Determination of minimal steady‐state plasma level of diazepam causing seizure threshold elevation in rats

OBJECTIVE:Diazepam, administered by the intravenous, oral, or rectal routes, is widely used for the management of acute seizures. Dosage forms for delivery of diazepam by other routes of administration, including intranasal, intramuscular, and transbuccal, are under investigation. In predicting what dosages are necessary to terminate seizures, the minimal exposure required to confer seizure protection must be known. Here we administered diazepam by continuous intravenous infusion to obtain near-steady-state levels, which allowed an assessment of the minimal levels that elevate seizure threshold. METHODS:The thresholds for various behavioral seizure signs (myoclonic jerk, clonus, and tonus) were determined with the timed intravenous pentylenetetrazol seizure threshold test in rats. Diazepam was administered to freely moving animals by continuous intravenous infusion via an indwelling jugular vein cannula. Blood samples for assay of plasma levels of diazepam and metabolites were recovered via an indwelling cannula in the contralateral jugular vein. RESULTS:The pharmacokinetic parameters of diazepam following a single 80-μg/kg intravenous bolus injection were determined using a noncompartmental pharmacokinetic approach. The derived parameters Vd , CL, t1/2α (distribution half-life) and t1/2β (terminal half-life) for diazepam were, respectively, 608 mL, 22.1 mL/min, 13.7 minutes, and 76.8 minutes, respectively. Various doses of diazepam were continuously infused without or with an initial loading dose. At the end of the infusions, the thresholds for various behavioral seizure signs were determined. The minimal plasma diazepam concentration associated with threshold elevations was estimated at approximately 70 ng/mL. The active metabolites nordiazepam, oxazepam, and temazepam achieved levels that are expected to make only minor contributions to the threshold elevations. SIGNIFICANCE:Diazepam elevates seizure threshold at steady-state plasma concentrations lower than previously recognized. The minimally effective plasma concentration provides a reference that may be considered when estimating the diazepam exposure required for acute seizure treatment

Sectoral linkages and industrial efficiency: a dilemma or a requisition in identifying development priorities?

O21, O52, D24, D57,

Conclusion: The science of conflict

This chapter discusses the application of scientific approaches to conflict studies. The emphasis is on recent advances in the field of biomolecular archaeology applied to human remains, most notably isotopic analyses, ancient DNA and radiocarbon dating. These techniques have the potential to address crucial questions regarding skeletons demonstrating violent injuries, such as the identity and origins of those involved. In addition, high-resolution dating can be crucial to determining whether a multiple burial represents a single or multiple events, as well as linking periods exhibiting greater violence with other social and/or environmental variables. This allows archaeologists to address broader questions concerning the role(s) of violent interactions in past societies