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Vol. i.sri. rr- ■*'"" «"■' •<'' Ami . . •.-. .'.iKiPii \i A--i'fiATii>\ I UK \(;n The Standardization of Digitalis and the Potency of American- ¥ Grown Digitalis i. (i ROW X r R i: I-. Ml) \| I XM Arii|.|> A X I > 1) I. M At ir|-. .M.I), i: \i;n \i()Ki: THK STANDARDIZAI lOX Ol" DKIllALIS AND Tin-: PO TF XC Y OF AMKRICAX- (;ro\vx i^ir.riAi.is* L. G. ROWNTRKH, M.D. MINNEAPOLIS AND D. I. MACJIT, M.D. nAI.TIMORE This study was undertaken by us, at the suggestion of Dr. Janeway, in the endeavor to insure digitalis preparations of maximum and known efTectiveness for use in the wards. These desiderata are so rarely ful- filled in any hospital that the results we have obtained seem worthy of a brief report. MKTIIiiDS OF STANDARDIZATION Two methods of biologically standardizing digitalis preparations are commonly employed: the so-called "frog" method, and the so-called "cat" method. After a number of preliminary experiments it was found that the frog method was less reliable for the standardiza- tion of the infusion than the cat methods the latter method was therefore exclusively employed in this work. The technic followed by us was suggested by Hatcher and Brody,^ and is somewhat similar ':o that described by them, and consisted in determining the minimal fatal dose per kilogram weight of cat, the drug being injected slowly into the femoral vein. Our procedure was briefly as follows: A heahhy cat was anesthetized witli ether, and a cannula inserted into a femoral vein, suhscquently a minimum amount of ether being administered, just sufficient to keep the animal * From the Medical Clinic of the Johns Hopkins Hospital, and Pharmacological Laboratory of the Johns Hopkins University. 1. It is advisable to m.ike three toxicity experiments with each I reparation and to take the average. As a rule wide variations are not encountered. 2. Hatcher and Brody: Am. Jour. Pharm., 1910, lxx.\ii, 360. qtiict. Ten c c. of the itifusion of digitali'^ were slnwly injected into the vein in the course of five minutes, and there- after 1 c.c. every two niiinitcs until the death of the animal. The total amount of the druR injected divided hy the weigiit of the animal pave tlic strenKth of the preparation in tirms of so-called "cat nnif.." The following protocol will serve as an illustration : F.xpcrinicnt. April 30, 1015. Cat weighing 2.f) kg. ("annula in left femoral vein, light ether anesthesia. .1:20 p. m. experiment begins. Pulse 160 per min. Slow injection uf infusioii digitalis. . liiiihlicil iiijti tiuii of 10 c'.< 1 c. ,1:27 InjpclCil .1:29 Injected .V.II Tiijerted ?:?^ Injected ,1 :.1S , , Injected .1 :.ir Injected ^■.y> In'ectcd ,1:41 Injected 3:4.1 Injected 3:45 Injected 3 :4r Injected 3:4') Injected .1 :.~1 InjcctPil 3:53 Injected 3:55 Injected 3:57 Injectett 3 :.^9 Injected 'rnt:d aiiinnnt of infnfir>n — Tlurrfore Ictli.il dusc -- . .Pulse 1 10 [ler niiniitc . .Pulse 120 1 c.i Pulse inn 1 c.c Pulse 72 rcspir.itinns rii'id 1 c.c Pu'se 72 vtnuits 1 c.c Pulse 72 1 c.c Pulse 60 1 c.c Pulse 14.S 1 c.c Pulse 160 1 c.c Pulse 160 1 c.c Pulse I.SO 1 c.c Pul.se 168 1 c.c Pulse 240 1 c.r Pulse 240 1 c.c Pulse 240 1 CA Pulse irrCKul ir, very iiiiid 1 c.c Pulse irrrcnl.ir, very rapul 1 c.c Pulse dc .^11 c.c. id: li(,irt in systole 2.6 10 c.c. per kj.- I'lV this luclhud dillcrciil infusions of digitalis pre- pared from two batches of Allen's English leaves were assayed: the one from the stock of the pharmacy of the Johns Hopkins Hospital, the other an infusion ])rocurcd from a well-known pharmacy in New York. The lethal dose of the former was found to be 13.5 c.c. per kilogram; that of the latter, 7.5 c.c. per kilogram. This difference in potency could be accounted for only in two ways : cither by dilTercnces in the method of jircparation or by variations in the intrinsic quality of the leaves. DIFFEREXCi:S IN POTENCY DUE TO METHOD OF PREPARATION A comparison was made between a New York infu- sior. of digitalis and an infusion from the same stock of leaves ])repared by our own pharmacist. The lethal ildse of the New York preparation wa ". 6.6 c.c. per The lethal dose of our O'.mi infusion froai / tlir >.imc kavcs was 9 c.c. per kil()<,'rani. I'uur days latrr the -anic prciiaratioiis, having been kept on ice, were rc>taiiikir(li/C(i, and f,'avc •'" '"hal doses of ().S r.c. and 9 c.c. per kilogran:, re -••vely, showing that the preparation did not dete.i< irate rapidly on -landing, a fact which has hccn pui.Ucd out recently by I lately r These ligurcs uidicated clearly a difference in ])otency due to the met'iod of preparation. The New Vork technic for preparing he infusion was then ascertained^ and applied to our own stock of English leaves. The lethal dose of this infusion was found to be 11.1 c.c. per kilogram of cat. An infusion made from the same leaves by the method formerly employed by our pharmacist gave a lethal dosage of 13.5 c.c. In order to ascertain still further how great a differ- ence in potency of infusions may result from varia- tions in the methods of preparing them, our pharma- cist, Dr. Wahl. prepared three infusions from the same lot of Allen's English leaves, by slightly different phar- maceutic nietboiis. Infusion 1 was ])repared accord- ing to the U. S. Pharmacopeia.