FARMERS VICTORIOUS - 1949
BY DR. WM. J. HALE PH.D.
The use of specific chemical compounds to combat specific human ailments has long been the goal of the biochemist. The Incas of Peru had early hit upon cinchona bark extract for relief against malaria, and by 1639 this “quinine” was introduced into Europe. Though only partially effective it gave abundant indication of the manner in which certain chemicals may serve as specifics. Somewhat later this dreaded malaria, resulting from infection with the protozoan Plasmodia as transmitted by the female of the Anopheles mosquito, was brought up against two synthetic antimalarials—Schulemann’s “Plasmochin” of quinoline base in 1926, and “Atebrin” of acridine base in 1930 by Mauss and Mietzsch, all from the I. G. Farbenindustrie laboratories.
But practically speaking, chemotherapy had its inception in the work of Ehrlich. In the application of various dyes for staining tissues Ehrlich, in 1907, modified benzopurpurin into an azo dye, Trypan Red, and found it effective in mice against trypanosome parasites—thereby constituting the first synthetic chemotherapeutic agent. Thus Ehrlich came to describe chemotherapeutic agents as possessing various degrees of specificity against protozoal and bacterial invaders in animals without injury to the host. The appearance of Ehrlich’s “arsphenamine” (Salvarsan) in1910 marks the beginning of a new day in Medicine.
In 1913 Eisenberg discovered that the azo dye Chrysoidine (2,4-diamino azobenzene) was bactericidal in vitro; on December 25, 1932, Mietzsch and Klarer of I.G. Farbenindustrie were granted a German Patent on Sulfonamido-chrysoidine or Prontosil. In 1932 Gerhard Domagk of the Institute of Experimental Pathology of I.G. Farbenindustrie at Elberfeld, Germany, proved that Prontosil was relatively nontoxic yet protected mice against hemolytic streptococcal infections—in fact his experiments were perfect: 100 percent of the mice infected came through alive. Strangely enough, Domagk showed that Prontosil displayed no bactericidal action in vitro—to quote him: “It acts as a true chemotherapeutic agent only in the living animal.” The announcement of these discoveries was not made until February 15, 1935.
Next in turn the French took up the problem of ascertaining what part of Prontosil carried the effective group. Mr. and Mme. Trefouël, Nitto and Bovet at the Pasteur Institute in Paris soon reported that Prontosil underwent a dissociation in animal tissues to yield paraamino benzene sulfonamide. Whereupon Professor Fournenu of the same Institute prepared pure p-amino benzene sulfonamide (sulfanilamide) and tested it against streptococcal infections in mice and rabbits and found it just as effective as Prontosil, thus proving that the double-nitrogen or azo linkage (the dye-forming linkage) possessed no therapeutical value.
In England, Buttle, Gray, and Stephenson, in Lancet for June 6, 1936, confirmed the results of the French Scientists and undertook the synthesis of a large number of derivatives of the active p-amino benzene sulfonamide.
Eventually American biochemists awoke to the significance of this new synthetic. Drs. Perrin H. Long and Eleanor A. Bliss of Johns Hopkins Medical School led the way to far-reaching researches in this field. The first publication in this country was of January 2, 1937, in the Journal of the American Medical Association.
From the Lederle Laboratories came the announcement last year of a new sulfa drug called Phenosulfazole. This new drug, known also as Darvisul, has proved to be effective against poliomyelitis in mice and is now under test on humans at Columbia University.
The remarkable results securable by sulfanilamide against modern scourges may be measured by the reduction of pneumonia fatalities from 30 percent a decade ago to less than 10 percent today. The entire gamut of sulfanilamides is now known to interfere with the nutrition of bacteria setting up a virtual bacteriostasis. As bacteria require p-amino benzoic acid, a factor in the vitamin B complex, they are confronted here with a closely analogous structure, and when once fixed by sulfanilamides, have no other recourse than starvation.
Likewise these sulfa compounds, as well as thiourea and thiobarbituric acid, serve as antihormone drugs inhibiting production of thyroxine because of their close structural relationship to the amino acid tyrosine, the precursor of thyroxine, thereby interfering with the enzyme system called upon for production of this thyroxine. Furthermore, this close analogy between sulfa antivitamin and antihormone compounds may indicate that hormone like carcinogens may, in their turn, actually interfere with normal metabolism under some particular cellular enzyme systems and thus make possible the metamorphosis of a normal cell into a cancer cell. Even vitamin D, which is a dehydrocholesterol closely similar to a sex hormone, can be pictured as one possible of such diversion.
As far back as 1877 Pasteur and. Joubert announced that certain airborne organisms were found to interfere with the growth of the anthrax bacillus; indeed they intimated that some day this phenomenon of antibiosis might be brought under such control as to be of value in treatment of infection. Today microorganisms are known to produce any number of chemical entities capable of combating the growth of other organisms. Hence the entree of antibiotics into the realm of chemotherapy.
