Literature of Radioactive Pharmaceuticals - Advances in Chemistry

Literature of Radioactive Pharmaceuticals D. L. TABERN and W. A. SOUTHERN

Downloaded by EAST CAROLINA UNIV on January 4, 2018 | http://pubs.acs.org Publication Date: January 1, 1956 | doi: 10.1021/ba-1956-0016.ch003

Abbott Laboratories, North Chicago, Ill.

It has been slightly more than ten years since man's initiation of the nuclear chain reaction, and only about seven years since the first shipment of a pile-produced radioisotope. In that short time these isotopes have not only become an integral part of medical practice, but have proved most valuable research tools. Many industrial groups, including some in the medical field, have set up groups to employ these new techniques safely. One of their very important functions is to survey the widely scattered reports, evaluate them technically, and sell management, as well as their fellow research workers, on the advantages to be gained by employing isotopes for selected problems. Abbott has gone further and developed as a part of its research department a division having to do with the development, production, and distribution of radioactive pharmaceuticals conforming to and tested by good pharmaceutical standards.

W h e n i t is realized that only a few months more than 10 years ago the first n u clear chain reaction was made to take place under the stands i n Stagg F i e l d , one can only be astonished at the progress that has been made i n this field. The difficulties have been many. F i r s t of a l l , there came wartime secrecy, and then the necessity for keeping many of the data classified. Almost equally important has been the fact that i t has been necessary to t r a i n , almost from scratch, groups of highly specialized research workers. Only i n the past 5 years has adequate instrumentation been commercially available. Some of the pitfalls and unusual problems presented by isotope studies are just beginning to be appreciated. It cannot be emphasized too strongly that isotopes themselves, and their use, are no guarantee of successful experimentation. I n fact, much of the evidence i n the biological field is contrary to what would have been anticipated on the basis of older theories. Perhaps the most s t r i k i n g phenomenon is the growth of a group of hybrid scientists. We, of course, had the biochemist and physical chemist, but we now have the biophysicist, the health physicist, the radiation chemist, the radiobiologist, and a host of analogs whom Brucer grossly calls "isotopologists." It is typical of this development that the younger, and sometimes some of the older, men i n a given field have acquired t r a i n i n g i n this new field and have applied this new knowledge to their own fields of specialization. In industry, for instance, many companies have groups of specialists working w i t h isotopes, but always welcome the suggestions of others who think they see i n radioisotopes new avenues of research approach. It is thought to be the r i g h t p l a n f o r men w i t h ideas and technical skill to come to the isotope group, w i t h its background of specialized equipment and radiation protection, work w i t h i t f o r as long as may be necessary to prove or disprove their points, and then return to their regular fields of activity. This situation is very definitely reflected i n the chemical literature of radioisotopes. Journals

Except perhaps for Nucleonics

(which is rather unfortunately tending more and

more to the physics side), there is no really specialized j o u r n a l i n this

field.

A

f a i r l y complete resume of the references on radioactive isotopes appearing i n Null

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


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clear Science Abstracts and the Current List of Medical Literature between J a n u ary 1952 and June 1953 shows that references appeared i n more than 600 publica tions. The Journal of the American Chemical Society contained one of the largest number of references. It was at one time felt that this field was rather closely allied to the work of the radiologist. Y e t an analysis of the reports shows that Radiology and the Ameri can Journal of Roentgenology carried fewer such publications than a number of other journals, p a r t i c u l a r l y those i n the biochemical and physical fields. Obviously, the diverse places of publication make i t practically essential to rely, for the most part, and certainly i n the medical field, upon abstract journals or ab stract publications to keep i n touch w i t h the latest developments. A s always, Chemical Abstracts is doing a very excellent job, but here again i t is necessary to cover many pages i n order to be reasonably sure of comprehensive coverage. In that respect Nuclear Science Abstracts, which is now i n its tenth volume, de serves special commendation. This is an official publication of the U . S. Atomic E n e r g y Commission through the Technical Information Service at Oak Ridge, Tenn. Perhaps the most valuable single feature is a l i s t i n g of a l l unclassified and de classified reports from the many agencies and contracting laboratories of A E C as well as the corresponding European atomic energy installations, some 50 i n a l l . Most of these are subsequently reported i n very brief form as abstracts. The availability of each report included i n Nuclear Science Abstracts is indi cated i n its abstract. Declassified reports may be purchased through the Office of Technical Services i n Washington, they may be obtained from the agencies issuing them, they may be borrowed from cooperating A E C libraries, or they may not be available for distribution. Of particular interest is the fact that the abstracts covering biology and medi cine, chemistry, engineering, metallurgy, physics, etc., are carried under these headings. It thus becomes possible i n a reasonable amount of time to check leading articles. Two extensive bibliographies on the literature of radioactive isotopes are wortftiy of mention. The first is a bibliography of more than 400 references which ap peared i n connection w i t h the article, "Radioisotopes i n Pharmaceutical and Medical Studies," i n the November and December 1950 and J a n u a r y 1951 issues of Nu cleonics. The second is an annotated bibliography of radiobiology released by the Technical Information Service of the U . S. Atomic E n e r g y Commission at Oak Ridge. Books and Manuals

