The Contribution of cocoa additive to cigarette smoking addiction

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Page 36 of 207 RIVM report 650270002 Caffeine fluorouracil), caffeine enhanced the teratogenic effect of these agents. With 5azacytidine in rats, caffeine suppressed limb malformations. Administration of inhibitors of beta-adrenergic function reduces the teratogenic effect of caffeine in mice. The interpretation of the experimental studies in terms of human hazard is complicated by the general use of high-dose bolus exposures, which are not typical of human exposures, and the use of test systems that are not readily applicable to human (30). The ability of caffeine to inhibit mutation repair, has been investigated thoroughly (33); it is well known that under specific conditions caffeine is able to enhance radiation risk of mammalian cells by a factor of approximately 1.5-2. It was shown that at the concentration necessary for increasing radiation risk (2 mmol/l), caffeine effectively inhibits the restitution of radiation-damaged DNA (34). Caffeine caused a moderate increase of spontaneous micronucleus frequency in human hepatoma cells at high concentration. Caffeine reduced micronucleus frequency significantly in HCA 2-amino-3-methylimidazo-[3,4-f]quinoline micronucleus at low concentration (35). Caffeine and derivatives are compounds with pleiotropic effects on the genetic material, which are thought to originate from binding of these drugs to DNA. Using 2 different topologic methods showed, that methylated oxypurines, at biological relevant concentrations, unwind DNA in a fashion similar to that of known intercalators. The methylated oxypurines could be ranked by decreasing unwinding potency: 8-methoxycaffeine > 8-ethoxycaffeine > 8-chlorocaffeine > caffeine > theophylline. These findings confirm, with a different assay, the interaction of caffeine and its analogs with DNA and add additional support for an intercalative mode of binding of these drugs to DNA (36). Caffeine has also protecting properties against DNA-intercalating antitumor drugs (Novantrone (mitoxantrone, doxorubicin, ellipticine, or the doxorubicin analogue AD198)). It inhibits the DNA-intercalating properties of these drugs by complexformation (37). Caffeine is an effective analgesic adjuvant because it increases the antinociceptive effect of NSAIDs (Non-Steriodal Anti-Inflammatory Drugs) while reducing the probability of side effects. The potentiation appears to be due to a pharmacokinetic mechanism including actions at the central and the peripheral levels (38). The thermogenic effect of tea is generally attributed to its caffeine content. Its thermogenic properties could reside primarily in an interaction between its high content in catechin-polyphenols and caffeine with sympathetically released noradrenaline (NA). Since catechin-polyphenols are known to be capable of inhibiting catechol-O-methyl-transferase (the enzyme that degrades NA), and caffeine to inhibit transcellular phosphodiesterases (enzymes that break down NA-induced cAMP), it is proposed that the green tea extract, via its catechin-polyphenols and caffeine, is effective in stimulating thermogenesis by relieving inhibition at different control points along the NA-cAMP axis (39). Several interactions with caffeine through the liver enzym system are described. Caffeine is an inducer of CYP1A2 in rat liver (40). Caffeine reduced the hepatotoxicity of acetaminophen (ACM) in mice when it was
RIVM report 650270002 Page 37 of 207 Caffeine administered immediately after ACM. However, the hepatotoxicity was increased when it was given before ACM. It is proposed that caffeine interferes with the metabolism of ACM when administered concomitantly, but induces the microsomal mixed function oxidase system when used in a pre-treatment regimen, leading to a more rapid rate of formation of the hepatotoxic arylating ACM biotransformation product (41). From the course of the plasma concentration of theophylline, a prolonged half-time of 7.4 to 10.4 h as well as a reduction of the total clearance of 0.71 to 0.37 mL/min/kg was observed if caffeine and theophylline are administered at the same time. As both methylxanthines have the same localization of metabolization in the microsomal enzyme system of the liver a competition by caffeine may be the cause of the delayed theophylline metabolization. During treatment with theophylline the daily caffeine consumption should be taken into consideration (42). The effects of the widely consumed drugs caffeine and phenylpropanolamine are mediated through activation of the central and sympathetic nervous systems. Greater increases in both systolic and diastolic blood pressures occurred after the combination than after either drug alone. Because caffeine levels can be increased greatly when certain other drugs are co-consumed, these data indicate that phenylpropanolamine may enhance absorption or inhibit elimination of caffeine and may explain increased side effects reported after their combined use (43). The influence of multiple doses of ciprofloxacin on the disposition of caffeine and its major metabolite, paraxanthine, was investigated in healthy volunteers. Ciprofloxacin increases the half-life of caffeine and the area under the caffeine concentration-time curve by reducing total body clearance. This interaction is due at least in part to a delay in the conversion of caffeine to paraxanthine. Also, caffeine may alter the kinetics of ciprofloxacin (44). Grapefruit juice inhibits the biotransformation of several drugs, including caffeine (23% clearance reduction), which is metabolised by the cytochrome P450 isoform CYP1A2 (45). Carbamazepine (CBZ) interacts with the adenosine receptor, which is related to the inhibition of release of neurotransmitter. The anticonvulsive and sedative effects of CBZ and its derivates appear due to action on adenosine receptors (A1 and partially A2) at the therapeutic level, while the methylxanthines, like caffeine have stimulant and convulsant effects due to occupation on both A1 and A2 adenosine receptors (46). In mice chronically administered caffeine decreased the ED50 for morphine-induced analgesia significantly while the naloxone ED50 for withdrawal jumping was increased by 2-fold after both types of morphine pre-treatment. Chronic administration of caffeine increases the potency of acutely administered morphine and reduces the development of morphine-induced tolerance and dependence. These effects of caffeine may be independent of adenosine receptor interaction (47). The interactive effects of caffeine in coffee and cigarette smoking were studied in 15 subjects. Subjective arousal showed antagonistic interaction between caffeine and
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