comparison of methadone and levomethadone in long-term treatment

Background This study aimed to investigate the development of opioid tolerance in patients receiving long-term methadone maintenance treatment (MMT). Methods A region-wide cross-sectional study was performed focusing on dosage and duration of treatment. Differences between racemic methadone and levomethadone were examined. All 20 psychiatric hospitals and all 110 outpatient clinics in Berlin licensed to offer MMT were approached in order to reach patients under MMT fulfilling the DSM IV criteria of opiate dependence. In the study, 720 patients treated with racemic methadone or levomethadone gave information on the dosage of treatment. Out of these, 679 patients indicated the duration of MMT. Results Treatment with racemic methadone was reported for 370 patients (54.5 %), with levomethadone for 309 patients (45.5 %). Mean duration of MMT was 7.5 years. We found a significant correlation between dosage and duration of treatment, both in a conjoint analysis for the two substances racemic methadone and levomethadone and for each substance separately. These effects remained significant when only patients receiving MMT for 1 year or longer were considered, indicating proceeding tolerance development in long-term treatment. When correlations were compared between racemic methadone and levomethadone, no significant difference was found. Conclusions Our data show a tolerance development under long-term treatment with both racemic methadone and levomethadone. Tolerance development did not differ significantly between the two substances

Catechol-O-methyltransferase (COMT) Genotype Affects Age-Related Changes in Plasticity in Working Memory: A Pilot Study

Objectives. Recent work suggests that a genetic variation associated with increased dopamine metabolism in the prefrontal cortex (catechol-O-methyltransferase Val158Met; COMT) amplifies age-related changes in working memory performance. Research on younger adults indicates that the influence of dopamine-related genetic polymorphisms on working memory performance increases when testing the cognitive limits through training. To date, this has not been studied in older adults.Method. Here we investigate the effect of COMT genotype on plasticity in working memory in a sample of 14 younger (aged 24-30 years) and 25 older (aged 60-75 years) healthy adults. Participants underwent adaptive training in the -back working memory task over 12 sessions under increasing difficulty conditions. Results. Both younger and older adults exhibited sizeable behavioral plasticity through training ( < .001), which was larger in younger as compared to older adults ( < .001). Age-related differences were qualified by an interaction with COMT genotype ( < .001), and this interaction was due to decreased behavioral plasticity in older adults carrying the Val/Val genotype, while there was no effect of genotype in younger adults.Discussion. Our findings indicate that age-related changes in plasticity in working memory are critically affected by genetic variation in prefrontal dopamine metabolism

Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis

Rationale: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. Objectives: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. Methods: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. Results: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. Conclusions: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy

IntroductionA titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11–21 ng/ml) that are expected under the approved dose range (10–20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy.MethodsFollowing our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram.ResultsOf 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C).ConclusionBased on our findings, we propose a target range of 20–40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram’s reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873]

The Astropy Problem

The Astropy Project (http://astropy.org) is, in its own words, "a community effort to develop a single core package for Astronomy in Python and foster interoperability between Python astronomy packages." For five years this project has been managed, written, and operated as a grassroots, self-organized, almost entirely volunteer effort while the software is used by the majority of the astronomical community. Despite this, the project has always been and remains to this day effectively unfunded. Further, contributors receive little or no formal recognition for creating and supporting what is now critical software. This paper explores the problem in detail, outlines possible solutions to correct this, and presents a few suggestions on how to address the sustainability of general purpose astronomical software

Diclofenac Hypersensitivity: Antibody Responses to the Parent Drug and Relevant Metabolites