There are a reasonable number of books which should be i n every l i b r a r y . These include the U n i v e r s i t y of C a l i f o r n i a series on "Advances i n Biology and Medical Physics," Hahn's " M a n u a l of Radioisotope Therapy," L o w Beer's " C l i n i c a l Use of Radioactive Isotopes," S i r i s ' "Isotopics Tracers and Nuclear Radiations," and Kamens' "Radioactive Tracers i n Biology." F r o m time to time manuals on various specialized fields such as gold therapy and brain tumor localization have been issued by Abbott Laboratories. Delay i n Publication. In connection w i t h publication, there have been two very serious problems. The first is delay. Articles submitted somewhat more than a year ago are currently coming to press i n magazines like Radiology and the Journal of the American Roetgenologic Society, whose official title is the American Journal of Roetgenology, Radium Therapy, and (as of last year) Nuclear Medicine. A second and somewhat "sore p o i n t " is the fact that a great deal of work i n this field is centered about method development. I n general, synthetic procedures must be directed toward a specific end and the greatest possible economy of a given isotope. W i t h certain short-lived isotopes, the time required for c a r r y i n g out a given reaction and the isolation may be the deciding factor. In others, the ability to c a r r y out a certain synthesis w i t h a minimum of handling and radiation expo sure to the operator may be the crucial point. To the nonisotopic editor, burdened w i t h problems of space limitation, these modifications seem relatively unimportant, and too many contributions which would have served a real purpose i n the furthering and enhancement of synthetic proceA Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

TABERN and SOUTHERN—LITERATURE OF RADIOACTIVE P H A R M A C E U T I C A L S

dures have been turned down as " u n o r i g i n a l . " are certainly not unimportant.


Recent

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They may be unoriginal, but they