To Alexander Fleming, of St. Mary’s Hospital in London, goes the honor of being first to observe the destruction of bacteria by blood leucocytes concentrating in pus of wounds studied during World War I. His report in 1929 on the destruction of certain staphylococcal colonies on slides accidentally subjected to traces of mold growth prepared the way for extraction of this mold, Penicillium notatum Westling, to secure the active principle, penicillin; furthermore, Fleming was able to show that penicillin was nontoxic to animals and even to leucocytes.
As reported in 1940 by Lancet, Howard W. Florey and his colleagues, of the Sir William Dunn School of Pathology in Oxford, England, had the honor of bringing penicillin to the foremost position among antibiotics. Within a year penicillin had been purified and brought into systematic use for the treatment of infection. The action of penicillin is essentially bacteriostatic against both streptococci and staphylococci, and in many instances in as low a concentration as 1 part in 32,000,000 of water—a far greater activity than that reported for sulfa drugs. Thus penicillin came into the role of an ideal therapeutic agent, and particularly so by reason of its effectiveness in the treatment of wounds by local applications. However, whether administered intravenously or intramuscularly, or even by mouth, this antibiotic passes out of the system in the course of three to four hours.
(thiazolidine-beta-lactam formula in Penicillin -X, R = para-hydroxybenzyl)
Naturally the story of penicillin opened up the study of a vast array of microscopic forms of life, both pathogenic and saprophytic. From acid soils we had need to study fungi; from dry and alkaline soils we had need to study actinomycetes; from all soils the study of bacteria—aerobic bacteria of sandy, aerated soils and anaerobic bacteria of waterlogged and peaty soils; with a study of protozoal life everywhere. Generally speaking, an extensive root system of growing plants bespeaks highest aeration. In all of this it must not be overlooked that the presence of trace elements and growth-promoting vitamins plays an all-important role in the nutrition of microorganisms. There is no doubt but that these antibiotic agents function as parts of enzyme systems, such systems being enabled to dissolve away or destroy the capsular material ordinarily protecting bacteria and thereby exposing the latter to the leukocytes of the blood stream.
The resolution of Prontosil of dye like structure into a far simpler type—Para-aminobenzene sulfonamide, or sulfanilamide—is thoroughly elucidative of what may be expected in the entire realm of chemotherapeutic agents. The simpler structures not only carry the effective agency but also are far less likely to undergo disintegration by body fluids. Penicillin will no doubt yield to centralization of its active residue. Already it is reported* that the effectiveness of penicillin against certain bacteria has been quadrupled by the addition of a mere trace of cobalt chloride. Among the other antibiotics from fungi, quite a few hark back in structure to just plain Parabenzoquinone, than which few antibiotics are more active.
(* Journal of the American Pharmaceutical Association, 37, 133, April 1948.)
A striking advance among antibiotics is that of Chloromycetin, discovered by Dr. Paul R. Burkholder of Yale University while studying soil from Venezuela. The mold yielding this antibiotic is known as Streptomyces venezuelae.
The antibiotic itself is effective against scrub typhus, typhoid, Rocky Mountain, and undulant fevers. Synthesis of this antibiotic was accomplished in 1948 by Harry M. Crooks, Jr., Mildred C. Rebstock, and John Controulis of Parke, Davis & Company. The synthetic product has been named “Chloramphenicol.” In the formula assigned it will be observed that the presence of a nitro group (NO2) and several chlorine atoms (Cl) are apparently without toxic effect—something exceptional in the course of therapeutic compounds. Only one of the four possible optical isomers displays antibiotic activity.
Space forbids too extensive enumeration of all the antibiotics under study in recent years; yet one recently discovered is of far reaching promise against tuberculosis. This is streptomycin, isolated in 1944 from Streptomyces griseus (of certain soils) by Dr. Selman A. Waksman and his colleagues at Rutgers University. Streptomycin presents a chemical configuration based upon inositol, the chief component of corn “steep-water.” This structure, elucidated in 1943 by Kuehl, Peck, Hoffhine, and Folkers of the Merck Laboratories, involves the individual replacement of each of two hydroxyl substituents in inositol by the guanidyl group, —NH-C(NH2)NH (imino-urea), and a third hydroxyl substituent tied into a specific disaccharide (or sugar type) group:
As far as is now known, the keto group (CO) or the thionyl group (SO) is common to all antibiotics, usually in juxtaposition to a carbon atom carrying a labile hydrogen, or preferably to a carbon atom carrying likewise an oxygen atom (a keto group); this latter grouping constituting what is called a “conjugated system.” In the human body amino acid oxidizes, previously mentioned as universally present, are most effective in transamination, wherein an oxygen atom will replace the hydrogen and guanidyl group on each of two carbon atoms of the inositol ring of streptomycin. Thus will arise a streptomycin carrying two keto groups, in place of the two-guanidyl groups, and thereby serving as an oxidant still carrying the disaccharide group. Yet here again a further dehydrogenation through the action of the aldehyde group of the disaccharide group present might well lead to a dihydroxy tetraketobenzene (rhodizonic acid) directly after the splitting away of the disaccharide group. Eventually we can expect an end product of hexaketocyclohexane (triquinoyl), of six keto or carbonyl groups in a ring.
