“Used here in properly selected cases, after due consideration by one who has good obstetric judgment, its results are usually happy, and it is a boon to the tired mother and her attendants.”“To step beyond these narrow confines of indications is indeed entering on dangerous territory. Especially is this true as regards the life of the baby. It is recommended in small doses by some good authorities and is frequently used in cases of slight contraction at the brim with sometimes very good results if the birth occurs within a few minutes, but frequently with disastrous results to the baby if delivery is delayed. In such cases, forceps are urgently indicated. Its use in such cases is risky beyond question. Pituitary extract is recommended in cases of postpartum hemorrhage, but ergot is undoubtedly to be preferred.”“All means should be exhausted to arrive at a definite diagnosis, and the dangers of its use should be fully appreciated and due consideration given before its administration in any case, for such a powerful drug, used indiscriminately, will surely produce sad results to mother or child or both.”“During the past two years a number of untoward effects and consequences of severe character have arisen. As far as the maternal accidents and complications are concerned, I firmly believe that were the slogan of the hour “safety first” borne in mind, a number of them could have been prevented, for beyond question this drug has been greatly abused, as it has been given in too large doses, in cases in which its use was strongly contraindicated, and often, I am sorry to say, for no reason other than the accoucheur’s expediency. Its use has been reckless and careless. The many reports of its rapid and safe action have been one of the greatest dangers. DeLee says, ‘It provides for the physician and his brother gynecologist a lot of chronic sufferers, often incurable, even after mutilating operations.’ ”“An analysis of the detailed reports of all these cases of ruptured uterus with one or two exceptions reveals the fact that pituitary extract was abused, being given to patients who should not have had it. To my mind, to give a dose of pituitary extract to a woman who has a contracted pelvis, mild or severe, when the head has not passed through the pelvis, is criminal and, if the obstetrician is not aware of the contraction, he is still little short of being a criminal.”
“Used here in properly selected cases, after due consideration by one who has good obstetric judgment, its results are usually happy, and it is a boon to the tired mother and her attendants.”
“To step beyond these narrow confines of indications is indeed entering on dangerous territory. Especially is this true as regards the life of the baby. It is recommended in small doses by some good authorities and is frequently used in cases of slight contraction at the brim with sometimes very good results if the birth occurs within a few minutes, but frequently with disastrous results to the baby if delivery is delayed. In such cases, forceps are urgently indicated. Its use in such cases is risky beyond question. Pituitary extract is recommended in cases of postpartum hemorrhage, but ergot is undoubtedly to be preferred.”
“All means should be exhausted to arrive at a definite diagnosis, and the dangers of its use should be fully appreciated and due consideration given before its administration in any case, for such a powerful drug, used indiscriminately, will surely produce sad results to mother or child or both.”
“During the past two years a number of untoward effects and consequences of severe character have arisen. As far as the maternal accidents and complications are concerned, I firmly believe that were the slogan of the hour “safety first” borne in mind, a number of them could have been prevented, for beyond question this drug has been greatly abused, as it has been given in too large doses, in cases in which its use was strongly contraindicated, and often, I am sorry to say, for no reason other than the accoucheur’s expediency. Its use has been reckless and careless. The many reports of its rapid and safe action have been one of the greatest dangers. DeLee says, ‘It provides for the physician and his brother gynecologist a lot of chronic sufferers, often incurable, even after mutilating operations.’ ”
“An analysis of the detailed reports of all these cases of ruptured uterus with one or two exceptions reveals the fact that pituitary extract was abused, being given to patients who should not have had it. To my mind, to give a dose of pituitary extract to a woman who has a contracted pelvis, mild or severe, when the head has not passed through the pelvis, is criminal and, if the obstetrician is not aware of the contraction, he is still little short of being a criminal.”
In the latter part of his article inThe Journal, Dr. Mundell analyzes the reports of twelve cases of rupture of the uterus, thirty-four cases of fetal deaths, and forty-one cases of asphyxia pallida in which “resuscitation was effected only after prolonged and vigorous efforts.” These also were not excerpted.—Ed.]—(Correspondence in The Journal A. M. A., Nov. 24, 1917.)
To the Editor:—The article inThe Journal, November 24, page 1818, on proprietorship in medicine does us a gross injustice, and in reply thereto we beg leave to submit the following:
For reasons which every publisher (yourself included) understands, it is not practicable for us to reproduce in full, in the columns ofTherapeutic Notes, all the clinical papers to which we wish to direct the attention of our readers. But that the article of Dr. Mundell was not garbled to make capital for Parke, Davis & Co. is quite apparent on comparison of the omitted portions with a previous paper by the same author, reprinted in the January (1917) issue of theNotes, and herewith submitted together with clippings from other issues of theNoteswhich prove that we have not hesitated to present to our readers the dangers incidental to the misuse of Pituitrin as well as the advantages of its proper use.
