The Making of Medicines
An interesting paper on the manufacture of drugs, showing the recent development along this line.
ROBERT KENNEDY DUNCAN IN HARPER'S MONTHLY
THE one hundred and thirty thousand physicians in America do not make the medicines with which they dose their patients: they prescribe. The thirty-five thousand pharmacists who fill the million and more prescriptions with which they are confronted every day do not make these medicines, either; they dispense. These medicines are all either made or gathered by industrial organizations known as “manufacturers of pharmaceutical preparations”; every ounce of medicine swallowed by every patient in America comes, practically, from some such shop. Now, the physician must undergo a most arduous training before he is permitted to prescribe; the druggist must undergo a training almost equally arduous before he may dispense; but the manufacturer of the substances which the physician prescribes and the druggist dispenses needs only “hang out his sign”; no professional training or educational qualification is deemed legally necessary for the manufacture of drugs.
What is interesting, and in a presentday and very literal sense vitally interesting, is the extent to which scientific method may possibly be applied in the making of these substances ; for to writer and reader alike there will come a time, and lucky shall he be if it comes but once, when from a vial or through a needle he will take in them the issue between life and death. Whether it be hypnotic, stimulant, antipyretic, antiseptic, antitoxin, or what not, if it be insincerely or ignorantly or carelessly made, the earth may cover a mistake but
for which he might be walking among men in the sunlight. Because of the vital interest related to this manufacture and because it illustrates beautifully what men may succeed in doing, when they have the will, in employing scientific method in a business where it would seem impossible of application, and because, finally, it affords an object-lesson of the fact that the intelligent application of scientific method pays, always and wholly, the subject of modern science and drug-making constitutes the substance of this paper.
The drugs come from the uttermost parts of the earth—from the dank forests of Brazil, from the frozen Siberian steppes, from the banks of the “ greygreen, greasy Limpopo River, all set about with fever-trees, ’ ’ or from ‘ ‘ silken Samarkand”; but almost everywhere they are gathered by barbarous peoples, the lowest of earth ’s denizens. It is small wonder, then, that with any one plant there should be a variation among its individual specimens in the proportion of the active medicinal agent it contains. But when we add to this the fact that, in general terms, the per cent, of the active ingredient depends on the amount of sunshine it enjoys, on the time of the year it is gathered, even time of the day, on the amount of moisture, the elevation, the character of the soil, and a dozen other factors, it becomes almost a necessity of thought that the amount of “medicine” in that plant must vary from a maximum to nothing at all.
Such crude drugs are now assayed for
their per cent, of medicinal activity, by a testing department consisting of a large corps of able chemists and pharmacologists provided with an equipment that would do credit to any university.
First there is the chemical assay. To take an example: There is the herb hyoscyamus. or henbane, a clammy, fetid, narcotic annual or biennial. In the old days it was used to cure the gout, in accordance with this running invocation delivered to it the night before: “Sacred herb, I bid thee, I bid thee, to-morrow I summon thee to the house of my patient to stop the rheum of his feet. * *
The next morning, before sunrise, the herb was dug up with the bone of a dead animal, sprinkled with salt and conjurations, and hung about the gouty patient’s neck. Nowadays, the crude drug is extracted in enormous quantity with alcohol, and a test sample of the “fluid extract” is then analyzed by setting free its active therapeutic alkaloids with ammonia, dissolving them out with chloroform. and ultimately titrating them with sulphuric acid. In this way the company positively knows the therapeutic activity of the extract which it has manufactured, and it is also able, through two subsequent analyses, to dilute or concentrate it to a liquid of standard strength, which as anodyne, hypnotic, or narcotic passes, through the physicians, to the people.
In such a manner does this firm and others that are equally sincere manufacture the 5,000 fluid, solid, and powdered extracts and concentrations of drugs that the physician not only employs but relies upon, and in such a manner do not those many other manufacturers that are insincere, ignorant, or careless.
But chemistry, even at its present best, is incapable of assaying the active principle of any drug whatever. There exist superactive principles of so delicate a texture that they break down under analysis. Therefore, Messrs. Method and Efficiency have developed a great department of physiological standardization, in which the determined and educated members thereof ask that refractory drug, not, “How much is there of you?” but, “How much can you do?”
Thus there is ergot. A man ’s wife
goes bravely down to the gates of Death to pass through, or, if it may hap, to come slowly back, bearing radiantly with her the flaming torch of another life. Ergot is required. Now, ergot is a fungus growing upon rye, where it destroys and displaces the ovary of the plant. It comes from Russia, Austria, Spain, Sweden, and where not ; its chemical analysis does not seem to yield reliable information, for its active constituents are not definitely understood. Finally, the physiological activity of the drug may be good, or little, or zero, just as it may chance, while after the lapse 'of a year it becomes unfit for use. Yet it is this substance, so utterly variable, that the physician trusts to decide the question of the woman and the child. That he may do so depends upon this most curious and interesting fact, that ergot which is therapeutically active will blacken the cock’s comb of a living fowl, and that the degree of blackening may be so carefully adjusted by strengthening or weakening the drug that a standard preparation may be prepared. Consequently in this laboratory there are kept certain redoubtable roosters that continually function as standardizes of ergot.
