three months with ramipril, in monotherapy for the last three weeks, were randomly allocated to two parallel groups and received for fifteen days, on a double-bind basis, either a placebo (withdrawal group W, n = 12) or ramipril at the previous doses (treated group T, n = 8). Blood pressure was measured using four different techniques. The active renin (AR), angiotensinogen, angiotensin I (ang I), angiotensin II (ang II) and aldosterone plasma concentrations were measured, as was plasma angiotensin I converting enzyme (ACE) activity in vitro (colorimetric and fluorimetric method) and in vivo (the ang II/ang I ratio). The biological effects of cessation of long-term ramipril treatment in hypertensives were a decline in AR and angiotensin I concentrations, an increase in ACE activity and no significant changes in angiotensinogen, angiotensin II and aldosterone levels. Fifteen days after withdrawal, the different parameters of the renin-angiotensin system appear to have returned to basal value. A slow rise in blood pressure was also observed but no rebound increase was noted during the 15 days neither in angiotensin II levels nor in blood pressure. Following the cessation of prolonged ramipril treatment, in vivo converting enzyme inhibition disappears slowly, probably on account of the slow tight binding inhibitor properties of ramiprilat, the active metabolite of this CEI. The gradual decline in AF, plasma levels, together with the prolonged ACE inhibition as measured in vivo by the ang II/ang I ratio, explains the absence of a rise in ang II synthesis. more...

The pathogenesis of venous leg ulcers is based on the leakage of fibrinogen leading to a pericapillary fibrin cuff and plugging of capillaries by white blood cells. On the basis of a previous work, we had assumed that the key event in the pathogenesis of venous leg ulcers is related to inflammation generated by activated white blood cells that accumulate under unrelieved blood pressure, because in ulcer biopsies we had detected the presence of tumor necrosis factor-alpha (TNF-alpha) in intracapillary monocytes, elastase in the polymorphonuclear leukocytes near the vessels, and a pericapillary undegraded fibrin cuff causing a diffusion barrier to oxygen. This concept was developed because TNF-alpha synthesized by activated monocytes is responsible for many deleterious effects. It has a potent mitogenic effect on fibroblasts, leading to new collagen deposition and angiogenesis, it induces an increase in collagenase production, it acts through upregulation of an intracellular adhesion molecule (ICAM-1), leading to leukocyte sequestration and consequently a release of toxic metabolites by the polymorphonuclear cells, an early step in chronic inflammation, it activates the coagulation pathway via a marked increase in monocyte-associated tissue factor (TF) procoagulant activity, and it inhibits fibrinolysis by promoting the release of PAI-1, contributing to undegraded fibrin deposition. Therefore, we were interested in evaluating, in patients with venous leg ulcers, the effect of pentoxifylline administered at 1,200 mg daily (versus placebo) for 2-months, as this drug induces a decrease in TNF-alpha synthesis and also blocks its activity. This pilot assay was performed in blind. Evolution of several parameters in ulcer biopsies are analyzed: TNF-alpha, intact fibrin, fibrin degradation products, ICAM-1, TF, and elastase. Pentoxifylline administration induced a decrease of local elastase and of fibrin deposit. These results support the hypothesis that accumulation of activated leukocytes is the key event in venous leg ulcers. more...

