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International audience; Neuroinflammation and iron accumulation are hallmarks of a variety of adult neurodegenerative diseases. In Sanfilippo syndrome (mucopolysaccharidosis type III, MPSIII, a pediatric neurodegenerative disease that shares some features with adult neurodegenerative diseases), the progressive accumulation of heparan sulfate oligosaccharides (HSOs) induces microglia and astrocytes to produce pro-inflammatory cytokines leading to severe neuroinflammation. The objectives of the present study were (1) to measure the local iron concentration and to assess iron metabolism in the brain of a MPSIIIB murine model and (2) to identify the brain cells involved in this accumulation. We found that iron accumulation in MPSIIIB mice primarily affected the cerebral cortex where hepcidin levels were higher than in wild-type mice, and increased with aging. This increase was correlated with low expression of ferroportin 1 (FPN1), and thus brain iron retention. Moreover, we showed in vitro that HSOs are directly responsible for the production of hepcidin and the relative decrease in FPN1 expression when added to cultures of microglia and, to a lesser extent, to cultures of astrocytes. In contrast, no significant differences were observed in neurons. Hepcidin induction results from activation of the TLR4 pathway and STAT3 signaling, and leads to iron retention within microglia. Our results show that microglia have a key role in cerebral hepcidin overexpression and thus in the brain iron accumulation observed in the MPSIIIB model.

Introduction Methotrexate is the ‘anchor’ of rheumatoid arthritis (RA) treatment and leflunomide is commonly added in resistant disease, or where methotrexate is contraindicated.[1] In Australia, biological disease-modifying anti-rheumatic drugs (bDMARDs) are considered when response to conventional DMARD therapy is inadequate.[1, 2] They are expensive and criteria have been developed to restrict their use on the Australian Commonwealth Government subsidised Pharmaceutical Benefits Scheme (PBS). Prior to 2010, to qualify for bDMARDs, a patient must have been treated for at least 12 weeks with: (i) weekly methotrexate; (ii) combination therapy with methotrexate and at least two other DMARDs; and (iii) received treatment with leflunomide or cyclosporine.[2] In August 2010, these restrictions were modified so they could be accessed by patients who failed to respond to 6 months of therapy, which must include at least 3 months of methotrexate (unless contraindicated) and 3 months of hydroxychloroquine, leflunomide or sulfasalazine.[2] We aimed to assess the influence of these changes on the use and expenditure on leflunomide and bDMARDs.

Purpose To examine the prescribing of prochlorperazine secondary to the prescribing of a medicine which could lead to symptoms for which prochlorperazine is indicated and commonly used. Given the range of potential hypotensive, sedative, dystonic and other extra-pyramidal side effects associated with prochlorperazine, its association with hip fracture was also examined. Methods Prescription/event sequence symmetry analyses were undertaken from 1st January 2003 to 31st December 2006, using administrative claims data from the Department of Veterans' Affairs, Australia. This method assesses asymmetry in the distribution of an incident event (either prescription of another medicine or hospitalization) before and after the initiation of prochlorperazine. Crude and adjusted sequence ratios (ASR) with 95% confidence intervals (CI) were calculated. Results A total of 34 235 persons with incident use of prochlorperazine were identified during the study period. Statistically significant positive associations were found for a number of commonly used medicines, including cardiovascular medicines, NSAIDs, opioids and sedatives and the subsequent initiation of prochlorperazine that ranged from 1.07 (95%CI 1.01–1.14) for diuretics to 1.50 (95%CI 1.40–1.61) for statins. Prescription event analysis showed a 49% (95%CI 1.19–1.86) increased risk of hospitalisation for hip fracture following dispensing of prochlorperazine. Conclusions Prescribers should consider the possible contributing role of newly initiated medicines with the potential to cause of dizziness, and where possible address this through dose reduction or cessation of the medicine, rather than prescribing prochlorperazine. Copyright © 2010 John Wiley & Sons, Ltd.

