Ethyl 2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Human case study published in peer reviewed literature, minor restrictions in design and/or reporting buth otherwise adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

Poisoning with tilidine and naloxone: toxicokinetic and clinical observations

Author:

Regenthal R.

Year:

1998

Bibliographic source:

Hum Exp Toxicol. 1998 Nov;17(11):593-7.

Materials and methods

Study type:

poisoning incident

Endpoint addressed:

basic toxicokinetics

acute toxicity: oral

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Case report of a women ingesting fixed combination of tilidine (about 6.94 g) and naloxone (about 555 mg). Clinical signs were reported and toxicokinetics determined.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl trans-(±)-2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate hydrochloride

EC Number:

248-226-0

EC Name:

Ethyl trans-(±)-2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate hydrochloride

Cas Number:

27107-79-5

IUPAC Name:

27107-79-5

Details on test material:

- Name of test material (as cited in study report): tilidine

Method

Type of population:

general

Subjects:

- Number of subjects exposed: 1
- Sex: female
- Age: 28 years
- Weight: 55 kg

Ethical approval:

not applicable

Route of exposure:

oral

Reason of exposure:

intentional

Exposure assessment:

measured

Details on exposure:

Attempted suicide by ingestion of a fixed combination of tilidine (about 6.94 g) and naloxone (about 555 mg).

Examinations:

- Pulse, heart rate and electrocardiogram.
- For toxicological analysis samples of urine, serum and first fraction of lavage were obtained 3 h after ingestion.
- Additional samples of serum were collected 24, 48, 72 and 96 h after ingestion.

Medical treatment:

1) Diazepam 10 mg intravenously.
2) intubation and mechanically ventilation
3) intravenous application of 1 mg epinephrine; infusion of 1000 mL of Ringer's solution and dopamine (20 µg/kg/min) over a time of 1 h.
4) Because of suspicion of poisoning from Valoron°N solution initially 0.8 mg naloxon (Narcati°) was given intravenous
5) Patiënt was atmitted to an ICU
6) Gastric lavage was performed 2 h after ingestion.
7) 30 g of activated charcoal and 15 g natrium sulfuricum were instilled.
8) Dopamine and norepiephrine had to be given for 4 after admission.
9) Forced artificial respiration (BIPAP, PEEP 1 cm H2O, respiration pressure 18 cm H2O, FIO2 0.6, Ve 10.2L, respiratory rate 14/min) was performed.
10) 33 hours after admission the patient was extubated.

Results and discussion

Clinical signs:

The patient was found comatose (grade 4) with cyanosis, insufficient spontaneous ventilation and centralisation. The patient revealed seizures, and was treated with 1).

Results of examinations:

- Pulse, heart rate: peripheral pulse not palpable, heart rate centrally 104/min.
- Electrocardiogram: sinus tachycardia
- Diagnosis of poisoning from Valoron°N was confirmed by the qualitative detection of tilidine, nortilidin, bisnortilidine and lanoxone in serum and the detection of tilidine, nortilidine and nalozine in urine about 3 h after ingestion. In addition tilitidne was detected in the first fraction of lavage.
- The highest serum concentrations of tilidine and its active metabolite nortilidine (found about 3h after ingestion) were about 38.1 and 18.8 mg/L, respectively. 96 h after ingestion the patient's serum concentration of tilidine was still 0.11 mg/L (within a therapeutic range of 0.05 - 0.12 mg/L). The elimination half life of tilidine was 23.9 h (coefficient of corrolation 0.94), whereas the approximated apparent distribution half life was about 3.8 h. The calculated AUC of tilidine was 508 mg.hour/L. Total serum clearance of tilidine was calculated to be 228 mL/min and the volume of distribution was 472 L or 7.61 L/kg. Approximated half life of nortilidine was 13.9 h.

Effectivity of medical treatment:

- Two minutes after treatment with 1) bradycardia and circulatory arrest was observed.
- Successful restoration of circulation was achieved with 2) & 3); Ten minutere after resuscitation systolic blood pressure was 75 mmHg
- No significant positive clinical effect with 4).

Outcome of incidence:

48 hours after admission increases of alaninaminotransferase (4.4 µkat/L) and aspartataminotransferase (14.1 µkat/L) were observed. Besides evidence of hepatotoxicity further clinical course was uneventful.

Applicant's summary and conclusion

Conclusions:

A case report on an attempted suicide by oral ingestion of a fixed combination of tilidine and naloxone. Serum concentrations and kinetics could be determined.

Executive summary:

One hour after attempted suicide by ingestion of a fixed combination of tilidine (about 6.94 g) and naloxone (about 555 mg) a 28-year-old woman weighing 55 kg was found comatose (grade 4) with cyanosis, insufficient spontaneous ventilation and centralisation. The patient wat treated with diazepam, intubated and received other medication. Serum concentrations of tilidine and metabolites were followed for 96 hours. The highest serum concentrations, measured by HPLC, of tilidine and its active metabolite nortilidine (found about 3h after ingestion) were about 38.1 and 18.8 mg/L, respectively. The elimination half life was 23.9 h whereas the approximated apparent distribution half life was about 3.8 h. The calculated AUC of tilidine was 508 mg.hour/L. Total serum clearance of tilidine was calculated to be 228 mL/min and the volume of distribution was 472 L or 7.61 L/kg. Approximated half life of nortilidine was 13.9 h.