Advances in the Field of Pharmaceuticals and Medicinals T H E O D O R E G . KLUMPP A N D JUSTUS B. RICE, Winthrop Chemical Co., Inc., Rensselaer, Ν . Y.
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THE year 1944 has been a fruitful one from the standpoint of the development of new remedial agents and the practical application of previously acquired knowledge to the treatment of disease. The demands of a nation at war have forced the attention of medical research on special problems directly related to the welfare of the armed forces and a civilian population subjected to unfamiliar stresses. Never before has the research potential of our country been so intensively directed into the narrow channels leading to the solution of immediate practical problems such as the large-scale production of urgently needed medicines, the development of new agents and metho d s of treatment, and the modification of older concepts and compounds to fit changing needs. It is inevitable that this preoccupation with applied therapeutics can be made only at some cost to fundamental research into the basic sciences of pathology, physiology, and chemistry. Unfortunately the most absorbing parts of the story of medical research in 1944 cannot be told for reasons of national security. There is no doubt that when the present war is over, an astonishing flood of practical information will be released which will render obsolete much of present day treatment. In this paper, therefore, only general remarks on the most outstanding developments, released from voluntary medical censorship, can be made.
Penicillin The most important contribution of 1944 is andoubtedly the expansion of production of penicillin. The year 1942 brought a realization of the importance of
this new antibiotic in the treatment of infectious diseases. During 1918 mass production got under w a y ; many improvements were made in growing the mold and extracting the active principle. The groundwork was thus laid for the most remarkable manufacturing effort ever made by the pharmaceutical industry. During the past year, these principles were applied and a new record set in t he production of a highly complex substance. Production during the last year probably totals close t o 1,600,000,000,000 Oxford units. This is approximately 8,000% of the total production of penicillin in all previous years. The tremendous expansion of penicillin production, begun in 1943 and reaching its full flood in 1944, is a tribute t o American productive genius and the fine work of the Drugs and Cosmetics Section, Chemicals Division, War Production Board. Although the drug was not discovered in this country, we are, as far a s is known, the only large scale producer. A large "bottle" plant, perhaps the largest of its kind in the world, has just begun operation in Great Britain at the time of writing. A t present we are justifiably sharing our output with most of the allied world. This explains why the drug is not y e t freely available in this country. During this year, also, penicillin was purified and small amounts of pure crystals having a potency of 1,650 units per mg. were prepared. Great strides were made also in the purification of commercial penicillin: in the beginning of the year a preparation containing 250 units per mg. was considered ex c l i e n t ; at the end of the year well over 5 0 % of penicillin produced in this country assayed more than 1,000 units per mg.
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The most noteworthy single contribution to penicillin therapy during the year was the development at Walter Reed Hospital of a suspension of penicillin calcius in oil and beeswax, which, by slowing absorption of the drug after intramuscular injection, confers a depot action on the drug. This technique obviates the necessity of frequent injections. By its use gonorrhea, for example, may be cured in a few hours by a single injection. The practical importance of this discovery to the armed forces is very great. During the year, also, the remarkable action of penicillin in the treatment of early syphilis was confirmed and its value in the treatment of late syphilis suggested. Vivicillin, i.e., a suspension of the finely ground living mycelium of penicillium mold injected intramuscularly has prolonged the activity of the drug but this mode of application remains experimental.
