A KILLER CURBED
Sulfapyridine—Medicine’s new weapon in the fight against pneumonia
ROYD E. BEAMISH
EVERY year 30,000 people in Canada get pneumonia. Every year up to now, more than 7,000 of them have died. But this year, if seven months of intensive experiments can be regarded as a fair indication of what lies ahead, two out of every three Canadians who would otherwise die of pneumonia will be saved.
Pneumonia, which has been the Dominion's fourth largest killer (exceeded only by diseases of the heart and arteries, and by cancer), is on its way down the scale, en route to join other dread diseases of the past such as diphtheria and typhoid.
Modern medical magic, wrapped up in a yellowish-white tablet, has struck a death blow at the deadly pneumococcus organism. The new drug, which has thus revolutionized the treatment of pneumonia, has been in use little more than a year, yet already it has benefitted hundreds of patients. In every clinical test to which it has been subjected, it has reduced the pneumonia death rate from its normal twenty-four per cent or higher, to eight per cent or lower. Where one out of every four pneumonia patients has died in the past, only one out of twelve has died when the drug has been used.
In a clinical test conducted in a Toronto hospital, fortyseven patients out of fifty treated with the drug recovered; in a similar test at Montreal, twenty-nine out of thirty were restored to health. These are the published results of clinical trials which took place between August, 1938, and March, 1939. Subsequent tests have maintained this record, until now even the most conservative authorities are. satisfied that a death rate of not more than eight per cent can be expected where the drug is used. What was only faint hope a year ago has become accepted fact.
So new is this surprisingly effective drug that medical men themselves are not yet fully agreed upon what to call it. It came into being identified simply by a number in May, 1938, and it is now known by four distinct names— dagenan, M&B 693, paramid and sulfapyridine—with the last mentioned rapidly gaining in preference.
The first two names hint at the place of origin of the drug— the English drug-making house of May & Baker in Dagenham. Essex. The last two offer a suggestion as to its chemical derivation. In the mystic language of the laboratory, the new compound is known as: 2 — (p — aminobenzenesulphonamido) pyridine.
By the layman it is often confused with sulphanilamide, of which it is a derivative. The Canadian Medical Association Journal describes it simply as “a chemical compound which contains an active sulphur radical, but which is not sulphanilamide, nor convertible into sulphanilamide in the body.’
Nor are research workers satisfied that they have learned how the drug acts in bringing about its spectacular cures. Many experimenters believe that the chemical attacks the germs directly, but there are others who feel that sulfapyridine merely slows down the growth of microbes and weakens the tough capsulelike shells with which they are surrounded, thereby permitting the white cells in the blood stream to attack and conquer them.
BUT, whatever the action of the drug, there has, so far, been no disputing its effectiveness as chemical ammunition in the war on pneumonia. From England, from the United States and Canada, have come reports which tell the same tale of promise.
Take the case of the fifty-year-old Toronto man who was admitted to hospital with a temperature of 105.6, his right lung choked with pneumonia infection. Examination of his sputum showed the presence of Type III pneumococcus or pneumonia microbe—a particularly virulent form of the disease. So far had the infection progressed that colonies of the microbes were found in the blood as well.
In the first day after receiving sulfapyridine, the patient’s temperature dropped to 104. At the end of the second day it was 100.6, and thereafter never rose above 101. A blood culture taken on the third day revealed no trace of pneumococcus in the blood, nor did the condition recur.
The combination of circumstances in this case was regarded by attending physicians as a severe test for any form of treatment. In the first place, Type III pneumonia — there are thirty-two types of pneumonia—produces an exceptionally high fatality rate. Secondly, mortality is usually twice the normal rate when the disease has progressed sufficiently to reveal itself in blood cultures. Thirdly, age is a factor in the death rate, nearly seventy per cent of all pneumonia deaths occurring among (>ersons over forty-five. It was three weeks before this patient’s temperature was reduced to normal, but the wonder was that he survived at all.
Contrast that case with the history of an “average” Type I patient, admitted to hospital with a temperature of 106. In one day the temperature dropped to 101.8, and twelve hours later it was normal, with no return of fever.
Miraculous such accomplishments are, when viewed by any previous standards. Until a few years ago. doctors and nurses could do little to aid their patients fight pneumonia beyond guarding them against complications. Pneumonia victims then were literally “nursed” back to health. The crisis came, and the patient either recovered or died.
