Personalized prescribing: a new medical model for clinical implementation of psychotropic drugs.

The use of pharmacogenetic tests was already being proposed in psychiatry in the early 2000s because genetic factors were known to influence drug pharmacokinetics and pharmacodynamics. However, sufficient levels of evidence to justify routine use have been achieved for only a few tests (eg, major histocompatibility complex, class I, B, allele 1502 [HLA-B*1502] for carbamazepine in epilepsy and bipolar disorders); many findings are too preliminary or, when replicated, of low clinical relevance because of a small effect size. Although drug selection and dose adaptation according to cytochrome P450 genotypes are sound, a large number of patients need to be genotyped in order to prevent one case of severe side effect and/or nonresponse. The decrease in cost for genetic analysis shifts the cost: benefit ratio toward increasing use of pharmacogenetic tests. However, they have to be combined with careful clinical evaluations and other tools (eg, therapeutic drug monitoring and phenotyping) to contribute to the general aim of providing the best care for psychiatric patients

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Population Genetic-Based Pharmacokinetic Modeling of Methadone and its Relationship with the QTc Interval in Opioid-Dependent Patients.

Methadone is a μ-opioid agonist widely used for the treatment of pain, and for detoxification or maintenance treatment in opioid addiction. It has been shown to exhibit large pharmacokinetic variability and concentration-QTc relationships. In this study we investigated the relative influence of genetic polymorphism and other variables on the dose concentration-QTc relationship. A population model for methadone enantiomers in 251 opioid-dependent patients was developed using non-linear mixed effect modeling (NONMEM(®)). Various models were tested to characterize the pharmacokinetics of (R)- and (S)-methadone and the pharmacokinetic-pharmacodynamic relationship, while including demographics, physiological conditions, co-medications, and genetic variants as covariates. Model-based simulations were performed to assess the relative increase in QTc with dose upon stratification according to genetic polymorphisms involved in methadone disposition. A two-compartment model with first-order absorption and lag time provided the best model fit for (R)- and (S)-methadone pharmacokinetics. (S)-methadone clearance was influenced by cytochrome P450 (CYP) 2B6 activity, ABCB1 3435C>T, and α-1 acid glycoprotein level, while (R)-methadone clearance was influenced by CYP2B6 activity, POR*28, and CYP3A4*22. A linear model described the methadone concentration-QTc relationship, with a mean QTc increase of 9.9 ms and 19.2 ms per 1000 ng/ml of (R)- and (S)-methadone, respectively. Simulations with different methadone doses up to 240 mg/day showed that <8 % of patients presented with a QTc interval above 450 ms; however, this might reach 12 to 18 % for (R)- and (S)-methadone, respectively, in patients with a genetic status associated with a decreased methadone elimination at doses exceeding 240 mg/day. Risk factor assessment, electrocardiogram monitoring, and therapeutic drug monitoring are beneficial to optimize treatment in methadone patients, especially for those who have low levels despite high methadone doses, or who are at risk of overdosing

Reconstruction of atrial ectopic focal and Re-entrant excitations from body surface potentials. Insights from 3D virtual human atria and torso

Non-invasive electrocardiographic imaging has been seen as a painless and economic method to map the electrical functions of the heart. However, it is still a great challenge to obtain accurate reconstruction of cardiac electrical activity from body surface potentials (BSP) due to the ill-posed behaviour of the cardiac inverse-problem. Though some advances have been made in solving the inverse-problem, few studies have been conducted for the atria, which have dramatic differences to the ventricles in their anatomical structures and electrophysiological properties. It is unclear either how the spatial resolution of electrodes on the BSP and rapid excitation rates of atrial activation during atrial fibrillation affect the accuracy of the inverse-problem. In this study, we used a biophysically detailed model of the human atria and torso to investigate effects of multi-lead ECG on the accuracy of reconstructed atrial excitation pattern on the epicardiac surface during the time courses of atrial fibrillation induced by electrical remodelling. It was shown that the solution of the atrial inverse-problem was dependent on the spatial resolution of electrodes on the body surface. The solution was also influenced by the morphology of the AP, rate and types of atrial excitation as well as the implantation of variant orders of the Tikhonov regularization method

A Speech Distortion and Interference Rejection Constraint Beamformer

Signals captured by a set of microphones in a speech communication system are mixtures of desired and undesired signals and ambient noise. Existing beamformers can be divided into those that preserve or distort the desired signal. Beamformers that preserve the desired signal are, for example, the linearly constrained minimum variance (LCMV) beamformer that is supposed, ideally, to reject the undesired signal and reduce the ambient noise power, and the minimum variance distortionless response (MVDR) beamformer that reduces the interference-plus-noise power. The multichannel Wiener filter, on the other hand, reduces the interference-plus-noise power without preserving the desired signal. In this paper, a speech distortion and interference rejection constraint (SDIRC) beamformer is derived that minimizes the ambient noise power subject to specific constraints that allow a tradeoff between speech distortion and interference-plus-noise reduction on the one hand, and undesire d signal and ambient noise reductions on the other hand. Closed-form expressions for the performance measures of the SDIRC beamformer are derived and the relations to the aforementioned beamformers are derived. The performance evaluation demonstrates the tradeoffs that can be made using the SDIRC beamformer

