Dothiepin

295.44

295.44

204-031-2

DTXSID2022961

N06AA16|N - Nervous system

28.54000

4.34

Pale yellow low melting solid

1.1022 (rough estimate)

55-57 °C

171-172 °C

214.4±28.4 °C

1.5300 (estimate)

In water, 1.5 mg/L @ 25 °C /Estimated/

Refrigerator

4.3X10-7 mm Hg @ 25 °C /Estimated/

LD50 oral in rat: 450mg/kg

Henry's Law constant = 1.4X10-9 atm-cu m/mol @ 25 °C /Estimated/

167.3 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

Hydroxyl radical reaction rate constant = 1.9X10-10 cu cm/molec-sec @ 25 °C /Estimated/

III

6.1(b)

3249

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P263, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501|Aggregated GHS information provided by 38 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Seizures or arrhythmias may be precipitated /SRP: by flumazenil/ in patients with a serious cyclic antidepressant overdose. /Flumazenil/

Death has followed ingestion of 50 25 mg capsules of dothiepin (total dose, 1250 mg).

Dothiepin and its metabolites have been detected in breast milk. The mean total daily infant exposure amounts to about 4.4% of the maternal dothiepin dosage.

The plasma dothiepin level was 4.5 ug/mL, with the northiaden metabolite at 1.28 ug/mL /in a 36- year old woman /who/ ingested 2 to 3 g of dothiepin.|Blood concentrations of dothiepin were measured in comparison in five of the volunteers. The mean blood/plasma ratio was 0.7 (0.6-0.8) /after seven healthy volunteers received a single oral dose of 75 mg dothiepin./

Dothiepin is a tricyclic antidepressant that is structurally related to amitriptyline.|EXPTL Therapy: The effectiveness of dothiepin (a tricyclic anti-depressant) ... given orally at night was compared with placebo for 4 weeks in alleviating pain in 60 patients with classical or definite active rheumatoid arthritis. Patients were classified as either 'depressed' or 'not depressed'. The week before, during and 2 weeks after the study, 600 mg ibuprofen was given orally three times daily to all patients. Compared with placebo, dothiepin produced a significant reduction in daytime pain by the end of the treatment period. The Hamilton rating scale in 'depressed' patients was significantly improved in patients given dothiepin. The Cassano-Castrogiovanni self-evaluation rating scale in both 'depressed' and 'not depressed' patients showed a tendency (not significant) to be improved following dothiepin treatment compared with placebo. These results suggest that patients with rheumatoid arthritis may experience an increase in pain symptoms due to an alteration of mood. Therapy with tricyclic anti-depressants, such as dothiepin, therefore, may determine an improvement of pain indexes besides having an anti-depressant effect.

A case of inappropriate ADH syndrome associated with dothiepin therapy, initially given at a dose of 75 mg then increased to 150 mg/day, is reported in a 39-yr-old depressed man with pancytopenia and portal hypertension. The patient became drowsy, disoriented and confused, and had persistent hyponatremia and raised arginine-vasopressin levels. Dothiepin was stopped and the patient was treated with fluid restriction and subsequently, demeclocycline. Serum sodium and osmolality returned to normal in 4 days and arginine vasopressin concentrations returned to normal.|To determine whether antidepressants are a risk factor for ischemic heart disease and to compare the risk for different subgroups of antidepressants and individual antidepressants. Case-control study. Nine general practices recruited from the Trent Focus Collaborative Research Network. 933 men and women with ischemic heart disease matched by age, sex, and practice to 5516 controls. Adjusted odds ratio for ischemic heart disease calculated by logistic regression. Odds ratios for ischemic heart disease were significantly raised for patients who had ever received a prescription for tricyclic antidepressants even after diabetes, hypertension, smoking, body mass index, and use of selective serotonin reuptake inhibitors had been adjusted for (1.56; 95% confidence interval 1.18 to 2.05). Patients who had ever taken dosulepin (dothiepin) had a significantly raised odds ratio for ischemic heart disease after adjustment for confounding factors and use of other antidepressants (1.67, 1.17 to 2.36). ... Increasing maximum doses of dosulepin were associated with increasing odds ratios for ischemic heart disease. Similarly, there was a significant positive trend associated with increasing numbers of prescriptions of dosulepin (adjusted odds ratio 1.52 for 1 prescription, 1.39 for 2-3, and 1.96 for >/=4, P<0.002). There is good evidence for an association between dosulepin and subsequent ischemic heart disease and for a dose-response relation.

Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin. (See all compounds classified as Adrenergic Uptake Inhibitors.)|Substances that contain a fused three-ring moiety and are used in the treatment of depression. These drugs block the uptake of norepinephrine and serotonin into axon terminals and may block some subtypes of serotonin, adrenergic, and histamine receptors. However the mechanism of their antidepressant effects is not clear because the therapeutic effects usually take weeks to develop and may reflect compensatory changes in the central nervous system. (See all compounds classified as Antidepressive Agents, Tricyclic.)

Dothiepin and its metabolites have been detected in breast milk. The mean total daily infant exposure amounts to about 4.4% of the maternal dothiepin dosage.|Dothiepin is readily absorbed in the gastrointestinal tract.|The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75 mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (+/-SD) peak plasma concentrations of dothiepin were 49 +/- 27 ug/L at 3 +/- 1.2hr. Mean (+/-SD) estimates of other parameters were as follows: absorption half-life 1.1 +/- 1.1hr; distribution half-life 2.2 +/- 0.8 hr; elimination half-life 25 +/- 7hr; apparent volume of distribution 70 +/- 62 L/kg; and oral clearance 2.1 +/- 1.6 L/kg/hr. The mean (+/-SD) peak plasma concentration of dothiepin S-oxide was 125 +/- 43 ug/L at 3.5 +/- 1.3hr with an elimination half-life of 22 +/- 12 hr. The mean peak plasma concentration of northiaden was 6 +/- 3 ug/L at 4.5 +/- 1.1hr, with an elimination half-life of 31 +/- 12 hr. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers. When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin. The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained following 4 weeks' treatment with dothiepin 150 mg /at night/.|Twenty-seven healthy men received three single oral doses of 50-, 100-, and 150-mg dothiepin hydrochloride capsules in a three-way randomized, crossover dose-proportionality study. Plasma concentration-time profiles of dothiepin (1) were described by both one- and two-compartment models with first-order absorption. The total intrinsic clearance of dothiepin decreased from 165.5 to 121.1 L/hr as the dose was increased from 50 to 150 mg, but there was no significant effect on the terminal half-life (approximately 20 hr). Plasma concentration-time profiles of the three major metabolites of dothiepin, the S-oxide derivative of dothiepin, N,N-dimethyl[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (2), the demethyl derivative, N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine (3) and the demethyl S-oxide derivative N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (4), were described by a one-compartment model with apparent first-order formation. The AUC infinity values of the S-oxide 2 and the demethyl S-oxide 4 increased proportionally with dose. The dose proportionality of the demethyl metabolite 3 may not be ascertained from the data in this study. The corresponding half-lives of the three metabolites, which are dose independent, were approximately 24, 28, and 40 hr, respectively. /Dothiepin Hydrochloride/|For more Absorption, Distribution and Excretion (Complete) data for DOTHIEPIN (6 total), please visit the HSDB record page.

Dothiepin-X-oxide is the major metabolite. Northiaden (desmethyl-dothiepin) is an N-demethylated derivative. Both metabolites have antidepressant activity.|Twenty-seven healthy men received three single oral doses of 50-, 100-, and 150-mg dothiepin hydrochloride capsules in a three-way randomized, crossover dose-proportionality study. ... Plasma concentration-time profiles of the three major metabolites of dothiepin, the S-oxide derivative of dothiepin, N,N-dimethyl[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (2), the demethyl derivative, N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine (3) and the demethyl S-oxide derivative N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (4), were described by a one-compartment model with apparent first-order formation. The AUC infinity values of the S-oxide 2 and the demethyl S-oxide 4 increased proportionally with dose. The dose proportionality of the demethyl metabolite 3 may not be ascertained from the data in this study. The corresponding half-lives of the three metabolites, which are dose independent, were approximately 24, 28, and 40 hr, respectively. /Dothiepin Hydrochloride/|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.|... Plasma and blood concentrations of northiaden and blood concentrations of dothiepin S-oxide, two metabolites of dothiepin, were measured. Dothiepin S-oxide was the major metabolic reaching a peak level of 81 (34-150) ug/l at 5 (4-6) hr. In comparison, northiaden reached a peak concentration of only 10 (3-21) ug/l at 5 (4-9) hr. The mean half-life of elimination of dothiepin S-oxide was 19 (13-35) hr while that for northiaden was 33 (22-60) hr.

The beta half-life (elimination) is about 20 hours.|The mean half-life of absorption of 1.2 hours. The distribution half-life is 2.6 hours.|Seven healthy volunteers received a single oral dose of 75 mg dothiepin. ... Mean estimates were as follows: absorption half life 1.2(0.07-3.0) hr, distribution half-life 2.6 (1.1-3.8) hr, elimination half-life 22 (14-40) hr ... . Plasma and blood concentrations of northiaden and blood concentrations of dothiepin S-oxide, two metabolites of dothiepin, were also measured. ... The mean half-life of elimination of dothiepin S-oxide was 19 (13-35) hr while that for northiaden was 33 (22-60) hr.

