Water-soluble propofol analogues with intravenous anaesthetic activity.

Propofol (2,6-diisopropylphenol) is a widely used intravenous anaesthetic that is formulated as an emulsion since it lacks water solubility. We report a range of water-soluble analogues of propofol, containing a para-alkylamino substituent, which retain good intravenous anaesthetic activity in rodents.

I.v. anaesthesia and EEG burst suppression in rats: bolus injections and closed-loop infusions.

We describe a system for monitoring and controlling i.v. anaesthesia in rats using burst suppression ratio (BSR) detection in the extradural EEG. After bolus injection, peak BSR values of 95% were achieved with propofol 8 mg kg-1, etomidate 3.5 mg kg-1 and alphaxalone 4.5 mg kg-1. Thiopental 32 mg kg-1 produced a peak BSR of 70% (larger doses were not tolerated). Recovery was fastest with propofol, followed by etomidate and alphaxalone with equal duration, and slowest with thiopental. In further experiments, a closed-loop infusion system maintained BSR accurately at targets of 30%, 50%, 70% or 90% for 60 min with propofol or etomidate. During these experiments the infusion rates were found to decrease with time, more so with etomidate (approximately 40%) than with propofol (approximately 20%). Recovery times were 2-3 times longer with etomidate than with propofol. This model demonstrated differences between i.v. anaesthetics and may be useful in screening new compounds in preclinical development.

Computer-controlled infusion of ORG 21465, a water soluble steroid i.v. anaesthetic agent, into human volunteers.

ORG 21465 has been found to possess anaesthetic properties in humans and its pharmacokinetics are known. We performed this study to confirm the characteristics associated with its administration and to define its pharmacodynamic profile, in particular to explore the relationship between sedation, anaesthesia, excitation and plasma drug concentrations. A water soluble preparation of ORG 21465 was administered to six male volunteers as a series of three 15-min computer-controlled, pharmacokinetic model-driven infusions targeting three exponentially increasing plasma concentrations: 0.5, 1 and 2 micrograms ml-1. The clinical characteristics of the resultant sedation and anaesthesia were observed. Plasma concentrations of ORG 21465 were measured during and for 500 min after the infusions and the EEG recorded. A sigmoid e-max effect compartment pharmacodynamic model was fitted to the plasma concentrations and an EEG derivative (spectral edge frequency (SEF)). Anaesthesia with ORG 21465 was associated with involuntary movements in all subjects. A steady state concentration of 1180 ng ml-1 depressed SEF by 50%, the Hill factor describing the sigmoid nature of the concentration-response curve was 1.42 and the equilibration rate constant of the biophase was 0.112 min-1. Anaesthesia with ORG 21465 was found to be unsatisfactory because of involuntary movements and slow equilibration with the biophase.

Non-linear dynamics of columns of cat visual cortex revealed by simulation and experiment.

Correlation images were derived from simultaneous recordings of 12 signals representing the synaptic activity at different layers of a column in cat visual cortex (area 18) and 12 signals representing the local average spiking activity at the same locations. Because the ongoing activity and the activity evoked by stroboscopic flashes yielded the same correlation image, ongoing activity is caused by an input to a column similar to flash-evoked activity and is thus not endogenous. Moving bar stimuli evoked bursts of oscillations (25-75 Hz band) in the correlation image. The rhythm of these oscillations was not related to any frequency component in the stimulus. In all correlation images we observed that synaptic activity in one layer resulted in simultaneous spiking activity in all layers with latency differences smaller than 2 ms (the sample interval used). Similar behaviour was observed in a simulation experiment where we 'realistically' modelled one column of visual cortex with 1000 three-compartmental neurons in 11 functional layers. When such a model column was tuned to yield a stable and excitable system with low ongoing activity, activation of any of the layers caused simultaneous activity in all 11 layers. Both the simulation and the experimental results suggest that a column can be regarded as a basic processing element sending the same information over all its outputs to other columns within the same cortical region, other visual areas and subcortical structures.

A random dipole model for spontaneous brain activity.

