Transmitted drug resistant HIV-1 and association with virologic and CD4 cell count response to combination antiretroviral therapy in the EuroSIDA Study.

OBJECTIVES: To investigate prevalence of transmitted drug-resistant human immunodeficiency virus (TDR) and factors associated with TDR and to compare virological and CD4 count response to combination antiretroviral therapy. METHODS: In this study, 525 mostly chronically infected EuroSIDA patients were included who had genotypic resistance tests performed on plasma samples collected while antiretroviral therapy naive. TDR was defined as at least one resistance mutation from a list proposed for genotypic TDR surveillance. Multivariable logistic regression was used to analyze factors associated with detection of TDR, with virological (viral load<500 copies/mL) and CD4 count response (>or=50% increase) to combination antiretroviral therapy at months 6-12. RESULTS: The overall prevalence of TDR was 11.4%, which was stable over 1996-2004. There were no significant differences in virological suppression (those resistant to at least one drug prescribed versus susceptible), adjusted odds ratio: 0.68 (95% confidence interval: 0.27 to 1.71; P=0.408) or CD4 count response, adjusted odds ratio: 1.65 (95% confidence interval: 0.73 to 3.73; P=0.231). CONCLUSIONS: Prevalence of TDR in antiretroviral-naive patients was found to be in line with other European studies. No significant differences were found in virological and CD4 count response after initiation of first-line combination antiretroviral therapy between resistant and susceptible patients, possibly due to the small number of patients with resistance and consequently low power.

Drug use and suicide attempts: the role of personality factors.

This study on suicide attempts is part of a large research project on dependent behavior in adolescents and young adults. 228 subjects aged 14-25 (107 "drug abusers," 121 controls) from the French speaking part of Switzerland were evaluated on the basis of a semi-structured interview (Mini International Neuropsychiatric Interview), enabling a DSM-IV diagnosis, and self-reports (SSS by Zuckermann, MMPI-2, IDI by Hirschfeld). 31.5% of "drug abuser" males and 41.2% of "drug abuser" females committed one or more suicide attempts. The results of a logistic regression show that the significant factor explaining suicide attempts in drug users is emotional reliance for males and experience-seeking for females.

Current trends in illegal drug use and drug related health problems in Switzerland.

As part of the evaluation of the Confederation's measures to reduce drug related problems, a review of available data on drug use and drug related problems in Switzerland has been conducted. Source of data included: population surveys (adults and teenagers), surveys among drug users, health statistics (drug related and AIDS related deaths, HIV case reporting, drug treatments) police statistics (denunciations for consumption). The aims of reducing the number of dependent hard drug users have been achieved where heroin is concerned. In particular, there seems to have been a decrease in the number of people becoming addicted to this substance. For all other illegal substances, especially cannabis, the trend is towards an increased use, as in many European countries. As regards dependent drug users, especially injecting drug users, progress has been made in the area of harm reduction and treatment coverage. This epidemiological assessment can be used in the discussions currently engaged about the revision of the Law governing narcotics and will be a baseline for future follow up of the situation.

iLOGP: A Simple, Robust, and Efficient Description of n-Octanol/Water Partition Coefficient for Drug Design Using the GB/SA Approach.

The n-octanol/water partition coefficient (log Po/w) is a key physicochemical parameter for drug discovery, design, and development. Here, we present a physics-based approach that shows a strong linear correlation between the computed solvation free energy in implicit solvents and the experimental log Po/w on a cleansed data set of more than 17,500 molecules. After internal validation by five-fold cross-validation and data randomization, the predictive power of the most interesting multiple linear model, based on two GB/SA parameters solely, was tested on two different external sets of molecules. On the Martel druglike test set, the predictive power of the best model (N = 706, r = 0.64, MAE = 1.18, and RMSE = 1.40) is similar to six well-established empirical methods. On the 17-drug test set, our model outperformed all compared empirical methodologies (N = 17, r = 0.94, MAE = 0.38, and RMSE = 0.52). The physical basis of our original GB/SA approach together with its predictive capacity, computational efficiency (1 to 2 s per molecule), and tridimensional molecular graphics capability lay the foundations for a promising predictor, the implicit log P method (iLOGP), to complement the portfolio of drug design tools developed and provided by the SIB Swiss Institute of Bioinformatics.

