THE MARGIN OF SAFETY OF INTRAVENOUS DIGITALIS IN CATS

SAMUEL A. LEVINE

doi:10.1001/archinte.1920.00100030037004

LEVINE, SAMUEL A.;

1920-09-01 00:00:00

THE MARGIN OF SAFETY OF INTRAVENOUS DIGITALIS IN CATS SAMUEL A. M.D. and DONALD M.D. LEVINE, T. CUNNINGHAM, BOSTON The medical has become interested in intra- profession greatly venous no in recent and evidence of therapy years, although particular this enthusiasm has been reflected in the treatment of heart disorders, the work of the administration of Eggleston,1 introducing large single doses of well lead others to the effect of mouth, digitalis by might try similar In the intravenous cardiac preparations intravenously. past, has been limited to of therapy essentially preparations strophanthin, which is considered be a With this to generally dangerous procedure. in an introduction was made to determine whether the mind, attempt into more the blood stream of in its and less potent digitalis complete form would to be a safe method for effect. prove obtaining therapeutic The of has been taken as the difference between the margin safety minimum lethal dose and the minimum toxic dose (M.L.D.) (M.T.D.). We introduce the of the of of concept margin safety digitalis prep- because in dose arations the use of the the practical drug therapeutic it is close to the toxic dose. is of Therefore, very great importance to know how far removed the lethal dose is from the toxic and dose, whether the is in than in others. some margin greater preparations The minimum lethal dose is that which is dose to cause just required standstill the heart of and death when the is digitalis preparation given in over a doses of about one similar to the interrupted hour, period method of Hatcher.2 In work one of us it was shown previous by that the toxic and lethal doses are of the of adminis¬ independent speed of tration of the from a fifteen minutes four to hours; drug period in this were and, therefore, work the not at con-, injections given any sometimes stant the lethal effect in about one-half speed, producing in hour and sometimes two hours or Some difference more. of opinion exist the as to occurrence of the toxic effect. It is might generally that the of heart appearance block, ventricular com¬ thought changing and indicate The latter is the most plexes, extrasystoles toxicity. common event in and this was considered cats, in the generally timing From the Medical Clinic of the Peter Bent Brigham Hospital, and the of Harvard Medical Department Medicine, School. 1. C.: Eggleston, Digitalis Arch. Int. Med. 16:1 1915. Dosage, (July) 2. R. and G.: A Standardization Hatcher, A., Brody, J. Biological of Drugs, Am. 1910. J. Pharmacy 82:360, 3. S. A.: The Levine, Action of on the Cat's Strophanthin Living Heart, M. 1919. J. Exper. 29:485, Downloaded From: http://archinte.jamanetwork.com/ by a University of Manitoba User on 06/17/2015 toxic dose. This criterion has the added it is the most advantage'that clinical of for heart block in itself important sign toxicity, rarely of the the while indicate circulation, impairs efficiency extrasystoles an increased of the and when cer¬ irritability ventricles, numerous, the diminish effective of the heart. The minimum toxic tainly output is calculated in these the dose, therefore, as smallest dose experiments that is to extraventricular required systoles. produce METHOD OF PROCEDURE Cats were used in other animals because to preference laboratory their reaction to is more like that the of human The digitalis subject. was cat on the animal etherized, board and the front placed right leg and left hind with A connected the cánula leg electrocardiograph. was inserted in the -vein and attached a small right saphenous by a cc as a rubber tube to 10 calibrated which served buret. The pipet was normal and the dose of the taken, electrocardiogram preparation was to be used then allowed to flow into the vein. One minute before an each dose was until a toxic effect was taken, electrocardiogram shown about where this was to expected, previous experience having occur. the two critical the of toxic and During periods, beginning lethal the movements were effects, of the watched galvanometer string and taken were to detect the earliest carefully, frequent tracings abnormality. different were The was Various used. first digitalis preparations an extract of aqueous powdered digitalis (Marion, Virginia leaf) pre¬ Pratt to the second was ;4 pared according Squibb's powdered digitalis leaves in the same the third was tincture of prepared way ; Squibb's in and three different digitalis, finally, digitalis preparations ampoules for and intramuscular details subcutaneous use were tested. The