Background: Hypersensitivity reactions against nonsteroidal antiinflammatory drugs (NSAIDs) like diclofenac (DF) can manifest as Type I-like allergic reactions including systemic anaphylaxis. However, except for isolated case studies experimental evidence for an IgE-mediated pathomechanism of DF hypersensitivity is lacking. In this study we aimed to investigate the possible involvement of drug-and/or metabolite-specific antibodies in selective DF hypersensitivity. Methodology/Principal Findings: DF, an organochemically synthesized linkage variant, and five major Phase I metabolites were covalently coupled to carrier proteins. Drug conjugates were analyzed for coupling degree and capacity to crosslink receptor-bound IgE antibodies from drug-sensitized mice. With these conjugates, the presence of hapten-specific IgE antibodies was investigated in patients' samples by ELISA, mediator release assay, and basophil activation test. Production of sulfidoleukotrienes by drug conjugates was determined in PBMCs from DF-hypersensitive patients. All conjugates were shown to carry more than two haptens per carrier molecule. Immunization of mice with drug conjugates induced drug-specific IgE antibodies capable of triggering mediator release. Therefore, the conjugates are suitable tools for detection of drug-specific antibodies and for determination of their anaphylactic activity. Fifty-nine patients were enrolled and categorized as hypersensitive either selectively to DF or to multiple NSAIDs. In none of the patients' samples evidence for drug/metabolite-specific IgE in serum or bound to allergic effector cells was found. In contrast, a small group of patients (8/59, 14%) displayed drug/metabolite-specific IgG. Conclusions/Significance: We found no evidence for an IgE-mediated effector mechanism based on haptenation of protein carriers in DF-hypersensitive patients. Furthermore, a potential involvement of the most relevant metabolites in DF hypersensitivity reactions could be excluded

A 6% measurement of the Hubble parameter at z~0.45 : direct evidence of the epoch of cosmic re-acceleration

MM, LP and AC acknowledge financial contributions by grants ASI/INAF I/023/12/0 and PRIN MIUR 2010-2011 "The dark Universe and the cosmic evolution of baryons: from current surveys to Euclid". RJ and LV thank the Royal Society for financial support and the ICIC at Imperial College for hospitality while this work was being completed. LV is supported by the European Research Council under the European Community's Seventh Framework Programme FP7-IDEAS-Phys.LSS 240117. Funding for this work was partially provided by the Spanish MINECO under projects AYA2014-58747-P and MDM-2014-0369 of ICCUB (Unidad de Excelencia "Maria de Maeztu") Funding for SDSS-III has been provided by the Alfred P. Sloan Foundation, the Participating Institutions, the National Science Foundation, and the U.S. Department of Energy Office of Science.Deriving the expansion history of the Universe is a major goal of modern cosmology. To date, the most accurate measurements have been obtained with Type Ia Supernovae (SNe) and Baryon Acoustic Oscillations (BAO), providing evidence for the existence of a transition epoch at which the expansion rate changes from decelerated to accelerated. However, these results have been obtained within the framework of specific cosmological models that must be implicitly or explicitly assumed in the measurement. It is therefore crucial to obtain measurements of the accelerated expansion of the Universe independently of assumptions on cosmological models. Here we exploit the unprecedented statistics provided by the Baryon Oscillation Spectroscopic Survey (BOSS, [1-3]) Data Release 9 to provide new constraints on the Hubble parameter H(z) using the cosmic chronometers approach. We extract a sample of more than 130000 of the most massive and passively evolving galaxies, obtaining five new cosmology-independent H(z) measurements in the redshift range 0.3 < z < 0.5, with an accuracy of ~11–16% incorporating both statistical and systematic errors. Once combined, these measurements yield a 6% accuracy constraint of H(z = 0.4293) = 91.8 ± 5.3 km/s/Mpc. The new data are crucial to provide the first cosmology-independent determination of the transition redshift at high statistical significance, measuring zt = 0.4 ± 0.1, and to significantly disfavor the null hypothesis of no transition between decelerated and accelerated expansion at 99.9% confidence level. This analysis highlights the wide potential of the cosmic chronometers approach: it permits to derive constraints on the expansion history of the Universe with results competitive with standard probes, and most importantly, being the estimates independent of the cosmological model, it can constrain cosmologies beyond—and including—the ΛCDM model.PostprintPeer reviewe