A national survey was performed in France from May to June, 1993. The aim of this study was to evaluate general practitioners' attitudes and behaviors when diagnosing and managing patients with lower extremity arterial disease (LEAD). One thousand general practitioners, randomly drawn from an exhaustive list, were contacted to participate in a telephone interview concerning the last patient with intermittent claudication seen in their practice. Four hundred seventy-six general practitioners participated. Risk factors noted for these 476 patients with intermittent claudication were in agreement with the literature : 86% were men aged 64 ± 10 years (mean ± SD) and 14% were women aged 73 ± 8 years. Sixty-two percent had a pain-free walking distance of between 100 and 500 meters at diagnosis. Forty-five percent were former smokers and 37% currently smoked ; 55% had hypertension, 14% diabetes, and 56% disturbances of lipid metabolism. A majority of them were hypercholesterolemic. The diagnosis of the disease was based primarily on a clinical assessment, confirmed for 33% by Doppler or echo Doppler. The mean duration of diagnosis was 4.4 + 4.1 years. Management of the disease was mainly by prescription of vasodilators (91%), antiplatelet agents (59%), and anticoagulants (8%). Use of Doppler or echo Doppler was recommended once a year. Infection was observed in 27% of patients. Thirty-eight percent had had a cardiac incident (angina pectoris or myocardial infarction) and 10% a cerebrovascular accident. They differed significantly from those with LEAD alone for the following parameters : age (68.5 ± 9.2 vs. 63.2 ± 10.3 years ; p < 0.001) ; duration of LEAD (5.6 ± 4.6 vs. 3.6 ± 3.5 years ; p < 0.001) ; hypertension (65% vs. 50% ; p < 0.01) ; and current smoking (29% vs. 43% ; p < 0.01). This survey confirmed the feasibility of telephone interviewing, on a large sample of general practitioners in France. The high level of association with other cardiac incidents was, for these patients, a much higher risk of mortality and morbidity than LEAD alone. It would be interesting to validate the associations observed with a prospective study of comorbidity. more...

A survey resulting from a partnership between CECEC (Centre d'Etudes en Circulation Extra-Corporelle) and Laboratoires Hoechst, France was carried out amongst all French adult cardiac surgery centres. The aim of this study was to investigate the various strategies used to decrease blood loss during open-heart surgery. Due to an exceptionally high response rate, we are able to report the current practice of French cardiac centres which account for 75% of open-heart adult surgery. The three most interesting strategies for blood conservation appear to be haemodilution, blood salvage from the extracorporeal circuit and previously deposited autologous blood transfusion, yet the three methods which are predominantly used are haemodilution (92.7%), aprotinin therapy (87.8%) and blood salvage from the extracorporeal circuit (82.9%). more...

The non-insulin-dependent DIABetes, HYpertension, microalbuminuria or proteinuria, CARdiovascular events, and Ramipril (DIABHYCAR) study is a randomized, prospective, double-blind, placebo-controlled, multicenter international trial of the ACE inhibitor ramipril (1.25 mg/day) in patients with type II diabetes and micro- or macroalbuminuria. The main outcome of the study is the time to first occurrence of either death from a cardiovascular origin, including sudden death, nonfatal myocardial infarction, stroke, or congestive heart failure, or requirement of hemodialysis or renal transplantation. The study was launched in France in early 1995 with the participation of general practitioners only, but had to be extended to 15 other countries in 1997 due to difficulties in recruitment. Since 2.5 years after the beginning of the trial the observed event rate was much less than anticipated, it was decided to increase recruitment and follow-up duration and to include congestive heart failure in the definition of the main outcome to keep the study power at a satisfactory level. Recruitment ended on April 1, 1998 with 4937 randomized patients. Following the early discontinuation for efficacy of another study of ramipril in high cardiovascular risk patients, the Heart Outcomes Prevention Evaluation study (HOPE), the second interim analysis of DIABHYCAR was performed early (when 406 instead of 500 patients presented a main outcome) and the Data Safety and Monitoring Board recommended that the study continue. Follow-up is planned to end on March 31, 2001. more...