Naturally we cannot avoid coming to the inference that possibly the organic chemist can supply the world with just those compounds ideally suited to each and every type of infection. Much of this we even now proclaim is within the bounds of synthetic organic chemistry. Starting back in 1918, Dr. William F. Koch of Detroit, now of Rio de Janeiro, Brazil, began his experiments striking at the heart of immunity. He employed Parabenzoquinone in extremely dilute solutions (one to a million) and injected two cc. of said solution into the patient intramuscularly.
His treatment of mastitis in cows has surpassed highest expectations. Notably among humans many cases suffering from tuberculosis yielded readily to treatment with this quinone, thereby proving that the quinone was serving as an oxygen carrier and exerting a high healing effect directly in the neighborhood where oxygen was inhaled by the individual. How much more likely, then, is the action of rhodizonic acid, of higher keto content, by way of streptomycin, to register itself as beneficial in treatment of tuberculosis!
Recent clinical reports from Mount Sinai Hospital, New York City, confirm the effect of certain keto compounds (among them rhodizonic acid) on reduction in blood pressure of hypertensive rats, and yet without disturbance to the blood pressure of normal rats.
But if the inositol ring can function so advantageously when dehydrogenated into rhodizonic acid, what should we expect of a further dehydrogenation—say, carried to completion; i.e., into hexaketocyclohexane or triquinoyl?
In practice triquinoyl has been found to act almost identically with “Glyoxylide” (O=C=C=O), a compound that Dr. Koch bad prepared by dehydration of glyoxylic acid (CHO-COOH). In brief, this so-called Glyoxylide, which has proved so efficacious in the hands of Dr. Koch against diabetes, arthritis, poliomyelitis, and even cancer, undoubtedly polymerizes under many conditions to 3(O=C=C=O) or triquinoyl, in which an oxygen atom is doubly linked to each of the six carbon atoms of the reduced (or saturated) benzene ring carbon structure, and plays a most effective role in the treatment of disease. In the likely dehydrogenation of inositol within the body we can now interpret the phenomenal action of inositol in replacing insulin for diabetics.
Thus when the valuable streptomycin is shorn of its disaccharide substituent, as well as guanidyl substituents, it becomes a simple compound of high oxidative potential and of highest efficacy in the treatment of disease. The most active end product, triquinoyl, constitutes a virtual super-streptomycin. But it does not constitute only a super-streptomycin; it constitutes a superpenicillin and superantibiotic in general.
Of outstanding effect here is the extreme dilution at which these antibiotic agents appear to function best. No one ever dreamed of such dilutions until penicillin made its entrance upon the stage of medicine, and here 1 part to 32,000,000 is nothing out of the ordinary. Dr. Koch merely stepped up this dilution some thousandfold when ideal results were found to arise. Of course, criticism emanating from unschooled biochemists scoffed at such dilutions: Ultimate analyses proved totally incapable of revealing the presence of the compounds used; and so they should. Only by application of radioactive technique can the presence of such compounds in such high dilutions be detected. Yet in a dose of triquinoyl of 2 cc’s in the dilution of 1:1,000,000,000, these 2 cc’s introduce into the system the amazing number of more than 5,000,000,000,000 molecules of the active agent! Only so recently as in Science Illustrated for February 1947 is it reported that Professor Gilbert M. Smith, at Stanford University, was able to affect a metamorphosis of the cells of a microscopic plant from the sessile, or asexual phase, to the actively motile, mate-seeking sexual cells, by the application of one part of crocetin (C13H22 (COOH) 2) in 250 trillion parts of water!
Now the role of these polyketocompounds is definitely oxidative. By their presence a higher level of metabolism is made possible in the system, and, like a passing wave over a golden wheat field, this wave of oxidative influence continues unabated for months upon months—sufficient, indeed, to heal improperly nourished organs and slough off decadent tissues. All of this is in accordance with findings of H. Wieland proving first the hydration of an active carbonyl group in body fluids into =C=(OH)2 and its subsequent dehydrogenation by enzymes into a peroxide type, =C=O=O, whereupon nascent oxygen is liberated and the carbonyl group (=C=O) regenerated to repeat the process. Just as Pasteur identified the microscopic organisms that led to plant disease, so Koch identifies the chemical agents that are capable of combating microorganisms.
