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Background: Standard treatment of chronic hepatitis C with pegylated interferon and ribavirin is associated with suboptimal virological response rates and substantial side effects. This study describes the in vitro and in vivo development of JTK-652, a novel pyrrolopyridazin-derived HCV infection inhibitor., Methods: JTK-652 was evaluated in multiple cell lines using an in vitro HCV infection model consisting of HCV pseudotype vesicular stomatitis virus bearing HCV E1/E2 envelope proteins. Safety, tolerability, pharmacokinetics and efficacy of JTK-652 were tested in a randomized double-blind and placebo-controlled study in healthy male volunteers (n=36) and chronic hepatitis C patients. A total of 10 HCV genotype-1-infected patients (treatment-naive [n=2] and treatment-experienced [n=8]) with HCV RNA>1x10(5) IU/ml received an oral dose of 100 mg JTK-652 three times daily or placebo (8:2 ratio) for 4 weeks., Results: JTK-652 showed potent inhibitory activity against HCV genotype 1a and 1b pseudotype viruses bearing HCV E1/E2 envelope proteins in HepG2 cells and in human primary hepatocytes. No significant clinical laboratory, vital sign, ECG or physical examination abnormalities were observed during the Phase I trial. JTK-652 was found to be well tolerated. No significant changes in HCV RNA levels compared with baseline were observed at the end of treatment., Conclusions: Although results from the preclinical studies indicated that JTK-652 has well-established antiviral properties and a Phase I clinical trial has showed that JTK-652 was safe and well tolerated at a 100 mg three times daily dose level, plasma HCV RNA levels in chronically HCV-infected patients did not decrease during 28 days of dosing at a 100 mg three times daily dose level.

The sickle cell trait-asymptomatic carriage is frequent in people originating from sub-Saharan Africa. Several host factors (including sickle cell anemia) have been previously reported to act upon the course of HIV disease. We studied the progression of infection in a cohort of African patients heterozygous for the sickle hemoglobin gene and harboring normal hemoglobin genes. No significant difference was evidenced between the two groups from this preliminary study.

Aims: We aimed to describe the pharmacokinetic interaction between phenytoin, a potent CYP3A4 and P-glycoprotein (P-gp) (ABCB1) inducer, and gefitinib, a CYP3A4, CYP2D6 and P-gp substrate., Methods: An open-label, randomized, two-phase crossover study was conducted. Eighteen healthy male volunteers (nine homozygous CC and nine homozygous TT as determined by their ABCB1 C3435T polymorphism in exon 26) received a single oral dose of 250 mg gefitinib alone or after 5 days treatment with phenytoin (5 mg kg(-1) daily). Gefitinib plasma concentrations were determined by high-performance liquid chromatography. Hepatic CYP3A4 activity was evaluated by the (14)C-erythromycin breath test (ERMBT) and the ABCB1 and CYP2D6 genetic polymorphisms were determined by the TaqMan allelic discrimination assay and long polymerase chain reaction, respectively., Results: Following treatment with phenytoin, mean gefitinib C(max) and AUC(0-infinity) decreased by 26 +/- 44% [95% confidence interval (CI) for the difference 5-48%, P= 0.005] and 47 +/- 26% (95% CI for the difference 34-60%, P= 0.001), respectively, and apparent oral clearance increased by 126 +/- 93% (95% CI for the difference 80-172%, P= 0.004). Concomitantly, phenytoin increased the mean ERMBT by 91 +/- 44% (95% CI 75-105%, P < 0.001) from baseline, but the extent of liver CYP3A4 induction was not correlated to the extent of interaction. Furthermore, this interaction was independent of ABCB1 genetic polymorphism. The CYP2D6 genotype was slightly but significantly related to gefitinib clearance (P= 0.04) during the control phase., Conclusions: The significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent of ABCB1 polymorphism, but may involve presystemic CYP3A-mediated intestinal first-pass.

Aims: To determine if amiodarone, highly lipophilic, accumulates in excess with respect to dose in fat tissue during long-term administration, and study if plasma and fat tissue concentrations are correlated with adverse effects., Methods: Trough concentrations of amiodarone and N-desethyl-amiodarone were measured simultaneously in plasma and fat tissue, in 30 consecutive patients treated with amiodarone for 3 months to 12 years. Subcutaneous adipose tissue was obtained by needle aspiration from lumbar and abdominal areas. Concentrations were measured by liquid chromatography-tandem mass spectrometry., Results: Plasma levels of amiodarone and N-desethyl-amiodarone were significantly correlated with daily maintenance doses (R= 0.52, P= 0.003). Amiodarone concentrations in fat tissue were four to 226 times (mean 55) higher than in plasma, and well correlated with plasma levels (R= 0.68, P < 0.001). Concentrations of amiodarone and N-desethyl-amiodarone in adipose tissue did not significantly increase with higher total cumulated doses or longer treatment duration. Nine of 12 patients who had received amiodarone for > or =2 years developed clinically important adverse effects, predominantly hypothyroidism (n= 6), compared with two of 18 patients treated for less time (relative risk 6.75; 95% confidence interval 1.8, 26). The incidence of those adverse effects was not significantly associated with amiodarone concentrations, whether in plasma or in adipose tissue., Conclusions: We found no evidence of excessive or unexpected accumulation of amiodarone in fat tissue on long-term administration. Late amiodarone adverse effects, particularly hypothyroidism, are associated with longer exposure times, but do not seem to be explained by higher concentrations in plasma or in fat tissue.

The clinical diagnosis of ocular toxoplasmosis is based on clinical features and biological tests: polymerase chain reaction (PCR) and the determination of intraocular specific antibody secretion (Goldmann-Witmer coefficient) on aqueous humor. Older patients may have a higher prevalence of ocular involvement and more severe ocular disease during the acute phase of recently acquired systemic infection because of altered cell-mediated immunity. Moreover, the genotype of the infecting parasite (particularly involving neotropical Type I Toxoplasma gondii strain), appears to be an important determinant of disease severity.

