A Critique on Literature of Antituberculous Compounds - Advances in

A Critique on Literature of Antituberculous Compounds H. HERBERT FOX

Downloaded by EAST CAROLINA UNIV on December 21, 2017 | http://pubs.acs.org Publication Date: January 1, 1956 | doi: 10.1021/ba-1956-0016.ch004

Research Laboratories, Hoffmann-LaRoche, Inc., Nutley, N. J.

Because of the successes achieved with the sulfones, strepto mycin, p-aminosalicylic acid, and the benzenoid thiosemicarbazones, the search for new and better compounds has been broadly extended in many laboratories and the literature of antitubercular compounds has grown enormously in recent years. Unfortunately, in vivo activity—the standard, which all compounds must meet before being judged suitable for clinical application—has not been applied to the classification of antitubercular compounds in the literature. In this situa tion, remedial measures appear to be called for and some correc tive suggestions are advanced.

T h e chemotherapy of tuberculosis, i n the modern sense of the term, dates f r o m 1939. In that year, Rist (11) and his coworkers (12) demonstrated for the first time, the i n vitro and i n vivo efficacy of 4,4'-diaminodiphenylsulfone against the hitherto apparently impregnable tubercle bacillus. On this basis, the literature of modern, antituberculous compounds covers at most a period of the last 14 years. This is not meant to imply that the chemotherapy of tuberculosis was not attempted prior to 1939 or that the number and range of substances used against tuberculosis were insignificant. Practically everything which had ever demonstrated activity against any disease was tried i n tuberculosis. In the Decennial Index of Chemical Abstracts for 1927 to 1936, a p a r t i a l listing of the substances which were reported to have been used or tried i n the treatment of tuberculosis includes antisera, calcium chloride, calcium ions and calcium compounds in general, camphor, cod liver oil, copper and copper compounds, chaulmoogra o i l , cholesterol, cinnamic acid, coramine, ethyl stéarate, ferric chloride, formates, gold salts, iodides, sodium ricinoleate, manganese salts, proteins, phenol, quinine, rare earth compounds, the vitamins from A to D, and tannins. These are among the more conventional therapeutic substances reported during that ten-year period. Less conventional perhaps but certainly of no greater efficacy was the recommenda tion of one investigator (10) that tuberculosis patients eat 100 to 150 grams of semiraw spleen daily as an important adjunct to gold salt therapy. T h i s recom mendation was based on the temperature and weight benefits demonstrated by two cases, which is a rather inadequate basis for any claim. A s medieval as the use of the splenic preparation may sound, i t is futuristic i n comparison to the use of char coal or pulverized animal carbon by injection (2). A n d yet, as recently as 1933, the intravenous administration of carbon for the treatment of tuberculosis was w a r m l y defended (7). Judging from some of the substances listed, the chemotherapy of tuberculosis p r i o r to 1936 appears to have been based on the premise that i f the patient could sur vive the drug, he could survive the disease. A c t u a l l y , the uncritical and unrestrained use of anything that came to hand was indicative of the long and desperate need for effective antituberculous agents. E v e r y clue, whether real or imaginary, was eagerly followed and phthisiologists were prepared to t r y the most unorthodox procedures i n the hope of favorably influencing the course of the disease. In surveying the literature on antituberculous compounds immediately prior to 1940, i t is difficult to realize that some of the papers were written only a few years ago—so great has been the progress i n the last decade. F o r example, i n 1936, i n the 28

A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.


