RT Journal Article
SR Electronic
T1 STUDIES ON STRYCHNIN
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 419
OP 482
VO 19
IS 6
A1 SOMA WEISS
A1 ROBERT A. HATCHER
YR 1922
UL http://jpet.aspetjournals.org/content/19/6/419.abstract
AB 1. The common grass frog, or leopard frog (Rana pipiens Shreder) obtained from Vermont reacts with a near approach to uniformity to small doses of strychnin so that it can be used after a period of fasting until the metabolism is reduced to the minimum for the quantitative estimation of strychnin in nearly pure solution. 2. A dose of crystalline strychnin sulphate (Merck's) equal to 0.15 mgm. per kilogram of weight suffices to cause perceptible increased reflex excitability in the grass frog after it has fasted until metabolism has become minimal. This period of fasting probably varies, but under the conditions described in this paper it is about three or four weeks. 3. Frogs which have been recently caught and in which metabolism is active also react nearly uniformly toward small doses of strychnin but the amounts then required by them to induce increased reflex excitability are several times greater relative to the weight than those required by frogs of the same lot after they have fasted until metabolism is minimal. 4. The tolerance of recently caught (and fed) frogs toward strychnin diminishes gradually, and apparently, irregularly. 5. Grass frogs which have fasted until their tolerance is minimal, may have their tolerance toward strychnin increased by suitable feeding. It is important, therefore, that frogs which are used for the quantitative estimation of strychnin shall be fed uniformly or that they shall be deprived of food, including insects. 6. The liver of the frog is concerned in the destruction or elimination of strychnin when the poison is administered during the period of active metabolism, but not when it is administered during a period of minimal metabolism, that is to say, after a long period of fasting. 7. The removal of the liver of the frog during a period of minimal metabolism (after long fasting) has little influence on the size of the dose of strychnin required to induce increased reflex excitability. The removal of the liver during active metabolism causes an increase in its susceptibility toward small doses of strychnin so that it then behaves like a frog which had fasted for a long period, or until its metabolism was minimal. 8. The frog having a minimal metabolism becomes apparently normal within a period of forty-eight hours after the injection of a dose of strychnin which is just sufficient to cause tetanus, so that no increased reflex excitability can be detected after the lapse of such a period, but there is a certain degree of latent persistent action, since such frogs exhibit an increased susceptibilty toward strychnin for periods of several weeks after the administration of much smaller doses than those from which they apparently recover within forty-eight hours. We are unable to offer any satisfactory explanation of this phenomenon. 9. It is immaterial, so far as the intensity of the reaction is concerned, whether the strychnin is injected into the dorsal, or into the ventral, lymph sac. 10. Variations in the weights of the animals within wide limits are without influence on the amount of strychnin per gram of weight required to cause increased reflex excitability. 11. The terms "summer frogs" and "winter frogs" as they are commonly used, are vague and tend to mislead. It is desirable that those who use frogs for the quantitative estimation of strychnin state the species employed and the conditions under which they are stored previous to use. 1. The Stas-Otto method for the extraction of poisons from animal tissues does not permit of the recovery of strychnin quantitatively when only very small amounts (but such as may be present exceptionally at the time of death) are present, but widely diffused in the organs. 2. When one part of strychnin is present in ten million parts of tissue it may be extracted almost quantitatively by liquefying the tissue by means of sodium hydrate and heat, and shaking the liquid with chloroform. When the blood of an adult human being contains as much as half a milligram of strychnin at the time of death, the poison probably can be detected by the means which we have described. 3. When the residue left after the distillation of the chloroform is sufficient in amount to interfere with the absorbability of the poison from the lymph sac of the frog (or with the characteristic color reaction) this residue should be heated with concentrated sulphuric acid in order to destroy the organic matter other than strychnin, as suggested by Rodgers and Girdwood, after which the residue is rendered alkaline and extracted by chloroform. 4. Troublesome emulsions are sometimes formed, but the chloroform may be separated from such emulsions by shaking with chloroform or with water as circumstances require. 5. Strychnin is lost during the process of extraction from tissues through adsorption by insoluble residues and by filter paper when in acid solution in water and in alcohol, but chloroformic solutions of the base may be filtered through small papers virtually without loss. 1. Strychnin was injected intravenously into cats in doses of 1 mgm. per kilogram of weight, and after intervals of time, varying from two minutes to forty minutes, blood was withdrawn from the carotid artery in measured amounts, and the percentages of strychnin present in the corpuscles and plasma (or serum) were determined separately in the manner described in a previous paper. 2. Strychnin sulphate leaves the blood stream rapidly, and after 2 minutes as much as 30 per cent may have left the circulation; within five minutes more than 50 per cent, and after forty minutes the blood may contain only about 4 per cent of that injected. 3. Young animals appear to eliminate strychnin from the circulation more rapidly than adults; this probably stands in relation with the greater tolerance of young animals toward strychnin, but the difference in the rate of elimination found in these experiments is greater than the difference in tolerance of animals of the age used and that of adults. 4. When strychnin sulphate is injected intravenously into the cat the poison passes from the plasma into the tissues in part, in part into the corpuscles, and after a time it begins to pass from the corpuscles back into the plasma and thence into the tissues, and in one experiment after an interval of forty minutes the corpuscles were found to contain about 4 per cent of the strychnin injected, while the plasma contained only traces, the concentration in the plasma being equal to 1 part in about 12,000,000. 5. The distribution of strychnin between the plasma (or serum) and the corpuscles following its intravenous injection into the cat does not appear to differ materially from that seen when the poison is added to the blood in vitro in an approximately similar concentration. 6. It is believed that the determination of the distribution of the poison between the plasma and the corpuscles will aid in the study of the behavior of strychnin in the body, and expecially of its elimination, by means of perfusion experiments. 1. Strychnin sulphate was administered orally and intramuscularly in single doses of 4 mgm. and in repeated oral doses; the urine was collected in periods of six hours, twelve hours and twenty-four hours, and the amounts of strychnin present were estimated by means of the frog tests previously described. 2. The kidneys excrete amounts equal to 20 per cent of that administered at one time, and a much lower percentage of larger doses taken by the mouth over periods of twelve and twenty-eight hours, respectively. 3. The percentage of the strychnin excreted by the kidneys is a measure of the eliminative efficiency of the liver, rather than that of the kidney itself, for the kidney excretes only that which the liver fails to excrete. 4. Diuresis hastens the elimination of strychnin by the kidney, but it does not necessarily increase the total amount eliminated in the urine after a single dose injected intramuscularly, and it may, in fact, be attended with the renal elimination of a smaller total than would occur in a similar experiment without diuresis. 5. The liver appears to be the principal protective organ with reference to acute poisoning by strychnin, the kidney to be concerned mainly with the elimination of traces of the poison which reënter the circulation after having been fixed temporarily in those tissues which are incapable of destroying the poison.