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American Association for the Advancement of Science—Pharmacy Subsection Meeting
500
JOURNAL OF THE
AMERICANPHARMACEUTICAL ASSOCIATION
Vol. XL. No. 10
TABLE I11
(I
b C
Drug
N. F. and u. s. P. Therapeutic Dose, Mg.
Ratio" to Dig. Tr.
Digitalis Tr. Digitoxin Digoxin Olnerin Strophanthus Tr.
100.0 0.1 0.5 0.1c 50.0
1000.0 200.0 1000.0 2.0
Chick Embryo
LDM,Mg.
52.0 0,042 0.490 0.046 19.0
Ratiob to Dig. Tr.
Confidence Limits
1238.0 106.0 1130.0 2.7
1529-961 155-72 1253-1019 4-1
19/20
.
Dig. Tr. therap. dose (mg.)/Drug therd dose (mg.). Digitalis Tr.LDMto chick embryo (rngJ/Drug LDw to chick embryo (mg.). Assumed.
Table I11 is a comparison of U. S. P. average therapeutic doses using digitalis tincture as a point of reference, and the relative potencies found by the chick embryo method. It may be seen that there is good agreement for all drugs, with the single exception of digoxin. This exception was not anticipated in view of the findings of DeGraff, Paff, and Lehman (2). Their comparison was with a different point of reference and was based on digitalizing dosage rather than an average dose.
A11 three time readings for the same dose range approximate a b value of 12, however, the 19/20 confidence limits for the EDm appear to be narrowed for a time interval of four hundred and fifty seconds. Due t o limited circumstances, the day t o day or week t o week changes that might occur in responses to the Same doses were not investigated. In view of the information presented, and with a potential method of bioassay in mind, four hundred and fifty seconds was chosen as the standard time for the response to be determined. A few preliminary observations established the dose ranges yielding adequate responses for strophanthus tincture, digitoxin, digoxin, and olnerin. The results are summarized in Table 11. There was no attempt made to investigate changes occurring a t increasing dose ranges for each of these drugs. It is probable that the values for the slopes could be increased with increasing doses, but it would be necessary to adjust t o a shorter time. However, the distribution of responses seems more desirable at the dose ranges shown. The 19/20 confidence limits for the ED60 of digitoxin (f140/,)and olnerin ( &12y0) parallel the limits for digitalis tincture. Those for digoxin ( f40y0) and strophanthus tincture (A7073 are extremely high. The reason for this is not known; however, there should be additional investigation as to the effect of varying dose ranges and time intervals on these two drugs. The range for strophanthus tincture is a t a maximum, since any increase results in 90 t o 100% response for all three doses within the specified time limit. Both strophanthus and digoxin seem to be troublesome in most bioassays.
CONCLUSIONS
A technique has been described for the assay of cardiotonic drugs using intact chick embryonic hearts. A three-dose pattern of assay has been utilized. A good correlation has been established between the therapeutic doses a n d the chick embryo LDao of t h e drugs tested. It appears that the intact chick embryonic heart affords a simple, cheap, a n d reliable medium for the evaluation of cardiotonic drugs.
REFERENCES (1) Chapman. C. W., Lecture, School of Pharmacy, Uni. versity of Maryland. (2) DeGraff, A. D., Paff. G. H., and Lehman, R. A,, J . Pharmacol. E x p f l . Thcrap., 72,223(1941). (3) Lehman, R. A., and Paff, G. H., ibid., 75, 207, 214. 21 .5(1942) _ _ _ \
(4) Paff, G. H.,ibid.,69,311.313(1940). (5) Hall, E. M., A m . J . Pharm., 104,311, 312(1932). (G) Litchfield. J. T.. and Wilcoxon, F., Federation Proc. 7, 240( 1948).
* American Association for the Advancement of Science-Pharmacy Subsection Meeting The next meeting of t h e American Association for the Advancement of Science will be held in Philadelphia on December 26-31, 1951. The program of the Pharmacy Subsection of the Medical Sciences is being made up. Six sessions of this Subsection will be held. Members are invited to attend the meetings of t h e Section on Medical Sciences, Subsection on Medicine, and the Section on Chemistry.
