Guidelines of the French Society of Otorhinolaryngology (SFORL): Nonsteroidal anti-inflammatory drugs (NSAIDs) and pediatric ENT infections. Short version.

OBJECTIVES: To present the guidelines of the French Society of Otolaryngology-Head and Neck Surgery concerning the use of non-steroidal anti-inflammatory drugs (NSAIDs) in pediatric ENT infections. METHODS: Based on a critical analysis of the medical literature up to November 2016, a multidisciplinary workgroup of 11 practitioners wrote clinical practice guidelines. Levels of evidence were classified according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system: GRADE A, B, C or "expert opinion". The first version of the text was reworked by the workgroup following comments by the 22 members of the reading group. RESULTS: The main recommendations are: NSAIDs are indicated at analgesic doses (e.g. 20-30 mg/kg/day for ibuprofen) in combination with paracetamol (acetaminophen) in uncomplicated pediatric ENT infections (acute otitis media, tonsillitis, upper respiratory infections, and maxillary sinusitis) if: o pain is of medium intensity (visual analogue scale (VAS) score 3-5 or "Evaluation Enfant Douleur" (EVENDOL) child pain score 4-7) and insufficiently relieved by first-line paracetamol (residual VAS≥3 or EVENDOL≥4); o pain is moderate to intense (VAS 5-7 or EVENDOL 7-10). When combined, paracetamol and ibuprofen are ideally taken simultaneously every 6h. It is recommended: (1) o not to prescribe NSAIDs in severe or complicated pediatric ENT infections; (2) o to suspend NSAIDs treatment in case of unusual clinical presentation of the infection (duration or symptoms); (3) o not to prescribe NSAIDs for more than 72h.

[Isolated primary nocturnal enuresis: international evidence based management. Consensus recommendations by French expert group]. / Enurésie nocturne primaire isolée: diagnostic et prise en charge. Recommandations par consensus formalisé d'experts.

OBJECTIVE: The causes and treatment of isolated primary nocturnal enuresis (PNE) are the subject of ongoing controversy. We are proposing consensus practical recommendations, based on a formalised analysis of the literature and validated by a large panel of experts. METHODOLOGY: A task force of six experts based its work on the guide for literature analysis and recommendations and recommendation grading of the French Haute Autorité de Santé (formalized consensus process methodological guidelines) to evaluate the level of scientific proof (grade of 1 to 4) and the strength of the recommendations (grade A, B, C) of the publications on PNE. As a result of this, 223 articles from 2003 on were identified, of which only 127 (57 %) have an evaluable level of proof. This evaluation was then reviewed by a 19-member rating group. Several recommendations, poorly defined by the literature, had to be proposed by a professional agreement resulting from a consultation between the members of the task force and those of the rating group. For its final validation, the document was submitted to a reading group of 21 members working in a wide range of specialist areas and practices but all involved in PNE. RESULTS: The definition of PNE is very specific: intermittent incontinence during sleep, from the age of 5, with no continuous period of continence longer than 6 months, with no other associated symptom, particularly during the day. Its diagnosis is clinical by the exclusion of all other urinary pathologies. Two factors must be identified during the consultation: nocturnal polyuria promoted by excessive fluid intake, inverse secretion of vasopressin, snoring and sleep apnoea. It is sensitive to desmopressin; small bladder capacity evaluated according to a voiding diary and the ICCS formula. It may be associated with diurnal hyperactivity of the detrusor (30 %). It is resistant to desmopressin. Problems associated with PNE are: abnormal arousal threshold, attention deficit hyperactivity disorder (ADHD) (10 %), low self-esteem. The psychological component is not very significant. CONCLUSION: PNE is not psychological in origin. The management of this condition includes: evaluating the intrafamilial tolerance and the child's motivation, evaluating the rate, the volume of urine and wet nights using a diurnal and nocturnal diary; education (sufficient fluid intake at the start of the day, decrease in hyperosmolar intake in the evening, regular and complete urination); specific treatments: desmopressin for polyuric forms (expected success rate of 60-70 %), alarms for forms involving small bladder capacity (expected success rate of 60-80 %); alternative treatments and/or treatments combined with the preceding ones, for refractory forms: oxybutinin, tricyclic antidepressants (risk). Results obtained with hypnosis, psychotherapy, acupuncture, homoeopathy or chiropractic are not currently validated (insufficient level of proof).

