zine)," pyrazinamide," methyltestosterone," phenylbutazone," and other agents whose toxic or idiosyncratic reactions are as yet only partially evaluated.

SPECIAL INSTANCES OF INTOXICATION Antibiotics.-Because of the enormous usage of antibiotics, intoxication assumes a prominent role even though it may be statistically infrequent. No antibiotic has as yet been found free from hazards or disadvantages. The side-actions and toxic effects of penicillin have been numerous. In addition to the sometimes fatal anaphylactic responses, there are eruptions of the most diverse type, all manifestations of serum sickness, disturbances of renal function, hypotension, cardiovascular collapse, or unconsciousness; there may be hematological disturbances as various as anemia, agranulocytosis, cosinophilia, and hypothrombinemia.

In their entirety, toxic reactions attributable to antibiotics and chemotherapy are impressive." Anaphylactic reactions have been reported occasionally from most, if not all, of the agents derived from fungi. Hepatic dysfunction has followed the use of streptomycin, chlortetracycline (Aureomycin), oxytetracycline (Terramycin), and chloramphenicol. Renal impairment has been noted after streptomycin therapy and appears as a toxic effect following administration of bacitracin, neomycin, and polymyxin. The incidence of aplastic anemia and other hematological dyscrasias developing during the use of chloramphenicol has been subjected to searching investigation by Welch and associates. Difficulties inherent in attribution of toxic action to any drug appeared in their study. In this instance, as in others, history of exposure did not establish proof of causation of unfavorable symptoms. While circumstantial evidence indicated that administration of chloramphenicol was followed by an increased incidence of bone marrow depression, statistical proof of its action was not established, and it remained questionable whether chloramphenicol is essentially more toxic than some other antibiotics whose record of toxicity has excited less attention. Unfavorable actions of sulfonamides that in some measure have been lost to view because of their replacement by other agents in many therapeutic situations are numerous and include fever, eruptions, blood dyscrasias, and neuritis.

Not the least of the toxic symptoms associated with antibiotics is irritation of the gastrointestinal tract that is particularly severe after the use of tetracycline derivatives. Not infrequently, administration of these drugs has been followed by invasion of the intestinal tract by drugresistant staphylococci causing infection that may be fatal unless administration of the offending drugs is discontinued and erythromycin therapy instituted." Less serious effects of antibiotics are the development of mycotic infections in the mouth and in the gastrointestinal tract and of vitamin deficiencies attributable to bacteriostatic action on the normal intestinal flora.

Cortisone, Hydrocortisone, and Corticotropin (ACTH). Unfavorable reactions from the long-term administration of cortisone, hydrocortisone, and corticotropin (ACTH) are well known. In addition to the obesity, hypertension, hirsutism, and osteoporosis of adrenal cortical hyperfunction (Cushing's syndrome), reactions may

include increased susceptibility to infection, hindrance of wound healing, or exacerbation of ulcers in the stomach and intestinal tract. A considerable danger results also from rapid withdrawal of the agents after prolonged

use."

Antihistaminics.—The antihistaminic agents, of which there are now no less than 20, must be regarded as serious causes of intoxication, more particularly since their use is chiefly among patients who are not seriously ill. Several fatalities have been attributed to them. Their side-effects, especially those observed on the nervous system, are so numerous and sometimes so severe as to suggest that their use is actually more hazardous than that of sulfonamides and antibiotics employed for the most part in treatment of infections that might otherwise result in death."

Phenylbutazone and Chlorpromazine.-Phenylbuta zone is a congener of aminopyrine, and its toxic effects, particularly on bone marrow, are reminiscent of the unfortunate experiences with aminopyrine. Side-effects are numerous and sometimes serious; they include edema, eruptions, and unfavorable actions on the gastrointestinal tract, hematopoietic system, central nervous system, and heart. Fatal hepatitis has recently been reported." It is perhaps illustrative of illogical practice that the use of aminopyrine was sharply limited by disclosure of rare instances of intoxication, while the use of a phenylbutazone may now be actually increasing. Current brochures describing clinical uses of chlorpromazine under the name of Thorazine mention its applicability for relief of nausea and vomiting, mental and emotional disturbances, alcoholism, intractable pain, and hiccoughs. Suggestions are included for its use in correction of nausea and vomiting caused by other drugs, such as diethylstilbestrol (Stilbestrol), digitalis, nitrogen mustards, broad-spectrum antibiotics, and general ancs