JOURNAL OF THE
AMERICANPHARMACEUTICAL ASSOCIATION
Vol. XL. No. 10
TABLE I11
(I
b C
Drug
N. F. and u. s. P. Therapeutic Dose, Mg.
Ratio" to Dig. Tr.
Digitalis Tr. Digitoxin Digoxin Olnerin Strophanthus Tr.
100.0 0.1 0.5 0.1c 50.0
1000.0 200.0 1000.0 2.0
Chick Embryo
LDM,Mg.
52.0 0,042 0.490 0.046 19.0
Ratiob to Dig. Tr.
Confidence Limits
1238.0 106.0 1130.0 2.7
1529-961 155-72 1253-1019 4-1
19/20
.
Dig. Tr. therap. dose (mg.)/Drug therd dose (mg.). Digitalis Tr.LDMto chick embryo (rngJ/Drug LDw to chick embryo (mg.). Assumed.
Table I11 is a comparison of U. S. P. average therapeutic doses using digitalis tincture as a point of reference, and the relative potencies found by the chick embryo method. It may be seen that there is good agreement for all drugs, with the single exception of digoxin. This exception was not anticipated in view of the findings of DeGraff, Paff, and Lehman (2). Their comparison was with a different point of reference and was based on digitalizing dosage rather than an average dose.
A11 three time readings for the same dose range approximate a b value of 12, however, the 19/20 confidence limits for the EDm appear to be narrowed for a time interval of four hundred and fifty seconds. Due t o limited circumstances, the day t o day or week t o week changes that might occur in responses to the Same doses were not investigated. In view of the information presented, and with a potential method of bioassay in mind, four hundred and fifty seconds was chosen as the standard time for the response to be determined. A few preliminary observations established the dose ranges yielding adequate responses for strophanthus tincture, digitoxin, digoxin, and olnerin. The results are summarized in Table 11. There was no attempt made to investigate changes occurring a t increasing dose ranges for each of these drugs. It is probable that the values for the slopes could be increased with increasing doses, but it would be necessary to adjust t o a shorter time. However, the distribution of responses seems more desirable at the dose ranges shown. The 19/20 confidence limits for the ED60 of digitoxin (f140/,)and olnerin ( &12y0) parallel the limits for digitalis tincture. Those for digoxin ( f40y0) and strophanthus tincture (A7073 are extremely high. The reason for this is not known; however, there should be additional investigation as to the effect of varying dose ranges and time intervals on these two drugs. The range for strophanthus tincture is a t a maximum, since any increase results in 90 t o 100% response for all three doses within the specified time limit. Both strophanthus and digoxin seem to be troublesome in most bioassays.
CONCLUSIONS
A technique has been described for the assay of cardiotonic drugs using intact chick embryonic hearts. A three-dose pattern of assay has been utilized. A good correlation has been established between the therapeutic doses a n d the chick embryo LDao of t h e drugs tested. It appears that the intact chick embryonic heart affords a simple, cheap, a n d reliable medium for the evaluation of cardiotonic drugs.
REFERENCES (1) Chapman. C. W., Lecture, School of Pharmacy, Uni. versity of Maryland. (2) DeGraff, A. D., Paff. G. H., and Lehman, R. A,, J . Pharmacol. E x p f l . Thcrap., 72,223(1941). (3) Lehman, R. A., and Paff, G. H., ibid., 75, 207, 214. 21 .5(1942) _ _ _ \
(4) Paff, G. H.,ibid.,69,311.313(1940). (5) Hall, E. M., A m . J . Pharm., 104,311, 312(1932). (G) Litchfield. J. T.. and Wilcoxon, F., Federation Proc. 7, 240( 1948).
* American Association for the Advancement of Science-Pharmacy Subsection Meeting The next meeting of t h e American Association for the Advancement of Science will be held in Philadelphia on December 26-31, 1951. The program of the Pharmacy Subsection of the Medical Sciences is being made up. Six sessions of this Subsection will be held. Members are invited to attend the meetings of t h e Section on Medical Sciences, Subsection on Medicine, and the Section on Chemistry.