post.uv.es

AIMS: The therapeutic action of tricyclic agents may be accompanied by unwanted effects on the cardiovascular system. The evidence for the effects on vascular and nonvascular smooth muscle comes from animal studies. Whether these studies can be extrapolated to human vessels remains to be determined. Therefore, the present study was designed to investigate the influence of amitriptyline, nortriptyline and sertraline on the contractile responses of human isolated mesenteric arteries to electrical field stimulation, noradrenaline and potassium chloride. METHODS: Arterial segments (lumen diameter 0.8-1.2 mm) were obtained from portions of the human omentum during the course of 41 abdominal operations (22 men and 19 women), and rings 3 mm long were mounted in organ baths for isometric recording of tension. In some artery rings the endothelium was removed mechanically. RESULTS: In precontracted artery rings amitriptyline, nortriptyline and sertraline (3x10(-7)-10(-4) m ) produced concentration-dependent relaxation that was independent of the presence or absence of vascular endothelium. Incubation with indomethacin (3x10(-6) m ) reduced the pD2 values thus indicating the participation of dilating prostanoid substances in this response. Amitriptyline and nortriptyline inhibited both the neurogenic-and noradrenaline-induced contractions. In contrast, only the highest concentration of sertraline reduced the adrenergic responses. Amitriptyline, nortriptyline and sertraline inhibited contractions elicited by KCl and produced rightward shifts of the concentration-response curve to CaCl2 following incubation in calcium-free solution. CONCLUSIONS: These results indicate that amitriptyline and nortriptyline could act as adrenoceptor antagonists and direct inhibitors of smooth muscle contraction of human mesenteric arteries, whereas sertraline might principally exert its action only as direct inhibitor of smooth muscle contraction. This relaxant mechanism involves an interference with the entry of calcium.

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Toxicology. 1999 Aug 13;136(1):1-13.
Amitriptyline-induced loss of tight junction integrity in a human endothelial--smooth muscle cell bi-layer model.

Dahlin KL, Bohlin K, Strindlund J, Ryrfeldt A, Cotgreave IA.

Division of Inhalation Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Tricyclic antidepressants can, when taken in overdose, cause serious pulmonary failure such as the adult respiratory distress syndrome (ARDS). In this study we have examined the effects of some tricyclic antidepressants (amitriptyline, imipramine, nortriptyline and desipramine) on the viability and morphology of human endothelial and smooth muscle cells derived from umbilical cord. Effects of amitriptyline on endothelial cell fluidity, as well as permeability changes to an endothelial-smooth muscle cell bi-layer, were also studied. The tricyclic antidepressants induced acute, sub-lethal toxicity in both cell types above 100 microM as assessed by the MTT reduction assay. Morphological changes were also observed at these concentrations. Such changes were, however, absent at 33 microM and below. Amitriptyline did, however, cause a concentration-dependent fall in the electrical resistance of an endothelial-smooth muscle cell bi-layer, with significant effects already evident at 33 microM. All of these observed effects were fairly rapid and appeared within 5-15 min of exposure. The rapidity of these permeabilisation effects suggests potential membrane perturbations, since tricyclic antidepressants are lipophilic molecules with affinity for cell membranes. However, fluorescence anisotropy measurements showed no significant difference in membrane fluidity between amitriptyline-treated and control endothelial cells. Collectively, these data point to specific mechanisms of action of amitriptyline, and probably also the other tricyclic antidepressants studied, on endothelial permeability, which is a hallmark of ARDS. The data suggest that increased endothelial permeability could be due to impaired tight junction function.

