The Contribution of cocoa additive to cigarette smoking addiction

More documents

Recommendations

Info

Page 166 of 207 RIVM report 650270002 Octopamine Other Critical assessment Octopamine is known to exert adrenergic effects in mammals, although specific receptors have been cloned only in invertebrates. Octopamine stimulates α2 and ß3adrenergic receptors in rats. Furthermore, it affected the cAMP level in the cell via the D1-receptor. No data are available on the pulmonary effects of inhaled octopamine. Because octopamine is much less potent than noradrenaline on the α and ß-adrenergic receptors, it is likely that a large amount of octopamine needs to be inhaled to affect the pulmonary system. Octopamine has positive chronotropic and inotropic effectson dog heart, but is significantly less potent than noradrenaline. Octopamine has a central hypotensive effect, and a peripheral hypertensive or hypotensive effect in rats depending on the α or ß-adrenergic effect. Octopamine does affect the central catechol amine level and thus affects the CNS. Conclusion No data are available on inhaled octopamine effect on the pulmonary system. Based on the in vitro data, octopamine is less potent than noradrenaline and therefore a large amount of octopamine needs to be inhaled to affect the pulmonary system. PHARMACOKINETICS Absorption The enteric absorption is complete. However, metabolic enzymes in the gut of human are responsible for a significant ‘first pass effect’ (29). Bioavailability The urinary excretion of the unchanged drug and its metabolites has been compared after intravenous and oral administration of 3 H-octopamine to eight patients. Identical amounts of 3 H-activity (80% of the dose) were excreted after the two routes of dosing. Significant differences were found in the fraction of free urinary octopamine, which amounted to 10.5% of the dose after infusion and 0.58% after oral administration (29). These differences indicate that the bioavailability through oral exposure is significantly lower than through i.v. exposure. Distribution The physiologically more active m-octopamine has been found in association with poctopamine in 10 organs of the rat. m-Octopamine is present in concentrations equal to those of p-octopamine in heart, spleen, and liver and in concentrations from 30 to 60% of p-octopamine in adrenals, vas deferens, brain, kidney, large intestine, bladder, and lungs. In vivo inhibition of monoamine oxidase (MAO) markedly increased the concentrations of both m- and p-octopamine in all organs examined. Both amines were virtually absent from all organs except the adrenals following chemical sympathectomy with 6-hydroxydopamine, thereby establishing that m- and poctopamine are localized within sympathic nerve endings (28). 3 H-octopamine was found to be accumulated in human platelets, achieving a maximum concentration gradient of 30:1 (30). The measured concentration (ng/g wet tissue) of octopamine in rat brain was as follows: whole brain (less cerebellum) (0.6); hypothalamus (3.2); striatum (0.5) and cortex (0.6). Administration of pargyline (MAO-B inhibitor) resulted in an increase
RIVM report 650270002 Page 167 of 207 Octopamine (around ten-fold) in octopamine concentration in all the above brain regions (31). Metabolism MAO-A metabolises octopamine. In vivo inhibition of this enzyme in rats, reduced the deamination of octopamine in liver, lung and brain significantly (32). The Nmethyltransferase seems to be also a metabolic pathway for octopamine in mammalian tissues (33). When octopamine was injected intraperitoneally into rats four metabolites were excreted in the urine: (i) unconjugated hydroxymandelic acid (OHMA) (16%), (ii) unconjugated hydroxyphenylglycol (OHPG) (4.5%), (iii) an acid-hydrolysable conjugate of OHPG (28%) and (iv) unconjugated octopamine (10%). Adult rats excreted OHMA (1.0 µg/day) but OHPG and octopamine