Then came discovery of various serums which, injected into the blood stream, aided the normal resistance mechanism of the patient, hastened the crisis and lowered the death rate. But the administration of serum was both costly and involved. Time was lost when time was most important, for the disease had to be “typed” before serum could be used. Each type of pneumonia required the use of a specific type of serum. Expert technique was required for its proper administration, and even then results were never sure. In cases of pneumonia which had progressed to the stage where the infection was present in the blood stream, for instance, a death rate of fifty per cent or higher was still to be expected—virtually no improvement on “untreated” cases in the same stage of virulence.
Discovery and Development
TN 1937 the medical world saw its first ray of hope for ultimate success in its search for a specific against pneumonia, for it was then that sulphanilamide burst across the horizon. This was the drug—discovered by two successive freaks of chance—that dealt sudden death to streptococcus germs, paving the way for the conquering of such diseases as streptococcus meningitis, childbed fever and erysipelas.
In France, Germany, Great Britain and the United States, pneumonia research workers took new heart. Perhaps at last the great cure-all had been found. Perhaps sulphanilamide was the “universal specific” for which medicine had searched in vain ever since Paul Ehrlich discovered Salvarsan or “606” more than twenty-five years ago.
In laboratories oí half a dozen countries, white-coated technicians turned to their time-proved testing grounds —white mice, which react most quickly to pneumonia infection. Thousands of mice were shot full of pneumonia germs. Half of them were then injected with doses of sulphanilamide.
The mice that did not get sulphanilamide died within forty-eight hours. The others lingered on for several days, but eventually they died too. Reluctantly it was agreed that the new drug was not the answer, but the experiment still offered an avenue of hope.
The sulphanilamide had not killed the pneumonia microbes, yet. mice dosed with the drug had staved off death many hours — in some cases days—longer than the others. Something in the drug had checked the microbes temporarily.
Since sulphanilamide itself was a lucky find, technicians reasoned, there was no reason to presume that it was the most effective form of the drug obtainable. Perhaps within the drug itself lay still more power.
On this assumption, the English drug firm of May & Baker began to tear down sulphanilamide and build up new compounds, based upon the same formula. Much as Ehrlich had labored through 605 arsenic compounds before he found the ”606” that conquered syphilis, British chemists fashioned hundreds of synthetic preparations, each carrying the magic of sulphanilamide in one form or another.
As fast as the compounds were prepared they were tested on the spot. Most were found lacking in some essential qualitymany were violent poisons—and were discarded. A few held out hope, and these were promptly shipped to Dr. Lionel E. H. Whitby, Birmingham pathologist, for testing on animals.
Sixty-five such compounds reached the patient doctor at Dudley Road Hospital in Birmingham, during the next few months—sixty-five hopeful-looking preparations, sifted from hundreds of specimens turned out by the British chemists. One by one they were discarded when they failed to protect mice against pneumococci until only one was left. To the drug firm it was only Compound No. 693, and its crystalline substance held no more promise than all the rest. To Dr. Whitby it was merely another drug to be tested.
Patiently and with disinterested precision. Whitby shot two batches of white mice full of pneumonia microbes. Into each mouse went enough to kill 10,000 mice. One batch was put aside to die. The mice in the second batch were given injections of Compound 693 in solution.
The mice that did not get 693 began to topple over that very same day. By the end of forty-eight hours almost all were dead, and the last mouse in the untreated batch died before the third day ended. Some of the other mice died too, but more than a third of them recovered completely from the infection. The long-sought drug had been found, it seemed, but thoroughgoing science was not yet satisfied.
Down the list of the thirty-two types of pneumonia known to medicine, the experiment was repeated, and Whitby found that the drug afforded a high degree of protection against Types I, II, III, V and VIII. With other types, 693 lessened the severity of the disease to a marked extent.
The news was particularly heartening because Type I pneumonia is the most prevalent of all, accounting for almost a third of all pneumonia cases, while Types II and III are generally regarded as the most severe forms of the disease, with the highest mortality rate. With the most prevalent and most severe types thus
offset, the drug seemed certain to have a telling effect on the pneumonia death rate generally.
There were still other questions to be answered before the drug could be tried on human beings, however. Was 693 poisonous. or did its use in curative quantities upset the system in any way? The first question was answered easily. Whitby fed mice with the drug until they died, and learned that the little animals could assimilate one part of the drug for sixty parts of their body weight before death ensued. The same proportion applied to human beings meant that three pounds of the medicine would be necessary to cause death in a 180-pound man, while only a fiftieth of the lethal dose was needed to give the required protection.