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Bulletin de la société de chimie biologique, two investigators (U) reported that per sons l i v i n g near a salt lake i n the vicinity of Tekirghiol, Dobrodgea, were wont to treat rickets and tuberculosis by coating the patients w i t h the black mud and slime of the lake shore. The bedaubed patients were then required to d r y out i n the sun. According to the investigators, the mud, rich i n algae and therefore i n ergosterol and other sterols, may owe its beneficial effects to the irradiated ergosterol which is absorbed presumably through the skin. The dearth of chemotherapeutants i n 1937 is evidenced i n a review article by Johnston (8) on the pharmacology of some newer drugs employed i n tuberculosis therapy. The review lists barbiturates, calcium compounds, and some newer gold salts. I n 1940, Jotten and Reploh (9) wrote that Solganol B-oleum and auric taurocholate T226, bismuth w i t h curcum dye, copper i n the form of Bayers' " E b e s a l s " and the benzyl esters of chaulmoogra fractions gave the best expectations for the successful chemotherapy of tuberculosis. I n effect, therefore, the literature of antituberculous compounds of true chemotherapeutic significance covers at most the period from 1939 to the present. Certainly none of the compounds which were widely used and accredited before 1939 are now accepted as effective tuberculostats. This was pointed out by D ' A r c y H a r t i n an excellent review of the chemotherapy of tuberculosis covering the 100-year period prior to 1939 (5). According to him, by 1935, a general reaction had taken place among the clinicians against antituberculous drugs w i t h the exception of a few valued symptomatics. This reaction was a some what belated recognition by the phthisiologists that most of the drugs used were without scientific basis and that the few drugs originating i n scientific laboratories were transferred to clinical application on inconclusive evidence. B r o w n i n g (3) i n a 1935 lecture on chemotherapy stated, " N o treatment at present can be aimed directly against the causal agent . . . " The literature of antituberculous agents is not confined to any one scientific sphere. Progress i n chemotherapy is the product of a joint enterprise involving several scientific disciplines. In consequence, the pertinent publications on anti tuberculous compounds are scattered through the chemical, biochemical, biological, pharmacological, bacteriological, medical, antibiotic, and general science literature. Since this critique is addressed to and directed toward chemical investigators, dis cussion is confined to those papers which deal w i t h the chemical nature of tuber culostatic compounds and the laboratory evidence for their activity. Discussion

The chemotherapy of tuberculosis had fallen into disrepute by the middle thirties because the drugs used up to then were of highly questionable efficacy and had been placed into clinical use without being firmly based on convincing and favorable lab oratory experiments. The advent of the sulf ones not only ushered i n a new class of tuberculostats but also paved the way for a new philosophical approach to the chemotherapy of tuberculosis. The era of the uncritical application of untested substances to human guinea pigs is passed and general recognition is given to the need for extensive and thorough laboratory experimentation before clinical t r i a l . This change of view was aided greatly by the fact that the sulf ones were the first compounds to show marked i n vivo activity against the tubercle bacillus. W i t h the knowledge that the "impossible" h a d been achieved and that the "impregnable" tubercle bacillus could be controlled w i t h i n the protective environment provided by the host, a new criterion was established for tuberculostatic substances. Proof of i n vivo activity has become a prime requisite to clinical application. Because of the successes achieved w i t h the sulf ones, and later w i t h streptomycin, p-aminosalicylic acid, and the benzenoid thiosemicarbazones, the search for new and better compounds has been broadly extended i n many laboratories throughout the world and the literature of antituberculous compounds has grown enormously these past few years. In tacit acknowledgment of the trend, Chemical Abstracts, i n its 1947 index under the heading, "tuberculosis," used for the first time the subheading, "antitubercular compounds." Unfortunately, the standard of i n vivo activity which a l l compounds must meet before clinical application has not been applied to the classification of antitubercular compounds i n the literature. Currently, no distinc tion is drawn i n literature classifications between i n vitro and i n vivo activity. Since the compounds w i t h i n vitro activity are legion and f a r exceed i n numbers those w i t h i n vivo activity, the literature of antitubercular substances is r a p i d l y A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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CHEMISTRY SERIES