* Infusion 2 was made by macerating the leaves with water plus 10 jicr cent, dilute alcohoi, iristcad of adding the alcfihol to the fmished product as directed in the U. S. Pharmacopeia. Infusion 3 was pre|)ared bv macerating tlie leaves with boiling water in a closed flask, and gently beating the contents of the flask during tlie whole jirocess of extraction. The lethal dose of Infusion 1 was found to be 11.4 c.c, that of Infusion 2, 9.5 c.c, and that of Infusion 3, 10.6 c.c. iicr kilogram weight of cat. Thus it will be seen that a considerable variation in the |)otency of an infusion of digitalis may result from (lifTerences in methods of preparation. I V.MU.XTIONS niT. TO TIIK SOrRCE OF Tiir, i.E.wr.s The (liiTerence in the potency between the New York infusion and our infusions just described could not be entirely explained by variations in the method of prep- aration, but were also obviously due to differences in 3. The method nf rrep.iring the infusion employed at Johns Honkin« is the offici.ll method of th- U: S. P. The New York technic differed from this in some details which need not be gone into in this place. 4. AlthouRh the U. S. P. gives specific direction for preparing the infusion of d-gitalis, we have good reason to believe that those directions are not always followed. Compare Alpcrs; Jour, of Am. Pharmaceut. Assn., June, 1915, p, 715. the inherent (luahlies of the leaves used. Tlic next step in the investifjation was therefore to assay infu- sions of (hgitahs prepared by a uniform method from various lots of (hgitalis leaves obtained from various sources. Great variations in the strength of the products were noted. It was found tliat an infusion prepared according to the U. S. rharniac()])eia from our stock of English leaves yielded a j)roduct with the lethal dose of 13.5 c.c. That of an infusion from another lot of English leaves was found to be 9.6 c.c, while still another lot of English leaves yielded an infusion, the lethal dose of whicli was 8.7 c.c. per kilogram. An infusion pre- pared from some (jcrman digitalis leaves found in the iiospital ])harmacy ,ir'^ved very inferior in quality, giv- ing a letlial dose of 19 c.c. per kilogram weight. rOTKXCV OF .\MK.RK.\N I.i:.\VKS It was especiallv interesting to fuid that certain American grown digitalis leaves yielded a product of a very higli (|uality. Two lots of .\nierican leaves were as:;aved l)v us. One was a .■Mpi)ly of Wisconsin leaves kindly ])rcsented by Dr. (jeorge B. Roth of the Ilvgienic Labor.i'or' 'm Washington. The second was obtained from Dr. i. Krcmers of the Pharmaceutical h'xperiment Station, University of Wisconsin. The first yielded an infusion with a lethal dose of 7.6 c.c, and the second an infusion with a potency of 7.8 c.c. per kilogram weight of cat. It is evident that both iiit'usinns made from the American grown leaves were -.uperior in potcncx to tlio^e made troni our stock i'.nglisb and ( icmian leaves, and in fact •-u]ierior to all other le.ivc< a>sa\ed liy ii-. We liave in America, ibercforc. ;i digitalis wliicb !•- unsur|iassc(l, Tlu-ougb tiie kindne---> ot' Dr. Kremers a -»upi)ly ol W i-consin Ic.iM's \\,iv '-ccinc'i au'l i-^ now being u-cd exclusively ill the w.irds ot' the Jolm^ llo]ikins llo'>pit,il. 1 II I MOK \i. riicM' in\ c-tig.itioiH s!rikiiij.;!\ em|iba'-i/c llu' iiitii 111' -landardi/atioii of digitali--. Xav.ilion^ in Utb.il (|o-e trmn ().() to 1") cc per kilogram weight - ,ii)proxi in.inb .>(K) per cent, were (ouikI m infii-ioiis pre- pared I'roni tiicsc N.irioii^ li.ive^. Certainly this is guaicr than ■~liould be tolrraled by liie profct-sion. S'ct in all ])rul)al)ilit\ still i,n-fatiT variati(jns cxi^t in liavf> |)nroliasi'(l in tlu' oi^-n niarkel. Standarilization reveals the strength of the digitalis lireparatioii and permits of graded dosage — more or less — according to the potency of the preparation, jhe physician's duty to his patient does not end with the prescribing of digitalis. Plainly it is incumbent on him to secure digitalis effects if the case is a suitable one. This is more likely to be acconi])l!shed if the potency of the ])re])aration is known. We are a'so brought face to face with another fact, that the name of this or that fnni does not always insure ])Otency or digitalis effect. .\s we have shown, American leaves can lie secured which are unsurpassed. The answer to the (luestion of potency is to be found in standardization, which is essential to the best treat- ment.