Even that was not enough to satisfy the pathologist, for there was still the possibility that the drug, while not fatal in its action, might yet upset the body chemistry of a patient sufficiently to make it useless as a medicine. The practical value of any drug depends on the ratio between its curative dose and the amount that can be tolerated without distress. Further experiments showed that the amount of the drug necessary to produce a cure did not have any upsetting effect on mice.
BY JUNE of 1938 the drug was ready for its final test—on human beings. Dr. G. Mary Evans and Dr. Wilfrid Gaisford took the new compound into Dudley Road Hospital to see how it would work in actual clinical practice, so that a true appraisal of its value might be made. Drugs that work on mice do not always work on man.
Pneumonia patients entering the hospital on one day were placed in Group A. to receive only routine treatment for the disease; those of the following day were put in Group B, receiving routine treatment plus sulfapyridine. Making the distinction was not easy, but it was essential if the effects of the drug were to be measured. If there were no “controls” to show the difference in result between treated and untreated patients, the medical world could never be sure whether the drug had accomplished its desired results, or whether the disease was simply less virulent than usual at the time the test was being made.
The process of grouping was continued until there were 100 patients in each category, ranging in age from eight to sixtyeight and representing all pneumonia types in every degree of severity. When the test had been completed, the sulfapyridine group showed a case mortality rate of only eight per cent, while the control (untreated) group showed twentyseven per cent—the normal death rate for that section of the country.
Everything pointed to the efficacy of the new drug. In some cases sulfapyridine was deliberately withheld when the patient showed signs of recovery. Immediately his condition became worse. The drug was restored and the patient improved. There was no longer any doubt that the drug was responsible.
All over England physicians began using sulfapyridine in similar tests, and in every case the same spectacular results were reported. In a group of forty children’s cases there were only two deaths, and both victims suffered from peritonitis as well as pneumonia.
In the United States also, series of control tests were undertaken. Of seventyfive pneumonia patients treated in Philadelphia. only six died— a mortality of eight per cent. In a large New \ork hospital, forty-seven patients out of fifty recovered after the use of sulfapyridine.
In Toronto, Dr. Duncan Graham, professor of medicine in the University of Toronto, launched a similar trial, assisted by Dr. W. P. Warner, Dr. J. A. Dauphinee and Dr. R. C. Dickson. Thirty control cases resulted in seven deaths, for a mortality rate of twenty-three per cent. Thirty other cases, in which sulfapyridine was used, showed only one death, establishing the amazing death rate of 3.3 per cent.
That was enough for the Toronto physicians. They knew that such a low mortality rate could not be expected to continue, but they were convinced that the drug had proved its worth. From the day their first experiment was concluded early in January, all pneumonia cases admitted to hospital were treated with sulfapyridine. By the end of March, fifty cases had been treated and only three had died, bringing the death rate up to six per cent.
All three fatalities occurred among patients over fifty years of age. Two of the three had serious heart conditions to complicate the disease, and the third was in a moribund condition when admitted to hospital.
Montreal experiments showed equally promising results. There Dr. J. C. Meakins and Dr. F. R. Hanson tried out sulfapyridine on thirty patients, and only one died. The sole casualty was a man of eighty-one, stricken with three distinct pneumonia types XX, XXII and XXIX. The drug reduced his temperature to normal in twenty-four hours, but his constitution could not stand the protracted strain and twelve days later he died.
Cheaper Than Serum
TO THE layman these results verge on the miraculous, and even the cautious reserve of the medical profession has been largely overcome by sulfapyridine’s success. Greeted at first with the scepticism* in which all newcomers to the medical field are viewed, the new drug is now beginning to receive full recognition as a specific for pneumonia.
The April issue of the Canadian Medical Association Journal reflects this new attitude of acceptance. In its editorial section, where each statement represents the view of responsible medical authority, the Journal devotes four pages to sulfapyridine.
“As will be seen,” it says, “no extravagant claims are made in its favor, but one cannot ignore a reduction in the mortality of Dr. Graham’s series to six per cent . . . Actually only one fatal case could be considered as due to pneumococcus infection alone, so that the mortality rate might well have been reported as only half as great.”
The Journal suggests, too, that sulfapyridine may soon displace even the serum treatment of pneumonia. Serum treatment, it finds, does not cut mortality to as low a figure, and “even if the drug were no more than just as effective, there are great advantages attaching to it.”
