Genotoxic evaluation for the tricyclic antidepressant drug,amitriptyline

Tryptizol^® [amitriptyline HCl (AT); El-Kahira Pharmacological and Chemical Co., Cairo, Egypt], a widely used antidepressant drug in Egypt, was evaluated for its genotoxicity. The evaluation was performed in somatic (bone marrow) and germ (spermatocytes) cells, as well as well as the sperm morphology (i.e., head and tail) and count of the resulting sperm. Three doses were tested (low, medium, and high); they were chosen according to the drug manufacturer. The low-dose group received orally 1?mg/kg body weight (b.w.) daily for a total period of 1 month; the medium-dose group received 1?mg/kg b.w. daily for 15 days and 2?mg/kg b.w. daily for another 15 days; and the high-dose group received 1?mg/kg b.w. daily for 10 days, then 2?mg/kg b.w. daily for another 10 days and, finally, 4?mg/kg b.w. daily for 10 more days. The results showed that AT treatment induced structural and numerical chromosome abnormalities in somatic cells (bone marrow) and germ cells (spermatocytes). Moreover, AT significantly reduced both the mitotic index and meiotic activity after the different treatments used. AT was found to increase significantly the incidence of sperm-cell head and tail abnormalities. The sperm-cell count was also significantly decreased with the 3 doses tested. In general, results of chromosome abnormalities in both somatic and germ cells as well as sperm morphology and count showed that the effect of AT was dose dependent. The results of the current study showed that AT is a genotoxic agent for both somatic and germ cells and should be taken under special precautions and medical supervision.     

Comparison of the cardiovascular toxicity of three tricyclic antidepressant drugs: imipramine, amitriptyline, and doxepin.

Experiments were conducted on puppies to compare the cardiovascular toxicity of imipramine, amitriptyline, and doxepin. The drugs were infused at weekly intervals to produce arrhythmias and/or hypotension. Imipramine was less arrhythmogenic and caused less fall in blood pressure for a given dose than amitriptyline or doxepin.     

Circulatory effects in man of nortriptyline,a tricyclic antidepressant drug

Summary In 40 depressed patients treated with 25 or 50 mg nortriptyline (NT) t. i. d. for 3 weeks the following circulatory variables were observed prior to and during drug therapy: heart rate and blood pressure at rest (in supine and standing positions), working capacity, ECG at rest and during exercise on a bicycle ergometer. During administration of NT the heart rate increased significantly at rest in both supine and standing positions, but the orthostatic heart rate reaction remained unchanged. Diastolic blood pressure in the supine position rose slightly; in the standing position the pretreatment increase in diastolic pressure was abolished. The positive chronotropic effect did not correlate with the steady-state plasma level of NT. In one patient on NT a right bundle branch block appeared during the work test; in the remaining 39 patients the ECG records at rest and during exercise showed no adverse effects of NT.     

The assessment of potential drug interactions with a new tricyclic antidepressant drug

1 Methods for the investigation of possible interactions with tricyclic antidepressant drugs are described. These methods have been applied to a new compound, Ciba 34276-Ba, which has been shown to have antidepressant activity.

2 In five normal volunteers tested before and during treatment with Ciba 34276-Ba, no abnormalities of resting or post-exercise electrocardiographs occurred. A three-fold reduction in tyramine-responsiveness was seen in three normal subjects studied, but no potentiation of the noradrenaline pressor effect occurred. One of six patients given Ciba 34276-Ba whilst on long-term treatment with bethanidine showed loss of blood pressure control.

3 The metabolic clearance of antipyrine was unaltered in two subjects studied, showing no evidence of induction or inhibition of hepatic microsomal oxidizing enzymes by Ciba 34276-Ba.

     

Therapeutic tricyclic antidepressant drug monitoring in younger and older depressive patients

The present study shows the evaluation of clinical state and serum level of tricyclic antidepressants in thirty-eight depressive younger and elderly patients during 8-week observation. We observed no statistically significant differences, neither in psychometric scale scores nor in drug serum levels in both groups of patients.     

Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline

1. Amitriptyline has been known to induce QT prolongation and torsades de pointes which causes sudden death. We studied the effects of amitriptyline on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus oocytes and on the rapidly activating delayed rectifier K(+) current (I(Kr)) in rat atrial myocytes. 2. The amplitudes of steady-state currents and tail currents of HERG were decreased by amitriptyline dose-dependently. The decrease became more pronounced at more positive potential, suggesting that the block of HERG by amitriptyline is voltage dependent. IC(50) for amitriptyline block of HERG current was progressively decreased according to depolarization: IC(50) values at -30, -10, +10 and +30 mV were 23.0, 8.71, 5.96 and 4.66 microM, respectively. 3. Block of HERG by amitriptyline was use dependent: exhibiting a much faster block at higher activation frequency. Subsequent decrease in frequency after high activation frequency resulted in a partial relief of HERG blockade. 4. Steady-state block by amitriptyline was obtained while depolarization to +20 mV for 0.5 s was applied at 0.5 Hz: IC(50) was 3.26 microM in 2 mM [K(+)](o). It was increased to 4. 78 microM in 4 mM [K(+)](o), suggesting that the affinity of amitriptyline on HERG was decreased by external K(+). 5. In rat atrial myocytes bathed in 35 degrees C, 5 microM amitriptyline blocked I(Kr) by 55%. However, transient outward K(+) current (I(to)) was not significantly affected. 6. In summary, the data suggest that the block of HERG currents may contribute to arrhythmogenic side effects of amitriptyline.     