Therapeutic Notes, in quoting other journals, puts into its readers’ hands the means of investigating the fairness of its quotations. It is a house organ—true enough; but the organ of a house which has always appealed to the honor as well as to the progressiveness of the medical profession. Its publishers could not afford to resort to deception in advertising their products, through this or any other medium.
The profession is indebted to Parke, Davis & Co. for Pituitrin (among other medicaments), and it is to the profession that the manufacturers look for the ultimate verdict. The contraindications are quite as important as the indications, and, as the excerpts submitted show, we have taken account of these, not only in forming our own estimate, but in presenting the evidence to the readers ofTherapeutic Notes.
We cite these facts that you may give us a square deal in an early issue ofThe Journalif so disposed.
Parke, Davis& Co., Detroit.
[Comment.—The Journalhas no desire to discuss Parke, Davis and Company’s motives in omitting certain parts of Dr. Mundell’s paper. WhatThe Journaldid was to publish those parts of Dr. Mundell’s paper on the “Present Status of Pituitary Extract in Labor” that Parke, Davis and Company left out of their circular. That it is not practicable, as Parke, Davis and Company points out, for the manufacturers of proprietary products to reproduce in fullall clinical papers dealing with such products is obvious. It is not so obvious why such concerns in abstracting or quoting papers of this kind should delete those parts that are unfavorable to the products dealt with rather than those that are favorable. Curiously, however, whenever an author is quoted only in part those parts are almost invariably those favorable to the product.—Ed.]—(Correspondence in The Journal A. M. A., Dec. 8, 1917.)
To the Editor:—The following experiences seem to add one more to the many reasons offered to explain why proprietaries and ready-made preparations flourish at the expense of the official drugs and preparations: A few days ago I prescribed Troches of Ammonium Chloride, U. S. P., for a patient of exceptional perseverance. The next day he had not yet secured the troches and told me that he had submitted the prescription to seven pharmacies, including the largest, and three of the best known and admittedly the best equipped in New York. All told him that these troches were “not being made any more,” and that they were therefore unable to supply him. He thereupon communicated with one of the largest wholesale manufacturing pharmaceutical houses in America and received precisely the same answer. I then took the matter up with a first class pharmacist whom I knew and induced him to prepare this difficult (!) troche, for which the U. S. Pharmacopeia gives the following directions: “Rub the powders together until they are thoroughly mixed; then form a mass with syrup of tolu and divide...”
Seven pharmacists declined to fill a prescription for an official preparation because they could not buy the preparation from a wholesaler, and it required some persuasion to get the eighth to make the preparation. But even worse, several of the pharmacists offered my patient some ready-made troche more or less resembling the official, or offered compressed tablets of ammonium chlorid.
That this is not an isolated example of what often poses as pharmacy is shown by the fact that I have found it extremely difficult to find a pharmacist who would extemporaneously coat pills with gelatin. Most want the physician to alter his prescription so that one of the ready-made gelatin coated pills can be dispensed, if a gelatin coating is necessary. Some gelatin, hot water, a large cork, and a few domestic sewing needles are all that is required for very satisfactory coating of pills with gelatin, yet few pharmacists seem willing to perform this simple procedure.
Two other illustrations, not so recent, have come to me from a colleague. A few years ago he was unable to obtain from either of two pharmacists an emulsion of cod liver oil without the hypophosphites because, as both said, “It does not come without hypophosphites.” On another occasion four of the best drug stores in Boston were asked for the Compound Laxative Pill, U. S. P., then official in the Pharmacopeia. In every case he was told that he must have meant the compound cathartic pill, which in no way resembles the pill he sought.
With this attitude on the part of the men supposed to be serving the public and the medical profession by the practice of pharmacy, is it any wonder that it is difficult to induce the medical profession to prescribe official preparations or combinations of official drugs in place of ready-made commercial substitutes largely drawn from among the proprietaries or specialties? Real pharmacy by real pharmacists is a necessity if we are to succeed in combating the proprietary evil.
Cary Eggleston, M.D., New York.
—(Correspondence in The Journal A. M. A., Aug. 21, 1920.)
Recent newspaper reports regarding the alleged “discovery of the Germ of Pernicious Anemia” and the development of “an antitoxin and serum” by Dr. Philip Rahtjen of Pasadena, California, have brought inquiries of which the two that follow are typical. This from a physician in Indiana:
“Please let me know about the supposed recent discovery of Dr. Philip Rahtjen concerning pernicious anemia. The information I have is from a newspaper clipping of October 21, Pasadena, California. Kindly omit my name.”
“Please let me know about the supposed recent discovery of Dr. Philip Rahtjen concerning pernicious anemia. The information I have is from a newspaper clipping of October 21, Pasadena, California. Kindly omit my name.”
A New York physician writes:
“If you could send me any information as to the enclosed I would appreciate it. The article impresses one as absolutely inconclusive. However, I promised the patient I would investigate the matter.”