[Current management of acute pediatric rhinosinusitis in France]. / Etat actuel de la prise en charge des infections rhinosinusiennes aiguës de l'enfant en France.

A multidisciplinary panel of specialists and general practitioners provided definitions for the different forms of acute pediatric rhinosinusitis, with a description of the main symptoms and signs. They emphasized the role of concomitant systemic diseases, such as allergy and immunological disorders. Incidence, description, and management of complications are presented. They also provided the indications for radiological examination and microbiological investigations. The adequate medical management, particularly the place and the type of antibiotics, is analyzed and discussed, and guidelines for practical situations are suggested.

Assessment of diabetes screening by general practitioners in France: the EPIDIA Study.

AIM: To audit Type 2 diabetes screening in general practice in France and to determine the frequency of undiagnosed diabetes in patients at high risk, after systematic screening and diagnosis. METHODS: For this study, 288 general practitioners volunteered to include all consecutive non-diabetic patients aged < 65 years who had at least two risk factors for diabetes, whatever the reason for consultation. If a plasma glucose had not been recorded in the previous 12 months, a fasting plasma glucose (FPG) was performed, with a second test if FPG >or= 7.0 mmol/l. RESULTS: There were 5950 patients included. The most frequent diabetes risk factors were: age >or= 40 years, 92%; overweight [body mass index (BMI) >or= 27 kg/m2], 59%; treated hypertension, 48%; treated dyslipidaemia, 37%; family history of diabetes, 24%. Of these subjects at high risk for diabetes, 88% had a FPG measurement in their medical record (75% measured during the preceding 12 months). In the 1499 patients in whom FPG was measured, diabetes was diagnosed in 40 patients (2.7% 95% CI 1.9-3.5) and 22% had impaired fasting glucose (IFG). Thus, the frequency of undiagnosed diabetes in the 5950 high-risk patients was 0.67% (0.46-0.88). CONCLUSION: Screening for diabetes by general practitioners in France appears to be adequate and undiagnosed diabetes is rare in patients with risk factors for diabetes, at least in those consulting the general practitioners studied.

[Flecainide acetate utilisation review among general practitioners and hospital or office-based cardiologists in France. Obepine: observational study of flecainide]. / Etude de l'usage de l'acétate de flécainide auprès des médecins généralistes et des cardiologues hospitaliers ou libéraux en France. OBEPINE: etude observationnelle des prescriptions de flécaïnide.

A pharmacoepidemiological cross-sectional observational study was performed among a representative sample of French general practitioners and cardiologists. The aim of this study was to describe the prescription modalities of flecainide acetate, an Ic class antiarrhythmic, and how these modalities match the marketing authorization and the current summary of product characteristics. A total of 941 physicians participated in the study, 496 GPs and 445 cardiologists, and 1116 patients treated with flecainide for more than one month were included. On average, the patients were 68.7-years-old and 54% of them were women. Most of the initial flecainide prescriptions came from cardiologists (96%) and the check-up included an electrocardiogram (98%), a Holter monitoring (56%) and/or an echocardiography (71%). The preferred indication was supraventricular rhythm disorders (95%) and mostly atrial fibrillation (63%). A small proportion of coronary patients (7%) and of patient suffering from cardiac insufficiency (4%) was found. Flecainide was prescribed with a median posology of 150 mg per day, mostly as LP form (64%). Overall, the indications specified in the summary of product characteristics were respected in 90% of the cases, the contraindications in 91% of the cases and the patient follow-up was appropriate in 99% of the cases. In conclusion, the study showed that the prescription's conditions of flecainide in France complied with the summary of product characteristics data for most of the prescribing physicians with a respect of the indications, contraindications and management recommendations in 84% of the cases.

