Polymeric membrane electrodes for selective determination of methiaden.

Polyvinyl chloride matrix membrane ion-selective electrodes for the determination of methiaden hydrochloride based on the ion-pair of methiaden cation with tetraphenylborate anion were prepared using bis(2-ethylhexyl)sebacate, (electrode A), 2-nitrophenyl octyl ether (electrode B). 2-nitrophenyl dodecyl ether (electrode C) and 1-isopropyl-4-nitrobenzene (electrode D) as the membrane solvents. The electrodes exhibit near-Nernstian response in different concentration ranges, depending on the used membrane solvents. The basic analytical parameters of these electrodes were evaluated. The potentiometric titration method was used to determine methiaden hydrochloride with good precision and accuracy.

Effect of exposure to dothiepin and northiaden in breast milk on child development.

BACKGROUND: This study looks at the outcome of infants exposed to dothiepin in breast milk in an attempt to guide clinicians on the risk-benefit ratio of breast-feeding when on antidepressants. METHOD: Thirty women, who had had HDRS scores > 15 within the first five years postpartum from the same women's hospital, were assessed with their children 3-5 years postpartum; half had breast-fed while on dothiepin (study group). Thirty-six non-depressed women were also assessed. Rating scales assessed depression, anxiety, self-esteem, personality, social support, marital relationship, child behaviour and temperament. The children were assessed by the McCarthy Scale. RESULTS: Comparisons of the two depressed groups showed no significant differences on any measures except marital conflict and child behaviour, which were the most disturbed in the study group (P < 0.001). Overall cognitive scores for the children did not differ between the groups. Higher levels of dothiepin and northiaden were associated with higher cognitive scores on subscales (P = 0.02). CONCLUSIONS: We are cautiously optimistic about the lack of any negative associations between cognitive development and exposure to dothiepin via breast milk.

Determination of dosulepin and its metabolite: application of high-performance liquid chromatography with electrochemical detection.

Dosulepin, 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo [b,e]thiepin hydrochloride, is a thio analogue of amitriptyline and is used for the treatment of anxiety and affective disorders. The present study developed a simple and sensitive procedure for the determination of this compound and its metabolite, northiaden, by a combination of high-performance liquid chromatography with electrochemical detection. Hydrodynamic voltammograms demonstrated an optimal applied potential at 1300 mV for both dosulepin and northiaden. A mobile phase consisting of 0.1 M acetate buffer-acetonitrile-perchloric acid-trichloroacetic acid (50:50:2:1.5) provided the best separation of the drugs. The extraction procedure, which used a heptane-isoamyl alcohol (99:1) mixture, was successfully applied with a recovery of over 90%. A preliminary pharmacokinetic study was performed by the proposed method.

Urinary excretion of conjugates of dothiepin and northiaden (mono-N-demethyl-dothiepin) after an oral dose of dothiepin to humans.

Only small amounts of unconjugated dothiepin (unchanged drug) and northiaden were excreted in urine over a 72 hr period. More than 10% of the dose was excreted as conjugated dothiepin and less than 0.8% of the dose as conjugated northiaden. Conjugated dothiepin was thus found to be an important metabolite of dothiepin. Conjugated dothiepin and northiaden were hydrolyzed with beta-glucuronidase, and their hydrolysis inhibited with 1,4 saccharolactone. Conjugated dothiepin and northiaden were found to be a quaternary ammonium-linked glucuronide and a tertiary N-glucuronide, respectively.

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.

Severe dothiepin intoxication--a report of two cases.

Two patients with severe dothiepin intoxication are described. The management of these cases is discussed and we draw attention to the prolonged elimination half-life of dothiepin and its metabolites, and the implication for treatment.

[The relationship of antihistaminics to cadmium necrosis in rat testes]. / Vztah antihistaminik ke kadmiové nekróze krysích varlat.

Selective necrosis of rat testicles is known to be produced by cadmium in subtoxic doses due to impairment of vessel structures. Classical antihistaminics in the same time in order to exclude that the lesion might have been produced by local release of histamine. Antihistaminics did not prevent necrosis. Instead, Clemastine stressed an interstitial testicular haemorrhage a bit. Methyldosulepine administered with calcium could decrease the vascular permeability because haemorrhage was almost lacking. The finding supports an idea of possible interaction between calcium and cadmium ions.

Assessment of the antidepressant activity of dothiepin and its metabolites by preclinical tests.

The affinities of dothiepin and its principal metabolites northiaden, dothiepin sulphoxide and northiaden sulphoxide for [3H]imipramine binding sites in the rat cortical homogenates, and for [3H]spiperone and [3H]serotonin receptor sites in preparations from the rat frontal cortex and hippocampus were studied. As inhibitors of [3H]imipramine binding, the strengths of the drugs are, in terms of their IC50 (concentration corresponding to 50% inhibition): dothiepin 2.8 X 10(-6) M, northiaden 5.0 X 10(-6) M, northiaden sulphoxide 4.0 X 10(-5) M and dothiepin sulphoxide 3.2 X 10(-5) M. The potencies of the drugs in inhibiting serotonergic binding followed a similar trend. Using frontal cortical tissue suspensions and [3H]spiperone, the IC50 values were determined to be: dothiepin 4.2 X 10(-6) M, northiaden 5.0 X 10(-6) M, northiaden sulphoxide 1.6 X 10(-4) M and dothiepin sulphoxide 1.6 X 10(-4) M; whereas in hippocampal suspensions and using [3H]serotonin, the IC50 values were 2.5 X 10(-6) M, northiaden 4.0 X 10(-5) M, dothiepin sulphoxide 2.5 X 10(-4) M and northiaden sulphoxide greater than 10(-3) M. The influence of the drugs on the uptake of [14C]serotonin into human platelets was also investigated. All had an inhibitory effect upon the uptake, the order of potency being dothiepin greater than northiaden greater than northiaden sulphoxide greater than dothiepin sulphoxide. Plots of 1/v versus 1/s showed that the inhibition was competitive for all four compounds.

Blood and plasma concentrations of dothiepin and its major metabolites and clinical response.

Ten patients suffering from primary depressive illness were treated with 150 mg/d of dothiepin for 4 weeks. Blood and plasma concentrations of dothiepin and two metabolites, dothiepin S-oxide and northiaden were measured by gas chromatography-mass spectrometry. Severity of depression was assessed using the Hamilton Depression Rating Scale. No significant correlation was found between amelioration score or percentage change and either blood or plasma concentrations of dothiepin, its metabolites or total drug and metabolite concentrations at week 4.

Simultaneous measurement of dothiepin and its major metabolites in plasma and whole blood by gas chromatography-mass fragmentography.

A method for the simultaneous measurement of dothiepin and two of its major metabolites, northiaden and dothiepin S-oxide in both plasma and whole blood is described. The method involves the use of gas chromatography-mass fragmentography. It is selective, sensitive (1 microgram/1) and reproducible. It has been used to analyse both plasma and blood samples following single oral doses of 75 mg dothiepin in seven volunteers.