Decreased 5-HT2 but not 5-HT1 receptor binding in cortex of rat after chronic administration of dothiepin. Application of the Woolf plot to analysis of binding parameters.

Prolonged administration of the antidepressant drug, dothiepin hydrochloride (30 mg/kg orally twice daily for 24 days), resulted in a significant decrease in the population of serotonin2 (5-HT2) binding sites in the frontal cortex of rats whereas serotonin1 (5-HT1) binding sites remained unaltered. No significant differences in affinity constants for either ligand-binding site interaction were observed. Analyses of the binding parameters was performed using linear transformation methods of the specific binding isotherms according to Scatchard (1949) [Ann. N.Y. Acad. Sci. 51: 660-672] or Woolf (see Haldane, 1957: Nature 179: 832). The resulting parameter estimates generated in each analysis were compared. Although both methods demonstrated the decreased Bmax for 5-HT2 binding sites with no change in 5-HT1 sites after prolonged administration of dothiepin, Woolf analyses gave reliably better estimates of the binding parameters as judged by examination of the respective correlation coefficients for best fit linear regression lines.

The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds.

1. Debate exists as to the nature of antidepressant-induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressant-induced antinociception. 2. All the antidepressants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin were also effective antinociceptive agents in this nociceptive assay. 3. Opioid antagonists, naloxone (0.5 mg kg(-1), s.c.) and naltrindole (1 mg kg(-1), s.c.), shifted the dose-response relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)-oxaprotiline and paroxetine). In this context the naloxone dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose-response relationship to the right, by a factor of 2.62, whilst naltrindole had no effect upon morphine antinociception. Aspirin antinociception remained unaffected by both opioid antagonists. 4. The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg(-1) (s.c.). However, at higher doses, acetorphan produced a linear dose-response relationship against acetic acid-induced abdominal constriction. 5. When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant- or morphine-induced antinociception. However, acetorphan had no effect on aspirin antinociception. 6. Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant-induced antinociception is different from that of the non-steroidal anti-inflammatory drugs. 7. These data are consistent with the view that antidepressants may induce endogenous opioid peptide release, as shown by the acetorphan study. In this context, the ability of naltrindole to displace the antidepressant dose-response relationship to the right without affecting morphine antinociception, implicates the delta-opioid receptor and endogenous opioid peptides in antidepressant-induced antinociception.

Dothiepin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness.

Dothiepin is a tricyclic antidepressant that is structurally related to amitriptyline. It appears that the antidepressant activity of dothiepin is mediated through facilitation of noradrenergic neurotransmission by uptake inhibition and possibly also by enhancement of serotoninergic neurotransmission. The overall therapeutic efficacy of dothiepin is very similar to that of amitriptyline. In addition, dothiepin appears to be comparable to imipramine, doxepin, maprotiline, mianserin, fluoxetine, fluvoxamine and trazodone. Dry mouth is the most commonly reported side effect of therapeutic doses but the incidence of this and other anticholinergic side effects is less among patients treated with dothiepin than with amitriptyline. However, the sedative/anxiolytic activity of dothiepin is similar to that of amitriptyline. Dothiepin has not been associated with cardiotoxicity at therapeutic doses. Thus, many years of extensive clinical use have shown that dothiepin is now an established and effective antidepressant in both inpatients and outpatients with depressive symptoms of varying severity and coexisting anxiety. Its therapeutic equivalence to other tricyclics ensures its place as a treatment alternative in these disorders.

Comparison of the electrocardiographic effect of dothiepin and amitriptyline.

Electrocardiograms of 65 patients treated with dothiepin, a sulphur substituted tricyclic antidepressant, were compared to those of 57 patients receiving amitriptyline and 62 patients given placebo. Amitriptyline produced an average heart rate increase of 10 beats/minute as compared to 5 beats/minute for dothiepin (p less than .02). Amitriptyline also produced a significant prolongation of the corrected QT interval as compared to both dothiepin and placebo (p less than .01 and p less than .001, respectively). Dothiepin had no significant effect on any index of myocardial conduction (PR interval, corrected QT interval, and QRS duration) as compared to placebo.

Effects of dothiepin on nociceptive flexion reflex and diffuse noxious inhibitory controls in humans.