Highlights

Radioactive Gold. Foremost is the use of radioactive gold. While this has ac tually been i n use f o r three years, the articles are just beginning to come through. The author's group has just finished compiling the " G o l d M a n u a l . " This contains some 85 references, to which another 15 could easily be added since that time. The radiation from the x-ray machine or from radium is essentially gamma r a diation which is, statistically speaking, a very poor agent for destroying cancer cells. In fact, as P a u l Aebersold pointed out i n an article appearing i n a recent radiological magazine, i f radium had been discovered as a part of this isotope pro gram, i t probably would never even have been very seriously considered for thera peutic application. On the other hand, the beta rays from artificial radioisotopes are characterized by a very limited degree of penetration, w i t h the utilization of their entire energy over a very thin layer. This has advantages, and some disadvantages. On the positive side, i t is possible to destroy the thyroid, and only one instance i n the en tire medical literature has been found where the immediately adjacent parathyroid has even been temporarily damaged. On the other hand, i f we wish to irradiate the entire mass of a tumor, and most materials do not localize as does the radioiodine used above, i t becomes necessary to t r y to infiltrate that area as uniformly as possible. This is a difficult situation, and one for which there is no very simple answer. Y e t the fact remains that today the use of radioactive gold infiltrated by direct ad ministration into the prostate of men w i t h prostate cancer offers one of the best possibilities of prompt alleviation, and perhaps even a reasonable percentage of permanent relief, from that disease. Even more important is the use of gold, given intrapleurally or intraperitoneally. Here its radiation does not penetrate more than the surface of the tumor or the peritoneal w a l l . It has very little effect upon the tumor itself, but i t does definite l y stop, i n somewhere between 50 and 7 5 % of the cases, the very detrimental ac cumulation of ascitic or pleural fluid associated w i t h breast and ovarian malig nancies. I n other words, i t is not a cure, but i t does give, i n a reasonable percent age of cases, more months of f a i r l y comfortable and occasionally even active life. Radioiodine. One of the earliest chemical reactions tried w i t h radioiodine was its incorporation w i t h proteins. A s most proteins contain tyrosine residues, i t is possible to iodinate them. M a n y reports have appeared, but i t is only w i t h i n the past 2 years that we are beginning to understand the proper means of iodination, so that the material retains to the maximum degree its naturalness as f a r as the body is concerned. It thus becomes possible to use such a tagged albumin f o r very simple determinations of both blood and plasma volumes, and to do this repeatedly and successfully upon the same patient over a period of time. V e r y surprisingly, this same material, which we call R I S A , localizes i n b r a i n and certain other tumors, and the gamma radiation therefrom may be used as a diag nostic test f o r the presence or absence as well as the exact localization of such brain tumors. It has been employed instead of Lipiodol to study where blocks have occurred i n the spinal canal. E v e n more interesting, and of probably consider able more importance, is its use for studying circulation. I n other words, i f one has one scintillation counter pointed over the heart and another at the sole of the foot, and gives a dose of albumin very rapidly, i t becomes possible to determine the time required for circulation between the heart and the foot. It is thus pos sible to detect derangement of circulation, a l l very quickly and harmlessly. This same material, given orally instead of intravenously, is digested just like any protein, and i t would seem that a f a i r l y simple determination of the iodine out put is a f a i r l y sensitive index of pancreatic enzyme function. Here, then, i t would seem as i f we had a f a i r l y universal "reagent" which could well be kept on hand i n many biological and clinical research laboratories f o r the many uses to which i t can be successfully applied. Radioactively tagged compounds have been extensively used f o r the study of d r u g metabolism. Some results have been good, some disappointing; but at least they A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.


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have altered materially our conception of d r u g distribution and handling w i t h i n the body. Hypnotics. D u r i n g his earlier days, the author may have been frequently guiltjr of pointing out that the hypnotics exerted their action by localizing i n the central nervous system. Studies carried out w i t h radioactive Pentothal, radioactive Nem butal, and their analogs show that this is not at a l l true. A c t u a l l y there may be less Nembutal i n the b r a i n than i n the surrounding plasma. We are beginning to recognize still another disturbing factor—the fact that a given barbiturate may actually be present i n the bloodstream is no indication that i t is i n an active form. A s Taylor and Richards of these laboratories recently reported, the effect of l i v e r dysfunction on the duration of action of barbiturates may not depend upon a dif ference i n the rate of metabolism, but rather upon a difference i n the amount o f proteins i n the blood. The more protein, the more barbiturate is held i n inactiveform, and the less is available for the exerting of its action. Isonicotinic Hydrazide. Everyone is very much interested i n the isonicotinic hydrazide or isoniazid. This has been made tagged with carbon-14 i n the carboxyl group by the group at Los Alamos and studied extensively at the U n i v e r s i t y of Chicago. A s seems to be true w i t h almost every drug, there was a f a i r l y general distribution i n the body, w i t h the blood, skin, and lungs each having about 5% of the total administered activity at the end of half an hour. A t the end of 8 hours a large portion of this had disappeared. The only major metabolite found was isonicotinic acid itself. It was possible to show that this material penetrated into enlarged caseous nodes relatively easily and that detectable amounts remained there for as long as 4 days. V e r y recently this same group has reported upon the use of the tagged material i n humans. A g a i n excretion was f a i r l y rapid, some 8 5 % the first 24 hours. Highest tissue levels were found i n the lungs and skin, w i t h concentrations i n actual lesions somewhat, but still not too much, higher than in other tissues. It could be established that such concentrations were theoretical l y sufficient to produce bacteriostasis for a number of days, and i t was concluded that this factor, plus the ability of the drug to permeate into the lesions and the accompanying diseased tissue, was responsible for its clinical activity. In a very recent paper it has been shown that Tuberculosis bacilli susceptible to isoniazid become radioactive when grown i n a medium containing carbon-14— labeled isoniazid, while resistant bacteria do not. Insulin. The L i l l y group employing pure cystine prepared by Abbott L a b o r a tories actually labeled insulin w i t h sulfur-35. Such methods are, of course, l a borious. Stadie and his group at the U n i v e r s i t y of Pennsylvania have been able to iodinate insulin as well as to prepare an insulin sulfate, both of which seem to retain their activity essentially unchanged. Gleason of the Abbott Laboratories likewise succeeded i n producing iodine-tagged insulin of a very high degree of pur ity. It was shown by three methods that both types are bound by strong, pre sumably chemical forces, by various tissues, such as the r a t diaphragm. This group feels that the activity of the insulin observed is a function of the quantity bound i n close association w i t h , not a p a r t of, enzymatic systems. Sucaryl. Sometimes it is best to ask simple questions of specifically designed radiosotope experiments. F o r instance, it became highly desirable to know how the new sweetening agent Sucaryl is handled by the animal body. Extensive chemical work had resulted i n a recovery of only about 50% of the injected mate r i a l , and as a result restrictions were imposed on the amount used i n any given day. V e r y fortunately, a very smooth synthetic procedure was developed for sulfurlabeled Sucaryl. Taylor and his group at Abbott were able to show that i t is very rapidly eliminated from the body completely unchanged. This seemed to satisfy the Food and D r u g A d m i n i s t r a t i o n and as a result a l l limitations have been re moved. Its usefulness i n a wide variety of fields, including dietetic foods and even diabetic beverages, is rapidly on the increase. A t least the resultant revenues, have helped pay for the many "unprofitable" ventures of the department. Penicillin G. The group is just at the " t u r n i n g p o i n t " of another valuable con tribution i n the antibiotic field. It has developed very satisfactory microbiological procedures for one incorporation of sulfur-35 as sulfate directly into penicillin G. T h i s material has been used by two laboratories for fundamental studies on the mechanism of antibiotic action. It has also been used by a leading a g r i c u l t u r a l