Whether ACE inhibition is useful for type 2 diabetic patients with micro- and macroalbuminuria remains unknown. The Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events and Ramipril (DIABHYCAR) Study was set up to address this issue through a multicenter double-blind parallel placebo-controlledor = 3-year trial in Europe and North Africa. In this article, we report the characteristics of the randomized patients.The main selection criteria were as follows: men or women agedor = 50 years with type 2 diabetes treated with oral antidiabetic drugs, with or without hypertension, with a plasma creatinine level150 mumol/l, and with persistent micro- or macroalbuminuria, as assessed centrally by two successive urine samples containing a urinary albumin concentrationor = 20 mg/l. Patient characteristics were studied by comparing patients who were randomized to those who were not, taking their geographical origin into account.There were 25,455 patients screened for urinary albumin (20,296 from France, 918 from Germany, 1,019 from Northwest Europe, 969 from Central Europe, 959 from Mediterranean Europe, and 1,294 from North Africa). Of these patients, 4,937 were randomized. Compared with the nonrandomized patients, the randomized patients were older, more often men, more obese, had higher systolic/diastolic blood pressure and plasma glucose, smoked more tobacco, drank more alcohol, and had complications more frequently. Using a logistic regression analysis, all the above-mentioned items appeared as independent determinants for randomization into the study, with the exception of alcohol intake. The contribution of each item varied slightly from one geographical origin to another.The physical, biological, and behavioral characteristics create a poor renal and cardiovascular prognosis for the type 2 diabetic patients randomized to the DIABHYCAR Study because of micro- and macroalbuminuria. Testing the usefulness of ACE inhibition for the type 2 diabetic patients with microalbuminuria seems feasible through the DIABHYCAR Study. more...

In this study, the tolerability and safety of ramipril, as monotherapy and in combination with a low dose of furosemide, were assessed in patients with mild-to-moderate hypertension in general practice. After a placebo run-in phase, patients received ramipril as monotherapy in a dose of 2.5 to 5 mg daily for 6 weeks. Nonresponders (diastolic blood pressure greater than 90 mm Hg) entered a double-blind treatment period, and received either 10 mg of ramipril daily, or 5 mg of ramipril in combination with 20 mg of furosemide daily. The tolerability of the study medication was assessed by reported adverse events, and by monitoring blood cell count, electrolytes, serum creatinine, fasting blood glucose, and apolipoproteins AI and B. Of a total of 770 patients who entered the placebo run-in phase, 661 patients were enrolled in the first active treatment period. The most commonly reported adverse events were headache, cough, dizziness, asthenia, cramps, diarrhea, and nausea, but not all of these events were related to ramipril treatment. A total of 38 patients discontinued active treatment due to nonserious adverse events, mainly cough, dizziness, or diarrhea. There appeared to be a relationship between the prevalence of cough and ramipril dosage; however, an increased incidence of cough was also observed during outbreaks of influenza in France. There were no significant changes in laboratory variables during the study. more...

Since the discovery at the end of the seventies of angiotensin converting enzyme inhibitors (ACEI), numerous clinical data became available in the indications for which these agents were initialy developed, taking into account the putative role of renin angiotensin system: first in severe hypertension, secondly in moderate hypertension and then in heart failure. At the same time, an increasing interest was raised for "evidence based medicine" leading to a change in clinical study design: from clinical documentation of effects based on intermediate end points such as blood pressure, serum lipids, serum electrolytes or physical training capabilities to clear demonstrations through double blind placebo controlled trial with a positive effect on morbi-mortality. This evolution was furthermore stimulated by advances of knowledge on physiopathological mechanisms as well as the emergence of new drugs within this therapeutic class both stimulating clinical research. In that prospective, three examples are obvious: treatment of myocardial infarction, slowing down of the progression of diabetic nephropathy and of chronic renal failure. All these new indications for ACEI were obtained though large morbi-mortality clinical studies which are reviewed in this article. Finally, clinical studies are running with ACEI in order to demonstrate a possible effect on primary or secondary prevention of cardiovascular morbi-mortality in high risk populations results which should be available at the beginning of the next century. more...

