Optimization of insulin regimen and glucose outcomes with short-term real-time continuous glucose monitoring (RT-CGM) in type 1 diabetic children with sub-optimal glucose control on multiple daily injections: The pediatric DIACCOR study.

BACKGROUND: The impact of 7-day real-time continuous glucose monitoring (RT-CGM) on type 1 diabetes (T1D) management remains unknown in youths with suboptimal control by multiple daily injections (MDI). The DIACCOR Study aimed to describe treatment decisions and glucose outcomes after a short-term RT-CGM sequence in real-life conditions. METHODS: This French multicenter longitudinal observational study included T1D youths with HbA1c>7.5% or a history of severe hypoglycemia (SH) or recurrent documented hypoglycemia. A sensor was inserted at the study-inclusion visit, and one of three predefined treatment changes was proposed by the investigator within 7-15 days: INT=MDI intensification, CSII=switch to continuous insulin infusion, or ER=educational reinforcement with no change in insulin regimen and a 4-month follow-up visit (M4) was scheduled. RESULTS: A total of 229 children (12.2±3.5 years old) were recruited by 74 pediatricians; 12.8% had a history of SH, 22.2% had recurrent hypoglycemia. Baseline HbA1c was 8.7±1.5% (>7.5% in 82.8%). Overall, 139 (79.4%), 19 (10.9%), and 17 patients (9.7%) were, respectively, included in the INT, CSII, and ER subgroups. At M4, the global incidence of SH and recurrent hypoglycemia dropped (3.4% vs. 12.8% and 6.0% vs. 22.2%, respectively) as well as the incidence of ketoacidosis (2.1% vs. 8.1%) or ketosis (6.9% vs. 11.4%). The HbA1c decrease was significant overall and in the INT subgroup (adjusted difference -0.29%, P=0.009). The satisfaction rate was≥93.0% among children. CONCLUSION: In a real-life setting, a 1-week RT-CGM can promote treatment optimization in youths with uncontrolled T1D resulting mostly in less acute events. CGM acceptance may improve with new-generation sensors.

[Persistent asthma: Chronic therapy quantitative compliance in daily practice]. / Observance du traitement de fond dans l'asthme persistant de l'adulte en pratique courante.

INTRODUCTION: The aim of the study was to assess, compliance with maintenance treatment in patients with persistent asthma in clinical practice. METHODS: This observational, cross-sectional, prospective, multicenter study was conducted in metropolitan France on patients with persistent asthma under the care of a representative sample of general practitioners and pneumologists. Compliance was determined via access to the Health Insurance database allowing comparison between the actual consumption of medications and the corresponding theoretical consumption related to prescription. Additional compliance data were obtained using the validated Morisky questionnaire. RESULTS: Eighty one physicians included 488 patients, mean age of 51 years, 55% women. The statement of consumption (SC) was available for 35% of patients however the Morisky questionnaire (present for 85% of patients) showed a similar compliance between patients with or without SC. The good compliance rate (compliance ≥80%) was observed in 51% based on the SC and in 38% based on the Morisky questionnaire. Among possible predictive factors, only obesity was associated with a bad compliance (19% vs 7%, P<0.05). Patients with poor compliances displayed more severe symptoms and a higher rate of non-control (21.7% vs 5.7%, P<0.01). CONCLUSIONS: The statement of consumption is a useful tool to provide quantitative measurement of compliance in daily practice.

Prevalence and impact on quality of life of post-herpetic neuralgia in French medical centers specialized in chronic pain management: the ZOCAD study.