of In the are in the table. three experiments given accompanying experi¬ the of of intra¬ ments margin safety (M.L.D. average M.T.D.) venous of extract was 50 aqueous digitalis (Virginia leaf) cent., per half that it as much of the is, to required approximately drug produce as to An extraventricular it did cause standstill of the heart. systoles identical was obtained in the per of three figure (50 cent.) average the extract of leaves. using aqueous experiments Squibb's digitalis The for tincture of was average Squibb's digitalis (five experiments) 40 cent.; for 50 per per cent.; digifolin ampoules (one experiment) for and 56 for per cent., digalen ampoules (one experiment) digi- 64 cent. It is evident that puratum ampoules (one experiment) per are individual variations in different there both in the cats, suscepti- 4. West, H. and P.: Clinical with a Standardized F., Pratt, J. Experience Extract of Digitalis, J. A. M. A. 74:1389 15) 1920. Aqueous (May Downloaded From: http://archinte.jamanetwork.com/ by a University of Manitoba User on 06/17/2015 a a a a s e 1 os sa µ tua al- . _ 5^ •5·« µ S S S .5 » tì *- . µ, S ft a s ¿a =i >s PS. 8 g g 3 * ^¿. rHîO l-l a a a a a^a^a^a^B^s"« 6g .X-0).J> . - Ç-t ^ .¡SOU Od Ow© OOOOOOOtN p. d « P^ w - O ^ o S s a a a a a s tuJcN cmao Ä0^- m öfiiö bo „, ,* CO - ¡vi <N Ift 0 O ri «g <M 00 * CO CO "* Tt< IO CO 1-1 .- r-i cg weg wco w55 co ^ woÌ *—-a a e a a il ! S a ¿"¿ — a" — — — HHNMMWC o Co >> >> ki * E* £· t- *-< t- 4) CJ ai S Oí Ö >_, >H. > -\ > t> 7" > rt O i « * a» ß s B B -S (j » á; á a « < .a o £ S s e .y .y _fl ^ « s s a ó s ao « a«a«a ó « «g¿s .a «a CO to aj to âj;^ cjç0 -* ci ^ eveo ü aï i*· ci ce co # - ^ «"·« =1 S "5 n S S :ä es o.: SI 1. — ~ 2 H * +2 "m M M y." y..' a 5 M i * ^ a> 'g , .Q ja ¿j . * - - 03 P <»·? od-~ µ·~ MÄ (K.Q «jui° . bei0 ¡ M.™ M S = = e e: il sj«sgagi3-=s-=s-ga oioioio2.oSoïí , 3t* gf> gP> g 3 g gœ garj g«; «< 02 02 GO CC 02 «:«<«! <· << «¡S Downloaded From: http://archinte.jamanetwork.com/ by a University of Manitoba User on 06/17/2015 to the and in the of which varied from 27 bility safety, drug margin 73 Similar variations are found in intravenous to cent. the use per ouabain.3 similar variations of individual in Undoubtedly, suscepti¬ human be to are in the and should taken bility digitalis present always into account in The of of practical therapy. average margin safety all the in this was 48 cent. This is identical per experiments study with the result obtained with or ouabain.3 crystalline strophanthin The consideration that follows from these practical experiments is that the various when are bodies, mouth, although digitalis given by as much safer than intravenous administration of generally regarded when the entire the strophanthin, digitalis glucosids (either aqueous or alcoholic are the same risk is encoun¬ extracts) given intravenously, tered as in the which In with the using fact, rapidity strophanthin. on the not'seem differ no act heart does to much matter drugs very is In one what into the circulation. preparation directly experi¬ put a was lethal dose and the toxic effect occurred in ment, single given two and standstill in sixteen minutes. doses of minutes, Large single death in from nine to minutes.3 In two strophanthin produce thirty the interval between was experiments injections purposely prolonged to minutes to allow the of how twenty-four opportunity determining soon after an the effect It found that the toxic was injection appears. effect occurred within three minutes after In the injection. experi¬ with an interval of six minutes menting crystalline strophanthin, between was found to out injections sufficiently long bring any that from twelve minutes is, did not changes, waiting to'twenty-four alter the results. same the were observed Practically findings using an occur i. if effect is to at all with digitalis; e., interrupted injections one. it will result within six minutes after the last CONCLUSIONS between 1. The of difference the mini¬ average margin safety (the dose of mum lethal and the minimum toxic various dose) digitalis when cats found be 48 to was to preparations given intravenously per cent. 2. The with intravenous similar which acts is to rapidity digitalis no and does not differ matter what strophanthin, prepara¬ appreciably is tion into the blood stream. put The 3. risk in intravenous from these appears digitalis therapy to be as as in intravenous great experiments strophanthin. We wish to our to Dr. of Atlantic express appreciation Philip Marvel, Jr., City, N. for his kind assistance in the first three J., experiments. Downloaded From: http://archinte.jamanetwork.com/ by a University of Manitoba User on 06/17/2015

