http://exhibits.library.stonybrook.edu/mfp/files/original/a6c4553e41644a6267038d4f7309d8e0.pdf ca0b7e6a698a15f01f233c0287893b6d PDF Text Text P- we? March 10, 1972 De. Daniel X. Freedman Professor and Chairman The University of Chicago Department of Psychiatry 950 East 59th Chicago, Street Illinois 60637 Dear Dan: It was a pleasure to discuss the opiate antagonists as a model for the treatment and prevention of Opiate abuse, and it may be useful to outline some issues of interest. Neither cyclazocine nor naloxone, as now formulated, are prac— of opiate dependence. At best, we have been able to sustain a select group of Opiate users with cyclazocine for up to 5 years, and some are now drug free __ but the number is small, and I believe our success to be as much a result of the dedication of my staff as to any specific pharmacologic activity. But these experi~ ments demonstrate that the antagonists provide effective narcotic blockade; that they are safe; and that tissue tolerance does not develop to the antagonistic actions. They also indicate that drug delivery ~~ a sustained delivery of weeks or months -- is the immediate hurdle to overcome. As the bnger duration of action of methadone and levomethadyl make maintenance therapy feasible, so too, a prolonged acting antagonist would make both deconditioning and phophylaxis clinically realistic. tical in the clinical treatment From this point of View, there are thcee practical problems: the development of a long-acting delivery system; identification of more potent additional 'pure' antagonists, of greater duration of action; and, biochemical synthesis methods to assure an adequate supply of medication. ,crn �Dr. Daniel X. Freeman March 10, 1972 - 1) Long-action. There are many routes that can be examined substitution of a long~chain fatty acid to delay absorption and degradatiOn (similar to fluphenazine enanthate and naloxone pamoate); modified crystallizations (as utilized by Janssen for a long acting antipsychotic drug); investment in a biodegradeable silastic (as suggested by the Population Council for anti—ovulatory agents); or other novel altered delivery systems as developed by some ingenious chemists for ophthalmic drugs. We have supported one study of silastic and defined the charmethod using naloxone as the base. The study was acteristics of this discontinued for lack of funds. It warrants continued support, despite the long term nature and potential expense of the investment. We have also completed observing that 6 initial human assays of naloxone pamoate, cc intramuscular prolongs the duration of antagonism diacetylmorphine/chlZ minutes (a 'heroin challenge') to 60 an increase in duration of at least 15 times. This salutary demonstrates the feasibility of the approach. step to 25 hours mg —~ A long~acting 'pure' antagonist. 0f the tested drugs, nal— the 'cleanest' compound, hut it has many disadvantages a" its is duration of action is 2—4 hours; it is ineffective on oral administra— tion (we required 3.0 grams to extend duration to 24 hours); and it is expensive and difficult to manufacture, limiting its supply. Other compounds warrant testing, and of these M 5050 has the most promise, based on animal trials. To test this compound, it is necessary to first complete adequate animal toxicology. (This step has precluded human 2) oxone assay for more than 2 years, for no agency which we approached was will— ing to provide the funds. Happily, funds were approved on March 3 for these trials). In addition to this compound, there are many others that war~ have been examined by the University of Michigan for antagonist potency, and these data are 'hidden' in the archives of the NRC/NAB. At the request of various agencies, Dr. Vil~ lareal nas agreed (February, 1972) to undertake a review of the data; and should other compounds be identified, these should be assayed in man, with particular emphasis on their 'purity', degree of antagonism, and duration. rant study. Many compounds ' Under the have returned to compounds. This Sterling stimulation of Congress, various industrial concerns their laboratories and examined their files for active is true for Merck (levellorphan), Bristol (BC 2605), Winthrop (fi-cyclazocine), and Geigy (GPA 2163) drugs warrant more intensive examinations. -- and these �March 10, 1972 Dr. Daniel X. Freedman Finally, perhaps an interested scientistwith experience in analgesics, could be encouraged to visit various laboratories to dis— cuss on an individual basis, the availability of compounds or congeners in their files. When this was recently done with Janssen in Belgium, we were able to identify two possible compounds of interest, and to stimulate their further study. 3) Biochemttal synthesis methods. The basic chemicals from which these antagonists are derived are in short supply, apparently because their manufacture is derived from thebaine, a proscribed commodity. Some effort should be made for chemists and botanists to iden— tify other manufacturing methods and other sources of the raw materials. In this review, I have neglected the need for training psychi- atrists and clinical pharmacologists in the special problems of studies in addicted persons (patients usually have a different agenda than the scientist); the need for studies of the extinction of learned patterns; and the need for the studies of the dependence process itself. These general issues are of special concern to the committees of the National Institute of Hental Health, and will surely occupy the attention of the new proposed centers. In our discussions of the ways in which these studies could attract the attention of scientists in universities and industry, one suggestion may be of Special interest. Should an agency, preferably non~governmental, outline the needs for a long acting antagonist, de— fine a reasonable deadline, and offer a prize of significance, would this not stimulate those men who may be unable to visualize the needs of the formulation, to attempt its development? Should an agency offer $50,000 or $100,000 for the development of a narcotic antagonist, with a duration of a single administration of 60 days, sufficient to block~ ade diacetylmorpnine 25 mg/2 cc/2 minutes, in man «s would this not stimulate some interest? (An example is the announcement of the Anna fionika Foundation prize). Two additional needs: support for academic scientists to work directly with industry on a 3»6 month 'fellowship' basis; and support for regular meetings of investigators interested in the narcotic antago onists, similar to the annual methadone meetings. (When we suggested the methadone meetings set aside time for the antagonist workers in York and in San Francisco, our suggestion was denied. The only special meeting was sponsored by NINE and the New York Medical College on June 4, 1970). Nan �{I Dr. Daniel X. Freedman March 10, 1972 These are some random notes. Should you be interested in the' will provide what I have. Meanwhile, my latest summary as prepared for Contemponaty Dnug Pnobfieme is enclosed. 'back—up', I Again, my thanks for lending ye your ears. My best regards. Sincerely yours, Max Fink, M.D. Professor of Psychiatry HF:ig Eflnc; � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Freedman, Daniel X. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-026-1-052 Date A point or period of time associated with an event in the lifecycle of the resource 1972 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. 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