Angiotensin-I-converting enzyme insertion/deletion polymorphism and high urinary albumin concentration in French Type 2 diabetes patients.

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

The non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and ramipril (DIABHYCAR) study: design, organization, and patient recruitment. DIABHYCAR Study Group.

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.

Determinants of elevated urinary albumin in the 4,937 type 2 diabetic subjects recruited for the DIABHYCAR Study in Western Europe and North Africa.

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.

[Conversion enzyme inhibitors against the progression of renal and vascular diseases: yes but again]. / Les inhibiteurs de l'enzyme de conversion contre la progression des maladies rénales et vasculaires: oui mais encore.

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.

The Eurevie Study: contrasting effect of piretanide and thiazides in mild to moderate hypertension.

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.

Interruption of prolonged ramipril treatment in hypertensive patients: effects on the renin-angiotensin system.

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.

[Determination of drug posology in pediatrics]. / Détermination de la posologie des médicaments en pédiatrie.

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.

[Prevalence of microalbuminuria in French type 2 diabetics followed by their general practitioner]. / Prévalence de la microalbuminurie chez les diabétiques de Type 2 français suivis par leur médecin généraliste. Comité Scientifique du groupe DIABHYCAR.

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)

Expression of elastase and fibrin in venous leg ulcer biopsies: a pilot study of pentoxifylline versus placebo.

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.

National study of obliterative arterial disease of the lower limbs involving general practitioners in France: Artemio study.

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.

Blood conservation techniques for cardiac surgery: a survey of French centres.

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%).

The French multicentre study of ramipril in ambulatory patients with mild-to-moderate hypertension.

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)

[Hypertension associated with diabetes: inquiry into the attitudes and behaviors of French physicians]. / Hypertension associée au diabète: enquête sur les attitudes et les comportements des médecins français.

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.

Long lasting arterial effects of the ACE inhibitor ramipril.

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.

Tolerability of ramipril in a multicenter study of mild-to-moderate hypertension in general practice.

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.

Comparison of response rates to the angiotensin-converting enzyme inhibitor ramipril in mild-to-moderate hypertension in a double-blind, parallel-group study and an open single-blind study.

Appropriate clinical trial methodologies in general practice and suitable end points for dose-finding studies are discussed with reference to antihypertensive drugs in general and angiotensin-converting enzyme (ACE) inhibitors in particular. Two clinical studies were conducted with ramipril, a new nonsulfhydryl ACE inhibitor, to identify the minimum effective dose for the management of mild-to-moderate hypertension. Study 1 was a double-blind, parallel-group, randomized design with three treatment groups (placebo and 2.5 and 5 mg of ramipril), and study 2 was an open, single-blind design with individual dose titration from 2.5 to 5 mg of ramipril if the diastolic blood pressure (DBP) was greater than 90 mm Hg after 3 weeks. Response rates and DBP reductions with 2.5 mg of ramipril were similar in both studies, although overall response rates, DBP reductions, and side effect incidence appeared to be greater in the open, single-blind, dose-titration study. It is concluded that study methodology apparently influences efficacy and tolerability.

Effects of ramipril on arterial hemodynamics.

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.

[How and when to create a pediatric file for authorization to market a new drug. A proposal of the SNIP clinical group (National Syndicate of Pharmaceutical Industry)]. / Comment et quand bâtir un dossier pédiatrique pour l'Autorisation de Mise sur le Marché d'un nouveau médicament. Une proposition du groupe clinique du SNIP.

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.