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1. The purpose of this investigation was to examine the influence of increasing age on the pharmacokinetics and the time course of the anticonvulsant response of oxazepam in BN/BiRij rats as an animal model of aging. 2. Oxazepam was administered intravenously in a dose of 12 mg kg-1 body weight and the anticonvulsant effect intensity was measured as elevation above baseline of a threshold for induction of localized seizure activity (TLS). Direct cortical stimulation with ramp shaped electrical pulse trains of increasing intensity was used to determine this threshold. 3. The pharmacological effect vs. time profile showed in young rats an anticonvulsant component followed by proconvulsant component which is suggestive for the occurrence of acute tolerance and/or withdrawal syndrome. With increasing age the proconvulsant component disappeared, resulting in a monophasic effect profile (anticonvulsant effect only) at the age of 35 months with significantly higher anticonvulsant effect intensity immediately following drug administration. No age-related changes in the pharmacokinetic parameters of oxazepam were observed. 4. In five animals of each age group, benzodiazepine receptor binding characteristics were determined in vitro with [3H]-flunitrazepam as a ligand. Both receptor density and affinity did not show age-related changes. Available literature data on post-receptor events do not indicate conclusive age-related changes. 5. It is concluded, that the observed change in the pharmacodynamics of anticonvulsant effect of oxazepam can be explained by the disappearance of the tolerance/withdrawal phenomenon. This is compatible with a decreased efficiency of homeostatic control mechanisms in the elderly.
A M Stijnen, and
I Postel-Westra, and
M W Langemeijer, and
A Hoogerkamp, and
R A Voskuyl, and
C F van Bezooijen, and
M Danhof
July 1993,
Pharmaceutical research,
A M Stijnen, and
I Postel-Westra, and
M W Langemeijer, and
A Hoogerkamp, and
R A Voskuyl, and
C F van Bezooijen, and
M Danhof
September 1992,
British journal of pharmacology,
A M Stijnen, and
I Postel-Westra, and
M W Langemeijer, and
A Hoogerkamp, and
R A Voskuyl, and
C F van Bezooijen, and
M Danhof
April 1992,
The Journal of pharmacology and experimental therapeutics,
A M Stijnen, and
I Postel-Westra, and
M W Langemeijer, and
A Hoogerkamp, and
R A Voskuyl, and
C F van Bezooijen, and
M Danhof
January 1990,
British journal of pharmacology,
A M Stijnen, and
I Postel-Westra, and
M W Langemeijer, and
A Hoogerkamp, and
R A Voskuyl, and
C F van Bezooijen, and
M Danhof
January 1994,
Alcohol (Fayetteville, N.Y.),
A M Stijnen, and
I Postel-Westra, and
M W Langemeijer, and
A Hoogerkamp, and
R A Voskuyl, and
C F van Bezooijen, and
M Danhof
November 1984,
Biochemical pharmacology,
A M Stijnen, and
I Postel-Westra, and
M W Langemeijer, and
A Hoogerkamp, and
R A Voskuyl, and
C F van Bezooijen, and
M Danhof
September 1996,
Journal of pharmaceutical sciences,
A M Stijnen, and
I Postel-Westra, and
M W Langemeijer, and
A Hoogerkamp, and
R A Voskuyl, and
C F van Bezooijen, and
M Danhof
January 1988,
Experimental gerontology,
A M Stijnen, and
I Postel-Westra, and
M W Langemeijer, and
A Hoogerkamp, and
R A Voskuyl, and
C F van Bezooijen, and
M Danhof
January 1987,
Gerontology,
A M Stijnen, and
I Postel-Westra, and
M W Langemeijer, and
A Hoogerkamp, and
R A Voskuyl, and
C F van Bezooijen, and
M Danhof
January 1992,
Drug metabolism and disposition: the biological fate of chemicals,