The analgesic activity of dothiepin (an antidepressant interacting with serotonin receptors) was studied (double-blind) in humans. A significant increase in nociceptive flexion reflex threshold and subjective pain threshold was observed after a 14-day dothiepin treatment. The effects of dothiepin on diffuse noxious inhibitory controls were also investigated using the cold-pressor test as conditioning stimuli. After dothiepin a reduced inhibition of nociceptive flexion reflex during the cold-pressor test and a significant facilitation immediately after the cold-pressor test were observed, while the subjective pain perception was normally inhibited. Our data suggest a serotonergic modulation of diffuse noxious inhibitory controls in humans.

Sibutramine induces potential-dependent exocytotic release but not carrier-mediated release of dopamine and 5-hydroxytryptamine.

In order to clarify the mechanism underlying the anti-obesity effects of sibutramine, we examined the effects of sibutramine on extracellular levels of dopamine and 5-hydroxytryptamine (5-HT) through microdialysis in the striatum in unanesthetized and freely moving rats. Sibutramine (5 mg/kg, oral administration (p.o.)) increased extracellular dopamine and 5-HT levels in rat striatum. The tricyclic antidepressant dosulepin (80 mg/kg, p.o. or 1 microM perfusion through the striatal probe) increased 5-HT levels only. Sibutramine-induced dopamine release was antagonized by perfusion of tetrodotoxin (1 microM) through the microdialysis probe in the striatum. However, sibutramine-induced dopamine release was not inhibited by prazosin (1 mg/kg, intraperitoneal injection (i.p.)), a suppressor of serotonergic activity in the striatum via blockade of alpha(1)-adrenoceptors, or perfusion with nomifensine (1 microM), an inhibitor of dopamine re-uptake. These results suggest that sibutramine increases dopamine levels in the striatum by exocytotic release and not by a carrier-mediated mechanism.

Effects of various tricyclic antidepressants on amine uptake.

A comparative study of the ability to block the amine pump was carried out on tricyclic antidepressants including dothiepin and northiaden in vivo. Dothiepin was found to prevent the 6-OHDA-induced depletion of cardiac noradrenaline but not the PCA-induced depletion of intracerebral serotonin. Northiaden, an active metabolite of dothiepin, also possessed the same ability with a greater potency than the parent drug. Neither compound affected the biosynthesis of catecholamines and indoleamine. However, neither dothiepin nor northiaden affected 5-HT uptake, as was also observed with imipramine and amitriptyline. These results suggest that the clinical efficacy of dothiepin may be due to inhibition of the amine pump, especially of the catecholamine uptake mechanism, which is qualitatively the same as for imipramine and amitriptyline.

Do alpha2-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds?

Antidepressants are analgesic in the absence or presence of depression. The underlying mechanisms probably involve a complex interplay between several neurotransmitter systems and neuroreceptors. Alpha-adrenoceptors play an important role in pain processing and alpha2-adrenoceptor agonists have been used in clinical pain management so we have investigated whether alpha-adrenoceptor sub-types mediate the antinociceptive activity of antidepressants. Thus, the abdominal constriction assay in mice was used to examine the antinociceptive responses of a diverse range of antidepressants following alpha1- or alpha2-adrenoceptor antagonism. The antidepressants or monoamine reuptake inhibitors included the serotonin selective reuptake inhibitor paroxetine, the serotonin-noradrenaline reuptake inhibitor sibutramine, the resolved (+)- and (-)-enantiomers of the noradrenaline reuptake inhibitor oxaprotiline, plus the tricyclics amitriptyline and dothiepin. All these compounds have been previously shown to be antinociceptive in this paradigm. The respective alpha1- and alpha2-adrenoceptor antagonists prazosin and RX821002 ([2-(2-methoxy-1,-4-benzodioxan-2-yl)-2-imidazoline]) did not produce antinociception though at 1.0 mg kg(-1); s.c., RX821002 but not prazosin blocked clonidine antinociception. The antinociceptive activity produced by sub-maximal doses of amitriptyline, dothiepin, sibutramine, paroxetine, (+)- and (-)-oxaprotiline were all blocked by RX821002 but not by prazosin. Additionally, both morphine and aspirin antinociception was resistant to alpha1- and alpha2-adrenoceptor antagonism. Thus, alpha2- rather than alpha1-adrenoceptors may play an integral role in antidepressant antinociception irrespective of the propensity for inhibiting reuptake of not only noradrenaline but also serotonin. It is probable, however, that other differing pharmacological properties of some antidepressants, such as opioid-like activity, may complicate any empirical correlation between monoamine uptake and analgesia.

