STUDIES ON PHYSOSTIGMINE AND RELATED SUBSTANCES I. QUANTITATIVE RELATION BETWEEN DOSAGE OF PHYSOSTIGMINE AND INHIBITION OF CHOLINESTERASE ACTIVITY IN THE BLOOD SERUM OF DOGS

¹ From the Department of Pharmacology, Harvard Medical School, Boston

1. The time course of the inhibition of serum cholinesterase activity has been followed in detail after single intravenous doses of physostigmine in dogs.

2. With continuous intravenous infusions of physostigmine in dogs a steady level of inhibited serum cholinesterase activity is reached within one hour and may be maintained for as long as the infusion lasts.

3. The percentage level of serum cholinesterase inhibition attained by a constant rate of infusion is reproducible and allows quantitative definition of "eserinization" when employed for physiological experiments involving cholinergic mechanisms.

4. The kidneys are proved to play a minor rôle in the disposal of physostigmine.

5. The recovery of serum cholinesterase activity in vivo after continuous infusion and after large single doses appears to follow a mechanism similar to the recovery of the inhibited enzyme activity in vitro.

6. The validity of determinations of inhibited enzymes is discussed from the standpoint of the various methods which may be employed in such determinations. Combination of inhibitor with enzyme, destruction of inhibitor, dilution, displacement of inhibitor by substrate, and time are shown to be among the factors by which methods differ, and which require proper correction. A basis is provided for understanding and evaluating the unfamiliar corrections applied to the data presented in this paper.