The Contribution of cocoa additive to cigarette smoking addiction

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Page 30 of 207 RIVM report 650270002 Caffeine administration (9, 17-20). The airway resistance by inhalation of theophylline aerosol, a caffeine derivative, was investigated. A dose of 15 mg theophylline aerosol showed significant decrease of the airway resistance after 60 min. of administration. The airway resistance decrease was not significant immediately or after 30 min of theophylline exposure (21). The caffeine activity as a bronchodilator is reported to be equipotent or less than of theophylline (5, 6). Cardiovascular system blood pressure: The systolic blood pressure increases abruptly about 10 mm of mercury with caffeine. However, tolerance develops quickly and longterm ingestion has little or no effect on the blood pressure and heart rate (9). The administration of 250 to 350 mg of caffeine to methylxanthine-naive individuals may produce modest increase in both systolic and diastolic blood pressure, but such doses are usually without effect on these parameters in those who consume caffeine regularly. The effects of therapeutic doses of caffeine on the peripheral blood flow or vascular resistance in man are variable. The conflicting hemodynamic patterns that are observed suggest that caffeine has little direct effect on the major resistance vessels. It is likely that caffeine affect the peripheral resistance through the brain stem (22). heart rate: After ingestion of ± 200 mg to ± 400 mg caffeine, the heart rate slows for about an hour, then increases for two to three hours thereafter; however longterm use does not have an effect on the heart rate (9, 19). At high caffeine plasma concentrations, caffeine produces tachycardia; sensitive individuals may experience other arrhythmias, such as premature ventricular contractions (22). Renal system diuresis: Methylxanthines increase the production of urine (22, 23). saluresis: An increase in diuresis and in urinary sodium, potassium, and osmol excretion was observed within 1 h after caffeine ingestion (23). Women were given a decaffeinated beverage to which 6 mg caffeine/kg lean body mass or no caffeine were added. Total urine output of water, calcium, magnesium, sodium, chloride, potassium, and creatinine increased in the 2 h following the caffeine ingestion when compared to the control beverage (24). Nervous system central nervous system: Caffeine acts principally as a stimulant and reduces fatigue. Caffeine has also substantial effects on sleep. It increases sleep latency, decreases total sleep time and substantially worsen subjective estimations of sleep quality (9). autonomic system: Caffeine could induce catecholamine release (9). Other Caffeine stimulates the secretion of gastric acid and pepsin (9). Caffeine has a pronounced effect on the blood components and coagulation time; caffeine inhibited and reversed platelet aggregation induced by adenosine diphosphate in vitro (2). The administration of caffeine (4 to 8 mg/kg) to normal or obese human subjects elevates the concentration of free fatty acids in plasma and increases the basal metabolic rate (22).
RIVM report 650270002 Page 31 of 207 Caffeine Critical assessment Caffeine has various effects in the body. It has a relaxation effect on the smooth muscles, notably on the bronchial muscle, stimulates the CNS, stimulates the cardiac muscle and increases the diuresis. Caffeine has contradicting effect on the vascular system, which is explained by the central action of caffeine. Relatively large oral doses are needed (> 200 mg) to exert effects on the respiration system. There are no data on pharmacology in animals and humans from respiratory studies of caffeine. The caffeine activity as a bronchodilator is reported to be equipotent or less than of theophylline. As compared to the bronchodilatory effects of a theophylline dosis of 15 mg applied as an aerosol in humans (21), it is questionable whether the caffeine dose of 0.02 mg per cigarette is high enough to have a bronchodilatory effect. Conclusion Caffeine exerts a bronchodilatory effect through oral administration, but the effects of caffeine through inhalation on the respiration system are unknown. Compared with inhalation studies of theophylline, it is unlikely that caffeine dose in cigarette have a bronchodilatory effect. As other methylxanthines (theobromine) also occur in cigarettes, the combined effects with these methylxanthines on the pulmonary system are not known. PHARMACOKINETICS Absorption Caffeine absorption from gastrointestinal routes is rapid and complete (1, 8). Bioavailability The absorption of oral doses quickly approaches that from the intravenous route (1, 8). Caffeine is 99 % absorbed from beverages and reaches peak serum concentrations within 30 to 60 min (9). Distribution The undissociated form of the molecule, which is soluble in the gastric membrane, penetrates all biologic membranes and is distributed to all body tissues. It does not accumulate in any organs and tissues. Caffeine readily crosses the blood-brain barrier and the placenta. It is also present in breast milk (1, 5, 8, 9). The percentage plasma binding for caffeine was 10 – 30 % (1, 8). Metabolism Caffeine, which is a N-methylated compound is degraded by demethylation. When administrated to 20 day old fetal rats, it is demethylated to yield primary metabolites such as theobromine, theophylline and paraxanthine. Caffeine is extensively metabolised in the liver through a complex process mediated primarily by the microsomal cytochrome P450 reductase system. The cytochrome P450 monooxygenase metabolises caffeine yielding trimethyl uric acids, paraxanthine and minor amounts of theobromine (8). Excretion From 2-3 % (w/w) of the ingested caffeine is excreted unchanged in the urine (9).
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