Gen Pharmacol. 1990;21(6):955-9.
Effects of amitriptyline and nortriptyline on cerebral activity of the CDF-1 mouse strain.

Messiha FS.

Department of Pharmacology, University of North Dakota School of Medicine, Grand Forks 58203.

1. Equal dose regimens of amitriptyline, a tertiary amine tricyclic antidepressant, were more potent than nortriptyline, a secondary amine derivative, in suppressing CDF-1 mouse locomotor activity. 2. A suggestive increase in dopamine turnover rate in mouse cerebral cortex and striatal brain regions was apparent by amitriptyline but not nortriptyline. 3. A suggestive increase in serotonin turnover in mouse cerebellum and striatum was determined for nortriptyline. 4. Both antidepressants increased cerebral cortex, midbrain and cerebellum serotonin levels from saline control. 5. Increases of regional brain dopamine by amitriptyline and serotonin by nortriptyline concurrent with reuptake blockade of the respective serotonin and dopamine may contribute to their differential extrapyramidal and sedating side effects.

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Pharmacopsychiatry. 1990 Nov;23(6):253-8.
REM-suppressing effects of amitriptyline and amitriptyline-N-oxide after acute medication in healthy volunteers: results of two uncontrolled pilot trials.

Riemann D, Velthaus S, Laubenthal S, Muller WE, Berger M.

Central Institute of Mental Health, Mannheim, FRG.

Almost all tricyclic and tetracyclic antidepressants as well as the MAO (monoamineoxidase) inhibitors suppress REM sleep significantly and sustainedly. This does not seem to be an epiphenomenon of antidepressant pharmacotherapy, since initial REM sleep suppression during pharmacological treatment correlated positively with antidepressant effect after three weeks. Furthermore, selective REM-sleep deprivation (by waking patients) had a marked antidepressive effect in depressed patients. The present study used rapid eye movement (REM) sleep suppression in healthy volunteers as a marker to compare the central nervous effects of 150 mg amitriptylineoxide (AMINO) with those of 75 mg amitriptyline (AMI). Both compounds exerted comparable sleep-inducing effects; suppression of REM sleep tended to be more pronounced after application of AMI, despite the higher dose of AMINO used. While this result is evidence of the immediate central nervous effects of a single dose of AMINO, they seem less marked than those of AMI.

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Brain Res Bull. 1990 Feb;24(2):207-12.
Effects of prenatal exposure to cocaine or related drugs on rat developmental and neurological indices.

Henderson MG, McMillen BA.

Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27858.

Although increasing numbers of infants born to cocaine abusing mothers are of grave concern, little is known of the long term development of these children. To determine the long term effects of cocaine on a developing fetus, gravid rats were dosed SC throughout pregnancy with either saline, amfonelic acid (AFA, 1.5 mg/kg), amitriptyline (10 mg/kg) or cocaine (15 mg/kg b.i.d.) and the male pups fostered by surrogate rats. Compared to saline offspring, cocaine- and amitriptyline-exposed litters were underweight at birth, but there were no differences between groups at 15 or 30 days of age. There were more birth defects and stillbirths in cocaine-exposed offspring, however, there were no differences in male/female sex ratios or litter size in any group. Number of days to righting reflex was delayed in the cocaine-exposed group, but there were no changes in time to eye opening. Cocaine- and amitriptyline-exposed pups were hyperactive at 30 days of age, though no differences were found in an initial 15-min exploration period. Only the AFA-exposed offspring were hyperactive at 60 days postnatal. Since cocaine and amitriptyline decreased birth weights, this effect may be related to the nondopaminergic effects of cocaine. These data demonstrate that cocaine exposure in utero at relevant doses can affect neonatal outcome and long term development in rat offspring.

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Eur J Pharmacol. 1990 Feb 20;177(1-2):43-54.
Inhibitory effects of amitriptyline on the stimulation-induced Ca2+ increase in parotid acini.

Dissing S, Hansen HJ, Unden M, Nauntofte B.

Department of General Physiology and Biophysics, University of Copenhagen, Denmark.

The present study demonstrates the effects of the antidepressant, amitriptyline, and the acetylcholine antagonist, atropine, on the stimulation-induced rise in cytosolic, free Ca2+ (Cai2+). The changes in Cai2+ of collagenase-isolated rat parotid acini were measured by means of the Ca2(+)-sensitive dye, fura-2. It was found that stimulation by carbachol resulted in a maximal increase of 582 +/- 34 nM (mean +/- S.E.) in Cai2+ with a ks of 5.8 +/- 1.3 microM. Adrenaline caused a rise of 380 +/- 22 nM in Cai2+ with a ks of 0.5 +/- 0.2 microM. Amitriptyline and atropine were found to inhibit the carbachol-induced rise in Cai2+ with dissociation constants (kI) of 105 and 1.25 nM, respectively, in the absence of agonist. The adrenergic-induced rise in Cai2+ was inhibited by amitriptyline with a kI of 45 nM. Amitriptyline was found to inhibit both receptor classes by a competitive or mixed type of inhibition. Similarly, atropine exerted the same type of inhibition on the acetylcholine receptor. Amitriptyline and atropine were found to be mutually exclusive for competing for substrate binding on the receptor. These findings are consistent with a common binding site for amitriptyline and atropine on the acetylcholine receptor, possibly in close proximity with, but different from the substrate binding site. The stimulation-induced cell shrinkage evoked by the loss of electrolytes and water from the acini was measured by a 90 degree light scattering signal. It was found that this method makes possible the detection of autonomic side-effects of antidepressants on acini suspended in protein-containing media.