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school i n experiments on cattle and milk production. B y employing this sulfurlabeled penicillin, and a method of isotope dilution, we have still another accurate, and certainly noncontroversial, method of penicillin-G assay. Selenium Residues. There is still another w a y i n which isotopes can be very useful from the analytical side. While there is every indication as to the safety of Selsun, a new selenium sulfide preparation for seborrheic dermatitis, there is naturally extreme interest i n how much of the material might be left on the skin, on the h a i r follicles, under any given set of conditions. A n a l y t i c a l procedures for selenium, i n this form, are just not applicable. If a skin sample containing a totally unweighable amount of such a selenium sulfide residue is taken and placed i n one of the more active piles for a few hours, the selenium is converted to a radioactive form. I n spite of the fact that its h a l f life is only 15 to 20 minutes, i t is possible to use radiochemical methods rather than straight chemical methods for the assay. The same techniques have been applied by our n u t r i t i o n a l group to arsenic assays on tissues of animals whose growth h a d been promoted by arsanilic acid. One of the earliest uses of radioisotopes was i n connection w i t h the study of the human antithyroid activity of certain compounds. The results were extremely clean cut, and at variance w i t h the result which had been determined earlier upon animals. One of the most interesting and certainly one of the most controversial subjects appearing i n the literature is the mechanism of radiation damage to the body. I n view of the possibility that we ourselves may some day be caught i n an atomic bombing r a i d , this becomes an extremely important and practical problem. Fortunately, Abbott Laboratories has chosen to keep its work as a part of the Research Department, and has welcomed collaborative efforts not only w i t h medical research groups but w i t h good friends i n the pharmaceutical industry as well. To cite but one example, Smith, K l i n e , and F r e n c h have supplied very pure syn thetic thyroxine and triiodothyronine which is labeled w i t h iodine-131 and supplied to a l l interested groups w i t h pooling of information as i t becomes available. Reference F i l e . F r o m the very beginning of the project, some 7 or 8 years ago, a f a i r l y up-to-date reference file has been kept, not of a l l subjects, but p r i m a r i l y those of interest i n the biological and medical field. Three resumes appeared i n Nucleonics f o r 1950-51, and i f the number of reprints requested is any criterion, i t aroused considerable interest. A t about this same time the laboratory distributed a very complete l i s t of a l l titles i n this field appearing d u r i n g that year. This did not prove to be anywhere near as valuable or as practical. A s a result, instead, several progress reports were supplied to a l l collaborators and those specifically requesting them. These deal w i t h the p r i n c i p a l subjects of interest and, i n not more than two pages, survey the current status of that particular use or project. These contain a reasonable n u m ber of references and, again to judge from the interest, have proved valuable. This is now being enlarged to include, not a l l references, but only those additional ones most likely to prove of value to research workers and to clinical investigators. The selection is somewhat arbitrary, b u t any pertinent omissions can easily be i n corporated i n the next edition i f the subject has grown i n interest. While perhaps not i n the field of " l i t e r a t u r e , " the group has been interested i n the education of prospective isotope workers i n the medical field. The radioac tive pharmaceutical plant i n Oak Ridge, the only institution of its kind i n the world, is always open to qualified visitors. Literature on Radioactive Isotopes