Drug-drug interactions (DDIs) contribute significantly to the incidence of adverse drug reactions. Important advances in the knowledge of human drug-metabolizing enzymes have fueled the integration of in vitro drug metabolism and clinical DDIs studies for use in drug development programs and in the clinical setting. The activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein are critical determinant of drug clearance, interindividual variability in drug disposition and clinical efficacy, and appears to be involved in the mechanism of numerous clinically relevant DDIs. Cell-based in vitro models are being increasingly applied in elucidating the pharmacokinetic profile of drug candidates during the preclinical steps of drug development. Human liver, intestinal samples and recombinant human CYP3A4 are now readily available as in vitro screening tools to predict the potential for in vivo DDIs. Although it is easy to determine in vitro metabolic DDIs, the interpretation and extrapolation of in vitro interaction data to in vivo situations requires a good understanding of pharmacokinetic principles. Clinicians and pharmacokineticists should recognize that in vitro models may not be clinically relevant in all situations. In the current article, research will be presented on drug metabolism and DDIs along with examples illustrating the utility of specific in vitro or in vivo approaches. In addition, the impact and clinical relevance of complexities such as dosing-route dependent effects, multi-site kinetics of drug-metabolizing enzymes and non-CYP determinants of metabolic clearance will be addressed.

Background: The antithrombotic, antiplatelet and endothelial activity of terutroban, a specific thromboxane prostaglandin receptor antagonist, was assessed in patients previously treated with aspirin for the prevention of ischemic stroke., Methods: This double-blind, parallel-group, 10-day study included 48 patients (age = 70.5 +/- 9.5 years) with cerebral ischemic event and/or carotid stenosis in 4 groups: terutroban 10 mg/day (n = 13), aspirin 300 mg/day (n = 12), terutroban 10 mg/day + aspirin 300 mg/day (n = 11) or clopidogrel 75 mg/day + aspirin 300 mg/day (n = 12). The measurements included parameters from an ex vivo model of thrombosis, platelet aggregation in platelet-rich plasma and plasma biomarkers of endothelial/platelet activation., Results: Between days 0 and 10, the mean cross-sectional surface of dense thrombus significantly decreased with terutroban (58%, p = 0.001), terutroban + aspirin (63%, p = 0.005) and clopidogrel + aspirin (61%, p < 0.05). On day 10, the value for terutroban was significantly lower than that for aspirin (p < 0.01) and was comparable to the dual therapy terutroban + aspirin or clopidogrel + aspirin. Similar results were found for total thrombus surface and platelet adhesion. Platelet aggregation induced by the specific thromboxane prostaglandin receptor agonist U46619 was almost completely inhibited on day 10 in both terutroban groups but not in the others. As regards markers of endothelial/platelet activation or lesions, thrombomodulin significantly increased and plasma soluble P selectin significantly decreased by day 10 in both terutroban groups, whereas the von Willebrand factor did not change significantly. Terutroban was found to be safe and well TOLERATED., Conclusions: Terutroban has demonstrated an antithrombotic activity that is superior to aspirin and similar to clopidogrel + aspirin; it induces a significant in vivo reduction in endothelial/platelet activation., (Copyright 2009 S. Karger AG, Basel.)

Objective: To determine the incidence of clinical venous thromboembolic events in home-care patients presenting an acute condition resulting in a significant and transitory reduction in mobility. To describe the measures implemented to prevent thromboembolic risks., Method: Prospective, multicenter, observational cohort study conducted among 2,895 general practitioners randomly drawn, who included the first 6 eligible patients: outpatients aged 40 years and over in which a reduction in mobility longer than 48 hours was expected due to acute medical condition. The primary endpoint was the incidence of deep venous thrombosis and symptomatic pulmonary embolism at 3 weeks., Results: 16,532 patients whose average age was 71 years were included between October 2002 and June 2003. The most common acute conditions resulting in a reduction in mobility were infections, acute rheumatologic diseases and falls without fracture. The incidences of deep venous thrombosis and symptomatic pulmonary embolism were respectively 1% (95% CI = 0.84-1.14) and 0.20% (95% CI = 0.13-0.27). Cancer and personal or family history of venous thromboembolic disease were independent risk factors for thromboembolic events. A thromboprophylaxis was initiated in 35% of patients. The main decisive factor for prescription was the personal history of venous thromboembolic disease., Discussion: The risk of symptomatic venous thromboembolic disease in outpatients whose mobility is reduced for medical reasons is close to that described in hospitalized patients.

Current guidelines for chronic Hepatitis C recommend peginterferon-alpha and ribavirin combination therapy for 24 or 48 weeks, based on viral factors (genotype, viral load), host factors (stage of liver disease) and virological response during treatment. The main goal of treatment is eradication of Hepatitis C virus (HCV) infection which is defined by HCV RNA negativity 24 weeks after end of treatment (i.e. sustained virological response, SVR). SVR can be achieved in up to 80% of patients. Most patients, however, experience adverse events during therapy which significantly affect drug compliance and treatment outcome. Several strategies have been evaluated in order to optimize outcome of current peginterferon-based therapy, including higher dosing of peginterferon and/or ribavirin, and adjusting therapy duration. Although some patients might benefit from these optimized treatment schedules, viral eradication remains unachievable in a substantial part of patients. In this perspective, there is a clear need for effective alternative or additional agents, especially as the burden of disease is expected to increase over the next decade. Potential novel antiviral targets are now being identified due to improved understanding of the HCV life cycle. Specifically targeted antiviral therapy for Hepatitis C (STAT-C) is in clinical development and has already shown to increase SVR rate. At this moment, however, SVR can only be achieved when combining new molecules with peginterferon therapy. The role of ribavirin has been questioned, but available evidence suggests that ribavirin has significant impact on treatment outcome and should therefore remain part of antiviral therapy. More than a decade of interferon-based therapy and potential new agents will be reviewed.

