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A plea for uniformity in the biological standardization of commercial preparations of digitalis
Correspondence
The chemistry of the digitalis glucosides is, as yet, but imperfectly undcrstood. Chemical assay is therefore not feasible, and it is necessary to resort to the technic of biological standardization. Most of the digit,alis products now marketed in America are so standardized. The present situation with respect to the biological assay of digitalis is unsatisfactory both to practitioners of medicine and to the manufacturing drug firms. The various fwct,ors which lcad to confusion arc as follows : 1. The one-hour frog method is official in the Pharmacopeia. of the United States. 2. Other methods of assay have been devised, and one or another of these is employed for the standardizat,ion of commercial products, e.g., the cat method of Hatcher and Brody, the guinea-pig method of Vandcrkleed, and the Magnus modification of the Hatcher-Brady technic. The establishment of an international unit has also been attempted, and at Icast one firm markets a preparation said to be assayed in terms of this unit. 3. There is abundant evidence which indicates that the cat mcthocl of Hatcher and Brady yields uniform and reliable result,s, and that the relative potencies of different preparations, as determined by this method, apply to human dosage. When a specimen is found to be twice as active as another by this method, it is also twice as active in man. 4. No standard of potency has been established for preparations that are assayed by the cat method. Thus, 1 cc. of a given tincture may COHta,in the equivalent of l/z cat unit; 1 c.c. of another tincture may contain 2 cat units. Tablets, pills and capsules vary in like fashion. When the physician prescribes digitalis, hc is entitled to receive a dependable and uniform product. The drug manufacturer requires, and is anxious for, guidance and support from the medical profession. He is confronted on the one hand by the IT. S. Pharmacopeia, which sets its stamp of approval upon the frog unit; and on the other hand, by a majority of competent cardiologists and pharmacologists, who favor the use of the cat unit. The Heart Committee of the New York Tuberculosis and Health Association has, for a number of years, distributed to its constituent cardiac 542
clinics tablets of digitalis leaf st,andardized by the cat method of Hatcher and Brady. The tablets have been made up to the strength of one cat The espcricncc with this unit, one-half cat unit, and two cat units. preparation has been entirely satisfactory. On the basis of the facts cited, the following rccommendatio~ls art made by the Heart Committee of the New York Tuberculosis and Health Association : 1. For the present, and until further knowledge may necessitate a change in point of view, digitalis preparat,ions should bc standardized For convenience the exact by the cat method of Hatcher and Brady. procedure now followed in 1Ir. Hatcher’s laboratory is appended. ‘2. In marketing commercial products, liquid preparations of digitalis should bc put up so that 1 C.C. (15 minims) contains the equivalent of 1 cat unit. 3. In marketing tablet,s, pills or capsules of digitalis, each of these Tablets, pills or capsules should contain the equivalent of 1 cat unit. containing stated fractions or multiples of 1 cat unit may he dispensed, if desired. It is hoped that the manufacturing drug firms will adopt these simple suggestions, for by so doing they will be rendering a real service to the members of the medical profession and their patients. These recommendations have been approved by the IXxccutive Cornmittcc of the American Heart Association. APPESDIX The rst method of Hatclwr and Brady, as carried out in the Department of Pharmacology of the Cornell University Medical College, is as follows: The digitalis leaf to be assayed is first made up into a tincture, in accordance with the directions given in the U. 9. Pharmscopeis. The tincture is then diluted twenty times with physiological salt solution. The diluted tincture is injected slowly a.nd continuously from a burette iuto the saphenous vein of the cat until death rcsuits from ventricular fibrillation. The rate of injeetion is such that the total dose is injected in about ninety minutes. The test may be made during light ether anesthesia; or only local anesthesia may be employed, 1 per cent novocaine being injected or 10 per cent phenol being rubbed into the skin for the’ exposure of the vein. Six cats are usually employed for one test. Pregnant, lactating or excessively fat animals arf.3 not used. The cat unit potency of the preparation is the average of the results obtained with the group of animals and is expressed as the volume, in cubic centimeters, of undiluted tincture per kilogram of the animal required to cause death under the conditions described. The amount of leaf contained in this unit of tincture is readily calculated. (Signed) Ernst Alfred Arthur
P. Boas E. Cohn C. de Graff
Digitalis
Committt*e.
Cary Eggleston Harry Gold Bernard S. Oppenheimer Robert
L. Levy,
Chairman.
