Am J Phys Med Rehabil. 1988 Feb;67(1):29-33.
Amitriptyline for post-traumatic agitation.

Mysiw WJ, Jackson RD, Corrigan JD.

Department of Physical Medicine, Ohio State University, Columbus.

Agitated behavior is exhibited in up to 30% of patients recovering from a traumatic brain injury. Past treatment protocols have included proactive behavioral management and major tranquilizers. We now report the use of amitriptyline for control of agitation. For a period of over 2 years, 43 male and 15 female patients with a "recent" severe brain injury were admitted for inpatient rehabilitation and subjected to traditional structured programming for treatment of post-traumatic amnesia (PTA). In 20 patients, 18 men and 2 women, where agitation persisted sufficiently to impede rehabilitation despite initiation of structure, amitriptyline was instituted. These patients were of a comparable age (29.4 years for the agitated group versus 25.6 years for the nonagitated group), but the agitated patients had a lower median Rancho Los Amigos Hospital Level of Cognitive Functioning in a comparison to nonagitated patients (V versus VI). All patients were monitored for cognitive performance by the Orientation Group Monitoring System, and a daily account of frequency, severity and type of agitation was recorded. Within 7 days of initiation of therapy, 12 of 17 patients within PTA had dramatic decrease in agitation (5/5 patients at Rancho IV; 4/8 at Rancho V; 3/4 at Rancho VI). Two of the three patients at Rancho VII had agitation that was unresponsive to amitriptyline. The amitriptyline-responsive patients were maintained on the drug through PTA, and the Orientation Group Monitoring System scale demonstrated no impedance in cognitive recovery. Thus, amitriptyline appears most useful as an adjunct for treatment of nondirected agitation; it also has a role in reducing the severity of the directed agitation that is seen during but not after PTA.

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Nippon Yakurigaku Zasshi. 1989 Sep;94(3):189-206.
[Behavioral pharmacological properties of the novel antidepressant paroxetine, a selective 5-HT uptake inhibitor]

[Article in Japanese]

Yamamoto T, Shibata S, Shimazoe T, Iwasaki K, Ohno M, Minamoto Y, Furuya Y, Miyamoto K, Watanabe S, Ueki S, et al.

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

The behavioral effects of paroxetine were investigated in mice and rats in comparison with imipramine and amitriptyline. 1) Locomotor activities were decreased by imipramine and amitriptyline but not by paroxetine in both animal species. 2) Paroxetine antagonized methamphetamine-induced hyperactivity in mice as did imipramine and amitriptyline. 3) Paroxetine showed a more potent antimuricidal effect in raphe-lesioned rats than imipramine and amitriptyline, and it also inhibited muricide in olfactory bulbectomized rats. 4) The immobility of rats in the forced swimming test was markedly decreased by imipramine and amitriptyline, but only slightly by paroxetine. 5) Like imipramine and amitriptyline, paroxetine potentiated the methamphetamine- or L-DOPA-induced stereotyped sniffing, and it inhibited oxotremorine-induced tremor. 6) Paroxetine antagonized reserpine-induced hypothermia, tetrabenazine-induced ptosis, and enhanced ether-induced anesthesia, all less potently than imipramine and amitriptyline. 7) The analgesic action of paroxetine was stronger than that of imipramine and amitriptyline. 8) Paroxetine did not antagonize maximal electroshock- or pentetrazol-induced convulsions and haloperidol- or THC-induced catalepsy in rats. In addition, paroxetine neither exerted muscle relaxation nor affected the shuttle-box type conditioned avoidance in rats. From these results, the behavioral effects of paroxetine, as compared with imipramine and amitriptyline, were characterized by its potent antimuricidal action in raphe-lesioned rats and its weak effect in the forced swimming test and by its less potent muscle relaxant, anticonvulsant, anticataleptic and anesthesia-potentiating actions.

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Clin Pharmacokinet. 1984 May-Jun;9(3):261-6.
Amitriptyline dosage prediction in elderly patients from plasma concentration at 24 hours after a single 100mg dose.

Dawling S, Ford S, Rangedara DC, Lewis RR.

Fifteen depressed elderly patients (14 female, 1 male; mean age 85 years) received a single oral dose of amitriptyline. The concentration of amitriptyline plus nortriptyline in a blood sample taken 24 hours later was used to predict by means of a nomogram the amitriptyline dosage required for each patient. Each dose was selected to produce steady-state amitriptyline plus nortriptyline concentrations close to 140 micrograms/L. The daily dosage ranged from 20 to 100mg (mean 62mg). Patients received the individually calculated dose each night, and weekly blood samples were obtained for drug analysis. At 2 weeks, mean amitriptyline plus nortriptyline concentrations were 118 +/- 21 micrograms/L. Eight of the patients were studied for a further 2 weeks and the mean amitriptyline plus nortriptyline concentration was then 111 +/- 19 micrograms/L. The dose prediction test is easy to use and ensures each patient receives an adequate but safer dose of amitriptyline than might otherwise be prescribed routinely.

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Neuropsychobiology. 1984;12(4):249-54.
Comparison of the (pro)convulsive properties of fluvoxamine and clovoxamine with eight other antidepressants in an animal model.

Krijzer F, Snelder M, Bradford D.