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Naunyn Schmiedebergs Arch Pharmacol. 1990 Mar;341(3):240-5.
Effects of antidepressants on the intraventricular conduction and the incidence of arrhythmias induced by programmed ventricular stimulation in the dog heart after myocardial infarction.

Nishimoto M, Hashimoto H, Ozaki T, Nagashima S, Nakashima M.

Department of Pharmacology, Hamamatsu University School of Medicine, Japan.

The effects of mianserin, a tetracyclic antidepressant, and adinazolam, a new triazolobenzodiazepine which has antidepressant activity, on intraventricular conduction and the incidence of arrhythmias induced by programmed ventricular stimulation were studied in the dog heart after myocardial infarction and compared to the effects of amitriptyline, a standard tricyclic antidepressant. Amitriptyline at a dose of 1 mg/kg significantly slowed ventricular conduction in a frequency-dependent manner and at doses of 2 and 3 mg/kg significantly slowed ventricular conduction in infarcted ventricular myocardium. Amitriptyline also significantly slowed ventricular conduction in normal myocardium. Amitriptyline increased the incidence of ventricular arrhythmias induced by the programmed ventricular stimulation and prolonged the intraventricular delayed conduction resulting in re-entrant ventricular arrhythmia. On the other hand, mianserin and adinazolam at doses of 1-3 mg/kg had no significant effects on intraventricular conduction in infarcted and normal myocardium and on the incidence of arrhythmias induced by programmed ventricular stimulation. From these results, we can expect that mianserin and adinazolam may have a much lower cardiac toxicity than amitriptyline.

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Biochem Pharmacol. 1990 Jun 15;39(12):1951-8.
Formation of cytotoxic metabolites from phenytoin, imipramine, desipramine, amitriptyline and mianserin by mouse and human hepatic microsomes.

Riley RJ, Roberts P, Kitteringham NR, Park BK.

Department of Pharmacology and Therapeutics, University of Liverpool, U.K.

The effects of enzyme induction on the generation of cytotoxic metabolites from phenytoin, mianserin, imipramine, desipramine and amitriptyline by mouse liver microsomes has been investigated and then compared with the bioactivation mediated by human hepatic microsomes. Cytotoxicity was assessed by co-incubation of drug and microsomes with human mononuclear leucocytes which served as target cells. Enzyme induction was assessed by measurement of hepatic cytochrome P-450 content, and determination of alkoxycoumarin O-dealkylase activity. None of the compounds investigated were metabolized to cytotoxic metabolites in the presence of control mouse microsomes. However, significant bioactivation could be observed for each drug when incubated with microsomes prepared from mice pretreated with either phenobarbitone (60 mg/kg) or beta-naphthoflavone (75 mg/kg). The rank order for metabolism-dependent cytotoxicity with phenobarbitone-induced mouse microsomes (expressed as % cell death) was phenytoin (14.6%) greater than desipramine (10.5%) greater than imipramine (7.5%) greater than mianserin (3.4%) greater than amitriptyline (3.1%). Expression of cytotoxicity with phenytoin required pre-exposure of the target cells to trichloropropane oxide, an opoxide hydrolase inhibitor. Only mianserin and desipramine were activated to cytotoxic metabolites by human liver microsomes. Analysis of stable metabolites revealed that mianserin underwent extensive (greater than 80%) metabolism by both control and induced mouse microsomes and that the principal metabolites, 8-hydroxymianserin, desmethylmianserin and mianserin N-oxide, were the same as those produced by human liver microsomes. These data suggest that mianserin is activated to a cytotoxic metabolite selectively by a constitutive form of human cytochrome P-450, whereas phenytoin, amitriptyline and imipramine are selectively activated by forms of mouse cytochrome P-450 which are induced by either phenobarbitone or beta-naphthoflavone.

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J Chromatogr. 1990 Jun 8;528(1):163-71.
Enantiomer analysis of E- and Z-10-hydroxy amitriptyline in human urine.

Nusser E, Nill K, Breyer-Pfaff U.

Department of Toxicology, University of Tubingen, F.R.G.

E- and Z-10-hydroxy amitriptyline (E- and Z-10-OH-AT) are racemic alcoholic metabolites of the antidepressant amitriptyline. Their enantiomers were separated by high-performance liquid chromatography as diastereomeric derivatives using R-(+)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride (Mosher's reagent). Although E-10-hydroxy amitriptyline excreted in patient urine in free form or as the O-glucuronide consisted primarily of the (-)-enantiomer, the N-glucuronide contained similar amounts of the two enantiomers. Z-10-OH-AT was analysed in one patient and an excess of the (+)-isomer was found in the unconjugated, total conjugated and N-glucuronidated metabolite. The specific optical rotation of (-)-E-10-OH-AT was determined.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2384550&dopt=Abstract Elavil amitriptyline