The statistical properties of the EEG and the MEG are described mathematically as the result of randomly distributed dipoles. These dipoles represent the interactions of cortical neurons. For certain dipole distributions, the first- and second-order moments of the electric and magnetic fields are derived analytically. If the dipoles are in a spherical volume conductor and have no preference for any direction, the variance of a differentially measured EEG-signal is only a function of the electrode distance. In this paper, the theoretically derived variance function will be compared with EEG- and MEG-measurements. It is shown that a dipole with a fixed position and a randomly fluctuating amplitude is an adequate model for the alpha-rhythm. An expression for the covariance between the magnetic field and a differentially measured EEG-signal is derived. This covariance is considered as a function of the magnetometer position, and is compared with the measurements of Chapman et al. [23]. The theory can be used to obtain a (spatial) covariance matrix of the background noise, which occurs in evoked potential measurements. Such a covariance matrix can be used to obtain a maximum likelihood estimator of the dipole parameters in evoked potential studies, to evaluate the merits of the so-called "Laplacian derivation," and for the interpolation of electromagnetic data.

Topography of occipital EEG-reduction upon visual stimulation.

Visual stimuli were designed to drive a high proportion of the neurons in restricted parts of the human visual cortex. These stimuli were used to examine changes in the ongoing EEG during visual stimulation. The topographic organization of these changes was studied. It was found that the EEG from those parts of the cortex that are exposed to the stimulus is strongly reduced in amplitude. This stimulus dependency is indicative that cortical processing results itself in a reduction of the ongoing EEG, presumably due to desynchronization of neurons. The method shows that ongoing EEG can be used for functional mapping of cortical areas and is therefore valuable in situations where stimulus locked activity can not be measured.

Visual stimulation reduces EEG activity in man.

Data are presented which show that background electric activity of the human brain is reduced by visual stimulation. Occipital EEG amplitude decreases 5-15% for all frequencies analyzed (0.2-40 Hz) upon pattern stimulation. The reduction is stimulus-specific, i.e. is the strongest for stimuli that activate a large number of visual cortical neurons.

A practical method for determining electrode positions on the head.

When multi-channel EP recordings are used for source localization, the electrode positions have to be determined with respect to a common reference frame. In this paper a method is described for determining the electrode positions on the head. Since it is difficult to fix electrodes accurately at a priori chosen positions, it is better to measure these positions afterwards. For this we have developed a practical method. The method also finds the best fitting sphere for the electrode position, which is useful when a multi-sphere volume conductor is used in the inverse algorithm.

Antithrombin III levels in preeclampsia correlate with maternal and fetal morbidity.

In 57 patients with pregnancy-induced or aggravated hypertension, antithrombin III levels correlated inversely with maternal morbidity. Morbidity was determined by the maximal diastolic blood pressure, disturbance of renal and liver function, and thrombocytopenia. Antithrombin III levels and platelet counts correlated inversely with the degree of placental infarction. Proteinuria (grams per 24 hours) was most predictive of fetal outcome, which was considered to be either favorable if a healthy baby could be discharged with its mother or unfavorable in case of perinatal death or a prolonged stay in the neonatal intensive care unit. Plasma antithrombin III and serum glutamic oxaloacetic transaminase levels, in that order, augmented the number of correct predictions. Antithrombin III inhibits blood coagulation by forming irreversible complexes with activated clotting enzymes, notably with factor Xa and thrombin. Evidence is presented which suggests that antithrombin III levels in preeclampsia are depressed as a result of increased consumption in the maternal vascular tree, rather than decreased synthesis or increased urinary loss.

Plasma antithrombin III levels in pre-eclampsia.

In a prospective study plasma AT III was determined in 2423 samples obtained from 653 women during pregnancy and post partum. The women were allocated to groups, according to the highest diastolic blood pressure, in the third trimester. AT III levels were normal throughout pregnancy, during labour and after vaginal delivery, except in 57 women with pregnancy induced or aggravated hypertension. We present evidence that AT III depression in pre-eclampsia is caused by increased consumption. AT III levels correlate with maternal morbidity as revealed by hepatorenal damage. A weak but significant correlation of AT III and platelets with placental infarction was demonstrated. Proteinuria was the best predictor of fetal outcome. AT III plasma levels increased the number of correct predictions. Following vaginal delivery AT III plasma levels rapidly returned to normal values.