11. (a) Zatuchni, J., and Miller, G.; Jaundice During Chlorpromazine Therapy, New England J. Med. 251: 1003, 1954. (b) Lemire, R. E., and Mitchell, R. A.: Regurgitation Type Jaundice Associated with Chlor. promazine ("Thorazine," SKF 2601-A) Administration, J. Lab, & Clin. Med. 44: 825, 1954. (c) van Ommen, R. A., and Brown, C. H: ObstrucLive-Type Jaundice Due to Chlorpromazine (Thorazine): Report of 3 Cases, J.A.M.A. 157: 321 (Jan. 22) 1955. (d) Hodges, H H., and Lazerte, G. D.: Jaundice and Agranulocytosis with Fatality Following Chlorpromazine Therapy, ibid. 158: 114 (May 14) 1955.

12. McDermott, W., and others; Pyrazinamide-Isoniazid in Tuberculosis, Ani. Rev. Tuberc, GD: 319, 1954.

13. Werner, S. C.; Hanger, F. M., and Kritzler, R. A.: Jaundice During Methyl Testosterone Therapy, Ain. J. Med. 8: 325, 1950.

14. Engleman, E. P., and others: Hepatitis Following the Ingestion of Phenylbutazone, J.A.M.A. 150:98 (Sept. 11) 1954.

15. Wilensky, A. O.: Fatal Delayed Anaphylactic Shock After Penicillin, Correspondence, J.A.M.A. 131:1384 (Aug. 17) 1946. Waldbolt, G. L.; Anaphylactic Death from Penicillin, ibid. 139: 526 (Feb. 19) 1949. Thomson, W. O.: Sudden Death Following an Injection of Penicillin, Ent. M. J. 21 79, 1952. Christensen, W. N.; Hedrick, G. W., and Schugmann, R. F. Fatal Anaphylactic Reaction Following Penicillin Injection, U. S. Armed Forces M. J. 4: 249, 1953.

16. Kutscher, A. I.; Lane, S. L., and Segall, R.: The Clinical Toxicity of Antibiotics and Sulfonamides: A Comparative Review of the Literature Hased on 164,672 Cases Treated Systemically, J. Allergy 25: 135, 1954. 17. Jackson, G. G., and others: Terramycin Therapy of Pneumonia: Clinical and Bacteriologic Studies in 91 Cases, Ann. Int. Med. 351 1175, 1951. Williams, E.: Staphylococcal Pseudomembranous Enterocolitis Complicating Treatment with Aureomycin. Lancet 2: 999, 1954.

18 Ragan, C.: Corticotropin, Cortisone, and Related Steroids in Clinical Medicine: Practical Considerations, Bull. New York Acad. Med. 20: 355, 1953.

19. Wyngaarden, J. B., and Seevers, M. H.: The Toxic Effects of Antihistaminic Drugs, J.A.M.A. 1431 277 Feb. 3) 1951.

20. Hemming. A. and Kuzell, W. C.: The Pharmacologic and Clinical Characteristics of Phenylbutazone (Butazolidin), Antibiotics & Chemother. 3: 614. 1951.

21. Deleted on proof.

thetics. It is thought to be good also for nausea and vomiting in pregnancy. In the psychoses the drug is now being used in large doses at a time when the danger of hidden toxicity, always inherent in new and potent drugs, has been only partially evaluated. Reports of agranulocytosis following its use are in the literature. The incidence of jaundice and disturbed liver function is subject to variable estimates; their nature and seriousness may be judged only by preliminary observations."

HIDDEN AND GENERAL DANGERS

The history of new drugs indicates that not all their potential dangers are immediately apparent. Examples of this are the experiences with cinchophen and aminopyrine. Many years of continued use of each of these drugs elapsed before the unfavorable actions could be established. Still more difficult to evaluate is the inference that past use of drugs may be responsible for the late appearance of symptoms or for development of a chronic disease such as lupus erythematosus or periarteritis. It seems inevitable that with the increasing potency of drugs and the multitude of different reactions caused by single agents that there could be production of syndromes Istrikingly like those of previously known discases. Recently, drugs have been introduced for specific purposes that may actually produce complete syndromes.