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$THE MARGIN OF SAFETY OF INTRAVENOUS DIGITALIS IN CATS SAMUEL A. M.D. and DONALD M.D. LEVINE, T. CUNNINGHAM, BOSTON The medical has become interested in intra- profession greatly venous no in recent and evidence of therapy years, although particular this enthusiasm has been reflected in the treatment of heart disorders, the work of the administration of Eggleston,1 introducing large single doses of well lead others to the effect of mouth, digitalis by might try similar In the intravenous cardiac preparations intravenously. past, has been limited to of therapy essentially preparations strophanthin, which is considered be a With this to generally dangerous procedure. in an introduction was made to determine whether the mind, attempt into more the blood stream of in its and less potent digitalis complete form would to be a safe method for effect. prove obtaining therapeutic The of has been taken as the difference between the margin safety minimum lethal dose and the minimum toxic dose (M.L.D.) (M.T.D.). We introduce the of the of of concept margin safety digitalis prep- because in dose arations the use of the the practical drug therapeutic it is close to the toxic dose. is of Therefore, very great importance to know how far removed the lethal dose is from the toxic and dose, whether the is in than in others. some margin greater preparations The minimum lethal dose is that which is dose to cause just required standstill the heart of and death when the is digitalis preparation given in over a doses of about one similar to the interrupted hour, period method of Hatcher.2 In work one of us it was shown previous by that the toxic and lethal doses are of the of adminis¬ independent speed of tration of the from a fifteen minutes four to hours; drug period in this were and, therefore, work the not at con-, injections given any sometimes stant the lethal effect in about one-half speed, producing in hour and sometimes two hours or Some difference more. of opinion exist the as to occurrence of the toxic effect. It is might generally that the of heart appearance block, ventricular com¬ thought changing and indicate The latter is the most plexes, extrasystoles toxicity. common event in and this was considered cats, in the generally timing From the Medical Clinic of the Peter Bent Brigham Hospital, and the of Harvard Medical Department Medicine, School. 1. C.: Eggleston, Digitalis Arch. Int. Med. 16:1 1915. Dosage, (July) 2. R. and G.: A Standardization Hatcher, A., Brody, J. Biological of Drugs, Am. 1910. J. Pharmacy 82:360, 3. S. A.: The Levine, Action of on the Cat's Strophanthin Living Heart, M. 1919. J. Exper. 29:485, Downloaded From: http://archinte.jamanetwork.com/ by a University of Manitoba User on 06/17/2015 toxic dose. This criterion has the added it is the most advantage'that clinical of for heart block in itself important sign toxicity, rarely of the the while indicate circulation, impairs efficiency extrasystoles an increased of the and when cer¬ irritability ventricles, numerous, the diminish effective of the heart. The minimum toxic tainly output is calculated in these the dose, therefore, as smallest dose experiments that is to extraventricular required systoles. produce METHOD OF PROCEDURE Cats were used in other animals because to preference laboratory their reaction to is more like that the of human The digitalis subject. was cat on the animal etherized, board and the front placed right leg and left hind with A connected the cánula leg electrocardiograph. was inserted in the -vein and attached a small right saphenous by a cc as a rubber tube to 10 calibrated which served buret. The pipet was normal and the dose of the taken, electrocardiogram preparation was to be used then allowed to flow into the vein. One minute before an each dose was until a toxic effect was taken, electrocardiogram shown about where this was to expected, previous experience having occur. the two critical the of toxic and During periods, beginning lethal the movements were effects, of the watched galvanometer string and taken were to detect the earliest carefully, frequent tracings abnormality. different were The was Various used. first digitalis preparations an extract of aqueous powdered digitalis (Marion, Virginia leaf) pre¬ Pratt to the second was ;4 pared according Squibb's powdered digitalis leaves in the same the third was tincture of prepared way ; Squibb's in and three different digitalis, finally, digitalis preparations ampoules for and intramuscular details subcutaneous use were tested. The of In the are in the table. three experiments given accompanying experi¬ the of of intra¬ ments margin safety (M.L.D. average M.T.D.) venous of extract was 50 aqueous digitalis (Virginia leaf) cent., per half that it as much of the is, to