being cluttered with reports on compounds which do not merit the classification, "antitubercular." Without regard to the pros and cons of the i n vitro test as a screening pro cedure, compounds w i t h only i n vitro activity should not be classed as "antitubercu l a r . " If the view is accepted that the purpose of research i n the chemotherapy of tuberculosis is to find compounds w i t h clinical potentialities, then standards must be established by which such compounds should be judged and these standards should be applied to classification i n the literature as well as i n the laboratory. The num ber of compounds active against the tubercle bacillus has grown to the point where serious consideration need only be given to those compounds which possess significant activity i n experimental tuberculosis and only compounds of this latter class should be called "antitubercular." Yet any survey of the current literature finds a large number of papers purporting to deal w i t h antitubercular compounds but which, i n reality, list compounds that are either totally inactive or are active only i n vitro. This is well illustrated by an analysis of the items listed under the heading, "tuber culosis," subheading, "antitubercular compounds," i n the Chemical Abstract Index for 1951. Of a total of 19 papers surveyed, 12 papers deal with compounds whose activity has been tested only i n vitro, five papers with compounds tested in vivo and two papers do not list activity at a l l . In two of the 12 papers based on i n vitro studies and i n two of the five based on i n vivo studies, a l l of the compounds re ported are inactive. In effect, therefore, only three of 19 papers purporting to deal w i t h antitubercular compounds actually report on chemotherapeutically active agents. To those interested i n the chemotherapy of tuberculosis, there would ap pear to be an overabundance of chaff w i t h the wheat. This is not to be interpreted as a denunciation of those papers which report on inactive compounds or on compounds whose activity has only been tested i n vitro. There is a definite place i n the scientific literature for a l l publications which add to the general knowledge. The problem is one of classification and not of exclusion. Therefore, the mere mention of the word "tuberculosis" i n a chemical paper should not qualify it for classification i n the literature of antitubercular compounds. A case in point is the paper by Basu and Banerjee entitled, " A Therapeutic Agent i n Tuber culosis" (1), i n which the authors reported on the preparation of the phthaloyl de rivative of p-aminobenzaldehyde thiosemicarbazone. The compound was prepared presumably as a less toxic substitute for Tibione. Regardless of its ultimate merits, the fact remains that the report does not mention either biological experiments or activity. Therefore, the compound may or may not be active, but the designation "therapeutic agent" is not warranted. Strictly speaking, the paper properly belongs i n the category of organic preparations. S i m i l a r l y , i n another paper (6), sl number of p-aminophenylazole derivatives substituted i n the azole r i n g were prepared i n con nection with the investigation of the "dependence of tuberculosis-inhibiting action on structural factors." The activity of none of the compounds is listed and there is no assurance that they are active—yet they are classified among the antitubercular compounds i n the index of the Chemical Abstracts. Another source of confusion is usually encountered i n review articles on the chemotherapy of tuberculosis. Authors of review articles sometimes f a i l to dis tinguish between i n vivo and i n vitro activity and i n so doing invest some com pounds w i t h unmerited importance. F o r example, Stenlake (IS), i n an excellent re view l i s t i n g over 230 references and covering the literature between 1939 and 1950 inclusively, states : Heterocyclic sulf ones such as promizole (4,2 -diaminophenyl-5'-thiazolylsulfone), diphenyl and heterocyclic sulfides and sulfoxides, diphenyl ethers, diphenylamines and diphenylmethanes possess tuberculostatic activity. W i t h the exception of promizole, few of these compounds have progressed beyond the stage of testing i n experimental animals. Actually, the diphenyl and heterocyclic sulfides, the diphenyl methanes, and most of the diphenyl ethers have been tested only i n vitro, and the diphenylamines, though tested i n vivo, were too toxic to permit an i n vivo effect to be observed. In short, these classes of compounds are not t r u l y antitubercular and grouping them w i t h the sulfones tends to confer on them an unwarranted significance. /


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Suggestions for Literature Classification