[Oxidatif-stress and COPD. Role of infection. Prevention]. / Stress oxydatif et BPCO. Rôle des infections. Prévention.

For the next decade, COPD will become the third cause of mortality in the world. COPD is mainly due to cigarette smoking and presents different levels of severity according to people, probably linked to environmental and genetic factors, which are not well documented. Recent publications pointed out bacterial bronchial colonization and exacerbations of infectious origin as worsening factors through a pro-inflammatory effect and oxidative stress. This should lead to a comprehensive review of anti-infectious prevention tools and to discuss the role of prophylactic antibiotherapy and antioxidants.

[Oxidative stress in bronchopulmonary disease: contribution of N-acetylcysteine (NAC)]. / Le stress oxydatif en pathologie broncho-pulmonaire: apport de la N-acétyl-cystéine (NAC).

Oxidative stress is a frequent mechanism involved in the pathogenesis of bronchopulmonary disease. The cause can be exogenous, in particular related to to atmospheric pollution and tobacco smoke, or endogenous, related to mobilization of inflammatory cells (macrophages and polymorphonuclear neutrophils). In this general review, we present work demonstrating this oxidative stress and activation of inflammatory cells. We discuss the effect of oxidative stress on the bronchial tree and the need to maintain an adequate balance between oxidants and anti-oxidants. This reviews focuses on experimental studies proving the anti-oxidant effect of NAC on glutathione synthesis and on different pharmacological models. We then discuss human trials, initially experimental then in different bronchopulmonary pathologies related to oxidative stress. Acetaminophen intoxication and pulmonary fibrosis are models for use of NAC. Recent work on COPD appears to show a decrease in exacerbations, improvement in symptoms and quality-of-life, and perhaps a reduction in the alteration of ventilatory function.

Findings of the Naftidrofuryl in Quality of Life (NIQOL) European study program.

BACKGROUND: We report in this paper the findings of a pooled analysis of 3 previously published studies undertaken in Germany, France and Belgium to assess the effects of naftidrofuryl on the quality of life of patients with intermittent claudication. METHODS: A total of 754 patients were randomised in the 3 studies, 709 of whom (358 naftidrofuryl, 351 placebo) were available for the primary intention-to-treat analysis. The primary outcome variable was the change in the disease-related limitation of the quality of life as measured by the CLAU-S questionnaire. This instrument which has been validated in an international study, comprises 47 questions covering 5 dimensions: "daily living", "pain", "social life", "disease specific anxiety" and "mood". RESULTS: A multivariate analysis of covariance adjusted for baseline values, study effect and first order study treatment interaction, demonstrated the global superiority of naftidrofuryl over placebo (p<0.001). A separate covariance analysis for the 5 dimensions showed highly significant differences for "daily living", "pain", "social life" and "mood" (all p<0.01). CONCLUSIONS: In conclusion, this pooled analysis has shown that naftidrofuryl can significantly improve the quality of life of patients with intermittent claudication. These findings, taken together with evidence from previous studies that it improves treadmill walking distances, suggest that naftidrofuryl can play a useful role in the treatment of this condition.

Epidemiological analysis of patients with Type 2 diabetes in France.

This paper presents the baseline epidemiological data from 5548 patients with type 2 diabetes enrolled in a French observational study that aims to examine the safety, tolerability and use of acarbose as prescribed by general practitioners (GPs). Patients were recruited and monitored by a representative sample of GPs. Recruitment did not depend on a patient's suitability for acarbose treatment. The data revealed that the mean age of the patient population was 63 years, and that more than 50% of patients were over 65 years old. The population was markedly overweight [mean body mass index(BMI): males, 28.4 kg/m(2); females, 29.1 kg/m(2)] and the mean duration of diabetes was 10 (+/-7.3) years. Over 37% of patients had at least one diabetic complication, and the frequency of complications increased with both age and the duration of diabetes. The most frequently reported complications were cardiac (17.8%), vascular (14.5%) and ocular (12%). At recruitment, almost 90% of patients were being treated with oral antidiabetic agents (OADs). Sulphonylureas (74%) and biguanides (50%) were the most commonly prescribed agents. Acarbose was used to treat 17% of patients and 1% were receiving insulin. GPs set glycaemic treatment goals for 44% of patients in the study. Fasting glycaemia was the primary goal for 37% of the total study population, and HbA(1c) levels for 21% of patients. Postprandial glycaemia was generally given as a secondary or tertiary goal. In conclusion, this study provides the most up-to-date epidemiological data for patients with type 2 diabetes in France.