“If you could send me any information as to the enclosed I would appreciate it. The article impresses one as absolutely inconclusive. However, I promised the patient I would investigate the matter.”
The enclosures referred to consisted of a reprint and a letter from “Ph. Rahtjen, M.A., Ph.D.,” Pasadena, Calif., both of which had been sent to a layman who had written to Rahtjen. The reprint was a translation of a brief article by Rahtjen “On the Etiology of Idiopathic Anemia,” translated from theCentralblatt für Bakteriologie Parasitenkunde und Infektionskrankheiten. Rahtjen’s letter to the layman read:
“Your inquiry relative to my isolation and classification of the Germ of Anemia received.“I herein enclose my paper published in August in theCentral Magazine of Bacteriology.“I have succeeded in immunizing goats against the Germ therein described. Five thousand injections of the Serum have been given. Three hundred cases diagnosed as Anemia and Chlorosis were treated under observation. Six cases of Pernicious Anemia were observed under treatment. All responded favorably.“The Serum is at your disposal from my laboratory here for the use of your physician. The price is five dollars for twelve ampoules each containing 1 ccm., the amount of one injection.“The treatment consists of intramuscular injection every second day accompanied with a nitrogenous free diet, preferably milk diet. Your attending physician should very easily give them.”
“Your inquiry relative to my isolation and classification of the Germ of Anemia received.
“I herein enclose my paper published in August in theCentral Magazine of Bacteriology.
“I have succeeded in immunizing goats against the Germ therein described. Five thousand injections of the Serum have been given. Three hundred cases diagnosed as Anemia and Chlorosis were treated under observation. Six cases of Pernicious Anemia were observed under treatment. All responded favorably.
“The Serum is at your disposal from my laboratory here for the use of your physician. The price is five dollars for twelve ampoules each containing 1 ccm., the amount of one injection.
“The treatment consists of intramuscular injection every second day accompanied with a nitrogenous free diet, preferably milk diet. Your attending physician should very easily give them.”
Just what Rahtjen’s serum is we do not know. Nor have we been able to find any information on the subject in any available medical literature. In fact, a rather careful search of American medical literature for some years past fails to reveal any article by Rahtjen on any subject.
Philip Rahtjen is not a physician. In the Propaganda files is a circular issued in 1917 by the “Rahtjen Tuberculosis Sanatorium” of San Francisco, Calif. This exploits “The Rahtjen Cure for Tuberculosis” and tells of “The Discovery of Dr. Philip Rahtjen.” The circular states that:
“Dr Rahtjen studied in Heidelberg, Berlin, Munich, Marburg, and Rostock, Germany, from which latter school in 1904, he graduated in chemical pathology as Doctor of Philosophy. He became assistant professor of pathology at the Imperial Biological Station at Heligoland, and was later appointed assistant to Dr. Piorkowsky, head of theDeutsche Schutz und Heilserum Gesellschaft.”
“Dr Rahtjen studied in Heidelberg, Berlin, Munich, Marburg, and Rostock, Germany, from which latter school in 1904, he graduated in chemical pathology as Doctor of Philosophy. He became assistant professor of pathology at the Imperial Biological Station at Heligoland, and was later appointed assistant to Dr. Piorkowsky, head of theDeutsche Schutz und Heilserum Gesellschaft.”
The same circular summarizes the potentialities of “Rahtjen’s Cure for Tuberculosis” thus:
“The remedy seems to cure tuberculosis in all its forms with equal celerity and certainty. The evidences indicate that it does not matter how far the disease has progressed, if there be tissue of the attacked organ remaining sufficient to sustain life, the disease can be wholly eradicated and the patient restored to health. This is indicated alike in tuberculosis of the lungs, of the throat, of the bladder, of the kidneys.”
“The remedy seems to cure tuberculosis in all its forms with equal celerity and certainty. The evidences indicate that it does not matter how far the disease has progressed, if there be tissue of the attacked organ remaining sufficient to sustain life, the disease can be wholly eradicated and the patient restored to health. This is indicated alike in tuberculosis of the lungs, of the throat, of the bladder, of the kidneys.”
The booklet stated further that patients might be treated at one of two places: at the offices of the sanatorium in the city of San Francisco, or at the sanatorium itself near Glenwood. The cost of treatment at the sanatorium was to be $1,000, which would entitle “the patient to residence and attention therefor four months.” According to the leaflet, “This is regarded as a period sufficient to restore the patient to health whatever be the stage of his disease; provided only, as we remark, that he has enough left of the infected organ to sustain life with the T. B. expelled.”
“At the end of four months the patient is sent to his home, not alone relieved of his disease, but in a highly vigorous state of health.”
“At the end of four months the patient is sent to his home, not alone relieved of his disease, but in a highly vigorous state of health.”
All this, as stated previously, was in 1917. And yet people are still dying of tuberculosis!
