Bacterial pathogens--a route to oral drug delivery.

biogenic amines both in the peripheral and central nervous systems. Unlike AADC, which is common to catecholaminergic and serotoninergic neurons, the preceding enzymes, tyrosine and tryptophan hydroxylases respectively, are siteand substrate-specific. In addition, hydroxylation represents the rate-determining step in amine synthesis and is subjcct t o several mechanisms of regulation. If a bioprecursor of the AADC inhibitor could be persuaded to enter the metabolic chains at the hydroxylation step, not only should this compound havc a selective effect on either catechol or indoleaminc synthesis, but these effects should also depend on thc many factors regulating the activity of the hydroxylases. a-Monofluoromcthyl-p-tyrosine (MFMT ) is the candidate of choice for catecholamines, and a-monofluoromethyltryptophan (MFMTrp) that for indoleamines. It was verified that neither compound blocks AADC directly and that both compounds were substrates of the corresponding hydroxylases. I n viw, MFMT (as its methyl ester) decreases AADC activity very slowly in the brains of rats or mice after oral administration. Dopamine levels are decreased in a timeand dose-dependent manner, while serotonin levels remain unchanged even at the higher doses of MFMT. The inhibitory effects on catecholamine synthesis increase in response to factors stimulating catecholaminergic activity (haloperidol, yohimbine, physical stress, etc.) and decrease with agents such as apomorphine known to down-regulate aminc synthesis. a-MFMTrp responds more sluggishly in vivo; it takes three administrations o f 100 mg/kg t o see an effect on AADC activity and 5-hydroxyindoleacetic acid levels in rat brains. The influence of factors regulating the activity o f tryptophan hydroxylase was not investigated. 1. Ilioprecrrrsor crppromh to (I brrriii-speeific nioiiouiriiiie oxiduse-A inhibitor. Monoamine oxidase inhibitors (MAO-1) were a well-accepted treatmcnt o f depression until they fell into disrepute (at least in U.S.A.), some 10 years ago. One of the rcasons for their disgracc was their propensity to produce hypertensive accidents when taken in combination with foodstuffs containing tyramine (cheese effect). This is due to the undcsirablc inhibition o f MAO-A in the peripheral sympathetic system. A very elegant solution was proposed by Palfreyman ef ul. [S] . B-Fluoromcthylene phenethylamines had been shown to be powerful, irreversible inhibitors o f MAO-A or -B depending o n the substitution of the aromatic ring. They reasoned that the corresponding amino acids ( i t . substituted pfluoromethylene phenylalanines) could be bioprecursors of the M A 0 inhibitors if they were substrates of AADC. Inhibition of AADC in the periphery by carbidopa, would prevent the formation of the fluoroallylamine outside the central nervous system, while allowing more amino acid t o reach the brain. B-Fluoromethylene-m-tyrosine combines the required characteristics: it is a good substrate of AADC, and the corresponding amine is a powerful inhibitor of M A 0 with a 100-fold preference for MAO-A. After administration of minute amounts ( < 1 mg/kg) to rats, there is a timeand dose-dependent decrease o f M A 0 activity in all organs, MAO-A being the most affected. Co-administration of carbidopa displaces the dose-response curve t o lower doses in the brain and to higher doses in the periphery as expected. When given alone to rats at a dose o f 0 . 1 mg/kg, the amino acid produced a marked elevation o f heart rate upon infusion of tyraminc. Pretreatment of the animals with carbidopa ( 100 mg/kg) abolished, nearly completely. this undesirable tyramine potentiation. This compound is presently being evaluated in the clinic for safety and efficacy as an antidepressant.