Other Antibiotics Many new antibiotics have been discovered and several of the most promising have been tested clinically. Streptothricin derived from Actinomyces lavendulae, is active on a great variety of bacteria, Gram negative (untouched by penicillin) as well as Gram positive. In the case of some of the Gram negative organisms such as E. coli, E. Typhi, and Salmonella aertrycke, it is far more effective than penicillin. However, streptothricin is also much more toxic. It is likely that streptothricin, because of its wider field of activity, may be used to supplement penicillin. It may be useful locally in the treatment of infected wounds and burns and possibly by oral administration for bacillary dysentery, typhoid fever, and E. coli infections'. Streptomycin, an antibiotic closely similar t o streptothricin both chemically and in biologic activity, appears t o be less toxic and may ultimately prove to be more useful than streptothricin. Early in the year hope was held out that clavacin (patulin), a substance derived from Aspergillis clavatus and other organisms would effectively prevent or cure the common cold. However, these hopes were
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Justus B. Rice
Theodore G . Klumpp not realized. Clavacin is a toxic substance when administered systemically but has interesting fungicidal properties in addi tion to its effect on bacteria. Like streptothricin it is bacteriostatic on Gram nega tive organisms including the colon-aerogenes group. It is hoped that clavicin may find a usefulness in local application to the skin or mucous membranes. The discovery of a substance (not peni cillin) isolated from a green mold having s particular affinity for the tubercle ba cillus, has been reported recently. It grows best on cultures of the tubercle bacillus and is capable of neutralizing tuberculin. Its role in the treatment of human tuberculosis has not y e t been as certained although .it protected 18 of 24 guinea pigs injected with a strain of hu man tubercle bacilli.
Chemotherapy Considerable progress appears to have been made in the chemotherapy of tuber culosis. One of the earliest compounds used in the experimental and clinical treatment of tuberculosis was Promin, the sodium salt of ρ,ρ'-diaminodiphenylsulfone-N,N'-didextrose sulfonate. How ever, the toxicity of Promin in effective doses limited its value. Diasone (disodium formaldehyde sulfoxylate diaminodiphenylsulfone) is better tolerated and may be given to animals in doses of 1 gram per kg. intravenously without toxic effects. It appears to be as effective as Promin in the experimental tuberculosis of animals. The newest member of the series, Promiaole (4,2 '-diaminopheny 1-5 '-thiazolesulfone), appears on the basis of preliminary studies to be superior t o both Promin and Diasone. I t is tolerated so well by human beings that doses of from 10 to 16 grams daily may be given orally for periods up to 4 months, apparently without harm. I t is difficult to evaluate the effectiveness of any chemotherapeutic agent in a disease as chronic as tuberculosis* however, pre liminary results are hopeful and although
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no cures can be claimed, there is no doubt that Promizole exercises a remarkably beneficial effect. It is easier to evaluate the results of chemotherapy in tuberculous meningitis which hitherto has been uni formly and rapidly fatal. Definite im provement has occurred in 6 days of treat ment with Promizole in such a case, and apparent cure after 36 days. The sulfonamide series of drugs has been so thoroughly explored in ths past decade that we have come to the inevitable resting stage that follows periods of in tense activity and unprecedented progress. However, three receiving recognition in 1944 are sulfamylon, sulfamerazine, and phthalysulfathiazole. Although sulfamylon was studied in this country as early as 1940, little progress was made because a t the time the atten tion of pharmacologists was confined al most exclusively to new compounds active against Gram positive organisms such as pneumococci, streptococci, staphylococci, etc. However, when sulfamylon, under the name of Marfanil or Mesudin, was captured on German prisoners during the North African campaign, the attention of American investigators was focused upon it and its remarkable properties. Sulfa mylon differs from the other sulfonamide compounds chemically in that the amino group is separated from the benzene ring by a methyl group. Pharmacologically, its activity is strikingly different from that of the other sulfonamide compounds. It is not inhibited by p-aminobenzoic acid and consequently its action is not im paired b y the presence of pus. Its range of activity is considerably wider than that of the other sulfonamides, attacking not only Gram positive organisms but also some Gram negative bacteria and anaerobic as well aa aerobic organisms. I t does not destroy epithelium nor delay wound healing. Curiously enough, sulfa mylon seems to be ineffective when ad ministered systemically, its activity in blood serum being greatly reduced. However, it appears at present that sul
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famylon is superior to any other sulfon amide drug, when applied locally t o i n fected wounds or burns. Sulfamerazine is similar to sulfadiazine in its activity but because of better and more complete absorption it may be given in doses one half to one third as large as· sulfadiazine. I t produces a high blood concentration and need be adminosteoedl less frequently. However, this drug appears to be somewhat more toxic than sulfadiazine and more largely bound b y protein elements in the blood. For these reasons its ultimate usefulness is at present in doubt. Phthalysulfathiazole 12-(N-phthalylsulfanilamide) thiazole], a condensation product of phthalic anhydride and sulfathiazole, appears to have advantages over older sulfonamide preparations developed for the treatment of infections of the in testinal tract, both from the standpoint of efficiency and tolerance. Approximately 9 5 % of the oral dose of phthalysulfathia zole passes unabsorbed through the gastro intestinal tract, only 5% being excreted by t h e kidneys. By its use a very high con centration of active drug can be main tained in the intestine and preliminary reports seem to indicate that it will be a valuable addition to sulfaguanidine and sulfasuecidinc. drugs which are useful in combating nonspecific diarrheas, baeillary dysentery, ulcerative colitis, and in t h e preoperative preparation of patients undergoing surgery of the large intestine where there is danger of soiling the peri toneum. Doses up to 18 grams dairy for short periods and up t o 6 grams daily for more prolonged administration have been given without evidence of serious toxicity.