OBJECTIVES: (1) We had for aim to determine the rate of patients consulting for post-herpetic neuralgia (PHN) in centers specialized in the management of chronic pain, (2) to assess the burden of PHN, (3) to compare the impact of PHN between new (newly consulting for PHN) and known (already treated by pain specialists) patients. PATIENTS AND METHODS: We conducted a prospective multicenter observational study including all chronic pain outpatients consulting for 3 consecutive weeks. The impact of PHN was assessed with the ZBPI, SF12, HADS, and a non-validated disability questionnaire. RESULTS: Among the patients, 4518 consulted 54 specialized centers from January 24th to July 21st 2008: 2.6% of patients (but 10.9% of patients 70 years of age or more) reported PHN. The acute herpes zoster episode had occurred more than 13.3 months before inclusion for half of the patients. 108 of the 118 PHN patients (33 new and 75 known) completed the questionnaires. Their mean scores were 3.7 (SD, 2.6) for ZBPI and 34.4 (SD, 10.9) and 55.9 (SD, 11.4) for SF12 PCS and MCS; 38% and 42% of PHN patients had HADS anxiety and depression scores > 10. Nearly all PHN patients had received antiepileptic and analgesic drugs. Tricyclic antidepressants and lidocaine patches were more frequently administered to known than to new patients. Pain relief was more effective for known than for new patients. CONCLUSIONS: PHN is a frequent cause of visit in French medical centers specialized in chronic pain management long after the rash has disappeared, and a reason for treatment with drugs that should be prescribed cautiously in elderly patients.

Access of children and adolescents with type 1 diabetes to insulin pump therapy has greatly increased in France since 2001.

AIM: Insulin pump therapy is an emerging option in the management of type 1 diabetes (T1D), but it often remains unused. For this reason, in 2007, a French national survey was carried out to update the frequency of insulin pump use in the paediatric population compared with a previous survey done in 2001. METHODS: The present survey was performed in hospital departments involved in paediatric diabetes management (n = 67) and in adult departments involved in adolescent diabetes management (n = 113). The number of T1D children (age < 18 years) treated in each department, with or without the use of an insulin pump, and the number of insulin pump therapies initiated during the previous year were collected. RESULTS: A total of 60 paediatric and 28 adult centres responded, involving 9073 T1D children and adolescents (93% in paediatric departments). Of these patients, 1461 (16%) were treated by insulin pump, 89% of which were managed in paediatric centres. However, pump use was more frequent in adult than in paediatric centres (32% versus 18%, respectively). Also, 38% of insulin pumps were initiated during the year prior to the survey. In addition, in 2001, 140 children were treated with insulin pump in 13 paediatric centres (versus 56 centres in 2007). CONCLUSION: The number of centres using insulin pump therapy for diabetic children and the number of children treated by insulin pump were increased fourfold and 10-fold, respectively, from 2001 to 2007, indicating greater access to pump therapy in the French paediatric population. The present survey is still ongoing to evaluate the decision-making criteria that influence the initiation of insulin pump therapy in T1D paediatric patients.

[Management of hypertension and obesity: the observatory of management of uncontrolled hypertensives with respect to the presence or absence of overweight (PHYSIObs)]. / Prise en charge de l'hypertension artérielle et surcharge pondérale Observatoire de la prise en charge de patients hypertendus non contrôlés en fonction de la présence ou non d'un surpoids (PHYSIObs).

The object of this study was to compare the management of uncontrolled hypertensives (BP > 140/90 mmHg) by general practitioners with respect to the presence or absence of overweight (BMI > or =25 Kg/m2). A 2/1 stratification allowed comparison of 4080 patients who were overweight and 1951 patients with a normal body weight (normal BMI < 25 Kg/m2). The BP of patients who were overweight (> or =25 Kg/m2) was slightly higher than those with a normal BMI (161 +/- 12 mmHg vs. 159 +/- 12 mmHg, p < 0.001). The presence of a metabolic syndrome (43% vs. 7%, ATPIII criteria) was, logically, commoner in the patients overweight. However, the practitioners only recognised the presence of a metabolic syndrome in 65% of the overweight patients (28% true positives and 37% true negatives). The practitioners fixed their target value of systolic BP at 136.5 +/- 5.6 mmHg, in accordance with the recent recommendations of the Health Authorities. The targets were judged to be difficult to obtain in 18% of the overweight group and in 5% of patients with normal body weights. This optimism contrasted with the prescriptions, especially in the overweight patients, 46% of whom were treated by monotherapy and who remained for 44% on monotherapy at the end of the consultation. This descriptive study confirms the lack of awareness of the metabolic syndrome in overweight patients and identifies barriers to effective management of the hypertension of these high risk patients.

