Antidepressants and Hepatotoxicity: A Cohort Study among 5 Million Individuals Registered in the French National Health Insurance Database.

BACKGROUND: Hepatotoxicity may be a concern when prescribing antidepressants. Nevertheless, this risk remains poorly understood for serotonin and noradrenaline reuptake inhibitors (SNRIs: venlafaxine, milnacipran, duloxetine) and 'other antidepressants' (mianserin, mirtazapine, tianeptine and agomelatine), particularly in comparison with selective serotonin reuptake inhibitors (SSRIs: fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, escitalopram), which are by far the most commonly prescribed antidepressants. OBJECTIVE: We quantified the risk of serious liver injury associated with new use of SNRIs and 'other antidepressants' compared with SSRIs in real-life practice. METHODS: Based on the French national health insurance database, this cohort study included 4,966,825 individuals aged 25 years and older with a first reimbursement of SSRIs, SNRIs or 'other antidepressants' between January 2010 and June 2015. We compared the risk of serious liver injury within the 6 months following antidepressant initiation according to antidepressant class, with SSRIs as the reference, using an inverse probability-of-treatment-weighted Cox proportional hazard model adjusted for demographic characteristics and risk factors of liver injury. RESULTS: We identified 382 serious liver injuries overall (none for milnacipran initiators). Age and gender standardized incidence rates per 100,000 person-years were 19.2 for SSRIs, 22.2 for venlafaxine, 12.6 for duloxetine, 21.5 for mianserin, 32.8 for mirtazapine, 31.6 for tianeptine and 24.6 for agomelatine initiators. Initiation of antidepressants of interest versus SSRIs was not associated with an increased risk of serious liver injury [adjusted hazard ratios (95% confidence interval): venlafaxine 1.17 (0.83-1.64), duloxetine 0.54 (0.28-1.02), mianserin 0.90 (0.58-1.41), mirtazapine 1.17 (0.67-2.02), tianeptine 1.35 (0.82-2.23) and agomelatine 1.07 (0.51-2.23)]. This finding was confirmed by the results of an additional study using a case-time-control design. CONCLUSION: These results do not provide evidence of an increased risk of serious liver injury following initiation of SNRIs or 'other antidepressants' compared with SSRIs in real-life practice. This could reflect an inherent lack of difference in risk between the drug classes, or the fact that individuals with higher susceptibility to drug-induced liver injury are not prescribed drugs considered to be more hepatotoxic.

Antipsychotics use: 2006-2013 trends in prevalence and incidence and characterization of users.

PURPOSE: The present study was conducted to describe antipsychotic (AP) prevalent and incident use, characteristics of AP users, and their trends in the French population. METHODS: A cross-sectional study was repeated yearly from January 1, 2007 to December 31, 2013 (for prevalence analysis) or to December 31, 2012 (for incidence analysis) using the French Health Insurance reimbursement database (Echantillon Généraliste de Bénéficiaires, EGB). For each year studied, prevalent and incident AP users were described in terms of age and gender overall, and according to the type of AP (FGAPs or SGAPs) used at index date. In addition, concurrent medications and comorbidities that a priori contraindicate the use of drugs having atropinic properties were researched. RESULTS: Prevalence and incidence remained relatively stable along the 2007-2013 period. Trends slightly decreased, from 2.07% (n = 10,252) to 2.05% (n = 11,015) for prevalence, and from 0.73% (n = 3461) to 0.66% (n = 3363) for incidence, especially in elderly, in contrast of children and adolescents (+ 39% for prevalence, from 184 to 271). The number of coprescribed drugs was found high (median = 5) and remained constant over time. In 2013, about 7% of prevalent AP users presented with a comorbidity increasing the risk of atropinic ADRs, and 36% used at least one concurrent atropinic drug. In incident AP users, these numbers were of 8 and 29%, respectively. CONCLUSIONS: The present study highlighted a marked shift from FGAPs toward SGAPs, as well as an increase in AP use in children and adolescents in France.

Homeopathic medical practice for anxiety and depression in primary care: the EPI3 cohort study.