Background: Several studies have shown that the Australian Medicare-funded chronic disease management programme can lead to improvements in care processes. No study has examined the impact on long-term health outcomes. Aims: This retrospective cohort study assessed the association between provision of a general practitioner management plan and time to next potentially preventable hospitalisation for older patients with heart failure. Methods: We used the Australian Government Department of Veterans' Affairs (DVA) claims database and compared patients exposed to a general practitioner management plan with those who did not receive the service. Kaplan–Meier analysis and Cox proportional hazards models were used to compare time until next potentially preventable hospitalisation for heart failure between the exposed and unexposed groups. Results: There were 1993 patients exposed to a general practitioner management plan and 3986 unexposed patients. Adjusted results showed a 23% reduction in the rate of potentially preventable hospitalisation for heart failure at any time (adjusted hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.92; P = 0.0051) among those with a general practitioner management plan compared with the unexposed patients. Within one year, 8.6% of the exposed group compared with 10.7% of the unexposed group had a potentially preventable hospitalisation for heart failure. Conclusions: A general practitioner management plan is associated with delayed time to next potentially preventable hospitalisation for heart failure.

Background: Several organizations have raised concerns about the excessive secrecy maintained by regulatory authorities around the world, in particular in the European Union, France, UK, Canada and Australia. However, limited research has assessed the provision of information by regulatory authorities. This study aimed to assess the type and availability of information provided on the regulatory authorities’ websites. Methods: Regulatory authorities’ websites in six countries (USA, Canada, UK, France, Australia and New Zealand) and at the European level (European Medicines Evaluation Agency) were surveyed by two reviewers between October 2005 and March 2006. The survey instrument included 16 criteria organized in 3 domains: information on marketed drugs, information on assessment of drugs and information on drug safety. Results: There was a great variability in the level of information provided. Several medicine agencies did not provide basic information on marketed drugs, such as the summary of products’ characteristics. Information on registration dossiers was scant on most websites except that of the US Food and Drug Administration. The European Medicines Evaluation Agency, the French agency and the Canadian agency released public assessment reports that contained only summarized information of registration data. Only one country, Canada, provided full access to pharmacovigilance data. The periodic safety update reports that companies have to provide regularly to regulatory authorities were not available in any country. Conclusion: Information on which regulatory authorities base their decisions for licensing new drugs and the rationales behind these decisions were often not publicly available.

Background Statins are associated with skeletal muscle adverse effects. These are generally considered mild and reversible, with more severe toxicity occurring rarely. There is little known regarding statin myotoxicity in Aboriginal and Torres Strait Islander Australians who are at high cardiovascular risk and likely to receive statins. Aims To describe features of serious statin-associated myotoxicity (SSAM) occurring in Indigenous Australians and increase awareness of this condition. Methods Observational case series of SSAM in Aboriginal or Torres Strait Islanders. Cases were identified from personal clinical experience, referrals, reports to the Therapeutic Goods Administration, medical literature, an Internet search and reports from a histopathology laboratory. Information was collected onto a standardised data collection form. Results Fifteen cases of serious myotoxicity in Aboriginal or Torres Strait Islanders exposed to statins were identified from 2006 to 2012. The mean age was 55 (range 35–69). Painless weakness was the most common presentation. Interacting drugs were involved in seven cases. Biopsies were done in eight cases, three showed inflammatory polymyositis and five necrotising myositis. Three patients died and two had permanent severe disability. Resolution of symptoms after statin cessation was variable. Conclusions SSAM has occurred in the Indigenous Australian population with some fatalities. Awareness of the potential for SSAM is essential for early recognition and effective management to reduce probability of avoidable catastrophic harm. Safe, as well as effective use of medication, is essential for optimum health outcomes. Effective pharmacovigilance and therapeutic risk management are important for Aboriginal and Torres Strait Islander Australians.

Purpose: This study aimed to examine the effect of antidepressant use on persistence with newly initiated oral antidiabetic medicines in older people. Methods: A retrospective study of administrative claims data from the Australian Government Department of Veterans' Affairs, from 1 July 2000 to 30 June 2008 of new users of oral antidiabetic medicines (metformin or sulfonylurea). Antidepressant medicine use was determined in the 6 months preceding the index date of the first dispensing of an oral antidiabetic medicine. The outcome was time to discontinuation of diabetes therapy in those with antidepressant use compared with those without. Competing risks regression analyses were conducted with adjustment for covariates. Results: A total of 29,710 new users of metformin or sulfonylurea were identified, with 7171 (24.2%) dispensed an antidepressant. Median duration of oral antidiabetic medicines was 1.81 years (95% CI 1.72–1.94) for those who received an antidepressant at the time of diabetes medicine initiation, by comparison to 3.23 years (95% CI 3.10–3.40) for those who did not receive an antidepressant. Competing risk analyses showed a 42% increased likelihood of discontinuation of diabetes medications in persons who received an antidepressant (subdistribution hazard ratio 1.42, 95% CI 1.37–1.47, p

