The Contribution of cocoa additive to cigarette smoking addiction

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Page 130 of 207 RIVM report 650270002 Tyramine which are rapidly metabolized in vivo, was ineffective up to 40 mg/kg to antagonize the effect of tetrabenazine in the shutlle box (24). The effect of tyramine on brain noradrenaline (NA) containing neurons in the locus coeruleus (LC) was analyzed using single unit recording techniques. In control rats, administration of high doses of tyramine caused a slight inhibition of firing. However, after pretreatment with the monoamineoxidase (MAO)-A inhibitors clorgyline (10 mg/kg, i.p., 1 h) or amiflamine (3 mg/kg, i.p., 1 h) administration of low doses of tyramine caused a consistent and dose-dependent inhibition of firing of the noradrenergic neurons. This inhibition was reversed by the α2-receptor antagonist yohimbine and prevented by depletion of endogenous stores of noradrenaline (pretreatment with reserpine (10 mg/kg, i.p., 5 h) ad αmethyl-p-tyrosine (250 mg/kg, i.p., 30 min). Pretreatment with the MAO-B inhibitor (-)-deprenyl (10 mg/kg, i.p., 1 h) did not promote tyramine to inhibit LC units and therefore it is suggested that this is related to a re-uptake blocking effect of its metabolite, I-amphetamine. Apparently, tyramine, although known to be a rather polar agent, can inhibit central noradrenergic firing rate via an indirect, α2receptor mediated effect. The present results indicate that the serious “cheese effect” of MAO-inhibitors may also have a central origin. Small amounts of pressor amines, which are normally considered to be harmless, in foods (especially cheese) can lead to a hypertensive crisis in patients on MAO-inhibitor drug regimens, which is often termed the ‘cheese reaction’ (25). autonomic system: Administration of tyramine (i.v. 300 µg/kg) to human volunteers, increased plasma noradrenaline level by 145 ± 39 pg/ml (n = 6) from the baseline. Tyramine did not affect plasma adrenaline (14). In another study, tyramine (i.v. 15.0 micrograms/kg/min for 30 min) increased plasma noradrenaline from 547 ± 184 to 836 ± 96 pg/ml in normal human volunteers; plasma adrenaline was unchanged (17). Other Tyramine hydrochloride eyedrops (75 mM; 2 x 10 µl) evoked a significant mydriasis both in light and dark in healthy male subjects (aged 18 – 22 years, n = 8), which was more prominent in the light condition (change in resting pupil size; mm ± s.e.m: light 1.05 ± 0.28; dark: 0.73 ± 0.15) (26). Critical assessment Tyramine is an indirect acting sympathomimetic substance. It increases the release of noradrenaline from the neural endings. The main pharmacological effect of tyramine is the increase of the blood pressure. About 21 mg tyramine (i.v. 20 µg/kg/min in 15 min) increased the systolic blood pressure significantly. It is unlikely that tyramine dose in cigarettes (estimated 0.4 mg/cigarette) will exert a significant increase in systolic blood pressure.Based on the mechanism of action of tyramine by releasing noradrenaline from the neural endings, it is expected that the dose of tyramine in cigarettes will not have a significant effect on the bronchial function. Conclusion It seems unlikely that the tyramine dose in one cigarette (estimated 0.4 mg/cigarette) could increase the systolic blood pressure significantly. The (longterm) effects of tyramine or its pyrolysis/combustion products on the pulmonary system are unknown and need further study.
RIVM report 650270002 Page 131 of 207 Tyramine PHARMACOKINETICS Absorption Tyramine is rapidly absorbed from the gastrointestinal tract and is very rapidly cleared from plasma (12). Bioavailability Studies with everted intestines showed that at concentrations above 10 µM over 70% of tyramine was deaminated during transport (27), which means that the oral tyramine bioavailability will be reduced. As tyramine is a good substrate for MAO-A, inhibition of MAO results in enhanced bioavailability of tyramine (12). Distribution 14 C- tyramine bound to plasma proteins of rabbits in dose- and time of incubationrelated manner. Maximal binding capacity was 70.2 ug/g affinity for plasma proteins, much lower than that of noradrenaline (4). Metabolism Tyramine can be deaminated by monoamine oxidase types A and B in a variety of tissues, including the wall of the gastro-intestinal tract, liver and the central nervous system (1, 4). About 70% of the total monoamineoxidase (MAO)-enzymes in the rat intestines constitued of the A-form. A similar proportion of that form of the enzyme was found in homogenates of biopsy samples of human intestine. Studies with everted intestines showed that at concentrations above 10 µM over 70% of tyramine was deaminated during transport and the use of selective inhibitors confirmed the Aform of monoamine oxidase to play the dominant role in that process (27).Tyramine taken orally is normally detoxicated by monoamine oxidase, present in intestine and liver, to yield para-hydroxyphenylethanol, para-hydroxyphenylacetic acid and its glycine conjugate, para-hydroxyphenaceturic acid, and n-acetyltyramine (1, 4). In a study with human hepatic microsomes, it was shown that CYP2D is capable of converting tyramine to dopamine. Those results suggest that dopamine is formed from endogenous and/or exogenous tyramine by this CYP2D isoform (28). Excretion Eight normal subjects ingested 125 mg of deuterium-labelled p-tyramine hydrochloride and the 3 h and following 21 h urine collections were analysed by monitoring for the deuterated metabolites: free and conjugated p-tyramine, free poctopamine, free and conjugated p-hydroxyphenylacetic acid, and free phydroxymandelic acid. These metabolites accounted for 72% of the ingested label, of which conjugated p-tyramine and free p-hydroxyphenylacetic acid constituted 90%. Approximately 50% of the total deuterated tyramine and 70% of the total deuterated p-hydroxyphenylacetic acid were excreted in the first three hours, although there was considerable variation between individuals. (29) Kinetic parameters The elimination half-life of tyramine is 0.30 ± 0.24 h (n=46) determined in normal human male subjects (12). Critical assessment Tyramine taken orally, is largely metabolised by the MAO-enzymes in the intestines.
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