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III. Studies in quinidine
KWIEWS
AND
705
ABSTRACT’S
nounced irregularities in rhythm, of which heart-block is the commonest. A11 the fundamental functions of the heart muscle are affected; thus, stimulus production, excitability, conductivity, contractility and tonicity are lessened., the effect on conduction being the most marked and occurring after doses which have comparatively lit.tle effect on the other functions. The action is a l.ocal toxic one on the h.ea.rl; muscle, the inhibitory mechanism taking no part in the production of the changes. Most of the changes also occur in perfused rabbits’ hearts. Intravenous injections of bismuth cause marked lowering of the blood pressure, a lowering which is secondary to a great extent to the changes in the heart. The fall in blood pressure and the changes in the heart are influenced by the rate at which the injection is given, and a second injection gives m@re pronounced changes caeteris parihus than the first. The actions of some other heavy metals on the circulatory system were investigated and compared with those of bismuth. Mercury and copper present marked similarity to bismuth in their effect,s; antimony, zinc, and iron present a somewhat distant similarity, and nickel and tin present no similarity.
Weis’s, Scuma, aud Hatcher, Pharmacol.
and Exper.
Robert A.: ‘rherap.,
II. Studies on Quinine.
1927, xxx,
Jour.
327.
The toxicity of quinine depends in part on the rate at which it enters the circulation. The fatal dose of the hydrochloride for the cat is about 140 mg. per kilogram of weight Tyhen it is injected intravenously at the rate of 2 mg. per kilogram per minute, and about 100 mg. is fatal when it is injected at the rate of 5 mg. per minute. The cat recovers within about three hours from the toxic effects of 70 per cent of the fatal dose injected intravenously a.t the rate of 5 mg. per kilogram per minute, and t,he animal then requires as much as the normal animal, or one which ha,d not previously had quinine, to cause death. The exclusion of the kidneys from. the circulation (by tying the renal arteries and veins) has no important influence on the rate of recovery after such toxic doses. The perfused liver is capable of destroying quinine rapidly, and t.he greater part of an intravenous dose of quinine is almost certainly destroyed in the liver.
Weiss, Soma, *aandHatcher, Robert A. : III. Pharmacol.
and Exper.
Therap.,
Studies in Quinidine.
1.927, xxx,
Jour.
335.
Quinidine present in tissues ma.y be recovered almost quantitatively by liquefying the tissues with hot solution of sodium hydrate and shaking the solution with chloroform. It can be extracted from one
706
THE
AMERICAN
HEART
JOURNAL
million parts of blood by shaking the latter with 25 volumes of chloroform. It can be estimated quantitatively in extracts of tissues by titration with bromine water. About 95 per cent of an intravenous dose of quinidine leaves the blood within five minutes; the concentration in the blood thpn sinks gradually and about 1 per cent of that injected intravenously is pres-. ent in the circulation after an interval of one hour. After an interval of from three to four hours, only traces remain in the blood. The rate of disa.ppearance from the blood varies in different individuals. The capillaries of the organs fix quinidin.e loosely at first and much of that so fixed can be removed by perfusion. Proba,bly all capillaries of the body fix it to some degree. The concentration of quinidine in the various organs changes eonstantly. The lungs fix it in the greatest concentration at first because it reaches them in the highest concentration; later the kidneys and liver hold it in higher concentration than the lungs. The toxicity of quinidine varies widely with the rate of its intravenous injection. The average fatal dose of the sulphate for the cat when it is injected at the rate of 5 mg. per kilogram per minute is about 80 mg. per kilogram. Much smaller doses are sometimes fatal with rapid injection. The essential elimination is practically complete within from three to four hours after which the animal requires as much to cause deat.h as one that had not received a previous dose. The organs, including the liver and kidneys, still retain the poison in concentrations, about equal to that which they would hold were the alkaloid distributed uniformly throughout the body and had none been eliminated, but the concentration in these organs is somewhat lower than it is shortly after the rapid intravenous injection of a nearly fatal dose. The liver destroys quinidine during perfusion at approximately the same rate that it destroys quinine. The behavior of quinidine in the body resembles that of quinine in the various ways in which its behavior has been determined by us. Toxic doses of quinidine or quinine are not synergistic with the toxic action of ouabain (a digitalis body) on the heart.
eatcheir,
Robwt A., and Gomld, Hmry:
Pharmacol.
and Exper.
Therap.,
IV. Studies on Quinine.
1927, xxx,
Jour.
347.
Three specimens of blood were drawn” from three patients after intervals of from six to twenty minutes following the intravenous injection of doses of 10 grains’ (650 mg.) of quinine &hydrochloride in each case and examined for quinine, None of the three contained more than a fraction of a milligram, shqwing that much the greater part of the quinine injected had left the circulation.
