Therapeutisches Drug-Monitoring in der Psychiatrie : Kurze Zusammenfassung des neuen Konsensuspapiers der Arbeitsgruppe TDM der AGNP [Therapeutic drug monitoring in psychiatry : A brief summary of the new consensus paper by the task force on TDM of the AGNP].

In October 2011 the Task Force Therapeutic Drug Monitoring of the Association for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update (Pharmacopsychiatry 2011, 44: 195-235) of the first version of the consensus paper on therapeutic drug monitoring (TDM) published in 2004. This article summarizes the essential statements to make them accessible to a wider readership in German speaking countries.

Disposition of valganciclovir during continuous renal replacement therapy in two lung transplant recipients.

OBJECTIVES: To determine whether valganciclovir 450 mg every 48 h for cytomegalovirus (CMV) prophylaxis provides appropriate ganciclovir exposure in solid organ transplant recipients during continuous renal replacement therapy (CRRT). PATIENTS AND METHODS: Ganciclovir pharmacokinetics was intensively studied in two lung transplant recipients under valganciclovir 450 mg every 48 h over one dosing interval. In vitro experiments using blank whole blood spiked with ganciclovir further investigated exchanges between plasma and erythrocytes. RESULTS: Ganciclovir disposition was characterized by apparent total body clearance of 3.3 and 5.8 L/h, terminal half-life of 16.9 and 14.1 h, and apparent volume of distribution of 60.3 and 104.9 L in Patients 1 and 2, respectively. The observed sieving coefficient was 1.05 and 0.96, and the haemofiltration clearance was 3.3 and 3.1 L/h. In vitro experiments confirmed rapid efflux of ganciclovir from red blood cells into plasma, increasing the apparent efficacy of haemofiltration. CONCLUSIONS: A valganciclovir dosage of 450 mg every 48 h appears adequate for patients under CRRT requiring prophylaxis for CMV infection, providing concentration levels in the range reported for 900 mg once daily dosing outside renal failure.

Sensorimotor Plasticity after Music-Supported Therapy in Chronic Stroke Patients Revealed by Transcranial Magnetic Stimulation

BACKGROUND: Several recently developed therapies targeting motor disabilities in stroke sufferers have shown to be more effective than standard neurorehabilitation approaches. In this context, several basic studies demonstrated that music training produces rapid neuroplastic changes in motor-related brain areas. Music-supported therapy has been recently developed as a new motor rehabilitation intervention. METHODS AND RESULTS: In order to explore the plasticity effects of music-supported therapy, this therapeutic intervention was applied to twenty chronic stroke patients. Before and after the music-supported therapy, transcranial magnetic stimulation was applied for the assessment of excitability changes in the motor cortex and a 3D movement analyzer was used for the assessment of motor performance parameters such as velocity, acceleration and smoothness in a set of diadochokinetic movement tasks. Our results suggest that the music-supported therapy produces changes in cortical plasticity leading the improvement of the subjects' motor performance. CONCLUSION: Our findings represent the first evidence of the neurophysiological changes induced by this therapy in chronic stroke patients, and their link with the amelioration of motor performance. Further studies are needed to confirm our observations.

Successes and limitations of targeted cancer therapy in melanoma.

The treatment of stage IV melanoma has witnessed a very impressive pace of innovation in recent years, to a point where the management of these patients has very little in common to what was standard practice 5 years ago. If the gain in overall survival, the high response rates or the induction of a significant fraction of long survivors are all very exciting news for our patients and their families, the path that led to these discoveries is as important. Rather than empirical, the development of these new strategies has been extremely rational, based on state-of-the-art basic biology and immunology, exemplary translational research and, finally, hypothesis-driven targeted trials that led to rapid approval. In this review, we will cover all the new targeted therapies that have emerged as the results of these translational programs, focusing mainly on signaling pathway- and immune checkpoint-targeted therapies. Taken collectively, these new developments set the bar for a new paradigm in future translational and clinical research in both melanoma as well as other tumor types.

Smoking and life expectancy among HIV-infected individuals on antiretroviral therapy in Europe and North America.

BACKGROUND: Cardiovascular disease and non-AIDS malignancies have become major causes of death among HIV-infected individuals. The relative impact of lifestyle and HIV-related factors are debated. METHODS: We estimated associations of smoking with mortality more than 1 year after antiretroviral therapy (ART) initiation among HIV-infected individuals enrolled in European and North American cohorts. IDUs were excluded. Causes of death were assigned using standardized procedures. We used abridged life tables to estimate life expectancies. Life-years lost to HIV were estimated by comparison with the French background population. RESULTS: Among 17 995 HIV-infected individuals followed for 79 760 person-years, the proportion of smokers was 60%. The mortality rate ratio (MRR) comparing smokers with nonsmokers was 1.94 [95% confidence interval (95% CI) 1.56-2.41]. The MRRs comparing current and previous smokers with never smokers were 1.70 (95% CI 1.23-2.34) and 0.92 (95% CI 0.64-1.34), respectively. Smokers had substantially higher mortality from cardiovascular disease, non-AIDS malignancies than nonsmokers [MRR 6.28 (95% CI 2.19-18.0) and 2.67 (95% CI 1.60-4.46), respectively]. Among 35-year-old HIV-infected men, the loss of life-years associated with smoking and HIV was 7.9 (95% CI 7.1-8.7) and 5.9 (95% CI 4.9-6.9), respectively. The life expectancy of virally suppressed, never-smokers was 43.5 years (95% CI 41.7-45.3), compared with 44.4 years among 35-year-old men in the background population. Excess MRRs/1000 person-years associated with smoking increased from 0.6 (95% CI -1.3 to 2.6) at age 35 to 43.6 (95% CI 37.9-49.3) at age at least 65 years. CONCLUSION: Well treated HIV-infected individuals may lose more life years through smoking than through HIV. Excess mortality associated with smoking increases markedly with age. Therefore, increases in smoking-related mortality can be expected as the treated HIV-infected population ages. Interventions for smoking cessation should be prioritized.

