While studying certain diphenyl pentanones as possible neuromuscular blocking agents, it was found that 1: 5-bis(4-trimethyl-ammoniumphenyl)-n-pentan-3-one diiodide (62C47, Wellcome) had a marked selective inhibitory action on " true cholinesterase." The distribution of this type of activity was therefore investigated in further members of this and analogous series. The general formula of the compounds iswherein R, and R2 are usually substituted quaternary nitrogens of varying degrees of complexity, and A is usually either CO or CHOH (Table I). Copp (1953) has described their chemical properties. The present paper deals with some of their pharmacological actions. METHODSCholinesterase Inhibition.-Anticholinesterase activity was determined manometrically at 37' C. in the Warburg apparatus (Ammon, 1933) with 0.025 MNaHCO3 as medium equilibrated with 5% CO2 and 95% N2. Rat brain, homogenized in 15 parts by weight of 0.025M-NaHCO3, was the source of the true enzyme and horse serum that of pseudo-cholinesterase. The enzyme preparation-i ml. rat brain homogenate or 0.3 ml. horse serum-was introduced into the main compartment of the bottle together with a fresh solution of the inhibitor dissolved in 0.025 MNaHCO3. The substrate, also dissolved in 0.025 MNaHCO3, was placed in the side arm. The total fluid volume, adjusted by the addition of 0.025 M-NaHCO3, was always 3.0 ml. The final substrate concentrations were 0.003 M or 0.012 M-acetylcholine (bromide) when testing true cholinesterase activity and 0.008 Mbenzoylcholine (iodide) when testing pseudo-cholinesterase inhibition. Enzyme and inhibitor were in contact for 25 min. while gaseous and thermal equilibria were being established, before the substrate was added. All the results were corrected for non-enzymic * The gist of this paper formed a communication (by Gertrude E. Glock and G. A. M.) to the British Pharmacological Society in Edinburgh, July, 1948: a few members of the series were included in a demonstration (by J. W. Trevan and G. A. M.) to the Society at Beckenham, January, 1948. t Present address: Department of Pharmacology, University of Leeds.hydrolysis of the substrate, and the inhibitor values were calculated from the results obtained after equilibrium had been established between enzyme, substrate and inhibitor.Action on Nerve-Muscle Preparations.-The rat diaphragm-phrenic nerve preparation (Btilbring, 1946) was used to investigate (a) the ability to increase the response to indirect stimulation by square pulses of 0.34 msec. duration, (b) antagonism to the paralysing action of (+)-tubocurarine chloride by the method of Mogey and Young (1949), and (c) paralysing activity. This last was compared directly against, and expressed as a percentage of, the activity of (+)-tubocurarine in the way described by Mogey, Trevan, and Young (1949) except that, instead of allowing drugs to act for a standard period, time was given for equilibrium to be reached. The compounds were added at intervals until activity was shown or a concentration of 10-'5 had been ...
Summary The scarcity and conflicting nature of the existing evidence on the relationship between effective doses of bacterial pyrogens in man and rabbit is pointed out. The dose/quantal response curve for man to a pyrogen prepared from P. vulgaris has been determined and the intravenous ED50 for this preparation is estimated to lie between 0·084 and 0·101 μg./kg. (P = 0·95). The dose/temperature response curves for the rabbit to the same pyrogen preparation, in a variety of different experimental circumstances, have been determined. The relative sensitivities of man and rabbit to this pyrogen have been calculated on a weight‐for‐weight basis. Taking as the criteria of pyrogenic response (a) a rise of 0·6° C. in the temperature of the rabbit and (b) shivering in man, it is found that the rabbit is one‐third to 7 times as sensitive as man, depending on the experimental conditions. The expected efficiencies of the B.P. and U.S.P. tests, in detecting a human ED5 of Pyrogen Test Preparation No. 1 in differing volumes of solution, have been calculated. Some evidence that pyrogens may interact with other substances has been discussed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.