Cytochromes of the c-type contain hemes covalently attached via one or, more generally, two thioether bonds between the vinyls of heme b and the thiols of cysteine residues of apocytochromes. This post-translational modification relies on membrane-associated specific biogenesis proteins, referred to as cytochrome c maturation systems. At least three different versions (i.e. Systems I–III) are found on the positive side of bioenergetic membranes in different organisms and compartments. The present minireview is concerned with systems on the negative side of the membranes. It describes System IV, also referred to as cofactor assembly on complex C subunit B, for heme binding on cytochrome b6 through one thioether bond; this covalent heme is usually called ci. This system is found in all organisms with oxygenic photosynthesis but not in Firmicutes, although they also have a cytochrome b protein with an additional heme ci covalently attached via a single thioether bond.

Aim: To identify and evaluate the management and care of older people with multiple chronic health problems (MCHP). Methods: Administrative health data from the Department of Veterans' Affairs and bio-social data from the Australian Longitudinal Study of Ageing are used to determine prevalence of MCHP, treatment patterns and patient outcomes. Focus groups and semistructured interviews are used to gain patient and health practitioner perspectives. Results: The prevalence of MCHP in older people is high (65%) and is associated with increased use of health services, mortality and poorer self-rated health. Australian disease-specific guidelines fail to address MCHP, and treatment conflicts with the potential to cause harm, were common. Conclusion: Improvements in the care and management of older people with MCHP requires: a multifaceted approach, across the health-care system; better coordination of holistic, patient-centred multidisciplinary care; and effective communication and education of all stakeholders. The Health reform agenda in Australia provides an opportunity for change.

Purpose: Warfarin management in the elderly population is complex as medicines prescribed for concomitant diseases may further increase the risk of major bleeding associated with warfarin use. We aimed to quantify the excess risk of bleeding-related hospitalisation when warfarin was co-dispensed with potentially interacting medicines. Methods: A retrospective cohort study was undertaken over a 4-year period from July 2002 to June 2006 to examine bleeding risk associated with medications co-administered in patients taking warfarin using an administrative claims database from the Australian Department of Veterans' Affairs. All veterans aged 65 years and over who were new users of warfarin were followed until death or study end. Risk of bleeding was assessed using a Poisson GEE model adjusting for age, gender, socioeconomic status, co-morbidity index, previous bleeding related hospitalisations and indicators of health service use. Results: Overall, 17661 veterans who used warfarin at any time during the study period were included. The overall incidence rate of bleeding-related hospitalisations was 4.1 (95% CI 3.7-4.6) per 100 person-years in veterans who were not receiving potentially interacting medicines. Bleeding-related hospitalisation rates were significantly increased when warfarin was co-prescribed with low-dose aspirin (Adjusted rate ratio (AdjRR) 1.44, 95% CI 1.00-2.07), clopidogrel (AdjRR 2.23, 95% CI 1.48-3.36), clopidogrel with aspirin (AdjRR 3.44, 95% CI 1.28-9.23), amiodarone (AdjRR 3.33, 95% CI 1.38-8.00) and antibiotics (AdjRR 2.34, 95% CI 1.55-3.54). Conclusions: Models assessing bleeding risk with warfarin should take account of the range of potentially harmful medicine combinations used in elderly people with comorbid conditions.

An unexpected interaction with a thioglycerol matrix appeared in the liquid secondary ion mass spectrometry (LSIMS) spectra of two pyranosyl mercaptans [2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose (1a) and 2,3,4,6-tetra-O-acetyl-1,5-dithio-β-D-glucopyranose (1b)] often used to prepare glucosinolates, important thiosaccharidic metabolites found in all plants of the order Brassicales. The reactions, probably occurring in the solvent cage, seem to involve radical mechanisms.