Sulfapyridine is much cheaper than serum, and this is considered an important factor. In addition, being in a form that can be taken by mouth, its administration calls for no more technique than opening the mouth and swallowing, in contrast to the elaborate details surrounding the giving of serum.
Official medical journals do not grant even this qualified approval to new drugs until their editors are convinced that the products merit it. And the editors are all hardheaded, practical physicians. So far, practically no serious criticisms of sulfapyridine have been made. One disadvantage seen in the use of the drug is that its administration is sometimes followed bynausea and vomiting.
In the Toronto experiment, nausea was reported in sixty-six per cent of all cases treated, and troublesome vomiting in thirty per cent. At Montreal, twenty of the thirty cases treated vomited one or more times during the course of treatment, while in three cases the condition became severe
enough to require discontinuing of the drug. Dr. Graham found, however, that if administration of the drug were continued, the nausea tended to decrease rather than increase, and the use of sedatives usually brought about “toleration” of the drug. Research chemists now have perfected a preparation of sulfapyridine in a soluble salt form, which may be injected into the veins, thus obviating the stomach discomfort experienced in some patients when the drug is taken by mouth.
Saving Canadian Lives
C ULFAPYRIDINE is regarded and ^ rightly so among the very newest drugs developed by man to wage war against murderous microbes, but the story of its.5 beginning goes back much farther than May, 1938. For, without the earlier discovery of sulphanilamide, the newer drug would not yet have been dreamed of.
Most of us consider sulphanilamide an almost equally new development, and from a purely medical standpoint the supposition is correct. It was not until 1937 that the sensational curative powers of the drug became generally known, although five years of laboratory experiment lay behind its introduction to the public.
Gerhardt Domagk, of Elberfeld, Germany, was heralded as the “discoverer” of sulphanilamide, and in the wave of jubilation that followed its successful use in hospitals, nobody bothered to question the matter. All they cared was that sulphanilamide was saving lives—murdering the murderous streptococci which caused such diseases as strep meningitis, childbed fever, erysipelas, gonorrhoea and septic sore throat.
When the first flush of enthusiasm had subsided, medical men checked back and found, to their dismay, that the magic of sulphanilamide had been available for nearly thirty years before its worth was revealed by Domagk. It was discovered by a man named Gelmo, who was neither a famous scientist nor a doctor, but simply an industrial chemist employed by one of the world’s largest chemical manufacturers the I. G. FarbenindUstrie of Germany.
Busy making chemicals in one of his firm’s many laboratories, Gelmo compounded a coal-tar derivative with the ponderous name of para-aminobenzenesulphonamide. The chemical was duly classified, but its medical powers were neither suspected nor explored. Along with hundreds of other combinations for which no practical use could be found, the coni]xrund was placed on a laboratory shelf and practically forgotten.
In 1932 Domagk and a co-worker began experimenting with the chemical, linking it with a naphthalene substance to obtain a red dye, which they named prontosil. For three years German physicians tried it in their clinics, and made an amazing discovery. Prontosil was effecting cures in many difficult cases of blood poisoning and other infections; and yet when prontosil was poured into a test tube teeming with streptococcus germs, the bacteria went on living as before.
The mystery was finally cleared up by Paris pathologists, who found that the body broke the bond between the naphthalene and the strange chemical, and that the latter substance was doing the germ killing. Mercifully shortening the chemical’s name to sulphanilamide, research workers put it through a rigorous series of tests that enabled them to announce its amazing properties in 1937.
From sulphanilamide, in turn, came sulfapyridine, harnessing the magic of its parent drug and applying it expressly to the pneumonia microbe. Through the tortuous pathway along which all chemical discoveries must travel to gain acceptance it has come, passing each exacting test that medicine has devised to protect humanity. Efforts are now being made to apply it in the treatment of tuberculosis.
But here a word of warning. It should never be forgotten that the new life-saving drug, sulfapyridine, is also a toxic drug. In isolated cases, the toxic effects have been so serious as to cause death. For this reason, the drug should be administered only by persons skilled in its use. Such a drug has no place in the treatment of minor ailments; and the best medical opinion is that it should not be prescribed unless the disease condition is serious enough to warrant the taking of risks.
The conservative, guarded phrases of the medical journals, however, are ample testimony to its effectiveness when in the proper hands. Praise of the new drug and tribute to its discoverers flow easily from those who have seen its effects. But the most soul-stirring thought inspired by it3 discovery is this:
Two out of three persons marked for death by Canada’s fourth largest killer will be saved this year.