The literature references of interest to those w o r k i n g i n the field of radioactive isotopes which appeared i n Nuclear Science Abstracts and the Current List of Medi cal Literature d u r i n g the period J a n u a r y 1952 to June 1953 were tabulated i n order to find which serial publications carried the greatest number of articles on this subject. References appeared i n more than 600 publications. The publications listed below covered the greatest number of articles on radio active isotopes. A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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SERIES

Medical Journals, American


American Journal of Physiology American Journal of Roentgenology Cancer Research Journal of the American Medical Association Journal of Cellular and Comparative Physiology Journal of Clinical Endocrinology and Metabolism Journal of Laboratory and Clinical Medicine Journal of the National Cancer Institute Journal of Pharmacology and Experimental Therapeutics Mississippi Valley Medical Journal New England Journal of Medicine Proceedings of the Society for Experimental Biology and Medicine Radiology Scientific Journals, American

Analytical Chemistry Archives of Biochemistry and Biophysics Canadian Journal of Chemistry Journal of the American Chemical Society Journal of Biological Chemistry Journal of Chemical Physics Journal of Physical Chemistry Nucleonics Science X-Ray

Technician

Medical Journals, Foreign

Acta Radiologica Acta Unio Internationales Contra Cancrum British Journal of Radiology British Medical Bulletin Bulletin de l'Association Française pour VEtude du Cancer Fortschritte auf dem Gebiete der Roentgenstrahlen Journal Belge de Radiologie Journal de Radiologie et oVElectrologie Radiologia Medica Radioterapia, Radiobiologia e Fisica Medica S trahlentherapie Scientific Journals, Foreign

Analyst Analytica Chimica Acta Bulletin de la Société chimique de France Journal of the Chemical Society (London) Comptes Rendus de la Société de Biologie Doklady Akademii Nauk, S.S.S.R. Nature Naturwissenschaften Zeitschrift fur anorganische C hernie Zeitschrift fur Naturforschung Research Reports

A E C D Reports. Atomic E n e r g y Commission. Declassified Reports. A E C U Reports. Atomic E n e r g y Commission. Unclassified Reports. B E R E Reports. Atomic E n e r g y Research Establishment, H a r w e l l , England. A N L Reports. Argonne N a t i o n a l Laboratory B N L Reports. Brookhaven N a t i o n a l Laboratory *NP Reports. Atomic E n e r g y Commission Nonproject. N Y O Reports. N e w Y o r k Operations Office, Atomic E n e r g y Commission. U C L A Reports. Radiation Laboratories, U n i v e r s i t y of California, L o s Angeles. U C R L Reports. Radiation Laboratory, U n i v e r s i t y of California. U R Reports. Atomic E n e r g y Project, U n i v e r s i t y of Rochester. A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.


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Recent Publications

Atomic E n e r g y Commission " E i g h t - Y e a r Summary of Isotope D i s t r i b u t i o n , " M a r c h 1955, contains more than 7000 references, divided into 30 fields of work. Includes author index. Book T I D 4000, F e b r u a r y 1955, provides a cumulative numerical list of avail able unclassified U S A E C reports. The Isotope Division has released bibliographies covering the recent literature on several of the more widely used isotopes (I , P , A u , etc.). Abbott Laboratories has published at approximately 6-month intervals bibliog raphies and resumes covering current developments, both published and unpub lished. 131

September

14,

198

1954.


RECEIVED

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Literature of Radioactive Pharmaceuticals - Advances in Chemistry

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