An interstitial compartment is necessary to link the pharmacokinetics and pharmacodynamics of mivacurium.

BACKGROUND AND OBJECTIVE: The time course of action of mivacurium does not correlate with its rapid breakdown by plasma cholinesterase. Pharmacokinetic-pharmacodynamic (PK-PD) modelling was applied to obtain more insight in the concentration-effect relationship. METHODS: Fourteen patients between 25 and 55yr, undergoing non-major surgery, American Society of Anesthesiologists Grade I-II, were included. All patients received thiopentone/fentanyl/isoflurane/oxygen/nitrous oxide anaesthesia. Neuromuscular block was monitored mechanomyographically using single twitch stimulation (0.1 Hz). Mivacurium was administered as a short-term infusion, mean (standard deviation) duration 4.7 (1.0) min and dose 145 (33) microg kg(-1). Arterial blood samples were obtained, and plasma was analysed using high performance liquid chromatography. PK-PD modelling was performed using an iterative Bayesian two-stage approach, assuming that the trans-trans and cis-trans isomers are equally potent. RESULTS: A PK-PD model with an effect compartment linked to plasma did not fit to the data satisfactorily. A model using an interstitial space compartment between plasma and effect compartment fitted significantly better. Parameters (mean (percentage coefficient of variation)) of the best fitting model were: k(ip) 0.374 min(-1) (46%), k(ei) 0.151 min(-1) (36%), EC50 98 microg L(-1) (29%) and gamma 3.7 (22%). CONCLUSIONS: The PK-PD behaviour of mivacurium could be described using a model with an interstitial space compartment interposed between plasma and effect compartment. This model shows that the time course of mivacurium is mainly governed by the concentration decline in this interposed compartment and only indirectly related to the rapid plasma clearance.

No vasopressin cell loss in the human hypothalamus in aging and Alzheimer's disease.

The total number of immunocytochemically identified vasopressin (AVP) cells was determined morphometrically in the paraventricular (PVN) and dorsolateral part of the supraoptic nucleus (dl-SON) of the human hypothalamus in 30 subjects ranging in age from 15 to 97 years, including 10 Alzheimer's disease (AD) patients. The aim of the present study was to test the hypothesis that the increased activity of AVP neurons reported earlier is accompanied by an absence of cell loss in these nuclei in senescence and AD. The results show that numbers of immunoreactive AVP cells in the PVN and dl-SON do not decline during aging or in AD. During aging, the number of neurons expressing AVP even increased in the PVN of control subjects. The nuclear diameter of the AVP cells in the PVN and dl-SON showed an increase in old AD patients. It is concluded that no cell loss occurs in the AVP cell population in the PVN and dl-SON during aging and in AD, and that AVP expression increases in the PVN during normal aging, but not in AD.

Oxytocin cell number in the human paraventricular nucleus remains constant with aging and in Alzheimer's disease.

Total cell numbers in the paraventricular nucleus (PVN) were previously shown to remain unaltered with aging and in AD. The aim of the present study was to determine the aging pattern of the oxytocin (OXT) cell population in the PVN. For this purpose, the number of immunocytochemically identified oxytocin cells was determined in the PVN of the human hypothalamus in 20 control subjects ranging in age from 15 to 90 years and in 10 Alzheimer's disease (AD) patients aged 46 to 97 years. The results show that the number of OXT cells in the PVN is similar in males and females and remains unaltered in senescence and AD. It is concluded that the remarkable stability of the PVN in these conditions also applies for the subpopulation of OXT cells in this nucleus and that reports in the literature on diminished OXT secretion in AD do not seem to be based on a decrease in the number of OXT expressing neurons from the PVN.

Use of partial stimulus information in response processing.

We examined the reaction time benefit that is obtained when salient features of the stimulus set and response set correspond. Components of the event-related brain potentials were used to measure the timing of stimulus-related and response-related processes in order to determine the locus of this effect. Of particular importance was the development of a new index of selective response preparation, the corrected motor asymmetry (CMA). We found no evidence for the use of preliminary, partial stimulus information in response preparation. These results suggest that the benefit is located primarily in response selection processes and probably reflects a more efficient algorithm for stimulus-response translation. Also, we found trial-to-trial variability in the duration of response selection to be the major determinant of variability in reaction time, whereas the durations of subsequent response-related processes were relatively invariant. Implications of these results for discrete and continuous models of choice reaction performance are discussed.