BACKGROUND: The purpose of the study was to compare utilization of conventional psychotropic drugs among patients seeking care for anxiety and depression disorders (ADDs) from general practitioners (GPs) who strictly prescribe conventional medicines (GP-CM), regularly prescribe homeopathy in a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho). METHODS: This was one of three epidemiological cohort studies (EPI3) on general practice in France, which included GPs and their patients consulting for ADDs (scoring 9 or more in the Hospital Anxiety and Depression Scale, HADS). Information on all medication utilization was obtained by a standardised telephone interview at inclusion, 1, 3 and 12 months. RESULTS: Of 1562 eligible patients consulting for ADDs, 710 (45.5 %) agreed to participate. Adjusted multivariate analyses showed that GP-Ho and GP-Mx patients were less likely to use psychotropic drugs over 12 months, with Odds ratio (OR) = 0.29; 95 % confidence interval (CI): 0.19 to 0.44, and OR = 0.62; 95 % CI: 0.41 to 0.94 respectively, compared to GP-CM patients. The rate of clinical improvement (HADS <9) was marginally superior for the GP-Ho group as compared to the GP-CM group (OR = 1.70; 95 % CI: 1.00 to 2.87), but not for the GP-Mx group (OR = 1.49; 95 % CI: 0.89 to 2.50). CONCLUSIONS: Patients with ADD, who chose to consult GPs prescribing homeopathy reported less use of psychotropic drugs, and were marginally more likely to experience clinical improvement, than patients managed with conventional care. Results may reflect differences in physicians' management and patients' preferences as well as statistical regression to the mean.

Utilization of psychotropic drugs by patients consulting for sleeping disorders in homeopathic and conventional primary care settings: the EPI3 cohort study.

BACKGROUND: Utilization of sedative hypnotic drugs for sleeping disorders (SD) raises concerns, particularly among older people. This study compared utilization of conventional psychotropic drugs for SD among patients seeking care from general practitioners (GPs) who strictly prescribe conventional medications (GP-CM), regularly prescribe homeopathy in a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho). METHODS: This was a French population-based cohort study of GPs and their patients consulting for SD, informed through the Pittsburgh sleep quality index (PSQI) questionnaire. Information on psychotropic drugs utilization was obtained from a standardized telephone interview at inclusion, one, three and 12 months. RESULTS: 346 patients consulting for SD were included. Patients in the GP-Ho group experienced more often severe SD (41.3%) than patients in the GP-CM group (24.3%). Adjusted multivariate analyses showed that patients who chose to be managed by GP-Ho were less likely to use psychotropic drugs over 12 months as opposed to the GP-CM group, with Odds ratio (OR) = 0.25; 95% confidence interval (CI): 0.14 to 0.42. Patients in the GP-Mx group also used less psychotropic drugs but the result was not statistically significant (OR = 0.67; 95% CI: 0.39-1.16). Rates of clinical improvement of the SD did not differ between groups. CONCLUSIONS: Patients with SD who chose to consult GPs certified in homeopathy consumed less psychotropic drugs and had a similar evolution of their condition to patients treated with conventional medical management. This result may translate in a net advantage with reduction of adverse events related to psychotropic drugs.

Effects of Cydonia oblonga Miller leaf and fruit flavonoids on blood lipids and anti-oxydant potential in hyperlipidemia rats.

OBJECTIVE: To study the effects of Cydonia oblonga Miller (COM) total flavonoids (TF) from leaves and fruit on the blood lipid and antioxidant potentials using hyperlipidaemic rat models. METHODS: Hyperlipidaemic rat models were created with high-lipid emulsion. Rats were distributed into normal controls, hyperlipidaemic models, and daily high (160mg/kg), medium (80mg/kg) and low (40mg/kg) TF from leaves and fruit and simvastatin (5mg/kg) groups. After four weeks, serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), as well as hepatic superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured. RESULTS: Compared with the hyperlipidaemic model group, TF significantly reduced serum TC, TG, LDL-C (P<0.01), ALT and AST (P<0.01 or P<0.05) and increased HDL-C (P<0.05 or P<0.01). TF also reduced MDA (P<0.01 or P<0.01). CONCLUSION: COM total flavonoids can effectively regulate the metabolism of lipids, and remove oxygen free radicals. This confirms its potential value in the prevention and treatment of hyperlipidaemia.