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.

The high degree of protein binding, together with the extensive volume of distribution, tends to preclude the potential usefulness of hemodialysis and hemoperfusion.|Following a dothiepin overdose leading to ventricular fibrillation and cardiac arrest, an adult was treated with intravenous sodium bicarbonate, dopamine, and lidocaine with hyperventilation. His condition remained unstable. One hour later, intravenous sodium chloride ... was given over 5 minutes. The blood pressure rose immediately; the QRS complexes narrowed and cardiac abnormalities became less frequent. Similar episodes of hypotension and cardiac abnormalities over the following days were reversed by rapid infusion of sodium chloride.|Treatment consists largely of gastric lavage and activated charcoal (either single or multiple doses). Although use of activated charcoal suggests a role in decreasing the half-life of dothiepin, other studies with TCAs show little or no such significant decrease in half-life.|Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|For more Antidote and Emergency Treatment (Complete) data for DOTHIEPIN (8 total), please visit the HSDB record page.

/CASE REPORTS/ To assess the clinical toxicity of dothiepin and other tricyclic antidepressants in overdose, 287 patients admitted for tricyclic poisoning were evaluated for seizures, tachyarrhythmias, sedation, and electrocardiographic changes. Results indicated that 75 of the patients had taken dothiepin. General seizures were more likely after dothiepin than after other tricyclic antidepressants (9/67 vs 5/220) as were arrhythmias (4/67 vs 3/220). In addition, the dothiepin group had ingested a larger dose, attributable to the larger average tablet strength.|/CASE REPORTS/ Ingestion of 1 to 4.5 g of dothiepin by a series of eight adults was followed by impaired consciousness (7/8), grand mal seizures (2/8), and tachycardia (7/8). All survived. An adult man ingested 1.5 g of dothiepin and became comatose, developing cardiac arrest within minutes of arrival at a hospital; he survived.|/CASE REPORTS/ A 41 year old man was admitted following an overdose of 40, 25 mg pills of dothiepin. He was drowsy but otherwise well. ECG on admission showed only minimal broadening of the QRS consistent with a tricyclic overdose, but symmetrical T wave repolarisation abnormalities appeared within nine hours mimicking an acute anteroseptal myocardial infarction. Serial cardiac enzyme estimates (creatine kinase and aspartate transaminase) did not confirm an ischemic event. Cross sectional echocardiography was normal with no evidence of focal hypokinesis. ECG changes persisted for six weeks. An exercise tolerance test following the Bruce protocol was normal. Coronary angiography was performed three months later after the patient complained of exertional chest pain. This was also normal. Such changes in ventricular repolarisation are rare but are a reminder of the electrical dangers inherent in tricyclic use. The changes in conduction were likely to be due either to the quinidine-like activity of dothiepin, or to an alteration in membrane permeability allowing differences in potassium concentrations between different areas of the myocardium, rather than to any ischemic damage to the myocardium.|/CASE REPORTS/ A 36 year old woman ingested 2 to 3 g of dothiepin, developed ventricular tachycardia, and was treated with gastric lavage and charcoal hemoperfusion, but she began to hallucinate 48 hours after ingestion. At 56 hours postoverdose, she became apneic with ventricular fibrillation. The plasma dothiepin level was 4.5 ug/mL, with the northiaden metabolite at 1.28 ug/mL. Patients with only mild sedation and normal limb-lead QRS width may still have complications.|/CASE REPORTS/ A case of inappropriate ADH syndrome associated with dothiepin therapy, initially given at a dose of 75 mg then increased to 150 mg/day, is reported in a 39-yr-old depressed man with pancytopenia and portal hypertension. The patient became drowsy, disoriented and confused, and had persistent hyponatremia and raised arginine-vasopressin levels. Dothiepin was stopped and the patient was treated with fluid restriction and subsequently, demeclocycline. Serum sodium and osmolality returned to normal in 4 days and arginine vasopressin concentrations returned to normal.

Dosulepin

Trade Names: ... Idom (Kanoldt, Germany), Prothiaden (Boots; Boots Dacour, France; Spofa, Czechoslovakia), Xerenal (Kwizda, Austria). /Hydrochloride/|Dothiepin hydrochloride is available in capsules of 25 mg and tablets of 75 mg.

Preparation: M. Protiva et al, US 3527766 (1962, 1970 both to SPOFA)

Pharmaceuticals