A characteristic of the rate response which is common to several compounds that stimulate the heart.

Chronotropic effects of increasing concentrations of histamine, epinephrine, norepinephrine (when catecholamine uptake is blocked by amitriptyline), theophylline and caffeine were observed using isolated atrial pairs. Linear transformations of the dose-response curves for all the agents revealed similar straight line relationships. Inverse plots of the data of the chronotropic response to these compounds produces a series of linear curves analogous to similar plots of enzymatic activity. It has been well documented that all these agents have the common property of increasing cyclic AMP levels. Therefore, the present results lend support to the concept that cyclic AMP may play a critical role at some step in the regulation of the heart rate.     

Blood noradrenaline and 5-HT levels in depressed women during amitriptyline or lithium treatment

Noradrenaline levels and platelet and free serotonin concentrations were studied in depressed women in-patients (n=78) before and during amitriptyline (n=41) or lithium treatment (n=37). Pronounced monthly differences in platelet serotonin level have been shown in these subjects before treatment. In all clinical subgroups (neurotic, involutional, manic-depressive patients) a significant fall in platelet serotonin level was observed with amitriptyline medication while an increase was noted with lithium. No significant correlations between serotonin concentrations and clinical outcome were found. Amitriptyline treatment also produced a decrease in peripheral noradrenaline concentration in all subgroups, while an increase was observed with lithium. Some correlations between noradrenaline level and degree of depression were noted in patients treated with amitriptyline or lithium. A more extended analysis of blood amine levels could supply meaningful information on the peripheral action of antidepressive drugs on noradrenaline and serotonin concentrations in depression.     

Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients

Despite their widespread use, there are few data concerning the effects of tricyclic antidepressants on EEG sleep in depression. The present study documented the effects of desipramine (DMI, n=17) and amitriptyline (AT, n=16) upon EEG sleep in hospitalized depressed patients as part of a double-blind protocol involving 28 days of active treatment. Compared to placebo, patients receiving DMI showed somewhat worsened sleep continuity, particularly after 1 week of administration when the dose was 150 mg/day. On the other hand, sleep architecture and REM measures showed a rapid suppression of REM sleep, and then partial tolerance for this effect was observed with continued administration of DMI for 3 weeks. DMI was a more potent suppressor of REM sleep, while AT was more sedative. Based on these differences in effects upon EEG sleep, a discriminant function was derived and resulted in a correct classification of 87.5% of AT cases and 76.5% of DMI cases. These results are discussed in terms of the differences in pharmacological profiels for uptake blockade and anticholinergic potency for these two compounds.     

Brain concentrations of tricyclic antidepressants: Single-dose kinetics and relationship to plasma concentrations in chronically dosed rats

A previously reported method of measuring tricyclic antidepressant concentrations in brain tissue and plasma was used to measure amitriptyline (AMI) in rats following drug administration using different routes, doses, and time intervals. In rats given AMI intraperitoneally (IP), brain concentrations increased during the first 30 min after drug adminstration and then declined. Brain concentrations increased linearly with changes in IP dosage and increased logarithmically with changes in intravenous dosage. No simple relationship existed between brain and plasma concentrations in acutely dosed rats. However, a linear relationship existed between plasma and brain concentrations in chronically treated animals (r=0.96, P<0.001). The brain: plasma drug ratios observed in chronically treated rats corresponded to ratios reported in man. Thus, conclusions drawn from these studies can probably be extrapolated to the clinical situation. Based on our data, the molar concentration of drug achieved on therapeutic doses is 10^-5–10^-6 M. This information may aid in understanding the clinical relevance of in vitro drug: receptor binding studies which are typically reported in molar concentrations.     

Nonspecific factors and side effect complaints. Factors affecting the incidence of drowsiness in drug and placebo treated anxious and depressed outpatients.

Discriminant function analyses were applied to data obtained from anxious psychiatric outpatients treated with either chlordiazepoxide (n = 353) or placebo (n = 259) and depressed outpatients treated with either amitriptyline (n = 310) or placebo (n = 328), who had participated in controlled drug trials of 4 weeks' duration, in an attempt to identify factors associated with complaints of drowsiness made by these patients. Although the magnitude of the relationships between individual predictors and drowsiness was small, several factors emerged which had consistent impact across treatment groups. Predictors of complaints of drowsiness attributed to active drugs arose primarily from demographic attributes probably reflective of life style, and from illness and treatment history. In contrast, predictors of drowsiness attributed to placebo were almost exclusively confined to indices of the severity of several aspects of presenting symptomatology. In particular, more frequent complaints of drug-induced drowsiness were found among better educated individuals with an illness of long duration. Complaints of placebo-induced drowsiness were more common among patients with more severe emotional (phobic-obsessive) symptomatology and more frequent headaches and among those individuals in whom hypochondriasis was less severe.     

Effects of chronic amitriptyline administration on saliva from the parotid and submandibular glands of the rat

The effect of prolonged treatment with amitriptyline on the secretory activity of rat salivary glands evoked by parasympathetic nerve stimulation and isoprenaline administration has been studied. Low doses of amitriptyline (10 mg/kg per day for 2 or 4 weeks), did not significantly affect salivary flow evoked by either parasympathetic nerve or isoprenaline stimulation. Higher doses of amitriptyline (50 mg/kg/day for 2 or 4 weeks) however, markedly decreased parasympathetic-evoked salivary secretion (flow and volume) from both parotid and submandibular glands, while isoprenaline-evoked secretions were unaffected. Sodium, potassium, and calcium concentrations of nerve-elicited or isoprenaline-evoked saliva were not significantly altered by amitriptyline treatment. Protein concentration and amylase activity of nerve-elicited parotid saliva were, however, greatly increased by chronic amitriptyline administration. Possible mechanisms for drug-induced increase in nerveelicited salivary protein concentration include changes in cholinergic receptor binding, release of neuropeptides and variations in phosphatidylinositol turnover, which need further study.     

汉族志愿者阿米替林代谢与异喹呱羟化代谢的关系

8名男性健康志愿者po阿米替林100 mg后,以阿米替林及其3种代谢物的血浓度曲线下面积(AUC₀^∞)计算阿米替林的脱甲基化代谢及羟基化代谢能力。结果提示个体间阿米替林及其3种代谢物的AUC差异很大。其中7名志愿者测定异喹呱羟化代谢表型,6例为异喹呱强代谢者,1例为弱代谢者。尿中异喹呱的羟化代谢率与阿米替林的羟基化代谢率、阿米替林和10-羟基阿米替林的AUC₀^∞呈显著相关。阿米替林总血浆清除率与异喹呱羟化代谢率呈弱相关。此结果表明阿米替林和异喹呱的羟化代谢可能由同一酶控制,阿米替林的羟基化代谢和脱甲基化代谢可能为两个独立的代谢途径。     

Cardiovascular effects of paroxetine

In a double-blind clinical study, electrocardiogram, blood pressure and systolic time intervals were measured in 40 depressive patients treated with either paroxetine (30 mg/day) or amitriptyline (150 mg/day) for 6 weeks. While amitriptyline significantly increased the heart rate, the QTc interval and the PEP/LVET ratio, paroxetine did not alter any of the cardiovascular parameters measured.