Proper use of drugs can be defined as the use of the right product, in a correct dosage, during an adequate length of time, for a given patient and provided he has no serious side effects. It is virtually impossible, with such a number of drugs, such a number of clinical situations to prescribe adequately without using references or guidelines. References may lead to a unique choice, when the diagnosis is certain and the drug to be given is unique. With a good initial and continuous medical education, doctors can take easily this type of decision. The Summary of Products Characteristics (SPC) helps them; by sticking to this fundamental reference, prescription might be more precise and safe. In a lot of clinical situations the choice between a large numbers of therapeutic strategies necessitates use of a guideline based on scientific knowledge. Finally, a given therapeutic strategy can be as effective as and considerably less expensive than another. In such cases, payers can drive doctors to the prescription of the less expensive strategy. Some difficulties are common to all references and guidelines., (Copyright © 2008 Société Française de Pharmacologie et de Thérapeutique. Publié par Elsevier Masson SAS.)

This pilot study investigated the immunomodulatory properties of seven probiotic strains. Eighty-three healthy volunteers aged 18-62 years consumed 2 x 10(10) CFU of bacteria or a placebo (maltodextrin) over 3 weeks (D0-D21). Subjects received an oral cholera vaccine at D7 and at D14; blood and saliva samples were collected at D0, D21 and D28. Serum samples were analyzed for specific IgA, IgG and IgM, and saliva samples were analyzed for specific IgA only, by ELISA. Statistical analyses were based on Wilcoxon's signed-rank test (intragroup analyses) and exact median t-test (intergroup analyses). Salivary analysis showed no difference in specific IgA concentrations between groups. Serum analysis indicated an effect of some of the tested strains on specific humoral responses. Between D0 and D21, IgG increased in two probiotic groups, for example, Bifidobacterium lactis Bl-04 and Lactobacillus acidophilus La-14, compared with controls (P=0.01). Trends toward significant changes in immunoglobulin serum concentrations compared with controls (P<0.1) were found for six out of the seven probiotic strains. In conclusion, some strains of probiotics demonstrated a faster immune response measured with serum immunoglobulin indicators, especially IgG, although overall vaccination was not influenced. Specific strains of probiotics may thus act as adjuvants to the humoral immune response following oral vaccination.

To move from a chemical entity to a real drug, preclinical trials have to be followed by phase I human studies to evaluate human toxicity, phase II studies to demonstrate the pharmacological activity in healthy volunteers and patients, followed by phase III studies to evaluate the real therapeutic efficacy. Then new drug authorization is granted for a product that shows good pharmaceutical quality and a positive risk-benefit ratio. However, full knowledge of a new drug is available only after several years of clinical use.

Background: High-dose peginterferon-alpha (PegIFN-alpha) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non-responders, although a higher and a longer dosing of PegIFN-alpha may intensify side effects., Methods: We randomized 53 patients, who previously failed with standard IFN-alpha+/-ribavirin, to a high-dose induction and an extended regimen with PegIFN-alpha-2b [3.0 microg/kg once weekly (q.w.) 12 weeks-->2.0 microg/kg q.w. 12 weeks-->1.5 microg/kg q.w. 48 weeks] or a standard regimen (1.5 microg/kg q.w. 48 weeks). All patients received daily weight-based ribavirin (800-1200 mg/day). The short-form 36 health survey was used to evaluate health-related quality of life (HRQL)., Results: Intention-to-treat analysis showed no significant difference in SVR rate (44% vs. 37%, P=0.62) and relapse rate (9% vs. 31%, P=0.17) between experimental and standard treatment. Overall, 80% of the [positive predictive value (PPV)] patients with rapid virological response (RVR, HCV-RNA negativity at week 4) achieved SVR. No significant dose-related differences in HRQL were seen between both groups. At baseline, genotype 2 or 3 [odds ratio (OR): 7.4, 95% confidence interval (CI): 1.4-33.3, P=0.01] and gamma-glutamyltransferase (GGT) levels <2 x ULN (upper limit of normal) (OR: 6.76, 95% CI: 1.5-31.3, P=0.009) were significantly associated with SVR. Multivariate logistic regression at week 4 showed that only baseline GGT <2 x ULN (OR: 7.3, 95% CI: 1.4-38.5, P=0.01) and RVR (OR: 15.6, 95% CI: 3.2-76.9, P<0.001) were independently predictive for SVR., Conclusion: Retreatment with PegIFN-alpha-2b and ribavirin for a minimum of 48 weeks should be considered in all patients unresponsive to previous IFN-based therapies. Baseline GGT values and RVR are highly predictive for retreatment outcome.