[Age fifty and menopause. Complaints expressed and unexpressed by women. Practitioners' perception and therapeutic impact]. / La cinquantaine et la ménopause. Plaintes exprimées et non exprimées par les patientes. Perception par les médecins et impact sur la prise en charge.

OBJECTIVE: Identification of symptoms appearing at the time of menopause, and evaluation of their spontaneous expression level, connection with menopause and therapeutic impact. POPULATION AND METHOD: Opinion survey carried out with 1229 French gynaecologists. RESULTS: The classical symptoms of menopause (hot flushes, night sweats, dry vagina) are spontaneously expressed by women. Atypical symptoms of menopause (sexual, relational and neuropsychological disorders) are less expressed. They are considered by practitioners as related to menopause, but less than classical symptoms. The ageing symptoms (muscle loss, joint pain, skin ageing, and disappearance of phantasms...) are scarcely expressed by women and connected with menopause by a minority of gynaecologists. The stronger the connection with menopause is, the more the symptom justifies a hormonal treatment of menopause. Thus, when classical symptoms are present, the hormonal treatment is almost always justified but it is less justified in case of atypical symptoms, and more disputable for the ageing symptoms. DISCUSSION AND CONCLUSION: Beyond the most evident signs of menopause, several other symptoms scarcely expressed by women can justify a hormonal treatment of menopause even when the connection with menopause is not demonstrated. Improvement of menopause treatment strategy requires taking into account all these symptoms, and a hormonal substitution that might be sometimes broader than the estrogenic therapy (androgenic, for example).

[Representative observations of therapies in arterial hypertension]. / Observatoire représentatif des usages dans l'hypertension artérielle.

An enquiry was conducted by 125 general practitioners in 1998 concerning 1,204 hypertensive patients (55.5% women, 71% aged 60 or over, 54% with normalised blood pressures). At the first visit (inclusion) the most frequently described therapeutic classes were: diuretics (19%), betablockers (19%), ACE inhibitors (14%), angiotensin II inhibitors (7%). The use of fixed associations was uncommon except for that of ACE inhibitors with diuretics (10.5%). The incidence of normalisation of blood pressure was the same in all therapeutic classes, about 55%, comparable to reported data; however, 42% of non-normalised patients were on monotherapy. Only 7.4% of patients had their treatment changed at inclusion: 3.8% of normalised and 11.2% of non-normalised hypertensives. This low incidence of change of treatment is partially explained by the patients' own opinion about the treatment of their hypertension. In fact, the majority of therapeutic changes is observed when the patient and the doctor both concur. This data on the treatment of hypertension confirms the respective usage of the main therapeutic classes but the limited number of treatment changes at inclusion does not allow yet assessment of these new choices. One year follow-up of this cohort to the second phase of results should provide important information with respect to this point.

Ambulatory heart failure management in private practice in France.

UNLABELLED: Management of ambulatory heart failure was assessed in a group of 600 patients, mean age 73, 64% males, NYHA I: 9%; II: 52%; III: 33%; IV: 6%; followed up by a representative sample of private cardiologists. Fifty-two percent of patients had been previously hospitalised for worsening heart failure with a mean duration of stay of 13.1 days, for those hospitalised in the year preceding the survey (26%). First diagnosis of heart failure had been performed by a cardiologist (57%), a general practitioner (37%) or another category of physician (6%). Seventy percent of patients received three or more different classes of heart failure medications. Diuretics were prescribed to 71%, angiotensin converting enzyme inhibitors to 54% and digitalis to 35% of the population. Beta-blockers were given to only 14% of the patients. In patients aged over 80 years, only 45% received angiotensin converting enzyme inhibitors. CONCLUSION: This survey of ambulatory heart failure patients confirms that the disease is predominantly observed in elderly patients, and associated with prolonged and recurrent hospitalisations. The underuse of recommended therapeutic classes including angiotensin converting enzyme inhibitors and beta-blockers deserves further investigation.