Then there is cannabis indica, or Indian hemp, the dried flowering tops of a plant growing in the East Indies, and forming in different confections the “'hashish” or “bhang” of the East. This drug develops a resinous exudation that constitutes a powerful and valuable narcotic. The quantitative estimation of its active constituents is impossible in the present state of chemical science, and yet because it is perhaps the most variable drug of all materia medica some method of estimating its value is positively demanded. In order to standardize it, therefore, recourse is had to' the fact that when it is administered to a dog of a certain weight the normal active drug of a given quantity will cause a lack of muscular control or co-ordination. The company in this way has worried out a method of so preparing its extract that the physician may implicitly rely upon its action.
Again, there is digitalis, and for this drug the ocular observation of symptoms is not sufficient. As it is a valuable.^
heart tonic and stimulant, and as its chemical composition is wholly a vexed question, and because the crude drug is often adulterated, it is necessary in order to standardize it to determine the actual effect of a given quantity upon the heart’s action. For this purpose an animal is anesthetized, and its heart having been fixed between a little clamping apparatus, registers in the form of a curve its every movement upon a rotating smoked cylinder.
Another such substance is strophanthus, which is estimated by determining the least possible dose that will prove fatal to a frog of a definite weight. So determinate is this method that it has almost the accuracy of a chemical analysis. Thus a frog weighing from fifteen to seventeen grams is killed by a standard tincture of strophanthus in a dose of 0.00016 gram, but with 0.00015 gram it lives !
This drug, strophanthus, is a new remedy, an arrow-poison coming from the heart of savage Africa, and its mention leads one, in a search for significances, altogether away from the standardization laboratory, at the work of which we have but barely glanced, to a wholly different work of this firm —the discovery of new drugs.
Even in the early days this earnest, aggressive company recognized that among the strange peoples of the world there must be strange pharmacologies, and because of this it organized expeditions to seek out new medicinal plants. The Pacific slope of North America, the Fiji Islands, the West -Indies, the Amazon River, and Peru were exhaustively searched, and thus through their efforts, though others doubtless helped, there have come into the hands of the medical profession certain drugs that are invaluable—cocaine, from the yearly production of one hundred million pounds of coca; cascara sagrada, the temporal salvation of infants the land over; guaraña, for headache; yerbasanta, the balsam; grindelia robusta, the sedative; manaca, for rheumatism; tonga, checkan, pechi, jaborandi, and others.
But, and this is altogether significant, the search for new drugs among savage
peoples is by no means prosecuted with its old-time vigor.
The discovery that in coal-tar there existed many substances that could be used as a basis in building up the numberless aniline dyes led to the assumption that such substances might have valuable physiological properties, and the assumption was wholly justified; the investigative research along these lines began with the attempt to attain the philosopher ’s stone of druggery—the synthesis of quinine. Soon , it became recognized that not only the compounds of the benzene ring might have physiological properties, but that any one of the 50,006 organic compounds might have, and probably would have, properties that would affect the human organism. As a result, there is to-day an incredible number of new “synthetic” remedies introduced, through the physicians, to and into the people.
An ideal hypnotic is one that will produce a normal sleep as differentiated from a narcotic which produces unconsciousness by intoxication. The first of this series of drugs arose in 1869 with chloral hydrate, and this substance, even to-day, is the subject of a wide usage. But chloral hydrate, while it certainly does produce sleep, has a depressing action upon the heart, it sometimes acts as a toxic agent, and, very bad, there is an extreme danger of habituation— the chloral habit. Out of the proposed substitutes for it, there are some that appear only to disappear, others linger in practice a year or two, and some bid fair to become an integral part of medicine, but always there is something of disadvantage, and it takes years of experimentation upon patients before there can be a fully determined verdict. An ideal hypnotic seems impossible of present attainment.
The manufacturer of pharmaceutical preparations must be as careful of his reputation as a maid. Because this is so, it will be interesting to watch Messrs. Method and Efficiency in their search Method and Efficiency in their search for a new “synthetic” remedy. The search begins in their laboratory of organic chemistry. There, after it is decided
by the higher powers to seek for a better medicinal agent for some one of the numerous human ills, there will be found a member of the staff, a trained organic chemist, busily endeavoring to correlate with their chemical constitution the physiological properties of all the substances used for that particular ill. This is to a slight, but very slight, degree possible. Having studied the matter in this way, he is able to think of other compounds which because of their struction he thinks, or rather hopes, may manifest this therapeutic property in a greater degree. Having determined upon them, then, he proceeds to make them. This may take him a month or more, but finally, as definite, beautifully crystalline or liquid bodies, they pass out of his control into another laboratory altogether—that of physiological testing. Here they are one after another carefully and observingly administered to animals, and every visible physiological change is noted by efficient instruments—changes in respiration, in heart-action, in excretion, in metabolism, in their action upon nerve-centres, and others. This being accomplished after additional months of labor, some one of these substances, let us say, manifests in a superior degree a curative action upon that one human ill. It may now be supposed that the firm is ready to market its product; but not at all: a dog is one thing and a man is quite another. The firm now proceeds to send out to expert experimenting physicians privately in their employ sample packages of this substance for secret experimentation upon human subjects. This must be done, for there is no other way to obtain information. Now, this discreet experimentation on the human subject on the part of the employed physicians is extraordinarily difficult, and it sometimes takes a year or two before these men hammer out a consensus of opinion. Any physiological effect upon one organ reverberates through all the others, and by-effects and after-effects are often insidiously masked or unconscionably delayed. Even now the company does not feel satisfied, for it hereupon proceeds to send out packages of this same substance to the clinics, and it is only when the hospitals using the
directions and dosage of the company’s physicians obtain the same good results that the company goes to market with its new ware. When it does go to market, it goes, it must be confessed, with all the aggressive force of the company back of it, and with no uncertain advertising; though it ought also to be said that any advertising statement made to physician or pharmacist must first obtain the sanction of the scientific men on the staff; the company finding it advisable in this way to curb the temptations of its own advertising department.
