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DOPAMINE D[1] RECEPTOR ANTAGONISTS MAY PROVE TO BE EFFECTIVE ANTIPSYCHOTICS WITHOUT TARDIVE DYSKINESIA SIDE EFFECT, RESEARCHER TELLS NEUROLOGICAL CONFERENCE

Executive Summary

Dopamine antagonists with D[1] receptor affinities could be a source of new antipsychotic drugs that do not produce the side effect of tardive dyskinesia, Ian Creese, PhD, University of California, San Diego, suggested at a conference on neurological disorders held Nov. 12 in Washington D.C. Noting that neuroleptic drugs currently on the market for schizophrenia block both the D[1] and D[2] receptor sites, Creese explained that D[2] blockade appears to be associated with an increase in D[2] receptors. Research suggests, Creese said, "that this D[2] receptor upregulation is responsible for tardive dyskinesia." However, he commented, "if schizophrenia can be successfully treated by direct blockade of D[1] receptors, the symptoms of tardive dyskinesia may not occur, as D[1] antagonists would not increase D[2] receptor density." Creese made his remarks at a conference entitled "Neurological Disorders: Recent Advances in Diagnostic and Drug Development." The conference, which was sponsored by Yorktown Heights, N.Y.-based Communitech Market Intelligence, a health care and biotechnology consulting firm, focused on new market opportunities in the neurological drug and device field. Creese said that an example of a D[1] specific agent was Schering's SCH-23390, since discontinued by the firm. He reported that in rat studies there was "a significant increase in D[1] receptors following treatment with the D[1] antagonist, but it [was] selective -- D[2] receptors [were] not increased." Perhaps, Creese suggested, "if [the] Schering [compound] or similar D[1] antagonists are antipsychotic, they might not be associated with the production of tardive dyskinesia." Creese noted that the Schering compound was observed very early on "to block dopenergic mediated responses to amphetamine, [a technique] used by the pharmaceutical industries to screen for potential antipsychotic activity." This "suggests then that dopamine D[1] receptors might well be involved in schizophrenia and that D[1] receptor antagonists might be potential antipsychotic drugs," Creese said. Another presenter, Robert Langer, SC.D., Massachusetts Institute of Technology (MIT), presented data on a polymer drug delivery system developed at MIT. The delivery technology is licensed to Nova for use with certain drug products. Nova is working with Celanese, under the joint venture Novacel, on use of the system in the treatment of brain cancer ("The Pink Sheet" July 7, T&G-8). Lilly also has a licensing agreement with MIT for use of the delivery system with insulin. Langer explained that the delivery system utilizes biodegrable polymers (polyanhydrides) which allow long-term release of drugs at a constant rate. Langer said that while most polymers dissolve through bulk erosion, "which can lead to dumping of the drug," the polymer delivery technology developed at MIT dissolves through surface erosion so that "the drug release is totally determined by how fast the polymer dissolves, and the rate of release is predictable." To illustrate how surface erosion allows uniform release of the drug, Langer used the analogy of pages from a book, each containing the same amount of drug, dissolving one at a time at a specified rate. In addition to controlled delivery rate, the polymer system has the advantage, Langer said, of allowing agents to be delivered to specific parts of the body without affecting other areas. Langer noted that in studies at Johns Hopkins (sponsored by Nova) "they have looked at some of these [polymer] implants in the brain for treating tumor patients. Their idea is that they can take some substances that are generally quite toxic, like CCNU, [and] which have significant liver toxicity and kidney toxicity and put them in these implants. By controlling the level [of drug release] and directing it to where you want it, these [toxicity] problems [can be eliminated]." Langer said the Johns Hopkins studies have used CCNU (Bristol-Myers' CeeNu) in the polyanhydride delivery system with mice that have leukemia. "They have found that they can . . . double the survival time of mice in a tumor model which illustrates that you can release this in active form," Langer said. "They're currently working on optimizing this for brain tumor patients," Langer said, "so that they can use this in their clinics." Nova said it hopes to begin clinical trials in early 1987. Discussing preclinical toxicity results from MIT studies on the delivery system, Langer said the polyanhydrides "appear to be quite inert." When implanted in the brains of rabbits for 21 days, Langer said, there is "no inflammation." Toxicity tests also show that "blood, liver function, kidney function, electrolytes and glucose are all normal at very high levels -- probably 100 times more than would be put in the [human] brain." Langer added that no cytotoxicity, mutagenicity or teratogenicity has been seen in the studies. Langer said that by changing the chemistry of the polymer, "we can get 800-fold changes in the erosion rate and you can begin to think about designing it for any release system you want . . . from one day to literally 10 years." Noting that the release rate can also be altered by ultrasound, Langer said: "Our idea is that in the long run one might be able to wear an [ultrasound] watch or carry a little system that could actually regulate how fast the polymer dissolves and hence how fast the drug is released." Nova Senior VP and Scientific Director S. J. Enna, PhD, in his presentation to the conference, suggested in vitro receptor binding assay screening tests are a method for discovering potentially useful pharmaceuticals from a company's library of compounds. Enna maintained that a drug screening approach to product discovery could give a pharmaceutical company a competitive advantage. Noting that pharmaceutical firms most often develop new drugs from their knowledge about the physiological mechanisms of action of compounds, he said this method of discovery makes it "very difficult to come up woth something novel vis a vis your competitors [since we are] all basically working from the same basic biological data base." Using a "blind" screening approach, however, "gives you a better chance of coming up with something novel," Enna asserted. Receptor binding assays, Enna maintained, "are a useful, if not mandatory, component of a drug discovery program since many therapeutic agents act by attaching to specific receptor sites at the target organ." The Nova exec explained that "the data generated from these assays reveal whether or not a given agent interacts with a specific receptor site, or group of sites, and its affinity for these sites." Such information, he stated, is "invaluable in considering whether a test substance will have therapeutic potential and in predicting possible side effects." Enna noted that "the receptor screen is particularly useful for identifying novel compounds that are site-specific, especially for those systems (i.e., peptide and amino acid receptors) in which there are few chemical leads." Currently, there are approximately 75 receptor systems "that can be analyzed in this way," Enna said. He noted that the assay tests are also useful in designing more potent and selective agents. Nova has an agreement with Kodak to screen its 500,000-plus library of compounds for potential therapeutic uses ("The Pink Sheet" Jan. 13, T&G-5).

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