Background Although incidence and mortality data are numerous, population-based studies including clinical and pathological characteristics of melanoma are rare. Objectives To describe the characteristics of melanoma in a rural French region during 2004–2008 and to identify differences according to age, gender and geographical areas. Methods Pathology reports of cutaneous melanomas diagnosed in residents from the Champagne-Ardenne region during 2004–2008 were anonymously collected from pathology laboratories. Demographic, clinical and pathological data were extracted and analysed by experts, including dermatologists, pathologists and epidemiologists. Results One hundred and seventy-seven in situ melanomas were diagnosed in 177 patients (female/male ratio : 1.72). Patients with head and neck in situ melanomas were older than patients with melanomas in other locations (72 vs. 54 years; P

Background: Endocrine therapies, aromatase inhibitors and tamoxifen, are commonly used as an adjuvant treatment in women with breast cancer. Aims: This study examined the trends in use of endocrine therapies in Australia between 1996 and 2008, including a comparison between Australian states. Methods: Prescription and expenditure data for tamoxifen and aromatase inhibitors (1996–2008) were obtained from the Drug Utilisation Sub-Committee. We converted prescription data to defined daily doses (DDD)/1000 population/day, the international unit of drug utilization. Utilization data in each state/territory (2003–2008) were adjusted for female population and age-standardized incidence rates of breast cancer. Results: Total utilization of endocrine therapies increased by 30% from 1.66 to 2.14 DDD/1000/day between 1996 and 2008. Over this period, there was a shift in use from tamoxifen to aromatase inhibitors which became the highest used products in 2008. Anastrozole was the most used aromatase inhibitor and its use increased markedly after being listed on Australia's national Pharmaceutical Benefits Scheme (PBS) for early breast cancer in 2005 (average increase of 0.14 DDD/1000/day per annum between 2005 and 2008). PBS expenditure for endocrine therapies increased by 265% from $16 million to $58 million between 1996 and 2008. Utilization of endocrine therapies was overall comparable between regions except that it was substantially lower in the Northern Territory. Conclusions: Use of aromatase inhibitors has overtaken use of tamoxifen in 2008. Further real-world effectiveness data are required to evaluate whether large associated increases in expenditures partly because of the higher costs of aromatase inhibitors are actually justified.

Diabet. Med. 27, 65–71 (2010) Abstract Objective To examine the impact of co-morbidity on health service utilization by Australian veterans with diabetes. Methods A retrospective cohort study was undertaken including veterans aged ≥ 65 years dispensed medicines for diabetes in 2006. Data were sourced from the Australian Department of Veterans’ Affairs health claims database. Utilization of preventive health services for diabetes was assessed, including claims for glycated haemoglobin (HbA1c) test, microabuminuria, podiatry services, diabetes care plans, medication reviews, case conferences, general practitioner (GP) management plans and ophthalmology/optometry services. Results Among the 17 095 veterans dispensed medicines for diabetes, more than 80% had four or more co-morbid conditions. Those with a higher number of co-morbidities were more likely to have had claims for optometry/ophthalmology services and podiatry services, but not for other services. Veterans with at least one diabetes-related hospital admission had no more claims for diabetes health services than those who had no diabetics-related hospital admission, except for endocrinology services (relative risk = 1.26, 95% confidence intervals 1.15–1.37). Veterans with dementia were less likely to have had claims for diabetes health services while patients with renal failure were more likely to have had claims for the services. Conclusions Low utilization of preventive diabetes care services is apparent in all co-morbidity groups. Patients with renal failure or dementia used more and less health services resources, respectively. Given the high mean age of this population, there may be valid reasons for the low use, such as competing health demands and patients’ preferences.

Behavioral manifestations mark the onset of disease expression in children with mucopolysaccharidosis type III (MPSIII, Sanfilippo syndrome), a genetic disorder resulting from interruption of the lysosomal degradation of heparan sulfate. In the mouse model of MPSIII type B (MPSIIIB), cortical neuron pathology and dysfunction occur several months before neuronal loss and are primarily cell autonomous. The gene coding for GAP43, a neurite growth potentiator, is overexpressed in the MPSIIIB mouse cortex, and neurite dystrophy was reported in other types of lysosomal storage diseases. We therefore examined the development of the neuritic trees in pure populations of MPSIIIB mouse embryo cortical neurons grown for up to 12 days in primary culture. Dynamic observation of living neurons and quantification of neurite growth parameters indicated more frequent neurite elongation and branching and less frequent neurite retraction, resulting in a relative overgrowth of MPSIIIB neuron neuritic trees, involving both dendrites and axons, compared with normal controls. Neurite overgrowth was concomitant with more than twofold increased expression of GAP43 mRNAs and proteins. Correction of the genetic defect leads to expression of the missing lysosomal enzyme, normal GAP43 mRNA expression, and reduced neurite outgrowth. These results indicate that heparan sulfate oligosaccharide storage modifies GAP43 expression in MPSIIIB cortical neurons with potential consequences for neurite development and neuronal functions that may be relevant to clinical manifestations.