Background: Atrial fibrillation (AF) is the most frequent sustained arrhythmia. After restoration of normal sinus rhythm, the recurrence rate of AF is high. Antiarrhythmic drugs have been widely used to prevent recurrence, but the effect of these drugs on mortality and other clinical outcomes is unclear., Objectives: To determine, in patients who recovered sinus rhythm after AF, the effect of long-term treatment with antiarrhythmic drugs on death, stroke and embolism, adverse effects, pro-arrhythmia and recurrence of AF. If several antiarrhythmics were effective our secondary aim was to compare them., Search Strategy: The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Libary (Issue 2, 2005), MEDLINE (1950 to May 2005) and EMBASE (1966 to May 2005) were searched. The reference lists of retrieved articles, recent reviews and meta-analyses were checked. No language restrictions were applied., Selection Criteria: Two independent reviewers selected randomised controlled trials comparing any antiarrhythmic with a control (no treatment, placebo or drugs for rate control) or with another antiarrhythmic, in adults who had AF and in whom sinus rhythm was restored. Post-operative AF was excluded., Data Collection and Analysis: Two reviewers independently assessed quality and extracted data, on an intention-to-treat basis. Disagreements were resolved by discussion. Studies were pooled, if appropriate, using Peto odds ratio (OR)., Main Results: 45 studies met inclusion criteria, comprising 12,559 patients. All results were calculated at 1 year of follow-up. Class IA drugs (disopyramide, quinidine) were associated with increased mortality compared with controls (OR 2.39, 95% confidence interval (CI) 1.03 to 5.59, P = 0.04, number needed to harm (NNH) 109, 95% CI 34 to 4985). Other antiarrhythmics did not modify mortality. Several class IA (disopyramide, quinidine), IC (flecainide, propafenone) and III (amiodarone, dofetilide, dronedarone, sotalol) drugs significantly reduced recurrence of AF (OR 0.19 to 0.60, number needed to treat 2 to 9), but all increased withdrawals due to adverse affects (NNH 17 to 36) and all but amiodarone and propafenone increased pro-arrhythmia (NNH 17 to 119)., Authors' Conclusions: Several class IA, IC and III drugs are effective in maintaining sinus rhythm but increase adverse events, including pro-arrhythmia, and disopyramide and quinidine are associated with increased mortality. Any benefit on clinically relevant outcomes (embolisms, heart failure, mortality) remains to be established.

The new treatments of orphan diseases must be assessed according to the methodologic rules of therapeutic trials, in order to ensure clinically and statistically significant evaluations: randomized controled trials, single primary end-point, statistically significant and clinically relevant efficience. Although these rules may be relaxed in orphan diseases, they have to maintain the standard of therapeutic efficiency.

Objective: Xerostomia is a subjective sensation of mouth dryness often occurring as an unwanted effect of psychotropic drugs., Methods: The clinical efficacy and acceptability of a new oxygenated glycerol triester (OGT) oral spray (1 or 2 sprays up to 4 times daily) in the treatment of xerostomia was compared with those of a commercially available artificial saliva substitute (ASS [Saliveze]) in a 2-week, open-labeled, randomized, parallel-group study. Clinical assessment of xerostomia included evaluation of mouth dryness by means of a 10-cm-long visual analog scale, objective blinded assessment of the oral tissue condition by a dental hygienist by means of a 4-point ordinal scale, and subjective patient-based assessment of dry mouth symptoms by means of dichotomous responses to a questionnaire. [Day 14 - baseline] patient-based mouth dryness score was the primary end point., Results: Seventy-four patients (41 women and 33 men, 44 +/- 15 years) undergoing long-term psychotropic drug treatment were consecutively enrolled. At day 14, OGT resulted in better efficacy than ASS in mouth dryness score (mean difference, 1.2 +/- 0.4; P = 0.006), speech difficulties (mean difference, 1.2 +/- 0.4; P = 0.005), taste (mean difference, 1.1 +/- 0.4; P = 0.02), and overall mouth condition (mean difference, 1.4 +/- 0.9; P = 0.005). Taste of OGT was better than that of ASS (mean difference, 1.4 +/- 0.6; P = 0.04), as was OGT acceptability (mean difference, 1.4 +/- 0.9; P = 0.005)., Conclusion: Oxygenated glycerol triester lubricant oral spray was superior to a commercially available ASS in improving xerostomia and overall condition of the oral tissue.

Objective: To assess the interest of a second computed tomography (CT) scan of the brain during hospitalization of stroke patients in an internal medicine department and study the characteristics of these patients., Method: This retrospective study included 110 patients diagnosed with stroke between January 1, 2002, and August 31, 2004 in an internal medicine department., Result: All patients had a brain CT scan soon after admission - within three hours, on average, of arrival at the hospital; however, the mean delay between the onset of symptoms and hospital arrival was 40 hours. Mean hospital stay was 19 days. Eighty patients (73%) had at least one more scan. Indications for these scans were: no acute cerebral ischemia on the initial image (34%), routine follow-up or reason not specified (34%), worsening of neurologic status (15%), before oral anticoagulation (5%), to search a tumor (5%), to look for a cause (4%), and clinic-radiologic discordance (3%). Only 29% of the indications had any diagnostic or therapeutic reason. Among these 80 patients, the repeat brain scan resulted in a change in the initial diagnosis for 4 patients (5%) and in a change of therapy for 11 (14%)., Conclusion: In our study, repeat CT imaging was frequently ordered in ischemic stroke, despite the not uncommon absence of any diagnostic or therapeutic reasons. To optimize the use of medical resources and avoid unnecessary imaging, it would be useful to identify subgroups of patients for whom repeat imaging might be of interest.

The quality of a therapeutic trial depends on several parameters. The ideal trial in prostate cancer should be a high-quality trial on a well-defined and significant population. The method used to calculate the number of subjects necessary should appear in the study. There should be a single and significant evaluation criterion and follow-up should be long given the natural history of the disease. Intention to treat is also a quality terion. Finally, the therapeutic class effect does not exist; therefore, the efficacy of inoma any new drug must be proven.