In Brazil this new interpretation of immunity is meeting with wholehearted cooperation on the part of the government. Happily the Brazilian authorities are sufficiently open-minded to recognize that the cure for many diseases, when once established, will prove to be an oxidant capable of restoring normal functions in cell growth. In this country many able physicians are applying the carbonyl therapy, notably Dr. Edwin D. MacKinnon of Saginaw, Michigan, and Dr. George W. Palm of Prudenville and Detroit, Michigan. There is no more interesting presentation on this subject by a physician than that published by the late Dr. Albert L. Wahl of Mount Vision, New York. This brochure is entitled A Least Common Denominator in Antibiotics.
Intelligence Digest* has recently published a short account of the remarkable curative properties of H.11 against cancer. This H.11 is prepared by the Hosa Research Laboratories Windmill Road, Sunbury-on-Thames of London, England, and is an oxidant similar to the Koch compounds in structure.
Highly germane to the program of stepped-up oxidative processes within the human system is the absolute necessity for careful selection of proper foods to accompany these treatments. In fact, it is generally stated that half of the treatment lies in the diet. Thus highly reductive agents contained in foods and medicines must be shunned.
For perfect health there is only one correct course to follow: the selection of those foods that carry the whole gamut of vitamins and amino acids and. trace elements. It thus becomes necessary to learn something of the agricultural areas on which our fruits, grains, and vegetables are grown if we are to be assured of the proper nutrient. Meats, of course, will now and then need to be selected; but as time passes, the requirements for meat will fade away in the light of synthetic supply of the required amino acids and proteins. Above all, our foods must carry a sufficient supply of oxidants to maintain metabolism at its highest level. These oxidants are ever present in the coverings of seeds and tubers; they are not present in highly refined foods. Old age comes upon us primarily by reason of the absence of these oxidants. With oxidants in full supply, the digestion of foods proceeds normally and the wear and tear on our blood vessels is reduced to a minimum.
Kenneth de Courcy, Chap. 5, Intelligence Digest, Vol. XI (April 1. 1949)
1912 – 1939
- 1925 IS A CURE FOR CANCER POSSIBLE BY ANTITOXIN AND SERUM TREATMENT EIGHTEEN MONTHS WITH THE KOCH CANCER ANTITOXIN
- 1925 THE KOCH CHEMICAL FORMULA IN THE TREATMENT OF CANCER
- 1925 THE KOCH TREATMENT OF CANCER
- 1926 CAN CANCER BE SUCCESSFULLY TREATED BY NON-SURGICAL METHODS?
- 1926 CANCER—ITS CAUSE AND PREVENTION
- 1926 THE CANCER SITUATION
- 1929 THE PERIODIC MEDICAL EXAMINATION AND THE EARLY DIAGNOSIS OF CANCER
- 1933 DR. WILLIAM H DOW, ALONG WITH OTHER SCIENTISTS, SPEAK OUT ON KOCH REAGENTS
- 1933 CANCER BY DR. D. W DEWEY M.D.
- 1935 KOCH COOK BOOK / INDIAN SUN SYMBOL
- 1937 ACQUIRED IMMUNITY TO TUBERCULOSIS
- 1938 NEOPLASMS, INFECTIONS, AND ALLERGY, DR. H. MAISIN, M.D.
- 1938 REVERSING THE PATHOLOGICAL TREND IN RHEUMATIC FEVER AND CORONARY THROMBOSIS
- 1938 THE USE OF PEROXIDE
- PHAGOCYTOSIS OF THE TUBERCLE BACILLUS
1940 – 1959
- 1941 IMPORTANT FACTS ABOUT THE KOCH TREATMENT
- 1941 THE CURE OF CORONARY THROMBOSIS
- 1944 SCIENTISTS SEEK LEPROSY CURE
- 1945 A LEAST COMMON DENOMINATOR IN ANTIBIOTICS
- 1949 FARMERS VICTORIOUS
- 1949 THE BIRTH OF A SCIENCE, BY DRS. WAHL, REHWINKEL AND REILLY
- 1950 THE NEW SCIENCE IN THE TREATMENT OF DISEASE SYMPOSIUM
- 1950 THE PROSECUTION OF DR. WM. F. KOCH
- 1951 JOURNAL OF AMERICAN ASSOCIATION OF PHYSICIANS – 8 REPORTS
- 1952 THE INCREDIBLE FEDERAL TRADE COMMISSION, BY DR. D. H. ARNOTT, M.D.
- 1952 THE KOCH CATALYTIC AGENTS, BY DR. JULIAN F. BALDOR, M.D.
- CATTLE EXPERIMENTS IN THE U.S. AND CANADA; A SERIES OF ARTICLES
- NATURE OF ACTION OF KOCH ANTITOXIN