In view of the inevitable growth of the literature on antituberculous com pounds, the inclusion of so much irrelevant material promises to be a severe handi cap to future workers i n the field and measures should be taken to correct the situa tion. The execution of such remedial measures devolves mainly upon the j o u r n a l editors but the authors can do much to make the literature of antitubercular com pounds more meaningful to the laboratory or literature researcher. The following definitive steps i n the right direction are suggested: A l l authors should be required to confine the adjective antituberculous (or anti tubercular) to those compounds that show activity i n experimental tuberculosis— preferably w i t h the human or w i t h the bovine strain of tubercle bacillus. The titles of papers i n which the activities of the compounds are not given should not suggest chemotherapeutic application unless some properly qualifying term is included. F o r example, the paper by Basu and Banerjee should not have been entitled, " A Therapeutic Agent for Tuberculosis," because no statement is given on activity, either i n vivo or i n vitro. A more correct title would have read, " T h e Synthesis of a Compound to Be Tested in Tuberculosis." Better still, a l l ref erence to tuberculosis i n the title should have been omitted. The classification of compounds i n indexes should separate and clearly distin guish between i n vivo activity and i n vitro activity. Under the heading, " T u b e r c u losis," Chemical Abstracts should have two subheadings: "antitubercular com pounds" for those active i n vivo and " i n vitro active compounds" for those whose testing has not progressed beyond the i n vitro stage or for those active only i n vitro and not i n vivo. Review articles should also carefully distinguish between i n vitro and i n vivo active compounds. To be i n accord w i t h convention, reviews on the chemotherapy of tuberculosis should include only those compounds which have been chemotherapeutically—i.e., i n vivo—tested. A further suggestion to those who contemplate working i n the field is to concen trate their attention on those publications dealing with i n vivo active compounds and save for leisure reading those which report only i n vitro activities. Adherence to this principle has served the author very well these past few years and has been an ex cellent guide through the maze of publications to those of most significance. In this regard the review articles have been particularly valuable i n highlighting the more fundamental and more concrete contributions to the chemotherapy of tubercu losis. Therefore, a list of six review articles providing a f a i r l y complete coverage of the entire field until early 1953, is appended to the literature cited. Literature Cited

(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13)

Basu, U . P., and Banerjee, S., Science and Culture (India), 16, 331 (1951). Bingel, Deut. Arch. klin. Med., 165, 213 (1929). Browning, H . C., Trans. Roy. Med.-Chir. Soc. Glasgow, 30, 1 (1935). Cosmovici, N . L., and A n t a n a s i u , J. S., Bull. soc. chim. biol., 18, 1425 (1936). D ' A r c y H a r t , P., Brit. Med. J., 2, 805, 849 (1946). Eckenstein, J., Brogle, E . , Sorkin, E . , and Erlenmeyer, H . , Helv. Chim. Acta, 33, 1353 (1950). Gandolfo, C. F., Lavelle, F., and Fowler, E . F., Semana méd. (Buenos A i r e s ) , 1, 1109 (1933). Johnston, J. M . , Edinburg Med. J., 44, 184 (1937). Jotten, K. W., and Reploh, H . Z., Immunitäts, 99, 103 (1940). Kamsler, Α., Beitr. Klin. Tuberk., 76, 754 (1931). Rist, N., Compt. rend. soc. biol. ( P a r i s ) , 130, 972 (1939). Rist, N . , Bloch, F., and Hamon J., Ann. inst. Pasteur, 64, 203 (1940). Stenlake, J. B., J. Pharm. and Pharmacol., 3, 129 (1951).

Review Articles on Chemotherapy of Tuberculosis

(1) (2) (3) (4) (5) (6)

D ' A r c y H a r t , P., Brit. Med. J., 2, 805, 849 (1946) (over 240 references). Fox, Η. H . , Science, 116, 129 (1952) (56 references). Ibid., 118, 497 (1953) (51 references). Mietzsch, F., Angew. Chem., 11, 250 (1951) (over 34 references). Stenlake, J. B., J. Pharm. and Pharmacol., 3, 129 (1951) (over 230 references). Tytler, W. H . , Tubercle, 25, 95 (1944) (59 references).

RECEIVED

September

13,

1954.


A Critique on Literature of Antituberculous Compounds - Advances in

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