Antimalarials From the viewpoint of the American soldier fighting in intensely malarious areas of the Pacific, cut off from supplies of quinine, undoubtedly the most impor tant medical development of 1944 was the belated recognition on the part of scientific advisory bodies in America of the value a n d safety of the synthetic antimalarial Atabrine (the nonproprietary pharmaco poeia! name of which is quinacrine hydro chloride) in the treatment and prevention of malaria. Extensive experience of t h e armed forces during 1944 has clearly dem onstrated the following facts even to t h e m o s t timid and conservative. In the case of malaria due to Plasmodium falciparum, Atabrine is rapidly curative, whereas evi dence for a similar effect in the case of quinine is wanting. With vivax malaria, both Atabrine and quinine can be counted upon to terminate any acute attack. However, neither will surely prevent de layed relapses; with Atabrine, however, t h e interval between relapses is definitely longer than when quinine is used. F o r suppressive treatment, or the prevention o f clinical attacks of malaria, Atabrine i s also superior to quinine although in t h e
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case of both drugs clinical symptoms may supervene after discontinuance of suppressive treatment unless a full therapeutic dose is administered. This is especially true in the case of malaria due to. Plasmodium vivax and Plasmodium malariae. T h e toxicity of Atahrine has been shown to be minimal and in similarly effective doses less likely to produce deleterious effects than quinine. Fears that control of the world's supply of quinine by the Japanese would impair the war effort of the United Nations in the Pacific area have been completely dissipated. By the efficient employment of Atabrine, suppressive treatment and other measures such as control of mosquito breeding and destruction of adult mosquitoes, the malaria problem of the armed forces in the Pacific is approaching solution. In some areas, such as New Guinea, for example, the disability produced by malaria has been reduced 95% in the last year. In the Burma campaign, Atabrine suppression has been approximately 8 0 % effective. It is quite clear now that largely through Atabrine, malaria can no longer prevent the effective deployment of armies in even the most highly malarious localities. During the year the synthesis of quinine by Woodward and Doering was announced. While this accomplishment represents a fundamental chemical achievement of great importance, it is nevertheless unfortunate that the steps in the synthesis are so complex that there is very little if any likelihood that it will ever prove to be commercially useful. Of even greater scientific interest are new antimalarials developed in the past year and now in process of clinical trial. Although there is good evidence that some of these new compounds may have advantages over Atabrine, no details regarding them can b e divulged.
Antiparasitics The occurrence of fiiariasis among troops stationed in certain islands in the Pacific theatre of war has stimulated an intensive research program to find a drug which will destroy the adult worm in the tissues of the human host. Hitherto filariasis has been entirely incurable; the only treatment for some of its manifestations has been surgery. Recently two antimony compounds have been tested o n the fiiariasis of animals and human beings. They are the Univalent antimony compound Anthiomaline and the pentavalent antimony compound Neostibosan. Both these drugs must be given in large doses and neither appears to be completely successful although in some instances all of the adult worms are destroyed and in most instances many of them are killed. There is every hope that persistence in the treatment of filariasis with these drugs may accomplish results in most instances or that other more effective preparations will be found.