required approximately drug produce as to An extraventricular it did cause standstill of the heart. systoles identical was obtained in the per of three figure (50 cent.) average the extract of leaves. using aqueous experiments Squibb's digitalis The for tincture of was average Squibb's digitalis (five experiments) 40 cent.; for 50 per per cent.; digifolin ampoules (one experiment) for and 56 for per cent., digalen ampoules (one experiment) digi- 64 cent. It is evident that puratum ampoules (one experiment) per are individual variations in different there both in the cats, suscepti- 4. West, H. and P.: Clinical with a Standardized F., Pratt, J. Experience Extract of Digitalis, J. A. M. A. 74:1389 15) 1920. Aqueous (May Downloaded From: http://archinte.jamanetwork.com/ by a University of Manitoba User on 06/17/2015 a a a a s e 1 os sa µ tua al- . _ 5^ •5·« µ S S S .5 » tì *- . µ, S ft a s ¿a =i >s PS. 8 g g 3 * ^¿. rHîO l-l a a a a a^a^a^a^B^s"« 6g .X-0).J> . - Ç-t ^ .¡SOU Od Ow© OOOOOOOtN p. d « P^ w - O ^ o S s a a a a a s tuJcN cmao Ä0^- m öfiiö bo „, ,* CO - ¡vi <N Ift 0 O ri «g <M 00 * CO CO "* Tt< IO CO 1-1 .- r-i cg weg wco w55 co ^ woÌ *—-a a e a a il ! S a ¿"¿ — a" — — — HHNMMWC o Co >> >> ki * E* £· t- *-< t- 4) CJ ai S Oí Ö >_, >H. > -\ > t> 7" > rt O i « * a» ß s B B -S (j » á; á a « < .a o £ S s e .y .y _fl ^ « s s a ó s ao « a«a«a ó « «g¿s .a «a CO to aj to âj;^ cjç0 -* ci ^ eveo ü aï i*· ci ce co # - ^ «"·« =1 S "5 n S S :ä es o.: SI 1. — ~ 2 H * +2 "m M M y." y..' a 5 M i * ^ a> 'g , .Q ja ¿j . * - - 03 P <»·? od-~ µ·~ MÄ (K.Q «jui° . bei0 ¡ M.™ M S = = e e: il sj«sgagi3-=s-=s-ga oioioio2.oSoïí , 3t* gf> gP> g 3 g gœ garj g«; «< 02 02 GO CC 02 «:«<«! <· << «¡S Downloaded From: http://archinte.jamanetwork.com/ by a University of Manitoba User on 06/17/2015 to the and in the of which varied from 27 bility safety, drug margin 73 Similar variations are found in intravenous to cent. the use per ouabain.3 similar variations of individual in Undoubtedly, suscepti¬ human be to are in the and should taken bility digitalis present always into account in The of of practical therapy. average margin safety all the in this was 48 cent. This is identical per experiments study with the result obtained with or ouabain.3 crystalline strophanthin The consideration that follows from these practical experiments is that the various when are bodies, mouth, although digitalis given by as much safer than intravenous administration of generally regarded when the entire the strophanthin, digitalis glucosids (either aqueous or alcoholic are the same risk is encoun¬ extracts) given intravenously, tered as in the which In with the using fact, rapidity strophanthin. on the not'seem differ no act heart does to much matter drugs very is In one what into the circulation. preparation directly experi¬ put a was lethal dose and the toxic effect occurred in ment, single given two and standstill in sixteen minutes. doses of minutes, Large single death in from nine to minutes.3 In two strophanthin produce thirty the interval between was experiments injections purposely prolonged to minutes to allow the of how twenty-four opportunity determining soon after an the effect It found that the toxic was injection appears. effect occurred within three minutes after In the injection. experi¬ with an interval of six minutes menting crystalline strophanthin, between was found to out injections sufficiently long bring any that from twelve minutes is, did not changes, waiting to'twenty-four alter the results. same the were observed Practically findings using an occur i. if effect is to at all with digitalis; e., interrupted injections one. it will result within six minutes after the last CONCLUSIONS between 1. The of difference the mini¬ average margin safety (the dose of mum lethal and the minimum toxic various dose) digitalis when cats found be 48 to was to preparations given intravenously per cent. 2. The with intravenous similar which acts is to rapidity digitalis no and does not differ matter what strophanthin, prepara¬ appreciably is tion into the blood stream. put The 3. risk in intravenous from these appears digitalis therapy to be as as in intravenous great experiments strophanthin. We wish to our to Dr. of Atlantic express appreciation Philip Marvel, Jr., City, N. for his kind assistance in the first three J., experiments. Downloaded From: http://archinte.jamanetwork.com/ by a University of Manitoba User on 06/17/2015$

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THE MARGIN OF SAFETY OF INTRAVENOUS DIGITALIS IN CATS

THE MARGIN OF SAFETY OF INTRAVENOUS DIGITALIS IN CATS

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THE MARGIN OF SAFETY OF INTRAVENOUS DIGITALIS IN CATS

THE MARGIN OF SAFETY OF INTRAVENOUS DIGITALIS IN CATS

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