[Observations on the management of cardiac failure in ambulatory patients. Results of a survey of cardiologists]. / Observatoire de la prise en charge de l'insuffisance cardiaque en ambulatoire. Enquête auprès des cardiologues.

An enquiry was undertaken amongst 71 cardiologists in 1999 evaluating 600 ambulatory patients with cardiac failure (64% men; mean age 73 years; NYHA Class I: 9%, Class II: 52%, Class III: 33%, Class IV: 6%). Cardiac failure is commoner in men (81%) before the age of 70. After the age of 80, the tendency is inversed (53% of women). Fifty-two per cent of patients had a history of hospital admission for cardiac failure: 26% in the year before the enquiry (on average 13.1 days' hospital stay). On inclusion, the diagnosis was made 4.2 +/- 4.6 years previously and the patients had been followed up for an average of 3.04 +/- 3.3 years. The diagnosis of cardiac failure was made by the cardiologist (57%), the general practitioner (37%), or another category of physician (6%). Eight per cent of patients were treated with a single drug before inclusion, 22% had a bi-therapy and 70% a polytherapy. The most frequently prescribed drugs were: diuretics (71%), angiotensin converting enzyme (ACE) inhibitors (54%) and digitalis (35%). The prescription of betablockers was only reported in 14% of the population. In the over-80's, only 45% of patients were prescribed ACE inhibitors. These results confirm that ambulatory patients with cardiac failure are mainly in NYHA Classes II and III, that the pathology concerns elderly patients and that it is the cause of recurrent hospital admission. The prescription of diuretics is the main therapy in all NYHA Classes. ACE inhibitors were only prescribed in 2/3 of patients and in less than half of patients over 80 years of age. The prescription of betablockers remains marginal. The reason for the underprescription of recommended drugs (International Recommendations) would justify further investigation.

Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine.

BACKGROUND: Very-low-calorie diets are a well established method to achieve substantial short-term weight loss in obese patients, but long-term maintenance of the weight loss is very disappointing. A combined very-low-calorie diet and pharmacologic approach could be an effective means of prolonging its benefits. PATIENTS AND METHODS: Eligible patients had a body-mass index greater than 30 kg/m2; those who lost 6 kg or more during a 4-week treatment with a very-low-calorie diet were randomly assigned to 1 year of treatment with sibutramine (10 mg) or identical placebo. RESULTS: In an intention-to-treat analysis, mean (+/-SD) absolute weight change at 1 year (or study endpoint) was -5.2 (+/-7.5) kg in the 81 patients in the sibutramine group and +0.5 (+/-5.7) kg in the 78 patients in the placebo group (P = 0.004). When compared with their weight at study entry (before the very-low-calorie diet), 86% of patients in the sibutramine group had lost at least 5% of their weight, compared with only 55% of those in the placebo group (P <0.001) at the study endpoint. Similarly, at month 12, 75% of subjects in the sibutramine group maintained at least 100% of the weight loss achieved with a very-low-calorie diet, compared with 42% in the placebo group (P <0.01). CONCLUSION: Following a very-low-calorie diet, sibutramine is effective in maintaining and improving weight loss for up to 1 year.

A comparison of sibutramine and dexfenfluramine in the treatment of obesity.