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One of the most terrible of all tropical diseases is African sleeping sickness or trypanosomiasis, a disease which has rendered uninhabitable by man, large areas of the dark continent. Reasonably effective treatment by Naphuride and tryparsamide has been available for years but the remarkable property of Naphuride to act as a prophylactic in African sleeping sickness has been put to test on a large scale in 1944. A single intravenous injection of 1 gram effectively protects an individual from acquiring the disease for as long as 3 months although he may be. bitten repeatedly by infected tsetse flies. This is the only instance of a synthetic chemotherapeutic agent conferring immunity to a disease over an extended period of time. It is the most important factor in the protection of the Armies of the United N a tions stationed in parts of Africa where this dreaded disease is endemic.
Blood Plasma The machinery of the Red Cross and other agencies for the procurement and processing of blood plasma, although started as long ago as 1941, reached i t s peak of efficiency in 1944. The role which blood plasma has played in the prevention of fatalities from battle casualties is second to no other. It is estimated that in 1944, 5,500,000 donors were bled and approximately 4 million separate units of blood plasma made available. Twelve commercial-firms took part in processing this enormous volume of plasma. Although the importance of blood plasma t o the armed forces and through them to the nation as a whole can hardly be overemphasized, less widely publicized work on the fractionation of blood has even greater potential interest. It has been found that the red blood cells, formerly discarded in the manufacture of human plasma, when dried, powdered, and sterilized, favor wound healing. What substances present in the red blood cells are responsible is unknown; probably glutathione, tripeptids, and other constituents containing the sulfhydryl group play a part. Six major fractions of blood plasma have been developed and one fraction has been further separated into t w o subfractions. Fraction I contains fibrinogen and small quantities of gamma globulins. Fibrinogen is one of two useful constituents in hemostasis. I t is also employed in surgery as a tissue supporting plastic and covering film. Its great value is t h a t such films cause no reaction by the tissue. Sponges of fibrin soaked in thrombin are effective hemostatic agents, especially useful in brain surgery where they are slowly absorbed and can be left in the wound. Fraction II contains immune antibodies present in gamma globulins. These i m mune antibodies include typhoid agglutinin "H", the mumps complement-fixation agent, influenzae antibodies, diph-
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theria a n d streptococcus antitoxins. So far this fraction has been IIWOÎ, ^seful in the propbylaris of measles and other infectious diseases. I t can be expected that further work along these lines will eventually l e a d to the production of pure antibodies for m a n y diseases which will ol>viate t h e necessity of injecting whole serum w i t h i t s attendant dangers. Fraction IΙΙ-1 contains isohemagglutinins a n d other chemical substances such as cholesterol. These isohemagglutinin are useful in the rapid typing of blood. Fraction III-2 contains thrombin and prothrombin which are useful in hemo stasis. Fraction IV contains alpha- and beta-globulins forming 2 5 % of the protein constituents of plasma. I t may be used in certain instances as a substitute for blood in transfusions. Fraction V con tains serum albumin which, because of its smaller bulk, is useful as a substitute for w h o l e plasma. It can be given in a 25% solution and has m o s t of the osmotic pressure effects of plasma, thus preventing seepage o f fluid from the circulatory bed into tissue interspaces and even with drawing fluid from the tissues back into the circulation. Fraction VI also contains alpha-globulins, the follicle stimulating hormones and perhaps other hormones to be isolated later. Blood substitutes cheaper and available in larger quantities have been tested in laboratory animals and in human beings. The greatest advance along these lines has been, the degradation of gelatin to re duced molecular size so t h a t solutions m a y exercise similar effects t o those of blood plasma i n t h e treatment of shock. Ar terial a n d venous pressure is increased, fluid is withdrawn from tissue spaces into the circulation, thus reducing hemoconcentration, cardiac output is increased, and the effects of shock on the pulse and stroke v o l u m e of the heart are neutralized. Although no substitute can take the place of w h o l e blood or plasma, gelatin may prove a life—saving boon to our Asiatic allies. A I o n s step has been taken in the rec ognition of t h e importance of the essential amino acids a s replacement in certain conditions—"that is, in the treatment of immature infants and children unable t o assimilate adequate quantities of proteins; in the treatment of bacillary dysentery which prevents absorption of protein in children; and, in the postoperative care of a d u l t s who have undergone extensive operations on the gastro-intestinal tract. The intravenous administration of amino acids t o such individuals can tide them over a crisis a n d prevent hypoproteinemia until healing has taken place. T h e boom in the use of vitamin prepara tions which h a s continued steadily upward for more than 15 years appears to have reached its climax in 1944. T h e with drawal o f one of the brands most heavily advertised t o the public, and the few y e t significant unfavorable scientific out-
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cropping during the year are suiiieieni to suggest that the vitamins will find their field of usefulness in food enrichment and restoration programs and in pharmaceuti cals dispensed on the advice of physicians.