This study compares the loop diuretic piretanide 6 mg in a slow-release formulation (PIR) with hydrochlorothiazide 25 mg (HCT) and the fixed combination altizide 15 mg-spironolactone 25 mg (ALT-SP) in hypertension. 1105 mild to moderate hypertensive patients entered a three-week placebo wash-out period; 899 were randomized in a 6-month, double-blind, parallel group treatment phase; 800 completed the study. Primary end-points; serum potassium concentration and quality of life at one month; secondary end-points: ionic, renal and metabolic variables; blood pressure (BP) measurements. HCT and ALT-SP were compared only to PIR using Dunnett's or chi 2 tests.No difference was found for the overall quality of life. No change of serum potassium concentration at one month was found in PIR while small decreases were detected with ALT-SP (-0.1 mM) and HCT (-0.26 mM). Serum creatinine concentration increased significantly in ALT-SP when compared to PIR. All the drugs were effective in reducing BP: HCT had a higher rate of responders than PIR with similar mean BP falls and ALT-SP induced greater falls in blood pressure.PIR proves to be a potent antihypertensive drug without significant effect on serum electrolytes, plasma glucose and lipids. HCT was slightly more potent but induced a fall in serum potassium concentration with a significant risk of hypokalaemia. The addition of SP to ALT led to a more potent diuretic with a higher level of serum potassium and plasma creatinine disturbances. more...

The dosage of drugs which might be used in children must be determined to avoid empirical use, even when no application has been submitted for a paediatric licence. Toxicological evaluation and assessment of the effects on growth, an adapted pharmaceutical form and paediatric pharmacokinetic and adult clinical data are essential before conducting trials designed to determine the paediatric dosage. The dose used during preliminary studies is extrapolated from the adult dose expressed in relation to weight, tested in a dose-effect study, and then more accurately defined on the basis of pharmacokinetic data in different age groups. Obtaining consent from both parents for studies whose direct benefit is not always obvious, as well as the global cost of these studies, constitute drawbacks to paediatric drug development. Incentives to determine a paediatric dosage could consist of public participation in funding, prolongation of the patent, and granting an advantageous price for a specifically paediatric pharmaceutical form or indication. more...

Microalbuminuria is a risk marker for cardiovascular morbidity and mortality in Type 2 diabetes. We studied microalbuminuria among French Type 2 diabetic patients in general practice, because we set-up a trial using cardiovascular events as end-points. Two thousand twenty four volunteer patients were studied for Urinary Albumin Concentration (UAC) during outpatient visit to general practitioners. The UAC was measured on first samples. If UAC was positive (or = 20 mg/l), a second sample was requested. If UAC was positive two times, persistently elevated UAC was identified (micro or macroalbuminuria). Clinical characteristic, cardiovascular antecedents and risk factors were studied. One hundred five first samples were excluded due to urinary infection; 1,217 others displayed normal UAC (20 mg/l); 63.4%; group N), 557 microalbuminuria (20-200 mg/l; 29.0%, group mu), and 145 others macroalbuminuria (200 mg/l; 7.6%; group M). Among subjects with positive first sample, 26.5% had persistent albuminuria. There was no intergroup difference for age, but males were more frequent in groups mu or M than N (p10(-4)). Blood pressure and body mass index varied between groups. Smokers and alcoholic subjects were more frequent in groups mu and M than N (p = 0.037 and p = 0.0003 respectively), as were cases with myocardial infarction (p = 0.0026), lower limb arteritis (p10(-4)), and laser-treated diabetic retinopathy (p = 0.0002). Antihypertensive treatments were taken by 61% of the subjects. Elevated UAC (micro or macroalbuminuria) is frequent among french Type 2 diabetic patients cared by their general practitioners, and is associated with a high cardiovascular risk profile.(ABSTRACT TRUNCATED AT 250 WORDS) more...

The aim of this 16-week trial was to determine the safety and efficacy of a step-care regimen of ramipril, an angiotensin converting enzyme inhibitor, from the minimal active dose (2.5 mg) in patients treated for mild to moderate hypertension. The trial was conducted by 102 general practitioners in 770 patients with mild to moderate hypertension. After a response rate to a 4-week placebo therapy of 9.1%, 57.0% of patients given active treatment with ramipril responded to daily doses of 2.5 mg. Ramipril 5 mg daily was effective in 55.6% of the remaining patients. There was no apparent statistically significant difference between the treatments with ramipril 10 mg or a combination of ramipril 5 mg + Lasix 20 mg daily (44.7% and 47.4% response respectively) in a 6-week double-blind arm of the study. In total, more than 90% of patients responded to treatment with ramipril by the end of the study. The incidence of adverse events was generally low, such as headache, cough, dizziness, asthenia, cramps and nausea. The incidence of cough appeared to be related both to the dosage of ramipril given and to outbreaks of influenza syndrome. Thirty-eight patients discontinued active treatment as a result of minor events such as cough, dizziness or diarrhoea, and one case each of myalgia and papular rash. There were no significant variations in laboratory parameters during the study, especially fasting blood glucose and apolipoprotein A1 and B. The results of this study provide evidence of the safety and efficacy.(ABSTRACT TRUNCATED AT 250 WORDS) more...