OBJECTIVE: Because long-term weight reduction is often unsuccessful with dietary restriction alone, pharmacological agents have been used to promote weight loss. We have compared the novel (multiple monoamine neurotransmitter reuptake inhibitor) antiobesity drug sibutramine (10 mg once daily) with the extensively studied serotonin-releasing antiobesity agent dexfenfluramine (15 mg twice daily). RESEARCH METHODS AND PROCEDURES: 226 healthy outpatients (aged 18 to 65 years; body mass index > or =27 kg/m2) were included in a 12-week, randomized, double-blind, parallel group study. The main outcome measures were changes in weight, body mass index, waist and hip circumference and ratio, and safety profiles. RESULTS: Mean (+/-SEM) absolute weight loss was 4.5 +/- 0.4 kg in the sibutramine group (n = 112) and 3.2 +/- 0.3 kg in the dexfenfluramine group (n = 112) (endpoint analysis); 4.7 +/- 0.4 kg in the sibutramine group (n = 101); and 3.6 +/- 0.3 kg in the dexfenfluramine group (n = 94) (completers analysis). Comparing the two treatments under the conventional null hypothesis of equality as a secondary analysis, weight loss at endpoint in patients receiving sibutramine was significantly greater than that achieved with dexfenfluramine (p<0.05). Both drugs had similar adverse events profiles: 174 patients (77%) experienced adverse events; 17 patients withdrew due to adverse events (sibutramine, n = 6; dexfenfluramine, n = 11). Pulse rate increased significantly in sibutramine-treated patients (3.6 bpm), but decreased in dexfenfluramine-treated patients (-0.9 bpm). DISCUSSION: Sibutramine (10 mg once daily) is at least as effective as dexfenfluramine (15 mg twice daily) in achieving weight loss in patients with obesity.

[Microcirculatory consequences of a venous striction in the rat. Effect of a coumarine-rutine association]. / Conséquences microcirculatoires d'une striction veineuse chez le rat. Effet d'une association coumarine-rutine.

The aim of this study was to investigate the consequences of a venous striction on capillary red blood cell distribution and venular blood return and the effect of a coumarin derivative-rutoside combination. The study was conducted, in vivo, in the rat cremaster muscle using intravital microscopy. The striction lasted thirty minutes and was obtained by clamping the epigastric vein. This mechanical constraint was sufficient to induce microcirculatory modifications without disrupting microvessels. Before the striction (t-5 min), the velocities and diameters of the veins and arteries were comparable in all groups. After the striction (t5 min), in the control group, venous blood flow decreased by 60%, from 0.48 +/- 0.09 mm3/s (t-5 min) to 0.20 +/- 0.06 mm3/s (t5 min). The results showed that after thirty minutes reperfusion, venular blood flow in the control animals was only 34% of initial blood flow. The mean red blood cell velocity dropped by 56%, the percentage of low perfused capillaries increased from 7.5% to 50%. Treatment of animals with a coumarin derivative-rutoside combination, particularly at 4 mg/kg coumarin derivative-100 mg/kg rutoside, has significantly improved the microcirculation. After thirty minutes reperfusion venular blood flow was 60% and the percentage of low perfused capillaries was only 10%. The effect seemed to be more pronounced for rutoside than coumarin derivatives. The interest of this study was to set up an experimental model of a venous striction not too severe to induce micro-hemorrages but enough to modify microcirculation. This model was used to quantify the beneficial effects of a coumarin derivative-rutoside combination.

Plasma insulin and ankle on brachial systolic blood pressure ratio in overweight men with hypertension.

BACKGROUND: Hypertension is often associated with multiple metabolic abnormalities included in the insulin resistance syndrome. In hypertensive individuals, the ratio between ankle and brachial systolic blood pressure (ABI) is considered to be an independent cardiovascular risk factor. Insulin resistance has not been studied in relation to ABI ratio in men with essential hypertension and who are moderately overweight. OBJECTIVE: To identify whether a decrease in the ABI ratio is associated with the degree of abdominal obesity and, hence, with the biochemical characteristics of resistance to insulin. METHODS: In 166 overweight men with mild-to-moderate essential hypertension, insulinaemia was measured using radioimmunoassay. The ABI ratio was measured by using a pressure cuff of appropriate diameter, a standard mercury sphygmomanometer and a Doppler probe. Patients with diabetes or arteriosclerosis obliterans of the lower limbs, or both, were excluded from the study. RESULTS: The ABI ratio was significantly associated with the degree of abdominal obesity, but also with plasma triglycerides and cholesterol, low high-density lipoprotein cholesterol, plasma glucose and insulin. In a multiple regression analysis, the ABI ratio was significantly and negatively associated with only two variables: age and plasma insulin. This result was independent of age and drug treatment of hypertension. CONCLUSION: Because alterations in the ABI ratio may be considered markers of the changes in the structure and function of the arteries of lower limbs, the study provides evidence that plasma insulin, independently of atherosclerotic occlusive lesions, can significantly influence the status of conduit arteries of the lower limbs.