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mail.wsu.edu

A retrospective intent-to-treat analysis (N = 1,339) was conducted to discern the natural course of antidepressant use and direct health service expenditures for the treatment of single-episode depression (DSM-IV code 296.20) among patients initiating antidepressant pharmacotherapy with either a tricyclic antidepressant (TCA) (amitriptyline, N = 237) or a selective serotonin reuptake inhibitor (SSRI) (citalopram, N = 71; fluoxetine, N = 411; paroxetine, N = 334; or sertraline, N = 286). Data were derived from the computer archive of a network-model health maintenance organization for the period of January 1, 1996, through April 30, 1999. Comparisons at the end of the 6-month post-period (180 days) were undertaken between cohorts initiating antidepressant pharmacotherapy with citalopram and each SSRI or TCA. Consistent with the intent-to-treat design, all accrued health service expenditures were assigned to the pharmacotherapeutic option initially prescribed. Multivariate models were adjusted for patient's age, gender, number of concomitant disease state processes, use of health services in the 6-month time frame (180 days) before initiating antidepressant pharmacotherapy, specialty of physician recording a diagnosis of single-episode depression, and the presence or absence of a previous diagnosis of single-episode depression and receipt of antidepressant pharmacotherapy. Patients initiating antidepressant pharmacotherapy with citalopram were far more likely to (1) have been diagnosed by a psychiatrist (37%; p < or = 0.05); (2) continue with the original pharmacotherapeutic option (79%) compared with patients originally prescribed amitriptyline (51%; chi2 = 17.29, df = 1, p < or = 0.05) or sertraline (65%; chi2 = 36.91, df = 1, p < or = 0.05); no significant difference was found compared with patients initiating antidepressant pharmacotherapy with paroxetine (72%; p = not significant [NS]) or fluoxetine (83%; p = NS); (3) obtain 90 days or more of antidepressant pharmacotherapy (86%) compared with those prescribed amitriptyline (69%; chi2 = 8.09, df = 1, p < or = 0.05); no significant difference was found compared with sertraline (77%), paroxetine (81%), or fluoxetine (84%); and (4) obtain 6 months (180 days) of antidepressant pharmacotherapy (68%) compared with those prescribed amitriptyline (39%; chi2 = 18.26, df = 1, p < or = 0.05) or sertraline (51%; chi2 = 6.02, df = 1, p < or = 0.05); no significant difference was found compared with paroxetine (56%) or fluoxetine (59%). Receipt of amitriptyline or sertraline as initial medication was associated with a per capita increase (p < or = 0.05) in health service utilization (17% and 9%, respectively) relative to citalopram. No significant difference (p > 0.05) in health service utilization was discerned between citalopram and either fluoxetine or paroxetine. Multivariate models adjusted for nonrandom assignment to the initial pharmacotherapeutic option confirmed these findings. Further research over a longer time course is warranted.

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Br J Pharmacol. 1999 Sep;128(2):479-85.
Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline.

Teschemacher AG, Seward EP, Hancox JC, Witchel HJ.

Department of Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD.

1 Tricyclic antidepressants (TCAs) are associated with cardiovascular side effects including prolongation of the QT interval of the ECG. In this report we studied the effects of two TCAs (imipramine and amitriptyline) on ionic current mediated by cloned HERG potassium channels. 2 Voltage clamp measurements of HERG currents were made from CHO cells transiently transfected with HERG cDNA. HERG-encoded potassium channels were inhibited in a reversible manner by both imipramine and amitriptyline. HERG tail currents (IHERG) following test pulses to +20 mV were inhibited by imipramine with an IC50 of 3.4+/-0.4 microM (mean+/-s.e.mean) and a Hill coefficient of 1.17+/-0.03 (n = 5). 3 microM amitriptyline inhibited IHERG by 34+/-6% (n = 3). The inhibition showed only weak voltage dependence. 3 Using an 'envelope of tails' comprised of pulses to +20 mV of varying durations, the tau of activation was found to be 155+/-30 ms for control and 132+/-26 ms for 3 microM imipramine (n = 5). Once maximal channel activation was achieved after 320 ms (as demonstrated by maximal tail currents), further prolongation of depolarization did not increase imipramine-mediated HERG channel inhibition. 4 Taking current measurements every second during a 10 s depolarizing pulse from -80 mV to 0 mV, block was observed during the first pulse in the presence of imipramine and the level of IHERG block was similar throughout the pulse (n=5). 5 A three pulse protocol (two depolarizing pulses to +20 mV separated by 20 ms at -80 mV) revealed that imipramine did not significantly alter the kinetics of IHERG inactivation. The tau of inactivation was 8+/-2 ms and 5.6+/-0.4 ms (n = 5) in the absence and presence of 3 microM imipramine, respectively, and currents inactivated to a similar extent. 6 Our data are consistent with TCAs causing components of block of the HERG channel in both the closed and open states. Any component of open channel block occurs rapidly upon depolarization. Inhibition of IHERG by the prototype TCAs imipramine and amitriptyline may suggest a mechanism for QT prolongation associated with risks of arrhythmia and sudden death that accompany high concentrations of TCAs following overdose.

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Eur J Drug Metab Pharmacokinet. 1999 Apr-Jun;24(2):163-8.
Comparison of two approaches to amitriptyline dose individualisation.

Jankovic SM, Timotijevic I, Mihajlovic GS, Dukic-Dejanovic S.

Clinical Hospital Center, Kragujevac, Serbia, Yugoslavia.