Harold E. B. Par&e Homer F. Swift John Wyckoff
The chemistry of the digitalis glucosides is, as yet, but imperfectly undcrstood. Chemical assay is therefore not feasible, and it is necessary to resort to the technic of biological standardization. Most of the digit,alis products now marketed in America are so standardized. The present situation with respect to the biological assay of digitalis is unsatisfactory both to practitioners of medicine and to the manufacturing drug firms. The various fwct,ors which lcad to confusion arc as follows : 1. The one-hour frog method is official in the Pharmacopeia. of the United States. 2. Other methods of assay have been devised, and one or another of these is employed for the standardizat,ion of commercial products, e.g., the cat method of Hatcher and Brody, the guinea-pig method of Vandcrkleed, and the Magnus modification of the Hatcher-Brady technic. The establishment of an international unit has also been attempted, and at Icast one firm markets a preparation said to be assayed in terms of this unit. 3. There is abundant evidence which indicates that the cat mcthocl of Hatcher and Brady yields uniform and reliable result,s, and that the relative potencies of different preparations, as determined by this method, apply to human dosage. When a specimen is found to be twice as active as another by this method, it is also twice as active in man. 4. No standard of potency has been established for preparations that are assayed by the cat method. Thus, 1 cc. of a given tincture may COHta,in the equivalent of l/z cat unit; 1 c.c. of another tincture may contain 2 cat units. Tablets, pills and capsules vary in like fashion. When the physician prescribes digitalis, hc is entitled to receive a dependable and uniform product. The drug manufacturer requires, and is anxious for, guidance and support from the medical profession. He is confronted on the one hand by the IT. S. Pharmacopeia, which sets its stamp of approval upon the frog unit; and on the other hand, by a majority of competent cardiologists and pharmacologists, who favor the use of the cat unit. The Heart Committee of the New York Tuberculosis and Health Association has, for a number of years, distributed to its constituent cardiac 542
clinics tablets of digitalis leaf st,andardized by the cat method of Hatcher and Brady. The tablets have been made up to the strength of one cat The espcricncc with this unit, one-half cat unit, and two cat units. preparation has been entirely satisfactory. On the basis of the facts cited, the following rccommendatio~ls art made by the Heart Committee of the New York Tuberculosis and Health Association : 1. For the present, and until further knowledge may necessitate a change in point of view, digitalis preparat,ions should bc standardized For convenience the exact by the cat method of Hatcher and Brady. procedure now followed in 1Ir. Hatcher’s laboratory is appended. ‘2. In marketing commercial products, liquid preparations of digitalis should bc put up so that 1 C.C. (15 minims) contains the equivalent of 1 cat unit. 3. In marketing tablet,s, pills or capsules of digitalis, each of these Tablets, pills or capsules should contain the equivalent of 1 cat unit. containing stated fractions or multiples of 1 cat unit may he dispensed, if desired. It is hoped that the manufacturing drug firms will adopt these simple suggestions, for by so doing they will be rendering a real service to the members of the medical profession and their patients. These recommendations have been approved by the IXxccutive Cornmittcc of the American Heart Association. APPESDIX The rst method of Hatclwr and Brady, as carried out in the Department of Pharmacology of the Cornell University Medical College, is as follows: The digitalis leaf to be assayed is first made up into a tincture, in accordance with the directions given in the U. 9. Pharmscopeis. The tincture is then diluted twenty times with physiological salt solution. The diluted tincture is injected slowly a.nd continuously from a burette iuto the saphenous vein of the cat until death rcsuits from ventricular fibrillation. The rate of injeetion is such that the total dose is injected in about ninety minutes. The test may be made during light ether anesthesia; or only local anesthesia may be employed, 1 per cent novocaine being injected or 10 per cent phenol being rubbed into the skin for the’ exposure of the vein. Six cats are usually employed for one test. Pregnant, lactating or excessively fat animals arf.3 not used. The cat unit potency of the preparation is the average of the results obtained with the group of animals and is expressed as the volume, in cubic centimeters, of undiluted tincture per kilogram of the animal required to cause death under the conditions described. The amount of leaf contained in this unit of tincture is readily calculated. (Signed) Ernst Alfred Arthur
P. Boas E. Cohn C. de Graff
Digitalis
Committt*e.
Cary Eggleston Harry Gold Bernard S. Oppenheimer Robert
L. Levy,
Chairman.
Harold E. B. Par&e Homer F. Swift John Wyckoff