Objective: To describe the characteristics of hepatitis B (HBV) infection in HIV-infected patients and the impact of anti-HBV treatments., Patients and Methods: All the patients with past or present chronic HBV infection seen in October 2005 in 17 French hospitals were included. Data were retrospectively collected from their first visit in a time-dependent manner, through a detailed standardized questionnaire., Results: Among 477 HBV-infected patients, 261 (55%) were co-infected with HIV. The HBV-HIV co-infected patients underwent fewer serological, virological and histological evaluations. Initial positive HBe antigenemia (HBe Ag) was more frequent in these patients (57.9 versus 28.6%; P < 10), as was cirrhosis on the initial liver biopsy (17.9 versus 7.6%; P = 0.05). Throughout the mean 5-year follow-up, HBe Ag loss was less frequent (P = 0.04), as was HBe seroconversion (incidence rate 2.6 versus 10/100 patient-years; P < 10). HBe Ag loss was associated with fibrosis improvement (METAVIR score -0.5 +/- 0.4 versus +0.2 +/- 0.6 if persistent positive HBe Ag, P = 0.01). In co-infected patients on tenofovir, adefovir or interferon, HBe seroconversions were seen in patients on combined HBV treatment, the use of which is increasing (58% in 2005). Nevertheless, no significant difference in virological, immunological or biochemical evolution was observed between these different treatments., Conclusions: In HBV-HIV co-infected patients, the assessment of HBV infection still needs to be improved, the HBV wild-type remains predominant, and HBe Ag loss is rare and associated with a better histological evolution. There is insufficient evidence of the superiority of combined HBV treatment, and this still needs be demonstrated in long term studies.

Low-molecular-weight heparins (LMWHs) accumulate in patients with impaired renal function. As this accumulation depends on heparin chain length and subsequent reticulo-endothelial/renal elimination, LMWHs might have different pharmacodynamic profiles. The primary objective was to examine if any accumulation effect of two LMWHs, enoxaparin and tinzaparin, occurred after repeated administration of a prophylactic dose over eight days in elderly patients (age >75 years) with creatinine clearance between 20 and 50 ml/min and body weight <65Kg. Patients were openly randomized to two groups (enoxaparin 4,000 IU or tinzaparin 4,500 IU once daily). Anti-Xa was measured on day 1 and day 8. Blood samples were taken at 0, 2, 4, 5, 6, 9, 12, 16 and 24 hours. The primary end point was the accumulation factor calculated as a ratio between the maximal anti-Xa activity on day 1and day 8. Fifty-five patients were included (mean age 87.9 +/- 5.5). The creatinine clearance was 34.7 +/- 11.4 ml/min; the body weight was 52.3 +/- 8.6 kg. The accumulation factor defined was not significant for tinzaparin (1.05, p = 0.29) while it was significantly enhanced for enoxaparin (1.22, p < 0.0001). In this pharmacodynamic study performed in elderly patients with impaired renal function, a statistically significant accumulation effect was observed after eight days of prophylactic treatment with enoxaparin but not with tinzaparin, which are two LMWHs with different chain lengths. Trials based on clinical end points should be conducted to evaluate the clinical relevance of these observations.

Clinical trials are the foundation of therapeutic evaluation. Their interpretation and usefulness depend on their compliance with strict methodological rules. Departments of internal medicine admit patients with many different diseases, a variety that makes it difficult to organize and conduct clinical trials in their standard form. This article reviews the rules of clinical trials that are essential to their validity and reliability. The prospective randomized double-blinded clinical trial is the most scientifically rigorous method for assessing treatment. Rare diseases and those involving several specialties can and should be performed in accordance with the standard methodological rules, despite their particular aspects. This article considers ways to improve the participation of departments of internal medicine to future clinical trials.

To evaluate the ability of two graphologists and two practising internists not trained in graphology to differentiate letters written by subjects who have attempted to commit suicide by self-poisoning and healthy volunteers, we performed a maximal blind controlled study vs. healthy volunteers. Forty fully recovered patients who had attempted to commit suicide and 40 healthy volunteers wrote and signed a short letter or story not related to the parasuicide or their mental health status. The evaluators classified the 80 letters as 'suicide' or 'no suicide' in an intention-to-treat analysis. Letters expressing sadness were subsequently excluded for a per-protocol analysis. Correct diagnosis of suicide and of healthy controls was made in, respectively, 32 of 40 and 33 of 40 letters by the graphologists and in 27 of 40 and 34 of 40 letters by the internists. After the exclusion of 12 letters expressing sadness, the sensitivity, specificity, positive predictive value and negative predictive value were, respectively, 73, 88, 81 and 82% for the graphologists and 53, 89, 80 and 71% for the internists. Both classified the letters with significantly more effectiveness than chance (p < 0.001) with no statistically significant difference between the two groups of evaluators. We concluded that graphological analysis is able to differentiate letters written by patients who attempt suicide from those written by healthy controls. This technique shows an acceptable degree of accuracy and could therefore become an additional discharge or decision-making tool in Psychiatry or Internal Medicine.

Background: By inhibiting prostaglandins, aspirin may be deleterious in heart failure (HF) and/or may counteract angiotensin-converting enzyme (ACE) inhibitor efficacy. Conversely, clopidogrel has no effect on prostaglandin metabolism., Aim: To investigate the effect of aspirin and clopidogrel on brain natriuretic peptide (BNP) levels in HF patients treated with ACE inhibitors., Methods: 36 patients with stable HF (65+/-13 years, 24 males/12 females, NYHA class II to IV, ejection fraction <40%, 13 with coronary disease, all treated with ACE inhibitors) were enrolled in this prospective, double-blind study and randomised to aspirin 325 mg/day or clopidogrel 75 mg/day for 14 days. BNP was determined at day 0 and day 14., Results: 19 patients were randomised to aspirin and 17 to clopidogrel. Baseline characteristics were similar in both groups. BNP levels increased in the aspirin group from day 0 to day 14 (107+/-103 to 144+/-149 pg/ml, p=0.04) whereas clopidogrel had no effect (104+/-107 and 97+/-99 pg/ml respectively, p=0.61)., Conclusion: This study demonstrates an adverse effect of aspirin 325 mg/day on BNP plasma levels in HF patients treated with ACE inhibitors. In contrast clopidogrel 75 mg/day had no effect.