In order to assess the prevalence of arterial hypertension, diabetes mellitus, and of the association of both diseases, and furthermore, to underline the behaviours and feelings of French physicians in front of these combined diseases, a survey has been undertaken by the SOFRES Medical institute and by Laboratoires Hoechst, which involved 304 physicians in private practice and 67 hospital doctors. After face-to-face interviews, each participant had to fill up a questionnaire dealing with his general feelings and attitudes, and then completed 2 case record forms (5 cases for hospital doctors) from their last patients who presented with hypertension and diabetes mellitus. All these informations have allowed us to describe their behaviours. The 304 physicians have been selected with a regional stratification by a random survey quota method that gave a valid sample from the French medical population: 213 general practitioners (GPs), 67 cardiologists, 24 endocrinologists have been involved in the survey. They have been able to observe 149 hypertensive insulin-dependent diabetic patients and 470 hypertensive non insulin-dependent diabetic patients (respectively 24% and 76%). In addition, 67 hospital doctors (32 cardiologists, 17 diabetologists, 18 nephrologists) have been involved and have filled 255 case record forms (120 insulin-dependent and 135 non insulin-dependent diabetic patients). The association between hypertension and diabetes mellitus is very common: 55% out of the diabetic patients treated by GPs presented with hypertension, 20% out of the hypertensive patients presented with diabetes mellitus. The discovery of hypertension is usually followed by the discovery of non insulin-dependent diabetes mellitus. The opposite feature is observed for the insulin-dependent diabetic patients. The majority of the doctors feels that the cardiovascular prognosis of the association is worse than each single disease. The level of blood pressure that is suitable to start an antihypertensive treatment in hypertensive insulin-dependent and non insulin-dependent diabetic patients is generally lower than for non diabetic hypertensive patients, especially for the diabetologists. Concerning antihypertensive treatments, discrepancies have been observed in between feelings and behaviours of physicians. The class of drug that is thought to be used is obviously different from the one which is really used: angiotensin-converting enzyme inhibitors and calcium antagonists, two rather new classes of drugs are popular while classical classes of antihypertensive agents like diuretics and betablockers are still commonly used. Non pharmacological interventions which are useful for both the treatment of hypertension and diabetes mellitus are not commonly recommended by GPs and specialists. more...

The aim of this study was to determine the acute and chronic arterial effects of the ACE inhibitor, ramipril. Fourteen patients (mean age 47 years) with mild to moderate essential hypertension completed the study. A first haemodynamic examination was performed at the end of a 15-day placebo period (D15) before and 3 hours after oral administration of ramipril, 5 mg. Then all the patients started a 4-week treatment with ramipril, 5 mg/day. At the end of this period (D42) the haemodynamic examination was repeated 24 hours after the last capsule intake, and then 3 hours after administration of ramipril 5 mg. Brachial and carotid artery haemodynamics were evaluated by a bidimensional pulsed Doppler system. Arterial distensibility was non-invasively studied in three different arterial segments (carotido-femoral, brachio-radial, femoro-tibial) by the evaluation of the pulse wave velocity. Ramipril significantly decreased BP after acute or chronic administration. Chronic treatment with ramipril was followed by a long lasting increase in brachial artery diameter, a decrease in forearm vascular resistance, and an improvement in aortic distensibility. The other investigated arterial segments did not show any significant changes. Our results suggest that long lasting arterial effects of the ACE inhibitor ramipril are partly pressure-independent and are related to an effect of this drug on arterial tone. These effects may be able to reduce the hypertensive cardiac and arterial abnormalities. more...