Efficacy and tolerability of sibutramine in obese patients: a dose-ranging study.

OBJECTIVES: To assess the weight-reducing effects and tolerability of 5 mg, 10 mg and 15 mg daily doses of sibutramine, a novel serotonin and noradrenaline reuptake inhibitor (SNRI). DESIGN: Multicentre, double-blind, and placebo-controlled study. After a one week run-in period, patients were randomized to receive placebo or sibutramine over a 12-week period. Advice on diet and behaviour modification was provided. One follow-up was conducted four weeks after cessation of treatment. SUBJECTS: 235 obese outpatients, aged 18-65 y with a body mass index (BMI) within the range 27-40 kg/m2. MEASUREMENTS: Weight, height, waist and hip circumference, and medical history, assessment of hunger, satiety, appetite and craving for sweet, savoury and carbohydrate foods, and also for carbohydrate snacking, standard laboratory assessments, blood pressure, heart rate and ECG. RESULTS: The group mean (+/- s.e.m.) weight loss at end-point was 1.4 +/- 0.5 kg for placebo (n = 59), 2.4 +/- 0.5 kg for 5 mg sibutramine (n = 56), 5.1 +/- 0.5 kg for 10 mg sibutramine (n = 59) and 4.9 +/- 0.5 kg (n = 62) for 15 mg sibutramine. The difference observed between the placebo and the 10 mg and 15 mg groups was statistically significant from week 2 onwards (P < 0.01), but there was no significant difference between these sibutramine groups. The percentage of patients losing > 5% of initial bodyweight was significantly greater for 15 mg sibutramine (55%) and 10 mg sibutramine (49%) than for treatment with placebo (19%), (P < 0.001). During the double-blind period, 41 patients (17%) withdrew prematurely and 168 patients (71%) reported 453 adverse events. The incidence and type of adverse event and the rates of withdrawal, were not significantly different in the four groups. No significant differences between the groups were observed, in respect of changes in systolic and diastolic blood pressure, but a significant increase in heart rate (about 4 beats/min) was noted for patients who received 10 mg or 15 mg sibutramine, compared with the placebo (P < 0.001). CONCLUSION: These data demonstrate dose-related weight loss with sibutramine treatment for up to 12 weeks in obese patients. Doses of 10 mg and 15 mg once daily were shown to be similarly effective, well tolerated and significantly more effective than the placebo.

A comparison of an atypical and typical antipsychotic, zotepine versus haloperidol in patients with acute exacerbation of schizophrenia: a parallel-group double-blind trial.

The atypical antipsychotic zotepine was compared to haloperidol in 126 patients suffering from acute exacerbation of schizophrenia (DSM-III-R) in a randomized, double-blind study. After 8-weeks, 150 to 300 mg zotepine improved scores on the Brief Psychiatric Rating Scale (BPRS) more than 10 to 20 mg haloperidol (-17.03 versus -13.45; 95%CI for zotepine-haloperidol -9.34/2.04). BPRS subscores and Clinical Global impressions (CGI) Severity and improvement subscales showed comparable gains, but scores on the Scale for the Assessment of Negative Symptoms (SANS) improved significantly more with zotepine (-23.82) than haloperidol (-15.15; P < .05; 95%CI for zotepine haloperidol -18.03/-0.18). Adverse events were reported by 71 percent of zotepine and 78 percent of haloperidol patients. Extrapyramidal side effect (EPMS) scores decreased with zotepine (-0.34) but increased with haloperidol (+2.32; P < .05). Seven haloperidol patients reported akathisia but no zotepine patients did (p < .05). Uric acid reductions (which appear to have no clinical consequence) and transient raised liver enzymes were recorded with zotepine. Weight increased on zotepine (2.32 kg; P < .001) and a small increase in pulse rate occurred (P < .05). Both drugs were effective in reducing positive symptoms of schizophrenia; zotepine was significantly more effective against negative symptoms and reduced EPMS.