Background and Objectives Autologous transplantation of either bone marrow (BM) or peripheral blood (PB) mononuclear cells (MNC) induces therapeutic angiogenesis in patients with peripheral arterial occlusive disease. Yet, the precise nature of the cellular product obtained from BM or PB and used in these therapeutic strategies remains unclear. Materials and Methods We have analysed the characteristics of BM-MNC and PB-MNC collected without mobilization and implanted in patients with critical limb ischaemia in a clinical trial of cellular therapy including 16 individuals treated by BM-MNC and eight by PB-MNC. These MNCs were characterized by cell counts, viability assessment and enumeration of leucocyte subsets, CD34 stem and endothelial progenitor cells (EPCs) (CD34+/CD133+/VEGF-R2+) by flow cytometry. Mean fluorescence intensity ratios were determined for CD34, CD133 and VEGF-R2 markers. All analyses were simultaneously performed in two laboratories. Results Accuracy and reliability between both laboratories were achieved. BM-MNCs and PB-MNCs were quantitatively and qualitatively heterogeneous and quite different from each other. Stem cells and EPCs were significantly more present in BM- compared to PB-cell products, but with similar mean fluorescence intensity ratios. A weakly positive correlation was observed between CD34+ cell counts and EPCs levels, confirming the specificity of cell identification. Conclusion A great variability was observed in cell product characteristics according to their origin and also between individuals. These data stress the necessity of optimal characterization of cell products especially in multicentric clinical trials.

Background: Drug promotion is one of the main factors that influence prescribing practices, but there are limited data available to quantify the relationship between drug advertising and prescription sales. Aim: To investigate the relationship between advertising for antihypertensive medicines and prescription sales in Australia between 1993 and 2002. Methods: Retrospective observational study. Advertising trends were monitored by counting the number of advertisements published in three Australian medical journals. Monthly prescription dispensing data were obtained from Drug Utilisation Sub-Committee and expressed as numbers of defined daily doses/1000 inhabitants/day. Linear regression and cross-correlations of time series were used in the analysis. Results: The drug classes the most heavily advertised, angiotensin-converting enzyme inhibitors and calcium channel blockers, were also the most prescribed during the study period, while the drugs the least advertised, thiazide diuretics and beta-blockers, were the least used. In 5 of the 7 main antihypertensive classes, the product the most advertised was also the most prescribed. Other factors, such as the publication of large clinical trials, may have also influenced prescribing patterns. Conclusion: Prescription sales of antihypertensives in Australia are correlated with promotional advertising. The newest and most expensive medicines may be chosen over older effective drugs by prescribers. New policies on drug promotion control need to be developed.

The aim of this study was to determine the course of pregnancy and the neonatal outcome of fetuses with cystic hygroma diagnosed at 10-14 weeks' gestation.Maternal and fetal data (nuchal translucency, karyotype, pregnancy outcome) in cases of fetal cystic hygroma, admitted or referred to our antenatal diagnostic centre, were prospectively entered into a computer database. Paediatric outcome was analysed when relevant.Some 72 fetuses had cystic hygroma. The mean size of the cystic hygroma was 7.9 mm. Chromosomal abnormalities were present in 52.7% of cases (38/72), including 14 cases (36.8%) of Down syndrome. A total of 34 chromosomally normal pregnancies gave rise to 18 live births (52.9%), with no visible serious structural abnormalities. The outcome of pregnancy was unfavourable (miscarriage, elective termination, serious structural abnormalities) in 77.7% of cases (56/72). The 18 live-born infants were followed up for 17-98 months. Sixteen infants developed normally, while 1 developed Noonan's syndrome and 1 had a urinary tract abnormality (pyelo-ureteral junction; PUJ).These data suggest that the prognosis of fetal cystic hygroma detected during the first trimester is poor, and show that sonographic evaluation of fetal nuchal translucency thickness in the first trimester is crucial.