In order to recommend the pediatric use of a new drug, the registration file should include several types of studies. Existing data on toxicological and pharmacological studies in animal and human have to be thoroughly examined. In addition, the splitting potential of single doses to be adapted to the child should be studied, according to the galenic formula. In all cases, the clinical file should have one pharmacokinetic study on acute intake of one or several doses in the specific age bracket. When the efficacy of a drug has been demonstrated in adults for the same disease, and if the results are extrapolated to children, the file should include one or several open studies designs in order to assess the tolerability. On the contrary, for example when the disease is different in or specific for children, one or several double blind randomized studies against reference treatment are necessary. All those studies should show the therapeutical value of the drug, and should allow precise recommendations for the dosages, depending on the body weight and/or the body surface compatible with the galenic formula. more...

Triatec is a new ACE inhibitor. The initial recommended dose is a single daily intake of 2.5 to 10 mg. In order to validate a dose escalation schedule allowing each patient to be treated with the minimal effective dose, a multicenter clinical trial has been conducted by 102 general practitioners, under conditions close to their habits, on 770 mild hypertension patients with a 16 weeks follow-up. The trial consisted in 4 periods: after a placebo run-in period, the patients whose hypertension remained (supine diastolic blood pressure -DBP-between 95 and 115 mmHg) would receive 2.5 mg of Triatec a day, for 3 weeks. After completion of this first treatment period, non-responders (DBP greater than 90 mmHg) to Triatec 2.5 mg would receive 5 mg of Triatec a day, during 3 weeks. Non responders to Triatec 5 mg a day would then be randomized into a 6 weeks double-blind parallel group trial comparing monotherapy by 10 mg of Triatec to the association of Triatec 5 mg with Lasilix 20 mg. In France, Good Clinical Practice (GCP) is a set of recommendations aiming to ensure a high quality standard for clinical trials. To put these recommendations into practice within the context of a large study of Triatec, national and local structures were implemented for a computer-assisted follow-up. Real-time data control for the 770 patients enrolled in this trial made a first presentation of the results to the Scientific Committee possible a mere 10 weeks after the last visit of the last patient was recorded. It also ensured the most reliable data to be processed.(ABSTRACT TRUNCATED AT 250 WORDS) more...

After oral administration, ramipril, a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, is transformed in the liver into its active metabolite ramiprilat. Because of its pentane ring it is at least 23 times more lipophilic than enalaprilat. The in vitro affinity for ACE is 7 times higher than for enalaprilat and 47 times higher than for captopril. The ramiprilat-ACE complex is therefore very stable and dissociates 6 times more slowly than the enalaprilat ACE complex and 72 times more slowly than the captopril ACE complex. Consequently, ramipril is pharmacologically more potent and has a longer duration of action than enalapril and captopril. The blood pressure lowering effect of ACE inhibitors is attributed to the decrease in angiotensin II in serum and locally in target organs of hypertension: heart, vessel wall, kidney and brain. Inhibition of tissue renin-angiotensin system by ramipril has been described in target organs of hypertension in animal models and in clinical studies. Possibly due to its high lipophilicity, and strong affinity to the converting enzyme a better tissue penetration and a more pronounced local ACE inhibition in the target organs has been observed, as compared to other ACE inhibitors. In a preliminary investigation a direct action of ramipril on the tissue RAS in hypertensive patients could also be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS) more...

