Mirtazapine decreases stimulatory effects of reboxetine on cortisol, adrenocorticotropin and prolactin secretion in healthy male subjects

Reboxetine is a selective noradrenaline reuptake inhibitor, whereas mirtazapine acts as an antagonist at noradrenergic alpha(2), serotonin (5-HT2), 5-HT3 and histamine H-1 receptors. In a former study we could demonstrate an inhibitory impact of mirtazapine on cortisol secretion. In the present investigation, the influence of combined administration of 15 mg mirtazapine and 4 mg reboxetine on the cortisol ( COR), adrenocorticotropin ( ACTH), growth hormone (GH), and prolactin (PRL) secretion was examined in 12 healthy male subjects, compared to reboxetine alone ( 4 mg). In a randomized order, the subjects received reboxetine ( 4 mg) alone or the combination of reboxetine ( 4 mg) and mirtazapine ( 15 mg) at 8: 00 a. m. on two different days. After insertion of an intravenous catheter, blood samples were drawn 1 h prior to the administration of single reboxetine or the combination ( reboxetine and mirtazapine), at time of administration, and during the time of 5 h thereafter in periods of 30 min. Serum concentrations of COR, GH, and PRL as well as plasma levels of ACTH were determined in each blood sample by means of double antibody RIA, fluoroimmunoassay and chemiluminescence immunometric assay methods. The area under the curve (AUC) was used as parameter for the COR, ACTH, GH, and PRL response. For statistical evaluation, the Wilcoxon signed-ranks test was performed. There was a pronounced stimulation of COR, ACTH, GH, and PRL concentrations after single administration of reboxetine. When reboxetine was given in combination with mirtazapine, a significant reduction of the COR, ACTH, and PRL stimulation was observed whereas GH secretion patterns remained unchanged, compared to single administration of reboxetine. Apparently, the stimulatory effects of reboxetine on pituitary hormone secretion via noradrenergic mechanisms are counteracted in part by the alpha(2)-blocking properties of mirtazapine and its inhibitory influence on cortisol secretion. Copyright (C) 2004 S. Karger AG, Basel

Discretisations and Preconditioners for Magnetohydrodynamics Models

The magnetohydrodynamics (MHD) equations are generally known to be difficult to solve numerically, due to their highly nonlinear structure and the strong coupling between the electromagnetic and hydrodynamic variables, especially for high Reynolds and coupling numbers. In the first part of this work, we present a scalable augmented Lagrangian preconditioner for a finite element discretisation of the $\mathbf{B}$-$\mathbf{E}$ formulation of the incompressible viscoresistive MHD equations. For stationary problems, our solver achieves robust performance with respect to the Reynolds and coupling numbers in two dimensions and good results in three dimensions. Our approach relies on specialised parameter-robust multigrid methods for the hydrodynamic and electromagnetic blocks. The scheme ensures exactly divergence-free approximations of both the velocity and the magnetic field up to solver tolerances. In the second part, we focus on incompressible, resistive Hall MHD models and derive structure-preserving finite element methods for these equations. We present a variational formulation of Hall MHD that enforces the magnetic Gauss's law precisely (up to solver tolerances) and prove the well-posedness of a Picard linearisation. For the transient problem, we present time discretisations that preserve the energy and magnetic and hybrid helicity precisely in the ideal limit for two types of boundary conditions. In the third part, we investigate anisothermal MHD models. We start by performing a bifurcation analysis for a magnetic Rayleigh--B\'enard problem at a high coupling number $S=1{,}000$ by choosing the Rayleigh number in the range between 0 and $100{,}000$ as the bifurcation parameter. We study the effect of the coupling number on the bifurcation diagram and outline how we create initial guesses to obtain complex solution patterns and disconnected branches for high coupling numbers.Comment: Doctoral thesis, Mathematical Institute, University of Oxford. 174 page

