RT Journal Article
SR Electronic
T1 THE INFLUENCE OF AGING ON THE ACTIVITY OF ANTICONVULSANT DRUGS
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 443
OP 448
VO 150
IS 3
A1 W. Clayton Petty
A1 Ralph Karler
YR 1965
UL http://jpet.aspetjournals.org/content/150/3/443.abstract
AB The influence of aging on the activity of five anticonvulsant agents was studied in rats and mice. In addition, the relation of aging to the CO2 content of the cerebral cortex of the rat was investigated. In the rat, the ED50 values in four of the five agents studied decreased with age. Three of the drugs whose ED50 values fell with age are considered to act through the same mechanism, an increase in the CO2 content of the central nervous system. These anticonvulsants are C02, acetazolamide, and sulfanilamide. The increase in sensitivity of the nervous syste to CO2 was not related to detectable changes in the amount of CO2 in the cerebral cortex. In addition, changes in the amount of CO2 could not be measured in the cortex after administration of anticonvulsant doses of acetazolamide. The marked sensitivity of the central nervous system to CO2 in old rats indicates that changes in tissue CO2 below the limits of manometric detection are sufficient to produce anticonvulsant effects. At present it is not possible to relate any changes in blood-brain barrier, in rates of drug metabolism, in the level of central nervous system excitability, or in carbonic anhydrase activity to the decrease in ED50 observed for acetazolamide and sulfanilamide. It appears that the decrease in ED50 of these agents is the consequence of an increase in sensitivity of the nervous system to CO2. The ED50 for phenobarbital also decreased with age, and this decrease may be the consequence of a decrease in the rate of metabolism of the barbiturates with age. The mice data demonstrate some species differences from the rat. The ED50 for both acetazolamide and diphenylhydantoin increased with age. Mice, nevertheless, resemble rats in that the ED50 for CO2 decreased with age. Therefore, in both species aging is associated with an increase in sensitivity of the nervous system to the anticonvulsant effects of CO2. The Williams & Wilkins Comapny