In March, 1920, Rahtjen (so the newspapers have it) was offering a “New-Life Fluid.” According to a San Francisco paper, Dr. Philip Rahtjen “announces the discovery that by the injection of secretions from the ductless glands the human body may be reinvigorated.” The paper described the discovery “as a long step forward in the fight to counteract old age” and stated that a syndicate was being formed by Rahtjen and others to “produce the extract in such quantity that it may be available for every one.” The newspaper article showed the learned doctor in a laboratory apron in the characteristic pose of the newspaper “scientist” pouring something from a beaker into a test tube—and gazing intently at the camera while doing it! This was in March, 1920; yet people still grow old.
Within the last month theLos Angeles Examinerhas heralded some more wonderful accomplishments of Rahtjen. According to this paper Rahtjen has:
1. Isolated the “germ of pernicious anemia.”
2. Found the “serum” for the cure of this disease.
3. Discovered the secret of human virility.
4. Evolved a fluid “from the glands of selected bulls and cows” which will “restore ‘pep’ for worn-out human bodies! Give added weight, clearer eyes, brighter minds, quicker bodies and a generally ‘firmer grip’ on oneself!”
This “amazing discovery” was, according to the Los Angeles paper, the culmination of “five years of continuous study” and had only just been revealed by Rahtjen.
“Dr. Rahtjen has for years been working silently in a bio-chemical laboratory in Pasadena, surrounded by microscopes, scales, test-tubes, acids, alkalis, reagents and all the accompanying stage settings that spell bio-chemical science.”
“Dr. Rahtjen has for years been working silently in a bio-chemical laboratory in Pasadena, surrounded by microscopes, scales, test-tubes, acids, alkalis, reagents and all the accompanying stage settings that spell bio-chemical science.”
All of these wonders might still have been a closed book to the public had not “friends” of Dr. Rahtjen brought the matter to the attention of theExaminer.
“Dr. Rahtjen yesterday, with the usual reserve of the ethical scientist, was disinclined to talk of his work until publication of it in a scientific journal.”
“Dr. Rahtjen yesterday, with the usual reserve of the ethical scientist, was disinclined to talk of his work until publication of it in a scientific journal.”
Fortunately for a palpitating public, theLos Angeles Examiner“was able to learn the essence of his study” and pass the information on. It seems from this newspaper report that Rahtjen first made his extracts from the glands of goats and sheep but these extracts “were found to be too strong.” As a result “Dr. Rahtjen is now using the glands of specially selected Mexican bulls and cows.” The male patients who are “weak, uninterested in life, unable to concentrate in thought” are given the extract of bull; the female patients who are in a similarly deplorable condition receive an “injection of the cow gland extract.”
We have not yet learned whether theLos Angeles Examinerhas deprecated Dr. Rahtjen’s use of Mexican bovines. Remembering the attitude of the Hearst papers toward all things Mexican, one may look for the suggestion that Mr. Rahtjen use 100 per cent. American bull.—(From The Journal A. M. A., Nov. 26, 1921.)
To the Editor:—I was much interested in the study of this subject by Dr. H. N. Cole (The Journal, Dec. 30, 1916, p. 2012.)
In 1913 I treated a series of cases of syphilis with sodium cacodylate; but, not getting the desired results, I discontinued its use. In 1915, I became interested again because of the writings of Dr. J. B. Murphy, and applied it in three cases in which the patients had initial lesions:
Case1.—J. M., man aged 21, single, shoeworker, came to me with an initial lesion of the penis to the right of the frenum. I began intramuscular injections of sodium cacodylate, 5 grains, in ampules made by Parke, Davis & Co., every day for ten days. Then I halted for ten days and repeated ten more injections. The sore on the penis entirely disappeared about the ninth day. There was a slight, faintly macular eruption of the forearms and abdomen, which soon disappeared. There was no alopecia. When he returned, after the last series of ten injections, there were mucous patches in the throat and some involvement of the left tonsil. I put the patient on mixed treatment, which cleared his throat. He had, at end of twenty doses of 5 grains of sodium cacodylate each, a positive Wassermann reaction. After mercury and potassium iodid for two months there was a positive Wassermann reaction. To date, after three salvarsan treatments intravenously there have been two negatives.
Case2.—F. S., man, aged 28, married, machinist, had an initial lesion on the penis. Treatment with sixty injections of 5 grains of sodium cacodylate gave results as follows: The initial sore on the penis disappeared in ten injections; there were severe mucous patches of the mouth; the tonsils were badly infected. There was a positive Wassermann reaction. There were syphilids of both arms and shins; marked papular eruption; malaise, and a slight trace of albumin in the urine. I placed the patient on mercurials and at last give him three salvarsan injections three weeks apart. The result was a negative Wassermann reaction, the skin was clear and the patient felt fine.
Case3.—D. C., woman, aged 21, single, seamstress, had an initial lesion on the left side of the cervix, and a macular eruption on the face, neck and shoulders, and also, though faint, on the forearms. Thirty injections of sodium cacodylate of 5 grains each were given. The initial lesion disappeared in one week. Mucous patches of the mouth appeared and persisted. The Wassermann reaction was positive. I gave mercurials and potassium iodid for seven months, and salvarsan once. The Wassermann reaction is now negative.