Influence of mirtazapine on salivary cortisol in depressed patients

Unlike other antidepressants, mirtazapine does not inhibit the reuptake of norepinephrine or serotonin but acts as an antagonist at presynaptic alpha(2)-receptors, at postsynaptic 5-HT2 and 5-HT3 receptors, and at histaminergic H1 receptors. Furthermore, mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on salivary cortisol secretion was investigated in 12 patients (4 men, 8 women) suffering from major depression according to DSM-IV criteria. Patients were treated with mirtazapine for 3 weeks, receiving 15 mg mirtazapine on day 0, 30 mg on day 1 and 45 mg per day from day 2 up to the end of the study (day 21). Response to mirtazapine treatment was defined by a reduction of at least 50% in the Hamilton Rating Scale for Depression after 3 weeks of therapy. Salivary cortisol concentrations were measured before treatment (day -1), at the beginning of treatment (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Saliva samples were collected hourly from 08.00 until 20.00 h. The area under the curve values served as parameter for the salivary cortisol secretion. Following analysis of variance with a repeated measures design, tests with contrasts revealed a significant reduction of cortisol concentrations already after 1 day of mirtazapine treatment that was comparable in responders and nonresponders. In addition to new pharmacological approaches such as CRH1 receptor antagonists, mirtazapine therefore appears to be an effective strategy to decrease hypercortisolism and restore HPA system dysregulation in depression. However, the importance of the acute inhibitory effects of mirtazapine on cortisol secretion for its antidepressant efficacy has to be further clarified. Copyright (C) 2003 S. Karger AG, Basel

An Explicit Policy Lever for Patent Scope

Since its inception in 1982, the Federal Circuit has declined to take an overt role in setting patent policy. Dan Burk and Mark Lemley have observed that the court instead implicitly engineers patent policy through selective application of its patentability rules, which operate as policy levers. Recent decisions on the patentability of diagnostic and therapeutic methods illustrate a significant problem with this approach. By maintaining a façade of adjudicative rule formalism while tacitly manipulating its rules to approximate policy goals, the court perpetuates empirical uncertainty about the patent law\u27s practical effects. This Article proposes that the Federal Circuit use the patentable subject matter doctrine as an explicit policy lever for calibrating patent scope. By prompting litigants to directly address factual questions underlying patent disputes, expressly pragmatic adjudication may serve an information-eliciting function and shed light on longstanding theoretical debates. The Delaware Chancery Court\u27s adjudication of corporate law should serve as a model for the Federal Circuit\u27s adjudication of patent law. This Article identifies queries specifically pertinent to recent and ongoing cases involving medical methods and suggests that the Federal Circuit raise similar empirical questions with respect to software patents, business method patents, and other inventions whose patentability is contested

Endocrinological effects of high-dose Hypericum perforatum extract WS 5570 in healthy subjects

In this single-blind study, the effects of acute oral administration of high-dose Hypericum perforatum extract WS 5570 on the cortisol ( COR), adrenocorticotropic hormone ( ACTH), growth hormone (GH), and prolactin (PRL) secretions were examined in 12 healthy male volunteers. In a randomized order, the subjects received placebo or WS 5570 at several dosages (600, 900, and 1,200 mg) at 08.00 h on 4 different days. After insertion of an intravenous catheter, blood samples were drawn 1 h prior to administration of placebo or WS 5570 ( 600, 900, or 1,200 mg), at the time of administration, and during 5 h thereafter at intervals of 30 min. The serum concentrations of COR, GH, and PRL as well as the plasma levels of ACTH were determined in each blood sample by means of double antibody radioimmunoassay, fluoroimmunoassay, and chemiluminescence immunometric assay methods. The area under the curve value was used as parameter for COR, ACTH, GH, and PRL responses. Repeated-measures Anova revealed a significant stimulatory effect of WS 5570 on the ACTH secretion, whereas COR and PRL secretions were not significantly influenced. Moreover, there was a stimulatory peak of GH release 240 min after challenge with WS 5570 in some but not all volunteers, without reaching statistical significance in comparison with placebo. Mean arterial blood pressure and heart rate remained unchanged after administration of WS 5570. Apparently, WS 5570 at the dosages given in this study inconsistently causes endocrinological effects in healthy subjects by influencing central neurotransmitters. Copyright (C) 2004 S. Karger AG, Basel

Restoring the Genetic Commons: A Common Sense Approach to Biotechnology Patents in the Wake of KSR v. Teleflex