Anesthetics This exigencies of war time surgery under improvised field conditions has created an unprecedented demand for rapidly-acting anesthetics of short duration requiring a minimum of special appara tus. * This demand has been met largely by short acting barbiturates suitable for intravenous injection, such a s Pentothal Sodium. Evipal Soluble, and Sodium Pen tobarbital. Curare, the South American arrow poison, has been purified and standardized. Its unique effect in causing paralysis of voluntary muscles by breaking the con nection between motor nerve endings and muscle fibers has been used to prevent injury to patients undergoing metrazol shock. It has also been used advantage ously to produce surgical relaxation during operations, especially on the abdomen. Curare, by producing surgical relaxa tion of muscles, may on the basis of pres ent studies render all general anesthesia safer because only sufficient amounts of the anesthetic agent t o produce uncon sciousness will be required. The use of Demerol (l-methyl-4-phenylpiperidine-4-carboxylate hydrochloride) in the control of pain has become widespread in 1944 and its field of usefulness further explored. Demerol not only possesses the analgesie properties of morphine but i s a powerful relaxant of smooth muscle. In addition, its tendency t o produce habitua tion is far less than that of morphine. In obstetrics it alleviates t h e pain of child birth, relaxes the cervix, and when given with Scopolamine or one of t h e barbituric compounds, produces amnesia. I t does not interfere with bladder or bowel ac tivity as does morphine.
Metabolism Control Several years ago in t h e intensive study of the sulfonamide compounds i t was found that they had a pronounced effect in inhibiting the production of hormone by the thyroid gland. This observation led directly to the use of thiouracil for the control of thyrotoxicosis. This drug has the remarkable property of preventing the overactive thyroid from producing ex cess quantities of i t s hormone. The ele vated basal metabolic rate and the in creased pulse rate can b e brought t o nor mal within a few weeks. Tremors and mental symptoms are corrected and a gain in body weight results from control of the hasal metabolic rate. T h e drug has been extensively tested clinically during 1944 and its usefulness is without question. However, it is not without toxicity, the most serious toxic effect being the occa
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sional production of granulocytopenia and agranulotosis Further study i s required to circumvent "these serious evi dences of toxicity to the bone marrow. There are reports t h a t folic acid, a con stituent of the scrap heap referred to as t h e Vitamin Β complex, tends t o prevent these complications, b u t proof of its use fulness in this connection is not y e t be yond the laboratory stage. T h e tendency for t h e new quaternary ammonium antiseptics to replace older preparations was accelerated during the year. Such products as Zephiran and Roccal considerably extended the field of antiseptics. These preparations in addi tion t o being germicidal are also deter gents and, therefore, their efficacy o n the skill is g r e a t l y increased over older prepara tions. T h e y have been found to be superior not only for operating room anti sepsis and the sterilization o f skin and mu cous membranes b u t have also been used widely for the disinfection of kitchens, kitchen utensils, overcrowded barracks a n d living quarters. These preparations m a k e i t possible for t h e first time t o d e stroy bacteria selectively; their effect on bacterial cells being far greater than on the tissue cells of the host. In 1944 a new sympathomimetic amine, Butanefrine, was placed i n clinical test. I t has the ability of relieving bronchial spasm in asthma without increasing blood pressure as does epinephrine. Its most important effect o n blood pressure is the reduction of the diastolic b y relaxing the capillary bed, in this way improving the efficiency of the heartbeat and increasing cardiac output. I t s toxicity is about with t h a t of epinephrine a n d it i s less likely t o produce unpleasant symptoms as precor dial pain, dizziness, and muscular trem ors. If present indications are confirmed, Butanefrine will h a v e a prominent place in t h e treatment of asthma and cardiac con ditions in failure of t h e left heart.
