Kinetics and dynamics of lorazepam during and after continuous intravenous infusion.

OBJECTIVE: To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point. METHODS: Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs. RESULTS: The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins. CONCLUSION: Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.

Binding of monoclonal antibody to CD16 causes calcium mobilization in large granular lymphocytes but inhibits NK killing.

A monoclonal antibody (mAb), CLB/FcR gran I, reactive with the CD16 Fc receptor (FcRlo/FcRIII) of human cells, leads to calcium mobilization in large granular lymphocytes (LGL) but not in granulocytes. Identical responses are obtained with F(ab')2 fragments of this antibody, indicating that the response is independent of Fc-FcR binding, and that bivalent cross-linking of this receptor is adequate for optimal calcium mobilization. The calcium response was greater in CD3- LGL compared to CD3+ LGL, although the response was augmented in the latter cells by prior rosetting with sheep red blood cells (SRBC). Calcium mobilization in CD3- LGL induced by CLB/FcR gran I is associated with inhibition of natural killer cell (NK) killing, and inhibition of the enhanced NK killing induced by the anti-CD2 low-density monoclonal antibody, 9.1. This supports the view that the NK-enhancing activity of 9.1 is due to simultaneous binding to CD2 and CD16, and may in fact be transduced through the CD16 molecule. The variable reported effects of anti-CD16 antibodies on NK killing are likely to reflect the epitope bound rather than the isotype of antibody used, since F(ab')2 fragments of CLB/FcR gran I also inhibit NK killing.

Arctic ocean ventilation studied with a suite of anthropogenic halocarbon tracers.

The chlorofluoromethanes (CFMs: CCl(2)F(2) and CCl(3)F), methyl chloroform (CH(3)CCl(3)), and carbon tetrachloride (CCl(4)) have been measured in deep waters of the Arctic Ocean. Oceanic and atmospheric inventories of these compounds result from known anthropogenic releases; because the CFMs and CCl(4) are also chemically nonreactive, they can be used as transient tracers of ocean circulation. The input history of CCl(4) is longer than that of any other transient tracer identified to date( approximately 70 years). This long input history, together with an e-folding time scale of increase(tau) of approximately 28 years, makes CCl(4) potentially the most useful tracer for calibrating models of the oceanic uptake of the fossil-fuel CO(2) transient(tau approximately 25 years). The bottom water of the Nansen Basin, Arctic Ocean, has detectable CCl(4) but undetectable CFM(s) and CH(3)CCl(3), which suggests either that the bottom water is approximately 50 years old, or that there is a small, nonanthropogenic component of atmospheric CCl(4)(<6 parts per trillion by volume).

Healing of surgical incisions in the disc and retrodiscal tissue of the rabbit temporomandibular joint.

The purpose of this study was to evaluate histologically the healing potential of surgical incisions placed in various areas of the TMJ disc and retrodiscal tissue. Eight weeks after surgery, it was found that incisions completely within retrodiscal tissue had healed and had a normal appearance. Incisions at the junction of the disc and retrodiscal tissue also had healed, but at a slower rate and with more random orientation of the collagen fibers. Defects within the disc had not healed, however, and degenerative changes had developed in the hard and soft tissues. The implications of these observations are discussed.