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The in vivo effect of sodium valproate (SV) on the activity of uridine diphosphate glucuronosyltransferase (UDP-GT) and hepatotoxicity in the mouse liver was studied. Mice were injected intraperitoneally (IP) with SV at doses varying from 50 to 800 mg/kg per day, for six consecutive days (dose-response group) or at a standard dose of 300 mg/g per day for 2-10 days (time-response group), whereas the controls were injected with normal saline. Valproic acid levels had a positive correlation to the dose (P < 0.001) and duration of drug administration (P = 0.006). A gradual increase in UDP-GT activity was observed in doses of up to approximately 400 mg/kg per day, whereas in higher doses the enzyme activity gradually decreased. The time course of UDP-GT activity at the standard dose of 300 mg/kg per day increased progressively, with a maximum up to the sixth day and then had a gradual reduction. Hepatic necrosis (which was unrelated to the dose or the duration of drug administration) was found in 13% of the SV-treated animals and in none of the controls. We conclude that at an optimal dose (300-400 mg/kg per day) and at a time course of 6 days, SV causes liver UDP-GT induction, whereas in higher doses and longer duration of administration, UDP-GT activity is gradually reduced. SV also causes hepatotoxicity unrelated to dose and time course.

Molecular dynamics studies of two generalized forms of the rough sphere model are reported. The generalization permits us to vary the coupling between rotational and translational motion through a stick parameter λ. The autocorrelation functions show deviations from the Enskog theory for all values of λ studied—indicating that collective effects are involved. It appears that the angular velocity correlation function is the sum of two exponentials. A simulation of a mixture of disparate sized rough spheres was also performed. It is found that the rotational motion of the small particle is not significantly altered upon introduction of the large particles, but the linear velocity correlation function of the small particle differes considerably from that of the neat fluid (in the time regime from 5–15 mean collision time units).

The structural and thermodynamic properties of water are studied using the force bias Monte Carlo simulation. In particular for ST2 water, the effect of system size is examined with 27, 125 and 216 water molecules. The role played by the truncation of the intermolecular potential is analysed using two different truncations, the spherical cut-off and the cubic cut-off. Also a recent simulation with the Watts potential using Ewald summation by McDonald and Klein is compared with one employing the spherical cut-off. In all cases the angular correlation functions show a strong dependence on the type of boundary condition used, whereas the usual radial functions g oo(r), g oh(r) and g hh(r) do not depend much on the boundary conditions. Because of this dependence of angular correlations on the boundary conditions, care must be exercised in comparing simulation results from small systems to real experiments.

The hydrophobic interaction between two apolar (Lennard–Jones) spheres dissolved in a model of liquid water (ST 2 water) is simulated using the force‐bias Monte Carlo technique recently devised by the authors. Importance sampling techniques are devised and used to give a relatively accurate determination of the potential of mean force of the two apolar spheres as a function of their separation. This determination shows that there are two relatively stable configurations for the spheres. In one configuration each member of the pair sits in its own water cage with one water molecule fitting between them. There is a free energy barrier separating this from the other stable configuration which is such that no water molecule sits between the spheres. This conclusion is shown to be quantitatively consistent with the recent semiempirical theory of Pratt and Chandler and is in disagreement with some previous Monte Carlo studies.

The structure of ST2 water around a pair of spherical nonpolar (Lennard‐Jones) particles, A1–A2, is studied as a function of pair separation, r, using a force‐bias Monte Carlo technique with importance sampling. The change in the water structure (or equivalently the hydrophobic hydration) is correlated with the potential of mean force, WAA (r), determined in a previous study. It is found that the second minimum in WAA (r) corresponds to a water molecule lying between the two apolar particles. The water always maintains a ’’linear hydrogen bond’’ network and is more ordered in the neighborhood of the two spheres except possibly when they are separated by a distance corresponding to the position of the free energy barrier, that is the maximum in WAA (r).