could not be detected in urine. After the administration of a monoamine oxidase inhibitor, unconjugated octopamine (0.3 µ/day) was excreted in urine but OHPG could not be detected (34). The only metabolic pathways for octopamine are deamination and conjugation. Following oral administration the percentage of conjugates was considerably higher than after intravenous infusion. This metabolic pattern appears typical of all phenylalkylamines with a hydroxyl group in the meta position. Ring hydroxylation to catecholamines was not observed. The enzymes mainly responsible for conjugation after oral administration are located in the gut wall. The resulting ‘first pass effect’, i.e. metabolism prior to the access to the central compartment, can account for the diminished pharmacodynamic effect after dosing by this route (29). Pulmonary mitochondrial monoamine oxidase (MAO) activity was examined in preparations from rat, rabbit and guinea-pig. The oxidation of octopamine was greater in guinea-pig lung mitochondria than in rat or rabbit preparations (35). Inactivation of octopamine was studied in a preparation of rabbit lung perfused with Krebs physiological medium at 37 ºC. Inactivation or removal of octopamine was calculated as the difference between the concentration of octopamine in the perfusion medium and the effluent, collected separately from each lung. 35 % of octopamine was inactivated by MAO. The deaminated metabolic products appeared in lung effluent within 90 sec beginning amine perfusion (36). Considering the presence of MAO in human lung tissue, it is likely that in situ elimination will occur in humans after inhalation. Excretion The urinary excretions of free and total octopamine were 5.7 ± 2.8 and 34.8 ± 16.6 ng/mg of creatinine, respectively, in normal human subjects (37). Kinetic parameters No data available. Critical assessment No data are available on pulmonary absorption of octopamine and on pulmonary bioavailability in human. The bioavailability through oral exposure is lower than through i.v. exposure in human, due to metabolization in the gut. In vitro studies with rabbit lung showed that 35 % of octopamine was inactivated by the pulmonary MAO. Considering the presence of MAO in human lung tissue, it is likely that in situ elimination will occur in humans after inhalation. Octopamine is widely distributed in the body. It is accumulated in the platelets. Mainly MAO-A metabolises octopamine. Because, octopamine is deaminated by MAO, it is likely that the octopamine turnover
Page 1 and 2:
RIVM report 650270002/2002 The cont
Page 3 and 4:
RIVM report 650270002 Page 3 of 207
Page 5 and 6:
Page 7 and 8:
Page 9 and 10:
Page 11 and 12:
Page 13 and 14:
Page 15 and 16:
Page 17 and 18:
Page 19 and 20:
Page 21 and 22:
Page 23 and 24:
Page 25 and 26:
Page 27 and 28:
Page 29 and 30:
Page 31 and 32:
Page 33 and 34:
Page 35 and 36:
Page 37 and 38:
Page 39 and 40:
Page 41 and 42:
Page 43 and 44:
Page 45 and 46:
Page 47 and 48:
Page 47 of 207 RIVM report 65027000
Page 49 and 50:
Page 51 and 52:
Page 53 and 54:
Page 55 and 56:
Page 57 and 58:
Page 59 and 60:
Page 61 and 62:
Page 63 and 64:
Page 65 and 66:
Page 67 and 68:
Page 69 and 70:
Page 71 and 72:
Page 73 and 74:
Page 75 and 76:
Page 77 and 78:
Page 79 and 80:
Page 81 and 82:
Page 83 and 84:
Page 85 and 86:
Page 87 and 88:
Page 89 and 90:
Page 91 and 92:
Page 93 and 94:
Page 95 and 96:
Page 97 and 98:
Page 99 and 100:
Page 101 and 102:
Page 103 and 104:
Page 105 and 106:
Page 107 and 108:
Page 109 and 110:
Page 111 and 112:
Page 113 and 114:
Page 115 and 116: RIVM report 650270002 Page 115 of 2
Page 125 and 126: Page 125 of 207 RIVM report 6502700
Page 165: RIVM report 650270002 Page 165 of 2
Page 207: RIVM report 650270002 Page 207 of 2
show all

The Contribution of cocoa additive to cigarette smoking addiction

Create successful ePaper yourself

Delete template?

Save as template?