In this Article, I argue that a new approach to biotechnology patenting is necessary to fully realize the tremendous potential of recent advances in our understanding of the human genome. Part I places the gene patenting debate in context by highlighting the key landmarks that have shaped the biotechnology industry and outlining the products and stakeholders that comprise the industry. Part II describes the current state of the law on biotechnology patents, summarizing the Federal Circuit\u27s application of the various doctrines that collectively define the patent landscape\u27s parameters. In this Part, I explain how the Federal Circuit\u27s jurisprudence is tied to its inaccurate characterization of the person having ordinary skill in the art (PHOSITA) of biotechnology. Part III discusses theoretical concerns raised by the Federal Circuit\u27s jurisprudence regarding biotechnology discoveries and proposals that have been offered to ameliorate these concerns. In Part IV, I assert that the Supreme Court\u27s recent decision in KSR v. Teleflex should serve as the impetus for the Federal Circuit to abandon its rigid, dogmatic treatment of biotechnology in favor of a flexible approach that will allow the court to align patent doctrine with the current state of the art. The Supreme Court\u27s mandate to insert common sense into the obviousness analysis should compel the Federal Circuit to reexamine its depiction of the biotechnology PHOSITA. This may impact the court\u27s application of patent doctrines conceptually linked to the obviousness standard and lead to changes in both the number and scope of biotechnology patents. Such alterations in the patent landscape will have an overall positive effect on the biotechnology industry by alleviating inefficiencies and impediments to scientific and commercial progress engendered by the existing patent regime

Customized Medicine and the Limits of Federal Regulatory Power

The Food and Drug Administration (FDA) plays a dominant role in setting national policy and standards for the biomedical industry. Yet there are significant statutory constraints on the agency\u27s power. The FDA\u27s main implementing statute, the Federal Food, Drug, and Cosmetic Act (FDCA), bounds the scope of the FDA\u27s regulatory authority. The FDCA cabins FDA power in two important ways: (1) with a few notable exceptions, the FDA lacks power to regulate local activities that are not directly connected to interstate commerce, and (2) the agency may regulate product manufacturers, but not service providers. The FDA has long grappled with the limits of its authority to regulate conduct that encompasses the practice of medicine or the practice of pharmacy, such as physician off-label prescribing and drug compounding. These tensions will intensify as the life science industry evolves from a mass-market distribution scheme to a more customized, service-oriented business model. Autologous stem cell therapies and 3D-printed drugs and devices are two prominent examples of medical innovation that may evade the FDA\u27s purview. Sophisticated, organized patient advocacy groups that develop and share individualized treatments further expose the limits of the FDA\u27s statutory authority. These technological and social changes in medical product development and dissemination raise profound questions about the FDA\u27s future place within our contemporary healthcare regulatory system

Bifurcation analysis of a two-dimensional magnetic Rayleigh-B\'enard problem

We perform bifurcation analysis of a two-dimensional magnetic Rayleigh-B\'enard problem using a numerical technique called deflated continuation. Our aim is to study the influence of the magnetic field on the bifurcation diagram as the Chandrasekhar number $Q$ increases, and compare it to the standard (non-magnetic) Rayleigh-B\'enard problem. We compute steady states at a high Chandrasekhar number of $Q=10^3$ over a range of the Rayleigh number $0\leq \text{Ra}\leq 10^5$. These solutions are obtained by combining deflation with a continuation of steady states at low Chandrasekhar number, which allows us to explore the influence of the strength of the magnetic field as $Q$ increases from low coupling, where the magnetic effect is almost negligible, to strong coupling at $Q=10^3$. We discover a large profusion of states with rich dynamics and observe a complex bifurcation structure with several pitchfork, Hopf and saddle-node bifurcations. Our numerical simulations show that the onset of bifurcations in the problem is delayed when $Q$ increases, while solutions with fluid velocity patterns aligning with the background vertical magnetic field are privileged. Additionally, we report a branch of states that stabilizes at high magnetic coupling, suggesting that one may take advantage of the magnetic field to discriminate solutions.Comment: 14 pages, 7 figure