The Contribution of cocoa additive to cigarette smoking addiction

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Page 128 of 207 RIVM report 650270002 Tyramine Conclusion The estimated natural tyramine amount from tobacco plant is at least 2700 times higher than the tyramine amount from added cocoa. Therefore, it is debatable whether tyramine should be considered as an additive to tobacco. The daily potential intake of tyramine from cigarettes (from tobacco plant and from cocoa) is higher than tyramine intake from other sources such as chocolate or wine, and is comparable with cheese. The plasma concentration reached after ingestion of tyramine from chocolate or other food sources is expected to be lower or equal to tyramine after exposure from cigarettes, assuming similar bioavailability and no loss by combustion. Also the different route of application via smoking as compared to other sources should be taken into account. Therefore, the systemic and the local effect of smoking related exposure to tyramine might be a point of concern. Since nothing is known about the pyrolysis/combustion products of tyramine, this may also be a point of concern. PHARMACODYNAMICS Mechanism of action Tyramine is an indirectly acting sympathomimetic substance. It is taken up by the neural endings where it stimulates the release of noradrenaline. Tyramine does not affect plasma adrenaline. The effect of endogenous noradrenaline (released by tyramine) is characterised by increased blood pressure. This increase in blood pressure results from its myocardial positive inotrope action, mainly mediated by cardial ß1-adrenoreceptor stimulation and is not due to vasoconstrictor effects (14). Pulmonary system Tyramine releases noradrenaline from the neural endings. Noradrenaline is a potent agonist of α- and ß1-adrenoreceptors, but has little action on ß2-receptors. Since, the smooth musculature in the respiratory system is mainly stimulated by ß2-receptors (15), it is not expected that noradrenaline released by tyramine in the respiratory system will lead to significant bronchial dilatation. breathing frequency: No data available. tidal volume: No data available. lung compliance: No data available. airway resistance: No data available. Cardiovascular system blood pressure: Tyramine (i.v. up to 20 µg/min/kg body weight for 15 min ≈ 21 mg) significantly lowered diastolic blood pressure (∆max –6.8 ± 3.1 mm Hg) and induced a marked increase in systolic blood pressure (∆max 56.9 ± 6.8 mm Hg) in healthy young male volunteers (26.1 ± 0.5 years, n = 12). The increased blood pressure by tyramine is suggested to be a result of myocardial positive inotropic action (14). Tyramine (i.v. up to 20 µg/min/kg body weight for 15 min) caused a smaller increase in systolic blood pressure in elder healthy volunteers (61 ± 2.2 years (3 females and 3 males)) than in the healthy young volunteers; in addition it slightly increased the diastolic blood pressure while it decreased diastolic blood
RIVM report 650270002 Page 129 of 207 Tyramine pressure in young healthy volunteers (16). In another study it was found that tyramine (i.v. 15.0 µg/kg/min for 30 min) elevated systolic blood pressure (SBP) from 122 ± 11 to 149 ± 4 mm Hg, without increasing diastolic blood pressure or heart rate (17). After ingestion of 400 - 600 mg tyramine added to meals by eight healthy volunteers of both sexes, it was shown that the SBP increased by more than 30 mmHg. When the subjects received moclobemide 600 mg/day (a monoamine oxidase inhibitor) for seven days, an average dose of 250 mg tyramine (range 150-400 mg) was needed to increase SBP by 36.6 mmHg (18) The pressor effect of intravenous tyramine was investigated in 19 healthy unmedicated subjects. The pressor dose (PD) that raised systolic blood pressure by 30 mm Hg (PD30) ranged from 2 to 8 mg for tyramine. Coefficients of variation ranged from 3 to 47%. A sex-related difference was found for the PD30 of i.v. tyramine: 4.4 mg for 11 males and 3.8 mg for 8 females. Additional results from supported this observation; PD30 of tyramine 4.6 mg in 34 males vs. 3.5 mg in 21 females (19). heart rate: Tyramine (i.v. up to 20 µg/min/kg body weight for 15 min) did not show any dose-related changes in heart rate during i.v. tyramine dosage; however, tyramine caused a pronounced shortening of QS2c and pre-ejection period of the left ventricle (14). Another study confirmed that tyramine (i.v. 15.0 µg/kg/min for 30 min) does not change the heart rate (17). Renal system diuresis: A non-pressor dose of intravenous tyramine of 4 µg/kg/min for 120 min in 8 healthy volunteers caused a significant increase in urinary flow rate (p < 0.05 (20). saluresis: A pressor dose of tyramine (i.v. 15 µg/ kg/min) in six normal volunteers induced increase in blood pressure and subsequent natriuresis (21). Nervous system central nervous system: No data are available on the effect of tyramine on the human central nervous system. Most of the tyramine data on central nervous system are from animal experiments. Both p- and m-tyramine are found in rat brain. The p- and m-tyramine are unevenly distributed among the nuclei. The highest concentrations of p-tyramine were measured in the olfactory tubercle, followed by the nucleus accumbens and septal nuclei, for m-tyramine the concentrations decreased in the following order: olfactory tubercle, nucleus accumbens, amygdala, septal nuclei, and nucleus tractus diagonalis (22). The brain microdialysis technique was used to examine the in vivo effects of tyramine on dopamine (DA) release and metabolites in the striatum of halothaneanesthetized rats. A dose-related release of DA was also observed following addition of tyramine (1-100 µM) to the perfusing buffer. Tyramine-induced DA release appears to involve a carrier-dependent process. Tyramine induces the release of DA from vesicular stores (23). Tetrabenazine induced depression of performance of rats in shuttle box and is antagonized by sympathomimetic amine with cateholamine enhancers. Tyramine,
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