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Objective: Intracranial hemorrhage (ICH) is an antithrombotic treatment complication. Our study's goal is to assess the proportion of ICH occurring while the patient is on antithrombotic treatment. The secondary goal is to assess the proportion of "avoidable" ICH (anticoagulant overdosage, debatables indications)., Methods: We conducted a descriptive epidemiological single-center study of ICH during 2 years. We analyzed the type of ICH, the type of antithrombotic treatment, the level of anticoagulation and the relevance of antithrombotic treatment indication., Results: Of the 400 patients admitted for an ICH, 131 (33%) were treated by antithrombotic therapy: oral anti-vitamin K anticoagulants (VKA) in 14.1% of cases and antiplatelet agents in 15.1%. Of VKA patients, overdosage rate was 30.2%. The indication of antithrombotic therapy was debatable in 18.3% of cases., Conclusion: Our study highlights the frequency of ICH occurring on antithrombotic therapy and the significant proportion of "avoidable" ICH., (© 2013 Société Française de Pharmacologie et de Thérapeutique.)

Meprobamate poisoning are serious and sometimes fatal. Faced with a potential stop of marketing, we conducted a multicenter retrospective study to assess the severity criteria presented by patients admitted to the ICU for severe meprobamate poisoning, whether with alone form or in combination with aceprometazine. One hundred fourty-six patients have been enrolled between January 2005 and June 2011: 38 had a single meprobamate poisoning, 104 to meprobamate and aceprometazine and 4 to both forms. At admission, 88% of patients exhibited coma (Glasgow ≤ 7) and half of them a systolic blood pressure ≤ 90 mmHg. Mortality rate was 3%. Our results did not find any significant between-group difference, either in regard of clinical or biological severity criteria. These data argue for a cessation of marketing of all meprobamate-based specialities., (© 2012 Société Française de Pharmacologie et de Thérapeutique.)

Objectives: State of the art of antithrombotics and their use recommendations during pregnancy., Methods: A review, Results: Aspirin and heparins remain the safest molecules during pregnancy, and oral anticoagulants are still used for mechanical valves. Heparinoids are the methods of choice in case of heparin-induced thrombopenia but other molecules could find their place: fondaparinux at first and possibly the direct thrombin inhibitors. Thrombolysis may be used in case of life-threatening incident. At present, the new oral forms can not be used during pregnancy, Conclusions: During pregnancy, all antithrombotics, except the oral forms, can be used, but the low molecular weight heparins replacing the unfractionated ones in the treatment and prevention of venous thromboembolism remain the treatment of choice., (© 2011 Société Française de Pharmacologie et de Thérapeutique.)

Objective: Analyze the most frequently reported drug in iatrogenic hyponatremia, explaining the mechanism in question., Methods: Retrospective study on 54 notified cases between the Jan.1(st) 2003 and Dec. 31(st) 2009. The analysis focuses on drug classes, accountability and mechanism; risk factors, severity and the evolution of the case., Results: Fourty-nine cases have been retained, 75,5% of the time it was an inappropriate secretion of antidiuretic hormone (SIADH) involving a selective serotonin reuptake inhibitor (SSRI) in 15 cases, an anticonvulsant in 7 cases, a proton pump inhibitor (PPI) in 7 cases or other drugs in 11. The hypo-osmolar hypovolemic hyponatremia was 12.2% of cases, incriminating a thiazide diuretic once in two. The mechanism was different or indeterminate in 12.2% of cases. In 67% cases were serious. The evolution was often favourable., Conclusion: Drug induced hyponatremia can be serious. It must control natremia with patients at risk or symptomatic and conduct the etiological diagnosis., (© 2011 Société Française de Pharmacologie et de Thérapeutique.)

Recommendations have recently been published regarding the prescription of low-molecular-weight heparin (LMWH) during pregnancy in women at risk of thromboembolism. To assess how well these recommendations are followed, we retrospectively recorded all pregnancy consultations in a thrombosis unit for two years. Of the 26 women included (mean age 30 +/- 4.8 years), 81% presented with a history of thromboembolism, 35% thrombophilia, and 15% a history of pregnancy termination for medical reasons. Clinical follow-up concerned 17% of the women; 8% were given aspirin, 63% LMWH at prophylactic dosages, 4% combination of aspirin and prophylactic LMWH, and 8% were on curative LMWH. Neither thromboembolic nor neonatal events were observed. One case of termination of pregnancy for medical reasons was observed at the 5th month. Although we also took into account the gravity of previous thromboembolism, our prescriptions were globally in compliance with the recommendations. This approach has still to be validated with a decision-making tree.