Managing type 2 diabetes in France: the ECODIA survey.

In order to describe the profile and medical management of type 2 diabetes patients in France, a descriptive cross-sectional survey was conducted in 1999 among a national random sample of 311 general practitioners and 51 specialists. A practitioner questionnaire was designed to collect information on a representative sample of 4,119 patients presenting with type 2 diabetes. Data collected included demographic and clinical information and a full description of diabetes management over a 6-month retrospective period. Over 50% of the patients were more than 67 years old; 54% were male. Diabetes had been diagnosed 8.9 years earlier on average, most frequently (73%) during a visit not related to diabetes' symptoms or complications. 42% of patients had a BMI > or =30 kg/m(2), 46% were hypertensive (BP > 140-80 mmHg), 53% had a LDL-Cholesterol over 1.3 g/l. Overall, 33% of patients had at least one diabetic complication. 60% of patients had had at least one HbA1c dosage in the last 6 months. Among them, 31% had a HbA1c level over 8% and 35% between 6. 5% and 8%. 85% of patients were treated with oral anti-diabetic drugs, 9.5% with diet and exercise only and 5% with insulin. Sulfonylureas were the most commonly prescribed anti-diabetic agent, either alone or in combination. This survey confirms that the management of patients with type 2 diabetes is still often inappropriate in France despite recent progress. Improved disease management and monitoring is required in France as in other developed countries.

2',6'-Dimethylphenoxyacetyl: a new achiral high affinity P(3)-P(2) ligand for peptidomimetic-based HIV protease inhibitors.

Starting from palinavir (1), our lead HIV protease inhibitor, we have discovered a new series of truncated analogues in which the P(3)-P(2) quinaldic-valine portion of 1 was replaced by 2', 6'-dimethylphenoxyacetyl. With EC(50)'s in the 1-2 nM range, some of these compounds are among the most potent inhibitors of HIV replication in vitro, reported to date. One of the most promising members in this series (compound 27, BILA 2185 BS) exhibited a favorable overall pharmacokinetic profile, with 61% apparent oral bioavailability in rat. X-ray crystal structures and molecular modeling were used to rationalize the high potency resulting from incorporation of this structurally simple, achiral ligand into the P(3)-P(2) position of hydroxyethylamine-based HIV protease inhibitors.

The human renin infused rat: use as an in vivo model for the biological evaluation of human renin inhibitors.

The human renin infused rat model (HRIRM) was used as an in vivo small-animal model for evaluating the efficacy of a collection of inhibitors of human renin. The intravenous infusion of recombinant human renin (2.4 microg x kg(-1) x min(-1)) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47+/-3 mm Hg (1 mm Hg = 133.3 Pa), which was reduced by captopril, enalkiren, and losartan in a dose-dependent manner following oral administration, with ED50 values of 0.3+/-0.1, 2.5+/-0.9, and 5.2+/-1.6 mg/kg, respectively. A series of peptidomimetic P2-P3 butanediamide renin inhibitors inhibited purified recombinant human renin in vitro in a concentration-dependent manner, with IC50 values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values (0.8-80 nM) observed at pH 7.4. Following i.v. administration of renin inhibitors, the pressor response to infused human renin in the HRIRM was inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600 microg/kg. The in vivo inhibition of human renin following i.v. administration in the rat correlated significantly better with the in vitro inhibition of human renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5). Oral administration of renin inhibitors also resulted in a dose-dependent inhibition of the pressor response to infused human renin, with ED50 values ranging from 0.4 to 6.0 mg/kg and the identification of six renin inhibitors with an oral potency of <1 mg/kg. The ED50 of renin inhibitors for inhibition of angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor response. These results demonstrate the high potency, dose dependence, and availability following oral administration of the butanediamide series of renin inhibitors.