An outstanding example is the state that develops with some frequency during treatment for hypertension by hydralazine (Apresoline) hydrochloride." In its complete form the syndrome may be manifested by fever; prostration; pleural, pericardial, and joint effusions; skin sensitivity to ultraviolet light; and erythematous eruptions. There may also be lymphadenopathy and splenomegaly. Laboratory studies may show decreased serum albumin and increased alpha and gamma globulin levels, increased sedimentation rate, transient false-positive tests for syphilis, and anemia and leukopenia. Sometimes L. E. cells may be demonstrated in peripheral blood and bone marrow. Histologically abnormal collagen has been seen in muscle and skin. In one case a typical rheumatic nodule was noted, and in another lymphorrhea in muscle resembling that of rheumatoid arthritis was observed. Thus a condition produced by action of a drug closely parallels the clinical, serologic, and histological picture of a serious collagen disease. Only in its reversibility and the relative infrequency of L. E. cells and renal manifestations does it deviate from spontaneously occurring lupus erythematosus disseminatus.

Such a striking simulation of disease as a side-action of a single drug lends some weight to observations that have led to suspicion that adverse action of drugs might be implicated in the pathogenesis of collagen diseases. Evidence of such a relationship has previously been less convincing for lupus erythematosus than for periarteritis nodosa, in which the work of Rich in animals has demonstrated morphological identity of lesions produced by serum sickness and sulfadiazine and the polyarteritic lesions of rheumatic fever and clinical periarteritis nodosa."

DANGERS FROM MULTIPLE PROCEDURES

The danger in diagnostic and therapeutic procedures comes not so much from the use of individual tests of drugs as from the multiplication of these measures now commonly used in so-called diagnostic surveys and therapeutic regimens in which each symptom receives some remedy. For patients in a diagnostic clinic or in the ward of a modern hospital, the application of 20 or 30 dagnostic tests is not uncommon. Many of these tests may be repeated on several occasions. A seriously ill pa tient or one who has been subjected to a major operation may receive 20 to 40 different drugs in addition to numerous mechanical procedures. His management may actually require use of anesthetics, sedatives, narcotics, antibiotics in variety, phenylephrine (Neo-Synephrine) hydrochloride, arterenol, digitalis, diuretics, bishydroxycoumarin, cortisone, transfusions, infusions, and finally antihistaminics, either for the correction of symptoms of his disease or to combat the toxic manifestations of other drugs. Since such combinations of measures and medicines are frequent, it is not surprising that iatrogenic disturbances are frequent.

In a medical service in a great hospital, over a period when approximately 1,000 patients were admitted, more than 50 major toxic reactions and accidents consequent to diagnostic or therapeutic measures were encountered. Many of the incidents and accidents took place before the patient's admission to the hospital and provided the occasion for hospitalization. Others developed in the course of diagnosis and treatment in the wards. The survey was not systematic or complete, and some instances of major intoxication may have been omitted from the list. The survey took no account of such fac tors as inconvenience and expense to the patient, prolongation of hospitalization, minor intoxications, or hidden and delayed reactions.

There were several cases of accidental intoxication, and among these no less than 10 instances of digitalis poisoning. In one of these, ventricular fibrillation and death occurred. Serious hematuria developed in one patient from the use of bishydroxycoumarin; in another there was methemoglobinemia following the use of bismuth subnitrate; one patient was admitted with mental confusion from bromism and another for delirium following therapy with atropine. There was one idiosyncratic response to diphenylhydantoin (Dilantin) sodium and a case of hypotension and vomiting from the use of pentolinium (Ansolysen) tartrate as an antihypertensive agent. There were four examples of reaction to penicillin; one of these was anaphylactic in nature and of such severity that death was averted only by prompt treatment. Two cases of hepatic dysfunction developed during use

22. Lomas. J.: Chlorpromazine and Agranulocytosis, Correspondens. Brit. M. J. 2: 358, 1954. Hodges."

23. Muller, J. C.; Rast, C. L., Jr.; Pryor. W. W., and Orgain, E. & Late Systemic Complications of Hydralazine (Apresoline) Theram. J.A.M.A. 157: 894 (March 12) 1955. Lansbury. J., and Rogers, F. & The Hydralazine Syndrome, Bull. Rheumat. Dis. &: 85, 1955.

24. Rich, A. R.: Hypersensitivity in Disease, with Especial Refervaci to Periarteritis Nodosa, Rheumatic Fever, Disseminated Lupus Erythema losus and Rheumatoid Arthritis, Harvey Lect. (1946-1947) 491 106, 1967,

of pyrazinamide. An acute hemolytic reaction occurred during the use of sulfadiazine. One case of monilial stomatitis and one of severe enterocolitis developed during treatment with tetracycline derivatives.