Individualisation of an amitriptyline dose regimen offers substantial advantages over non-individualised treatment. In our study, we have compared both clinical effects, adverse effects and plasma steady-state concentrations of amitriptyline in 15 patients with major depressive disorder divided in three groups; (i) patients in group A were taking non-individualised doses of amitriptyline; (ii) patients in group B were taking doses of amitriptyline individualised by modified Bayesian method; and (3) patients in group C were taking doses of amitriptyline individualised by the multiple point method. The treatment course was 8 weeks long, in the setting of a psychiatric clinic. The patients in group A were taking significantly higher doses throughout the treatment course; the initial doses for the patients in group B were higher than doses for the patients in group C, but after corrections based on measured steady-state plasma concentrations they became similar. While Hamilton score descended uniformly in all three groups, both adverse effects and steady-state plasma concentrations of amitriptyline were higher in non-individualised group during the whole treatment course. The results of our study suggest that the multiple points method is the most precise, but tedious and not practical. The modified Bayesian method with correction based on first measured plasma steady-state concentration of amitriptyline offers similar therapeutic outcome and adverse effects score combined with low cost and being easy-to-use.

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Arthritis Rheum. 1999 Dec;42(12):2561-8.
Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures.

Yaron I, Shirazi I, Judovich R, Levartovsky D, Caspi D, Yaron M.

Ichilov Hospital, Tel Aviv University, Israel.

OBJECTIVE: To evaluate the effects of fluoxetine and amitriptyline on nitric oxide (NO), prostaglandin E2 (PGE2), and hyaluronic acid (HA) production in human synovial cells and synovial tissue cultures. METHODS: Human synovial cells, synovial tissue, and cartilage were cultured in the presence or absence of cytokines, lipopolysaccharides (LPS), fluoxetine, or amitriptyline. Production of NO, PGE2, and HA was determined in culture media. Sulfated glycosaminoglycan (S-GAG) synthesis was evaluated in cartilage by 35S incorporation. RESULTS: Fluoxetine (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) inhibited NO release by 56%, 62%, and 71%, respectively, in the media of synovial cells stimulated by interleukin-1alpha (IL-1alpha; 1 ng/ml) plus tumor necrosis factor alpha (TNFalpha; 30 ng/ml). Amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) caused a 16%, 27.3%, and 51.4% inhibition of NO release. Fluoxetine and amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) significantly (P<0.05) inhibited PGE2 release in the media of human synovial cells in the presence of IL-1alpha plus TNFalpha, in a dose-dependent manner (up to 88% inhibition). Fluoxetine (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) and amitriptyline (1 microg/ml and 3 microg/ml) significantly (P<0.05) inhibited PGE2 release in the media of human synovial tissue in the presence of LPS. Fluoxetine and amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) also significantly (P<0.05) inhibited HA production by human synovial cells in the presence of IL-1beta plus TNFalpha. Fluoxetine and amitriptyline (1 microg/ml) partially reversed IL-1beta-induced inhibition of 35S-GAG synthesis by human cartilage cultures (P<0.05). Neither fluoxetine nor amitriptyline had a toxic effect on cells in the concentrations used. CONCLUSION: Inhibition of NO and PGE2 production by connective tissue cells is a mechanism by which some antidepressant medications may affect pain, articular inflammation, and joint damage.

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J Pharmacol Exp Ther. 2000 Mar;292(3):1015-23.
Block of human heart hH1 sodium channels by amitriptyline.

Nau C, Seaver M, Wang SY, Wang GK.

Department of Anesthesia, Harvard Medical School and Brigham & Women's Hospital, Boston, Massachusetts, USA.

Amitriptyline is a tricyclic antidepressant used to treat major depression and various neuropathic pain syndromes. This drug also causes cardiac toxicity in patients with overdose. We characterized the tonic and use-dependent amitriptyline block of human cardiac (hH1) Na(+) channels expressed in human embryonic kidney cells under voltage-clamp conditions. Our results show that, near the therapeutic plasma concentration of 1 microM, amitriptyline is an effective use-dependent blocker of hH1 Na(+) channels during repetitive pulses (approximately 55% block at 5 Hz). The tonic block for resting and for inactivated hH1 channels by amitriptyline (0.1-100 microM) yielded IC(50) values (50% inhibitory concentration) of 24.8 +/- 2.0 (n = 9) and 0.58 +/- 0.03 microM (n = 7), respectively. Substitution of phenylalanine with lysine at the hH1-F1760 position, a putative binding site for local anesthetics, eliminates the use-dependent block by amitriptyline at 1 microM. The time constants of recovery from the inactivated-state amitriptyline block in hH1 wild-type and hH1-F1760K mutant channels are 8.0 +/- 0. 5 (n = 6) and 0.45 +/- 0.07 s (n = 6), respectively. A substitution at either hH1-F1760K or hH1-Y1767K significantly increases the IC(50) values for resting and inactivated states of amitriptyline, but the increase is much more pronounced with the hH1-F1760K mutation. Because these two residues were proposed to form a part of the local anesthetic binding site, we conclude that amitriptyline and local anesthetics interact with a common binding site. Furthermore, at therapeutic concentrations, the ability of amitriptyline to act as a potent use-dependent blocker of Na(+) channels may, in part, explain its analgesic actions.

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