In glomeruli isolated from adult rats, arachidonic acid (C20:4) is metabolized through at least two different pathways: the lipoxygenase and the cyclooxygenase pathway, resulting in the synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE) and four prostaglandins (PG) respectively. Because renal blood flow (RBF) and glomerular filtration rate (GFR) increase during development, and because C20:4 metabolites are implicated in their local regulation, the conversion of 3H-C20:4 was studied in 3 groups of rats; group A: 4 days old, 10 g; group B: 10 days old, 25 g; group C: 60 days old, 200 g. Glomeruli mechanically isolated from blanched kidneys were incubated with 5.4 × 10––8M3H-C20:4. Lipoxygenase and cyclooxygenase products were extracted and resolved by high-performance liquid chromatography (HPLC); quantitative determination of PGs was performed by radioimmunoassay (RIA). The results are: (1) conversion of C20:4 to lipoxygenase product is predominant in comparison to cyclooxygenase products; (2) conversion of labeled C20:4 into 12-HETE is constant with age; (3) identified cyclooxygenase products, PGE2, and particularly PGF2α are maximum in group B; (4) the variation of C20:4 metabolism during development suggest that these products may be involved in the maturation and the regulation of glomerular functions. more...

The Hickman catheter is a single or double lumen catheter made of a silicone polymer; it is introduced surgically into the superior vena cava or the right atrium. The authors have used this catheter in 11 children, aged from 3 to 15 years and weighing from 10 to 40 kg, either for haemodialysis in children without arteriovenous fistula (n = 10), or for plasma exchanges (n = 1). In 5 of the 10 children, an arteriovenous fistula was created while the catheter was being installed. The catheter was left in place for a mean period of 48 days and a maximum period of 5 months. Data from the literature suggests that this instrument can be used for even longer periods. Dialysis was satisfactory in 8 out of 10 cases. No infection or thrombosis of the catheter was observed. The catheter was not perfused between haemodialysis sessions or blood exchanges. more...

Two cases of nephrotic syndrome discovered respectively at the ages of 3 and 7 weeks in 2 siblings are reported. Nephrosis was of the optically normal glomeruli-type in both cases. In spite of the very young age of the patients a good result of steroid-therapy was obtained after 6 and 8 weeks of treatment, respectively. Both children were not HLA-identical but had in common the A2-B12-DR4 haplotype. more...

Bacterial adhesivity test to epithelial cells in vitro was studied, in order to investigate whether urinary, and buccal cells, from children prone to recurrent urinary tract infections (UTI) are better adhered to by uropathogen Escherichia coli (E. coli), as compared to cells from control children, non-prone to recurrent UTI. Cells were withdrawn from 75 children, divided into 3 groups: with recurrent UTI without uropathy, with recurrent UTI and uropathy, and controls, without recurrent UTI and without uropathy. Values obtained showed that most of the children, prone or not to recurrent UTI, have cells allowing good adhesivity of the 2 uropathogen E. coli used and that there is no significant difference among these results and no relation with the 3 described groups. Bacterial adhesivity appears dependent on individual genetic variations of cell donors, presumably related to membrane receptors. Studies on in vitro bacterial adhesivity do not seem to be able to explain pathogenesis of recurrent UTI. more...

In recent studies were reported an inherited membrane defect which is closely related to the development of essential hypertension. This abnormality consists of a functional deficiency in the Na+--K+ co-transport mechanism in erythrocytes of essential hypertensives and some normotensives born of hypertensive parents. Here we report a case of juvenile essential hypertension including familial erythrocyte Na+, K+ measurements. The 2-year-old boy had essential hypertension and bore the abnormality, with no compensatory activity of the Na+, K+ pump. The mother had developed hypertension during pregnancy. She also bore the erythrocyte abnormality as the net Na+/K+ flux ratio was reduced. One sister bore the same abnormality without hypertension but a complete analysis of Na+ extrusion mechanisms in this patient demonstrated a compensatory effect of the Na+, K+ pump activity. Other members of the family were normotensive without the flux abnormality. It appears therefore that erythrocyte flux measurements might be of diagnostic and genetic interest in juvenile hypertension. more...