Determination of the Enantiomers of Mianserin and its Metabolites in Plasma by Capillary Electrophoresis After Liquid—Liquid Extraction and On-Column Sample Preconcentration

Capillary electrophoresis has drawn considerable attention in the past few years, particularly in the field of chiral separations because of its high separation efficiency. However, its routine use in therapeutic drug monitoring is hampered by its low sensitivity due to a short optical path. We have developed a capillary zone electrophoresis (CZE) method using 2mM of hydroxypropyl-β-cyclodextrin as a chiral selector, which allows base-to-base separation of the enantiomers of mianserin (MIA), desmethylmianserin (DMIA), and 8-hydroxymianserin (OHMIA). Through the use of an on-column sample concentration step after liquid-liquid extraction from plasma and through the presence of an internal standard, the quantitation limits were found to be 5 ng/mL for each enantiomer of MIA and DMIA and 15 ng/mL for each enantiomer of OHMIA. To our knowledge, this is the first published CE method that allows its use for therapeutic monitoring of antidepressants due to its sensitivity down to the low nanogram range. The variability of the assays, as assessed by the coefficients of variation (CV) measured at two concentrations for each substance, ranged from 2 to 14% for the intraday (eight replicates) and from 5 to 14% for the interday (eight replicates) experiments. The deviations from the theoretical concentrations, which represent the accuracy of the method, were all within 12.5%. A linear response was obtained for all compounds within the range of concentrations used for the calibration curves (10-150 ng/mL for each enantiomer of MIA and DMIA and 20-300 ng/mL for each enantiomer of OHMIA). Good correlations were calculated between [(R) + (S)]-MIA and DMIA concentrations measured in plasma samples of 20 patients by a nonchiral gas chromatography method and CZE, and between the (R)- and (S)-concentrations of MIA and DMIA measured in plasma samples of 37 patients by a previously described chiral high-performance liquid chromatography method and CZE. Finally, no interference was noted from more than 20 other psychotropic drugs. Thus, this method, which is both sensitive and selective, can be routinely used for therapeutic monitoring of the enantiomers of MIA and its metabolites. It could be very useful due to the demonstrated interindividual variability of the stereoselective metabolism of MI

Could pharmacogenetic data explain part of the interindividual sensitivity to methadone-induced respiratory depression?

In this issue of Critical Care, Megarbane and colleagues present a case report of methadone-induced respiratory depression and conduct a toxicokinetic/toxicodynamic evaluation. An opioid-dependent patient receiving methadone maintenance treatment (daily dose 70 mg) was found unconscious after ingesting 240 mg methadone and 2 mg flunitrazepam. Significant improvement in consciousness was achieved after an intravenous bolus of 0.3 mg naloxone followed by a continuous infusion of naloxone at 0.3 mg/hour. In patients receiving methadone maintenance treatment, an occasional intake of two to four times the usual daily dose of methadone is not an exceptional occurrence. However, few such patients experience episodes of life-threatening respiratory depression. Here, we discuss whether recent pharmacogenetic data could help us to understand interindividual variability in sensitivity to respiratory depression and, ultimately, to predict which patients are most likely to be affected

Wearable Communications in 5G: Challenges and Enabling Technologies

As wearable devices become more ingrained in our daily lives, traditional communication networks primarily designed for human being-oriented applications are facing tremendous challenges. The upcoming 5G wireless system aims to support unprecedented high capacity, low latency, and massive connectivity. In this article, we evaluate key challenges in wearable communications. A cloud/edge communication architecture that integrates the cloud radio access network, software defined network, device to device communications, and cloud/edge technologies is presented. Computation offloading enabled by this multi-layer communications architecture can offload computation-excessive and latency-stringent applications to nearby devices through device to device communications or to nearby edge nodes through cellular or other wireless technologies. Critical issues faced by wearable communications such as short battery life, limited computing capability, and stringent latency can be greatly alleviated by this cloud/edge architecture. Together with the presented architecture, current transmission and networking technologies, including non-orthogonal multiple access, mobile edge computing, and energy harvesting, can greatly enhance the performance of wearable communication in terms of spectral efficiency, energy efficiency, latency, and connectivity.Comment: This work has been accepted by IEEE Vehicular Technology Magazin