Three instances of intoxication followed the use of corticotropin and cortisone. One resulted in the formation of multiple gastric ulcers with perforation, hemorrhage, and fatal outcome. Four instances of troublesome acidosis followed use of ammonium chloride. Sensitization reactions were encountered from a number of agents. Eruptions developed from oxytetracycline, pentolinium tartrate, and myleran (1:4-dimethanesulphonyloxybutane); neutropenia from phenylbutazone; agranulocytosis from aminopyrine; and thrombocytopenic purpura from propylthiouracil.

Accidents were not limited to therapeutic procedures. In one instance, a severe blood stream infection following cystoscopy was controlled with difficulty with antibiotics. One young woman, the wife of a physician, died in acute anaphylactic shock 15 minutes after intravenous injection of dehydrocholic acid for determination of circulation rate. Another young woman, a nurse with a congenitally thin sternum, died from cardiac tamponade immediately after a sternal puncture.

In the aggregate, unfortunate sequelae and accidents attributable to sanctioned and well-intentioned diagnosis

and therapy were noted in about 5% of patients admitted to medical wards. In this sense, iatrogenic disease could be regarded as one of the commonest conditions encountered during the period.

CONCLUSIONS

It is realized that such concentration on toxic and unfavorable actions of diagnostic and therapeutic measures creates a distorted picture that can be corrected only by detailed recitation of simultaneous benefits. The discussion has been offered without nihilistic intent and with grateful recognition of the triumphs of modern diagnosis and therapy. Choice of topic developed from an ever-growing conviction of the extent and variety of dangers intrinsic in the medical practice of today and from a desire to suggest that discriminating selection of measures may be more important than unreflective completeness. It is suggested that it may be as useful to the patient that his physician know when not to treat as when to treat and that the use of potentially dangerous agents for trivial or inconsequential complaints may not be justifiable. Only by such discipline and understanding may we, as physicians, avoid doing unnecessary harm and minimize the price we and our patients pay for modern management of disease.

525 E. 68th St. (21).

NY DOCTOR writing on methods of testing the

A effectiveness of new drugs and other thera

peutic agents should do so with humility-for doctors have so often been mistaken about such matters. Let me start by citing an example of such an error of judgment, and let us then ask ourselves why the doctor was wrong and how we can avoid such errors ourselves.

At the time of the Philadelphia yellow fever epidemic of 1793. Benjamin Rush had many claims to be considered his new country's most distinguished physician. A signer of the Declaration of Independence and a pioneer in the humane treatment of the insane, Rush was in many ways far in advance of his contemporaries. The onset of the unexpected epidemic and the steady increase in its severity took the city by surprise: Rush, in grave doubt as to the best course to follow, tried one means of therapy after another as the deaths mounted. At the height of the epidemic he learned of a new treatment advocated by a doctor who was not well known: violent purgation by the "ten and ten"-10 grains of calomel and 10 grains of jalap-accompanied by copious bloodletting. So Rush began to purge and bleed his patients to the point of "removing all the inflammatory stimulus"; indeed. he advocated bleeding "up to 4/5 the blood in the body," if necessary, to attain this end. This system seemed to work. After trying it for a while, Rush wrote, "I now save 29 out of 30 of all to whom I am called on the first day, and many to whom I am called after it." He soon believed he had found the cure of yellow fever, for he wrote:'

Never before did I experience such sublime joy as I now felt in contemplating the success of my remedies. It repaid

Hartzell Research Professor of Therapeutics, University of Pennsyl vania, and Chairman, AMA Council on Drugs.

The tragic history of the purging-andbleeding treatment of yellow fever is an example of the errors of medical thinking in the past. Frequent reexamination of such episodes is necessary if similar errors are to be avoided in the future. When a new remedy is proposed, the favorable reports appear before the unfavorable. Elaborately designed investi gations, with precautions to eliminate bias, are necessary in many situations. But dramatic results like those given by insulin in diabetic coma can be observed by the individual physician. If he is trained to be objective and critical his place in the scheme of things will not be taken by the highly organized research team. He makes the decision as to whether a given patient was helped or harmed by a given drug, and it is he who makes the ultimate practical test.

me for all the toils and studies of my life. The conjust of this formidable disease was not the effect of acenderit. nor of the application of a single remedy, but it was the triumph of a principle in medicine.

During the crisis of the epidemic. Rush worked himself almost to exhaustion. Exposing himself fearlessly, he came down with yellow fever. Although about one-fourth of the population of the city and many of its doctors fled, he stayed with his patients. Before frost brought the tragedy to an end, over 7% of the city's population had died of the dread disease; the number of cases was 11counted. In everybody's mind, Rush was the hero of the epidemic.