My conclusion after two trials of the use of sodium cacodylate in small or large doses is that it has no effect toward curing the condition; in fact, the throat symptoms were seemingly increased in severity by its use. It has no effect on syphilids of the forearms and shins, and if anything makes them worse.
It improves the appetite, as one would expect. It has some effect on the kidneys, as noted in Case 2; it has some effect in healing the initial lesion, as noted in all three of this series; why, I do not know.
I am entirely satisfied that it has no beneficial effect on syphilitics and have discontinued its use entirely in my practice.
I am glad to have read Cole’s excellent article, as it shows me that I was correct in my decision not to use it again, as it was worthless.
William G. Ward, M.D., Lynn, Mass.
To the Editor:—Dr. William G. Ward’s letter (The Journal, Feb. 3, 1917, p. 390), and the recent admirable article by Dr. Harold N. Cole (The Journal, Dec. 30, 1916, p. 2012) recall to mind Dr. J. B. Murphy’s clinical note on the use of sodium cacodylate in the treatment of syphilis (The Journal, Sept. 24, 1910, p. 1113), and the experimental work of Cap. H. J. Nichols, U. S. Army(The Journal, Feb. 18, 1911, p. 492). The results of Nichols’ work conclusively proved, at least from a laboratory standpoint, that this drug was of very little value as a spirocheticide in combating syphilis. Prior to the publication of Dr. Murphy’s letter I had employed sodium cacodylate extensively as a remedy in psoriasis, and I still continue to use it in selected cases of the disease.
Adopting Dr. Murphy’s suggestion, I gave the agent an extensive trial in syphilis in all stages of the disease. The results were extremely disappointing, from both clinical and serologic points of view. More recently, during the scarcity of salvarsan, I gave the drug a second trial, employing it in large dosage in the hope that the previous failure had been due to the employment of insufficient amounts. The results were not tabulated, but, judging roughly from my experience in a score of cases, its therapeutic value as an antisyphilitic was nil. A few of the patients underwent a temporary improvement, probably owing to the tonic effect of the drug, but in every instance the serologic findings were unaffected.
R. L.Sutton, M.D., Kansas City, Mo.
—(Correspondence in The Journal A. M. A., Feb. 3, 1917.)
The tablet form of administering medicines is popular among many physicians because of its convenient availability and dosage. There is no doubt about the convenience of tablets, but the accuracy of the dosage content is not always to be depended on. One reason for this is that the demand for palatable and convenient “medicaments has led manufacturers to attempt to produce in tablet form mixtures which, from the nature of the case, are not suited to that method of compounding.” In a series of painstakingexperiments307on bismuth, opium and phenol tablets, conducted a number of years ago in the A. M. A. Chemical Laboratory, it was shown that no tablets on the market then contained the amount of phenol the label indicated, the variation being from 12.3 to 112.5 per cent. Similarly, the laboratory found that in the case of several different brands of Aromatic Digestive Tablets,308the amount of hydrochloric acid present in these absurd combinations was true to label in only one half of the specimens, notwithstanding the fact that the amounts claimed to be present were ridiculously small; in two specimens, there was no hydrochloric acid whatever present, while a third contained only a trace. These examples illustrated clearly the very evident unwisdom of attempting the pharmaceutically impossible merely for the sake of convenience or pharmaceutical “elegance.”
Another reason for doubting the accuracy of dosage, irrespective of the characteristics of the drugs composing the tablets, has been the manifest lack of care in their manufacture. In 1914,Kebler309reported the results of a far-reaching investigation of tablet compounding in which he pointed out that tablets on the market were not as uniform or accurate as was generally believed, the variations being “unexpectedly large in numbers and amount.” During the past year, the Connecticut Agricultural ExperimentStation310undertook the examination of tablets—proprietary and nonproprietary—taken from the stock of dispensing physicians. The variations found inweightsof the tablets were strikingly similar to those reported by Kebler.
VARIATION IN WEIGHTS OF TABLETS
VariationKeblerPer Cent.ConnecticutPer Cent.Less than 10 per cent.4344More than 10 per cent.5756More than 12 per cent.4435More than 15 per cent.2826More than 20 per cent.910
Less than 10 per cent.
More than 10 per cent.
More than 12 per cent.
More than 15 per cent.
More than 20 per cent.
The determinations of thecompositionof the tablets when compared with that claimed for them showed wide variation—from 54 per cent. above to 70.5 per cent. below; in almost two thirds of the tablets examined, the variation amounted to more than 10 per cent.; in three fifths of the tablets, the variation was more than 15 per cent.; in one fourth, more than 20 per cent., and in one twentieth, more than 50 per cent.; only in one eighth of the tablets was the variation less than 5 per cent.