Insecticides Great progress has been made during 1944 in the application of new insecti cides, one of the m o s t promising of which is D D T (dichlorodiphenyltrichloroethane) which can be manufactured easily and η large quantities from chlorobenzine a n d chloral. I t was first synthesized 7 0 years ago b y a German s t u d e n t b u t its usefulness w a s n o t discovered until 1939 w h e n the Swiss s h o w e d its value as a fruit a n d vegetable insecticide. Although D D T w a s first supplied to the Army in 1943, t h e demonstration of i t s unique properties a n d i t s use o n a large scale took place in 1944. T h e m o s t interesting property of D D T is its prolonged action compared w i t h other insecticides, such a s pyrethrum. It kills insects on c o n t a c t b y poi soning the insects' nervous system. W h e n impregnated into clothing, it ex ercises this toxic effect for as long as a m o n t h in spite of repeated launderings.
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It is erhoiei^t'^ii destroying adult diseasecarryinginsects,such as flies and mosqui toes, when sprayed about, and is an effi cient larvicide when sprayed on the breed ing places of anopheline mosquitoes. I t s most dramatic application has been in the destruction of body lice which are responsible for the transmission of typhus. History will probably remember the medi cal battles of Naples long after the military battle is forgotten. Late η 1943 typhus appeared in N a p l e s and threatened to reach epidemic proportions among the ragged, half-starved, and for the most part, unwashed, Neopolitans. T h i s epi demic was stopped i n its tracks in January 1944 by the prompt action of the American Typhus Commission. This victory is unique because never before in the world's history had a typhus epidemic been ar rested during the winter m o n t h s when heavy clothing favors the body louse. The first act of the commission was to seek out and delouse all typhus patients and their premises b y dusting with D D T . The next step was the establishment of 43 delousing stations throughout the city of Naples. Citizens of Naples, recognizing the awful consequences, cooperated with the military forces readily. During the single m o n t h of January more than 1,300,000 people were dusted with D D T and the epidemic was over. T h e importance of this accomplishment can hardly be overemphasized. Always before throughout world history, typhus has accompanied wars and great epidemics have ravaged populations impoverished by war. Typhus accounted tor more deaths after the first world war than any other single cause including battle casualties. This easily administered pre ventive measure cannot but have the greatest effect on t h e history of the world by averting war and postwar typhus in Europe and Asia, and will certainly have a pronounced effect on Europe's capacity to recover after the present conflict. However, it is well to mention here that recent laboratory studies on the toxicity of D D T introduce a note of caution on its indiscriminate use. It is possible that it will prove to b e more poisonous to human beings and other large animals than at first suspected. Its deleterious effect on benign and useful insect life is well known.
Conclusion I t has been said that the only lasting good mankind gains from war is the stimu lus it give* to science. If this be true it is a sad indictment of mankind and a bad bargain. In our opinion the small gains in technical skill, forced draft production, and immediately useful research are more than overshadowed by the interruption of long range research programs and the di version of untold numbers of capable ii* vestigators t o routine tasks. Progress in pharmaceuticals and medicinals in 1944 has been made on borrowed time. 135