Introduction: Bleeding complications of vitamin K antagonist (VKA) therapy are currently the most frequent iatrogenic event in France., Objectives: The aim of the ISAM study, an international longitudinal observational survey was to evaluate the use of VKA treatment and the quality of laboratory monitoring in everyday medical practice., Methods: In France, a representative sample of general practitioners and cardiologists selected patients with nonvalvular atrial fibrillation who had been treated with VKA for at least 60 days during the past 12 months. Physicians and patients responded to standardized questionnaires collecting retrospective data for the previous year., Results: Overall, 43 general practitioners and 20 cardiologists recruited 278 patients who completed questionnaires. INR was at least 2 for 264 patients during the study period. During the year preceding inclusion, INR had been within the target range (i.e., between 2.0 and 3.0) 59% of the time and above 3.0 27%. Physicians reported having giving approximately half their patients written recommendations about the VKA dosage regimen, but only 3% supplied a specific VKA information and monitoring booklet. Most patients (65%) reported receiving information on VKA therapy from their general practitioners, although 18% said they had not been informed about their treatment, 44% did not know their target INR, and 66% were unaware that bleeding events were a matter of concern. Finally, 45% of patients reported carrying a card indicating that they were taking VKA., Conclusion: Overall, these results show that better education of both physicians and patients could help to improve management, appropriate use and laboratory monitoring of VKA treatment.

Background and Objectives: Paracetamol (acetaminophen) has occasionally been reported to interact with warfarin. The primary end-point of this study was to investigate whether paracetamol initiation potentiates the anticoagulant effect of warfarin and the mechanism of the interaction., Design and Methods: In a double-blind placebo-controlled, randomized, cross-over study, 20 patients on stable oral anticoagulant therapy with warfarin for at least 1 month were randomized to receive placebo or paracetamol 1g four times daily for 14 days. International Normalized Ratio (INR) and clotting factors activities were measured before the first administration and then on days 2, 4, 7, 9, 11,14., Results: Mean INR rose rapidly after the start of paracetamol and was significantly increased within one week of paracetamol intake compared to placebo, p=0.0002. The INR values reached a mean maximum of 3.45+/-0.78 with paracetamol versus 2.66+/-0.73 with placebo (p=0.03), corresponding to a maximum increase from baseline of 1.20+/-0.62 with paracetamol versus 0.37+/-0.48 with placebo (p<0.001). Together with the rise in INR on paracetamol treatment there were significant reductions in the vitamin K-dependent clotting factors II, VII, IX and X., Interpretation and Conclusions: The most plausible hypothesis to explain the in vivo interaction is that paracetamol (or its metabolites) interfere with enzymes involved in vitamin K-dependent coagulation factor synthesis. Paracetamol at 4 g daily (a dose higher than that used in clinical practice) potentiates the anticoagulant response produced by warfarin. Clinicians should be aware of this clinically significant and underestimated interaction.

Purpose: To prospectively compare the efficacy and safety of 4 vs 2 mg intravitreal triamcinolone acetonide (TA) injection for diabetic macular edema., Design: Interventional case series., Patients: Thirty-two patients with diabetic macular edema unresponsive to laser photocoagulation., Intervention: Patients were randomly assigned to receive 4 or 2 mg intravitreal TA in one eye (16 patients in each group)., Main Outcome Measures: The main outcome was central macular thickness (CMT) measured by optical coherence tomography (OCT) at four, 12, and 24 weeks. Secondary outcomes were gain in Early Treatment Diabetic Retinopathy Study (ETDRS) scores, intraocular pressure (IOP), cataract progression, and duration of effect., Results: Before injection, mean (+/- SD) CMT was 564.5 +/- 119 microm and 522.9 +/- 148.5 microm in the 4- and 2-mg groups, respectively. At four, 12, and 24 weeks after injection, it was 275.0 +/- 79.8, 271.4 +/- 128.7, and 448.7 +/- 146.4 microm, respectively, in the 4-mg group, and 267.3 +/- 82.4, 289.8 +/- 111.4, and 394.7 +/- 178.9 microm, respectively, in the 2-mg group. At no time was the difference in CMT between both groups statistically significant (P> 0.3). The between-group differences in the gain in the ETDRS score and in IOP were not statistically significant either. Diabetic macular edema recurred after a median period of 20 weeks vs 16 weeks in the 4- and 2-mg groups, respectively (P = 0.11)., Conclusions: In the short term, intravitreal injection of 4 or 2 mg TA does not have different effects on CMT, visual acuity, or IOP.

Background: Complications caused by skin lightening practices have not been systematically studied in Europe., Objective: Our aim was to assess the complications of skin lightening among people of African descent living in Paris., Methods: This was a descriptive study. All patients presenting with complications from skin lightening procedures underwent a complete clinical examination and were questioned about their practice., Results: Forty-six patients from various African countries (39 women, 7 men) presented with skin changes suggestive of side effects from skin lightening practices. The complications seemed mainly related to the use of clobetasol and hydroquinone., Limitations: The selection bias does not allow assessment of uncomplicated skin lightening., Conclusion: Complications arising from skin lightening practices represent a significant health problem for people of African descent living in Paris.

