Receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling

receptor activation was evaluated using quinpirole as a paradigm compound. ), as well as plasma concentrations of 13 hormones and neuropeptides, were measured. Experiments were performed at day 1 and repeated after 7-day s.c. drug administration. PK/PD modelling was applied to identify the in vivo concentration-effect relations and neuroendocrine dynamics. receptor expression levels on the pituitary hormone-releasing cells predicted the concentration-effect relationship differences. Baseline levels (ACTH, prolactin, TSH), hormone release (ACTH) and potency (TSH) changed with treatment duration. agonists in clinical practice. Further development towards quantitative systems pharmacology models will eventually facilitate mechanistic drug development. BACKGROUND AND PURPOSE EXPERIMENTAL APPROACH KEY RESULTS CONCLUSIONS AND IMPLICATION

Sectorstructuur en economische groei: een eenvoedig groeimodel met zes sectoren van de Nederlandse economie in de periode na de Tweede Wereldoorlog

Economi

Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy

BACKGROUND-: Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that some cases of PPCM are part of the spectrum of familial DCM, presenting in the peripartum period. METHODS AND RESULTS-: We reviewed our database of 90 DCM families, focusing specifically on the presence of PPCM patients. Then, in a reverse approach, we reviewed 10 PPCM patients seen in our clinic since the early 1990s and performed cardiological screening of the first-degree relatives of 3 PPCM patients who did not show a full recovery. Finally, we analyzed the genes known to be most commonly involved in DCM in the PPCM patients. We identified a substantial number (5 of 90, 6%) of DCM families with PPCM patients. Second, cardiological screening of first-degree relatives of 3 PPCM patients who did not show full recovery revealed undiagnosed DCM in all 3 families. Finally, genetic analyses revealed a mutation (c.149A>G, p.Gln50Arg) in the gene encoding cardiac troponin C (TNNC1) segregating with disease in a DCM family with a member with PPCM, supporting the genetic nature of disease in this case. CONCLUSIONS-: Our findings strongly suggest that a subset of PPCM is an initial manifestation of familial DCM. This may have important implications for cardiological screening in such families

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D2 receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling

Background and PurposeBecause biological systems behave as networks, multi‐biomarker approaches increasingly replace single biomarker approaches in drug development. To improve the mechanistic insights into CNS drug effects, a plasma neuroendocrine fingerprint was identified using multi‐biomarker pharmacokinetic/pharmacodynamic (PK/PD) modelling. Short‐ and long‐term D2 receptor activation was evaluated using quinpirole as a paradigm compound.Experimental ApproachRats received 0, 0.17 or 0.86 mg·kg−1 of the D2 agonist quinpirole i.v. Quinpirole concentrations in plasma and brain extracellular fluid (brainECF), as well as plasma concentrations of 13 hormones and neuropeptides, were measured. Experiments were performed at day 1 and repeated after 7‐day s.c. drug administration. PK/PD modelling was applied to identify the in vivo concentration–effect relations and neuroendocrine dynamics.Key ResultsThe quinpirole pharmacokinetics were adequately described by a two‐compartment model with an unbound brainECF‐to‐plasma concentration ratio of 5. The release of adenocorticotropic hormone (ACTH), growth hormone, prolactin and thyroid‐stimulating hormone (TSH) from the pituitary was influenced. Except for ACTH, D2 receptor expression levels on the pituitary hormone‐releasing cells predicted the concentration–effect relationship differences. Baseline levels (ACTH, prolactin, TSH), hormone release (ACTH) and potency (TSH) changed with treatment duration.Conclusions and ImplicationsThe integrated multi‐biomarker PK/PD approach revealed a fingerprint reflecting D2 receptor activation. This forms the conceptual basis for in vivo evaluation of on‐ and off‐target CNS drug effects. The effect of treatment duration is highly relevant given the long‐term use of D2 agonists in clinical practice. Further development towards quantitative systems pharmacology models will eventually facilitate mechanistic drug development.Pharmacolog

Peripartum Cardiomyopathy: Euro Observational Research Program

Peripartum cardiomyopathy is a rare but potentially life-threatening form of heart failure affecting women late in pregnancy or in the first months after delivery. Peripartum cardiomyopathy is difficult to diagnose and its onset and progression are variable between individuals. The pathophysiology remains poorly understood, hence treatment options are limited and possibly harmful to the foetus. Furthermore, geographical incidence varies greatly and little is known about the incidence in Western countries. To gain further understanding of the pathophysiology and incidence of peripartum cardiomyopathy, the European Society of Cardiology initiated a study group to implement a registry. This review provides an overview of current insights into peripartum cardiomyopathy, highlights the need for such a registry and provides information about this Euro Observational Research Program

Development and testing of a fast fourier transform high dynamic-range spectral diagnostics for millimeter wave characterization

A fast Fourier transform (FFT) based wide range millimeter wave diagnostics for spectral characterization of scattered millimeter waves in plasmas has been successfully brought into operation. The scattered millimeter waves are heterodyne downconverted and directly digitized using a fast analog-digital converter and a compact peripheral component interconnect computer. Frequency spectra are obtained by FFT in the time domain of the intermediate frequency signal. The scattered millimeter waves are generated during high power electron cyclotron resonance heating experiments on the TEXTOR tokamak and demonstrate the performance of the diagnostics and, in particular, the usability of direct digitizing and Fourier transformation of millimeter wave signals. The diagnostics is able to acquire 4 GHz wide spectra of signals in the range of 136-140 GHz. The rate of spectra is tunable and has been tested between 200 000 spectra/s with a frequency resolution of 100 MHz and 120 spectra/s with a frequency resolution of 25 kHz. The respective dynamic ranges are 52 and 88 dB. Major benefits of the new diagnostics are a tunable time and frequency resolution due to postdetection, near-real time processing of the acquired data. This diagnostics has a wider application in astrophysics, earth observation, plasma physics, and molecular spectroscopy for the detection and analysis of millimeter wave radiation, providing high-resolution spectra at high temporal resolution and large dynamic range