The effect of methyl prednisolone therapy (PM) was studied in 18 children with severe idiopathic nephrotic syndrome (NS). Eight patients were defined as "corticosteroid-resistant" because there was no response to treatment after a minimum of 4 weeks of 2 mg/kg/day of prednisone; 10 patients had a corticosteroid-dependent NS with frequent relapses which occurred under a high threshold dose of prednisone (1 mg/kg/day). Each patient received 4-6 pulses of 1 g/1.73 m2 methylprednisolone. Tolerance was generally good. PM therapy permitted a more rapid remission than oral prednisone (average 9 +/- 4 days vs. 22 +/- 9 days). Remission occurred in 5 of the 8 corticosteroid-resistant patients three of these 5 patients developed corticosteroid-dependent NS. For the children with a corticosteroid-dependent nephrotic syndrome, PM therapy did not affect the threshold dose of prednisone. more...

2 brothers with identical HLA antigens presented an idiopathic membranous glomerulonephritis. This is, to our knowledge, the first report of familial membranous glomerulonephritis. The fact that both brothers had identical HLA antigens suggests a genetic predisposing background. more...

A neonate with pneumonia due to Chlamydia trachomatis is reported. The infection was probably generalized because there was hepato-splenomegaly and a granuloma was found on liver biopsy. The frequency of this infection in neonates is probably underestimated in view of the importance of Chlamydia in adult genital disorders. Recent advances in the methods of detection of this organism in cell culture and by serological means should make it easier to diagnose routinely. more...

In 36 children with nephrotic syndrome (NS) a significant decrease of their serum levels of the thymic-hormone--thymulin--was found, in parallel with a diminution of their mean blood zinc levels as compared to 33 control children. The serum level of thymulin normalized after the in vitro addition of ZnCl2. Similar results have previously been reported in mice subjected to a long term zinc deficient diet. It can therefore be assumed that the decreased biological activity of the thymic hormone noted in NS is secondary to a low serum zinc level. These data could explain certain anomalies of T lymphocytes described in childhood NS. more...

The authors describe a case which demonstrates that nephrotic syndromes occuring during the course of a myeloma are not always of the amyloid type. They emphasize the possibility of a dysglobulinemia being involved in a glomerular nephropathy syndrome, especially when there are histological lesions of a glomerulosclerosis. The published literature is reviewed and the possible pathogenesis of these nephropathies briefly discussed: either protein deposits, the nature of which has not been fully determined, or mesangial modifications induced by the filtered light chains. more...

A massive haemothorax occurring acutely during haemodialysis in a child of 8 1/2 years is reported. The pleural effusion occurred synchronously with a round, dense shadow in the parenchyma similar to an intra-pulmonary haematoma. The density became bullous in six weeks and disappeared in three months. The suggested cause of this haemothorax is a pulmonary embolism whose site of origin was the arteriovenous fistula. This would have been responsible for the adjacent pleural and parenchymal haemorrhage in the lung. The heparin given intravenously at the beginning of the haemodialysis session probably contributed to the size of the haemorrhage. more...

In patients with nephrotic syndrome the response to corticosteroids and the way these drugs are tolerated are extremely variable. The purpose of this study was to investigate possible correlations between the pharmacokinetic values of prednisolone and the main clinical criteria of effectiveness and safety. The study was performed on 18 children under corticosteroid therapy: 16 with nephrotic syndrome and 2 with a systemic disease. Measurements were performed by radiocompetition with transcortine after an oral dose of 1 mg/kg bodyweight. Pharmacokinetic values varied considerably, with peak plasma levels ranging from 1.2 to 6.1 micrograms/ml between 20 and 120 minutes, and T 1/2 values of 77 to 648 minutes. Within this scattering of values, some patients were clearly outside the mean T 1/2 value (3.1 +/- 1 hours) due to a particularly fast or slow metabolisation of the drug. In patients with nephrotic syndrome no correlation was found between pharmacokinetic values and criteria of clinical effectiveness, such as the time and dosage required to obtain remissions and the duration of these remissions. Hypoalbuminaemia had no influence on the metabolism of prednisolone. In contrast, there was a correlation between pharmacokinetic values and side-effects, since patients who presented with side-effects also had a significantly greater area under plasma concentration versus time curves. This pharmacokinetic test may be used when corticosteroids produce unusual or unexplainable therapeutic results or adverse reactions. more...