The effect of the tricyclic antidepressant drug,nortriptyline on left ventricular ejection fraction and left ventricular volumes

Eight patients with major depression but otherwise healthy underwent radionuclide cardiography before and during nortriptyline treatment. The second examination was performed when the nortriptyline plasma concentration was within the therapeutic range (60–150 g·l^–1). Heart rate, arterial blood pressure, left ventricular ejection fraction, left ventricular volumes, systolic pressure-volume ratio, and cardiac output were determined. Heart rate increased in mean by 13% (P<0.05). All other variables were unchanged. We conclude that nortriptyline in therapeutic doses produces no major adverse effect on left ventricular function. Routine radionuclide cardiography might be a suitable method to detect among those treated with tricyclic antidepressants the occasional susceptible patient. This may particularly apply to patients with known heart disease and to elderly patients.     

Behavioral effects of quinupramine, a new tricyclic antidepressant

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.     

The incidence of seizures during tricyclic antidepressant drug treatment in a brain-injured population

Tricyclic antidepressants (TCAs) have been associated with the occurrence of seizures both with overdoses and with therapeutic doses. Seizures with therapeutic doses of TCA have been reported in patients both with and without previous histories of seizures. The incidence of seizures possibly precipitated by TCAs was examined retrospectively in a population of 68 severely brain-injured patients, all of whom were at high risk for the development of seizures. Seizure histories, anticonvulsant use, comedication use, and other pertinent data were recorded before, during, and after TCA use. We conclude that 14 patients (19%) developed seizures largely caused by TCAs. Other possible contributing factors, clinical outcomes, and some recommendations are discussed.     

Ring flexibility within tricyclic antidepressant drugs

The internal flexibility of the central seven-membered ring of a series of tricyclic antidepressant drugs (TCAs), imipramine [1], amitriptyline [2], doxepin [3], and dothiepin [4], has been investigated by (1)H and (13)C nuclear magnetic (NMR) techniques. Two dynamic processes were examined: ring inversion and bridge flexing. (1)H NMR line-shape analysis was used to obtain ring inversion barriers for 2-4. These studies yielded energy barriers of 14.3, 16.7, and 15.7 +/- 0.6 kcal/mol for the hydrochloride salts of doxepin, dothiepin, and amitriptyline, respectively. The barriers for the corresponding free bases were lower by 0.6 kcal/mol on average. (13)C T(1) relaxation measurements were used to determine the degree of bridge flexing associated with the central seven-membered ring for all four compounds. By fitting the T(1) data to a two-state jump model, lifetimes and amplitudes of rapid bridge flexing motions were determined. The results show that imipramine has the fastest rate of bridge flexing, followed by amitriptyline, doxepin, and dothiepin. The pharmacological profiles of the TCAs are complex and they interact with many receptor sites, resulting in numerous side effects and a general lack of understanding of their precise mode of action in different anxiety-related disorders. They all have similar three-dimensional structures, which makes it difficult to rationalize their differing relative potency in different assays/clinical settings. However, the clear finding here that there are significantly different degrees of internal mobility suggests that molecular dynamics should be an additional factor considered when trying to understand the mode of action of this clinically important family of molecules.     

Clomipramine: an antiobsessional tricyclic antidepressant

The chemistry, pharmacology, pharmacokinetics, adverse effects, and dosage of clomipramine hydrochloride are described, and clinical studies of the use of clomipramine in treating obsessive-compulsive disorder (OCD), other psychiatric conditions, and chronic pain are reviewed. Clomipramine hydrochloride, a tricyclic antidepressant, is a potent inhibitor of serotonin reuptake and may affect dopaminergic neurotransmission, suppress rapid eye movement sleep, produce changes in electrocardiograms, and elevate plasma prolactin. The drug is well absorbed from the gastrointestinal tract and undergoes extensive first-pass metabolism. Peak plasma concentrations occur three to four hours after a 150-mg oral dose. The mean elimination half-life is 39 hours. Some 66% of a dose is excreted in the urine, the remainder being eliminated in the feces. In clinical trials, clomipramine was significantly more effective than placebo, clorgiline, amitriptyline, imipramine, and doxepin in ameliorating the symptoms of OCD. Initial effects are seen at four weeks; improvement may continue for up to 18 weeks. Clomipramine may also be effective in treating panic attacks, phobias, depression, and chronic pain. The most common adverse effects of clomipramine are anticholinergic; others include nausea, seizures, and sexual difficulties. Interactions between clomipramine and barbiturates, haloperidol, monoamine oxidase inhibitors, and cigarette smoking have been documented. The usual initial adult dosage is 25-50 mg/day, titrated gradually to 250 mg/day if necessary. Clomipramine hydrochloride is a welcome new agent for the treatment of obsessive-compulsive disorder. Although its adverse-effect profile is like that of other tricyclic antidepressants, sexual dysfunction and seizures may be more frequent with this agent and limit its use.