Old drugs from plants and new drugs from the tar-barrel do not, however, exhaust the company ’s repertory of activities. Much of its capital is employed in the extraction or elaboration of products resulting from the animal organism.
The story opens with the little bodies known as the suprarenal glands. These two little bodies, weighing each about four grams in the adult man, lie near the kidneys. It was at first supposed that they had no function, that, in fact, they were mere vestigial remnants of organs such as to-day we are given to imagining the vermiform appendix. In 1855, however, Addison showed that in the event of their becoming either atrophied or attacked by a malignant growth, a peculiar disease supervened in man, which has since been named, after its discoverer, “ Addison ’s disease.” Next, Brown-Sequard showed that the removal of these organs from animals meant inevitable death. After this came the discovery that an extract of the gland contained a specific substance which, introduced into the blood of an animal, caused a marked rise in blood-pressure; and at length, in 1901, the Japanese, Takamine, working in Columbia University, though in the employ of this firm, and followed closely by Aldrich, also in the employ of the firm, succeeded in isolating from the gland of oxen, and in a pure form, its active principle. This substance was called by Takamine adrenalin.
Adrenalin is a light-yellow, lightweighing substance which under the microscope shows a crystalline form ; it has a slightly bitter taste and, tempor-
arily, a benumbing effect upon the tongue. In practice it is dispensed usually in the form of the chloride—adrenalin chloride. Adrenalin is a physiological agent so enormously powerful that the injection of one-millionth of a gram for every two pounds weight of an animal will cause the blood-pressure of that animal to suspend a column of water over seven inches higher than it otherwise would; so powerful that one twomillionth of a gram will produce distinct physiological results in the body of an adult man; the small doses of the homoepathists are thus gigantic as compared with those of adrenalin. This tonic increase in blood-pressure will take place under any degree of shock. It stops bleeding, and thus becomes invaluable in the treatment of all kinds of hemorrhages; and, not only so, it prevents in large measure the possibility of bleeding, and so permits of bloodless, or practically bloodless, operations; it permits, in fact, the surgeon to work in a clear field, as, to give an insignificant example, in the removal of the turbinate bones. The literature of adrenalin therapy is to-day enormous, for it is used in a most extensive way in much special and in all general medical and surgical practice. Its utility may be taken for granted; what is sought for in this paper is significancy, and this is found in the statement that adrenalin was given to medicine by a firm of manufacturing chemists working wholly through the strictest methods of science.
Men are now able to make in the laboratory, and independently of the living animal, a substance similar to adrenalin in its chemical properties and possessed of a physiological activity just as great.
In the centre of this manufactory there are some twenty research laboratories devoted exclusively to its investigative progress. It is interesting and instructive to enter any one of them. Taking them at hazard, here is one in which there is to be found a Japanese bacteriologist whose definite, clean-cut object is to discover the best available germicide.
Still another laboratory concerns itself, for one thing, with “the typhoid agglutometer ” for the diagnosis of typhoid fever, one of the greatest triumphs of applied bacteriology.
Without going through the other laboratories or through the enormous factory operations which result from the work of these laboratories, it is obvious enough that this barest glimpse into these manifold activities affords ample justification for what must now be said.
The coterie of individuals constituting this firm started early with the ideal of doing “ethical business” based upon science, sincerity, and wisdom. They do this same type of business to-day because the intelligent application of scientific method' is always sincere and always wise ; furthermore, it always and wholly pays. It is seen in the unfeigned and spontaneous statement of one of its officials: “We did not have the face to oppose the Pure Food and Drug Law, but it will hurt our business because it will make our opponents both honest and scientific. ’ ’
It thus affords an object-lesson to every manufacturer in the country, and particularly to the smaller manufacturer, who, with the coming tightening of competition, will SÖ sorely need the intelligent application of scientific method. It always and wholly pays.
A strong individuality is indispensable to the achieve ment of great things. When you have stability and firmness of purpose—faith and confidence enough to reach the goal for which you are ambitious—you have a strong individuality.