The Connecticut investigators substantiate once again the work previously reported, namely, that there are a number of firms who are either incompetent or careless. For tablets of simple composition, a variation from the declaration of 10 per cent. should be amply sufficient to compensate for the errors of careful manufacture. It may be added that the best tablets originate generally from firms having competent chemical control.—(From The Journal A. M. A., July 27, 1918.)
According to the good old truism, the last and crucial proof of the pudding is in the eating thereof; and so, the last and crucial test of a therapeutic agent is its consumption by a patient. There is, however, one essential difference: When the pudding is eaten, with a sense of satisfaction, we know that it was a good, or at least an eatable, pudding.
If the patient improves after taking a remedy, we do not yet know that he improved on account of the remedy. Thepost hoctype of reasoning or logic is not respectable; but it is all too apt to creep in unawares, unless one takes great precautions indeed.
Clinical evidence needs especially to be on its guard against this pitfall, for the conditions of disease never remain constant; nor is it possible to foresee with certainty the direction which they are going to take. It is just this point which makes the clinical evidence so much more difficult to interpret than laboratory evidence, in which the conditions can be more or less exactly controlled, and any changes foreseen. It is on this account, also, that clinical experiments must be surrounded with extra painstaking precautions.
In brief, while the “proof” of a remedy is on the patient, that is not the whole story, but merely an introduction. The real problem is to establish the causative connection between the remedy and the events. The imperfect realization of this has blocked therapeutic advance, has disgusted critical men to the point of therapeutic nihilism, and has fertilized the ground for the commercial exploitation of drugs that are of doubtful value or worse.
This has been impressed on me particularly by my service on the Council on Pharmacy and Chemistry. In the course of its work of passing on the claims advanced for commercial remedies, this Council is forced to inquire critically into the basis of the claims of manufacturers.
It is interesting to note the qualitative differences in the evidence for the various kinds of claims: The chemical data are usually presented in such a form that it is possible to tell at a glance whether or not they are based on demonstrated facts, which could usually be verified or refuted without special difficulty. The deductions are usually such as can be legitimately drawn from the data, or else they are obviously absurd. All this agrees with the relatively exact status of chemical science.
In passing to data and deductions from animal experiments, a distinct change is noticeable: Not only are the data less reliable, and less worthy of confidence, but they are more often stated in a less straightforward manner. The presentation of the data often shows evidence of manipulation of the results, so as to make them most favorable to a preconceived conclusion that would recommend the drug. This is not always intentional, but is partly due to the less exact nature of animal experimentation, which leaves a wider play to the arbitrary interpretation of the reporter. A certain amount of this is unavoidable. No serious objection can be raised, provided the experimenter presents all the essential data, and discusses fairly all of the interpretations that would apply to them.
On the whole, it is usually possible to form a fairly definite estimate of the value of experimental data.
When one comes to the clinical evidence, an entirely different atmosphere obtains. When the Council demands evidence of the usefulness of a remedy, the manufacturers generally respond with every sign of enthusiasm. They may have ready a series of articles already published, or they instruct their agents to bring in letters from physicians. The last method seems to meet the most cordial response, judging from the deluge of letters and opinions that floods the Council.
The quality of the published papers is a fair reflection of the deficiencies of what is still the common type of clinical evidence. A little thought suffices to show that the greater part cannot be taken as serious evidence at all. Some of the data are merely impressions—usually the latest impressions of an impressionable enthusiast—the type of man who does not consider it necessary to present evidence for his own opinions; the type of man who does not even realize that scientific conclusions must be based on objective phenomena.
Some of the papers masquerade as “clinical reports,” sometimes with a splendid disregard for all details that could enable one to judge of their value and bearing, sometimes with the most tedious presentation of all sorts of routine observations that have no relation to the problem.
The majority of reports obtained by the agents belong to these classes, notwithstanding the fact that they are often written for the special use of the Council, and therefore with the realization that they are likely to be subjected to a thorough examination, and therefore presumably representing the best type of work of which the reporter is capable. So, at least, one would suppose.
It is also possible, however, that some of these reports are written merely out of thoughtlessness, or perhaps often to get rid of an importunate agent. This is illustrated by the following correspondence, taken literally from the files of the Council.
A letter from a prominent physician “A,” endorsing a certain preparation “D,” having been submitted to the Council, the secretary was directed to write to Dr. A as follows:
Dear Dr. A:—The B Company of C has requested the Council on Pharmacy and Chemistry to admit its preparation D to New and Nonofficial Remedies. As part evidence for the value of the preparation, the company submitted a letter from you which contains the following:
So far as my experience has thus far gone, they are certainly superior to a number of other iodine compounds now on the market, and I should judge that they ought to take a superior place in therapy involving the use of iodine.
So far as my experience has thus far gone, they are certainly superior to a number of other iodine compounds now on the market, and I should judge that they ought to take a superior place in therapy involving the use of iodine.