Traitement médicamenteux actuel de l'épiepsie [Current drug treatment for epilepsy]

If one patient is diagnosed with epilepsy, the first treatment line is represented by medications, which allow a seizure control in at least 2/3 of patients. Following the steady development of new compounds, there are currently more than 20 antiepileptic agents on the market, and several more will appear in the near future. This review, focusing on the indications and pitfalls of the most used drugs, with a particular attention to the new ones, aims at improving the orientation among this multitude of options. Since there is almost no difference regarding the efficacy on seizures, it is rather the profile of comorbidities and possible (positive and negative) side effects that will allow to select the best antiepileptic drug for each specific clinical situation, permitting a patient-tailored approach.

Evaluation of the Adolescent Drug Abuse Diagnosis instrument in a Swiss sample of drug abusers.

OBJECTIVE: The aim of this study was to evaluate a French language version of the Adolescent Drug Abuse Diagnosis (ADAD) instrument in a Swiss sample of adolescent illicit drug and/or alcohol users. PARTICIPANTS AND SETTING: The participants in the study were 102 French-speaking adolescents aged 13-19 years who fitted the criteria of illicit drug or alcohol use (at least one substance--except tobacco--once a week during the last 3 months). They were recruited in hospitals, institutions and leisure places. Procedure. The ADAD was administered individually by trained psychologists. It was integrated into a broader protocol including alcohol and drug abuse DSM-IV diagnoses, the BDI-13 (Beck Depression Inventory), life events and treatment trajectories. RESULTS: The ADAD appears to show good inter-rater reliability; the subscales showed good internal coherence and the correlations between the composite scores and the severity ratings were moderate to high. Finally, the results confirmed good concurrent validity for three out of eight ADAD dimensions. CONCLUSIONS: The French language version of the ADAD appears to be an adequate instrument for assessing drug use and associated problems in adolescents. Despite its complexity, the instrument has acceptable validity, reliability and usefulness criteria, enabling international and transcultural comparisons.

Neuropathies périphériques d'origine médicamenteuse [Drug-induced peripheral neuropathy].

Drug-induced peripheral neuropathies are common, secondary to multiple drug classes, in particular chemotherapeutic agents. They have an important impact on patients' quality of life. In recent years, significant progress has been made in the understanding of some pathophysiological mechanisms. The use of more objective assessment tools should allow the development of individualized and more effective therapeutic strategies.

Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity.

Resistance to alkylating agents via direct DNA repair by O(6)-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O(6)-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies.

Pharmacovigilance in pregnancy: adverse drug reactions associated with fetal disorders.

Abstract Objective: To provide the first update on drug safety profiles and adverse drug reactions (ADRs) associated with fetal disorders from the Swiss national ADR database. Methods: We conducted a retrospective study using data from 202 pharmacovigilance reports on drug-associated fetal disorders from the Swiss national ADR database from 1990 to 2009. Evaluated aspects included administrative information on the report, drug exposure, and disorders. Results: The ADR reporting frequency on the topic of fetal disorders has increased during the last 20 years, from only 1 report in 1991 to a maximum of 31 reports in 2008. Nervous system drugs were the most frequently reported drug group (40.2%) above all antidepressants and antiepileptics. The highest level of overall drug intake could be observed for the 1st trimester (85.4%), especially for the first 6 weeks of pregnancy. The most frequently reported types of fetal disorders were malformations (68.8%), especially those of the musculoskeletal and circulatory systems. A positive association was discovered between antiepileptics and malformations in general and in particular of the circulatory system and the eye, ear, face, and neck. Conclusions: The results suggest that the nervous system drug group bears an especially high risk for malformations. The most commonly identified drug exposures can help focus pharmacoepidemiologic efforts in drug-induced birth defects.

Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features.