Cutaneously applied acyclovir acts systemically in the treatment of herpetic infection in the hairless mouse.

Using the SKH-1 hairless mouse (HM) we have addressed the issue as to whether topically applied acyclovir (ACV) may mediate some of its antiviral actions by a systemic effect. When topically applied in a formulation consisting of polyvinyl alcohol (25% w/v):DMSO:cremophor EL:linoleic acid (63:16:16:5, v/v/v/v), ACV penetrated hairless mouse skin in a concentration-dependent manner and dose-dependently reduced cutaneous herpes simplex virus 1 (HSV-1) KOS infection. Topically applied ACV also effectively reduced the mortality associated with disseminated HSV-2 HG-52 infection. At 1 h following topical application of 1.7% w/v ACV the plasma and skin concentrations of ACV were 5.5 nmoles/ml and 120 nmoles/g. At 1 h following an oral dose of ACV with antiviral efficacy comparable to topically applied ACV (1.7% w/v) the plasma and skin concentrations of ACV were 21.3 nmoles/ml and 51 nmoles/g. These findings imply that when applied topically to the HM, ACV can mediate a portion of its antiviral activity through a systemic mode of action.

Potent HIV protease inhibitors containing a novel (hydroxyethyl)amide isostere.

A series of HIV protease inhibitors containing a novel (hydroxyethyl)amidosuccinoyl core has been synthesized. These peptidomimetic structures inhibit viral protease activity at low nanomolar concentrations (IC50 < 10 nM for HIV-1 protease). The inhibition constant (Ki) for inhibitor 19 was determined to be 7.5 pM against HIV-1 and 1.2 nM against HIV-2 proteases, respectively. Several compounds (19-24) inhibited HIV-1 replication in cell culture assays with 50% effective concentrations (EC50) = 3.7-35 nM. This series of inhibitors was found to exhibit poor bioavailability (< 10%) in the rat, following oral administration. The synthesis and biological properties of these compounds are discussed. In addition, an X-ray structure of one of these inhibitors (23) in complex with HIV-2 protease provides insight into the binding mode of this novel class of HIV protease inhibitors.

Determination of the HIV protease inhibitor BILA 2185 BS in rat plasma by liquid-liquid extraction and high performance liquid chromatography photodiode array detector.

A novel series of hydroxyethylamine-based inhibitors of HIV protease which contain a substituted pipecolinic amide were developed. After preliminary screening, a representative of this series, compound BILA 2185 BS, demonstrated an IC50 value of 3.3 nM in the enzymatic assay and an EC50 value of 2.0 nM in cell culture. The plasma profile and bioavailability values for BILA 2185 BS in the rat will be presented. The analyte was isolated from rat plasma using a liquid-liquid extraction procedure. The analytical technique used utilizes a high performance liquid chromatography system with photodiode array detector. The range of the standard curve was from 10 to 5000 nM. Recovery values averaged 72.4 +/- 8.6% (mean +/- S.D.). The limit of detection for BILA 2185 BS was 6-12 nM.

Characterization of intestinal smooth muscle responses and binding sites for endothelin.