Effects of dothiepin on delayed conduction produced by ventricular arrhythmia in the canine heart after myocardial infarction.

1. In order to clarify the arrhythmogenic effects of antidepressants, the authors examined the effects of dothiepin and amitriptyline on the ventricular activation time (VAT), effective refractory periods(ERP) and incidence of arrhythmias induced by programmed electrical stimulation(PES) in the dog heart in situ after myocardial infarction. 2. Myocardial infarction was produced by two-stage ligation of the left anterior descending coronary artery. Seven days after ligation, bipolar electrodes were sutured on the ventricular surface of the infarcted and normal zones to apply an electrical stimulation or record ventricular activation. An electrical stimulation with coupling interval 250 or 180 ms was applied on the ventricular surface, and AT was measured. 3. Dothiepin at doses of 1-3 mg/kg increased the heart rate. The VAT of coupling interval 180 ms in the infarcted zone was increased by the administration of 3 mg/kg dosulepin. Dothiepin at 3 mg/kg increased the incidence of ventricular arrhythmias induced by PES. 4. Amitriptyline, at doses of 1-3 mg/kg, significantly increased the heart rate. Amitriptyline increased the VAT dose- and frequency-dependently(2,3 mg/kg zone), and prolonged the ERP and QT c interval. Amitriptyline at doses of 1-3 mg/kg increased the incidence of ventricular arrhythmias by PES. 5. These results indicate that dothiepin, 1-3 mg/kg, has lesser effects on cardiac delayed conduction produced by ventricular arrhythmia than amitriptyline.

Demonstration of a Na+: Mg2+ exchange in human red cells by its sensitivity to tricyclic antidepressant drugs.

Iminodibenzyl-, iminostilbene-, dibenzocycloheptadiene-, dibenzooxepine- and dibenzothiepine-derivatives of tricyclic antidepressant drugs were able to inhibit Na+-stimulated Mg2+ efflux in human erythrocytes at concentrations of 10(-5) -10(-3) mol/l. Tricyclic antidepressant drugs belonging to other chemical groups, non-tricyclic antidepressant drugs and phenothiazines were less potent inhibitors (IC50 of 10(-4) mol/l or higher). Imipramine and dothiepine, the most potent compounds, inhibited the Mg2+ carrier with IC50 of 2.5 and 4 x 10(-5) mol/l respectively. These IC50 are of similar order of magnitude to those of some classical transport inhibitors (such as furosemide for the [Na+ K+, Cl-]-cotransport system). In addition, these concentrations of imipramine and dothiepine were free of: i) side effects on other erythrocyte Na+ and K+ transport pathways (with the exception of a slight inhibition of Ca2+-sensitive K+-channels and [Na+,K+,Cl-]- and [K+,Cl-]-cotransport systems) and ii) toxic effects on the membrane leak for divalent or monovalent cations. Therefore, we selected imipramine as an useful tool for investigating fluxes catalyzed by the Na+-stimulated Mg2+ carrier. Imipramine was tested on the initial rate of ouabain and bumetanide-resistant net Na+ influx in Na+-depleted, Mg2+-loaded erythrocytes. The compound was able to inhibit a Na+ influx of about 300-500 mumol (1.cells x h)-1 with an IC50 of about 3 x 10(-5) mol/l. This imipramine-sensitive Na+ influx was coupled with an imipramine-sensitive Mg2+ efflux in a stoichiometry of 3.03 +/- 0.34 (mean +/- SEM of 7 experiments).

Sleep and daytime sleepiness the next day following single night-time dose of fluvoxamine, dothiepin and placebo in normal volunteers.