Effects of Cydonia oblonga Miller extracts on blood hemostasis, coagulation and fibrinolysis in mice, and experimental thrombosis in rats.

INTRODUCTION: Cydonia oblonga Miller (COM) is traditionally used in Uyghur medicine for the prevention of cardiovascular disease. The present study is designed to explore the effects of COM extracts on models and markers of thrombosis and related biomarkers. MATERIALS AND METHODS: 20, 40, 80 mg/kg/day COM aqueous extracts and 5mg/kg/day aspirin, orally for 14 days were compared to untreated controls in mice on bleeding and clotting times, using the tail cutting and glass slide methods and for death rates in collagen-epinephrine pulmonary thrombosis, thrombolysis in vitro and euglobulin lysis time (ELT). In rats, common carotid artery FeCl3-induced thrombus and inferior vena cava thrombosis occlusion time, plasma concentrations of thromboxane B2 (TXB2) and 6-keto-prostaglandine F1α (6-keto-PGF1α) were measured. RESULTS AND CONCLUSION: Compared to controls, COM extracts dose-dependently prolonged bleeding by 2.17, 2.78 and 3.63 times, vs. aspirin 2.58, and the clotting time by 1.44, 2.47 and 2.48 times, vs. aspirin 1.91. COM reduced pulmonary embolus mortality by 27, 40 and 53%, vs. 47% for aspirin. COM dose-dependently increased thrombolysis by 45, 55 and 63%, vs. 56% for aspirin, and shortened ELT to 71, 61 and 43%, vs. 43% for aspirin. In rats, venous occlusion time was prolonged. Arterial and venous thrombus weights were dose-dependently reduced in COM groups. TXB2 decreased and 6-keto-PGF1α increased with COM and aspirin, with an association between 6-keto-PGF1α/TXB2 and arterial or venous thrombus weight for all products, and for occlusion time with COM but not for aspirin. CONCLUSION: We confirm the experimental effects of COM on hemostasis and thrombosis. Further exploration of putative clinical effects appear justified.

Management of upper respiratory tract infections by different medical practices, including homeopathy, and consumption of antibiotics in primary care: the EPI3 cohort study in France 2007-2008.

BACKGROUND: Prescribing of antibiotics for upper respiratory tract infections (URTI) varies substantially in primary care. OBJECTIVES: To describe and compare antibiotic and antipyretic/anti-inflammatory drugs use, URTI symptoms' resolution and occurrence of potentially-associated infections in patients seeking care from general practitioners (GPs) who exclusively prescribe conventional medications (GP-CM), regularly prescribe homeopathy within a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho). METHOD: The EPI3 survey was a nationwide population-based study of a representative sample of 825 GPs and their patients in France (2007-2008). GP recruitment was stratified by self-declared homeopathic prescribing preferences. Adults and children with confirmed URTI were asked to participate in a standardized telephone interview at inclusion, one-, three- and twelve-month follow up. Study outcomes included medication consumption, URTI symptoms' resolution and potentially-associated infections (sinusitis or otitis media/externa) as reported by patients. Analyses included calibration to account for non-respondents and groups were compared using multivate analyses adjusting for baseline differences with a propensity score. RESULTS: 518 adults and children with URTI (79.3% rhinopharyngitis) were included (36.9% response rate comparable between groups). As opposed to GP-CM patients, patients in the GP-Ho group showed significantly lower consumption of antibiotics (Odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.27-0.68) and antipyretic/anti-inflammatory drugs (OR = 0.54, 95% CI: 0.38-0.76) with similar evolution in related symptoms (OR = 1.16, 95% CI: 0.64-2.10). An excess of potentially-associated infections (OR = 1.70, 95% CI: 0.90-3.20) was observed in the GP-Ho group (not statistically significant). No difference was found between GP-CM and GP-Mx patients. CONCLUSION: Patients who chose to consult GPs certified in homeopathy used less antibiotics and antipyretic/anti-inflammatory drugs for URTI than those seen by GPs prescribing conventional medications. No difference was observed in patients consulting GPs within mixed-practice. A non-statistically significant excess was estimated through modelling for associated infections in the GP-Ho group and needs to be further studied.