To isolate the bound aroma compounds (BVC fraction) from Quercus petraea Liebl. heartwood, two different methods, XAD-2 adsorption and liquid–liquid extractions, were applied. Only the extraction procedures per-mitted, for the first time, the isolation and separation of this fraction. The free volatiles were first extracted with pentane:dicholoromethane in a ratio 2:1 (v[sol ]v) and the bound compounds with ethyl acetate. The bound aroma was determined directly by trifluoroacetamide (TFA) derivatives analysis, and indirectly by acid hydrolysis release of aglycons. Analyses were achieved, in each case, by GC–MS (EI and CI): several bound components were isolated and different aglycons identified, e.g. whisky lactones (cis + trans), eugenol, megastigmatrienones, vanillin and syringaldehyde. Each of these can be considered as a source of potential aroma; they have a specific odour in their free form. Copyright © 2005 John Wiley & Sons, Ltd.

This paper introduces a new fractionation method by selective extractions and precipitations making it possible to collect the three groups of oak heartwood extractable polymers in a single operation. The three families, lignins, polysaccharides and ellagitannins, were obtained and each was characterized by different techniques. We grouped together the techniques used to characterize these different oak wood groups of polymers: IR, GC, GC-MS, LC-MS, 1H NMR, SEC, MALDI-TOF/MS. This work focuses on the qualitative aspect only. Copyright © 2004 Society of Chemical Industry

The Tat pathway is a major route for protein export in prokaryotes and for protein targeting to thylakoids in chloroplasts. Based on in vitro studies, protein translocation through this pathway is thought to be strictly dependent on a transmembrane delta pH. In this paper, we assess the delta pH sensitivity of the Tat pathway in vivo. Using Chlamydomonas reinhardtii, we observed changes in the efficiency of thylakoid targeting in vivo by mutating the Tat signal of the Rieske protein. We then employed two endogenous pH probes located on the lumen side of the thylakoid membranes to estimate spectroscopically the delta pH in vivo. Using experimental conditions in which the trans-thylakoid delta pH was almost zero, we found no evidence for a delta pH dependence of the Tat pathway in vivo. We confirmed this observation in higher plants using attached barley leaves. We conclude that the Tat pathway does not require a delta pH under physiological conditions, but becomes delta pH sensitive when probed in vitro/in organello because of the loss of some critical intracellular factors.

To study the biology and repair capacities of mouse oligodendroglial cells, we established cultures of cells purified from neonatal wild-type and 9.6-kb MBP-LacZ transgenic newborn mice cerebral hemispheres as free-floating aggregates in the continuous presence of neurblastoma conditioned medium (N1-B104). In vitro analysis indicated that the initial cell preparations were enriched in oligodendrocyte pre-progenitors that expressed PSA-NCAM and GAP-43 but not GD3, O4, NF68 or glial fibrillary acidic protein (GFAP) markers. These pre-progenitors required increased concentrations of insulin and progesterone to allow their survival in vitro. With time in culture, spheres composed of oligodendrocyte pre-progenitors became oligospheres enriched in oligodendrocyte progenitors expressing GAP-43 and GD3. As well as conserving bipotentiality in vitro, these spheres were able to form myelin in vivo after transplantation into the neonatal shiverer mouse brain. Thus, the oligosphere strategy is a powerful method for generating large populations of mouse oligodendrocyte pre-progenitors and progenitors. The ability to generate oligospheres from transgenic mice will be instrumental in the further dissection of the molecular and cellular mechanisms of myelination and remyelination of the central nervous system. J. Neurosci. Res. 58:735–751, 1999. © 1999 Wiley-Liss, Inc.

The composition of various commercial tannin extracts were determined by liquid secondary ion mass spectrometry (LSIMS). Spectra were obtained directly from tannin extracts without any pre-separation. Eight different tannin powders were analysed : three gallotannins (Chinese, Turkish, tara), three ellagitannins (sweet chestnut, pendunculata oak, sessile oak), one mixed hydrolysable tannin (myrabolans) and one proanthocyanidin (grape seeds). This method enabled the main molecules in these powders to be identified.

