vaxiac.iac.rm.cnr.it

The effects of two cognition enhancers on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box avoidance acquisition and in previously trained mice of the DBA/2 strain. The nootropic agent piracetam (50, 100 or 200 mg/kg, i.p.) had slight or no effect in mice receiving amitriptyline (5 or 10 mg/kg, i.p.). Conversely, the acetylcholinesterase inhibitor tacrine (0.5, 1, 2 or 3 mg/kg, i.p.) prevented the avoidance impairment induced by 5 mg/kg amitriptyline on shuttle-box avoidance acquisition as well as on a previously learned avoidance response. The avoidance disrupting action produced by 10 mg/kg of the antidepressant drug was not affected by the anticholinesterase drug. The preventing action of tacrine seems specifically related to the avoidance impairment induced by amitriptyline, since the acetylcholinesterase inhibitor did not reduce, but enhanced the avoidance impairing action of the neuroleptic chlorpromazine. Taken together, the results indicate that amitriptyline-induced avoidance impairment, and the related preventing action of tacrine, may be ascribed to drug effects on the performance of the avoidance response, rather than to interferences with learning processes.

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J Clin Pharmacol. 1998 Feb;38(2):112-21.
Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4.

Venkatakrishnan K, Greenblatt DJ, von Moltke LL, Schmider J, Harmatz JS, Shader RI.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.

The human cytochromes P450 (CYPs) mediating amitriptyline N-demethylation have been identified using a combination of enzyme kinetic and chemical inhibition studies. Amitriptyline was N-demethylated to nortriptyline by microsomes from cDNA transfected human lymphoblastoid cells expressing human CYPs 1A2, 2C9, 2C19, 2D6, and 3A4. CYP 2E1 showed no detectable activity. While CYP 2C19 and CYP 2D6 showed high affinity, CYP 3A4 showed low affinity; CYP 2C9 and 1A2 showed intermediate affinities. Based on these kinetic parameters and estimated relative abundance of the different CYPs in human liver, CYP 2C19 was identified as the major amitriptyline N-demethylase at low (therapeutically relevant) amitriptyline concentrations, whereas CYP 3A4 may be more important at higher amitriptyline concentrations. Chemical inhibition studies with ketoconazole and omeprazole indicate that CYP 3A4 is the major amitriptyline N-demethylase at 100 mumol/L amitriptyline, while CYP 2C19 is equally important at a substrate concentration of 5 mumol/L. The CYP 1A2 inhibitor alpha-naphthoflavone and the CYP 2C9 inhibitor sulfaphenazole produced much less inhibition of amitriptyline N-demethylation at both substrate concentrations. Quinidine produced no detectable inhibition. The kinetics of amitriptyline N-demethylation by human liver microsomes were consistent with a two enzyme model, with the high affinity component exhibiting Michaelis Menten kinetics and the low affinity component exhibiting Hill enzyme kinetics. No difference was apparent in the kinetics of amitriptyline N-demethylation in two liver samples with low levels of CYP 2C19 activity compared with two other samples with relatively normal 2C19 activity. This may reflect the importance of higher substrate concentration values in estimation of kinetic parameters in vitro.

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Pol J Pharmacol. 1997 Nov-Dec;49(6):453-62.
Promazine pharmacokinetics during concurrent treatment with tricyclic antidepressants.

Syrek M, Wojcikowski J, Daniel WA.

Department of Pharmacokinetics and Drug Metabolism, Polish Academy of Sciences, Krakow, Poland.

The aim of the present study was to search for a possible effect of tricyclic antidepressants on the pharmacokinetics of promazine. Male Wistar rats received promazine and/or an antidepressant (amitriptyline, imipramine) at a dose of 10 mg/kg i.p. twice a day for two weeks. Amitriptyline increased the plasma concentrations of promazine and N-desmethylpromazine. The concentration of promazine sulfoxide was lowered after 30 min, but later it was raised after 6 and 12 h. The interaction was pronounced after 6 and 12 h when the concentration of promazine was 3 times as high, that of N-desmethylpromazine 25 times as high, and that of sulfoxide 22 times as high as those observed after administration of promazine alone. Similar results were obtained in the brain. Imipramine produced less distinct changes in promazine pharmacokinetics. It did not produce any significant changes in promazine concentration (a tendency to raise it after 30 min was observed) in plasma, but it significantly increased the concentration of N-desmethylpromazine and decreased that of promazine sulfoxide. Changes in the brain did not follow closely those in the plasma. In the brain, significant increases in the levels of promazine and its metabolites were observed after 6 and 12 h. In vitro studies with liver microsomes showed that chronic co-administration of the antidepressants did not significantly influence the rate of promazine demethylation and sulfoxidation. Instead, the Lineweaver-Burk's analysis showed that both amitriptyline and imipramine competitively inhibited the two metabolic pathways of the neuroleptic. The potency of imipramine to inhibit the promazine metabolism in vitro was lower than that of amitriptyline, which was in line with its weaker effect on the pharmacokinetics of promazine in vivo. The observed increase in the sum of concentrations of the measured compounds (promazine + metabolites) in the plasma suggests additional inhibition by amitriptyline of another, metabolic pathway of promazine (e.g. hydroxylation). It is concluded that amitriptyline and imipramine which interfere with the metabolism (and probably distribution) of promazine produce potent increases in the brain (in the case of amitriptyline also in the plasma) concentrations of the neuroleptic.