Implementation of bayesian therapeutic drug monitoring in modern patient care

The variability observed in drug exposure has a direct impact on the overall response to drug. The largest part of variability between dose and drug response resides in the pharmacokinetic phase, i.e. in the dose-concentration relationship. Among possibilities offered to clinicians, Therapeutic Drug Monitoring (TDM; Monitoring of drug concentration measurements) is one of the useful tool to guide pharmacotherapy. TDM aims at optimizing treatments by individualizing dosage regimens based on blood drug concentration measurement. Bayesian calculations, relying on population pharmacokinetic approach, currently represent the gold standard TDM strategy. However, it requires expertise and computational assistance, thus limiting its large implementation in routine patient care. The overall objective of this thesis was to implement robust tools to provide Bayesian TDM to clinician in modern routine patient care. To that endeavour, aims were (i) to elaborate an efficient and ergonomic computer tool for Bayesian TDM: EzeCHieL (ii) to provide algorithms for drug concentration Bayesian forecasting and software validation, relying on population pharmacokinetics (iii) to address some relevant issues encountered in clinical practice with a focus on neonates and drug adherence. First, the current stage of the existing software was reviewed and allows establishing specifications for the development of EzeCHieL. Then, in close collaboration with software engineers a fully integrated software, EzeCHieL, has been elaborated. EzeCHieL provides population-based predictions and Bayesian forecasting and an easy-to-use interface. It enables to assess the expectedness of an observed concentration in a patient compared to the whole population (via percentiles), to assess the suitability of the predicted concentration relative to the targeted concentration and to provide dosing adjustment. It allows thus a priori and a posteriori Bayesian drug dosing individualization. Implementation of Bayesian methods requires drug disposition characterisation and variability quantification trough population approach. Population pharmacokinetic analyses have been performed and Bayesian estimators have been provided for candidate drugs in population of interest: anti-infectious drugs administered to neonates (gentamicin and imipenem). Developed models were implemented in EzeCHieL and also served as validation tool in comparing EzeCHieL concentration predictions against predictions from the reference software (NONMEM®). Models used need to be adequate and reliable. For instance, extrapolation is not possible from adults or children to neonates. Therefore, this work proposes models for neonates based on the developmental pharmacokinetics concept. Patients' adherence is also an important concern for drug models development and for a successful outcome of the pharmacotherapy. A last study attempts to assess impact of routine patient adherence measurement on models definition and TDM interpretation. In conclusion, our results offer solutions to assist clinicians in interpreting blood drug concentrations and to improve the appropriateness of drug dosing in routine clinical practice.

Toward a rational design of combination therapy in cancer.

By merging computational systems modeling and experimental approaches, we have uncovered treatments reprogramming pro-angiogenic monocytes present in breast tumor into immunologically potent cells capable of mediating an anti-tumor immune response. The unraveled pathways and ligands which underlie monocyte pro-angiogenic activity have a strong predictive value for breast cancer patient relapse - free survival.

Initiation of rivaroxaban in patients with nonvalvular atrial fibrillation at the primary care level: the Swiss Therapy in Atrial Fibrillation for the Regulation of Coagulation (STAR) Study.

BACKGROUND: Rivaroxaban has become an alternative to vitamin-K antagonists (VKA) for stroke prevention in non-valvular atrial fibrillation (AF) patients due to its favourable risk-benefit profile in the restrictive setting of a large randomized trial. However in the primary care setting, physician's motivation to begin with rivaroxaban, treatment satisfaction and the clinical event rate after the initiation of rivaroxaban are not known. METHODS: Prospective data collection by 115 primary care physicians in Switzerland on consecutive nonvalvular AF patients with newly established rivaroxaban anticoagulation with 3-month follow-up. RESULTS: We enrolled 537 patients (73±11years, 57% men) with mean CHADS2 and HAS-BLED-scores of 2.2±1.3 and 2.4±1.1, respectively: 301(56%) were switched from VKA to rivaroxaban (STR-group) and 236(44%) were VKA-naïve (VN-group). Absence of routine coagulation monitoring (68%) and fixed-dose once-daily treatment (58%) were the most frequent criteria for physicians to initiate rivaroxaban. In the STR-group, patient's satisfaction increased from 3.6±1.4 under VKA to 5.5±0.8 points (P<0.001), and overall physician satisfaction from 3.9±1.3 to 5.4±0.9 points (P<0.001) at 3months of rivaroxaban therapy (score from 1 to 6 with higher scores indicating greater satisfaction). In the VN-group, both patient's (5.4±0.9) and physician's satisfaction (5.5±0.7) at follow-up were comparable to the STR-group. During follow-up, 1(0.19%; 95%CI, 0.01-1.03%) ischemic stroke, 2(0.37%; 95%CI, 0.05-1.34%) major non-fatal bleeding and 11(2.05%; 95%CI, 1.03-3.64%) minor bleeding complications occurred. Rivaroxaban was stopped in 30(5.6%) patients, with side effects being the most frequent reason. CONCLUSION: Initiation of rivaroxaban for patients with nonvalvular AF by primary care physicians was associated with a low clinical event rate and with high overall patient's and physician's satisfaction.