Freely moving rats were implanted with cortical, caudal, thalamic, and reticular electrodes. Drugs were infused intravenously at a constant rate up to a final cumulative dose of 40, 50, or 60 mg/kg. Doses of 10 mg/kg imipramine, viloxazine, desmethylimipramine, mianserin, and maprotiline produced spike-wave complexes, spikes, and increased spindling. General sustained discharges occurred after 20 mg/kg of mianserin, viloxazine, imipramine, desmethylimipramine and amitriptyline, and after 30 mg/kg of maprotiline. An abnormal high-amplitude pattern was evident after mianserin, amitriptyline, imipramine, and desmethylimipramine. On the average, seizures were observed at 40 mg/kg and were seen after desmethylimipramine (50 mg/kg), mianserin (30 mg/kg), amitriptyline (20 mg/kg), imipramine (40 mg/kg), maprotiline (40 mg/kg), and zimelidine (50 mg/kg). Ranking the tested antidepressants in decreasing order in accordance with their relative (pro)convulsive properties gives: amitriptyline greater than mianserin much greater than imipramine greater than desmethylimipramine greater than viloxazine much greater than maprotiline much greater than zimelidine greater than clovoxamine greater than nomifensine = fluvoxamine.

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Acta Pharmacol Toxicol (Copenh). 1980 Jul;47(1):53-7.
Neuropharmacological properties of amitriptyline, nortriptyline and their metabolites.

Hyttel J, Christensen AV, Fjalland B.

Amitriptyline, nortriptyline and their metabolites, desmethylnortriptyline, cis and trans 10-hydroxy amitriptyline, cis and trans 10-hydroxynortriptyline and amitriptyline-N-oxide, have been tested for inhibitory effect on the uptake of serotonin (rabbit thrombocytes in vitro) and noradrenaline (mouse atria in vitro and mouse heart in vivo), for anticholinergic activity (guinea-pig ileum in vitro) and for antagonism against tetrabenazine induced inactivity as well as apomorphine and 5-hydroxytryptophan potentiating effect in mice. Amitriptyline inhibits serotonin and noradrenaline uptake equally, whereas nortriptyline is a more potent inhibitor of noradrenaline than of serotonin uptake. The metabolites resemble nortriptyline in this respect. The 10-hydroxylated metabolites are equipotent with amitriptyline as regards noradrenaline uptake inhibition. All the metabolites are less anticholinergic than amitriptyline and nortriptyline. The in vitro results are reflected in the in vivo behavioural tests, although some discrepancies are found, probably due to differences in absorption, distribution, metabolism and excretion. The importance of knowledge concerning pharmacological properties of the metabolites in comparison with amitriptyline and nortriptyline for correlating plasma levels of these and their metabolites to clinical outcome is discussed.

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Nippon Yakurigaku Zasshi. 1988 Jun;91(6):359-69.
[Behavioral effects of quinupramine, a new tricyclic antidepressant]

[Article in Japanese]

Ueki S, Yamamoto T, Shimazoe T, Shibata S, Tani Y, Machida K, Hojo M, Yoshida Y, Tatsumi H.

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

The effects of a new tricyclic antidepressant quinupramine (5-(3-quinuclidinyl)-10,11-dihydro-5H-dibenz [b, f] azepine) on various animal behaviors were examined in mice and rats and compared with those of imipramine, amitriptyline and maprotiline. Quinupramine antagonized haloperidol-induced catalepsy and tetrabenazine-induced ptosis and potentiated methamphetamine- and apomorphine-induced stereotyped behavior. These effects were almost the same as or even more potent than those of imipramine and amitriptyline. Quinupramine decreased locomotor activity in mice, but potentiated methamphetamine-induced hyperactivity to a greater degree than imipramine and amitriptyline. On the other hand, quinupramine inhibited muricide in accumbens-lesioned rats, but did not prominently inhibit muricide in olfactory-bulbectomized and raphe-lesioned rats. Quinupramine decreased the duration of immobility in low doses without affecting locomotor activity, and this effect was almost the same as that of imipramine and amitriptyline and more potent than that of maprotiline. Quinupramine antagonized physostigmine lethality and oxotremorine-induced tremor, suggesting that quinupramine has a central anticholinergic action. Quinupramine, like imipramine and amitriptyline, has no effect on conditioned avoidance behavior. In conclusion, quinupramine generally has the same behavioral profile as typical tricyclic antidepressants, but it has somewhat different effects from imipramine and amitriptyline since quinupramine has a potent central anticholinergic and a weak antimuricide effect.

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Arch Int Pharmacodyn Ther. 1977 Jun;227(2):294-301.
Studies of excretion in rabbit milk after administration of carbon-14 labelled amitriptyline and nortriptyline.

Aaes-Jorgensen T, Jorgensen A.

The excretion with rabbit milk has been investigated after subcutaneous administration of carbon-14 labelled amitriptyline and nortriptyline. The amounts of drug material in suckling neonates from nursing rabbits dosed repeatedly with the two drugs were also measured. It was found that the concentrations of radioactivity in milk were of the same size as the concentration in serum. The concentrations of radioactivity in the organs of neonates, which had received milk from rabbits dosed for five days with either amitriptyline or nortriptyline were considerably below those found in the corresponding organs of the dam. Amitriptyline administration to the dams seems to lead to higher concentrations in the organs of the offspring than does nortriptyline administration.

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