Most unhappily, the yellow fever returned to Philadelphia in later years. Tried on the rising trend of the new epidemics, the heroic bloodletting and purging lacked their supposed beneficial effect. Rush's following among the profession diminished, despite his vigorous defense of his ideas. At length he was publicly attacked by William Cobbett, then editing a newspaper in Philadelphia, who later proved to be one of the greatest masters of vituperation ever to write in English. Cobbett accused Rush of killing his patients, and Rush lost most of his practice.

The difficulty in which Rush found himself still besets doctors today, and it is well to remember that we have no claim to possess keener minds than our medical ancestors, even though they sometimes made claims for remedies that, judged from the vantage point of the years, appear to us to be absurd. There is no evidence that the human mind has increased in capacity since Aristotle. Why then were our medical ancestors so often wrong?

Difficulties like those that beset Rush in the past occur in the present also, and one of the most common of the modern forms is best illustrated by a general rather than a specific example. Let us consider the situation which arises in the treatment of chronic diseases that tend to fluctuate in severity. When no method of therapeutics is very effective, doctors, in attempting to aid their suffering patients, try first one thing and then another. It is proper and logical for them to do this, for, in the medical game where so much is at stake, action is no more hazardous then sitting idly by. Much valuable information has been gained, and much aid to patients provided, by the time-honored method of "trial and error."

If a new drug appears on the scene and there is reason to think it might be of benefit and no good reason against using it exists, it will be tried by a considerable number of doctors. Since the severity of the chronic diseases tends to fluctuate spontaneously, the laws of chance dictate that, in some of the cases, the use of the new drug will be followed by improvement. Thus, some of the doctors concerned are happy about the results and their patients are happy also. These doctors feel that they have a right to be proud of themselves and regard it as a duty to inform their associates of their success, so the experience is published. The patients tell their friends of their improvement and the "good news" gets around.

The "good news" gets a head start because the other doctors concerned are under no such compulsion to tell their story. In their hands, the new treatment was followed by increasing disability; widespread knowledge of this experience would bring no new patients to the doctor's door! Only after they have seen the publications of the first

group, attributing an effectiveness to the new drug which is contrary to their experience, are these doctors stimulated to inform others in order to correct what they believe to be an error. Thus, only after some time does the true state of affairs come to light.

This type of happening is so familiar and so in accord with human nature that one might readily formulate a law: "For any new remedy, the favorable reports will appear before the unfavorable." Stated another way: "Whenever a new remedy is introduced, there is likely to be a period when all the reports are favorable."

These examples should convince anyone that judging a new remedy is a matter of great difficulty. It is indeed! Leaving the judgment to experts is not always a perfect solution. For instance, cod liver oil long had the reputation among practitioners of medicine of being useful in the treatment of debilitating diseases. But some time ago, when advancing knowledge of chemistry showed it to be a fat rather than a drug of the usual kind, the experts of the U.S. Pharmacopeia removed cod liver oil from their book. Later, when vitamins were recognized, cod liver oil was, of course, replaced in the Pharmacopeia. But there was a period when the judgment of practitioners was right and that of experts wrong.

What has modern scientific medicine to offer which will help us to circumvent these many pitfalls? Will our methods, viewed from the vantage point of 100 years hence, seem as clumsy and as futile as do those of 100 years ago? None of us know the answer to this, but it is of interest to try to formulate general terms the methods of thought which characterize the odern efforts, methods based on ways of thinking ditioreet in some respects from those of our medical ancestors.

Modern thinking has been greatly influenced by what is known as the scientific method, and the underlying philosophy was so clearly stated by one of the founders of modern scientific medicine that I shall quote him at length. In a book published almost 100 years ago, Claude Bernard' wrote:

But it is characteristic of criticism in pathology and therapeutics, first and foremost to require comparative observation and experiment. How, indeed, can a physician judge the etiology, if he does not make a comparative experiment to eliminate all the secondary circumstances, that might become sources of error, and make him take mere coincidences for relations of cause and effect. Especially in therapeutics, the need of comparative experiment has always struck physicians endowed with the scientific spirit. We cannot judge the influence of a remedy on the course and outcome of a disease if we do not previously know the natural course and outcome of the disease. That is why Pinel said in his clinic: "This year we will observe diseases without treating them, and next year we will treat them." Scientifically, we ought to adopt Pinel's idea without, however, accepting the long-range, comparative experiment which he proposed. Diseases, in fact, may vary in serious

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