Metabolism and toxicity of coumarin on cultured human, rat, mouse and rabbit hepatocytes.

We compared the cytotoxic effect of coumarin and its derivatives, 7-hydroxycoumarin (7-OHC), 4-hydroxycoumarin (4-OHC), o-hydroxyphenyl acetic acid (OHPAA) and o-coumaric acid (CA), on cultured hepatocytes from human, rat, mouse and rabbit liver. At 10(-5) and 5 x 10(-5) M, coumarin and its derivatives did not give rise to any signs of toxicity on cultured hepatocytes of the four species. At 10(-4) M, coumarin, but not its derivatives, induced release of lactate dehydrogenase (LDH) into the medium, especially in rat hepatocyte cultures. Intracellular LDH activities were correspondingly reduced. The cytotoxic effect of coumarin in cultured rat hepatocytes was evidenced on morphological examination and from the results of the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium (MTT) reduction test. At higher concentrations (5 x 10(-4) M), 7-OHC and CA were also found to be cytotoxic in cultured rat hepatocytes. The cytotoxic effect of coumarin (5 x 10(-4) M) was decreased in the presence of SKF 525-A, a cytochrome P450 inhibitor. Interspecies comparisons showed that rat hepatocytes were the most sensitive to the toxicity of coumarin and its derivatives, whereas human hepatocytes were the most resistant. Our results suggest that the cytotoxicity of coumarin is metabolism and species-dependent. Thus, the rat may not be a suitable model for evaluating the pharmacological hazards of coumarin in humans.

[Prescription of non-steroidal anti-inflammatory agents and risk of iatrogenic adverse effects: a survey of 1072 French general practitioners]. / Prescription des anti-inflammatoires non stéroïdiens et pratiques à risque de iatrogènie: étude chez 1072 médecins généralistes français.

As a group, non-steroidal anti-inflammatory drugs (NSAIDs) rank first among commonly prescribed drugs for serious adverse reactions. We conducted a cross-sectional survey in which 1072 French general practitioners (GPs) were evaluated for their basic pharmacological knowledge and practice of NSAIDs prescription. Results suggest that GPs have insufficient pharmacological knowledge and provide inadequate management of adverse reaction risk. Well-established risk factors for serious adverse reactions, such as age, are not taken enough into account, and tolerance is not correctly monitored. Drugs allegedly protecting against peptic ulcers are frequently associated but, most of the time, without any relevant justification, such as the patient's risk level or drug's efficacy. Our findings demonstrate a need for greater information among GPs about prescription and tolerance monitoring of NSAIDs.

Pharmacokinetic comparison of oral and local action transcutaneous flurbiprofen in healthy volunteers.

Flurbiprofen is a propionic acid-derived non-steroidal anti-inflammatory drug (NSAID) used widely in the treatment of rheumatism and non-arthritic pain. The pharmacokinetics of topically and orally administered flurbiprofen were compared in a two-part, open study involving healthy adult volunteers. In the first (cross-over) part of the study, 12 Caucasians were randomized to receive either a single oral dose of 50 mg flurbiprofen or a single topical application of a novel 40 mg flurbiprofen-containing patch on the right wrist for 12 h. In the second part of the study, each subject applied a flurbiprofen-containing patch twice daily to the same wrist for 7 days. Plasma concentrations of flurbiprofen and urinary concentrations of the NSAID and its metabolites were measured by high-performance liquid chromatography assay, to enable comparison of the pharmacokinetic parameters for delivery of the drug by both routes. Maximum concentrations of the NSAID in plasma (Cmax) were much lower after a single application of the topical 40 mg flurbiprofen patch than after a single oral dose of 50 mg of the NSAID (mean +/- SD: 43 +/- 16 ng/ml versus 5999 +/- 1300 ng/ml, respectively). After repeated application of the topical patch, Cmax increased only slightly to 103 +/- 57 ng/ml. The mean relative bioavailability of flurbiprofen from the patch was 3.5 +/- 1.7%, calculated from plasma area under the curve data and 4.4 +/- 2.8% from urinary excretion data.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of a combination of coumarin derivatives and rutoside on venous and lymphatic circulations during severe constriction of the caudal vena cava in rabbits.