Objective: To assess the effectiveness of providing doctors with written thromboprophylaxis prescription aids based on current recommendations., Design: A prospective trial of specific anticoagulant prescription forms: a 1-day survey before and after the intervention in each centre., Setting: 30 Internal Medicine departments of Assistance Publique-Hôpitaux de Paris., Subjects: All inpatients were included, except those who were either admitted or discharged on the day of the survey, and those receiving curative anticoagulant treatment., Interventions: The study included three parts: (i) a 1-day baseline survey; (ii) over the following 3-month period, departments were randomized into two groups: all practitioners in wards allocated to the intervention group were required to systematically use specific anticoagulant prescription forms, whilst doctors in the control group continued prescribing according to their usual practices and (iii) a 1-day postintervention survey., Main Outcome Measure: The proportion of prescriptions in accordance with the recommendations., Results: 1,469 patients were included. The intervention produced a significant reduction in the frequency of over-prescriptions, from 25% to 14% of the patients who did not meet the guideline criteria (adjusted OR: 0.3; 95% CI: 0.1-0.8). Using specific forms did not improve under-prescription of anticoagulants. A little over 60% of the patients who met guideline criteria for thromboprophylaxis were prescribed anticoagulants in both intervention and control wards, either at baseline or after intervention., Conclusions: Multitargeted interventions using a variety of means and strategies should still be considered to improve prescriptions that may have a significant impact on health expenses and, most importantly, on patients outcomes.

Aim: Numerous intravenously-administered medications are also available in equally effective oral forms. To assess the number of avoidable intravenous infusions, we retrospectively analyzed consecutive infusions prescribed in a department of internal medicine., Methods: Between November and December 2004, we analyzed all patients who received at least one intravenous drug during hospitalization. Intravenous administration was considered unavoidable when prescribed for no more than 2 days in a patient unstable at admission, when oral administration or feeding was impossible, or when the drug was not available in oral form., Results: During the study period 133 patients were admitted to the department. In all, 65 infusions were prescribed, 30% of which lasted more than 2 days for no medical reason. Four intravenous antibiotics were prescribed in patients when their antibiotic susceptibility tests indicated that another oral antibiotic could easily be given. Infusions for 16 other patients continued longer than 48 hours, although the oral route was not contraindicated in these patients and the medication was available in oral form., Conclusion: Systematic analysis of the daily prescriptions may be helpful in preventing or shortening use of intravenous medications and thereby decreasing iatrogenic infections and injuries, length of hospitalization, and costs.

Purpose: To evaluate prospectively the efficacy and safety of one intravitreal injection of 4 mg triamcinolone acetonide for refractory diffuse diabetic macular edema., Methods: Seventeen patients with bilateral diabetic macular edema unresponsive to laser photocoagulation. In all patients, one eye was injected, and the other served as a control. The intervention consisted in intravitreal injection of 4 mg triamcinolone acetonide. The main outcome measure was central macular thickness (CMT) at 4, 12 and 24 weeks, measured by Optical Coherence Tomography. Secondary outcomes were Early Treatment Diabetic Rentinopathy Study (ETDRS) scores, intraocular pressure and cataract PROGRESSION., Results: Before injection, mean +/- SD CMT was 566.4 +/- 182.4 mum in injected eyes. Four, 12, and 24 weeks after injection, it was 228.4 +/- 47.5 mum, 210.9 +/- 87.2 mum and 358.5 +/- 160.5 mum respectively. CMT was significantly lower in injected eyes vs. control eyes except 24 weeks after injection because of a recurrence of macular edema in 9/17 injected eyes. Mean +/- SD gain in ETDRS score was significantly better in injected eyes vs. control eyes 4, 12 and 24 weeks after TA injection. In 9 of the 17 injected eyes, intraocular pressure exceeded 24 mmHg and was controlled by topical medication., Conclusion: In the short-term, intravitreal injection of triamcinolone effectively reduces macular thickening due to diffuse diabetic macular edema and improves visual acuity in most cases. The long-term effect of this treatment and predictive factors of visual recovery remain to be elucidated.

Patients with human immunodeficiency virus (HIV) infection who were native to sub-Saharan Africa but lived in France were less adherent to antiretroviral therapy during a visit back to Africa, compared with their level of adherence in France. This was mainly related to self-perceived insufficient support from family members and/or fear of the consequences of disclosure of their HIV infection status to their family.

Objectives: The study was performed to determine the incidence of symptomatic venous thromboembolism in outpatients with an acute medical event causing temporary reduced mobility. Risk factors for venous thromboembolism and thromboprophylaxis practices were also studied., Design: This was a prospective, observational, multicentre, cohort study., Setting: General practitioners randomly selected from a registry of 25,000 active representative doctors in France including eligible outpatients., Subjects: Outpatients aged at least 40 years anticipated to have reduced mobility for at least 48 h due to an acute medical event were eligible., Interventions: None required., Main Outcome Measures: Symptomatic deep-vein thrombosis and pulmonary embolism at 3 weeks were the main study end-points., Results: Overall, 16,532 evaluable patients of mean age 71 years were recruited between October 2002 and June 2003 by 2895 doctors. The main acute medical events leading to reduced mobility were infection, acute rheumatism and falls without fracture. The incidence rates (95% confidence interval) of symptomatic deep-vein thrombosis and pulmonary embolism were 1% (0.84-1.14) and 0.20% (0.13-0.27) respectively. Venous insufficiency in legs, cancer, and a personal or family history of venous thromboembolism were independent risk factors for venous thromboembolism. Pharmacological thromboprophylaxis was initiated in 35.0% (n=5782) of the patients. The principal driver of prescription was a personal history of venous thromboembolism., Conclusions: The risk of symptomatic venous thromboembolism in outpatients with reduced mobility for medical reasons is close to that reported in medical and surgical inpatients. This risk and the potential need for thromboprophylaxis should be taken into account by primary care doctors.