The contractile activity of and binding sites for endothelin-1 (ET-1) were investigated in isolated guinea-pig ileal longitudinal smooth muscle (GPILM). ET-1 produced concentration-dependent contractions of GPILM that either slowly subsided in the continued presence of ET-1 or rapidly subsided following washing of the tissue. The ED50 value for ET-1 contractions was 4.2 +/- 1.3 x 10(-9) M. The removal of extracellular calcium or pretreatment with nifedipine produced a complete inhibition of the contractions to ET-1. The IC50 value of nifedipine for inhibition of ET-1 mediated contractions was 3.0 +/- 0.8 x 10(-8) M. ET-1 produced a marked prolonged homologous desensitization of its contractile response but did not affect the responses mediated by carbachol, histamine, serotonin, substance P, and PLA2. High-affinity binding sites for 125I-labelled ET-1 were identified on microsomal membranes prepared from GPILM with Kd and Bmax values obtained by Scatchard analysis of 3.5 +/- 0.6 x 10(-10) M and 2138 +/- 159 fmol/mg protein, respectively. The binding of 125I-labelled ET-1 to GPILM microsomes was characterized by a rapid association (kob value of 0.077 min-1 at a radioligand concentration of 0.45 nM and an extremely slow dissociation (k1 value of 0.011 min-1; t1/2 value of 793 min). The binding was unaffected by the calcium channel antagonists nifedipine, verapamil, and diltiazem (10(-6) M); the receptor antagonists phenoxybenzamine, atropine, and naloxone (10(-6) M) and propranolol; and the peripheral benzodiazepine receptor antagonists Ro 5-4864 and PK 11195 and psychotomimetic drug phencyclidine (10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac responses and binding sites for endothelin in normal and cardiomyopathic hamsters.

The effects of endothelin-1 in the spontaneously beating atrium and the field-stimulated right ventricular strip preparation and the binding of [125I]endothelin-1 to membrane preparations from the atrium, ventricle, lung parenchyma, kidney and brain were compared using the 90-day-old dystrophic hamster strain CHF 147 (a strain displaying marked cardiomyopathologies at this age) and its age/genetically matched normal control, CHF 148. In the atrium, endothelin-1 produced dose-dependent positive inotropic and positive chronotropic effects in both CHF 148 and CHF 147 over the dose range of 10(-8) M to 3 x 10(-7) M. However, although no significant difference between CHF 148 and CHF 147 was observed for the positive chronotropic effects of endothelin-1, it produced a small, but significantly less positive inotropic effect in CHF 147 compared to CHF 148 at endothelin-1 concentrations of 2 x 10(-8) M and 3 x 10(-8) M. Field-stimulated right ventricular strips from CHF 148 contracted with a greater force compared to those from CHF 147. Endothelin-1 produced a dose-dependent decrease in the developed tension of the field-stimulated ventricular strip preparation, the extent of which did not differ between CHF 148 and CHF 147. [125I]Endothelin-1 bound with high affinity and in an apparently irreversible manner to membranes from both CHF 148 and CHF 147 atrium, ventricle, lung parenchyma, kidney and brain. No significant differences were noted between CHF 148 and CHF 147 for [125I]endothelin-1 binding to membranes prepared from the various tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions between endothelin and atrial natriuretic factor in the rat aortic ring preparation.

The potential interaction (s) between atrial natriuretic factor (ANF) and porcine--human endothelin (ET-1) was investigated in the endothelium-denuded rat aortic ring preparation. ET-1 produced a sustained contraction of aortic rings with an ED50 of 3.6 +/- 0.49 x 10(-9) M. Within the concentration range of 10(-9) to 10(-7) M, both rat ANF 103-126 and rat ANF 99-126 when preincubated with tissues reduced the contractile efficacy of ET-1 especially at low concentrations resulting in a small but significant rightward shift of the dose--response curve to ET-1. In contrast, at a concentration of 10(-10) M, rANF 99-126 but not rANF 103-126 produced a significant leftward shift of the dose--response curve to ET-1 and an increase in the maximal developed tension for the dose--response curve to ET-1. For tissues incubated in the absence of extracellular calcium or in the presence of the calcium channel blocker nifedipine (5 x 10(-7) M), both ANF derivatives produced a dose-dependent decrease in the maximum contraction, but no change in potency to ET-1. Addition of either rANF 103-126 or rANF 99-126 to tissues maximally contracted with ET-1 resulted in relaxation, reaching a maximum of 70%. The ED50 values for relaxation were 2.7 +/- 0.51 x 10(-8) and 3.5 +/- 0.60 +/- 10(-8) M for rANF 103-126 and rANF 99-126, respectively. ET-1 did not interact with biologically responsive and clearance receptors for ANF.(ABSTRACT TRUNCATED AT 250 WORDS)