Application Of Constant Rate Research Articles

Development of tolerance to the anticonvulsant effect of GABAmimetic drugs in genetically epilepsy-prone gerbils

Three drugs which increase GABA-mediated inhibitory neurotransmission in the brain, namely the GABA degradation inhibitors aminooxyacetic acid (AOAA) and γ-acetylenic GABA (GAG), and the GABA receptor agonist THIP (gaboxadol), were administered to epilepsy-prone gerbils via subcutaneously implanted osmotic minipumps for 2 weeks. The antiepileptic drugs valproic acid (VPA) and diazepam were also included in the experiments. After one day of constant rate application, all GABAmimetics markedly suppressed seizure activity induced in the gerbils by air blast stimulation, but anticonvulsant efficacy of the drugs was lost after 8 and 14 days of treatment. With VPA, only moderate anticonvulsant effects were found because only sub-therapeutic drug levels (about 40 μg/ml plasma) were reached via minipump administration. The experiments with diazepam could only be evaluated in part because of instability of the drug in aqeous solution. Determination of brain GABA metabolism in the gerbils indicated that reduction of GABA synthesis may be responsible, at least in part, for development of tolerance to the antoconvulsant effects of AOAA and GAG.

Pharmacokinetics of valproic acid and metabolites in mouse plasma and brain following constant-rate application of the drug and its unsaturated metabolite with an osmotic delivery system.

Human therapeutic valproic acid (VPA) levels could be maintained in the mouse for a period of 1 week by constant rate application via subcutaneously implanted osmotic minipumps. Also, the concentrations of VPA metabolites observed in mouse plasma were similar to those seen in human plasma. The drug application could be prolonged by replacing exhausted pumps with freshly-filled devices. Removal of the implanted pumps and measurement of the decay of the drug levels revealed that the half-life of the main plasma metabolite 2-en(2-propyl-2-pentenoic acid) exceeded that of VPA. This result was confirmed by constant-rate application of this metabolite; the plasma clearance of 2-en (as calculated from the steady-state levels observed) was found to be lower than that of VPA. Brain levels of VPA and 2-en during steady-state were 3-10 per cent of corresponding plasma levels. The blood-brain kinetics of 2-en following administration of VPA were similar to those observed following application of 2-en itself. VPA was cleared faster from the brain than from the plasma, while 2-en was more persistent in the brain than in the plasma. Our results indicate that controlled, constant-rate application of drugs such as VPA, via implantable osmotic minipumps, may be a valuable procedure for a number of pharmacological and toxicological studies, particularly where persistent drug levels must be maintained for extended time periods.

A new model for embryotoxicity testing: teratogenicity and pharmacokinetics of valproic acid following constant-rate administration in the mouse using human therapeutic drug and metabolite concentrations

The limitations of a conventional testing procedure for embryotoxicity-multiple dosing throughout the organogenesis period of the mouse or rat-are discussed for drugs such as valproic acid (VPA) which exhibit pharmacokinetic properties in these species which are very different from those in the human. Administration of VPA to the mouse, once each day, resulted in peak plasma drug concentrations 10 fold higher than human therapeutic plasma levels, after which the drug levels rapidly decreased to insignificant levels which persisted until the time of the next dose. Dose-dependent growth retardation, a sharp increase in the resorption rate and a high incidence of exencephaly were observed with this dosing regimen. A new mouse model was developed where constant-rate application of the drug with osmotic minipumps resulted in drug levels throughout the organogenesis period which were similar to those observed during human therapy. Such therapeutic drug levels produced a slight but significant fetal growth retardation and increased resorption rates, but not exencephaly. It is suggested that maintaining plasma concentrations in the experimental animal comparable to human therapeutic drug levels should offer a more realistic model for drug-embryotoxicity testing.

Measured and Approximate Flux‐Concentration Relations for Absorption of Water by Soil

AbstractThe flux‐concentration relation of Philip (1973) is calculated using moisture profiles measured during absorption of water by a fine sand when water was supplied at both constant hydraulic potential and constant rate. The general behavior of the measured flux‐concentration relations was found to be consistent with those of the model soils calculated by Philip. Within the accuracy of the measurements, no significant time‐dependence of the relation was found for the constant flux boundary condition over a large time span. Measurements of the time‐averaged flux‐concentration relation, however, suggest some significant time‐dependence for short times. Simple approximations for the flux‐concentration relation, based on these observations, are suggested. These approximations enable easily evaluated predictions to be made of the salient features of constant rate application of water to soil, which are sufficiently accurate for most practical purposes.