The Contribution of cocoa additive to cigarette smoking addiction

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Page 96 of 207 RIVM report 650270002 Tryptophan Other Critical assessment Tryptophan is essentiel in the diet and is a precursor for several biological active compounds. High tryptophan doses are needed to observe any effects on the cardiovascular, the renal system and the CNS. Tryptophan deficiency affects also the CNS. No data are available on the effect of tryptophan on the pulmonary system. Conclusion High doses of tryptophan are needed to observe any pharmacological effect. Therefore it is unlikely that the tryptophan dose occurring in cigarettes is enough to exert any systemic pharmacological effect. The (longterm) effect of tryptophan on the pulmonary system is unknown and needs further study. PHARMACOKINETICS Absorption L-Tryptophan is well absorbed from the mammalian small intestine and to some extent from the stomach (1, 21). Bioavailability The tryptophan bioavailability depends on the tryptophan source. In rats the tryptophan bioavailability ranged between 85 % and 100 % for several products. Lower bioavailability was obtained for wheat cereal (73 %) and pinto beans (59 %) (22). Tryptophan bioavailability from soybean in ducks was 92 % (23). Distribution Tryptophan is distributed throughout the body and is extensively bound to plasma albumin (85 %)(21, 24). Tryptophan uptake in the brain is affected by plasma levels of other large neutral amino acids (LNAA). All these LNAA, including tryptophan, share a common transport system that moves them from blood to brain. Hence the ratio of other LNAA and tryptophan must be low before relatively large amount of tryptophan is able to cross the blood brain barrier and enter the brain (10). Metabolism Quantitatively, the most important pathway for tryptophan metabolism, after protein synthesis, is the kynurenine pathway which is responsible for over 90% of tryptophan catabolism. Two enzymes initiate this pathway, tryptophan-2,3-dioxygenase in the liver and indoleamine-2,3-dioxygenase which is present in a variety of tissues including intestine, stomach, lungs and brain. The former is induced by glucocorticoids and tryptophan. The latter is induced by interferon gamma. There are several important metabolites along the kynurenine pathway including kynurenic acid, which is a glutamate receptor antagonist and quinolinic acid, which is a
RIVM report 650270002 Page 97 of 207 Tryptophan glutamate agonist. The majority of tryptophan is eventually converted to carbon dioxide but a small amount can act as a precursor of the coenzymes NAD and NADP (10). Of the fraction of tryptophan that enters the brain, part is metabolised to tryptamine and possibly to kynurenine in addition to serotonin. It has been estimated that only 1 % of ingested tryptophan is metabolised to serotonin. Biosynthesis of serotonin requires two enzymatic steps: L-tryptophan is first hydroxylated by tryptophan hydroxylase to L-5-hydroxytryptophan (L-5HTP) and L-5HTP is then decarboxylated into serotonin by decarboxylase. Tryptophan hydroxylase is restricted to serotonin neurons and therefore oral administration of tryptophan gives rise to selective increases in serotonin synthesis and release. A range of 6-8 g/day, given in divided doses, seems sufficient to keep tryptophan hydroxylase reasonably close to saturation throughout most of the day. Higher doses would only increase synthesis of tryptamine and induce tryptophan dioxygenase enzyme (25). Excretion No data available Kinetic parameters The half-life of plasma tryptophan in healthy individuals is 2.0 ± 0.1 h (26). After oral administration of L-tryptophan, 100 mg per kg body weight, the peak concentration of tryptophan in plasma occurred after 1 to 2 h. Tryptophan disappeared linearly from 2 to 5 h and exponentially from 5 to 8 h after administration (27). Critical assessment The oral data indicate a high bioavailabilty, extensive distribution and metabolism of tryptophan. There are no data on pharmacokinetics in animals and humans from respiratory studies on tryptophan. Tryptophan is bound extensively to albumin in plasma. Tryptophan is extensively metabolised resulting in several biologically active compounds. Conclusion There are no data available on kinetics after respiratory exposure. Conclusions on potential differences in pharmacokinetics between respiratory and oral administration can neither be drawn based on the pharmacological and toxicological data. TOXICOLOGY Acute toxicity Human Tryptophan alone seems to produce no more side effects than placebo when given at a moderate dose (3 g per day orally). (10). Nausea, headache, lightheadedness and drowsiness have been reported as side effects of tryptophan (21). Single intake of high doses of tryptophan (> 2 g) with monoamine oxidase inhibitors may lead to development of neurological complications. These symptoms are related to serotonin syndrome (25).
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The Contribution of cocoa additive to cigarette smoking addiction

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