Reports of Societies

1926 BMJ (Clinical Research Edition)  
confined himself, in some opening remiiarks, to laying downt certain geineral principles, some of which in the past, he said, -1ad been left oult of sight. Everyone would agree as to the desirability of havilng the activity of every remedy which was potent in therapeutics indicated in sormle clear and intelligent notation. There was a large and rapidly growinig class of important remiiedies to which chemical standards for one reason or another wer-e not applicable, and in these the necessity
more » ... se the necessity for biological measurement had never been called in question. No one ha(l suggested, for example, that diphtheria antitoxin slhould be measured simply bv the quantity injected; insuliin wi-as in the same position. There had been, however, a teniden-cy in some qua-ters to doubt the need for and even the valuie of a biological test in the case of remedies such as digitalis and its allies, which had behind them a long historv of more or less successful application in therapeutics before biological miethods of assay were available, and it was urged that as diogitalis differed in its action with different individuals the value of a biological standard was impaired. That point of view was not likely to appeal to the experimental worker, who held that the thing to keep in view was tlie absolute necessity of being able to isolate one variable factor for observation while the others were nmainitainied as rigidly conistant as possible. When a remedy had a definite and specific action w-hich could not be accurately gauged by cherrical tests, but couild be measured by a biological test, this latter ought, always to be made. Aniotlher obvious principle was that the word " standardizatioin " hlad no1 proper use except in relation to some generally accepted standard. Hitlherto progressive manufacturers who recognized the need of controlling the activity of certain remedies by biological tests had had no official stanidard to work to. They had accordingly worked to standards of their own-no blame was imputed to the manufacturers-and the result had been to strengthen the resistance of conservatism aid-scepticisin with regard to the desii-ability of general standardization. Already, however, the standards for diphtheria and tetanus anititoxins, insulill, tand salvar san, to mention no others, had been defined ,by internationial agr eemiienit at conferenices attended by representatives of as many as nine nationalities meeting under the auspices of the Health Committee of the League of Nat ions, and much useful work had beeni dione in that direction, and was continuing. Dr. Dale gvent on to urge that the proper basis of all biological stan1dardization must be comparative. To lay down biological tests in absolute ternms of some aninimal reaction was bound to lead to confusion-a point which he exemplified by the confusion which was threatened in the case of inisulin wheni people in different counitries tried to define its activity in terms of differlent animal reactions. The Edinburgh conference in 1923 declared that the activity of inisulin ought to be evaluated by comparison with a stable standard, anid this had niow been prepared and was kept at the Institute -at Hampstead. With regard to the methods of biological comparison, it might seem almost superfluous to demand that they should be reasonably accurate in measurement, and that what was measured should be the therapeutic activity of the substanice under test; but experience had shown that it was really nlecessary to insist uponi so elementary a point as that. Dr. J. W. TREVAN gave details of oertain well established tests for remedies niot standardizable by chemical methods. The errors which came in were largely-almost entirelydue to the variability of the animal or isolated organ which was u.sed for the test. He indicated the difficulty by describing an experiment in which 250 frogs had been injected with strophanthus, and it took three times as much pel animal to kill all the frogs as it took to kill IZATION OF R1EMEDIES. I[ THE BRItS A 39 a very smiiall proportion of them. Similar variations6 took p)lace with the isolated organs. The variations as between onie frog's heart anid anothler -ere of the rallge of 1 to 200. The first method of eliminating this factor of variability was to use some reaction of the animal or the isolatedl orgain which w-as quickly reversible so that the test could be repeated withinl a comparatively short time. Not all drugs couild be so tested, but the method lia(1 been used witlh adrenalinie and pituitary extract and with some preparations of dligitalis. If the action was iiot reversible the conditions of exp)eriment were much more difficuilt. In that case the way to elinminate the errors due to varilability was by usig large numllbers of mice or of frogs, a-s the case might be, so increasing tlhe number of tests, and working out the values for the proportion that died. This applied to the testing of digitalis on frogs and on cats and the testing of insulin on mice. Not only did one aniimal differ from another in sensitivity, but the whole stock of aniimals showed p)eriodical chaniges. The average lethal dose for insulin and digitalis and for a number of other drugs-though not for all-miiight vary. Until it hiad beeni demonstrated that any given lethal dose method (lid not suffer from the shift in the average lethal dose it muist always be assumed that such a shift might take place. There was another way in which the disadvan-tage of nionireversibility in the action of a drug might be overconme namely, the method of injecting digitalis tincture inito the vein of an anaesthetized cat until the heart just stopped, and finding out the dose necessary to produce that effect. The statistical eirror in that method was rather less tlhaii in the method of injecting a large number of animals anid working out the figures from the percentage of mortality. Dr. J. H. BURN drew attention to the close relations which had now been determined between the results of laboratory and clinical methods in many instanices. In a comparison which had been carried out between the laboratory miiethod of testing insulin and the clinical method the agreement was extreimiely good. Certain laboratory tests with rabbits carried out at Hampstead by Dr. H. P. Marks had been compared with certain clinical tests donie by Drs. Lawrence and Harrison, and the results made it clear that the laboratory was measuring what the cliniician wanted. The same was true with regard to digitalis. There had been one or two previous attempts to show that the vaiiations in the testing of digitalis by the laboratorv method were significant for the clinician, and such efforts had not always been successful; but certain figures which he showed, obtained in Baltimore, indicated that the effect of various preparations of digitalis on the cat and oIn the patient followed the same order. The workers in Baltimore, in their clinical observations, instead of using small doses maintaine4 over a series of days, gave one single large dose and determined the effect. All the cases were of auricular fibrillation which had not had digitalis for some long time. While there was no close identification between the two sets of figures, there was a general miieasure of agreemiient, and that, in the case of an agent given by the miouth, was, he thought, all that could be expected. It was important that clinicians should realize that pharmaoologists did work on the understanding that what they were measuring in the laboratory was what the cliniciani wanted. Dr. GEORGE GRAHAM (from the chair) said that he di(l not think cliniicians had any idea of the amount of work done for their service in the laboratory. He agreed that the-fact that patients exhibited idiosyncrasies to digitalis was no ground for objecting to the standardization of the drug. There were no means of calculating for these idiosyncrasies, but he thought the original introducer of digitalis into medicine would be heartily with Dr. Dale IIL insisting on its standardization. Dr. DALE, in reply to a remark of Dr. Trevan's on the difficulty of standardizing vitamin value, said that he thought the compilers of the United States Pharnmacopoeia had been precipitate in introducing a test supposedly for the vitamin A activity of cod-liver oil, in view of tho fact that the whole vitamin question was in a state of flux. If anything was going to be done along that line, the only sound principle would be to establish in this case also a stable standard by which workers in different *6OV. 20,-i926] I
doi:10.1136/bmj.2.3437.939 fatcat:qcavrrzbjfbshhonk4vgdepnru