The referee of the Council in charge of D writes that he was interested by your letter and asks that I inquire: As compared with sodium or potassium iodid, what would you say are the differences between, and real advantages of, D and the alkaline iodids? Did you make any comparative experiments and keep a record of them? If so, the referee would like to receive an account of your trials. In what direction could D be expected to occupy a superior place in iodin therapy?
I hope that you can give the information asked by the referee and thus aid the Council in arriving at a correct estimate regarding the value of D.
I hope that you can give the information asked by the referee and thus aid the Council in arriving at a correct estimate regarding the value of D.
The following reply was received from the physician in response to the foregoing:
Dear Professor Puckner:—In reply to yours of January 19, I did not proceed far enough in the investigation of D to draw conclusions of any particular value for the purpose of the Council on Pharmacy and Chemistry; and I so stated in my letter to the proprietors of that remedy.Answers to the questions you put in your letter require an amount of investigation of the remedy far beyond anything I undertook. As a matter of fact, I returned about five sixths of the capsules sent me, because of lack of time and opportunity to carry out the extensive clinical experiments that I plainly saw would be required to give an opinion at all worth while. I believe you had better not consider me in the matter at all.
Dear Professor Puckner:—In reply to yours of January 19, I did not proceed far enough in the investigation of D to draw conclusions of any particular value for the purpose of the Council on Pharmacy and Chemistry; and I so stated in my letter to the proprietors of that remedy.
Answers to the questions you put in your letter require an amount of investigation of the remedy far beyond anything I undertook. As a matter of fact, I returned about five sixths of the capsules sent me, because of lack of time and opportunity to carry out the extensive clinical experiments that I plainly saw would be required to give an opinion at all worth while. I believe you had better not consider me in the matter at all.
The report was furnished by a physician for whom I have a high personal regard. I introduce it here, not so much in a spirit of criticism, but as a justification of the opinion that I have formed of clinical evidence obtained by manufacturers through their clinical adjutors.
When commercial firms claim to base their conclusions on clinical reports, the profession has a right to expect that these reports should be submitted to competent and independent review. When such reports are kept secret, it is impossible for any one to decide what proportion of them are trustworthy, and what proportion thoughtless, incompetent or accommodating. However, if this were done it is quite possible that such firms would find much more difficulty in obtaining the reports. Those who collaborate should realize frankly that under present conditions they are collaborating, not so much in determining the scientific value, but rather in establishing the commercial value of the article.
Often the best type of clinical reports—those in which the observations are directed to the significant events and not to mere side lines, and in which the significant events are correctly and adequately reported—generally lack one important essential, namely, an adequate control of the natural course of the disease.
Since this cannot be controlled directly, it must be compensated indirectly. For this purpose, there are available two methods:
The first is the statistical method, in which alternate patients receive or do not receive the treatment. This method can usually only be of value when a very large series of patients is available. Even then, its value is limited or doubtful, because it cannot take sufficient account of the individuality of cases.
The second method consists in the attempt to distinguish unknown preparations by their effects—the method that might be called the “comparative method” or the “blind test.”
In this, the patient, or a series of patients, is given the preparation which is to be tested, and another preparation which is inactive, and the observer aims to distinguish the two preparations by their effects on the patient. Surely if the drug has any actions at all it will be possible to select correctly in a decided majority of the administrations.
The same principle can be applied in distinguishing the superiority of one preparation over another. In this case, the two preparations would be given alternately to different patients, and the observer would try to distinguish them by their effects. Here again, if one drug is really superior or otherwise different from another, to a practically important extent, the observer will surely be able to make the distinction.
This method is really the only one that avoids the pitfalls of clinical observation; it is the only method that makes the results purely objective, really independent of the bias of the observer and the patient. It is the only method, therefore, which determines whether it was really the pudding that was eaten and not some other dessert.
In principle this method does not usually offer any very great difficulties. It is, of course, necessary that the two preparations to be compared shall resemble each other so closely or shall be flavored, etc., so that they cannot be distinguished by their physical properties. This is usually not a very difficult matter. The method does not jeopardize the interests of the patient, for it is understood that no drug would be tested in this way unless there is some reason to believe that it has a value. When the patient’s condition is such as to demand treatment, then he would be receiving either the standard drug or the drug which the experimenter believes may be superior to the standard.
The final and crucial test of a remedy is on the patient; but the test must be framed so as to make it really crucial. Most clinical therapeutic evidence falls far short of this. The “blind test” is urged to meet the deficiencies.—(From The Journal A. M. A., July 21, 1917.)
Under the title “Vaccines in Toxic Conditions,” what purports to be a scientific contribution appears in the original department of the official organ of a state medical society.311The apparent purpose of the article is to overcome any hesitancy on the part of practitioners to use vaccines in toxic infectious conditions for fear that they might thereby cause harm. Such a thesis is interesting and might be important—if true. Two outstanding facts, however, give pause. First, the theory promulgated is contrary to the experience of those who have studied the subject; second, the man who writes the article is in the business of making and selling vaccines! The former fact is a matter of fairly general knowledge among the better informed members of the medical profession; the latter fact is nowhere made evident in the article, which the reader might infer came from a disinterested investigator in the realms of immunology.