The Berlin Shape Trail Test – validation of a new trail making test

Einleitung. Der Trail Making Test (TMT) ist eines der am häufigsten eingesetzten neuropsychologischen Instrumente in der klinischen Diagnostik kognitiver Störungen. Die Aufgabe besteht im Verbinden einer Zahlenfolge (TMT-A) bzw. im alternierenden Verbinden einer Zahlen- und einer Buchstabenfolge (TMT-B). Bedingt durch die alphabetische Folge beim TMT-B ergeben sich Limitationen hinsichtlich der Anwendbarkeit des Tests im interkulturellen Kontext sowie bei Analphabetismus. In der vorliegenden Arbeit wurde mit dem Berliner Shape Trail Test (B-STT) eine Variante des Trail Making Tests validiert, die auf Buchstaben als Stimulusmaterial verzichtet. Ziel der Studie war es, die Einflüsse demografischer Faktoren auf die Bearbeitungszeit im B-STT zu untersuchen und Reliabilität, Validität und Ökonomie des Verfahrens zu überprüfen. Methodik. Für die Studie wurden 235 gesunde Probanden im Alter von 20–80 Jahren und 118 Patienten im Alter von 65–80 Jahren, darunter 82 Patienten mit leichter kognitiver Störung (MCI) und 36 Patienten mit Demenz bei Alzheimerkrankheit (DAT), rekrutiert. Der B-STT wurde als Teil einer neuropsychologischen Testbatterie eingesetzt, die in jedem Falle den TMT A und TMT-B sowie subgruppenabhängig weitere Testverfahren enthielt. Ergebnisse. Bei den gesunden Probanden bestanden signifikante Zusammenhänge zwischen der Bearbeitungszeit im B-STT und dem Alter und Bildungsniveau, wobei eine langsamere Bearbeitung bei höherem Alter und geringerer Bildung beobachtet wurde. Die Test-Retest-Reliabilität war angemessen. Stichprobenübergreifend zeigten sich hohe Korrelationen zwischen den Bearbeitungszeiten im B-STT und im TMT-B, wobei der B-STT im Vergleich zum TMT-B schneller bearbeitet wurde. Die Bearbeitungszeiten von Patienten mit MCI, Patienten mit DAT und gesunden Probanden im gleichen Altersbereich unterschieden sich signifikant. Dabei zeigten die gesunden Probanden die schnellste und Patienten mit DAT die langsamste Bearbeitung. Analysen der Effektstärken bzw. Trennschärfe indizieren eine gute Diskriminierbarkeit der Untersuchungsgruppen. Schlussfolgerung. Der B-STT erweist sich als geeignetes Instrument in der neuropsychologischen Leistungsdiagnostik und darüber hinaus als valide Alternative zum TMT B. Durch die schnellere Bearbeitung besteht zudem ein Vorteil hinsichtlich der Testökonomie. Vor dem klinischen Einsatz in der Diagnostik kognitiver Störungen ist jedoch eine Normierung des B-STT erforderlich.Introduction. The Trail Making Test (TMT) is one of the most frequently used neuropsychological tasks for the clinical assessment of cognitive function. In the TMT, subjects are required to connect numbers (TMT-A) or to alternately connect numbers and letters (TMT B) in sequence. Owing to its reliance on the alphabetic sequence, the TMT-B is of limited use in a cross-cultural context and in the examination of patients with analphabetism. In the present study, the Berlin Shape Trail Test (B-STT), a new variant of the TMT which does not use letters as stimuli, is validated. The study aims to characterise the demographic influences on the completion time of the B-STT and to explore the reliability, validity, and test efficiency. Methods. 235 healthy subjects aged 20–80 years and 118 patients aged 65–80 years participated in the study. The patient group consisted of two subpopulations, 82 patients with mild cognitive impairment (MCI) and 36 patients with Alzheimer-type dementia (DAT). The B-STT was employed as part of a neuropsychological assessment battery, which consisted of TMT-A and TMT-B and, depending on the subpopulation, further cognitive testing procedures. Results. In healthy subjects, age and education were significantly correlated with completion time in the B-STT, with slower performance in older and less educated subjects. Test-retest reliability was adequate. In all groups, completion times of B-STT and TMT-B were highly correlated, while the B-STT was completed faster than the TMT-B. Completion times differed significantly between patients with MCI, patients with DAT, and healthy subjects of the same age. Fastest completion times were observed in healthy subjects, while patients with DAT required the most time. Effect size and power analyses indicated a good distinguishability between the groups. Conclusion. The B-STT has proved to be an adequate instrument in neuropsychological assessment and, beyond that, a valid alternative to the TMT-B. In addition, it has a distinct advantage with regard to test efficiency compared to the TMT-B. Prior to systematic application in clinical settings, however, normative data for the B-STT has to be collected