Meprobamate is a carbamate, main active metabolite of carisoprodol [1], used as an anxiolytic agent and prescribed in Europe and the USA. Carisoprodol is a prescribed centrally active muscle relaxant analgesic. Carisoprodol is extensively converted to meprobamate. Meprobamate plasmatic levels exceed those of carisoprodol 2.5 h after oral administration of 700 mg of carisoprodol to healthy volunteers [2]. Meprobamate is involved in 7% of psychotropic poisonings [3]. Meprobamate has a barbiturate-like mode of action at the GABAA receptor and at high concentrations is able to cause chloride ion infuse. Well-known toxic effects of a meprobamate overdose include central nervous system (CNS) depression, weakness, clonus and hyperactive reflexes, tachycardia, hypotension and respiratory depression. Meprobamate produces CNS-depressing symptoms [4]. Meprobamate intoxications are often serious and sometimes fatal (5%), resulting from haemodynamic disturbance and circulatory collapse, secondary to severe acute cardiac failure [3]. The mechanism of cardiac toxicity is unknown. An overdose of meprobamate results in coma, generally estimated by the Glasgow Coma Scale (GCS). Only one study, including few patients (n= 21), has evaluated the relationship between meprobamate plasmatic concentrations and GCS [5]. Classically, a nonsevere coma appears with meprobamate concentration between 60 and 120 mg l−1 and deep coma >120 mg l−1. We have studied the relationship between GCS and meprobamate plasma concentration in meprobamate intoxication and evaluated the pertinence of determining the meprobamate plasma level. We have reviewed all toxicological analyses made from January 2002 to September 2007. All patients with a plasma concentration of meprobamate higher than normal (>20 mg l−1) have been included. Blood samples were collected when the patient was admitted to the Emergency Department of the University Hospital. Meprobamate plasma concentrations and GCS were analysed. Meprobamate plasma concentrations were determined by a simplified, rapid and accurate gas chromatographic method [6], using a Delsi Instrument Series 30 gas chromatograph equipped with a flame ionization detector and split-splitless injection. GCS was classified into three groups: as severe group A (GCS 3–8); moderate group B (GCS 9–12); and mild group C (GCS 13–15). Statistical analysis was conducted using an analysis of variance (anova) and the Kruskal–Wallis test, with a level of significance P= 0.05. The research was conducted in compliance with the requirements of our Institutional Review Board. A total of 59 cases were collected. Mean age was 43 years (range 16–69) with a male : female ratio of 0.6. The mean plasma meprobamate concentration was 99.9 ± 13 mg l−1 (therapeutic range 10–25 mg l−1) with a maximal concentration of 271 mg l−1. Mean GCS was 7.1 ± 0.95 (range 3–15). The GCS partition was group A, n= 42; group B, n= 9; and group C, n= 8. In 87% of cases (n= 51), meprobamate had been ingested with concomitant drugs, mainly benzodiazepines (n= 35) or alcohol (n= 17). In 25 cases, the drug involved was the associated meprobamate/aceprometazine, brand name Mepronizine® in France. Meprobamate was the only drug detected in eight cases. Combination with tricyclic antidepressants was found in three cases. Concomitant ingestion of benzodiazepine was equally distributed among the three groups. Fifty-eight patients recovered. One fatal outcome was observed in a 57-year-old woman with a plasma level of meprobamate of 147 mg l−1, associated with a lethal concentration of propranolol of 1260 µg l−1, (therapeutic range 50–150 µg l−1). A high concentration of meprobamate was associated with low GCS (P= 0.0194) (Table 1). Table 1 Analysis by groups For patients with GCS = 3, meprobamate was detected in three cases, with a plasma concentration from 37 to 177 mg l−1. At a high level of consciousness (GCS = 15) a patient presented a meprobamate plasma concentration of 95 mg l−1. In the fatal case, the cause of death could not be attributed to meprobamate alone. According to the American Association of Poison Control Centers, propranolol is responsible for 71% of fatal β-blocker ingestion [7]. In our study, some interindividual variations were observed. Genetics differences have been studied only with carisoprodol. The study about CYP2C19 genotype and the pharmacokinetics of carisoprodol [8] concluded that there are no significant differences with respect to normal and nonfunctional CYP2C19 alleles in acute impairing effects of a single dose of carisoprodol. Conscious patients, with high meprobamate concentrations, are probably addicted to this drug. GCS, as a surrogate marker of meprobamate toxicity, is inferior to direct objective serum measurement and meprobamate levels, despite a high correlation based upon patient sample. Meprobamate concentration determination remains essential for the diagnosis of poisoning and ensures appropriate care of patients (electrocardiogram, intensive care). In our hospital, when meprobamate intoxication is suspected, we systematically determine the dosage of plasma meprobamate. This attitude may explain the absence of fatal outcomes.