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Ten percent of the world's population is affected by chronic kidney disease that can lead to kidney failure. In France, nearly three million people are concerned, half of whom are undiagnosed, 85,000 people are on dialysis or waiting for a kidney transplant. Each year, 11,000 new diagnoses of severe renal failure are made, one third of which had not been treated before. Kidney failure is constantly increasing due to the aging of the population and the resurgence of chronic diseases, including obesity and cardiovascular diseases such as high blood pressure and diabetes, two conditions that impair renal function. The pharmacist, a local actor, is well placed to help patients adhere to their treatment and manage it to the best of their quality of life. It is up to the pharmacist to check the dosages according to the degree of renal involvement, ideally noted on the prescription or, failing that, by asking the patient the results of his recent biological examinations. The consultation of the pharmaceutical file and, ultimately, the shared medical file, will make it possible, in a concerted management of the patient's care pathway, to also detect possible drug interactions. By dispensing the prescribed drugs, the pharmacist can also warn against those known to be known for their nephrotoxicity, especially nonsteroidal anti-inflammatory drugs. In the case of over-the-counter products, the pharmacist may discourage a person at risk from taking certain drugs containing nonsteroidal anti-inflammatory drugs, including aspirin and ibuprofen. Because of their potential renal toxicity, the pharmacist is competent to alert, especially on certain food supplements, herbal products, and is legitimate to participate in screening campaigns., (Copyright © 2019 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Despite very different aetiologies and clinical expressions, advancing knowledge in the physiopathology and treatment of immune and inflammatory diseases (IID) prompts us to consider them as a whole. These are chronic, often incapacitating and painful illnesses that progress and destroy organs. Management by discipline too often leads to erroneous diagnoses and sometimes inappropriate treatment. More integrated translational research would further understanding of the complex relationships between cytokines and organ damage, which vary with the conditions and patients, making it possible to develop new biomarkers and personalize treatment. The research in France has very many strengths but its organization is fragmented. Better coordinated research into IID, which could be based on creating a strategic valorization field (domaine de valorisation stratégique, DVS) and thematic multi-organization institute (Institut thématique multi-organismes ITMO), would advance patient management., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

A "competitive cluster" is a partnership between businesses, research units and training centers, working together to generate synergies for innovative projects in a particular geographic area. Since 2005, the first five calls for cluster projects have led to the funding of 645 R&D projects involving 13,000 researchers. Together, the R&D expenditure of these projects has so far totaled nearly Euro 3.6 billion. This included public funding of Euro 1300 million, Euro 840 million of which was provided by central government. In the biomedical field, 80 R&D projects have been funded to the tune of Euro 140 million (Euro 81 million from central government and Euro 59 million from local government). A total of 288 agreements have been signed, 12% with large companies, 36% with SMEs and 49.8% with public research laboratories. Alongside the more classical biomedical research funding sources, such as the National Research Agency and government-sponsored projects (on cancer, Alzheimer's disease, rare diseases, etc.), competitive clusters provide the impetus for profound changes in research culture. They draw on the principle of professional guidance and public-private partnerships to build a bridge between the "academic" and "industrial" research arenas. By facilitating knowledge generation and sharing, competitive clusters create a climate of action-driven mutual respect and trust.

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

Objective: 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-controlled > or = 3-year trial in Europe and North Africa. In this article, we report the characteristics of the randomized patients., Research Design and Methods: The main selection criteria were as follows: men or women aged > or = 50 years with type 2 diabetes treated with oral antidiabetic drugs, with or without hypertension, with a plasma creatinine level < 150 mumol/l, and with persistent micro- or macroalbuminuria, as assessed centrally by two successive urine samples containing a urinary albumin concentration > or = 20 mg/l. Patient characteristics were studied by comparing patients who were randomized to those who were not, taking their geographical origin into account., Results: 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., Conclusions: 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.

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.

Unlabelled: 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., Results: 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., Conclusion: 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.

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.

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 (p < 10(-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 (p < 10(-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)

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)

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.

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.

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.

The acute and chronic arterial effects of the angiotensin-converting enzyme (ACE) inhibitor ramipril were studied in hypertensive patients. Hemodynamic and biological parameters were measured 3 h after the first dose of 5 mg of ramipril, and then again after 4 weeks of treatment, 3 and 24 h after drug administration. Brachial and carotid artery hemodynamics were evaluated using a two-dimensional pulsed Doppler system. Arterial distensibility was studied noninvasively in three arterial segments (carotidofemoral, brachioradial, and femorotibial) by evaluating the pulse wave velocity. Ramipril lowered the blood pressure significantly after acute and 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 arterial segments studied did not show any significant changes. Our results suggest that the long-lasting arterial effects of the ACE inhibitor ramipril are partly pressure independent and are related to effects on arterial tone that may reduce the cardiovascular abnormalities associated with hypertension.

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.

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)

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)

Evidence for angiotensin-converting enzyme (ACE) on isolated human glomeruli was furnished by specific binding of tritium-labeled ramiprilat, a potent inhibitor of ACE. 3H-ramiprilat bound to isolated glomeruli, depending on time and temperature displaying a KD of 3.8 nmol/l and a Bmax of 853 fmol/mg protein. Specific binding represented more than 90% of total binding. Dissociation occurred rapidly after dilution of the sample with incubation buffer or after addition of an excess of unlabeled inhibitor. Binding of 3H-ramiprilat was also inhibited by increasing concentrations of enalaprilat, another ACE-inhibitor or by preincubation of the glomeruli with polyclonal antibodies against ACE. ACE is a zinc-containing enzyme. Addition of EGTA to the assay, which chelates zinc ions, completely inhibited binding. This inhibitory effect of EGTA was reversed by divalent Zn2+ and Ca2+ ions but not by magnesium. Binding of 3H-ramiprilat to isolated glomeruli was maximal when the pH of the assay medium was brought to pH 8. In conclusion, the binding of 3H-ramiprilat to isolated human glomeruli is specific and resembles the characteristics which have been found earlier for enzyme activity of ACE. Thus, binding of 3H-ramiprilat to isolated glomeruli can be assumed to be directed to ACE.

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.

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.

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.