To explore the effects of sedating and non-sedating antidepressants, we conducted a placebo-controlled, double-blind cross-over study in 12 normal subjects of the effects of a single night-time dose of fluvoxamine 100 mg, dothiepin 100 mg or placebo on night-time sleep recorded at home, and sleepiness and performance the following day. Night-time sleep was altered significantly by both drugs, with main effects on rapid eye movement (REM) sleep and sleep continuity. Dothiepin increased total sleep time, REM latency and stage 2 sleep and decreased arousals, wake after sleep onset and stage 1, whereas fluvoxamine decreased total sleep time and REM time and increased wake after sleep onset. Sleep latencies in daytime naps were significantly shorter for dothiepin and longer for fluvoxamine, showing that subjects were more sleepy when taking dothiepin. Electroencephalograms (EEG) performed during performance tasks failed to distinguish significantly between drugs. There were no significant differences between groups on our measures of tracking performance or reaction time; however, these tasks were designed primarily to provide a standard setting in which to monitor continuous EEG, and were unsuitable to detect sleepiness effects themselves. Saccadic eye movement velocity, acceleration and deceleration showed small non-significant changes after both drugs. Mood self ratings showed no significant differences among the groups. Subjective measures of night-time sleep reflected the objective measures of sleep continuity, and the items for difficulty and speed of wakening in the morning were significantly higher (i.e. more difficulty and slower) in the dothiepin group. The home-recorded sleep findings after fluvoxamine in this study were very similar to sleep laboratory studies with other antidepressant drugs, thus providing more validation of the home recording method.

Effects of 5 weeks of administration of fluoxetine and dothiepin in normal volunteers on sleep, daytime sedation, psychomotor performance and mood.

This was a placebo-controlled, double-blind randomized crossover study of long-term (5 weeks) administration of fluoxetine (20 mg/day) and dothiepin (75 mg/day for 1 week followed by 150 mg/day for 4 weeks) in 12 healthy male volunteers. Subjects were studied on day 10 and day 36 of treatment, with tests of nocturnal sleep, driving performance, continuous electroencephalogram (EEG), sleep during scheduled naps, computerized visual attention tasks, saccadic eye movement measurement and visual analogue ratings of mood. Both drugs had a marked suppressive effect on nocturnal rapid eye movement (REM) sleep; these effects were less at 36 days than at 10 days, and fluoxetine decreased and dothiepin increased REM in daytime naps. Sleep fragmentation after fluoxetine is similar to that reported in the literature. We found no sleep-promoting effects of dothiepin, in contrast to our previous single-dose study, and no subjective sleep effects of either drug. Subjects were less sleepy after both antidepressants than placebo at 5 weeks measured by sleep latencies and EEG. Saccadic eye movement measures were significantly faster after 5 weeks of fluoxetine than after 5 weeks of placebo. Reaction times to a peripheral stimulus during computerized tracking task were shorter after 10 days of dothiepin compared with placebo. Driving performance, visual attention and mood ratings showed no treatment effects. Subjective health reports during each 5 weeks of treatment were similar in number for the two drugs but showed a different profile of side-effects.

Absence of noxious effects of selected neuroleptics in dominant-lethal mutagenesis assay.

In a dominant-lethal assay in mice the following tricyclic neuroleptics were tested: prothiaden, imipramine, oxyprothepin decanoate and docloxythepin. No dominant-lethal effect was induced by these neuroleptics, even when administered at doses many times as great as clinical doses. The reduced percentages of pregnancies, in females who had copulated with males receiving docloxythepin, observed during and immediately after its administration, were directly connected with marked sedation induced in the males by this neuroleptic.

Effects of fluvoxamine and dothiepin on psychomotor abilities in healthy volunteers.

We gave 12 healthy male volunteers single doses of 50 mg fluvoxamine, 100 mg fluvoxamine, 75 mg dothiepin, and placebo in a double-blind crossover study. Subjects completed a test battery that was sensitive to the behaviourally toxic effects of psychoactive drugs prior to dosing, and then at 1, 2, 3, 4, and 6 h after dose. The test battery included tasks of choice reaction time, tracking, critical flicker fusion threshold, and memory scanning. Subjective feelings were assessed using the line analogue rating scales and the Milford-Epworth sleepiness scale. Daytime activity was recorded by means of wrist actigraphy. The results show that the positive internal control (dothiepin) had a sedative effect in that it impaired performance in the majority of the tests and also reduced daytime activity. Both doses of fluvoxamine remained relatively neutral throughout and did not impair psychomotor performance or cognitive ability in any of the tests. These results indicate that fluvoxamine may be a safe and efficacious antidepressant for outpatients who wish to carry on with the tasks of everyday life without being sedated.

The effects of antidepressant drugs on salivary flow and content of sodium and potassium ions in human parotid saliva.