Characteristics of patients consulting their regular primary care physician according to their prescribing preferences for homeopathy and complementary medicine.

BACKGROUND: Homeopathic care has not been well documented in terms of its impact on patients' utilization of drugs or other complementary and alternative medicines (CAM). The objective of this study was to describe and compare patients who visit physicians in general practice (GPs) who prescribe only conventional medicines (GP-CM), regularly prescribe homeopathy within a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho). MATERIAL AND METHODS: The EPI3-LASER study was a nationwide observational survey of a representative sample of GPs and their patients from across France. Physicians recorded their diagnoses and prescriptions on participating patients who completed a self-questionnaire on socio-demographics, lifestyle, quality of life Short Form 12 (SF-12) and the complementary and alternative medicine beliefs inventory (CAMBI). RESULTS: A total of 6379 patients (participation rate 73.1%) recruited from 804 GP practices participated in this survey. Patients attending a GP-Ho were slightly more often female with higher education than in the GP-CM group and had markedly healthier lifestyle. They did not differ greatly in their comorbidities or quality of life but exhibited large differences in their beliefs in holistic medicine and natural treatments, and in their attitude toward participating to their own care. Similar but less striking observations were made in patients of the GP-Mx group. CONCLUSION: Patients seeking care with a homeopathic GP did not differ greatly in their socio-demographic characteristics but more so by their healthier lifestyle and positive attitude toward CAM. Further research is needed to explore the directionality of those associations and to assess the potential economic benefits of homeopathic management in primary care.

Who seeks primary care for sleep, anxiety and depressive disorders from physicians prescribing homeopathic and other complementary medicine? Results from the EPI3 population survey.

OBJECTIVES: To describe and compare patients seeking treatment for sleep, anxiety and depressive disorders (SADD) from physicians in general practice (GPs) with three different practice preferences: strictly conventional medicine (GP-CM), mixed complementary and conventional medicine (GP-Mx) and certified homeopathic physicians (GP-Ho). DESIGN AND SETTING: The EPI3 survey was a nationwide, observational study of a representative sample of GPs and their patients, conducted in France between March 2007 and July 2008. PARTICIPANTS: 1572 patients diagnosed with SADD. PRIMARY AND SECONDARY OUTCOMES: The patients' attitude towards complementary and alternative medicine; psychotropic drug utilisation. RESULTS: Compared to patients attending GP-CM, GP-Ho patients had healthier lifestyles while GP-Mx patients showed similar profiles. Psychotropic drugs were more likely to be prescribed by GP-CM (64%) than GP-Mx (55.4%) and GP-Ho (31.2%). The three groups of patients shared similar SADD severity. CONCLUSION: Our results showed that patients with SADD, while differing principally in their sociodemographic profiles and conventional psychotropic prescriptions, were actually rather similar regarding the severity of SADD in terms of comorbidities and quality of life. This information may help to better plan resource allocation and management of these common health problems in primary care.

Immunomodulatory and antitumour effects of abnormal Savda Munziq on S180 tumour-bearing mice.