The effect of a coumarin (CAS 91-64-5) derivatives-rutoside (CAS 153-18-4) combination (Esberiven) has been investigated in an in vivo model of venous hind leg stasis elicited by severe constriction of the caudal vena cava in anesthetized rabbits. The vena cava flow is initially reduced by 80% compared to reference values; then, it significantly declines over time. The venous femoral pressure drops as well as the perfusion pressure whereas the peripheral resistance increases. The popliteal lymph flow gradually slows down after the constriction. Moreover, this venous constriction results in a marked reduction of the right ventricular stroke volume responsible for a left ventricle failure and for the exitus of 30% of the rabbits within 1-3 h post-constriction. A 5-day pretreatment (i.v.) with the coumarin derivatives-rutoside combination at a dose of 4 mg of coumarin derivatives + 200 mg of rutoside/rabbit/day increases the lymph flow but does not suppress the mechanically-induced venous flow decrease. The 6th-day treatment (infusion at the respective doses of 5 mg of coumarin derivatives + 250 mg of rutoside/kg or 10 mg of coumarin derivatives + 500 mg of rutoside/kg) induces a dose-related significant increase of both venous and lymph flows and of the femoral pressure. At the same time, the peripheral venous resistance decreases in a dose-response relationship. Furthermore, after administration of coumarin derivatives and rutoside, the right ventricle stroke volume increases and no death occurs.

[Action and tolerance of dothiepin hydrochloride (Prothiaden) in depressive states during the evolution of psychotic disorders]. / Activité et tolérance du chlorhydrate de dosulépine (Prothiaden) dans les états dépressifs survenant au cours de l'évolution d'une psychose.

During psychosis evolution, depressions occur frequently with a prevalence between 10% and 70% (average 25%-50%). Depression aggravates psychosis prognosis by increasing the risk of suicide, relapse and hospitalization. So antidepressant and neuroleptic treatments are often associated. Many studies with contradictory results were realized. Some concluded a favourable effect of this association, others considered this concomitant medication aggravates psychotic symptoms and adverse reactions. However this association appears to be efficient especially in deficitary or depressive forms of schizophrenia. The objective of this multicentre, non comparative, open study is to assess during 6 weeks the efficacy and tolerability of dothiepin in the treatment of depression occurring during the evolution of psychosis. The initial score on HDRS (17 items) had to be at least 18. 124 patients (40.7 years, 63.1% male) suffering from chronic psychosis associated with depressive syndrome were included in 29 hospital centres. According to DSM III-R criteria, 71.9% of patients were schizophrenic and 43% were suffering from major depressive illness. 16 patients (12.9%) stopped prematurely the treatment and side effects were reported for 8 of them. Any unexpected side effect occurred and pre-existing psychotic disorders reappeared for one patient. During the whole study, 63% of the population were treated with 75 mg as daily dosage of dothiepin. All concomitant treatments except antidepressant were authorized. 115 patients (95%) received at least one associated neuroleptic treatment and 54 patients (44.6%) a concomitant antiparkinsonian treatment. The significant decrease, between day 0 and day 45, of the global score on HDRS (from 23.78 to 8.48, p < 0.01), confirms the improvement of depression.(ABSTRACT TRUNCATED AT 250 WORDS)