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Nihon Shinkei Seishin Yakurigaku Zasshi. 1998 Feb;18(1):23-5.
Differential effects of chronic administration of the antidepressants amitriptyline and rolipram on adenylyl cyclase activity.

Saito T, Ozawa H, Kamata H, Maeda H, Takahata N.

Department of Occupational Therapy, School of Health Sciences, Sapporo Medical University, Chuo-ku, Japan.

Significant increases were observed in guanylylimidodiphosphate- and fluoride-stimulated adenylyl cyclase activities in synaptic membrane preparations from rat cerebral cortex subsequent to the repeated administration of rolipram and amitriptyline. The potency of GppNHp-dependent inhibition of adenylyl cyclase was decreased by chronic treatment with rolipram but not by amitriptyline treatment. These findings suggest that chronically administered rolipram and amitriptyline share the augmentation of adenylyl cyclase activity by different actions on post-receptor signaling.

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Synapse. 1998 Jul;29(3):248-56.
Differential inhibition of catecholamine secretion by amitriptyline through blockage of nicotinic receptors, sodium channels, and calcium channels in bovine adrenal chromaffin cells.

Park TJ, Shin SY, Suh BC, Suh EK, Lee IS, Kim YS, Kim KT.

Department of Life Science, Pohang University of Science and Technology, Korea.

We investigated the effects of amitriptyline, a tricyclic antidepressant, on [3H]norepinephrine ([3H]NE) secretion and ion flux in bovine adrenal chromaffin cells. Amitriptyline inhibited [3H]NE secretion induced by 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) and 70 mM K+. The half maximal inhibitory concentration (IC50) was 2 microM and 9 microM, respectively. Amitriptyline also inhibited the elevation of cytosolic calcium ([Ca2+]i) induced by DMPP and 70 mM K+ with IC50 values of 1.1 microM and 35 microM, respectively. The rises in cytosolic sodium ([Na+]i) and [Ca2+]i induced by the Na+ channel activator veratridine were also inhibited by amitriptyline with IC50 values of 7 microM and 30 microM, respectively. These results suggest that amitriptyline at micromolar concentrations inhibits both voltage-sensitive calcium (VSCCs) and sodium channels (VSSCs). Furthermore, submicromolar concentrations of amitriptyline significantly inhibited DMPP-induced [3H]NE secretion and [Ca2+]i rise, but not veratridine- or 70 mM K+-induced responses, suggesting that nicotinic acetylcholine receptors (nAChR) as well as VSCCs and VSSCs can be targeted by amitriptyline. DMPP-induced [Na+]i rise was much more sensitive to amitriptyline than the veratridine-induced rise, suggesting that the influx of Na+ and Ca2+, through the nAChR itself is blocked by amitriptyline. Receptor binding competition analysis showed that binding of [3H]nicotine to chromaffin cells was significantly affected by amitriptyline at submicromolar concentrations. The data suggest that amitriptyline inhibits catecholamine secretion by blocking nAChR, VSSC, and VSCC.

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Headache. 1998 Jun;38(6):453-7.
Amitriptyline is effective in chronic but not in episodic tension-type headache: pathogenetic implications.

Cerbo R, Barbanti P, Fabbrini G, Pascali MP, Catarci T.

Department of Neurosciences, University La Sapienza, Rome, Italy.

The tricyclic antidepressant, amitriptyline, is an effective drug for the treatment of chronic tension-type headache and for other chronic pain syndromes, but it is also effective in the prophylaxis of an episodic type of headache such as migraine. However, its efficacy in episodic tension-type headache has not yet been clarified. We compared the efficacy of amitriptyline (25 mg/day) in 82 nondepressed patients with either chronic or episodic tension-type headache in an open-label study. Amitriptyline significantly reduced (P < 0.05) frequency and duration of headache as well as analgesic consumption in chronic, but not in episodic, tension-type headache. Further placebo-controlled trials, possibly with higher doses of amitriptyline, might confirm if the different pattern of response to amitriptyline can be explained in terms of different involvement of central nociception and of peripheral myofascial factors in the chronic and in the episodic forms of tension-type headache.

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Eur J Clin Pharmacol. 1981;19(6):403-8.
Interaction of desipramine and amitriptyline with adrenergic mechanisms in the human iris in vivo.

Szabadi E, Gaszner P, Bradshaw CM.

Mydriatic responses of the pupil were evoked by locally instilled noradrenaline and methoxamine in eight healthy volunteers. The effects of three single oral doses (25 mg, 50 mg and 100 mg) of amitriptyline and desipramine were compared on the mydriatic responses. Both antidepressants potentiated the mydriasis evoked by noradrenaline; desipramine appeared to be approximately four times more potent than amitriptyline. Both antidepressants antagonised the mydriasis evoked by noradrenaline; desipramine appeared to be approximately four times more potent than amitriptyline. Both antidepressants antagonised the mydriasis evoked by methoxamine, amitriptyline being approximately twice as potent as desipramine. It is suggested that the potentiation of the response to noradrenaline may reflect the blockade of the uptake of noradrenaline into adrenergic nerve terminals, whereas the antagonism of the response to methoxamine may reflect the blockade of postsynaptic alpha-adrenoceptors by the antidepressants. It is argued that the interaction of the antidepressants with adrenergic mechanisms could explain why amitriptyline, a potent anticholinergic agent, causes no significant change in resting pupil diameter, while desipramine, a relatively weaker anticholinergic agent, produces a significant mydriasis.

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