The venous thromboembolic risk seems to be demonstrated in medical patients since the incidence of symptomatic and asymptomatic deep vein thrombosis (DVT) without any prophylactic methods is respectively about 50 per cent in stroke, 25 per cent in acute myocardial infarction (AMI) and 15 per cent in internal medicine. A synthesis of clinical trials performed in medical patients shows that prophylactic doses of heparins (unfractionated heparin or low molecular weight heparins) reduce the incidence of DVT by 40 to 60 per cent compared with the lack of any antithrombotic agents but without any significant effect on total mortality. Other antithrombotic agents such as antiplatelet agents seem to reduce the incidence of DVT by about 40 per cent associated with a significant decrease in total mortality of stroke or AMI. But the recommendations made on the basis of these results have to be extremely cautious since the number of medical patients included in clinical trials is quite limited compared with the surgical area. Moreover, each of these recommendations is not sufficiently proven. Thus more clinical trials have to be carried out with a placebo control group in internal medicine and an aspirin control group for stroke and AMI.

The development and evaluation of new drugs often rely on surrogacy. An intermediate outcome becomes a surrogate outcome if it fulfils certain criteria, it should be easier to measure compared with the clinical outcome, a statistical relationship should exist between the clinical outcome and the surrogate outcome, a relation should exist allowing prediction of the degree of clinical effect based on the measured effect on the surrogate outcome. Development and authorization of drugs today often rely on so-called surrogate outcomes. Is this use sound? The validity of such outcomes has been reviewed in different therapeutic areas: hypertension, venous thromboembolism, AIDS, osteoporosis, hepatitis C. Based on this review, a pragmatic strategy is proposed which allows for the validation and proper use of surrogate outcomes.

Heparin treatment of venous thromboembolic disease has been validated since 1960. Nevertheless no study was sufficient to determine an optimal therapeutic schedule between sub-cutaneous (SC) unfractionated heparin (UFH), intravenous (IV) UFH and low molecular weight heparin (LMWH). One meta-analysis showed a significant risk reduction of recurrent thromboembolic events (OR = 0.58, CI 95 per cent [0.34-0.99]) and a non-significant risk reduction of haemorrhagic events (OR = 0.78 [0.40-1.52]) with UFH SC compared to UFH IV, but homogeneity testing was significant (p < 0.001). Some discrepancy was shown between the results of the three metaanalyses which compared LMWH to UFH according to the selection criteria of clinical trials used. With an exhaustive selection, LMWH involved a non-significant risk reduction of recurrent thromboembolic events (OR = 0.66 [0.41-1.07], p = 0.09), and a non-significant risk reduction of haemorrhagic events (OR = 0.65 [0.36-1.16], p = 0.15). So no definitive conclusion could be drawn but it seems that UFH can be recommended whatever the administration route or LMWH for deep vein thrombosis treatment.

This study evaluated the effect of injection time on pharmacodynamic of a single subcutaneous bolus of nadroparine (7500 anti-Xa IC U) evaluated by anti-Xa activity (Hepaclot and Heptest) and by activated partial thromboplastin time (APTT by auto PTT reagent). 10 healthy male volunteers were studied at 4 different 24 hours periods with 4 different injection times (6 am, 12 am, 6 pm, 12 pm) and with a one week wash-out period between each period. No chronopharmacological variation of the anti-Xa activity evaluated by Hepaclot was found. However the anti-Xa activity evaluated by Heptest was higher at the sixth hour after 12 am injection (p = 0.0022). No difference on APTT values was observed whatever the injection time. So the injection time of nadroparine has a weak influence on anti-Xa activity and no effect on APTT; Before to conclude on the lack of chronopharmacological effect of nadroparine, it seems necessary to evaluate such a possibility with higher dosage, with sick and older subjects.