Stimulated parotid saliva was collected, using the Carlson-Crittenden cup, from normal controls and patients on antidepressant drugs. The saliva from patients using amitriptyline, dothiepin (tricyclics), fluoxetine and paroxetine (selective serotonin re-uptake inhibitors; SSRI) was analysed for flow rate, [Na+] and [K+], and was compared with that from unmedicated, non-depressed volunteers for all variables. The tricyclic antidepressants produced a significant reduction in flow (amitriptyline, p < 0.01; dothiepin, p < 0.05), and consequent decrease in [Na+] and increase in [K+]. These effects were presumably due to muscarinic receptor blockade. The SSRIs produced no significant change in these variables. A prospective study of dothiepin in non-depressed patients confirmed that it decreases stimulated parotid flow. This finding also suggested that depression itself contributed little to the oral dryness observed in and reported by the depressed patients. The patients' subjective rating of oral dryness related well to a reduction in stimulated flow. This applied to those taking either tricyclics or SSRI, both showing a reduced flow rate relative to control (p < 0.001 and p < 0.05, respectively). This amounted to a 58% reduction in flow rate in the tricyclic group. The data suggest that measurement of stimulated parotid salivary flow is a reliable indicator of drug-induced oral dryness.

A comparison of the therapeutic and cardiovascular effects of a single nightly dose of Prothiaden (dothiepin, dosulepin) and Lentizol (sustained-release amitriptyline) in depressed elderly patients.

This was a single-blind 4-week parallel group comparative trial in fifty depressed patients. Twenty-five patients received 50 mg of Lentizol, a sustained-release form of amitriptyline, and twenty-five received 75 mg of Prothiaden. Both groups took their drugs as a single night-time dose. Patient response was measured on a symptom check-list which was completed by the doctor and a self-rating depression scale. Tolerance was assessed by recording volunteered and observed side-effects and also by taking the pulse, blood pressure and an electrocardiogram before treatment and after 2 and 4 weeks. A statistically better response was seen with Prothiaden at each follow-up assessment (1, 2 and 4 weeks) compared to Lentizol as measured by both the symptom check-list and the self-rating scale. Less side-effects was also seen with Prothiaden. Minor changes were seen in the ECG records of two patients on Prothiaden and three on Lentizol. These changes were not associated with any clinical change in the patients' cardiovascular state. No consistent changes of any clinical significance were seen in the pulse and blood pressure recordings.

Effect of dothiepin on nociceptive response in diabetic rats.

In alloxan-diabetic rats of 4 wk duration with blood glucose levels of about 300 mg/100 ml, the tail flick reaction time (TFRT) to thermal stimuli was significantly elevated (P less than 0.25), indicating hypoalgesia. Intraperitoneal dothiepin, injections of 25 mg & 50 mg/kg body weight per day did not significantly alter the TFRT, either in control or in diabetic rats, following either acute (one dose), or short term (once a day for five days) administration. It is concluded that at least in the dosage schedule used herein, dothiepin does not influence hypoalgesia of diabetic neuropathy.

[Dispersion of QT intervals--a myth or a diagnostic symptom?]. / Disperze QT intervalu. Mýtus nebo diagnostický ukazatel?

BACKGROUND: QT interval dispersion (QTd) is conventionally interpreted as a result of repolarization heterogeneity in ventricular myocardium. However, another concept of QTd origin has been discussed recently, suggesting that different projections of the repolarization vector into individual ECG leads could be responsible for the differences in QT interval duration. Moreover, the reproducibility could be influenced by factors both electrocardiographic (T wave amplitude, U wave) and extracardiac (noise, ECG measures). In the presented study we have followed the QTd in two groups of patients with proved changes of an electric heart field. METHODS AND RESULTS: Studied groups: 1. Control group, 2. Healthy pregnant women, 3. Patients treated with dosulepine. QT interval was measured from 80 unipolar chest leads used for body surface potential mapping. The QTd was significantly higher in both experimental groups in comparison with the control group (p < 0.001). Significant correlation was found between the QTd and dosulepine plasma level (p < 0.001). Also amplitude of the T wave loop was in both groups decreased and its width increased (both p < 0.001). CONCLUSIONS: If appropriate procedure of measurement is used, the QTd is significantly increased in many physiological and pathological states. Clinical relevancy of borderline increased values has to be interpreted very carefully.