BACKGROUND: Abnormal Savda Munziq (ASMq), a traditional uyghur medicine, has shown anti-tumour properties in vitro. This study attempts to confirm these effects in vivo and measure effects on the immune system. METHODS: Kunming mice transplanted with Sarcoma 180 cells were treated with ASMq (2-8 g/kg/day) by intra-gastric administration compared to model and cyclophosphamide (20 mg/kg/day). After the 14th day post tumour implant, thymus, liver, spleen and tumours were removed, weighed, and processed for histopathological analysis. Blood samples were also taken for haematological and biochemical analyses including TNF-α , IL-1 ß and IL-2. Splenic lymphocyte function was measured with MTT; lymphocyte subpopulations were measured by flow cytometry. RESULTS: ASMq treated animals had reduced tumour volume compared to model and increased concentrations of TNF-α, IL-1ß and IL-2 compared to untreated and to cyclophosphamide-treated animals. No histopathological alterations were observed. The absence of viable S180 cells and the presence of necrotic cells and granulation tissue were observed in tumour tissue of treated animals. The effect on T lymphocytes was unclear. CONCLUSIONS: ASMq confirmed in vivo anti-tumour effects observed in vitro, which may be at least in part mediated by increased immune activity.

Impact of physician preferences for homeopathic or conventional medicines on patients with musculoskeletal disorders: results from the EPI3-MSD cohort.

OBJECTIVE: The objective of this study was to assess the effect of physician practicing preferences (PPP) in primary care for homeopathy (Ho), CAM (Complementary and alternative medicines) with conventional medicine (Mx) or exclusively conventional medicine (CM) on patients with musculoskeletal disorders (MSDs), with reference to clinical progression, drug consumption, side effects and loss of therapeutic opportunity. METHODS: The EPI3-MSD study was a nationwide observational cohort of a representative sample of general practitioners (GP) and their patients in France. Recruitment of GP was stratified by PPP, which was self-declared. Diagnoses and comorbidities were recorded by GP at inclusion. Patients completed a standardized telephone interview at inclusion, one, three and twelve months, including MSD-functional scales and medication consumption. RESULTS: 1153 MSD patients were included in the three PPP groups. Patients did not differ between groups except for chronicity of MSDs (>12 weeks), which was higher in the Ho group (62.1%) than in the CM (48.6%) and Mx groups (50.3%). The twelve-month development of specific functional scores was identical across the three groups after controlling for baseline score (p > 0.05). After adjusting for propensity scores, NSAID use over 12 months was almost half in the Ho group (OR, 0.54; 95%CI, 0.38-0.78) as compared to the CM group; no difference was found in the Mx group (OR, 0.81; 95% CI: 0.59-1.15). CONCLUSION: MSD patients seen by homeopathic physicians showed a similar clinical progression when less exposed to NSAID in comparison to patients seen in CM practice, with fewer NSAID-related adverse events and no loss of therapeutic opportunity.

Relevance of a "Dear Doctor letter" to alert healthcare providers to new recommendations for vitamin D administration.

PURPOSE: After reports of malaise in infants immediately after the oral administration of two brands of vitamin D solutions, a "Dear Doctor letter" (DDL) containing recommendations for the administration of vitamin D was sent to all French paediatricians and pharmacies and a large number of French general practitioners (GPs) with a predominantly paediatric practice. The DDL and a press release were published on the French Medicines Agency website and distributed via a mailing list. The objective of this study was to assess the effectiveness of such a DDL and to collect the opinions of healthcare professionals on the best way to provide them with information. METHODS: A questionnaire was sent to a national random sample of 145 paediatricians, 680 GPs and 230 pharmacists. RESULTS: Only 49% of responding paediatricians, 48% of GPs and 67% of pharmacists were aware of the warning. Among the participating healthcare professionals aware of the warning and who prescribed/dispensed these vitamins, 50% of paediatricians and 68% of GPs stated that they had changed their prescribing behaviour, and 68% of pharmacists stated that they had modified their advice when dispensing. According to the responding healthcare professionals, postal letters remained the best way to issue safety warnings. Some of the respondents suggested that the DDL be more distinctive in terms of being a DDL and that the information be more widely disseminated to other stakeholders involved in the healthcare system. CONCLUSIONS: This survey of a national random sample of healthcare professionals revealed that many of the respondents paid little attention to the DDL and were therefore unlikely to change their practices. A potential supplementary method for disseminating recommendations for medicine administration could be to apply stickers on medicine boxes, as this approach has the additional advantage of directly informing the concerned population, i.e. the parents.