AND
705
ABSTRACT’S
nounced irregularities in rhythm, of which heart-block is the commonest. A11 the fundamental functions of the heart muscle are affected; thus, stimulus production, excitability, conductivity, contractility and tonicity are lessened., the effect on conduction being the most marked and occurring after doses which have comparatively lit.tle effect on the other functions. The action is a l.ocal toxic one on the h.ea.rl; muscle, the inhibitory mechanism taking no part in the production of the changes. Most of the changes also occur in perfused rabbits’ hearts. Intravenous injections of bismuth cause marked lowering of the blood pressure, a lowering which is secondary to a great extent to the changes in the heart. The fall in blood pressure and the changes in the heart are influenced by the rate at which the injection is given, and a second injection gives m@re pronounced changes caeteris parihus than the first. The actions of some other heavy metals on the circulatory system were investigated and compared with those of bismuth. Mercury and copper present marked similarity to bismuth in their effect,s; antimony, zinc, and iron present a somewhat distant similarity, and nickel and tin present no similarity.
Weis’s, Scuma, aud Hatcher, Pharmacol.
and Exper.
Robert A.: ‘rherap.,
II. Studies on Quinine.
1927, xxx,
Jour.
327.
The toxicity of quinine depends in part on the rate at which it enters the circulation. The fatal dose of the hydrochloride for the cat is about 140 mg. per kilogram of weight Tyhen it is injected intravenously at the rate of 2 mg. per kilogram per minute, and about 100 mg. is fatal when it is injected at the rate of 5 mg. per minute. The cat recovers within about three hours from the toxic effects of 70 per cent of the fatal dose injected intravenously a.t the rate of 5 mg. per kilogram per minute, and t,he animal then requires as much as the normal animal, or one which ha,d not previously had quinine, to cause death. The exclusion of the kidneys from. the circulation (by tying the renal arteries and veins) has no important influence on the rate of recovery after such toxic doses. The perfused liver is capable of destroying quinine rapidly, and t.he greater part of an intravenous dose of quinine is almost certainly destroyed in the liver.
Weiss, Soma, *aandHatcher, Robert A. : III. Pharmacol.
and Exper.
Therap.,
Studies in Quinidine.
1.927, xxx,
Jour.
335.
Quinidine present in tissues ma.y be recovered almost quantitatively by liquefying the tissues with hot solution of sodium hydrate and shaking the solution with chloroform. It can be extracted from one
706
THE
AMERICAN
HEART
JOURNAL
million parts of blood by shaking the latter with 25 volumes of chloroform. It can be estimated quantitatively in extracts of tissues by titration with bromine water. About 95 per cent of an intravenous dose of quinidine leaves the blood within five minutes; the concentration in the blood thpn sinks gradually and about 1 per cent of that injected intravenously is pres-. ent in the circulation after an interval of one hour. After an interval of from three to four hours, only traces remain in the blood. The rate of disa.ppearance from the blood varies in different individuals. The capillaries of the organs fix quinidin.e loosely at first and much of that so fixed can be removed by perfusion. Proba,bly all capillaries of the body fix it to some degree. The concentration of quinidine in the various organs changes eonstantly. The lungs fix it in the greatest concentration at first because it reaches them in the highest concentration; later the kidneys and liver hold it in higher concentration than the lungs. The toxicity of quinidine varies widely with the rate of its intravenous injection. The average fatal dose of the sulphate for the cat when it is injected at the rate of 5 mg. per kilogram per minute is about 80 mg. per kilogram. Much smaller doses are sometimes fatal with rapid injection. The essential elimination is practically complete within from three to four hours after which the animal requires as much to cause deat.h as one that had not received a previous dose. The organs, including the liver and kidneys, still retain the poison in concentrations, about equal to that which they would hold were the alkaloid distributed uniformly throughout the body and had none been eliminated, but the concentration in these organs is somewhat lower than it is shortly after the rapid intravenous injection of a nearly fatal dose. The liver destroys quinidine during perfusion at approximately the same rate that it destroys quinine. The behavior of quinidine in the body resembles that of quinine in the various ways in which its behavior has been determined by us. Toxic doses of quinidine or quinine are not synergistic with the toxic action of ouabain (a digitalis body) on the heart.
eatcheir,
Robwt A., and Gomld, Hmry:
Pharmacol.
and Exper.
Therap.,
IV. Studies on Quinine.
1927, xxx,
Jour.
347.
Three specimens of blood were drawn” from three patients after intervals of from six to twenty minutes following the intravenous injection of doses of 10 grains’ (650 mg.) of quinine &hydrochloride in each case and examined for quinine, None of the three contained more than a fraction of a milligram, shqwing that much the greater part of the quinine injected had left the circulation.