Two of the most serious health problems ever to face us in the United States are the AIDS crisis and the widespread misuse and abuse of drugs of all kinds. These two problems have a meeting point, namely the spread of AIDS by addicts who inject their street drugs using unsanitary apparatus, a practice common among heroin (opiates) and cocaine addicts. About 25% of those exhibiting AIDS contracted the disease as the result of drug abuse, many of them total innocents; consequently, repressing the use of street opiates to block the spread of AIDS is a matter of grave urgency. Methadone maintenance therapy is one at the same time the most successful and the most controversial treatment for opiate abuse, its most serious shortcoming being that its concomitant use with cocaine creates a pleasurable experience, reinforcing abuse of both drugs. Indications are that the narcotic agonist-antagonist, buprenorphine, is a better drug for treating opiate abuse. It can be substituted for heroin without precipitating withdrawal, and it appears to block the euphoric experience of concomitantly administered cocaine. It is also potent, so much so that we hypothesize the drug can be delivered through the skin to gain its clinical effect, a seemingly ideal means of treating addicts. However, it will take manipulation of buprenorphine's chemical structure to reach delivery rates adequate to repress street drug use; therefore we present a prodrug strategy to resolve the problems attending transdermal delivery. We plan to design and synthesize derivatives (or make salts) which are inherently more skin permeable than buprenorphine, but which are converted back to buprenorphine once in the body. An integrated study of the absorption, metabolism, distribution and elimination of buprenorphine and its altered forms is offered, with specific aims: (1) to synthesize bioreversible derivatives and salts of buprenorphine, (2) to characterize the physical properties of buprenorphine, its derivatives and its salts, including their permeability coefficients through skin , (3) to characterize the enzymatic liability of the prodrugs, and (4) to characterize the kinetics of absorption, metabolism, distribution and elimination of buprenorphine and its prodrugs (and salts). The above information, when collated and integrated, should reveal which of the two different approaches set forth is best to take forward in the development of an adhesive transdermal delivery system.
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