Aims: To evaluate the effects of combined antiretroviral drugs (HAART) on liver CYP3A4 activity using the [(14)C-N-methyl]-erythromycin breath test (ERMBT)., Methods: HIV-infected patients (31 women, 30 men) with mean (+/- SD) age of 38 +/- 9 years were enrolled and underwent complete clinical and laboratory evaluation. Patients were divided into five groups and were treated with two nucleoside analogues (NAs) and one of the following: nelfinavir alone (n = 13), any ritonavir-boosted protease inhibitor with (n = 8) or without (n = 13) nevirapine, nevirapine alone (n = 15), or a third NA (n = 12). Three or four ERMBTs were performed 7 days prior to (D-7) and at the beginning of treatment (D0), D14 (only for patients taking nevirapine) and on D28., Results: Mean baseline liver CYP3A4 activity displayed high interindividual variability (47%) but low intraindividual variability (15%). Women had 30% higher ERMBT values than men [2.7 +/- 1.3 vs. 1.9 +/- 0.7; 95% confidence interval (CI) 20.5, 49.5; P = 0.003]. The ERMBT data correlated with body weight, alpha- and beta-globulins and alanin aminotransferases (0.10 < r(s) < 0.20; P < 0.01). Whereas nevirapine had no effect on liver CYP3A4 activity, nelfinavir-based and ritonavir-boosted drug regimens inhibited it by 69% (95% CI 64.7, 72.9; P = 0.005) and by 95% (95% CI 93.3, 96.7; P = 0.001), respectively., Conclusion: Evaluation of the effect of HAART on liver CYP3A4 activity may aid in preventing inappropriate treatment regimens in HIV-infected patients.

Unlike solitary parenchymal cysts, chronic meningitis is unusual in patients with neurocysticercosis and may poorly respond to treatment. We report the case of neurocysticercosis characterized by severe headache and chronic eosinophilic meningitis occurring 30 years after infestation with Taenia solium. The patient showed considerable improvement following treatment with albendazole and prednisone.

Drugs used in oncology represent more than half of the innovative and costly drugs which are not covered by a Group Homogène de Soins (DRG type classification) within the context of the case-mix based payment system (termed T2A). For these drugs, good practice reference guidelines have been drawn up by scientific societies and registration agencies. Recognised indications, relevant indications and situations where the treatment should not be prescribed are defined by the National Institute of Cancer. The reference guidelines should lead towards the good use of these drugs and allow the sick funds to control prescriptions. They should evolve with time, which means that bibliographic monitoring and independent expert opinion is necessary to update them as science provides new data. Manufacturers are involved in this process which in no case should undermine developmental efforts leading to registration. The objective of this protocolisation is to allow all patients early and legitimate access to drugs representing real therapeutic progress. These reference guidelines should be integrated into the life-cycle of a drug and should give rise to new developments allowing the good use of cancer products in situations which have been properly validated.

Cataract surgery requires a satisfactory degree of mydriasis throughout the entire operation. A phase I, open-labelled, randomised, cross-over trial was conducted in 18 healthy volunteers to compare mydriasis obtained with subsequent administration of phenylephrine 10% and tropicamide 0.5% eyedrops or a new insoluble-matrix retropalpebral ophthalmic insert containing 5.38 mg phenylephrine and 0.28 mg tropicamide. Phenylephrine serum concentrations were measured over 6 hr following each treatment administration. Secondary end-points included cardiovascular, general and local tolerance and quantification of bacterial colonisation of the conjunctiva and the cultured insert, respectively. When normalized to the pupil diameter after conventional treatment, the diameter achieved with the insert was 1.13 (95% confidence interval, 0.94-1.48, P=0.38). Moreover, standard eye drops provided faster effective mydriasis than the insert, starting 30 min. as compared to 90 min. upon treatment administration (P<0.01, repeated-measures ANOVA). Phenylephrine concentrations remained almost undetectable for both treatments and no change in heart rate or blood pressure were observed throughout the study. Only three superficial punctuate keratitis were diagnosed with the insert and two with the eye drops. No significant bacterial contamination of conjunctiva swab and cultured insert was observed. The new insoluble-matrix retropalpebral ophthalmic mydriatic insert produced similar but delayed effective and prolonged mydriasis as compared to the standard delivery system. In addition to its potential usefulness in patients undergoing cataract surgery, such new ophthalmic delivery system may be an advantage in children who need to undergo fundus photography due to the single administration and excellent tolerance as well.

Background: A variety of antiarrhythmic drugs have been used to prevent recurrence of atrial fibrillation after conversion to sinus rhythm. We performed a systematic review to determine the effect of long-term treatment with those drugs on death, embolisms, adverse effects, and atrial fibrillation recurrence., Methods: We searched MEDLINE, EMBASE, the Cochrane Library (all up to May 2005), and the reference lists of retrieved articles. We included randomized controlled trials that compared any antiarrhythmic against control (placebo or no treatment) or another antiarrhythmic, for more than 6 months. Postoperative atrial fibrillation was excluded. Two evaluators independently reviewed the retrieved studies and extracted all data. Disagreements were resolved by discussion. All results were calculated at 1 year of follow-up., Results: Forty-four trials were included, with a total of 11 322 patients. Several class IA (disopyramide phosphate, quinidine sulfate), class IC (flecainide acetate, propafenone hydrochloride), and class III (amiodarone, dofetilide, sotalol hydrochloride) drugs significantly reduced recurrence of atrial fibrillation (number needed to treat, 2-9), but all increased withdrawals due to adverse effects (number needed to harm [NNH], 9-27) and all but amiodarone and propafenone increased proarrhythmia (NNH, 17-119). Class IA drugs, pooled, were associated with increased mortality compared with controls (Peto odds ratio, 2.39; 95% confidence interval, 1.03-5.59; P = .04; NNH, 109). No other antiarrhythmic showed a significant effect on mortality compared with controls. We could not analyze other outcomes because data were lacking., Conclusion: Class IA, IC, and III drugs are effective in maintaining sinus rhythm but increase adverse effects, and class IA drugs may increase mortality.