Are traditional NSAIDs prescribed appropriately among French elderly with osteoarthritis? Results from the CADEUS cohort.

AIM: To describe the inappropriate use of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) in elderly subjects in the CADEUS cohort using the Beers 2003 criteria modified by recommendations from the French Medicines Agency. METHODS: Of the 23,217 subjects in the CADEUS cohort, 1,851 were ≥65 years old, had bee diagnosed with osteoarthritis (OA), and had been dispensed a tNSAID at least once in the 6 months before the index date. Data were obtained from the French national reimbursement database and from patient and prescriber questionnaires. The Beers criteria for inappropriate use were modified to include all tNSAIDs, and long-term high-dose use was defined as having been dispensed at least five dispensations for tNSAID over a 6-month period with a gap of <45 days between each dispensation and when the gap was >45 days, medicine availability >50% [i.e., defined daily dose (DDD) delivered/theoretical DDD] for the gap. RESULTS: The most frequently dispensed tNSAIDs were piroxicam (25%), diclofenac (24%), ibuprofen (18%), ketoprofen (18%), and naproxen (10%). Of the study population, 1.5% were dispensed indomethacin; 15%, two tNSAIDs; 15%, a tNSAIDs with a platelet aggregation inhibitor; 4.6%, a tNSAID with low-dose aspirin; 0.2%, a tNSAID with vitamin K antagonists. The analysis revealed that 18% of the study population were high-dose and long-term users of tNSAIDs and that 70% of these were dispensed a proton pump inhibitor. CONCLUSIONS: The most common inappropriate tNSAID dispensation was the co-prescription of two different tNSAIDs within 1 month or of a platelet aggregation inhibitor. The real-life consequences of our results need to be ascertained, and it would be interesting to update the Beers criteria.

Who seeks primary care for musculoskeletal disorders (MSDs) with physicians prescribing homeopathic and other complementary medicine? Results from the EPI3-LASER survey in France.

BACKGROUND: There is a paucity of information describing patients with musculoskeletal disorders (MSDs) using complementary and alternative medicines (CAMs) and almost none distinguishing homeopathy from other CAMs. The objective of this study was to describe and compare patients with MSDs who consulted primary care physicians, either certified homeopaths (Ho) or regular prescribers of CAMs in a mixed practice (Mx), to those consulting physicians who strictly practice conventional medicine (CM), with regard to the severity of their MSD expressed as chronicity, co-morbidity and quality of life (QOL). METHODS: The EPI3-LASER study was a nationwide observational survey of a representative sample of general practitioners and their patients in France. The sampling strategy ensured a sufficient number of GPs in each of the three groups to allow comparison of their patients. Patients completed a questionnaire on socio-demographics, lifestyle and QOL using the Short Form 12 (SF-12) questionnaire. Chronicity of MSDs was defined as more than twelve weeks duration of the current episode. Diagnoses and co-morbidities were recorded by the physician. RESULTS: A total of 825 GPs included 1,692 MSD patients (predominantly back pain and osteoarthritis) were included, 21.6% in the CM group, 32.4% Ho and 45.9% Mx. Patients in the Ho group had more often a chronic MSD (62.1%) than the CM (48.6%) or Mx (50.3%) groups, a result that was statistically significant after controlling for patients' characteristics (Odds ratio = 1.43; 95% confidence interval (CI): 1.07 - 1.89). Patients seen by homeopaths or mixed practice physicians who were not the regular treating physician, had more often a chronic MSD than those seen in conventional medicine (Odds ratios were 1.75; 95% CI: 1.22 - 2.50 and 1.48; 95% CI: 1.06 - 2.12, respectively). Otherwise patients in the three groups did not differ for co-morbidities and QOL. CONCLUSION: MSD patients consulting primary care physicians who prescribed homeopathy and CAMs differed from those seen in conventional medicine. Chronic MSD patients represented a greater proportion of the clientele in physicians offering alternatives to conventional medicine. In addition, these physicians treated chronic patients as consulting rather than regular treating physicians, with potentially important impacts upon professional health care practices and organisation.