BACKGROUND: Differences exist between the proximal and distal colon in terms of developmental origin, exposure to patterning genes, environmental mutagens, and gut flora. Little is known on how these differences may affect mechanisms of tumorigenesis, side-specific therapy response or prognosis. We explored systematic differences in pathway activation and their clinical implications. MATERIALS AND METHODS: Detailed clinicopathological data for 3045 colon carcinoma patients enrolled in the PETACC3 adjuvant chemotherapy trial were available for analysis. A subset of 1404 samples had molecular data, including gene expression and DNA copy number profiles for 589 and 199 samples, respectively. In addition, 413 colon adenocarcinoma from TCGA collection were also analyzed. Tumor side-effect on anti-epidermal growth factor receptor (EGFR) therapy was assessed in a cohort of 325 metastatic patients. Outcome variables considered were relapse-free survival and survival after relapse (SAR). RESULTS: Proximal carcinomas were more often mucinous, microsatellite instable (MSI)-high, mutated in key tumorigenic pathways, expressed a B-Raf proto-oncogene, serine/threonine kinase (BRAF)-like and a serrated pathway signature, regardless of histological type. Distal carcinomas were more often chromosome instable and EGFR or human epidermal growth factor receptor 2 (HER2) amplified, and more frequently overexpressed epiregulin. While risk of relapse was not different per side, SAR was much poorer for proximal than for distal stage III carcinomas in a multivariable model including BRAF mutation status [N = 285; HR 1.95, 95% CI (1.6-2.4), P < 0.001]. Only patients with metastases from a distal carcinoma responded to anti-EGFR therapy, in line with the predictions of our pathway enrichment analysis. CONCLUSIONS: Colorectal carcinoma side is associated with differences in key molecular features, some immediately druggable, with important prognostic effects which are maintained in metastatic lesions. Although within side significant molecular heterogeneity remains, our findings justify stratification of patients by side for retrospective and prospective analyses of drug efficacy and prognosis.

Stage of change of cigarette smoking in drug dependent patients.

Nicotine cessation programmes in Switzerland, which are commonly based on the stage of change model of Prochaska and DiClemente (1983), are rarely offered to patients with illicit drug dependence. This stands in contrast to the high smoking rates and the heavy burden of tobacco-related problems in these patients. The stage of change was therefore assessed by self-administered questionnaire in 100 inpatients attending an illegal drug withdrawal programme. Only 15% of the patients were in the contemplation or decision stage. 93% considered smoking cessation to be difficult or very difficult. These data show a discrepancy between the motivation to change illegal drug consumption habits and the motivation for smoking cessation. The high proportion of patients remaining in the precontemplation stage for smoking cessation, in spite of their motivation for illicit drug detoxification, may be due to the perception that cessation of smoking is more difficult than illicit drug abuse cessation.

HIV-1 co/super-infection in intravenous drug users.

BACKGROUND: The frequency of HIV-1 co/super-infection is unknown despite their implications for public health and vaccine development. This issue was addressed during an epidemic of both CRF11 and B subtype among intravenous drug users (IVDUs). METHODS: Bulk sequencing of reverse transcriptase, protease and C2V3 regions and subtype-specific nested polymerase chain reaction (PCR) in plasma and proviral DNA were performed using baseline and follow-up samples collected in recently infected IVDUs between 1998-2002 and in IVDUs with chronic infection living in the same area and presenting an unexpected rise of viremia (> 1 log10). RESULTS: In 58 recently infected patients, three B/CRF-11 co-infections, 25 B, 28 CRF-11 and two other subtypes were detected at baseline. In the three co-infected patients, both CRF-11 and B were detected in plasma and proviral DNA and persisted during follow-up. B- and CFR-11-specific PCR performed on follow-up samples of 40 of 58 recently infected patients (median follow-up, 14.5 months) revealed a transient B super-infection in a patient initially infected by CRF-11. Five of 156 chronic IVDUs (total follow-up: 346 years) had an unexpected rise of viremia. In two of them, aviremic without treatment for years after an initial B infection, a symptomatic CRF-11 super-infection occurred and was associated with high viral load and a fall of CD4 cell count. CONCLUSIONS: In recently infected IVDUs, co-infection B/CRF-11 is relatively frequent (5%). In chronically infected IVDUs super-infection may be transient and may occur in patients controlling efficiently HIV infection by the initial strain.