The Contribution of cocoa additive to cigarette smoking addiction

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Page 14 of 207 RIVM report 650270002 Theobromine Cardiovascular system Blood pressure: Due to peripheral vasodilation the blood pressure could become slightly decreased (18). Heart rate: Theobromine, at a dose of 500 mg, increased pulse rate slightly, but not significantly more than placebo (18). Theobromine is a cardiotonic (2). Renal system Diuresis: An increased diuresis is observed with theobromine (2, 9, 18) Saluresis: The excretion of uric acid was not increased by theobromine (18). Nervous system Central nervous system: Theobromine has the general properties of the other xanthines. However, it has a much weaker activity than theophylline or caffeine on the CNS. Large doses can cause nausea and vomiting (8). Autonomic system: Theobromine (50 mg/kg dose) increased catecholamine concentration in the rat myocardium 1 hr after intraperitonial injection (18). Other The gastric juice acidity and volume increased following intravenously or orally administered xanthine vasodilators (18). Critical assessment Theobromine has various effects in the body, but is effects are weaker compared with other methylxanthines. It has a relaxation effect on the smooth muscles, thereby exerting a weak bronchodilating and a vasodilating effect. It increases the heart rate at high doses. It has also a stimulating effect on the CNS. Theobromine is significantly less active as a bronchodilator than theophylline. As compared to the bronchodilatory effects of a theophylline dosis of 15 mg applied as an aerosol in humans (20), it is questionable whether the theobromine dose of 0.19 mg per cigarette is high enough to have a bronchodilatory effect. Conclusion Although theobromine exerts a broad active spectrum in the body, at least 100 fold higher doses than obtained from the daily consumption of cigarettes are needed to be clinical active. Whether theobromine has bronchodilatory effects is questionable, due to the low pharmacological effects compared with other methylxanthines. As other methylxanthines (caffeine) also occur in cigarettes, the combined effects of these methylxanthines on the pulmonary system are not known. PHARMACOKINETICS Absorption In humans, theobromine is readily absorbed from food (4). Bioavailability No data available. Distribution Human
RIVM report 650270002 Page 15 of 207 Theobromine After oral intake, theobromine is evenly distributed in body fluids and has been reported to pass into the breast milk of nursing mothers. The apparent volumes of distribution and clearance were estimated to be 0.76 l/kg bw and 0.88 ml/min/kg body weight, respectively (4). The plasma clearance of theobromine is known to be enhanced in cigarette smokers (21). Theobromine has a low protein binding capacity in both serum (15 – 21 %) and breast milk (12 %) (4). Animal Transport across the placental membrane into the fetus has been identified for theobromine in rats (9). Furthermore, the disposition of theobromine in the fetal rat brain is reported at single doses of 5 or 25 mg/kg caffeine. Unlike the adult, the fetal rat brain accumulates theobromine when exposed to caffeine doses comparable to those attainable by normal human consumption (22). Theobromine was identified in the brain of mice after chronic ingestion of caffeine (23). Metabolism The major metabolite of theobromine in human urine is 7-methylxanthine (34 – 48 %), followed by 3-methylxanthine (20 %) and 7-methyluric acid (7 – 12 %), 6-amino- 5-[N-methylformylamino]-1-methyluracil (6 – 9 %) and 3,7-dimethuluric acid (1 %) (4). Cytochrome P450 monoxygenase is an enzyme involved in the metabolism of theobromine (9). A week of daily theobromine consumption in the form of dark chocolate did not alter the elimination kinetics or metabolic pattern of theobromine (12). Excretion Of the dose in humans, 1 – 18 % is recovered in the urine as unchanged theobromine (4). Kinetic parameters The half-times in plasma and saliva are highly correlated. The mean half-time of theobromine in human serum ranged from 6.1 to 10 h (4). In man the disposition of theobromine follows first order kinetics (9). Critical assessment Orally, theobromine is readily absorbed and widely distributed in tissues, including brain. Transplacental transport in rats and human was reported and theobromine was identified in fetal rat brain. There are no data on pharmacokinetics in animals and humans from respiratory studies. Conclusion Conclusions on potential differences in kinetics between respiratory and oral administration can neither be drawn based on the pharmacogical and toxicological data. TOXICOLOGY Acute toxicity Human Oral human dose of 26 mg/kg bw (TDLo, LOAEL) showed central nervous system
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The Contribution of cocoa additive to cigarette smoking addiction

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