How reimbursement databases can be used to support drug utilisation studies: example using the main French national health insurance system database.

INTRODUCTION: Reimbursement databases are potentially invaluable tools to develop and conduct pharmacoepidemiological studies on drug use. However, two types of factors that may influence the performance of a database can be distinguished: firstly, factors related to the constitution of the database, and secondly, factors related to the data. For the latter, we think that two are important: the presence of the drug in the database and the capacity to capture real-life use, both of which are influenced by the marketing status (e.g., OTC) and whether reimbursement is possible. OBJECTIVES: To illustrate and discuss to what extent reimbursement databases are relevant tools to conduct drug utilization studies with regard to the data on drugs. METHODS: In order to illustrate the reliability of data in reimbursement databases, data from the main French national health insurance database (55 million individuals) were compared to national drug sales in France (units) during the same year. RESULTS: Depending on the ATC class, the capture in the database of drugs actually sold ranged from 32 to 81%. DISCUSSION: Capture of classes of drugs in the database may be explained by the specific characteristics of the French health insurance system (reimbursable drugs, OTC market share). These characteristics influence the studies that can be performed both in terms of the topic but also the methodology. This problem probably exists for the other reimbursement databases used worldwide. CONCLUSION: Studies should be designed according to the strengths and weaknesses of reimbursement databases that were not originally developed for pharmacoepidemiology.

Cytotoxicity of abnormal Savda Munziq aqueous extract in human hepatoma (HepG2) cells.

Abnormal Savda Munziq (ASMq) is a traditional Uighur medicinal herbal preparation commonly used to treat diseases such as diabetes, cardiovascular diseases, chronic asthma and especially digestive cancer. Earlier studies have shown that ASMq is a free radical scavenger and could prevent mitochondrial and DNA oxidative damage. In this study, we tested the effects of aqueous extract of ASMq on human hepatoma cells (HepG2) to explore the possible mechanism of its putative anticancer properties. Aqueous extract of ASMq was tested on HepG2 proliferation (MTT assay) at 72 h, cell viability at 48 h (neutral red assay), lactate dehydrogenase release over 48 or 72 h as a measure of cytoplasmic leakage, lipid peroxidation (malondialdehyde-thiobarbituric acid adducts) at 48 h, and incorporation of [3H]-leucine, [3H]-thymidine and [3H]-uridine into cellular protein, DNA and RNA, respectively, at 24 or 48 h to assess the inhibition effects to cellular macromolecule synthesis. Our results showed a significant (P < 0.05) time- and concentration-dependent inhibition of HepG2 proliferation and viability, with increased cytoplasmic leakage, and time- and concentration-dependent inhibition of protein, DNA and RNA synthesis. No lipid peroxidation was found at these concentrations. The results of the present study suggest that the putative anticancer mechanisms of ASMq may at least involve cytotoxicity.

NSAID use profiles derived from reimbursement data in France.

Because extrapolation of adverse event rates from clinical trials to the general population relies on the assumption of similar drug-usage patterns, we have studied usage patterns for nonsteroidal anti-inflammatory drugs (NSAIDs) from the National Health Insurance claims database. Reimbursement patterns of NSAIDs and analgesics were studied in a cohort of 232 users, half selected from authorisations of reimbursed spa cures, and the other half - strictly matched according to age and gender - who had redeemed at study onset at least one prescription for NSAIDs, analgesics or other antirheumatic drugs. Drug utilisation was measured as the total number of defined daily doses (DDD) bought over the 9-month study period. Over this time, the patients bought a median 45 DDD of NSAIDs out of the 270 needed to cover the whole period. Only two patients bought 270 DDD or more. Median paracetamol use (alone or combined) was 26 days. This study shows that patients use NSAIDs either intermittently or at lower than recommended doses, which is consistent with a primarily symptomatic use. Intermittent or on-demand use of NSAIDs, or at doses lower than full, could partly explain the lower rates of gastrointestinal bleeding and other ulcer complications in postmarketing epidemiological studies than could be expected from the findings of clinical trials.