The article purports to prove that the special investigations carried on by its author show that there is no basis for the well-grounded fear that vaccines might be harmful to a patient suffering from toxic infectious conditions. Thus:
From a closer study of these infective processes we find that this toxic condition is due to the rapid multiplication of the infecting organisms with the incidental production of ferments which the germs secrete to digest the food on which they live. These toxic ferments have a distinct destructive tendency on tissue cells, without any marked influence in stimulating tissue cells for antibody production. The crying need, however, in these extensive acute infections is rapid antibody formation to neutralize these germ-produced poisons and to eliminate the germs.
From a closer study of these infective processes we find that this toxic condition is due to the rapid multiplication of the infecting organisms with the incidental production of ferments which the germs secrete to digest the food on which they live. These toxic ferments have a distinct destructive tendency on tissue cells, without any marked influence in stimulating tissue cells for antibody production. The crying need, however, in these extensive acute infections is rapid antibody formation to neutralize these germ-produced poisons and to eliminate the germs.
Now vaccines, we are informed, are not toxic and so stimulate the production of antibodies. In other words, the same organism that in the body is toxic and without marked antigenic properties becomes nontoxic and actively antigenic when converted into a vaccine. The details of the experiments of the “closer study” made by the author of this paper (and the manufacturer of vaccines) which give such definite and convincing results are not published. Possibly the article is a preliminary contribution, and future issues of the same publication will carry further articles on the same subject. The follow-up system is well recognized in the advertising world. At all events, this “closer study” has convinced the author of the article that:
... even in extreme toxic conditions, in acute infections, bacterial vaccines may be employed without the least fear of doing any harm. In fact, we find that in extreme acute infections, bacterial vaccines not only give the best clinical results, but they may also be given in larger doses at shorter intervals with less reactions than in minor or chronic infections and the earlier they are given the better the results.
... even in extreme toxic conditions, in acute infections, bacterial vaccines may be employed without the least fear of doing any harm. In fact, we find that in extreme acute infections, bacterial vaccines not only give the best clinical results, but they may also be given in larger doses at shorter intervals with less reactions than in minor or chronic infections and the earlier they are given the better the results.
Here again no details are given; there are no comparative results of the careful study of a series of cases. The sum and substance of this remarkable contribution to a scientific publication is to the effect (1) that the organism that in the body is toxic becomes nontoxic when introduced in vaccine form; (2) that the organism that in the body is but little antigenic becomes when introduced in vaccine form actively antigenic, and (3) that “in extreme acute infections” when the body is affected profoundly by the infectious agent and its product, the oftener and the more one injects of these very materials, the better the results!
And this astounding plea for the use of vaccines in conditions in which vaccines are generally held to be contraindicated, or even injurious, is made by one whose business is the manufacture of vaccines and selling them to the medical profession!—(Editorial from The Journal A. M. A., Oct. 23, 1920.)
Our knowledge of the accessory food factors, commonly spoken of as vitamins, is so recent, comparatively speaking, and the exact nature of these factors still so enveloped in mystery, that it was inevitable that the public’s lack of knowledge on the subject should be capitalized. It is not surprising that there are on the market a number of preparations of the “patent medicine” type that are being sold under the claim that they are rich in vitamins—although the exploiters of these fail to explain which, if any, of the three accessory food factors their products contain. The renaissance of yeast as a therapeutic agent has given an opportunity to the manufacturers of this product of unduly stressing the fact that yeast is particularly rich in the antineuritic vitamin (water-soluble B). Because milk and certain milk products are rich in the fat-soluble A factor, the dairy interests would apparently have the public believe that this particular vitamin is to be obtained only from theirproducts. Thus, a journal devoted to the dairy interests recently claimed that those who want vitamins must get them in their milk, butter, cheese and other milk products. The truth is, the accessory food factors are so well distributed throughout the dietary of modern man that, generally speaking, the individual who uses ordinary judgment in selecting his food is in no danger of suffering from a deficiency of any of these three factors. It would be well if every physician might read the excellent monograph on the present state of knowledge concerning accessory food factors written by a committee appointed jointly by the Lister Institute and Medical Research Committee. In this report the distribution of the vitamins in our common foodstuffs is thus briefly summarized: “... broadly speaking it is safe to say that the individual always finds sufficient supply of vitamins in his food so long as that food is reasonably varied and has received no artificial or accidental separation into parts, and so long as no destructive influence has been applied to it.” At the end of the committee’s report is a table (reproduced on page 562) which shows the distribution of the three accessory factors in the commoner foodstuffs.—(Editorial from The Journal A. M. A., Aug. 13, 1921.).
Distribution of Three Accessory Factors in Commoner Foodstuffs